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Found 35817 matches. Displaying 41-50
Jove V, Gong ZY, Hol FJH, Zhao ZL, Sorrells TR, Carroll TS, Prakash M, McBride CS, Vosshall LB
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Sensory Discrimination of Blood and Floral Nectar by Aedes aegypti Mosquitoes

NEURON 2020 DEC 23; 108(6):?
Blood-feeding mosquitoes survive by feeding on nectar for metabolic energy but require a blood meal to develop eggs. Aedes aegypti females must accurately discriminate blood and nectar because each meal promotes mutually exclusive feeding programs with distinct sensory appendages, meal sizes, digestive tract targets, and metabolic fates. We investigated the syringe-like blood-feeding appendage, the stylet, and discovered that sexually dimorphic stylet neurons taste blood. Using pan-neuronal calcium imaging, we found that blood is detected by four functionally distinct stylet neuron classes, each tuned to specific blood components associated with diverse taste qualities. Stylet neurons are insensitive to nectar-specific sugars and respond to glucose only in the presence of additional blood components. The distinction between blood and nectar is therefore encoded in specialized neurons at the very first level of sensory detection in mosquitoes. This innate ability to recognize blood is the basis of vector-borne disease transmission to millions of people worldwide.
Morse KW, Heinz NK, Abolade JM, Wright-Chisem JI, Russell LA, Zhang M, Mirza SZ, Orange DE, Figgie MP, Sculco PK, Goodman SM
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Response to Letter to the Editor on: Tranexamic Acid Does Not Reduce the Risk of Transfusion in Rheumatoid Arthritis Patients Undergoing Total Joint Arthroplasty

JOURNAL OF ARTHROPLASTY 2020 DEC; 35(12):3778-3779
Wang QQ, Conlon EG, Manley JL, Rio DC
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Widespread intron retention impairs protein homeostasis in C9orf72 ALS brains

GENOME RESEARCH 2020 DEC; 30(12):?
The GGGGCC hexanucleotide expansion in C9orf72 (C9) is the most frequent known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet a clear understanding of how C9 fits into the broader context of ALS/FTD pathology has remained lacking. The repetitive RNA derived from the C9 repeat is known to sequester hnRNPH, a splicing regulator, into insoluble aggregates, resulting in aberrant alternative splicing. Furthermore, hnRNPH insolubility and altered splicing of a robust set of targets have been observed to correlate in C9 and sporadic ALS/FTD patients alike, suggesting that changes along this axis are a core feature of disease pathogenesis. Here, we characterize previously uncategorized RNA splicing defects involving widespread intron retention affecting almost 2000 transcripts in C9ALS/FTD brains exhibiting a high amount of sequestered, insoluble hnRNPH. These intron retention events appear not to alter overall expression levels of the affected transcripts but rather the protein-coding regions. These retained introns affect transcripts in multiple cellular pathways predicted to be involved in C9 as well as sporadic ALS/FTD etiology, including the proteasomal and autophagy systems. The retained intron pre-mRNAs display a number of characteristics, including enrichment of hnRNPH-bound splicing enhancer motifs and a propensity for G-quadruplex (G-Q) formation, linking the defective splicing directly to high amounts of sequestered hnRNPH. Together, our results reveal previously undetected splicing defects in high insoluble hnRNPH-associated C9ALS brains, suggesting a feedback between effective RNA-binding protein dosage and protein quality control in C9, and perhaps all, ALS/FTD.
Zheng FW, Georgescu RE, Li HL, O'Donnell ME
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Structure of eukaryotic DNA polymerase 8 bound to the PCNA clamp while encircling DNA

