bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between physical activity and cognitive dysfunction in older companion dogs: Results from the Dog Aging Project
Authors: Bray Emily E. , Raichlen David A. , Forsyth Kiersten K. , Promislow Daniel E.L. , Alexander Gene E. , MacLean Evan L. ,   Dog Aging Project Consortium
Published: May 2022

AbstractCanine Cognitive Dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer’s disease. Given that physical activity is believed to reduce risk of Alzheimer’s disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6-18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity—with several important covariates—as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = -0.10, 95% CI: -0.11 to - 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate = -0.07, 95% CI: -0.09 to -0.05, p <0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p <0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimer’s disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical-activity interventions.
Investigating the antioxidant effects of Aloe vera: Possible role in regulating lipid profile and liver function in high fat and fructose diet (HFFD) fed mice
Authors: Abubakar Abdullahi Mukhtar , Dibal Nathan Isaac , Attah Martha Orendu Oche , Chiroma Samaila Musa 
Published: May 2022

AbstractFat rich diets are believed to induce obesity and contributes to the development of diabetes and cardiovascular disease while high fructose diet was reported to increase gut surface area and enhance nutrient uptake resulting in weight gain. The study investigate the role of Aloe vera supplementation on lipid profiles, oxidative stress as well as liver and hear histology in high fat and fructose diet fed mice. Twenty mice were distributed into four groups (n=5). The groups received regular diet, high fat and fructose died (HFFD), HFFD plus 10% Aloe vera (HFFD+AV1) and HFFD plus 20% Aloe vera (HFFD+AV2) respectively for 10 weeks. The cholesterol level of HFFD+AV treated mice were significantly lower compared to HFFD treated mice. The ALT level was significantly increased in HFFD treated mice relative to the control. Aloe vera significantly improve albumin level as well as Catalase and superoxide dismutase activities of HFFD treated mice. The liver tissues of control and HFFD+AV2 treated mice showed normal hepatocytes. The study suggest that Aloe vera supplementation could protect against HFFD induced oxidative stress and hyperlipidemia. These findings might be used for further research on food supplementation for the control of metabolic disorders.
Glutamatergic projections from ventral hippocampus to nucleus accumbens cholinergic neurons are altered in a mouse model of depression
Authors: Medrihan Lucian , Knudsen Margarete , Ferraro Tatiana , Vasques Pedro Del Cioppo , Romin Yevgeniy , Fujisawa Sho , Greengard Paul , Milosevic Ana 
Published: May 2022

AbstractThe cholinergic interneurons (ChATs) of the nucleus accumbens (NAc) have a critical role in the activity of this region, specifically in the context of major depressive disorder. To understand the circuitry regulating this behavior we sought to determine the areas that directly project to these cells/interneurons by utilizing the monosynaptic cell-specific tracing technique. Mapping showed monosynaptic projections that are exclusive to NAc ChATs. To determine if some of these projections are altered in a depression mouse model, we used mice that do not express the calcium binding protein p11 specifically in ChATs (ChAT-p11 cKO) and display a depressive-like phenotype. Our data demonstrated that while the overall projection areas remain similar between wild type and in ChAT-p11 cKO mice, the number of projections coming from the ventral hippocampus (vHIP) is significantly reduced in the ChAT-p11 cKO mice. Furthermore, using optogenetics and electrophysiology we showed that glutamatergic projections from vHIP to NAc ChATs are severely altered in mutant mice. These results show that specific alterations in the circuitry of the accumbal ChAT interneurons could play an important role in the regulation of depressive-like behavior, reward seeking behavior in addictions, or psychiatric symptoms in neurodegenerative diseases.
Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence
Authors: Belk Julia A. , Yao Winnie , Ly Nghi , Freitas Katherine A. , Chen Yan-Ting , Shi Quanming , Valencia Alfredo M. , Shifrut Eric , Kale Nupura , Yost Kathryn E. , Duffy Connor V. , Hwee Madeline A. , Miao Zhuang , Ashworth Alan , Mackall Crystal L. , Marson Alexander , Carnevale Julia , Vardhana Santosh A. , Satpathy Ansuman T. 
Published: May 2022

