bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma Growth Hormone Pulses Induce Male-biased Pulsatile Chromatin Opening and Epigenetic Regulation in Adult Mouse Liver
Authors: Rampersaud Andy , Connerney Jeannette , Waxman David J. 
Published: August 2023

AbstractSex-differences in plasma growth hormone (GH) profiles, pulsatile in males and persistent in females, regulate sex differences in hepatic STAT5 activation linked to sex differences in gene expression and liver disease susceptibility, but little is understood about the fundamental underlying, GH pattern-dependent regulatory mechanisms. Here, DNase hypersensitivity site (DHS) analysis of liver chromatin accessibility in a cohort of 18 individual male mice established that the endogenous male rhythm of plasma GH pulse-stimulated liver STAT5 activation induces dynamic, repeated cycles of chromatin opening and closing at several thousand liver DHS and comprises a novel mechanism conferring male bias to liver chromatin accessibility. Strikingly, a single physiological replacement dose of GH given to hypophysectomized male mice restored, within 30 min, liver STAT5 activity and chromatin accessibility at 83% of the pituitary hormone-dependent dynamic male-biased DHS. Sex-dependent transcription factor binding patterns and chromatin state analysis identified key genomic and epigenetic features distinguishing this dynamic, STAT5-driven mechanism of male-biased chromatin opening from a second GH-dependent mechanism operative at static male-biased DHS, which are constitutively open in male liver. Dynamic but not static male-biased DHS adopt a bivalent-like epigenetic state in female liver, as do static female-biased DHS in male liver, albeit using distinct repressive histone marks in each sex, namely, H3K27me3 at female-biased DHS in male liver, and H3K9me3 at male-biased DHS in female liver. Moreover, sex-biased H3K36me3 marks are uniquely enriched at static sex-biased DHS, which may serve to keep these sex-dependent hepatocyte enhancers free of H3K27me3 repressive marks and thus constitutively open. Pulsatile chromatin opening stimulated by endogenous, physiological hormone pulses is thus one of two distinct GH-determined mechanisms for establishing widespread sex differences in hepatic chromatin accessibility and epigenetic regulation, both closely linked to sex-biased gene transcription and the sexual dimorphism of liver function.
DENND6A couples Arl8b to a Rab34/RILP/dynein complex regulating retrograde lysosomal trafficking and autophagy
Authors: Kumar Rahul , Francis Vincent , Khan Maleeha , Aguila Adriana , Kulasekaran Gopinath , McPherson Peter S. 
Published: August 2023

AbstractLysosomes help maintain cellular proteostasis, and defects in lysosomal positioning and function lead to diseases including neurodegenerative disorders. The spatiotemporal distribution of lysosomes is regulated by small GTPases, including Rabs, which are activated by guanine nucleotide exchange factors (GEFs). DENN domain–bearing proteins are the largest family of Rab GEFs. Using a cell-based assay, we screened the DENN domain protein family member DENND6A for potential GEF activity toward all 60 Rabs and identified 20 potential DENND6A substrates, including Rab34. Here, we demonstrate that DENND6A activates Rab34, which recruits a RILP/dynein complex to the lysosomes, promoting lysosomal retrograde trafficking from the cell periphery to the minus ends of microtubules. Further, we identify DENND6A as an effector of Arl8b, a major regulatory GTPase on lysosomes. Initially known for promoting anterograde transport of lysosomes, Arl8b also facilitates lysosomal retrograde transport. We demonstrate that Arl8b recruits DENND6A to peripheral lysosomes to activate Rab34 and initiate retrograde transport, regulating nutrient-dependent lysosomal juxtanuclear repositioning and loss of DENND6A impairs autophagic flux. Our findings support a model whereby Arl8b/DENND6A/Rab34-dependent lysosomal retrograde trafficking controls autophagy.
A suppressor screenin C. elegansidentifies a multi-protein interaction interface that stabilizes the synaptonemal complex
Authors: Kursel Lisa E. , Martinez Jesus E. Aguayo , Rog Ofer 
Published: August 2023

