bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying high-risk comorbidities of short and long-term opioid prescription use
Authors: Jennings Mariela V , Lee Hyunjoon , Rocha Daniel B , Bianchi Sevim B , Coombes Brandon J , Crist Richard C , Faucon Annika , Hu Yirui , Kember Rachel L , Mallard Travis T , Niarchou Maria , Poulsen Melissa N , Straub Peter , Urman Richard D , Walsh Colin G ,   PsycheMERGE Substance Use Disorder Workgroup, Davis Lea K , Smoller Jordan W , Troiani Vanessa , Sanchez-Roige Sandra 
Published: November 2021

ABSTRACTBackgroundElectronic health records (EHR) are useful tools for understanding complex medical phenotypes, but they have been underutilized for opioid use disorders (OUD). Patterns of prescription opioid use might provide an objective measure of OUD risk.MethodsWe extracted data for over 2.6 million patients across three health registries (Vanderbilt University Medical Center, Mass General Brigham, Geisinger) between 2005 and 2018. We defined three groups based on levels of opioid exposure: No Prescription, Minimal Exposure (2 prescriptions within 90 days at least once, but never 3 prescriptions <90 days apart), and Chronic Exposure (≥10 opioid prescriptions in a year), and compared them to the full registries and to patients with OUD diagnostic codes. We extracted demographic and clinical characteristics known to co-occur with OUD, including psychiatric and substance use disorders, pain-related diagnoses, HIV, and hepatitis C.ResultsThe prevalence of substance (alcohol, tobacco, cannabis) use disorders was higher in patients with OUD and Chronic Exposure than those with No Prescription or Minimal Exposure. Patients in the OUD and Chronic Exposure groups had more psychiatric (anxiety, depression, schizophrenia, bipolar disorder) and medical comorbidities (pain, hepatitis C, HIV) than those in the Minimal Exposure group. Notably, patients in the Minimal Exposure group had different comorbidity profiles (higher rates of substance use and psychiatric disorders, more pain conditions) than those in the Unscreened or No Prescription groups, highlighting the value of including opioid exposure in studies of OUD.ConclusionsLong-term opioid prescription use may serve as an additional tool to characterize OUD risk.
BrainPalmSeq: A curated RNA-seq database of palmitoylating and de-palmitoylating enzyme expression in the mouse brain
Authors: Wild AR , Hogg PW , Flibotte S , Nasseri G , Hollman R , Haas K , Bamji SX 
Published: November 2021

AbstractProtein S-palmitoylation is a reversible post-translational lipid modification that plays a critical role in neuronal development and plasticity, while dysregulated S-palmitoylation underlies a number of severe neurological disorders. Dynamic S-palmitoylation is regulated by a large family of ZDHHC palmitoylating enzymes, their accessory proteins, and a small number of known de-palmitoylating enzymes. Here, we curated and analyzed expression data for the proteins that mediate S-palmitoylation from publicly available RNAseq datasets, providing a comprehensive overview of their distribution in the mouse nervous system. We developed a web-tool that enables interactive visualization of the expression patterns for these proteins in the nervous system (http://brainpalmseq.med.ubc.ca/), and explored this resource to find region and cell-type specific expression patterns that give insight into the function of palmitoylating and de-palmitoylating enzymes in the brain and neurological disorders. We found coordinated expression of ZDHHC enzymes with their accessory proteins, de-palmitoylating enzymes and other brain-expressed genes that included an enrichment of S-palmitoylation substrates. Finally, we utilized ZDHHC expression patterns to predict and validate palmitoylating enzyme-substrate interactions.
Fuzzy set intersection based paired-end short-read alignment
Authors: Bolosky William J. , Subramaniyan Arun , Zaharia Matei , Pandya Ravi , Sittler Taylor , Patterson David 
Published: November 2021

AbstractMuch genomic data comes in the form of paired-end reads: two reads that represent genetic material with a small gap between. We present a new algorithm for aligning both reads in a pair simultaneously by fuzzily intersecting the sets of candidate alignment locations for each read. This algorithm is often much faster and produces alignments that result in variant calls having roughly the same concordance as the best competing aligners.
Directing iPSC Differentiation into iTenocytes using Combined Scleraxis Overexpression and Cyclic Loading
Authors: Papalamprou Angela , Yu Victoria , Chen Angel , Stefanovic Tina , Kaneda Giselle , Salehi Khosrowdad , Castaneda Chloe , Gertych Arkadiusz , Glaeser Juliane D , Sheyn Dmitriy 
Published: November 2021

