bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Nirmatrelvir/Ritonavir Treatment with Long COVID Symptoms in an Online Cohort of Non-Hospitalized Individuals Experiencing Breakthrough SARS-CoV-2 Infection in the Omicron Era
Authors: Durstenfeld Matthew S. , Peluso Michael J. , Lin Feng , Peyser Noah D. , Isasi Carmen , Carton Thomas W. , Henrich Timothy J. , Deeks Steven G. , Olgin Jeffrey E. , Pletcher Mark J. , Beatty Alexis L. , Marcus Gregory M. , Hsue Priscilla Y.
Published: March 2023

Background

Oral nirmatrelvir/ritonavir is a treatment for COVID-19, but whether treatment during the acute phase reduces the risk of developing Long COVID is unknown.

Methods

Using the Covid Citizen Science (CCS) online cohort, we surveyed individuals who reported their first SARS-CoV-2 positive test between March and August 2022 regarding Long COVID symptoms. We excluded those who were pregnant, unvaccinated, hospitalized for COVID-19, or received other antiviral therapy. The primary exposure was oral nirmatrelvir/ritonavir. The primary outcome was the presence of any Long COVID symptoms reported on cross-sectional surveys in November and December 2022. We used propensity-score models and inverse probability of treatment weighting to adjust for differences in treatment propensity. Our secondary question was whether symptom or test positivity rebound were associated with Long COVID.

Results

4684 individuals met the eligibility criteria, of whom 988 (21.1%) were treated and 3696 (78.9%) were untreated; 353/988 (35.7%) treated and 1258/3696 (34.0%) untreated responded to the survey. Median age was 55 years and 66% were female. We did not identify an association between nirmatrelvir/ritonavir treatment and Long COVID symptoms (OR 1.15; 95%CI 0.80-1.64). Among n=666 treated with nirmatrelvir/ritonavir who responded who responded to questions about rebound, rebound symptoms or test positivity were not associated with Long COVID symptoms (OR 1.34; 95%CI 0.74-2.41; p=0.33).

Conclusions

Within this cohort, treatment with nirmatrelvir/ritonavir among vaccinated, non-hospitalized individuals was not associated with lower prevalence of Long COVID symptoms or severity of Long COVID. Experiencing rebound symptoms or test positivity is not strongly associated with developing Long COVID.
Astrocyte glypican 5 regulates synapse maturation and stabilization
Authors: Bosworth AP , Contreras M , Weiser Novak S , Sancho L , Salas IH , Manor U , Allen NJ
Published: March 2023

The maturation and stabilization of appropriate synaptic connections is a vital step in the development of neuronal circuits, however the molecular signals underlying these processes are not fully understood. We show that astrocytes, through production of glypican 5 (GPC5), are required for maturation and refinement of synapses in the developing mouse cortex. In the absence of astrocyte GPC5 thalamocortical synapses in the visual cortex show structural immaturity during the critical period, including smaller presynaptic terminals, decreased postsynaptic density area, and presence of more postsynaptic partners at multisynaptic connections. This structural immaturity is accompanied by a delay in developmental incorporation of GLUA2-containing calcium impermeable AMPARs at intracortical synapses. The functional impact of this is that mice lacking astrocyte GPC5 exhibit increased levels of ocular dominance plasticity in adulthood. This shows astrocyte GPC5 is necessary for maturation and stabilization of synaptic connections in typical development, with implications for understanding disorders with altered synaptic function, including Alzheimer’s disease, where GPC5 levels are altered.
Environmentally stressed human nucleus pulposus cells trigger the onset of discogenic low back pain
Authors: Jiang Wensen , Glaeser Juliane D , Kaneda Giselle , Sheyn Julia , Wechsler Jacob T , Stephan Stephen , Salehi Khosrowdad , Chan Julie L. , Tawackoli Wafa , Avalos Pablo , Johnson Christopher , Castaneda Chloe , Kanim Linda EA , Tanasansomboon Teerachat , Burda Joshua , Shelest Oksana , Yameen Haneen , Perry Tiffany G , Kropf Michael , Cuellar Jason M , Seliktar Dror , Bae Hyun W , Stone Laura S , Sheyn Dmitriy
Published: March 2023

Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing nucleus pulposus cells (NPCs), generated by the environmental stress in degenerating discs, that triggered the onset of discogenic LBP. Single-cell transcriptomic analysis of human tissues showed a strong correlation between this specific pain-triggering subtype and the pain conditions in human degenerated discs. Next, we recreated this pain-triggering subtype by applying known exogenous stressors to healthy NPCsin vitro. The recreated pain phenotype activated functional sensory neurons responsein vitroand induced local inflammatory responses, hyperalgesia, and mechanical sensitivity in a healthy rat IVDin vivo. Our findings provide strong evidence of a previously unknown pain-inducing mechanism mediated by NPCs in degenerating IVDs. This newly defined pathway will aid in the development of NPC-targeted therapeutic strategies for clinically unmet need to attenuate discogenic LBP.

