bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity
Authors: Gomez Gustavo A. , Rundle Charles H. , Xing Weirong , Kesavan Chandrasekhar , Pourteymoor Sheila , Lewis Robert E. , Powell David R. , Mohan Subburaman 
Published: August 2022

AbstractPathological obesity and its complications are associated with an increased propensity for bone fractures. Humans with certain genetic polymorphisms at the kinase suppressor of ras2 (Ksr2) locus develop severe early-onset obesity and type 2 diabetes (T2D). Both conditions are phenocopied in mice with Ksr2 deleted, but whether this affects bone health remains unknown. Here we studied the bones of global Ksr2 null mice and found that Ksr2 negatively regulates femoral, but not vertebral, bone mass in two genetic backgrounds, while the paralogous gene, Ksr1, was dispensable for bone homeostasis. Mechanistically, KSR2 regulates bone formation by influencing adipocyte differentiation at the expense of osteoblasts in the bone marrow. Compared with Ksr2’s known role as a regulator of feeding by its function in the hypothalamus, pair feeding and osteoblast-specific conditional deletion of Ksr2 reveals that Ksr2 can regulate bone formation autonomously. Despite the gains in appendicular bone mass observed in absence of Ksr2, bone strength, as well as fracture healing response remains compromised in these mice. This study highlights the interrelationship between adiposity and bone health and provides mechanistic insights into how Ksr2, an adiposity and diabetic gene, regulates bone metabolism.
The Day-1 Mobility Loss Model: Development, Validation, and Clinical Applicability of a Model to Predict Hospital Acquired Mobility Loss in Older Adults
Authors: Shah Sachin J. , Hoffman Ari , Pierce Logan , Covinsky Kenneth E. 
Published: August 2022

ABSTRACTBackgroundMobility loss is common in hospitalized older adults, and resources to prevent mobility loss are finite. Our goal was to develop a rapid, universal screening tool that identifies individuals at risk of losing the ability to walk during hospitalization on the first hospital day. Second, we determined if the model could inform the use of mobility-preserving interventions.MethodsWe included patients admitted to a general medical service, aged ≥65 years, who could walk on admission (Braden Scale Activity subset >=3). Patients were considered to have a new mobility impairment if the activity score was <3 on discharge. We used predictors available on the first hospital day to develop (2017-18) and validate (2019) a prediction model. We determined the association between predicted risk and therapy use in the validation cohort to highlight the model’s clinical utility.Results5542 patients were included (median age 76yrs, 48% women); 7.6% were discharged unable to walk. The model included six predictors: age, marital status, medication administrations, Glasgow Coma Scale verbal score, serum albumin, and urinary catheter presence. In the validation cohort, the model discriminated well (c-statistic 0.75) and was strongly associated with hospital-acquired mobility loss (lowest decile 1%, highest decile 24%). In the validation cohort, therapy consultation ordering increased linearly with predicted risk; however, observed mobility loss increased exponentially.ConclusionThe Day-1 Mobility Loss model predicts the risk of mobility loss in hospitalized older adults on the first hospital day. Further, it identifies at-risk older adults who may benefit from mobility interventions.
Genome-wide association study of ischemic stroke risk in Sickle Cell confirms ADAMTS2, CDK18, uncovers 12 novel loci
Authors: Earley Eric Jay , Kelly Shannon , Fang Fang , Alencar Cecília Salete , de Oliveira Werneck Rodrigues Daniela , Soares Cruz Dahra Teles , Sabino Ester , Custer Brian , Dinardo Carla , Page Grier P. 
Published: August 2022

