bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV Outcomes Among Women Living With HIV Who Experienced Early Sexual Violence Across Four Sub-Saharan African Countries
Authors: Lee Chiara-lyse , Low Andrea , Kreniske Philip , Mugurungi Owen , Ndagije Felix , Tenthani Lyson , Abrams Elaine J. , Teasdale Chloe A. 
Published: July 2024

Background:
Early experiences of sexual violence may influence HIV care and treatment outcomes among women living with HIV (WLHIV). We examined whether self-report by WLHIV of being forced into their first sexual experience was associated with awareness of HIV-positive status, being on antiretroviral therapy (ART) and being virologically suppressed.

Setting:
We conducted a secondary analysis using nationally representative, cross-sectional Population-based HIV Impact Assessment surveys from Lesotho, Malawi, Zambia, and Zimbabwe conducted from 2015 through 2017.

Methods:
Adjusted logistic regression models with survey weights and Taylor series linearization were used to measure the association between forced first sex and 3 HIV outcomes: (1) knowledge of HIV status among all WLHIV, (2) being on ART among WLHIV with known status, and (3) virological suppression among WLHIV on ART.

Results:
Among WLHIV, 13.9% reported forced first sex. Odds of knowledge of HIV status were not different for WLHIV with forced first sex compared with those without (adjusted odds ratio [aOR], 1.17; 95% CI: 0.95 to 1.45). Women living with HIV with forced first sex had significantly lower odds of being on ART (aOR 0.74, 95% CI: 0.57 to 0.96) but did not have lower odds of virological suppression (aOR 1.06, 95% CI: 0.80 to 1.42) compared with WLHIV without forced first sex.

Conclusions:
While high proportions of WLHIV were on ART, report of nonconsensual first sex was associated with a lower likelihood of being on ART which may suggest that early life trauma could influence long-term health outcomes.
Functional properties of a disease mutation for migraine in Kv2.1/6.4 channels
Authors: Tewari Debanjan , Sattler Christian , Benndorf Klaus 
Published: July 2024

AbstractVoltage-gated potassium (Kv) channels are integral to cellular excitability, impacting the resting membrane potential, repolarization, and shaping action potentials in neurons and cardiac myocytes. Structurally, Kv channels are homo or heterotetramers comprising four α-subunits, each with six transmembrane segments (S1-S6). Silent Kv (KvS), includes Kv5.1, Kv6.1-6.4, Kv8.1-8.2, and Kv9.1-9.3, they do not form functional channels on their own but modulate the properties of heteromeric channels. Recent studies have identified the Kv6.4 subunit as a significant modulator within heteromeric channels, such as Kv2.16.4. The Kv2.16.4 heteromer exhibits altered biophysical properties, including a shift in voltage-dependent inactivation and a complex activation. Current genetic studies in migraine patients have revealed a single missense mutation in the Kv6.4 gene. The single missense mutation, L360P is in the highly conserved S4-S5 linker region. This study aims to demonstrate the biophysical effects of the L360P mutation in Kv2.1 6.4 channels with a fixed 2:2 stoichiometry, using monomeric (Kv2.1/6.4) and tandem dimer (Kv2.1_6.4) configurations. Our findings suggest that the L360P mutation significantly impacts the function and regulation of Kv2.1/6.4 channels, providing insights into the molecular mechanisms underlying channel dysfunction in migraine pathology.Statement of significanceThis study elucidates the biophysical properties of the Kv6.4 L360P mutation, providing insights into its role in Kv2.1 6.4 channel function. Given the high conservation of the leucine residue in the Kv channel family and its association with migraine, our findings have significant implications for understanding the molecular basis of migraine pathophysiology. By analyzing channels with a fixed 2:2 stoichiometry, we highlight the impact of the L360P mutation on channel gating and inactivation. This research advances the knowledge of the silent Kv6.4 channel mechanism and its role in pathophysiology.
Vcam1+ Fibro-adipogenic Progenitors Mark Fatty Infiltration in Chronic Limb Threatening Ischemia
Authors: Dai Qunsheng , Wan Changxin , Xu Yueyuan , Fei Kaileen , Olivere Lindsey A. , Garrett Brianna , Akers Leo , Peters Derek , Otto James , Kontos Christopher D. , Ji Zhiceng , Diao Yarui , Southerland Kevin W. 
Published: July 2024

