bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of Novel and Selective GPR17 Antagonists as Pharmacological Tools for Developing New Therapeutic Strategies in Diabetes and Obesity
Authors: Zhu Hu , Conley Jason M. , Karavadhi Surendra , LaVigne Justin E. , Watts Val J. , Sun Hongmao , Shen Min , Hall Matthew D. , Ren Hongxia , Patnaik Samarjit 
Published: December 2024

AbstractG protein coupled receptors (GPCRs) are promising targets for diabetes and obesity therapy due to their roles in metabolism and excellent potential for pharmacological manipulation. We previously reported thatGpr17ablation in the brain-gut axis leads to improved metabolic homeostasis, suggesting GPR17 antagonism could be developed for diabetes and obesity treatment. Here, we performed high throughput screening (HTS) and identified two new GPR17 antagonists (compound 978 and 527). Both compounds antagonized downstream Gαi/o, Gαq and β-arrestin signaling with high selectivity for GPR17, but not the closely related purinergic and cysteinyl leukotriene receptors. The molecular mechanisms of antagonism were revealed through Schild analysis, structure-activity relationship (SAR) studies and homology modelling. Compound 978 and its analog (793) attenuated GPR17 signaling and promoted glucagon-like peptide-1 (GLP-1) secretion in enteroendocrine cells. In summary, we identified selective GPR17 antagonists through HTS, which represent promising pharmacological tools for developing new therapeutic strategies in diabetes and obesity.SignificanceOur work highlights the therapeutic potential of GPR17 antagonism in the treatment of diabetes and obesity by leveraging its role in metabolic regulation. In previous studies, we have shown thatGpr17ablation improves metabolic homeostasis, and here we expanded our research by identifying two novel small molecule antagonists of GPR17 through high-throughput screening. The compounds inhibited multiple downstream signaling pathways of GPR17 with high selectivity over other closely related receptors. Of particular significance, compound 978 and its analogs not only attenuated GPR17 signaling but also increased glucagon-like peptide-1 (GLP-1) secretion, a critical hormone for glucose homeostasis and appetite regulation. These findings shed new light into the molecular mechanisms of GPR17 antagonism and introduce valuable pharmacological tools for further exploration of therapeutic strategies in diabetes and obesity.
Buca della Iena and Grotta del Capriolo: new chronological, lithic, and faunal analyses of two late Mousterian sites in Central Italy
Authors: Gennai Jacopo , Higham Tom , Romboni Marco , Fiorillo Angelica , Giannì Maddalena , van der Sluis Laura , Marchi Damiano , Starnini Elisabetta 
Published: December 2024

AbstractNew radiocarbon, lithic, faunal, and documentary analyses of two sites, Buca della Iena and Grotta del Capriolo, excavated in the 1970s, enhance our understanding of late Neanderthal settlement in the northwestern Italian peninsula and provide insights into their demise.Reassessment of stratigraphical and fieldwork documentation identified areas of stratigraphic reliability, supporting robust interpretations. Radiocarbon dating reveals broadly contemporaneous occupations at both sites between 50–40 ka cal BP, with Buca della Iena showing occupation from approximately 47 to 42.5 ka cal BP. Lithic analyses demonstrate the consistent application of the samechaîne opératoireacross both sites. Faunal analyses indicate that carnivores, particularlyCrocuta spelaea, were the dominant accumulating agents in Buca della Iena, while limited preservation at Grotta del Capriolo prevents detailed taxonomic determination. However, hominin presence at both sites is evidenced by cut-marked bones. This study provides new perspectives on the Middle-to- Upper Palaeolithic transition in the northwestern Italian peninsula.
Role Of Pcdh15 In The Development Of Intrinsic Polarity Of Inner Ear Hair Cells
Authors: Kaushik Raman , Pandey Shivangi , Prakash Anubhav , Abe Takaya , Kiyonari Hiroshi , Ladher Raj K. 
Published: December 2024