ABSTRACTBackgroundIschemic stroke is a common complication of sickle cell disease (SCD) and without screening or intervention can affect 11% of children with SCD before the age of 20. This study sought to find genetic biomarkers for risk of stroke occurring at younger ages.MethodsWithin the Trans-Omics for Precision Medicine (TOPMed), a genome-wide association study (GWAS) of ischemic stroke was performed on 1,333 individuals with SCD from Brazil (178 cases, 1155 controls). Via a novel proportional hazards analysis approach, we searched for variants associated with strokes occurring at younger ages.ResultsFourteen genomic regions were associated with early ischemic stroke at genome wide significance (P<5×10−8). This included variants near two genes which have been previously linked to non-SCD early onset stroke (<65 years): ADAMTS2 (rs147625068, P= 3.70 × 10−9) and CDK18 (rs12144136, P= 2.38 × 10−9), respectively. Individuals harboring multiple risk alleles exhibited increasing rates of stroke at earlier timepoints (P < 0.001, Gehan-Wilcoxon) than those carrying only one. Enrichment tests suggest systemic dysregulation of gene expression in the hypothalamus (P = 0.03, FDR), substantia nigra (P = 0.03), spleen (P = 0.005) and coronary (P = 0.0005), tibial (P = 0.03) and aorta arteries (P = 0.03.ConclusionsThis findings from this study support a model of shared genetic architecture underlying ischemic stroke risk between SCD individuals and non-SCD individuals <65 years. In addition, results suggest an additive liability due to carrying multiple risk alleles.
Perspectives on the enhancement of commercially available antibiotics by natural products
Authors: Nitsch-Velasquez Lucia , Barrios Sara B. , Montoya Ricardo A. , Canales Rosy 
Published: August 2022

AbstractBackgroundOpportunistic resistant bacteria are health and economically relevant in the health care systems and in industries worldwide, especially in the so-called resistant bacteria era (RBE). Enhancing the activity of commercially available antibiotics (CAAs) with different types of natural products (NPs) is a successful antimicrobial strategy, for instance the amoxicillin and clavulanate mixture.ObjectiveTo find research trends in this field during 2015-2020 and to detect potential drug hits with potential to diversify formulations and materials design that can be useful to manage the RBE.Systematic review resultsIt yielded 190 reports of synergistic effects of CAAs and NPs. The analyzed variables were: a) natural products origin: plant family, genera, secondary metabolite type; b) strains: +/- Gram, genera, most frequent species, application field; and c) CAAs: family, most frequent CAAs. The families with potential to have more bioactive species were Apocynaceae, Rubiaceae, Euphorbiaceae (Isbio factor). Lonicera had the highest reports amount.Polyphenols and flavonoids were the majority of pure NPs tested. Several potential drug hits for antibiotic activity enhancement at synergistic level were identified together with potential mechanisms of action: berberine (drug efflux inhibitor–DEI, biofilm inhibitor–BI), curcumin (BI), essential oils (BI), 3-o-metyl-butylgallato (inhibition of fatty acid saturation), among others. About the half of the tested strains were gram positive, being Methicillin Resistant Staphylococcus aureus (MRSA) the most frequently tested. Escherichia coli was the gram negative strain most frequently reported, including enterotoxigenic and extended spectrum beta-lactamases producers. The growth of other foodborne genera strains, such as Listeria and Salmonella, were also inhibited. Aminoglycosides were the family most reported, with gentamicin as the most commonly studied.ConclusionsNPs as either as plant extracts from a variety of families, or as purified compounds specially flavonoids and polyphenols, have shown effective results to enhance the antibiotic activity of CAAs against gram positive and negative strains relevant to HC and FI. Their mechanisms of action are starting to be determined, as the case EPIs and BIs. Further research is needed to achieve co-formulations and materials design useful for those fields, that can certainly be positively impacted by pursuing this strategy.
A randomized stepped wedge trial of an intensive combination approach to roll back the HIV epidemic in Nigerian Adolescents: iCARE Nigeria treatment support protocol
Authors: Taiwo Babafemi O. , Kuhns Lisa M. , Omigbodun Olayinka , Awolude Olutosin , Kuti Kehinde M. , Adetunji Adedotun , Berzins Baiba , Janulis Patrick , Akanmu Sulaimon , Agbaji Oche , David Agatha N. , Akinbami Akinsegun , Adekambi Abiodun Folashade , Johnson Amy K. , Okonkwor Ogochukwu , Oladeji Bibilola D. , Cervantes Marbella , Adewumi Olubusuyi M. , Kapogiannis Bill , Garofalo Robert 
Published: August 2022

