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This research was supported by the “Acción Transversal del Cancer”, approved by the Spanish Council of Ministers on 11th October 2007, by the Instituto de Salud Carlos III-FEDER [grant number:PI08/1770, PI08/0533, PI08/1359, PS09/00773-Cantabria, PS09/01286-León, PS09/01903-Valencia, PS09/02078-Huelva, PS09/ 01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI11/01810, PI14/01219, PI11/02213, PIE16/00049, PI17/01179, PI17-00092], by the Fundación Marqués de Valdecilla [grant number: API 10/09], by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII)), by the Red Temática de Investigación del Cáncer (RTICC) del ISCIII [grant number: RD12/0036/0036], by the Junta de Castilla y León [grant number: LE22A10-2], by the Consejería de Salud of the Junta de Andalucía [grant number: PI-0571-2009, PI-0306-2011, salud201200057018tra], by the Conselleria de Sanitat of the Generalitat Valenciana [grant number: AP_061/10], by the Recercaixa [grant number: 2010ACUP00310], by the Regional Government of the Basque Country, by the Consejería de Sanidad de la Región de Murcia, by the European Commission [grant number: FOOD-CT-2006-036224-HIWATE], by the Spanish Association Against Cancer (AECC) Scientific Foundation [grant number: GCTRA18022MORE], by the Catalan Government-Agency for Management of University and Research Grants (AGAUR) [grant number: 2014SGR647, 2014SGR850 and 2017SGR723], by the Fundación Caja de Ahorros de Asturias and by the University of Oviedo. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., There is evidence for the influence of socioeconomic status (SES) on healthy behaviours but the effect of social mobility (SM) is not yet well known. This study aims to analyse the influence of origin and destination SES (O-SES and D-SES) and SM on healthy behaviours and co-occurrence, from an integrated gender and age perspective. Data were obtained from the controls of MCC-Spain between 2008–2013 (3,606 participants). Healthy behaviours considered: healthy diet, moderate alcohol consumption, non-smoking and physical activity. SM was categorized as stable high, upward, stable medium, downward or stable low. Binary and multinomial logistic regression models were adjusted. Those aged, “Acción Transversal del Cancer” by the Spanish Council of Ministers, Instituto de Salud Carlos III-FEDER [grant number:PI08/1770, PI08/0533, PI08/1359, PS09/00773-Cantabria, PS09/01286-León, PS09/01903-Valencia, PS09/02078-Huelva, PS09/ 01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI11/01810, PI14/01219, PI11/02213, PIE16/00049, PI17/01179, PI17-00092, Fundación Marqués de Valdecilla [grant number: API 10/09], ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII)), Red Temática de Investigación del Cáncer (RTICC) del ISCIII [grant number: RD12/0036/0036], Junta de Castilla y León [grant number: LE22A10-2], Consejería de Salud of the Junta de Andalucía [grant number: PI-0571-2009, PI-0306-2011, salud201200057018tra], Conselleria de Sanitat of the Generalitat Valenciana [grant number: AP_061/10], Recercaixa [grant number: 2010ACUP00310], Regional Government of the Basque Country, Consejería de Sanidad de la Región de Murcia, European Commission [grant number: FOOD-CT-2006-036224-HIWATE], Spanish Association Against Cancer (AECC) Scientific Foundation [grant number: GCTRA18022MORE, Catalan Government-Agency for Management of University and Research Grants (AGAUR) [grant number: 2014SGR647, 2014SGR850 and 2017SGR723], Fundación Caja de Ahorros de Asturias, University of Oviedo

Classic swine fever is a highly contagious and often fatal viral disease that is caused by the classical swine fever virus (CSFV). Protein p7 of CFSV is a prototype of viroporin, a family of small, highly hydrophobic proteins postulated to modulate virus-host interactions during the processes of virus entry, replication and assembly. It has been shown that CSFV p7 displays substantial ion channel activity when incorporated into membrane systems, but a deep rationalization of the size and dynamics of the induced pores is yet to emerge. Here, we use high-resolution conductance measurements and current fluctuation analysis to demonstrate that CSFV p7 channels are ruled by equilibrium conformational dynamics involving protein-lipid interactions. Atomic force microscopy (AFM) confirms the existence of a variety of pore sizes and their tight regulation by solution pH. We conclude that p7 viroporin forms subnanometric channels involved in virus propagation, but also much larger pores (1-10 nm in diameter) with potentially significant roles in virus pathogenicity. Our findings provide new insights into the sources of noise in protein electrochemistry and demonstrate the existence of slow complex dynamics characteristic of crowded systems like biomembrane surfaces., Authors acknowledge financial support by the Spanish Government (Project PID2019-108434GB-I00 to M.Q.M. and A.A. and project IJC2018-035283-I to M.Q.M), Universitat Jaume I (Project UJI-B2018-53 to A.A.), the Agricultural Research Service of the US (ARS-USDA Project 8064-32000-056-18S to E.L. and J.L.N.) and the Basque Government (Project IT1196-19 to E.L., P.C., and J.L.N.). P.C. acknowledges a postdoctoral fellowship from the Basque Government (POS_2018_1_0066)

Adjectival comparatives like txiki baino txikiago ‘smaller than small’ in Basque exhibit some striking properties that present a challenge for previous analyses of inequality comparatives. The research on this unstudied type of adjectival comparatives in Basque – henceforth small comparatives – is especially interesting due to the rich morphology and freedom of word order that Basque displays. These two properties are vital for the testing of the hypotheses on the structure of these comparatives. First, the examination of the underlying structure of the standard of comparison reveals that these adjectival modifiers are inequality comparatives with a phrasal standard. Second, the study of the extraction constraints of the standard and the particular distribution of small comparatives evidence the fact that the standard marker in these comparatives behaves as a coordinating conjunction, and that these modifiers can appear inside a Determiner Phrase, in contrast with previously analysed adjectival comparatives. These properties are explained by assuming the functional analysis of adjectives and comparative markers (-ago ‘-er, more’), and proposing a coordination analysis of these phrasal comparatives. The study of small comparatives hence shows that the coordination analysis of comparative structures is necessary not only for clausal comparatives (Napoli & Nespor 1983 for Italian; Sáez 1992 for Spanish; and Lechner 2004 for English and German) but also for phrasal comparatives such as small comparatives.

