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International audience; The geological units on the floor of Jezero crater, Mars, are part of a wider regional stratigraphy of olivine-rich rocks, which extends well beyond the crater. We investigate the petrology of olivine and carbonate-bearing rocks of the Séítah formation in the floor of Jezero. Using multispectral images and x-ray fluorescence data, acquired by the Perseverance rover, we performed a petrographic analysis of the Bastide and Brac outcrops within this unit. We find that these outcrops are composed of igneous rock, moderately altered by aqueous fluid. The igneous rocks are mainly made of coarse-grained olivine, similar to some Martian meteorites. We interpret them as an olivine cumulate, formed by settling and enrichment of olivine through multi-stage cooling of a thick magma body.

Per- and polyfluoroalkyl substances (PFAS) are globally distributed in the natural environment, and their persistent and bioaccumulative potential illicit public concern. The production of certain PFAS has been halted or controlled by regulation due to their adverse effect on the health of humans and wildlife. However, new PFAS are continuously developed as alternatives to legacy PFAS. Additionally, many precursors are unknown, and their metabolites have not been assessed. To better understand the PFAS profiles in the Lake Ontario (LO) aquatic food web, a quadrupole time-of-flight mass spectrometer (QToF) coupled to ultrahigh-performance liquid chromatography (UPLC) was used to generate high-resolution mass spectra (HRMS) from sample extracts. The HRMS data files were analyzed using an isotopic profile deconvoluted chromatogram (IPDC) algorithm to isolate PFAS profiles in aquatic organisms. Fourteen legacy PFAAs (C5-C14) and 15 known precursors were detected in the LO food web. In addition, over 400 unknown PFAS features that appear to biomagnify in the LO food web were found. Profundal benthic organisms, deepwater sculpin(

International audience; Mighei-type carbonaceous chondrites (CM) figure among the most primitive objects in the solar system. Yet, they all have experienced various degrees of aqueous alteration having modified their insoluble organic matter (IOM), in a sequence that remains to be accurately constrained. Here, we exposed the IOM of Paris, the least altered CM available, to hydrothermal conditions at 150 °C for 49 days and compared the experimental residue to the IOM of two altered CMs likely originating from the same parent body as Paris, namely Aguas Zarcas and Mukundpura. The experimental residue shows a chemical and isotopic composition similar to those of Aguas Zarcas and Mukundpura IOMs, confirming that these CMs can be seen as altered counterparts of Paris. The abundance of organic radicals also increases significantly during the experiment. Isotopic hotspots do not seem to have been lost during the experiment, suggesting that the hotspots generally observed within the CM IOMs may date back from pre-accretion era. Of note, the Raman signature of the residue differs from that of the CM IOMs, highlighting the need for further experiments better mimicking asteroidal-like conditions.

The aim of this article is to empirically investigate the relationships among interpersonal guilt, as conceived within control-mastery theory (CMT), and attachment, altruism, and personality pathology in an English-speaking sample. An online sample of 393 participants was recruited to complete the Interpersonal Guilt Rating Scale self-report version-15 (IGRS-15s), together with other empirically validated measures for the assessment of attachment, altruism, and personality pathology. On the basis of previous studies conducted in Italian-speaking samples, we hypothesized that survivor guilt, separation/disloyalty guilt, and omnipotent responsibility guilt would be associated with attachment anxiety and avoidance, altruism, and personality pathology; self-hate was hypothesized to be associated only with attachment anxiety and avoidance and personality pathology. Analyses examined bivariate associations as well as the network of partial correlations among variables. The results largely confirmed hypothesized associations, with self-hate evincing the strongest unique association with personality dysfunction. Findings provide a basis for further research regarding interpersonal guilt and personality and relational functioning, with potential implications for clinical conceptualizations of the role of guilt in psychopathology.

