bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas
Authors: Bonglack Emmanuela N. , Messinger Joshua E. , Cable Jana M. , Parnell K. Mark , Ch’ng James , Christofk Heather R. , Luftig Micah A. 
Published: December 2020

ABSTRACTEpstein-Barr Virus (EBV) is a ubiquitous herpesvirus that typically causes asymptomatic infection but can promote B lymphoid tumors in the immune-suppressed.In vitro, EBV infection of primary B cells stimulates glycolysis during immortalization into lymphoblastoid cell lines (LCLs). Lactate export during glycolysis is crucial for continued proliferation of many cancer cells-part of a phenomenon known as the “Warburg effect,” and is mediated by the monocarboxylate transporters 1 and 4 (MCT1 and MCT4). However, the role of MCT1/4 has yet to be studied in EBV-associated malignancies which display Warburg-like metabolismin vitro. Here, we show that EBV infection of B lymphocytes directly promotes temporal induction of MCT1 and MCT4 through the viral proteins EBNA2 and LMP1 respectively, with MCT1 being induced early after infection and MCT4 late. Remarkably, singular MCT1 inhibition early, and dual MCT1/4 inhibition in LCLs using a novel MCT4-selective inhibitor led to growth arrest and lactate buildup. Metabolic profiling in LCLs revealed significatly reduced oxygen consumption rates (OCR) and NAD+/NADH ratios, contrary to prevous observations of increased OCR and unaltered NAD+/NADH ratios in MCT1/MCT4-inhibited cancer cells. Furthermore, U-13C6 glucose labeling of MCT1/4-inhibited LCLs also revealed increased labeling of glutathione in the presence of elevated ROS and depleted glutathione pools, as well as increased labeling ofde novopyrimidine biosynthetic intermediates, suggesting broad effects on LCL metabolism. These vulnerabilities sensitized LCLs as well as EBV+, and the related gammaherpesvirus KSHV+ lymphoma cell lines to killing by metformin and phenformin, pointing at a novel therapeutic approach for viral lymphomas.
Elevated SARS-CoV-2 Antibodies Distinguish Severe Disease in Early COVID-19 Infection
Authors: Haddad Natalie S. , Nguyen Doan C. , Kuruvilla Merin E. , Morrison-Porter Andrea , Anam Fabliha , Cashman Kevin S. , Ramonell Richard P. , Kyu Shuya , Saini Ankur Singh , Cabrera-Mora Monica , Derrico Andrew , Alter David , Roback John D. , Horwath Michael , O’Keefe James B. , Wu Henry M. , Ian Wong An-Kwok , Dretler Alexandra W. , Gripaldo Ria , Lane Andrea N. , Wu Hao , Lee Saeyun , Hernandez Mindy , Engineer Vanessa , Varghese John , Le Sang , Sanz Iñaki , Daiss John L. , Eun-Hyung Lee F. 
Published: December 2020

AbstractBackgroundSARS-CoV-2 has caused over 36,000,000 cases and 1,000,000 deaths globally. Comprehensive assessment of the multifaceted anti-viral antibody response is critical for diagnosis, differentiation of severe disease, and characterization of long-term immunity. Initial observations suggest that severe disease is associated with higher antibody levels and greater B cell/plasmablast responses. A multi-antigen immunoassay to define the complex serological landscape and clinical associations is essential.MethodsWe developed a multiplex immunoassay and evaluated serum/plasma from adults with RT-PCR-confirmed SARS-CoV-2 infections during acute illness (N=52) and convalescence (N=69); and pre-pandemic (N=106) and post-pandemic (N=137) healthy adults. We measured IgA, IgG, and/or IgM against SARS-CoV-2 Nucleocapsid (N), Spike domain 1 (S1), receptor binding domain (S1-RBD) and S1-N-terminal domain (S1-NTD).ResultsTo diagnose infection, the combined [IgA+IgG+IgM] or IgG for N, S1, and S1-RBD yielded AUC values −0.90 by ROC curves. From days 6-30 post-symptom onset, the levels of antigen-specific IgG, IgA or [IgA+IgG+IgM] were higher in patients with severe/critical compared to mild/moderate infections. Consistent with excessive concentrations of antibodies, a strong prozone effect was observed in sera from severe/critical patients. Notably, mild/moderate patients displayed a slower rise and lower peak in anti-N and anti-S1 IgG levels compared to severe/critical patients, but anti-RBD IgG and neutralization responses reached similar levels at 2-4 months.ConclusionThis SARS-CoV-2 multiplex immunoassay measures the magnitude, complexity and kinetics of the antibody response against multiple viral antigens. The IgG and combined-isotype SARS-CoV-2 multiplex assay is highly diagnostic of acute and convalescent disease and may prognosticate severity early in illness.One Sentence SummaryIn contrast to patients with moderate infections, those with severe COVID-19 develop prominent, early antibody responses to S1 and N proteins.
Strawberry sweetness and consumer preference are enhanced by specific volatile compounds
Authors: Fan Zhen , Hasing Tomas , Johnson Timothy S. , Garner Drake M. , Barbey Christopher R. , Colquhoun Thomas A. , Sims Charles A. , Resende Marcio F. R. , Whitaker Vance M. 
Published: December 2020

