bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Covid-19 case mortality rate without time delay systematics
Authors: Lieu Richard , Quenby Siobhan , Jiang Ally Bi-Zhu 
Published: April 2020

AbstractConcerning the two approaches to the Covid-19 case mortality rate published in the literature, namely computing the ratio of (a) the daily number of deaths to a time delayed daily number of confirmed infections; and (b) the cumulative number of deaths to confirmed infections up to a certain time, both numbers having been acquired in the middle of an outbreak, it is shown that each suffers from systematic error of a different source. We further show that in the absence of detailed knowledge of the time delay distribution of (a), the true case mortality rate is obtained by pursuing method (b) at the end of the outbreak when the fate of every case has decisively been rendered. The approach is then employed to calculate the mean case mortality rate of 13 regions of China where every case has already been resolved. This leads to a mean rate of 0.527 ± 0.001 %.
A snapshot of SARS-CoV-2 genome availability up to 30thMarch, 2020 and its implications
Authors: Mavian Carla , Marini Simone , Prosperi Mattia , Salemi Marco 
Published: April 2020

AbstractThe SARS-CoV-2 pandemic has been growing exponentially, affecting nearly 900 thousand people and causing enormous distress to economies and societies worldwide. A plethora of analyses based on viral sequences has already been published, in scientific journals as well as through non-peer reviewed channels, to investigate SARS-CoV-2 genetic heterogeneity and spatiotemporal dissemination. We examined full genome sequences currently available to assess the presence of sufficient information for reliable phylogenetic and phylogeographic studies in countries with the highest toll of confirmed cases. Although number of-available full-genomes is growing daily, and the full dataset contains sufficient phylogenetic information that would allow reliable inference of phylogenetic relationships, country-specific SARS-CoV-2 datasets still present severe limitations. Studies assessing within country spread or transmission clusters should be considered preliminary at best, or hypothesis generating. Hence the need for continuing concerted efforts to increase number and quality of the sequences required for robust tracing of the epidemic.Significance StatementAlthough genome sequences of SARS-CoV-2 are growing daily and contain sufficient phylogenetic information, country-specific data still present severe limitations and should be interpreted with caution.
Long-term development of white matter fibre density and morphology up to 13 years after preterm birth
Authors: Kelly Claire E , Thompson Deanne K , Genc Sila , Chen Jian , Yang Joseph YM , Adamson Chris , Beare Richard , Seal Marc L , Doyle Lex W , Cheong Jeanie LY , Anderson Peter J 
Published: April 2020

AbstractBackgroundIt is well documented that infants born very preterm (VP) are at risk of brain injury and altered brain development in the neonatal period, however there is a lack of long-term, longitudinal studies on the effects of VP birth on white matter development over childhood. Most previous studies were based on voxel-averaged, non-fibre-specific diffusion magnetic resonance imaging (MRI) measures, such as fractional anisotropy. In contrast, the novel diffusion MRI analysis framework, fixel-based analysis (FBA), enables whole-brain analysis of microstructural and macrostructural properties of individual fibre populations at a sub-voxel level. We applied FBA to investigate the long-term implications of VP birth and associated perinatal risk factors on fibre development in childhood and adolescence.MethodsDiffusion images were acquired for a cohort of VP (born <30 weeks’ gestation) and full-term (FT, ≥37 weeks’ gestation) children at two ages: mean (SD) 7.6 (0.2) years (n=138 VP and 32 FT children) and 13.3 (0.4) years (n=130 VP and 45 FT children). 103 VP and 21 FT children had images at both ages for longitudinal analysis. At every fixel (individual fibre population within an image voxel) across the white matter, we compared FBA metrics (fibre density (FD), cross-section (FC) and a combination of these properties (FDC)) between VP and FT groups cross-sectionally at each age, and longitudinally between ages. We also examined associations between perinatal risk factors and FBA metrics in the VP group.ResultsCompared with FT children, VP children had lower FD, FC and FDC throughout the white matter, particularly in the corpus callosum, tapetum, inferior fronto-occipital fasciculus, fornix and cingulum at ages 7 and 13 years, as well as the motor pathways at age 13 years. VP children also had slower FDC development in the corpus callosum and corticospinal tract between ages 7 and 13 years compared with FT children. Within VP children, earlier gestational age at birth, lower birth weight z-score, and neonatal brain abnormalities were associated with lower FD, FC and FDC throughout the white matter at both ages.ConclusionsVP birth and concomitant perinatal risk factors are associated with fibre tract-specific alterations to axonal development in childhood and adolescence.
Viral Induced Genetics Revealed by Multi-Dimensional Precision Medicine Transcriptional Workflow
Authors: Prokop Jeremy W , Gupta Ruchir , Leimanis Mara L. , Nedveck Derek , Shankar Rama , Uhl Katie , Chen Bin , Hartog Nicholas L. , Van Veen Jason , Sisco Joshua S. , Sirpilla Olivia , Lydic Todd , Boville Brian , Hernandez Angel , Braunreiter Chi , Kuk ChiuYing Cynthia , Singh Varinder , Mills Joshua , Wegener Marc , Adams Marie , Rhodes Mary , Bachmann Andre S , Pan Wenjing , Byrne-Steele Miranda L. , Smith D. Casey , Depinet Mollye , Brown Brittany E. , Eisenhower Mary , Han Jian , Haw Marcus , Madura Casey , Sanfilippo Dominic J , Seaver Laurie H. , Bupp Caleb , Rajasekaran Surender 
Published: April 2020