AbstractSkeletal muscle health and function is a critical determinant of clinical outcomes in patients with peripheral arterial disease (PAD). Herein, we identify fatty infiltration, the ectopic deposition of adipocytes in skeletal muscle, as a histological hallmark of end-stage PAD, also known as chronic limb threatening ischemia (CLTI). Leveraging single cell transcriptome mapping in mouse models of PAD, we identify a pro-adipogenic mesenchymal stromal cell population marked by expression of Vcam1 (termed Vcam1+ FAPs) that expands in the ischemic limb. Mechanistically, we identify Sfrp1 and Nr3c1 as regulators of Vcam1+ FAP adipogenic differentiation. Loss of Sfrp1 and Nr3c1 impair Vcam1+ FAP differentiation into adipocytesin vitro. Finally, we show that Vcam1+ FAPs are enriched in human CLTI patients. Collectively, our results identify a pro-adipogenic FAP subpopulation in CLTI patients and provide a potential therapeutic target for muscle regeneration in PAD.
A look beyond topography: transient phenomena ofEscherichia colicell division captured with high-speed in-line force mapping
Authors: Ganser Christian , Nishiguchi Shigetaka , Chan Feng-Yueh , Uchihashi Takayuki 
Published: July 2024

AbstractLife on the nanoscale has been made accessible in recent decades by the development of techniques that are fast and non-invasive. High-speed atomic force microscopy (HS-AFM) is one such technique that has proven to shed light on elusive mechanisms involving single proteins. Extending HS-AFM to effortlessly incorporate mechanical property mapping while maintaining fast imaging speed allows us to look deeper than topography and reveal more details of the nanoscale mechanisms that govern life. Here, we present high-speed in-line force mapping (HS-iFM), which enables the recording of mechanical properties and topography maps with high spatiotemporal resolution. Employing this method, a detailed study of the dynamic nanoscale mechanical properties of livingEscherichia colibacteria reveals localized stiffening during division, intricate details of the division process, formation and diffusion of pores in the membrane, and the impact of depressurization of a cell. All of these phenomena were recorded with a frame time as low as 15 s and a spatial resolution of 5.5 nm/pixel in topography and 22 nm/pixel in force maps, allowing the capture of transient phenomena on bacterial surfaces in striking detail.
Faster model-based estimation of ancestry proportions
Authors: Santander Cindy G. , Refoyo Martinez Alba , Meisner Jonas 
Published: July 2024

AbstractAncestry estimation from genotype data in unrelated individuals has become an essential tool in population and medical genetics to understand demographic population histories and to model or correct for population structure. TheADMIXTUREsoftware is a widely used model-based approach to account for population stratification, however, it struggles with convergence issues and does not scale to modern human datasets or the large number of variants in whole-genome sequencing data. Likelihood-free approaches optimize a least square objective and have gained popularity in recent years due to their scalability. However, this comes at the cost of accuracy in the ancestry estimates in more complex admixture scenarios. We present a new model-based approach,fastmixture, which adopts aspects from likelihood-free approaches for parameter initialization, followed by a mini-batch expectation-maximization procedure to model the standard likelihood. In a simulation study, we demonstrate that the model-based approaches offastmixtureandADMIXTUREare significantly more accurate than recent and likelihood-free approaches. We further show thatfastmixtureruns approximately 30×faster thanADMIXTUREon both simulated and empirical data from the 1000 Genomes Project such that our model-based approach scales to much larger sample sizes than previously possible. Our software is freely available athttps://github.com/Rosemeis/fastmixture.
Mineral Phase Changes During Intervertebral Disc Degeneration
Authors: Yenen Theresa Banu , Jugdaohsingh Ravin , Thom William D. , Khan Sam , Solano Viviana Rojas , Lampronti Giulio , Brown Andy , Saez Janire , Corbetta Davide , Eminağa Salih , Cherubini Giunio Bruto , Powell Jonathan , Hughes Kate , Freeman Paul 
Published: July 2024

