bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of mutations associated with Macozinone-resistant inMycobacterium Tuberculosis
Authors: Chen Xi , Li Yuanyuan , Wang Bin , Lu Yu 
Published: February 2021

AbSTRACTMacozinone is identified as a drug candidate and is currently under clinical development for the treatment of tuberculosis, but the mutations conferring resistance to Macozinone remain inadequately characterized. Herein, we investigated the Macozinone -resistance -associated mutations through selecting resistant isolatesin vitro. Macozinone-resistant isolates were obtained through inductionin vitro. The level of Macozinone -resistant strains was confirmed by MABA test. PCR sequencing analysis was carried out on dprE1 gene. Whole Genome Sequencing was performed to identify mutations associated with Macozinone -resistance. The totals of isolates obtained at Macozinone concentrations of 6.4ng/ml, 25.6ng/ml, 50ng/ml and 100ng/ml were 49, 20, 20 and 4 respectively. Among the 49 strains obtained by 6.4ng/ml Macozinone only one strain had C387S mutation in dprE1. C387S is only occurred in high-level resistant isolates (MIC > 500ng/ml). Meanwhile high-level resistance to Macozinone can occur in strains induced at 6.4ng/ml and the frequency of occurrence is low (1/49, 2.04%). The MIC90of other strains except the strains carrying C387S mutation is at the same level (11.5ng/ml > MIC90> 2ng/ml). The G61A or G248A mutations in dprE1 was discovered for the first time. Other gene mutations (rv0678, rrs, mbtF, rv2956,et al) were found in low-level resistant strains.ConclusionsHigh-level resistant isolates can be produced at low concentration of Macozinone. C387S mutation in dprE1 is directly related to high-level resistance. There may be new mechanisms involved in Macozinone-resistance independent of dprE1 mutations.
Aryl Hydrocarbon Receptor Blocks Aging-Induced Senescence in the Liver and Fibroblast Cells
Authors: Nacarino-Palma Ana , Rico-Leo Eva M. , Campisi Judith , Ramanathan Arvind , Merino Jaime M. , Fernández-Salguero Pedro M. 
Published: February 2021

ABSTRACTAging induces progressive organ degeneration and worsening of tissue homeostasis leading to multiple pathologies. Yet, little is known about the mechanisms and molecular intermediates involved. Here, we report that aged aryl hydrocarbon receptor-null mice (AhR-/-) had exacerbated senescence and larger numbers of liver progenitor cells. Senescence-associated markers β-galactosidase (SA-β-Gal), p16Ink4aand p21Cip1and genes of the senescence-associated secretory phenotype (SASP) TNF and IL1 were overexpressed in agedAhR-/-livers. AhR binding to the promoter of those genes, as shown by chromatin immunoprecipitation, likely had a repressive effect maintaining their physiological levels inAhR+/+livers. Furthermore, factors secreted by senescent cells MCP-2, MMP12 and FGF were also produced at higher levels in aged AhR-null livers. Supporting the linkage between senescence and stemness, liver progenitor cells were more abundant inAhR-/-mice, which could probably contribute to their increased hepatocarcinoma burden. These roles of AhR are not liver-specific since adult and embryonic AhR-null fibroblasts acquired cellular senescence upon culturing with overexpression of SA-β-Gal, p16Ink4aand p21Cip1. Notably, depletion of senescent cells with the senolytic agent navitoclax restored basal expression of senescent markers inAhR-/-fibroblasts. Oppositely, senescence promoter palbociclib induced an AhR-null like phenotype inAhR+/+fibroblasts. Moreover, doxycycline-induced senescence reduced AhR levels while depletion of p16Ink4a-expressing senescent cells restored basal AhR levels in mouse lungs. Thus, AhR is needed to restrict age-induced senescence, and such activity seems to correlate with a more differentiated phenotype and with increased resistance to liver tumorigenesis.
Positional and Compositional Analysis of Saturated, Monounsaturated and Polyunsaturated Fatty acids in Human Adipose Tissue Triglyceride by13C NMR
Authors: Torres Alejandra N. , Tavares Ludgero , Pereira Maria J. , Eriksson Jan W. , Jones John G. 
Published: February 2021

