bluuebunny/crossref_metadata_2025_split huggingface dataset:
α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation
Authors: Yuan Yexian , Xu Pingwen , Jiang Qingyan , Cai Xingcai , Wang Tao , Peng Wentong , Sun Jiajie , Zhu Canjun , Zhang Cha , Yue Dong , He Zhihui , Yang Jinping , Zeng Yuxian , Du Man , Zhang Fenglin , Ibrahimi Lucas , Schaul Sarah , Jiang Yuwei , Wang Jiqiu , Sun Jia , Wang Qiaoping , Wang Songbo , Wang Lina , Zhu Xiaotong , Gao Ping , Xi Qianyun , Yin Cong , Li Fan , Xu Guli , Zhang Yongliang , Shu Gang 
Published: November 2019

SummaryBeneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not fully understood. Here we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercisein vivo. We showed that substantial accumulation of the tricarboxylic acid cycle intermediate α-ketoglutaric acid (AKG) is a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysisin vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2-oxoglutarate receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss-of-function and gain-of-function mouse models, we showed that OXGR1 is essential for AKG-mediated exercise-induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for the salutary effects of resistance exercise, using AKG as a systemically-derived molecule for adrenal stimulation of muscle hypertrophy and fat loss.
Charting extracellular transcriptomes in The Human Biofluid RNA Atlas
Authors: Hulstaert Eva , Morlion Annelien , Cobos Francisco Avila , Verniers Kimberly , Nuytens Justine , Eynde Eveline Vanden , Yigit Nurten , Anckaert Jasper , Geerts Anja , Hindryckx Pieter , Jacques Peggy , Brusselle Guy , Bracke Ken R. , Maes Tania , Malfait Thomas , Derveaux Thierry , Ninclaus Virginie , Van Cauwenbergh Caroline , Roelens Kristien , Roets Ellen , Hemelsoet Dimitri , Tilleman Kelly , Brochez Lieve , Kuersten Scott , Simon Lukas , Karg Sebastian , Kautzky-Willers Alexandra , Leutner Michael , Nöhammer Christa , Slaby Ondrej , Prins Roméo Willinge , Koster Jan , Lefever Steve , Schroth Gary P. , Vandesompele Jo , Mestdagh Pieter 
Published: November 2019

AbstractExtracellular RNAs present in biofluids have emerged as potential biomarkers for disease. Where most studies focus on plasma or serum, other biofluids may contain more informative RNA molecules, depending on the type of disease. Here, we present an unprecedented atlas of messenger, circular and small RNA transcriptomes of a comprehensive collection of 20 different human biofluids. By means of synthetic spike-in controls, we compared RNA content across biofluids, revealing a more than 10 000-fold difference in RNA concentration. The circular RNA fraction is increased in nearly all biofluids compared to tissues. Each biofluid transcriptome is enriched for RNA molecules derived from specific tissues and cell types. In addition, a subset of biofluids, including stool, sweat, saliva and sputum, contains high levels of bacterial RNAs. Our atlas enables a more informed selection of the most relevant biofluid to monitor particular diseases. To verify the biomarker potential in these biofluids, four validation cohorts representing a broad spectrum of diseases were profiled, revealing numerous differential RNAs between case and control subjects. Taken together, our results reveal novel insights in the RNA content of human biofluids and may serve as a valuable resource for future biomarker studies. All spike-normalized data is publicly available in the R2 web portal and serve as a basis to further explore the RNA content in biofluids.
ApoC-III overexpression and LDLr-/- protect mice from DSS-colitis: identifying a new role for lipoprotein metabolism in Tregs
Authors: Rodia Cayla N , Li Diana , Tambini Nicholas S , Johnson Zania K , Jellison Evan R , Vella Anthony T , Kohan Alison B 
Published: November 2019

