bluuebunny/crossref_metadata_2025_split huggingface dataset:
CYK-1/Formin activation in cortical RhoA signaling centers promotes organismal left-right symmetry breaking
Authors: Middelkoop Teije C. , Garcia-Baucells Júlia , Quintero-Cadena Porfirio , Pimpale Lokesh G. , Yazdi Shahrzad , Sternberg Paul , Gross Peter , Grill Stephan W. 
Published: January 2021

1AbstractProper left-right symmetry breaking is essential for animal development and in many species the actin cytoskeleton plays an instrumental role in this process. Active torque generation in the actomyosin layer promotes left-right symmetry breaking inC. elegansembryos by driving chiral counter-rotating cortical flows. While both Formins and Myosins have been implied in left-right symmetry breaking, and both can rotate actin filamentsin vitro, it remains unclear if active torques in the actomyosin cortex are generated by Formins, Myosins, or both. We combined the strength ofC. elegansgenetics with quantitative imaging and thin film, chiral active fluid theory to show that, while Non-Muscle Myosin II activity drives cortical actomyosin flows, it is permissive for chiral counter-rotation and dispensable for chiral symmetry breaking of cortical flows. Instead, we find that CYK-1/Formin activation in RhoA foci is instructive for chiral counter-rotation and promotes in-plane, active torque generation in the actomyosin cortex. Notably, we observe that artificially generated large active RhoA patches undergo rotations with consistent handedness in a CYK-1/Formin-dependent manner. Altogether, we conclude that, CYK-1/Formin-dependent active torque generation facilitates chiral symmetry breaking of actomyosin flows and drives organismal left-right symmetry breaking in the nematode worm.2SignificanceActive torque generation in the actin cytoskeleton has been implicated in driving left-right symmetry breaking of developing embryos, but which molecules generate the active torque and how active torque generation is organized subcellularly remains unclear. This study shows that cortical Formin, recruited to cortical regions where RhoA signaling is active, promotes active torque generation in the actomyosin layer. We find that active torque tends to locally rotate the cortex in a clockwise fashion, which drives the emergence of chiral counter-rotating flows with consistent handedness and facilitates left-right symmetry breaking ofC. elegansembryos.
Cysteine is a limiting factor for glioma proliferation and survival
Authors: Ruiz-Rodado Victor , Dowdy Tyrone , Lita Adrian , Kramp Tamalee , Zhang Meili , Jung Jinkyu , Dios-Esponera Ana , Herold-Mende Christel C. , Camphausen Kevin , Gilbert Mark R. , Larion Mioara 
Published: January 2021

AbstractNutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. We report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential.13C-tracing and the analysis of cystathionine synthase and cystathioninase levels revealed the metabolic landscape attributable to cysteine deprivation, and the disconnection between the methionine cycle and the transsulfuration pathway. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine-free diet survived longer, with concomitant reductions in glutathione and cysteine plasma levels. At the end point, however, tumors displayed the ability to synthesize glutathione, although higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine-related metabolites in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.
Genetic modulation of initial sensitivity to Δ9-tetrahydrocannabinol (THC) among the BXD family of mice
Authors: Parks C. , Rogers C.M. , Prins J.P. , Williams R.W. , Chen H. , Jones B.C. , Moore B.M. , Mulligan M.K. 
Published: January 2021

