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Telomere length (TL) is associated with biological aging, consequently influencing the risk of age-related diseases such as Alzheimer’s disease (AD). We aimed to evaluate the potential causal role of TL in AD endophenotypes (i.e., cognitive performance, N = 2233; brain age and AD-related signatures, N = 1134; and cerebrospinal fluid biomarkers (CSF) of AD and neurodegeneration, N = 304) through a Mendelian randomization (MR) analysis. Our analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study, a population of cognitively healthy individuals at risk of AD. A total of 20 single nucleotide polymorphisms associated with TL were used to determine the effect of TL on AD endophenotypes. Analyses were adjusted by age, sex, and years of education. Stratified analyses by APOE-ɛ4 status and polygenic risk score of AD were conducted. MR analysis revealed significant associations between genetically predicted longer TL and lower levels of CSF Aβ and higher levels of CSF NfL only in APOE-ɛ4 non-carriers. Moreover, inheriting longer TL was associated with greater cortical thickness in age and AD-related brain signatures and lower levels of CSF p-tau among individuals at a high genetic predisposition to AD. Further observational analyses are warranted to better understand these associations., The project leading to these results has received funding from the Alzheimer’s Association (Grant AARG-19-618265). This project has received funding from Instituto de Salud Carlos III (PI19/00119). Additional support has been received from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004, the Alzheimer’s Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007), the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016-2020 grant# SLT002/16/00201), and the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017-SGR-892. All CRG authors acknowledge the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. NV-T is funded by a post-doctoral grant, Juan de la Cierva Incorporación Programme (IJC2020-043216-I), Ministry of Science and Innovation–Spanish State Research Agency. EMAU is supported by the Spanish Ministry of Science, Innovation and Universities - Spanish State Research Agency (RYC2018-026053-I). MS-C receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement no. 948677). MS-C also receives funding from the Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532); the European Research Council (#681712); Swedish State Support for Clinical Research (#ALFGBG-720931); the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862); the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C); the Olav Thon Foundation; the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228); the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE); and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915); the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615); the Swedish Alzheimer Foundation (#AF-742881); Hjärnfonden, Sweden (#FO2017-0243); the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986); the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236); and the National Institute of Health (NIH), USA, (grant #1R01AG068398-01). JDG is supported by the Spanish Ministry of Science and Innovation (RYC-2013-13054). AS-V. is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029).

17 p.-6 fig., Vascular smooth muscle cell (VSMC) proliferation is essential for arteriogenesis to restore blood flow after artery occlusion, but the mechanisms underlying this response remain unclear. Based on our previous findings showing increased VSMC proliferation in the neonatal aorta of mice lacking the protease MT4-MMP, we aimed at discovering new players in this process. We demonstrate that MT4-MMP absence boosted VSMC proliferation in vitro in response to PDGF-BB in a cell-autonomous manner through enhanced p38 MAPK activity. Increased phospho-p38 in basal MT4-MMP-null VSMCs augmented the rate of mitochondrial degradation by promoting mitochondrial morphological changes through the co-activator PGC1α as demonstrated in PGC1α−/− VSMCs. We tested the in vivo implications of this pathway in a novel conditional mouse line for selective MT4-MMP deletion in VSMCs and in mice pre-treated with the p38 MAPK activator anisomycin. Priming of p38 MAPK activity in vivo by the absence of the protease MT4-MMP or by anisomycin treatment led to enhanced arteriogenesis and improved flow recovery after femoral artery occlusion. These findings may open new therapeutic opportunities for peripheral vascular diseases., Funding was provided by the Spanish Ministerio de Ciencia e Innovación (AEI/FEDER, UE), SAF2017-83229-R and PID2020-112981RB-I00 (AGA), PID2020-114709RA-I00 (AGD), PID2019-104399RB-I00 (GS), RTI2018-093864-B-I00 (MM), PGC2018-098557-B-I00 (PB), PRE2019-088222 (JIJL) and the Spanish Ministerio de Educación, Cultura y Deporte, FPU15-05802 (LHM). ASE was supported by fellowships from Obra Social La Caixa, Ford-Apadrina La Ciencia and La Residencia de Estudiantes. AGD is an Atracción de Talento M1 Fellow from Comunidad de Madrid (Spain) [2019-T1BMD-14236].

Better understanding on interactions between SARS-CoV-2andhost cells should help to identify host factors that may be tar-getable to combat infection and COVID-19pathology. To this end,we have conducted a genome-wide CRISPR/Cas9-based loss-of-function screen in human lung cancer cells infected with SARS-CoV-2-pseudotyped lentiviruses. Our results recapitulate manyfindings from previous screens that used full SARS-CoV-2viruses,but also unveil two novel critical host factors: the lysosomal effluxtransporter SPNS1and the plasma and lysosomal membrane pro-tein PLAC8. Functional experiments with full SARS-CoV-2virusesconfirm that loss-of-function of these genes impairs viral entry.We find that PLAC8is a key limiting host factor, whose overexpres-sion boosts viral infection in eight different human lung cancer celllines. Using single-cell RNA-Seq data analyses, we demonstratethat PLAC8is highly expressed in ciliated and secretory cells of therespiratory tract, as well as in gut enterocytes, cell types that arehighly susceptible to SARS-CoV-2infection. Proteomics and cellbiology studies suggest that PLAC8and SPNS1regulate theautophagolysosomal compartment and affect the intracellular fateof endocytosed virions., This work was supported by Instituto de Salud Carlos III(COV20/00652, MS19/00100, PI20/01267, COV20/00571 and PT17/0019/0003), Ministerio de Ciencia e Innovación (Spain) (PDI2020-118394RB-100, SAF2017-87655-R, PID2021-127534OB-100, and PGC2018-097019-B-I00), “laCaixa” Banking Foundation (HR17-00247) and Consejería de Ciencia, Innovación y Universidad del Gobierno del Principado de Asturias (AYUD/2021/57167). D.R.V and D.M are supported by PhD fellowships from Ministerio de Ciencia e Innovación(Spain).

Communication through cell-cell contacts and extracellular vesicles (EVs) enables immune cells to coordinate their responses against diverse types of pathogens. The function exerted by EVs in this context depends on the proteins and nucleic acids loaded into EVs, which elicit specific responses involved in the resolution of infection. Several mechanisms control protein and nucleic acid loading into EVs; in this regard, acetylation has been described as a mechanism of cellular retention during protein sorting to exosomes. HDAC6 is a deacetylase involved in the control of cytoskeleton trafficking, organelle polarity and cell migration, defense against Listeria monocytogenes (Lm) infection and other immune related functions. Here, we show that the protein content of dendritic cells (DCs) and their secreted EVs (DEVs) vary during Lm infection, is enriched in proteins related to antiviral functions compared to non-infected cells and depends on HDAC6 expression. Analyses of the post-translational modifications revealed an alteration of the acetylation and ubiquitination profiles upon Lm infection both in DC lysates and DEVs. Functionally, EVs derived from infected DCs upregulate anti-pathogenic genes (e.g. inflammatory cytokines) in recipient immature DCs, which translated into protection from subsequent infection with vaccinia virus. Interestingly, absence of Listeriolysin O in Lm prevents DEVs from inducing this anti-viral state. In summary, these data underscore a new mechanism of communication between bacteria-infected DC during infection as they alert neighboring, uninfected DCs to promote antiviral responses., This study was supported by grant PDI-2020-120412RB-I00, PDC2021-121797-I00, BIO2015-67580-P and PGC2018-097019-B-I00 from the Spanish Ministry of Economy and Competitiveness (MINECO), grant S2017/BMD-3671-INFLAMUNE-CM from the Comunidad de Madrid, a grant from the Ramón Areces Foundation “Ciencias de la Vida y la Salud” (XIX Concurso-2018), “la Caixa” Banking Foundation (grants HR17-00016 and HR17-00247), BIOIMID (PIE13/041) and PRB3 (IPT17/0019 - ISCIII-SGEFI/ERDF, ProteoRed) from Instituto de Salud Carlos III, CIBER Cardiovascular (CB16/11/00272), and Fondo de Investigación Sanitaria del Instituto de Salud Carlos III and co-funding by Fondo Europeo de Desarrollo Regional FEDER). IF-D is supported by a Fellowship from the Spanish Ministry of Science, Innovation, and Universities (FPU15/02539). DC-F is supported by a Fellowship from “la Caixa” Foundation (LCF/BQ/DR19/11740010). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (CEX2020-001041-S). Funding agencies did not intervene in the design of the studies, with no copyright over the study.

COVID-19-specific vaccines are efficient prophylactic weapons against SARS-CoV-2 virus. However, boosting innate responses may represent an innovative way to immediately fight future emerging viral infections or boost vaccines. MV130 is a mucosal immunotherapy, based on a mixture of whole heat-inactivated bacteria, that has shown clinical efficacy against recurrent viral respiratory infections. Herein, we show that the prophylactic intranasal administration of this immunotherapy confers heterologous protection against SARS-CoV-2 infection in susceptible K18-hACE2 mice. Furthermore, in C57BL/6 mice, prophylactic administration of MV130 improves the immunogenicity of two different COVID-19 vaccine formulations targeting the SARS-CoV-2 spike (S) protein, inoculated either intramuscularly or intranasally. Independently of the vaccine candidate and vaccination route used, intranasal prophylaxis with MV130 boosted S-specific responses, including CD8+-T cell activation and the production of S-specific mucosal IgA antibodies. Therefore, the bacterial mucosal immunotherapy MV130 protects against SARS-CoV-2 infection and improves COVID-19 vaccines immunogenicity., CF was supported by AECC Foundation (INVES192DELF) and is currently funded by the Miguel Servet program (ID: CP20/00106) (ISCIII). IH-M receives the support of a fellowship from la Caixa Foundation (ID 100010434, fellowship code: LCF/BQ/IN17/11620074) and from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 713673. AJ-C is a postgraduate fellow of the City Council of Madrid at the Residencia de Estudiantes (2020–2021). GD is supported by an European Molecular Biology Organization (EMBO) Long-term fellowship (ALTF 379-2019). This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. Project number 892965. OL and JA-C acknowledge Comunidad de Madrid (Tec4Bio-CM, S2018/NMT-4443, FEDER). Work in OL laboratory was funded by CNIO with the support of the projects Y2018/BIO4747 and P2018/NMT4443 from Comunidad de Madrid and co-funded by the European Social Fund and the European Regional Development Fund. The CNIO is supported by the Instituto de Salud Carlos III (ISCIII). Work at CNB and CISA is funded by the Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII), Fondo COVID-19 grant COV20/00151, and Fondo Supera COVID-19 (Crue Universidades-Banco Santander) (to JG-A). Work in the DS laboratory is funded by the CNIC; by the European Research Council (ERC-2016-Consolidator Grant 725091); by Agencia Estatal de Investigación (PID2019-108157RB); by Comunidad de Madrid (B2017/BMD-3733 Immunothercan-CM); by Fondo Solidario Juntos (Banco Santander); by a research agreement with Inmunotek S.L.; and by Fundació La Marató de TV3 (201723). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MICINN, and the Pro CNIC Foundation.

[Background]: Psoriasis is a frequent inflammatory skin disease that is mainly mediated by IL-23, IL-1β, and IL-17 cytokines. Although psoriasis is a hyperproliferative skin disorder, the possible role of amino acid transporters has remained unexplored., [Objective]: We sought to investigate the role of the essential amino acid transporter L-type amino acid transporter (LAT) 1 (SLC7A5) in psoriasis., [Methods]: LAT1 floxed mice were crossed to Cre-expressing mouse strains under the control of keratin 5, CD4, and retinoic acid receptor–related orphan receptor γ. We produced models of skin inflammation induced by imiquimod (IMQ) and IL-23 and tested the effect of inhibiting LAT1 (JPH203) and mammalian target of rapamycin (mTOR [rapamycin])., [Results]: LAT1 expression is increased in keratinocytes and skin-infiltrating lymphocytes of psoriatic lesions in human subjects and mice. LAT1 deletion in keratinocytes does not dampen the inflammatory response or their proliferation, which could be maintained by increased expression of the alternative amino acid transporters LAT2 and LAT3. Specific deletion of LAT1 in γδ and CD4 T cells controls the inflammatory response induced by IMQ. LAT1 deletion or inhibition blocks expansion of IL-17–secreting γ4+δ4+ and CD4 T cells and dampens the release of IL-1β, IL-17, and IL-22 in the IMQ-induced model. Moreover, inhibition of LAT1 blocks expansion of human γδ T cells and IL-17 secretion by human CD4 T cells. IL-23 and IL-1β stimulation upregulates LAT1 expression and induces mTOR activation in IL-17+ γδ and TH17 cells. Deletion or inhibition of LAT1 efficiently controls IL-23– and IL-1β–induced phosphatidylinositol 3-kinase/AKT/mTOR activation independent of T-cell receptor signaling., [Conclusion]: Targeting LAT1-mediated amino acid uptake is a potentially useful immunosuppressive strategy to control skin inflammation mediated by the IL-23/IL-1β/IL-17 axis., Supported by grants SAF2017-82886-R (to F.S.-M.), PI17/01972 (to E.D.), and SAF2013-42850-R (to M.F.) from the Spanish Ministry of Economy and Competitiveness; CAM (S2017/BMD-3671-INFLAMUNE-CM) from the Comunidad de Madrid (to F.S.-M.); and CIBERCV, BIOIMID PIE13/041 from Instituto de Salud Carlos III and Fundacion La Marato TV3 (20152330 31). The project leading to these results has also received funding from FUNDACION BBVA A EQUIPOS DE INVESTIGACION CIENTIFICA 2018 and from ‘‘la Caixa’’ Banking Foundation under the project code HR17-00016 (to F.S.-M.) and from Agencia Estatal de Investigacion, Fondo Europeo de Desarrollo Regional, European Union.

Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment., Y.-H.O. received fellowships from Alborada Scholarship (University of Cambridge), Trinity-Henry Barlow Scholarship (University of Cambridge), and R.O.C. Government Scholarship to Study Abroad (GSSA). A.G.G. received fellowships from the Ramón Areces Foundation and the LaCaixa Foundation. C.K. was supported by Marie Curie Career Integration (H2020-MSCA-IF-2015-70841). S.M.-F. was supported by Red TerCel (ISCIII-Spanish Cell Therapy Network). V.A. is supported by grants from the Spanish Ministerio de Economía, Industria y Competitividad (MEIC) with cofunding from the Fondo Europeo de Desarrollo Regional (FEDER, “Una manera de hacer Europa”) (SAF2016-79490-R), the Instituto de Salud Carlos III (AC16/00091 and AC17/00067), the Fundació Marató TV3 (122/C/2015), and the Progeria Research Foundation (Established Investigator Award 2014–52). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCIU), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work was supported by core support grants from the Wellcome Trust and the MRC to the Cambridge Stem Cell Institute, MEIC (SAF-2011-30308), Ramón y Cajal Program Grant (RYC-2009-04703), ConSEPOC-Comunidad de Madrid (S2010/BMD-2542), National Health Service Blood and Transplant (United Kingdom), European Union’s Horizon 2020 research (ERC-2014-CoG-64765 and Marie Curie Career Integration grant FP7-PEOPLE-2011-RG-294096), and a Programme Foundation Award from Cancer Research UK to S.M.-F., who was also supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute.

et al., Coenzyme Q (CoQ) plays a crucial role in mitochondria as an electron carrier within the mitochondrial respiratory chain (MRC) and is an essential antioxidant. Mutations in genes responsible for CoQ biosynthesis (COQ genes) cause primary CoQ deficiency, a rare and heterogeneous mitochondrial disorder with no clear genotype–phenotype association, mainly affecting tissues with high-energy demand including brain and skeletal muscle (SkM). Here, we report a four-year-old girl diagnosed with minor mental retardation and lethal rhabdomyolysis harboring a heterozygous mutation (c.483G > C (E161D)) in COQ4. The patient's fibroblasts showed a decrease in [CoQ], CoQ biosynthesis, MRC activity affecting complexes I/II + III, and respiration defects. Bona fide induced pluripotent stem cell (iPSCs) lines carrying the COQ4 mutation (CQ4-iPSCs) were generated, characterized and genetically edited using the CRISPR-Cas9 system (CQ4-iPSCs). Extensive differentiation and metabolic assays of control-iPSCs, CQ4-iPSCs and CQ4-iPSCs demonstrated a genotype association, reproducing the disease phenotype. The COQ4 mutation in iPSC was associated with CoQ deficiency, metabolic dysfunction, and respiration defects. iPSC differentiation into SkM was compromised, and the resulting SkM also displayed respiration defects. Remarkably, iPSC differentiation in dopaminergic or motor neurons was unaffected. This study offers an unprecedented iPSC model recapitulating CoQ deficiency-associated functional and metabolic phenotypes caused by COQ4 mutation., This work was supported by the ISCIII/FEDER (E-Rare-2 Call PI12/03112 to P.M.), FIS/ISCIII/FEDER project (PI14/01962 to P.N.) and the European Research Council (ERC-2014-CoG646903 to P.M.). D.R.M. and C.P. are supported by PFIS scholarships (FI11/0511 and FI12/00468, respectively). C.B is supported by a Miguel Servet II contract (CPII13/00011). P.M. also acknowledges the financial support from The Obra Social La Caixa-Fundacio Josep Carreras and The Generalitat de Catalunya (SGR330). P.M. and J.L.-B. are investigators of the Spanish Cell Therapy cooperative network (TERCEL). A.G. is supported by Ramon y Cajal Program (RyC-2013–13221).

16 pages, 10 figures, supplementary information https://doi.org/10.1038/s41467-023-39051-x.-- Data availability: The diffraction data and coordinates of the p38α complexes bound to NC-p38i compounds have been deposited in the Protein Data Bank under accession codes 7PVU, 7Z6I and 7Z9T. We have also used the following PDB structures: 4LOO, 1A9U, 3COI, 7N8T, 2ZOQ, 1PME, 3GC9, 1CM8, 4UX9. Source data are provided with this paper, p38α is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of p38α signaling has been linked to several diseases including inflammation, immune disorders and cancer, suggesting that targeting p38α could be therapeutically beneficial. Over the last two decades, numerous p38α inhibitors have been developed, which showed promising effects in pre-clinical studies but results from clinical trials have been disappointing, fueling the interest in the generation of alternative mechanisms of p38α modulation. Here, we report the in silico identification of compounds that we refer to as non-canonical p38α inhibitors (NC-p38i). By combining biochemical and structural analyses, we show that NC-p38i efficiently inhibit p38α autophosphorylation but weakly affect the activity of the canonical pathway. Our results demonstrate how the structural plasticity of p38α can be leveraged to develop therapeutic opportunities targeting a subset of the functions regulated by this pathway, This work was supported by grants from the Spanish Ministerio de Ciencia e Innovación (MICINN, PID2019-109521RB-I00 and PID2021-122478NB-I00), the BioMedTec program of IRB-Fundació La Caixa, the European Research Council (Proof of Concept p38_InTh-825763), AGAUR (2016 LLAV 00043 and 2019 PROD 00138 supported by FEDER, and 2017 SGR-557, 2017 SGR-50, 2021 SGR-909, and 2021 SGR-866), BBVA Foundation, and the European Union’s Horizon 2020 research and innovation program (euCanSHare 825903 and BioExcel-3 101093290). L.G. and B.B. were funded by predoctoral contracts from MICINN (BES-2016-077122) and the Marie Skłodowska-Curie COFUND action of IRB Barcelona and the PREBIST Predoc Programme (PREBIST_754558), respectively. F.C. is a Ramon y Cajal Fellow (RYC2019-026768-I). Access to ALBA was granted through the BAG proposals 2018092972 and 2020094472. We gratefully acknowledge institutional funding from IRB Barcelona, the CERCA Programme of the Catalan Government, and the MICINN through the Centres of Excellence Severo Ochoa award. M.J.M. and A.R.N. are supported by the Institució Catalana de Recerca i Estudis Avancats (ICREA), With the institutional support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S)

10 Pág., Schmallenberg Virus (SBV), an arbovirus from the Peribunyaviridae family and Orthobunyavirus genus, was discovered in late 2011 in Germany and has been circulating in Europe, Asia and Africa ever since. The virus causes a disease associated with ruminants that includes fever, fetal malformation, drop in milk production, diarrhoea and stillbirths, becoming a burden for small and large farms. Building on previous studies on SBV nucleoprotein (SBV-N) as a promising vaccine candidate, we have investigated the possible protein regions responsible for protection. Based on selective truncation of domains designed from the available crystal structure of the SBV-N, we identified both the N-terminal domain (N-term; Met1 – Thr133) and a smaller fragment within (C4; Met1 – Ala58) as vaccine prototypes. Two injections of the N-term and C4 polypeptides protected mice knockout for type I interferon (IFN) receptors (IFNAR-/-) challenged with virulent SBV, opposite to control groups that presented severe signs of morbidity and weight loss. Viremia analyses along with the presence of IFN-γ secreted from splenocytes re-stimulated with the N-terminal region of the protein corroborate that these two portions of SBV-N can be employed as subunit vaccines. Apart from both proteinaceous fragments being easily produced in bacterial cells, the C4 polypeptide shares a high sequence homology (∼87.1 %) with the corresponding region of nucleoproteins of several viruses of the Simbu serogroup, a group of Orthobunyaviruses that comprises SBV and veterinary pathogens like Akabane virus and human infecting viruses like Oropouche. Thus, we propose that this smaller fragment is better suited for vaccine nanoparticle formulation, and it paves the way to further research with other related Orthobunyaviruses., This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades RTI2018-095700-B-I00 (NGAA), RTI2018-096494-B-I00 (JA), AGL2017-83226 (AB) and “La Caixa” Foundation (ID 100010434) INPhINIT “La Caixa” fellowship LCF/BQ/DI19/11730041 (GSG and NGAA).

Summary Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming “boosters” also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency., Graphical Abstract, Highlights • Neither primary B-ALL blasts nor leukemic B cell lines can be reprogrammed to iPSCs • Global transcriptome and DNA methylome suggest a developmental refractoriness, Despite the interest in generating iPSCs from human primary acute leukemias for disease modeling, reprogramming leukemias is an extremely inefficient process. In this article, Menéndez, Bueno, and colleagues show that many reprogramming strategies reported to date are not sufficient to generate B-ALL-derived iPSCs. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of B-ALL to reprogramming into pluripotency.

23 p.-5 fig., Toll-like receptor 7 (TLR7) is an endosomal Pathogen-Associated Molecular Pattern (PAMP) receptor that senses single-stranded RNA (ssRNA) and whose engagement results in the production of type I IFN and pro-inflammatory cytokines upon viral exposure. Recent genetic studies have established that a dysfunctional TLR7-initiated signaling is directly linked to the development of inflammatory responses. We present evidences that TLR7 is preferentially expressed by monocyte-derived macrophages generated in the presence of M-CSF (M-MØ). We now show that TLR7 activation in M-MØ triggers a weak MAPK, NFκB and STAT1 activation and results in low production of type I IFN. Of note, TLR7 engagement re-programs MAFB+ M-MØ towards a pro-inflammatory transcriptional profile characterized by the expression of neutrophil-attracting chemokines (CXCL1-3, CXCL5, CXCL8), whose expression is dependent on the transcription factors MAFB and AhR. Moreover, TLR7-activated M-MØ display enhanced pro-inflammatory responses and a stronger production of neutrophil-attracting chemokines upon secondary stimulation. As aberrant TLR7 signaling and enhanced pulmonary neutrophil/lymphocyte ratio associate with impaired resolution of virus-induced inflammatory responses, these results suggest that targeting macrophage TLR7 might be a therapeutic strategy for viral infections where monocyte-derived macrophages exhibit a pathogenic role., This work was supported by Grant PID2020-114323RB-I00 from Ministerio de Ciencia e Innovación, “Ayudas FUNDACIÓN BBVA a equipos de investigación científica SARS-CoV-2 y COVID-19” and Grant 201619.31 from Fundació La Marató/TV3 to ALC, grants from the Instituto de Investigación Carlos III, ISCIII,(PI2100989), European Commission Horizon 2020 FP (Project VIRUSCAN FETPROACT-2016: ID 731868), Horizon Europe FP (Project EPIC-CROWN-2 ID: 101046084) and Fundación Caixa-Health Research (Project StopEbola HR18-00469) to RD, and Red de Investigación en Enfermedades Reumáticas (RIER, RD16/0012/0007), and co-financed by the European Regional Development Fund “A way to achieve Europe” (ERDF) to ALC. This research work was also funded by the European Commission – NextGenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global). MSF was funded by a Formación de Personal Investigador predoctoral fellowship from Ministerio de Ciencia e Innovación (Grant PRE2018-083396).

19 p.-6 fig.-7 tab.-1 graph. abst., Ebola virus (EBOV) is a single-strand RNA virus belonging to the Filoviridae family, which has been associated to most Ebola virus disease outbreaks to date, including the West African and the North Kivu epidemics between 2013 and 2022. This unprecedented health emergency prompted the search for effective medical countermeasures. Following up on the carbazole hit identified in our previous studies, we synthetized a new series of compounds, which demonstrated to prevent EBOV infection in cells by acting as virus entry inhibitors. The in vitro inhibitory activity was evaluated through the screening against surrogate models based on viral pseudotypes and further confirmed using replicative EBOV. Docking and molecular dynamics simulations joined to saturation transfer difference–nuclear magnetic resonance (STD–NMR) and mutagenesis experiments to elucidate the biological target of the most potent compounds. Finally, in vitro metabolic stability and in vivo pharmacokinetic studies were performed to confirm their therapeutic potential., The project leading to these results has received funding from “la Caixa” Foundation under the project code LCF/PR/HR19/52160012. This research was partially supported through ERA-NET-2021-862605. Cofounded by AEI, Spain (PCI2021-121939 (C.A.), PID2019-105237GB-I00 (A.C.), PID2021-122825OB (C.A.), and PID2021-122223OB-I00 (C.G.)), Instituto de Salud Carlos III (CIBERINFEC and FIS PI2100989), and the European Commission Horizon 2020 Framework Programme (Project VIRUSCAN FETPROACT-2016: 731868 and Project EPIC-CROWN-2 ID: 101046084). This research work was also funded by the European Commission–NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global). M.M.-T holds a predoctoral FPU grant (FPU18/03493) from MICINN