High pressure (20 MPa), cyclic, supercritical carbon dioxide (scCO2) treatments can reduce the moisture content of green Pinus radiata sapwood from 150–200% to 35–40%. Such treatments can be used as a dewatering pre-treatment before the kiln-drying of timber. Kiln-drying can utilise various temperature and humidity schedules, targeting around 10% moisture content, with a final stress-relieving steam-conditioning step. After scCO2 treatment and kiln-drying of samples, kiln brown stain was evaluated using the CIE L*a*b* colour space while drying stress was assessed by stress-cup measurements. The most significant results of scCO2 pre-treatment of Pinus radiata sapwood followed by kiln-drying plus steam-conditioning were as follows: Drying from green (36 h from a moisture content (MC) of 164%) using a conventional temperature schedule (90 °C/60 °C) took 2–5 times longer than kiln-drying scCO2 pre-treated boards (37.5% MC) to a target of 10% MC. Colour measurements proved that kiln brown stain does not occur. The use of a steam-conditioning step in reducing internal drying stresses was important irrespective of whether or not there was a scCO2 pre-treatment step. Over all drying schedule combinations, internal drying stress of both green and scCO2 pre-treated timber was similar after kiln-drying plus steam-conditioning. However, using only 90 °C/60 °C schedule data, with steam-conditioning, drying stresses were lower using kiln-drying without the scCO2 pre-treatment. This was surprising since the scCO2 step reduced the moisture content to around 37.5% without significant moisture gradients and so a secondary kiln-drying to 10% moisture content could have been expected to yield lower internal stress levels by preventing large moisture gradients to develop during drying. This result confirms the efficacy of the steam-conditioning step following standard kiln-drying. The colour data demonstrating the prevention of kiln brown stain using kiln-drying schedules offers a path to increasing timber quality for interior applications.

Bococizumab is an anti-PCSK9 monoclonal antibody that was intended for the treatment of hypercholesterolemia. After reviewing the 6-month rat toxicity study data, in which there was a low spontaneous tumor incidence, unrelated to bococizumab administration, the U.S. FDA granted a carcinogenicity waiver request based on a weight-of-evidence assessment of low carcinogenic risk. Subsequently, after reviewing 6-month rat toxicity study data from another anti-PCSK9 antibody, RN317, with a similar low tumor incidence (unrelated to RN317), the U.S. FDA rescinded the bococizumab carcinogenicity study waiver and requested a full 2-year rat carcinogenicity study be conducted. The resulting 2-year carcinogenicity study demonstrated no bococizumab-related increase in tumors, confirming the weight-of-evidence evaluation and alleviating concerns regarding the carcinogenic potential. Here we report the scientific and regulatory background that led to the request for a rat carcinogenicity study, the feedback on the design of the carcinogenicity study, and the results from this study which affirmed the original weight-of-evidence assessment of low carcinogenic risk.

Introduction: SARS-CoV-2 is a fatal disease of global public health concern. Measures to reduce its spread critically depend on timely and accurate diagnosis of virus-infected individuals. Biobanks can have a pivotal role in elucidating disease etiology, translation, and advancing public health. In this article, we show how a biobank has been a critical resource in the rapid response to coronavirus disease of 2019 (COVID-19) in Uganda. Materials and Methods: The Integrated Biorepository of H3Africa Uganda established a COVID-19 biobank. Standard Operating Procedures for sample and data collection, sample processing, and storage were developed. An e-questionnaire data tool was used to collect sociodemographic factors. Samples were collected at 7-day intervals from patients, analyzed for key parameters, processed, annotated, characterized, and stored at appropriate temperatures. Results: Stored samples have been used in validation of 17 diagnostic kits, the Cepheid Xpert Xpress SARS-CoV-2 assay, as well as a sample pooling technique for mass screening and polymerase chain reaction assay validation. Kits that passed validation were deployed for mass screening boosting early detection, isolation, and treatment of COVID-19 cases. Also, 10 applications from researchers and biotech companies have been received and approved and 4 grants have been awarded Conclusion: The CoV-Bank has proven to be an invaluable resource in the fight against the COVID-19 pandemic in Uganda, as samples have been resources in the validation and development of COVID-19 diagnostic tools, which are important in tracing and isolation of infected cases to confront, delay, and stop the spread of the SARS-CoV-2 virus.

