bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictors of Clinical Outcomes among People with HIV and Tuberculosis Symptoms after Rapid Treatment Initiation in Haiti
Authors: Richterman Aaron , Dorvil Nancy , Rivera Vanessa , Bang Heejung , Severe Patrice , Lavoile Kerylyne , Pierre Samuel , Apollon Alexandra , Dumond Emelyne , Forestal Guyrlaine Pierre Louis , Rouzier Vanessa , Joseph Patrice , Cremieux Pierre-Yves , Pape Jean W , Koenig Serena P 
Published: June 2024

ABSTRACTIntroductionFew studies have evaluated baseline predictors of clinical outcomes among people with HIV starting antiretroviral therapy (ART) in the modern era of rapid ART initiation.MethodsWe conducted a secondary analysis of a randomized controlled trial of two rapid treatment initiation strategies for people with treatment-naïve HIV and tuberculosis symptoms at an urban clinic in Haiti. We used logistic regression models to assess associations between baseline characteristics and (1) retention in care at 48 weeks, (2) HIV viral load suppression at 48 weeks (among participants who underwent viral load testing), and (3) all-cause mortality.Results500 participants were enrolled in the study 11/2017-1/2020. Eighty-eight (18%) participants were diagnosed with tuberculosis, and ART was started in 494 (99%). After adjustment, less than secondary education (adjusted odds ratio [AOR] 0.21, 95% CI 0.10-0.46), dolutegravir initiation (AOR 2.57, 95% CI 1.22-5.43), age (AOR 1.42 per 10-year increase, 95% CI 1.01-1.99), and tuberculosis diagnosis (AOR 3.92, 95% CI 1.36-11.28) were significantly associated with retention. Age (AOR 1.36, 95% CI 1.05-1.75), dolutegravir initiation (AOR 1.75, 95% CI 1.07-2.85), and tuberculosis diagnosis (AOR 0.50, 95% CI 0.28-0.89) were associated with viral suppression. Higher CD4 cell count at enrollment (unadjusted odds ratio [OR] 0.69, 95% CI 0.55-0.87) and anemia (OR 4.86, 95% CI 1.71-13.81) were associated with mortality.ConclusionsWe identified sociodemographic, treatment-related, clinical, and laboratory-based predictors of clinical outcomes. These characteristics may serve as markers of sub- populations that could benefit from additional interventions to support treatment success after rapid treatment initiation.
Community pharmacists’ referrals to General Practice with suspected need of antibiotics: a national prospective pilot
Authors: Stehlik Paulina , Moles Rebekah , Jones Mark , Murray Amanda , El-Den Sarira , Morgan Mark , Del Mar Chris 
Published: June 2024

AbstractBackgroundInterventions to minimise community antibiotic use have focused on the GP and patient behaviour rather than the community pharmacist. Patient expectations are a known driver for antibiotic prescribing, and pharmacists may be inveterately contributing to these expectations by referring patients for GPs for suspected antibiotic-requiring infections (S-ARI). We sought to quantify these referral rates.MethodPharmacists and GPs were recruited independently using convenience sampling and completed prospective data collection on 20 minor ailment encounters and consecutive consultations respectively. Pharmacists recorded patient gender, age, referral reason and comments (if any). GPs recorded patient age, gender, reason for visit, and origin of patient referral including self-referral.All data were analysed descriptively. Generalised estimating equations, multivariable logistic regression was used to investigate factors that may be associated with pharmacist referral rates.ResultsNineteen pharmacists representing 466 minor ailments encounters, and 19 GPs representing 394 consultations were recruited.Pharmacists referred 16.5% (77/466) of all minor ailments encounters for S-ARI. Comments suggested that reasons included upper-respiratory tract, ear nose and throat, and urinary tract infections. Most of S-ARI referrals were to a GP (62/466).None of the 88 consultations for infection in GP data were documented as being referred by a pharmacist; majority were self-referred (77.3%; 68/88).DiscussionPharmacists referred 1 in 8 minor ailments encounters to the GP for S-ARI, with some indication they were for conditions that do not require antibiotics. Most GP consultations for infection were documented as self-referrals. Both provide potential points of intervention to minimise antibiotic use.
The Effects of Lamin B Receptor knockdown on a Myeloid Leukemia Cell
Authors: Mark Welch David B. , Olins Ada L. , Olins Donald E. 
Published: June 2024