ABSTRACTIn vertebrates, auditory information is transduced in the cochlea by mechanosensory hair cells (HC) through an eccentrically organised structure known as the hair bundle. This consists of a true cilium, known as the kinocilium, and modified microvilli, known as stereocilia. The hair bundle has a distinct structure with stereocilia organised in graded rows, with the longest abutting the kinocilia. The hair bundles of all HC are aligned to the tissue axis and are planar polarised. Important in the development and physiology of HC are protein bridges consisting of cadherin-23 and protocadherin-15. These link the tips of stereocilia, where they play a role in mechanotransduction, and between the kinocilia and the stereocilia, where they are involved in development. Both cadherin-23 and protocadherin-15 mutations result in defects in planar polarity; however, the mechanism through which this defect arises is unclear. Using a novel mutant for the Pcdh15-CD2 isoform, we show that while the initial deflection of the kinocilium occurs, its peripheral migration to register with Gαi3 is perturbed. Pcdh15-CD2 genetically interacts with Gpsm2, perturbing vestibular function. We find that the earliest expression of Pcdh15-CD2 is at the base of the kinocilia, and the defects in morphogenesis occur before the formation of kinocilial links. By re-introducing functional Pcdh15-CD2, we show that polarity can be restored, suggesting that Pcdh15-CD2 couples kinocilial and stereocilial development through a mechanism independent of kinocilial links.
Strengthening evidence for text-based telehealth in post-operative care: A pragmatic study of the reach and effectiveness of two-way, text-based follow-up after voluntary medical male circumcision in South Africa
Authors: Feldacker Caryl , Fabens Isabella , Dong Tracy , Moyo Khumbulani , Makhele Calsile , Phohole Motshana , Igaba Nelson , Hlongwane Sizwe , Pienaar Jacqueline , Sardini Maria , Ndebele Felex , Tweya Hannock , Holec Marrianne , Waweru Evelyn , Setswe Geoffrey 
Published: December 2024

AbstractBuilding upon evidence of safety and efficiency gains from a randomized control trial (RCT) in South Africa, we further scaled implementation of two-way, short message service (SMS), text-based (2wT) follow-up after voluntary medical male circumcision (VMMC). We aimed to determine if gains in adverse event (AE) identification and reduced follow-up visits could be maintained when 2wT was implemented in routine VMMC settings. A pragmatic, stepped wedge design (SWD) study was implemented across three districts in South Africa. Men ages 15 and older could opt into the 2wT telehealth follow-up approach when their facility was in the intervention period. Men in routine periods were offered the standard of care (SoC): in-person post-operative visits on days 2 and 7 as per national VMMC guidelines. 2wT participants were not required to attend any postoperative visits but could return for care if desired or referred. Two quality of care markers, safety (AE ascertainment rate) and efficiency (# in-person follow-up visits), were compared between groups. We aimed for at least 200 men per step to have 80% power to detect a change in AE rate from before to after 2wT was implemented. Secondary analysis explored response rates; client and site uptake; and AE details. Among 6842 clients in the intervention period, 2856 opted into 2wT (37.8%) across three intervention waves and two platforms (SMS or WhatsApp). Among those with post-operative follow-up, the AE ascertainment rate was higher among 2wT (0.60%) than SoC (0.13%) clients (p = 0.0018), demonstrating safety gains. On average, 2wT participants had 2.1 fewer visits compared to SoC clients (p<0.001), demonstrating gains in follow-up efficiency. Among 2wT men, 2069/2586 (80%) responded via 2wT over 14 days, demonstrating engagement in post-operative care. Of all intervention clients, 93 2wT (3.6%) and 342 (8.0%) SoC were considered lost to follow-up. In this expansion trial, we provided additional evidence that the 2wT approach maintains the quality of post-operative care for adult VMMC clients. 2wT should be scaled to augment in-person, post-operative visits after VMMC for eligible, interested males ages 15 and older. To achieve potential impact, effort is needed to improve access and uptake to 2wT among providers and sites, expanding the 2wT approach for other acute follow-up care especially among men.
Plasma proteomics for novel biomarker discovery in childhood tuberculosis
Authors: Fossati Andrea , Wambi Peter , Jaganath Devan , Calderon Roger , Castro Robert , Mohapatra Alexander , McKetney Justin , Luiz Juaneta , Nerurkar Rutuja , Nkereuwem Esin , Franke Molly F. , Mousavian Zaynab , Collins Jeffrey M. , Sigal George B. , Segal Mark R. , Kampman Beate , Wobudeya Eric , Cattamanchi Adithya , Ernst Joel D. , Zar Heather J. , Swaney Danielle L. ,   the COMBO Study
Published: December 2024