Sub-Saharan Africa has increased morbidity and mortality related to chronic obstructive pulmonary disease (COPD). COPD among people living with HIV (PLWH) has not been well studied in this region, where HIV/AIDS is endemic. Increasing evidence suggests that respiratory microbial composition plays a role in COPD severity. Therefore, we aimed to investigate microbiome patterns and associations among PLWH with COPD in Sub-Saharan Africa. We conducted a cross-sectional study of 200 adults stratified by HIV and COPD in rural Uganda. Induced sputum samples were collected as an easy-to-obtain proxy for the lower respiratory tract microbiota. We performed 16S rRNA gene sequencing and used PICRUSt2 (version 2.2.3) to infer the functional profiles of the microbial community. We used a statistical tool to detect changes in specific taxa that searches and adjusts for confounding factors such as antiretroviral therapy (ART), age, sex, and other participant characteristics. We could cluster the microbial community into three community types whose distribution was shown to be significantly impacted by HIV. Some genera, e.g., Veillonella, Actinomyces, Atopobium, and Filifactor, were significantly enriched in HIV-infected individuals, while the COPD status was significantly associated with Gammaproteobacteria and Selenomonas abundance. Furthermore, reduced bacterial richness and significant enrichment in Campylobacter were associated with HIV-COPD comorbidity. Functional prediction using PICRUSt2 revealed a significant depletion in glutamate degradation capacity pathways in HIV-positive patients. A comparison of our findings with an HIV cohort from the United Kingdom revealed significant differences in the sputum microbiome composition, irrespective of viral suppression. IMPORTANCE: Even with ART available, HIV-infected individuals are at high risk of suffering comorbidities, as shown by the high prevalence of noninfectious lung diseases in the HIV population. Recent studies have suggested a role for the respiratory microbiota in driving chronic lung inflammation. The respiratory microbiota was significantly altered among PLWH, with disease persisting up to 3 years post-ART initiation and HIV suppression. The community structure and diversity of the sputum microbiota in COPD are associated with disease severity and clinical outcomes, both in stable COPD and during exacerbations. Therefore, a better understanding of the sputum microbiome among PLWH could improve COPD prognostic and risk stratification strategies. In this study, we observed that in a virologically suppressed HIV cohort in rural Uganda, we could show differences in sputum microbiota stratified by HIV and COPD, reduced bacterial richness, and significant enrichment in Campylobacter associated with HIV-COPD comorbidity.

The traditional method of taking attendance using paper sheets is prone to errors like impersonation, loss, or theft. To solve this issue, automatic attendance systems utilizing identification technology such as barcode badges, electronic tags, touch screens, magnetic stripe cards, and biometrics have been implemented. Biometric technology uses physiological or behavioral characteristics for identification purposes, but traditional biometric systems have limitations such as vulnerability to damage or alteration over time, and variations in occlusions, poses, facial expressions, and illumination can affect face recognition accuracy. Fingerprint identification relies on the distinctiveness of fingerprints and involves comparing two impressions of the friction ridges on human fingers or toes to determine if they belong to the same individual. There are five primary categories of fingerprints: arch, tented arch, left loop, right loop, and whorl. Various algorithms have been developed to recognize fingerprints using minutiaebased matching, which involves identifying key features like ridge ending and bifurcation. Deep learning algorithms, particularly convolutional neural networks, have been successful in improving identification accuracy by extracting features automatically from fingerprint images. In recent times, securing personal data has become increasingly important, and the Convolutional Neural Network (CNN) identification system is recommended for improving accuracy and performance. This paper proposes a fingerprint identification system that combines three models: CNN, Softmax, and Random Forest (RF) classifiers. The conventional system uses K-means and DBSCAN algorithms to separate the foreground and background regions and extracts features using CNNs and dropout approach. The Softmax acts as a recognizer. The proposed algorithm is evaluated on a public database and shows promising results, providing an accurate and efficient biometric identification system. &nbsp

Isothermal Titration Calorimetry curves obtained by adding the different phosphopeptides at (A-B) 200 mM onto the WT BRCT domains at 20 mM and (C-D) 100 mM onto the WT BRCT domains at 10 mM .