AbstractSuccessful chromosome segregation into gametes depends on tightly-regulated interactions between the parental chromosomes. During meiosis, chromosomes are aligned end-to-end by an interface called the synaptonemal complex, which also regulates exchanges between them. However, despite the functional and ultrastructural conservation of this essential interface, how protein-protein interactions within the synaptonemal complex regulate chromosomal interactions remains poorly understood. Here we describe a novel interaction interface in theC. eleganssynaptonemal complex, comprised of short segments of three proteins, SYP-1, SYP-3 and SYP-4. We identified the interface through a saturated suppressor screen of a mutant that destabilizes the synaptonemal complex. The specificity and tight distribution of suppressors point to a charge-based interface that promotes interactions between synaptonemal complex subunits and, in turn, allows intimate interactions between chromosomes. Our work highlights the power of genetic studies to illuminate the mechanisms that underly meiotic chromosome interactions.Significance StatementGamete production requires tightly regulated interactions between the parental chromosomes, which co-align and exchange information. These events are mediated by the synaptonemal complex – a thread-like structure that assembles between the parental chromosomes. The molecular interactions that underly synaptonemal complex assembly remain poorly understood due to rapid sequence divergence and challenges in biochemical reconstitution. Here we identify a novel three-component interface in the nematode synaptonemal complex. Destabilization and subsequent restoration of this interface link the integrity of the synaptonemal complex with chromosome alignment and regulation of exchanges. Beyond mechanistic understanding of chromosomal interactions, our work provides a blueprint for genetic probing of large cellular assemblies that are refractory to structural analysis and sheds light on the forces that shape their evolution.
Analysis ofPseudomonas aeruginosatranscription in anex vivocystic fibrosis sputum model identifies metal restriction as a gene expression stimulus
Authors: Neff Samuel L. , Doing Georgia , Reiter Taylor , Hampton Thomas H. , Greene Casey S. , Hogan Deborah A. 
Published: August 2023

AbstractChronicPseudomonas aeruginosalung infections are a distinctive feature of cystic fibrosis (CF) pathology, that challenge adults with CF even with the advent of highly effective modulator therapies. CharacterizingP. aeruginosatranscription in the CF lung and identifying factors that drive gene expression could yield novel strategies to eradicate infection or otherwise improve outcomes. To complement publishedP. aeruginosagene expression studies in laboratory culture models designed to model the CF lung environment, we employed an ex vivo sputum model in which laboratory strain PAO1 was incubated in sputum from different CF donors. As part of the analysis, we compared PAO1 gene expression in this “spike-in” sputum model to that forP. aeruginosagrown in artificial sputum medium (ASM). Analyses focused on genes that were differentially expressed between sputum and ASM and genes that were most highly expressed in sputum. We present a new approach that used sets of genes with correlated expression, identified by the gene expression analysis tool eADAGE, to analyze the differential activity of pathways inP. aeruginosagrown in CF sputum from different individuals. A key characteristic ofP. aeruginosagrown in expectorated CF sputum was related to zinc and iron acquisition, but this signal varied by donor sputum. In addition, a significant correlation betweenP. aeruginosaexpression of the H1-type VI secretion system and corrector use by the sputum donor was observed. These methods may be broadly useful in looking for variable signals across clinical samples.ImportanceIdentifying the gene expression programs used byPseudomonas aeruginosato colonize the lungs of people with cystic fibrosis (CF) will illuminate new therapeutic strategies. To capture these transcriptional programs, we cultured the commonP. aeruginosalaboratory strain PAO1 in expectorated sputum from CF patient donors. Through bioinformatics analysis, we defined sets of genes that are more transcriptionally active in real CF sputum compared to artificial sputum media (ASM). Many of the most differentially active gene sets contained genes related to metal acquisition, suggesting that these gene sets play an active role in scavenging for metals in the CF lung environment which is inadequately represented in ASM. Future studies ofP. aeruginosatranscription in CF may benefit from the use of an expectorated sputum model or modified forms of ASM supplemented with metals.
A bacterial expression cloning screen reveals tardigrade single-stranded DNA-binding proteins as potent desicco-protectants
Authors: Hibshman Jonathan D. , Clark-Hachtel Courtney M. , Bloom Kerry S. , Goldstein Bob 
Published: August 2023