ABSTRACTCannabinoid receptor 1 activation by the major psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), produces motor impairments, hypothermia, and analgesia upon acute exposure. In previous work, we demonstrated significant sex and strain differences in acute responses to THC following administration of a single dose (10 mg/kg,i.p.) in C57BL/6J (B6) and DBA/2J (D2) inbred mice. To determine the extent to which these differences are heritable, we quantified acute responses to a single dose of THC (10 mg/kg,i.p.) in males and females from 20 members of the BXD family of inbred strains derived by crossing and inbreeding B6 and D2 mice. Acute THC responses (initial sensitivity) were quantified as changes from baseline for: 1. spontaneous activity in the open field (mobility), 2. body temperature (hypothermia), and 3. tail withdrawal latency to a thermal stimulus (analgesia/antinociception). Initial sensitivity to the immobilizing, hypothermic, and antinociceptive effects of THC varied substantially across the BXD family. Heritability was highest for mobility and hypothermia traits, indicating that segregating genetic variants modulate initial sensitivity to THC. We identified genomic loci and candidate genes, includingNdufs2, Scp2, Rps6kb1or P70S6K,Pde4d, andPten, that may control variation in THC initial sensitivity. We also detected strong correlations between initial responses to THC and legacy phenotypes related to intake or response to other drugs of abuse (cocaine, ethanol, and morphine). Our study demonstrates the feasibility of mapping genes and variants modulating THC responses in the BXDs to systematically define biological processes and liabilities associated with drug use and abuse.
Decoupling of global brain activity and cerebrospinal fluid flow in Parkinson’s cognitive decline
Authors: Han Feng , Brown Gregory L. , Zhu Yalin , Belkin-Rosen Aaron E. , Lewis Mechelle M. , Du Guangwei , Gu Yameng , Eslinger Paul J. , Mailman Richard B. , Huang Xuemei , Liu Xiao 
Published: January 2021

AbstractBackgroundDeposition and spreading of misfolded proteins (α-synuclein and tau) have been linked to Parkinson’s cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep-dependent global brain activity is coupled to CSF flow that may reflect glymphatic function.ObjectiveTo determine if the decoupling of brain activity-CSF flow is linked to Parkinson’s cognitive dysfunction.MethodsFunctional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment, MoCA) scores were collected from 60 Parkinson’s and 58 control subjects. Parkinson’s patients were subgrouped into those with (MoCA < 26; N = 29) and without (MoCA ≥ 26; N = 31) mild cognitive impairment (MCI).The coupling strength between the resting-state global blood-oxygen-level-dependent signal (gBOLD) and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements.ResultsgBOLD-CSF coupling decreased significantly (p< 0.006) in Parkinson’s patients showing MCI, compared to those without MCI and controls. Reduced gBOLD-CSF coupling was associated with decreased MoCA scores that was present in Parkinson’s patients (p= 0.005) but not in controls (p= 0.65). Weaker gBOLD-CSF coupling in Parkinson’s patients also was associated with a thinner right entorhinal cortex (Spearman’s correlation = − 0.36;p= 0.012), an early structural change often seen in Alzheimer’s.ConclusionsThe decoupling between global brain activity and associated CSF flow is related to Parkinson’s cognitive impairment.
Differential regulation of progranulin derived granulin peptides
Authors: Zhang Tingting , Du Huan , Santos Mariela Nunez , Wu Xiaochun , Reinheckel Thomas , Hu Fenghua 
Published: January 2021

AbstractHaploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN is comprised of 7.5 granulin repeats and is processed into individual granulin peptides in the lysosome. However, very little is known about the levels and regulations of individual granulin peptides due to the lack of specific antibodies. Here we report the generation and characterization of antibodies specific to each granulin peptide. We found that the levels of granulins C, E and F are differentially regulated compared to granulins A and B. Furthermore, we demonstrated that granulin B, C and E are heavily glycosylated and the glycosylation pattern of granulin C varies in different physiological and pathological conditions. Deficiency of lysosomal proteases leads to alterations in the levels of a specific subset of granulins. These data support that the levels of individual granulin peptides are differentially regulated under physiological and pathological conditions and provide novel insights into how granulin peptides function in the lysosome.
Super-Resolution Label-free Volumetric Vibrational Imaging
Authors: Qian Chenxi , Miao Kun , Lin Li-En , Chen Xinhong , Du Jiajun , Wei Lu 
Published: January 2021