BRCA1 mutations have been identified that increase the risk of developing hereditary breast and ovarian cancers. Genetic screening is now offered to patients with a family history of cancer, to adapt their treatment and the management of their relatives. However, a large number of BRCA1 variants of uncertain significance (VUS) are detected. To better understand the significance of these variants, a high-throughput structural and functional analysis was performed on a large set of BRCA1 VUS. Information on both cellular localization and homology-directed DNA repair (HR) capacity was obtained for 78 BRCT missense variants in the UMD-BRCA1 database and measurement of the structural stability and phosphopeptide-binding capacities was performed for 42 mutated BRCT domains. This extensive and systematic analysis revealed that most characterized causal variants affect BRCT-domain solubility in bacteria and all impair BRCA1 HR activity in cells. Furthermore, binding to a set of 5 different phosphopeptides was tested: all causal variants showed phosphopeptide-binding defects and no neutral variant showed such defects. A classification is presented on the basis of mutated BRCT domain solubility, phosphopeptide-binding properties, and VUS HR capacity. These data suggest that HR-defective variants, which present, in addition, BRCT domains either insoluble in bacteria or defective for phosphopeptide binding, lead to an increased cancer risk. Furthermore, the data suggest that variants with a WT HR activity and whose BRCT domains bind with a WT affinity to the 5 phosphopeptides are neutral. The case of variants with WT HR activity and defective phosphopeptide binding should be further characterized, as this last functional defect might be sufficient per se to lead to tumorigenesis.Implications:The analysis of the current study on BRCA1 structural and functional defects on cancer risk and classification presented may improve clinical interpretation and therapeutic selection.

The black bar corresponds to WT BRCA1, the blue bars to VUS of classes 1 and 2, the grey bars to VUS of class 3 and the red bars to VUS of classes 4 and 5. Bars boxed in green correspond to mutants that are defective in phosphopeptide-binding, as observed using fluorescence based thermal shift assays. HR- marks VUS that are HR-defective.

FBTSA assay revealing that binding of the WT BRCA1 BRCT domains to ACC1-P, BACH1-P, CtiP-P, AB-1P and AB-2P induce a measurable increase in the BRCT thermostability that raises with peptide concentration.

Mutated BRCT domains fused to GST were expressed in E. coli and purified by affinity chromatography using glutathione beads. This figure shows a SDS-PAGE gel with samples from the bacterial pellet (P), supernatant (S) and the glutathione beads (G) after incubation with the supernatant and washing. VUS were classified into 3 groups as a function of the amount of (1) soluble and (2) purified protein obtained from bacterial cultures. Lanes corresponding to a typical insoluble fusion protein, a typical poorly soluble fusion protein and a typical fusion protein as soluble as the WT fusion protein are boxed in orange, grey and black, respectively (colors are as in Figure 4 excepted for mutations that cause aggregation during purification, which are in yellow on Figure 4 even if they displayed a "grey-like" profile at the expression and first affinity purification stages).

Plot of the HR efficiencies measured after expression of either WT BRCA1 or VUS normalized to the HR efficiency after expression of WT BRCA1. The HR efficiencies are here plotted as a function of the position of the mutation in the BRCA1 sequence. Statistical significance was calculated using a one-side paired student t-test. To account for the multiple testing, the p-values were adjusted using the Benjamini-Horchberg method at a level a=0.05. HR efficiencies significantly different from the WT value are marked by asterisks. They are indicated by * if p < 0.05 and ** if p < 0.01. All 7 (likely) causal (noted LC or C) variants (in red) caused a significantly decreased HR efficiency whereas all 6 (likely) neutral (noted LN or N) variants (in blue) caused no significant HR difference. Twenty-four VUS of class 3 could not provide WT HR efficiency.