ABSTRACTBreeding crops for improved flavor is challenging due to the high cost of sensory evaluation and the difficulty of connecting sensory experience to chemical composition. The main goal of this study was to identify the chemical drivers of sweetness and consumer liking for fresh strawberries (Fragaria ×ananassa). Fruit of 148 strawberry samples from cultivars and breeding selections were grown and harvested over seven years and were subjected to both sensory and chemical analyses. Each panel consisted of at least 100 consumers, resulting in more than 15,000 sensory data points per descriptor. Three sugars, two acids and 113 volatile compounds were quantified. Consumer liking was highly associated with sweetness intensity, texture liking, and flavor intensity, but not sourness intensity. Partial least square analyses revealed 20 volatile compounds that increased sweetness perception independently of sugars; 18 volatiles that increased liking independently of sugars; and 15 volatile compounds that had positive effects on both. Machine learning-based predictive models including sugars, acids, and volatiles explained at least 25% more variation in sweetness and liking than models accounting for sugars and acids only. Volatile compounds such as γ-dodecalactone; 5-hepten-2-one, 6-methyl; and multiple medium-chain fatty acid esters may serve as targets for breeding or quality control attributes for strawberry products. A genetic association study identified two loci controlling ester production, both on linkage group 6A. Co-segregating makers in these regions can be used for increasing multiple esters simultaneously. This study demonstrates a paradigm for improvement of fruit sweetness and flavor in which consumers drive the identification of the most important chemical targets, which in turn drives the discovery of genetic targets for marker-assisted breeding.
Chromosomal-scaleDe novoGenome Assemblies of Cynomolgus Macaque and Common Marmoset
Authors: Jayakumar Vasanthan , Nishimura Osamu , Kadota Mitsutaka , Hirose Naoki , Sano Hiromi , Murakawa Yasuhiro , Yamamoto Yumiko , Nakaya Masataka , Tsukiyama Tomoyuki , Seita Yasunari , Nakamura Shinichiro , Kawai Jun , Sasaki Erika , Ema Masatsugu , Kuraku Shigehiro , Kawaji Hideya , Sakakibara Yasubumi 
Published: December 2020

AbstractCynomolgus macaque (Macaca fascicularis) and common marmoset (Callithrix jacchus) have been widely used in human biomedical research. Their genomes were sequenced and assembled initially using short-read sequences, with the advent of massively parallel sequencing. However, the resulting contig sequences tended to remain fragmentary, and long-standing primate genome assemblies used the human genome as a reference for ordering and orienting the assembled fragments into chromosomes. Here we performedde novogenome assembly of these two species without any human genome-based bias observed in the genome assemblies released earlier. Firstly we assembled PacBio long reads, and the resultant contigs were scaffolded with Hi-C data. The scaffolded sequences obtained were further refined based on assembly results of alternate de novo assemblies and Hi-C contact maps by resolving identified inconsistencies. The final assemblies achieved N50 lengths of 149 Mb and 137 Mb for cynomolgus macaque and common marmoset, respectively, and the numbers of scaffolds longer than 10Mb are equal to their chromosome numbers. The high fidelity of our assembly is ascertained by concordance to the BAC-end read pairs observed for common marmoset, as well as a high resemblance of their karyotypic organization. Our assembly of cynomolgus macaque outperformed all the available assemblies of this species in terms of contiguity. The chromosome-scale genome assemblies produced in this study are valuable resources for non-human primate models and provide an important baseline in human biomedical research.
Light-harvesting in mesophotic corals is powered by a spatially efficient photosymbiotic system between coral host and microalgae
Authors: Kramer Netanel , Tamir Raz , Ben-Zvi Or , Jacques Steven L. , Loya Yossi , Wangpraseurt Daniel 
Published: December 2020