SummaryTardigrades are known for their ability to survive remarkable extremes, but relatively little is known about the molecular underpinnings that allow for their extraordinary stress tolerance. We devised an expression cloning approach to screen for novel protectants from desiccation-tolerant tardigrades. We expressed cDNA libraries from the tardigradesHypsibius exemplarisandRamazzottius varieornatusinE. coliand subjected the bacteria to desiccation. Sequencing the populations of surviving bacteria revealed enrichment of mitochondrial single-stranded DNA-binding proteins (mtSSBs) from both tardigrade species. Expression of mtSSBs in bacteria improved desiccation survival to similar levels as some of the best protectants known to date. The DNA-binding activity of the oligonucleotide/oligosaccharide binding (OB) fold domain of mtSSB was necessary and sufficient to improve desiccation tolerance. By comparing the efficacy of mtSSBs from multiple organisms, we provide evidence that desicco-protection is a conserved feature of mtSSBs. More broadly, any OB-fold containing protein may act similarly to promote desiccation tolerance, likely by coating ssDNA to limit damage during desiccation. These results identify single-stranded DNA-binding activity as a potent contributor to extreme desiccation tolerance.
Pharmacologic Targeting of PDIA1 Inhibits NLRP3 Inflammasome Assembly and Activation
Authors: Rosarda Jessica D. , Stanton Caroline R. , Chen Emily B. , Bollong Michael J. , Wiseman R. Luke 
Published: August 2023

SUMMARYThe NLRP3 inflammasome is a cytosolic protein complex that regulates innate immune signaling in response to diverse pathogenic insults through the proteolytic processing and secretion of pro-inflammatory cytokines such as IL-1β. Hyperactivation of NLRP3 inflammasome signaling is implicated in the onset and pathogenesis of numerous diseases, motivating the discovery of new strategies to suppress NLRP3 inflammasome activity. We sought to define the potential for the proteostasis regulator AA147 to inhibit the assembly and activation of the NLRP3 inflammasome. AA147 is a pro-drug that is metabolically converted to a reactive metabolite at the endoplasmic reticulum (ER) membrane to covalently modify ER-localized proteins such as protein disulfide isomerases (PDIs). We show that AA147 inhibits NLRP3 inflammasome activity in monocytes and monocyte-derived macrophages through a mechanism involving impaired assembly of the active inflammasome complex. This inhibition is mediated through AA147-dependent covalent modification of PDIA1. Genetic depletion or treatment with other highly selective PDIA1 inhibitors similarly blocks NLRP3 inflammasome assembly and activation. Our results identify PDIA1 as a potential therapeutic target to mitigate NLRP3 inflammasome-mediated pro-inflammatory signaling implicated in etiologically diverse diseases.
Incidence and Clinical Parameters of HIV-1 Paradoxical and Unmasking Immune Reconstitution Syndrome in Antiretroviral Naïve Pregnant Women attending selected facilities in Kenya
Authors: Muthuka K. John , Nyamai M. Everlyn , Kelly J. Oluoch , Charles Maibvise , Nabaweesi Rosemary 
Published: August 2023

