bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sexual dimorphism of MASLD-driven bone loss
Authors: Goldscheitter Galen M , Seneshaw Mulugeta , Mirshahi Faridoddin , Buettmann Evan G , Genetos Damian C , Sanyal Arun J , Donahue Henry J 
Published: November 2024

ABSTRACTMetabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is highly prevalent with major risk of progression to Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Hepatocellular Carcinoma (HCC). Recently, osteoporosis and bone fracture have emerged as sexually-dimorphic comorbidities of MASLD yet the mechanisms of this bone loss are unknown. Herein, we address these knowledge gaps using DIAMOND mice which develop MASLD, MASH, and HCC via Western diet exposure. We examined the skeletal phenotype of male DIAMOND mice after 16, 36, and 48 weeks of exposure to Western or control diet. At 16 weeks, male DIAMOND mice with MASLD lose trabecular bone but retain mechanical bone integrity. At 48 weeks, males lose cortical bone and mechanical integrity, indicating severe skeletal weakening. Female DIAMOND mice were protected from cortical and trabecular MASLD-associated bone loss and skeletal fragility at all timepoints. Using NicheNet, a publicly available database of hepatic mRNA expression in DIAMOND mice, and a PTH-induced model of bone loss, we suggestCtgf, Rarres2, Anxa2, Fgf21,andMmp13are liver-secreted ligands inducing bone resorption. This study is the first preclinical investigation of bone loss in MASLD, and the first to suggest the role ofCtgf, Rarrest2, Anxa2, Fgf21,andMmp13as drivers of this pathology.
CASTER-DTA: Equivariant Graph Neural Networks for Predicting Drug-Target Affinity
Authors: Kumar Rachit , Romano Joseph D. , Ritchie Marylyn D. 
Published: November 2024

AbstractAccurately determining the binding affinity of a ligand with a protein is important for drug design, development, and screening. With the advent of accessible protein structure prediction methods such as AlphaFold, several approaches have been developed that make use of information determined from the 3D structure for a variety of downstream tasks. However, methods for predicting binding affinity that do consider protein structure generally do not take full advantage of such 3D structural protein information, often using such information only to define nearest-neighbor graphs based on inter-residue or inter-atomic distances. Here, we present a joint architecture that we call CASTER-DTA (Cross-Attention with Structural Target Equivariant Representations for Drug-Target Affinity) that makes use of an SE(3)-equivariant graph neural network to learn more robust protein representations alongside a standard graph neural network to learn molecular representations, and we further augment these representations by incorporating an attention-based mechanism by which individual residues in a protein can attend to atoms in a ligand and vice-versa to improve interpretability. In this manner, we show that using equivariant graph neural networks in our architecture enables CASTER-DTA to approach and exceed state-of-the-art performance in predicting drug-target affinity without the inclusion of external information, such as protein language model embeddings. We do so on the Davis and KIBA datasets, common benchmarks for predicting drug-target affinity. We also discuss future steps to further improve performance.
The G protein inhibitor YM-254890 is an allosteric glue
Authors: Trent Tony , Miller Justin J. , Bowman Gregory R 
Published: November 2024

AbstractGiven the prominence of G protein coupled receptors (GPCRs) as drug targets, targeting their immediate downstream effectors, G proteins, could be of immense therapeutic value. The discovery that the natural product YM-254890 (YM) can arrest uveal melanoma by specifically inhibiting constitutively active Gq/11without impacting other G protein families demonstrates the potential of this approach. However, efforts to find other G protein family-specific inhibitors have had limited success. Better understanding the mechanism of YM could facilitate efforts to develop other highly specific G protein inhibitors. We hypothesized that differences between the conformational distributions of various G proteins play an important role in determining he specificity of inhibitors like YM. To explore this hypothesis, we built Markov state models (MSMs) from molecular dynamics simulations of the Gα subunits of three different G proteins, as YM predominantly contacts Gα. We also modeled the heterotrimeric versions of these proteins where Gα is bound to the Gβγ heterodimer. We find that YM-sensitive Gα proteins have a higher probability of adopting YM-bound-like conformations than insensitive variants. There is also strong allosteric coupling between the YM- and Gβγ-binding interfaces of Gα. This allostery gives rise to positive cooperativity, wherein the presence of Gβγ enhances preorganization for YM binding. We predict that YM acts as an “allosteric” glue that allosterically stabilizes the complex between Gα and Gβγ despite the minimal contacts between YM and Gβγ.
Epstein-Barr viral product-containing exosome facilitates LIF-associated immunosuppressive polarization of macrophage in nasopharyngeal carcinoma
Authors: Liu Tzu-Tung , Sui Yun-Hua , Jiang Shih-Sheng , Tsai Fang-Yu , Chang Kai-Ping , Tsang Ngan-Ming , Lee Meng-Hsin , Huang Chen-Han , Liu Shu-Chen 
Published: November 2024