AbstractT cell exhaustion limits anti-tumor immunity, but the molecular determinants of this process remain poorly understood. Using a chronic antigen stimulation assay, we performed genome-wide CRISPR/Cas9 screens to systematically discover genetic regulators of T cell exhaustion, which identified an enrichment of epigenetic factors. In vivo CRISPR screens in murine and human tumor models demonstrated that perturbation of several epigenetic regulators, including members of the INO80 and BAF chromatin remodeling complexes, improved T cell persistence in tumors. In vivo paired CRISPR perturbation and single-cell RNA sequencing revealed distinct transcriptional roles of each complex and that depletion of canonical BAF complex members, including Arid1a, resulted in the maintenance of an effector program and downregulation of terminal exhaustion-related genes in tumor-infiltrating T cells. Finally, Arid1a-depletion limited the global acquisition of chromatin accessibility associated with T cell exhaustion and led to improved anti-tumor immunity after adoptive cell therapy. In summary, we provide a comprehensive atlas of the genetic regulators of T cell exhaustion and demonstrate that modulation of the epigenetic state of T cell exhaustion can improve T cell responses in cancer immunotherapy.
The licorice metabolite enoxolone attenuates Clostridioides difficile pathophysiology by corrupting its metabolic and toxin production networks
Authors: Marreddy Ravi K. R. , Picker Jonathan , Phelps Gregory A. , Powell Reid , Cherian Philip T. , Bowling John J. , Stephan Clifford C. , Lee Richard E. , Hurdle Julian G. 
Published: May 2022

ABSTRACTToxins TcdA and TcdB are the main virulence factors of Clostridioides difficile, a leading cause of hospital-acquired diarrhea. We investigated the therapeutic potential of inhibiting the biosynthesis of TcdA and TcdB. Accordingly, screening of structurally diverse phytochemicals with medicinal properties identified 18β-glycyrrhetinic acid (enoxolone) as an inhibitor of TcdA and TcdB biosynthesis. Enoxolone also inhibited sporulation. In a CDI colitis model, enoxolone when combined with vancomycin protected mice from becoming moribund and the combination was more effective than vancomycin alone, a standard of care antibiotic for CDI. While enoxolone alone reduced the in vivo load of toxins, the monotherapy did not protect mice from CDI. Affinity based proteomics identified ATP synthase subunit alpha (AtpA) and adenine deaminase (Ade) as possible molecular targets for enoxolone. Silencing of mRNA for Ade and AtpA also reduced toxin biosynthesis, while molecular interaction analysis showed that enoxolone directly bound to Ade. Ade converts adenine to hypoxanthine as an early step in the purine salvage pathway. Metabolomics revealed enoxolone caused cells to accumulate adenosine and deplete hypoxanthine and ATP. Accordingly, supplementation with hypoxanthine partly restored toxin production. Enoxolone also impacted phosphate metabolism by reducing the amounts of cellular phosphate. Thus, supplementation with triethyl phosphate as a source of phosphate also partly restored toxin production. When hypoxanthine and triethyl phosphate were combined, toxin production was fully restored in the presence of enoxolone. Taken together, studies with enoxolone revealed metabolic pathways that affect C. difficile toxin production and could represent potential anti-virulence drug targets.IMPORTANCEClostridioides difficile, a leading cause of hospital-acquired diarrhea, produces two co-regulated toxins (TcdA and TcdB) that are the focus of most anti-virulence discovery efforts for C. difficile infection (CDI). Exploration of an alternate anti-virulence strategy led to the discovery that the licorice metabolite enoxolone inhibits C. difficile virulence by blocking the cellular biosynthesis of TcdA and TcdB. Blockage of toxin production by enoxolone was associated with multiple effects on cells, including inhibiting adenine deaminase and ATP synthase leading to disruption of purine biosynthesis and phosphate metabolism. In mice infected with C. difficile, the efficacy of enoxolone in combination with vancomycin was superior to vancomycin alone. These findings contribute to establishing toxin biosynthesis inhibition as a newer therapeutic concept for CDI.
A statistical genomics framework to trace bacterial genomic predictors of clinical outcomes in Staphylococcus aureus bacteraemia
Authors: Giulieri Stefano G. , Guérillot Romain , Holmes Natasha E. , Baines Sarah L. , Hachani Abderrahman , Daniel Diane S. , Seemann Torsten , Davis Joshua S. , Van Hal Sebastiaan , Tong Steve Y. C. , Stinear Timothy P. , Howden Benjamin P. 
Published: May 2022

