bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal Associations of Experienced and Perceived Community Stigma With Antiretroviral Therapy Adherence and Viral Suppression in New-to-Care People With HIV: Mediating Roles of Internalized Stigma and Depression Symptoms
Authors: Yigit Ibrahim , Turan Bulent , Kurt Gülşah , Weiser Sheri D. , Johnson Mallory O. , Mugavero Michael J. , Turan Janet M.
Published: January 2024

Background:

Although cross-sectional studies have suggested that HIV-related stigma and depression symptoms may result in poor HIV treatment and health outcomes, few studies have investigated potential longitudinal mechanisms in these relationships. Furthermore, longitudinal effects of HIV-related stigma on health outcomes have not been examined in people with HIV (PWH) newly initiating HIV clinical care. We examined longitudinal associations between experienced and perceived community stigma and health outcomes (antiretroviral therapy [ART] adherence and viral load), mediated by internalized stigma and depression symptoms among new-to-care PWH in the United States.

Setting/Methods:

Data were obtained from 371 PWH who initiated HIV medical care at 4 HIV sites at baseline and 48 weeks later between December 2013 and 2018. Validated measures were used to assess experienced stigma, perceived community stigma, internalized stigma, depression symptoms, and ART adherence, and viral load was obtained from medical records at the final study visit.

Results:

Serial mediation models revealed significant indirect effects of experienced stigma and perceived community stigma on ART adherence and on viral suppression, first through internalized stigma and then through depression symptoms.

Conclusions:

These results suggest that PWH may tend to internalize HIV-related stigma when they experience acts of stigmatization or perceive negative attitudes in society, which in turn may result in negative effects on psychological and physical well-being. These findings about how stigma in society may be an antecedent mechanism for PWH to develop internalized stigma, which in turn affects individual health outcomes, can be used to tailor both individual-level and community-level interventions.
EEG Source Imaging in Presurgical Evaluations
Authors: Ebersole John S.
Published: January 2024

Presurgical evaluations to plan intracranial EEG implantations or surgical therapies at most epilepsy centers in the United States currently depend on the visual inspection of EEG traces. Such analysis is inadequate and does not exploit all the localizing information contained in scalp EEG. Various types of EEG source modeling or imaging can provide sublobar localization of spike and seizure sources in the brain, and the software to do this with typical long-term monitoring EEG data are available to all epilepsy centers. This article reviews the fundamentals of EEG voltage fields that are used in EEG source imaging, the strengths and weakness of dipole and current density source models, the clinical situations where EEG source imaging is most useful, and the particular strengths of EEG source imaging for various cortical areas where spike/seizure sources are likely.
Setting up EEG Source Imaging in Practice
Authors: Stoub Travis R. , Stein Michael A. , Bermeo-Ovalle Adriana
Published: January 2024

Adding EEG source imaging to a clinical practice has clear advantages over visual inspection of EEG. This article offers insight on incorporating EEG source imaging into an EEG laboratory and the best practices for producing optimal source analysis results.
Single missense mutations in Vi capsule synthesis genes confer hypervirulence toSalmonellaTyphi
Authors: Lee Gi Young , Song Jeongmin
Published: January 2024

Many bacterial pathogens, including the human exclusive pathogenSalmonellaTyphi, express capsular polysaccharides as a crucial virulence factor. Here, throughS.Typhi whole genome sequence analyses and functional studies, we found a list of single point mutations that makeS. Typhi hypervirulent. We discovered a single point mutation in the Vi biosynthesis enzymes that control the length or acetylation of Vi is enough to create different capsule variants ofS.Typhi. All variant strains are pathogenic, but the hyper-capsule variants are particularly hypervirulent, as demonstrated by the high morbidity and mortality rates observed in infected mice. The hypo-capsule variants have primarily been identified in Africa, whereas the hyper-capsule variants are distributed worldwide. Collectively, these studies increase awareness about the existence of different capsule variants ofS.Typhi, establish a solid foundation for numerous future studies onS.Typhi capsule variants, and offer valuable insights into strategies to combat capsulated bacteria.
Evaluation of Microplate Handling Accuracy for Applying Robotic Arms in Laboratory Automation
Authors: Harazono Yoritaka , Shimono Haruko , Hata Kikumi , Mitsuyama Toutai , Horinouchi Takaaki
Published: January 2024

An inexpensive single-arm robot is widely utilized for recent laboratory automation solutions. The integration of a single-arm robot as a transfer system into a semi-automatic liquid dispenser without a transfer system can be realized as an inexpensive alternative to a fully automated liquid handling system. However, there has been no quantitative investigation of the positional accuracy of robot arms required to transfer microplates. In this study, we constructed a platform comprising aluminum frames and digital gauges to facilitate such measurements. We measured the position repeatability of a robot arm equipped with a custom-made finger by repeatedly transferring microplates. Further, the acceptable misalignment of plate transfer was evaluated by adding an artificial offset to the microplate position using this platform. The results of these experiments are expected to serve as benchmarks for the selection of robot arms for laboratory automation in biology. Furthermore, all information for replicating this device will be made publicly available, thereby allowing many researchers to collaborate and accumulate knowledge, hopefully contributing to advances in this field.
Enhancing Sustainable Agriculture in Sub-Saharan Africa: The Potentials of Entomopathogenic Nematodes for Pest Control
Authors: Nosa Osawe
Published: January 2024