The European Union Common Fisheries Policy has established a discard ban, which states that fish below a reference size cannot be sold directly for human consumption. In a fishing effort-regulated fishery, the discard ban can result in extra handling, storing and landing costs. In an output-regulated fishery, this policy might also limit the effort levels as all the catches count against the quota. In both cases, this regulation can reduce the economic performance of the companies, even in single-species fisheries. A possible solution is to increase the mesh size, thus retaining fewer small individuals. To study this option, a bioeconomic simulation of a change in the gear selectivity from 100- to 120-mm minimum mesh size (MMS) was performed. The results show that the private perspective (profits) does not change. Furthermore, due to the lower retention of 120 mm MMS, the efficiency of a fishing day was reduced by 5% and 2.5%, from the point of view of capital and labour productivity, respectively. In contrast, gross revenues increased by 1.5% and crew compensation by 2%. Given a societal benefit of this change in the mesh size, this gain could be re-distributed to provide an incentive for selectivity improvements., La Política Pesquera Común de la Unión Europa ha introducido la prohibición de descartar, estableciendo que todo pescado por debajo de una talla de referencia no puede ser vendido para consumo humano directo. En una pesquería regulada a través de limitaciones del esfuerzo de pesca, la prohibición de descartar puede generar sobrecostes de manipulación, almacenamiento y desembarque adicionales. En una pesquería regulada a través de límites en las capturas, esta política podría incluso limitar los niveles de esfuerzo ya que todas las capturas deben ser deducidas de la cuota. En ambos casos, esta regulación puede reducir el resultado económico de las empresas, incluso en el caso de una pesquería mono-específica. Una posible solución sería aumentar el tamaño mínimo de la malla, y así reducir la retención de los individuos más pequeños. Con el fin de estudiar esta opción, se ha realizado una simulación bioeconómica de un cambio en el tamaño mínimo de la malla de 100 a 120-mm. Los resultados muestran cómo la perspectiva económica privada (beneficios) no varía. Más aun, debido a la menor retención de la malla de 120 mm, la eficiencia de un día de pesca se ve reducida en un 5% y en un 2.5%, desde el punto de vista de la productividad del capital y del trabajo, respectivamente. Por el contrario, los beneficios brutos aumentan un 1.5% y la remuneración al trabajo en un 2%. Debido a la existencia de un beneficio social, la ganancia podría ser redistribuida para así ofrecer un incentivo a esta mejora de la selectividad.

International audience; Silicon-mediated fluoride abstraction is demonstrated as a means of generating the first fluorido-cyanido transition metal complexes. This new synthetic approach is exemplified by the synthesis and characterization of the heteroleptic complexes, trans-[M IV F 4 (CN) 2 ] 2À (M = Re, Os), obtained from their homoleptic [M IV F 6 ] 2À parents. As shown by combined high-field electron paramagnetic resonance spectroscopy and magnetization measurements, the partial substitution of fluoride by cyanide ligands leads to a marked increase in the magnetic anisotropy of trans-[ReF 4 (CN) 2 ] 2À as compared to [ReF 6 ] 2À , reflecting the severe departure from an ideal octahedral (O h point group) ligand field. This methodology paves the way toward the realization of new heteroleptic transition metal complexes that may be used as highly anisotropic building-blocks for the design of high-performance molecule-based magnetic materials.

The numerical simulation of the diffusion MRI signal arising from complex tissue micro-structures is helpful for understanding and interpreting imaging data as well as for designing and optimizing MRI sequences. The discretization of the Bloch-Torrey equation by finite elements is a more recently developed approach for this purpose, in contrast to random walk simulations, which has a longer history. While finite element discretization is more difficult to implement than random walk simulations, the approach benefits from a long history of theoretical and numerical developments by the mathematical and engineering communities. In particular, software packages for the automated solutions of partial differential equations using finite element discretization, such as FEniCS, are undergoing active support and development. However, because diffusion MRI simulation is a relatively new application area, there is still a gap between the simulation needs of the MRI community and the available tools provided by finite element software packages. In this paper, we address two potential difficulties in using FEniCS for diffusion MRI simulation. First, we simplified software installation by the use of FEniCS containers that are completely portable across multiple platforms. Second, we provide a portable simulation framework based on Python and whose code is open source. This simulation framework can be seamlessly integrated with cloud computing resources such as Google Colaboratory notebooks working on a web browser or with Google Cloud Platform with MPI parallelization. We show examples illustrating the accuracy, the computational times, and parallel computing capabilities. The framework contributes to reproducible science and open-source software in computational diffusion MRI with the hope that it will help to speed up method developments and stimulate research collaborations., La Caixa 2016

Phytophthora capsici causes root and crown rot of protected pepper (Capsicum annuum L.) crops in the Basque Country (northern Spain), a humid temperate climate area. The objective was to determine the effect of winter biofumigation and plastic cover (biodisinfestation) with Sinapis alba L. (cultivar 'Ludique') fresh green manure on the survival of introduced P. capsici inoculum (oospores) in a greenhouse soil. After autumn-winter Brassica cover crop soil incorporation in February, oospores remained at 15 and 30 cm depth for four weeks´ time exposure in two consecutive years, 2009 and 2010. Oospores viability was estimated with a plasmolysis method and infectivity with a potted pepper bioassay. Viability was significantly higher in biodisinfestated oospores than in the non-treated control in both years (81% and 21% relative increase in 2009 and 2010, respectively) and significantly higher at 30 cm depth than at 15 cm in 2009 (24% relative increase). Conversely, biodisinfestation significantly delayed disease incidence progression until the first half of infectivity bioassays in both years compared to the non-treated soils (83% and 75% relative decrease of dead plants in 2009 and 2010 respectively). The low soil temperatures could explain the low oospore survival reduction and suggest that the suppressiveness expressed in the infectivity bioassay was related with an increase of microbial activity in the biodisinfestation treatment. We conclude that winter biodisinfestation with fresh Brassica green manure is a promising management strategy for Phytophthora root rot control of protected peppers crops in regions of humid temperate climate such us northern Spain.

SUMMARY The contribution of membrane interfacial interactions to recognition of membrane-embedded antigens by antibodies is currently unclear. This report demonstrates the optimization of this type of antibodies via chemical modification of regions near the membrane but not directly involved in the recognition of the epitope. Using the HIV-1 antibody 10E8 as a model, linear and polycyclic synthetic aromatic compounds are introduced at selected sites. Molecular dynamics simulations predict the favorable interactions of these synthetic compounds with the viral lipid membrane, where the epitope of the HIV-1 glycoprotein Env is located. Chemical modification of 10E8 with aromatic acetamides facilitates the productive and specific recognition of the native antigen, partially buried in the crowded environment of the viral membrane, resulting in a dramatic increase of its capacity to block viral infection. These observations support the harnessing of interfacial affinity through site-selective chemical modification to optimize the function of antibodies that target membrane-proximal epitopes., Graphical Abstract, In Brief Rujas et al. describe the site-selective chemical modification of antibodies to improve the molecular recognition of epitopes at membrane surfaces. The modification using aromatic compounds dramatically enhanced the virus neutralization potency and native antigen binding efficiency of HIV-1 antibodies directed against the membrane-embedded MPER epitope.

