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Abstract In kidney transplant recipients, urine CXCL9 and CXCL10 (uCXCL9/10) chemokines have reached a sufficiently high level of evidence to be recommended by the European Society of Organ Transplantation for the monitoring of immune quiescence. To assess the risk of acute rejection (AR), the advantage of uCXCL9/10 is their cost-effectiveness and their high diagnostic performance. Here, we evaluated the feasibility of a next-generation immunoassay for quantifying uCXCL9/10 levels. It demonstrated high efficiency with minimal workflow and a 90-min time to result. Preanalytical studies indicated stability of uCXCL9/10 levels and analytical studies confirmed excellent linearity and precision. In a cohort of 1048 samples collected at biopsy, the results correlated significantly with ELISA quantification and were integrated into a previously validated 8-parameter urine chemokine model. The next generation immunoassay achieved an accuracy of 0.84 for AR diagnosis. This study validates this technology as a robust, locally available and unexpensive platform and marks a significant step towards the widespread implementation of uCXCL9/10, for immune quiescence monitoring. Therefore, we developed an open-access web application using uCXCL9/10 to calculate AR risk and improve clinical decision-making to perform biopsy, ushering in a new era in kidney transplantation, where personalized, data-driven care becomes the norm.

Abstract Background School-based water, sanitation and hygiene (WASH) may improve the health and attendance of schoolchildren, particularly post-menarcheal girls, but existing evidence is mixed. We examined the impact of an urban school-based WASH programme (Project WISE) on child health and attendance. Methods The WISE cluster-randomised trial, conducted in 60 public primary schools in Addis Ababa, Ethiopia over one academic year, enrolled 2–4 randomly selected classes per school (~ 100 pupils) from grades 2 to 8 (aged 7–16) in an ‘open cohort’. Schools were assigned 1:1 by stratified randomisation to receive the intervention during the 2021/2022 or the 2022/2023 academic year (waitlist control). The intervention included improvements to drinking water storage, filtration and access, handwashing stations and behaviour change promotion. Planned sanitation improvements were not realised. At four unannounced classroom visits post-intervention (March–June 2022), enumerators recorded primary outcomes of roll-call absence, and pupil-reported respiratory illness and diarrhoea in the past 7 days among pupils present. Analysis was by intention-to-treat. Results Of 83 eligible schools, 60 were randomly selected and assigned. In total, 6229 eligible pupils were enrolled (median per school 101.5; IQR 94–112), 5987 enrolled at study initiation (23rd November–22nd December 2021) and the remaining 242 during follow-up. Data were available on roll-call absence for 6166 pupils (99.0%), and pupil-reported illness for 6145 pupils (98.6%). We observed a 16% relative reduction in odds of pupil-reported respiratory illness in the past 7 days during follow-up in intervention vs. control schools (aOR 0.84; 95% CI 0.71–1.00; p = 0.046). There was no evidence of effect on pupil-reported diarrhoea in the past 7 days (aOR 1.15; 95% CI 0.84–1.59; p = 0.39) nor roll-call absence (aOR 1.07; 95% 0.83–1.38; p = 0.59). There was a small increase in menstrual care self-efficacy (aMD 3.32 on 0–100 scale; 95% CI 0.05–6.59), and no evidence of effects on other secondary outcomes. Conclusions This large-scale intervention to improve school WASH conditions city-wide had a borderline impact on pupil-reported respiratory illness but no effect on diarrhoeal disease nor pupil absence. Future research should establish relationships between WASH-related illness, absence and other educational outcomes. Trial registration ClinicalTrials.gov, number NCT05024890.

Abstract Oncogene-induced senescence (OIS) arrests cell proliferation in response to replication stress (RS) induced by oncogenes. OIS depends on the DNA damage response (DDR), but also on the cGAS-STING pathway, which detects cytosolic DNA and induces type I interferons (IFNs). Whether and how RS and IFN responses cooperate to promote OIS remains unknown. Here, we show that the induction of OIS by the H-RASV12 oncogene in immortalized human fibroblasts depends on the MRE11 nuclease. Indeed, treatment with the MRE11 inhibitor Mirin prevented RS, micronuclei formation and IFN response induced by RASV12. Overexpression of the cytosolic nuclease TREX1 also prevented OIS. Conversely, overexpression of a dominant negative mutant of TREX1 or treatment with IFN-β was sufficient to induce RS and DNA damage, independent of RASV12 induction. These data suggest that the IFN response acts as a positive feedback loop to amplify DDR in OIS through a process regulated by MRE11 and TREX1.

Abstract Cutaneous T‐cell lymphomas (CTCLs) are unique non‐Hodgkin lymphomas due to the proliferation of skin‐homing T cells. Sezary syndrome (SS), a subtype of CTCL, typically presents as erythroderma with specific blood involvement and seldomly evolves from tumor‐stage mycosis fungoides (MF). The article examines the case of a 62‐year‐old female patient who developed SS while under atezolizumab treatment for tumor‐stage transformed MF. Postdiagnosis, she underwent treatments including topical corticosteroids, phototherapy, and other drug regimens, experiencing both complete responses and relapses over the years. Three years postdiagnosis, her condition deteriorated with facial tumor lesions, confirmed as MF. Despite multiple treatments, including oral drugs, radiation therapy, and a range of other therapeutic agents, her condition did not show sustained improvement. The patient was then administered atezolizumab, an antibody targeting programmed death ligand 1 (PD‐L1). Although initial results saw a disappearance of her skin tumors, the subsequent cycles led to symptoms consistent with stage IVA1 SS, coupled with an evident shift in malignant T‐cell clone dominance. Atezolizumab, a humanized monoclonal antibody, impedes the interaction of PD‐L1 with its receptor PD1, which is notably overexpressed in malignant T‐cells of SS. This case illustrates the emergence of SS during the course of atezolizumab treatment for a transformed MF condition, underlining the potential risks and complexities in using PD‐L1 inhibitors for treating CTCL.

Summary: Human-specific genes are potential drivers of brain evolution. Among them, SRGAP2C has contributed to the emergence of features characterizing human cortical synapses, including their extended period of maturation. SRGAP2C inhibits its ancestral copy, the postsynaptic protein SRGAP2A, but the synaptic molecular pathways differentially regulated in humans by SRGAP2 proteins remain largely unknown. Here, we identify CTNND2, a protein implicated in severe intellectual disability (ID) in Cri-du-Chat syndrome, as a major partner of SRGAP2. We demonstrate that CTNND2 slows synaptic maturation and promotes neuronal integrity. During postnatal development, CTNND2 moderates neuronal excitation and excitability. In adults, it supports synapse maintenance. While CTNND2 deficiency is deleterious and results in synaptic loss of SYNGAP1, another major ID-associated protein, the human-specific protein SRGAP2C, enhances CTNND2 synaptic accumulation in human neurons. Our findings suggest that CTNND2 regulation by SRGAP2C contributes to synaptic neoteny in humans and link human-specific and ID genes at the synapse.

