bluuebunny/crossref_metadata_2025_split huggingface dataset:
A mathematical model of whole-body potassium regulation: Global parameter sensitivity analysis*
Authors: Stadt Melissa M. , Layton Anita T. 
Published: November 2023

AbstractPotassium (K+) is an essential electrolyte that is tightly regulated by various complex physiological mechanisms. In this study, we analyze a mathematical model of whole-body K+regulation to investigate the sensitivity of different model outcomes to parameter values. We used the Morris method, a global sensitivity analysis technique, to evaluate the impact of the parameters on both steady state results and transient simulations during a single-meal. Our results shows that the most influential parameters and processes depend on what you are measuring. Specifically, steady state results relied primarily on parameters that were involved in kidney function, while transient results relied on hormonal feedback mechanisms. This study shows that our mathematical model of whole-body potassium regulation captures known physiological function of potassium regulation despite a large number of uncertain parameters.MSC codes68Q25, 68R10, 68U05
Understanding the bacterial imbalance in Hidradenitis Suppurativa patients: Insights into microbial community shifts and colonization by opportunistic pathogens
Authors: Bens Lene , Vanhoutvin Tine , Kerremans Alison , Jansen Daan , Depypere Melissa , Hillary Tom , Vermeire Séverine , Green Sabrina I. , Matthijnssens Jelle , Sabino João , Lavigne Rob , Laethem An Van , Wagemans Jeroen 
Published: November 2023

AbstractPatients suffering from hidradenitis suppurativa (HS) develop painful skin lesions, significantly decreasing their quality of life. This chronic disease is triggered by plugged hair follicles resulting in an aberrant immune response, skin microbiome imbalance and secondary bacterial colonization. As a result, a diversity of treatment options are currently applied, including antibiotics, biologicals like adalimumab and surgery, which often provide only short-term relief. Alternative strategies, like phage therapy, have been proposed but identification of the target bacterium is key. Therefore, a spatial and longitudinal analysis was performed on skin swabs of lesions from 39 HS patients and 18 healthy controls, leading to a total collection of 108 lesional samples and 35 control samples at different time points and locations throughout the body. Samples were subjected to 16S rRNA community analysis, as well as bacterial isolation using aerobic and anaerobic culturing in combination with MALDI-TOF. Our data demonstrate that the bacterial community present in lesions of patients with HS is out of balance compared to healthy individuals, in which the niche ofStaphylococcusandCorynebacteriumis taken over byEscherichia-Shigella. Overall, three bacterial community profiles of HS lesions and one of healthy individuals could be distinguished. Although the overall bacterial composition was not associated with the disease severity defined by the Hurley classification system, lesions often become colonized with opportunistic pathogens includingStaphylococcus aureusandPseudomonas aeruginosaat increasing disease severities. Furthermore, patients with a concurrent IBD diagnosis did not reveal a significantly different bacterial skin community.
Efficient genome editing using modified Cas9 proteins in zebrafish
Authors: Dorner Laura , Stratmann Benedikt , Bader Laura , Podobnik Marco , Irion Uwe 
Published: November 2023

AbstractThe zebrafish (Danio rerio) is an important model organism for basic as well as applied bio-medical research. One main advantage is its genetic tractability, which was greatly enhanced by the introduction of the CRISPR/Cas method a decade ago. The generation of loss-of-function alleles via the production of small insertions or deletions in the coding sequences of genes with CRISPR/Cas systems is now routinely achieved with high efficiency. The method is based on the error prone repair of precisely targeted DNA double strand breaks by non-homologous end joining (NHEJ) in the cell nucleus. However, editing the genome with base pair precision, by homology-directed repair (HDR), is by far less efficient and therefore often requires large-scale screening of potential carriers by labour intensive genotyping. Here we show that the Cas9 protein variant SpRY with relaxed PAM requirement can be used for gene targeting in zebrafish, thus expanding the versatility of the method. In addition, we demonstrate that the incorporation of an artificial nuclear localisation signal (aNLS) into the Cas9 protein variants not only enhances the efficiency of gene knock-out but also the frequency of HDR thereby facilitating the efficient modification of single base pairs in the genome. Our protocols provide a guide for a cost-effective generation of versatile and potent Cas9 protein variants and efficient gene editing in zebrafish.
Perturbed sulfur homeostasis allowsC. elegansto escape growth retardation onActinobacteriafrom its natural microbiome
Authors: Patange Om , Breen Peter , Ruvkun Gary 
Published: November 2023

