bluuebunny/crossref_metadata_2025_split huggingface dataset:
A drug repurposing screen for whipworms informed by comparative genomics
Authors: Coghlan Avril , Partridge Frederick A. , Duque-Correa María Adelaida , Rinaldi Gabriel , Clare Simon , Seymour Lisa , Brandt Cordelia , Mkandawire Tapoka T. , McCarthy Catherine , Holroyd Nancy , Nick Marina , Brown Anwen E. , Tonitiwong Sirapat , Sattelle David B. , Berriman Matthew 
Published: March 2023

AbstractHundreds of millions of people worldwide are infected with the whipwormTrichuris trichiura. Novel treatments are urgently needed as current drugs, such as albendazole, have relatively low efficacy. We have investigated whether drugs approved for other human diseases could be repurposed as novel anti-whipworm drugs. In a previous comparative genomics analysis, we identified 409 drugs approved for human use that we predicted to target parasitic worm proteins. Here we tested theseex vivoby assessing motility of adult worms ofTrichuris muris, the murine whipworm, an established model for human whipworm research. We identified 14 compounds with EC50 values of≤50μM againstT. muris ex vivo, and selected nine for testingin vivo. However, the best worm burden reduction seen in mice was just 19%. The high number ofex vivohits againstT. murisshows that we were successful at predicting parasite proteins that could be targeted by approved drugs. In contrast, the low efficacy of these compounds in mice suggest challenges due to their chemical properties (e.g. lipophilicity, polarity, molecular weight) and pharmacokinetics (e.g. absorption, distribution, metabolism, and excretion) that may (i) promote absorption by the host gastrointestinal tract, thereby reducing availability to the worms embedded in the large intestine, and/or (ii) restrict drug uptake by the worms. This indicates that identifying structural analogues that have reduced absorption by the host, and increased uptake by worms, may be necessary for successful drug repurposing against whipworms. Therefore, we recommend that prior toin vivostudies, future researchers first assess drug absorption by the host, for example, using human intestinal organoids or cell lines, and drug uptake by whipworms using intestinal organoids infected withT. muris.
A novel minimally invasive and reproducible large animal ischaemia-reperfusion-infarction model: methodology and model validation
Authors: Pius Charlene , Niort Barbara , Radcliffe Emma J. , Trafford Andrew W. 
Published: March 2023

AbstractIschaemic heart disease remains a leading cause of premature mortality and morbidity. Understanding the associated pathophysiological mechanisms of cardiac dysfunction arising from ischaemic heart disease and the identification of sites of novel therapeutic intervention requires a preclinical model that reproduces the key clinical characteristics of myocardial ischaemia, reperfusion and infarction. Here we describe and validate a refined and minimally invasive translationally relevant approach to induce ischaemia, reperfusion and infarction in the sheep. The protocol uses clinical cardiology devices and approaches and would be readily adopted by researchers with access to standard fluoroscopic instrumentation. In addition to being minimally invasive, the major refinements associated with the described methodology are the implantation of an intracardiac defibrillator prior to coronary engagement and use of an antiarrhythmic medication protocol during the procedure. These refinements lead to a reduction of intraoperative mortality to 6.7 %. The model produces key characteristics associated with the 4thUniversal Definition of Myocardial Infarction including electrocardiographic changes, elevated cardiac biomarkers and cardiac wall motility defects. In conclusion, the model closely replicates the clinical paradigm of myocardial ischaemia, reperfusion and infarction in a translationally relevant large-animal setting and the applied refinements reduce the incidence of intraoperative mortality typically associated with preclinical myocardial infarction models.
The pregnancy-associated protein glycodelin as a potential sex-specific target for resistance to immunotherapy in non-small cell lung cancer
Authors: Richtmann Sarah , Marwitz Sebastian , Muley Thomas , Koistinen Hannu , Christopoulos Petros , Thomas Michael , Kazdal Daniel , Allgäuer Michael , Winter Hauke , Goldmann Torsten , Meister Michael , Klingmüller Ursula , Schneider Marc A. 
Published: March 2023