Summary: Cerebral cortex biopsies enable the investigation of native developing and mature human brain tissue. Here, we present a protocol to process human cortical biopsies from the surgical theater to the laboratory. We describe steps for the preparation of viable acute slices for patch-clamp recording using dedicated chemical solutions for transport and sectioning. We then explain procedures for tissue fixation and post hoc immunostaining to correlate physiological properties to morphological features and protein detection.For complete details on the use and execution of this protocol, please refer to Libé-Philippot et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract For most patients with childhood myelodysplastic syndrome (cMDS), allogeneic hematopoietic stem cell transplantation (allo‐HSCT) remains the only curative option. In the case of increased blasts (cMDS‐IB), the benefit of pretransplant cytoreductive therapy remains controversial. In this multicenter retrospective study, the outcomes of all French children who underwent allo‐HSCT for cMDS reported in the SFGM‐TC registry between 2000 and 2020 were analyzed (n = 84). The median age at transplantation was 10.2 years. HSCT was performed from matched sibling donors (MSD) in 29% of the cases, matched unrelated donors (MUD) in 44%, haploidentical in 6%, and cord blood in 21%. Myeloablative conditioning was used in 91% of cases. Forty‐eight percent of patients presented with cMDS‐IB at diagnosis (median BM blasts: 8%). Among them, 50% received pretransplant cytoreductive therapy. Five‐year overall survival (OS), cumulative incidence of nonrelapse mortality (NRM), and relapse were 67%, 26%, and 12%, respectively. Six‐month cumulative incidence of grade II–IV acute graft‐versus‐host disease was 46%. Considering the whole cohort, age under 12, busulfan/cyclophosphamide/melphalan conditioning or MUD were associated with poorer 5‐year OS. In the cMDS‐IB subgroup, pretransplant cytoreductive therapy was associated with a better OS in univariate analysis. This seems to be mainly due to a decreased NRM since no impact on the incidence of relapse was observed. Overall, those data may argue in favor of cytoreduction for cMDS‐IB. They need to be confirmed on a larger scale and prospectively.

Antibody-mediated rejection (ABMR) remains one of the main causes of long-term graft failure after kidney transplantation, despite the development of powerful immunosuppressive therapy. A detailed understanding of the complex interaction between recipient-derived immune cells and the allograft is therefore essential. Until recently, ABMR mechanisms were thought to be solely caused by adaptive immunity, namely, by anti-human leucocyte antigen (HLA) donor-specific antibody. However recent reports support other and/or additive mechanisms, designating monocytes/macrophages as innate immune contributors of ABMR histological lesions. In particular, in mouse models of experimental allograft rejection, monocytes/macrophages are readily able to discriminate non-self via paired immunoglobulin receptors (PIRs) and thus accelerate rejection. The human orthologs of PIRs are leukocyte immunoglobulin-like receptors (LILRs). Among those, LILRB3 has recently been reported as a potential binder of HLA class I molecules, shedding new light on LILRB3 potential as a myeloid mediator of allograft rejection. In this issue, we review the current data on the role of LILRB3 and discuss the potential mechanisms of its biological functions.

Field Portable X-Ray Fluorescence (FPXRF) was investigated as an alternative analysis tool for the detection and quantification of gold in hyperaccumulator plants in the field. First, synthetic gold standards were prepared with materials chosen to best simulate plant material, using microcrystalline cellulose (mcc) or ash by adding known amounts of gold. Powder samples were obtained containing gold in amounts ranging from 10 to 1000 ppm of gold. They were analysed, as well as blank samples of mcc and ash, using a NITON xl3t GOLDD+ FPXRF spectrometer in AllGeo and Soil modes with an analysis time of 60 s. Results were compared to Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) analysis of the synthetic gold standards after digestion in aqua regia. Gold was detected and accurately quantified in synthetic gold standards containing more than 25 ppm of gold in AllGeo mode. At lower concentration, results were much more inaccurate, with no gold being detected at 10 ppm. In Soil mode, similar results to AllGeo mode were obtained with mcc synthetic standards. However, with ash synthetic standard gold quantification was very poor over the whole concentration range and gold was detected in the blank ash sample, which was confirmed as a false positive by the subsequent ICP analysis. Samples of Phyllanthus stipulatus, suspected gold hyperaccumulators, collected on gold-bearing sites in French Guiana were then analysed following the same protocol. The same false positive phenomenon was observed in some of them, with gold being detected by FPXRF in Soil mode but not by ICP analysis. Furthermore, analysis of the FPXRF spectra revealed that none of the characteristic gold emission ray was present. This false positive was attributed to an interference caused by zinc, present in significant amount in the ash of the synthetic standard and the collected plants.

Auditory verbal hallucinations (AVHs) are among the most common and disabling symptoms of schizophrenia. They involve the superior temporal sulcus (STS), which is associated with language processing; specific STS patterns may reflect vulnerability to auditory hallucinations in schizophrenia. STS sulcal pits are the deepest points of the folds in this region and were investigated here as an anatomical landmark of AVHs. This study included 53 patients diagnosed with schizophrenia and past or present AVHs, as well as 100 healthy control volunteers. All participants underwent a 3-T magnetic resonance imaging T1 brain scan, and sulcal pit differences were compared between the two groups. Compared with controls, patients with AVHs had a significantly different distributions for the number of sulcal pits in the left STS, indicating a less complex morphological pattern. The association of STS sulcal morphology with AVH suggests an early neurodevelopmental process in the pathophysiology of schizophrenia with AVHs.

Abstract Regenerative life support systems (RLSS) will play a vital role in achieving self-sufficiency during long-distance space travel. Urine conversion into a liquid nitrate-based fertilizer is a key process in most RLSS. This study describes the effects of simulated microgravity (SMG) on Comamonas testosteroni, Nitrosomonas europaea, Nitrobacter winogradskyi and a tripartite culture of the three, in the context of nitrogen recovery for the Micro-Ecological Life Support System Alternative (MELiSSA). Rotary cell culture systems (RCCS) and random positioning machines (RPM) were used as SMG analogues. The transcriptional responses of the cultures were elucidated. For CO2-producing C. testosteroni and the tripartite culture, a PermaLifeTM PL-70 cell culture bag mounted on an in-house 3D-printed holder was applied to eliminate air bubble formation during SMG cultivation. Gene expression changes indicated that the fluid dynamics in SMG caused nutrient and O2 limitation. Genes involved in urea hydrolysis and nitrification were minimally affected, while denitrification-related gene expression was increased. The findings highlight potential challenges for nitrogen recovery in space.

