Miracle-dz/UniFAR-FTUs huggingface dataset:
An Association Test of the Spatial Distribution of Rare Missense Variants within Protein Structures Improves Statistical Power of Sequencing Studies

Over 90% of variants are rare, and 50% of them are singletons in the Alzheimer’s Disease Sequencing Project Whole Exome Sequencing (ADSP WES) data. However, either single variant tests or unit-based tests are limited in the statistical power to detect the association between rare variants and phenotypes. To best utilize rare variants and investigate their biological effect, we exam their association with phenotypes in the context of protein. We developed a protein structure-based approach, POKEMON (Protein Optimized Kernel Evaluation of Missense Nucleotides), which evaluates rare missense variants based on their spatial distribution on the protein rather than allele frequency. The hypothesis behind this is that the three-dimensional spatial distribution of variants within a protein structure provides functional context and improves the power of association tests. POKEMON identified four candidate genes from the ADSP WES data, namely two known Alzheimer’s disease (AD) genes (TREM2 and SORL) and two novel genes (DUSP18 and CSF1R). For known AD genes, the signal from the spatial cluster is stable even if we exclude known AD risk variants, indicating the presence of additional low frequency risk variants within these genes. DUSP18 has a cluster of variants primarily shared by case subjects around the ligand-binding domain, and this cluster is further validated in a replication dataset with a larger sample size. POKEMON is an open-source tool available at https://github.com/bushlab-genomics/POKEMON.
Clonal reconstruction from co-occurrence of vector integration sites allows accurate quantification of expanding clones in vivo

High transduction rates of viral vectors in gene therapies (GT) and experimental hematopoiesis ensure a high frequency of gene delivery, although multiple integration events can occur in the same cell. Therefore, tracing of integration sites (IS) leads to misquantification of the true clonal spectrum and limits safety considerations in GT. Hence, we use correlations between repeated measurements of IS abundances to estimate their mutual similarity and identify clusters of co-occurring IS, for which we assume a clonal origin. We evaluate the performance, robustness and specificity of our methodology using clonal simulations. The reconstruction methods, implemented and provided as an R-package, are further applied to experimental clonal mixes and to a preclinical model of hematopoietic GT. Our results demonstrate that clonal reconstruction from IS data allows to overcome systematic biases in the clonal quantification as an essential prerequisite for the assessment of safety and long-term efficacy of GT involving integrative vectors.
Predictive Modeling of Multiplex Chemical Phenomics for Novel Cells and Patients: Applied to Personalized Alzheimer’s Disease Drug Repurposing

Chemical phenomics which measures multiplex chemical-induced phenotypic response of cells or patients, particularly dose-dependent transcriptomics and drug-response curves, provides new opportunities for in silico mechanism-driven phenotype-based drug discovery. However, state-of-the-art computational methods only focus on predicting a single phenotypic readout and are less successful in screening compounds for novel cells or individual patients. We designed a new deep learning model, MultiDCP, to enable high-throughput compound screening based on multiplex chemical phenomics for the first time, and further expand the scope of chemical phenomics to unexplored cells and patients. The novelties of MultiDCP lie in a multi-task learning framework with a novel knowledge-driven autoencoder to integrate incoherent labeled and unlabeled omics data, and a teacher-student training strategy to exploit unreliable data. MultiDCP significantly outperforms the state-of-the-art for novel cell lines. The predicted chemical transcriptomics demonstrate a stronger predictive power than noisy experimental data for downstream tasks. We applied MultiDCP to repurpose individualized drugs for Alzheimer’s disease, suggesting that MultiDCP is a potentially powerful tool for personalized medicine.
Development of motor neurons and motor activity in zebrafish requires F-actin nucleation by Fmn2b