ABSTRACTIntervertebral disc disease is a common cause of pain and neurological deficits and is known to be associated with degeneration and calcification. Here we analysed samples of herniated disc material and compared it to material taken from non-herniated discs following surgical treatment in dogs. Our clinical approach to these cases allows collection of samples providing a unique opportunity for a case-controlled study such as this, an opportunity which is not available to the human neurosurgeon. We analysed all samples using Fourier transform infrared (FTIR) spectroscopy, as well as a proportion with X-ray diffraction (XRD) and transmission electron microscopy (TEM). FTIR spectra of the majority of herniated samples were consistent with the presence of crystalline hydroxyapatite, whereas most of the non-herniated discs showed spectra consistent with amorphous phosphate material. XRD analysis and TEM confirmed these findings and identified the amorphous material as amorphous calcium phosphate nanoparticle clusters of ∼ 20 nm diameter and the crystalline hydroxyapatite material as needles up to 100 nm in length.The differences between the herniated and non-herniated discs indicate that the degenerative process involves a conversion of amorphous calcium phosphate into crystalline hydroxyapatite which precedes and may predispose the disc to herniate.
Slow diffusion and signal amplification on membranes regulated by phospholipase D
Authors: Honda Gen , Tanaka Chihuku , Sawai Satoshi , Yanagisawa Miho 
Published: July 2024

AbstractControl of molecular diffusion is pivotal for highly fluidic membranes to serve as substrates for biochemical reactions and the self-assembly of molecular machinery driving membrane protrusions. Lateral diffusion in membranes depends on lipid composition, which is highly diverse and homeostatically controlled in living cells. Due to the complexity of the underlying processes, its impact on molecular diffusion remain largely unclear. In this study, we show that lipid diffusion in model membranes is markedly decreased in cytosolic extracts. The reduction in lipid diffusivity could be pharmacologically inhibited by targeting phospholipase D (PLD), and addition of PLD to membranes mimicked the reduction in diffusion. Phosphatidic acid, a direct product of PLD, diffused slowly in model membranes and reduced the diffusivity of surrounding lipids. Furthermore, we demonstrated that PLD specifically controls the lateral diffusion of a myristoylated protein in cells, possibly due to auxiliary electrostatic interactions between cationic residues located near the lipidated tail and anionic phospholipids. PLD controlled the size and lifetime of localized patches of phosphatidylinositol (3,4,5) triphosphates that specify regions of membrane protrusions. Overall, the results of this study suggest that PLD controls the lateral diffusion of certain membrane proteins, which play key roles in phosphoinositide signaling.Significance StatementIn living cells, many biochemical reactions occur in confined regions on the membranes, facilitating the local occurrence of specific events, such as membrane protrusion. This is puzzling from a physical perspective because the membrane is a two-dimensional fluidic structure that should allow molecules to spread freely. Herein, we found that the fluidity of artificial membranes was markedly reduced by adding extracts from the cell cytoplasm. A lipid-modifying protein phospholipase D (PLD) was found to be responsible for this and it regulates the diffusion of membrane proteins in cells. This study suggests the novel role of PLD as a regulator of molecular diffusion and its impact on phosphoinositide production that serves as an important signal for cell deformation.
Live-cell single-molecule dynamics of eukaryotic RNA polymerase machineries
Authors: Ling Yick Hin , Liang Chloe , Wang Sixiang , Wu Carl 
Published: July 2024

AbstractEukaryotic gene expression in the nucleus is orchestrated by three RNA polymerases (RNAP-I, -II, and -III) and associated factors1,2. Despite extensive biochemical, genomic, structural, and imaging studies, the real-time dynamics of these transcription complexes remain obscure. Here, we employ single-molecule tracking in living yeast to assess the physiological kinetics of over 50 representative proteins encompassing all three RNAP machineries. Components of RNAPI and RNAPIII pre-initiation complexes (PICs) engage in long-lived interactions on chromatin, reflecting their roles for constitutive rRNA and tRNA synthesis, in contrast to the transient RNAPII PIC. We further report the dynamics of key components across the RNAPII transcription cycle2–5—factors for upstream regulation, elongation, histone modification, RNAPII C-terminal domain (CTD) modification, RNA processing, and termination—revealing unprecedented insights into the temporal landscape of RNAPII transcription. Strikingly, many elongation factors, previously thought to travel processively with RNAPII, display transient residence times, suggesting highly dynamic interactions rather than constant association. Systematic screening of RNAPII-associated factors shows that truncation of RNAPII-CTD substantially reduces U1 snRNP residence time and decreases intron retention in ribosomal protein genes, providing insights into how CTD length influences co-transcriptional splicing. Our findings establish a framework for dynamic chromatin interactions of RNA polymerase machineries in living cells.
Human Gastric Multi-Regional Assembloids Favour Functional Parietal Maturation and Allow Modelling of Antral Foveolar Hyperplasia
Authors: Jones Brendan C , Benedetti Giada , Calà Giuseppe , Tullie Lucinda , Simcock Ian C , Lutman Roberto , Balys Monika , Amiri Ramin , Sufi Jahangir , Arthurs Owen , Eaton Simon , Anderson Glenn , Elvassore Nicola , Li Vivian SW , Jones Kelsey DJ , Tape Christopher J. , Luni Camilla , Giobbe Giovanni Giuseppe , De Coppi Paolo 
Published: July 2024