Excreció; Genètica humana; Mutació Excreción; Genética humana; Mutación Excretion; Human genetics; Mutation Introduction Type III Bartter syndrome (BS) is an autosomal recessive renal tubule disorder caused by loss-of-function mutations in the CLCNKB gene, which encodes the chloride channel protein ClC-Kb. In this study, we carried out a complete clinical and genetic characterization in a cohort of 30 patients, one of the largest series described. By comparing with other published populations, and considering that 80% of our patients presented the p.Ala204Thr Spanish founder mutation presumably associated with a common phenotype, we aimed to test the hypothesis that allelic differences could explain the wide phenotypic variability observed in patients with type III BS. Methods Clinical data were retrieved from the referral centers. The exon regions and flanking intronic sequences of the CLCNKB gene were screened for mutations by polymerase chain reaction (PCR) followed by direct Sanger sequencing. Presence of gross deletions or duplications in the region was checked for by MLPA and QMPSF analyses. Results Polyuria, polydipsia and dehydration were the main common symptoms. Metabolic alkalosis and hypokalemia of renal origin were detected in all patients at diagnosis. Calciuria levels were variable: hypercalciuria was detected in 31% of patients, while 23% had hypocalciuria. Nephrocalcinosis was diagnosed in 20% of the cohort. Two novel CLCNKB mutations were identified: a small homozygous deletion (c.753delG) in one patient and a small deletion (c.1026delC) in another. The latter was present in compound heterozygosis with the already previously described p.Glu442Gly mutation. No phenotypic association was obtained regarding the genotype. Conclusion A poor correlation was found between a specific type of mutation in the CLCNKB gene and type III BS phenotype. Importantly, two CLCNKB mutations not previously described were found in our cohort This study was supported by two grants (PI09/90888 and PI11/01412) from the FIS of the Instituto de Salud Carlos III, Madrid, Spain, the Department of Health of the Basque Government (2014111064), and the Department of Education of the Basque Government (IT795-13).

International audience; Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.

International audience; BACKGROUND: Several studies have reported that prenatal exposure to some persistent organic pollutants (POPs) is associated with higher adiposity in childhood. Few studies have assessed whether this finding persists into adolescence, and few have considered exposure to POPs as a mixture. This study aims to assess the association between prenatal exposure to multiple POPs and adiposity markers and blood pressure in preadolescents. METHODS: This study included 1667 mother-child pairs enrolled in the PELAGIE (France) and the INMA (Spain) mother-child cohorts. Three polychlorobiphenyls (PCB 138, 153 and 180, treated as a sum of PCBs) and three organochlorine pesticides (p,p’-Dichlorodiphenyldichloroethylene [p,p’-DDE], β-hexachlorocyclohexane [β-HCH], and hexachlorobenzene [HCB]) were assessed in maternal or cord serum. Body mass index z-score (zBMI), abdominal obesity (waist-to-height ratio > 0.5), percentage of fat mass, and blood pressure (mmHg) were measured at around 12 years of age. Single-exposure associations were studied using linear or logistic regressions, and the POP mixture effect was evaluated using quantile G-computation (qgComp) and Bayesian Kernel Machine Regression (BKMR). All models were adjusted for potential confounders and performed for boys and girls together and separately. RESULTS: Prenatal exposure to the POP mixture was associated with higher zBMI (beta [95 % CI] of the qgComp = 0.15 [0.07; 0.24]) and percentage of fat mass (0.83 [0.31; 1.35]), with no evidence of sex-specific association. These mixture effects were also statistically significant using BKMR. These associations were driven mainly by exposure to HCB and, to a lesser extent, to β-HCH. In addition, the single-exposure models showed an association between β-HCH and p,p’-DDE and higher systolic blood pressure, especially in girls (p,p’-DDE for girls = 1.00 [0.15; 1.86]). No significant associations were found for PCBs. CONCLUSION: This study suggests that prenatal exposure to POPs, particularly organochlorine pesticides, remains associated with unfavorable cardiometabolic health up to the age of 12.

Version pre-proof à remplacer par la VOR quand sera publiée; International audience; Bacteria use type II secretion systems (T2SS) to secrete to their surface folded proteins that confer diverse functions, from nutrient acquisition to virulence. In the Klebsiella species, T2SS-mediated secretion of pullulanase (PulA) requires assembly of a dynamic filament called the endopilus. The inner membrane assembly platform (AP) subcomplex is essential for endopilus assembly and PulA secretion. AP components PulL and PulM interact with each other through their C-terminal globular domains and transmembrane segments. Here, we investigated the roles of their periplasmic helices, predicted to form a coiled coil, in assembly and function of the PulL–PulM complex. PulL and PulM variants lacking these periplasmic helices were defective for interaction in the bacterial two-hybrid (BACTH) assay. Their functions in PulA secretion and assembly of PulG subunits into endopilus filaments were strongly reduced. Interestingly, deleting the cytoplasmic peptide of PulM nearly abolished the function of variant PulMN and its interaction with PulG, but not with PulL, in the BACTH assay. Nevertheless, PulL was specifically proteolyzed in the presence of the PulMN variant, suggesting that PulM N-terminal peptide stabilizes PulL in the cytoplasm. We discuss the implications of these results for the T2S endopilus and type IV pilus assembly mechanisms.

Correction to: Five-year follow-up mortality prognostic index for colorectal patients. Int J Colorectal Dis. 2023 Jun 24;38(1):177. doi: 10.1007/s00384-023-04472-z. PMID: 37354325. Purpose: To identify 5-year survival prognostic variables in patients with colorectal cancer (CRC) and to propose a survival prognostic score that also takes into account changes over time in the patient's health-related quality of life (HRQoL) status. Methods: Prospective observational cohort study of CRC patients. We collected data from their diagnosis, intervention, and at 1, 2, 3, and 5 years following the index intervention, also collecting HRQoL data using the EuroQol-5D-5L (EQ-5D-5L), European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30), and Hospital Anxiety and Depression Scale (HADS) questionnaires. Multivariate Cox proportional models were used. Results: We found predictors of mortality over the 5-year follow-up to be being older; being male; having a higher TNM stage; having a higher lymph node ratio; having a result of CRC surgery classified as R1 or R2; invasion of neighboring organs; having a higher score on the Charlson comorbidity index; having an ASA IV; and having worse scores, worse quality of life, on the EORTC and EQ-5D questionnaires, as compared to those with higher scores in each of those questionnaires respectively. Conclusions: These results allow preventive and controlling measures to be established on long-term follow-up of these patients, based on a few easily measurable variables. Implications for cancer survivors: Patients with colorectal cancer should be monitored more closely depending on the severity of their disease and comorbidities as well as the perceived health-related quality of life, and preventive measures should be established to prevent adverse outcomes and therefore to ensure that better treatment is received. Trial registration: ClinicalTrials.gov identifier: NCT02488161. Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported in part by grants from the Instituto de Salud Carlos III and the European Regional Development Fund (PS09/00314, PS09/00910, PS09/00746, PS09/00805, PI09/90460, PI09/90490, PI09/90453, PI09/90441, PI09/90397); the Spanish Ministry of the Economy (PID2020-115738 GB-I00); the Departments of Health (2010111098) and Education, Language Policy and Culture (IT1456-22; IT1598-22; IT-1187–19) of the Basque Government; the Research Committee of Galdakao Hospital; the REDISSEC (Red de Investigación en Servicios de Salud en Enfermedades Crónicas) thematic network of the Instituto de Salud Carlos III; and the Department of Education of the Basque Government through the Consolidated Research Group MATHMODE (IT1456-22) and the Basque Government through BMTF “Mathematical Modeling Applied to Health” Project. Sí