Abstract Background Angioimmunoblastic T‐cell lymphoma (AITL) is one of the most frequent peripheral T‐cell lymphomas (PTCL) in western countries. Skin involvement is common and may reveal the malignancy. Despite its frequency, skin involvement in AITL has been poorly described. Objectives We aimed to analyze the cutaneous expression of PTCL of TFH origin and its prognostic impact. Methods We conducted a multicenter retrospective cohort study by retrieving histopathological reports including the mention ‘AITL’ or ‘PTCL with T‐follicular helper phenotype’ (PTCL‐TFH) from five French tertiary hospital centers. Results From 2000 to 2022, we reviewed 382 histopathological records and identified 52 AITL cases and 5 PTCL‐TFH cases with cutaneous involvement. Thirty‐two (56%) patients were males with a mean age of 63 years. Fifty‐six (98%) patients presented with lymphadenopathy, 32 (56%) splenomegaly and 17 (30%) hepatomegaly. B signs were present in 34 (60%) patients. Skin lesions were present on the lower limbs in 44 (77%) patients, trunk in 38 (67%) patients, upper limbs in 35 (61%) and head in 27 (47%). Macules and papules were the most frequent lesions found in 47 (82%) patients, followed by nodules in 10 (17%) patients, erythemato‐squamous plaques in 10 (17%) patients, purpura in 9 (16%), urticaria in 9 (16%) and blisters in 5 (9%) patients. Erythroderma affected seven patients (12%). A skin biopsy was taken in 50 patients and revealed a specific lymphomatous infiltrate in 36 cases. A dominant skin T‐cell clone was detected in 13 out of 17 (76%) patients. Among the 14 patients with a nonspecific dermatitis, various histopathological patterns were observed including interface dermatitis, psoriasiform dermatitis, vasculitis, bullous dermatitis, granulomatous dermatitis and thrombotic vasculopathy. After a median follow‐up of 24 months (range, 0–121 months), median overall survival was 121 months (95% CI, 25.2–NA). At last follow‐up, 33 patients (58%) were alive, 20 (35%) were in complete remission and 7 (12%) were in partial remission; 30 (53%) patients experienced at least one relapse, including nodal relapses in 24 (80%) cases and cutaneous relapses in 12 (40%). Conclusions This study revealed the deep heterogeneity of skin presentations in AITL. Atypical skin presentations were common and included blistering, purpuric and psoriasiform eruptions.

Abstract Background Thanks to an improved therapeutic regimen in childhood B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL), 5 year‐overall survival now exceeds 90%. Unfortunately, the 25% of children who relapse have an initial poor prognosis, potentially driven by pre‐existing or emerging molecular anomalies. The latter are initially and essentially identified by cytogenetics. However, some subtle alterations are not visible through karyotyping. Methods Single nucleotide polymorphisms (SNP) array is an alternative way of chromosomal analysis allowing for a more in‐depth evaluation of chromosomal modifications such as the assessment of copy number alterations (CNA) and loss of heterozygosity (LOH). This method was applied here in retrospective diagnosis/relapse paired samples from seven children with BCP‐ALL and in a prospective cohort of 38 newly diagnosed childhood cases. Results In the matched study, compared to the initial karyotype, SNP array analysis reclassified two patients as poor prognosis cases. Modulation during relapse was seen for 4 CNA and 0.9 LOH. In the prospective study, SNP reclassified the 10 patients with intermediate karyotype as 7 good prognosis and 3 poor prognosis. Ultimately, in all the children tested, SNP array allowed to identify additional anomalies compared to conventional karyotype, refine its prognostic value and identify some druggable anomalies that could be used for precision medicine. Overall, the anomalies detected could be segregated in four groups respectively involved in B‐cell development, cell proliferation, transcription and molecular pathways. Conclusion SNP therefore appears to be a method of choice in the integrated diagnosis of BCP ALL, especially for patients initially classified as intermediate prognosis. This complementary method of both cytogenetics and high throughput sequencing allows to obtain further classified information and can be useful in case of failure of these techniques.

BackgroundCholera outbreaks are on the rise globally, with conflict-affected settings particularly at risk. Case-area targeted interventions (CATIs), a strategy whereby teams provide a package of interventions to case and neighboring households within a predefined "ring," are increasingly employed in cholera responses. However, evidence on their ability to attenuate incidence is limited.Methods and findingsWe conducted a prospective observational cohort study in 3 conflict-affected states in Nigeria in 2021. Enumerators within rapid response teams observed CATI implementation during a cholera outbreak and collected data on household demographics; existing water, sanitation, and hygiene (WASH) infrastructure; and CATI interventions. Descriptive statistics showed that CATIs were delivered to 46,864 case and neighbor households, with 80.0% of cases and 33.5% of neighbors receiving all intended supplies and activities, in a context with operational challenges of population density, supply stock outs, and security constraints. We then applied prospective Poisson space-time scan statistics (STSS) across 3 models for each state: (1) an unadjusted model with case and population data; (2) an environmentally adjusted model adjusting for distance to cholera treatment centers and existing WASH infrastructure (improved water source, improved latrine, and handwashing station); and (3) a fully adjusted model adjusting for environmental and CATI variables (supply of Aquatabs and soap, hygiene promotion, bedding and latrine disinfection activities, ring coverage, and response timeliness). We ran the STSS each day of our study period to evaluate the space-time dynamics of the cholera outbreaks. Compared to the unadjusted model, significant cholera clustering was attenuated in the environmentally adjusted model (from 572 to 18 clusters) but there was still risk of cholera transmission. Two states still yielded significant clusters (range 8-10 total clusters, relative risk of 2.2-5.5, 16.6-19.9 day duration, including 11.1-56.8 cholera cases). Cholera clustering was completely attenuated in the fully adjusted model, with no significant anomalous clusters across time and space. Associated measures including quantity, relative risk, significance, likelihood of recurrence, size, and duration of clusters reinforced the results. Key limitations include selection bias, remote data monitoring, and the lack of a control group.ConclusionsCATIs were associated with significant reductions in cholera clustering in Northeast Nigeria despite operational challenges. Our results provide a strong justification for rapid implementation and scale-up CATIs in cholera-response, particularly in conflict settings where WASH access is often limited.