Size Exclusion Chromatography profiles obtained on BRCA1 BRCT domains free (red curve) or in complex with BACH1-P (purple), AB-1P (green), AB-2P (blue). The experiment was performed using a Superdex-75 10/300 GL column (GE Healthcare) pre-equilibrated with 50mM Tris-HCl pH 7.5, 150 mM NaCl, 10 mM β-mercaptoethanol and protease inhibitors (Roche).

FBTSA assays performed to measure binding of the mutated BRCA1 BRCT domains to ACC1-P, BACH1-P, CtiP-P, AB-1P and AB-2P.

Mouse body weights of LS1034 tumor bearing mice treated with GUCY2C(M)-CD3 using adoptive T cell transfer

Table S2. Surface Plasmon Resonance binding affinities of anti-GUCY2C/anti-CD3ε bispecifics to human, mouse and cynomolgus GUCY2C

Table S1. Mean ({plus minus}SD) Toxicokinetic Parameters for Ipilimumab and Novolumab in Cynomolgus Monkeys Table S2 - Differentially expressed genes in the heart of ipilimumab and nivolumab treated cynos (adjusted P-value {less than or equal to} 0.05) Table S3 - Top 50 enriched pathways identified by IPA when using the data set of 882 analysis ready differentially expressed genes (adjusted P-value {less than or equal to} 0.05). Ratio: number of DE genes in a pathway divided by the number of genes comprised in the same pathway. Table S4: Top 25 networks identified based upon differentially expressed genes (adjusted P-value {less than or equal to} 0.05) in ipilimumab and nivolumab treated cynos. Table S5: Regulator effects networks generated using genes that are differentially expressed (adjusted P-value {less than or equal to} 0.05) in ipilimumab and nivolumab treated cynos. Upstream regulator and diseae& function cutoffs were each log P-value {less than or equal to} 10 and a z-score {greater than or equal to} |3| Table S6 - Differential expression of myocarditis- associated genes in the heart of ipilimumab and nivolumab treated cynos

Supplemental Figure S1. Concentration versus time profiles of ipilimumab and nivolumab following four weekly intravenous dose administrations of 15 mg/kg or 20 mg/kg, respectively. Supplementary Figure S2. Hematoxylin and eosin stained sections of tissues from control and monkeys dosed with ipilimumab and nivolumab. Supplementary Figure S3. Quantification of mononuclear cell infiltrates from IHC images of heart sections.

Purpose:Immune checkpoint inhibitors (ICI) targeting PD1, PDL1, or CTLA4 are associated with immune-related adverse events (irAE) in multiple organ systems including myocarditis. The pathogenesis and early diagnostic markers for ICI-induced myocarditis are poorly understood, and there is currently a lack of laboratory animal model to enhance our understanding. We aimed to develop such a model using cynomolgus monkeys.Experimental Design:Chinese-origin cynomolgus monkeys were dosed intravenously with vehicle or nivolumab 20 mg/kg plus ipilimumab 15 mg/kg once weekly and euthanized on day 29.Results:Multiple organ toxicities were observed in cynomolgus monkeys, and were characterized by loose feces, lymphadenopathy, and mononuclear cell infiltrations of varying severity in heart, colon, kidneys, liver, salivary glands, and endocrine organs. Increased proliferation of CD4+ and CD8+ T lymphocytes as well as an increase in activated T cells and central memory T cells in the blood, spleen, and lymph nodes, were observed. Transcriptomic analysis suggested increased migration and activation of T cells and increased phagocytosis and antigen presentation in the heart. Mononuclear cell infiltration in myocardium was comprised primarily of T cells, with lower numbers of macrophages and occasional B cells, and was associated with minimal cardiomyocyte degeneration as well as increases in cardiac troponin-I and NT-pro-BNP. Morphologically, cardiac lesions in our monkey model are similar to the reported ICI myocarditis in humans.Conclusions:We have developed a monkey model characterized by multiple organ toxicities including myocarditis. This model may provide insight into the immune mechanisms and facilitate biomarker identification for ICI-associated irAEs.