The emergence of drug-resistant Mycobacterium tuberculosis strains highlights the need to discover anti-tuberculosis drugs with novel mechanisms of action. Here we discovered a mycobactericidal strategy based on the prodrug activation of selected chemical derivatives classified as nitronaphthofurans (nNFs) mediated by the coordinated action of the sigH and mrx2 genes. The transcription factor SigH is a key regulator of an extensive transcriptional network that responds to oxidative, nitrosative, and heat stresses in M. tuberculosis. The nNF action induced the SigH stress response which in turn induced the mrx2 overexpression. The nitroreductase Mrx2 was found to activate nNF prodrugs, killing replicating, non-replicating and intracellular forms of M. tuberculosis. Analysis of SigH DNA sequences obtained from spontaneous nNF-resistant M. tuberculosis mutants suggests disruption of SigH binding to the mrx2 promoter site and/or RNA polymerase core, likely promoting the observed loss of transcriptional control over Mrx2. Mutations found in mrx2 lead to structural defects in the thioredoxin fold of the Mrx2 protein, significantly impairing the activity of the Mrx2 enzyme against nNFs. Altogether, our work brings out the SigH/Mrx2 stress response pathway as a promising target for future drug discovery programs.

31 p.-12 fig.-1 tab. We dedicate this paper to Takashi Umekawa, who generated the HI model at the Karolinska Institute, and unfortunately passed away in 2018., Microglial phagocytosis of apoptotic debris prevents buildup damage of neighbor neurons and inflammatory responses. Whereas microglia are very competent phagocytes under physiological conditions, we report their dysfunction in mouse and preclinical monkey models of stroke (macaques and marmosets) by transient occlusion of the medial cerebral artery (tMCAo). By analyzing recently published bulk and single cell RNA sequencing databases, we show that the phagocytosis dysfunction was not explained by transcriptional changes. In contrast, we demonstrate that the impairment of both engulfment and degradation was related to energy depletion triggered by oxygen and nutrient deprivation (OND), which led to reduced process motility, lysosomal exhaustion, and the induction of a protective macroautophagy/autophagy response in microglia. Basal autophagy, in charge of removing and recycling intracellular elements, was critical to maintain microglial physiology, including survival and phagocytosis, as we determined both in vivo and in vitro using pharmacological and transgenic approaches. Notably, the autophagy inducer rapamycin partially prevented the phagocytosis impairment induced by tMCAo in vivo but not by OND in vitro, where it even had a detrimental effect on microglia, suggesting that modulating microglial autophagy to optimal levels may be a hard to achieve goal. Nonetheless, our results show that pharmacological interventions, acting directly on microglia or indirectly on the brain environment, have the potential to recover phagocytosis efficiency in the diseased brain. We propose that phagocytosis is a therapeutic target yet to be explored in stroke and other brain disorders and provide evidence that it can be modulated in vivo using rapamycin. Abbreviations: AIF1/IBA1: allograft inflammatory factor 1; AMBRA1: autophagy/beclin 1 regulator 1; ATG4B: autophagy related 4B, cysteine peptidase; ATP: adenosine triphosphate; BECN1: beclin 1, autophagy related; CASP3: caspase 3; CBF: cerebral blood flow; CCA: common carotid artery; CCR2: chemokine (C-C motif) receptor 2; CIR: cranial irradiation; Csf1r/v-fms: colony stimulating factor 1 receptor; CX3CR1: chemokine (C-X3-C motif) receptor 1; DAPI: 4’,6-diamidino-2-phenylindole; DG: dentate gyrus; GO: Gene Ontology; HBSS: Hanks’ balanced salt solution; HI: hypoxia-ischemia; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MCA: medial cerebral artery; MTOR: mechanistic target of rapamycin kinase; OND: oxygen and nutrient deprivation; Ph/A coupling: phagocytosis-apoptosis coupling; Ph capacity: phagocytic capacity; Ph index: phagocytic index; SQSTM1: sequestosome 1; RNA-Seq: RNA sequencing; TEM: transmission electron microscopy; tMCAo: transient medial cerebral artery occlusion; ULK1: unc-51 like kinase 1. © 2023 The Author(s)., This work was supported by grants from the Spanish Ministry of Science and Innovation Competitiveness MCIN/AEI/10.13039/501100011033 (https://www.ciencia.gob.es/) and ERDF “A way to make Europe” (RTI2018-099267-B-I00 and RYC-2013-12817 to AS; RTI2018–097948-A-100 and RYC-2016–20480 to OP), a Tatiana Foundation Award (P-048-FTPGB 2018) to AS a Basque Government Department of Education project (PIBA 2020_1_0030; http://www.euskadi.eus/basque-government/department-education/) to AS, a Basque Government Department of Economic development, Sustainability and environment (ELKARTEK KK-2020/00034; https://www.spri.eus/en/) to ECZ, and . SB is recipient of predoctoral fellowship from the Spanish Ministry of Economy and Competitiveness, and VST is recipient of predoctoral fellowship from the Basque Government.