8 pages, 2 figures, 3 tables, supplementary material https://www.frontiersin.org/articles/10.3389/fmicb.2023.1130695/full#supplementary-material.-- Data availability statement: The sequencing data presented in this study are deposited in the NCBI repository, under the accession number: PRJNA946153 (https://www.ncbi.nlm.nih.gov/sra/PRJNA946153), The multiple symbiotic partnerships between closely related species of the haptophyte algae Braarudosphaera bigelowii and the nitrogen-fixing cyanobacteria Candidatus Atelocyanobacterium thalassa (UCYN-A) contribute importantly to the nitrogen and carbon cycles in vast areas of the ocean. The diversity of the eukaryotic 18S rDNA phylogenetic gene marker has helped to identify some of these symbiotic haptophyte species, yet we still lack a genetic marker to assess its diversity at a finer scale. One of such genes is the ammonium transporter (amt) gene, which encodes the protein that might be involved in the uptake of ammonium from UCYN-A in these symbiotic haptophytes. Here, we designed three specific PCR primer sets targeting the amt gene of the haptophyte species (A1-Host) symbiotic with the open ocean UCYN-A1 sublineage, and tested them in samples collected from open ocean and near-shore environments. Regardless of the primer pair used at Station ALOHA, which is where UCYN-A1 is the pre-dominant UCYN-A sublineage, the most abundant amt amplicon sequence variant (ASV) was taxonomically classified as A1-Host. In addition, two out of the three PCR primer sets revealed the existence of closely-related divergent haptophyte amt ASVs (>95% nucleotide identity). These divergent amt ASVs had higher relative abundances than the haptophyte typically associated with UCYN-A1 in the Bering Sea, or co-occurred with the previously identified A1-Host in the Coral Sea, suggesting the presence of new diversity of closely-related A1-Hosts in polar and temperate waters. Therefore, our study reveals an overlooked diversity of haptophytes species with distinct biogeographic distributions partnering with UCYN-A, and provides new primers that will help to gain new knowledge of the UCYN-A/haptophyte symbiosis, FC-C has received the support of the European Union’s Horizon 2020 research programme through a Marie Skłodowska-Curie global fellowship (UCYN2PLAST; grant 749380), a fellowship (grant 105090) from “La Caixa” Foundation (ID 100010434) and from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie actions (grant 847648), the Spanish Ministry of Science and Innovation through a “Ramón y Cajal” fellowship (RYC2021-032949-I), and acknowledges funding from the Spanish government through the “Severo Ochoa Centre of Excellence” accreditation (CEX2019-000928-S). JZ and KT-K were partially supported by Simons Foundation grants (Life Sciences #545171, #824082 and Simons SCOPE #724220)

13 p.-2 fig., Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein, a type III intermediate filament protein expressed in astrocytes. Both early (infantile or juvenile) and adult onsets of the disease are known and, in both cases, astrocytes present characteristic aggregates, named Rosenthal fibers. Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner. Although the presence of aggregates suggests a proteostasis problem of the mutant forms, this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased. Additionally, several isoforms of glial fibrillary acidic protein have been described to date, while the impact of the mutations on their expression and proportion has not been exhaustively studied. Moreover, the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered, leading to functional changes that may modify the morphology, positioning, and/or the function of several organelles, in turn, impairing astrocyte normal function and subsequently affecting neurons. In particular, mitochondrial function, redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes. To study the disease and to develop putative therapeutic strategies, several experimental models have been developed, a collection that is in constant growth. The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations, together with the availability of new and more relevant experimental models, holds promise for the design and assay of novel therapeutic strategies., Work at the authors’ laboratories is supported by grants from “la Caixa” Foundation, Grant Agreement LCF/PR/HR21/52410002 and EJP RD COFUND-EJP N° 825575 “Alexander” to DPS and MP; Agencia Estatal de Investigación, MICINN and ERDF Grant No. RTI2018-097624-B-I00 and PID2021-126827OB-I00 to DPS, and grants from the Swedish Research Council (2017-02255), ALF Gothenburg (146051), The Swedish Society for Medical Research, Hjärnfonden, Söderberg’s Foundations, Hagströmer’s Foundation Millennium, Amlöv’s Foundation, E. Jacobson’s Donation Fund, and the Swedish Stroke Foundation, NanoNet COST Action (BM1002), and EU FP 7 Program TargetBraIn (279017) to MP.

This article is part of the Anisotropic Nanomaterials special issue., The pseudo-two-dimensional (2D) morphology of plate-like metal nanoparticles makes them one of the most anisotropic, mechanistically understood, and tunable structures available. Although well-known for their superior plasmonic properties, recent progress in the 2D growth of various other materials has led to an increasingly diverse family of plate-like metal nanoparticles, giving rise to numerous appealing properties and applications. In this review, we summarize recent progress on the solution-phase growth of colloidal plate-like metal nanoparticles, including plasmonic and other metals, with an emphasis on mechanistic insights for different synthetic strategies, the crystallographic habits of different metals, and the use of nanoplates as scaffolds for the synthesis of other derivative structures. We additionally highlight representative self-assembly techniques and provide a brief overview on the attractive properties and unique versatility benefiting from the 2D morphology. Finally, we share our opinions on the existing challenges and future perspectives for plate-like metal nanomaterials., M.R.J. thanks the Robert A. Welch Foundation (grant C-1954), the David and Lucile Packard Foundation (grant 2018-68049), the National Science Foundation for a CAREER award (grant 2145500), and Rice University for financial support. L.S. receives support from the 2020 “la Caixa”Foundation Postdoctoral Junior Leader-Incoming Fellowship (ID 100010434, fellow-ship code LCF/BQ/PI20/11760028), and from a 2022 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation. L.M.L.-M. acknowledges funding from the European Research Council (ERC Advanced grant 787510, 4DbioSERS) and the Spanish Ministerio de Ciencia e Innovación, MCIN/AEI/10.13039/501100011033 (grant PID2020-117779RB-I00). X.Z. acknowledges financial support from the Juan de la Cierva fellowship (FJC2018-036104-I) and CUHK-Shenzhen (UDF01002665). M.S. thanks the Natural Science Foundation of China for their support (grant no. 22202133). J.E.M. thanks Leo and Theresa Wegemer for their generous support., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).

Cellular senescence is a state of irreversible cell cycle arrest that often emerges after tissue damage and in age-related diseases. Through the production of a multicomponent secretory phenotype (SASP), senescent cells can impact the regeneration and function of tissues. However, the effects of senescent cells and their SASP are very heterogeneous and depend on the tissue environment and type as well as the duration of injury, the degree of persistence of senescent cells and the organism's age. While the transient presence of senescent cells is widely believed to be beneficial, recent data suggest that it is detrimental for tissue regeneration after acute damage. Furthermore, although senescent cell persistence is typically associated with the progression of age-related chronic degenerative diseases, it now appears to be also necessary for correct tissue function in the elderly. Here, we discuss what is currently known about the roles of senescent cells and their SASP in tissue regeneration in ageing and age-related diseases, highlighting their (negative and/or positive) contributions. We provide insight for future research, including the possibility of senolytic-based therapies and cellular reprogramming, with aims ranging from enhancing tissue repair to extending a healthy lifespan. Work in the authors’ laboratory is supported by MINECO-Spain (RTI2018-096068), H2020 European Research Council-2016-AdG-741966, LaCaixaHEALTH-HR17-00040, MWRF, French Muscular Dystrophy Association, Muscular Dystrophy Association, Fundacio LaMarató TV3 (80/19-202021 and 137/ 38-202033) and UPGRADE-H2020-825825; and María-de-Maeztu-Program for Units of Excellence to UPF (MDM-2014-0370), Severo Ochoa-Program for Centers of Excellence to CNIC (SEV-2015-0505). Sí

Intracranial hemorrhage is a serious medical problem that requires rapid and often intensive medical care. Identifying the location and type of any hemorrhage present is a critical step in the treatment of the patient. Detection of, and diagnosis of, a hemorrhage that requires an urgent procedure is a difficult and time-consuming process for human experts. In this paper, we propose methods based on EfficientDet's deep-learning technology that can be applied to the diagnosis of hemorrhages at a patient level and which could, thus, become a decision-support system. Our proposal is two-fold. On the one hand, the proposed technique classifies slices of computed tomography scans for the presence of hemorrhage or its lack of, and evaluates whether the patient is positive in terms of hemorrhage, and achieving, in this regard, 92.7% accuracy and 0.978 ROC AUC. On the other hand, our methodology provides visual explanations of the chosen classification using the Grad-CAM methodology., MAGN was funded by two Research Projects of the Ministerio de Ciencia e Innovación of Spain, grant numbers PID2019-107339GB-I00 and TED2021-129438B-I00. He is also funded by the European Commission, grant agreement 101070028. For MB, the project leading to these results have received funding from “la Caixa” Foundation (ID 100010434), under the agreement CI19-0068 (Barcelona, Spain). The HUVR patients for this study were recruited thanks to a grant from Consejería de Igualdad, Salud y Políticas Sociales de Andalucía, Spain (PI-0136-2012).

13 pages, 7 figures, 1 table, supplementary material https://www.frontiersin.org/articles/10.3389/fmicb.2023.1078469/full#supplementary-material.-- Data availability statement: The raw sequence data have been deposited in the Figshare data repository, together with the non-rarefied OTU table, the taxonomy table and the environmental data used in this study, doi: 10.6084/m9.figshare.21385215.v1, Antarctic polynyas are highly productive open water areas surrounded by ice where extensive phytoplankton blooms occur, but little is known about how these surface blooms influence carbon fluxes and prokaryotic communities from deeper waters. By sequencing the 16S rRNA gene, we explored the vertical connectivity of the prokaryotic assemblages associated with particles of three different sizes in two polynyas with different surface productivity, and we linked it to the magnitude of the particle export fluxes measured using thorium-234 (234Th) as particle tracer. Between the sunlit and the mesopelagic layers (700 m depth), we observed compositional changes in the prokaryotic communities associated with the three size-fractions, which were mostly dominated by Flavobacteriia, Alphaproteobacteria, and Gammaproteobacteria. Interestingly, the vertical differences between bacterial communities attached to the largest particles decreased with increasing 234Th export fluxes, indicating a more intense downward transport of surface prokaryotes in the most productive polynya. This was accompanied by a higher proportion of surface prokaryotic taxa detected in deep particle-attached microbial communities in the station with the highest 234Th export flux. Our results support recent studies evidencing links between surface productivity and deep prokaryotic communities and provide the first evidence of sinking particles acting as vectors of microbial diversity to depth in Antarctic polynyas, highlighting the direct influence of particle export in shaping the prokaryotic communities of mesopelagic waters, The project that gave rise to these results received the support of a fellowship to VP from “la Caixa” Foundation (ID 100010434) and from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no 847648 (fellowship code LCF/BQ/PI21/11830020). VP also received funding from Edith Cowan University (G1003456) and from the School of Science at Edith Cowan University (G1003362) to support this work. CR-G was supported by the grants RTI2018-101025-B-I00 and a Ramon y Cajal contract (RYC2019-026758-I) and JG by grants CTM2015-70340-R and PID2021-125469NB-C31 of the Spanish Ministry of Science and Innovation and by the Generalitat de Catalunya Consolidated Research Group 2017SGR/1568. [...] This work acknowledges the “Severo Ochoa Centre of Excellence” accreditation (CEX2019-000928-S)

We study the surface crystalline and electronic structures of the antiferromagnetic topological insulator MnBi2Te4 using scanning tunneling microscopy/spectroscopy (STM/S), micro(μ)-laser angle-resolved photoemission spectroscopy (ARPES), and density functional theory calculations. Our STM images reveal native point defects at the surface that we identify as BiTe antisites and MnBi substitutions. Bulk X-ray diffraction further evidences the presence of the Mn-Bi intermixing. Overall, our characterizations suggest that the defects concentration is nonuniform within crystals and differs from sample to sample. Consistently, the ARPES and STS experiments reveal that the Dirac point gap of the topological surface state is different for different samples and sample cleavages, respectively. Our calculations show that the antiparallel alignment of the MnBi moments with respect to those of the Mn layer can indeed cause a strong reduction of the Dirac point gap size. The present study provides important insights into a highly debated issue of the MnBi2Te4 Dirac point gap., We acknowledge support by the Spanish Ministerio de Ciencia e Innovacion (Grant no. PID2019-103910GB-I00, PGC2018–093291–B–I00, PGC2018-097028–A–I00, and PGC2018-098613–B–C21) and Saint Petersburg State University (project ID No. 73028629). IMDEA Nanociencia acknowledges support from the “Severo Ochoa” Program for Centres of Excellence in R&D (MINECO, Grant SEV-2016-0686). M.G. has received financial support through the Postdoctoral Junior Leader Fellowship Program from “la Caixa” Banking Foundation. Z.S.A. and N.T.M. acknowledge the support of the Science Development Foundation under the President of the Republic of Azerbaijan (Grant No. EIF-BGM-4-RFTF-1/2017-21/04/1-M-02). I.I.K., D.E., and A.M.S. acknowledge the support from the Russian Science Foundation (Grant No. 18-12-00062) and the Russian Foundation of Basic Researches (Grant No. 20-32-70179).

