bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interpretable deep learning framework for understanding molecular changes in human brains with Alzheimer’s disease: implications for microglia activation and sex differences
Authors: Trivedi Maitry Ronakbhai , Joshi Amogh Manoj , Shah Jay , Readhead Benjamin P , Wilson Melissa A , Su Yi , Reiman Eric M , Wu Teresa , Wang Qi 
Published: December 2023

AbstractINTRODUCTIONThe objective of this study is to characterize the dysregulation of gene expression in AD affected brain tissues through an interpretable deep learning framework.METHODSWe trained multi-layer perceptron models for the classification of neuropathologically confirmed AD vs. controls using transcriptomic data from three brain regions of ROSMAP study. The disease spectrum was then modeled as a progressive trajectory. SHAP value was derived to explain model predictions and identify significantly implicated genes for subsequent gene co-expression network analysis.RESULTSThe models achieved excellent performance in classification and prediction in two external datasets from Mayo RNA-seq cohort and Mount Sinai Brain Bank cohort. SHAP explainer revealed common and specific transcriptomic signatures from different brain regions.DISCUSSIONWe identified common gene signatures among different brain regions in microglia and sex specific modules in neurons implicated in AD. This work paves the way for utilizing artificial intelligence approaches in studying AD at the molecular level.Research-in-ContextSystematic review: Postmortem brain transcriptomes have been analyzed to study the molecular changes associated with Alzheimer’s disease, usually by a direct contrast approach such as differential gene expression analysis. Nuanced gene regulatory networks thus cannot be easily pinpointed from convoluted data such as those from bulk-tissue profiling. We applied a novel interpretable deep learning approach to dissect the RNA-seq data collected from three different brain regions of a large clinical cohort and identified significant genes for network analysis implicated for AD.Interpretation: Our models successfully predicted neuropathological and clinical traits in both internal and external validations. We corroborated known microglial biology in addition to revealing novel sex chromosome-linked gene contributing to sex dimorphism in AD.Future directions: The framework could have broad utility for interpreting multi-omic data such as those from single-cell profiling, to advance our understanding of molecular mechanisms of complex human disease such as AD.HighlightsWe applied novel interpretable deep learning methods to postmortem brain transcriptomes from three different brain regionsWe interpreted the models to identify genes most strongly implicated in ADNetwork analysis corroborated known microglial biology and revealed novel sex specific transcriptional factors associated with neuronal loss in AD
Re-coding of G protein-coupled receptor signaling enables emergent cellular behavior
Authors: Dehkhoda Farhad , Ringuet Mitchell T. , Whitfield Emily A. , Mutunduwe Keith , Nowell Cameron J. , Misganaw Desye , Xu Zheng , Hossain Akhter M. , Fothergill Linda J. , McDougall Stuart J. , Furness John B. , Furness Sebastian G.B. 
Published: December 2023

SummaryAll cells face the challenge of integrating multiple extracellular signals to produce relevant physiological responses. Different combinations of G protein-coupled receptors, when co-expressed, can lead to distinct cellular outputs, yet the molecular basis for this co-operativity is controversial. One such interaction is the reversal, from inhibition to excitation, at the dopamine D2 receptor in the ghrelin receptor’s presence, relevant for defecation control. Here we demonstrate that this reversal of dopamine D2 activity, to excitatory, occurs through a dominant switch in downstream signaling. This dominant switch, mediated by downstream signaling, enables fidelity in cellular responses not possible under alternative models, and provides an explanation for previously unresolved observations. Importantly, the switch in D2 signaling does not require ghrelin receptor agonism, rather its constitutive activity, thus accounting for the importance of central nervous system-ghrelin receptor in the absence of endogenous ligands. This re-coding has important implications for our understanding of how atypical receptor pharmacology can occur as well as how sequential signaling at individual neurons may be encoded to produce new outputs.
Spatial profiling of the interplay between cell type- and vision-dependent transcriptomic programs in the visual cortex
Authors: Xie Fangming , Jain Saumya , Xu Runzhe , Butrus Salwan , Tan Zhiqun , Xu Xiangmin , Shekhar Karthik , Zipursky S. Lawrence 
Published: December 2023

