bluuebunny/crossref_metadata_2025_split huggingface dataset:
Objective olfactory testing in patients presenting with sudden onset olfactory dysfunction as the first manifestation of confirmed COVID-19 infection
Authors: Lechien Jerome R. , Cabaraux Pierre , Chiesa-Estomba Carlos M. , Khalife Mohamad , Plzak Jan , Hans Stéphane , Martiny Delphine , Calvo-Henriquez Christian , Hopkins Claire , Saussez Sven 
Published: April 2020

AbstractBackgroundThe aims of this study are to investigate the COVID-19 status of patients with initial sudden olfactory anosmia (ISOA) using nasopharyngeal swabs for RT-PCR analysis and to explore their olfactory dysfunctions with psychophysical olfactory evaluation.MethodologyThis prospective study included 78 ISOA patients who fulfilled a patient-reported outcome questionnaire and underwent a nasopharyngeal swabs. Among these, 46 patients performed psychophysical olfactory evaluation using sniffing tests. Based on the duration of the ISOA, two groups of patients were compared: patients with anosmia duration ≤12 days (group 1) and those with duration >12 days (group 2).ResultsAmong group 1, 42 patients (87.5%) had a positive viral load regarding RT-PCR while 6 patients (12.5%) were negative. In group 2, 7 patients (23%) had a positive viral load and 23 patients (77%) were negative. Among the 46 patients having performed a psychophysical olfactory evaluation, we observed anosmia in 52% (N=24), hyposmia in 24% (N=11) and normosmia in 24% (N=11) of patients. The viral load significantly decreased throughout the 14-days following the onset of the olfactory disorder.ConclusionsOur results support that a high proportion of ISOA patients are Covid+. Our study supports the need to add anosmia to the list of symptoms used in screening tools for possible COVID-19 infection.
Social Isolation as a predictor for mortality: Implications for COVID-19 prognosis
Authors: Banerjee Sri , Burkholder Gary , Sana Beyan , Szirony G. Mihalyi 
Published: April 2020

AbstractThe health benefits of social support have been widely documented. However, the social distancing practices from the COVID-19 pandemic is causing social disruption on a grand scale, potentially causing poor health outcomes. Through Google Trends analysis, we found a COVID-19-related surge in interest surrounding “loneliness.” We assessed if social isolation and loneliness increase the risk for all-cause and cardiovascular disease (CVD) mortality (ICD-10: I00–I99) and used the data to create a conceptual framework. Using the 10-year overall and cardiovascular mortality follow-up data (n = 12,019) from the National Health and Nutrition Examination Survey (1999–2008), we conducted survival analyses and found that individuals who experience social isolation or loneliness have a significantly higher likelihood of overall and CVD mortality than those without support. These effects generally remained strong with further adjustment for NHANES-detected health and demographic differences showing the need to address COVID-19 related loneliness through increasing social nearing.
Epigenomic profiles of African American Transthyretin Val122Ile carriers reveals putatively dysregulated amyloid mechanisms
Authors: Pathak Gita A , Wendt Frank R , De Lillo Antonella , Nunez Yaira Z. , Goswami Aranyak , De Angelis Flavio , Fuciarelli Maria , Kranzler Henry R , Gelernter Joel , Polimanti Renato 
Published: April 2020