Summary: The advancement of regenerative life support systems (RLSS) is crucial to allow long-distance space travel. Within the Micro-Ecological Life Support System Alternative (MELiSSA), efficient nitrogen recovery from urine and other waste streams is vital to produce liquid fertilizer to feed food and oxygen production in subsequent photoautotrophic processes. This study explores the effects of ionizing radiation on nitrogen cycle bacteria that transform urea to nitrate. In particular, we assess the radiotolerance of Comamonas testosteroni, Nitrosomonas europaea, and Nitrobacter winogradskyi after exposure to acute γ-irradiation. Moreover, a comprehensive whole transcriptome analysis elucidates the effects of spaceflight-analogue low-dose ionizing radiation on the individual axenic strains and on their synthetic community o. This research sheds light on how the spaceflight environment could affect ureolysis and nitrification processes from a transcriptomic perspective.

Drinking water intakes (DWIs) face significant pressure due to global changes, including urbanization and climate change. The common approach relies mainly on climate projections generated by global climate models to simulate large scale hydroclimatic conditions. However, it is crucial to discern the impact of global changes on water scarcity at the local level, including in regions where available data are limited. This paper proposes an approach that focuses on studying the vulnerability of surface DWIs to low water levels and water demand in current and future climates within a cold-climate region.Low flows at DWIs were simulated using historical water level data obtained from hydrometric stations situated along the studied river. After defining four scenarios for climate change and anthropogenic activities affecting raw water withdrawals at DWIs, the full potential range of level variations was simulated. This study employed a combined water scarcity index derived from two sub-indices based on water level and water demand. The resulting index ranges from 0 to 1, where a higher value indicates a greater vulnerability to water scarcity. The simulation results demonstrate the vulnerability of water scarcity in both current and future climates.The calculated index, selecting the current vulnerability to water scarcity for the five studied DWIs, ranged from 0.61 to 0.76. The results for the vulnerability of these DWIs under future climate conditions exhibited significant variability across the different scenarios representing possible maximum daily withdrawal. These scenarios were defined to encompass a spectrum of options related to the government's policy for drinking water conservation strategy implementation. While exploring the full range of potential risks, the study's results demonstrated that the DWIs were especially vulnerable to anthropogenic changes affecting water demand.The framework developed in this study can provide a decision-support basis for municipalities and water managers to adapt to global change and achieve greater water supply resilience.

Brain development and function are highly reliant on adequate establishment and maintenance of vascular networks. Early impairments in vascular health can impact brain maturation and energy metabolism, which may lead to neurodevelopmental anomalies. Our recent work not only provides novel insights into the development of cerebrovascular networks but also emphasizes the importance of their well-being for proper brain maturation. In particular, we have demonstrated that endothelial dysfunction in autism spectrum disorders (ASD) mouse models is causally related to altered behavior and brain metabolism. In the prenatal human brain, vascular cells change metabolic states in the second trimester. Such findings highlight the need to identify new cellular and molecular players in neurodevelopmental disorders, raising awareness about the importance of a healthy vasculature for brain development. It is thus essential to shift the mostly neuronal point of view in research on ASD and other neurodevelopmental disorders to also include vascular and metabolic features.

IntroductionCoronavirus disease 2019 (COVID-19) poses an important risk of morbidity and of mortality, in patients after solid organ transplantation. Recommendations have been issued by various transplantation societies at the national and European level to manage the immunosuppressive (IS) regimen upon admission to intensive care unit (ICU).MethodThe aim of this study was to evaluate the adequacy of IS regimen minimization strategy in kidney transplant recipients hospitalized in an ICU for severe COVID-19, in relation to the issued recommendations.ResultsThe immunosuppressive therapy was minimized in all patients, with respectively 63% and 59% of the patients meeting the local and european recommendations upon admission. During ICU stay, IS was further tapered leading to 85% (local) and 78% (european) adequacy, relative to the guidelines. The most frequent deviation was the lack of complete withdrawal of mycophenolic acid (22%). Nevertheless, the adequacy/inadequacy status was not associated to the ICU- or one-year-mortality.DiscussionIn this single-center cohort, the only variable associated with a reduction in mortality was vaccination, emphasizing that the key issue is immunization prior to infection, not restoration of immunity during ICU stay.

Abstract Background The spread of COVID-19 has brought challenges to health, social and economic systems around the world. With little to no prior immunity in the global population, transmission has been driven primarily by human interaction. However, as with common respiratory illnesses such as influenza some authors have suggested COVID-19 may become seasonal as immunity grows. Despite this, the effects of meteorological conditions on the spread of COVID-19 are poorly understood. Previous studies have produced contrasting results, due in part to limited and inconsistent study designs. Methods This study investigates the effects of meteorological conditions on COVID-19 infections in England using a Bayesian conditional auto-regressive spatio-temporal model. Our data consists of daily case counts from local authorities in England during the first lockdown from March–May 2020. During this period, legal restrictions limiting human interaction remained consistent, minimising the impact of changes in human interaction. We introduce a lag from weather conditions to daily cases to accommodate an incubation period and delays in obtaining test results. By modelling spatio-temporal random effects we account for the nature of a human transmissible virus, allowing the model to isolate meteorological effects. Results Our analysis considers cases across England’s 312 local authorities for a 55-day period. We find relative humidity is negatively associated with COVID-19 cases, with a 1% increase in relative humidity corresponding to a reduction in relative risk of 0.2% [95% highest posterior density (HPD): 0.1–0.3%]. However, we find no evidence for temperature, wind speed, precipitation or solar radiation being associated with COVID-19 spread. The inclusion of weekdays highlights systematic under reporting of cases on weekends with between 27.2–43.7% fewer cases reported on Saturdays and 26.3–44.8% fewer cases on Sundays respectively (based on 95% HPDs). Conclusion By applying a Bayesian conditional auto-regressive model to COVID-19 case data we capture the underlying spatio-temporal trends present in the data. This enables us to isolate the main meteorological effects and make robust claims about the association of weather variables to COVID-19 incidence. Overall, we find no strong association between meteorological factors and COVID-19 transmission.

Abstract Primary cutaneous follicle centre lymphomas (PCFCLs) are cutaneous proliferation of centrocytes and centroblasts, with a generally indolent evolution. Secondary systemic spread of disease is a rare event, which significantly impairs prognosis. Recently published study by Zhou and al. proposed criteria aiming to predict such evolution at initial stage: (i) rearrangement of Bcl2, (ii) Ki67% index 30% Ki67% indexes and no mutations among the four proposed genes. These findings run contrary to these previously proposed criteria, highlighting the molecular heterogeneity of this rare disease.