AbstractIn an effort to extend our understanding of the genetic functions of the nuclear envelope protein Lamin B Receptor (LBR), we examined the effect of a stable short hairpin (sh1) RNAi knockdown of LBR on the transcriptome and immunostained morphology of the human myeloid leukemia cell line (HL-60/S4). This examination was on sh1 cells induced to granulocytic form with Retinoic Acid (RA) versus sh1 cells maintained undifferentiated (0). By comparison to control cells (i.e., not sh1), we obtained gene lists that were differentially expressed only in the LBR knockdown cell line (i.e., “only-sh1-down” and “only-sh1-up”), in RA versus 0 cells. These curated gene lists were examined by Gene Ontology (GO) analysis. Aside from chromatin related GO terms, the most surprising finding was a significant downregulation of Golgi related genes only in the sh1 cells. Possible relationships between the “Cis-Golgi-Network” and LBR are discussed. Another surprise was a significant upregulation of “Ribosome” protein transcripts only in the sh1 cells. In parallel to these findings, an immunostaining comparison of nucleoli in S4 and sh1 cells demonstrated that the number and location of nucleoli in a single nucleus differs, depending upon the presence of LBR. Speculations on the influence of LBR levels upon the liquid-liquid phase separation model of nucleolar condensation are presented.
A Spike Trimer Dimer-Inducing Nanobody with Anti-Sarbecovirus Activity
Authors: Swart Iris C. , Debski-Antoniak Oliver J. , Zegar Aneta , de Bouter Thijs , Chatziandreou Marianthi , van den Berg Max , Drulyte Ieva , Pyrć Krzysztof , de Haan Cornelis A.M. , Hurdiss Daniel L. , Bosch Berend-Jan , Oliveira Sabrina 
Published: June 2024

AbstractThe continued emergence and zoonotic threat posed by coronaviruses highlight the urgent need for effective antiviral strategies with broad reactivity to counter new emerging strains. Nanobodies (or single-domain antibodies) are promising alternatives to traditional monoclonal antibodies, due to their small size, cost-effectiveness and ease of bioengineering. Here, we describe 7F, a llama-derived nanobody, targeting the spike receptor binding domain of sarbecoviruses and SARS-like coronaviruses. 7F demonstrates potent neutralization against SARS-CoV-2 and cross-neutralizing activity against SARS-CoV and SARS-like CoV WIV16 pseudoviruses. Structural analysis reveals 7F’s ability to induce the formation of spike trimer dimers by engaging with two SARS-CoV-2 spike RBDs, targeting the highly conserved class IV region. Bivalent 7F constructs substantially enhance neutralization potency and breadth, up to more recent SARS-CoV-2 variants of concern. Furthermore, we demonstrate the therapeutic potential of 7F against SARS-CoV-2 in the fully differentiated 3D tissue cultures mirroring the epithelium of the human airway ex vivo. The broad sarbecovirus activity and distinctive structural features of 7F underscore its potential as promising antiviral against emerging and evolving sarbecoviruses.
The JNK and Hippo pathways control epithelial integrity and prevent tumour initiation by regulating an overlapping transcriptome
Authors: Mitchell Katrina A. , Vissers Joseph H. A. , Pojer Jonathan M. , Brooks Elliot , Hilmi Abdul Jabbar Saiful , Papenfuss Anthony T. , Schröder Jan , Harvey Kieran F. 
Published: June 2024