AbstractNasopharyngeal carcinoma (NPC) is characterized by Epstein-Barr virus (EBV) infection and severe immune cell infiltration. How tumor-derived EBV or viral products regulate macrophage polarization within NPC microenvironment remains to be explored. Here, we investigated the exosome-mediated intercellular communications between EBV+NPC cells and tumor-associated macrophages (TAMs). We demonstrate that leukemia inhibitory factor (LIF) expression correlates with poorer metastasis/recurrence-free survival in NPC patients. Immunohistochemical analyses revealed that LIF is highly expressed by both tumor cells and macrophages. The uptake of NPC-derived exosomes by human monocyte-derived macrophages induced an immunosuppressive polarization and enhanced LIF expression, exhibiting a reduced cytotoxicity against primary cancer cells. Blocking LIF suppressed the pro-tumor functions mediated by tumor-derived exosomes, in bothin vitroandin vitrozebrafish xenografts model. Furthermore, single-cell transcriptomic analysis (scRNA-seq) suggested that tumor- derived exosomes remodeled the NPC microenvironment by increasing the proportion of a pro-tumoral TAM subtype, CCL18-MΦ. Intercellular analysis revealed that exosome-treated macrophages could modulate T cell cytotoxicity and promoting Treg-mediated immunosuppression. Collectively, EBV shapes the tumor microenvironment by driving macrophage toward an immunosuppressive phenotype via exosome cargos, facilitating a pro-tumoral niche and contribute to NPC progression.
Atheroprone Flow Activates SMAD-FOXO1 to drive Endothelial-to-Mesenchymal Transition and Atherosclerosis
Authors: Mendez Paul-Lennard , Raaz Lion , Jatzlau Jerome , Xiao Yunyun , Vrancaert Pieter , Ksiazkiewicz Jakub , Wallentin Jakob , Trumpp Michael , Scharnitzki Stefanie , Mundlos Stefan , Luttun Aernout , Zwijsen An , Itoh Fumiko , Knaus Petra 
Published: November 2024

AbstractBackgroundCardiovascular diseases are the leading cause of death worldwide with atherosclerosis as the main underlying pathology. A hallmark of atherosclerotic lesion formation is endothelial-to-mesenchymal transition (EndoMT) triggered by perturbed blood flow patterns at arterial bifurcations and curvatures. SMAD transcription factors (TFs), activated by bone morphogenetic protein (BMP) 9/10 or transforming growth factor beta (TGFβ) signaling, are indispensable for endothelial homeostasis. Yet, they also play a significant role in stimulating EndoMT. How different interacting co-factors mediate the shift towards a pathological SMAD response remains elusive.MethodsWe generated endothelial cell (EC)-specific SMAD1/5 or SMAD2/3 knock-out mice and performed assay for transposase accessible chromatin sequencing (ATAC-Seq) of EC nuclei from regions of atheroprone (aortic arch) and atheroprotective (descending thoracic aorta) flow to identify transcriptional co-regulators of SMADs. We validated this using single-cell (sc)ATAC-Seq and immunofluorescence staining data from wild-type mice. To assess conservation of our findings for the human situation, we performed co-immunoprecipitation and proximity ligation assays in human aortic ECs (HAoECs). We exposed HAoECs to pathological or physiological (i.e. oscillatory or pulsatile) flow and performed ATAC- and RNA-Seq. Next, transcriptomic and chromatin accessibility data were integrated and motif enrichment and TF footprinting analysis were performed. Finally, we used siRNA-mediated approaches, TF inhibition, and luciferase-based reporter gene assays to analyze the transcriptional response of target TFs and explored their presence in plaques of atheroprone low-density lipoprotein receptor-deficient mice.ResultsWe observed enrichment of FOXO TF family motifs in DNA loci with increased accessibility in response to atheroprone flowin vitroandin vivo. These motifs were associated with genes displaying enhanced mRNA expression. We observed that FOXO motifs are enriched in peaks lost upon EC-specific SMAD KO in mice. We identified SMADs and FOXO1 as interacting partners that form complexes upon atheroprone flow stimulation. Inhibitor experiments revealed that FOXO1 and SMADs mediate EndoMT upon atheroprone flow exposure by upregulatingSNAI2.ConclusionWe identified SMAD/FOXO1 complexes that mediate EndoMT in response to atheroprone flow. Targeting this interaction can potentially reduce atherosclerotic burden by interfering with pathological flow-induced EndoMT and thus disease progression.
Distinct medical and substance use histories associate with cognitive decline in Alzheimer’s Disease
Authors: Mansel Clayton , Mazzotti Diego R. , Townley Ryan , Sardiu Mihaela E , Swerdlow Russell H. , Honea Robyn A , Veatch Olivia J 
Published: November 2024