AbstractFailure to rapidly diagnose tuberculosis disease (TB) and initiate treatment is a driving factor of TB as a leading cause of death in children. Current TB diagnostic assays have poor performance in children, and identifying novel non-sputum-based TB biomarkers to improve pediatric TB diagnosis is a global priority. We sought to develop a plasma biosignature for TB by probing the plasma proteome of 511 children stratified by TB diagnostic classification and HIV status from sites in four low- and middle-income countries, using high-throughput data-independent acquisition mass-spectrometry (DIA-PASEF-MS). We identified 47 proteins differentially regulated (BH adjusted p-values < 1%) between children with microbiologically confirmed TB and children with non-TB respiratory diseases (Unlikely TB). We further employed machine learning to derive three parsimonious biosignatures encompassing 4, 5, or 6 proteins that achieved AUCs of 0.86-0.88 all of which exceeded the minimum WHO target product profile accuracy thresholds for a TB screening test (70% specificity at 90% sensitivity, PPV 0.65-0.74, NPV 0.92-0.95). This work provides insights into the unique host response in pediatric TB disease, as well as a non-sputum biosignature that could reduce delays in TB diagnosis and improve detection and management of TB in children worldwide.
Epigenome-wide Association Analysis of Mitochondrial Heteroplasmy Provides Insight into Molecular Mechanisms of Disease
Authors: Lai Meng , Kim Kyeezu , Zheng Yinan , Castellani Christina A. , Ratliff Scott M. , Wang Mengyao , Liu Xue , Haessler Jeffrey , Huan Tianxiao , Bielak Lawrence F. , Zhao Wei , Joehanes Roby , Ma Jiantao , Guo Xiuqing , Manson JoAnn E. , Grove Megan L. , Bressler Jan , Taylor Kent D. , Lappalainen Tuuli , Kasela Silva , Blackwell Thomas W. , Lake Nicole J. , Faul Jessica D. , Ferrier Kendra R. , Hou Lifang , Kooperberg Charles , Reiner Alexander P. , Zhang Kai , Peyser Patricia A. , Fornage Myriam , Boerwinkle Eric , Raffield Laura M. , Carson April P. , Rich Stephen S. , Liu Yongmei , Levy Daniel , Rotter Jerome I. , Smith Jennifer A. , Arking Dan E. , Liu Chunyu ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Published: December 2024

ABSTRACTThe relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA (nDNA) methylation (CpGs) remains to be studied. We conducted an epigenome-wide association analysis of heteroplasmy burden scores across 10,986 participants (mean age 77, 63% women, and 54% non-White races/ethnicities) from seven population-based observational cohorts. We identified 412 CpGs (FDR p < 0.05) associated with mtDNA heteroplasmy. Higher levels of heteroplasmy burden were associated with lower nDNA methylation levels at most significant CpGs. Functional inference analyses of genes annotated to heteroplasmy-associated CpGs emphasized mitochondrial functions and showed enrichment in cardiometabolic conditions and traits. We developed CpG-scores based on heteroplasmy-count associated CpGs (MHC-CpG scores) using elastic net Cox regression in a training cohort. A one-unit higher level of the standardized MHC-CpG scores were associated with 1.26-fold higher hazard of all-cause mortality (95% CI: 1.14, 1.39) and 1.09-fold higher hazard of CVD (95% CI: 1.01–1.17) in the meta-analysis of testing cohorts, adjusting for age, sex, and smoking. These findings shed light on the relationship between mtDNA heteroplasmy and DNA methylation, and the role of heteroplasmy-associated CpGs as biomarkers in predicting all-cause mortality and cardiovascular disease.
Risk of root resorption between Invisalign and fixed orthodontic treatment: A retrospective study
Authors: Sabban Hanadi M. , Al-Labban Linah , Baeshen Nouf , Turkistani Khadijah A. 
Published: December 2024

