bluuebunny/crossref_metadata_2025_split huggingface dataset:
Higher genome mutation rates of Beijing lineage of Mycobacterium tuberculosis during human infection
Authors: Hakamata Mariko , Takihara Hayato , Iwamoto Tomotada , Tamaru Aki , Hashimoto Atsushi , Tanaka Takahiro , Kaboso Shaban A. , Gebretsadik Gebremichal , Ilinov Aleksandr , Yokoyama Akira , Ozeki Yuriko , Nishiyama Akihito , Tateishi Yoshitaka , Moro Hiroshi , Kikuchi Toshiaki , Okuda Shujiro , Matsumoto Sohkichi 
Published: October 2020

AbstractMycobacterium tuberculosis (Mtb) strains of Beijing lineage have caused great concern because of their rapid emergence of drug resistance and worldwide spread. DNA mutation rates that reflect evolutional adaptation to host responses and the appearance of drug resistance have not been elucidated in human-infected Beijing strains. We tracked and obtained an original Mtb isolate of Beijing lineage from the 1999 tuberculosis outbreak in Japan, as well as five other isolates that spread in humans, and two isolates from the patient caused recurrence. Three isolates were from patients who developed TB within one year after infection (rapid-progressor, RP), and the other three isolates were from those who developed TB more than one year after infection (slow-progressor, SP). We sequenced genomes of these isolates and analyzed the propensity and rate of genomic mutations. Generation time versus mutation rate curves were significantly higher for RP. The ratio of oxidative versus non-oxidation damages induced mutations was higher in SP than RP, suggesting that persistent Mtb are exposed to oxidative stress in the latent state. Our data thus demonstrates that higher mutation rates of Mtb Beijing strains during human infection is likely to account for the higher adaptability and an emergence ratio of drug resistance.
Non-compulsory measures sufficiently reduced human mobility in Tokyo during the COVID-19 epidemic
Authors: Yabe Takahiro , Tsubouchi Kota , Fujiwara Naoya , Wada Takayuki , Sekimoto Yoshihide , Ukkusuri Satish V. 
Published: October 2020

AbstractWhile large scale mobility data has become a popular tool to monitor the mobility patterns during the COVID-19 pandemic, the impacts of non-compulsory measures in Tokyo, Japan on human mobility patterns has been under-studied. Here, we analyze the temporal changes in human mobility behavior, social contact rates, and their correlations with the transmissibility of COVID-19, using mobility data collected from more than 200K anonymized mobile phone users in Tokyo. The analysis concludes that by April 15th (1 week into state of emergency), human mobility behavior decreased by around 50%, resulting in a 70% reduction of social contacts in Tokyo, showing the strong relationships with non-compulsory measures. Furthermore, the reduction in data-driven human mobility metrics showed correlation with the decrease in estimated effective reproduction number of COVID-19 in Tokyo. Such empirical insights could inform policy makers on deciding sufficient levels of mobility reduction to contain the disease.
Synthesis of computer simulation and machine learning for achieving the best material properties of filled rubber
Authors: Kojima Takashi , Washio Takashi , Hara Satoshi , Koishi Masataka 
Published: October 2020

AbstractMolecular dynamics (MD) simulation is used to analyze the mechanical properties of polymerized and nanoscale filled rubber. Unfortunately, the computation time for a simulation can require several months’ computing power, because the interactions of thousands of filler particles must be calculated. To alleviate this problem, we introduce a surrogate convolutional neural network model to achieve faster and more accurate predictions. The major difficulty when employing machine-learning-based surrogate models is the shortage of training data, contributing to the huge simulation costs. To derive a highly accurate surrogate model using only a small amount of training data, we increase the number of training instances by dividing the large-scale simulation results into 3D images of middle-scale filler morphologies and corresponding regional stresses. The images include fringe regions to reflect the influence of the filler constituents outside the core regions. The resultant surrogate model provides higher prediction accuracy than that trained only by images of the entire region. Afterwards, we extract the fillers that dominate the mechanical properties using the surrogate model and we confirm their validity using MD.
Towards middle-up analysis of polyclonal antibodies: subclass-specific N-glycosylation profiling of murine immunoglobulin G (IgG) by means of HPLC-MS
Authors: Blöchl Constantin , Regl Christof , Huber Christian G. , Winter Petra , Weiss Richard , Wohlschlager Therese 
Published: October 2020