AbstractRegenerative therapies for tendon are falling behind other tissues due to the lack of an appropriate and potent cell therapeutic candidate. This study aimed to induce cell tenogenesis using stable Scleraxis (Scx) overexpression in combination with uniaxial mechanical stretch of mesenchymal stromal cells (MSCs) of different origins. Scleraxis (Scx) is the single direct molecular regulator of tendon differentiation known to date. Mechanoregulation is known to be a central element guiding tendon development and healing. Cells explored were bone marrow-derived (BM-)MSCs as well as MSCs differentiated from induced pluripotent stem cells (iMSCs). Mechanical stimulation combined with Scx overexpression resulted in morphometric and cytoskeleton-related changes, upregulation of early and late tendon markers, increased ECM deposition and alignment, and tenomodulin perinuclear localization in iMSCs, which was greater compared to BM-MSCs and controls. Our findings suggest that these cells can be differentiated into tenocytes and may be a better candidate for tendon cell therapy applications than BM-MSCs.
Interferometric imaging of thermal expansion for temperature control in retinal laser therapy
Authors: Veysset David , Ling Tong , Zhuo Yueming , Palanker Daniel 
Published: November 2021

AbstractPrecise control of the temperature rise is a prerequisite for proper photothermal therapy. In retinal laser therapy, the heat deposition is primarily governed by the melanin concentration, which can significantly vary across the retina and from patient to patient. In this work, we present a method for determining the optical and thermal properties of layered materials, directly applicable to the retina, using low-energy laser heating and phase-resolved optical coherence tomography (pOCT). The method is demonstrated on a polymer-based tissue phantom heated with a laser pulse focused onto an absorbing layer buried below the phantom’s surface. Using a line-scan spectral-domain pOCT, optical path length changes induced by the thermal expansion were extracted from sequential B-scans. The material properties were then determined by matching the optical path length changes to a thermo-mechanical model developed for fast computation. This method determined the absorption coefficient with a precision of 2.5% and the temperature rise with a precision of about 0.2°C from a single laser exposure, while the peak did not exceed 8°C during 1 ms pulse, which is well within the tissue safety range and significantly more precise than other methods.
Peptidoglycan recycling contributes to outer membrane integrity and carbapenem tolerance inAcinetobacter baumannii
Authors: Islam Nowrosh , Kazi Misha I. , Kang Katie N. , Biboy Jacob , Gray Joe , Ahmed Feroz , Schargel Richard D. , Boutte Cara C. , Dörr Tobias , Vollmer Waldemar , Boll Joseph M. 
Published: November 2021

AbstractThe Gram-negative cell envelope is an essential structure that not only protects the cell against lysis from the internal turgor, but also forms a barrier to limit entry of antibiotics. Some of our most potent bactericidal antibiotics, the β-lactams, exploit the essentiality of the cell envelope by inhibiting its biosynthesis, typically inducing lysis and rapid death. However, many Gram-negative bacteria exhibit “antibiotic tolerance”, the ability to sustain viability in the presence of β-lactams for extended time periods. Despite several studies showing that antibiotic tolerance contributes directly to treatment failure, and is a steppingstone in acquisition of true resistance, the molecular factors that promote intrinsic tolerance are not well-understood.Acinetobacter baumanniiis a critical-threat nosocomial pathogen notorious for its ability to rapidly develop multidrug resistance. While typically reserved to combat multidrug resistant infections, carbapenem β-lactam antibiotics (i.e., meropenem) are first-line prescriptions to treatA. baumanniiinfections. Meropenem tolerance in Gram-negative pathogens is characterized by morphologically distinct populations of spheroplasts, but the impact of spheroplast formation is not fully understood. Here, we show that susceptibleA. baumanniiclinical isolates demonstrate high intrinsic tolerance to meropenem, form spheroplasts with the antibiotic and revert to normal growth after antibiotic removal. Using transcriptomics and genetics screens, we characterized novel tolerance factors and found that outer membrane integrity maintenance, drug efflux and peptidoglycan homeostasis collectively contribute to meropenem tolerance inA. baumannii. Furthermore, outer membrane integrity and peptidoglycan recycling are tightly linked in their contribution to meropenem tolerance inA. baumannii.ImportanceCarbapenem treatment failure associated with “superbug” infections has rapidly increased in prevalence, highlighting an urgent need to develop new therapeutic strategies. Antibiotic tolerance can directly lead to treatment failure but has also been shown to promote acquisition of true resistance within a population. While some studies have addressed mechanisms that promote tolerance, factors that underlie Gram-negative bacterial survival during carbapenem treatment are not well-understood. Here, we characterized a role for peptidoglycan recycling in outer membrane integrity maintenance and carbapenem tolerance inA. baumannii. These studies suggest that the pathogen limits antibiotic concentrations in the periplasm and highlights physiological processes that could be targeted to improve antimicrobial treatment.
Age Differences in Diffusivity in the Locus Coeruleus and its Ascending Noradrenergic Tract
Authors: Porat Shai , Sibilia Francesca , Yoon Josephine , Shi Yonggang , Dahl Martin J. , Werkle-Bergner Markus , Düzel Sandra , Bodammer Nils , Lindenberger Ulman , Kühn Simone , Mather Mara 
Published: November 2021