ABSTRACTBackgroundNigeria is one of six countries with half the global burden of youth living with HIV. Interventions to date have been inadequate as AIDS-related deaths in Nigeria’s youth have remained unchanged in recent years. The iCARE Nigeria HIV treatment support intervention, a combination of peer navigation and SMS text message medication reminders to promote viral suppression, demonstrated initial efficacy and feasibility in a pilot trial among youth living with HIV in Nigeria. This paper describes the study protocol for the large-scale trial of the intervention.MethodsThe iCARE Nigeria-Treatment study is a randomized stepped wedge trial of a combination (peer navigation and text message reminder) intervention, delivered to youth over a period of 48 weeks to promote viral suppression. Youth receiving HIV treatment at six clinical sites in the North Central and South Western regions of Nigeria were recruited for participation. Eligibility criteria included registration as a patient at participating clinics, aged 15-24 years, on antiretroviral therapy for at least three months, ability to understand and read English, Hausa, Pidgin English, or Yoruba, and intent to remain a patient at the study site during the study period. The six clinic sites were divided into three clusters and randomized to a sequence of control and intervention periods for comparison. The primary outcome is plasma HIV-1 viral load suppression, defined as viral load ≤ 200 copies/mL, in the intervention period versus the control period at 48 weeks of intervention.DiscussionEvidence-based interventions to promote viral load suppression among youth in Nigeria are needed. This study will determine efficacy of a combination intervention (peer navigation and text message reminder) and collect data on potential implementation barriers and facilitators to inform scale-up if efficacy is confirmed.Trial registrationClinicalTrials.gov number, NCT 04950153, retrospectively registered July 6, 2021, https://clinicaltrials.gov/.
Beyond mean fitness: demographic stochasticity and resilience matter at tree species climatic edges
Authors: Guyennon Arnaud , Reineking Björn , Salguero-Gomez Roberto , Dahlgren Jonas , Lehtonen Aleksi , Ratcliffe Sophia , Ruiz-Benito Paloma , Zavala Miguel A. , Kunstler Georges 
Published: August 2022

AbstractAimLinking local population dynamics and species distributions is critical to predicting the impacts of climate change. While many studies focus on the mean fitness of populations, theory shows that species distributions can be shaped by demographic stochasticity or population resilience. Here we examine how mean fitness (measured by invasion rate), demographic stochasticity, and resilience (measured by the ability to recover from disturbance) constrain populations at the edges compared to the climatic center.LocationEurope: Spain, France, Germany, Finland, and Sweden.PeriodForest inventory data used for fitting the models cover the period from 1985 to 2013.Major taxaDominant European tree species; Angiosperms and Gymnosperms.MethodsWe developed dynamic population models covering the entire life cycle of 25 European tree species with climatically dependent recruitment models fitted to forest inventory data. We then ran simulations using integral projection and individual-based models to test how invasion rates, risk of stochastic extinction, and ability to recover from stochastic disturbances differ between the center and edges of species’ climatic niches.ResultsResults varied among species, but in general, demographic constraints were stronger at warm edges and for species in harsher climates. Conversely, recovery was more limiting at cold edges. In addition, we found that for several species, constraints at the edges were due to demographic stochasticity and recovery capacity rather than mean fitness.Main conclusionOur results highlight that mean fitness is not the only mechanism at play at the edges; demographic stochasticity and population capacity to recover also matter for European tree species. To understand how climate change will drive species range shifts, future studies will need to analyse the interplay between population mean growth rate and stochastic demographic processes as well as disturbances.
DNA language models are powerful predictors of genome-wide variant effects
Authors: Benegas Gonzalo , Batra Sanjit Singh , Song Yun S. 
Published: August 2022