This work was funded by the French National Cancer Institute (grant number 2015-166). Mathilde His' work reported here was undertaken during the tenure of a postdoctoral fellowship awarded by the International Agency for Research on Cancer, financed by the Fondation ARC. The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF) (The Netherlands); Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology-ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); and Cancer Research UK (14136 to EPIC-Norfolk (DOI 10.22025/2019.10.105.00004); C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143, MR/N003284/1, MC-UU_12015/1 and MC_UU_00006/1 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (UK). The funders were not involved in designing the study; collecting, analyzing, or interpreting the data; or writing or submitting the manuscript for publication., Background: Metabolomics is a promising molecular tool for identifying novel etiological pathways leading to cancer. In an earlier prospective study among pre- and postmenopausal women not using exogenous hormones, we observed a higher risk of breast cancer associated with higher blood concentrations of one metabolite (acetylcarnitine) and a lower risk associated with higher blood concentrations of seven others (arginine, asparagine, phosphatidylcholines (PCs) aa C36:3, ae C34:2, ae C36:2, ae C36:3, and ae C38:2). Methods: To identify determinants of these breast cancer-related metabolites, we conducted a cross-sectional analysis to identify their lifestyle and anthropometric correlates in 2358 women, who were previously included as controls in case-control studies nested within the European Prospective Investigation into Cancer and Nutrition cohort and not using exogenous hormones at blood collection. Associations of each metabolite concentration with 42 variables were assessed using linear regression models in a discovery set of 1572 participants. Significant associations were evaluated in a validation set (n = 786). Results: For the metabolites previously associated with a lower risk of breast cancer, concentrations of PCs ae C34: 2, C36:2, C36:3, and C38:2 were negatively associated with adiposity and positively associated with total and saturated fat intakes. PC ae C36:2 was also negatively associated with alcohol consumption and positively associated with two scores reflecting adherence to a healthy lifestyle. Asparagine concentration was negatively associated with adiposity. Arginine and PC aa C36:3 concentrations were not associated to any of the factors examined. For the metabolite previously associated with a higher risk of breast cancer, acetylcarnitine, a positive association with age was observed. Conclusions: These associations may indicate possible mechanisms underlying associations between lifestyle and anthropometric factors, and risk of breast cancer. Further research is needed to identify potential non-lifestyle correlates of the metabolites investigated., Institut National du Cancer (INCA) France 2015-166, International Agency for Research on Cancer - Fondation ARC, World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, German Cancer Research Center (DKFZ) (Germany), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) (Germany), Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Consiglio Nazionale delle Ricerche (CNR), Netherlands Government, World Cancer Research Fund International (WCRF), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII) (Spain), Junta de Andalucia, Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain), Regional Government of Navarra (Spain), Catalan Institute of Oncology-ICO (Spain), Swedish Cancer Society, Swedish Research Council, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) 1000143 MR/N003284/1 MC-UU_12015/1 MC_UU_00006/1 MR/M012190/1

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

Recent systematic reviews show that, overall, and across governance levels and sectors, climate change adaptation monitoring and evaluation (M&E) systems are rarely programmed and implemented. As a result, there is a generalized lack of knowledge and practice regarding the definition and use of adaptation indicators and metrics from which to effectively learn. This paper focuses on understanding the emergent state of practice regarding adaptation indicators and metrics at the local level: what indicators and metrics are used? What aspects of the adaptation process are they measuring? How will they be monitored, evaluated, and reported? Out of a sample of the largest 136 coastal cities worldwide, only 59 cities have adaptation-related plans and only 11 (Athens, Auckland, Barcelona, Glasgow, Lima, Montreal, Nagoya, New York City, Portland, Tokyo, and Vancouver) list indicators and metrics. Sourced from these documents, we compile and code a total of 1971 indicators, of which 1841 focus fully or partially on adaptation-related aspects. We study the level of detail (objective, indicator, metric), type (target, input, output, outcome, or impact), scale, dimension, units of measurement, target, and proposed monitoring timeframe, among other aspects. Data shows that current adaptation measurement frameworks are tied to the degree to which each city integrates and addresses adaptation in its policies. A majority of adaptation indicators and metrics measure outputs, i.e. implementation aspects. Outcome indicators are generally connected to users or beneficiaries of adaptation measures and impact indicators are mostly related to health (e.g. hospitalizations). Targets and monitoring timeframes, as well as data sources, are rarely defined. We connect this to a lack of definition of local adaptation goals and a poor understanding of how specific adaptation actions lead to vulnerability reductions and resilience increases. Based on the identified gaps, we propose a metric development guiding framework to stimulate discussion around effective and feasible approaches to measure adaptation progress based on improved adaptation decision-making. We argue, that our results should fuel a critical revision of current adaptation planning practices that might ultimately facilitate processes of learning, experimentation and innovation in this embryonic field. © 2022 This study was funded by AXA Research Fund under Grant Agreement No. 4771. This research was also supported by María de Maeztu excellence accreditation 2018-2022 (Ref. MDM-2017-0714), funded by MCIN/AEI/10.13039/501100011033/; and by the Basque Government through the BERC 2022-2025 program.

Integrase strand transfer inhibitor (INSTI)-containing regimens in HIV-1-infected patients have experienced a global increase. Recently, WHO has emphasized the need to fast-track the transition to dolutegravir (DTG)-based antiretroviral (ARV) treatments. However, continued surveillance of INSTI resistance is recommended. In this study, clinical, epidemiological, and virological features associated with INSTI resistance diagnosed in Spain were analyzed. Samples collected between 2008 and 2021 from HIV-1-infected patients were analyzed in integrase, protease, and reverse transcriptase using Sanger population sequencing. ARV drug resistance was evaluated with the Stanford University HIVdb program. Among 2,696 patients, 174 (6.5%) had INSTI resistance, all of them to first-generation INSTIs, and 71 (2.6%) had also resistance to second-generation INSTIs. Of these, only 5 individuals were exposed to DTG as the only INSTI, in whom resistance development was associated with poor treatment adherence and/or resistance to other ARV classes. Of newly HIV-1-diagnosed individuals, 0.92% harbored INSTI-resistant viruses, with low prevalences maintained along time, and only one had low-level resistance to DTG. Persons who inject drugs, age over 39 years, resistance to other ARV classes, and longer time from diagnosis were associated with INSTI resistance (p

Based on numerous pharmacological studies that have revealed an interaction between cannabinoid and opioid systems at the molecular, neurochemical, and behavioral levels, a new series of hybrid molecules has been prepared by coupling the molecular features of two wellknown drugs, ie, rimonabant and fentanyl. The new compounds have been tested for their affinity and functionality regarding CB1 and CB2 cannabinoid and μ opioid receptors. In [35S]-GTPγS (guanosine 5'-O-[gamma-thio]triphosphate) binding assays from the post-mortem human frontal cortex, they proved to be CB1 cannabinoid antagonists and μ opioid antagonists. Interestingly, in vivo, the new compounds exhibited a significant dual antagonist action on the endocannabinoid and opioid systems. © 2014 Fernández-Fernández et al.