AbstractHow early sensory experience during “critical periods” of postnatal life affects the organization of the mammalian neocortex at the resolution of neuronal cell types is poorly understood. We previously reported that the functional and molecular profiles of layer 2/3 (L2/3) cell types in the primary visual cortex (V1) are vision-dependent (Tan et al.,Neuron,108(4), 2020; Cheng et al.,Cell,185(2), 2022). Here, we characterize the spatial organization of L2/3 cell types with and without visual experience. Spatial transcriptomic profiling based on 500 genes recapitulates the zonation of L2/3 cell types along the pial-ventricular axis in V1. By applying multi-tasking theory (Adler et al.,Cell Systems,8, 2019), we suggest that the spatial zonation of L2/3 cell types is linked to the continuous nature of their gene expression profiles, which can be represented as a 2D manifold bounded by three archetypal cell types (“A”, “B”, and “C”). By comparing normally reared and dark reared L2/3 cells, we show that visual deprivation-induced transcriptomic changes comprise two independent gene programs. The first, induced specifically in the visual cortex, includes immediate-early genes and genes associated with metabolic processes. It manifests as a change in cell state that is orthogonal to cell type-specific gene expression programs. By contrast, the second program impacts L2/3 cell type identity, regulating a subset of cell type-specific genes and shifting the distribution of cells within the L2/3 manifold, with a depression of the B-type and C-type and a gain of the A-type. Through an integrated analysis of spatial transcriptomic measurements with single-nucleus RNA-seq data from our previous study, we describe how vision patterns L2/3 cortical cell types during the postnatal critical period.Significance statementLayer 2/3 (L2/3) glutamatergic neurons are important sites of experience-dependent plasticity and learning in the mammalian cortex. Their properties vary continuously with cortical depth and depend upon experience. Here, by applying spatial transcriptomics and different computational approaches in the mouse primary visual cortex, we show that vision regulates orthogonal gene expression programs underlying cell states and cell types. Visual deprivation not only induces an activity-dependent cell state, but also alters the composition of L2/3 cell types, which are appropriately described as a transcriptomic continuum. Our results provide insights into how experience shapes transcriptomes that may, in turn, sculpt brain wiring, function, and behavior.
Chlamydiae as symbionts of photosynthetic dinoflagellates
Authors: Maire Justin , Collingro Astrid , Tandon Kshitij , Jameson Vanta J. , Judd Louise M. , Horn Matthias , Blackall Linda L. , van Oppen Madeleine J. H. 
Published: December 2023

AbstractChlamydiae are ubiquitous intracellular bacteria and infect a wide diversity of eukaryotes, including mammals. However, chlamydiae have never been reported to infect photosynthetic organisms. Here, we describe a novel chlamydial genus and species,CandidatusAlgichlamydia australiensis (A. australiensisthereafter), capable of infecting the photosynthetic dinoflagellateCladocopiumsp. (originally isolated from a scleractinian coral).A. australiensiswas confirmed to be intracellular by fluorescencein situhybridization and confocal laser scanning microscopy, and temporally stable at the population level by monitoring its relative abundance across four weeks of host growth. Using a combination of short- and long-read sequencing, we recovered a high-quality (completeness 91.73% and contamination 0.27%) metagenome-assembled genome ofA. australiensis. Phylogenetic analyses show that this chlamydial taxon represents a new genus and species within the Simkaniaceae family.A. australiensispossesses all the hallmark genes for chlamydiae-host interactions, including a complete type III secretion system. In addition, a type IV secretion system is encoded on a plasmid and has previously been observed for only three other chlamydial species. Twenty orthologous groups of genes are unique toA. australiensis, one of which is structurally similar to a protein known from Cyanobacteria and Archaeplastida involved in thylakoid biogenesis and maintenance, hinting at potential chlamydiae interactions with the chloroplasts ofCladocopiumcells. DespiteCladocopiumbeing itself a symbiont of cnidarians, a meta-analysis of 12,009 cnidarian 16S rRNA gene metabarcoding samples only returned five samples withA. australiensissequences, suggestingA. australiensisdoes not associate with cnidarians. Our study shows that chlamydiae infect dinoflagellate symbionts of cnidarians, the first photosynthetic organism reported to harbor chlamydiae, thereby expanding the breadth of chlamydial hosts and providing a new contribution to the discussion around the role of chlamydiae in the establishment of the primary plastid.
Mapping Structural and Dynamic Divergence Across the MBOAT family
Authors: Ansell T. Bertie , Healy Megan , Coupland Claire E. , Sansom Mark S. P. , Siebold Christian 
Published: December 2023

SummaryMembrane BoundO-acyltransferases (MBOATs) are membrane embedded enzymes which catalyse acyl chain transfer to a diverse group of substrates including lipids, small-molecules and proteins. Recent MBOAT structures reveal a conserved structural core, despite wide-ranging functional specificity across both prokaryotes and eukaryotes. The structural basis of catalytic specificity, regulation and interactions with the surrounding environment remain uncertain, hindering effective therapeutic targeting. Here, we combine comparative molecular dynamics (MD) simulations with bioinformatics to assess molecular and interactional divergence across the family. In simulations, MBOATs differentially distort the bilayer depending on their substrate type. Additionally, we identify specific lipid binding sites surrounding MBOAT reactant gates into the surrounding membrane. We use bioinformatics to reveal a conserved role for re-entrant loop-2 in stabilisation of the MBOAT fold and identify a key hydrogen bond involved in DGAT1 dimerisation. Finally, we predict differences in MBOAT core solvation and water gating properties across the family. These data are pertinent to the design of MBOAT specific inhibitors that encompass dynamic information within cellular mimetic environments.
Agonism between family groups of cooperative breeding smooth-coated otters (Lutrogale perspicillata)
Authors: Zheng Fan , Chuin How Darren Ang , Heng Yee Mei-Mei Tan , Johns Philip 
Published: December 2023