Nitro-fatty acids (NO2-FAs) are unsaturated fatty acid nitration products that exhibit anti-inflammatory actions in experimental mouse models of autoimmune and allergic diseases. These electrophilic molecules interfere with intracellular signaling pathways by reversible post-translational modification of nucleophilic amino-acid residues. Several regulatory proteins have been identified as targets of NO2-FAs, modifying their activity and promoting gene expression changes that result in anti-inflammatory effects. Herein, we report the effects of nitro-oleic acid (NO2-OA) on pro-inflammatory T cell functions, showing that 9- and 10-NOA, but not their oleic acid precursor, decrease T cell proliferation, expression of activation markers CD25 and CD71 on the plasma membrane, and IL-2, IL-4, and IFN-γ cytokine gene expressions. Moreover, we have found that NO2-OA inhibits the transcriptional activity of nuclear factor of activated T cells (NFAT) and that this inhibition takes place through the regulation of the phosphatase activity of calcineurin (CaN), hindering NFAT dephosphorylation, and nuclear translocation in activated T cells. Finally, using mass spectrometry-based approaches, we have found that NO2-OA nitroalkylates CaNA on four Cys (Cys129, 228, 266, and 372), of which only nitroalkylation on Cys372 was of importance for the regulation of CaN phosphatase activity in cells, disturbing functional CaNA/CaNB heterodimer formation. These results provide evidence for an additional mechanism by which NO2-FAs exert their anti-inflammatory actions, pointing to their potential as therapeutic bioactive lipids for the modulation of harmful T cell-mediated immune responses., This work was supported by grant RTI2018-100815-B-I00 Ministerio de Ciencia e Innovación (MICIU)/Fondo Europeo de Desarrollo Regional (FEDER) and the accompanying 2021 CSIC Exceptional Grant to M.A.Í. and J.M.S. Additional funding was obtained from grants PID2021-122348NB-I00 (MICIU) and “La Caixa” Banking Foundation (HR22-00253) to E.C. and J.V., R01GM125944-05 and DK112854-04 to F.J.S., and from Universidad de la República Comisión Intersectorial de Investigación Científica Grupos_2018, Espacio Interdisciplinario_2020 to R.R. The CBMSO receives an institutional grant from the Fundación Ramón Areces.

The archetypical folded shape of the human cortex has been a long-standing topic for neuroscientific research. Nevertheless, the accurate neuroanatomical segmentation of sulci remains a challenge. Part of the problem is the uncertainty of where a sulcus transitions into a gyrus and vice versa. This problem can be avoided by focusing on sulcal fundi and gyral crowns, which represent the topological opposites of cortical folding. We present Automated Brain Lines Extraction (ABLE), a method based on Laplacian surface collapse to reliably segment sulcal fundi and gyral crown lines. ABLE is built to work on standard FreeSurfer outputs and eludes the delineation of anastomotic sulci while maintaining sulcal fundi lines that traverse the regions with the highest depth and curvature. First, it segments the cortex into gyral and sulcal surfaces; then, each surface is spatially filtered. A Laplacian-collapse-based algorithm is applied to obtain a thinned representation of the surfaces. This surface is then used for careful detection of the endpoints of the lines. Finally, sulcal fundi and gyral crown lines are obtained by eroding the surfaces while preserving the connectivity between the endpoints. The method is validated by comparing ABLE with three other sulcal extraction methods using the Human Connectome Project (HCP) test-retest database to assess the reproducibility of the different tools. The results confirm ABLE as a reliable method for obtaining sulcal lines with an accurate representation of the sulcal topology while ignoring anastomotic branches and the overestimation of the sulcal fundi lines. ABLE is publicly available via https://github.com/HGGM-LIM/ABLE . This work was supported by the project exAScale ProgramIng models for extreme Data procEssing (ASPIDE), that has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 801091. This work has received funding from “la Caixa” Foundation under the project code LCF/PR/HR19/52160001. Susanna Carmona funded by Instituto de Salud Carlos III, co-funded by European Social Fund “Investing in your future” (Miguel Servet Type I research contract CP16/00096). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Yasser Alemán-Gómez is supported by the Swiss National Science Foundation (185897) and the National Center of Competence in Research (NCCR) SYNAPSY - The Synaptic Bases of Mental Diseases, funded as well by the Swiss National Science Foundation (51AU40-1257). Sí

In response to different types and intensities of mechanical force, cells modulate their physical properties and adapt their plasma membrane (PM). Caveolae are PM nano-invaginations that contribute to mechanoadaptation, buffering tension changes. However, whether core caveolar proteins contribute to PM tension accommodation independently from the caveolar assembly is unknown. Here we provide experimental and computational evidence supporting that caveolin-1 confers deformability and mechanoprotection independently from caveolae, through modulation of PM curvature. Freeze-fracture electron microscopy reveals that caveolin-1 stabilizes non-caveolar invaginations-dolines-capable of responding to low-medium mechanical forces, impacting downstream mechanotransduction and conferring mechanoprotection to cells devoid of caveolae. Upon cavin-1/PTRF binding, doline size is restricted and membrane buffering is limited to relatively high forces, capable of flattening caveolae. Thus, caveolae and dolines constitute two distinct albeit complementary components of a buffering system that allows cells to adapt efficiently to a broad range of mechanical stimuli. We thank R. Parton (Institute for Molecular Biosciences, Queensland), P. Pilch (Boston University School of Medicine) and L. Liu (Boston University School of Medicine) for kindly providing PTRFKO cells and reagents, S. Casas Tintó for kindly providing SH-Sy5y cells, P. Bassereau (Curie Institute, Paris) for kindly providing OT setup, V. Labrador Cantarero from CNIC microscopy Unit for helping with ImageJ analysis, O. Otto and M. Herbig for providing help with RTDC experiments, S. Berr and K. Gluth for technical assistance in cell culture, F. Steiniger for support in electron tomography, and A. Norczyk Simón for providing pCMV-FLAG-PTRF construct. This project received funding from the European Union Horizon 2020 Research and Innovation Programme through Marie Sklodowska-Curie grant 641639; grants from the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033): SAF2014-51876-R, SAF2017-83130-R co-funded by ‘ERDF A way of making Europe’, PID2020-118658RB-I00, PDC2021-121572-100 co-funded by ‘European Union NextGenerationEU/PRTR’, CSD2009- 0016 and BFU2016-81912-REDC; and the Asociación Española Contra el Cáncer foundation (PROYE20089DELP) all to M.A.d.P. M.A.d.P. is member of the Tec4Bio consortium (ref. S2018/NMT¬4443; Comunidad Autónoma de Madrid/FEDER, Spain), co-recipient with P.R.-C. of grants from Fundació La Marató de TV3 (674/C/2013 and 201936- 30-31), and coordinator of a Health Research consortium grant from Fundación Obra Social La Caixa (AtheroConvergence, HR20-00075). M.S.-A. is recipient of a Ramón y Cajal research contract from MCIN (RYC2020-029690-I). The CNIC Unit of Microscopy and Dynamic Imaging is supported by FEDER ‘Una manera de hacer Europa’ (ReDIB ICTS infrastructure TRIMA@CNIC, MCIN). We acknowledge the support from Deutsche Forschungsgemeinschaft through grants to M.M.K. (KE685/7-1) and B.Q. (QU116/6-2 and QU116/9-1). Work in D.N. laboratory was supported by grants from the European Union Horizon 2020 Research and Innovation Programme through Marie Sklodowska-Curie grant 812772 and MCIN (DPI2017-83721-P). Work in C.L. laboratory was supported by grants from Curie, INSERM, CNRS, Agence Nationale de la Recherche (ANR-17-CE13-0020-01) and Fondation ARC pour la Recherche (PGA1-RF20170205456). Work in P.R.-C. lab is funded by the MCIN (PID2019-110298GB-I00), the EC (H20 20-FETPROACT-01-2016-731957). Work in X.T. lab is funded by the MICIN (PID2021-128635NB-I00), ERC (Adv-883739) and La Caixa Foundation (LCF/PR/HR20/52400004; co-recipient with P.R.-C.). IBEC is recipient of a Severo Ochoa Award of Excellence from the MINECO. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MCIN and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033). Sí

Sleep is a complex process and is needed both in health and illness. Deprivation of sleep is known to have multiple negative physiological effects on people's bodies and minds. Despite the awareness of these harmful effects, previous studies have shown that sleep is poor among hospitalised patients. We utilized an observational design with 343 patients recruited from medical and surgical units in 12 hospitals located in nine Spanish regions. Sociodemographic and clinical characteristics of patients were collected. Sleep quality at admission and during hospitalisation was measured by the Pittsburgh Sleep Quality Index. Sleep quantity was self-reported by patients in hours and minutes. Mean PSQI score before and during hospitalisation were respectively 8.62 ± 4.49 and 11.31 ± 4.04. Also, inpatients slept about an hour less during their hospital stay. Lower educational level, sedative medication intake, and multi-morbidity was shown to be associated with poorer sleep quality during hospitalisation. A higher level of habitual physical activity has shown to correlate positively with sleep quality in hospital. Our study showed poor sleep quality and quantity of inpatients and a drastic deterioration of sleep in hospital versus at home. These results may be helpful in drawing attention to patients' sleep in hospitals and encouraging interventions to improve sleep. This project received a research grant from the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain), awarded on the 2018 call under the Health Strategy Action 2013–2016, with reference PI18/00732, PI18/00743, PI18CIII/0012, co-funded with the European Union ERDF funds (European Reginal Development Fund “a way to make Europe) and the Predoctoral staff in training program from the University of Lleida, Jade Plus and La Caixa Bank Foundation 2019. Sí

The study was partially funded by the ‘Accion Transversal del Cancer’, approved by the Spanish Ministry Council on 11 October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889, PI11/02213; PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI17CIII/00034, CIBERESP CB06/02/0073), the Fundación Marqués de Valdecilla (API 10/09), the Junta de Castilla y León (LE22A10- 2), the Consejería de Salud of the Junta de Andalucía (PI-0571-2009, PI-0306-2011, salud201200057018tra), the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), the Recercaixa (2010ACUP 00310), the Regional Government of the Basque Country, the European Commission grants FOOD-CT-2006-036224-HIWATE, the Spanish Association Against Cancer (AECC) Scientific Foundation, the Catalan Government DURSI grant 2014SGR647, 2017SGR723, 2017SGR1085 and 2014SGR850, the Fundación Caja de Ahorros de Asturias and by the University of Oviedo. MCT is funded by a Ramón y Cajal fellowship (RYC-2017-01892) from the Spanish Ministry of Science, Innovation and Universities and co-funded by the European Social Fund. ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program., Supplementary Information The online version contains supplementary material available at https://doi.org/10.1038/s41598-022-25789-9., Breast and prostate cancers have been associated with circadian disruption. Some previous studies examined associations of sleep duration and breast or prostate cancer risk though findings remain inconsistent. This study examines associations of a range of detailed sleep characteristics and breast and prostate cancer risk in a large-scale population-based case–control study, MCC-Spain. A total of 1738 incident breast cancer cases, 1112 prostate cancer cases and frequency matched controls (n = 1910, and 1493 respectively) were recruited. Detailed data on habitual sleep duration, quality, timing, and daytime napping (“siesta”) were collected at recruitment. Additional data on sleep habits during both the previous year and at age 40 years were also subsequently captured. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) were estimated. There were no associations of habitual sleep duration (h), timing of sleep, or any or specific sleep problems, and either breast and prostate cancer risk. There was a significant positive association of ever taking habitual siestas at recruitment and breast cancer risk (OR = 1.22, 95% CI 1.06–1.42), which strengthened with increased frequency or duration. There were also significant positive associations observed for both breast and prostate cancer, among those reporting recent sleep problems, but not sleep problems at age 40 years, in a subsequent circadian questionnaire. Adverse associations with siesta and disturbed sleep during the previous year likely reflect symptoms of developing/diagnosed cancer and comorbidities. Overall, there was no clear association between various sleep characteristics and breast or prostate cancer risk observed., Basque Country, Catalan Government DURSI 2014SGR647, 2014SGR850, 2017SGR1085, 2017SGR723, Consejería de Salud of the Junta de Andalucía PI-0306-2011, PI-0571-2009, Spanish Association Against Cancer, Fundación Bancaria Caja de Ahorros de Asturias, Ministerio de Ciencia, Innovación y Universidades, Eno Scientific Foundation, European Commission FOOD-CT-2006-036224-HIWATE, Fundación Científica Asociación Española Contra el Cáncer, Generalitat de Catalunya, Instituto de Salud Carlos III CIBERESP CB06/02/0073, PI08/1359, PI08/1770, PI09/00773, PI09/01286, PI09/01662, PI09/01903, PI09/02078, PI11/01403, PI11/01889, PI11/02213, PI12/00150, PI12/00265, PI12/00715, PI12/01270, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI17CIII/00034, Ministerio de Ciencia e Innovación CEX2018-000806-S, European Social Fund, Universidad de Oviedo RYC-2017-01892, Consejería de Educación, Junta de Castilla y León LE22A10-2, Conselleria de Sanitat Universal i Salut Pública 2010ACUP 00310, AP_061/10, Fundación Marqués de Valdecilla API 10/09