Supplementary Methods

Purpose:Gastrointestinal cancers remain areas of high unmet need despite advances in targeted and immunotherapies. Here, we demonstrate potent, tumor-selective efficacy with PF-07062119, a T-cell engaging CD3 bispecific targeting tumors expressing Guanylyl Cyclase C (GUCY2C), which is expressed widely across colorectal cancer and other gastrointestinal malignancies. In addition, to address immune evasion mechanisms, we explore combinations with immune checkpoint blockade agents and with antiangiogenesis therapy.Experimental Design:PF-07062119 activity was evaluated in vitro in multiple tumor cell lines, and in vivo in established subcutaneous and orthotopic human colorectal cancer xenograft tumors with adoptive transfer of human T cells. Efficacy was also evaluated in mouse syngeneic tumors using human CD3ϵ transgenic mice. IHC and mass cytometry were performed to demonstrate drug biodistribution, recruitment of activated T cells, and to identify markers of immune evasion. Combination studies were performed with anti–PD-1/PD-L1 and anti-VEGF antibodies. Toxicity and pharmacokinetic studies were done in cynomolgus macaque.Results:We demonstrate that GUCY2C-positive tumors can be targeted with an anti-GUCY2C/anti-CD3ϵ bispecific, with selective drug biodistribution to tumors. PF-07062119 showed potent T-cell–mediated in vitro activity and in vivo efficacy in multiple colorectal cancer human xenograft tumor models, including KRAS- and BRAF-mutant tumors, as well as in the immunocompetent mouse syngeneic tumor model. PF-07062119 activity was further enhanced when combined with anti–PD-1/PD-L1 treatment or in combination with antiangiogenic therapy. Toxicity studies in cynomolgus indicated a monitorable and manageable toxicity profile.Conclusions:These data highlight the potential for PF-07062119 to demonstrate efficacy and improve patient outcomes in colorectal cancer and other gastrointestinal malignancies.

Supplementary Figure 4 from Bcl-2 Inhibits Nuclear Homologous Recombination by Localizing BRCA1 to the Endomembranes

Supplementary Figure 1 from AKT1 Inhibits Homologous Recombination by Inducing Cytoplasmic Retention of BRCA1 and RAD51

Supplementary Figure 2 from Bcl-2 Inhibits Nuclear Homologous Recombination by Localizing BRCA1 to the Endomembranes

Supplementary Figure 5 from AKT1 Inhibits Homologous Recombination by Inducing Cytoplasmic Retention of BRCA1 and RAD51

Supplementary Figure 6 from Bcl-2 Inhibits Nuclear Homologous Recombination by Localizing BRCA1 to the Endomembranes

Supplementary Figure 6 from AKT1 Inhibits Homologous Recombination by Inducing Cytoplasmic Retention of BRCA1 and RAD51

Supplementary Figure 4 from AKT1 Inhibits Homologous Recombination by Inducing Cytoplasmic Retention of BRCA1 and RAD51

Supplementary Figure 3 from Bcl-2 Inhibits Nuclear Homologous Recombination by Localizing BRCA1 to the Endomembranes

Supplementary Figure 7 from Bcl-2 Inhibits Nuclear Homologous Recombination by Localizing BRCA1 to the Endomembranes

Supplementary Figure 2 from AKT1 Inhibits Homologous Recombination by Inducing Cytoplasmic Retention of BRCA1 and RAD51

Supplementary Figure 3 from AKT1 Inhibits Homologous Recombination by Inducing Cytoplasmic Retention of BRCA1 and RAD51

Supplementary Movie from AKT1 Inhibits Homologous Recombination by Inducing Cytoplasmic Retention of BRCA1 and RAD51