SummaryThe coral-algal photosymbiosis fuels global coral-reef primary productivity, extending from sea level to as deep as 150 m (i.e., mesophotic). Currently, it is largely unknown how such mesophotic reefs thrive despite extremely limited light conditions. Here, we show that corals exhibit a plastic response to mesophotic conditions that involves a spatially optimized regulation of the bio-optical properties by coral host and symbiont. In contrast to shallow corals, mesophotic corals absorbed up to three-fold more light, resulting in excellent photosynthetic response under light conditions of only ~3% of the incident surface irradiance. The enhanced light harvesting capacity of mesophotic corals is regulated by average refractive index fluctuations in the coral skeleton that give rise to optical scattering and facilitate light transport and absorption by densely pigmented host tissue. The results of this study provide fundamental insight into the energy efficiency and light-harvesting mechanisms underlying the productivity of mesophotic coral reef ecosystems, yet also raise concerns regarding their ability to withstand prolonged environmental disturbances.
Gut Microbe-Targeted Choline Trimethylamine Lyase Inhibition Improves Obesity Via Rewiring of Host Circadian Rhythms
Authors: Schugar Rebecca C. , Gliniak Christy M. , Helsley Robert N. , Brown Amanda L. , Burrows Amy , Finney Chelsea , Fung Kevin K. , Allen Frederick M. , Ferguson Daniel , Gromovsky Anthony D. , Neumann Chase , McMillan Amy , Buffa Jennifer A. , Anderson James T. , Mehrabian Margarete , Goudzari Maryam , Willard Belinda , Mak Tytus D. , Armstrong Andrew R. , Swanson Garth , Keshavarzian Ali , Garcia-Garcia Jose Carlos , Wang Zeneng , Lusis Aldons J. , Hazen Stanley L. , Brown J. Mark 
Published: December 2020

AbstractObesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (ob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake, but is instead associated with beneficial remodeling of the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism, and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have untapped potential as anti-obesity therapeutics.
Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem
Authors: Das Soumyaparna , Popp Valerie , Power Michael , Groeneveld Kathrin , Melle Christian , Rogerson Luke , Achury Marlly , Schwede Frank , Strasser Torsten , Euler Thomas , Paquet-Durand François , Nache Vasilica 
Published: December 2020

ABSTRACTHereditary degeneration of photoreceptors has been linked to over-activation of Ca2+-permeable channels, excessive Ca2+-influx, and downstream activation of Ca2+-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca2+-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca2+-influx, most probably by blocking the pore of Ca2+-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca2+and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca2+-independent degenerative mechanisms.
Diversity of developing peripheral glia revealed by single cell RNA sequencing
Authors: Tasdemir-Yilmaz OE , Druckenbrod NR , Olukoya OO , Yung AR , Bastille I , Pazyra-Murphy MF , Sitko A , Hale EB , Vigneau S , Gimelbrant AA , Kharchenko P , Goodrich LV , Segal RA 
Published: December 2020

AbstractThe peripheral nervous system responds to a wide variety of sensory stimuli, a process that requires great neuronal diversity. These diverse peripheral sensory neurons are closely associated with glial cells that originate from the neural crest (NC). However, the molecular nature and origins of diversity among peripheral glia is not understood. Here we used single cell RNA sequencing to profile and compare developing and mature glia from somatosensory lumbar dorsal root ganglia (DRG) and auditory spiral ganglia (SG). We found that the glial precursors (GPs) differ in their transcriptional profile and prevalence in these two systems. Despite their unique features, somatosensory and auditory GPs undergo convergent differentiation to generate myelinating and non-myelinating Schwann cells that are molecularly uniform. By contrast, although satellite glia surround the neuronal cell bodies in both ganglia, we found that those in the SG express multiple myelination-associated genes, while DRG satellite cells express components that suppress myelination. Lastly, we identified a set of glial signature genes that are also expressed by placode-derived supporting cells, providing new insights into commonalities among glia across the nervous system. This comprehensive survey of gene expression in peripheral glia constitutes a valuable resource for understanding how glia acquire specialized functions and how their roles differ across sensory modalities.
Granzyme B prevents aberrant IL-17 production and intestinal pathogenicity in CD4+T cells
Authors: Hoek Kristen L. , Greer Michael J. , McClanahan Kathleen G. , Nazmi Ali , Piazuelo M. Blanca , Singh Kshipra , Wilson Keith T. , Olivares-Villagómez Danyvid 
Published: December 2020