ABSTRACTOutcomes for patients with severe bacterial infections are determined by the interplay between host, pathogen, and treatments. Most notably, patient age and antibiotic resistance contributes significantly to poor outcomes. While human genomics studies have provided insights into the host genetic factors impacting outcomes of Staphylococcus aureus infections, comparatively little is known about S. aureus genotypes and disease severity. Building on the idea that bacterial pathoadaptation is a key driver of clinical outcomes, we develop a new genome-wide association study (GWAS) framework to identify adaptive bacterial mutations associated with clinical treatment failure and mortality in three large and independent S. aureus bacteraemia cohorts, comprising 1358 episodes. We discovered S. aureus loci with previously undescribed convergent mutations linked to both poorer infection outcomes and reduced susceptibility to vancomycin. Our research highlights the potential of vancomycin-selected mutations and vancomycin MIC as key explanatory variables to predict SAB severity. The contribution of bacterial variation was much lower for clinical outcomes (heritability < 5%), however, GWAS allowed us to identify additional, MIC-independent candidate pathogenesis loci. Using supervised machine-learning, we were able to quantify the predictive potential of these adaptive S. aureus signatures, along with host determinants of bacteraemia outcomes. The statistical genomics framework we have developed is a powerful means to capture adaptive mutations and find bacterial factors that influence and predict severe infections. Our findings underscore the importance of systematically collected, rich clinical and microbiological data to understand bacterial mechanisms promoting treatment failure.
Prevalence and associated factors of khat chewing among pregnant women: A Systematic Review and Meta-analysis
Authors: Basa Muluken , Comiskey Catherine 
Published: May 2022

AbstractBackgroundKhat (Catha edulis) is a stimulant plant, broadly cultivated and consumed in the Horn of Africa and the Arabian Peninsula. It contains Cathinone, which is an amphetamines-like chemical and causes various adverse outcomes for pregnant women and babies when it is consumed during pregnancy. Decisive estimates of the prevalence of khat chewing and related risk factors which may increase this practice have not been determined.AimTo determine the pooled prevalence and associated factors of khat chewing among pregnant women in the Horn Africa and the Arabian Peninsula countries with a view to informing targeted interventions for the region.MethodThe study protocol was prepared and registered on PROSPERO, ID CRD42021190837. A database search including Gray literature and Google scholar was explored to identify 667 studies. Finally, 14 studies were considered relevant for meta-analysis, after removing 259 duplicates, 388 unrelated topics and 6 studies with full text examination. The Newcastle-Ottawa Scale quality assessment tool was used to assess the quality of the studies. The pooled prevalence was determined by using the random-effect model and the p- values of ≤ 0.05 were considered stastically significant to examine associations. Statistical heterogeneity amongst the studies was assessed by Cochrane chi-square and the I2statistical test.Main FindingsFrom the meta-analysis of 14 studies with 15,343 study participants, the pooled prevalence of khat chewing among pregnant women was 21.42%, 95% CI (14.49 - 29.29); (I2=99.05% (p<0.0001). The results of the meta-analysis demonstrated that pregnant women who had a khat chewing partner [OR 6.50 (95% CI 5.01, 8.43)]; low educational status [OR 2.53 (95% CI 2.24 - 2.85)], lived in rural area [OR 1.69 (95% CI 1.52 – 1.88)] or had a low level of income [OR 1.70 (95% CI 1.55 – 1.87)] were significantly more likely to chew khat during pregnancy.ConclusionThe prevalence of khat chewing amongst pregnant women in the Horn of Africa and the Arabian Peninsula has never been measured before and was found to be high. Partners khat chewing status, maternal low educational and economic status were the main factors associated with the problem. Designing intervention strategies to specifically target these risk factors and reduce the burden of the problem for women and their babies is urgently needed.
Ubiquitination occurs in the mitochondrial matrix by eclipsed targeted components of the ubiquitin machinery
Authors: Zhang Yu , Karmon Ofri , Koyeli Das , Mark Maayan , Lehming Norbert , Pines Ophry 
Published: May 2022