AbstractInnovations in high-resolution optical imaging have allowed visualization of nanoscale biological structures and connections. However, super-resolution fluorescence techniques, including both optics-oriented and sample-expansion based, are limited in quantification and throughput especially in tissues from photobleaching or quenching of the fluorophores, and low-efficiency or non-uniform delivery of the probes. Here, we report a general sample-expansion vibrational imaging strategy, termed VISTA, for scalable label-free high-resolution interrogations of protein-rich biological structures with resolution down to 82 nm. VISTA achieves decent three-dimensional image quality through optimal retention of endogenous proteins, isotropic sample expansion, and deprivation of scattering lipids. Free from probe-labeling associated issues, VISTA offers unbiased and high-throughput tissue investigations. With correlative VISTA and immunofluorescence, we further validated the imaging specificity of VISTA and trained an image-segmentation model for label-free multi-component and volumetric prediction of nucleus, blood vessels, neuronal cells and dendrites in complex mouse brain tissues. VISTA could hence open new avenues for versatile biomedical studies.
Endogenous Retroviral Elements Generate Pathologic Neutrophils and Elastase Rich Exosomes in Pulmonary Arterial Hypertension
Authors: Taylor Shalina , Contrepois Kévin , Benayoun Bérénice A. , Jiang Lihua , Isobe Sarasa , Wang Lingli , Melemenidis Stavros , Ozen Mehmet O. , Otsuki Shoichiro , Shinohara Tsutomu , Sweatt Andrew J. , Kaplan Jordan , Cao Aiqin , Moonen Jan-Renier , Marciano David P. , Gu Mingxia , Miyagawa Kazuya , Del Rosario Patricia A. , Hsi Andrew , Thompson A. A. Roger , Ariza Maria-Eugenia , Demirci Utkan , Zamanian Roham T. , Haddad Francois , Nicolls Mark R. , Snyder Michael P. , Rabinovitch Marlene 
Published: January 2021

ABSTRACTNeutrophil elastase (NE) is implicated in pulmonary arterial hypertension (PAH) but the role of neutrophils in the pathogenesis of PAH is unclear. Here we show that neutrophils from PAH vs. control subjects produce and release increased NE associated with enhanced extracellular trap formation. PAH neutrophils are highly adherent and show decreased migration consistent with increased vinculin, identified on proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic interferon signature in PAH neutrophils and an increase in human endogenous retrovirus (HERV-K) envelope protein. NE and interferon genes are induced by HERV-K envelope and vinculin is increased by HERV-K dUTPase that is elevated in PAH plasma. Neutrophil exosomes from PAH plasma contain increased NE and HERV-K envelope and induce pulmonary hypertension in mice, that is mitigated by the NE inhibitor and antiviral agent, elafin. Thus, elevated HERVs explain pathological neutrophils linked to PAH induction and progression.
Influence of Fara-darmani Consciousness Field on Bacterial Population Growth
Authors: Taheri Mohammad Ali , Zarrini Gholamreza , Torabi Sara , Nabavi Noushin , Semsarha Farid 
Published: January 2021

AbstractThe treatment of bacterial infections and the rising challenges of antibiotics resistance are global concerns and the primary topics in basic science and clinical microbiology. In the present study, the effectiveness of treatment of selected populations of bacteria using an immaterial and non-energetic method called Fara-darmani Consciousness Field treatment is investigated. Population growth was assessed by turbidimetry, colony counting and tetrazolium chloride reduction assays in non-treated control and Fara-darmani-treated groups. Our results suggest effectiveness of the Fara-darmani Consciousness Field on reducing various types of bacterial strain growth rates (up to 46%). In addition, along with a decrease in bacterial population, evidence of increased survival can be seen in the larger healthy population (up to about 60%). Thus, in this study, we confirm the effects of the Consciousness Field on bacterial population survival. This study also warrants additional research.
Chromosome-scale assembly of theSparassis latifoliagenome obtained using long-read and Hi-C sequencing
Authors: Yang Chi , Ma Lu , Xiao Donglai , Liu Xiaoyu , Jiang Xiaoling , Ying Zhenghe , Lin Yanquan 
Published: January 2021