Abstract Astrocytes are intimately linked with brain blood vessels, an essential relationship for neuronal function. However, astroglial factors driving these physical and functional associations during postnatal brain development have yet to be identified. By characterizing structural and transcriptional changes in mouse cortical astrocytes during the first two postnatal weeks, we find that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, is highly expressed in astrocytes at birth and then decreases rapidly. Astrocyte-selective ablation of Hmgb1 at birth affects astrocyte morphology and endfoot placement, alters distribution of endfoot proteins connexin43 and aquaporin-4, induces transcriptional changes in astrocytes related to cytoskeleton remodeling, and profoundly disrupts endothelial ultrastructure. While lack of astroglial Hmgb1 does not affect the blood-brain barrier or angiogenesis postnatally, it impairs neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as an important player in postnatal gliovascular maturation.

Abstract Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the cell-to-cell interactions of the alloreactive inflammatory infiltrate. Here, we performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies with varying phenotypes and severities of rejection and without rejection, and identified cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derived FCGR3A+ monocytes, FCGR3A + NK cells and the severity of intragraft inflammation. Activated FCGR3A+ monocytes overexpressed CD47 and LILR genes and increased paracrine signaling pathways promoting T cell infiltration. FCGR3A + NK cells overexpressed FCRL3, suggesting that antibody-dependent cytotoxicity is a central mechanism of NK-cell mediated graft injury. Multiplexed immunofluorescence using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results highlight the central involvement of innate immune cells in the pathogenesis of allograft rejection and identify several potential therapeutic targets that might improve allograft longevity.

À la question de savoir si la lectrice est un lecteur comme les autres, cet article fait le choix de répondre en analysant la figure de la lectrice dans l’imaginaire d’un auteur masculin : Pierre Michon. Plus précisément, il inter­roge la place du genre dans le dispositif narratif de « Dieu ne finit pas » et des Onze. Ces deux textes sont des « récits adressés » dans lesquels une instance narratoriale apostrophe un ou une narrataire. Ce phénomène narratif permet de considérer l’instance-narrataire comme une image de l’interprète du texte. L’hypothèse de cet article est la suivante : en fonction de leur genre, les narrataires ne renvoient pas à la même représentation de la lecture, au même « imaginaire de la lecture » (Estelle Mouton-Rovira). Afin d’étayer cette hypothèse, j’envi­­sagerai d’abord le rôle du genre dans la construction stéréotypée de la structure énonciative des textes à l’étude. Je confronterai ensuite ces figures de narrataires aux figures d’interprètes que Michon construit dans Vies minuscules. Ainsi, je montrerai que la lectrice michonienne, loin d’être un lecteur comme les autres, possède des compétences interprétatives spécifiques.

Abstract We experimentally investigate the role of illumination on the collective dynamics of a large school (ca. 50 individuals) of Hemigrammus rhodostomus. The structure of the group, defined using two order parameters, is quantified while progressively altering the visual range of the fish through controlled cycles of ambient light intensity. We show that, at low light levels, the individuals within the group are unable to form a cohesive group, while at higher illuminance the degree of alignment of the school correlates with the light intensity. When increasing the illuminance, the school structure is successively characterized by a polarized state followed by a highly regular and stable rotational configuration (milling). Our study shows that vision is necessary to achieve cohesive collective motion for free swimming fish schools, while the short-range lateral line sensing is insufficient in this situation. The present experiment therefore provides new insights into the interaction mechanisms that govern the emergence and intensity of collective motion in biological systems.

Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated up-regulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus, with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.

Abstract Despite significant advancements in in vitro cardiac modeling approaches, researchers still lack the capacity to obtain in vitro measurements of a key indicator of cardiac function: contractility, or stroke volume under specific loading conditions—defined as the pressures to which the heart is subjected prior to and during contraction. This work puts forward a platform that creates this capability, by providing a means of dynamically controlling loading conditions in vitro. This dynamic tissue loading platform consists of a thin magnetoresponsive hydrogel cantilever on which 2D engineered myocardial tissue is cultured. Exposing the cantilever to an external magnetic field—generated by positioning magnets at a controlled distance from the cantilever—causes the hydrogel film to stretch, creating tissue load. Next, cell contraction is induced through electrical stimulation, and the force of the contraction is recorded, by measuring the cantilever's deflection. Force–length‐based measurements of contractility are then derived, comparable to clinical measurements. In an illustrative application, the platform is used to measure contractility both in untreated myocardial tissue and in tissue exposed to an inotropic agent. Clear differences are observed between conditions, suggesting that the proposed platform has significant potential to provide clinically relevant measurements of contractility.

Summary: Background: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. Methods: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016–2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. Findings: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92–5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07–7.59), Group A streptococcus (OR 2.73, 95% CI 1.13–6.09) and E. coli (OR 2.7, 95% CI 1.02–6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11–0.46), influenza B (OR 0.12, 95% CI 0.02–0.37) and RSV (OR 0.16, 95% CI: 0.06–0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23–0.72) and EBV (OR 0.71, 95% CI 0.56–0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. Interpretation: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics. Funding: EU Horizon 2020 grant 668303.

Land surface temperature is an essential climate variable that can serve as a proxy for detecting water deficiencies in croplands and wooded areas. Its measurement can, however, be influenced by anisotropic properties of surface targets leading to the occurrence of directional effects on the signal. This may lead to an incorrect interpretation of thermal measurements. In this article, we perform model assessments and check the influence of thermal radiation directionality using data over a vineyard. To derive the overall directional surface temperatures, elemental values measured by individual cameras were aggregated according to the respective cover fractions/weights in viewing direction. Aggregated temperatures from the turbid model were compared to corresponding temperatures simulated by the 3-D discrete anisotropic radiative transfer model. The reconstructed temperatures were then used in surface energy balance (SEB) simulations to assess the impact of the sun-target-sensor geometry on retrievals. Here, both the pseudoisotropic Soil Plant Atmosphere Remote Sensing of Evapotranspiration (SPARSE) dual-source model and its nonisotropic version (SPARSE4) were used. Both schemes were able to retrieve overall fluxes satisfactorily, confirming a previous study. However, the sensitivity (of flux and component temperature estimates) of the schemes to viewing direction was tested for the first time using reconstructed sets of directional thermal data to force the models. Degradation (relative to nadir) in flux retrieval cross-row was observed, with better consistency along rows. Overall, it was nevertheless shown that SPARSE4 is less influenced by the viewing direction of the temperature than SPARSE, particularly for strongly off-nadir viewing. Some directional/asymmetrical artifacts are, however, not well reproduced by the simple radiative transfer methods, which can then manifest in and influence the subsequent thermal-infrared-driven SEB modeling.

Ganglion cells classically respond to either light increase (ON) or decrease (OFF). Here, the authors show that during natural scene stimulation, a single ganglion cell can switch between ON and OFF depending on the visual context.