SummaryThe rate at which organisms grow is influenced by their biotic environment. The nematodeCaenorhabditis elegansgrows slower in the presence ofActinobacteria, but it is unknown why. Here, we show how perturbed levels of hydrogen sulfide and cysteine modulate the growth rate ofC. elegansonActinobacteria. Using an unbiased forward genetic screen ofC. eleganswe discovered alleles of the conserved cystathionine gamma-lyase (cth-2/CTH)that improved animal growth rate onActinobacteria. Conversely, null alleles ofcth-2cause developmental arrest of animals grown onActinobacteria, which can be rescued by exogenous H2S. We also discovered a leucine rich repeat gene that regulates cysteine and H2S production,lrr-2/LRRC58.A wild isolate ofC. elegansthat naturally grows well onActinobacteriahas a mutant allele oflrr-2, suggesting this sulfur metabolism pathway is important for the regulation of animal growth rate in its natural ecological context. We propose a model in which wild-type worms use sulfurous compounds to promote growth of their favored bacterial food sources by inhibitingActinobacteriagrowth. This strategy becomes a liability whenActinobacteriaare the sole food source but can be bypassed by mutations in sulfur metabolism. This study reveals how the homeostasis of sulfurous compounds controls the growth rate of animals in an ecological context.
A comparative medical genomics approach may facilitate the interpretation of rare missense variation
Authors: Haque Bushra , Guirguis George , Curtis Meredith , Mohsin Hera , Walker Susan , Morrow Michelle M. , Costain Gregory 
Published: November 2023

ABSTRACTPurposeTo determine the degree to which likely causal missense variants of single-locus traits in non-human livestock and domestic species have features suggestive of pathogenicity in a human genomic context.MethodsWe extracted missense variants from the Online Mendelian Inheritance in Animals database for nine animals (cat, cattle, chicken, dog, goat, horse, pig, rabbit, sheep), mapped coordinates to the human reference genome, and annotated variants using genome analysis tools. We also searched a private commercial laboratory database of genetic testing results from >400,000 individuals with suspected rare disorders.ResultsOf 339 variants that were mappable to the same residue and gene in the human genome, 56 had been previously classified with respect to pathogenicity: 31 (55.4%) pathogenic/likely pathogenic, 1 (1.8%) benign/likely benign, and 24 (42.9%) uncertain/other. The odds ratio for a pathogenic/likely pathogenic classification in ClinVar was 7.0 (95% confidence interval: 4.1-12.0, p<0.0001), compared to all other germline missense variants in these same 220 genes. The remaining 283 variants disproportionately had allele frequencies and REVEL scores that supported pathogenicity.ConclusionCross-species comparisons could facilitate the interpretation of rare missense variation. These results provide further support for comparative medical genomics approaches that connect big data initiatives in human and veterinary genetics.
Lymphocyte profiles after a first demyelinating event suggestive of multiple sclerosis reveal early monocyte and B cell alterations
Authors: Alvarez-Gonzalez Cesar , Wiedemann Annika , Schroeder-Castagno Maria , Schepanski Steven , Asseyer Susanna , Chien Claudia , Kuchling Joseph , Bellmann-Strobl Judith , Ruprecht Klemens , Infante-Duarte Carmen , Dörner Thomas , Paul Friedemann 
Published: November 2023

AbstractIntroductionOften, an isolated clinical event suggestive of CNS demyelination confers a risk of conversion to multiple sclerosis. In this study, we investigate lymphocyte profiles after a first clinical event suggestive of multiple sclerosis (MS), which could contribute to the current understanding of early inflammatory responses in this demyelinating disease.MethodsTwenty treatment-naïve clinically isolated syndrome (CIS) patients and fifteen healthy participants were included in our assessment of lymphocyte profiles and B cell subsets using multicolour flow cytometry. Analysis was made at 3-6 months (Baseline), 12, and 24 months after a first clinical event. We also performed a sub-analysis of patients that received glatiramer acetate (GLAT) after their baseline visit up to 24 months after the first clinical event.ResultsOur analysis revealed monocyte and B cell differences between groups. Percentages of CD19+CD20+B cells were lower in CIS patients compared to healthy individuals at baseline. Additionally, monocyte distribution among groups was different. A subgroup analysis of patients treated with GLAT (n= 10) showed an increased percentage of naïve (p<0.05) and memory pre-switched (p<0.01) B cells up to 24 months after their baseline visit compared to the untreated group (n= 10).ConclusionOur results showed early monocyte and B cell subsets alterations in pwCIS. Moreover, GLAT-treated patients showed an increased percentage of naïve and memory pre-switched B cells after 24 months of treatment. Further research is needed to elucidate the role of B cells and monocyte disturbances during inflammatory processes after a first clinically-MS suggestive event.
MaSk-LMM: A Matrix Sketching Framework for Linear Mixed Models in Association Studies
Authors: Burch Myson , Bose Aritra , Dexter Gregory , Parida Laxmi , Drineas Petros 
Published: November 2023