AbstractPrecision medicine requires the translation of basic biological understanding to medical insights, mainly applied to characterization of each unique patient. In many clinical settings, this requires tools that can be broadly used to identify pathology and risks. Patients often present to the intensive care unit with broad phenotypes, including multiple organ dysfunction syndrome (MODS) resulting from infection, trauma, or other disease processes. Etiology and outcomes are unique to individuals, making it difficult to cohort patients with MODS, but presenting a prime target for testing/developing tools for precision medicine. Using multi-time point whole blood (cellular/acellular) total transcriptomics in 27 patients, we highlight the promise of simultaneously mapping viral/bacterial load, cell composition, tissue damage biomarkers, balance between syndromic biology vs. environmental response, and unique biological insights in each patient using a single platform measurement. Integration of a transcriptome workflow yielded unexpected insights into the complex interplay between host genetics and viral/bacterial specific mechanisms, highlighted by a unique case of virally induced genetics (VIG) within one of these 27 patients. The power of RNAseq to study unique patient biology while investigating environmental contributions can be a critical tool moving forward for translational sciences applied to precision medicine.One Sentence SummaryRNAseq shows the potential of a multidimensional workflow to define molecular signatures for precision/individualized medicine within the pediatric intensive care unit, identifying mechanisms such as viral-induced dominant genetics and infection signatures.
Confronting COVID-19: Surging critical care capacity in Italy
Authors: Rodriguez-Llanes Jose M , Delgado Rafael Castro , Pedersen Morten Gram , González Pedro Arcos , Meneghini Matteo 
Published: April 2020

SummaryThe current spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Europe threats Italian’s capacity and that of other national health systems to effectively respond to the needs of patients who require intensive care, mostly due to pneumonia and derived complications from concomitant disease and age. Predicting the surge in capacity has proved difficult due to the requirement of a subtle combination of diverse expertise and difficult choices to be made on selecting robust measures of critical care utilization, and parsimonious epidemic modelling which account for changing government measures. We modelled the required surge capacity of ICU beds in Italy exclusively for COVID-19 patients at epidemic peak. Because new measures were imposed by the Italian government, suspending nearly all non-essential sectors of the economy, we included the potential impacts of these new measures. The modelling considered those hospitalized and home isolated as quarantined, mimicking conditions on the ground. The percentage of patients in intensive care (out of the daily active confirmed cases) required for our calculations were chosen based on clinical relevance and robustness, and this number was consistently on average 9·9% from February 24 to March 6, 2020. Five different scenarios were produced (two positive and three negative). Under most positive scenarios, in which R0 is reduced below 1 (i.e., 0 ·71), the number of daily active confirmed cases will peak at nearly 89 000 by the early days of April and the total number of intensive care beds exclusively dedicated to COVID-19 patients required in Italy estimated at 8791. Worst scenarios produce unmanageable numbers. Our results suggest that the decisive moment for Italy has come. Jointly reinforcement by the government of the measures approved so far, including home confinement, but even more important the full commitment of the civil society in respecting home confinement, social distancing and hygiene will be key in the next days. Yet, even under the best circumstances, intensive care capacity will need to get closer to 9000 units in the country to avoid preventable mortality. So far, only strong measures were effective in Italy, as shown by our modelling, and this may offer an opportunity to European countries to accelerate their interventions.
Disability-Adjusted Life-Years (DALYs) for Breast Cancer and Risk Factors in 195 countries: Findings from Global Burden of Disease Study 2017
Authors: Liu Jieyu , Wang Jiaxiang 
Published: April 2020

AbstractBackgroundBreast cancer is a leading cancer burden for females. In order to picture the patterns and time trends of the breast cancer burden across different regions, the disability-adjusted life years (DALYs) were used to estimate breast cancer burden in 1990–2017.MethodsData from Global Burden of Disease Study 2017 (GBD 2017) was used to estimate the disability-adjusted life-years (DALYs) for the burden of breast cancer by locations, regions, years (with corresponding 95% uncertainty intervals [UI]). Besides, the associated potentially modifiable risk factors were estimated to provide targeted means for controlling the burden of breast cancer.ResultsAll-age numbers of DALYs reached over 17.42 million years in 2017 globally, despite the decreasing trends in all-age and age-standardized rate. The rates for DALYs was the highest in Western Sub-Saharan Africa [694.23 (534.43 to 906.05)] in 2017. High fasting plasma glucose [1.07 million (0.20 to 2.43) DALYs] and high body-mass index (BMI) [0.81 million (0.27 to 1.53) DALYs] have become great attributors to DALYs of breast cancer in 2017.ConclusionsThe levels and trends in causes of DALYs of breast cancer, generally show similiarities between 2007 and 2017, although differences exist. The differences observed countries can be attributed high fasting plasma glucose and high body-mass index across the world. Concerned efforts at national and regional levels are required to tackle the emerging burden of breast cancer in the world.
Topological Analysis of SARS CoV-2 Main Protease
Authors: Estrada Ernesto 
Published: April 2020