Warm autoimmune hemolytic anemia (wAIHA) is a rare acquired autoimmune disease mediated by antibodies targeting red blood cells. The involvement of CD4 T-helper cells has been scarcely explored, with most findings extrapolated from animal models. Here, we performed quantification of both effector T lymphocytes (Teff) and regulatory T cells (Treg), associated with functional and transcriptomic analyses of Treg in human wAIHA. We observed a shift of Teff toward a Th17 polarization concordant with an increase in serum interleukin-17 concentration that correlates with red blood cell destruction parameters, namely lactate dehydrogenase and bilirubin levels. A decrease in circulating Treg, notably effector Treg, associated with a functional deficiency, as represented by their decrease capability to inhibit Teff proliferation, were also observed. Treg deficiency was associated with a reduced expression of Foxp3, the master transcription factor known to maintain the Treg phenotype stability and suppressive functions. Transcriptomic profiling of Treg revealed activation of the tumor necrosis facto (TNF)-α pathway, which was linked to increased serum TNF-α concentrations that were twice as high as in controls. Treg transcriptomic profiling also suggested that post-translational mechanisms possibly accounted for Foxp3 downregulation and Treg dysfunctions. Since TNF-α participates in the rupture of immune tolerance during wAIHA, its inhibition could be of interest. To this end, the effects of fostamatinib, a SYK inhibitor, were investigated in vitro, and we showed that besides the inhibition of erythrocyte phagocytosis by monocytes, fostamatinib is also able to dampen TNF-α production, thus appearing as a promising multitargeting therapy in wAIHA (clinicaltrials gov. Identifier: NCT02158195).

BackgroundPsychosocial interventions delivered by nonspecialists can be effective at reducing common adolescent mental health problems in low-resource settings. However, there is a lack of evidence on resource-efficient methods for building capacity to deliver these interventions. ObjectiveThe objective of this study is to evaluate the effects of a digital training (DT) course, delivered in a self-guided format or with coaching, on nonspecialists’ competency to deliver a problem-solving intervention intended for adolescents with common mental health problems in India. MethodsWe will conduct a pre-post study with a nested parallel, 2-arm, individually randomized controlled trial. The study aims to recruit 262 participants, randomized 1:1 to receive either a self-guided DT course or a DT course with weekly individualized coaching provided remotely by telephone. In both arms, the DT will be accessed over 4 to 6 weeks. Participants will be nonspecialists (ie, without prior practice-based training in psychological therapies) recruited from among university students and affiliates of nongovernmental organizations in Delhi and Mumbai, India. ResultsOutcomes will be assessed at baseline and 6 weeks post randomization using a knowledge-based competency measure that incorporates a multiple-choice quiz format. The primary hypothesis is that self-guided DT will lead to increased competency scores among novices with no prior experience of delivering psychotherapies. The secondary hypothesis is that digital training with coaching will have an incremental effect on competency scores compared with DT alone. The first participant was enrolled on April 4, 2022. ConclusionsThe study will address an evidence gap on the effectiveness of training methods for nonspecialist providers of adolescent mental health interventions in low-resource settings. The findings from this study will be used to support wider efforts to scale up evidence-based mental health interventions for young people. Trial RegistrationClinicalTrials.gov NCT05290142; https://clinicaltrials.gov/ct2/show/NCT05290142 International Registered Report Identifier (IRRID)DERR1-10.2196/41981

At CRYPTO’22, Ranea, Vandersmissen, and Preneel proposed a new way to design white-box implementations of ARX-based ciphers using so-called implicit functions and quadratic-affine encodings. They suggest the Speck block-cipher as an example target. In this work, we describe practical attacks on the construction. For the implementation without one of the external encodings, we describe a simple algebraic key recovery attack. If both external encodings are used (the main scenario suggested by the authors), we propose optimization and inversion attacks, followed by our main result - a multiple-step round decomposition attack and a decomposition-based key recovery attack. Our attacks only use the white-box round functions as oracles and do not rely on their description. We implemented and verified experimentally attacks on white-box instances of Speck-32/64 and Speck-64/128. We conclude that a single ARX-round is too weak to be used as a white-box round.

Objectives. To determine the ferritin inter-assay differences between three “Conformité Européenne” (CE) marked tests, the impact on reference intervals (RI), and the proportion of individuals with iron deficiency (ID), we used plasma and serum from healthy blood donors (HBD) recruited in three different Switzerland regions. Design and Methods. Heparinized plasma and serum from HBD were obtained from three different transfusion centers in Switzerland (Fribourg, Geneva, and Neuchatel). One hundred forty samples were recruited per center and per matrix, with a gender ratio of 50%, for a total of 420 HBD samples available per matrix. On both matrices, ferritin concentrations were quantified by three different laboratories using electrochemiluminescence (ECL), latex immunoturbidimetric assay (LIA), and luminescent oxygen channeling immunoassay (LOCI) assays, respectively. The degree of agreement between matrices and between the three sites/methods was assessed by Passing–Bablok and we evaluated the proportion of individuals deemed to have ID per method. Results. Overall, no difference between serum and heparinized plasma ferritin values was observed according to Passing–Bablok analyses (proportional bias range: 1.0–3.0%; maximum constant bias: 1.84 µg/L). Significant median ferritin differences (p < 0.001 according to Kruskal–Wallis test) were observed between the three methods (i.e., 83.6 µg/L, 103.5 µg/L, and 62.1 µg/L for ECL, LIA, and LOCI in heparinized plasma, respectively), with proportional bias varying significantly between ±16% and ±32% on serum and from ±14% to ±35% on plasma with no sign of gender-related differences. Affecting the lower end of RI, the proportion of ID per method substantially varied between 4.76% (20/420) for ECL, 2.86% (12/420) for LIA, and 9.05% (38/420) for LOCI. Conclusions. Serum and heparinized plasma are exchangeable for ferritin assessment. However, the order of magnitude of ferritin differences across methods and HBD recruitment sites could lead to diagnostic errors if uniform RI were considered. Challenging the recently proposed use of uniform ferritin thresholds, our results highlight the importance of method- and region-specific RI for ferritin due to insufficient inter-assay harmonization. Failing to do so significantly impacts ID diagnosis.