AbstractIntraspecific agonistic interactions are common in the animal kingdom and have significant consequences for animals. With a growing population and limited resources, these interactions have been observed more frequently among smooth-coated otters in Singapore. However, little is known about the behavioral patterns of these interactions and the factors that may affect their outcomes. To address this, we analyzed intraspecific agonistic interactions through publicly available videos from citizen scientists. Our analysis revealed different behavioral patterns and typical behaviors between winning and losing family groups in different environments. We also found suggestive evidence that larger family groups with more individuals than opponents have an advantage in these interactions. The environment in which an interaction occurs may also affect its intensity.
STAIG: Spatial Transcriptomics Analysis via Image-Aided Graph Contrastive Learning for Domain Exploration and Alignment-Free Integration
Authors: Yang Yitao , Cui Yang , Zeng Xin , Zhang Yubo , Loza Martin , Park Sung-Joon , Nakai Kenta 
Published: December 2023

AbstractSpatial transcriptomics is an essential application for investigating cellular structures and interactions and requires multimodal information to precisely study spatial domains. Here, we propose STAIG, a novel deep-learning model that integrates gene expression, spatial coordinates, and histological images using graph-contrastive learning coupled with high-performance feature extraction. STAIG can integrate tissue slices without prealignment and remove batch effects. Moreover, it was designed to accept data acquired from various platforms, with or without histological images. By performing extensive benchmarks, we demonstrated the capability of STAIG to recognize spatial regions with high precision and uncover new insights into tumor microenvironments, highlighting its promising potential in deciphering spatial biological intricates.
Ants hold a grudge: Associative learning of non-nestmate cues improves enemy recognition
Authors: Bey Mélanie , Endermann Rebecca , Raudies Christina , Steinle Jonas , Nehring Volker 
Published: December 2023

SummaryRecognition protects biological systems of all scales, from cells to societies. Social insects recognize their nestmates by colony-specific chemical labels, which individuals store as “templates” in their memories. The distributed model of nestmate recognition predicts that individual experiences cause variation between the recognition templates that different individuals store in their memory. Here, we show for the first time that ants associatively learn recognition labels of both friends and enemies during brief encounters. Because different individuals will accumulate different experiences throughout their lives, their later decisions on whether to accept or reject other individuals will also vary. Individual associative learning can thus explain many phenomena from nasty neighbour effects to age polyethism. To avoid chaos caused by inconsistent decisions across individuals, decisions are made in a distributed manner at the colony level. Group-level decision can thus be much more accurate than any individual decision alone.
Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication
Authors: Hafner Adam , Meurs Noah , Garner Ari , Azar Elaine , Passalacqua Karla D. , Nagrath Deepak , Wobus Christiane E. 
Published: December 2023

AbstractViruses are obligate intracellular parasites that rely on host cell metabolism for successful replication. Thus, viruses rewire host cell pathways involved in central carbon metabolism to increase the availability of building blocks for replication. However, the underlying mechanisms of virus-induced alterations to host metabolism are largely unknown. Noroviruses (NoVs) are highly prevalent pathogens that cause sporadic and epidemic viral gastroenteritis. In the present study, we uncovered several strain-specific and shared host cell metabolic requirements of three murine norovirus (MNV) strains, the acute MNV-1 strain and the persistent CR3 and CR6 strains. While all three strains required glycolysis, glutaminolysis, and the pentose phosphate pathway for optimal infection of macrophages, only MNV-1 relied on host oxidative phosphorylation. Furthermore, the first metabolic flux analysis of NoV-infected cells revealed that both glycolysis and glutaminolysis are upregulated during MNV-1 infection of macrophages. Glutamine deprivation affected the MNV lifecycle at the stage of genome replication, resulting in decreased non-structural and structural protein synthesis, viral assembly, and egress. Mechanistic studies further showed that MNV infection and overexpression of the MNV non-structural protein NS1/2 increased the enzymatic activity of the rate-limiting enzyme glutaminase. In conclusion, the inaugural investigation of NoV-induced alterations to host glutaminolysis identified the first viral regulator of glutaminolysis for RNA viruses, which increases our fundamental understanding of virus-induced metabolic alterations.Author SummaryAll viruses critically depend on the host cells they infect to provide the necessary machinery and building blocks for successful replication. Thus, viruses often alter host metabolic pathways to increase the availability of key metabolites they require. Human noroviruses (HNoVs) are a major cause of acute non-bacterial gastroenteritis, leading to significant morbidity and economic burdens. To date, no vaccines or antivirals are available against NoVs, which demonstrates a need to better understand NoV biology, including the role host metabolism plays during infection. Using the murine norovirus (MNV) model, we show that host cell glutaminolysis is upregulated and required for optimal virus infection of macrophages. Additional data point to a model whereby the viral non-structural protein NS1/2 upregulates the enzymatic activity of glutaminase, the rate-limiting enzyme in glutaminolysis. Insights gained through investigating the role host metabolism plays in MNV replication may assist with improving HNoV cultivation methods and development of novel therapies.
Training of third-party employees and its outcomes: a systematic literature review
Authors: Anand Mahima , Waraich Sushmita Biswal 
Published: December 2023