The DNA polymerase (Pol) 8 of Saccharomyces cerevisiae (S.c.) is composed of the catalytic subunit Pol3 along with two regulatory subunits, Pol31 and Pol32. Pol 8 binds to proliferating cell nuclear antigen (PCNA) and functions in genome replication, repair, and recombination. Unique among DNA polymerases, the Pol3 catalytic subunit contains a 4Fe-4S cluster that may sense the cellular redox state. Here we report the 3.2-angstrom cryo-EM structure of S.c. Pol 8 in complex with primed DNA, an incoming ddTTP, and the PCNA clamp. Unexpectedly, Pol 8 binds only one subunit of the PCNA trimer. This singular yet extensive interaction holds DNA such that the 2-nm-wide DNA threads through the center of the 3-nm interior channel of the clamp without directly contacting the protein. Thus, a water-mediated clamp and DNA interface enables the PCNA clamp to "waterskate" along the duplex with minimum drag. Pol31 and Pol32 are positioned off to the side of the catalytic Pol3-PCNA-DNA axis. We show here that Pol31-Pol32 binds single stranded DNA that we propose underlies polymerase recycling during lagging strand synthesis, in analogy to Escherichia coli replicase. Interestingly, the 4Fe-4S cluster in the C-terminal CysB domain of Pol3 forms the central interface to Pol31-Pol32, and this strategic location may explain the regulation of the oxidation state on Pol 8 activity, possibly useful during cellular oxidative stress. Importantly, human cancer and other disease mutations map to nearly every domain of Pol3, suggesting that all aspects of Pol 8 replication are important to human health and disease.
Bar N, Korem T, Weissbrod O, Zeevi D, Rothschild D, Leviatan S, Kosower N, Lotan-Pompan M, Weinberger A, Le Roy CI, Menni C, Visconti A, Falchi M, Spector TD, Adamski J, Franks PW, Pedersen O, Segal E
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A reference map of potential determinants for the human serum metabolome

NATURE 2020 DEC 3; 588(7836):?
The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment(1). The origins of specific compounds are known, including metabolites that are highly heritable(2,3), or those that are influenced by the gut microbiome(4), by lifestyle choices such as smoking(5), or by diet(6). However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites-in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts(7,8) that were not available to us when we trained the algorithms. We used feature attribution analysis(9) to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites. The levels of 1,251 metabolites are measured in 475 phenotyped individuals, and machine-learning algorithms reveal that diet and the microbiome are the determinants with the strongest predictive power for the levels of these metabolites.
Seo JS, Wei J, Qin L, Kim Y, Yan Z, Greengard P
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Cellular and molecular basis for stress-induced depression (vol 22, pg 1440, 2017)

MOLECULAR PSYCHIATRY 2020 DEC; 25(12):3453-3453
Cohen JE, Davis RA, Samorodnitsky G
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Heavy-tailed distributions, correlations, kurtosis and Taylor's Law of fluctuation scaling

Pillai & Meng (Pillai & Meng 2016 Ann. Stat.44, 2089-2097; p. 2091) speculated that 'the dependence among [random variables, rvs] can be overwhelmed by the heaviness of their marginal tails ..'. We give examples of statistical models that support this speculation. While under natural conditions the sample correlation of regularly varying (RV) rvs converges to a generally random limit, this limit is zero when the rvs are the reciprocals of powers greater than one of arbitrarily (but imperfectly) positively or negatively correlated normals. Surprisingly, the sample correlation of these RV rvs multiplied by the sample size has a limiting distribution on the negative half-line. We show that the asymptotic scaling of Taylor's Law (a power-law variance function) for RV rvs is, up to a constant, the same for independent and identically distributed observations as for reciprocals of powers greater than one of arbitrarily (but imperfectly) positively correlated normals, whether those powers are the same or different. The correlations and heterogeneity do not affect the asymptotic scaling. We analyse the sample kurtosis of heavy-tailed data similarly. We show that the least-squares estimator of the slope in a linear model with heavy-tailed predictor and noise unexpectedly converges much faster than when they have finite variances.
Luchsinger LL, Ransegnola BP, Jin DK, Muecksch F, Weisblum Y, Bao WL, George PJ, Rodriguez M, Tricoche N, Schmidt F, Gao CJ, Jawahar S, Pal M, Schnall E, Zhang H, Strauss D, Yazdanbakhsh K, Hillyer CD, Bieniasz PD, Hatziioannou T
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Serological Assays Estimate Highly Variable SARS-CoV-2 Neutralizing Antibody Activity in Recovered COVID-19 Patients