AbstractThe Val122Ile mutation in Transthyretin (TTR) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure and several other non-cardiac phenotypes such as carpal tunnel syndrome, peripheral edema, and arthroplasty which are top reasons for ambulatory/outpatient surgeries in the country. We conducted first-ever epigenome-wide association study in Val122Ile carriers of African descent for heart disease (HD) and multiple outpatient surgeries (OS) - an early disease indicator. Five differentially methylated sites (p≤2.1e-08) in genes – FAM129B, SKI, WDR27, GLS, and an intergenic site near RP11-550A5.2 and one differentially methylated region containing KCNA6 and GALNT3 (p=1.1e-12) were associated with HD. For OS, we observe four sites – two sites in UBE2E3 and SEC14L5, and other two in intergenic regions (p≤1.8e-07) and three regions overlapping SH3D21, EVA1B, LTB4R2 and CIDEB (p≤3.9e-07). Functional PPI module analysis identified ABCA1 (p=0.001) for HS. Six cis-mQTLs were associated with one of the significant CpG sites (FAM129B; p=4.1e-24). We replicated two CpG sites (cg18546846 and cg06641417; p<0.05) in an external cohort of biopsy-confirmed cases of TTR amyloidosis. The genes identified are involved in transport and clearance of amyloid deposits (GLS, ABCA1, FAM129B); cardiac fibrosis (SKI); and muscle tissue regulation (SKI, FAM129B). These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.
The role of motor and environmental visual rhythms in structuring auditory cortical excitability
Authors: O’Connell M.N. , Barczak A. , McGinnis T. , Mackin K. , Mowery T. , Schroeder C.E. , Lakatos P. 
Published: April 2020

SUMMARYOne of the ways we perceive our external world is through the process of active sensing in which biological sensors (e.g. fingers and eyes) sample the environment utilizing mostly rhythmic motor routines. Previous studies indicate that these motor sampling patterns modulate neuronal excitability in sensory brain regions by entraining brain rhythms, a process termed motor-initiated entrainment. Additionally, rhythms of the external environment, that are independent of internal motor commands, are also capable of entraining rhythmic brain activity. The goal of our study was twofold. First, we aimed to investigate the properties of motor-initiated entrainment in the auditory system using the most prominent motor sampling pattern in primates, eye movements. Second, we wanted to determine whether/how motor-initiated entrainment by eye movements interacts with visual environmental entrainment. By examining laminar profiles of neuronal ensemble activity in the primary auditory cortex of non-human primates, we found that while motor-initiated entrainment has a suppressive, visual environmental entrainment has an enhancive effect. We also found that the two processes are temporally coupled during free viewing, and their temporal relationship ensures that their effect on neuronal ensemble excitability is complementary rather than interfering. Taken together, our results provide strong evidence that motor and sensory systems continuously interact in orchestrating the brain’s rhythmic context for the optimal sampling of our multisensory environment.
RNA-seq of Human T-Cells After Hematopoietic Stem Cell Transplantation Identifies Linc00402 as a Novel Regulator of T-Cell Alloimmunity
Authors: Peltier Daniel , Radosevich Molly , Hou Guoqing , Zajac Cynthia , Oravecz-Wilson Katherine , Sokol David , Henig Israel , Wu Julia , Kim Stephanie , Taylor Austin , Fujiwara Hideaki , Sun Yaping , Reddy Pavan 
Published: April 2020

ABSTRACTMechanisms governing allogeneic T-cell responses after allogeneic hematopoietic stem cell (HSC) and solid organ transplantation are incompletely understood. Long non-coding RNAs (lncRNA) do not code for, but control gene expression with tissue specificity. However, their role in T-cell alloimmunity is unknown. We performed RNA-seq on donor T-cells from HSCT patients and found that increasing strength of allogeneic stimulation caused greater differential expression of lncRNAs. The differential expression was validated in an independent patient cohort, and also following ex vivo allogeneic stimulation of healthy human T-cells. Linc00402, a novel, conserved lncRNA, was identified as the most differentially expressed and was enriched 88 fold in human T-cells. Mechanistically, it was mainly located in the cytoplasm, and its expression was rapidly reduced following T-cell activation. Consistent with this, tacrolimus preserved the expression of Linc00402 following T-cell activation, and lower levels of Linc00402 were found in patients who subsequently went on to develop acute graft versus host disease (GVHD). The dysregulated expression of Linc00402 was also validated in murine T-cells, both in vitro and in vivo. Functional studies using multiple modalities to deplete Linc00402 in both mouse and human T-cells, demonstrated a critical role for Linc00402 in the T-cell proliferative response to an allogeneic stimulus but not a non-specific anti-CD3/CD28 stimulus. Thus, our studies identified Linc00402 as a novel, conserved regulator of allogeneic T-cell function. Because of its T-cell specific expression and its impact on allogeneic T-cell responses, targeting Linc00402 may improve outcomes after allogeneic HSC and solid organ transplantation.One sentence summaryLncRNAs are differentially expressed by allogeneic antigen-stimulated T-cells, and the novel lncRNA, Linc00402, is a specific regulator of mouse and human allogeneic T-cells.
Corticostriatal Plasticity Established by Initial Learning Persists After Behavioral Reversal
Authors: Ghosh Sanchari , Zador Anthony M 
Published: April 2020