AbstractSparassis latifoliais a valuable edible mushroom cultivated in China. In 2018, our research group reported an incomplete and low quality genome ofS. latifoliawas obtained by Illumina HiSeq 2500 sequencing. These limitations in the available genome have constrained genetic and genomic studies in this mushroom resource. Herein, an updated draft genome sequence ofS. latifoliawas generated by Oxford Nanopore sequencing and the Hi-C technique. A total of 8.24 Gb of Oxford Nanopore long reads representing ~198.08X coverage of theS. latifoliagenome were generated. Subsequently, a high-quality genome of 41.41 Mb, with scaffold and contig N50 sizes of 3.31 Mb and 1.51 Mb, respectively, was assembled. Hi-C scaffolding of the genome resulted in 12 pseudochromosomes containing 93.56% of the bases in the assembled genome. Genome annotation further revealed that 17.47% of the genome was composed of repetitive sequences. In addition, 13,103 protein-coding genes were predicted, among which 98.72% were functionally annotated. BUSCO assay results further revealed that there were 92.07% complete BUSCOs. The improved chromosome-scale assembly and genome features described here will aid further molecular elucidation of various traits, breeding ofS. latifolia, and evolutionary studies with related taxa.ImportanceSparassis latifoliaY.C. Dai et Z. Wang (Sparassidaceae, Polyporales, Agaricomycetes), collections from AsianSparassis(Dai et al., 2006) exhibits diverse biological and pharmacologic activities. To date, total fresh fruit production in Chinese factories is over 20 tons/d. Despite the significant economic and medical value ofS. latifolia, the assembly level of genome was under chromosome-scale. This study assembles a high-quality chromosome-scale reference genome ofS. latifoliausing Oxford Nanopore sequencing combined with Hi-C (High-through chromosome conformation capture) scaffolding. The improved reference genome will facilitate molecular breeding ofS. latifoliaand advance our understanding of its genetics and evolution.
Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-cell Growth and Survival
Authors: Liang Jin-Hua , Wang Chong , Tung Yiu Stephanie Pei , Zhao Bo , Guo Rui , Gewurz Benjamin E. 
Published: January 2021

AbstractEpstein-Barr virus (EBV) is associated with 200,000 cancers annually, including B-cell lymphomas in immunosuppressed hosts. Hypomorphic mutations of thede novopyrimidine synthesis pathway enzyme cytidine 5’ triphosphate synthase 1 (CTPS1) suppress cell mediated immunity, resulting in fulminant EBV infection and EBV+ central nervous system (CNS) lymphomas. Since CTP is a critical precursor for DNA, RNA and phospholipid synthesis, this observation raises the question of whether the isozyme CTPS2 or cytidine salvage pathways help meet CTP demand in EBV-infected B-cells. Here, we found that EBV upregulated CTPS1 and CTPS2 with distinct kinetics in newly infected B-cells. While CRISPR CTPS1 knockout caused DNA damage and proliferation defects in lymphoblastoid cell lines (LCL), which express the EBV latency III program observed in CNS lymphomas, double CTPS1/2 knockout caused stronger phenotypes. EBNA2, MYC and non-canonical NF-□B positively regulated CTPS1 expression. CTPS1 depletion impaired EBV lytic DNA synthesis, suggesting that latent EBV may drive pathogenesis with CTPS1 deficiency. Cytidine rescued CTPS1/2 deficiency phenotypes in EBV-transformed LCL and Burkitt B-cells, highlighting CTPS1/2 as a potential therapeutic target for EBV-driven lymphoproliferative disorders. Collectively, our results suggest that CTPS1 and CTPS2 have partially redundant roles in EBV-transformed B-cells and provide insights into EBV pathogenesis with CTPS1 deficiency.
Chikungunya virus ECSA lineage reintroduction in the northeasternmost region of Brazil
Authors: Xavier Joilson , Fonseca Vagner , Bezerra Joao Felipe , do Monte Alves Manoella , Mares-Guia Maria Angélica , Claro Ingra Morales , de Jesus Ronaldo , Adelino Talita , Araújo Emerson , Jardim Cavalcante Karina Ribeiro Leite , Tosta Stephane , de Souza Themis Rocha , da Cruz Flavia Emanuelle Moreira , de Araújo Fabri Allison , de Oliveira Elaine Cristina , de Moura Noely Fabiana Oliveira , do Carmo Said Rodrigo Fabiano , de Albuquerque Carlos Frederico Campelo , Azevedo Vasco , de Oliveira Tulio , de Filippis Ana Maria Bispo , da Cunha Rivaldo Venâncio , Luz Kleber Giovanni , Giovanetti Marta , Junior Alcantara Luiz Carlos 
Published: January 2021

