bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arylsulfonamide mediated RBM39 degradation causes aberrant splicing of mitotic kinesins
Authors: Coomar Seemon , Penson Alexander , Schwaller Jürg , Abdel-Wahab Omar , Gillingham Dennis 
Published: February 2021

AbstractCertain arylsulfonamides (ArSulfs) induce an interaction between the E3 ligase substrate adaptor DCAF15 and the critical splicing factor RBM39, ultimately causing its degradation. Although molecules like the ArSulfs, which interfere with splicing decisions, are exciting potential medicines, the molecular glue mechanism of RBM39 degradation introduces complex pleiotropic effects that are difficult to untangle. For example, DCAF15 inhibition, RBM39 degradation, and the downstream proteome effects of splicing changes will all cause different yet overlaid effects. As such the precise cell-killing mechanism by RBM39 loss is largely unknown. By overlaying transcriptome and proteome datasets, we distinguish transcriptional from post-transcriptional effects, pinpointing those proteins most impacted by splicing changes. Our proteomic profiling of several ArSulfs suggests a selective DCAF15/ArylSulf/RBM39RRM2 interaction with a narrow degradation profile. We identify two mitotic kinesin motor proteins that are aberrantly spliced upon RBM39 degradation, and we demonstrate that these are likely contributors to the antiproliferative activity of ArSulfs.
Increasing age is independently associated with higher free water in non-active MS brain - A multi-compartment analysis using FAST-T2
Authors: Zhou Liangdong , Li Yi , Wang Xiuyuan , Sweeney Elizabeth , Zhang Hang , Tanzi Emily B. , Prince Jennette , Su-Ortiz Victor Antonio , Gauthier Susan A. , Nguyen Thanh D. 
Published: February 2021

AbstractPurposeTo explore the relationship between the cerebral cortical perivascular space (PVS) and aging in non-active MS subjects by using the multi-echo T2 relaxometry based cerebrospinal fluid fraction (CSFF) map.MethodsMulti-echo spiral T2 data from 111 subjects with non-active multiple sclerosis (MS) were retrospectively investigated by fitting the T2 data into a three-compartment model, the three water compartments including myelin water, intra-extracellular water, and cerebrospinal fluid. Segmentation of T1w image was performed to get the region of interest (ROI) in cerebral cortical regions. The white matter lesion segmentation was conducted using a convolutional neural network (CNN) based segmentation tool. The CSFF in the ROIs were correlated with age by controlling the gender, white matter hyperintensity lesion burden, and MS disease duration. Multiple linear models were created for the analysis of aging effect on the CSFF.ResultsThe ROI analysis shows that the CSFF in the cerebral cortical regions (temporal, occipital, parietal, front, hippo, and mtl) are significantly linear increasing with age (p<0.01). The intra-extracellular water fraction (IEWF) in the ROIs are significantly linear decreasing (p<0.01).ConclusionThe multi-echo T2 based three-compartment model can be used to quantify the CSFF. The linear increase of CSF water contents in the cerebral cortical regions indicates increased perivascular space load in cortex with aging. The quantification of CSFF may provide a way to understand the glymphatic clearance function in aging and neurodegenerations.HighlightsMR T2 relaxometry is a valid method to quantify the cerebrospinal fluid fraction (CSFF) in cerebral cortical regionsThe CSFF in the cerebral cortical regions are positively correlated with age by controlling the white matter lesion load in non-active MS subjects.Quantification of cerebral CSFF may reflect the perivascular space load in cortex and better interpret the disease progression in neurodegenerative disease, such as MS.
An unusual aspartic acid cluster in the reovirus attachment fiber σ1 mediates stability at low pH
Authors: Glorani Giulia , Ruwolt Max , Holton Nicole , Neu Ursula 
Published: February 2021

ABSTRACTThe reovirus attachment protein σ1 mediates cell attachment and receptor binding and is thought to undergo conformational changes during viral disassembly. σ1 is a trimeric filamentous protein with an α-helical coil-coiled Tail, a triple β-spiral Body, and a globular Head. The Head domain features an unusual and conserved aspartic acid cluster at the trimer interface, which forms the only significant intra-trimer interactions in the Head, and must be protonated to allow trimer formation.Here we show that all domains of σ1 are remarkably thermostable across a wide range of pH, even at the low pH of the stomach. Interestingly, we determine the optimal pH for stability to be between pH 5-6, a value close to the pH of the endosome and of the jejunum. The σ1 Head is stable at acidic and neutral pH, but detrimerizes at basic pH. When Asp345in the aspartic acid cluster is mutated to asparagine, the σ1 Head loses stability at low pH and is more prone to detrimerize. Overall, the presence of the Body stabilizes the σ1 Head.Our results confirm a role of the aspartic acid cluster as a pH-dependent molecular switch, and highlight its role in enhancing σ1 stability at low pH.
A functional bacterial-derived restriction modification system in the mitochondrion of a heterotrophic protist
Authors: Milner David S. , Wideman Jeremy G. , Stairs Courtney W. , Dunn Cory D. , Richards Thomas A. 
Published: February 2021