AbstractLung cancer has been shown to be targetable by novel immunotherapies which reactivate the immune system and enable tumor cell killing. However, treatment failure and resistance to these therapies is common. Consideration of sex as a factor influencing therapy resistance is still rare. We hypothesize that the success of the treatment is impaired by the presence of the immunosuppressive pregnancy-associated glycoprotein glycodelin that is expressed in patients with non-small-cell lung cancer (NSCLC). We demonstrate that the glycan pattern of NSCLC-derived glycodelin detected by a lectin-based enrichment assay highly resembles amniotic fluid-derived glycodelin A, which is known to have immunosuppressive properties. NSCLC-derived glycodelin interacts with immune cellsin vitroand regulates the expression of genes associated with inflammatory and tumor microenvironment pathways. In tumor microarray samples of patients, high glycodelin staining in tumor areas results in an impaired overall survival of female patients. Moreover, glycodelin colocalizes to tumor infiltrating CD8+ T cells and pro-tumorigenic M2 macrophages. High serum concentrations of glycodelin prior to immunotherapy are associated with a poor progression-free survival (p < 0.001) of female patients receiving PD-(L)1 inhibitors. In summary, our findings suggest that glycodelin not only is a promising immunological biomarker for early identification of female patients that do not benefit from the costly immunotherapy, but also represents a promising immunotherapeutic target in NSCLC to improve therapeutic options in lung cancer.BackgroundImmunotherapy is one of the major achievements in the last decade of lung cancer treatment. However, resistance to treatment is common und not well understood. Glycodelin is an immunosuppressive protein well described during the establishment of a pregnancy. We investigated its influence on immune cells and patients receiving immunotherapy with a focus on the sex of the patients.Translational relevanceOur study examined that NSCLC-derived glycodelin shares similarities to amniotic fluid-derived glycodelin A and is predictive for a worse response to immunotherapy in female patients. Therefore, glycodelin might be a key player influencing a sex-specific response to immunotherapy in lung cancer.
In-vitro Modeling of Intravenous Drug Precipitation by the Optical Spatial Precipitation Analyzer (OSPREY)
Authors: Radosevich Andrew J. , Martin Ruth L. , Buck Wayne R. , Hicks Lauren , Wilsey Amanda , Pan Jeffrey Y 
Published: March 2023

AbstractIntravenous (IV) administration of poorly water-soluble small molecule therapeutics can lead to precipitation during mixing with blood. This can limit characterization of pharmacological and safety endpoints in preclinical models. Most often, tests of kinetic and thermodynamic solubility are used to optimize the formulation for solubility prior to infusion in animals, but these do not capture the dynamic precipitation processes that take place duringin-vivoadministration. To better capture the fluid dynamic processes that occur during IV administration, we developed the Optical Spatial Precipitation AnalYzer (OSPREY) as a method to quantify the amount and size of compound precipitates in whole blood using a flow-through system that mimics IV administration. Here, we describe the OSPREY device and its underlying imaging processing methods. We then validate the ability to accurately segment particles according to their size using monodisperse suspensions of microspheres (diameter 50 to 425 microns). Next, we use a tool compound, ABT-737, to study the effects of compound concentration, vessel flow rate, compound infusion rate and vessel diameter on precipitation. Finally, we use the physiological diameter and flow rate of rat femoral vein and dog saphenous vein to demonstrate the potential of OSPREY to modelin-vivoprecipitation in a controlled, dynamicin-vitroassay.HighlightsProspective small molecule therapeutics are often solubility challenged when injected into whole blood at elevated concentrations for toxicology studies.Improvedin-vitrosolubility measurements in a flowing system are needed to better understandin-vivointravenous precipitationOSPREY is a novelin-vitroflow-through system that quantifies solubility in whole bloodGraphical Abstract
3D Co-culture Model on the Role of Vimentin in Notch Signaling and Vascularization
Authors: Dayekh Khalil , Mequanint Kibret 
Published: March 2023