One Sentence Summary

Discogenic low back pain can be initiated by a stress-induced subtype of nucleus pulposus cells present in human degenerating intervertebral discs
Identifying the environmental drivers of corridors and predicting connectivity between seasonal ranges in multiple populations of Alpine ibex (Capra ibex) as tools for conserving migration
Authors: Chauveau Victor , Garel Mathieu , Toïgo Carole , Anderwald Pia , Beurier Mathieu , Bunz Yoann , Bouche Michel , Cagnacci Francesca , Canut Marie , Cavailhes Jérôme , Champly Ilka , Filli Flurin , Frey-Roos Alfred , Gressmann Gunther , Herfindal Ivar , Jurgeit Florian , Martinelli Laura , Papet Rodolphe , Petit Elodie , Ramanzin Maurizio , Semenzato Paola , Vannard Eric , Loison Anne , Coulon Aurélie , Marchand Pascal
Published: March 2023

Seasonal migrations are central ecological processes connecting populations, species and ecosystems in time and space. Land migrations, such as those of ungulates, are particularly threatened by habitat transformations and fragmentation, climate change and other environmental changes caused by anthropogenic activities. Mountain ungulate migrations are neglected because they are relatively short, although traversing highly heterogeneous altitudinal gradients particularly exposed to anthropogenic threats. Detecting migration routes of these species and understanding their drivers is therefore of primary importance to predict connectivity and preserve ecosystem functions and services. The populations of Alpine ibexCapra ibex, an iconic species endemic to the Alps, have all been reintroduced from the last remnant source population. Because of their biology and conservation history, Alpine ibex populations are mostly disconnected. Hence, despite a general increase in abundance and overall distribution range, their conservation is strictly linked to the interplay between external threats and related behavioral responses, including space use and migration. By using 337 migratory tracks from 425 GPS-collared individuals from 15 Alpine ibex populations distributed across their entire range, we (i) identified the environmental drivers of movement corridors in both spring and autumn and (ii) compared the abilities of three modeling approaches to predict migratory movements between seasonal ranges of the 15 populations. Trade-offs between energy expenditure, food, and cover seemed to be the major driver of migration routes: steep south-facing snow-free slopes were selected while high elevation changes were avoided. This revealed the importance of favorable resources and an attempt to limit energy expenditures and perceived predation risk. Based on these findings, we provided efficient connectivity models to inform conservation of Alpine ibex and its habitats, and a framework for future research investigating connectivity in migratory species.
Early Differentiation Signatures in Human Induced Pluripotent Stem Cells Determined by Non-Targeted Metabolomics Analysis
Authors: Abdalkader Rodi , Chaleckis Romanas , Fujita Takuya
Published: March 2023

Human induced pluripotent stem cells (hiPSCs) possess immense potential as a valuable source for the generation of a wide variety of human cells yet monitoring the early cell differentiation towards a specific lineage remains challenging. In this study, we employed a non-targeted metabolomic analysis technique to analyze the extracellular metabolites present in samples as small as one microliter. The hiPSCs were subjected to differentiation by initiating culture under the basal medium E6 in combination with chemical inhibitors that have been previously reported to direct differentiation towards the ectodermal lineage such as Wnt/β- catenin and TGF-β kinase/activin receptor alone or in combination with bFGF, and the inhibition of glycogen kinase 3 (GSK-3), which is commonly used for the diversion of hiPSCs towards mesodermal lineage. At 0 hr and 48 hrs 107 metabolites were identified, including biologically relevant metabolites such as lactic acid, pyruvic acid, and amino acids. By determining the expression of the pluripotency marker OCT3/4, we were able to correlate the differentiation status of cells with the shifted metabolites. The group of cells undergoing ectodermal differentiation showed a greater reduction in OCT3/4 expression. Moreover, metabolites such as pyruvic acid and kynurenine showed dramatic change under ectodermal differentiation conditions where pyruvic acid consumption increased 1-2-folds, while kynurenine secretion decreased 2-folds. Further metabolite analysis uncovered a group of metabolites specifically associated with ectodermal lineage, highlighting the potential of our findings to determine the characteristics of hiPSCs during cell differentiation, particularly under ectodermal lineage conditions.