AbstractThe overarching trend in mitochondrial evolution is functional streamlining coupled with gene loss; therefore, gene acquisition by mitochondria is considered to be exceedingly rare. Selfish elements in the form of self-splicing introns occur in many organellar genomes, but the wider diversity of selfish elements, and how they persist in organellar genomes, has not been explored. In the mitochondrial genome of a marine heterotrophic katablepharid protist, we identify a functional type II restriction modification system originating from a horizontal gene transfer event involving bacteria related to flavobacteria. This restriction modification system consists of an HpaII-like endonuclease and a cognate cytosine methyltransferase. We demonstrate that these proteins are functional by heterologous expression in both bacterial and eukaryotic cells. These results suggest that toxin-antitoxin selfish elements, such as restriction modification systems, could be co-opted by eukaryotic genomes to drive uniparental organellar inheritance.
Identification ofPectobacteriumspecies isolated from the soft rot of tetecho (Neobuxbaumia tetetzo), a columnar cactus, and associated metagenomics
Authors: Vargas-Peralta David , Narváez-Barragán Delia A. , de Sandozequi Andrés , Romero-Gutiérrez Miguel F. , Segovia Lorenzo , Martínez-Anaya Claudia , Alcaraz Luis David , de la Torre Almaraz Rodolfo 
Published: February 2021

AbstractNeobuxbaumia tetetzo, commonly known as tetecho, is a columnar cactus endemic to Mexico. In the last 15 years, damage has been observed in young and adult plants ofN. tetetzo, ranging from chlorotic spots with a wet appearance in early stages to tissue necrosis in advanced stages and finally the death of the plant;Pectobacterium brasilienseis the causal agent of the damages. Disease progression may be delayed or accelerated by the involvement of other bacteria, either pathogenic or endophytic, at the site of infection. Our goal was to confirm the presence ofPectobacterium brasiliense, in the soft rot ofN. tetetzoand to determine the presence of other bacteria associated with the rot. We isolated three bacterial strains (A1, A3 and A8) from diseased tissue from three separateN. tetetzoplants, and compare them using biochemical and molecular techniques, such as whole-genome sequencing of strains A1 and A3. Phylogenetic analyzes confirmed that A1 corresponded toP. brasiliense, whereas A3 was more misimlar toP. polaris. Additionally, sequencing of 16S rRNA gene from metagenomic DNA isolated from healthy and diseased tissue ofN. tetetzoindicated the presence of four operational taxonomic units (OTUs) at the order level, unique to the diseased tissue: Actinomycetales, Burkholderiales, Caulobacterales, and Sphingomonadales, with probable participation in the soft rot process.
Video-based quantification of human movement frequency using pose estimation
Authors: Cornman Hannah L. , Stenum Jan , Roemmich Ryan T. 
Published: February 2021

ABSTRACTAssessment of repetitive movements (e.g., finger tapping) is a hallmark of motor examinations in several neurologic populations. These assessments are traditionally performed by a human rater via visual inspection; however, advances in computer vision offer potential for remote, quantitative assessment using simple video recordings. Here, we evaluated a pose estimation approach for measurement of human movement frequency from smartphone videos. Ten healthy young participants provided videos of themselves performing five repetitive movement tasks (finger tapping, hand open/close, hand pronation/supination, toe tapping, leg agility) at four target frequencies (1-4 Hz). We assessed the ability of a workflow that incorporated OpenPose (a freely available whole-body pose estimation algorithm) to estimate movement frequencies by comparing against manual frame-by-frame (i.e., ground-truth) measurements for all tasks and target frequencies using repeated measures ANOVA, Pearson’s correlations, and intraclass correlations. Our workflow produced largely accurate estimates of movement frequencies; only the hand open/close task showed a significant difference in the frequencies estimated by pose estimation and manual measurement (while statistically significant, these differences were small in magnitude). All other tasks and frequencies showed no significant differences between pose estimation and manual measurement. Pose estimation-based detections of individual events (e.g., finger taps, hand closures) showed strong correlations with manual detections for all tasks and frequencies. In summary, our pose estimation-based workflow accurately tracked repetitive movements in healthy adults across a range of tasks and movement frequencies. Future work will test this approach as a fast, low-cost, accessible approach to quantitative assessment of repetitive movements in clinical populations.
Differential activation of parathyroid and renal Ca2+-sensing receptors underlies the renal phenotype in autosomal dominant hypocalcemia 1
Authors: van Megen Wouter H. , Tan Rebecca , Alexander R. Todd , Dimke Henrik 
Published: February 2021

