bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of dendritic cell-T cell interactions driving immune responses to food
Authors: Canesso Maria C.C. , Castro Tiago B.R. , Nakandakari-Higa Sandra , Lockhart Ainsley , Esterházy Daria , Reis Bernardo S. , Victora Gabriel D. , Mucida Daniel
Published: October 2022

The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Dendritic cells (DCs) orchestrate these immune responses by presenting luminal antigens and inducing functional differentiation of CD4+T cells into regulatory (pTreg) or pro-inflammatory (Th) subsets. However, the exact nature of the DCs inducing tolerance or inflammation to dietary antigens has been difficult to define. Using an intestine-adapted Labeling Immune Partnerships by SorTagging Intercellular Contacts (LIPSTIC) combined with single-cell transcriptomics, we characterized DCs presenting dietary antigens in the context of tolerance or infection. At steady-state, migratory cDC1 and cDC2 DCs, but not resident DCs, were found to present dietary antigen to cognate CD4+T cells. Whereas cDC2s promoted T cell activation, only cDC1s induced their differentiation into pTregs. Infection with the helminthStrongyloides venezuelensisabrogated cDC1 presentation of dietary antigens, preventing pTreg and oral tolerance induction. In contrast,Heligmosomoides polygyrusinfection only partially affected cDC1s, allowing oral tolerance to be maintained. An expanded population of cDC2s that induced type-2 immunity during both helminth infections did not present dietary antigens, demonstrating that compartmentalized presentation of luminal antigens can prevent food-specific Th2 responses during inflammatory conditions. Our data uncover novel cellular mechanisms by which tolerance to food is induced and can be disrupted during infections.
An automated workflow to assess completeness and curate GenBank for eDNA metabarcoding: the marine fish assemblage as case study
Authors: Claver Cristina , Canals Oriol , de Amézaga Leire G. , Mendibil Iñaki , Rodriguez-Ezpeleta Naiara
Published: October 2022

Expectations are high regarding the potential of eDNA metabarcoding for diversity monitoring. To make this approach suitable for this purpose, the completeness and accuracy of reference databases used for taxonomic assignment of eDNA sequences are among the challenges to be tackled. Yet, despite ongoing efforts to increase coverage of reference databases, sequences for key species are lacking, and incorrect records in widely used repositories such as GenBank have been reported. This compromises eDNA metabarcoding studies, especially for high diverse groups such as marine fishes. Here, we have developed a workflow that evaluates the completeness and accuracy of GenBank. For a given combination of species and barcodes a gap analysis is performed, and potentially erroneous sequences are identified. Our gap analysis based on the four most used genes (cytochrome c oxidase subunit 1, 12S rRNA, 16S rRNA and cytochrome b) for fish eDNA metabarcoding found that COI, the universal choice for metazoans, is the gene covering the highest number of Northeast Atlantic marine fishes (70%), while 12S rRNA, the preferred region for fish-targeting studies, only covered about 50% of the species. The presence of too close and too distant barcode sequences as expected by their taxonomic classification confirms presence of erroneous sequences in GenBank that our workflow can detect and eliminate. Comparing taxonomic assignments of real marine eDNA samples with raw and clean reference databases for the most used 12S rRNA barcodes (teleoandMiFish), we found that both barcodes perform differently, and demonstrated that the application of the database cleaning workflow can result in drastic changes in community composition. Besides providing an automated tool for reference database curation, this study confirms the need to increase 12S rRNA reference sequences for European marine fishes, encourages the use of a multi-marker approach for better community composition assessment, and evidences the dangers of taxonomic assignments by directly querying GenBank.
Knockdown of the TRPM4 channel alters cardiac electrophysiology and hemodynamics in a sex- and age-dependent manner in mice
Authors: Arullampalam Prakash , Essers Maria C. , Rougier Jean-Sébastien , Abriel Hugues
Published: October 2022

Background

TRPM4 is a calcium-activated, voltage-modulated, non-selective ion channel widely expressed in various types of cells and tissues. TRPM4 regulates the influx of sodium ions, thus playing a role in regulating the membrane potential. In the heart, TRPM4 is expressed in both cardiomyocytes and cells of the conductive pathways. Clinical studies have linkedTRPM4mutations to several cardiac disorders. While data from experimental studies have demonstrated TRPM4’s functional significance in cardiac physiology, its exact roles in the heart remain unclear.

Aim

To investigate the role of TRPM4 in cardiac physiology in a newly generated knockdownTrpm4mouse model.

Methods and results

Male and femaleTrpm4knockdown (Trpm4-/-) and wild-type mice 5- to 12-weeks-old (young) or 24-week-old or more (adult) were characterized using a multimodal approach, encompassing surface electrocardiograms (ECG), echocardiography recordings, pseudo and intracardiac ECGs, western blots, and mRNA quantifications. The assessment of cardiac electrophysiology by surface ECGs revealed no significant differences between wild type andTrpm4-/-5- to 12-weeks-old mice of either sex. Above 24 weeks of age, adult maleTrpm4-/-mice showed significantly reduced heart rate and increased heart rate variability. Echocardiography reveals that only adult maleTrpm4-/-mice exhibited slight left ventricular hypertrophic alterations with an alteration of the mitral valve pressure half time, the mitral valve E/A ratio, the isovolumetric relaxation time, and the mitral valve deceleration. In addition, an assessment of the right ventricular systolic function by scanning the pulmonary valve highlighted an alteration in pulmonary valve peak velocity and pressure in maleTrpm4-/-adult mice. Finally, intracardiac ECG recordings showed that the application of 5 µM NBA triggered a third-degree atrioventricular block on 40% of wild-type hearts only.