AbstractIn recent years, advanced HPLC-MS strategies based on intact protein (“top-down”) or protein subunit (“middle-up/middle-down”) analysis have been implemented for the characterization of therapeutic monoclonal antibodies. Here, we assess feasibility of middle-up/middle-down analysis for polyclonal IgGs exhibiting extensive sequence variability. Specifically, we addressed IgGs from mouse, representing an important model system in immunological investigations. To obtain Fc/2 portions as conserved subunits of IgGs, we made use of the bacterial protease SpeB. For this purpose, we initially determined SpeB cleavage sites in murine IgGs. The resulting Fc/2 portions characteristic of different subclasses were subsequently analysed by ion-pair reversed-phase HPLC hyphenated to high-resolution mass spectrometry. This enabled simultaneous relative quantification of IgG subclasses and theirN-glycosylation variants, both of which influence IgG effector functions. To assess method capabilities in an immunological context, we applied the analytical workflow to polyclonal antibodies obtained from BALB/c mice immunized with the grass pollen allergen Phl p 6. The study revealed a shift in IgG subclasses and Fc-glycosylation patterns in total and antigen-specific IgGs from different mouse cohorts, respectively. Eventually, Fc/2 characterization may reveal other protein modifications including oxidation, amino acid exchanges, and C-terminal lysine, and may thus be implemented for quality control of functional antibodies.
The soluble neurexin-1β ectodomain causes calcium influx and augments dendritic outgrowth and synaptic transmission
Authors: Wierda Keimpe D. B. , Toft-Bertelsen Trine L. , Gøtzsche Casper R. , Pedersen Ellis , Korshunova Irina , Nielsen Janne , Bang Marie Louise , Kønig Andreas B. , Owczarek Sylwia , Gjørlund Michelle D. , Schupp Melanie , Bock Elisabeth , Sørensen Jakob B. 
Published: October 2020

AbstractClassically, neurexins are thought to mediate synaptic connections through trans interactions with a number of different postsynaptic partners. Neurexins are cleaved by metalloproteases in an activity-dependent manner, releasing the soluble extracellular domain. Here, we report that in both immature (before synaptogenesis) and mature (after synaptogenesis) hippocampal neurons, the soluble neurexin-1β ectodomain triggers acute Ca2+-influx at the dendritic/postsynaptic side. In both cases, neuroligin-1 expression was required. In immature neurons, calcium influx required N-type calcium channels and stimulated dendritic outgrowth and neuronal survival. In mature glutamatergic neurons the neurexin-1β ectodomain stimulated calcium influx through NMDA-receptors, which increased presynaptic release probability. In contrast, prolonged exposure to the ectodomain led to inhibition of synaptic transmission. This secondary inhibition was activity- and neuroligin-1 dependent and caused by a reduction in the readily-releasable pool of vesicles. A synthetic peptide modeled after the neurexin-1β:neuroligin-1 interaction site reproduced the cellular effects of the neurexin-1β ectodomain. Collectively, our findings demonstrate that the soluble neurexin ectodomain stimulates growth of neurons and exerts acute and chronic effects on trans-synaptic signaling involved in setting synaptic strength.
Synthesis, characterization of two matrine derivatives and their cytotoxic effect on Sf9 cell of Spodoptera frugiperda
Authors: He Huiqing , Qin Xiangjing , Dong Fangyun , Ye Jingmin , Xu Chunbao , Zhang Hanhui , Liu Zhanmei , Lv Xiaojing , Wu Yuehua , Jiang Xuhong , Cheng Xingan 
Published: October 2020

AbstractThe invasion ofSpodoptera frugiperdahas imposed a serious impact on global food security. Matrine is a botanical pesticide with a broad spectrum of insecticidal activity which was recommended for controllingSpodoptera frugiperda. In order to discover effective insecticide forSpodoptera frugiperda, two matrine derivatives modified with carbon disulfide and nitrogen-containing groups were systhesized. And their inhibition activities onSf9cell were evaluated. The structural configuration of compounds were characterized by IR, HPLC, MS, NMR and XRD, with yields of 52% and 65%, respectively. The IC50of the two newly synthesized compounds onSf9cell reduced to 0.648 mmol/L and 1.13 mmol/L, respectively, compared with that of matrine (5.330 mmol/L). In addition, microscopic observation ofSf9cell treated with the compounds showed that the number of adherent cells decreased, the cells shrunk, vacuolated and apoptotic bodies appeared. The two newly synthesized compounds exhibited better inhibitory effect onSf9cell than that of the parent matrine, suggesting that the positive effect of the introduction of 1-pyrrolidinecarbodithioate and diethylcarbamodithioate groups to matrine. The morphological observation ofSf9cell induced by derivatives indicated that apoptosis induction may be a mechanism that inhibits insect cell proliferation and exerts insecticidal effect.
CELF2 regulates the species-specific alternative splicing of TREM2
Authors: Yanaizu Motoaki , Washizu Chika , Nukina Nobuyuki , Satoh Jun-ichi , Kino Yoshihiro 
Published: October 2020