AbstractThe noradrenergic locus coeruleus (LC) is a small brainstem nucleus that promotes arousal and attention. Recent studies have examined the microstructural properties of the LC using diffusion-weighted magnetic resonance imaging and found unexpected age-related differences in fractional anisotropy - a measure of white matter integrity. Here, we used three datasets (Berlin Aging Study-II, N = 301, the Leipzig Study for Mind-Body-Emotion Interactions, N = 220, and Stockholm Sleepy Brain, N = 49), to replicate published findings and expand them by investigating diffusivity in the LC’s ascending noradrenergic bundle. In younger adults, LC fractional anisotropy was significantly lower, compared to older adults. However, in the LC’s ascending noradrenergic bundle, we observed significantly higher fractional anisotropy in younger adults, relative to older adults. These findings indicate that diffusivity in the LC versus the ascending noradrenergic bundle are both susceptible to microstructural changes in aging that have opposing effects on fractional anisotropy.HighlightsFractional anisotropy in the locus coeruleus was lower in younger adultsFractional anisotropy in the noradrenergic bundle was higher in younger adultsSleep deprivation may affect diffusivity in younger adults more than older adults
Genetic and chemical validation of Plasmodium falciparum aminopeptidase PfA-M17 as a drug target in the hemoglobin digestion pathway
Authors: Edgar Rebecca C.S. , Siddiqui Ghizal , Hjerrild Kathryn , Malcolm Tess R. , Vinh Natalie B. , Webb Chaille T. , MacRaild Christopher A. , Counihan Natalie A. , Creek Darren J. , Scammells Peter J , McGowan Sheena , de Koning-Ward Tania F. 
Published: November 2021

AbstractPlasmodium falciparum, a causative agent of malaria, continues to remain a global health threat since these parasites have developed increasing resistance to all anti-malaria drugs used throughout the world. Accordingly, drugs with novel modes of action are desperately required to combat malaria. P. falciparum parasites infect human red blood cells where they digest the hosts main protein constituent, hemoglobin. Leucine aminopeptidase PfA-M17 is one of several aminopeptidases that have been implicated in the last step of this digestive pathway. Here we utilize both reverse genetics and a compound specifically designed to inhibit the activity of PfA-M17 to show that PfA-M17 is essential for P. falciparum survival as it provides parasites with free amino acids for growth, many of which are highly likely to originate from hemoglobin. We further show that our inhibitor is on-target for PfA-M17 and has the ability to kill parasites at nanomolar concentrations. Thus, in contrast to other hemoglobin-degrading proteases that have overlapping redundant functions, we validate PfA-M17 as a potential novel drug target.
Astrocytic expression of ALS-causative mutant FUS leads to TNFα-dependent neurodegeneration in vivo
Authors: Jensen Brigid K. , McAvoy Kevin J. , Heinsinger Nicolette M. , Lepore Angelo C. , Ilieva Hristelina , Haeusler Aaron R. , Trotti Davide , Pasinelli Piera 
Published: November 2021