Background: Lead is a cardiotoxic metal with a variety of adverse health effects. In the absence of data on bone lead exposure, epigenetic biomarkers can serve as indicators of cumulative lead exposure and body burden. Herein, we leveraged novel epigenetic biomarkers of lead exposure to investigate their association with cardiovascular disease (CVD) incidence and mortality. Methods and Results: Blood DNA methylation was measured using the Illumina MethylationEPIC BeadChip among 2231 participants of the Strong Heart Study (SHS) at baseline (1989-1991). Epigenetic biomarkers of lead levels in blood, patella, and tibia were estimated using previously identified cytosine-guanine dinucleotide (CpG) sites. CVD incidence and mortality data were available through 2017. Median concentrations of lead epigenetic biomarkers were 13.8 μg/g, 21.3 μg/g, and 2.9 μg/dL in tibia, patella, and blood, respectively. In adjusted models, the hazard ratio (HR) (95% CI) of CVD mortality per doubling increase in lead epigenetic biomarkers were 1.42 (1.07-1.87) for tibia lead, 1.22 (0.93-1.60) for patella lead, and 1.57 (1.16-2.11) for blood lead. The corresponding HRs for incident CVD were 0.99 (0.83-1.19), 1.07 (0.89-1.29), and 1.06 (0.87-1.30). The association between the tibia lead epigenetic biomarker and CVD mortality was modified by sex (interaction P value: 0.014), with men at increased risk (HR, 1.42 [95% CI, 1.17-1.72]) compared with women (HR, 1.04 [95% CI, 0.89-1.22]). Conclusions: Tibia and blood epigenetic biomarkers were associated with increased risk of CVD mortality, potentially reflecting the cardiovascular impact of cumulative and recent lead exposures. These findings support that epigenetic biomarkers of lead exposure may capture some of the disease risk associated with lead exposure. This work was funded by the National Institute of Environmental Health Sciences (T32 ES007322). This work was supported by grants by the National Heart, Lung, and Blood Institute (under contract numbers 75N92019D00027, 75N92019D00028, 75N92019D00029, and 75N92019D00030) and previ-ous grants (R01HL090863, R01HL109315, R01HL109301, R01HL109284, R01HL109282, and R01HL109319) and cooperative agreements (U01HL41642, U01HL41652, U01HL41654, U01HL65520, and U01HL65521), by the National Institute of Environmental Health Sciences (R01ES021367, R01ES025216, P42ES010349, and P30ES009089) and by the Spanish Funds for Research in Health Sciences, Carlos III Health Institute, cofunded by European Regional Development Fund (CP12/03080 and PI15/00071). A. Domingo- Relloso was supported by a fellowship from “la Caixa” Foundation (identifier 100010434) (fellowship code “LCF/BQ/DR19/11740016”). Dr Gao was supported by the Peking University Start-up Grant (BMU2021YJ044). During the preparation of this article, Dr Colicino was supported by R01 ES032242 and P30 ES023515. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Indian Health Service. The funders had no role in study design, data collection and analysis, preparation of the manuscript, or decision to submit the manuscript for publication. Sí

Strain relaxation mechanisms during epitaxial growth of core-shell nanostructures play a key role in determining their morphologies, crystal structure and properties. To unveil those mechanisms, we perform atomic-scale aberration-corrected scanning transmission electron microscopy studies on planar core-shell ZnSe@ZnTe nanowires on α-Al2O3 substrates. The core morphology affects the shell structure involving plane bending and the formation of low-angle polar boundaries. The origin of this phenomenon and its consequences on the electronic band structure are discussed. We further use monochromated valence electron energy-loss spectroscopy to obtain spatially resolved band-gap maps of the heterostructure with sub-nanometer spatial resolution. A decrease in band-gap energy at highly strained core-shell interfacial regions is found, along with a switch from direct to indirect band-gap. These findings represent an advance in the sub-nanometer-scale understanding of the interplay between structure and electronic properties associated with highly mismatched semiconductor heterostructures, especially with those related to the planar growth of heterostructured nanowire networks., J.A., S.M.-S., M.B., and M.C.S. were supported by the Severo Ochoa program from Spanish MCIN/AEI /10.13039/501100011033/ (Grant No. SEV-2017-0706) and are funded by the CERCA Program / Generalitat de Catalunya. Part of the present work has been performed in the framework of Universitat Autònoma de Barcelona Materials Science Ph.D. program. J.A., S.M.-S., M.B., and M.C.S. acknowledge funding from Generalitat de Catalunya 2017SGR327. S.M.S. acknowledges funding from ICN2 SO EXEM project. The HAADF-STEM microscopy was conducted in the Laboratorio de Microscopias Avanzadas at Instituto de Nanociencia de Aragon-Universidad de Zaragoza. Additional imaging and electron energy loss spectroscopy was carried out at SuperSTEM, the UK National Research Facility for Advanced Electron Microscopy, supported by the Engineering and Physical Sciences Research Council (EPSRC). Authors acknowledge the LMA-INMA for offering access to their instruments and expertise. We acknowledge support from CSIC Research Platform on Quantum Technologies PTI-001 (QTEP). M.B. acknowledges support from SUR Generalitat de Catalunya and the EU Social Fund; project ref. 2020 FI 00103. C.K. acknowledges funding from InPhINIT Scholarships LaCaixa Foundation. M.C.S. have received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 754510 (PROBIST). J.G.d.A. has been supported by European Research Council (Advanced Grant 789104-eNANO). V.D.G. and J.G.d.A have received funding from Spanish MCINN (PID2020-112625GB-I00 and CEX2019-000910-S), Fundació Cellex, Fundació Mir-Puig, and Generalitat de Catalunya (CERCA, AGAUR). E.J. acknowledges support from the Israel Science Foundation (Grant No. 2444/19). J.A., S.M.-S., M.B. and M.C.S. were supported by MCIN with funding from European Union NextGenerationEU (PRTR-C17.I1), by Generalitat de Catalunya and by “ERDF A way of making Europe”, by the “European Union”.

Early heart development depends on the coordinated participation of heterogeneous cell sources. As pioneer work from Adriana C. Gittenberger-de Groot demonstrated, characterizing these distinct cell sources helps us to understand congenital heart defects. Despite decades of research on the segregation of lineages that form the primitive heart tube, we are far from understanding its full complexity. Currently, single-cell approaches are providing an unprecedented level of detail on cellular heterogeneity, offering new opportunities to decipher its functional role. In this review, we will focus on three key aspects of early heart morphogenesis: First, the segregation of myocardial and endocardial lineages, which yields an early lineage diversification in cardiac development; second, the signaling cues driving differentiation in these progenitor cells; and third, the transcriptional heterogeneity of cardiomyocyte progenitors of the primitive heart tube. Finally, we discuss how single-cell transcriptomics and epigenomics, together with live imaging and functional analyses, will likely transform the way we delve into the complexity of cardiac development and its links with congenital defects. Grant support PGC2018-096486-B-I00 from the Spanish Ministerio de Ciencia eInnovación and Grant H2020-MSCA-ITN-2016-722427 from the EU Horizon 2020 program to MT.MS was supported by a La Caixa Foudation PhD fellowship (LCF/BQ/DE18/11670014) and TheCompany of Biologists travelling fellowship (DEVTF181145). OH.O. is supported by the Ministerio deCiencia e Innovación (grant RTI2018-097617-J-I00). The CNIC is supported by the Spanish Ministeryof Science and the ProCNIC Foundation. Sí

Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury., This work was supported by Ministerio de Ciencia, Innovación y Universidades MICINN: PID2020-117116RB-I00 integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovación, cofinanciado con Fondos FEDER (to MLM-C), Ministerio de Ciencia e Innovación CONSOLIDER-INGENIO 2010 Program Grant CSD2008-00005 (to LAM-C); Spanish Ministry of Economy and Competitiveness Grant BFU2013-47531-R, BFU2016-77408-R, PID2019-109055RB-100 (to L.A.M.-C.) (MINECO/FEDER, UE); Asociación Española contra el Cáncer (MLM-C, TC-D), Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M.-C.), La Caixa Foundation Program (to M.L.M.-C.), Fundacion BBVA UMBRELLA project (to M.L.M.-C.), Ayuda RYC2020-029316-I financiada por MICIN/AEI/10.13039/501100011033 (to TC-D), Plataforma de Investigación Clínica-SCReN (PT17 0017 0020) (to M.I.-L.), programa retos RTC2019-007125-1 (to M.L.M.-C, J.S.), Proyectos Investigacion en Salud DTS20/00138 (to M.L.M.-C., J.S), ERA-Net E-Rare EJP RD Joint Translational Call for Rare Diseases FIGHT-CNNM2 (EJPRD19-040) and from Instituto Carlos III, Spain (REF G95229142) (to L.A.M.-C.), US National Institutes of Health under grant CA217817 (to D.B.), Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644) and PhD fellowship from MINECO (REF BES-2017-080435) awarded to I.G.-R. The collection and storage of patients tissues was supported by the Newcastle Biomedicine Biobank and the European Community’s Seventh Framework Programme (FP7/2001–2013) and Cancer Research UK awards Cancer Research UK grants C18342/A23390; C9380/A18084 and C9380/A26813.

Thyroid hormones (THs) play a major role regulating energy balance and brown adipose tissue (BAT) thermogenesis, as well as body temperature, as shown in hyperthyroid patients. However, the current landscape of preclinical thyroid hormone models is complex. For example, while rats become catabolic after TH administration, mice gain weight; so, these differences in species need to be analyzed in detail and specially whether temperature could be a factor. Here, we aimed to investigate the effect of environmental temperature on those actions. Rats were subcutaneously treated with L-thyroxine (T4) or stereotaxically within the ventromedial nucleus of the hypothalamus (VMH) with triiodothyronine (T3) and housed at 23°C, 4°C or 30°C; energy balance, BAT thermogenesis and AMP-activated protein kinase (AMPK) in the VMH were analyzed. Our data showed that the effect of both systemic T4 of central T3 on energy balance and BAT thermogenesis was dependent upon environmental temperature. This evidence is of interest in the design of experimental settings highlighting the species-specific metabolic actions of THs, and in understanding its physiological role in the adaptation to temperature., This research was funded by: Ministerio de Ciencia y Universidades co-funded by the FEDER Program of EU (CD: BFU 2017-87721; RN: RTI 2018-099413-B-I00 and RED 2018-102379-T; ML: RTI 2018-101840-B-I00, PID2021-128145NB-I00 and PDC2022-133958-I00). “la Caixa” Foundation (ID100010434), under the agreement LCF/PR/HR19/52160022 (ML); European Research Council (RN: ERC Synergy Grant-2019-WATCH- 810331).

15 p.-6 fig., Fragile X syndrome (FXS) is caused by the loss of function of Fragile X mental retardation protein (FMRP). FXS is one of the leading monogenic causes of intellectual disability (ID) and autism. Although it is caused by the failure of a single gene, FMRP that functions as an RNA binding protein affects a large number of genes secondarily. All these genes represent hundreds of potential targets and different mechanisms that account for multiple pathological features, thereby hampering the search for effective treatments. In this scenario, it seems desirable to reorient therapies toward more general approaches. Neuronal calcium sensor 1 (NCS-1), through its interaction with the guanine-exchange factor Ric8a, regulates the number of synapses and the probability of the release of a neurotransmitter, the two neuronal features that are altered in FXS and other neurodevelopmental disorders. Inhibitors of the NCS-1/Ric8a complex have been shown to be effective in restoring abnormally high synapse numbers as well as improving associative learning in FMRP mutant flies. Here, we demonstrate that phenothiazine FD44, an NCS-1/Ric8a inhibitor, has strong inhibition ability in situ and sufficient bioavailability in the mouse brain. More importantly, administration of FD44 to two different FXS mouse models restores well-known FXS phenotypes, such as hyperactivity, associative learning, aggressive behavior, stereotype, or impaired social approach. It has been suggested that dopamine (DA) may play a relevant role in the behavior and in neurodevelopmental disorders in general. We have measured DA and its metabolites in different brain regions, finding a higher metabolic rate in the limbic area, which is also restored with FD44 treatment. Therefore, in addition to confirming that the NCS-1/Ric8a complex is an excellent therapeutic target, we demonstrate the rescue effect of its inhibitor on the behavior of cognitive and autistic FXS mice and show DA metabolism as a FXS biochemical disease marker., This work was supported by the Caixa Research foundation (Caixa Impulse program CI18-00026) from Spain, the Fragile X Research Foundation from USA and the Spanish Ministerio de Ciencia e Innovación (PID2019-106608RB-I00), and the Instituto de Salud Carlos III (CIBERNED, CB18/05/00040). AlM is funded with the Ramon y Cajal program from The Spanish Ministerio de Ciencia e Innovación (RYC-2017-22392).

Patients with common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, are characterized by hypogammaglobulinemia, poorly protective vaccine titers and increased susceptibility to infections. New pathogens such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), might constitute a particular threat to these immunocompromised patients since many of them experience a slower recovery and do not achieve full response to SARS-CoV-2 vaccines. To define the molecular basis of the altered immune responses caused by SARS-CoV-2 infection in CVID patients, we generated longitudinal single-cell datasets of peripheral blood immune cells along viral infection and recovery. We sampled the same individuals before, during and after SARS-CoV-2 infection to model their specific immune response dynamics while removing donor variability. We observed that COVID-19 CVID patients show defective canonical NF-κB pathway activation and dysregulated expression of BCR-related genes in naïve B cells, as well as enhanced cytotoxic activity but incomplete cytokine response in NK and T cells. Moreover, monocytes from COVID-19 CVID patients show persistent activation of several inflammasome-related genes, including the pyrin and NLRC4 inflammasomes. Our results shed light on the molecular basis of the prolonged clinical manifestations observed in these immunodeficient patients upon SARS-CoV-2 infection, which might illuminate the development of tailored treatments for COVID-19 CVID patients., We thank the CERCA Program/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. This publication is part of the Human Cell Atlas: www.humancellatlas.org/publications. This study was funded by ”la Caixa” Foundation under the grant agreement LCF/PR/HR22/52420002, Spanish Ministry of Science and Innovation (grant number PID2020-117212RB-I00/AEI/10.13038/501100011033) (E.B.), by the Wellcome Trust Grant 206194 and 108413/A/15/D (R.V.-T.), Instituto de Salud Carlos III (ISCIII), Ref. AC18/00057, associated with i-PAD project (ERARE European Union program) (E.B.), and the Chan Zuckerberg Initiative (grant 2020-216799) (R.V.-T. and E.B.). This publication has also been supported by the Unstoppable campaign of the Josep Carreras Leukaemia Foundation. We are indebted to the donors for participating in this research.