AbstractBackgroundParathyroid Ca2+-sensing receptor (CaSR) activation inhibits parathyroid hormone (PTH) release, while activation of CaSRs in kidneys and intestine attenuates local transepithelial Ca2+transport. In patients with autosomal dominant hypocalcemia 1 (ADH1) due to activatingCASRmutations, treatment of symptomatic hypocalcemia can be complicated by treatment-induced hypercalciuria, resulting in nephrocalcinosis and renal insufficiency. Although CaSRs throughout the body are activated by increased extracellular Ca2+concentrations, it is not understood why some ADH1 patients have reduced PTH, but not hypercalciuria at presentation, despite CaSR expression in both kidney and parathyroid.MethodsActivation of the CaSR was studied in mouse models and a ADH1 patient.In vitroCaSR activation was studied in HEK293 cells.ResultsMice with a gain-of-function mutation inCasrare hypocalcemic with reduced plasma PTH levels. However, renal CaSRs are not activated as indicated by normal urinary calcium handling and unaltered renalCldn14expression. Activation of renal CaSRs only occurred after increasing plasma Ca2+levels. Similarly, calcimimetic administration to wildtype mice induced hypocalcemia without activating renal CaSRs. Moreover, significant hypercalciuria was not observed in an ADH1 patient until blood Ca2+was normalized.In vitroexperiments suggest that increased CaSR levels in the parathyroid relative to the kidney contribute tissue-specific CaSR activation thresholds.ConclusionHere we delineate tissue-specific CaSR activation thresholds, where parathyroid CaSR overactivity can reduce plasma Ca2+to levels insufficient to activate renal CaSRs, even with overactivating mutations. These findings may aid in the management of ADH1 patients.
Hybridization dynamics and extensive introgression in theDaphnia longispinaspecies complex: new insights from a high-qualityDaphnia galeatareference genome
Authors: Nickel Jana , Schell Tilman , Holtzem Tania , Thielsch Anne , Dennis Stuart R. , Schlick-Steiner Birgit C. , Steiner Florian M. , Möst Markus , Pfenninger Markus , Schwenk Klaus , Cordellier Mathilde 
Published: February 2021

AbstractHybridization and introgression are recognized as an important source of variation that influence adaptive processes; both phenomena are frequent in the genusDaphnia,a keystone zooplankton taxon in freshwater ecosystems that comprises several species complexes. To investigate genome-wide consequences of introgression between species, we provide here the first high-quality genome assembly for a member of theDaphnia longispinaspecies complex,Daphnia galeata. We further re-sequenced 49 whole genomes of three species of the complex and their interspecific hybrids both from genotypes sampled in the water column and from single resting eggs extracted from sediment cores. Populations from habitats with diverse ecological conditions offered an opportunity to study the dynamics of hybridization linked to ecological changes and revealed a high prevalence of hybrids. Using phylogenetic and population genomic approaches, we provide first insights into the intra- and interspecific genome-wide variability in this species complex and identify regions of high divergence. Finally, we assess the length of ancestry tracts in hybrids to characterize introgression patterns across the genome. Our analyses uncover a complex history of hybridization and introgression reflecting multiple generations of hybridization and backcrossing in theDaphnia longispinaspecies complex. Overall, this study and the new resources presented here pave the way for a better understanding of ancient and contemporary gene flow in the species complex and facilitate future studies on resting egg banks accumulating in lake sediment.
Properties of multi-vesicular release from rod photoreceptors support transmission of single photon responses
Authors: Hays CL , Sladek AL , Field GD , Thoreson WB 
Published: February 2021

