bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma Amino Acids Metabolomics’ Profile Important for Glucose Management in Jordanian people with Type 2 Diabetes
Authors: Alqudah Abdelrahim , Wedyan Mohammed , Qnais Esam , Jawarneh Hassan , McClements Lana 
Published: February 2021

AbstractBackgroundThe disturbances in plasma free amino acid metabolome in diabetes mellitus was studied before but not in Jordanian population. This study aimed to assess the association between type 2 diabetes (T2D) and amino acid metabolome in a representative group of people from Jordan.MethodsBlood samples from 124 people with T2D and 67 age-, gender- and BMI-matched healthy controls were collected and assayed for glucose and HbA1c. Twenty one amino acids belonging to different categories (essential, non-essential, semi-essential, and metabolic indicators) were evaluated in both groups using amino acids analyser.ResultsPlasma free amino acids concentrations of total amino acids, total essential amino acids, total non-essential amino acids, and total semi-essential amino acids were not different in T2D compared to healthy controls. However, plasma concentrations of four essential amino acids (Leucine, Lysine, Phenylalanine, Tryptophan) were increased in the presence of T2D (Leucine, p<0.01, Lysine, p<0.001, Phenylalanine, p<0.01, Tryptophan, p<0.05). Conversely, amongst the non-essential amino acids, Alanine and Serine were reduced in type 2 diabetes (Alanine, p<0.01, Serine, p<0.001), whereas, Aspartate and Glutamate were increased in T2D compared to healthy control plasma (Aspartate, p<0.001, Glutamate, p<0.01). A semi-essential amino acid, Cystine, was also increased in T2D compared to healthy controls (p<0.01). Citrulline, a metabolic indicator amino acid, demonstrated lower plasma concentration in T2Dcompared to healthy controls (p<0.01).ConclusionSeveral amino acids from different categories are dysregulated in T2D, which could be used as a therapeutic target to improve T2D management and its complications.
Bamlanivimab does not neutralize two SARS-CoV-2 variants carrying E484K in vitro
Authors: Widera Marek , Wilhelm Alexander , Hoehl Sebastian , Pallas Christiane , Kohmer Niko , Wolf Timo , Rabenau Holger F , Corman Victor , Drosten Christian , Vehreschild Maria JGT , Goetsch Udo , Gottschalk Rene , Ciesek Sandra 
Published: February 2021

AbstractThe IgG1 monoclonal antibody (mAb) bamlanivimab (LY-CoV555) prevents viral attachment and entry into human cells by blocking attachment to the ACE2 receptor. However, whether bamlanivimab is equally effective against SARS-CoV-2 emerging variants of concern (VOC) is not fully known. Hence, the aim of this study was to determine whether bamlanivimab is equally effective against SARS-CoV-2 emerging VOC. The ability of bamlanivimab to neutralize five SARS-CoV-2 variants including B.1.1.7 (mutations include N501Y and del69/70), B.1.351 (mutations include E484K and N501Y) and P.2 (mutations include E484K in the absence of a N501Y mutation) was analyzed in infectious cell culture using CaCo2 cells. Additionally, we analyzed vaccine-elicited sera after immunization with BNT162b2, and convalescent sera for its ability to neutralize SARS-CoV-2 variants.We found that the variant B.1.1.7, as well as two isolates from early 2020 (FFM1 and FFM7) could be efficiently neutralized by bamlanivimab (titer 1/1280, respectively), however, no neutralization effect could be detected against either B.1.135 or P.2, both harboring the E484K substitution. Vaccine-elicited sera showed slightly decreased neutralizing activity against B1.1.7, B.1.135 and P.2Our in vitro findings indicate that, in contrast to vaccine-elicited sera, bamlanivimab may not provide efficacy against SARS-CoV-2 variants harboring the E484K substitution. Confirmation of the SARS-CoV-2 variant, including screening for E484K, may be needed before initiating mAb treatment with bamlanivimab to ensure both efficacious and efficient use of the antibody product. Hence, variant-specific mAb agents may be required to treat emerging VOC.
SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc- SMPDL3B
Authors: Fan Wei , Tang Shuang , Fan Xiaojuan , Fang Yi , Xu Xiaojiang , Li Leping , Xu Jian , Li Jian-Liang , Wang Zefeng , Li Xiaoling 
Published: February 2021

