bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of left atrial structure and function with cognitive function among adults with metabolic syndrome
Authors: Casanova Ines Gonzalez , M. Alonso-Gómez Ángel , Romaguera Dora , Toledo Estefanía , Fortuny Elena , López Luis , Ramallal Raúl , Salas-Salvadó Jordi , Tojal-Sierra Lucas , Castañer Olga , Alonso Alvaro 
Published: March 2022

AbstractBackgroundAtrial fibrillation has been associated with cognitive impairment. Whether subclinical abnormalities in atrial function and substrate predisposing to atrial fibrillation impact cognitive function has received limited attention.MethodsWe tested associations of echocardiographic markers of atrial structure and function with cognitive functioning and decline among 510 participants with overweight/obesity and metabolic syndrome (mean age [standard deviation] of 64.4 [5.2] years in men and 66.5 [3.9] in women). Left atrial markers (volume index, emptying fraction, strain, function index, and stiffness index) were estimated based on transthoracic echocardiography. General cognitive functioning (Mini-mental examination), verbal ability (verbal fluency test), memory and attention (Digit Span Tests), and processing speed and executive function (Trail-Making Tests A and B) were assessed at baseline and at the two-year follow-up. Multiple linear regression was used to test associations of atrial markers (modeled in standard deviation units) with baseline and two-year changes in cognitive scores adjusting for demographic and health covariates.ResultsLeft atrial structure and function was not associated with cognitive function at baseline. Larger left atrial volume index (standardized β [95% confidence interval] = -0.13 [-0.22, -0.03]), lower peak longitudinal strain (−0.11 [-0.20, -0.01]), and higher stiffness index (−0.18 [-0.28, -0.08) were associated with 2-year worsening in Trail-Making Test A. Strain measurements were also associated with 2-year change in the Controlled Oral Word Association Test.ConclusionOverall, adverse markers of left atrial structure and function were associated with 2-year detrimental executive function-related cognitive changes in a sample of participants at high risk for cardiovascular disease, highlighting left atrial substrate as a potential risk factor for cognitive decline and dementia.
Ion channel model reduction using manifold boundaries
Authors: Whittaker Dominic G. , Wang Jiahui , Shuttleworth Joseph G. , Venkateshappa Ravichandra , Kemp Jacob M. , Claydon Thomas W. , Mirams Gary R. 
Published: March 2022

AbstractMathematical models of voltage-gated ion channels are used in basic research, industrial and clinical settings. These models range in complexity, but typically contain numerous variables representing the proportion of channels in a given state, and parameters describing the voltage-dependent rates of transition between states. An open problem is selecting the appropriate degree of complexity and structure for an ion channel model given data availability. Here, we simplify a model of the cardiac human Ether-à-go-go Related Gene (hERG) potassium ion channel, which carries cardiac IKr, using the manifold boundary approximation method (MBAM). The MBAM approximates high-dimensional model-output manifolds by reduced models describing their boundaries, resulting in models with fewer parameters (and often variables). We produced a series of models of reducing complexity starting from an established 5-state hERG model with 15 parameters. Models with up to 3 fewer states and 8 fewer parameters were shown to retain much of the predictive capability of the full model and were validated using experimental hERG1a data collected in HEK293 cells at 37°C. The method provides a way to simplify complex models of ion channels that improves parameter identifiability and will aid in future model development.
Crystal structures and fragment screening of SARS-CoV-2 NSP14 reveal details of exoribonuclease activation and mRNA capping and provide starting points for antiviral drug development
Authors: Imprachim Nergis , Yosaatmadja Yuliana , Newman Joseph A 
Published: March 2022