AbstractGenetic variations of TREM2 have been implicated as a risk factor of Alzheimer’s disease (AD). Recent studies suggest that the loss of TREM2 function compromises microglial responses to the accumulation of amyloid beta. Previously, we found that exon 3 of TREM2 is an alternative exon whose skipping leads to a reduction in full-length TREM2 protein by inducing nonsense-mediated mRNA decay. Here, we aimed to identify factors regulating TREM2 splicing. Using a panel of RNA-binding proteins, we found that exon 3 skipping of TREM2 was promoted by two paralogous proteins, CELF1 and CELF2, which were both linked previously with risk loci of AD. Although the overexpression of both CELF1 and CELF2 enhanced exon 3 skipping, only CELF2 reduced the expression of full-length TREM2 protein. Notably, the TREM2 ortholog in the green monkey, but not in the mouse, showed alternative splicing of exon 3 like human TREM2. Similarly, splicing regulation of exon 3 by CELF1/2 was found to be common to humans and monkeys. Using chimeric minigenes of human and mouse TREM2, we mapped a CELF-responsive sequence within intron 3 of human TREM2. Collectively, our results revealed a novel regulatory factor of TREM2 expression and highlighted a species-dependent difference of its regulation.
Integrated stress response inhibition provides sex-dependent protection against noise-induced cochlear synaptopathy
Authors: Rouse Stephanie L. , Matthews Ian R. , Li Jiang , Sherr Elliott H. , Chan Dylan K. 
Published: October 2020

AbstractNoise-induced hearing loss (NIHL) is a common health concern with significant social, psychological, and cognitive implications. Moderate levels of acoustic overstimulation associated with tinnitus and impaired speech perception cause cochlear synaptopathy, characterized physiologically by reduction in wave I of the suprathreshold auditory brainstem response (ABR) and reduced number of synapses between sensory hair cells and auditory neurons. The unfolded protein response (UPR), an endoplasmic reticulum stress response pathway, has been implicated in the pathogenesis and treatment of NIHL as well as neurodegeneration and synaptic damage in the brain. In this study, we used the small molecule UPR modulator Integrated Stress Response InhiBitor (ISRIB) to treat noise-induced cochlear synaptopathy in a mouse model. Mice pretreated with ISRIB prior to noise-exposure were protected against noise-induced synapse loss. Male, but not female, mice also exhibited ISRIB-mediated protection against noise-induced suprathreshold ABR wave-I amplitude reduction. Female mice had higher baseline wave-I amplitudes but greater sensitivity to noise-induced wave-I reduction. Our results suggest that the UPR is implicated in noise-induced cochlear synaptopathy, and can be targeted for treatment.
Clinical manifestations and perinatal outcomes of pregnant women with COVID-19: a systematic review and meta-analysis
Authors: Yee Jeong , Kim Woorim , Han Ji Min , Yoon Ha Young , Lee Nari , Lee Kyung Eun , Gwak Hye Sun 
Published: October 2020

AbstractThis systematic review and meta-analysis aimed to evaluate the impact of COVID-19 on pregnant women. We searched for qualified studies in PubMed, Embase, and Web of Science. The clinical characteristics of pregnant women with COVID-19 and their infants were reported as means and proportions with 95% confidence interval. Eleven studies involving with 9032 pregnant women with COVID-19 and 338 infants were included in the meta-analysis. Pregnant women with COVID-19 have relatively mild symptoms. However, abnormal proportions of laboratory parameters were similar or even increased, compared to general population. Around 30% of pregnant women with COVID-19 experienced preterm delivery, whereas the mean birth weight was 2855.9 g. Fetal death and detection of SARS-CoV-2 were observed in about 2%, whereas neonatal death was found to be 0.4%. In conclusion, the current review will serve as an ideal basis for future considerations in the treatment and management of COVID-19 in pregnant women.
Hypomethylation of the DAZ3 promoter in idiopathic asthenospermia: a screening tool for liquid biopsy
Authors: Zhang Shichang , Xu Li , Yu Mengyao , Zhang Jiexin 
Published: October 2020