BackgroundFollowing ART initiation, a spectrum of HIV-associated immune reconstitution inflammatory syndrome (IRIS), as opportunistic infections occurs, presenting as either paradoxical or unmasking IRIS. There are benefits of ART for maternal health and prevention of perinatal transmission, however, some risks may be possible with IRIS. The study sought to estimate the incidence, compare survival times to, and investigate the baseline clinical predictors of HIV-1 paradoxical and unmasking IRIS as well as identify the homogeneity defined by combinations of specific covariates in Art Naïve Pregnant Women.MethodsA prospective, active records observational study [P609/08/-2018-E] was conducted among ART-naive pregnant women attending antenatal care unit (ANCu) from Kenyatta National andMbagathiHospitals in Kenya. Participants enrolled were between the ages of 20 - 49 years with a clear documentation of HIV status and, an independent review committee adjudicated IRIS diagnosis. Associations between baseline pre-ART characteristics, biomarkers, and IRIS diagnosis were assessed with Cox models. Decision-tree analysis was finally performed to identify homogeneity defined by combinations of specific parameters.ResultsOf the initial total 532 women, (24.8%) (n=133) participants experienced IRIS by the 12thweek post ART initiation, 27.3 % (n= 36) and 72.7% (n = 96) paradoxical and unmasking respectively. Maternal Basal Metabolic Index (MBMI) of (25 -29.9) significantly predicted unmasking IRIS [(β)=0.907, Wald test (β^) = 6.550, (HR = 2.478, 95% C.I 1.237 – 4.965, P = 0.010] same case to gravidity of above 5 [(β)=0.743, P = 0.338] while that of 2-3 predicted paradoxical IRIS [(β)= - 0.542, P = 0.037. WHO-HIV clinical stage 1 and 2 showed a link towards paradoxical IRIS, [(β)=- 0.111 and (β)= - 0.276 (P < 0.05)], clinical stage 4 with unmasking IRIS [(β)= 0.047, HR = 1.048, P = 0.941]. CD4 count > 500 cells/mm3skewed towards unmasking IRIS diagnosis [(β)= 0.192, HR = 1.211, P = 0.416], while RNA-HIV viral loads > 50 copies/ml towards paradoxical IRIS [(β)= - 0.199, HR = 0.820, P = 0.360. On decision tree analysis, 76% (P = 0.729) of ART naïve pregnant women aged 20-29 and 40-49 years of age presented with unmasking IRIS and a gravidity of 4-5 and 1 predicted 88% (P = 0.045) unmasking IRIS as compared to that of 2-3 62 % (P = 0.045).ConclusionUnmasking IRIS was the common type of IRIS post-ART initiation. Maternal BMI and RNA-HIV viral loads level predicted paradoxical IRIS while the baseline CD4 count and WHO-HIV clinical infection stage 1 and 4 were associated with unmasking IRIS. Gravidities of 1 and 4 – 5 predicted unmasking IRIS.
Comprehensive and quantitative analysis of intracellular structure polarization at the apical–basal axis in elongatingArabidopsiszygotes
Authors: Hiromoto Yukiko , Minamino Naoki , Kikuchi Suzuka , Kimata Yusuke , Matsumoto Hikari , Nakagawa Sakumi , Ueda Minako , Higaki Takumi 
Published: August 2023

AbstractA comprehensive and quantitative evaluation of multiple intracellular structures or proteins is a promising approach to provide a deeper understanding of and new insights into cellular polarity. In this study, we developed an image analysis pipeline to obtain intensity profiles of fluorescent probes along the apical–basal axis in elongatingArabidopsis thalianazygotes based on two-photon live-cell imaging data. This technique showed the intracellular distribution of actin filaments, mitochondria, microtubules, and vacuolar membranes along the apical–basal axis in elongating zygotes from the onset of cell elongation to just before asymmetric cell division. Hierarchical cluster analysis of the quantitative data on intracellular distribution revealed that the zygote may be compartmentalized into two parts, with a boundary located 43.6% from the cell tip, immediately after fertilization. To explore the biological significance of this compartmentalization, we examined the positions of the asymmetric cell divisions from the dataset used in this distribution analysis. We found that the cell division plane was reproducibly inserted 20.5% from the cell tip. This position corresponded well with the midpoint of the compartmentalized apical region, suggesting a potential relationship between the zygote compartmentalization, which begins with cell elongation, and the position of the asymmetric cell division.
WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS
Authors: Chen Huimei , You Ran , Guo Jing , Zhou Wei , Chew Gabriel , Devapragash Nithya , Loh Jui Zhi , Gesualdo Loreto , Li Yanwei , Jiang Yuteng , Tan Elisabeth Li Sa , Chen Shuang , Pontrelli Paola , Pesce Francesco , Behmoaras Jacques , Zhang Aihua , Petretto Enrico 
Published: August 2023