AbstractThe SARS-CoV-2 non-structural protein 14 (NSP14) is a dual function enzyme containing an N-terminal exonuclease domain (ExoN) and C-terminal Guanine-N7-methyltransferase (N7-MTase) domain. Both enzymatic activities appear to be essential for the viral life cycle and thus may be targeted for anti-viral therapeutics. NSP14 forms a stable complex with the SARS-CoV-2 zinc binding protein NSP10, and this interaction greatly enhances the nuclease but not the methyltransferase activity. In this study, we have determined the crystal structure of SARS-CoV-2 NSP14 in the absence of NSP10 to 1.7 Å resolution. Comparisons of this structure with the structure of NSP14/NSP10 complexes solved to date reveal significant conformational changes that occur within the NSP14 ExoN domain upon binding of NSP10, including significant movements and helix to coil transitions that facilitate the formation of the ExoN active site and provide an explanation of the stimulation of nuclease activity by NSP10. Conformational changes are also seen in the MTase active site within a SAM/SAH interacting loop that plays a key role in viral mRNA capping. We have also determined the structure of NSP14 in complex with cap analogue 7MeGpppG, offering new insights into MTase enzymatic activity. We have used our high resolution crystals to perform X-ray fragment screening of NSP14, revealing 72 hits bound to potential sites of inhibition of the ExoN and MTase domains. These structures serve as excellent starting point tools for structure guided development and optimization of NSP14 inhibitors that may be used to treat COVID-19 and potentially other future viral threats.
Optical photothermal infrared spectroscopy can differentiate equine osteoarthritic plasma extracellular vesicles from healthy controls
Authors: Clarke Emily J , Lima Cassio , Anderson James R , Castanheira Catarina , Beckett Alison , James Victoria , Hyett Jacob , Goodacre Roy , Peffers Mandy J 
Published: March 2022

AbstractBackgroundEquine osteoarthritis is a chronic degenerative disease of the articular joint, characterised by cartilage degradation resulting in pain and reduced mobility and thus is a prominent equine welfare concern. Diagnosis is usually at a late stage through radiographic examination, whilst treatment is symptomatic not curative. Extracellular vesicles are small nanoparticles that are involved in intercellular communication. The objective of this study was to investigate the feasibility of Raman and optical photothermal infrared spectroscopy to detect osteoarthritis using plasma-derived extracellular vesicles.MethodsPlasma samples were derived from thoroughbred racehorses. A total of 14 samples were selected (control; n= 6 and diseased; n=8). Extracellular vesicles were isolated using differential ultracentrifugation and characterised using nanoparticle tracking analysis, transmission electron microscopy, and human tetraspanin chips. Samples were then analysed using Raman and optical photothermal infrared spectroscopy.ResultsInfrared spectra were analysed between 950-1800 cm-1. Raman spectra had bands between the wavelengths of 900-1800 cm-1 analysed. Bands below 900 cm-1. Spectral data for both Raman and optical photothermal infrared spectroscopy was used to obtain a classification model and confusion matrices, characterising the techniques ability to distinguish diseased samples. Optical photothermal infrared spectroscopy could differentiate osteoarthritic extracellular vesicles from healthy with good classification (93.4%) whereas Raman displayed poor classification (64.3%). Plasma-derived extracellular vesicles from osteoarthritic horses contained increased signal for proteins, lipids and nucleic acids.Discussion/ conclusionFor the first time we demonstrated the ability to use optical photothermal infrared spectroscopy to interrogate extracellular vesicles and osteoarthritis-related samples. Optical photothermal infrared spectroscopy was superior to Raman in this study, and could distinguish osteoarthritis samples, suggestive of its potential use diagnostically to identify osteoarthritis in equine patients. This study demonstrates the potential of Raman and optical photothermal infrared spectroscopy to be used as a diagnostic tool in clinical practice, with the capacity to detect changes in extracellular vesicles from clinically derived samples.
Structure and regulation of the myotonic dystrophy kinase-related Cdc42-binding kinase
Authors: Truebestein Linda , Waltenberger Elisabeth , Gehin Charlotte , Gavin Anne-Claude , Leonard Thomas A. 
Published: March 2022

SummaryRemodeling of the cytoskeleton underlies myriad processes essential for life. Protein kinases of the DMPK family are critical regulators of actomyosin contractility in cells. In the nematode worm, Caenorhabditis elegans, MRCK1 is required for the activation of myosin, leading to the development of cortical tension, apical constriction and early gastrulation. Here, we present the structure, conformation, and membrane-binding properties of C. elegans MRCK1. MRCK1 forms an obligate homodimer with N-terminal kinase domains, a parallel coiled-coil of 55 nm, and a C-terminal tripartite module of C1, PH and CNH domains. High-throughput liposome binding assays indicate binding to specific phosphoinositides, while the C-terminal Cdc42-binding (CRIB) motif binds specifically to activated Cdc42. The length of the coiled-coil domain of MRCK, as well as those of the related DMPK kinases ROCK, CRIK and DMPK, is remarkably conserved over millions of years of evolution, suggesting that they may function as molecular rulers to precisely position kinase activity at a fixed distance from the membrane.
Optimized high-throughput screening of non-coding variants identified from genome-wide association studies
Authors: Morova Tunc , Ding Yi , Huang Chia-Chi Flora , Sar Funda , Schwarz Tommer , Giambartolomei Claudia , Baca Sylvan C. , Grishin Dennis , Hach Faraz , Gusev Alexander , Freedman Matthew L. , Pasaniuc Bogdan , Lack Nathan A. 
Published: March 2022