SUMMARYEpithelial organs maintain their integrity and prevent tumour initiation by actively removing defective cells, such as those that have lost apicobasal polarity. Here, we identify how transcription factors of two key signalling pathways – Jun-N-terminal kinase (JNK) and Hippo – regulate epithelial integrity by controlling transcription of an overlapping set of target genes. Targeted DamID experiments reveal that in proliferating cells of theDrosophila melanogastereye, the AP-1 transcription factor Jun, and the Hippo pathway transcription regulators Yorkie and Scalloped bind to a common suite of target genes that regulate organ growth. In defective neoplastic cells, AP-1 transcription factors repress transcription of growth genes together with the CtBP co-repressor. If gene repression by AP-1/CtBP fails, neoplastic tumour growth ensues, driven by Yorkie/Scalloped. Thus, AP-1/CtBP eliminates defective cells and prevents tumour initiation by acting in parallel to Yorkie/Scalloped to repress expression of a shared transcriptome. These findings shed new light on the maintenance of epithelial integrity and tumour suppression.
Early-Life Group Size Does Not Influence Japanese Quails’ Learning in a Response Inhibition Task
Authors: Willcox Kathryn , Vernouillet Alizée , Lens Luc , Verbruggen Frederick 
Published: June 2024

AbstractIn complex social environments, animals benefit from suppressing inappropriate responses (known as Response Inhibition - RI) to avoid conflicts and maintain group cohesion. Recent research suggests that an individual’s early-life social environment can shape their RI. However, these findings have mostly been correlational, and results vary across species. Furthermore, the role of learning is often overlooked when measuring RI, despite its potential importance to understanding group differences. We investigated the effect of early-life group size, a key determinant of social complexity, on RI in Japanese quails (Coturnix japonica), whilst taking the role of learning into account. Quails (n = 120) were raised in either small groups of five or large groups of 15 individuals. RI was assessed using the cylinder task. Up to 10 trials were administered to assess whether the birds’ responses changed with increasing experience of the task. Among the quails that completed 10 trials, we found that those raised in large groups consistently spent less time pecking the cylinder than those raised in small groups. The quails’ responses were also influenced by their body condition, food motivation, and sex. Importantly, the quails learned to inhibit their responses - successful trials increased, and time spent pecking the cylinder decreased, across 10 trials. However, learning rates did not differ between the treatment groups. These findings suggest that early-life social group size promotes the development of RI in quails, but not their learning during the cylinder task.
Time-resolved mitochondrial-focused screening identifies regulatory components of oxidative metabolism
Authors: Zamora-Dorta Marcos , Laine-Menéndez Sara , Abia David , González-García Pilar , López Luis C. , Fernández-Montes Díaz Paula , Calvo Enrique , Vázquez Jesús , Enríquez José Antonio , Balsa Eduardo 
Published: June 2024

SUMMARYDefects in mitochondrial oxidative metabolism contribute to various genetic inherited disorders, termed mitochondrial diseases, with limited treatment options. Given the lack of functional annotation for numerous mitochondrial proteins, there is a necessity for an extensive gene inventory related to mitochondrial function, with special interest in Oxidative Phosphorylation (OXPHOS). To address this gap, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings at various time points to uncover novel regulators of mitochondrial function. Our study resulted in a gene catalog essential for mitochondrial oxidative metabolism, and constructed a dynamic timeline mapping a broad network of mitochondrial pathways, with a particular focus on the OXPHOS complexes. Computational analysis pinpointed RTN4IP1 and ECHS1 as key genes strongly associated with OXPHOS and whose mutations are associated with mitochondrial diseases in humans. RTN4IP1 was found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Deletion of ECHS1 leads to reduced catabolism of branched-chain amino acids (BCAAs), which impairs the activity of lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.
Immunoactive signatures of circulating tRNA- and rRNA-derived RNAs in chronic obstructive pulmonary disease
Authors: Shigematsu Megumi , Kawamura Takuya , Deshpande Deepak A. , Kirino Yohei 
Published: June 2024