AbstractThe Notch signaling pathway is a conserved pathway that is central in vascular tissue development and pathology. Because this pathway controls such important events, it is regulated at multiple steps of its cascade, such as post-translational modification of its ligand and receptor. Recent studies have suggested regulation of the Notch signaling by a pulling force to be required to activate Notch signaling. In this exploratory study, 3D fibrin gels were used as a co-culture system of endothelial cells and 10T1/2 cells to assess whether vimentin is implicated in the regulation of Notch signaling and neovascularization. The results show that 10T1/2 cells increase the expression of Hes-1, Hes-5, and Acta2 during co-culture with human coronary artery endothelial cells (HCAECs) and that vimentin knock-down using siRNA partially reduced the expression under static conditions. On the other hand, while the same trend was observed for Hes-5 under dynamic conditions, Acta2 was overexpressed, and vimentin knock-down did not affect its expression levels. Moreover, the development of newly formed micro-vessels is observed in 3D fibrin gels in the presence of VEGF but could not be formed when vimentin expression was knocked down. These results suggest that vimentin plays a secondary role in Notch signaling; however, it is essential for neovascularization.
Expanding the molecular language of protein liquid-liquid phase separation
Authors: Rekhi Shiv , Garcia Cristobal Garcia , Barai Mayur , Rizuan Azamat , Schuster Benjamin S. , Kiick Kristi L. , Mittal Jeetain 
Published: March 2023

AbstractUnderstanding the relationship between an amino acid sequence and its phase separation has important implications for analyzing cellular function, treating disease, and designing novel biomaterials. Several sequence features have been identified as drivers for protein liquid-liquid phase separation (LLPS), leading to the development of a “molecular grammar” for LLPS. In this work, we further probed how sequence modulates phase separation and the material properties of the resulting condensates. Specifically, we used a model intrinsically disordered polypeptide composed of an 8-residue repeat unit and performed systematic sequence manipulations targeting sequence features previously overlooked in the literature. We generated sequences with no charged residues, high net charge, no glycine residues, or devoid of aromatic or arginine residues. We report that all but one of the twelve variants we designed undergo LLPS, albeit to different extents, despite significant differences in composition. These results support the hypothesis that multiple interactions between diverse residue pairs work in tandem to drive phase separation. Molecular simulations paint a picture of underlying molecular details involving various atomic interactions mediated by not just a handful of residue types, but by most residues. We characterized the changes to inter-residue contacts in all the sequence variants, thereby developing a more complete understanding of the contributions of sequence features such as net charge, hydrophobicity, and aromaticity to phase separation. Further, we find that all condensates formed behave like viscous fluids, despite large differences in their viscosities. The results presented in this study significantly advance the current sequence-phase behavior and sequence-material properties relationships to help interpret, model, and design protein assembly.
Synapse-specific diversity of distinct postsynaptic GluN2 subtypes defines transmission strength in spinal lamina I
Authors: Pitcher Graham. M. , Garzia Livia , Morrissy A.S. , Taylor Michael D. , Salter Michael. W. 
Published: March 2023

ABSTRACTThe unitary postsynaptic response to presynaptic quantal glutamate release is the fundamental basis of excitatory information transfer between neurons. The view, however, of individual glutamatergic synaptic connections in a population as homogenous, fixed-strength units of neural communication is becoming increasingly scrutinized. Here, we used minimal stimulation of individual glutamatergic afferent axons to evoke single synapse resolution postsynaptic responses from central sensory lamina I neurons in anex vivoadult rat spinal slice preparation. We detected unitary events exhibiting a NMDA receptor component with distinct kinetic properties across synapses conferred by specific GluN2 subunit composition, indicative of GluN2 subtype-based postsynaptic heterogeneity. GluN2A, 2A and 2B, or 2B and 2D synaptic predominance functioned on distinct lamina I neuron types to narrowly, intermediately, or widely tune, respectively, the duration of evoked unitary depolarization events from resting membrane potential, which enabled individual synapses to grade differentially depolarizing steps during temporally-patterned afferent input. Our results lead to a model wherein a core locus of proteomic complexity prevails at this central glutamatergic sensory synapse that involves distinct GluN2 subtype configurations. These findings have major implications for subthreshold integrative capacity and transmission strength in spinal lamina I and other CNS regions.
RNA scaffolds the Golgi ribbon by forming condensates with GM130
Authors: Zhang Yijiun , Seemann Joachim 
Published: March 2023