AbstractGiven the role of the deleted in azoospermia gene in male infertility, whether the somatic deleted in azoospermia methylation status is associated with idiopathic asthenospermia should be determined. To investigate the methylation levels of the deleted in azoospermia promoter in peripheral white blood cells from idiopathic asthenospermia patients relative to those in normozoospermia controls, 61 ethylene diamine tetraacetic acid anticoagulant blood samples were drawn from all participants for DNA isolation. The deleted in azoospermia promoter methylation ratio was detected by MassARRAY-based methylation quantification and confirmed by quantitative methylation-specific polymerase chain reaction. A MassARRAY-based methylation analysis showed that the deleted in azoospermia 3 promoter (0 to − 2 kbp) was significantly hypomethylated in peripheral white blood cells from idiopathic asthenospermia males, specifically one CpG site (− 246 to − 247). Quantitative methylation-specific polymerase chain reaction data further confirmed that the methylation level of the deleted in azoospermia 3 promoter region in idiopathic asthenospermia patients was significantly lower than that in normozoospermia males. The area under the receiver operating characteristic curve determined by quantitative methylation-specific polymerase chain reaction was 0.737 (95% confidence interval: 0.552 to 0.924), with a sensitivity of 53.9% and a specificity of 88.2% at a cut-off level of 74.7%. Therefore, our results suggested that methylation ratio detection of the deleted in azoospermia 3 promoter region by real-time polymerase chain reaction assay is a promising and feasible tool for liquid biopsy in the clinical laboratories. The methylation status of other reported infertility-related genes should also be investigated in peripheral white blood cells.
The antiandrogenic vinclozolin induces differentiation delay of germ cells and changes in energy metabolism in 3D cultures of fetal ovaries
Authors: González-Sanz Silvia , Barreñada Odei , Rial Eduardo , Brieño-Enriquez Miguel A. , del Mazo Jesús 
Published: October 2020

AbstractVinclozolin is a pesticide with antiandrogenic activity as an endocrine disruptor compound. Its effects upon the progression of primordial follicles were assessed in cultures of mouse fetal ovaries from the onset of meiotic differentiation of germ cells (13.5 days post coitum) and from both in vivo exposed mice and in vitro exposed ovaries. Exposure of ovaries to vinclozolin—at in vitro dosages ranging from 10 to 200 μM and in 3D ex vivo culture following in vivo exposure to 50 mg/kg bw/day—showed delays in meiocyte differentiation and in follicle growth, even at the lowest in vitro dose exposure. Immunofluorescent analysis showed the presence of the proteins MSY2 and NOBOX in the primary follicles but no difference in the level of protein signals or in the number of follicles in relation to treatment. However, assessing the cytological differentiation of germ cells by detecting the synaptonemal complex protein SYCP3, the exposure to vinclozolin delayed meiotic differentiation from both in vitro- and in vivo-exposed ovaries. These effects were concomitant with changes in the energy metabolism, detected as a relative increase of glycolytic metabolism in live-cell metabolic assays in exposed ovaries.
Trophic downgrading reduces spatial variability on rocky reefs
Authors: Edwards Matthew S. , Konar Brenda 
Published: October 2020

AbstractTrophic downgrading in coastal waters has occurred globally during recent decades. On temperate rocky reefs, this has resulted in widespread kelp deforestation and the formation of sea urchin barrens. We hypothesize that the intact kelp forest communities are more spatially variable than the downgraded urchin barren communities, and that these differences are greatest at small spatial scales where the influence of competitive and trophic interactions is strongest. To address this, benthic community surveys were done in kelp forests and urchin barrens at nine islands spanning 1230 km of the Aleutian Archipelago where the loss of predatory sea otters has resulted in the trophic downgrading of the region’s kelp forests. We found more species and greater total spatial variation in community composition within the kelp forests than in the urchin barrens. Further, the kelp forest communities were most variable at small spatial scales (within each forest) and least variable at large spatial scales (among forests on different islands), while the urchin barren communities followed the opposite pattern. This trend was consistent for different trophic guilds (primary producers, grazers, filter feeders, predators). Together, this suggests that Aleutian kelp forests create variable habitats within their boundaries, but that the communities within these forests are generally similar across the archipelago. In contrast, urchin barrens exhibit relatively low variability within their boundaries, but these communities vary substantially among different barrens across the archipelago. We propose this represents a shift from small-scale biological control to large-scale oceanographic control of these communities.
Transport of ultrasmall gold nanoparticles (2 nm) across the blood–brain barrier in a six-cell brain spheroid model
Authors: Sokolova Viktoriya , Mekky Gehad , van der Meer Selina Beatrice , Seeds Michael C. , Atala Anthony J. , Epple Matthias 
Published: October 2020