AbstractThe neural mechanisms that allow animals to adapt their previously learned associations in response to changes in the environment remain poorly understood. To probe the synaptic mechanisms that mediate such adaptive behavior, we trained mice on an auditory-motor reversal task, and tracked changes in the strength of corticostriatal synapses associated with the formation of learned associations. Using a ChR2-based electrophysiological assay in acute striatal slices, we measured the strength of these synapses after animals learned to pair auditory stimuli with specific actions. Here we report that the pattern of synaptic strength initially established by learning remains unchanged even when the task contingencies are reversed. Our results suggest that synaptic changes associated with the initial acquisition of this task are not erased or over-written, and that behavioral reversal of learned associations may recruit a separate neural circuit.
Loss of Caspase-8 function in combination with SMAC mimetic treatment sensitizes Head and Neck Squamous Carcinoma to radiation through induction of necroptosis
Authors: Uzunparmak Burak , Gao Meng , Lindemann Antje , Erikson Kelly , Wang Li , Lin Eric , Frank Steven J. , Gleber-Netto Frederico O. , Zhao Mei , Skinner Heath D. , Newton Jared , Sikora Andrew G. , Myers Jeffrey N. , Pickering Curtis R. 
Published: April 2020

AbstractCaspase-8 (CASP8) is one of the most frequently mutated genes in head and neck squamous carcinomas (HNSCC), and mutations ofCASP8are associated with poor overall survival. The distribution of these mutations in HNSCC suggests that they are likely to be inactivating. Inhibition ofCASP8has been reported to sensitize cancer cells to necroptosis, a unique cell death mechanism. Here, we evaluated howCASP8regulates necroptosis in HSNCC using cell line models and syngeneic mouse xenografts.In vitro, knockdown ofCASP8rendered HNSCCs susceptible to necroptosis induced by a second mitochondria-derived activator of caspase (SMAC) mimetic, Birinapant, when combined with pan-caspase inhibitors Z-VAD-FMK or Emricasan. Strikingly, inhibition ofCASP8function via knockdown or Emricasan treatment was associated with enhanced radiation killing by Birinapant through induction of necroptosis. In a syngeneic mouse model of oral cancer, Birinapant, particularly when combined with radiation delayed tumor growth and enhanced survival underCASP8loss. Exploration of molecular underpinnings of necroptosis sensitivity confirmed that the level of functional receptor-interacting serine/threonine-protein kinase-3 (RIP3), a key enzyme in the necroptosis pathway was crucial in determining susceptibility to this mode of death. Although anin vitroscreen revealed that many HNSCC cell lines were resistant to necroptosis due to low levels of RIP3, patient tumors maintain RIP3 expression and should therefore remain sensitive. Collectively, these results suggest that targeting the necroptosis pathway with SMAC mimetics, especially in combination with radiation, may be a relevant therapeutic approach in HNSCC with compromisedCASP8status, provided that RIP3 function is maintained.SignificanceCASP8status regulates necroptotic death in HNSCC and this pathway can be exploited therapeutically.
Anin silicomap of the SARS-CoV-2 RNA Structurome
Authors: Andrews Ryan J. , Peterson Jake M. , Haniff Hafeez S. , Chen Jonathan , Williams Christopher , Grefe Maison , Disney Matthew D. , Moss Walter N. 
Published: April 2020