Conclusions

These results confirm the important role of TRPM4 in the proper structure and electrical function of the heart. It also reveals significant differences between male and female animals that have never been reported before. In addition, the investigation of the effects of NBA on heart function highlights the role of TRPM4 in atrioventricular conduction and provides the first evidence showing the efficacy of this compound on native cardiac tissues.
IntestLine: a Shiny-based application to map the rolled intestinal tissue onto a line
Authors: Yuzeir Altay , Bejarano David , Grein Stephan , Hasenauer Jan , Schlitzer Andreas , Yu Jiangyan
Published: October 2022

To allow the comprehensive histological analysis of the whole intestine in one image, the tissue is often rolled to a spiral before imaging. This Swiss-rolling technique facilitates robust experimental procedures, but it limits the possibilities to comprehend changes along the intestine. Here, we present IntestLine, a Shiny-based open-source application to map imaging data of intestinal tissues in spiral shape onto a line. The mapping of intestinal tissues improves the visualization of the whole intestine in both proximal-distal and serosa-luminal axis, and facilitates the observation of location-specific cell types and markers. In summary, IntestLine serves as a tool to visualize and characterize intestine in future imaging studies.
A non-human primate model with Alzheimer’s disease-like pathology induced by hippocampal overexpression of human tau
Authors: Jiang Zhouquan , Wang Jing , Luo Bin , Bai Fan , Qin Yongpeng , Wei Huiyi , Zhang Shaojuan , Wei Junjie , Ding Guoyu , Ma Long , He Shu , Chen Rongjie , Wang Lu , Xu Hao , Wang Xiangyu , Chen Gong , Lei Wenliang
Published: October 2022

Alzheimer’s disease (AD) is one of the most burdening diseases of the century with no disease-modifying treatment yet. Non-human primates (NHPs) share genetic, anatomical and physiological similarities with humans, making them an ideal model for investigating the pathogenesis and therapeutics of AD. However, the applications of NHPs in AD research have been hindered by the paucity of spontaneous or induced monkey models for AD due to their long generation time, ethical considerations and technical challenges in making genetically modified monkeys. Here we developed an AD-like NHP model by overexpressing human tau in bilateral hippocampi of adult rhesus macaque monkeys. We evaluated the pathological features of these monkeys with immunostaining, cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI), positron emission tomography (PET) scan, and behavioral tests. We demonstrated that after hippocampal overexpression of human tau, the rhesus macaque monkeys displayed multiple pathological features of AD, including neurofibrillary tangle formation, neuronal loss, hippocampal atrophy, neuroinflammation, Aβ clearance deficit, blood vessel damage and cognitive decline. This work establishes a human tau-induced AD-like NHP model that may facilitate mechanistic studies and therapeutic treatments for AD.
High throughput evaluation of genetic variants with prime editing sensor libraries
Authors: Gould Samuel I. , Wuest Alexandra N. , Dong Kexin , Johnson Grace A. , Hsu Alvin , Narendra Varun K. , Levine Stuart S. , Liu David R. , Sánchez Rivera Francisco J.
Published: October 2022

Many human diseases have a strong association with diverse types of genetic alterations. These diseases include cancer, in which tumor genomes often harbor a complex spectrum of single-nucleotide alterations and chromosomal rearrangements that can perturb gene function in ways that remain poorly understood. Some cancer-associated genes exhibit a tremendous degree of mutational heterogeneity, which may impact disease initiation, progression, and therapy responses. For example,TP53, the most frequently mutated gene in cancer, shows extensive allelic variation that leads to the generation of altered proteins that can produce functionally distinct phenotypes. Whether distinct variants ofTP53and other genes encode proteins with loss-of-function, gain-of-function, or otherwise neomorphic phenotypes remains both controversial and technically challenging to assess, particularly at the endogenous level. Here, we present a high-throughput prime editing “sensor” strategy to quantitatively assess the functional impact of diverse types of endogenous genetic variants. We used this strategy to screen the largest collection of endogenous cancer-associatedTP53variants assembled to date, identifying both known and novel alleles that impact p53 function in mechanistically diverse ways. Intriguingly, we find that certain types of endogenousTP53variants, particularly those in the p53 oligomerization domain, display opposite phenotypes in exogenous overexpression systems. These include disease-relevant variants found in humans with cancer predisposition syndromes that encode altered proteins with unique molecular properties. Our results emphasize the physiological importance of gene dosage in shaping native protein stoichiometry and protein-protein interactions, highlight the dangers of using exogenous overexpression systems to interpret pathogenic alleles, and establish a powerful computational and experimental framework for studying diverse types of genetic variants in their endogenous sequence context at scale.
Hidden GPCR structural transitions addressed by multiple walker supervised molecular dynamics (mwSuMD)
Authors: Deganutti Giuseppe , Pipito Ludovico , Rujan Roxana Maria , Weizmann Tal , Griffin Peter , Ciancetta Antonella , Moro Stefano , Reynolds Christopher Arthur
Published: October 2022