AbstractObjectivesThe aim of our study is to evaluate and compare the presence and severity of external root resorption in patients treated with either clear aligners (Invisalign) versus conventional fixed orthodontic appliances.Material and MethodsA retrospective study was performed on 203 patients, which includes 30 treated with Invisalign and 173 with fixed appliances. 60 cases (30 per group) were matched based on extraction status, treatment duration, gender, age, and malocclusion classification after inclusion criteria were applied. Radiographic evaluations were conducted with standardized periapical radiographs and Panoramic radiographs (OPG). Comparing radiographs taken before and after treatment allowed for the measurement of the extent of external root resorption.ResultsIn the matched cases, external root resorption was present in 92% of patients in the Invisalign group and 77% of patients in the fixed appliance group. Maxillary incisors were the most afflicted teeth, particularly in situations involving tooth extractions. The greatest percentage of root resorption (100%) was recorded in Class II malocclusion, which was followed by Class I (84%) and Class III (77%). Although Invisalign treatments demonstrated an increased incidence of root resorption, fixed appliances were associated with more severe root reduction. There were not significant distinctions between the groups, according to statistical analysis (p > 0.05).ConclusionsA frequent adverse effect of orthodontic treatments involving both fixed appliances and Invisalign is external root resorption. Root resorption was more common in Invisalign patients, but it was greater in fixed appliance cases. These results highlight the need for more expansive prospective studies to confirm these findings and enable clinicians minimize side effects associated with treatment.
Modeling early-onset cancer kinetics to study changes in underlying risk, detection, and impact of population screening
Authors: Mirzaei Navid Mohammad , Hur Chin , Terry Mary Beth , Dalerba Piero , Yang Wan 
Published: December 2024

ABSTRACTRecent studies have reported increases in early-onset cancer cases (diagnosed under age 50) and call into question whether the increase is related to earlier diagnosis from other medical tests and reflected by decreasing tumor-size-at-diagnosis (apparent effects) or actual increases in underlying cancer risk (true effects), or both. The classic Multi-Stage Clonal Expansion (MSCE) model assumes cancer detection at the emergence of the first malignant cell, although later modifications have included lag-times or stochasticity in detection to more realistically represent tumor detection requiring a certain size threshold. Here, we introduce an approach to explicitly incorporate tumor-size-at-diagnosis in the MSCE framework and account for improvements in cancer detection over time to distinguish between apparent and true increases in early-onset cancer incidence. We demonstrate that our model is structurally identifiable and provides better parameter estimation than the classic model. Applying this model to colorectal, female breast, and thyroid cancers, we examine changes in cancer risk while accounting for detection improvements over time in three representative birth cohorts (1950-1954, 1965-1969, and 1980-1984). Our analyses suggest accelerated carcinogenic events and shorter mean sojourn times in more recent cohorts. We further use this model to examine the screening impact on the incidence of breast and colorectal cancers, both having established screening protocols. Our results align with well-documented differences in screening effects between these two cancers. These findings underscore the importance of accounting for tumor-size-at-diagnosis in cancer modeling and support true increases in early-onset cancer risk in recent years for breast, colorectal, and thyroid cancer.SignificanceThis study models recent increases in early-onset cancers, accounting for both true factors contributing to cancer risk and those caused by improved detection. We show that while advancement in detection has led to earlier detection, our model estimates shorter sojourn times and more aggressive carcinogenic events for recent cohorts, suggesting faster tumor progression. Further, a counterfactual analysis using this model reveals the known statistically significant reduction in colorectal cancer incidence (supporting a robust modeling approach), likely due to screening and timely removal of precancerous polyps. Overall, we introduce an enhanced model to detect subtle trends in cancer risk and demonstrate its ability to provide valuable insights into cancer progression and highlight areas for future refinement and application.
Inhibiting heme-piracy by pathogenicEscherichia coliusingde novo-designed proteins
Authors: Fox Daniel R. , Asadollahi Kazem , Samuels Imogen , Spicer Bradley , Kropp Ashleigh , Lupton Chris , Lim Kevin , Wang Chunxiao , Venugopal Hari , Dramicanin Marija , Knott Gavin , Grinter Rhys 
Published: December 2024

AbstractIron is an essential nutrient for most bacteria and is often growth-limiting during infection, due to the host sequestering free iron as part of the innate immune response. To obtain the iron required for growth, many bacterial pathogens encode transporters capable of extracting the iron-containing cofactor heme directly from host proteins. PathogenicE. coliandShigella spp. produce the outer membrane transporter ChuA, which binds host hemoglobin and extracts its heme cofactor, before importing heme into the cell. Heme extraction by ChuA is a dynamic process, with the transporter capable of rapidly extracting heme from hemoglobin in the absence of an external energy source, without forming a stable ChuA-hemoglobin complex. In this work, we utilise a combination of structural modelling, Cryo-EM, X-ray crystallography, mutagenesis, and phenotypic analysis to understand the mechanistic detail of this process. Based on this understanding we utilise artificial intelligence-based protein design to create binders capable of inhibitingE. coligrowth by blocking hemoglobin binding to ChuA. By screening a limited number of these designs, we identify several binders that inhibitE. coligrowth at low nanomolar concentrations, without experimental optimisation. We determine the structure of a subset of these binders, alone and in complex with ChuA, demonstrating that they closely match the computational design. This work demonstrates the utility ofde novo-designed proteins for inhibiting bacterial nutrient uptake and uses a workflow that could be applied to integral membrane proteins in other organisms.
Chromatin Compaction Follows a Power Law Scaling with Cell Size from Interphase Through Mitosis
Authors: Stockinger Petra , Oddone Anna , Lakadamyali Melike , Mendoza Manuel , Solon Jérôme 
Published: December 2024