AbstractSphingolipids are important structural components of cell membranes and prominent signaling molecules controlling cell growth, differentiation, and apoptosis. Sphingolipids are particularly abundant in the brain, and defects in sphingolipid degradation are associated with several human neurodegenerative diseases. However, molecular mechanisms governing sphingolipid metabolism remain unclear. Here we report that sphingolipid degradation is under transcriptional control of SIRT1, a highly conserved mammalian NAD+-dependent protein deacetylase, in mouse embryonic stem cells (mESCs). Deletion of SIRT1 results in accumulation of sphingomyelin in mESCs, primarily due to reduction of SMPDL3B, a GPI-anchored plasma membrane bound sphingomyelin phosphodiesterase. Mechanistically, SIRT1 regulates transcription ofSmpdl3bthrough c-Myc. Functionally, SIRT1 deficiency-induced accumulation of sphingomyelin increases membrane fluidity and impairs neural differentiationin vitroandin vivo. Our findings discover a key regulatory mechanism for sphingolipid homeostasis and neural differentiation, further imply that pharmacological manipulation of SIRT1-mediated sphingomyelin degradation might be beneficial for treatment of human neurological diseases.
The monocyte-to-lymphocyte ratio: defining a normal range, sex-specific differences in the tuberculosis disease spectrum and diagnostic indices
Authors: Buttle Thomas S. , Hummerstone Claire Y. , Billahalli Thippeswamy , Ward Richard J. B. , Barnes Korina E. , Marshall Natalie J. , Spong Viktoria C. , Bothamley Graham H. 
Published: February 2021

AbstractBackgroundThe monocyte-to-lymphocyte ratio has been advocated as a biomarker in tuberculosis. Our objective was to evaluate its clinical role in diagnosis, prognosis and treatment outcome.MethodsComplete blood counts from an unselected population aged 16 to 65 years defined normal values of the ratio and associations with other indices. Blood counts, inflammatory markers and clinical parameters were measured in patients with and those screened for tuberculosis. We examined the ratio for its associations with these variables and for diagnosis, screening, prediction of poor prognosis and response to treatment. Results. In the unselected population, monocyte-to-lymphocyte ratios were higher in males than females and correlated with neutrophil counts (Spearman’s rho=0.48, P<0.00001, n=14,573). In 356 patients notified with tuberculosis, ratios were higher in males (high monocyte counts), especially in smear-positive pulmonary tuberculosis (S+PTB), lung cavitation and raised inflammatory markers. The sensitivities for confirmed tuberculosis were 42% (males) and 32% (females), with specificities of 70% and 71% respectively. Using sex-specific cut-offs in 629 adults screened for tuberculosis and with a positive tuberculin skin test or interferon-gamma release assay, diagnostic sensitivities for active tuberculosis were better in males (25%; all and contacts of a S+PTB index, respectively) than females (14-17%) with specificities of 89-96%. Positive likelihood ratios were better with upper limits alone but were still poor (6.64 when screening for tuberculosis, with an area under the curve of 0.688). Ratios did not predict death or response to treatment. Ratios were especially higher in males than female ratios in the 16-45 years age group.ConclusionsSevere tuberculosis and male sex associated with high monocyte-to-lymphocyte ratios. The ratio performed poorly as a clinical aid. (269 words)
Polyvalent Guide RNAs for CRISPR Antivirals
Authors: Bagchi Rammyani , Tinker-Kulberg Rachel , Supakar Tinku , Chamberlain Sydney , Ligaba-Osena Ayalew , Josephs Eric A. 
Published: February 2021