Graphical abstract
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

Hundreds 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.
Human white matter myelination rate slows down at birth
Authors: Grotheer Mareike , Bloom David , Kruper John , Richie-Halford Adam , Zika Stephanie , Aguilera González Vicente A. , Yeatman Jason D. , Grill-Spector Kalanit , Rokem Ariel
Published: March 2023

The formation of myelin, the fatty sheath that insulates nerve fibers, is critical for healthy brain function. A fundamental open question is what is the impact of being born on myelin growth. To address this question, we evaluated a large (n=300) cross-sectional sample of newborns from the Developing Human Connectome Project (dHCP). First, we developed new software for the automated identification of 20 white matter bundles in individuals that is well-suited for large samples. Next, we fit linear models that quantify T1w/T2w, a myelin-sensitive imaging contrast, increases along bundles. We found faster growth of T1w/T2w along the lengths of all bundles before birth than right after birth. Further, in a separate longitudinal sample of preterm infants (N=34), we found lower T1w/T2w at term-equivalent age than in full-term peers. By applying the linear models fit on the cross-section sample to the longitudinal sample of preterm infants, we find that their delay in T1w/T2w growth is well explained by the amount of time preterm infants spend developing in utero and ex utero. These results suggest that being born slows the rate of myelin growths. This reduction in the rate of myelin growth at birth, in turn, explains lower myelin content in individuals born preterm, and could account for long-term cognitive, neurological, and developmental consequences of preterm birth. We hypothesize that closely matching the environment of infants born preterm to what they would have experienced in the womb may reduce delays in myelin growth and hence improve developmental outcomes.
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

Ischaemic 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

Lung 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.

Background

Immunotherapy 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 relevance

Our 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

Intravenous (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.

Highlights

Prospective 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 precipitation

OSPREY is a novelin-vitroflow-through system that quantifies solubility in whole blood

Graphical Abstract
3D Co-culture Model on the Role of Vimentin in Notch Signaling and Vascularization
Authors: Dayekh Khalil , Mequanint Kibret
Published: March 2023

The 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

Understanding 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

The 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

The 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

Background and aims

Bempedoic 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.

Methods

This 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.

Results

The 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.

Conclusions

These data suggest that bempedoic acid is a suitable therapy for patients with MetS who require additional lipid lowering.

Highlights

Bempedoic 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

Background

Liver 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.

Methods

We 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.

Results

We 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.

Conclusions

EAML/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

Background

The 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 findings

We 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.

Conclusions

These 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

The 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.
Feeder-Free Generation of Endocardial and Cardiac Valve Cells from Human Pluripotent Stem Cells
Authors: Liu Clifford Z. , Prasad Aditi , Jadhav Bharati , Sharp Andrew J. , Gelb Bruce D.
Published: March 2023

Valvular heart disease presents a significant health burden, yet advancements in valve biology and novel therapeutics have been hindered by the lack of accessibility to human valve cells. In this study, we have developed a scalable and feeder-free method to differentiate human induced pluripotent stem cells (iPSCs) into endocardial cells. Importantly, we show that these endocardial cells are transcriptionally and phenotypically distinct from vascular endothelial cells and can be directed to undergo endothelial-to-mesenchymal transition (EndMT) to generate cardiac valve cell populations. Following this, we identified two distinct populations—one population undergoes EndMT to become valvular interstitial cells (VICs), while the other population reinforces their endothelial identity to become valvular endothelial cells (VECs). Lastly, we confirmed the identities of our iPSC-derived cell populations and identified putative markers through transcriptomic analyses. By increasing the accessibility to these cell populations, we aim to accelerate discoveries for cardiac valve biology and disease.
Proteomic-based stratification of intermediate-risk prostate cancer patients
Authors: Zhong Qing , Rui Sun , Aref Adel T. , Noor Zainab , Anees Asim , Zhu Yi , Lucas Natasha , Poulos Rebecca C. , Lyu Mengge , Zhu Tiansheng , Wang Bo , Chen Guo-Bo , Wang Yingrui , Ding Xuan , Rutishauser Dorothea , Rupp Niels J. , Rueschoff Jan H. , Poyet Cédric , Hermanns Thomas , Fankhauser Christian , Martínez María Rodríguez , Shao Wenguang , Buljan Marija , Neumann Janis Frederick , Beyer Andreas , Hains Peter G. , Reddel Roger R. , Robinson Phillip J. , Aebersold Ruedi , Guo Tiannan , Wild Peter J.
Published: March 2023