Purpose Health-related quality of life (HRQoL) measurement represents an important outcome in cancer patients. We describe the evolution of HRQoL over a 5-year period in colorectal cancer patients, identifying predictors of change and how they relate to mortality. Methods Prospective observational cohort study including colorectal cancer (CRC) patients having undergone surgery in nineteen public hospitals who were monitored from their diagnosis, intervention and at 1-, 2-, 3-, and 5-year periods thereafter by gathering HRQoL data using the EuroQol-5D-5L (EQ-5D-5L), European Organization for Research and Treatment of Cancer’s Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30), and Hospital Anxiety and Depression Scale (HADS) questionnaires. Multivariable generalized linear mixed models were used. Results Predictors of Euroqol-5D-5L (EQ-5D-5L) changes were having worse baseline HRQoL; being female; higher Charlson index score (more comorbidities); complications during admission and 1 month after surgery; having a stoma after surgery; and needing or being in receipt of social support at baseline. For EORTC-QLQ-C30, predictors of changes were worse baseline EORTC-QLQ-C30 score; being female; higher Charlson score; complications during admission and 1 month after admission; receiving adjuvant chemotherapy; and having a family history of CRC. Predictors of changes in HADS anxiety were being female and having received adjuvant chemotherapy. Greater depression was associated with greater baseline depression; being female; higher Charlson score; having complications 1 month after intervention; and having a stoma. A deterioration in all HRQoL questionnaires in the previous year was related to death in the following year. Conclusions These findings should enable preventive follow-up programs to be established for such patients in order to reduce their psychological distress and improve their HRQoL to as great an extent as possible. ClinicalTrials.gov Identifier: NCT02488161

Background: Toenails are commonly used as biomarkers of exposure to zinc (Zn), but there is scarce information about their relationship with sources of exposure to Zn. Objectives: To investigate the main determinants of toenail Zn, including selected sources of environmental exposure to Zn and individual genetic variability in Zn metabolism. Methods: We determined toenail Zn by inductively coupled plasma mass spectrometry in 3,448 general population controls from the MultiCase-Control study MCC-Spain. We assessed dietary and supplement Zn intake using food frequency questionnaires, residential proximity to Zn-emitting industries and residential topsoil Zn levels through interpolation methods. We constructed a polygenic score of genetic variability based on 81 single nucleotide polymorphisms in genes involved in Zn metabolism. Geometric mean ratios of toenail Zn across categories of each determinant were estimated from multivariate linear regression models on log-transformed toenail Zn. Results: Geometric mean toenail Zn was 104.1 μg/g in men and 100.3 μg/g in women. Geometric mean toenail Zn levels were 7 % lower (95 % confidence interval 1–13 %) in men older than 69 years and those in the upper tertile of fibre intake, and 9 % higher (3–16 %) in smoking men. Women residing within 3 km from Zn-emitting industries had 4 % higher geometric mean toenail Zn levels (0–9 %). Dietary Zn intake and polygenic score were unrelated to toenail Zn. Overall, the available determinants only explained 9.3 % of toenail Zn variability in men and 4.8 % in women. Discussion: Sociodemographic factors, lifestyle, diet, and environmental exposure explained little of the individual variability of toenail Zn in the study population. The available genetic variants related to Zn metabolism were not associated with toenail Zn., Instituto de Salud Carlos III, Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), FEDER funds-a way to build Europe PI08/1770 PI09/0773 PI12/00715 PI09/1903 PI09/2078 PI09/1662 PI11/01403 PI12/00150 PI12/00488 PI15/00914 PI17CIII_00034, Fundacion Marques de Valdecilla grant API 10/09, Junta de Andalucia 2009-S0143, Conselleria de Sanitat of the Generalitat Valenciana AP061/10, Regional Government of the Basque Country, Principality of Asturias, University of Oviedo, Spanish Ministry of Economy and Competitiveness Juan de la Cierva de Incorporacion IJCI-2014-20900 Instituto de Salud Carlos III

Author Correction: Identifcation of CRF89_BF, a new member of an HIV‑1 circulating BF intersubtype recombinant form family widely spread in South America. Sci Rep. 2021 Aug 3;11(1):16115. DOI: 10.1038/s41598-021-95679-z. Circulating recombinant forms (CRFs) contribute substantially to the HIV-1 pandemic. Among 105 CRFs described in the literature, 16 are BF intersubtype recombinants, most of South American origin, of which CRF12_BF is the most widely spread. A BF recombinant cluster identified in Bolivia was suggested to represent a new CRF_BF. Here we find that it belongs to a larger cluster incorporating 39 viruses collected in 7 countries from 3 continents, 22 of them in Spain, most from Bolivian or Peruvian individuals, and 12 in South America (Bolivia, Argentina, and Peru). This BF cluster comprises three major subclusters, two associated with Bolivian and one with Peruvian individuals. Near full-length genome sequence analyses of nine viruses, collected in Spain, Bolivia, and Peru, revealed coincident BF mosaic structures, with 13 breakpoints, 6 and 7 of which coincided with CRF12_BF and CRF17_BF, respectively. In a phylogenetic tree, they grouped in a clade closely related to these CRFs, and more distantly to CRF38_BF and CRF44_BF, all circulating in South America. These results allowed to identify a new HIV-1 CRF, designated CRF89_BF. Through phylodynamic analyses, CRF89_BF emergence was estimated in Bolivia around 1986. CRF89_BF is the fifth CRF member of the HIV-1 recombinant family related to CRF12_BF. This work was funded through Acción Estratégica en Salud Intramural (AESI), Instituto de Salud Carlos III, projects “Estudios sobre vigilancia epidemiológica molecular del VIH-1 en España”, PI16CIII/00033, and “Epidemiología molecular del VIH en España y su utilidad para investigaciones biológicas y en vacunas”, PI19CIII/00042; Red de Investigación en SIDA (RIS), Instituto de Salud Carlos III, Subdirección General de Evaluación y Fondo Europeo de Desarrollo Regional (FEDER), Plan Nacional I+D+I, project RD16ISCIII/0002/0004; and scientific agreement with Osakidetza-Servicio Vasco de Salud, Government of Basque Country, MVI 1001/16. Sí