AbstractThe vast majority of disease-associated single nucleotide polymorphisms identified from genome-wide association study (GWAS) are localized in non-coding regions. A significant fraction of these variants impact transcription factors binding to enhancer elements and alter gene expression. To functionally interrogate the activity of such variants we developed snpSTARRseq, a high-throughput experimental method that can interrogate the functional impact of hundreds to thousands of non-coding variants on enhancer activity. snpSTARRseq dramatically improves signal-to-noise by utilizing a novel sequencing and bioinformatic approach that increases both insert size and number of variants tested per loci. Using this strategy, we interrogated 70 of 140 known prostate cancer (PCa) risk-associated loci and demonstrated that 26 (37%) of them harbor 36 SNPs that significantly altered enhancer activity. Combining these results with chromosomal looping data we could identify interacting genes and provide a mechanism of action for 20 PCa GWAS risk regions. When benchmarked to orthogonal methods, snpSTARRseq showed a strong correlation with in vivo experimental allelic-imbalance studies whereas there was no correlation with predictive in silico approaches. Overall, snpSTARRseq provides an integrated experimental and computational framework to functionally test non-coding genetic variants.
Bayesian hierarchical model for dose finding trial incorporating historical data
Authors: Han Linxi , Deng Qiqi , He Zhangyi , Fleischer Frank , Yu Feng 
Published: March 2022

AbstractThe Multiple Comparison Procedure and Modelling (MCPMod) approach has been shown to be a powerful statistical tool that can significantly improve the design and analysis of dose finding studies under model uncertainty. Due to its frequentist nature, however, it is difficult to incorporate into MCPMod information from historical trials on the same drug. Recently, a Bayesian version of MCPMod has been introduced by Fleischer et al. (2022) to resolve this issue, which is particularly tailored to the situation where there is information about the placebo dose group from historical trials. In practice, information may also be available on active dose groups from early phase trials, e.g., a dose escalation trial and a preceding small Proof of Concept trial with only a placebo and a high dose. To address this issue, we introduce a Bayesian hierarchical framework capable of incorporating historical information about both placebo and active dose groups with the flexibility of modelling both prognostic and predictive between-trial heterogeneity. Our method is particularly useful in the situation where the effect sizes of two trials are different. Our goal is to reduce the necessary sample size in the dose finding trial while maintaining its target power.
Unplanned ICU transfer from post-anesthesia care unit following cerebral surgery: A retrospective study
Authors: Cao Qinqin , Fan Chengjuan , Li Wei , Bai Shuling , Dong Hemin , Meng Haihong 
Published: March 2022

AbstractBackgroundUnplanned transfer to intensive care unit (ICU) lead to reduced trust of patients and their families in medical staff and challenge medical staff to allocate scarce ICU resources. This study aimed to explore the incidence and risk factors of unplanned transfer to ICU during emergence from general anesthesia after cerebral surgery, and to provide guidelines for preventing unplanned transfer from post-anesthesia care unit (PACU) to ICU following cerebral surgery.MethodsThis was a retrospective case-control study and included patients with unplanned transfer from PACU to ICU following cerebral surgery between January 2016 and December 2020. The control group comprised patients matched (2:1) for age (±5 years), sex, and operation date (±48 hours) as those in the case group. Stata14.0 was used for statistical analysis, and p <0.05 indicated statistical significance.ResultsA total of 11,807 patients following cerebral surgery operations were cared in PACU during the study period. Of the 11,807 operations, 81 unscheduled ICU transfer occurred (0.686%). Finally, 76 patients were included in the case group, and 152 in the control group. The following factors were identified as independent risk factors for unplanned ICU admission after neurosurgery: low mean blood oxygen (OR=1.57, 95%CI: 1.20–2.04), low mean albumin (OR=1.14, 95%CI: 1.03–1.25), slow mean heart rate (OR=1.04, 95%CI: 1.00–1.08), blood transfusion (OR=2.78, 95%CI: 1.02–7.58), emergency surgery (OR=3.08, 95%CI: 1.07–8.87), lung disease (OR=2.64, 95%CI: 1.06–6.60), and high mean blood glucose (OR=1.71, 95%CI: 1.21–2.41).ConclusionWe identified independent risk factors for unplanned transfer from PACU to ICU after cerebral surgery based on electronic medical records. Early identification of patients who may undergo unplanned ICU transfer after cerebral surgery is important to provide guidance for accurately implementing a patient’s level of care.
Humans prioritize walking efficiency or walking stability based on environmental risk
Authors: Kulkarni Ashwini , Cui Chuyi , Rietdyk Shirley , Ambike Satyajit 
Published: March 2022