AbstractSARS-CoV-2 is a positive-sense single-stranded RNA virus that has exploded throughout the global human population. This pandemic coronavirus strain has taken scientists and public health researchers by surprise and knowledge of its basic biology (e.g. structure/function relationships in its genomic, messenger and template RNAs) and modes for therapeutic intervention lag behind that of other human pathogens. In this report we used a recently-developed bioinformatics approach, ScanFold, to deduce the RNA structural landscape of the SARS-CoV-2 transcriptome. We recapitulate known elements of RNA structure and provide a model for the folding of an essential frameshift signal. Our results find that the SARS-CoV-2 is greatly enriched in unusually stable and likely evolutionarily ordered RNA structure, which provides a huge reservoir of potential drug targets for RNA-binding small molecules. Our results also predict regions that are accessible for intermolecular interactions, which can aid in the design of antisense therapeutics. All results are made available via a public database (the RNAStructuromeDB) where they may hopefully drive drug discovery efforts to inhibit SARS-CoV-2 pathogenesis.
Nonallosteric Sirtuin Enzyme Activation: Characterization of Hit Compounds
Authors: Upadhyay A , Guan X , Munshi S , Chakrabarti R 
Published: April 2020

ABSTRACTMammalian sirtuins (SIRT1-SIRT7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases that play critical roles in lifespan and age-related diseases. The physiological importance of sirtuins has stimulated intense interest in designing sirtuin-activating compounds. However, except for allosteric activators of SIRT1-catalyzed reactions that are limited to particular substrates, a general framework for the design of sirtuin-activating compounds has been lacking. Recently, we introduced a general mode of sirtuin activation that is distinct from the known modes of enzyme activation, establishing biophysical properties of small molecule modulators that can, in principle, result in enzyme activation for various sirtuins and substrates. Here, we characterize small molecules reported in the literature to activate the SIRT3 enzyme using a variety of computational, biochemical and biophysical techniques including protein-ligand docking, molecular dynamics simulation, nonlinear reaction dynamics simulation, kinetic assays and thermodynamic assays with multiple substrates and protocols. In particular, we identify the mechanism of action of the compound honokiol on the human SIRT3 enzyme, modeling its effect on active site conformational degrees of freedom and demonstrating how it nonallosterically activates the human SIRT3 enzyme under physiologically relevant conditions. We show that honokiol constitutes a hit compound for the design of a new generation of nonallosteric activators that can activate SIRT3 through the proposed mechanism-based mode of activation.
Lisdexamfetamine alters BOLD-fMRI activations induced by odor cues in impulsive children
Authors: Hidalgo Tobón Silvia S. , Suárez Pilar Dies , Barragán Pérez Eduardo , Hernández López Javier M. , García Julio , de Celis Alonso Benito 
Published: April 2020

AbstractIntroductionLisdexamfetamine (LDX) is a drug used to treat ADHD/impulsive patients. Impulsivity is known to affect inhibitory, emotional and cognitive function. On the other hand, smell and odor processing are known to be affected by neurological disorders, as they are modulators of addictive and impulsive behaviors specifically. We hypothesize that, after LDX ingestion, inhibitory pathways of the brain would change, and complementary behavioral regulation mechanisms would appear to regulate decision-making and impulsivity.Methods20 children were studied in an aleatory crossover study. Imaging of BOLD-fMRI activity, elicited by olfactory stimulation in impulsive children, was performed after either LDX or placebo ingestion.ResultsFindings showed that all subjects that underwent odor stimulation presented activations of similar intensities in the olfactory centers of the brain. This contrasted with inhibitory regions of the brain such as the cingulate cortex and frontal lobe regions, which demonstrated changed activity patterns and intensities. While some differences between the placebo and medicated states were found in motor areas, precuneus, cuneus, calcarine, supramarginal, cerebellum and posterior cingulate cortex, the main changes were found in frontal, temporal and parietal cortices. When comparing olfactory cues separately, pleasant food smells like chocolate seemed not to present large differences between the medicated and placebo scenarios, when compared to non-food-related smells.ConclusionsWe demonstrated that LDX, first, altered the inhibitory pathways of the brain, second, increased activity in large amounts of brain regions which were not activated by smell in drug-naïve patients, third, facilitated a complementary behavioral regulation mechanism, run by the cerebellum, which regulated decision-making and impulsivity in motor and frontal structures.
Extensive hybridization between pig and humanAscarisidentifies a highly interbred species complex infecting humans
Authors: Easton Alice V. , Gao Shenghan , Lawton Scott P , Bennuru Sasisekhar , Khan Asis , Dahlstrom Eric , Oliveira Rita G , Kepha Stella , Porcella Steve F , Webster Joanne P , Anderson Roy M , Grigg Michael E. , Davis Richard E , Wang Jianbin , Nutman Thomas B 
Published: April 2020