ABSTRACTUbiquitination is a critical type of post translational modification in eukaryotic cells. It is involved in regulating nearly all cellular processes in the cytosol and nucleus. Mitochondria, known as the metabolism heart of the cell, are organelles that evolved from bacteria. Using the subcellular compartment-dependent α-complementation, we detect multiple components of ubiquitination machinery as being eclipsed distributed to yeast mitochondria. Subsequently, the results with respect to MTS (mitochondrial targeting sequence) targeted HA-tagged ubiquitin demonstrate that certain ubiquitination events specifically occur in yeast mitochondria and are independent of proteasome activity in the cytosol/nucleus. Importantly, we show that the E2 Rad6 affects the pattern of protein ubiquitination in mitochondria and provides an in vivo assay for its activity in the matrix of the organelle. This study shows that ubiquitination occurs in the mitochondrial matrix by eclipsed targeted components of the ubiquitin machinery, providing a new perspective of mitochondrial and ubiquitination research.
CAPG: Comprehensive Allopolyploid Genotyper
Authors: Kulkarni Roshan , Zhang Yudi , Cannon Steven B. , Dorman Karin S. 
Published: May 2022

AbstractMotivationGenotyping by sequencing is a powerful tool for investigating genetic variation in plants, but many economically important plants are allopolyploids, where homoeologous similarity obscures the subgenomic origin of reads and confounds allelic and homoeologous SNPs. Recent polyploid genotyping methods use allelic frequencies, rate of heterozygosity, parental cross or other information to resolve read assignment, but good subgenomic references offer the most direct information. The typical strategy aligns reads to the joint reference, performs diploid genotyping within each subgenome, and filters the results, but persistent read misassignment results in an excess of false heterozygous calls.ResultsWe introduce the Comprehensive Allopolyploid Genotyper (CAPG), which formulates an explicit likelihood to weight read alignments against both subgenomic references and genotype individual allopolyploids from whole genome resequencing (WGS) data. We demonstrate CAPG in allotetraploids, where it performs better than GATK’s HaplotypeCaller applied to reads aligned to the combined subgenomic references.AvailabilityCode and tutorials are available athttps://github.com/Kkulkarni1/CAPG.git.
DiffBrainNet: differential analyses add new insights into the response to glucocorticoids at the level of genes, networks and brain regions
Authors: Gerstner Nathalie , Krontira Anthi C. , Cruceanu Cristiana , Roeh Simone , Pütz Benno , Sauer Susann , Rex-Haffner Monika , Schmidt Mathias V. , Binder Elisabeth B. , Knauer-Arloth Janine 
Published: May 2022