The structural basis for the pharmacology of G protein-coupled receptors (GPCRs), the most abundant membrane proteins and the target of about 35% of approved drugs, is still a matter of intense study. What makes GPCRs challenging to study is the inherent flexibility and the metastable nature of interaction with extra- and intracellular partners that drive their effects. Here, we present a molecular dynamics (MD) adaptive sampling algorithm, namely multiple walker supervised molecular dynamics (mwSuMD), to address complex structural transitions involving GPCRs without energy input. We first report the binding and unbinding of the vasopressin peptide from its receptor V2. Successively, we present the complete transition of the glucagon-like peptide-1 receptor (GLP-1R) from inactive to active, agonist and Gs-bound state, and the GDP release from Gs. To our knowledge, this is the first time the whole sequence of events leading from an inactive GPCR to the GDP release is simulated without any energy bias. We demonstrate that mwSuMD can address complex binding processes intrinsically linked to protein dynamics out of reach of classic MD.
The dispensability of 14-3-3 proteins for the regulation of human cardiac sodium channel Nav1.5
Authors: Iamshanova Oksana , Hämmerli Anne-Flore , Ramaye Elise , Seljmani Arbresh , Ross-Kaschitza Daniela , Schärz Noëlia , Essers Maria , Guichard Sabrina , Rougier Jean-Sébastien , Abriel Hugues
Published: October 2022

Background

14-3-3 proteins are ubiquitous proteins that play a role in cardiac physiology (e.g., metabolism, development, and cell cycle). Furthermore, 14-3-3 proteins were proposed to regulate the electrical function of the heart by interacting with several cardiac ion channels, including the voltage-gated sodium channel Nav1.5. Given the many cardiac arrhythmias associated with Nav1.5 dysfunction, understanding its regulation by the protein partners is crucial.

Aims

In this study, we aimed to investigate the role of 14-3-3 proteins in the regulation of the human cardiac sodium channel Nav1.5.

Methods and Results

Amongst the seven 14-3-3 isoforms, only 14-3-3η (encoded byYWHAHgene) weakly co-immunoprecipitated with Nav1.5 when heterologously co-expressed in tsA201 cells. Total and cell surface expression of Nav1.5 was however not modified by 14-3-3η overexpression or inhibition with difopein, and 14-3-3η did not affect physical interaction between Nav1.5 α-α subunits. The current-voltage relationship and the amplitude of Nav1.5-mediated sodium peak current density were also not changed.

Conclusions

Our findings illustrate that the direct implication of 14-3-3 proteins in regulating Nav1.5 is not evident in a transformed human kidney cell line tsA201.

This work shows that only 14-3-3η, exhibits weak/transient interaction with Nav1.5, and does not modify its total protein expression, plasmalemmal trafficking, and basal biophysical properties of the whole-cell current. Furthermore, inhibition of endogenous 14-3-3/ligand interactions with difopein does not affect the dimerization of Nav1.5. Therefore, 14-3-3 proteins are suggested to be dispensable for the Nav1.5 regulation in a heterologous expression system.
Complex changes in serum protein levels in COVID-19 convalescents
Authors: Pushalkar Smruti , Wu Shaohuan , Maity Shuvadeep , Pressler Matthew , Rendleman Justin , Vitrinel Burcu , Jeffrey Lauren , Abdelhadi Ryah , Chen Mechi , Ross Ted , Carlock Michael , Choi Hyungwon , Vogel Christine
Published: October 2022

The COVID-19 pandemic, triggered by severe acute respiratory syndrome coronavirus 2, has affected millions of people worldwide. Much research has been dedicated to our understanding of COVID-19 disease heterogeneity and severity, but less is known about recovery associated changes. To address this gap in knowledge, we quantified the proteome from serum samples from 29 COVID-19 convalescents and 29 age-, race-, and sex-matched healthy controls. Samples were acquired within the first months of the pandemic. Many proteins from pathways known to change during acute COVID-19 illness, such as from the complement cascade, coagulation system, inflammation and adaptive immune system, had returned to levels seen in healthy controls. In comparison, we identified 22 and 15 proteins with significantly elevated and lowered levels, respectively, amongst COVID-19 convalescents compared to healthy controls. Some of the changes were similar to those observed for the acute phase of the disease, i.e. elevated levels of proteins from hemolysis, the adaptive immune systems, and inflammation. In contrast, some alterations opposed those in the acute phase, e.g. elevated levels of CETP and APOA1 which function in lipid/cholesterol metabolism, and decreased levels of proteins from the complement cascade (e.g. C1R, C1S, and VWF), the coagulation system (e.g. THBS1 and VWF), and the regulation of the actin cytoskeleton (e.g. PFN1 and CFL1) amongst COVID-19 convalescents. We speculate that some of these shifts might originate from a transient decrease in platelet counts upon recovery from the disease. Finally, we observed race-specific changes, e.g. with respect to immunoglobulins and proteins related to cholesterol metabolism.
Tumor-educated Gr1+CD11b+cells instigate breast cancer metastasis by twisting cancer cells plasticity via OSM/IL6–JAK signaling
Authors: Peyvandi Sanam , Bulliard Manon , Kauzlaric Annamaria , Coquoz Oriana , Huang Yu-Ting , Duffey Nathalie , Gafner Laetitia , Lorusso Girieca , Fournier Nadine , Lan Qiang , Rüegg Curzio
Published: October 2022