ABSTRACTCRISPR biotechnologies, where CRISPR effectors recognize and degrade specific nucleic acid targets that are complementary to their guide RNA (gRNA) cofactors, have been primarily used as a tool for precision gene editing1but possess an emerging potential for novel antiviral diagnostics, prophylactics, and therapeutics.2–5In gene editing applications, significant efforts are made to limit the natural tolerance of CRISPR effectors for nucleic acids with imperfect complementarity to their gRNAs in order to prevent degradation and mutation at unintended or “off-target” sites; here we exploit those tolerances to engineer gRNAs that are optimized to promote activity at multiple viral target sites, simultaneously, given that multiplexed targeting is a critical tactic for improving viral detection sensitivity,3expanding recognition of clinical strain variants,6and suppressing viral mutagenic escape from CRISPR antivirals.7We demonstratein vitroand in higher plants that single “polyvalent” gRNAs (pgRNAs) in complex with CRISPR effectors Cas9 or Cas13 can effectively degrade pairs of viral targets with significant sequence divergence (up to 40% nucleotide differences) that are prevalent in viral genomes. We find that CRISPR antivirals using pgRNAs can robustly suppress the propagation of plant RNA viruses,in vivo, better than those with a “monovalent” gRNA counterpart. These results represent a powerful new approach to gRNA design for antiviral applications that can be readily incorporated into current viral detection and therapeutic strategies, and highlight the need for specific approaches and tools that can address the differential requirements of precision gene editingvs. CRISPR antiviral applications in order to mature these promising biotechnologies.
Comparison of the pathogenicity and virus shedding of SARS CoV-2 VOC 202012/01 and D614G variant in hamster model
Authors: Mohandas Sreelekshmy , Yadav Pragya D , Nyayanit Dimpal , Deshpande Gururaj , Shete-Aich Anita , Sapkal Gajanan , Kumar Sanjay , Jain Rajlaxmi , Kadam Manoj , Kumar Abhimanyu , Patil Deepak Y , Sarkale Prasad , Gawande Pranita , Abraham Priya 
Published: February 2021

AbstractThe emergence of SARS-CoV-2 variants has posed a serious challenge to public health system and vaccination programs across the globe. We have studied the pathogenicity and virus shedding pattern of the SARS-CoV-2 VOC 202012/01 and compared with D614G variant in Syrian hamsters. VOC 202012/01 could produce disease in hamsters characterized by body weight loss and respiratory tract tropism but mild lung pathology. Further, we also documented that neutralizing antibodies developed against VOC 202012/01 could equally neutralize D614G variant. Higher load of VOC 202012/01 in the nasal wash specimens was observed during the first week of infection outcompeting the D614G variant. The findings suggest increased fitness of VOC 202012/01 to the upper respiratory tract which could lead to higher transmission. Further investigations are needed to understand the transmissibility of new variants.One-Sentence SummarySARS-CoV-2 VOC 202012/01 infected hamsters demonstrated high viral RNA shedding through the nasal secretions and significant body weight loss with mild lung pathology compared to the D614G variant.
Experimental increases in temperature mean and variance alter reproductive behaviors in the dung beetlePhanaeus vindex
Authors: Kirkpatrick William H. , Sheldon Kimberly S. 
Published: February 2021

AbstractTemperature profoundly impacts insect development, but plasticity of reproductive behaviors may mediate the impacts of temperature change on earlier life stages. Few studies have examined the potential for behavioral plasticity of adults to buffer developing offspring from warmer, more variable temperatures associated with climate change. We used a field manipulation to examine whether the dung beetlePhanaeus vindexalters breeding behaviors in response to climate change and whether adult behavioral shifts protect offspring from temperature increases. Dung beetles lay eggs inside brood balls made of dung that are buried underground for the entirety of offspring development. Depth of the brood ball impacts the temperatures offspring experience with consequences for beetle development. We placed females in either control or greenhouse treatments that simultaneously increased temperature mean and variance. We found that females produced smaller brood balls but buried them deeper in the greenhouse treatment, suggesting burial depth may come at a cost to brood ball size, which can impact offspring nutrition. Despite being buried deeper, brood balls from the greenhouse treatment experienced warmer mean temperatures but similar amplitudes of temperature fluctuation relative to the controls. Our findings suggest adult behaviors may buffer offspring from increased temperature variation due to climate change.
ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation
Authors: van der Weegen Yana , de Lint Klaas , van den Heuvel Diana , Nakazawa Yuka , Narayanan Ishwarya V. , Klaassen Noud H.M. , Wondergem Annelotte P. , Roohollahi Khashayar , van Schie Janne J.M. , Hara Yuichiro , Ljungman Mats , Ogi Tomoo , Wolthuis Rob M.F. , Luijsterburg Martijn S. 
Published: February 2021