AbstractGenome-wide gene expression analyses are invaluable tools for increasing our knowledge of biological and disease processes, allowing a hypothesis-free comparison of gene expression profiles across experimental groups, tissues and cell types. Traditionally, transcriptomic data analysis has focused on gene-level effects found by differential expression. In recent years, network analysis has emerged as an important additional level of investigation, providing information on molecular connectivity, especially for diseases associated with a large number of linked effects of smaller magnitude, like neuropsychiatric disorders and their risk factors, including stress. In this manuscript, we describe how combined differential expression and prior-knowledge-based differential network analysis can be used to explore complex datasets. As an example, we analyze the transcriptional responses following administration of the glucocorticoid/stress hormone receptor agonist dexamethasone in C57Bl/6 mice, in 8 brain regions important for stress processing: the prefrontal cortex, the amygdala, the paraventricular nucleus of the hypothalamus, the cerebellar cortex, and sub regions of the hippocampus: the dorsal and ventral Cornu Ammonis 1, the dorsal and ventral dentate gyrus. By applying a combination of differential network- and differential expression-analyses, we find that these explain distinct but complementary aspects and biological mechanisms of the responses to the stimulus. In addition, network analysis identifies new differentially connected partners of important genes and can be used to generate hypotheses on specific molecular pathways affected. With this work, we provide an analysis framework and a publicly available resource for the study of the transcriptional landscape of the mouse brain: DiffBrainNet (http://diffbrainnet.psych.mpg.de), which can identify molecular pathways important for basic functioning and response to glucocorticoids in a brain-region specific manner.
UMINT: Unsupervised Neural Network For Single Cell Multi-Omics Integration
Authors: Maitra Chayan , Seal Dibyendu Bikash , Das Vivek , De Rajat K. 
Published: May 2022

AbstractMulti-omics studies have enabled us to understand the mechanistic drivers behind complex disease states and progressions, thereby providing novel and actionable biological insights into health status. However, integrating data from multiple modalities is challenging due to the high dimensionality of data and noise associated with each platform. Non-overlapping features and technical batch effects in the data make the task of learning more complicated. Conventional machine learning (ML) tools are not quite effective against such data integration hazards. In addition, existing methods for single cell multi-omics integration are computationally expensive. This has encouraged the development of a novel architecture that produces a robust model for integration of high-dimensional multi-omics data, which would be capable of learning meaningful features for further downstream analysis. In this work, we have introduced a novel Unsupervised neural network for single cell Multi-omics INTegration (UMINT). UMINT serves as a promising model for integrating variable number of single cell omics layers with high dimensions, and provides substantial reduction in the number of parameters. It is capable of learning a latent low-dimensional embedding that can capture useful data characteristics. The effectiveness of UMINT has been evaluated on benchmark CITE-seq (paired RNA and surface proteins) datasets. It has outperformed existing state-of-the-art methods for multi-omics integration.
GABAergic regulation of cell proliferation within the adult mouse spinal cord
Authors: New Lauryn E , Yanagawa Yuchio , McConkey Glenn A , Deuchars Jim , Deuchars Susan A 
Published: May 2022

AbstractManipulation of neural stem cell proliferation and differentiation in the postnatal CNS is receiving significant attention due to therapeutic potential. In the spinal cord, such manipulations may promote repair in conditions such as multiple sclerosis or spinal cord injury, but may also limit excessive cell proliferation contributing to tumours such as ependymomas. Here we show that when ambient GABA is increased in vigabatrin-treated or decreased in glutamic acid decarboxylase67-green fluorescent protein (GAD67-GFP) mice, the numbers of proliferating cells respectively decreased or increased. Thus, intrinsic spinal cord GABA levels are correlated with the extent of cell proliferation, providing important evidence for the possibility of manipulating these levels. Diazepam binding inhibitor, an endogenous protein that interacts with GABA receptors and its breakdown product, octadecaneuropeptide, which preferentially activates central benzodiazepine (CBR) sites, were highly expressed in the spinal cord, especially in ependymal cells surrounding the central canal. Furthermore, animals with reduced CBR activation via treatment with flumazenil or Ro15-4513, or with a G2F77I mutation in the CBR binding site had greater numbers of Ethynyl-2’-deoxyuridine positive cells compared to control, which maintained their stem cell status since the proportion of newly proliferated cells becoming oligodendrocytes or astrocytes was significantly lower. Altering endogenous GABA levels or modulating GABAergic signaling through specific sites on the GABA receptors therefore influences NSC proliferation in the adult spinal cord. These findings provide a basis for further study into how GABAergic signaling could be manipulated to enable spinal cord self-regeneration and recovery or limit pathological proliferative activity.