JOURNAL OF CLINICAL MICROBIOLOGY 2020 DEC; 58(12):? Article e02005-20
The development of neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) following infection or vaccination is likely to be critical for the development of sufficient population immunity to drive cessation of the coronavirus disease of 2019 (COVID-19) pandemic. A large number of serologic tests, platforms, and methodologies are being employed to determine seroprevalence in populations to select convalescent plasma samples for therapeutic trials and to guide policies about reopening. However, the tests have substantial variations in sensitivity and specificity, and their ability to quantitatively predict levels of NAbs is unknown. We collected 370 unique donors enrolled in the New York Blood Center Convalescent Plasma Program between April and May of 2020. We measured levels of antibodies in convalescent plasma samples using commercially available SARS-CoV-2 detection tests and in-house enzyme-linked immunosorbent assays (ELISAs) and correlated serological measurements with NAb activity measured using pseudotyped virus particles, which offer the most informative assessment of antiviral activity of patient sera against viral infection. Our data show that a large proportion of convalescent plasma samples have modest antibody levels and that commercially available tests have various degrees of accuracy in predicting NAb activity. We found that the Ortho anti-SARS-CoV-2 total Ig and IgG high-throughput serological assays (HTSAs) and the Abbott SARS-CoV-2 IgG assay quantify levels of antibodies that strongly correlate with the results of NAb assays and are consistent with gold standard ELISA results. These findings provide immediate clinical relevance to serology results that can be equated to NAb activity and could serve as a valuable roadmap to guide the choice and interpretation of serological tests for SARSCoV-2.
Jishage M, Roeder RG
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Regulation of hepatocyte cell cycle re-entry by RNA polymerase II-associated Gdown1

CELL CYCLE 2020 DEC 1; 19(23):3222-3230
Liver is the central organ responsible for whole-body metabolism, and its constituent hepatocytes are the major players that carry out liver functions. Although they are highly differentiated and rarely divide, hepatocytes re-enter the cell cycle following hepatic loss due to liver damage or injury. However, the exact molecular mechanisms underlying cell cycle re-entry remain undefined. Gdown1 is an RNA polymerase II (Pol II)-associated protein that has been linked to the function of the Mediator transcriptional coactivator complex. We recently found that Gdown1 ablation in mouse liver leads to down-regulation of highly expressed liver-specific genes and a concomitant cell cycle re-entry associated with the induction of cell cycle-related genes. Unexpectedly, in view of a previously documented inhibitory effect on transcription initiation by Pol II in vitro, we found that Gdown1 is associated with elongating Pol II on the highly expressed genes and that its ablation leads to a reduced Pol II occupancy that correlates with the reduced expression of these genes. Based on these observations, we discuss the in vitro and in vivo functions of Gdown1 and consider mechanisms by which the dysregulated Pol II recruitment associated with Gdown1 loss might induce quiescent cell re-entry into the cell cycle.
Bournazos S, Corti D, Virgin HW, Ravetch JV
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Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection

NATURE 2020 DEC 17; 588(7838):485-490
Antibodies against viral pathogens represent promising therapeutic agents for the control of infection, and their antiviral efficacy has been shown torequire the coordinated function of both the Fab and Fc domains(1). The Fc domain engages a wide spectrum of receptors on discrete cells of the immune system to trigger the clearance of viruses and subsequent killing of infected cells(1-4). Here we report that Fc engineering of anti-influenza IgG monoclonal antibodies for selective binding to the activating Fc. receptor Fc.RIIa results in enhanced ability to prevent or treat lethal viral respiratory infection in mice, with increased maturation of dendritic cells and the induction of protective CD8(+) T cell responses. These findings highlight the capacity for IgG antibodies to induce protective adaptive immunity to viral infection when they selectively activate a dendritic cell and T cell pathway, with important implications for the development of therapeutic antibodies with improved antiviral efficacy against viral respiratory pathogens.