SummaryCells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. The binding of the TCR-specific repair factor CSB triggers DNA damage-induced ubiquitylation of RNA polymerase II (RNAPII) at a single lysine (K1268) by the CRL4CSAubiquitin ligase. However, how the CRL4CSAligase is specifically directed toward the K1268 site is unknown. Here, we identify ELOF1 as the missing link that facilitates RNAPII ubiquitylation, a key signal for the assembly of downstream repair factors. This function requires its constitutive interaction with RNAPII close to the K1268 site, revealing ELOF1 as a specificity factor that positions CRL4CSAfor optimal RNAPII ubiquitylation. Furthermore, drug-genetic interaction screening reveals an unanticipated compensatory TCR pathway in which ELOF1 together with known factors DOT1L and HIRA protect CSB-deficient cells from collisions between transcription and replication machineries. Our study provides a genetic framework of the transcription stress response and reveals key insights into the molecular mechanism of TCR.
A functional logic for neurotransmitter co-release in the cholinergic forebrain pathway
Authors: Nair Aditya , Graf Martin , Teo Yue Yang , Augustine George J. 
Published: February 2021

AbstractThe forebrain cholinergic system has recently been shown to co-release both acetylcholine and GABA. We have discovered that such co-release by cholinergic inputs to the claustrum differentially affects neurons that project to cortical versus subcortical targets. The resulting changes in neuronal gain toggles network efficiency and discriminability of output between two different projection subcircuits. Our results provide a potential logic for neurotransmitter co-release in cholinergic systems.
Intrinsic Gating Behavior of Voltage-Gated Sodium Channels Predetermines Regulation by Auxiliary β-subunits
Authors: Brake Niklas , Mancino Adamo S , Yan Yuhao , Shimomura Takushi , Silveira Heika , Kubo Yoshihiro , Khadra Anmar , Bowie Derek 
Published: February 2021

AbstractVoltage-gated sodium (Nav) channels mediate rapid millisecond electrical signaling in excitable cells. Auxiliary subunits, β1-β4, are thought to regulate Nav channel function through covalent and/or polar interactions with the channel’ s voltage-sensing domains. How these interactions translate into the diverse and variable regulatory effects of β-subunits remains unclear. Here, we find that the intrinsic movement order of the voltage-sensing domains during channel gating is unexpectedly variable across Nav channel isoforms. This movement order dictates the channel’ s propensity for closed-state inactivation, which in turn modulates the actions of β1 and β3. We show that the differential regulation of skeletal muscle, cardiac, and neuronal Nav channels is explained by their variable levels of closed-state inactivation. Together, this study provides a unified mechanism for the regulation of all Nav channel isoforms by β1 and β3, which explains how the fixed structural interactions of auxiliary subunits can paradoxically exert variable effects on channel function.
Kasugamycin is a novel chitinase 1 inhibitor with strong antifibrotic effects on pulmonary fibrosis
Authors: Lee Jae-Hyun , Lee Chang-Min , Lee Joyce H. , Kim Mun-Ock , Park Jin Wook , Kamle Suchitra , Akosman Bedia , Herzog Erica L. , Peng Xue Yan , Elias Jack A. , Lee Chun Geun 
Published: February 2021

ABSTRACTRationalePulmonary fibrosis is a devastating lung disease with few therapeutic options. Chitinase 1 (CHIT1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through regulation of Transforming Growth Factor (TGF)-β signaling and effector function. Therefore, CHIT1 is a potential therapeutic target of pulmonary fibrosis.ObjectivesThis study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis.MethodsExtensive screening of small molecule libraries identified the aminoglycoside antibiotic Kasugamycin as a potent CHIT1 inhibitor.Measurements and Main ResultsElevated levels of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In vivo bleomycin- and TGF-β-stimulated murine models of pulmonary fibrosis, Kasugamycin showed impressive anti-fibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that Kasugamycin inhibits fibrotic macrophage activation, fibroblast proliferation and myofibroblast transformation. Null mutation of transforming growth factor beta associated protein 1 (TGFBRAP1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of Kasugamycin in in vivo lungs and in vitro fibroblasts responses. Kasugamycin inhibits physical association between CHIT1 and TGFBRAP1, suggesting that antifibrotic effect of Kasugamycin is mediated through regulation of TGFBRAP1, at least in part.ConclusionsThese studies demonstrate that Kasugamycin is a novel CHIT1 inhibitor with strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.
Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30
Authors: Otarigho Benson , Aballay Alejandro 
Published: February 2021