Gleason grading is an important prognostic indicator for prostate adenocarcinoma and is crucial for patient treatment decisions. However, intermediate-risk patients diagnosed in Gleason Grade Groups (GG) 2 and GG3 can harbour either aggressive or non-aggressive disease, resulting in under- or over-treatment of a significant number of patients. Here, we performed proteomic, differential expression, machine learning, and survival analyses for 1,348 matched tumour and benign sample runs from 278 patients. Three proteins (F5, TMEM126B and EARS2) were identified as candidate biomarkers in patients with biochemical recurrence. Multivariate Cox regression yielded 18 proteins, from which a risk score was constructed to dichotomise prostate cancer patients into low- and high-risk groups. This 18-protein signature is prognostic for the risk of biochemical recurrence and completely independent of the intermediate GG. Our results suggest that markers generated by computational proteomic profiling have the potential for clinical applications including integration into prostate cancer management.
Seven naturally variant loci serve as genetic modifiers ofLamc2jebinduced non-Herlitz Junctional Epidermolysis Bullosa in mice
Authors: Sproule Thomas J. , Philip Vivek M. , Chaudhry Nabig A. , Roopenian Derry C. , Sundberg John P.
Published: March 2023

Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian patterns of inheritance, their clinical presentations and severities can vary greatly, implying genetic modifiers. TheLamc2jebmouse model of non-Herlitz junctional EB (JEB-nH) demonstrated that genetic modifiers can contribute substantially to the phenotypic variability of JEB and likely other forms of EB. The innocuous changes in an ‘EB related gene’,Col17a1, have shown it to be a dominant modifier ofLamc2jeb. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease inLamc2jeb/jebmice. Three QTL include other known ‘EB related genes’, with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (Dst-e/Bpag1-e). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivatorPpargc1aas its primary candidate and the others contain related genesPpargandIgf1, suggesting modifier pathways. These results, demonstrating the potent disease modifying effects of normally innocuous genetic variants, greatly expand the landscape of genetic modifiers of EB and therapeutic approaches that may be applied.
Arabidopsis thalianaBBX14 is a target of GLK1 and involved in high-light acclimation, photomorphogenesis and GUN-type retrograde signaling
Authors: Atanasov Vasil , Schumacher Julia , Muiño Jose M , Larasati Catharina , Wang Liangsheng , Kaufmann Kerstin , Leister Dario , Kleine Tatjana
Published: March 2023

Development of photosynthetically competent seedlings requires both light and retrograde biogenic signaling pathways. The transcription factor GLK1 functions at the interface between these pathways, and receives input from the biogenic-signaling integrator GUN1. BBX14 was previously identified, together with GLK1, in a core module that mediates the response to high light levels and biogenic signaling. To gain insight into the function of BBX14, we generatedBBX14overexpressors and CRISPR/Cas-mediatedbbx14mutant plants, conducted high-light, RT-qPCR and ChIP-Seq experiments, measured photosynthetic parameters, chlorophyll contents and growth rates, and analyzed alterations in transcriptomics. We found that, although overexpression of BBX14 is deleterious under normal growth conditions, BBX14 is needed to acclimate plants to high light stress.BBX14is a direct target of GLK1, and RNA-Seq analysis suggests that BBX14 is involved in the circadian clock. Knockout ofBBX14results in a long-hypocotyl phenotype that depends on a retrograde signal, andBBX14expression during biogenic signaling requires GUN1. Finally, we clarify the role of BBX14 in GUN-type biogenic signaling. We conclude that BBX14 is an integrator of photomorphogenetic and biogenic signals, and suggest that BBX14 is a nuclear target of retrograde signals downstream of the GUN1/GLK1 module.
Sensing volatiles throughout the body: Geographic and tissue-specific olfactory receptor expression in the fig waspCeratosolen fusciceps
Authors: Krishnan Sushma , Karpe Snehal Dilip , Kumar Hithesh , Nongbri Lucy B , Ramanathan Sowdhamini , Grosse-Wilde Ewald , Hansson Bill S. , Borges Renee M.
Published: March 2023