Cancer cell plasticity contributes to tumor therapy resistance and metastasis formation, which represent the main causes of cancer-related death for most cancers, including breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis and, thus, unravelling the underlying cues may provide novel effective strategies to manage metastatic disease. Here, we show that stem cell antigen-1 positive (Sca-1+) murine breast cancer cells enriched during tumor progression and metastasis have higherin vitrocancer stem cell-like properties, enhancedin vivometastatic ability, and initiate primary tumors rich in Gr1highCD11b+Ly6Clowcells. In turn, tumor-educated Gr1+CD11b+(Tu-Gr1+CD11b+) cells rapidly and transiently convert low metastatic 4T1-Sca-1-cells into highly metastatic 4T1-Sca-1+cells via secreted OSM and IL6. Moreover, chemotherapy- resistant and highly metastatic 4T1-derived cells maintain high Sca-1+frequency through cell autonomous IL6 production. Inhibition of OSM, IL6 or JAK suppressed Tu-Gr1+CD11b+-induced Sca-1+population enrichmentin vitro, while JAK inhibition abrogated metastasis of chemotherapy-enriched Sca-1+cellsin vivo. Importantly, Tu-Gr1+CD11b+cells invoked a gene signature in tumor cells predicting shorter OS and RFS in breast cancer patients. Collectively, our data identified OSM/IL6-JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity triggering metastasis.
Aligning Distant Sequences to Graphs using Long Seed Sketches
Authors: Joudaki Amir , Meterez Alexandru , Mustafa Harun , Koerkamp Ragnar Groot , Kahles André , Rätsch Gunnar
Published: October 2022

Sequence-to-graph alignment is an important step in applications such as variant genotyping, read error correction and genome assembly. When a query sequence requires a substantial number of edits to align, approximate alignment tools that follow the seed-and-extend approach require shorter seeds to get any matches. However, in large graphs with high variation, relying on a shorter seed length leads to an exponential increase in spurious matches. We propose a novel seeding approach relying on long inexact matches instead of short exact matches. We demonstrate experimentally that our approach achieves a better time-accuracy trade-off in settings with up to a 25% mutation rate.

We achieve this by sketching a subset of graph nodes and storing them in aK-nearest neighbor index. While sketches are more robust to indels, finding the nearest neighbor of a sketch in a high-dimensional space is more computationally challenging than finding exact seeds. We demonstrate that if we store sketch vectors in aK-nearest neighbor index, we can circumvent the curse of dimensionality. Our long sketch-based seed scheme contrasts existing approaches and highlights the important role that tensor sketching can play in bioinformatics applications. Our proposed seeding method and implementation have several advantages: i) We empirically show that our method is efficient and scales to graphs with 1 billion nodes, with time and memory requirements for preprocessing growing linearly with graph size and query time growing quasi-logarithmically with query length. ii) For queries with an edit distance of 25% relative to their length, on the 1 billion node graph, longer sketch-based seeds yield a 4× increase in recall compared to exact seeds. iii) Conceptually, our seeder can be incorporated into other aligners, proposing a novel direction for sequence-to-graph alignment.

The implementation is available at:https://github.com/ratschlab/tensor-sketch-alignment.
Spatial organization of the 3D genome encodes gene co-expression programs in single cells
Authors: Dong Peng , Zhang Shu , Xie Liangqi , Wang Lihua , Lemire Andrew L. , Lander Arthur D. , Chang Howard Y. , Liu Zhe J.
Published: October 2022

Deconstructing the mechanism by which the 3D genome encodes genetic information to generate diverse cell types during animal development is a major challenge in biology. The contrast between the elimination of chromatin loops and domains upon Cohesin loss and the lack of downstream gene expression changes at the cell population level instigates intense debates regarding the structure-function relationship between genome organization and gene regulation. Here, by analyzing single cells after acute Cohesin removal with sequencing and spatial genome imaging techniques, we discover that, instead of dictating population-wide gene expression levels, 3D genome topology mediated by Cohesin safeguards long-range gene co-expression correlations in single cells. Notably, Cohesin loss induces gene co-activation and chromatin co-opening between active domains incisup to tens of megabase apart, far beyond the typical length scale of enhancer-promoter communication. In addition, Cohesin separates Mediator protein hubs, prevents active genes incisfrom localizing into shared hubs and blocks intersegment transfer of diverse transcriptional regulators. Together, these results support that spatial organization of the 3D genome orchestrates dynamic long-range gene and chromatin co-regulation in single living cells.
High level and molecular nature of transcriptional noise in yeast cells
Authors: Gvozdenov Zlata , Barcutean Zeno , Struhl Kevin
Published: October 2022

“Biological noise” is defined as functionally insignificant events that occur in living cells due to imperfect fidelity of biological processes. Distinguishing between biological function and biological noise is often difficult, and experiments to measure biological noise have not been performed. Here, we measure biological noise in yeast cells by analyzing chromatin structure and transcription of an 18 kb region of DNA whose sequence was randomly generated and hence lacks biological function. Nucleosome occupancy on random-sequence DNA is comparable to that on yeast genomic DNA. However, nucleosome-depleted regions are much less frequent, and there are fewer well-positioned nucleosomes and shorter nucleosome arrays. Steady-state levels of RNAs expressed from random-sequence DNA are comparable to those of typical yeast mRNAs, although transcription and mRNA decay rates are higher. Transcriptional initiation (5’ ends) from random-sequence DNA occurs at numerous sites at low levels, indicating very low intrinsic specificity of the Pol II machinery. In contrast, poly(A) profiles (relative levels and clustering of 3’ isoforms) of random-sequence RNAs are roughly comparable to those within 3’ untranslated regions of yeast mRNAs, suggesting limited evolutionary constraints on poly(A) site choice. RNAs expressed from random-sequence DNA show higher cell-to-cell variability than RNAs expressed from yeast genomic DNA, suggesting that functional elements limit the variability among individual cells within a population. These observations indicate that transcriptional noise occurs at high levels in yeast, and they provide insight into how chromatin and transcription patterns arise from the evolved yeast genome.
Circular RNAs are Associated with Floral Fate Acquisition in Soybean Shoot Apical Meristem
Authors: Babaei Saeid , Singh Mohan B. , Bhalla Prem L
Published: October 2022

Soybean (Glycine max), a major oilseed and protein source, requires a short-day photoperiod for floral induction. Though key transcription factors controlling flowering have been identified, the role of the non-coding (dark) genome is limited. circular RNAs (circRNAs) recently emerged as a novel class of RNAs with critical regulatory functions. However, a study on circRNAs during the floral transition of a crop plant is lacking. We investigated the expression and potential function of circRNAs in floral fate acquisition by soybean shoot apical meristem in response to short-day treatment. Using deep sequencing andin-silicoanalysis, we denoted 384 circRNAs, with 129 exhibiting short-day treatment-specific expression patterns. We also identified 38 circRNAs with predicted binding sites for miRNAs that could affect the expression of diverse downstream genes through the circRNA-miRNA-mRNA network. Notably, four different circRNAs with potential binding sites for an important microRNA module regulating developmental phase transition in plants, miR156 and miR172, were identified. We also identified circRNAs arising from hormonal signaling pathway genes, especially abscisic acid, and auxin, suggesting an intricate network leading to floral transition. This study highlights the gene regulatory complexity during the vegetative to reproductive transition and paves the way to unlock floral transition in a crop plant.

Highlight

A new class of regulatory RNAs, circular RNAs, modulate floral transition in a crop plant, soybean, by regulating hormonal pathways and post-transcriptional processes.
Recapitulating the life cycle of the global pathogenEntamoebain mice
Authors: Cavazos Carolina Mendoza , Heredia Marienela Y. , Owens Leah A. , Knoll Laura J.
Published: October 2022

There are severalEntamoebaspecies that colonize humans, but onlyEntamoeba histolyticacauses severe disease.E. histolyticais transmitted through the fecal-oral route to colonize the intestinal tract of 50 million people worldwide. The current mouse model to studyE. histolyticaintestinal infection directly delivers the parasite into the surgically exposed cecum, which circumvents the natural route of infection and does not produce infectious cysts. To develop a fecal-oral mouse model, we screened our vivarium for a natural murineEntamoebacolonizer via a pan-EntamoebaPCR targeting the 18S ribosomal gene. We determined that C57BL/6 mice were chronically colonized byEntamoeba muris. This amoeba is closely related toE. histolytica, as determined by 18S sequencing and cross-reactivity with anE. histolytica-specific antibody. In contrast, outbred Swiss Webster (SW) mice were not chronically colonized byE. muris. We orally challenged SW mice with 1×105E. muriscysts and discovered they were susceptible to infection, with peak cyst shedding occurring between 5-7 days post-infection. Most infected SW mice did not lose weight significantly but trended toward decreased weight gain throughout the experiment when compared to mock-infected controls. Infected mice treated with paromomycin, an antibiotic used against non-invasive intestinal disease, do not become colonized byE. muris. Within the intestinal tract,E. murislocalizes exclusively to the cecum and colon. PurifiedE. muriscysts treated with bovine bilein vitroexcyst into mobile, pre-trophozoite stages. Overall, this work describes a novel fecal-oral mouse model for the important global pathogenE. histolytica.

Importance

Infection with parasites from theEntamoebagenus are significantly underreported causes of diarrheal disease that disproportionally impact tropical regions. There are several species ofEntamoebathat infect humans to cause a range of symptoms from asymptomatic colonization of the intestinal tract to invasive disease with dissemination. AllEntamoebaspecies are spread via the fecal-oral route in contaminated food and water. Studying the life cycle ofEntamoeba, from host colonization to infectious fecal cyst production, can provide targets for vaccine and drug development. Because there is not an oral challenge rodent model, we screened for a mouseEntamoebaspecies and identifiedEntamoeba murisas a natural colonizer. We determine the peak of infection after an oral challenge, the efficacy of paromomycin treatment, the intestinal tract localization, and the cues that trigger excystation. This oral infection mouse model will be valuable for the development of novel therapeutic options forEntamoebainfections.
Sex-specific genetic loci linked to early and late onset type 2 diabetes
Authors: Berumen Jaime , Orozco Lorena , Gallardo-Rincón Héctor , Benuto Rosa Elba , Ramos-Martinez Espiridión , Rivas Fernando , García-Ortiz Humberto , Marin-Medina Melissa , Barrera Elizabeth , Juárez-Torres Eligia , Alvarado Silva Anabel , MartÍnez-Juárez Luis Alberto , Lomelín-Gascón Julieta , Montoya Alejandra , Ortega-Montiel Janinne , Alvarez-Hernández Diego-Abelardo , Tapia-Conyer Roberto
Published: October 2022

Purpose

To investigate the effect of sex and age on the timing of a type 2 diabetes (T2D) diagnosis and the influence T2D-related genes, parental history of T2D, and obesity on T2D development.

Methods

In this case-control study, 1012 T2D cases and 1008 healthy subjects were selected from the Diabetes in Mexico Study database. Participants were stratified by sex and age at T2D diagnosis (early, ≤45 years; late, ≥46 years). Seventy T2D-associated SNPs were explored and the percentage contribution (R2) of T2D-related genes, parental history of T2D, and obesity (body mass index [BMI] and waist-hip ratio [WHR]) on T2D development was calculated using univariate and multivariate logistic regression models.

Results

T2D-related genes influenced T2D development most in males who were diagnosed early (R2= 23.5%; females diagnosed early, R2= 13.5%; males and females diagnosed late, R2= 11.9% and R2= 7.3%, respectively). With an early diagnosis, insulin production genes were more influential in males (76.0% of R2) whilst peripheral insulin resistance genes were more influential in females (52.3% of R2). With a late diagnosis, insulin production genes from chromosome region 11p15.5 notably influenced males while peripheral insulin resistance and inflammation genes notably influenced females. Influence of parental history was higher among those diagnosed early (males, 19.9%; females, 17.5%) versus late (males, 6.4%; females, 5,3%). Unilateral maternal T2D history was more influential than paternal T2D history. BMI influenced T2D development for all, while WHR exclusively influenced males.

Conclusions

The influence of T2D-related genes, maternal T2D history, and fat distribution on T2D development was greater in males than females.
Single nucleus and spatially resolved intra-tumor subtype heterogeneity in bladder cancer
Authors: Lindskrog Sia V. , Schmøkel Sofie S. , Nordentoft Iver , Lamy Philippe , Knudsen Michael , Prip Frederik , Strandgaard Trine , Jensen Jørgen Bjerggaard , Dyrskjøt Lars
Published: October 2022

Current transcriptomic classification systems for bladder cancer do not consider the level of intra-tumor subtype heterogeneity. Here we present an investigation of the extent and possible clinical impact of intra-tumor heterogeneity across early and more advanced disease stages of bladder cancer. We performed single nucleus RNA-sequencing of 48 bladder tumors and four of these tumors were additionally analyzed using spatial transcriptomics. Total bulk RNA-sequencing and spatial proteomics data were available from the same tumors for comparison, along with detailed clinical follow-up of the patients. We demonstrate that tumors display varying levels of intra-tumor subtype heterogeneity and show that a higher class 2a weight estimated from bulk RNA-sequencing data is associated with worse outcome in patients with molecular high-risk class 2a tumors. Our results indicate that discrete subtype assignments from bulk RNA-sequencing data may lack biological granularity and continuous class scores could improve clinical risk stratification of patients.

Highlights

Single nucleus RNA-sequencing of tumors from 48 bladder cancer patients.

Tumors display varying levels of intra-tumor subtype heterogeneity at single nucleus and bulk tumor level.

The level of subtype heterogeneity could be estimated from both single nucleus and bulk RNA-sequencing data with a high concordance between the two.

High class 2a weight estimated from bulk RNA-sequencing data is associated with worse outcome in patients with molecular high-risk class 2a tumors.
Crystal structure of DNA polymerase I from Thermus phage G20c
Authors: Ahlqvist Josefin , Linares-Pastén Javier A. , Jasilionis Andrius , Welin Martin , Håkansson Maria , Svensson L. Anders , Wang Lei , Watzlawick Hildegard , Ævarsson Arnþór , Friðjónsson Ólafur H. , Hreggviðsson Guðmundur Ó. , Ketelsen Striberny Bernd , Glomsaker Eirin , Lanes Olav , Al-Karadaghi Salam , Nordberg Karlsson Eva
Published: October 2022

This study describes the structure of DNA polymerase I from Thermus phage G20c, termed PolI_G20c. This is the first structure of a DNA polymerase originating from a group of related thermophilic bacteriophages infecting Thermus thermophilus, including phages G20c, TSP4, P74-26, P23-45 and phiFA and the novel phage Tth15-6. Sequence and structural analysis of PolI_G20c revealed a 3′–5′ exonuclease domain and a DNA polymerase domain, and activity screening confirmed that both domains were functional. No functional 5′–3′ exonuclease domain was present. Structural analysis also revealed a novel specific structure motif, here termed SβαR, that was not previously identified in any polymerase belonging to the DNA polymerases I (or the DNA polymerase A family). The SβαR motif did not show any homology to the sequences or structures of known DNA polymerases. The exception was the sequence conservation of the residues in this motif in putative DNA polymerases encoded in the genomes of a group of thermophilic phages related to Thermus phage G20c. The structure of PolI_G20c was determined with the aid of another structure that was determined in parallel and was used as a model for molecular replacement. This other structure was of a 3′–5′ exonuclease termed ExnV1. The cloned and expressed gene encoding ExnV1 was isolated from a thermophilic virus metagenome that was collected from several hot springs in Iceland. The structure of ExnV1, which contains the novel SβαR motif, was first determined to 2.19 Å resolution. With these data at hand, the structure of PolI_G20c was determined to 2.97 Å resolution. The structures of PolI_G20c and ExnV1 are most similar to those of the Klenow fragment of DNA polymerase I (PDB entry 2kzz) from Escherichia coli, DNA polymerase I from Geobacillus stearothermophilus (PDB entry 1knc) and Taq polymerase (PDB entry 1bgx) from Thermus aquaticus.
Exiting the tunnel of uncertainty: crystal soak to validated hit
Authors: Martin Mathew P. , Noble Martin E. M.
Published: October 2022

Crystallographic fragment screens provide an efficient and effective way to identify small-molecule ligands of a crystallized protein. Due to their low molecular weight, such hits tend to have low, often unquantifiable, affinity for their target, complicating the twin challenges of validating the hits as authentic solution-phase ligands of the target and identifying the `best' hit(s) for further elaboration. In this article, approaches that address these challenges are assessed. Using retrospective analysis of a recent ATAD2 hit-identification campaign, alongside other examples of successful fragment-screening campaigns, it is suggested that hit validation and prioritization are best achieved by a `triangulation' approach in which the results of multiple available biochemical and biophysical techniques are correlated to develop qualitative structure–activity relationships (SARs). Such qualitative SARs may indeed be the only means by which to navigate a project through the tunnel of uncertainty that prevails before on-scale biophysical, biochemical and/or biological measurements become possible.
Bibliometric approach to inclusive entrepreneurship: what has been written in scientific academia?
Authors: Rodrigues Margarida , Silva Rui , Franco Mário , Oliveira Cidália
Published: October 2022

Purpose

The year 2020 was heavily marked by an unprecedented pandemic affecting society as a whole. However, under-represented groups may have seen their financial and social situation affected differently from other groups. Thus, it was found that in the literature, the term inclusive entrepreneurship, which addresses these issues, was fragmented in view of its similarity and association with social entrepreneurship, inclusive business and sustainability. In this sense, this paper aims to map the scientific knowledge on this topic.

Design/methodology/approach

To fulfil this aim, a systematic literature review was supported by bibliometrics (performance analysis and scientific mapping) and by the use of the software Bibliometrix R and VoSviewer.

Findings

The results obtained show that in the Web of Science, there are 121 documents related to this topic whose content analysis revealed that they are distributed between sustainability, entrepreneurship and inclusive entrepreneurship in the close triple association.

Practical implications

The main contributions of this study are the connection established between the three concepts and the emergence of continuing to develop research on inclusive entrepreneurship, given its binary function: employment generation for disadvantaged groups and inclusive business creation.

Originality/value

The relevance of this bibliometric analysis stands out, providing the positioning of academics on the importance of leveraging emerging research on this topic, not only in poor countries but also in others.
Trade show visitors and key technological trends: from a literature review to a conceptual framework
Authors: Vitali Veronica , Bazzani Claudia , Gimigliano Annamaria , Cristani Marco , Begalli Diego , Menegaz Gloria
Published: October 2022

Purpose

This study proposes a literature review and, based on the findings, the authors develop a conceptual framework, attempting to explain how technology may influence visitor behavior and eventually trade show performance.

Design/methodology/approach

The present research explores the role of visitors in the trade show context. The analysis specifically focuses on the variables that influence visitors’ participation at business-to-business trade shows and how their satisfaction and perception can be related to exhibition performance. The authors also take into consideration technological trends that prior to COVID-19 pandemics were slowly emerging in the trade show industry.

Findings

The findings highlight a continuity between pre-, at and postexhibition phases. Visitors’ behavior represents a signal of how a trade show is perceived as postexhibition purchases and next visit emerge as signals of an exhibition evaluation in relation to visitors’ perception. Besides being urgent tools for the continuity of the sector due to the pandemics, emerging technological trends can be key elements in understanding visitors’ behavior and in boosting their interest and loyalty toward trade shows.

Originality/value

The paper proposes a conceptual model including top notch and innovative technological trends to improve the understandment of visitors’ behavior. Both practitioners in companies and academics might find the study useful, given the digital uplift generated by the pandemics.
Spiritual leadership and corporate social entrepreneurial orientation: the mediating role of workplace spirituality
Authors: Luu Tien Dung
Published: October 2022

Purpose

The main aim of this study is to examine a moderated–mediated model empirically to understand whether and how spiritual leadership (SL) affects corporate social entrepreneurial orientation (SEO) with the role of workplace spirituality (WS).

Design/methodology/approach

The study adopts a sample of 524 key role employees at 76 four–five-star hotels and tourism firms in Ho Chi Minh City of Vietnam, using a partial least square structural equation model (PLS-SEM).

Findings

SL of social entrepreneurs can vigorously promote corporate SEO's formation and development, with WS's mediating role.

Originality/value

This study demonstrates how SL and WS can help organisations achieve higher corporate SEO levels in contradictory empirical evidence and a lack of theoretical framework.
Concordant genetic structures of sika deer and Japanese land leeches suggest that the current range expansion of Haemadipsa japonica is dependent on sika deer migration: A case study from Tochigi Prefecture, Japan
Authors: Morishima Kaori , Fukui Emiko , Aizawa Mineaki
Published: October 2022

Haemadipsa japonica is a Japanese land leech that feeds on the blood of host animals, mainly the sika deer (Cervus nippon). The distribution of H. japonica has expanded since the 1990s, possibly due to sika deer population increases. Haemadipsa japonica populations were found in the northern and southern regions of Tochigi Prefecture, central Japan. Previous investigations reported that these populations are genetically differentiated between the north and south, although the sika deer distribution extends throughout the northern and southern regions. We hypothesized that the migration of sika deer might be limited, thus maintaining the two H. japonica genetic groups and restricting its range expansion. We evaluated this hypothesis by investigating the genetic structure of the mitochondrial DNA (mtDNA) and nuclear microsatellites (nSSR) of sika deer samples collected from Tochigi Prefecture and from H. japonica bloodmeal samples (invertebrate‐derived DNA; iDNA). The sika deer mtDNA presented two haplotypes (G‐ and A‐haplotypes) without a clear genetic structure. Conversely, the sika deer nSSR analysis indicated clear genetic differentiation between deer in the northern and southern regions, corresponding to the two H. japonica genetic groups. This indicates that sika deer movement is restricted to narrow regions in Tochigi Prefecture. Therefore, we conclude that the current H. japonica expansion in the prefecture likely depends on the migration of sika deer, only occurring within the northern and southern regions, even though this is driven by sika deer migration.
Responses of Salmonella biofilms to oxidizing biocides: Evidence of spatial clustering
Authors: Guest Kerry , Whalley Thomas , Maillard Jean‐Yves , Artemiou Andreas , Szomolay Barbara , Webber Mark A.
Published: October 2022

The spatial organization of biofilm bacterial communities can be influenced by several factors, including growth conditions and challenge with antimicrobials. Differential survival of clusters of cells within biofilms has been observed. In this work, we present a variety of methods to identify, quantify and statistically analyse clusters of live cells from images of two Salmonella strains with differential biofilm forming capacity exposed to three oxidizing biocides. With a support vector machine approach, we showed spatial separation between the two strains, and, using statistical testing and high‐performance computing (HPC), we determined conditions which possess an inherent cluster structure. Our results indicate that there is a relationship between biocide potency and inherent biofilm formation capacity with the tendency to select for spatial clusters of survivors. There was no relationship between positions of clusters of live or dead cells within stressed biofilms. This work identifies an approach to robustly quantify clusters of physiologically distinct cells within biofilms and suggests work to understand how clusters form and survive is needed.

Significance statement

Control of biofilm growth remains a major challenge and there is considerable uncertainty about how bacteria respond to disinfection within a biofilm and how clustering of cells impacts survival. We have developed a methodological approach to identify and statistically analyse clusters of surviving cells in biofilms after biocide challenge. This approach can be used to understand bacterial behaviour within biofilms under stress and is widely applicable.
Effet du mobile money sur la résilience des ménages exerçant des activités génératrices de revenus au Cameroun
Authors: Mvogo Gregory , Djouaka Christèle Gladisse Awounang
Published: October 2022

Partant d'une enquête réalisée en mai 2020 auprès de 1136 ménages au Cameroun, cet article évalue l'effet du mobile money sur les ménages exerçant des activités génératrices de revenus. Les résultats obtenus, par l'estimation d'un modèle de probabilité linéaire à variables instrumentales, montrent que le mobile money permet aux ménages, pour ce qui est des chocs économiques, de faire face aux tensions de trésorerie liées à leur activité tout en payant les factures et à la pandémie COVID‐19. De plus, concernant les chocs sociaux, le mobile money permet aux ménages d'être résilients face à la mort d'un membre important de la famille et aux différentes sollicitations de la famille. Sur la base de cette embellie de l'effet du mobile money, les offreurs du produit gagneraient à intensifier sa diffusion surtout dans les zones rurales où les coûts de transaction sont encore importants.
When men fight with women (versus other men): Limited offending during disputes
Authors: Felson Richard B. , Berg Mark T. , Rogers Ethan M. , Krajewski Andrew T.
Published: October 2022

What transpires in a dispute, even a violent dispute, is affected by the tendency for adversaries to engage in “limited offending.” We focus on one restraint: the tendency of men to limit their aggression in their disputes with women. Analyses are based on an incident‐level survey about interpersonal disputes administered to 503 men who are incarcerated and 220 men who had never been incarcerated. Using multinomial and logistic regression models, we examined the extent to which an adversary's gender predicted dispute‐related behaviors. The evidence suggests that the chivalry norm has pervasive effects on the behavior of men during their disputes with women. Men are more likely to engage in remedial actions (e.g., apologies) when their adversary is a woman, as opposed to another man. In addition, men are less likely to make violent threats and engage in physical attacks when their adversary is a woman, even after they have themselves been physically attacked. When men are violent, they are less likely to injure a woman than a man. However, the chivalry norm does not inhibit verbal aggression in these disputes: men are just as likely to engage in verbal attacks and nonviolent threats when the adversary is a woman.