Despite recent efforts to increase diversity in genome-wide association studies (GWASs), most loci currently associated with kidney function are still limited to European ancestry due to the underlying sample selection bias in available GWASs. We set out to identify susceptibility loci associated with estimated glomerular filtration rate (eGFRcrea) in 80027 individuals of African-ancestry from the UK Biobank (UKBB), Million Veteran Program (MVP), and Chronic Kidney Disease genetics (CKDGen) consortia. We identified 8 lead loci, 7 of which were previously associated with eGFR in other populations. We identified one novel variant, rs77408001 which is an intronic variant mapped to the ELN gene. We validated seven previously reported loci at GATM-SPATA5L1 and AGPAT3. Fine-mapping analysis identified variants rs77121243 and rs201602445 as having a 99.9% posterior probability of being causal. Our results warrant designing bigger studies within individuals of African ancestry to gain new insights into the pathogenesis of Chronic Kidney Disease (CKD) and identify genomic variants unique to this ancestry that may influence renal function and disease.

The impact of endemic infections on protective immunity is critical to inform vaccination strategies. In this study, we assessed the influence ofSchistosoma mansoniinfection on host responses in a Ugandan fishing cohort given a Hepatitis B (HepB) vaccine. Concentrations of schistosome-specific circulating anodic antigen (CAA) pre-vaccination showed a significant bimodal distribution associated with HepB titers, which were lower in individuals with high CAA. We established that participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination and higher regulatory T cells (Tregs) post-vaccination. Polarization towards higher frequencies of Tregs: cTfh cells can be mediated by changes in the cytokine environment favoring Treg differentiation. In fact, we observed higher levels of CCL17 and soluble IL-2R pre-vaccination (important for Treg recruitment and development), in individuals with high CAA that negatively associated with HepB titers. Additionally, alterations in pre-vaccination monocyte function correlated with HepB titers, and changes in innate-related cytokines/chemokine production were associated with increasing CAA concentration. We report, that by influencing the immune landscape, schistosomiasis has the potential to modulate immune responses to HepB vaccination. These findings highlight multipleSchistosoma-related immune associations that could explain abrogated vaccine responses in communities with endemic infections.Author SummarySchistosomiasis drives host immune responses for optimal pathogen survival, potentially altering host responses to vaccine-related antigen. Chronic schistosomiasis and co-infection with hepatotropic viruses are common in countries where schistosomiasis is endemic. We explored the impact ofSchistosoma mansoni(S. mansoni) infection on Hepatitis B (HepB) vaccination of individuals from a fishing community in Uganda. We demonstrate that high schistosome-specific antigen (circulating anodic antigen, CAA) concentration pre-vaccination, is associated with lower HepB antibody titers post-vaccination. We show higher pre-vaccination levels of cellular and soluble factors in instances of high CAA that are negatively associated with HepB antibody titers post-vaccination, which coincided with lower frequencies of circulating T follicular helper cell populations (cTfh), proliferating antibody secreting cells (ASCs), and higher frequencies of regulatory T cells (Tregs). We also show that monocyte function is important in HepB vaccine responses, and that high CAA is associated with alterations in the early innate cytokine/chemokine microenvironment. Our findings suggest that in individuals with high CAA and likely high worm burden, schistosomiasis creates and sustains an environment that is polarized against optimal host immune responses to the vaccine, which puts many endemic communities at risk for infection against HepB and other diseases that are preventable by vaccines.

Introduction The clinical presentation of childhood-onset systemic lupus erythematosus (SLE) is generally perceived to differ from that of adult-onset SLE. Objective We aimed to compare the demographic and clinical manifestation between childhood-onset vs. adult-onset SLE in a cohort of Indonesian patients at tertiary care centers. Methods This retrospective study included patients in the Hasan Sadikin Lupus Registry from 2008 until December 2017. The demographics, clinical presentations, and outcomes were compared between childhood-onset SLE (Results Eight hundred seventy patients were involved into this study. The proportion of childhood-onset SLE was 20% (174 patients). The mean age of group 1 versus group 2 was 13.56 ± 3.04 vs 30.41 ± 8.54 years. The following clinical manifestations at SLE diagnosis were significantly more common in childhood-onset than in adult-onset SLE patients: hematological disorder ( p = 0.033) and arthritis ( p = 0.006). While discoid rash ( p = 0.036) and photosensitivity ( p < 0.001) were significantly found higher in adult-onset SLE. Cyclophosphamide therapy was significantly more common to be used in childhood-onset (38.5% vs 21.0%, p = Conclusion Arthritis and hematologic involvements at SLE diagnosis were more prominent in childhood-onset compared to adult-onset patients, and mortality in childhood-onset SLE during follow-up relatively higher. This data may suggest the need for more aggressive management approach to childhood-onset patients with SLE.

Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals detected throughout the environment. To better understand the distribution of PFAS in an aquatic system (the Laurentian Great Lakes), stable isotope enrichment (δ13C and δ15N), fatty acid (FA) profiles, and PFAS were measured in various species from the Lake Ontario (LO) aquatic food web. Sampled organisms included top predator fish, prey fish, and benthic and pelagic macroinvertebrates. The trophic level of each species in the LO food web was determined using δ15N, and FA concentrations (range: C8) did not exhibit increasing biomagnification factors (BMFs) and trophic magnification factors (TMFs) with log Kow, suggesting hydrophobicity does not govern the movement of PFAS from low to high trophic levels in the LO food web.

Selection of the appropriate DNA double-strand break (DSB) repair pathway is decisive for genetic stability. It is proposed to act according to two steps: 1-canonical nonhomologous end-joining (C-NHEJ) versus resection that generates single-stranded DNA (ssDNA) stretches; 2-on ssDNA, gene conversion (GC) versus nonconservative single-strand annealing (SSA) or alternative end-joining (A-EJ). Here, we addressed the mechanisms by which RAD51 regulates this second step, preventing nonconservative repair in human cells. Silencing RAD51 or BRCA2 stimulated both SSA and A-EJ, but not C-NHEJ, validating the two-step model. Three different RAD51 dominant-negative forms (DN-RAD51s) repressed GC and stimulated SSA/A-EJ. However, a fourth DN-RAD51 repressed SSA/A-EJ, although it efficiently represses GC. In living cells, the three DN-RAD51s that stimulate SSA/A-EJ failed to load efficiently onto damaged chromatin and inhibited the binding of endogenous RAD51, while the fourth DN-RAD51, which inhibits SSA/A-EJ, efficiently loads on damaged chromatin. Therefore, the binding of RAD51 to DNA, rather than its ability to promote GC, is required for SSA/A-EJ inhibition by RAD51. We showed that RAD51 did not limit resection of endonuclease-induced DSBs, but prevented spontaneous and RAD52-induced annealing of complementary ssDNA in vitro. Therefore, RAD51 controls the selection of the DSB repair pathway, protecting genome integrity from nonconservative DSB repair through ssDNA occupancy, independently of the promotion of CG.

Scientific research has been changing medical practice at an increasing pace. To keep up with this change, physicians of the future will need to be lifelong learners with the skills to engage with emerging science and translate it into clinical care. How medical schools can best prepare students for ongoing scientific change remains unclear. Adding to the challenge is reduced time allocated to basic science in curricula and rapid expansion of relevant scientific fields. A return to science with greater depth after clinical clerkships has been suggested, although few schools have adopted such curricula and implementation can present challenges. The authors describe an innovation at Harvard Medical School, the Advanced Integrated Science Courses (AISCs), which are taken after core clerkships. Students are required to take 2 such courses, which are offered in a variety of topics. Rather than factual content, the learning objectives are a set of generalizable skills to enable students to critically evaluate emerging research and its relationship to medical practice. Making these generalizable skills the defining principle of the courses has several important advantages: it allows standardization of acquired skills to be combined with diverse course topics ranging from basic to translational and population sciences; students can choose courses and projects aligned with their interests, thereby enhancing engagement, curiosity, and career relevance; schools can tailor course offerings to the interests of local faculty; and the generalizable skills delineate a unique purpose of these courses within the overall medical school curriculum. For the 3 years AISCs have been offered, students rated the courses highly and reported learning the intended skill set effectively. The AISC concept addresses the challenge of preparing students for this era of rapidly expanding science and should be readily adaptable to other medical schools.