AbstractPatient-derived human organoids have the remarkable capacity to self-organise into more complex structures. However, to what extent gastric organoids can recapitulate human stomach physiological functions remain unexplored. Here, we report how region-specific gastric organoids can self-assemble into complex multi-regional assembloids showing functional response to drugs targeting the ATPase H+/K+ pump. The assembloids show preserved fundus, body, and antrum regional identity, and gastric-specific crosstalk pathways arise. The increased complexity and cross-communication between the different gastric regions, allow for the emergence of the elusive parietal cell type, responsible for the production of gastric acid, with functional response to drugs targeting the ATPase H+/K+ pump. Remarkably, we generated assembloids from PMM2-HIPKD-IBD paediatric patients (Phosphomannomutase 2 – Hyperinsulinemic hypoglycaemia and autosomal recessive polycystic kidney disease - Inflammatory bowel disease), a genetic condition found to be associated with unusual antral foveolar hyperplasia and hyperplastic polyposis. The cellular mechanisms behind such phenomena are poorly understood, and an exhaustive experimental model is needed. The ΔPMM2 multi-regional assembloid we have generated efficiently recapitulates hyperplastic-like antral regions, with decreased mucin secretion and glycosylated ATP4b, which results in impaired gastric acid secretion. Multi-regional gastric assembloids, generated using adult-stem cell-derived organoids, successfully recapitulate the structural and functional characteristics of the human stomach, offering a promising tool for studying gastric epithelial interactions and disease mechanisms previously challenging to investigate in primary models.
Priming lymphocyte responsiveness and differential T cell signaling in pediatric IBD patients withCannabisuse
Authors: Sanctuary Megan R. , Hudacheck Cinthia L. , Jones Ashleigh J. , Murphy Brittany V. , Welsh Nichole , Klawitter Jost , Hoffenberg Edward J. , Collins Colm B. 
Published: July 2024

AbstractThe prevalence of inflammatory bowel disease (IBD) has increased dramatically in recent years, particularly in pediatric populations. Successful remission with current therapies is limited and often transient, leading patients to seek alternative therapies for symptom relief, including the use of medical marijuana (Cannabis sativa). However, chronic cannabis use among IBD patients is associated with increased risk for surgical interventions. Therefore, determining the direct impact of cannabis use on immune modulation in IBD patients is of critical importance. Peripheral blood mononuclear cells of cannabis using and non-using pediatric IBD patients were phenotyped by flow cytometry and functionally assessed for their cytokine production profile. A phospho-kinase array was also performed to better understand changes in immune responses. Results were then compared with serum phytocannabinoid profiles of each patient to identify cannabinoid-correlated changes in immune responses.Results demonstrated elevated levels of a myriad of pro-inflammatory cytokines in users versus non-users. Differences in signaling cascades of activated T cells between users and non-users were also observed. A number of anti-inflammatory cytokines were inversely correlated with serum phytocannabinoids. These results suggest that cannabis exposure, which can desensitize cannabinoid receptors, may prime pro-inflammatory pathways in pediatric IBD patients.Article SummaryThis observational study examines the impact of chronic cannabis use on peripheral immune cell function in adolescent IBD patients from Children’s Hospital Colorado. Cannabis users displayed altered T cell phenotype, increased pro-inflammatory cytokine release and dephosphorylation of protective protein kinases.
Single cell profiling to determine influence of wheeze and early-life viral infection on developmental programming of airway epithelium
Authors: Berdnikovs Sergejs , Newcomb Dawn C , McKernan Kaitlin E , Kuehnle Shelby N , Haruna Nana-Fatima , Gebretsadik Tebeb , McKennan Christopher , Ma Siyuan , Cephus Jacqueline-Yvonne , Rosas-Salazar Christian , Anderson Larry J , Gern James E , Hartert Tina 
Published: July 2024