ABSTRACTThe Northeast region of Brazil registered the second highest incidence proportion of chikungunya fever in 2019. In that year an outbreak consisting of patients presented with febrile disease associated with joint pain were reported by the public primary health care service in the city of Natal, Rio Grande do Norte state, in March 2019. At first, the aetiological agent of the disease was undetermined. Since much is still unknown about chikungunya virus (CHIKV) genomic diversity and evolutionary history in this northeasternmost state, we used a combination of portable whole genome sequencing, molecular clock, and epidemiological analyses that revealed the re-introduction of the CHIKV East-Central-South-African (ECSA) lineage into Rio Grande do Norte. We estimated CHIKV ECSA lineage was first introduced into Rio Grande do Norte in early June 2014, while the 2019 outbreak clade diverged around April 2018 during a period of increased chikungunya incidence in the Southeast region, which might have acted as a source of virus dispersion towards the Northeast region. Together, these results confirm the ECSA lineage continues to spread across the country through interregional importation events likely mediated by human mobility.HIGHLIGHTSCHIKV ECSA lineage introduction into Rio Grande do Norte state, Northeast Brazil, was estimated to early June 2014At least two CHIKV importation events occurred in Rio Grande do Norte state, BrazilThe 2019 chikungunya outbreak in Rio Grande do Norte was likely caused by a second event of CHIKV introduction imported from Rio de Janeiro state.
Targeting EGFR in glioblastoma with a novel brain-penetrant small molecule EGFR-TKI
Authors: Ni Jing , Yang Yanzhi , Wang Qiwei , Bergholz Johann S. , Jiang Tao , Roberts Thomas M. , Gray Nathanael S. , Zhao Jean J. 
Published: January 2021

SummaryEpidermal growth factor receptor (EGFR) is mutated or amplified in a majority of glioblastoma (GBM), and its mutation and focal amplification correlate with a more aggressive disease course. However, EGFR-directed tyrosine kinase inhibitors (TKIs) tested to date have yielded minimal clinical benefit. Here, we report a novel covalent-binding EGFR-TKI, CM93, as a potential drug to target adult GBMs with aberrant EGFR. CM93 has extraordinary brain exposure, with a brain-to-plasma ratio greater than 20-fold at estimated steady state. While all approved EGFR-TKIs are subject to extensive efflux transporter activity, CM93 does not inhibit the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters in Caco-2 cells at expected clinically relevant plasma concentrations. Equally, CM93 demonstrates moderate absorption and permeation in Caco-2 cell monolayers with efflux ratios < 2, suggesting that it is not likely a substrate of an efflux transporter. Collectively, thesein vitrodata may account for the dramatic increase in brain exposure over plasma as noted above. Pre-clinical efficacy studies showed that CM93 is more effective than other EGFR-TKIs in blocking the proliferation of GBM tumor cells from both patient-derived and cultured human GBM cell lines with EGFR amplification and/or EGFRvIII mutation. In addition, CM93 administered as a single agent was able to attenuate the growth of orthotopic U251-EGFRvIII xenografts and extend the survival of tumor-bearing mice in a dose-dependent manner. Moreover, CM93 inhibited EGFR phosphorylation in GBM tumors derived from a novel genetically-engineered mouse (GEM) model of GBM with EGFRvIII expression bothin vitroandin vivo. CM93 also extended the survival of mice bearing orthotopic allografts of GBM. Notably, mice maintained stable body weight during treatments with increasing doses of CM93 up to 75 mg/kg per day. Together, these data suggest that CM93 is a potential EGFR-TKI well suited for the treatment of adult GBM with mutant EGFR.