AbstractLinear mixed models (LMMs) have been widely used in genome-wide association studies (GWAS) to control for population stratification and cryptic relatedness. Unfortunately, estimating LMM parameters is computationally expensive, necessitating large-scale matrix operations to build the genetic relatedness matrix (GRM). Over the past 25 years, Randomized Linear Algebra has provided alternative approaches to such matrix operations by leveragingmatrix sketching, which often results in provably accurate fast and efficient approximations. We leveragematrix sketchingto develop a fast and efficient LMM method calledMatrix-SketchingLMM(MaSk-LMM) by sketching the genotype matrix to reduce its dimensions and speed up computations. Our framework comes with both theoretical guarantees and a strong empirical performance compared to current state-of-the-art.
Mapping the common barriers to optimal COPD care in high and middle-income countries: qualitative perspectives from clinicians
Authors: Shahaj Orjola , Meiwald Anne , Sudhir Krishnan Puri , Gara-Adams Rupert , Wark Peter , Cazaux Alexis , Rios Abelardo Elizondo , Avdeev Sergey , Adams Elisabeth J 
Published: November 2023

BackgroundAlthough predominantly preventable and treatable, chronic obstructive pulmonary disease (COPD) is a leading cause of death globally. Guidelines for managing the condition are widely available, yet COPD care remains suboptimal in many settings, including high and middle-income countries (HICs and MICs). Several approaches are used to diagnose and manage COPD, resulting in substantial variation in its care pathways. This study aimed to explore how barriers to optimal COPD care vary across HICs and MICs by identifying common and unique barriers to COPD care in six countries to inform global policy initiatives for better care while addressing specific challenges.MethodsBased on international and national guidelines, we mapped COPD care pathways for Australia, Spain, Taiwan, Argentina, Mexico, and Russia. Country-specific pathways were populated with published epidemiological, health economic, and clinical data identified through a pragmatic literature review. Semi-structured interviews with 17 respiratory care clinicians further informed and validated the pathways, data inputs, and key issues arising in each country. Thematic content analysis was used to analyse common and unique barriers across countries.ResultsSix themes were common in most HICs and MICs:“Challenges in COPD diagnosis”, “Strengthening the role of primary care”, “Fragmented healthcare systems and coordination challenges”, “Inadequate management of COPD exacerbations”; “Limited access to specialised care” and, “Impact of underfinanced and overloaded healthcare systems”. One theme,“Insurance coverage and reimbursement challenges”, was more relevant for MICs.HICs and MICs differ in patient and healthcare provider awareness, primary care involvement, spirometry access, and specialised care availability. Both face issues with healthcare fragmentation, guideline adherence, and COPD exacerbation management. MICs also grapple with resource limitations and healthcare infrastructure challenges.ConclusionMany challenges to COPD care are the same in both HICs and MICs, underscoring the pervasive nature of these issues. While country-specific issues require customised solutions, there are untapped possibilities for implementing global respiratory strategies that motivate countries to manage COPD effectively. In addition to healthcare system-level initiatives, there is a crucial need for political prioritisation of COPD to secure the essential resources it requires.
Prevalence, treatment, and factors associated with cryptococcal meningitis post introduction of integrase inhibitors antiretroviral based regimens among people living with HIV in Tanzania
Authors: Minja Makyao , Mbilinyi Tusaligwe , Mkinga Bryceson , Philipo Erick G. , Owenya Joyce , Kilonzi Manase 
Published: November 2023