AbstractCoordination of mitotic chromosome compaction with cell size is crucial for proper genome segregation during mitosis. During development, DNA content remains constant but cell size evolves, necessitating a mechanism that scales chromosome compaction with cell size. In this study, we examined chromatin compaction in the developingDrosophilanervous system by analyzing the large neuronal stem cells and their smaller progeny, the ganglion mother cells. Using super-resolution 3D Stochastic Optical Reconstruction Microscopy and quantitative time-lapse fluorescence microscopy, we observed that nanoscale chromatin density during interphase scales with nuclear volume according to a power law. This scaling relationship is disrupted by inhibiting histone deacetylase activity, indicating that molecular cues rather than mechanical constraints primarily regulate chromatin compaction. Notably, this power law dependency is maintained into mitosis but the scaling exponent decreases, suggesting phase separation of chromatin events during mitotic compaction. We propose that the scaling of mitotic chromosome size relative to cell size depends on the power law behaviour of interphase chromatin volume, and that scaling of mitotic chromatin compaction is an emergent property of linear polymers undergoing phase separation with their solvent.Statement of SignificanceUnderstanding how chromatin compaction changes with cell size is essential for understanding the mechanisms ensuring accurate genome segregation during cell division. In this study, we combine Voronoi tessellation analysis of Stochastic Optical Reconstruction Microscopy and image processing methods based on fluorescence intensity spectrum analysis of live confocal images to measure chromatin volume in interphase and mitosis in cells of different sizes. This work reveals that chromatin density inDrosophilaneuronal cells follows a power law relationship with nuclear volume from interphase through mitosis, suggesting a fundamental principle underlying chromosome scaling across different cell sizes. We show that this scaling is regulated by molecular cues, such as histone deacetylase activity, and is conserved through a potential phase separation during mitosis, providing new insights into the biophysical processes that govern chromatin organization. This work broadens our understanding of chromosome biology and will have implications for understanding size-dependent chromatin dynamics in other organisms.
Pharmacological concentrations of vitamin C inhibit hypochlorous acid generation by myeloperoxidase, and oxidized vitamin C inhibits critical thiol proteins and growth of Jurkat cells
Authors: Peskin Alexander V , Magon Nicholas J , Bozonet Stephanie M 
Published: December 2024

AbstractThe controversy surrounding vitamin C treatment for cancer is addressed, specifically why only high doses are effective and why the outcomes are inconsistent. Our data suggest that the bona fide cause of toxicity was oxidized vitamin C rather than hydrogen peroxide. We found that vitamin C at millimolar concentrations, directly inhibits hypochlorous acid generation by myeloperoxidase, through competition with chloride rather than by scavenging the hypochlorous acid that is formed. Products of vitamin C oxidation reacted with the thiols of peroxiredoxin 2 and GAPDH, but failed to react with the cysteine of p16INK4a. The growth and viability of Jurkat cells were affected by oxidized vitamin C. These experiments were conducted in the presence of catalase, demonstrating that the biological effects were due to the products of vitamin C oxidation and not hydrogen peroxide. These findings may have practical implications for the treatment of cancer and diseases in which the deleterious effects of neutrophil activation are observed. For intravenous administration of pharmacological vitamin C to have a beneficial effect, its concentration in the blood must be maintained at millimolar levels and this can only be achieved via maintenance infusion. As a proof-of-concept, our data suggest that to enhance anticancer therapy interventions, it is crucial to implement treatments that facilitate the oxidation of vitamin C in the bloodstream.Progress in the art of healing has always been induced by progress in basic knowledge.Albert Szent-Gyorgyi (Woods Hole, Mass., USA, 1973)Graphical abstract