Abstract Forcibly displaced children are at increased risk of violence and mental health disorders. In refugee contexts, schools are generally perceived as protective environments where children can build a sense of belonging and recover from trauma. Evidence shows that positive school climates can support student skills development and socio-emotional wellbeing and protect them against a host of adverse outcomes. However, schools are also places where children may experience violence, from both teachers and peers. Prevalence estimates of violence against children in humanitarian settings are scarce and evidence on the relationship between school climate and student outcomes in these contexts is non-existent. The aim of the study is to estimate the prevalence of school-based violence against children and to explore the association between perceptions of school climate and students’ experiences and use of violence and their depression symptoms. We relied on data from a cross-sectional survey of students and teachers in all primary and secondary schools in Nyarugusu Refugee Camp in Tanzania, conducted as part of a cluster randomised controlled trial, to compute prevalence estimates and used mixed logistic regression analysis to assess the association between school climate and students’ outcomes. We found that students in Nyarugusu experienced high levels of violence from both peers and teachers in both primary and secondary schools in the camp, with little difference between boys and girls. Nearly one in ten students screened positive for symptoms of depression. We found that opportunities for students and teachers to be involved in decision-making were associated with higher odds of violent discipline and teachers’ self-efficacy was a significant protective factor against student depression symptoms. However, generally, school-level perceptions of school climate were not associated with student outcomes after adjusting for potential confounders. Our findings suggest that interventions to prevent and respond to teacher and peer violence in schools and to support students’ mental health are urgently needed. Our results challenge the assumption that education environments are inherently protective for children and call for further investigation of norms around violence among students and teachers to better understand the role of school climate in refugee settings.

Summary: Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2df/+ mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration. Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.

In this paper, we tackle innovation diffusion from the perspective of an institution which aims to encourage the adoption of a new product (i.e., an innovation) with mostly social rather than individual benefits. Designing such innovation adoption policies is a very challenging task because of the difficulty to quantify and predict its effect on the behaviors of non-adopters and the exponential size of the space of possible policies. To solve these issues, we propose an approach that uses agent-based modeling to simulate in a credible way the behaviors of possible adopters and (deep) reinforcement learning to efficiently explore the policy search space. An application of our approach is presented for the question of the use of digital technologies in agriculture. Empirical results on this case study validate our scheme and show the potential of our approach to learn effective innovation diffusion policies.

Abstract Immune effector cell‐associated neurotoxicity syndrome (ICANS) is a frequent adverse event after Chimeric antigen receptor T cells (CAR‐T cells). A patient treated with anti‐CD19 CAR‐T cells for a refractory mantle cell lymphoma presented at Day 8 post‐infusion with extensive myelitis. Unusual eosinophilia was disclosed in the patient's cerebrospinal fluid. After treatment with methylprednisolone and siltuximab, a decrease in clinical symptoms and magnetic resonance imaging lesions were obtained. This unprecedented presentation of eosinophilic meningitis after CAR‐T cells therapy highlights the need for a better understanding of the physiopathology of ICANS, especially to identify potentially targetable pathways.

In order to advance our understanding of the effects of maternal high-fat diet (mHFD) on the cerebrovascular health of offspring, Bordeleau et al. use a translational mouse model of mHFD exposure. They demonstrate that mHFD induces cerebrovascular and microglial changes in the offspring as well as behavioural alterations that are reminiscent of neurodevelopmental disorders associated with repetitive behaviours at adulthood.

We evaluated a digital learning programme for non-specialists to develop knowledge-based competencies in a problem-solving intervention for adolescents to examine the overall impact of training on knowledge-based competencies among learners; and to compare the effects of two training conditions (self-guided digital training with or without coaching) in a nested parallel, two-arm, individually randomised controlled trial. Eligible participants were 18 or older; fluent in Hindi or English; able to access digital training; and had no prior experience of delivering structured psychotherapies. 277 participants were enrolled from 31 March 2022 to 19 June 2022 of which 230 (83%) completed the study. There was a significant increase in competency score from pre-training (Mean = 7.01, SD = 3.29) to post-training (Mean = 8.88, SD = 3.80), 6 weeks after the pre-training assessment. Knowledge competency scores showed larger increase among participants randomised to the coaching arm (AMD = 1.09, 95% CI 0.26–1.92, p = 0.01) with an effect size (d) of 0.33 (95% CI 0.08–0.58). More participants completed training in the coaching arm (n = 96, 69.6%) compared to the self-guided training arm (n = 56, 40.3%). In conclusion, a coach-supported remote digital training intervention is associated with enhanced participation by learners and increased psychotherapeutic knowledge competencies.

EmpaTeach was the first intervention to address teacher violence to be tested in a humanitarian setting and the first to focus on reducing impulsive use of violence, but a cluster randomised trial found no evidence that the intervention was effective in reducing physical and emotional violence from teachers. We aimed to understand why. We conducted a quantitative process evaluation to describe the intervention implementation process (what was implemented and how); examine teachers' adoption of positive teaching practices (was the content of the intervention taken up by participants), and test mechanisms of impact underlying the program theory (how the intervention was supposed to produce change). Despite participation in the intervention activities and adoption of intervention-recommended strategies (classroom management and positive disciplinary methods), we show that teachers who used more positive discipline did not appear to use less violence; and teachers in intervention schools did not experience gains in intermediate outcomes such as empathy, growth mindset, self-efficacy or social support. Our findings suggest that the intervention did not work due to the failure of some key hypothesised mechanisms, rather than because of implementation challenges.

Background ‘POD Adventures’ is a gamified problem-solving intervention delivered via smartphone app, and supported by non-specialist counsellors for a target population of secondary school students in India during the COVID-19 pandemic. Aims To evaluate the feasibility and acceptability of undertaking a randomised controlled trial of POD Adventures when delivered online with telephone support from counsellors. Method We conducted a parallel, two-arm, individually randomised pilot-controlled trial with 11 secondary schools in Goa, India. Participants received either the POD Adventures intervention delivered over 4 weeks or usual care comprising information about local mental health services and national helplines. Outcomes were assessed at two timepoints: baseline and 6 weeks post-randomisation. Results Seventy-nine classroom sensitisation sessions reaching a total of 1575 students were conducted. Ninety-two self-initiated study referrals (5.8%) were received, but only 11 participants enrolled in the study. No intervention arm participants completed the intervention. Outcomes at 6 weeks were not available for intervention arm participants (n = 5), and only four control arm participants completed outcomes. No qualitative interviews or participant satisfaction measures were completed because participants could not be reached by the study team. Conclusions Despite modifications to address barriers arising from COVID-19 restrictions, online delivery was not feasible in the study context. Low recruitment and missing feasibility and acceptability data make it difficult to draw conclusions about intervention engagement and indicative clinical outcomes. Prior findings showing high uptake, adherence and engagement with POD Adventures when delivered in a school-based context suggest that an online study and delivery posed the biggest barriers to study participation and engagement.

Chimeric antigen receptor engineering in T cells has been shown to be of great potential therapeutic benefit in a range of immune pathologies, although the functionality of such cell therapies can be limited due to tonic signalling and the induction of dysfunction. Here the authors show transient inhibition of mTOR can rescue their 41-BB-CAR-Tregs from tonic signalling-induced dysfunction.