Entomopathogenic nematodes (EPNs) are a type of soil-dwelling nematodes with a remarkable ability to infect insect pests. Their employment for control of pests is a means to foster sustainable agricultural practices. These environmentally safe alternatives to pesticides are being researched in Sub-Saharan Africa (SSA), but there are many gaps to be filled, which this review exposes. The systematic analysis of peer-reviewed articles from 2003 to 2022 shows that about 56% of published articles on EPNs in Sub-Saharan Africa (SSA) come from studies in South Africa. In SSA, applied pest management studies of these nematodes have focused on Lepidopteran (41.7%), Coleopteran (22.2%), and Hemipteran (18.1%) pests, withCydiasp.,Planococcussp., andThaumatotibiasp. being the most targeted genera. Many areas in SSA remain unexplored for EPNs and knowledge of their use is still experimental. There is a paucity of knowledge regarding the bacteria symbionts of indigenous EPNs in SSA, with the possibility of variations in bacterial symbionts being associated with specific ecological populations. However, promising strides have been made, and further surveys are needed to explore untapped geographies. Utilizing native EPN species holds promise in curbing the reliance on hazardous pesticides and promoting integrated pest management approaches in SSA, representing a sustainable method for pest control.
Major role of S-glycoprotein in providing immunogenicity and protective immunity in mRNA lipid nanoparticle vaccines based on SARS-CoV-2 structural proteins
Authors: Bykonia Evgeniia N. , Kleymenov Denis A. , Gushchin Vladimir A. , Sinyavin Andrey E. , Mazunina Elena P. , Kuznetsova Nadezhda A. , Kozlova Sofia R. , Zolotar Anastasia N. , Shidlovskaya Elena V , Usachev Evgeny V. , Pochtovyi Andrei A. , Kustova Daria D , Ivanov Igor A. , Dmitriev Sergey E. , Ivanov Roman A. , Logunov Denis Y. , Gintsburg Alexander L.
Published: January 2024

Recently we have developed an mRNA lipid nanoparticle (mRNA-LNP) platform providing efficient long-term expression of an encoded genein vivoafter both intramuscular and intravenous application. Based on this platform, we have generated mRNA-LNP coding SARS-CoV-2 structural proteins M, N, S from different virus variants and studied their immunogenicity separately or in combinationsin vivo. As a result, all candidate vaccine compositions coding S and N proteins induced excellent anti-RBD and N titers of binding antibodies. T cell responses mainly represented specific CD4+ T cell lymphocyte producing IL-2 and TNF-α. mRNA-LNP coding M protein did not show high immunogenicity. High neutralizing activity was detected in sera of mice vaccinated with mRNA-LNP coding S protein (alone or in combinations) against closely related strains but was not detectable or significantly lower against an evolutionarily distant variant. Our data showed that the addition of mRNAs encoding S and M antigens to the mRNA-N in the vaccine composition enhanced immunogenicity of mRNA-N inducing more robust immune response to the N protein. Based on our results, we suggested that the S protein plays a key role in enhancement of immune response to the N protein in the mRNA-LNP vaccine.
SORBET: Automated cell-neighborhood analysis of spatial transcriptomics or proteomics for interpretable sample classification via GNN
Authors: Shimonov Shay , Cunningham Joseph M , Talmon Ronen , Aizenbud Lilach , Desai Shruti J , Rimm David , Schalper Kurt , Kluger Harriet , Kluger Yuval
Published: January 2024

Spatially resolved transcriptomics or proteomics data have the potential to contribute fundamental insights into the mechanisms underlying physiologic and pathological processes. However, analysis of these data capable of relating spatial information, multiplexed markers, and their observed phenotypes remains technically challenging. To analyze these relationships, we developed SORBET, a deep learning framework that leverages recent advances in graph neural networks (GNN). We apply SORBET to predict tissue phenotypes, such as response to immunotherapy, across different disease processes and different technologies including both spatial proteomics and transcriptomics methods. Our results show that SORBET accurately learns biologically meaningful relationships across distinct tissue structures and data acquisition methods. Furthermore, we demonstrate that SORBET facilitates understanding of the spatially-resolved biological mechanisms underlying the inferred phenotypes. In sum, our method facilitates mapping between the rich spatial and marker information acquired from spatial ‘omics technologies to emergent biological phenotypes. Moreover, we provide novel techniques for identifying the biological processes that comprise the predicted phenotypes.
Integrative mapping reveals molecular features underlying the mechanism of nucleocytoplasmic transport
Authors: Raveh Barak , Eliasian Roi , Rashkovits Shaked , Russel Daniel , Hayama Ryo , Sparks Samuel , Singh Digvijay , Lim Roderick , Villa Elizabeth , Rout Michael P , Cowburn David , Sali Andrej
Published: January 2024