ABSTRACTGenetic mutations that cause Amyotrophic Lateral Sclerosis (ALS), a progressively lethal motor neuron disease, are commonly found in ubiquitously expressed genes. In addition to direct defects within motor neurons, growing evidence suggests that dysfunction of non-neuronal cells is also an important driver of disease. Previously, we demonstrated that mutations in DNA/RNA binding protein Fused in Sarcoma (FUS) induce neurotoxic phenotypes in astrocytes in vitro, via activation of the NF-κB pathway and release of pro-inflammatory cytokine TNFα. Here, we developed an intraspinal cord injection model to test whether astrocyte-specific expression of ALS-causative FUSR521G variant (mtFUS) causes neuronal damage in vivo. We show that mtFUS expression causes TNFα upregulation, motor function deficits, and spinal motor neuron loss. We further demonstrate a lack of phenotype in TNFα knockout animals expressing mtFUS, and prevention of neurodegeneration in mtFUS-transduced animals through administration of TNFα neutralizing antibodies. Together, these studies strengthen evidence that astrocytes contribute to disease in ALS, establish that FUS-ALS astrocytes induce pathogenic changes to motor neurons in vivo, and provide insights identifying FUS-ALS specific potential therapeutic targets.
Interplay Between KRAS and LZTR1 Protein Turnover, Controlled by CUL3/LZTR1 E3 Ubiquitin Ligase, is Disrupted by KRAS Mutations
Authors: Damianou Andreas , Liang Zhu , Lassen Frederik , Vere George , Hester Svenja , Charles Philip D , Pinto-Fernandez Adan , Santos-Delgado Alberto , Fischer Roman , Kessler Benedikt M 
Published: November 2021

ABSTRACTKRAS is a proto-oncogene encoding a small GTPase. Mutations contribute up to 30% of human solid tumours including lung adenocarcinoma, pancreatic and colorectal carcinomas. Most KRAS activating mutations interfere with GTP hydrolysis, essential for its role as a molecular switch, leading to alterations in their molecular environment and oncogenic signalling. Here, APEX-2 proximity labelling was used to profile the molecular environment of wild type and G12D, G13D and Q61H activating mutants of KRAS under both, starvation and stimulation conditions. We demonstrate by quantitative proteomics the presence of known interactors of KRAS including a-RAF and LZTR1, which varied in abundance with wildtype and KRAS mutants. Notably, the KRAS mutations G12D, G13D and Q61H abrogate association with LZTR1. Wildtype KRAS and LZTR1, as part of the CUL3 ubiquitin E3 ligase complex, affect each other’s protein stability, revealing a direct feedback loop mechanism. KRAS mutations disconnect this regulatory circuit, thereby contributing to oncogenesis.
A newly-evolved chimeric lysin motif receptor-like kinase in Medicago truncatula spp. tricycla R108 extends its Rhizobia symbiotic partnership
Authors: Luu Thi-Bich , Ourth Anna , Pouzet Cécile , Pauly Nicolas , Cullimore Julie 
Published: November 2021

SummaryRhizobial lipochitooligosaccharidic Nod factors (NFs), specified by nod genes, are the primary determinants of host specificity in the legume-Rhizobia symbiosis.We examined the nodulation ability of Medicago truncatula cv Jemalong A17 and M. truncatula ssp. tricycla R108 with the Sinorhizobium meliloti nodF/nodL mutant, which produces modified NFs. We then applied genetic and functional approaches to study the genetic basis and mechanism of nodulation of R108 by this mutant.We show that the nodF/nodL mutant can nodulate R108 but not A17. Using genomics and reverse genetics, we identified a newly-evolved, chimeric LysM receptor-like kinase gene in R108, LYK2bis, which is responsible for the phenotype and can allow A17 to gain nodulation with the nodF/nodL mutant. We found that LYK2bis is involved in nodulation by mutants producing non-O-acetylated NFs and interacts with the key receptor protein NFP. Many, but not all natural S. meliloti and S. medicae strains tested require LYK2bis for efficient nodulation of R108.Our findings reveal that a newly-evolved gene in R108, LYK2bis, extends nodulation specificity to mutants producing non-O-acetylated NFs and is important for nodulation by many natural Sinorhizobia. Evolution of this gene may present an adaptive advantage to allow nodulation by a greater variety of strains.
Single virus assay reveals membrane determinants and mechanistic features of Sendai virus binding
Authors: Lam Amy , Kirkland Orville O. , Anderson Papa Freduah , Seetharaman Nandini , Vujovic Dragan , Thibault Patricia A. , Azarm Kristopher D. , Lee Benhur , Rawle Robert J. 
Published: November 2021