AbstractINTRODUCTIONPhenotype clustering reduces patient heterogeneity and could be useful when designing precision clinical trials. We hypothesized that the onset of early cognitive decline in patients would exhibit variance predicated on the clinical history documented prior to an Alzheimer’s Disease (AD) diagnosisMETHODSSelf-reported medical and substance use history (i.e., problem history) was used to cluster participants from the National Alzheimer’s Coordinating Centers (NACC) into distinct subtypes. Linear mixed effects modeling was used to determine the effect of problem history subtype on cognitive decline over two years.RESULTS2754 individuals were partitioned into three subtypes: minimal (n = 1380), substance use (n = 1038), and cardiovascular (n = 336) subtypes. The cardiovascular problem history subtype had significantly worse cognitive decline over a two-year follow-up period (p = 0.013).DISCUSSIONOur study highlights the need to account for problem history to reduce heterogeneity of outcomes in AD clinical trials.
Process evaluation of pragmatic cluster randomized trials of digital adherence technologies for tuberculosis treatment support: a mixed methods study in five countries
Authors: Madden N. , Tadesse A. , Leung A. , Gonçalves Tasca B. , Alacapa J. , Deyanova N. , Ndlovu N. , Mokone N. , Onjare B , Mganga A. , van Kalmthout K. , Jerene D. , Fielding K. 
Published: November 2024

AbstractBackgroundDigital adherence technologies (DATs) could improve the person-centredness of TB treatment. Acceptability of DATs is high, though evidence of their effectiveness is varied. Our objective was to understand the fidelity of DAT interventions within five cluster-randomized trials.MethodsTwo DATs (smart pill box, medication labels) were assessed, with real-time adherence data made available to healthcare providers (HCPs) on a digital platform in Ethiopia, the Philippines, South Africa, Tanzania, and Ukraine. The process evaluation framework assessed four components: inputs, processes, outputs, and outcomes. Fidelity of the most important intervention components was evaluated by quantitative indicators, with analysis conducted by country and DAT type. Content analysis of qualitative sub-studies supplemented some indicators.ResultsEngagement with DATs was high among persons with TB (PwTB). Pillbox users showed high levels of sustained engagement, with digitally recorded doses ranging from 82% to 91%. Sole ownership of a mobile phone was highest in South Africa (90%) and lowest in the Philippines (63%). Differences were also observed in the frequency of logins by HCPs to the adherence platform and the type of device used. In the Philippines and Ukraine, >50% of logins were from mobile phones. In Ethiopia, Tanzania, and Ukraine there was at least one login to the platform on 71% of weekdays per facility, compared with the Philippines and South Africa at 42% and 52%, respectively. A feeling of connection between PwTB and their HCP was reported by over 95% of participants surveyed in Ethiopia and Tanzania, this was 84% in South Africa and 76% Philippines, a finding underpinned by qualitative data.ConclusionWe observed varying levels of intervention fidelity between countries. Timeliness and intensity of utilization of real-time data, and taking required actions are impacted by staff and health system capacity. Acceptance of DATs is high; therefore, future work should focus on identifying optimal intervention strategies.
Associations between weather andPlasmodium vivaxmalaria in an elimination setting in Peru: a distributed lag analysis
Authors: Barratt Heitmann Gabriella , Wu Xue , Nguyen Anna T. , Altamirano-Quiroz Astrid , Fine Sydney , Fernandez-Camacho Bryan , Barja Antony , Cava Renato , Soto-Calle Verónica , Rodriguez Hugo , Carrasco-Escobar Gabriel , Bennett Adam , Llanos-Cuentas Alejandro , Mordecai Erin A. , Hsiang Michelle S. , Benjamin-Chung Jade 
Published: November 2024