Nuclear Pore Complexes (NPCs) enable rapid, selective, and robust nucleocytoplasmic transport. To explain how transport emerges from the system components and their interactions, we used experimental data and theoretical information to construct an integrative Brownian dynamics model of transport through an NPC, coupled to a kinetic model of transport in the cell. The model recapitulates key aspects of transport for a wide range of molecular cargos, including pre-ribosomes and viral capsids. It quantifies how flexible phenylalanine-glycine (FG) repeat proteins raise an entropy barrier to passive diffusion and how this barrier is selectively lowered in facilitated diffusion by the many transient interactions of nuclear transport receptors with the FG repeats. Selective transport is enhanced by "fuzzy" multivalent interactions, redundant FG repeats, coupling to the energy-dependent RanGTP concentration gradient, and exponential dependence of transport kinetics on the transport barrier. Our model will facilitate rational modulation of the NPC and its artificial mimics.
Plaat1l1 controls feeding induced NAPE biosynthesis and contributes to energy balance regulation in zebrafish
Authors: Mashhadi Zahra , Yin Linlin , Dosoky Noura S. , Chen Wenbiao , Davies Sean S.
Published: January 2024

Dysregulation of energy balance leading to obesity is a significant risk factor for cardiometabolic diseases such as diabetes, non-alcoholic fatty liver disease and atherosclerosis. In rodents and a number of other vertebrates, feeding has been shown to induce a rapid rise in the intestinal levels ofN-acyl-ethanolamines (NAEs) and the chronic consumption of a high fat diet abolishes this rise. Administering NAEs to rodents consuming a high fat diet reduces their adiposity, in part by reducing food intake and enhancing fat oxidation, so that feeding-induced intestinal NAE biosynthesis appears to be critical to appropriate regulation of energy balance. However, the contribution of feeding-induced intestinal NAE biosynthesis to appropriate energy balance remains poorly understood because the specific enzymes responsible for feeding-induced NAE biosynthesis have not been identified. The rate-limiting step in the intestinal biosynthesis of NAEs is formation of their immediate precursors, theN-acyl-phosphatidylethanolamines (NAPEs), by phosphatidylethanolamineN-acyltransferases (NATs). At least six NATs are found in humans and multiple homologs of these NATs are found in most vertebrate species. In recent years, the fecundity and small size of zebrafish (Danio rerio), as well as their similarities in feeding behavior and energy balance regulation with mammals, have led to their use to model key features of cardiometabolic disease. We therefore searched theDanio reriogenome to identify all NAT homologs and found two additional NAT homologs besides the previously reportedplaat1,rarres3, andrarres3l, and used CRISPR/cas9 to delete these two NAT homologs (plaat1l1andplaat1l2). While wild-type fish markedly increased their intestinal NAPE and NAE levels in response to a meal after fasting, this response was completely ablated inplaat1l1-/-fish.Furthermore,plaat1l1-/-fish fed a standard flake diet had increased weight gain and glucose intolerance compared to wild-type fish. The results support a critical role for feeding-induced NAE biosynthesis in regulating energy balance and suggest that restoring this response in obese animals could potentially be used to treat obesity and cardiometabolic disease.
Four Years of COVID-19: Saudi Arabia, Egypt and Pakistan Have the Highest Research Growth Rates From 2020-2023
Authors: Hassan Waseem , Zafar Mehreen
Published: January 2024

We tried to assess the global research scholarly output after COVID-19 (from 2020 to 2023). Based on Scopus record, the world has produced 15, 041, 579 publications with 86, 165, 933 citations. We analyzed those countries, which have published at least 150, 000 research papers. For each country, we retrieved total number of publications, % growth rate, total citations, citations per paper, Field Weighted Citation Impact (FWCI), and % international collaboration. Twenty-seven (n=27) countries were found to be highly productive, with China leading the way in number of publications. Citation metrics are dominated by the USA, China, and European countries. Specifically, Switzerland, Netherlands, and Australia are notable for their high impact and influence. Saudi Arabia achieved the highest growth rate of 53.5%, and highest international collaboration (76.5%). Infact Saudi Arabia also attained high citations per article (8.8), and an FWCI of 1.63. While, Pakistan exhibited an 8.4 citations per article, FWCI of 1.54, growth rate of 34.9%, and collaborative percentage of 64.9%. Egypt also attained the 2ndhighest growth rate (n=36.1). Based on four (n=4) distinct performance metrics, Pakistan and Saudi Arabia were in the top ten group.
Metatranscriptomic analysis indicates prebiotic effect of Isomalto/malto-polysaccharides on human colonic microbiotain-vitro
Authors: Borewicz Klaudyna , Hornung Bastian , Gu Fangjie , van der Zaal Pieter H. , Schols Henk A. , Schaap Peter J. , Smidt Hauke
Published: January 2024