AbstractA body of evidence indicates that metazoan immune and aging pathways are largely interconnected, but the mechanisms involved in their homeostatic control remain unclear. In this study, we found that the PITX (paired like homeodomain) transcription factor UNC-30 controls the tradeoff between immunity and longevity from the nervous system inCaenorhabditis elegans. PITX/UNC-30 functional loss enhanced immunity in a GATA/ELT-2- and p38 MAPK/PMK-1-dependent manner and reduced longevity by activating MXD/MDL-1 and the C2H2-type zinc finger transcription factor PQM-1. The immune inhibitory and longevity stimulatory functions of PITX/UNC-30 required the sensory neuron ASG and a neurotransmitter signaling pathway controlled by NPR-1, which is a G protein-coupled receptor related to mammalian neuropeptide Y receptors. Our findings uncovered a suppressive role of GABAergic signaling in the neural control of a biological tradeoff where energy is allocated towards immunity at the expense of longevity.
Regulation of DNA (de)methylation positively impacts seed germination during seed development under heat stress
Authors: Malabarba Jaiana , Windels David , Xu Wenjia , Verdier Jerome 
Published: February 2021

AbstractSeed development needs the coordination of multiple molecular mechanisms to promote correct tissue development, seed filling and the acquisition of germination capacity, desiccation tolerance, longevity and dormancy. Heat stress can negatively impact these processes and upon the increasing of global mean temperatures, global food security is threatened. Here, we explored the impact of heat stress on seed physiology, morphology, gene expression and methylation on three stages of seed development. Notably, Arabidopsis Col-0 plants under heat stress presented a decrease in germination capacity and also a decrease in longevity. We observed that upon mild stress, gene expression and DNA methylation were moderately affected. Nevertheless, upon severe heat stress during seed development, gene expression was intensively modified, promoting heat stress response mechanisms, including the activation of ABA pathway. By analyzing candidate epigenetic marks using mutants’ physiological assays, we observed that the lack of DNA demethylation byROS1gene impaired seed germination by affecting germination-related genes expression. On the other hand, we also observed that upon severe stress, a large proportion of differentially methylated regions (DMRs) were located in promoters and gene sequences of germination-related genes. To conclude, our results indicate that DNA (de)methylation could be a key regulatory process to ensure proper seed germination of seeds produced under heat stress.Graphic Abstract
Stratified Random Sampling Methodology for Observing Community Mask Use within Indoor Settings: Results from Louisville, Kentucky during the COVID-19 Pandemic
Authors: Karimi Seyed M. , Salunkhe Sonali S. , White Kelsey B. , Little Bert B. , McKinney W. Paul , Mitra Riten , Chen YuTing , Adkins Emily R. , Barclay Julia A. , Ezekekwu Emmanuel , He Caleb X. , Hurst Dylan M. , Popescu Martha M. , Swinney Devin N , Johnson David , Hollenbach Rebecca , Moyer Sarah , DuPré Natalie C. 
Published: February 2021

AbstractWearing a facial mask can limit COVID-19 transmission. Measurements of communities’ mask use behavior have mostly relied on self-report. This study’s objective was to devise a method for measuring the prevalence of mask-wearing and proper mask use in indoor public areas without relying on self-report. A stratified random sample of retail trade stores (public areas) in Louisville, Kentucky, USA, was selected and targeted for observation by trained surveyors during December 14−20, 2020. The stratification allowed for investigating mask use behavior by city district, retail trade group, and public area size. The average mask use prevalence among observed visitors of the 382 visited public areas was 96%, while the average prevalence of proper use was 86%. In 17% of the public areas, at least one unmasked visitor was among the observed visitors; in 48%, at least one improperly masked visitor was observed. The average mask use among staff was 92%, but unmasked staff were observed in fewer public areas, as an unmasked staff member was observed in 11% of the visited public areas. The average prevalence of proper make use among staff was 87%, similar to the average among visitors. However, the percentage of public areas where at least one improperly masked staff was observed was 33. Significant disparities in mask use and its proper use were observed among both visitors and staff by public area size, retail trade type, and geographical area. Observing unmasked and incorrectly masked visitors was more common in small (less than 1500 square feet) public areas than larger ones, also in food and grocery stores than other retail stores. Also, the majority of the observed unmasked persons were male and middle age adults.