AbstractThe mammalian Golgi apparatus is composed of stacks of cisternae that are laterally linked to form a continuous ribbon like structure, but the molecular mechanisms that maintain the Golgi ribbon remain unclear. Here, we show that ribbon formation is mediated by biomolecular condensates of RNA and the Golgi resident protein GM130. We identified GM130 as a membrane-bound RNA binding protein at the Golgi. Acute degradation of either RNA or GM130 in cells disrupted the Golgi ribbon. Under stress conditions, RNA was displaced from GM130 and the ribbon was disjoint, which was restored after cells recovered from stress. When overexpressed in cells, GM130 formed RNA-dependent liquid-like condensates. GM130 contains an intrinsically disordered domain at its N-terminus, which was sufficient to recruit RNA to drive condensate assemblyin vitro. Condensates of the N-terminal domain of GM130 and RNA were sufficient to link purified rat liver Golgi membranes which is a reconstruction of aspects of lateral linking of stacks into a ribbon-like structure. Together, these studies reveal that biomolecular condensates of GM130-RNA scaffold the Golgi ribbon.
Efficacy and Safety of Bempedoic Acid in Patients With and Without Metabolic Syndrome: Pooled Analysis of Data From Four Phase 3 Clinical Trials
Authors: Shapiro Michael D. , Taub Pam R. , Louie Michael J. , Lei Lei , Ballantyne Christie M. 
Published: March 2023

AbstractBackground and aimsBempedoic acid significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia but its effects in patients with metabolic syndrome (MetS) have not been well characterized. We sought to determine the efficacy and safety of bempedoic acid in patients with hypercholesterolemia by baseline MetS status.MethodsThis study used pooled data from four phase 3 studies. Using modified International Atherosclerosis Society guidelines, patients were grouped into two pools: those with and those without MetS. Patients with diabetes were excluded. Endpoints assessed change from baseline to week 12 in lipid and glycemic parameters and high-sensitivity C-reactive protein (hsCRP), and safety.ResultsThe study included 936 patients with MetS (bempedoic acid, 648; placebo, 288) and 1573 without MetS (bempedoic acid, 1037; placebo, 536). Significant placebo-corrected reductions in LDL-C were observed with bempedoic acid (p<0.0001), with a greater decrease in patients withvs. without MetS (−22.3%vs. −18.4%; interactionp=0.0472). Compared with placebo, bempedoic acid significantly (p<0.0001) lowered total cholesterol, non–high-density lipoprotein cholesterol, apolipoprotein B, and hsCRP, with a similar magnitude of benefit observed between MetS categories. Significant reductions in triglycerides (−4.4%;p=0.02) were only observed in patients without MetS; only patients with MetS experienced decreases in glycated hemoglobin (−0.07%;p<0.0001) and fasting plasma glucose (−2.4 mg/dL;p=0.002). Safety was comparable between MetS categories and treatment groups.ConclusionsThese data suggest that bempedoic acid is a suitable therapy for patients with MetS who require additional lipid lowering.HighlightsBempedoic acid lowered LDL-Cvs. placebo in patients with and without MetS.Placebo-corrected LDL-C reductions were greater in patients withvs. without MetS.Bempedoic acid lowered TC, non–HDL-C, ApoB, and hsCRP regardless of MetS category.Reductions in HbA1c and FPGvs. placebo were only observed in patients with MetS.Bempedoic acid safety was comparable between MetS categories.
Predicting Post-Liver Transplant Outcomes in Patients with Acute-on-Chronic Liver Failure using Expert-Augmented Machine Learning
Authors: Ge Jin , Digitale Jean C. , Fenton Cynthia , McCulloch Charles E. , Lai Jennifer C. , Pletcher Mark J. , Gennatas Efstathios D. 
Published: March 2023