Isomalto/malto-polysaccharides (IMMPs) are a novel type of soluble dietary fibres with a prebiotic potential promoting growth of beneficial microbes in the gut. However, the mode of action of IMMPs remains unknown. Previous studies on IMMPs showed an increase in total bacteria, especially lactobacilli, and higher production of short chain fatty acids (SCFA) when IMMPs were fed to rats or used duringin vitrofermentation. Here we investigated with metatranscriptomics how IMMPs with different amounts of α-(1→6) glycosidic linkages affected microbial function during incubation with human faecal inoculum. We showed that active microbial community dynamics during fermentation varied depending on the type of IMMP used and that the observed changes were reflected in the community gene expression profiles. Based on metatranscriptome analysis, members ofBacteroides,LactobacillusandBifidobacteriumwere the predominant degraders of IMMPs, and the increased gene expression in these bacteria correlated with high amounts of α-(1→6) glycosidic linkages. We also noted an increase in relative abundance of these bacteria and an activation of pathways involved in SCFA synthesis. Our findings could provide a baseline for more targeted approaches in designing prebiotics for specific bacteria and to achieve more controlled modulation of microbial activity towards desired health outcomes.
GTPase-activating protein ARAP1 regulates circular dorsal ruffles as a nutrient uptake mechanism in the Hep3B hepatocellular carcinoma cell line
Authors: Sun Xiaowei , Li Yanan , He Yuxin , Cheng Longjiao , Wei Jinzi , Du Linxuan , Shen Zhongyang , Yoshida Sei
Published: January 2024

Circular dorsal ruffles (CDRs), large-scale rounded membrane ruffles, function as precursors of macropinocytosis. We recently reported that CDRs are exposed in the Hep3B hepatocellular carcinoma cell line, while not in other hepatocellular carcinoma cell lines, indicating that the CDRs in Hep3B are associated with malignant potential. In this study, we investigated the cellular function of CDRs in Hep3B cells by focusing on the molecular mechanisms of the GTPase-activating protein ARAP1. ARAP1 was localized to the CDRs, the sizes of which were reduced by deletion of this protein. High-resolution scanning electron micrographs revealed that CDRs comprise small vertical lamellipodia, the expression pattern of which was disrupted in ARAP1 KO cells. Extracellular solute uptake, rate of cell growth, and malignant potential were attenuated in the KO cells. ARAP1 is also localized in Hep3B cell mitochondria, although not in those of the Huh7 hepatocellular carcinoma cell line. On the basis of these findings, we propose that the aberrant expression of ARAP1 in Hep3B cells modulates CDRs, thereby resulting in an excess uptake of nutrients as an initial event in cancer development.

SUMMARY STATEMENT

ARAP1 regulates circular dorsal ruffles (CDRs) in the Hep3B HCC cell line and deletion of this protein attenuates malignant potential, thereby indicating the involvement of CDRs in cancer development.
Imaging spectroscopy reveals topographic variability effects on grassland functional traits and drought responses
Authors: Dao Phuong D. , He Yuhong , Lu Bing , Axiotis Alexander
Published: January 2024

Functional traits and their variations are essential indicators of plant metabolism, growth, distribution, and survival and determine how a plant and an ecosystem function. Under the same climatic condition, traits can vary largely between species and within the same species growing in different topographic conditions. When drought stress occurs, plants that grow in these conditions may respond differently as their topography-driven tolerance and adaptability differ. Insights into topographic variability-driven trait variation and drought response can improve our prediction of ecosystem functioning and ecological impacts. Imaging spectroscopy allows accurate detection of plant species, retrieval of functional traits, and characterization of topography-driven and drought impacts on trait variation across space. However, the use of this data in a heterogeneous grassland ecosystem is challenging as species are small, high mixed, spectrally and texturally similar, and highly varied with small-scale variation in topography. In this paper, we introduce the first study that explores the use of high-resolution airborne imaging spectroscopy to characterize the variation of common traits, including chlorophylls (Chl), carotenoids (Car), Chl/Car ratio, water content (WC), and leaf area index (LAI), across topographic gradients and under drought stress at the species level in a heterogeneous grassland. The results reveal that there were significant relationships between functional traits and topographic variability, and the degree of the relationships deferred among species and under different environmental conditions. The results also show that drought-induced trait responses varied significantly within and between species, especially between drought-tolerant invasive species and native species, between lower and upper slope positions. The study contributes greatly to the advancement in understanding biological and ecological processes for a better prediction of ecosystem functioning under stressed environments.
Beige adipose tissue-derived extracellular vesicles: a potent metabolic regulator and a novel remedy for nonalcoholic fatty liver disease
Authors: Zhang Kai , Zhang Sha , Sui Bing-Dong , Yuan Yuan , Liu Lu , Ying Si-Qi , Li Cheng-Han , Zhang Kai-Chao , Xing Shu-Juan , Yang Zhi-Wei , Sun Yang , Yu Li-Juan , Liu Jin , Jin Yan , Zheng Chen-Xi , Kong Liang
Published: January 2024