AbstractAlthough childhood asthma is in part an airway epithelial disorder, the development of the airway epithelium in asthma is not understood. We sought to characterize airway epithelial developmental phenotypes in those with and without recurrent wheeze and the impact of infant infection with respiratory syncytial virus (RSV). Nasal airway epithelial cells (NAECs) were collected at age 2-3 years from ana prioridesigned nested birth cohort of children from four mutually exclusive groups of wheezers/non-wheezers and RSV-infected/uninfected in the first year of life. NAECs were cultured in air-liquid interface differentiation conditions followed by a combined analysis of single cell RNA sequencing (scRNA-seq) andin vitroinfection with respiratory syncytial virus (RSV). NAECs from children with a wheeze phenotype were characterized by abnormal differentiation and basal cell activation of developmental pathways, plasticity in precursor differentiation and a delayed onset of maturation. NAECs from children with wheeze also had increased diversity of currently known RSV receptors and blunted anti-viral immune responses toin vitroinfection. The most dramatic changes in differentiation of cultured epithelium were observed in NAECs derived from children that had both wheeze and RSV in the first year of life. Together this suggests that airway epithelium in children with wheeze is developmentally reprogrammed and characterized by increased barrier permeability, decreased antiviral response, and increased RSV receptors, which may predispose to and amplify the effects of RSV infection in infancy and susceptibility to other asthma risk factors that interact with the airway mucosa.SUMMARYNasal airway epithelial cells from children with wheeze are characterized by altered development and increased susceptibility to RSV infection.
VTA μ–opioidergic neurons facilitate low sociability in protracted opioid withdrawal
Authors: Jo Adrienne Y. , Xie Yihan , Rodrigues Amrith , Sandoval Ortega Raquel Adaia , Creasy Kate Townsend , Beier Kevin T. , Blendy Julie A. , Corder Gregory 
Published: July 2024

ABSTRACTOpioids initiate dynamic maladaptation in brain reward and affect circuits that occur throughout chronic exposure and withdrawal that persist beyond cessation. Protracted withdrawal is characterized by negative affective behaviors such as heightened anxiety, irritability, dysphoria, and anhedonia, which pose a significant risk factor for relapse. While the ventral tegmental area (VTA) and mu-opioid receptors (MORs) are critical for opioid reinforcement, the specific contributions of VTAMORneurons in mediating protracted withdrawal-induced negative affect is not fully understood. In our study, we elucidate the role of VTAMORneurons in mediating negative affect and altered brain-wide neuronal activities following opioid exposure and withdrawal in male and female mice. Utilizing a chronic oral morphine administration model, we observe increased social deficit, anxiety-related, and despair-like behaviors during protracted withdrawal. VTAMORneurons show heightened neuronal FOS activation at the onset of withdrawal and connect to an array of brain regions that mediate reward and affective processes. Viral re-expression of MORs selectively within the VTA of MOR knockout mice demonstrates that the disrupted social interaction observed during protracted withdrawal is facilitated by this neural population, without affecting other protracted withdrawal behaviors. Lastly, VTAMORscontribute to heightened neuronal FOS activation in the anterior cingulate cortex (ACC) in response to an acute morphine challenge, suggesting their unique role in modulating ACC-specific neuronal activity. These findings identify VTAMORneurons as critical modulators of low sociability during protracted withdrawal and highlight their potential as a mechanistic target to alleviate negative affective behaviors associated with opioid withdrawal.SIGNFICANCEThe compelling urge for relief from negative affective states during long-term opioid withdrawal presents a crucial challenge for maintaining abstinence. The ventral tegmental area (VTA) and its mu-opioid receptor-expressing (VTAMOR) neurons represent a critical target of opioidergic action that underlie dependence and withdrawal. Chronic activation of VTAMORneurons during opioid exposure induces maladaptations within these neurons and their structurally connected circuitries, which alter reward processing and contribute to negative affect. Using an oral morphine drinking paradigm to induce dependence, we demonstrate that withdrawal engages VTAMORneurons and identify this neuronal population as key mediators of opioid withdrawal-induced social deficits. These findings hold promise to inform development of targeted therapies aimed at alleviating negative affective states associated with protracted opioid withdrawal.