AbstractVision under starlight requires rod photoreceptors to transduce and transmit single photon responses to the visual system. This remarkable sensitivity depends on a small voltage change reliably reducing glutamate release such that post-synaptic rod bipolar cells can robustly detect the signal. To transmit this small signal, we have found that rod vesicle release deviates strongly from a Poisson process under conditions that mimic darkness. Specifically, at their resting membrane potential in darkness, rods exhibit coordinated and regularly timed multivesicular release events. Each release event consisted of ∼17 vesicles and occurred 2-3 times more regularly than expected from a Poisson process. Hyperpolarizing rods to mimic the voltage change produced by a single photon response abruptly reduced the probability of multivesicular release nearly to zero with a rebound increase in release probability at stimulus offset. Simulations of these release dynamics indicate that this regularly timed, multivesicular release promotes transmission of single photon responses to post-synaptic neurons. Furthermore, the mechanism is efficient, requiring fewer vesicles to be released per second than uniquantal release governed by Poisson statistics.
Effect of the COVID‐19 pandemic first wave and public policy on elective and emergency surgery provision in Southern Queensland
Authors: Fowler Samuel , Zahir Syeda F. , Manning Warrick , Kearney Allison , Sturgess David 
Published: February 2021

AbstractBackgroundSeveral public health initiatives in Australia were implemented in March 2020 to contain the spread of COVID‐19. The effect of these initiatives on surgical provision is unknown. The primary objective was to determine the effect of public health policies and surgical society guidelines implemented during the pandemic on elective and emergency caseload of surgical specialities operating within South East Queensland.MethodsThis observational study utilized non re‐identifiable electronic data to quantify the caseload of surgical specialities across five secondary and tertiary referral hospitals in South East Queensland prior to and during the implementation of such initiatives. All patients undergoing a surgical procedure between 1 March and 24 April 2019 and the same period in 2020 were included. Participants' demographic and clinical information, such as age, the American Society of Anesthesiologists score, surgical date and location, surgical subspecialty and procedure name, was included.ResultsDuring the 2020 time period, there were 2991 elective cases compared to 4422 surgeries occurring in the same period in 2019 (32.4% reduction). Meanwhile, 2082 emergency surgeries were performed in the 2020 period compared to 2362 in 2019 (12.0% decrease). Ophthalmology and dental/ear, nose and throat/maxillofacial surgery experienced the largest reduction in elective surgeries, whereas emergency caseload increased for vascular and cardiothoracic services, and only slightly decreased for plastics and urology.ConclusionThe public health initiatives and guidance implemented during the COVID‐19 pandemic reduced surgical specialties' elective caseload. However, emergency caseload was not affected to the same extent. This insight helps to guide resource allocation in future waves of the pandemic.
Intentional suspected suicide exposures by poisoning among adolescents from 2009 to 2018 reported to the Georgia Poison Center and compared nationally
Authors: Overall Britni , Hon Stephanie L. , Jones Alison , Moran Tim P. , Hunt Kevin 
Published: February 2021

AbstractThis retrospective chart review aimed to report the incidence and characteristics of intentional suspected suicide among 13‐ to 19‐year‐olds reported to the Georgia Poison Center (GPC) and compared nationally from 2009 to 2018. Of the 19 733 cases reported to the GPC, 74.9% were females. The total number of cases more than doubled from 2009 to 2018, increasing annually by 10%. Majority (90.1%) of the cases occurred in the home, and 60.4% of the cases resulted in either no effect or minor effect. More than half (66.5%) of the cases involved only one substance. Pharmaceuticals made up 94.5% of the substances used, with analgesics accounting for 42.10% and antidepressants at 20.77%. A significant difference was found in substances used between males and females (P < .001). Females were more likely to use analgesics (45.17% vs 32.90%), and males were more likely to use sedatives/hypnotics/antipsychotics (20.45% vs 13.58%). While the majority of the GPC patients were females, the GPC was more likely to have fewer female patients (74.7% vs 75.7%) and more male patients (25.3% vs 24.3%) than other poison centers. Intentional suspected suicide exposures by poisoning are on the rise and higher among females, demonstrating a need for strengthened intervention and prevention strategies.
CRKL promotes hepatocarcinoma through enhancing glucose metabolism of cancer cells via activating PI3K/Akt
Authors: Guo Chunmei , Gao Chao , Lv Xinxin , Zhao Dongting , Greenaway Frederick T. , Hao Lihong , Tian Yuxiang , Liu Shuqing , Sun Ming‐Zhong 
Published: February 2021

AbstractAbnormal glucose metabolism may contribute to cancer progression. As a member of the CRK (v‐crk sarcoma virus CT10 oncogene homologue) adapter protein family, CRKL (CRK‐like) associated with the development and progression of various tumours. However, the exact role and underlying mechanism of CRKL on energy metabolism remain unknown. In this study, we investigated the effect of CRKL on glucose metabolism of hepatocarcinoma cells. CRKL and PI3K were found to be overexpressed in both hepatocarcinoma cells and tissues; meanwhile, CRKL up‐regulation was positively correlated with PI3K up‐regulation. Functional investigations revealed that CRKL overexpression promoted glucose uptake, lactate production and glycogen synthesis of hepatocarcinoma cells by up‐regulating glucose transporters 1 (GLUT1), hexokinase II (HKII) expression and down‐regulating glycogen synthase kinase 3β (GSK3β) expression. Mechanistically, CRKL promoted glucose metabolism of hepatocarcinoma cells via enhancing the CRKL‐PI3K/Akt‐GLUT1/HKII‐glucose uptake, CRKL‐PI3K/Akt‐HKII‐glucose‐lactate production and CRKL‐PI3K/Akt‐Gsk3β‐glycogen synthesis. We demonstrate CRKL facilitates HCC malignancy via enhancing glucose uptake, lactate production and glycogen synthesis through PI3K/Akt pathway. It provides interesting fundamental clues to CRKL‐related carcinogenesis through glucose metabolism and offers novel therapeutic strategies for hepatocarcinoma.
Mangiferin prevents myocardial infarction‐induced apoptosis and heart failure in mice by activating the Sirt1/FoxO3a pathway
Authors: Chen Lingli , Li Santie , Zhu Jianyu , You Anfu , Huang Xingzhou , Yi Xinchu , Xue Mei 
Published: February 2021

AbstractMyocardial infarction (MI) commonly leads to cardiomyocyte apoptosis and heart failure. Mangiferin is a natural glucosylxanthone extracted from mango fruits and leaves, which has anti‐apoptotic and anti‐inflammatory properties in experimental cardiovascular diseases. In the present study, we investigated the role and detailed mechanism of mangiferin in MI. We used ligation of the left anterior descending coronary artery to establish an MI model in vivo, and cardiomyocyte‐specific Sirt1 knockout mice were used to identify the mechanism of mangiferin. For in vitro studies, oxygen and glucose deprivation (OGD) was used to mimic ischaemia in H9c2 cardiomyocytes. In mice, mangiferin treatment increased Sirt1 expression after MI, significantly reduced the infarct area, and prevented MI‐induced apoptosis and heart failure. Mangiferin reduced OGD‐induced cellular apoptosis in H9c2 cells. Meanwhile, Sirt1 knockout/silencing abolished the protective effects of mangiferin. Further studies revealed that mangiferin increased FoxO3a deacetylation by up‐regulating Sirt1, thus preventing apoptosis, and adenovirus‐mediated constitutive acetylation of FoxO3a restricted the anti‐apoptotic effects of mangiferin in vivo and in vitro. Our results indicate that mangiferin prevents cardiomyocyte apoptosis and the subsequent heart failure by activating the Sirt1/FoxO3a pathway in MI, and suggest that mangiferin may have an interesting potential in following studies towards clinical evaluation.
Roles of Krüppel‐like factor 5 in kidney disease
Authors: Li Jia , Liu Liang , Zhou Wen‐Qian , Cai Lu , Xu Zhong‐Gao , Rane Madhavi J. 
Published: February 2021

AbstractTranscription factor Krüppel‐like factor 5 (KLF5) is a member of the Krüppel‐like factors’ (KLFs) family. KLF5 regulates a number of cellular functions, such as apoptosis, proliferation and differentiation. Therefore, KLF5 can play a role in many diseases, including, cancer, cardiovascular disease and gastrointestinal disorders. An important role for KLF5 in the kidney was recently reported, such that KLF5 regulated podocyte apoptosis, renal cell proliferation, tubulointerstitial inflammation and renal fibrosis. In this review, we have summarized the available information in the literature with a brief description on how transcriptional, post‐transcriptional and post‐translational modifications of KLF5 modulate its function in a variety of organs including the kidney with a focus of its importance on the pathogenesis of various kidney diseases. Furthermore, we also have outlined the current and possible mechanisms of KLF5 activation in kidney diseases. These studies suggest a need for more systemic investigations, particularly for generation of animal models with renal cell‐specific deletion or overexpression of KLF5 gene to examine direct contributions of KLF5 to various kidney diseases. This will promote further experimentation in the development of therapies to prevent or treat various kidney diseases.