PurposeTraining has been an important tool for enhancing the skills and productivity of employees. Having productive employees helps organizations sustain themselves. Today, the authors organisations have an increasing number of employees on third-party payroll performing core as well as noncore business functions. However, due to the lack of ownership and moral obligation of employers, these employees are often not provided training, resulting in skills obsolesce and less productivity. The present study is a systematic literature review (SLR) on client organizations’ roles in training third-party employees (TPEs) and its related outcomes.Design/methodology/approachThe present study is a SLR on client organizations' roles in training TPEs and their related outcomes. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) approach, this study presents a review of 217 research papers on training of TPEs and its related outcomes.FindingsThe study identifies the outcomes of providing training to TPEs and presents the findings and suggestions made by researchers. The study concludes that TPEs are an important investment for the client organization. Training them would benefit the client organization, TPEs and the economy as a whole. The paper also suggests some avenues for future research.Research limitations/implicationsThis paper tries to answer an important question: What could drive productive behavior among TPEs? Based on the literature reviewed, the answer is that TPEs could be offered training opportunities with a view to enhancing their employability. This could induce, among them, a sense of being valued and supported while contributing to organizational performance and creating a feeling of reciprocal obligation. This is an important contribution to literature. Low investment in these employees affects their employability, i.e. be it in the same organization for another term or another organization and thus the need for training and development, for sustained productivity among TPEs, in organizations.Practical implicationsTraining and development, for them, would result in enhanced employability within as well as outside the organization. These employees could also be a good source for regular positions within the organization, if required, benefiting both the organization and the employee. Additionally, the economy would also benefit from a pool of skilled workforce. Therefore, it is suggested that governments initiate some policy framework regarding mandatory training of TPEs to increase their competencies, resulting in increased organizational productivity, especially for TPEs at lower and middle levels of management.Originality/valueThe paper is an original contribution by the researcher. An attempt has been made to highlight the training needs of TPEs and their related outcomes.
Factors affecting high-quality entrepreneurial performance in small- and medium-sized family firms
Authors: Mitropoulos Panagiotis , Mitropoulos Alexandros , Vlami Aimilia 
Published: December 2023

Purpose The purpose of this paper is to measure the high-quality entrepreneurial efficiency of family-owned small- and medium-sized enterprises (SMEs) while exploring the potential determinants of their performance. This study places particular emphasis on the firms' technological competencies and internationalization efforts. The authors aim to shed light on the internal and external characteristics that impact the efficiency of family SMEs.Design/methodology/approach This study adopts a two-stage approach. In the first stage, a data envelopment analysis model is utilized to measure the high-quality entrepreneurial efficiency of family SMEs. To achieve this, this study considered as outputs three key quality aspects of entrepreneurship, namely innovativeness, export orientation and turnover rate, while the inputs were the number of employees and the business environment. Then, in the second stage, the efficiency scores are regressed against a set of environmental factors that may affect the efficiency. The proposed efficiency measurement models are utilized with a particularly rich dataset of 1,910 family SMEs from 35 developed countries.Findings The results demonstrated that the efficiency of family SMEs primarily engaged in the production of goods was significantly higher than those providing services. Importantly, the presence of barriers related to innovation and digitalization had a pronounced negative impact on efficiency. Additionally, scale-up firms exhibited higher levels of efficiency. When examining family SMEs within their national context, it was observed that non-EU countries and countries with a higher gross domestic product displayed significantly higher efficiencies.Originality/value The findings of this research provide guidance for the development of entrepreneurship-oriented policies that consider both the internal characteristics of family SMEs and the diverse socioeconomic contexts in which they operate.