AbstractIn human gait, the body’s mechanical energy at the end of one step is reused to achieve forward progression during the subsequent step, thereby reducing the required muscle work. During the single stance phase, humans rely on the largely uncontrolled passive inverted pendular motion of the body to perpetuate forward motion. These passive body dynamics, while improving walking efficiency, also indicate that lower passive dynamic stability in the anterior direction since the individual will be less able to withstand a forward external perturbation. Here we test the novel hypothesis that humans manipulate passive anterior-posterior (AP) stability via active selection of step length to either achieve energy-efficient gait or to improve stability when it is threatened. We computed the AP margin of stability, which quantifies the passive dynamic stability of gait, for multiple steps as healthy young adults (N=20) walked on a clear and on an obstructed walkway. Participants used passive dynamics to achieve energy-efficient gait for all but one step; when crossing the obstacle with the leading limb, AP margin of stability was increased. This increase indicated caution to offset the greater risk of falling after a potential trip. Furthermore, AP margin of stability increased while approaching the obstacle, indicating that humans proactively manipulate the passive dynamics to meet the demands of the locomotor task. Finally, the step length and the center of mass motion co-varied to maintain the AP margin of stability for all steps in both tasks at the specific values for each step. We conclude that humans actively regulate step length to maintain specific levels of passive dynamic stability for each step during unobstructed and obstructed gait.
Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation
Authors: Tammineni Eshwar R. , Figueroa Lourdes , Manno Carlo , Varma Disha , Kraeva Natalia , Ibarra Carlos A , Klip Amira , Riazi Sheila , Ríos Eduardo 
Published: March 2022

AbstractCalcium ion movements between cellular stores and the cytosol govern muscle contraction, the most energy-consuming function in mammals, which confers skeletal myofibers a pivotal role in glycemia regulation. Chronic myoplasmic calcium elevation, found in malignant hyperthermia-susceptible (MHS) patients and multiple myopathies, has been suggested to underlie the progression from hyperglycemia to insulin resistance. What drives such progression remains elusive. We find that muscle cells derived from MHS patients have increased an activated fragment of GSK3β — a specialized kinase that inhibits glycogen synthase, impairing glucose utilization and delineating a path to hyperglycemia. We also find decreased content of junctophilin1, an essential structural protein that colocalizes in the couplon with the voltage-sensing CaV1.1, the calcium channel RyR1 and calpain1, accompanied by an increase in a 44-kDa junctophilin1 fragment (JPh44) that moves into nuclei. We trace these changes to activated proteolysis by calpain1, secondary to increased myoplasmic calcium. We demonstrate that a JPh44-like construct induces transcriptional changes predictive of increased glucose utilization in myoblasts, including less transcription and translation of GSK3β and decreased transcription of proteins that reduce utilization of glucose. These effects reveal a stress-adaptive response, mediated by the novel regulator of transcription JPh44.
The sunflower WRINKLED1 transcription factor regulates fatty acid biosynthesis genes through an AW box binding sequence with a particular base bias
Authors: Sánchez R , González-Thuillier I , Venegas-Calerón M , Garcés R , Salas JJ , Martínez-Force E 
Published: March 2022