AbstractHuman ascariasis is a major neglected tropical disease caused by the nematodeAscaris lumbricoides. We report a 296 megabase (Mb) reference quality genome comprised of 17902 protein-coding genes derived from a single, representativeAscarisworm collected from 60 human hosts in Kenyan villages where pig husbandry is rare. Notably, the majority of human isolates (63/68) possessed mitochondrial genomes that clustered closer to the pig parasiteAscaris suumthan toA. lumbricoides. Comparative phylogenomic analyses identified over 11 million nuclear-encoded SNPs but just two distinct genetic types that had recombined across the genomes analysed. The nuclear genomes had extensive heterozygosity and all samples existed as genetic mosaics with eitherA. suum-like orA. lumbricoides-like inheritance patterns supporting a highly interbredAscarisspecies genetic complex. As no barriers appear to exist for anthroponotic transmission of these “hybrid” worms, a one-health approach to control the spread of human ascariasis will be necessary.
Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity
Authors: Heer Collin D. , Sanderson Daniel J. , Voth Lynden S. , Alhammad Yousef M.O. , Schmidt Mark S. , Trammell Samuel A.J. , Perlman Stanley , Cohen Michael S. , Fehr Anthony R. , Brenner Charles 
Published: April 2020

ABSTRACTPoly-ADP-ribose polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using nicotinamide adenine dinucleotide (NAD) as the source of ADPR. While the well-known poly-ADP-ribosylating (PARylating) PARPs primarily function in the DNA damage response, many non-canonical mono-ADP-ribosylating (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust upregulation of several PARPs following infection with Murine Hepatitis Virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly upregulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while downregulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+and NADP+. Finally, we show that NAMPT activation, NAM and NR dramatically decrease the replication of an MHV virus that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD, and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.
Distinct Structural Flexibility within SARS-CoV-2 Spike Protein Reveals Potential Therapeutic Targets
Authors: Chen Serena H. , Young M. Todd , Gounley John , Stanley Christopher , Bhowmik Debsindhu 
Published: April 2020

AbstractThe emergence and rapid worldwide spread of the novel coronavirus disease, COVID-19, has prompted concerted efforts to find successful treatments. The causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), uses its spike (S) protein to gain entry into host cells. Therefore, the S protein presents a viable target to develop a directed therapy. Here, we deployed an integrated artificial intelligence with molecular dynamics simulation approach to provide new details of the S protein structure. Based on a comprehensive structural analysis of S proteins from SARS-CoV-2 and previous human coronaviruses, we found that the protomer state of S proteins is structurally flexible. Without the presence of a stabilizing beta sheet from another protomer chain, two regions in the S2 domain and the hinge connecting the S1 and S2 subunits lose their secondary structures. Interestingly, the region in the S2 domain was previously identified as an immunodominant site in the SARS-CoV-1 S protein. We anticipate that the molecular details elucidated here will assist in effective therapeutic development for COVID-19.