AbstractThe blood–brain barrier (BBB) is an efficient barrier for molecules and drugs. Multicellular 3D spheroids display reproducible BBB features and functions. The spheroids used here were composed of six brain cell types: Astrocytes, pericytes, endothelial cells, microglia cells, oligodendrocytes, and neurons. They form an in vitro BBB that regulates the transport of compounds into the spheroid. The penetration of fluorescent ultrasmall gold nanoparticles (core diameter 2 nm; hydrodynamic diameter 3–4 nm) across the BBB was studied as a function of time by confocal laser scanning microscopy, with the dissolved fluorescent dye (FAM-alkyne) as a control. The nanoparticles readily entered the interior of the spheroid, whereas the dissolved dye alone did not penetrate the BBB. We present a model that is based on a time-dependent opening of the BBB for nanoparticles, followed by a rapid diffusion into the center of the spheroid. After the spheroids underwent hypoxia (0.1% O2; 24 h), the BBB was more permeable, permitting the uptake of more nanoparticles and also of dissolved dye molecules. Together with our previous observations that such nanoparticles can easily enter cells and even the cell nucleus, these data provide evidence that ultrasmall nanoparticle can cross the blood brain barrier.
Tagging the proteasome active site β5 causes tag specific phenotypes in yeast
Authors: Waite Kenrick A. , Burris Alicia , Roelofs Jeroen 
Published: October 2020

AbstractThe efficient and timely degradation of proteins is crucial for many cellular processes and to maintain general proteostasis. The proteasome, a complex multisubunit protease, plays a critical role in protein degradation. Therefore, it is important to understand the assembly, regulation, and localization of proteasome complexes in the cell under different conditions. Fluorescent tags are often utilized to study proteasomes. A GFP-tag on the β5 subunit, one of the core particle (CP) subunits with catalytic activity, has been shown to be incorporated into proteasomes and commonly used by the field. We report here that a tag on this subunit results in aberrant phenotypes that are not observed when several other CP subunits are tagged. These phenotypes appear in combination with other proteasome mutations and include poor growth, and, more significantly, altered 26S proteasome localization. In strains defective for autophagy, β5-GFP tagged proteasomes, unlike other CP tags, localize to granules upon nitrogen starvation. These granules are reflective of previously described proteasome storage granules but display unique properties. This suggests proteasomes with a β5-GFP tag are specifically recognized and sequestered depending on physiological conditions. In all, our data indicate the intricacy of tagging proteasomes, and possibly, large complexes in general.
Urinary metabolomic investigations in vitiligo patients
Authors: Liu Wei , Liu Xiao-Yan , Qian Yue-Tong , Zhou Dong-Dong , Liu Jia-Wei , Chen Tian , Sun Wei , Ma Dong-Lai 
Published: October 2020

AbstractUrinary metabolomics is a useful non-invasive tool for large-scale screening of disease-related metabolites. However, no comprehensive urinary metabolomic analysis of vitiligo is presently available. To investigate the urine metabolic pattern of vitiligo patients, we conducted a combined cross-sectional and prospective self-control cohort study and an untargeted urinary metabolomic analysis. In the cross-sectional study, 295 vitiligo patients and 192 age‐ and sex‐matched controls were enrolled, and 71 differential metabolites between two groups were identified. Pathway enrichment analysis revealed that drug metabolism-cytochrome P450, biopterin metabolism, vitamin B9 (folate) metabolism, selenoamino acid metabolism, and methionine and cysteine metabolism showed significant enrichment in vitiligo patients compared with the status in healthy controls. In the self-control cohort, 46 active vitiligo patients were recruited to analyse the urinary metabolic signatures after treatment. All of these patients were asked to undertake follow-up visits every 2 months three times after first consulting and the disease stage was evaluated compared with that at the last visit. Folate metabolism, linoleate metabolism, leukotriene metabolism, alkaloid biosynthesis, and tyrosine metabolism were predicted to be involved in vitiligo activity. Our study is the first attempt to reveal urinary metabolic signatures of vitiligo patients and provides new insights into the metabolic mechanisms of vitiligo.