Background Cytoskeletal remodelling plays a pivotal role in the establishment of neuronal connectivity during development and in plasticity in adults. Mutations in the cytoskeleton regulatory protein Formin-2 (Fmn2) are associated with neurodevelopmental disorders like intellectual disability, though its function in neuronal morphogenesis has not been characterised in vivo. Results Here we develop a loss-of-function model for fmn2b, the zebrafish orthologue of Fmn2, using CRISPR/Cas9-mediated gene editing. fmn2b mutants display motor deficits starting from the earliest motor responses in the embryo. We find that fmn2b is expressed in spinal motor neurons and its loss reduces motor neuron innervation of the axial muscles without affecting myotome integrity. The translocation of caudal primary (CaP) motor neuron outgrowth is compromised in fmn2b mutants, while rostral primary (RoP) motor neurons have missing soma or stall at the horizontal myoseptum. Strikingly, axon collateral branching of the motor neurons is severely compromised and results in reduced synaptic coverage of the myotome. Rescue experiments identify the requirement for Fmn2-mediated actin nucleation for motor neuron outgrowth and arborisation. Conclusions The zebrafish loss-of-function model of Fmn2 reveals the specific requirement of F-actin polymerisation by Fmn2 in neuromuscular development. It also underscores the role of Fmn2 in motor neuropathies, especially as a proportion of individuals harbouring mutations in Fmn2 present with hypotonia.
Editorial: Emerging Roles of the Gut Microbiota in the Pathogenesis of Metabolic Disorders

1 Unidad de Gestión Clı́nica de Endocrinologı́a y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain, 2 Centro de Investigación Biomédica en Red de Fisiopatologı́a de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain, 3 Independent Researcher, Neufchâteau, Belgium, 4 Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, Netherlands
Reelin Is Required for Maintenance of Granule Cell Lamination in the Healthy and Epileptic Hippocampus

One characteristic feature of mesial temporal lobe epilepsy is granule cell dispersion (GCD), a pathological widening of the granule cell layer in the dentate gyrus. The loss of the extracellular matrix protein Reelin, an important positional cue for neurons, correlates with GCD formation in MTLE patients and in rodent epilepsy models. Here, we used organotypic hippocampal slice cultures (OHSC) from transgenic mice expressing enhanced green fluorescent protein (eGFP) in differentiated granule cells (GCs) to monitor GCD formation dynamically by live cell video microscopy and to investigate the role of Reelin in this process. We present evidence that following treatment with the glutamate receptor agonist kainate (KA), eGFP-positive GCs migrated mainly toward the hilar region. In the hilus, Reelin-producing neurons were rapidly lost following KA treatment as shown in a detailed time series. Addition of recombinant Reelin fragments to the medium effectively prevented the KA-triggered movement of eGFP-positive GCs. Placement of Reelin-coated beads into the hilus of KA-treated cultures stopped the migration of GCs in a distance-dependent manner. In addition, quantitative Western blot analysis revealed that KA treatment affects the Reelin signal transduction pathway by increasing intracellular adaptor protein Disabled-1 synthesis and reducing the phosphorylation of cofilin, a downstream target of the Reelin pathway. Both events were normalized by addition of recombinant Reelin fragments. Finally, following neutralization of Reelin in healthy OHSC by incubation with the function-blocking CR-50 Reelin antibody, GCs started to migrate without any direction preference. Together, our findings demonstrate that normotopic position of Reelin is essential for the maintenance of GC lamination in the dentate gyrus and that GCD is the result of a local Reelin deficiency.
The Chemokine CCL5 Inhibits the Replication of Influenza A Virus Through SAMHD1 Modulation