AbstractObjectiveCellular metabolism is a key regulator of CD4+Foxp3+regulatory T cell (Treg) homeostasis, but the foundational studies in this area use free fatty acid treatment as a proxy for plasma triglycerides. In vivo, plasma triglyceride is the main source of fatty acids for cells, not free fatty acids.Design/ResultsUsing apolipoprotein C-III transgenic and LDLr-/-mice, we report that the loss of lipoprotein triglycerides transport in these models results in protection from DSS-colitis and accumulation of intestinal Tregs and plasma IL-10. Total loss of apoC-III increases colitis severity. Tregs exposed to apoC-III increase lipolysis and fatty acid oxidation and apoC-III inhibits Bodipy-triglyceride uptake. Therapeutic treatment of WT mice with apoC-III-containing lipoproteins protects mice from colitis.ConclusionOur data suggest that therapies that reduce apoC-III could have negative effects in patients who are at risk of IBD, and conversely, that apoC-III could be a new therapeutic target to stimulate intestinal Tregs and IL-10 for the management of IBD. These data identify apoC-III and lipoprotein metabolism as a novel regulator of tolerance in the intestine.Summary Box*What is already known about this subject:▪The relative capacity to use either glucose or FFA to generate acetyl CoA for mitochondrial fatty acid oxidation is a critical driver of Treg and T cell activity and proliferation.▪ApoC-III is a known regulator of triglyceride and fatty acid metabolism in cells via LPL and LDLr endocytosis pathways▪ApoC-III is reduced in Crohn’s and Colitis patients.*What are the new findings:▪We show that Tregs express triglyceride transporters, and that LDLr expression is enriched in Tregs from the mesenteric lymph nodes.▪We show that T cells are capable of endocytosing triglyceride from lipoproteins, and this process is inhibited by apoC-III.▪Tregs fromapoC-IIITgare metabolically unique fromWTTregs and they upregulate the genes of lipolysis, and have an increase in basal respiration.▪The inhibition of TAG endocytosis, using 2 different models (LDLrKOand apoC-III-transgenic mice), protects mice from colitis and stimulates the accumulation of Tregs and IL-10 in the gut.▪Intraperitoneal delivery of apoC-III on chylomicrons protectsWTmice from DSS colitis.* How might it impact on clinical practice in the foreseeable future?▪Due to the protective role apoC-III plays in these mouse models of colitis, IBD risk should be carefully considered before prescribing patient anti-apoC-III lipid-lowering therapies.
Meiosis and Kinetochore genes are used by cancer cells as genome destabilizers and transformation catalysts
Authors: Thapa Roshina , Vasudevan Swetha , Ashqar Mimi Abo-Ayoub , Reich Eli , Kravchenko-Balasha Nataly , Klutstein Michael 
Published: November 2019

AbstractCancer cells have an altered transcriptome which contributes to their altered behaviors compared to normal cells. Indeed, many tumors express high levels of genes participating in meiosis or kinetochore biology, but the role of this high expression has not been fully elucidated. In this study we explore the relationship between this overexpression and genome instability and transformation capabilities of cancer cells. For this, we obtained expression data from 5 different cancer types which were analyzed using computational information-theoretic analysis. We were able to show that highly expressed meiotic/kinetochore genes were enriched in the altered gene expression subnetworks characterizing unstable cancer types with high chromosome instability (CIN). However, altered subnetworks found in the cancers with low CIN did not include meiotic and kinetochore genes. Representative gene candidates, found by the analysis to be correlated with a CIN phenotype, were further explored by transfecting genomically-stable (HCT116) and unstable (MCF7) cancer cell lines with vectors overexpressing those genes. This overexpression resulted in an increase in the numbers of abnormal cell divisions and defective spindle formations and in increased transformation properties in stable cancer HCT116 cells. Interestingly, the same properties were less affected by the overexpressed genes in the unstable MCF7 cancer cells. Our results indicate that overexpression of both meiosis and kinetochore genes is capable of driving genomic instability and cancer progression.
Causes and consequences of mitochondrial proteome size-variation in animals
Authors: Muthye Viraj , Lavrov Dennis 
Published: November 2019

AbstractDespite a conserved set of core mitochondrial functions, animal mitochondrial proteomes show a large variation in size. In this study, we analyzed the putative mechanisms behind and functional significance of this variation using experimentally-verified mt-proteomes of four bilaterian animals and two non-animal outgroups. We found that, of several factors affecting mitochondrial proteome size, evolution of novel mitochondrial proteins in mammals and loss of ancestral proteins in protostomes were the main contributors. Interestingly, gain and loss of conventional mitochondrial targeting signals was not a significant factor in the proteome size evolution.
RNA-binding protein altered expression and mislocalization in multiple sclerosis
Authors: Masaki Katsuhisa , Sonobe Yoshifumi , Ghadge Ghanashyam , Pytel Peter , Lépine Paula , Pernin Florian , Cui Qiao-Ling , Antel Jack P. , Zandee Stephanie , Prat Alexandre , Roos Raymond P. 
Published: November 2019