Phytophthora root and crown rot is a plant disease responsible for important economic losses in protected pepper crops. A greenhouse experiment was carried out in a temperate climate region (northern Spain) to assess the effects of repeated biodisinfection after three consecutive crop seasons with different organic amendments (a non-composted mixture of sheep manure and chicken litter, a semicomposted mixture of horse manure and chicken litter, Brassica carinata dehydrated pellets plus Sinapis alba fresh green manure) on disease incidence, crop yield and soil quality. Biodisinfection treatments were found to improve soil water properties through reduction in soil bulk density and increased water infiltration. Biodisinfested soils showed higher values of physicochemical and microbial properties than control (untreated) and plastic-mulched soils. In plots treated with the non-composted or semicomposted mixture, the observed higher levels of microbial activity were strongly related with an increase in soil microbial biomass. Brassica-Sinapis treatment had a weaker effect on soil properties than animal manure-based treatments. However, highest counts of total bacteria, actinomycetes and Pseudomonas spp. were found in Brassica-Sinapis-treated soils. It was concluded that repeated biodisinfection for the control of Phytophthora root and crown rot in protected pepper crops located in temperate climate regions can improve soil quality and suppressiveness, as well as allow for a reduction in the dose of organic amendment needed for biodisinfection. Among the studied organic amendments, the semicomposted amendment was the best option in terms of reduction in disease incidence., La podredumbre radicular y del cuello causada por Phytophthora es una enfermedad que genera importantes pérdidas económicas en cultivos de pimiento en invernadero. En una región de clima templado (norte de España) se realizó ensayo en invernadero para evaluar la reiteración de tratamientos de biodesinfección después de tres ciclos de cultivo consecutivos con diferentes enmiendas orgánicas (mezcla no-compostada de estiércol de oveja y gallinaza, mezcla semicompostada de estiércol de caballo y gallinaza, pellets deshidratados de Brassica carinata más Sinapis alba como abono verde fresco) sobre la incidencia de la enfermedad, la producción y la calidad del suelo. La biodesinfección mejoró las propiedades hídricas del suelo al reducir la densidad aparente y aumentar la infiltración. Los suelos biodesinfectados mostraron valores más altos en las propiedades físico-químicas y microbianas que los suelos control (no tratado) y acolchado con plástico. En las enmiendas no-compostada y semicompostada, los valores más altos de actividad microbiana estuvieron fuertemente relacionados con un aumento en la biomasa microbiana. La biodesinfección con Brassica-Sinapis tuvo menor efecto sobre las propiedades del suelo que con ambas enmiendas animales. No obstante, los recuentos de bacterias totales, actinomicetos y Pseudomonas spp. fueron más altos en los suelos tratados con Brassica-Sinapis. La biodesinfección reiterada para controlar la podredumbre radicular y del cuello causada por Phytophthora en cultivos de pimiento en invernadero en regiones de clima templado, puede mejorar la calidad del suelo y su supresividad, así como reducir dosis de enmienda requerida. La enmienda semicompostada fue la mejor en disminuir la incidencia de enfermedad.

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.

Validated physical activity (PA) questionnaires are crucial for collecting information in large epidemiological studies during childhood. Thus, this study analyzed the validity of a parent-reported PA questionnaire based on the Children's Leisure Activities Study Survey by accelerometry in European children aged from 6 to 12 years old. We used data from 230 children of the Human Early-Life Exposome and Infancia y Medio Ambiente projects. Mean differences between moderate-to-vigorous PA (MVPA) reported by the questionnaire and the accelerometer were calculated (min/day), and its associated factors were explored by multiple robust linear regression. The agreement between methods was examined using a Bland-Altman plot. The concurrent validity of assessing MVPA was analyzed by cohort-adjusted Spearman's partial correlations. ROC curve analysis was also used to explore the questionnaire's capability to identify active children based on the World Health Organization guidelines. A moderate correlation was found between parent-reported and accelerometer MVPA (rho = 0.41, p < 0.001). The child's sex (girl) was statistically associated with the mean MVPA difference between methods. However, this questionnaire accurately identified physically active children (area under the curve = 83.8% and 82.7% for boys and girls, cut-points = 68.6 and 45.4 min/day in MVPA, respectively). Consequently, this questionnaire is suitable for classifying active children in order to monitor public health interventions regarding PA. This study was supported by funding from the European Community’s Seventh Framework Programme [FP7/2007–2013] under grant agreement no. 308333—the HELIX project. INMA data collections were supported by grants from the Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; PI12/01890 incl. FEDER funds; CP13/00054 incl. FEDER funds; PI15/00118 incl. FEDER funds; CP16/00128 incl. FEDER funds; PI16/00118 incl. FEDER funds; PI16/00261 incl. FEDER funds; PI17/01340 incl. FEDER funds; PI18/00547 incl. FEDER funds, PI18/01237 incl. FEDER funds, PI18/00825 incl. FEDER funds); Generalitat Valenciana (GVA/2021/191); CIBERESP; and the Generalitat de Catalunya-CIRIT 1999SGR 00241; Generalitat de Catalunya-AGAUR (2009 SGR 501, 2014 SGR 822), Fundació La marató de TV3 (090430). 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, Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), Agence Nationale de Securite Sanitaire de l’Alimentation de l’Environnement et du Travail (1262C0010; EST-2016 RF-21), EU Commission (261357, 308333, 603794 and 634453); and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). M.C. and M.G. hold Miguel Servet fellowships (CP16/00128, CPII18/00018) funded by Instituto de Salud Carlos III and co-funded by European Social Fund “Investing in your future”. R.R.C.M. received funding from the National Institute for Health Research Applied Research Collaboration for Yorkshire and Humber.

The aim of this study was to explore the association between three previously identified dietary patterns (Western, Prudent, and Mediterranean) and colorectal cancer (CRC) risk by sex and cancer subtype. The Spanish cohort of the European Prospective Investigation into Cancer and Nutrition study provided dietary and epidemiological information from 15,629 men and 25,808 women recruited between 1992 and 1996. Among them, 568 CRC cases and 3289 deaths were identified during a median follow-up of 16.98 years. The associations between adherence to the three dietary patterns and CRC risk (overall, by sex, and by tumour location: proximal and distal colon and rectum) were investigated by fitting multivariate Cox proportional hazards regression models stratified by study centre and age. Possible heterogeneity of the effects by sex and follow-up time (1–10 vs. 10 years) was also explored. While no clear effect of the Prudent dietary pattern on CRC risk was found, a suggestive detrimental effect of the Western dietary pattern was observed, especially during the first 10 years of follow-up (HR1SD-increase (95% CI): 1.17 (0.99–1.37)), among females (HR1SD-increase (95% CI): 1.31 (1.06–1.61)), and for rectal cancer (HR1SD-increase (95% CI): 1.38 (1.03–1.84)). In addition, high adherence to the Mediterranean pattern seemed to protect against CRC, especially when restricting the analyses to the first 10 years of follow-up (HR1SD-increase (95% CI): 0.84 (0.73–0.98)), among males (HR1SD-increase (95% CI): 0.80 (0.65–0.98)), and specifically against distal colon cancer (HR1SD-increase (95% CI): 0.81 (0.63–1.03)). In conclusion, low adherence to theWestern diet and high adherence to the Mediterranean dietary pattern could prevent CRC, especially distal colon and rectal cancer., Autonomous community of Madrid CM/JIN/2019-042, World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, NIHR Imperial Biomedical Research Centre (BRC), Health Research Fund (FIS)-Instituto de Salud Carlos III (ISCIII), Junta de Andalucia, Principality of Asturias, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Catalan Institute of Oncology-ICO (Spain), Alcala de Henares