Influenza A virus (IAV) is the main etiological agent of acute respiratory tract infections. During IAV infection, interferon triggers the overexpression of restriction factors (RFs), the intracellular antiviral branch of the innate immune system. Conversely, severe influenza is associated with an unbalanced pro-inflammatory cytokine release. It is unclear whether other cytokines and chemokines released during IAV infection modulate RFs to control virus replication. Among the molecules enhanced in the infected respiratory tract, ligands of the CCR5 receptor play a key role, as they stimulate the migration of inflammatory cells to the alveoli. We investigated here whether ligands of the CCR5 receptor could enhance RFs to levels able to inhibit IAV replication. For this purpose, the human alveolar basal epithelial cell line (A549) was treated with endogenous (CCL3, CCL4 and CCL5) or exogenous (HIV-1 gp120) ligands prior to IAV infection. The three CC-chemokines tested reduced infectious titers between 30% to 45% upon 24 hours of infection. Eploying RT-PCR, a panel of RF mRNA levels from cells treated with CCR5 agonists was evaluated, which showed that the SAMHD1 expression was up-regulated four times over control upon exposure to CCL3, CCL4 and CCL5. We also found that IAV inhibition by CCL5 was dependent on PKC and that SAMHD1 protein levels were also increased after treatment with CCL5. In functional assays, we observed that the knockdown of SAMHD1 resulted in enhanced IAV replication in A549 cells and abolished both CCL5-mediated inhibition of IAV replication and CCL5-mediated cell death inhibition. Our data show that stimuli unrelated to interferon may trigger the upregulation of SAMHD1 and that this RF may directly interfere with IAV replication in alveolar epithelial cells.
In-Depth Profiling of T-Cell Responsiveness to Commonly Recognized CMV Antigens in Older People Reveals Important Sex Differences

The impact of biological sex on T-cell immunity to Cytomegalovirus (CMV) has not been investigated in detail with only one published study comparing CMV-specific T-cell responses in men and women. Many studies, however, have shown an association between CMV infection and immunosenescence, with broad effects on peripheral blood lymphocyte subsets as well as the T and B-cell repertoires. Here, we provide a detailed analysis of CMV-specific T-cell responses in (n=94) CMV+ older people, including 47 women and 47 men aged between 60 and 93 years. We explore sex differences with respect to 16 different CMV proteins arranged in 14 peptide pools (overlapping peptides). Following ex vivo stimulation, CD4 and CD8 T-cells producing IFN-γ, TNF, and IL-2 were enumerated by flow-cytometry (intracellular cytokine staining). T-cell responses were evaluated in terms of each cytokine separately or in terms of cytokines produced simultaneously (polyfunctionality). Surface memory phenotype and CD3 downmodulation were assessed in parallel. The polyfunctionality index and a memory subset differentiation score were used to identify associations between response size, cytokine production, polyfunctionality, and memory subset distribution. While no significant sex differences were found with respect to overall CMV target protein selection, the T-cell response in men appeared more focused and accompanied by a more prominent accumulation of CMV-specific memory CD4 and CD8 T-cells. T-cell polyfunctionality and differentiation were similar in the sexes, however, CMV-specific T-cells in men produced more pro-inflammatory cytokines. Particularly, TNF production by CD4 T-cells was stronger in men than in women. Also, compared with women, men had larger responses to CMV proteins with immediate-early/early kinetics than women, which might have been driven by CMV reactivation. In conclusion, the CMV-specific T-cell response in men was larger and more pro-inflammatory than in women. Our findings may help explain sex differences in CMV-associated pathologies.
Open Nephroureterectomy Compared to Laparoscopic in Upper Urinary Tract Urothelial Carcinoma: A Meta-Analysis

Background: In this meta-analysis, we will focus on evaluating the effects of open nephroureterectomy compared with laparoscopic nephroureterectomy on postoperative results in upper urinary tract urothelial carcinoma subjects. Methods: A systematic literature search up to January 2021 was performed, and 36 studies included 23,013 subjects with upper urinary tract urothelial carcinoma at the start of the study; of them, 8,178 were laparoscopic nephroureterectomy, and 14,835 of them were open nephroureterectomy. They were reporting relationships between the efficacy and safety of open nephroureterectomy compared with laparoscopic nephroureterectomy in the treatment of upper urinary tract urothelial carcinoma. We calculated the odds ratio (OR) or the mean difference (MD) with 95% CIs to evaluate the efficacy and safety of open nephroureterectomy compared with laparoscopic nephroureterectomy in the treatment of upper urinary tract urothelial carcinoma using the dichotomous or continuous method with a random or fixed-effect model. Results: Laparoscopic nephroureterectomy in subjects with upper urinary tract urothelial carcinoma was significantly related to longer operation time (MD, 43.90; 95% CI, 20.91–66.90, p < 0.001), shorter hospital stay (MD, −1.71; 95% CI, −2.42 to −1.00, p < 0.001), lower blood loss (MD, −133.82; 95% CI, −220.92 to −46.73, p = 0.003), lower transfusion need (OR, 0.56; 95% CI, 0.47–0.67, p < 0.001), and lower overall complication (OR, 0.79; 95% CI, 0.70–0.90, p < 0.001) compared with open nephroureterectomy. However, no significant difference was found between laparoscopic nephroureterectomy and open nephroureterectomy in subjects with upper urinary tract urothelial carcinoma in 2–5 years recurrence-free survival (OR, 0.90; 95% CI, 0.69–1.18, p = 0.46), 2–5 years cancer-specific survival (OR, 0.94; 95% CI, 0.69–1.28, p = 0.68), and 2–5 years overall survival (OR, 1.31; 95% CI, 0.91–1.87, p = 0.15). Conclusion: Laparoscopic nephroureterectomy in subjects with upper urinary tract urothelial carcinoma may have a longer operation time, shorter hospital stay, and lower blood loss, transfusion need, and overall complication compared to open nephroureterectomy. Further studies are required to validate these findings.
Obesity and Breast Cancer: A Paradoxical and Controversial Relationship Influenced by Menopausal Status

Breast cancer is the most common tumor in women worldwide, and an increasing public health concern. Knowledge of both protective and negative risk factors is essential for a better understanding of this heterogenous disease. We undertook a review of the recent literature and evaluated the relationship between obesity mediators and breast cancer development depending on menopausal status. Excess weight is now pandemic and has replaced tobacco as the main lifestyle-related risk factor for premature death. Although the prevalence of obesity/overweight has increased globally over the last 50 years, the potential harm attributable to excess fat has generally been underestimated. The relationship between overweight/obesity, breast cancer and overall risk appears to be highly dependent on menopausal status. Thus, obesity increases the risk of breast cancer in postmenopausal women but, conversely, it appears to be protective in premenopausal women. We evaluate the role of different clinical factors potentially involved in this seemingly contradictory relationship, including estrogen, mammogram density, adipokines, insulin-signaling pathway activation, and inflammatory status. A key focus of this review is to better understand the impact of body mass index and menopausal status on these clinical factors and, hence, provide some clarity into the inter-relationships involved in this controversial issue.
Air Pollution, Climate Change, and Human Health in Indian Cities: A Brief Review

Climate change and air pollution have been a matter of serious concern all over the world in the last few decades. The present review has been carried out in this concern over the Indian cities with significant impacts of both the climate change and air pollution on human health. The expanding urban areas with extreme climate events (high rainfall, extreme temperature, floods, and droughts) are posing human health risks. The intensified heat waves as a result of climate change have led to the elevation in temperature levels causing thermal discomfort and several health issues to urban residents. The study also covers the increasing air pollution levels above the prescribed standards for most of the Indian megacities. The aerosols and PM concentrations have been explored and hazardous health impacts of particles that are inhaled by humans and enter the respiratory system have also been discussed. The air quality during COVID-2019 lockdown in Indian cities with its health impacts has also been reviewed. Finally, the correlation between climate change, air pollution, and urbanizations has been presented as air pollutants (such as aerosols) affect the climate of Earth both directly (by absorption and scattering) and indirectly (by altering the cloud properties and radiation transfer processes). So, the present review will serve as a baseline data for policy makers in analyzing vulnerable regions and implementing mitigation plans for tackling air pollution. The adaptation and mitigation measures can be taken based on the review in Indian cities to reciprocate human health impacts by regular air pollution monitoring and addressing climate change as well.
Different Endurance Exercise Modalities, Different Affective Response: A Within-Subject Study