AbstractSunflower (Helianthus annuus L.) is an important oilseed crop in which the biochemical pathways leading to seed oil synthesis and accumulation have been widely studied. However, how these pathways are regulated is less well understood. The WRINKLED1 (WRI1) transcription factor is considered a master regulator in the transcriptional control of triacylglycerol biosynthesis, acting through the AW box binding element (CNTNG(N)7CG) that resides in the promoter of target genes. Here, we identified the sunflower WRI1 gene and characterized its activity in electrophoretic mobility shift assays. We studied its role as a co-regulator of sunflower genes involved in plastidial fatty acid synthesis, identifying genes bound by this transcription factor. Sunflower WRI1-targets included genes encoding all subunits of the pyruvate dehydrogenase complex, the α-CT and BCCP genes of the acetyl-CoA carboxylase complex, genes encoding acyl carrier proteins and key genes of the fatty acid synthase complex (KASIII, KASI and KAR), together with the FATA1 gene. As such, sunflower WRI1 regulates seed plastid fatty acid biosynthesis in a coordinated manner, establishing a WRI1 push and pull strategy that drives oleic acid synthesis for its export into the cytosol. We also analyzed the sequence of the functional sunflower AW box, determining the base bias at the N positions in the active sunflower AW box motif. Accordingly, we conclude that the sunflower AW box is sequence-sensitive at the non-conserved positions, enabling WRI1-binding. Moreover, we found that sunflower WRI1 could bind to a non-canonical AW-box motif, opening the possibility of searching for new target genes.
kb_DRAM: Annotating and functional profiling of genomes with DRAM in KBase
Authors: Shaffer Michael , Borton Mikayla A , Bolduc Ben , Ghadermazi Parsa , Edirisinghe Janaka N , Faria José P , Miller Christopher S , Chan Siu Hung Joshua , Sullivan Matt B , Henry Christopher S , Wrighton Kelly C. 
Published: March 2022

AbstractSummaryAnnotation is predicting the location of and assigning function to genes in a genome. DRAM is a tool developed to annotate bacterial, archaeal and viral genomes derived from pure cultures or metagenomes. DRAM distills multiple gene annotations to summaries of functional potential. Despite these benefits, a downside of DRAM is processing requires large computation resources, which limits its accessibility, and it did not integrate with downstream metabolic modelling tools. To alleviate these constraints, DRAM and the viral counterpart, DRAM-v, are now available and integrated in the freely accessible KBase cyberinfrastructure. With kb_DRAM users can generate DRAM annotations and functional summaries from microbial or viral genomes in a point and click interface, as well as generate genome scale metabolic models from these DRAM annotations.Availability and ImplementationThe kb_DRAM software is available at https://github.com/shafferm/kb_DRAM. The kb_DRAM apps on KBase can be found in the catalog at https://narrative.kbase.us/#catalog/modules/kb_DRAM. A narrative with examples of running all KBase apps is available at https://kbase.us/n/88325/84/.ContactMichael Shaffer, michael.t.shaffer@colostate.edu; Kelly Wrighton, kelly.wrighton@colostate.eduSupplementary InformationSupplementary data are available at Bioinformatics online.
Novel tuberculosis combination regimens of two and three-months therapy duration
Authors: Gumbo Tawanda , Chapagain Moti , Magombedze Gesham , Srivastava Shashikant , Deshpande Devyani , Pasipanodya Jotam G. , Gumbo Ruramai , Dheda Keertan , Diacon Andreas , Hermann David , Hanna Debra 
Published: March 2022

AbstractThe tuberculosis treatment duration is 4-6 months, but can be 18–20 months with multidrug resistance. Ultrashort regimens that cure regardless of resistance status [“pan-tuberculosis regimens”] would be a major step towards global tuberculosis control. Starting with seven drugs [bedaquiline, delamanid, pretomanid, OPC-167832, sutezolid, moxifloxacin, and pyrazinamide] in clinical testing, we calculated that there were thousands of possible novel combinations to evaluate. We used mathematical and pharmacokinetics/pharmacodynamic-based hollow fiber modeling to reduce this complexity to nine combinations, which we tested. Each regimen’s fast and slow growth bacteria kill-slope trajectories and times-to-extinction were estimated and translated to minimum required therapy duration in patients. Sputum microbial kill trajectories of two combination regimens that have undergone clinical testing were correctly predicted by this approach. Four pan-tuberculosis regimens were predicted to achieve relapse-free cure after 2-3 months therapy in patients. The kill-slopes were used to design expedited clinical trials that minimize patients’ risks.