ABSTRACTSendai virus (SeV, formally murine respirovirus) is a membrane-enveloped, negative sense RNA virus in the Paramyxoviridae family, and is closely related to human parainfluenza viruses. SeV has long been utilized as a model paramyxovirus and has recently gained attention as a viral vector candidate for both laboratory and clinical applications. To infect host cells, SeV must first bind to sialic-acid glycolipid or glycoprotein receptors on the host cell surface via its hemagglutinin-neuraminidase (HN) protein. Receptor binding induces a conformational change in HN, which allosterically triggers the viral fusion (F) protein to catalyze membrane fusion. While it is known that SeV binds to α2,3-linked sialic acid receptors, and there has been some study into the chemical requirements of those receptors, key mechanistic features of SeV binding remain unknown, in part because traditional approaches often convolve binding and fusion. Here, we develop and employ a fluorescence microscopy-based assay to observe SeV binding to supported lipid bilayers (SLBs) at the single particle level, which easily disentangles binding from fusion. Using this assay, we investigate mechanistic questions of SeV binding. We identify chemical structural features of ganglioside receptors that influence viral binding and demonstrate that binding is cooperative with respect to receptor density. We measure the characteristic decay time of unbinding and provide evidence supporting a “rolling” mechanism of viral mobility following receptor binding. We also study the dependence of binding on target cholesterol concentration. Interestingly, we find that while SeV binding shows striking parallels in cooperative binding with a prior report of Influenza A virus, it does not demonstrate a similar sensitivity to cholesterol concentration and receptor nano-cluster formation.STATEMENT OF SIGNIFICANCEParamyxoviruses are a family of membrane-enveloped viruses with many notable human and animal pathogens. In this study, we develop and use an assay to observe the initial step of infection – virus binding to the host membrane – for Sendai virus, the prototypical paramyxovirus, at the single virus level. This assay uses cell membrane mimics – supported lipid bilayers – as targets for virus binding to enable easy control of the membrane components with which the virus interacts. Using our assay, we gain insight into basic biophysical questions about Sendai virus binding, including the chemical characteristics of the receptor, the cooperative nature of binding, the influence of cholesterol, and the mechanism of viral mobility following binding.
START domain mediates Arabidopsis GLABRA2 transcription factor dimerization and turnover independently of homeodomain DNA binding
Authors: Mukherjee Thiya , Subedi Bibek , Khosla Aashima , Begler Erika M. , Stephens Preston M. , Warner Adara L. , Lerma-Reyes Ruben , Thompson Kyle A. , Gunewardena Sumedha , Schrick Kathrin 
Published: November 2021

ABSTRACTClass IV homeodomain leucine-zipper transcription factors (HD-Zip IV TFs) are key regulators of epidermal differentiation that are characterized by a DNA-binding homeodomain (HD) in conjunction with a lipid-binding domain termed START (Steroidogenic Acute Regulatory (StAR)-related lipid Transfer). Previous work established that the START domain of GLABRA2 (GL2), a HD-Zip IV member from Arabidopsis, is required for transcription factor activity. Here, we address the functions and possible interactions of START and the HD in DNA binding, dimerization, and protein turnover. Deletion analysis of the HD and missense mutations of a conserved lysine (K146) result in phenotypic defects in leaf trichomes, root hairs and seed mucilage, similar to those observed for START domain mutants, despite nuclear localization of the respective proteins. In vitro and in vivo experiments demonstrate that while HD mutations impair binding to target DNA, the START domain is dispensable for DNA binding. Vice versa, protein interaction assays reveal impaired GL2 dimerization for multiple alleles of START mutants, but not HD mutants. Using in vivo cycloheximide chase experiments, we provide evidence for the role of START, but not HD, in maintaining protein stability. This work advances our mechanistic understanding of HD-Zip TFs as multidomain regulators of epidermal development in plants.