AbstractObjectives and new findings, ends with short conclusion, no referencesThe synthesis and turnover of triglyceride in adipose tissue involves enzymes with preferences for specific fatty acid classes and/or regioselectivity with regard to the fatty acid position within the glycerol moiety. The focus of the present study was to characterize both the fatty acid composition and their positional distribution in triglycerides of biopsied human subcutaneous adipose tissue using13C NMR spectroscopy. The triglyceridesn2 position was significantly more enriched with monounsaturated fatty acids compared to thesn1,3 sites, while saturated fatty acids abundance was significantly lower in thesn2 position compared to that ofsn1,3. Furthermore, the analysis revealed significant positive correlations between the total fraction of palmitoleic acid with both BMI and HOMA-IR scores. Additionally, we established that13C NMR chemical shifts for ω −3 signals, centered at 31.9 ppm, provided superior resolution of the most abundant FA species, including palmitoleate, compared to the ω −2 signals that were used previously.13C NMR spectroscopy reveals for the first time a highly non-homogenous distribution of FA in the glycerol sites of human adipose tissue triglyceride and that these distributions are correlated with different phenotypes such as BMI and insulin resistance.
Withaferin A promotes white adipose browning and prevents obesity through sympathetic nerve-activated Prdm16-FATP1 axis
Authors: Guo Bingbing , Liu Jiarui , Wang Bingwei , Zhang Chenyu , Su Zhijie , Zhao Miao , Zheng Ruimao 
Published: February 2021

AbstractThe increasing prevalence of obesity has resulted in demands for the development of new effective strategies for obesity treatment. The Withaferin A (WA) shows a great potential for prevention of obesity by sensitizing leptin signaling in the hypothalamus. However, the mechanism underlying the weight- and adiposity-reducing effects of WA remains to be elucidated. Here, we report that WA treatment induced white adipose tissue (WAT) browning, elevated energy expenditure (EE), decreased respiratory exchange ratio (RER), and prevented high-fat diet (HFD)-induced obesity. The sympathetic chemical denervation dampened the WAT browning and also impeded the reduction of adiposity in WA-treated mice. WA markedly up-regulated the levels of Prdm16 and FATP1 (Slc27a1) in the inguinal WAT (iWAT), and this was blocked by sympathetic denervation. Prdm16 or FATP1 knockdown in iWAT abrogated the WAT browning-inducing effects of WA, and restored the weight gain and the adiposity in WA-treated mice. Together, these findings suggest that WA induces WAT browning through the sympathetic nerve-adipose axis; and the adipocytic Prdm16-FATP1 pathway mediates the promotive effects of WA on white adipose browning.
Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3
Authors: Meyer James O. , Dolphin Annette C. 
Published: February 2021

AbstractN-type voltage-gated calcium channels (CaV2.2) are predominantly expressed at presynaptic terminals, and their function is regulated by auxiliary α2δ and β subunits. All four mammalian α2δ subunits enhance calcium currents through CaV1 and CaV2 channels, and this increase is attributed, in part, to increased CaVexpression at the plasma membrane. In the present study we provide evidence that α2δ-1, like α2δ-2, is recycled to the plasma membrane through a Rab11a-dependent endosomal recycling pathway. Using a dominant-negative Rab11a mutant, Rab11a(S25N), we show that α2δ-1 increases plasma membrane CaV2.2 expression by increasing the rate and extent of net forward CaV2.2 trafficking in a Rab11a-dependent manner. Dominant-negative Rab11a also reduces the ability of α2δ-1 to increase CaV2.2 expression on the cell-surface of hippocampal neurites. In contrast, α2δ-3 does not enhance rapid forward CaV2.2 trafficking, regardless of whether Rab11a(S25N) is present. In addition, whole-cell CaV2.2 currents are reduced by co-expression of Rab11a(S25N) in the presence of α2δ-1, but not α2δ-3. Taken together these data suggest that α2δ subtypes participate in distinct trafficking pathways which in turn influence the localisation and function of CaV2.2.Summary statementThe calcium channel auxiliary subunit α2δ-1 but not α2δ-3 participates in Rab11a-dependent recycling, which in turn influences the localisation and function of CaV2.2.
Underlying environmental factors and geomagnetic fields linked to 45 pilot whalesGlobicephala macrorhynchusstranding in Modung white beach, Indonesian coast on 19thFebruary 2021
Authors: Wibowo Andri 
Published: February 2021

AbstractThe reason whale and dolphin stranding is not fully understood and it is not linked to a standalone variable. Theories assume intertwined factors including sickness, underwater noise, navigational error, geographical features, the presence of predators, poisoning from pollution or algal blooms, geomagnetic field, and extreme weather are responsible to whale stranding. On 19thFebruary 2021, a pod consists of 45 pilot whalesGlobicephala macrorhynchuswas stranded in a remote 7050 m2Modung white beach of Indonesian coast. This paper aims to assess the environmental factors that may be can explain and link to this stranding cases. Those factors include bathymetry, plankton cell density measured using MODIS, water sediment load measured using Sentinel 2 Bands 4,3,1, vessel traffic, precipitation (inch) and thunder (CAPE index J/kg), water salinity and temperature, and geomagnetic field (nT). The results show the water near stranding sites were shallow, has sediment load, high plankton density, warmer, receiving torrential rain prior stranding, having weak geomagnetic field and high total magnetic field change/year. The combination of those environmental covariates may influence the behavior, navigation, and echolocation of the said stranded pilot whale.
Scaling concepts in ’omics: nuclear lamin-B scales with tumor growth and predicts poor prognosis, whereas fibrosis can be pro-survival
Authors: Vashisth Manasvita , Cho Sangkyun , Irianto Jerome , Xia Yuntao , Wang Mai , Hayes Brandon , Jafarpour Farshid , Wells Rebecca , Liu Andrea , Discher Dennis E. 
Published: February 2021

AbstractSpatiotemporal relationships between genes expressed in tissues likely reflect physicochemical principles that range from stoichiometric interactions to co-organized fractals with characteristic scaling. For key structural factors within the nucleus and extracellular matrix (ECM), gene-gene power laws are found to be characteristic across several tumor types in The Cancer Genome Atlas (TCGA) and across single-cell RNA-seq data. The nuclear filamentLMNB1scales with many tumor-elevated proliferation genes that predict poor survival in liver cancer, and cell line experiments showLMNB1regulates cancer cell cycle. Also high in the liver, lung, and breast tumors studied here are the main fibrosis-associated collagens,COL1A1andCOL1A2, that scale stoichiometrically with each other and super-stoichiometrically with a pan-cancer fibrosis gene set. However, high fibrosis predicts prolonged survival of patients undergoing therapy and does not correlate withLMNB1. Single-cell RNA-seq data also reveal scaling consistent with the pan-cancer power laws obtained from bulk tissue, allowing new power law relations to be predicted. Lastly, although noisy data frustrate weak scaling, concepts such as stoichiometric scaling highlight a simple, internal consistency check to qualify expression data.ClassificationApplied Physical Sciences (major) and Cell Biology (minor)Significance StatementNon-linear scaling analyses pervade polymer physics and chemistry and conceivably provide new insight into polymeric assemblies of genes expressed in tissues as well as co-regulated gene sets. Fractal scaling and stoichiometric scaling are among the gene-gene power law results identified here for key structural polymers in nuclei or extracellular matrix in human cancer data. Among nuclear envelope factors that might scale with DNA mass, only one nuclear filament scales with tumor proliferation and predicts poor survival in some cancer types. Collagen-1 scales with fibrosis and also tends to increase in multiple tumor types, but patients in therapy surprisingly survive longest with the highest levels of fibrosis, consistent with a therapeutic response.
Aerobic growth physiology ofSaccharomyces cerevisiaeon sucrose is strain-dependent
Authors: Rodrigues Carla Inês Soares , Wahl Aljoscha , Gombert Andreas K. 
Published: February 2021

AbstractPresent knowledge on the quantitative aerobic physiology of the yeastSaccharomyces cerevisiaeduring growth on sucrose as sole carbon and energy source is limited to either adapted cells or to the model laboratory strain CEN.PK113-7D. To broaden our understanding of this matter and open novel opportunities for sucrose-based biotechnological processes, we characterized three strains, with distinct backgrounds, during aerobic batch bioreactor cultivations. Our results reveal that sucrose metabolism inS. cerevisiaeis a strain-specific trait. Each strain displayed a distinct extracellular hexose concentration and invertase activity profiles. Especially, the inferior maximum specific growth rate (0.21 h−1) of the CEN.PK113-7D strain, with respect to that of strains UFMG-CM-Y259 (0.37 h−1) and JP1 (0.32 h−1), could be associated to its low invertase activity (0.04 to 0.09 U mgDM−1). Moreover, comparative experiments with glucose or fructose alone, or in combination, suggest mixed mechanisms of sucrose utilization by the industrial strain JP1, and points out the remarkable ability of the wild isolate UFMG-CM-259 to grow faster on sucrose than on glucose in a well-controlled cultivation system. This work hints to a series of metabolic traits that can be exploited to increase sucrose catabolic rates and bioprocess efficiency.Abstract Figure
A triple threat: theParastagonospora nodorumSnTox267 effector exploits three distinct host genetic factors to cause disease in wheat
Authors: Richards Jonathan K. , Kariyawasam Gayan , Seneviratne Sudeshi , Wyatt Nathan A. , Xu Steven S. , Liu Zhaohui , Faris Justin D. , Friesen Timothy L. 
Published: February 2021

AbstractParastagonospora nodorumis a fungal pathogen of wheat. As a necrotrophic specialist, it deploys a suite of effector proteins that target dominant host susceptibility genes to elicit programmed cell death (PCD). Nine effector – host susceptibility gene interactions have been reported in this pathosystem, presumed to be governed by unique pathogen effectors. This study presents the characterization of the SnTox267 necrotrophic effector that hijacks two separate host pathways to cause necrosis. An association mapping approach identifiedSnTox267and the generation of gene-disrupted mutants and gain-of-function transformants confirmed its role inSnn2-,Snn6-, andSnn7-mediated necrosis. TheSnn2andSnn6host susceptibility genes were complementary, and together they functioned cooperatively to elicit SnTox267-induced necrosis in the same light-dependent PCD pathway. Additionally, we showed that SnTox267 targetedSnn7, resulting in light-independent necrosis. Therefore, SnTox267 co-opts two distinct host pathways to elicit PCD.SnTox267sequence comparison among a natural population of 197 North AmericanP. nodorumisolates revealed 20 protein isoforms conferring variable levels of virulence, indicating continuing selection pressure on this gene. Protein isoform prevalence among discrete populations indicated that SnTox267 has likely evolved in response to local selection pressures and has diversified more rapidly in the Upper Midwest. Deletion ofSnTox267resulted in the upregulation of the unrelated effector genesSnToxA,SnTox1, andSnTox3, providing evidence for a complex genetic compensation mechanism. These results illustrate a novel evolutionary path by which a necrotrophic fungal pathogen uses a single proteinaceous effector to hijack two host pathways to induce cell death.
Graphene oxide/silver nanoparticle ink formulations rapidly inhibit influenza A virus and OC43 coronavirus infectionin vitro
Authors: Crane Meredith J. , Devine Stephen , Jamieson Amanda M. 
Published: February 2021

AbstractRespiratory tract infections present a significant risk to the human population, both through seasonal circulation and novel introductions with pandemic potential. There is a strong need for antiviral compounds with broad antimicrobial activity that can be coated onto filtration systems and personal protective equipment to augment their ability to remove infectious particles from the environment. Graphene oxide and silver nanoparticles are both materials with documented antimicrobial properties. Here, we tested thein vitroantiviral properties of several graphene oxide–silver nanoparticle composite materials, which were prepared through three different methods: reduction with silver salt, direct addition of silver nanospheres, and direct addition of silver nanospheres to thiolized graphene. These materials were tested over short time scales for their antiviral activity against two enveloped RNA viruses, influenza A virus and OC43 coronavirus, by performing viral plaque assays after exposure of the viruses to each material. It was found that the graphene oxide – silver nanoparticle materials generated by direct addition of the silver nanospheres were able to completely inhibit plaque formation by both viruses within one minute of exposure. Materials generated by the other two methods had varying levels of efficacy against influenza A virus. These studies indicate that graphene oxide-silver nanoparticle composite materials can rapidly neutralize RNA viruses and demonstrate their potential for use in a wide range of applications.Abstract Figure
High-resolution, genome-wide mapping of positive supercoiling in chromosomes
Authors: Guo Monica S. , Kawamura Ryo , Littlehale Megan , Marko John F. , Laub Michael T. 
Published: February 2021

AbstractSupercoiling impacts DNA replication, transcription, protein binding to DNA, and the three-dimensional organization of chromosomes. However, there are currently no methods to directly interrogate or map positive supercoils, so their distribution in genomes remains unknown. Here, we describe a method, GapR-seq, based on the chromatin immunoprecipitation of GapR, a bacterial protein that preferentially recognizes overtwisted DNA, for generating high-resolution maps of positive supercoiling. Applying this method toE. coliandS. cerevisiae, we find that positive supercoiling is widespread, associated with transcription, and particularly enriched between convergently-oriented genes, consistent with the “twin-domain” model of supercoiling. In yeast, we also find positive supercoils associated with centromeres, cohesin binding sites, autonomously replicating sites, and the borders of R-loops (DNA-RNA hybrids). Our results suggest that GapR-seq is a powerful approach, likely applicable in any organism, to investigate aspects of chromosome structure and organization not accessible by Hi-C or other existing methods.
Vascular and renal telomere shortening in mice exposed to chronic intermittent hypoxia
Authors: Badran Mohammad , Abuyassin Bisher , Ayas Najib , Sin Don D. , Laher Ismail 
Published: February 2021

AbstractObstructive sleep apnea (OSA) is a chronic condition characterized by chronic intermittent hypoxia (IH) and is associated with cardiovascular (CVD) and chronic kidney diseases (CKD). There is increased biomarkers of aging, such as telomere shortening, in patients with OSA. We assessed telomere lengths in aortic and renal tissues from mice exposed to 8 weeks of IH using a PCR protocol, and demonstrate significant telomere shortening in both tissues. This data indicates that IH, a hallmark of OSA, can accelerate vascular and renal aging that may contribute to OSA-induced CVD and CKD
FrequentPIK3CAmutations in eutopic endometrium of patients with ovarian clear cell carcinoma
Authors: Murakami Kosuke , Kanto Akiko , Sakai Kazuko , Miyagawa Chiho , Takaya Hisamitsu , Nakai Hidekatsu , Kotani Yasushi , Nishio Kazuto , Matsumura Noriomi 
Published: February 2021

AbstractRecent studies have reported cancer-associated mutations in normal endometrium. Mutations in eutopic endometrium may lead to endometriosis and endometriosis-associated ovarian cancer. We investigatedPIK3CAmutations (PIK3CAm) for three hotspots (E542K, E545K, H1047R) in eutopic endometrium in patients with ovarian cancer and endometriosis from formalin-fixed paraffin-embedded specimens by laser-capture microdissection and droplet digital PCR. The presence ofPIK3CAm in eutopic endometrial glands with mutant allele frequency ≥15% were as follows: ovarian clear cell carcinoma (OCCC) withPIK3CAm in tumors, 20/300 hotspots in 11/14 cases; OCCC withoutPIK3CAm, 42/78 hotspots in 11/12 cases; high-grade serous ovarian carcinoma, 8/45 hotspots in 3/5 cases; and endometriotic cysts, 5/63 hotspots in 5/6 cases. These rates were more frequent than in non-cancer non-endometriosis controls (7/309 hotspots in 5/17 cases). In OCCC withoutPIK3CAm, 7/12 (58%) cases showed multiple hotspot mutations in the same eutopic endometrial glands. In 3/54 (5.6%) cases,PIK3CAm was found in eutopic endometrial stroma. Multi-sampling of the OCCC tumors withPIK3CAm showed intratumor heterogeneity in three of eight cases. In two cases,PIK3CAm was detected in the stromal component of the tumor. HomogenousPIK3CAm in the epithelial component of the tumor matched the mutation in eutopic endometrial glands in only one case. Eutopic endometrial glands in ovarian cancer and endometriosis show high frequency ofPIK3CAm that is not consistent with tumors, and multiple hotspot mutations are often found in the same glands. Our results suggest that mostPIK3CAm in eutopic endometrial glands are passenger rather than driver mutations.
Long-range promoter-enhancer contacts are conserved during evolution and contribute to gene expression robustness
Authors: Laverré Alexandre , Tannier Eric , Necsulea Anamaria 
Published: February 2021

AbstractGene expression is regulated through complex molecular interactions, involvingcis-acting elements that can be situated far away from their target genes. Data on long-range contacts between promoters and regulatory elements is rapidly accumulating. However, it remains unclear how these regulatory relationships evolve and how they contribute to the establishment of robust gene expression profiles. Here, we address these questions by comparing genome-wide maps of promoter-centered chromatin contacts in mouse and human. We show that there is significant evolutionary conservation ofcis-regulatory landscapes, indicating that selective pressures act to preserve not only regulatory element sequences but also their chromatin contacts with target genes. The extent of evolutionary conservation is remarkable for long-range promoter-enhancer contacts, illustrating how the structure of regulatory landscapes constrains large-scale genome evolution. We show that the evolution ofcis-regulatory landscapes, measured in terms of distal element sequences, synteny or contacts with target genes, is significantly associated with gene expression evolution.