Adipose tissue (AT) is an essential metabolic and endocrine organ, which are categorized into the white adipose tissue (WAT) and the brown adipose tissue (BAT), as well as the beige adipose tissue (BeAT) that derives from WAT browning. Notably, extracellular vesicles (EVs), especially tissue-produced EVs, have been recognized to be critical players in multiple physiological and pathophysiological settings and provide efficient strategy for disease treatment. However, little is known about the BeAT-derived EVs (BeEVs). In this study, we induced BeEV formation by cold stimulation and extracted EVs from three kinds of ATviaenzyme digestion combined with gradient centrifugation. The isolated BeEVs possess typical morphological, structural and marker characteristics of EVs. Proteomics analysis further demonstrated that the BeEVs hold a distinct protein profile while are enriched with multiple metabolic regulatory proteins. Importantly, systemic injection of BeEVs into mice improved metabolic dysfunction in a nonalcoholic fatty liver disease (NAFLD) model induced by high-fat diet (HFD). Moreover, we demonstrated that the BeEVs alleviated liver steatosisviadecreasing the lipogenesis. These findings promote the understanding of AT-EVs and shed light on the isolation, identification and applications of BeEVs as a potent metabolic regulator and novel remedy for metabolic diseases.
Transoceanic pathogen circulation in the age of sail and steam
Authors: Blackmore Elizabeth N. , Lloyd-Smith James O.
Published: January 2024

In the centuries following Christopher Columbus’s 1492 voyage to the Americas, transoceanic travel opened unprecedented pathways for global pathogen circulation. Yet no biological transfer is a single, discrete event. We use mathematical modeling to quantify historical risk of shipborne pathogen introduction, exploring the respective contributions of journey time, ship size, population susceptibility, transmission intensity, density dependence, and pathogen biology. We contextualize our results using port arrivals data from San Francisco, 1850–1852, and from a selection of historically significant voyages, 1492–1918. We offer numerical estimates of introduction risk across historicallyrealistic ranges of journey time and ship population size, and show that both steam travel and shipping regimes that involved frequent, large-scale movement of people substantially increased risk of transoceanic pathogen circulation.
Image-Based Recognition of Parasitoid Wasps Using Advanced Neural Networks
Authors: Shirali Hossein , Hübner Jeremy , Both Robin , Raupach Michael , Schmidt Stefan , Pylatiuk Christian
Published: January 2024

Hymenoptera have some of the highest diversity and number of individuals among insects. Many of these species potentially play key roles as food sources, pest controllers, and pollinators. However, little is known about their diversity and biology, and about 80% of the species have not been described yet. Classical taxonomy based on morphology is a rather slow process, but DNA barcoding has already brought considerable progress in identification. Innovative methods such as image-based identification and automation can even further speed up the process. We present a proof of concept for image data recognition of a parasitic wasp family, the Diapriidae (Hymenoptera), obtained as part of the GBOL III project. These tiny (1.2 - 4.5 mm) wasps were photographed and identified using DNA barcoding to provide a solid ground truth for training a neural network. Subsequently, three different neural network architectures were trained, evaluated, and optimized. As a result, 11 different classes of diaprids and one class of “other Hymenoptera ’’ can be classified with an average accuracy of 96%. Additionally, the sex of the specimen can be classified automatically with an accuracy of > 96%.
Identifying Factors Important for Conservation at Sites of Synonymous Variations
Authors: Ramasubramanian Abhirami , Sunderam Uma , Srinivasan Rajgopal
Published: January 2024

Synonymous mutations can have a deleterious effect leading to disease, even though they are not protein altering. Variations at genomic sites leading to synonymous variants are frequently highly conserved across species. Several prediction methods have been developed to assess the impact of synonymous mutations and are highly dependent on having validated sets of both deleterious and benign synonymous mutations. However, validated data available for deleterious synonymous mutations is sparse unlike for missense mutations. Rather than develop a model for predicting pathogenicity of synonymous variants, we seek to understand the relative importance of various factors that lead to conservation at sites of synonymous variants. Our study built machine learning models using various features on a large set of reported and generated synonymous variants (Zeng Z et al, 2019) to predict conservation (Genomic Evolutionary Rate Profiling – Rejected Substitution (GERP RS) base scores and Phylogenetic p-values for 100 vertebrates (PP100)) at genomic sites. We used the extreme gradient boosting classifier to classify sites as high, medium and low conservation at different cutoffs. Our experiments report an AUC between 0.74-0.79 and the sensitivity was significant. Of the features we explored, a few alternate allele independent properties were repeatedly flagged as having high impact. These findings provide information for predictors to further improve models for synonymous variant impact.
Disruption of consciousness depends on insight in OCD and on positive symptoms in schizophrenia
Authors: Tumkaya Selim , Yücens Bengü , Gündüz Muhammet , Maheu Maxime , Berkovitch Lucie
Published: January 2024

Disruption of conscious access contributes to the advent of psychotic symptoms in schizophrenia but could also explain lack of insight in other psychiatric disorders.

In this study, we explored how insight and psychotic symptoms related to disruption of consciousness. We explored consciousness in patients with schizophrenia, patients with obsessive-compulsive disorder (OCD) with good vs. poor insight and matched controls. Participants underwent clinical assessments and performed a visual masking task allowing us to measure individual consciousness threshold. We used a principal component analysis to reduce symptom dimensionality and explored how consciousness measures related to symptomatology.

We found that clinical dimensions could be well summarized by a restricted set of principal components which also correlated with the extent of consciousness disruption. More specifically, positive symptoms were associated with impaired conscious access in patients with schizophrenia whereas the level of insight delineated two subtypes of OCD patients, those with poor insight who had consciousness impairments similar to patients with schizophrenia, and those with good insight who resemble healthy controls.