AbstractChronic obstructive pulmonary disease (COPD) is the most prevalent lung disease, and macrophages play a central role in the inflammatory response in COPD. We here report a comprehensive characterization of circulating short non-coding RNAs (sncRNAs) in plasma from patients with COPD. While circulating sncRNAs are increasingly recognized for their regulatory roles and biomarker potential in various diseases, the conventional RNA-seq method cannot fully capture these circulating sncRNAs due to their heterogeneous terminal structures. By pre-treating the plasma RNAs with T4 polynucleotide kinase, which converts all RNAs to those with RNA-seq susceptible ends (5′-phosphate and 3′-hydroxyl), we comprehensively sequenced a wide variety of non-microRNA sncRNAs, such as 5′-tRNA halves containing a 2′,3′-cyclic phosphate. We discovered a remarkable accumulation of the 5′-half derived from tRNAValCACin plasma from COPD patients, whereas the 5′-tRNAGlyGCChalf is predominant in healthy donors. Further, the 5′-tRNAValCAChalf activates human macrophages via Toll-like receptor 7 and induces cytokine production. Additionally, we identified circulating rRNA-derived fragments that were upregulated in COPD patients and demonstrated their ability to induce cytokine production in macrophages. Our findings provide evidence of circulating, immune-active sncRNAs in patients with COPD, suggesting that they serve as inflammatory mediators in the pathogenesis of COPD.
Rapid degradation of Histone Deacetylase 1 (HDAC1) reveals essential roles in both gene repression and active transcription
Authors: English David M , Lee Samuel N , Sabat Khadija A , Baker India M , Pham Trong Khoa , Collins Mark O , Cowley Shaun M 
Published: June 2024

AbstractHistone Deacetylase 1 (HDAC1) removes acetyl groups from lysine residues on the core histones, a critical step in the regulation of chromatin accessibility. Despite histone deacetylation being an apparently repressive activity, suppression of HDACs causes both up- and down-regulation of gene expression. Here we exploited the degradation tag (dTAG) system to rapidly degrade HDAC1 in embryonic stem cells (ESCs) lacking its paralog, HDAC2. Unlike HDAC inhibitors that lack isoform specificity, the dTAG system allowed specific degradation and removal of HDAC1 in <1 hour (100x faster than genetic knockouts). This rapid degradation caused increased histone acetylation in as little as 2 hours, with H2BK5 and H2BK11 being the most sensitive. The majority of differentially expressed genes following 2 hours of HDAC1 degradation were upregulated (275 genes up vs 15 down) with increased proportions of downregulated genes observed at 6 (1,153 up vs 443 down) and 24 hours (1,146 up vs 967 down) respectively. Upregulated genes showed increased H2BK5ac and H3K27ac around their transcriptional start site (TSS). In contrast, decreased acetylation of super-enhancers (SEs) was linked to the most strongly downregulated genes. These findings suggest a paradoxical role for HDAC1 in the maintenance of histone acetylation levels at critical enhancer regions required for the pluripotency-associated gene network.
PBP4 is required for serum-induced cell wall thickening and antibiotic tolerance inStaphylococcus aureus
Authors: Ledger Elizabeth V. K. , Massey Ruth C. 
Published: June 2024

AbstractThe bacterial pathogenStaphylococcus aureusresponds to the host environment by synthesising a thick peptidoglycan cell wall which protects the bacterium from membrane-targeting antimicrobials and the immune response. However, the proteins required for this response were previously unknown. Here, we demonstrate by three independent approaches that the penicillin binding protein PBP4 is crucial for serum-induced cell wall thickening. Firstly, mutants lacking various non-essential cell wall synthesis enzymes were tested, revealing that a mutant lackingpbp4was unable to generate a thick cell wall in serum. This resulted in reduced serum-induced tolerance of thepbp4mutant towards the last resort antibiotic daptomycin relative to wildtype cells. Secondly, we found that serum-induced cell wall thickening occurred in each of a panel of 134 clinical bacteraemia isolates, except for one strain with a naturally-occurring mutation that confers a S140R substitution in the active site of PBP4. Finally, inhibition of PBP4 with cefoxitin prevented serum-induced cell wall thickening and the resulting antibiotic tolerance in the USA300 strain and in clinical MRSA isolates. Together, this provides a rationale for combining daptomycin with cefoxitin, a PBP4 inhibitor, to potentially improve treatment outcomes for patients with invasive MRSA infections.
Spine loss in depression impairs dendritic signal integration in human cortical microcircuit models
Authors: Yao Heng Kang , Mazza Frank , Prevot Thomas , Sibille Etienne , Hay Etay 
Published: June 2024