Naked mole-rats are hypoxia-tolerant mammals, and during hypoxia their body temperature decreases via unknown mechanisms. Here the authors report that the hypoxia-induced body temperature decrease in naked mole rats occurs through decreased brown adipose tissue thermogenesis via decreases in a key thermogenic mitochondrial protein: UCP1.

Preterm birth is the leading cause of death in children under 5 years of age. Premature infants who receive life-saving oxygen therapy often develop bronchopulmonary dysplasia (BPD), a chronic lung disease. Infants with BPD are at a high risk of abnormal neurodevelopment, including motor and cognitive difficulties. While neural progenitor cells (NPCs) are crucial for proper brain development, it is unclear whether they play a role in BPD-associated neurodevelopmental deficits. Here, we show that hyperoxia-induced experimental BPD in newborn mice led to lifelong impairments in cerebrovascular structure and function as well as impairments in NPC self-renewal and neurogenesis. A neurosphere assay utilizing nonhuman primate preterm baboon NPCs confirmed impairment in NPC function. Moreover, gene expression profiling revealed that genes involved in cell proliferation, angiogenesis, vascular autoregulation, neuronal formation, and neurotransmission were dysregulated following neonatal hyperoxia. These impairments were associated with motor and cognitive decline in aging hyperoxia-exposed mice, reminiscent of deficits observed in patients with BPD. Together, our findings establish a relationship between BPD and abnormal neurodevelopmental outcomes and identify molecular and cellular players of neonatal brain injury that persist throughout adulthood that may be targeted for early intervention to aid this vulnerable patient population.

Mature spermatozoa are almost completely devoid of cytoplasm; as such it has long been believed that they do not contain ribosomes and are therefore not capable of synthesising proteins. However, since the 1950s, various studies have shown translational activity within spermatozoa, particularly during their in vitro capacitation. But the type of ribosomes involved (cytoplasmic or mitochondrial) is still debated. Here, we investigate the presence and activity of the two types of ribosomes in mature human spermatozoa. By targeting ribosomal RNAs and proteins, we show that both types of ribosomes are localized in the midpiece as well as in the neck and the base of the head of the spermatozoa. We assessed the impact of cycloheximide (CHX) and chloramphenicol (CP), inhibitors of cytoplasmic and mitochondrial ribosomes, respectively, on different sperm parameters. Neither CHX, nor CP impacted sperm vitality, mitochondrial activity (measured through the ATP content), or capacitation (measured through the content in phosphotyrosines). However, increasing CP concentrations induced a decrease in total and progressive motilities as well as on some kinematic parameters while no effect was observed with CHX. A quantitative proteomic analysis was performed by mass spectrometry in SWATH mode to compare the proteomes of spermatozoa capacitated in the absence or presence of the two ribosome inhibitors. Among the ∼700 proteins identified in the different tested conditions, 3, 3 and 25 proteins presented a modified abundance in the presence of 1 and 2 mg/ml of CHX, and 1 mg/ml of CP, respectively. The observed abundance variations of some CP-down regulated proteins were validated using Multiple-Reaction Monitoring (MRM). Taken together, our results are in favor of an activity of mitochondrial ribosomes. Their inhibition by CP results in a decrease in the abundance of several proteins, at least FUNDC2 and QRICH2, and consequently induces sperm motility deficits.

In this paper, a brushless motor with a three-phase inverter is investigated under healthy and multiple open-circuit faults. The occurrence of faults in an inverter will lead to atypical characteristics in the current measurements. This is why many usual entropies and multiscale entropies have been proposed to evaluate the complexity of the output currents by quantifying such dynamic changes. Among this multitude of entropies, only some are able to differentiate between healthy and faulty open-circuit conditions. In addition, another selection is made between these entropies in order to improve diagnostic speed. After the fault detection based on the mean values, the open-circuit faults are localized based on the fault diagnostic method. The simulation results ensure the ability of these entropies to detect and locate open-circuit faults. Moreover, they are able to achieve fault diagnostics for a single switch, double switches, three switches, and even four switches. The diagnostic time to detect and to isolate faults is between 10.85 ms and 13.67 ms. Then, in order to prove the ability of the fault diagnostic method, a load variation is performed under the rated speed conditions of the brushless motor. The validity of the method is analyzed under different speed values for a constant torque. Finally, the fault diagnostic method is independent from power levels.

Nowadays, MILP is a very popular tool to help cryptographers search for various distinguishers, in particular for integral distinguishers based on the division property. However, cryptographers tend to use MILP in a rather naive way, modeling problems in an exact manner and feeding them to a MILP solver. In this paper, we show that a proper use of some features of MILP solvers such as lazy constraints, along with using simpler but less accurate base models, can achieve much better solving times, while maintaining the precision of exact models. In particular, we describe several new modelization techniques for division property related models as well as a new variant of the Quine-McCluskey algorithm for this specific setting. Moreover, we positively answer a problem raised in [DF20] about handling the large sets of constraints describing valid transitions through Super S-boxes into a MILP model. As a result, we greatly improve the solving times to recover the distinguishers from several previous works ([DF20], [HWW20], [SWW17], [Udo21], [EY21]) and we were able to search for integral distinguishers on 5-round ARIA which was out of reach of previous modeling techniques.

In the field of signal processing, it is interesting to explore signal irregularities. Indeed, entropy approaches are efficient to quantify the complexity of a time series; their ability to analyze and provide information related to signal complexity justifies their growing interest. Unfortunately, many entropies exist, each requiring setting parameter values, such as the data length N, the embedding dimension m, the time lag τ, the tolerance r and the scale s for the entropy calculation. Our aim is to determine a methodology to choose the suitable entropy and the suitable parameter values. Therefore, this paper focuses on the effects of their variation. For illustration purposes, a brushless motor with a three-phase inverter is investigated to discover unique faults, and then multiple permanent open-circuit faults. Starting from the brushless inverter under healthy and faulty conditions, the various possible switching faults are discussed. The occurrence of faults in an inverter leads to atypical characteristics of phase currents, which can increase the complexity in the brushless response. Thus, the performance of many entropies and multiscale entropies is discussed to evaluate the complexity of the phase currents. Herein, we introduce a mathematical model to help select the appropriate entropy functions with proper parameter values, for detecting open-circuit faults. Moreover, this mathematical model enables to pick up many usual entropies and multiscale entropies (bubble, phase, slope and conditional entropy) that can best detect faults, for up to four switches. Simulations are then carried out to select the best entropy functions able to differentiate healthy from open-circuit faulty conditions of the inverter.