AbstractObjectiveThis study aimed to assess the prevalence of CM, treatment practice, and the associated factor’s post-introduction of Tenofovir Lamivudine and Dolutegravir (TLD) regimen among PLHIV in Tanzania.MethodsThis was an analytical cross-sectional study, and the data was collected retrospectively in three public regional referral hospitals (RRHs) in Dar es Salaam, Tanzania. A total of 405 files of the PLHIV admitted in the medical wards on the TLD regimen from January 2019 to December 2022 were reviewed. The collected information includes patient demographic characteristics, Cryptococcal status, CD4 level at the time of CM diagnosis, status of using ART, CM treatment approach, and outcome. Data was analyzed using SPSS software version 23.ResultsOut of 405, the majority 267(65.9%) were female, 224(55.3%) were aged between 36 - 55 years, and 293(72.3%) married. ART defaulters were found to be 37(9.1%). The prevalence of CM was found to be 48(11.9%), out of which 42(87.5%) received fluconazole alone. ART defaulter and marital status significantly (p-value < 0.05) were associated with those who tested CM positive.ConclusionThe study found the prevalence of CM among PLHIV to be significantly high and the majority were treated with fluconazole alone. ART defaulters and marital status were significantly associated with one being CM positive. Responsible authorities and stakeholders should enforce guideline adherence and PLHIV should be encouraged on medication adherence.
Cryptococcus neoformans rapidly invades the murine brain by sequential breaching of airway and endothelial tissues barriers, followed by engulfment by microglia
Authors: Francis Vanessa I. , Liddle Corin , Camacho Emma , Kulkarni Madhura , Junior Samuel R.S. , Harvey Jamie A , Ballou Elizabeth R. , Thomson Darren D. , Hardwick J. Marie , Casadevall Arturo , Witton Jonathan , Coelho Carolina 
Published: November 2023

AbstractThe fungusCryptococcus neoformanscauses lethal meningitis in humans with weakened immune systems and is estimated to account for 10-15% of AIDS-associated deaths worldwide. There are major gaps in our understanding of how this environmental fungus evades the immune system and invades the mammalian brain before the onset of overt symptoms. To investigate the dynamics ofC. neoformanstissue invasion, we mapped early fungal localisation and host cell interactions at early times in infected brain, lung, and upper airways using mouse models of systemic and airway infection. To enable this, we developed anin situimaging pipeline capable of measuring large volumes of tissue while preserving anatomical and cellular information by combining thick tissue sections, tissue clarification, and confocal imaging. Made possible by these techniques, we confirm high fungal burden in mouse upper airway turbinates after nasal inoculation. Surprisingly, most yeasts in turbinates were titan cells, indicating this microenvironment enables titan cell formation with faster kinetics than reported in mouse lungs. Importantly, we observed one instance of fungal cells enmeshed in lamina propria of upper airways, suggesting penetration of airway mucosa as a possible route of tissue invasion and dissemination to the bloodstream. We extend previous literature positing bloodstream dissemination ofC. neoformans, via imagingC. neoformanswithin blood vessels of mouse lungs and finding viable fungi in the bloodstream of mice a few days after intranasal infection, suggesting that bloodstream access can occur via lung alveoli. In a model of systemic cryptococcosis, we show that as early as 24 h post infection, majority ofC. neoformanscells traversed the blood-brain barrier, and are engulfed or in close proximity to microglia. Our work establishes thatC. neoformanscan breach multiple tissue barriers within the first days of infection. This work presents a new method for investigating cryptococcal invasion mechanisms and demonstrates microglia as the primary cells responding to C. neoformans invasion.
Transcriptomic reprogramming screen identifies SRSF1 as rejuvenation factor
Authors: Plesa Alexandru M. , Jung Sascha , Wang Helen H. , Omar Fawad , Shadpour Michael , Buentello David Choy , Perez-Matos Maria C. , Horwitz Naftali , Cai George , Ngian Zhen-Kai , de Magalhaes Carol V. , Wagers Amy J. , Mair William B. , del Sol Antonio , Church George M. 
Published: November 2023