Our study provides new insights about consciousness disruption in psychiatric disorders, showing that it relates to positive symptoms in schizophrenia and with insight in OCD. In OCD, it revealed a distinct subgroup sharing neuropathological features with schizophrenia. Our findings refine the mapping between symptoms and cognition, paving the way for a better treatment selection.
Patient-Derived Tumor Organoid and Fibroblast Assembloid Models for interrogation of the tumor microenvironment in Esophageal Adenocarcinoma
Authors: Sharpe Benjamin P. , Nazlamova Liliya A. , Tse Carmen , Johnston David A. , Blyth Rhianna , Pickering Oliver J. , Grace Ben , Harrington Jack , Rajak Rushda , Rose-Zerilli Matthew , Walters Zoe S. , Underwood Tim J.
Published: January 2024

The tumor microenvironment (TME) comprises all non-tumor elements of cancer and strongly influences disease progression and phenotype. To understand tumor biology and accurately test new therapeutic strategies, representative models should contain both tumor cells and normal cells of the TME. Here we describe and characterize co-culture tumor-derived organoids and cancer-associated fibroblasts (CAFs), a major component of the TME, in matrix-embedded assembloid models of esophageal adenocarcinoma (EAC). We demonstrate that the assembloid models faithfully recapitulate the differentiation status of EAC and different CAF phenotypes found in the EAC patient TME. We evaluate cell phenotypes by combining tissue clearing techniques with wholemount immunofluorescence and histology, providing a practical framework for characterization of cancer assembloids.
Beyond benchmarking: towards predictive models of dataset-specific single-cell RNA-seq pipeline performance
Authors: Fang Cindy , Selega Alina , Campbell Kieran R
Published: January 2024

The advent of single-cell RNA-sequencing (scRNA-seq) has driven significant computational methods development for all steps in the scRNA-seq data analysis pipeline, including filtering, normalization, and clustering. The large number of methods and their resulting parameter combinations has created a combinatorial set of possible pipelines to analyze scRNA-seq data, which leads to the obvious question: which is best? Several benchmarking studies have sought to compare methods to answer this, but frequently find variable performance depending on dataset and pipeline characteristics. Alternatively, the large number of publicly available scRNA-seq datasets along with advances in supervised machine learning raise a tantalizing possibility: could the optimal pipeline be predicted for a given dataset? Here we begin to answer this question by applying 288 scRNA-seq analysis pipelines to 86 datasets and quantifying pipeline success via a range of measures evaluating cluster purity and biological plausibility. We build supervised machine learning models to predict pipeline success given a range of dataset and pipeline characteristics. We find both that prediction performance is significantly better than random and that in many cases pipelines predicted to perform well provide clustering outputs similar to expert-annotated cell type labels. Finally, we identify characteristics of scRNA-seq datasets that correlate with strong prediction performance that could guide when such prediction models may be useful.
Experimental evaluation of Eastern box turtle (Terrapene carolina carolina) detectability in visual search surveys
Authors: Heinle William , Beswick Noelle , Wapman Emily , Royle J. Andrew
Published: January 2024

Understanding how detection probability varies over time, space, or in response to measurable covariates is important to inform the monitoring and assessment of many species. A standard model to understand detectability – the availability/perception model – admits that detection probability is the composite of two components: availability and perception. Availability is largely affected by environmental and behavioral factors, whereas perception is primarily affected by attributes of individual observers and survey protocols, and thus can potentially be partially controlled by survey design. We designed and implemented a field study to understand the perception component of detection for Eastern box turtles (Terrapene carolina carolina) using visual encounter surveys. We obtained and deployed museum specimens of Eastern box turtle shells and subjected them to visual search surveys by observers in realistic field situations. Overall, about 50% of the box turtle shells were detected by observers including, 41.5% in the ‘partially visible’ state and 63% in the ‘fully visible’ state. There were significant differences among observers, which may be due to observer-specific variation in search technique -- the observers varied in how well they achieved the protocol guidance.
FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA
Authors: Liu Yaping , Reed Sarah C. , Lo Christopher , Choudhury Atish D. , Parsons Heather A. , Stover Daniel G. , Ha Gavin , Gydush Gregory , Rhoades Justin , Rotem Denisse , Freeman Samuel , Katz David , Bandaru Ravi , Zheng Haizi , Fu Hailu , Adalsteinsson Viktor A. , Kellis Manolis
Published: January 2024

Analysis of DNA methylation in cell-free DNA (cfDNA) reveals clinically relevant biomarkers but requires specialized protocols and sufficient input material that limits its applicability. Millions of cfDNA samples have been profiled by genomic sequencing. To maximize the gene regulation information from the existing dataset, we developed FinaleMe, a non-homogeneous Hidden Markov Model (HMM), to predict DNA methylation of cfDNA and, therefore, tissues-of-origin directly from plasma whole-genome sequencing (WGS). We validated the performance with 80 pairs of deep and shallow-coverage WGS and whole-genome bisulfite sequencing (WGBS) data.
Architecture and infection-sensing mechanism of the bacterial PARIS defense system
Authors: Deep Amar , Liang Qishan , Enustun Eray , Pogliano Joe , Corbett Kevin D.
Published: January 2024