(1) Background: To explore the association between microbial phenolic metabolites (MPM) and metabolic syndrome (MetS) and its clinical features in adolescents aged 12.02 ± 0.41 years. (2) Methods: a cross-sectional study was conducted in 560 participants at baseline in the SI! Program for Secondary Schools trial. The following MPM, coumaric acids (m-, o-, p-coumaric acids), dihydroxyphenylpropionic acid, dihydroresveratrol, enterolignans, gallic acid, hydroxybenzoic acids, hydroxyphenylacetic acid, hydroxytyrosol, protocatechuic acid, syringic acid, urolithins (A, B), and vanillic acid, were analyzed by HPLC-LTQ-Orbitrap-HRMS. MetS and its clinical features were defined in accordance with the International Diabetes Federation. (3) Results: Out of all MPM, urolithin A was inversely associated with the diastolic blood pressure z-score. Urolithin B was inversely associated with the MetS score and waist circumference z-score. Additionally, higher levels of gallic acid were associated with lower odds of presenting MetS (OR = 0.85, 95% CI: 0.77; 0.93) and abdominal obesity (OR = 0.93, 95% CI: 0.89; 0.98). Higher urolithin B levels were inversely associated with abdominal obesity (OR = 0.94, 95% CI: 0.89; 0.98) and high blood glucose (OR = 0.92, 95% CI:0.88; 0.96); (4) Conclusions: gallic acid, urolithin A and B were associated with lower odds of presenting MetS or some of its clinical features in adolescents. This is the first study that evaluates several MPM with MetS in adolescents, highlighting the importance of MPM on cardiometabolic health at early life stages. This study was supported within the framework of the SI! Program for Secondary Schools trial from the SHE Foundation, and by the grant “la Caixa” Foundation (LCF/PR/CE16/10700001), and the award of 369/C/2016 from Fundació la Marató de TV3. Grant was also provided by the Ministerio de Ciencia, Innovación y Universidades (MCIN) (PID2020-114022RB-I00), Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición from the Instituto de Salud Carlos III (ISCIII) and Generalitat de Catalunya. J.M.-G. is supported by the MCIN at the Residencia de Estudiantes (2020–ongoing). R.F-J. is supported by the Fondo de Investigación Sanitaria- ISCIII (grant PI19/01704) and co-funded by the European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future” funded by The Centro Nacional de Investigaciones cardiovasculares (CNIC) from the ISCIII, the MCIN and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (CEX2020-001041-S). G.S-B. is supported by “la Caixa” Foundation (ID 100010434) with the grant LCF/PR/MS19/12220001. A.T.-R. is a Serra Húnter Fellow. E.P.L.-S. is supported by FI-SDUR (EMC/503/2021) fellowship program from the Generalitat de Catalunya. Anna Vallverdú-Queralt is a recipient of a grant RYC-2016-19355 from the MCIN for the Ramon y Cajal program. M.M.-M. is supported by the FPU17/00513 fellowship program. Sí

24 pages, 11 figures, 4 tables, supplementary material https://www.frontiersin.org/articles/10.3389/fmars.2022.911522/full#supplementary-material.-- Data availability statement: The datasets used to generate the transect and biological turnover figures in this study are archived in the Biological and Chemical Oceanography-Data Management Office (BCO-DMO) for data management and can be accessed using the following two links doi: 10.26008/1912/bco-dmo.879142.1 and doi: 10.26008/1912/bco-dmo.879158.1. Data presented in this study that are not available from BCO-DMO are provided in Tables S1, S2 in the SM, Shallow-water coral reefs hold large quantities of acrylate and its precursor dimethylsulfoniopropionate (DMSP), but production and removal processes for these compounds are poorly characterized. Here we determined the concentrations and cycling of acrylate and DMSP in a transect from a coral reef ecosystem to the open ocean, 2 km beyond the reef in Mo’orea, French Polynesia, during April 2018. Concentrations of dissolved acrylate and DMSP were low throughout the reef-ocean transect, ranging from 0.8–3.9 nM and 0.2–3.0 nM, respectively, with no difference observed between the coral reef and open ocean when comparing mean concentrations (± std dev) of dissolved acrylate (1.7 ± 0.7 vs 2.3 ± 0.8 nM) or DMSP (0.9 ± 0.7 vs 1.3 ± 0.6 nM). In the coral reef, dissolved acrylate was rapidly taken up by the heterotrophic community with a fast turnover time averaging ~ 6 h, six times faster than in the open ocean, and nearly as fast as the average turnover time of dissolved DMSP (~ 3 h). A clear diel trend was observed for the heterotrophic consumption of dissolved acrylate and DMSP in the coral reef, with higher uptake rate constants during daylight hours, synchronized with the larger daytime release of acrylate and DMSP from the coral compared to the nighttime release of these compounds. We also measured photochemical production rates of acrylate in Mo’orean waters, but rates were one to two orders of magnitude slower compared to its rates of biological consumption. Coral and macroalgae were the main sources of dissolved acrylate and DMSP to the reef ecosystem. Our results indicate there is rapid turnover of acrylate and DMSP in the coral reef with a tight coupling between production and removal pathways that maintain dissolved concentrations of these two compounds at very low levels. These algal and coral-derived substrates serve as important chemical links between the coral and heterotrophic communities, two fundamental components in the ecological network in coral reefs, This work was supported by funding from the National Science Foundation Chemical Oceanography program (CO–1756907) to DK, from the Spanish Research Agency through the BIOGAPS project (CTM2016-81008-R) to RS, and from EU’s Horizon H2020 research and innovation programme through a European Research Council Advanced Grant (ERC-2018-ADG-834162) to RS. The ICM-CSIC holds the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S). MC-B, MM-N and PR-R were supported by predoctoral grants from the Spanish government (FPU16-01925 and BES-2017-080048) and “La Caixa” Foundation, respectively. SG was supported by an Australian Government Endeavour Research Fellowship

The NEXT collaboration: et al., The Neutrino Experiment with a Xenon TPC (NEXT) searches for the neutrinoless double-beta (0νββ) decay of 136Xe using high-pressure xenon gas TPCs with electroluminescent amplification. A scaled-up version of this technology with about 1 tonne of enriched xenon could reach in less than 5 years of operation a sensitivity to the half-life of 0νββ decay better than 1027 years, improving the current limits by at least one order of magnitude. This prediction is based on a well-understood background model dominated by radiogenic sources. The detector concept presented here represents a first step on a compelling path towards sensitivity to the parameter space defined by the inverted ordering of neutrino masses, and beyond., The NEXT Collaboration acknowledges support from the following agencies and institutions: the European Research Council (ERC) under the Advanced Grant 339787-NEXT; the European Union’s Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Grant Agreements No. 674896, 690575 and 740055; the Ministerio de Economía y Competitividad and the Ministerio de Ciencia, Innovación y Universidades of Spain under grants FIS2014-53371-C04, RTI2018-095979, the Severo Ochoa Program grants SEV-2014-0398 and CEX2018-000867-S, and the María de Maeztu Program MDM2016-0692; the Generalitat Valenciana of Spain under grants PROMETEO/2016/120 and SEJI/2017/011; the Portuguese FCT under project PTDC/FIS-NUC/2525/2014 and under projects UID/FIS/04559/2020 to fund the activities of LIBPhys-UC; the Pazy Foundation (Israel) under grants 877040 and 877041; the US Department of Energy under contracts number DE-AC02-06CH11357 (Argonne National Laboratory), DE-AC02-07CH11359 (Fermi National Accelerator Laboratory), DE-FG02-13ER42020 (Texas A&M) and DE-SC0019223 / DE-SC0019054 (University of Texas at Arlington); and the University of Texas at Arlington. DGD acknowledges support from the Ramón y Cajal program (Spain) under contract number RYC-2015-18820. JM-A acknowledges support from Fundación Bancaria la Caixa (ID 100010434), grant code LCF/BQ/PI19/11690012, and from the Plan GenT program of the Generalitat Valenciana, grant code CIDEGENT/2019/049.

Cells are subjected to multiple mechanical inputs throughout their lives. Their ability to detect these environmental cues is called mechanosensing, a process in which integrins play an important role. During cellular mechanosensing, plasma membrane (PM) tension is adjusted to mechanical stress through the buffering action of caveolae; however, little is known about the role of caveolae in early integrin mechanosensing regulation. Here, we show that Cav1KO fibroblasts increase adhesion to FN-coated beads when pulled with magnetic tweezers, as compared to wild type fibroblasts. This phenotype is Rho-independent and mainly derived from increased active β1-integrin content on the surface of Cav1KO fibroblasts. Florescence recovery after photobleaching analysis and endocytosis/recycling assays revealed that active β1-integrin is mostly endocytosed through the clathrin independent carrier/glycosylphosphatidyl inositol (GPI)-enriched endocytic compartment pathway and is more rapidly recycled to the PM in Cav1KO fibroblasts, in a Rab4 and PM tension-dependent manner. Moreover, the threshold for PM tension-driven β1-integrin activation is lower in Cav1KO mouse embryonic fibroblasts (MEFs) than in wild type MEFs, through a mechanism dependent on talin activity. Our findings suggest that caveolae couple mechanical stress to integrin cycling and activation, thereby regulating the early steps of the cellular mechanosensing response.Cells can physically sense their immediate environment by pulling and pushing through integrins, a type of proteins which connects the inside and outside of a cell by being studded through the cellular membrane. This sensing role can only be performed when integrins are in an active state. Two main mechanisms regulate the relative amount of active integrins: one controls the activation of the proteins already at the cell surface; the other, known as recycling, impacts how many new integrins are delivered to the membrane. Both processes are affected by changes in cell membrane tension, which is itself controlled by dimples (or ‘caveolae’ – little caves in Latin) present in the cell surface. Caveolae limit acute changes in tension by taking in (pinching off the dimples) or releasing (dimples flattening) segments of the membrane. However, it is still unclear how integrins and caveolae mechanically interact to regulate the ability for a cell to read its environment. To understand this process, Lolo et al. focused on mouse cells genetically manipulated to not build caveolae on their surfaces, and which cannot properly sense mechanical changes in their surroundings. These were exposed to beads covered in an integrin-binding protein and manipulated using magnetic tweezers. The manipulation showed that mutated cells bound to the beads more strongly than non-modified cells, indicating that they had more active integrins on their surface. This change was due to both an accelerated recycling mechanism (which resulted in more integrin being brought at the surface) and an increase in integrin activation (which was triggered by a higher membrane tension). Caveolae therefore couple mechanical inputs to integrin recycling and activation. Healthy tissues rely on cells correctly sensing physical changes in their environment so they can mount an appropriate response. This ability, for example, is altered in cancerous cells which start to form tumours. The findings by Lolo et al. bring together physics and biology to provide new insights into the potential mechanisms causing such impairments.

Atherosclerosis is a chronic inflammatory disease of the arteries that can lead to thrombosis, infarction, and stroke and is the leading cause of mortality worldwide. Immunization of pro-atherogenic mice with malondialdehyde-modified low-density lipoprotein (MDA-LDL) neo-antigen is athero-protective. However, the immune response to MDA-LDL and the mechanisms responsible for this athero-protection are not completely understood. Here, we find that immunization of mice with MDA-LDL elicits memory B cells, plasma cells, and switched anti-MDA-LDL antibodies as well as clonal expansion and affinity maturation, indicating that MDA-LDL triggers a bona fide germinal center antibody response. Further, Prdm1fl/flAicda-Cre+/kiLdlr-/- pro-atherogenic chimeras, which lack germinal center-derived plasma cells, show accelerated atherosclerosis. Finally, we show that MDA-LDL immunization is not athero-protective in mice lacking germinal-center-derived plasma cells. Our findings give further support to the development of MDA-LDL-based vaccines for the prevention or treatment of atherosclerosis. We thank all members of the B Cell Biology Laboratory for useful discussions, A. Rodriguez-Ronchel for the design of the graphical abstract, V.G. de Ye´benes for critical reading of the manuscript, and V. Labrador for help with microscopy and image analysis. I.M.-F. and C.L. were fellows of the research training program funded by Ministerio de Economı´a y Competitividad (SVP-2014-068216 and SVP-2014-068289, respectively), A.d.M.M. is funded by ‘‘la Caixa’’ Foundation HR17–00247, and A.R.R. was supported by Centro Nacional de Investigaciones Cardiovasculares (CNIC). The project leading to these results has received funding from la Caixa Banking Foundation under the project code HR17-00247 and from SAF2016-75511-R and PID2019-106773RB-I00/AEI/10.13039/501100 011033 grants to A.R.R. (Plan Estatal de Investigacio´ n Cientı´fica y Te´ cnica y de Innovacio´ n 2013–2016 Programa Estatal de I+D+i Orientada a los Retos de la Sociedad Retos Investigacio´ n: Proyectos I + D + i 2016, Ministerio de Economı´a,Industria y Competitividad) and co-funding by Fondo Europeo de Desarrollo Regional (FEDER). CIBERCV (J.L.M.-V.) and CIBERDEM (J.C.E.-G.) are Instituto de Salud Carlos III projects. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovacio´ n (MCIN), and the Pro CNIC Foundation and is a Severo Ochoa institute (CEX2020-001041-S grant funded by MCIN/AEI/10.13039/501100011033). Sí