Background: Nutrition and lifestyle have been long established as risk factors for colorectal cancer (CRC). Modifiable lifestyle behaviours bear potential to minimize long-term CRC risk; however, translation of lifestyle information into individualized CRC risk assessment has not been implemented. Lifestyle-based risk models may aid the identification of high-risk individuals, guide referral to screening and motivate behaviour change. We therefore developed and validated a lifestyle-based CRC risk prediction algorithm in an asymptomatic European population. Methods: The model was based on data from 255,482 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study aged 19 to 70 years who were free of cancer at study baseline (1992–2000) and were followed up to 31 September 2010. The model was validated in a sample comprising 74,403 participants selected among five EPIC centres. Over a median follow-up time of 15 years, there were 3645 and 981 colorectal cancer cases in the derivation and validation samples, respectively. Variable selection algorithms in Cox proportional hazard regression and random survival forest (RSF) were used to identify the best predictors among plausible predictor variables. Measures of discrimination and calibration were calculated in derivation and validation samples. To facilitate model communication, a nomogram and a web-based application were developed. Results: The final selection model included age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary. The risk score demonstrated good discrimination overall and in sex-specific models. Harrell’s C-index was 0.710 in the derivation cohort and 0.714 in the validation cohort. The model was well calibrated and showed strong agreement between predicted and observed risk. Random survival forest analysis suggested high model robustness. Beyond age, lifestyle data led to improved model performance overall (continuous net reclassification improvement = 0.307 (95% CI 0.264–0.352)), and especially for young individuals below 45 years (continuous net reclassification improvement = 0.364 (95% CI 0.084–0.575)). Conclusions: LiFeCRC score based on age and lifestyle data accurately identifies individuals at risk for incident colorectal cancer in European populations and could contribute to improved prevention through motivating lifestyle change at an individual level., German Research Foundation (DFG) AL 1784/3-1, European Commission European Commission Joint Research Centre, International Agency for Research on Cancer, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ) (Germany), Federal Ministry of Education & Research (BMBF), Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro (AIRC), Consiglio Nazionale delle Ricerche (CNR), Netherlands Government, World Cancer Research Fund International (WCRF), Instituto de Salud Carlos III PI13/00061 PI13/01162, Junta de Andalucia, Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain) 6236, Regional Government of Navarra (Spain), Regional Government of Catalonia (Catalan Institute of Oncology -ICO-IDIBELL) (Spain), Swedish Cancer Society, Swedish Research Council, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK C864/A14136 C8221/A19170, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/N003284/1 MC-UU_12015/1 MR/M012190/1, Projekt DEAL

In this article, we use quasifree reduction to derive the time-dependent Hartree-Fock-Bogoliubov (HFB) equations describing the dynamics of quantum fluctuations around a Bose-Einstein condensate in $\mathbb R^d$. We prove global well-posedness for the HFB equations for sufficiently regular pair interaction potentials, and establish key conservation laws. Moreover, we show that the solutions to the HFB equations exhibit a symplectic structure, and have a form reminiscent of a Hamiltonian system. In particular, this is used to relate the HFB equations to the HFB eigenvalue equations encountered in the physics literature. Furthermore, we construct the Gibbs states at positive temperature associated with the HFB equations, and establish criteria for the emergence of Bose-Einstein condensation., Comment: Revision of earlier manuscript [3] correcting an error in the proof of local existence

Viruses of HIV-1-infected individuals whose transmission is related group phylogenetically in transmission clusters (TCs). The study of the phylogenetic relations of these viruses and the factors associated with these individuals is essential to analyze the HIV-1 epidemic. In this study, we examine the role of TCs in the epidemiology of HIV-1 infection in Galicia and the Basque County, two regions of northern Spain. A total of 1,158 HIV-1-infected patients from both regions with new diagnoses (NDs) in 2013-2018 were included in the study. Partial HIV-1 pol sequences were analyzed phylogenetically by approximately maximum-likelihood with FastTree 2. In this analysis, 10,687 additional sequences from samples from HIV-1-infected individuals collected in Spain in 1999-2019 were also included to assign TC membership and to determine TCs' sizes. TCs were defined as those which included viruses from ≥4 individuals, at least 50% of them Spaniards, and with ≥0.95 Shimodaira-Hasegawa-like node support in the phylogenetic tree. Factors associated to TCs were evaluated using odds ratios (OR) and their 95% CI. Fifty-one percent of NDs grouped in 162 TCs. Male patients (OR: 2.6; 95% CI: 1.5-4.7) and men having sex with men (MSM; OR: 2.1; 95% CI: 1.4-3.2) had higher odds of belonging to a TC compared to female and heterosexual patients, respectively. Individuals from Latin America (OR: 0.3; 95% CI: 0.2-0.4), North Africa (OR: 0.4; 95% CI: 0.2-1.0), and especially Sub-Saharan Africa (OR: 0.02; 95% CI: 0.003-0.2) were inversely associated to belonging to TCs compared to native Spaniards. Our results show that TCs are important components of the HIV-1 epidemics in the two Spanish regions studied, where transmission between MSM is predominant. The majority of migrants were infected with viruses not belonging to TCs that expand in Spain. Molecular epidemiology is essential to identify local peculiarities of HIV-1 propagation. The early detection of TCs and prevention of their expansion, implementing effective control measures, could reduce HIV-1 infections. This work was funded through Acción Estratégica en Salud Intramural (AESI), Instituto de Salud Carlos III, Project “Estudios sobre vigilancia epidemiológica molecular del VIH-1 en España,” PI16CIII/00033 and Project “Epidemiología molecular del VIH-1 en España y su utilidad para investigaciones biológicas y en vacunas“PI19CIII/0042; Red de Investigación en SIDA (RIS), Instituto de Salud Carlos III, Subdirección General de Evaluación y Fondo Europeo de Desarrollo Regional (FEDER), Plan Nacional ICDCI, project RD16ISCIII/0002/0004; and scientific agreements with Consellería de Sanidade, Government of Galicia (MVI 1004/16), and Osakidetza-Servicio Vasco de Salud, Government of Basque Country (MVI 1001/16). Sí

This work considers the {\em gravitational} $N$-body problem and introduces global time-renormalization {\em functions} that allow the efficient numerical integration with fixed time-steps. First, a lower bound of the radius of convergence of the solution to the original equations is derived, which suggests an appropriate time-renormalization. In the new fictitious time $\tau$, it is then proved that any solution exists for all $\tau \in \mathbb{R}$, and that it is uniquely extended as a holomorphic function to a strip of fixed width. As a by-product, a global power series representation of the solutions of the $N$-body problem is obtained. Noteworthy, our global time-renormalizations remain valid in the limit when one of the masses vanishes. Finally, numerical experiments show the efficiency of the new time-renormalization functions for some $N$-body problems with close encounters., Comment: 26 pages; acknowledgments added; remarks 5 and 7 added in second version; remark 4 added and a few minor changes made in third version