AbstractBackgroundLiver transplantation (LT) is a treatment for acute-on-chronic liver failure (ACLF) but up to 40% mortality post-LT has been reported. Existing post-LT models in ACLF have been limited by small samples. In this study, we developed a novel Expert-Augmented Machine Learning (EAML) model to predict post-LT outcomes.MethodsWe identified ACLF patients in the University of California Health Data Warehouse (UCHDW). We used EAML, which uses the RuleFit machine learning (ML) algorithm to extract rules from decision-trees that are then evaluated by human experts, to predict post-LT outcomes. We compared EAML/RuleFit’s performances versus other popular models.ResultsWe identified 1,384 ACLF patients. For death at one-year: areas-under-the-receiver-operating characteristic curve (AUROCs) were 0.707 (Confidence Interval [CI] 0.625-0.793) for EAML and 0.719 (CI 0.640-0.800) for RuleFit. For death at 90-days: AUROCs were 0.678 (CI 0.581-0.776) for EAML and 0.707 (CI 0.615-0.800) for RuleFit. In pairwise comparisons, EAML/RuleFit models outperformed cross-sectional models. Divergences between experts and ML in rankings revealed biases and artifacts in the underlying data.ConclusionsEAML/RuleFit outperformed cross-sectional models. Significant discrepancies between experts and ML occurred in rankings of biomarkers used in clinical practice. EAML may serve as a method for ML-guided hypothesis generation in further ACLF research.
Ethnic differences in early onset multimorbidity and associations with health service use, long-term prescribing, years of life lost, and mortality: an observational study using person-level clustering in the UK Clinical Practice Research Datalink
Authors: Eto Fabiola , Samuel Miriam , Henkin Rafael , Mahesh Meera , Ahmad Tahania , Angdembe Alisha , McAllister-Williams R. Hamish , Missier Paolo , Reynolds Nick J , Barnes Michael R , Hull Sally , Finer Sarah , Mathur Rohini 
Published: March 2023

AbstractBackgroundThe population prevalence of multimorbidity (the existence of at least 2 or more long-term conditions (LTCs) in an individual) is increasing among young adults, particularly in minority ethnic groups and individuals living in socioeconomically deprived areas. In this study, we applied a data-driven approach to identify clusters of individuals who had an early onset multimorbidity in an ethnically and socioeconomically diverse population. We identified associations between clusters and a range of health outcomes.Methods and findingsWe analysed the electronic health records from 837,869 individuals in England with early onset multimorbidity (aged between 16 and 39 years old when the second LTC was recorded) using linked primary and secondary care data between 2010 and 2020 from the Clinical Practice Research Datalink GOLD (CPRD GOLD). A total of 204 LTCs were included. Latent class analysis stratified by ethnicity unveiled 4 clusters of multimorbidity in White groups and 3 clusters in South Asian and Black groups. We found that early onset multimorbidity is the most common form of multimorbidity among minority ethnic (59% and 56%, in the South Asian and Black populations, respectively) in the UK compared to the White population (42%). At the end of the study, 4% of the White early onset multimorbidity population had died compared to 2% of the South Asian and Black populations, however, the latter groups died younger and lost more years of life. The three ethnic groups displayed a cluster of individuals with increased rates of primary care consultations, hospitalisations, long-term prescribing, and odds of mortality. These presented a combination of physical and mental health conditions that are common across all groups (hypertension, depression and painful conditions being the leading conditions). However, they also presented exclusive LTCs and had different sociodemographic profiles: Whites were mostly men (54%), South Asian and Black groups were more socioeconomically deprived than White groups, with a consistent deprivation gradient across all multimorbidity clusters. In White groups, the highest risk cluster was more socioeconomically deprived than the lowest risk cluster.ConclusionsThese findings emphasise the need to identify, prevent and manage multimorbidity early in the life course. Our work provides additional insights into the need to ensure healthcare improvements are equitable and reach those from socioeconomically deprived and diverse groups who are disproportionately and more severely affected by multimorbidity.
An IL-1β driven neutrophil-stromal cell axis fosters a BAFF-rich microenvironment in multiple myeloma
Authors: de Jong Madelon M.E. , Fokkema Cathelijne , Papazian Natalie , van Heusden Teddie , Vermeulen Michael , Hoogenboezem Remco , van Beek Gregory , Tahri Sabrin , Sanders Mathijs A. , van de Woestijne Pieter , Gay Francesca , Moreau Philippe , Büttner-Herold Maike , Bruns Heiko , van Duin Mark , Broijl Annemiek , Sonneveld Pieter , Cupedo Tom 
Published: March 2023

SummaryThe bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor-supportive, transcribing increased levels of IL-1β, and myeloma cell survival factor BAFF. Interactions with inflammatory stromal cells can induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting treatment, patient bone marrow retains residual stromal inflammation and newly-formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma.