bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis for kinase inhibition in the tripartiteE. coliHipBST toxin-antitoxin system
Authors: Bærentsen René L. , Nielsen Stine Vang , Skjerning Ragnhild Bager , Lyngsø Jeppe , Bisiak Francesco , Pedersen Jan Skov , Gerdes Kenn , Sørensen Michael A. , Brodersen Ditlev. E. 
Published: January 2022

ABSTRACTMany bacteria encode multiple toxin-antitoxin (TA) systems targeting separate, but closely related, cellular functions. The toxin of theE. coli hipBAsystem, HipA, is a kinase that inhibits translation via phosphorylation of glutamyl-tRNA synthetase. EnteropathogenicE. coli(EPEC) O127:H6 encodes thehipBA-like, tripartite TA system;hipBST, in which the HipT toxin specifically targets the tryptophanyl-tRNA synthetase, TrpS. Notably, in the tripartite system, the function as antitoxin has been taken over by the third protein, HipS, but the molecular details of how activity of HipT is inhibited remain poorly understood. Here, we show that HipBST is structurally different fromE. coliHipBA and that the unique HipS protein, which is homologous to the N-terminal subdomain of HipA, inhibits the kinase through insertion of a conserved Trp residue into the active site. We also show how auto-phosphorylation at two conserved sites in the kinase toxin serve different roles and affect the ability of HipS to neutralize HipT. Finally, solution structural studies show how phosphorylation affects overall TA complex flexibility.
Brainstem evoked auditory potentials in tinnitus: a best-evidence synthesis and meta-analysis
Authors: Jacxsens Laura , De Pauw Joke , Cardon Emilie , van der Wal Annemarie , Jacquemin Laure , Gilles Annick , Michiels Sarah , Van Rompaey Vincent , Lammers Marc J.W. , De Hertogh Willem 
Published: January 2022

AbstractIntroductionAccumulating evidence suggests a role of the brainstem in tinnitus generation and modulation. Several studies in chronic tinnitus patients have reported latency and amplitude changes of the different peaks of the auditory brainstem response, possibly reflecting neural changes or altered activity. The aim of the systematic review was to assess if alterations within the brainstem of chronic tinnitus patients are reflected in short- and middle-latency auditory evoked potentials (AEPs).MethodsA systematic review was performed and reported according to the PRISMA guidelines. Studies evaluating short- and middle-latency AEPs in tinnitus patients and controls were included. Two independent reviewers conducted the study selection, data extraction, and risk of bias assessment. Meta-analysis was performed using a multivariate meta-analytic model.ResultsTwenty-seven cross-sectional studies were included. Multivariate meta-analysis revealed that in tinnitus patients with normal hearing, significantly longer latencies of auditory brainstem response (ABR) waves I (SMD = 0.66 ms, p < 0.001), III (SMD = 0.43 ms p < 0.001), and V (SMD = 0.47 ms, p < 0.01) are present. The results regarding possible changes in middle-latency responses (MLRs) and frequency-following responses (FFRs) were inconclusive.DiscussionThe discovered changes in short-latency AEPs reflect alterations at brainstem level in tinnitus patients. More specifically, the prolonged ABR latencies could possibly be explained by high frequency sensorineural hearing loss, or other modulating factors such as cochlear synaptopathy or somatosensory tinnitus generators. The question whether middle-latency AEP changes, representing subcortical level of the auditory pathway, are present in tinnitus still remains unanswered. Future studies should identify and correctly deal with confounding factors, such as age, gender and the presence of somatosensory tinnitus components.
Left ventricular hypertrophy subtype and long-term mortality in those with subclinical cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Ha Edward T. , Ivanov Alexander , Yeoboah Joseph , Seals Austin , Peterson Stephen J. , Parikh Manish , Aronow Wilbert S. , Frishman William H. 
Published: January 2022

AbstractThe clinical and biochemical profile of differing LVH phenotypes and its effect on long term outcomes is ill-defined. The study investigated the differences in risk profiles and prognostic effect of concentric (CH) and eccentric hypertrophy (EH) on long-term adverse outcomes in a contemporary, ethnically diverse cohort. We analyzed follow-up data over 15 years from the Multi-Ethnic Study of Atherosclerosis study, an ongoing multicenter, prospective population-based study in the United States that enrolled 6,814 participants with subclinical cardiovascular disease between 2000 and 2002. 4,979 participants with left ventricular mass and wall thickness, derived from cardiac MRI at baseline enrollment were included. Descriptive statistics, Kaplan-Meier curves, and regression models were applied. Independent variables associated with CH were Black and Hispanic race/ethnicity, systolic blood pressure, and metabolic syndrome. Independent variables associated with EH were systolic blood pressure, urine creatinine, whereas serum creatinine had an inverse association. The primary endpoint of all-cause death (n=1,137, 22.8%) occurred in 21.7%, 47.4%, and 56.6% of participants with no, concentric, or eccentric hypertrophy, respectively (p<0.001). Age (HR per year = 1.10 [1.09, 1.11], p<0.001), male gender (HR=1.48 [1.29, 1.69], p<0.001), Black race (HR=1.17 [1.005,1.36], p=0.04), fasting glucose (HR=1.005 [1.003, 1.007], p<0.001), baseline creatinine (HR per mg/dL = 1.29 [1.15-1.46], p<0.001), LVEF (HR per 1% = 0.98 [0.98, 0.99], p=0.005), IL-6 (HR per pg/mL = 1.17 [1.12, 1.22], p<0.001), concentric hypertrophy (HR=1.84 [1.41-2.41], p<0.001), and eccentric hypertrophy (HR=2.58 [1.77-3.76], p<0.001) were significant predictors of all-cause mortality. We conclude that CH and EH are two distinct clinical phenotypes of left ventricular hypertrophy with differing gender and racial predisposition, both associated with worse long-term adverse outcomes.
Single-nuclei transcriptomics of dog hippocampus reveals the distinct cellular mechanism of domestication
Authors: Zhou Qi-Jun , Liu Xingyan , Zhang Longlong , Wang Rong , Yin Tingting , Li Xiaolu , Li Guimei , He Yuqi , Ding Zhaoli , Ma Pengcheng , Wang Shi-Zhi , Mao Bingyu , Zhang Shihua , Wang Guo-Dong 
Published: January 2022

AbstractThe process of dog domestication leads to dramatic differences in behavioral traits compared to grey wolves. A class of putative positively selected genes is related to learning and memory, for instance, long-term potentiation and long-term depression. In this study, we constructed a single-nuclei transcriptomic atlas of the dog hippocampus to illustrate its cell types, cell lineage, and molecular features. Using the transcriptomes of 105,057 single-nuclei from the hippocampus of a Beagle dog, we identified 26 cell clusters and a putative trajectory of oligodendrocyte development. Comparative analysis revealed a significant convergence between dog differentially expressed genes (DEGs) and putative positively selected genes (PSGs). 40 putative PSGs were DEGs in the glutamatergic neurons, especially in the cluster 14, which is related to the regulation of nervous system development. In summary, this study provided a blueprint to understand the cellular mechanism of dog domestication.
Purifying selection against spurious splicing signals contributes to the base composition evolution of the polypyrimidine tract
Authors: Yıldırım Buŗcin , Vogl Claus 
Published: January 2022

AbstractAmong eukaryotes, the major spliceosomal pathway is highly conserved. While long introns may contain additional regulatory sequences, the ones in short introns seem to be nearly exclusively related to splicing. Although these regulatory sequences involved in splicing are well-characterized, little is known about their evolution. At the 3’ end of introns, the splice signal nearly universally contains the dimerAG, which consists of purines, and the polypyrimidine tract upstream of this 3’ splice signal is characterized by over-representation of pyrimidines. If the over-representation of pyrimidines in the polypyrimidine tract is also due to avoidance of a premature splicing signal, we hypothesize thatAGshould be the most under-represented dimer. Through the use of DNA-strand asymmetry patterns, we confirm this prediction in fruit flies of the genusDrosophilaand by comparing the asymmetry patterns to a presumably neutrally evolving region, we quantify the selection strength acting on each motif. Moreover, our inference and simulation method revealed that the best explanation for the base composition evolution of the polypyrimidine tract is the joint action of purifying selection against a spurious 3’ splice signal and the selection for pyrimidines . Patterns of asymmetry in other eukaryotes indicate that avoidance of premature splicing similarly affects the nucleotide composition in their polypyrimidine tracts.
ACCURATE DECODING OF THE SPINAL CORD OUTPUT IN HUMANS WITH IMPLANTED HIGH-DENSITY ELECTRODE ARRAYS
Authors: Muceli Silvia , Poppendieck Wigand , Holobar Aleš , Gandevia Simon , Liebetanz David , Farina Dario 
Published: January 2022

ABSTRACTInvasive electromyography opened a new window to explore motoneuron behaviour in vivo. However, the technique is limited by the small fraction of active motoneurons that can be concurrently detected, precluding a population analysis in natural tasks. Here, we developed a high-density intramuscular electrode for in vivo human recordings along with a fully automatic methodology that could detect the discharges of action potentials of up to 67 concurrently active motoneurons with 99% accuracy. These data revealed that motoneurons of the same pool receive common synaptic input at frequencies up to 75 Hz and that late recruited motoneurons inhibit the discharges of those recruited earlier. These results constitute an important step in the population coding analysis of the human motor system in vivo.
Development of 3D breast cancer models with human T cells expressing engineered MAIT cell receptors
Authors: Dey Madhuri , Kim Myong Hwan , Nagamine Momoka , Karhan Ece , Kozhaya Lina , Dogan Mikail , Unutmaz Derya , Ozbolat Ibrahim T. 
Published: January 2022

ABSTRACTImmunotherapy has revolutionized cancer treatment with the advent of advanced cell engineering techniques aimed at targeted therapy with reduced systemic toxicity. However, understanding the underlying immune-cancer interactions require development of advanced three-dimensional (3D) models of human tissues. In this study, we developed proof-of-concept 3D tumor models with increasing complexity to study the cytotoxic responses of CD8+ T cells, genetically engineered to express mucosal-associated invariant T (MAIT) cell receptors, towards MDA-MB-231 breast cancer cells. Homotypic MDA-MB-231 and heterotypic MDA-MB-231/human dermal fibroblast (HDF) tumor spheroids were primed with precursor MAIT cell ligand 5-amino-6-D-ribitylaminouracil (5-ARU). Engineered T cells effectively eliminated tumors after a 3-day culture period, demonstrating that the engineered TCR recognized MR1 expressing tumor cells in the presence of 5-ARU. Tumor cell killing efficiency of engineered T cells were also assessed by encapsulating these cells in fibrin, mimicking a tumor extracellular matrix microenvironment. Expression of proinflammatory cytokines such as IFNγ, IL-13, CCL-3 indicated immune cell activation in all tumor models, post immunotherapy. Further, in corroborating the cytotoxic activity, we found that granzymes A and B were also upregulated, in homotypic as well as heterotypic tumors. Finally, a 3D bioprinted tumor model was employed to study the effect of localization of T cells with respect to tumors. T cells bioprinted proximal to the tumor had reduced invasion index and increased cytokine secretion, which indicated a paracrine mode of immune-cancer interaction. Development of 3D tumor-T cell platforms may enable studying the complex immune-cancer interactions and engineering MAIT cells for cell-based cancer immunotherapies.
Neuronal membrane proteasomes homeostatically regulate neural circuit activity in vivo and are required for learning-induced behavioral plasticity
Authors: He Hai-yan , Ramachandran Kapil , McLain Natalie , Faulkner Regina , Ahsan Arifa , Bera Reshmi , Margolis Seth S , Cline Hollis T 
Published: January 2022

ABSTRACTProtein degradation is critical for brain function through processes that remain poorly understood. Here we investigated the in vivo function of a recently reported neuronal membrane-associated proteasome (NMP) in the brain of Xenopus laevis tadpoles. We demonstrated that NMPs are present in the tadpole brain with biochemistry and electron microscopy, and showed that they actively degrade neuronal activity-induced nascent proteins. Using in vivo calcium imaging in the optic tectum, we showed that acute inhibition of NMP function rapidly increased spontaneous neuronal activity, resulting in hyper-synchronization among tectal neurons. At the circuit level, inhibiting NMPs abolished learning-dependent improvement in a visuomotor behavior paradigm in live animals. Our data provide the first in vivo characterization of NMP functions in the vertebrate nervous system and suggest that NMP-mediated degradation of activity-induced nascent proteins may serve as a homeostatic modulatory mechanism in neurons that is critical for regulating neuronal activity and experience-dependent circuit plasticity.
Genomic analyses identify key molecules and significant signaling pathways in AZIN1 regulated prostate cancer cells
Authors: Chang Tingxiang , Gu Hanming , Liu James 
Published: January 2022

AbstractAntizyme inhibitor 1 (AZIN1) is a critical target in prostate cancer, which regulates the adenosine-to-inosine (A to I) RNA editing during the cancer progression. However, the potential signaling pathways and functions remain unknown. Here, our objective is to figure out the functional molecules and signaling pathways by analyzing the RNA-seq data. The GSE189379 was produced by the Illumina HiSeq 2000 (Homo sapiens). The KEGG and GO analyses showed that focal adhesion and proteoglycans are the mainly affected processes in prostate cancer with the loss of AZIN1. Moreover, we identified ten key molecules including FN1, HRAS, CCND1, RAD51, PCNA, TYMS, CASP3, RRM2, BIRC5, and CCNE2. Therefore, this study provides novel knowledge of AZIN1 mediated prostate cancer.
Liver Protein Expression in Nash Mice on a High-Fat Diet
Authors: Varani James , McClintock Shannon D , Knibbs Randall N , Harber Isabelle , Zeidan Dania , Jawad-Makki Mohamed Ali H , Aslam Muhammad N 
Published: January 2022

ABSTRACTMale MS-NASH mice were maintained on a high-fat diet for 16 weeks with and without red algae-derived minerals. Obeticholic acid (OCA) was used as a comparator in the same strain and diet. C57BL/6 mice maintained on a standard (low-fat) rodent chow diet were used as a control. At the end of the in-life portion of the study, body weight, liver weight, liver enzyme levels and liver histology were assessed. Samples obtained from individual livers were subjected to Tandem Mass Tag labeling / mass spectroscopy for protein profile determination. As compared to mice maintained on the low-fat diet, all high-fat-fed mice had increased whole body and liver weight, increased liver enzyme (aminotransferases) levels and widespread steatosis / ballooning hepatocyte degeneration. Histological evidence for liver inflammation and collagen deposition was also present, but changes were to a lesser extent. A moderate reduction in ballooning degeneration and collagen deposition was observed with mineral supplementation. Control mice on the high-fat diet alone demonstrated multiple protein changes associated with dysregulated fat and carbohydrate metabolism, lipotoxicity and oxidative stress. Cholesterol metabolism and bile acid formation were especially sensitive to diet. In mice receiving multi-mineral supplementation along with the high-fat diet, there was reduced liver toxicity as evidenced by a decrease in levels of several cytochrome P450 enzymes and other oxidantgenerating moieties. Additionally, elevated expression of several keratins was also detected in mineral-supplemented mice. The protein changes observed with mineral supplementation were not seen with OCA. Our previous studies have shown that mice maintained on a high-fat diet for up to 18 months develop end-stage liver injury including hepatocellular carcinoma. Mineral-supplemented mice were substantially protected against tumor formation and other end-state consequences of high-fat feeding. The present study identifies early (16-week) protein changes occurring in the livers of the high-fat diet-fed mice, and how the expression of these proteins is influenced by mineral supplementation. These findings help elucidate early protein changes that contribute to end-stage liver injury and potential mechanisms by which dietary minerals may mitigate such damage.
Photoclick Phase-separating Hydrogels for 3D Cell Culture and Volumetric Bioprinting
Authors: Müller Monica Z. , Bernero Margherita , Qiu Wanwan , Style Robert W. , Müller Ralph , Qin Xiao-Hua 
Published: January 2022

AbstractMacroporous scaffolds facilitate solute transport and cell-cell communication, but materials allowing forin situpore formation and 3D printing in aqueous solutions are scarce. Here, we introduce an efficient thiol-ene photoclick resin for light-assisted fabrication of cell-compatible macroporous hydrogels via photopolymerization-induced phase separation (PIPS). This resin consists of norbornene-functionalized polyvinyl alcohol, di-thiol crosslinker and dextran sulfate, which can rapidly form a hydrogel with interconnected pores by PIPS. The pore size is tunable in the range of 2-40 μm as a function of light intensity, polymer composition and molecular charge. Unlike conventional methods to porous materials, PIPS uniquely allowsin situpore formation in the presence of living cells, thereby enabling 3D cell culture and bioprinting applications. We demonstrate fast 3D photoencapsulation of living cells, enhanced cell spreading in macroporous hydrogels, and tomographic volumetric bioprinting of cm-scale hydrogel constructs with hierarchical pores within 20 seconds. Collectively, this resin is cell-compatible, low-cost, easy-to-make and highly efficient for PIPS, offering promises for fast photofabrication of living tissues with complex porous structures.
A lymphatic-stem cell interactome regulates intestinal stem cell activity
Authors: Niec Rachel E. , Chu Tinyi , Gur-Cohen Shiri , Schernthanner Marina , Hidalgo Lynette , Pasolli Hilda Amalia , Kataru Raghu P. , Mehrara Babak J. , Pe’er Dana , Fuchs Elaine 
Published: January 2022

SummaryBarrier epithelia depend on resident stem cells for homeostasis, defense and repair. Intestinal stem cells (ISCs) of the small and large intestines respond to their local microenvironments (niches) to fulfill a continuous demand for tissue turnover, yet the complexity of their niches is still unfolding. Here, we report an extensive lymphatic network that intimately associates with ISCs within these niches. Devising a lymphatic:organoid coculture system, we show that lymphatic-secreted factors maintain ISCs while inhibiting precocious differentiation. Employing a new deconvolution algorithm, BayesPrism, to pair single-cell and spatial transcriptomics, we cartograph the lymphatic ligand:ISC receptor interactomes at high resolution. We unearth crypt lymphatics as a major source of WNT-signaling factors (WNT2, R-SPONDIN-3) known to drive ISC behavior, and REELIN, a hitherto unappreciated ISC regulator secreted by crypt lymphatics. Together, our studies expose lymphatics as a central hub for niche factors that govern the regenerative potential of ISCs.
Multidimensional Bayesian Estimation for Deep Brain Stimulation Using the SafeOpt Algorithm
Authors: Cooper Scott E. , Netoff Théoden I. 
Published: January 2022

AbstractSome symptoms treated with Deep Brain Stimulation (DBS) such as gait in Parkinson’s disease (PD), are often poorly responsive to DBS. This may be because DBS settings are usually optimized to other symptoms. To test this, we require an efficient, safe optimization algorithm. To develop such a tool, we extend the BayesOpt algorithm whose successful application to DBS settings we previously published [Louie et al 2021J Neuroeng Rehabil], using, as a test bed, a simulated cost function constructed for biological plausibility, with measurement noise based on experimental data.We found that the SafeOpt algorithm [Sui et al 2015Proc Machine Learning Res] converged to the optimum as well, and as fast as the BayesOpt algorithm, while avoiding high-cost points much more effectively. In three dimensions, SafeOpt converged in about 30 iterations, which is a feasible number for physical experiments in real patients. Convergence was slower when measurement nose was greater, but this could be overcome by running it for more iterations. The algorithm was relatively robust to misspecification of hyperparameters, and considerably more robust when hyperparameter fitting was incorporated into the algorithm. The algorithm did not perform as well when the quantization of stimulation settings was coarser, suggesting that it will work better with neurostimulators capable of independent current control. Finally, the algorithm was able to cope with a cost function having multiple local minima.
The indirect effect of the psychosocial work environment on the association between precarious employment and the production of steroid hormones: A cross sectional analysis
Authors: Méndez Rivero Fabrizio , Pozo Oscar J , Julià Mireia 
Published: January 2022

ABSTRACTObjectivesThe main objectives of this article are (i) to explore the potential relationship between precarious employment and the production of steroid hormones (both adrenal and gonadal) and (ii) to evaluate the psychosocial risk factors at work (i.e. demands, control, and support) and work-life conflicts in this relationship.MethodsCross-sectional data were derived from a sample of workers from Barcelona (n=255 —125 men, 130 women). A set of 23 markers were determined from hair samples to evaluate the chronic production of both adrenal and gonadal steroids. Linear regression models were used to estimate the association between precarious employment and the production of adrenal and gonadal steroids, and decomposition analyses were applied to estimate the indirect effect of psychosocial risk factors and work-life conflict on this relationship.ResultsGender differences in the association with PE-steroid production were found. Among men, gonadal axis steroids were associated with precarious employment (specifically, androstenedione and testosterone), while among women, adrenal axis steroids, primarily cortisol and markers derived from its metabolism, were associated with precarious employment. Psychosocial risk factors and work-life conflicts had significant positive indirect effects only among women.ConclusionsGender differences were found in respect of the indirect effects of psychosocial risk factors and work-life conflicts on the association between precarious employment and the production of adrenal and gonadal steroids, which suggests that, beyond the biochemical differences, the physiological effect of PE could be mediated by the social construction of gender identities, positions and roles in society and family.KEY MESSAGESWhat is already known about this subject?Previous studies suggest that precarious employment is associated with workers’ health; however, most studies are based on self-rated health indicators and do not explore the causal mechanisms behind this association.What are the new findings?Precarious employment was associated with the production of some adrenal and gonadal steroids, and the psychosocial work environment had an indirect effect on this association, although with significant gender differences.How might this impact on policy or clinical practice in the foreseeable future?An occupational health policy aimed at improving the quality of employment and, at the same time, the psychosocial work environment can reduce the production of hormones that are associated with stress.