Affect experienced during an exercise session is supposed to predict future exercise behavior. However, empirical evidence reveals high variability in affective response to different exercise modalities. Thus, the purpose of the present study was to compare acute affective response and its variation during three different endurance exercise modalities: (a) moderate-intensity continuous exercise (MICE), (b) vigorous-intensity continuous exercise (VICE), and (c) high-intensity interval exercise (HIIE). Using the dual-mode theory as a theoretical framework, cognitive and interoceptive factors were considered as potential predictors of in-task affective response. In a within-subject design, 40 insufficiently active healthy participants (aged from 20 to 40 years) attended three sessions per exercise modality on a cycle ergometer. Affective valence (measured by the Feeling Scale), two cognitive factors (perceived competence and awareness of interoceptive cues), and one interoceptive factor (heart rate) were assessed before, during, and after each exercise session. Mixed models with three levels (subject, exercise session, and time point) revealed more positive affective valence during MICE compared with VICE (p < 0.001) and HIIE (p < 0.01), while there was no significant difference between the latter two. Levene's test results showed the highest variability of in-task affective valence during VICE (ps < 0.01). Regarding the course across the session, MICE was associated with a constant slight increase in affective valence from pre- to post-exercise (p < 0.05), whereas VICE and HIIE caused a decline in pleasure, followed by an affective rebound immediately after exercise termination (ps < 0.01). The highest importance of cognitive and interoceptive factors for in-task affective valence was observed in VICE (ps < 0.05). The current findings provide support for the tenets of the dual-mode theory, however, indicating that there may be differences in the affect-intensity relationship between continuous and interval exercise. In conclusion, the study results concerning previously insufficiently active individuals extend the knowledge of how exercise can positively shape affective well-being depending on exercise modality and psychophysiological influences. This knowledge enables public health practitioners to design more individualized activity recommendations, thereby improving the subjective experience of exercise.
Black Seedcoat Pigmentation Is a Marker for Enhanced Nodulation and N2 Fixation in Bambara Groundnut (Vigna Subterranea L. Verdc.) Landraces

Field studies on the effect of differing seedcoat colour on plant growth and symbiotic performance of three Bambara groundnut landraces using the 15N natural abundance technique and ureide analysis in the xylem stream and petiole extracts revealed a consistent pattern in nodule function between ureide levels and shoot δ15N values, as well as between ureide levels and percent N derived from fixation at Gbalahi, Kpalisogu, and Manga. At those three sites, where shoot δ15N was low and percent N derived from fixation high, ureide concentrations in the xylem sap and petiole extracts were also high, indicating that the two techniques were comparatively quite robust in estimating N2 fixation at a higher precision in the test Bambara groundnut landraces. A comparison of the effect of differing seedcoat pigmentation on the concentration of phenolics released by imbibed seeds showed that the Black landrace contained higher levels of flavonoids and anthocyanins, followed by the Red, and lowest in the Cream landrace. The Black landrace also recorded much higher nodule number and nodule fresh weight per plant, greater shoot biomass, lower shoot δ15N values, greater N derived from fixation, higher symbiotic N contribution, and increased water-use efficiency across all the five study sites, followed by the Red landrace, which produced the highest grain yield. Black seedcoat pigmentation in Bambara groundnut is therefore a marker for increased nodulation, N2 fixation, and plant growth that can be tapped in breeding programs for developing high N2-fixing, water-use efficient grain legumes for use by farmers in Africa.
Construction Industry Training Assessment Framework

The construction industry suffers from a lack of structured assessment methods to consistently gauge the efficacy of workforce training programs. To address this issue, this study presents a framework for construction industry training assessment that identifies established practices rooted in evaluation science and developed from a review of archival construction industry training literature. Inclusion criteria for the evaluated studies are: archival training studies focused on the construction industry workforce and integration of educational theory in training creation or implementation. Literature meeting these criteria are summarized and a case review is presented detailing assessment practices and results. The assessment practices are then synthesized with the Kirkpatrick Model to analyze how closely industry assessment corresponds with established training evaluation standards. The study culminates in a training assessment framework created by integrating practices described in the identified studies, established survey writing practices, and the Kirkpatrick Model. This study found that two-thirds of reviewed literature used surveys, questionnaires, or interviews to assess training efficacy, two studies that used questionnaires to assess training efficacy provided question text, three studies measured learning by administering tests to training participants, one study measured changed behavior as a result of training, and one study measured organizational impact as a result of training.