Bacteria and the viruses that infect them (bacteriophages or phages) are engaged in an evolutionary arms race that has resulted in the development of hundreds of bacterial defense systems and myriad phage-encoded counterdefenses1–5. While the mechanisms of many bacterial defense systems are known1, how these systems avoid toxicity outside infection yet activate quickly upon sensing phage infection is less well understood. Here, we show that the bacterialPhageAnti-Restriction-InducedSystem (PARIS) operates as a toxin-antitoxin system, in which the antitoxin AriA sequesters and inactivates the toxin AriB until triggered by the T7 phage counterdefense protein Ocr. Using cryoelectron microscopy (cryoEM), we show that AriA is structurally similar to dimeric SMC-family ATPases but assembles into a distinctive homohexameric complex through two distinct oligomerization interfaces. In the absence of infection, the AriA hexamer binds up to three monomers of AriB, maintaining them in an inactive state. Ocr binding to the AriA-AriB complex triggers rearrangement of the AriA hexamer, releasing AriB and allowing it to dimerize and activate. AriB is a toprim/OLD-family nuclease whose activation arrests cell growth and inhibits phage propagation by globally inhibiting protein translation. Collectively, our findings reveal the intricate molecular mechanisms of a bacterial defense system that evolved in response to a phage counterdefense protein, and highlight how an SMC-family ATPase has been adapted as a bacterial infection sensor.
Deciphering the molecular mechanisms underlying anti-pathogenic potential of a polyherbal formulation Enteropan®against multi-drug resistantPseudomonas aeruginosa
Authors: Parmar Sweety , Gajera Gemini , Thakkar Nidhi , Palep Hanmanthrao S , Kothari Vijay
Published: January 2024

Anti-pathogenic potential of a polyherbal formulation Enteropan®was investigated against a multidrug resistant strain of the bacteriumPseudomonas aeruginosa. Enteropan-pre-exposedP. aeruginosadisplayed reduced (∼70%↓) virulence towards the model hostCaenorhabditis elegans. Enteropan affected various traits like biofilm formation, protein synthesis and secretion, quorum-modulated pigment production, antibiotic susceptibility, nitrogen metabolism etc. in this pathogen.P. aeruginosacould not develop complete resistance to the virulence-attenuating activity of Enteropan even after repeated exposure to this polyherbal formulation. Whole transcriptome analysis showed 17% ofP. aeruginosagenome to get differentially expressed under influence of Enteropan. Major mechanisms through which Enteropan exerted its anti-virulence activity were found to be generation of nitrosative stress, oxidative stress, envelop stress, quorum modulation, disturbance of protein homeostasis and metal homeostasis. Network analysis of the differently expressed genes resulted in identification of 10 proteins with high network centrality as potential targets from among the down-regulated genes. Differential expression of genes coding for five (rpoA, tig, rpsB, rpsL, andrpsJ) of these targets was validated through RT-PCR too, and they can further be pursued as potential targets by various drug discovery programmes.
First evidence of a causal link between genetic variation and thermal adaptation in a schistosome host snail
Authors: Maes Tim , Verheyen Julie , Senghor Bruno , Mudavanhu Aspire , Schols Ruben , Hellemans Bart , Geslain Enora , Volckaert Filip A.M. , Gante Hugo F. , Huyse Tine
Published: January 2024

Freshwater snails are pivotal in transmitting schistosomiasis, a tropical parasitic disease affecting over 150 million people. The adaptive potential of these snails is a critical factor in determining how climate change and other environmental factors influence disease transmission dynamics, yet it has remained unexplored.Bulinus truncatusis the schistosome intermediate host snail with the widest geographic distribution and therefore plays a pivotal role in determining the maximum range of urogenital schistosomiasis. In this study, we assessed the local adaptation capacity ofB. truncatusto temperature through an integrative approach encompassing phenotypic, ecophysiological, and genomic data. Ten snail populations from diverse thermal environments were collected in three countries, with eight populations reared in a common garden. The F2 generation (total N= 2592) was exposed to eight chronic temperature treatments and various life-history traits were recorded for over 14 weeks. Subsequently, ecophysiological analyses were conducted on the ten last surviving snails per population. Genotyping the parental generation collected in the field using a genotyping-by-sequencing (GBS) approach, revealed 12,875 single nucleotide polymorphisms (SNPs), of which 4.91 % were potentially under selection. We observed a significant association between these outlier SNPs, temperature, and precipitation. Thermal adaptations in life-history traits were evident, with lower survival rates at high temperatures of warm- origin snails compensated for by higher reproduction rates. Cold-origin snails, on the other hand, exhibited higher growth rates adapted to a shorter growing season. Ecophysiological adaptations included elevated sugar and haemoglobin contents in cold-adapted snails. In contrast, warm-adapted snails displayed increased protein levels but also more oxidative damage. Furthermore, heightened phenoloxidase levels indicated a more robust immune response in snails from parasite-rich regions. The substantial local adaptation capacity ofB. truncatusholds profound implications for its response to climate change, future schistosomiasis risk, and the effectiveness of schistosomiasis control measures.