ABSTRACTBackgroundPlasmodium vivax(Pv) is the predominant malaria species in countries approaching elimination. In the context of climate change, understanding environmental drivers of transmission can guide interventions, yet evidence is limited, particularly in Latin America.ObjectivesWe estimated the association between temperature and precipitation andPvmalaria incidence in a malaria elimination setting in Peru.MethodsWe analyzed malaria incidence data from 2021-2023 from 30 communities in Loreto, Peru with hourly weather data from the ERA5 dataset and land cover data from MapBiomas. Predictors included average weekly minimum and maximum temperature, high heat (>90th percentile mean temperature), total weekly precipitation, and heavy rain (>90th percentile total precipitation). We fit non-linear distributed lag models for continuous weather predictors and generalized additive models for binary predictors and the lookback period was 2—16 weeks. Temperature models adjusted for total precipitation; precipitation models adjusted for maximum temperature. We performed subgroup analyses by season, community type, and distance to forest edge.ResultsThe median vs. lowest values of weekly average minimum temperature was associated with 2.16 to 3.93-fold higher incidence 3-16 weeks later (5-week lag incidence ratio (IR) =3.93 [95% CI 2.18, 7.09]); for maximum temperature, the association was hump-shaped across lags, with protective associations at 1-2 and 15-16 week lags and 1.07-1.66-fold higher incidence at 6-13 week lags. High heat (>27.5°C) was associated with 1.23 to 1.37-fold higher incidence at 5--9 week lags (9-week lag IR = 1.25 [1.02, 1.53]). Associations between total precipitation and malaria incidence were hump-shaped across lags, with the strongest positive association at 750 mm of precipitation at a 9-week lag (IR=1.56; [1.27, 1.65]). Heavy rain (>186mm) was associated with 1.22–1.60-fold higher incidence at 2–10 week lags (9-week lag IR=1.23 [1.02, 1.49]).DiscussionHigher temperatures and precipitation were generally associated with higher malaria incidence over 1–4 months.
Epidemiology and Risk Factors of Cutaneous Leishmaniasis in the West Bank, Palestine: A Cross-Sectional Study
Authors: AbuZaaroor Elaf , AlShakhra Kamal , Alawneh Moath 
Published: November 2024

AbstractBackgroundLeishmaniasis Is a vector-borne disease caused by obligate intracellular protozoan flagellate parasite, that is transmitted by the bite of infected female phlebotomine sandflies. Cutaneous Leishmaniasis (CL) is endemic in the Middle East, it’s a major public health concern in Palestine, the current control strategies for Leishmaniasis depend on reservoir and vector control, active case detection and treatment of their disease and the use of insecticides.ObjectivesThis study aims to describe the epidemiology, clinical features, and risk factors of CL in the West Bank, Palestine, from 2020 to 2023.MethodsA retrospective study included all cases of CL that had been reported to the Leishmaniasis Surveillance System in the Department of preventive medicine at the Palestinian Ministry of Health during the period from 2020 to 2023. A total of 322 cases were reported and met the case definition. demographic details, lesion characteristics, and environmental risk factors., Independent t-test and ANOVA were used to obtain the differences between the groups according to lesion duration, number of lesion.FindingsA total of 322 cases of Cutaneous Leishmaniasis were diagnosed in preventive medicine departments in West bank during the period 2020 till 2023, the ages of patients ranges between less than one year to 82 years old, most cases were young, with mean age of 24 years old, the male to female ratio was 3:2, most patients were illiterate,.The number of skin lesions was significantly higher in males, farmers and most patients have face lesions mainly nodules. while the duration of the skin lesions was significantly higher in older patients.ConclusionsCL is endemic in the West Bank. Public health strategies should emphasize early detection, community awareness, and targeted vector control measures.FundingNo funding was provided for this research.
Brisk: Exact resource-efficient dictionary fork-mers
Authors: Smith Caleb , Martayan Igor , Limasset Antoine , Dufresne Yoann 
Published: November 2024