AbstractThe expanding catalog of genome-wide association studies (GWAS) provides biological insights across a variety of species, but identifying the causal variants behind these associations remains a significant challenge. Experimental validation is both labor-intensive and costly, highlighting the need for accurate, scalable computational methods to predict the effects of genetic variants across the entire genome. Inspired by recent progress in natural language processing, unsupervised pre-training on large protein sequence databases has proven successful in extracting complex information related to proteins. These models showcase their ability to learn variant effects in coding regions using an unsupervised approach. Expanding on this idea, we here introduce theGenomicPre-trainedNetwork (GPN), a model designed to learn genome-wide variant effects through unsupervised pre-training on genomic DNA sequences. Our model also successfully learns gene structure and DNA motifs without any supervision. To demonstrate its utility, we train GPN onunalignedreference genomes ofArabidopsis thalianaand seven related species within the Brassicales order, and evaluate its ability to predict the functional impact of genetic variants inArabidopsis thalianaby utilizing allele frequencies from the 1001 Genomes Project and a comprehensive database of GWAS. Notably, GPN outperforms predictors based on popular conservation scores such as phyloP and phastCons. Our predictions forArabidopsis thalianacan be visualized as sequence logos in the UCSC Genome Browser (https://genome.ucsc.edu/s/gbenegas/gpn-arabidopsis). We provide code (https://github.com/songlab-cal/gpn) to train GPN for any given species using its DNA sequence alone, enabling unsupervised prediction of variant effects across the entire genome.
Single-cell functional genomics of natural killer cell evasion in blood cancers
Authors: Dufva Olli , Gandolfi Sara , Huuhtanen Jani , Dashevsky Olga , Saeed Khalid , Klievink Jay , Nygren Petra , Bouhlal Jonas , Lahtela Jenni , Näätänen Anna , Ghimire Bishwa R , Hannunen Tiina , Ellonen Pekka , Duàn Hanna , Theodoropoulos Jason , Laajala Essi , Härkönen Jouni , Pölönen Petri , Heinäniemi Merja , Yamano Shizuka , Shirasaki Ryosuke , Barbie David , Roth Jennifer , Romee Rizwan , Sheffer Michal , Lähdesmäki Harri , Lee Dean A. , De Matos Simoes Ricardo , Kankainen Matti , Mitsiades Constantine S , Mustjoki Satu 
Published: August 2022

SUMMARYNatural killer (NK) cells are emerging as a promising therapeutic option in cancer. To better understand how cancer cells evade NK cells, we studied interacting NK and blood cancer cells using single-cell and genome-scale functional genomics screens. At single-cell resolution, interaction of NK and cancer cells induced distinct activation states in both cell types depending on the cancer cell lineage and molecular phenotype, ranging from more sensitive myeloid to more resistant B-lymphoid cancers. CRISPR screens uncovered cancer cell-intrinsic genes driving sensitivity and resistance, including antigen presentation and death receptor signaling mediators, adhesion molecules, protein fucosylation genes, and transcriptional regulators. CRISPR screens with a single-cell transcriptomic readout revealed how these cancer cell genes influenced the gene expression landscape of both cell types, including regulation of activation states in both cancer and NK cells by IFNγ signaling. Our findings provide a resource for rational design of NK cell-based therapies in blood cancers.HIGHLIGHTSTranscriptomic states of interacting NK cells and cancer cells depend on cancer cell lineageMolecular correlates of increased sensitivity of myeloid compared to B-lymphoid cancers include activating receptor ligands NCR3LG1, PVR, and ULBP1New regulators of NK cell resistance from 12 genome-scale CRISPR screens include blood cancer-specific regulators SELPLG, SPN, and MYBSingle-cell transcriptomics CRISPR screens targeting 65 genome-wide screen hits identify MHC-I, IFNy, and NF-κB regulation as underlying mechanisms
Metabolic enhancement of mammalian developmental pausing
Authors: van der Weijden Vera A. , Stoetzel Maximilian , Fauler Beatrix , Iyer Dhanur P. , Shahraz Mohammed , Meierhofer David , Rulands Steffen , Alexandrov Theodore , Mielke Thorsten , Bulut-Karslioglu Aydan 
Published: August 2022