Highlights

Local adaptation influences species’ responses to climate change

The snailBulinus truncatusshowed a high thermal local adaptation (LA) potential

LA is apparent through variations in life history and ecophysiological traits

We identified a significant genetic basis underlying this LA

LA of the hosts could sustain schistosomiasis transmission under global warming
Metabolic heterogeneity of colorectal cancer as a prognostic factor: insights gained from fluorescence lifetime imaging
Authors: Komarova Anastasia D , Sinyushkina Snezhana D , Shchechkin Ilia D , Druzhkova Irina N , Smirnova Sofia A , Terekhov Vitaliy M , Mozherov Artem M , Ignatova Nadezhda I , Nikonova Elena E , Shirshin Evgeny A , Shimolina Liubov E , Gamayunov Sergey V , Shcheslavskiy Vladislav I , Shirmanova Marina V
Published: January 2024

Heterogeneity of tumor metabolism is an important, but still poorly understood aspect of tumor biology. Present work is focused on the visualization and quantification of cellular metabolic heterogeneity of colorectal cancer using fluorescence lifetime imaging (FLIM) of redox cofactor NAD(P)H. FLIM-microscopy of NAD(P)H was performed in vitro in four cancer cell lines, in vivo in the four types of tumors in mice and ex vivo in patients’ tumor samples. The dispersion and bimodality of the decay parameters were evaluated to quantify the intercellular metabolic heterogeneity. Our results demonstrate that patients’ tumors have significantly higher heterogeneity of energy metabolism compared with cultured cells and tumor xenografts, which was displayed as a wider and frequently bimodal distribution of a contribution of a free (glycolytic) fraction of NAD(P)H within a sample. Among patients’ tumors, the dispersion was larger in the high-grade and early stage ones, without, however, any association with bimodality. These results indicate that cell-level metabolic heterogeneity assessed from NAD(P)H FLIM has a potential to become a clinical prognostic factor.
Generative whole-brain dynamics models from healthy subjects predict functional alterations in stroke at the level of individual patients
Authors: Idesis Sebastian , Allegra Michele , Vohryzek Jakub , Yonatan Sanz Perl , Metcalf Nicholas V. , Griffis Joseph C. , Corbetta Maurizio , Shulman Gordon L. , Deco Gustavo
Published: January 2024

Computational whole-brain models describe the resting activity of each brain region based on a local model, inter-regional functional interactions, and a structural connectome that specifies the strength of inter-regional connections. Strokes damage the healthy structural connectome that forms the backbone of these models and produce large alterations in inter-regional functional interactions. These interactions are typically measured by correlating the timeseries of activity between two brain regions, so-called resting functional connectivity. We show that adding information about the structural disconnections produced by a patient’s lesion to a whole-brain model previously trained on structural and functional data from a large cohort of healthy subjects predicts the resting functional connectivity of the patient about as well as fitting the model directly to the patient’s data. Furthermore, the model dynamics reproduce functional connectivity-based measures that are typically abnormal in stroke patients as well as measures that specifically isolate these abnormalities. Therefore, although whole-brain models typically involve a large number of free parameters, the results show that even after fixing those parameters, the model reproduces results from a population very different than the population on which the model was trained. In addition to validating the model, these results show that the model mechanistically captures relationships between the anatomical structure and functional activity of the human brain.
Rare genetic variation in Fibronectin 1 (FN1) protects againstAPOEe4in Alzheimer’s disease
Authors: Bhattarai Prabesh , Gunasekaran Tamil Iniyan , Reyes-Dumeyer Dolly , Jülich Dörthe , Tayran Hüseyin , Yilmaz Elanur , Flaherty Delaney , Lantigua Rafael , Medrano Martin , Rivera Diones , Recio Patricia , Ertekin-Taner Nilüfer , Teich Andrew F , Dickson Dennis W , Holley Scott , Mayeux Richard , Kizil Caghan , Vardarajan Badri N
Published: January 2024

The risk of developing Alzheimer’s disease (AD) significantly increases in individuals carrying theAPOEε4allele. Elderly cognitively healthy individuals withAPOEε4also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects ofAPOEε4; however, these mechanisms are unknown. We hypothesized thatAPOEε4carriers without dementia might carry genetic variations that could protect them from developingAPOEε4-mediated AD pathology. To test this, we leveraged whole genome sequencing (WGS) data in National Institute on Aging Alzheimer’s Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffectedAPOEε4carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms,(FN1)and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood-brain barrier (BBB), for postmortem validation andin vivofunctional studies. The FN1 and COL6A2 protein levels were increased at the BBB inAPOEε4carriers with AD. Brain expression of cognitively unaffected homozygousAPOEε4carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygousAPOEε4carriers with AD, suggesting that FN1 might be a downstream driver ofAPOEε4-mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations infn1b– the ortholog for humanFN1. We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated withFN1LOF. Our study suggests vascular deposition of FN1 is related to the pathogenicity ofAPOEε4, LOF variants in FN1 may reduceAPOEε4-related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.