AbstractCD4+T cell activation and differentiation are important events that set the stage for proper immune responses. Many factors are involved in the activation and differentiation of T cells, and these events are tightly controlled to prevent unwanted and/or exacerbated immune responses that may harm the host. It has been well documented that granzyme B, a potent serine protease involved in cell-mediated cytotoxicity, is readily expressed by certain CD4+T cells, such as regulatory T cells and CD4+CD8αα+intestinal intraepithelial lymphocytes, both of which display cytotoxicity associated with granzyme B. However, because not all CD4+T cells expressing granzyme B are cytotoxic, additional roles for this protease in CD4+T cell biology remain unknown. Here, using a combination ofin vivoandin vitroapproaches, we report that granzyme B-deficient CD4+T cells display increased IL-17 production. In the adoptive transfer model of intestinal inflammation, granzyme B-deficient CD4+T cells triggered a more rapid disease onset than their WT counterparts, and presented a differential transcription profile. Similar results were also observed in granzyme B-deficient mice infected withCitrobacter rodentium. Our results suggest that granzyme B modulates CD4+T cell differentiation, providing a new perspective into the biology of this enzyme.
Significant inactivation of SARS-CoV-2 by a green tea catechin, a catechin-derivative and galloylated theaflavinsin vitro
Authors: Ohgitani Eriko , Shin-Ya Masaharu , Ichitani Masaki , Kobayashi Makoto , Takihara Takanobu , Kawamoto Masaya , Kinugasa Hitoshi , Mazda Osam 
Published: December 2020

AbstractPotential effects of teas and their constituents on SARS-CoV-2 infection were studiedin vitro. Infectivity of SARS-CoV-2 was significantly reduced by a treatment with green tea, roasted green tea or oolong tea. Most remarkably, exposure to black tea for 1 min decreased virus titer to an undetectable level (less than 1/1,000 of untreated control). An addition of (-) epigallocatechin gallate (EGCG) significantly inactivated SARS-CoV-2, while theasinensin A (TSA) and galloylated theaflavins including theaflavin 3, 3’-di-gallate (TFDG) had more remarkable anti-viral activities. Virus treated with TSA at 500 μM or TFDG at 100 μM showed less than 1/10,000 infectivity compared with untreated virus. TSA and TFDG significantly inhibited interaction between recombinant ACE2 and RGD of S protein. These results strongly suggest that EGCG, and more remarkably TSA and galloylated theaflavins, inactivate the novel coronavirus.
Chromatin remodeling in peripheral blood cells reflects COVID-19 symptom severity
Authors: Giroux Nicholas S. , Ding Shengli , McClain Micah T. , Burke Thomas W. , Petzold Elizabeth , Chung Hong A. , Palomino Grecia R. , Wang Ergang , Xi Rui , Bose Shree , Rotstein Tomer , Nicholson Bradly P. , Chen Tianyi , Henao Ricardo , Sempowski Gregory D. , Denny Thomas N. , Ko Emily R. , Ginsburg Geoffrey S. , Kraft Bryan D. , Tsalik Ephraim L. , Woods Christopher W. , Shen Xiling 
Published: December 2020