AbstractThe quest to model and modulate embryonic development became a recent cornerstone of stem cell and developmental biology. Mammalian developmental timing is adjustable in vivo by preserving preimplantation embryos in a dormant state called diapause. Inhibition of the growth regulator mTOR (mTORi) pauses mouse development in vitro, yet constraints to pause duration are unrecognized. By comparing the response of embryonic and extraembryonic stem cells to mTORi-induced pausing, we identified lipid usage as a bottleneck to developmental pausing. Enhancing fatty acid oxidation (FAO) boosts embryo longevity, while blocking it reduces the pausing capacity. Genomic and metabolic analyses of single embryos point toward a deeper dormant state in FAO-enhanced pausing and reveal a link between lipid metabolism and embryo morphology. Our results lift a constraint on in vitro embryo survival and suggest that lipid metabolism may be a critical metabolic transition relevant for longevity and stem cell function across tissues.One-Sentence SummaryFacilitating fatty acid oxidation by carnitine supplementation enhances mTOR inhibition-mediated developmental pausing.
Mechanistic Insight into AP-Endonuclease 1 Cleavage of Abasic Sites at Stalled Replication Forks
Authors: Hoitsma Nicole M. , Norris Jessica , Khoang Thu H. , Kaushik Vikas , Antony Edwin , Hedglin Mark , Freudenthal Bret D. 
Published: August 2022

1.AbstractMany types of DNA damage stall replication fork progression, including abasic sites. AP-Endonuclease 1 (APE1) has been shown to cleave abasic sites in ssDNA substrates. Importantly, APE1 cleavage of ssDNA at a replication fork has significant biological implications by generating double strand breaks that could collapse the replication fork. Despite this, the molecular basis and efficiency of APE1 processing abasic sites at a replication fork remains elusive. Here, we investigate APE1 cleavage of several abasic substrates that mimic potential APE1 interactions at replication forks. We determine that APE1 has robust activity on these substrates, similar to dsDNA, and report rapid rates for cleavage and product release. X-ray crystal structures visualize the APE1 active site, highlighting that a similar mechanism is used to process ssDNA substrates as canonical APE1 activity on dsDNA. However, mutational analysis reveals R177 to be uniquely critical for the APE1 ssDNA cleavage mechanism. Additionally, we investigate the interplay between APE1 and Replication Protein A (RPA), the major ssDNA-binding protein at replication forks, revealing that APE1 can cleave an abasic site while RPA is still bound to the DNA substrate. Together, this work provides molecular level insights into abasic ssDNA processing by APE1, including the presence of RPA.
Cortical interneuron development is affected in leukodystrophy 4H
Authors: Dooves Stephanie , Kok Liza M.L. , Holmes Dwayne B. , Breeuwsma Nicole , Breur Marjolein , Bugiani Marianna , Wolf Nicole I. , Heine Vivi M. 
Published: August 2022

Abstract4H leukodystrophy is a rare genetic disorder classically characterized by hypomyelination, hypodontia and hypogonadotropic hypogonadism. With the discovery that 4H is caused by mutations that affect RNA polymerase III, mainly involved in the transcription of small non-coding RNAs, also patients with atypical presentations with mainly a neuronal phenotype were identified. Pathomechanisms of 4H brain abnormalities are still unknown and research is hampered by a lack of preclinical models. We aimed to identify cells and pathways that are affected by 4H mutations using induced pluripotent stem cell models.RNA sequencing analysis on induced pluripotent stem cell-derived cerebellar cells revealed several differentially expressed genes between 4H patients and control samples, including reduced ARX expression. As ARX is involved in early brain and interneuron development, we studied and confirmed interneuron changes in primary tissue of 4H patients. Subsequently, we studied interneuron changes in more depth and analyzed induced pluripotent stem cell-derived cortical neuron cultures for changes in neuronal morphology, synaptic balance, network activity and myelination. We showed a decreased percentage of GABAergic synapses in 4H, which correlated to increased neuronal network activity. Treatment of cultures with GABA antagonists led to a significant increase in neuronal network activity in control cells but not in 4H cells, also pointing to lack of inhibitory activity in 4H. Myelination and oligodendrocyte maturation in cultures with 4H neurons was normal, and treatment with sonic hedgehog agonist SAG did not improve 4H related neuronal phenotypes. qPCR analysis revealed increased expression of parvalbumin interneuron marker ERBB4, suggesting that the development rather than generation of interneurons may be affected in 4H.Together, these results indicate that interneurons are involved, possibly parvalbumin interneurons, in disease mechanisms of 4H leukodystrophy.