An essential adaptive strategy in insects is the evolution of olfactory receptors (ORs) to recognize important volatile environmental chemical cues. Our model species,Ceratosolen fusciceps,a specialist wasp pollinator ofFicus racemosa, likely possesses an OR repertoire that allows it to distinguish fig-specific volatiles in highly variable environments. Using a newly assembled genome-guided transcriptome, we annotated 63 ORs in the species and reconstructed the phylogeny ofCeratosolenORs in conjunction with other hymenopteran species. Expression analysis showed that though ORs were mainly expressed in the antennae, 20 percent were also expressed in non-antennal tissues such as the head, thorax, abdomen, legs, wings, and ovipositor. Specific upregulated expression was observed in OR30C in the head and OR60C in the wings. We identified OR expression from all major body parts ofC. fusciceps, suggesting novel roles of ORs throughout the body. Further examination of OR expression ofC. fuscicepsin widely separated geographical locations, i.e., south (urban) and northeast (rural) India, revealed distinct OR expression levels in different locations. This discrepancy likely parallels the observed variation in fig volatiles between these regions and provides new insights into the evolution of insect ORs and their expression across geographical locations and tissues.
The global distribution of paired eddy covariance towers
Authors: Stoy Paul C. , Chu Housen , Dahl Emma , Cala Daniela S. , Shveytser Victoria , Wiesner Susanne , Desai Ankur R. , Novick Kimberly A.
Published: March 2023

The eddy covariance technique has revolutionized our understanding of ecosystem-atmosphere interactions. Eddy covariance studies often use a “paired” tower design in which observations from nearby towers are used to understand how different vegetation, soils, hydrology, or experimental treatment shape ecosystem function and surface-atmosphere exchange. Paired towers have never been formally defined and their global distribution has not been quantified. We compiled eddy covariance tower information to find towers that could be considered paired. Of 1233 global eddy covariance towers, 692 (56%) were identified as paired by our criteria. Paired towers had cooler mean annual temperature (mean = 9.9 °C) than the entire eddy covariance network (10.5 °C) but warmer than the terrestrial surface (8.9 °C) from WorldClim 2.1, on average. The paired and entire tower networks had greater average soil nitrogen (0.57-0.58 g/kg) and more silt (36.0-36.4%) than terrestrial ecosystems (0.38 g/kg and 30.5%), suggesting that eddy covariance towers sample richer soils than the terrestrial surface as a whole. Paired towers existed in a climatic space that was more different from the global climate distribution sampled by the entire eddy covariance network, as revealed by an analysis of the Kullback-Leibler divergence, but the edaphic space sampled by the entire network and paired towers was similar. The lack of paired towers with available data across much of Africa, northern, central, southern, and western Asia, and Latin America with few towers in savannas, shrublands, and evergreen broadleaf forests point to key regions, ecosystems, and ecosystem transitions in need of additional research. Few if any paired towers study the flux of ozone and other atmospherically active trace gases at the present. By studying what paired towers measure – and what they do not – we can make infrastructural investments to further enhance the value of FLUXNET as it moves toward its fourth decade.
Scrutinizing the Feasibility of Macroscopic Quantum Coherence in the Brain: A Field-Theoretical Model of Cortical Dynamics
Authors: Keppler Joachim
Published: March 2023

The neural activity patterns associated with advanced cognitive processes are characterized by a high degree of collective organization, which raises the question of whether macroscopic quantum phenomena play a significant role in cortical dynamics. In order to pursue this question and scrutinize the feasibility of macroscopic quantum coherence in the brain, a model is developed regarding the functioning of microcolumns, which are the basic functional units of the cortex. This model assumes that the operating principle of a microcolumn relies on the interaction of a pool of neurotransmitter (glutamate) molecules with the vacuum fluctuations of the electromagnetic field, termed zero-point field (ZPF). Quantitative calculations reveal that the coupling strength of the glutamate pool to the resonant ZPF modes lies in the critical regime in which the criterion for the initiation of a phase transition is fulfilled, driving the ensemble of initially independent molecules toward a coherent state and resulting in the formation of a coherence domain that extends across the full width of a microcolumn. The formation of a coherence domain turns out to be an energetically favored state shielded by a considerable energy gap that protects the collective state against thermal perturbations and entails decoherence being greatly slowed down. These findings suggest that under the special conditions encountered in cortical microcolumns the emergence of macroscopic quantum phenomena is feasible. This conclusion is further corroborated by the insight that the presence of a coherence domain gives rise to downstream effects which may be crucial for the cortical communication and the formation of large-scale activity patterns. Taken together, the presented model sheds new light on the fundamental mechanism underlying cortical dynamics and suggests that long-range synchronization in the brain results from a bottom-up orchestration process involving the ZPF.