AbstractSARS-CoV-2 infection triggers highly variable host responses and causes varying degrees of illness in humans. We sought to harness the peripheral blood mononuclear cell (PBMC) response over the course of illness to provide insight into COVID-19 physiology. We analyzed PBMCs from subjects with variable symptom severity at different stages of clinical illness before and after IgG seroconversion to SARS-CoV-2. Prior to seroconversion, PBMC transcriptomes did not distinguish symptom severity. In contrast, changes in chromatin accessibility were associated with symptom severity. Furthermore, single-cell analyses revealed evolution of the chromatin accessibility landscape and transcription factor motif occupancy for individual PBMC cell types. The most extensive remodeling occurred in CD14+ monocytes where sub-populations with distinct chromatin accessibility profiles were associated with disease severity. Our findings indicate that pre-seroconversion chromatin remodeling in certain innate immune populations is associated with divergence in symptom severity, and the identified transcription factors, regulatory elements, and downstream pathways provide potential prognostic markers for COVID-19 subjects.One sentence summaryChromatin accessibility in immune cells from COVID-19 subjects is remodeled prior to seroconversion to reflect disease severity.
The Genetic Architecture of Robustness for Flight Performance inDrosophila
Authors: Spierer Adam N. , Rand David M. 
Published: December 2020

ABSTRACTA central challenge of quantitative genetics is partitioning phenotypic variation into genetic and non-genetic components. These non-genetic components are usually interpreted as environmental effects; however, variation between genetically identical individuals in a common environment can still exhibit phenotypic variation. A trait’s resistance to variation is called robustness, though the genetics underlying it are poorly understood. Accordingly, we performed an association study on a previously studied, whole organism trait: flight performance. Using 197 of the Drosophila Genetic Reference Panel (DGRP) lines, we surveyed variation at the level of single nucleotide polymorphisms and whole genes using additive, marginal, and epistatic analyses that associated with robustness for flight performance. Many genes had developmental and neurodevelopmental annotations, and many more were identified from associations that differed between sexes. Additionally, many genes were pleiotropic, with several annotated for fitness-associated traits (e.g. gametogenesis and courtship). Our results corroborate a previous study for genetic modifiers of micro-environmental variation, and have sizable overlap with studies for modifiers of wing morphology and courtship behavior. These results point to an important and shared role for genetic modifiers of robustness of flight performance affecting development, neurodevelopment, and behavior.
Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-induced Weight Gain in Male Mice
Authors: Morris E. Matthew , Noland Roberto D. , Ponte Michael E. , Montonye Michelle L. , Christianson Julie A. , Stanford John A. , Miles John M. , Hayes Matthew R. , Thyfault John P. 
Published: December 2020

AbstractCentral integration of peripheral neural signals is one mechanism by which systemic energy homeostasis is regulated. Previous work described increased acute food intake following chemical reduction of hepatic fatty acid oxidation and ATP levels, which was prevented by common hepatic branch vagotomy (HBV). However, possible offsite actions of the chemical compounds confound the precise role of liver energy metabolism. Herein, we used a liver-specific PGC1a heterozygous (LPGC1a) mouse model, with associated reductions in mitochondrial fatty acid oxidation and respiratory capacity, to assess the role of liver energy metabolism in systemic energy homeostasis. LPGC1a male mice have 70% greater high-fat/high-sucrose (HFHS) diet-induced weight gain and 35% greater positive energy balance compared to wildtype (WT) (p<0.05). The greater energy balance was associated with altered feeding behavior and lower activity energy expenditure during HFHS in LPGC1a males. Importantly, no differences in HFHS-induced weight gain or energy metabolism was observed between female WT and LPGC1a mice. WT and LPGC1a mice underwent sham or HBV to assess whether vagal signaling was involved in HFHS-induced weight gain of male LPGC1a mice. HBV increased HFHS-induced weight gain (85%, p<0.05) in male WT, but not LPGC1a mice. As above, sham LPGC1a males gain 70% more weight during short-term HFHS feeding than sham WT (p<0.05). These data demonstrate a sexspecific role of reduced liver energy metabolism in acute diet-induced weight gain, and the need of more nuanced assessment of the role of vagal signaling in short-term diet-induced weight gain.Key Points SummaryReduced liver PGC1a expression results in reduced mitochondrial fatty acid oxidation and respiratory capacity in male mice.Male mice with reduced liver PGC1a expression (LPGC1a) demonstrate greater short-term high-fat/high-sucrose diet-induced weight gain compared to wildtype.Greater positive energy balance during HFHS feeding in male LPGC1a mice is associated with altered food intake patterns and reduced activity energy expenditure.Female LPGC1a mice do not have differences in short-term HFHS-induced body weight gain or energy metabolism compared to wildtype.Disruption of vagal signaling through common hepatic branch vagotomy increases short-term HFHS-induced weight gain in male wildtype mice, but does not alter male LPGC1a weight gain.