AbstractAging is a complex process that manifests through the time-dependent functional decline of a biological system. Age-related changes in epigenetic and transcriptomic profiles have been successfully used to measure the aging process1,2. Moreover, modulating gene regulatory networks through interventions such as the induction of the Yamanaka factors has been shown to reverse aging signatures and improve cell function3,4. However, this intervention has safety and efficacy limitations forin vivorejuvenation5,6, underscoring the need for identifying novel age reversal factors. Here, we discovered SRSF1 as a new rejuvenation factor that can improve cellular functionin vitroandin vivo. Using a cDNA overexpression screen with a transcriptomic readout we identified that SRSF1 induction reprograms the cell transcriptome towards a younger state. Furthermore, we observed beneficial changes in senescence, proteasome function, collagen production, and ROS stress upon SRSF1 overexpression. Lastly, we showed that SRSF1 can improve wound healingin vitroandin vivoand is linked to organismal longevity. Our study provides a proof of concept for using transcriptomic reprogramming screens in the discovery of age reversal interventions and identifies SRSF1 as a promising target for cellular rejuvenation.
3-phenyllactic acid promotes healthspan through SKN-1/ATFS-1-mediated mitochondrial activation and stress resilience
Authors: Kim Juewon , Jo Yunju , Lim Gyumin , Ji Yosep , Roh Jong-Hwa , Kim Wan-Gi , Yi Hyon-Seung , Choi Dong Wook , Cho Donghyun , Ryu Dongryeol 
Published: November 2023

SummaryThe mechanisms underlying the impact of probiotic supplementation on health remain largely elusive. While previous studies have primarily focused on the discovery of novel bioactive bacteria and alterations in the microbiome environment to explain potential probiotic effects, our research delves into the role of living lactic acid bacteria (LAB) and their conditioned media, highlighting that only the former, not dead bacteria, enhance the healthspan ofCaenorhabditis elegans. To elucidate the underlying mechanisms, we conducted transcriptomic profiling through RNA-seq analysis inC. elegansexposed to LAB or 3-phenyllactic acid (PLA), mimicking the presence of key candidate metabolites of LAB and evaluating healthspan. Our findings reveal that PLA treatment significantly extends the healthspan ofC. elegansby promoting energy metabolism and stress resilience in a SKN-1/ATFS-1-dependent manner. Moreover, PLA-mediated longevity is associated with a novel age-related parameter, the Healthy Aging Index (HAI), introduced in this study, which comprises healthspan-related factors such as motility, oxygen consumption rate (OCR), and ATP levels. Extending the relevance of our work to humans, we observed an inverse correlation between blood PLA levels and physical performance in patients with sarcopenia, when compared to age-matched non-sarcopenic controls. Our investigation thus sheds light on the pivotal role of the metabolite PLA in probiotics-mediated enhancement of organismal healthspan, and also hints at its potential involvement in age-related sarcopenia. These findings warrant further investigation to delineate PLA’s role in mitigating age-related declines in healthspan and resilience to external stressors.HighlightsMetabolites Produced by Lactic Acid Bacteria Function as Mediators of Longevity inC. elegans3-Phenyllactic Acid (PLA) Augmented Lifespan Extension and Elevated the Healthy Aging Index (HAI)PLA Facilitated Healthy Aging by Inducing Mitochondrial Activation and Stress Resistance Dependent on SKN-1/ATFS-1Patients with Sarcopenia and Symptoms of Frailty Exhibited Reduced Blood PLA Levels.
Effects of high fat and sugar diet on motivation for food and resistance to punishment in rats: role of sex and age of exposure
Authors: Desmercieres Stevenson , Lardeux Virginie , Longueville Jean-Emmanuel , Dugast Emilie , Thiriet Nathalie , Solinas Marcello 
Published: November 2023

ABSTRACTExposure to food rich in fat and sugar (High Fat and Sugar Diet, HFSD) is believed to induce behavioral and neurobiological changes that would produce addiction-like behavior and increase the risks of obesity and overweight. Studies in rodents have led to conflicting results suggesting that several factors such as sex and age of exposure contribute to the development of maladaptive behavior towards food. In addition, it is not clear whether the effects of exposure to HFSD persist after its discontinuation which would indicate long-term risk to develop addiction-like behavior. In this study, we investigated the persistent effects of an intermittent 8-week exposure to HFSD in male and female rats as a function of age of exposure (adult and adolescent). We found that intermittent exposure to HFSD did not alter body weight, but it affected consumption of standard food during the time of exposure in all groups. In addition, in adults, HFSD produced a decrease in the initial baseline responding in FR1 schedules that persisted for 4 weeks in males but not in female rats. However, we found that exposure to HFSD did not affect resistance to punishment measured by progressive shock strength (PSS) break points or motivation for food measured by progressive-ratio break points regardless of sex or age of exposure. Altogether, these results do not provide support to the hypothesis that intermittent exposure to HFSD produce persistent increases in the vulnerability to develop addiction-like behaviors towards palatable food.