Background and Objectives Increased anxious-depressive symptomatology is observed in the preclinical stage of Alzheimer disease (AD), which may accelerate disease progression. We investigated whether β-amyloid, cortical thickness in medial temporal lobe structures, neuroinflammation, and sociodemographic factors were associated with greater anxious-depressive symptoms during the COVID-19 confinement. Methods This retrospective observational study included cognitively unimpaired older adults from the Alzheimer's and Families cohort, the majority with a family history of sporadic AD. Participants performed the Hospital Anxiety and Depression Scale (HADS) during the COVID-19 confinement. A subset had available retrospective (on average: 2.4 years before) HADS assessment, amyloid [18F] flutemetamol PET and structural MRI scans, and CSF markers of neuroinflammation (interleukin-6 [IL-6], triggering receptor expressed on myeloid cells 2, and glial fibrillary acidic protein levels). We performed multivariable linear regression models to investigate the associations of prepandemic AD-related biomarkers and sociodemographic factors with HADS scores during the confinement. We further performed an analysis of covariance to adjust by participants' prepandemic anxiety-depression levels. Finally, we explored the role of stress and lifestyle changes (sleep patterns, eating, drinking, smoking habits, and medication use) on the tested associations and performed sex-stratified analyses. Results We included 921 (254 with AD biomarkers) participants. β-amyloid positivity (B = 3.73; 95% CI = 1.1 to 6.36; p = 0.006), caregiving (B = 1.37; 95% CI 0.24–2.5; p = 0.018), sex (women: B = 1.95; 95% CI 1.1–2.79; p < 0.001), younger age (B = −0.12; 95% CI −0.18 to −0.052; p < 0.001), and lower education (B = −0.16; 95% CI −0.28 to −0.042; p = 0.008) were associated with greater anxious-depressive symptoms during the confinement. Considering prepandemic anxiety-depression levels, we further observed an association between lower levels of CSF IL-6 (B = −5.11; 95% CI −10.1 to −0.13; p = 0.044) and greater HADS scores. The results were independent of stress-related variables and lifestyle changes. Stratified analysis revealed that the associations were mainly driven by women. Discussion Our results link AD-related pathophysiology and neuroinflammation with greater anxious-depressive symptomatology during the COVID-19-related confinement, notably in women. AD pathophysiology may increase neuropsychiatric symptomatology in response to stressors. This association may imply a worse clinical prognosis in people at risk for AD after the pandemic and thus deserves to be considered by clinicians., This research was supported by Alzheimer's Association research grants (AARG 2019-AARG-644641 and AARG 2019-AARG-644641-RAPID) to E.M. Arenaza-Urquijo. E.M. Arenaza-Urquijo holds a Ramón y Cajal fellowship (RYC2018-026053-I) and a grant of the Ministry of Science and Innovation (PID2019-111514RA-I00). The research leading to these results has received funding from la Caixa Foundation (LCF/PR/GN17/10300004), the Alzheimer's Association, and an international anonymous charity foundation through the TriBEKa Imaging Platform project. Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under grant 2017-SGR-892.

The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression., This work was funded by Spanish Ministry of Science and Innovation - ISCIII (PI15/00623, PI18/00458, PI21/01208, CP18/00076, and FI19/00193); European Regional Development (FEDER) funds; Basque Department of Health (2017111011); Fundación SEOM (Beca SEOM-Font Vella); Fundación Gangoiti; and Ikerbasque Basque Research Foundation. The group also received funds from the breast cancer patient’s charity Katxalin and from Roche Farma S.A. AMA and AA are funded by Basque Government Doctoral Training Grants. JILV is funded by an AECC PhD Fellowship. FVM is supported by the Career Development Fellowship from the Cancer Institute New South Wales (2019/CDF002). AP’s research is funded by the European Research Council (ERC, ERC-2018-StG 804236-NEXTGEN-IO), and by the Spanish Ministry of Science and Innovation (PID2019-107956RA-I00 and RYC2018-024183-I). AC’s research is supported by the Basque Department of Industry, Tourism and Trade (Elkartek); the MICINN (PID2019-108787RB-I00 [FEDER/EU]; Excellence Network (SAF2016-81975-REDT); European Training Networks Project (H2020-MSCA-ITN-308 2016 721532); the AECC (GCTRA18006CARR), Vencer el Cáncer Foundation; La Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR17/; and the ERC (Consolidator Grant 819242). CIBERONC was cofunded with FEDER funds and funded by ISCIII. DGO is supported by a Cancer Council NSW project grant (RG18-03) and the National Breast Cancer Foundation Elaine Henry Fellowship (IIRS-21-096). FC is funded by Institute of Cancer Research, Spanish Ministry of Science and Innovation (RYC-2016-20352 and RTI2018-096778-A-I00); Asociacion Española Contra el Cancer (LAB-AECC, LABAE19044CALV); and BBVA Leonardo Awards (IN[19]_BBM_BAS_0076).

[Background] [18F]Flortaucipir (FTP) PET quantification is usually hindered by spill-in counts from off-target binding (OFF) regions. The present work aims to provide an in-depth analysis of the impact of OFF in FTP PET quantification, as well as to identify optimal partial volume correction (PVC) strategies to minimize this problem., [Methods] 309 amyloid-beta (Aβ) negative cognitively normal subjects were included in the study. Additionally, 510 realistic FTP images with different levels of OFF were generated using Monte Carlo simulation (MC). Images were corrected for PVC using both a simple two-compartment and a multi-region method including OFF regions. FTP standardized uptake value ratio (SUVR) was quantified in Braak Areas (BA), the hippocampus (which was not included in Braak I/II) and different OFF regions (caudate, putamen, pallidum, thalamus, choroid plexus (ChPlex), cerebellar white matter (cerebWM), hemispheric white matter (hemisWM) and cerebrospinal fluid (CSF)) using the lower portion of the cerebellum as a reference region. The correlations between OFF and cortical SUVRs were studied both in real and in simulated PET images, with and without PVC., [Results] In-vivo, we found correlations between all OFF and target regions, especially strong for the hemisWM (slope>0.63, R2>0.4). All the correlations were attenuated but remained significant after applying PVC, except for the ChPlex. In MC simulations, the hemisWM and CSF were the main contributors to PVE in all BA (slopes 0.15-0.26 and 0.13-0.21 respectively). The hemisWM (slope=0.2), as well as the ChPlex (slope=0.02), influenced SUVRs in the hippocampus. The CerebWM was negatively correlated with all target regions (slope0.8). While no other correlations between OFF and target regions were found, hemisWM was correlated with all OFF regions but the cerebWM (slopes 0.06-0.33). HemisWM correlations attenuated (slopes, [Conclusion] HemisWM is the main driver of spill-in effects in FTP PET, affecting both target regions and the rest of OFF regions. PVC successfully reduces PVE, even when using a simple two-compartment method. Despite PVC, non-zero correlations were still observed between target and OFF regions in vivo, which suggests the existence of biological or tracer-related contributions to these correlations., This work is partly funded by the public projects funded by ERDF: PI16/01416 (ISCIII) and EAPA_791/2018 NeuroATLANTIC (UE Interreg). Francisco J. López-González and José Paredes-Pacheco are funded by PhD scholarships (FPU17/04470 and FPU16/05108, respectively) from the Spanish Ministry of Education, Culture and Sport under the FPU program. The project that gave rise to these results received the support of a fellowship from ”la Caixa” Foundation (ID 100010434). The fellowship code is LCF/BQ/DR20/11790012. Pablo Aguiar is a Ramon y Cajal Fellow (RYC-2015/17430). Jesús Silva-Rodríguez is a Sara Borrell Fellow (CD21/00067).

Comment; 5 pages, 3 figures., In the work of Das and Sharma [Phys. Rev. A 105, 033716 (2022)] the phase transitions of the Dicke model are studied. Its main result is that, besides the well-known quantum phase transition, excited-state quantum phase transition and thermal phase transition exhibited by the model, there exists an upper bound energy, $E_{*}$, beyond which the model ceases to exhibit quantum chaotic behavior and the structure of the eigenfunctions changes. Based on this finding, a number of well-established results about the Dicke model are called into question. We argue that this result and all its consequences are spurious numerical effects resulting from an improper truncation of the infinite-dimensional Hilbert space necessary for numerical diagonalization., This work has been supported by the Spanish Grant No. PGC-2018-094180-B-I00 funded by Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación MCIN/AEI/10.13039/501100011033 and FEDER “A way of making Europe.” A.L.C. acknowledges financial support from “la Caixa” Foundation (ID 100010434) through the fellowship LCF/BQ/DR21/11880024.

Altruism and solidarity are concepts that are closely related to organ donation for transplantation. On the one hand, they are typically used for encouraging people to donate. On the other hand, they also underpin the regulations in force in each country to different extents. They are often used indistinctly and equivocally, despite the different ethical implications of each concept. This paper aims to clarify to what extent we can speak of altruism and solidarity in the predominant models of organ donation. It also raises the ethical question of whether these categories are adequate as a basis for such models, bearing in mind that organs are a scarce resource and that a shortage of them may mean that fewer lives are saved or improved., INEDyTO [Investigation on the Ethics of Organ Donation and Transplantation], Spanish Government European Commission MINECO FFI2017-88913-P, "Bioethics and end-of-life practices" (INEDyTOII) MINECO PID2020-118729RB, Spanish Government FPU19/06027, La Caixa Foundation LCF/BQ/DR20/11790005

12 pages, 6 figures, supplementary information https://doi.org/10.1038/s41396-022-01319-3.-- Data availability: Data are available in the main text or the supplementary materials. Sequences have been deposited to NCBI with accession numbers SAMN24579080-SAMN24579145, Diazotrophs are widespread microorganisms that alleviate nitrogen limitation in 60% of our oceans, thereby regulating marine productivity. Yet, the group-specific contribution of diazotrophs to organic matter export has not been quantified, which so far has impeded an accurate assessment of their impact on the biological carbon pump. Here, we examine the fate of five groups of globally-distributed diazotrophs by using an original combination of mesopelagic particle sampling devices across the subtropical South Pacific Ocean. We demonstrate that cyanobacterial and non-cyanobacterial diazotrophs are exported down to 1000 m depth. Surprisingly, group-specific export turnover rates point to a more efficient export of small unicellular cyanobacterial diazotrophs (UCYN) relative to the larger and filamentous Trichodesmium. Phycoerythrin-containing UCYN-B and UCYN-C-like cells were recurrently found embedded in large (>50 µm) organic aggregates or organized into clusters of tens to hundreds of cells linked by an extracellular matrix, presumably facilitating their export. Beyond the South Pacific, our data are supported by analysis of the Tara Oceans metagenomes collected in other ocean basins, extending the scope of our results globally. We show that, when diazotrophs are found in the euphotic zone, they are also systematically present in mesopelagic waters, suggesting their transport to the deep ocean. We thus conclude that diazotrophs are a significant part of the carbon sequestered in the deep ocean and, therefore, they need to be accounted in regional and global estimates of export, This research is a contribution of the TONGA project (Shallow hydroThermal sOurces of trace elemeNts: potential impacts on biological productivity and the bioloGicAl carbon pump; TONGA cruise https://doi.org/10.17600/18000884) funded by the Agence Nationale de la Recherche (grant TONGA ANR-18- CE01-0016 and grant CINNAMON ANR-17-CE2-0014-01), the LEFE-CyBER program (CNRS-INSU), the A-Midex foundation, the Institut de Recherche pour le Développement (IRD). FMCC and LG acknowledge funding from the European Union’s Horizon 2020 research programme under the Marie Sklodowska-Curie grant agreement No. 749380 (UCYN2PLAST). FMCC has also received the support of a fellowship (grant no. 105090) from”la Caixa” Foundation (ID 100010434) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 847648”, and acknowledges funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S)

The humoral response requires rapid growth, biosynthetic capacity, proliferation and differentiation of B cells. These processes involve profound B-cell phenotypic transitions that are coupled to drastic changes in metabolism so as to meet the extremely different energetic requirements as B cells switch from resting to an activated, highly proliferative state and to plasma or memory cell fates. Thus, B cells execute a multi-step, energetically dynamic process of profound metabolic rewiring from low ATP production to transient and large increments of energy expenditure that depend on high uptake and consumption of glucose and fatty acids. Such metabolic plasticity is under tight transcriptional and post-transcriptional regulation. Alterations in B-cell metabolism driven by genetic mutations or by extrinsic insults impair B-cell functions and differentiation and may underlie the anomalous behavior of pathological B cells. Herein, we review molecular switches that control B-cell metabolism and fuel utilization, as well as the emerging awareness of the impact of dynamic metabolic adaptations of B cells throughout the different phases of the humoral response. AE lab is supported by the Retos Projects Program of the Spanish Ministry of Science, Innovation and Universities, the Spanish State Research Agency (AEI/10.13039/501100011033) co-funded by the European Regional Development Fund (PID 2019-104012RB-I00), a FERO Grant for Research in Oncology, and La Caixa Foundation (HR21-00046). AE is an EMBO Young Investigator. YV-G is a recipient of a CNIO Friends Fellowship supported by the Fundacion Domingo Martinez. Sí

Long non-coding RNAs (lncRNAs) have emerged as key regulators in a wide range of biological processes. Here, we identified a mouse miRNA-host gene lncRNA (Lnc-Nr6a1) upregulated early during epithelial-to-mesenchymal transition (EMT). We show that when lncRNA is processed, it gives rise to two abundant polyadenylated isoforms, lnc-Nr6a1-1 and lnc-Nr6a1-2, and a longer non-polyadenylated microprocessor-driven lnc-pri-miRNA containing clustered pre-miR-181a2 and pre-miR-181b2 hairpins. Ectopic expression of the lnc-Nr6a1-1 or lnc-Nr6a1-2 isoform enhanced cell migration and the invasive capacity of the cells, whereas the expression of the isoforms and miR-181a2 and miR-181b2 conferred anoikis resistance. Lnc-Nr6a1 gene deletion resulted in cells with lower adhesion capacity and reduced glycolytic metabolism, which are restored by lnc-Nr6a1-1 isoform expression. We performed identification of direct RNA interacting proteins (iDRIP) to identify proteins interacting directly with the lnc-Nr6a1-1 isoform. We defined a network of interacting proteins, including glycolytic enzymes, desmosome proteins and chaperone proteins; and we demonstrated that the lnc-Nr6a1-1 isoform directly binds and acts as a scaffold molecule for the assembly of ENO1, ALDOA, GAPDH, and PKM glycolytic enzymes, along with LDHA, supporting substrate channeling for efficient glycolysis. Our results unveil a role of Lnc-Nr6a1 as a multifunctional lncRNA acting as a backbone for multiprotein complex formation and primary microRNAs., This research was funded by Ministerio de Economía y Competitividad, grant number SAF2017-861892-P and PID2020-119732RB-100 to J.A.P.-T. and PGC2018-097019-B-100 and PID2021- 122348NB-100 to J.V., and by la Caixa Banking Foundation, project codes HR17-00247 and HR22-00253 to J.V.