AbstractMajor depressive disorder (depression) is associated with altered dendritic structure and function in excitatory cortical pyramidal neurons, due to decreased inhibition from somatostatin interneurons and loss of spines and associated synapses, as indicated in postmortem human studies. Dendrites play an important role in signal processing as they receive the majority of synaptic inputs and exhibit nonlinear properties including backpropagating action potentials and dendritic Na+spikes that enhance the computational power of the neuron. However, it is currently unclear how depression-related dendritic changes impact the integration of signals. Here, we expanded our previous data-driven detailed computational models of human cortical microcircuits in health and depression to include active dendritic properties that enable backpropagating action potentials as measured in human neurons, and spine loss in depression in terms of synapse loss and altered intrinsic property. We show that spine loss dampens signal response and thus results in a larger impairment of cortical function such as signal detection than due to reduced somatostatin interneuron inhibition alone. We further show that the altered intrinsic properties due to spine loss abolish nonlinear dendritic integration of signals and impair recurrent microcircuit activity. Our study thus mechanistically links cellular changes in depression to impaired dendritic processing in human cortical microcircuits.
Structural architecture of TolQ-TolR inner membrane protein complex from opportunistic pathogenAcinetobacter baumannii
Authors: Karimullina Elina , Guo Yirui , Khan Hanif M. , Emde Tabitha , Quade Bradley , Leo Rosa Di , Otwinowski Zbyszek , Tieleman Peter D. , Borek Dominika , Savchenko Alexei 
Published: June 2024

AbstractGram-negative bacteria harness the proton motive force (PMF) within their inner membrane (IM) to uphold the integrity of their cell envelope, an indispensable aspect for both division and survival. The IM TolQ-TolR complex is the essential part of the Tol-Pal system, serving as a conduit for PMF energy transfer to the outer membrane. Here we present cryo-EM reconstructions ofAcinetobacter baumanniiTolQ in apo and TolR- bound forms at atomic resolution. The apo TolQ configuration manifests as a symmetric pentameric pore, featuring a trans-membrane funnel leading towards a cytoplasmic chamber. In contrast, the TolQ-TolR complex assumes a proton non-permeable stance, characterized by the TolQ pentamer’s flexure to accommodate the TolR dimer, where two protomers undergo a translation-based relationship. Our structure-guided analysis and simulations support the rotor-stator mechanism of action, wherein the rotation of the TolQ pentamer harmonizes with the TolR protomers’ interplay. These findings broaden our mechanistic comprehension of molecular stator units empowering critical functions within the Gram-negative bacterial cell envelope.TeaserApo TolQ and TolQ-TolR structures depict structural rearrangements required for cell envelope organization in bacterial cell division.
Unraveling the effects of polyhydroxyalkanoates accumulation inPseudomonas extremaustralisgrowth and survival under different pH conditions
Authors: Brito María Gabriela , López Nancy I. , Raiger Iustman Laura J. 
Published: June 2024

AbstractPolyhydroxyalkanoates (PHAs) are intracellular polymers that enhance bacterial fitness against various environmental stressors.Pseudomonas extremaustralis14-3b is an Antarctic bacterium capable of accumulating, short-chain-length PHAs (sclPHAs), composed of C3–C5 monomers, as well as medium-chain-length PHAs (mclPHAs) containing ≥C6 monomers. Since pH changes are pivotal in bacterial physiology, influencing microbial growth and metabolic processes, we propose that accumulated PHA increasesP. extremaustralisfitness to cope with pH changes. To test this, we analyzed the production of sclPHA and mclPHA at different pH levels and its effect on bacterial survival against pH stress.P. extremaustraliswas able to grow and accumulate PHA when the culture media pH ranged from 6.0 to 9.5, showing a marked loss of viability outside this range. Additionally, based on the analysis of different PHA-deficient mutants, we found that when exposed to both acidic and alkaline conditions, sclPHA and mclPHA conferred different protection against pH stress, with sclPHA making the main contribution. These results highlight the importance of PHA in supporting survival in pH-stressful environments.