ABSTRACTThe rapid advancements in DNA sequencing technology have led to an unprecedented increase in the generation of genomic datasets, with modern sequencers now capable of producing up to ten terabases per run. However, the effective indexing and analysis of this vast amount of data pose significant challenges to the scientific community. K-mer indexing has proven crucial in managing extensive datasets across a wide range of applications, including alignment, compression, dataset comparison, error correction, assembly, and quantification. As a result, developing efficient and scalablek-mer indexing methods has become an increasingly important area of research. Despite the progress made, current state-of-the-art indexing structures are predominantly static, necessitating resource-intensive index reconstruction when integrating new data. Recently, the need for dynamic indexing structures has been recognized. However, many proposed solutions are only pseudo-dynamic, requiring substantial updates to justify the costs of adding new datasets. In practice, applications often rely on standard hash tables to associate data with theirk-mers, leading to highk-mer encoding rates exceeding 64 bits perk-mer. In this work, we introduce Brisk, a drop-in replacement for mostk-mer dictionary applications. This novel hashmap-like data structure provides high throughput while significantly reducing memory usage compared to existing dynamic associative indexes, particularly for largek-mer sizes. Brisk achieves this by leveraging hierarchical minimizer indexing and memory-efficient super-k-mer representation. We also introduce novel techniques for efficiently probingk-mers within a set of super-k-mers and managing duplicated minimizers. We believe that the methodologies developed in this work represent a significant advancement in the creation of efficient and scalablek-mer dictionaries, greatly facilitating their routine use in genomic data analysis.
Systematic exploration of domain assortments in NOD-like receptors uncovers two types of NACHT domains inSordarialesfungi
Authors: Bonometti Lucas , Charriat Florian , Hensen Noah , Miñana-Posada Silvia , Johannesson Hanna , Gladieux Pierre 
Published: November 2024

AbstractBackgroundFungi have NOD-Like receptors (NLRs), analogous to the innate immune receptors found in animals, plants and bacteria. Fungal NLRs are characterized by a great variability of domain organizations, but the identity of the nucleotide-binding domains, the genomic localization, and the factors associated with variation in the composition of repertoires of fungal NLRs are not yet fully understood. To better understand the variability of fungal NLR repertoires and the underlying determinants, we conducted a thorough analysis of genome data from the ascomycete orderSordariales.ResultsUsing similarity searches based on hidden Markov models profiles for canonical N-terminal, nucleotide-binding, or C-terminal domains, we characterized 4613 NLRs in 82Sordarialestaxa. By examining the Helical Third section of the nucleotide-binding domains, we substantially improved their annotation. We demonstrated that fungi have NACHT domains of both NAIP-like and TLP1-like types, similar to animals. We found that the number of NLR genes was highly variable amongSordarialesfamilies, and independent of the stringency of defense mechanisms against genomic repeat elements. NLRs were organized in clusters in the majority of taxa, and the strong correlation between the number of NLRs and the number of NLR clusters suggested that organizing in clusters may contribute to repertoire diversification.ConclusionsOur work highlights the similarity of fungal and animal NLRs in terms of nucleotide-binding domain types, and between fungal and plant NLRs in terms of genomic organization in clusters. Our findings will aid in the comparative analysis of the patterns and processes of diversification of NLR repertoires in various lineages of fungi and between the different kingdoms and domains of life.
Structural and functional insights into activation and regulation of the dynein-dynactin-NuMA complex
Authors: Aslan Merve , d’Amico Ennio A. , Cho Nathan H. , Taheri Aryan , Zhao Yuanchang , Zhong Xinyue , Blaauw Madeline , Carter Andrew P. , Dumont Sophie , Yildiz Ahmet 
Published: November 2024

AbstractDuring cell division, NuMA orchestrates the focusing of microtubule minus-ends in spindle poles and cortical force generation on astral microtubules by interacting with dynein motors, microtubules, and other cellular factors. Here we used in vitro reconstitution, cryo-electron microscopy, and live cell imaging to understand the mechanism and regulation of NuMA. We determined the structure of the processive dynein/dynactin/NuMA complex (DDN) and showed that the NuMA N-terminus drives dynein motility in vitro and facilitates dynein-mediated transport in live cells. The C-terminus of NuMA directly binds to and suppresses the dynamics of the microtubule minus-end. Full-length NuMA is autoinhibited, but mitotically phosphorylated NuMA activates dynein in vitro and interphase cells. Together with dynein, activated full-length NuMA focuses microtubule minus-ends into aster-like structures. The binding of the cortical protein LGN to the NuMA C-terminus results in preferential binding of NuMA to the microtubule plus-end. These results provide critical insights into the activation of NuMA and dynein for their functions in the spindle body and the cell cortex.