To study the relationship between urinary total polyphenol excretion (TPE) in adolescents and ideal cardiovascular (CVH) metrics. 1151 adolescents aged 12.04 (0.46) years participating in the SI! Program for Secondary Schools were selected based on the availability of urine samples and information required to assess CVH metrics. Data on health behaviours (smoking status, body mass index, physical activity, and healthy diet) and health factors (blood pressure, total cholesterol, and blood glucose) were used to calculate the CVH metrics. TPE in urine was analysed by a Folin-Ciocalteu method after solid-phase extraction. Associations between TPE (categorized into tertiles) and CVH metrics (total and separate scores) were assessed using multilevel mixed-effect regression models. Higher TPE levels were associated with higher (healthier) CVH scores and ideal smoking status (OR 1.54, 95% CI 1.10; 1.87, p value = 0.007), physical activity (OR 1.12, 95% CI 1.02; 1.23, p value = 0.022) and total cholesterol (OR 1.78, 95% CI 1.16; 2.73, p value = 0.009) after multivariate adjustment. An association between TPE and total CVH scores was observed only in boys. Girls with higher TPE had higher rates of ideal total cholesterol and blood pressure. According to our findings, higher urinary TPE is related to better CVH scores, with relevant differences in this association by gender. The authors wish to thank all the volunteers and their families, teachers, and schools for their contribution to the SI! Program for Secondary Schools. The SI! Program for Secondary Schools trial was supported by the SHE Foundation, the “la Caixa” Foundation (grant numbers LCF/PR/CE16//10700001 and LCF/PR/MS19/12220001), and the Fundació la Marató de TV3 (grant number 369/C/2016). Support was also provided by the Ministerio de Ciencia, Innovación y Universidades (grant number AGL2016–75329-R), and Generalitat de Catalunya. Rodrigo Fernández-Jiménez is a recipient of grant PI19/01704 funded by the Fondo de Investigación Sanitaria- Instituto de Salud Carlos III (ISCIII) and co-funded by the European Regional Development Fund/European Social Fund "A way to make Europe"/"Investi ng in your future". The Centro Nacional de Investigaciones Cardiovasculares is supported by the ISCIII, the Ministerio de Ciencia e Innovación, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (CEX2020-001041-S). Anna Tresserra-Rimbau was supported by a Serra Húnter Fellowship. Emily P. Laveriano-Santos is thankful for the FI-SDUR (EMC/3345/2020) fellowship from the Generalitat de Catalunya. Isabella Parilli-Moser thanks the FI-SDUR (EMC/2703/2019) fellowship. Sí

Background: Coronavirus-19 (COVID-19) disease is driven by an unchecked immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus which alters host mitochondrial-associated mechanisms. Compromised mitochondrial health results in abnormal reprogramming of glucose metabolism, which can disrupt extracellular signalling. We hypothesized that examining mitochondrial energy-related signalling metabolites implicated in host immune response to SARS-CoV-2 infection would provide potential biomarkers for predicting the risk of severe COVID-19 illness. Methods: We used a semi-targeted serum metabolomics approach in 273 patients with different severity grades of COVID-19 recruited at the acute phase of the infection to determine the relative abundance of tricarboxylic acid (Krebs) cycle-related metabolites with known extracellular signaling properties (pyruvate, lactate, succinate and α-ketoglutarate). Abundance levels of energy-related metabolites were evaluated in a validation cohort (n=398) using quantitative fluorimetric assays. Results: Increased levels of four energy-related metabolites (pyruvate, lactate, a-ketoglutarate and succinate) were found in critically ill COVID-19 patients using semi-targeted and targeted approaches (p, This work has been developed in the framework of the COVIDOMICS’ project supported by Direcció General de Recerca i Innovació en Salut (DGRIS), Departament de Salut, Generalitat de Catalunya (PoC-6-17 and PoC1-5). The research was also funded by the Programa de Suport als Grups de Recerca AGAUR (2017SGR948), the SPANISH AIDS Research Network [RD16/0025/0006]-ISCIII-FEDER (Spain) and the Centro de Investigación Biomédica en Red de Enfermedades Infecciosas-ISCIII [CB21/13/00020], Madrid, Spain. LR is supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CD20/00105” through the program “Contratos Sara Borrell”. FV is supported by grants from the Programa de Intensificación de Investigadores (INT20/00031)-ISCIII and by “Premi a la Trajectòria Investigadora dels Hospitals de l’ICS 2018”. AR is supported by a grant from IISPV through the project “2019/IISPV/05” (Boosting Young Talent), by GeSIDA through the “III Premio para Jóvenes Investigadores 2019” and by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CP19/00146” through the Miguel Servet Program. This study was also supported by grants SAF2015–65019-R and RTI2018–093919-B-100 (to SF-V.) funded by MCIN/AEI and by “ERFD A way of making Europe”; PI19/01337 to FV, PI20/00095 to VC.-M, PI20/00326 to AR and PI20/00338 to JV funded by ISCIII, cofinanced by the European Regional Development Fund (ERDF), and from Fundación Bancaria Caixa d’Estalvis i Pensions de Barcelona (HR20-00051 to SF-V). The Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM) (CB07708/0012) is an initiative of the Instituto de Salud Carlos III. SF-V acknowledges support from the Miguel Servet tenure-track program (CP10/00438 and CPII16/00008) from the Fondo de Investigación Sanitaria, cofinanced by the ERDF. VC-M acknowledges support from the Ramón y Cajal program (RYC2019-026490-I) from the Spanish Ministry of Science and Innovation, cofinanced by the ERDF. The work was also supported by Consejeria de Salud y Familia (COVID-0005-2020), Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades Junta de Andalucia (CV20-85418to ER-M) and Instituto de Salud Carlos III (ISCIII) under grant agreement CP19/00159 to AGV “a way to make Europe”. ER-M was supported by the Spanish Research Council (CSIC). The funders have no roles in study design, data collection, data analysis, interpretation or the writing of this research.

Angiogenesis is a multi-factorial physiological process deregulated in human diseases characterised by excessive or insufficient blood vessel formation. Emerging evidence highlights a novel role for microRNAs as regulators of angiogenesis. Previous studies addressing the effect of miR-133a expression in endothelial cells during blood vessel formation have reported conflicting results. Here, we have assessed the specific effect of mature miR-133a strands in angiogenesis and the expression of endothelial angiogenic genes. Transfection of miR-133a-3p or -5p mimics in primary human endothelial cells significantly inhibited proliferation, migration, and tubular morphogenesis of transfected cells. Screening of gene arrays related to angiogenic processes, and further validation by TaqMan qPCR, revealed that aberrant expression of miR-133a-3p led to a decrease in the expression of genes encoding pro-angiogenic molecules, whilst increasing those with anti-angiogenic functions. Ingenuity Pathway Analysis of a collection of genes differentially expressed in cells harbouring miR-133a-3p, predicted decreased cellular functions related to vasculature branching and cell cycle progression, underlining the inhibitory role of miR-133a-3p in angiogenic cellular processes. Our results suggest that controlled delivery of miR-133a-3p mimics, or antagomirs in diseased endothelial cells, might open new therapeutic interventions to treat patients suffering from cardiovascular pathologies that occur with excessive or insufficient angiogenesis. We thank Ben Small for technical assistance in the cell cycle fow cytometry experiments. Tis work was supported by the Research Institute in Healthcare Sciences, Faculty of Science and Engineering, University of Wolverhampton (to A.L.A) and by generous donations from the charities “Wolverhampton Coronary Afercare Support Group” (to A.L.A and J.C) and “Rotha Abraham Bequest” (to A.L.A and J.C). S.A. is the recipient of a University of Wolverhampton-Wolverhampton Royal NHS Trust joint PhD studentship. JMR has received funding from the “La Caixa” Banking Foundation HR18-00068 (to J.M.R.); Spanish Ministerio de Ciencia e Innovación grant RTI2018-099246-B-I00 (MICIU/AEI/FEDER, UE) to J.M.R and the Instituto de Salud Carlos III (CIBER-CV CB16/11/00264) to J.M.R. Te Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) and the Pro-CNIC Foundation. Sí

9 pags., 4 figs., Engineering long-range interactions in cold-atom quantum simulators can lead to exotic quantum many-body behavior. Fermionic atoms in ultracold atomic mixtures can act as mediators, giving rise to long-range Ruderman-Kittel-Kasuya-Yosida-type interactions characterized by the dimensionality and density of the fermionic gas. Here, we propose several tuning knobs, accessible in current experimental platforms, that allow one to further control the range and shape of the mediated interactions, extending the existing quantum simulation toolbox. In particular, we include an additional optical lattice for the fermionic mediator, as well as anisotropic traps to change its dimensionality in a continuous manner. This allows us to interpolate between power-law and exponential decays, introducing an effective cutoff for the interaction range, as well as to tune the relative interaction strengths at different distances. Finally, we show how our approach allows one to investigate frustrated regimes that were not previously accessible, where symmetry-protected topological phases as well as chiral spin liquids emerge., J. A. L. acknowledges support from ’la Caixa’ Foundation (ID 100010434) through the fellowship LCF/BQ/ES18/ 11670016, Severo Ochoa Grant CEX2019-000910-S [MCIN/AEI/10.13039/501100011033], Generalitat de Catalunya (CERCA program), Fundació Cellex, and Fundació Mir-Puig. A. G. T. acknowledges support from CSIC Interdisciplinary Thematic Platform (PTI+) on Quantum Technologies (PTI-QTEP+), from Spanish project PGC2018-094792-B-100(MCIU/AEI/FEDER, EU), and from the Proyecto Sinergico CAM 2020 Y2020/TCS-6545 (NanoQuCo-CM). D. G. C. is supported by the Simons Collaboration on Ultra-Quantum Matter, which is a grant from the Simons Foundation (651440, P. Z.).

Circadian nutritional behaviors, defined by the daily eating/fasting cycle, have been linked with breast cancer. This study aimed to further disentangle the association of nighttime fasting duration and time of breakfast with breast cancer risk. We analyzed data from 1,181 breast cancer cases and 1,326 population controls from the Spanish multicase-control study (MCC-Spain), 2008–2013. We collected circadian nutritional behaviors at mid-age via a telephonic interview. We applied logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of nighttime fasting duration and time of breakfast with breast cancer risk in all women and stratified by menopausal status. Models were adjusted for age, center, education, family history of breast cancer, age at menarche, number of children, breastfeeding, age at first child, body mass index (BMI), contraceptive use, and hormonal replacement therapy (HRT). A later time of breakfast was associated with a non-significant increased risk of breast cancer (OR = 1.05, 95% CI: 0.95–1.16, per hour increase). This association was stronger among premenopausal women, among whom each hour later, the time of breakfast was associated with an 18% increase in breast cancer risk (OR = 1.18, 95% CI: 1.01–1.40). The association was not observed in postmenopausal women. We did not observe an association between nighttime fasting duration and breast cancer risk after adjusting for the time of breakfast. In this study, late breakfast was associated with increased breast cancer risk, especially among premenopausal women, compared with early breakfast. Aside from nutritional quality, circadian nutritional behaviors should be further studied in relation to cancer., This study was partially funded by the “Accion Transversal del Cancer,” approved on the Spanish Ministry Council on the 11 October 2007, Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PS09/00773, PS09/01286, PS09/01903, PS09/02078, PS09/01662, PI11/01889, PI11/02213, PI12/00488, PI12/01270, PI12/00715, PI14/01219, PI14/0613, and PI17/01388), Fundación Marqués de Valdecilla (API 10/09), the ICGC International Cancer Genome Consortium CLL [The ICGC CLL-Genome Project was funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) del ISCIII (RD12/0036/0036)], the Junta de Castilla y León (LE22A10- 2), the Consejería de Salud of the Junta de Andalucía (PI-0571-2009, PI-0306-2011, and salud201200057018tra), the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), the Recercaixa (2010ACUP 00310), the Regional Government of the Basque Country, the Consejería de Sanidad de la Región de Murcia, by the European Commission grants FOOD-CT-2006-036224-HIWATE, the Spanish Association Against Cancer (AECC) Scientific Foundation, by the Catalan Government—Agency for Management of University and Research Grants (AGAUR) grants 2017SGR723 and 2014SGR850, the Fundación Caja de Ahorros de Asturias, and the University of Oviedo. ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S) and support from the Generalitat de Catalunya through the CERCA Program. AP-C was supported by the MINECO (Ministry of Economy in Spain) Grant no. PRE2019-089038, fellowship.