AbstractObjectiveNuclear depletion and mislocalization of RNA-binding proteins (RBPs) trans-activation response DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS) are thought to contribute to the pathogenesis of a number of disorders, including amyotrophic lateral sclerosis (ALS). We recently found that TDP-43 as well as polypyrimidine tract binding protein (PTB) have decreased expression and mislocalization in oligodendrocytes in demyelinated lesions in an experimental mouse model of multiple sclerosis (MS) caused by Theiler’s murine encephalomyelitis virus infection.MethodsThe latter finding prompted us to investigate TDP-43, FUS, and PTB in the demyelinated lesions of MS and inin vitro culturedhuman brain-derived oligodendrocytes.ResultsWe found: i) mislocalized TDP-43 in oligodendrocytes in active lesions in some MS patients; ii) decreased PTB1 expression in oligodendrocytes in mixed active/inactive demyelinating lesions; iii) decreased nuclear expression of PTB2 in neurons in cortical demyelinating lesions; iv) nuclear depletion of TDP-43 in oligodendrocytes under metabolic stress induced by low glucose/low nutrient conditions compared to optimal culture conditions.ConclusionTDP-43 has been found to have a key role in oligodendrocyte function and viability, while PTB is important in neuronal differentiation, suggesting that altered expression and mislocalization of these RBPs in MS lesions may contribute to the pathogenesis of demyelination and neurodegeneration. Our findings also identify nucleocytoplasmic transport as a target for treatment.
Towards Practical and Robust DNA-Based Data Archiving Using ‘Yin-Yang Codec’ System
Authors: Ping Zhi , Chen Shihong , Zhou Guangyu , Huang Xiaoluo , Zhu Sha Joe , Zhang Haoling , Lee Henry H. , Lan Zhaojun , Cui Jie , Chen Tai , Zhang Wenwei , Yang Huanming , Xu Xun , Church George M. , Shen Yue 
Published: November 2019

ABSTRACTDNA is a promising data storage medium due to its remarkable durability and space-efficient storage. Early bit-to-base transcoding schemes have primarily pursued information density, at the expense however of introducing biocompatibility challenges or at the risk of decoding failure. Here, we propose a robust transcoding algorithm named the “Yin-Yang Codec” (YYC), using two rules to encode two binary bits into one nucleotide, to generate DNA sequences highly compatible with synthesis and sequencing technologies. We encoded two representative file formats and stored them in vitro as 200-nt oligo pools and in vivo as an ~54-kb DNA fragment in yeast cells. Sequencing results show that YYC exhibits high robustness and reliability for a wide variety of data types, with an average recovery rate of 99.94% at 104molecule copies and an achieved recovery rate of 87.53% at 100 copies. In addition, the in vivo storage demonstration achieved for the first time an experimentally measured physical information density of 198.8 EB per gram of DNA (44% of the theoretical maximum for DNA).
Turanose induced WOX5 restores symbiosis in the Medicago truncatula cytokinin perception mutant cre1
Authors: Kundu Anindya , Molla Firoz , DasGupta Maitrayee 
Published: November 2019

ABSTRACTRhizobia-legume interaction recruits cytokinin-signaling that causes local auxin accumulation for the induction of nodule primordia in the cortex. Since sugar signaling can trigger auxin responses and regulate developmental processes, we explored whether sugar treatments could rescue cre1. Here we demonstrate that turanose, a non-metabolizable sucrose analogue can recover functional symbiosis in cytokinin perception mutant cre1. Additionally, turanose significantly upregulated the expression of WUSCHEL-related homeobox 5 (MtWOX5) which prompted us to check if ectopic expression of WOX5 could rescue cre1. Overexpression of WOX5 from Arachis hypogaea (AhWOX5), but not the intrinsic MtWOX5 could completely restore functional symbiosis in cre1 though both WOX5 (Mt and Ah) were functionally equivalent in inducing the expression of cytokinin inducible transcription factor Nodule Inception (NIN). Among the tested markers for cytokinin and auxin responses, significant differences were noted in the expression of IAA-Ala Resistant3 (MtIAR33), an auxin conjugate hydrolase. Turanose and AhWOX5 overexpression resulted in upregulation of MtIAR33 that further increased significantly in presence of rhizobia. On the other hand, MtIAR33 expression was unaffected in MtWOX5 overexpressed roots suggesting deconjugation driven auxin pool to be critical for rescuing symbiosis in cre1. We hypothesize a working model for sugar and WOX5 mediated rescue of symbiosis in cre1.One sentence summaryActivation of sugar-WOX5 signaling axis restores root nodule symbiosis in cytokinin perception mutant cre1
PointSite: a point cloud segmentation tool for identification of protein ligand binding atoms
Authors: Li Zhen , Yan Xu , Wei Qing , Gao Xin , Wang Sheng , Cui Shuguang 
Published: November 2019

AbstractAccurate identifications of ligand binding sites (LBS) on protein structure is critical for understanding protein function and designing structure-based drug. As the previous pocket-centric methods are usually based on the investigation of pseudo surface points (PSPs) outside the protein structure, thus inherently cannot incorporate the local connectivity and global 3D geometrical information of the protein structure. In this paper, we propose a novel point clouds segmentation method, PointSite, for accurate identification of protein ligand binding atoms, which performs protein LBS identification at the atom-level in a protein-centric manner. Specifically, we first transfer the original 3D protein structure to point clouds and then conduct segmentation through Submanifold Sparse Convolution (SSC) based U-Net. With the fine-grained atom-level binding atoms representation and enhanced feature learning, PointSite can outperform previous methods in atom-IoU by a large margin. Furthermore, our segmented binding atoms can work as a filter on predictions achieved by previous pocket-centric approaches, which significantly decreases the false-positive of LBS candidates. Through cascaded filter and re-ranking aided by the segmented atoms, state-of-the-art performance can be achieved over various canonical benchmarks and CAMEO hard targets in terms of the commonly used DCA criteria. Our code is publicly available throughhttps://github.com/PointSite.
A novel experimental system reveals immunoregulatory responses as mediators of persistent orthohantavirus infections in a rodent reservoir host
Authors: Strandin Tomas , Smura Teemu , Ahola Paula , Aaltonen Kirsi , Sironen Tarja , Hepojoki Jussi , Eckerle Isabella , Ulrich Rainer G. , Vapalahti Olli , Kipar Anja , Forbes Kristian M. 
Published: November 2019

AbstractOrthohantaviruses are globally emerging zoonotic pathogens. Human infections are characterized by an overt immune response that is efficient at counteracting virus replication but can also cause severe tissue damage. In contrast, orthohantavirus infections in rodent reservoir hosts are persistent and asymptomatic. The mechanisms facilitating asymptomatic virus persistence in reservoir hosts are not well understood but could help to guide therapeutic strategies for human infections. Here we report on a study usingin vivoandin vitroexperiments to investigate immune responses associated with persistent Puumala orthohantavirus (PUUV) infections in the bank vole (Myodes glareolus), its reservoir host. We examined adaptive cellular and humoral responses by quantifying changes in T-cell related gene expression in the spleen and immunoglobulin (Ig) responses in blood, respectively. Since existing Vero E6-cell adapted hantavirus isolates have been demonstrated to have lost their wild-type infection characteristics, infections were conducted with a novel PUUV strain isolated on a bank vole cell line. Whole virus genome sequencing revealed that only minor sequence changes occurred during the isolation process, and critically, experimental infections of bank voles with the new isolate resembled natural infections.In vitroinfection of bank vole splenocytes with the novel isolate demonstrated that PUUV promotes immunoregulatory responses by inducing interleukin-10, a cytokine strongly associated with chronic viral infections. A delayed virus-specific humoral response occurred in experimentally infected bank voles, which is likely to allow for initial virus replication and the establishment of persistent infections. These results suggest that host immunoregulation facilitates persistent orthohantavirus infections in reservoir hosts.ImportanceOrthohantaviruses are a group of global pathogens that regularly spillover from rodent reservoirs into humans and can cause severe disease. Conversely, infections in reservoir hosts do not cause obvious adverse effects. The mechanisms responsible for persistent asymptomatic reservoir infections are unknown, and progress has been hindered by the absence of an adequate experimental system. Knowledge on these mechanisms could help provide strategies to treat human infections. We developed and validated an experimental system based on an orthohantavirus isolated in cells of its vole reservoir host. Using animal and cell culture experiments in the reservoir host system, we demonstrated that infection suppresses immunity in the vole reservoir via specific mechanisms, likely allowing the virus to take hold and preventing immune responses that can cause self-damage.
Direct synthesis of self-organized blastocyst-like cysts derived from human pluripotent stem cells
Authors: Wen Xiaopeng , Terada Shiho , Yoshimoto Koki , Kamei Ken-ichiro 
Published: November 2019

AbstractWe introduce a simple, robust and scalable method to generate self-organized blastocyst-like cysts (soBLCs) from human pluripotent stem cells (hPSCs). We use a copolymer hydrogel of poly(N-isopropylacrylamide) and poly(ethylene glycol) (PNIPAAm-PEG). hPSC aggregates with a diameter of approximately 117.2 ± 5.1 µm are cultured in a medium supplemented with a hydrogel and a serum for three days. Molecular signatures in the medium revealed the generation of trophoblasts and inner cell mass at specific positions in the soBLCs.
Control and simulation impact on nonlinear Hepatitis-B model by using Padé-approximation based Differential Evolution
Authors: Farman Muhammad , Tabassum Muhammad Farhan , Saeed Muhammad , Chaudhry Nazir Ahmad 
Published: November 2019

AbstractHepatitis B is the main public health problem of the whole world. In epidemiology, mathematical models perform a key role in understanding the dynamics of infectious diseases. This paper proposes Padé approximation (Pa) with Differential Evolution (DE) for obtaining solution of Hepatitis-B model which is nonlinear numerically. The proposed strategy transforms the nonlinear model into optimization problem by using Padé approximation. Initial conditions are converted into problem constraints and constraint problem become unconstraint by using penalty function.DEis obtained numerical solution of Hepatitis-B model by solving the established problem of optimization. There is no need to choose step lengths in proposed Padé-approximation based Differential Evolution (PaDE) technique and alsoPaDEconverges to true steady state points. Finally, a convergence and error analysis evidence that the convergence speed ofPaDEis greater than Non-Standard Finite Difference (NSFD) method for different time steps.
Analysis of unusual and signature APOBEC-mutations in HIV-1polnext-generation sequences
Authors: Tzou Philip L. , Kosakovsky Pond Sergei L. , Avila-Rios Santiago , Holmes Susan P. , Kantor Rami , Shafer Robert W. 
Published: November 2019

ABSTRACTIntroductionAt low mutation-detection thresholds, next generation sequencing (NGS) for HIV-1 genotypic resistance testing is susceptible to artifactual detection of mutations arising from PCR error and APOBEC-mediated G-to-A hypermutation.MethodsWe analyzed published HIV-1polIllumina NGS data to characterize the distribution of mutations at eight NGS thresholds: 20%, 10%, 5%, 2%, 1%, 0.5%, 0.2%, and 0.1%. At each threshold, we determined the proportion of amino acid mutations that were unusual (defined as having a prevalence <0.01% in HIV-1 group M sequences) or were signature APOBEC mutations.ResultsEight studies, containing 855 samples, in the NCBI Sequence Read Archive were analyzed. As detection thresholds were lowered, there was a progressive increase in the proportion of positions with both usual and unusual mutations and in the proportion of all mutations that were unusual. The median proportion of positions with an unusual mutation increased gradually from 0% at the 20% threshold to 0.3% at the 1% threshold and then exponentially to 1.3% (0.5% threshold), 6.9% (0.2% threshold), and 23.2% (0.1% threshold). In two of three studies with available plasma HIV-1 RNA levels, the proportion of positions with unusual mutations was negatively associated with virus levels. Although the complete set of signature APOBEC mutations was much smaller than that of unusual mutations, the former outnumbered the latter in one-sixth of the samples at the 0.5%, 1%, and 2% thresholds.ConclusionsThe marked increase in the proportion of positions with unusual mutations at thresholds below 1% and in samples with lower virus loads suggests that, at low thresholds, many unusual mutations are artifactual, reflecting PCR error or G-to-A hypermutation. Profiling the numbers of unusual and signature APOBECpolmutations at different NGS thresholds may be useful to avoid selecting a threshold that is too low and poses an unacceptable risk of identifying artifactual mutations.