AbstractRenal fibrosis is a common pathological endpoint in chronic kidney disease (CKD) that is challenging to reverse. Although myofibroblasts are mainly responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM) in fibrotic kidney, recent studies have unveiled their diversity in terms of proliferative and fibrotic characteristics. This diversity could be linked with the existence of different metabolic states, and myofibroblast metabolic reprogramming may contribute to the pathogenesis and progression of renal fibrosis. Here, we reveal an unexpected role of the E3 ubiquitin-protein ligase WWP2 in the metabolic reprogramming of myofibroblasts during renal fibrosis. The tubulointerstitial expression of WWP2 contributes to the progression of fibrosis in CKD patients, and in pre-clinical murine models of CKD. WWP2 deficiency increases fatty acid oxidation and activates the pentose phosphate pathway, boosting mitochondrial respiration at the expense of glycolysis. This concurrently promotes myofibroblast proliferation and halts pro-fibrotic activation, reducing the severity of kidney fibrosis. Mechanistically, WWP2 suppresses the transcription of PGC-1α, a metabolic mediator shaping myofibroblast fibrotic response. Pharmacological interventions targeting PGC-1α reverse the effects of WWP2 on fibrotic myofibroblasts. These findings demonstrate the influence of WWP2 on essential metabolic pathways involved in fibrogenesis, uncovering the WWP2-PGC-1α axis that orchestrates the metabolic reprogramming of myofibroblasts during renal fibrosis. Our study presents a potential novel target for therapeutic intervention in the treatment of chronic kidney disease.Graphical abstractHighlightsWWP2 expression is elevated in the tubulointerstitium of fibrotic kidneys and contributes to CKD pathogenesis and progression.WWP2 uncouples the pro-fibrotic activation and cell proliferation in renal myofibroblasts.WWP2 controls mitochondrial respiration in renal myofibroblasts through the metabolic regulator PGC-1αMyofibroblast metabolic reprogramming mediates the effect of WWP2 on fibrotic myofibroblasts.
An analysis of British Michelin-starred restaurants: guests' online reviews
Authors: Saydam Mehmet Bahri , Altun Özlem 
Published: August 2023

PurposeThis study aims to explore the perspectives of patrons and the underlying factors influencing luxury consumption in British Michelin-starred restaurants. While numerous studies have investigated consumers' purchase behavior of luxury items, there is limited research focusing on the utilization of premium restaurant services. Additionally, the hospitality literature has rarely addressed the emergence of discreet luxury consumption. Therefore, this research aims to examine the experiences of British Michelin-starred restaurants by incorporating online reviews from some of the most renowned establishments in the country. The initial objective of this study was to identify the predominant themes within British Michelin-starred restaurant experiences. Furthermore, the authors sought to analyze whether these main themes varied across different market segments based on guest types.Design/methodology/approachUsing text mining tools, the authors analyzed a sample of 4,393 online reviews. Qualitative data analysis was conducted using the Leximancer program, which identified the dominant themes. Additionally, the authors performed an analysis to identify the major narratives associated with different types of guests.FindingsThe results of this analysis demonstrate that guests express a high level of satisfaction with their experiences at British Michelin-starred restaurants. The dominant themes within the narratives include food, wine, restaurant, time, reservation and innovation. It is important to note that these narratives vary depending on the type of guest.Originality/valuePrevious studies have highlighted the importance of market segmentation in Michelin-starred restaurants. This research addresses this need by specifically categorizing British Michelin-starred restaurants based on traveler type and the main concerns of their customers. The extensive data the authors collected and the authors' approach to utilizing guests' testimonials instead of traditional surveys contribute significantly to the field of academia and restaurant management.
Understanding the characteristics of work that foster workplace well-being in an apprenticeship programme and their effects on apprentices' employability. Exploring the gender moderation effect
Authors: Ullibarriarana-Garate Ainhoa , Agirre-Aramburu Izaskun , Mesonero-De Miguel Mikel 
Published: August 2023

PurposeThis study seeks to show whether workplace experience (WE) in an apprenticeship programme affects the duration of joblessness amongst recent university graduates and to determine the antecedents that support a workplace well-being experience during an apprenticeship programme. Additionally, the research introduces the moderating effect of gender in order better to understand under what circumstances apprenticeship reduces the time taken to find employment.Design/methodology/approachThe research proposes PLS equation modelling constructed with a sample of 129 students from the Business Administration and Management degree at Mondragon University.FindingsThe research finds that social support and job demand are key features of work that should be addressed to ensure a workplace well-being experience in an apprenticeship programme. In addition, a workplace well-being experience during apprenticeship reduced the time taken by students to access their first job. This means that job training in a company helps students get their first job, but it is not the primary factor. The study also shows that men who had workplace well-being experience in an apprenticeship programme take less time to find their first job.Originality/valueThe study proposes an exclusive analysis of apprenticeship programmes in higher education systems from the perspective of workplace well-being experience, based on the DCS model. This research also adds to the literature on apprenticeship by providing evidence that a positive experience of work during an apprenticeship programme facilitates undergraduate students in securing employment. Furthermore, this paper confirms that workplace well-being experiences in apprenticeship programmes constitute a valid tool for tackling youth unemployment, and finds that it is more efficient amongst males than females.