AbstractThere is an urgent necessity of effective medication against SARS CoV-2, which is producing the COVID-19 pandemic across the world. Its main protease (Mpro) represents an attractive pharmacological target due to its involvement in essential viral functions. The crystal structure of free Mproshows a large structural resemblance with the main protease of SARS CoV (nowadays known as SARS CoV-1). Here we report that as average SARS CoV-2 Mprois 1900% more sensitive than SARS CoV-1 Mproin transmitting tiny structural changes across the whole protein through long-range interactions. The largest sensitivity of Mproto structural perturbations is located exactly around the catalytic site Cys-145, and coincides with the binding site of strong inhibitors. These findings, based on a simplified representation of the protein as a residue network, may help in designing potent inhibitors of SARS CoV-2 Mpro.The main protease of the new coronavirus SARS CoV-2 represents one of the most important targets for the antiviral pharmacological actions againsts COVID-19. This enzyme is essential for the virus due to its proteolytic processing of polyproteins. Here we discover that the main protease of SARS CoV-2 is topologically very similar to that of the SARS CoV-1. This is not surprising taking into account that both proteases differ only in 12 amino acids. However, we remarkable found a topological property of SARS CoV-2 that has increased in more than 1900% repect to its SARS CoV-1 analogue. This property reflects the capacity of the new protease of transmitting perturbations across its domains using long-range interactions. Also remarkable is the fact that the amino acids displaying such increased sensitivity to perturbations are around the binding site of the new protease, and close to its catalytic site. We also show that this sensititivy to perturbations is related to the effects of powerful protease inhibitors. In fact, the strongest inhibitors of the SARS CoV-2 main protease are those that produce the least change of this capacity of transmitting perturbations across the protein. We think that these findings may help in the design of new potent anti-SARS CoV-2 inhibitors.
Bacterial lipoproteins induce distinct IL-8 inductions relying on their lipid moieties in pulmonary epithelial cells
Authors: Woo Sang Su 
Published: April 2020

AbstractPulmonary epithelial cells play a crucial role in host defense against bacterial insult. However, the innate immunity in pulmonary epithelium is relatively less characterized than that of professional immune cells. In the current study, we investigated IL-8 induction by bacterial cell wall components in human lung epithelial A549 cells and primary human bronchial epithelial cells. We found that lipoproteins are the most potent IL-8 inducers among bacterial cell wall components. Using synthetic lipopeptides that mimic bacterial lipoprotein pam2CSK4 and pam3CSK4, we further investigated signal transduction mechanism. Interestingly, IL-8 secretion appeared higher upon diacylated pam2CSK4 treatment than triacylated pam3CSK4. A role of TLR2 in lipopeptide-induced IL-8 secretion was monitored by siRNA transfection and functional blocking antibodies. We found that TLR2 in A549 cell localizes to intracellular compartment. Activation mechanism for the intracellular TLR2 differed between pam2CSK4 and pam3CSK4. Pam2CSK4 utilized a lipid-raft dependent mechanism while pam3CSK4 utilizes clathrin-dependnet endocytosis. Using CHO/CD14/TLR2 cell line, we found the distinct IL-8 induction level initiates at the receptor activation level. Subsequent pharmacological inhibitor studies showed that pam2CSK4 and pam3CSK4 utilizes different MAPK pathways. Downstream transcription factor activation was determined by electro-mobility shift assay (EMSA) and luciferase reporter assays. The results showed distinct pattern of activation for NF-κB, NF-IL6 and AP-1 from human IL-8 promoter. These results suggest that bacterial lipoproteins from cell walls are an important determinant in initiating tissue inflammation in pulmonary epithelium upon bacterial insult.
Food intake dependent and independent effects of heat stress on lactation and mammary gland development
Authors: Xiao Yao , Kronenfeld Jason M. , Renquist Benjamin J. 
Published: April 2020

ABSTRACTWith a growing population, a reliable food supply is increasingly important. Heat stress reduces livestock meat and milk production. Genetic selection of high producing animals increases endogenous heat production, while climate change increases exogenous heat exposure. Both sources of heat exacerbate the risk of heat-induced depression of production. Rodents are valuable models to understand mechanisms conserved across species. Heat exposure suppresses feed intake across homeothermic species including rodents and production animal species. We assessed the response to early-mid lactation or late gestation heat exposure on milk production and mammary gland development/function, respectively. Using pair-fed controls we experimentally isolated the food intake dependent and independent effects of heat stress on mammary function and mass. Heat exposure (35°C, relative humidity 50%) decreased daily food intake. When heat exposure occurred during lactation, hypophagia accounted for approximately 50% of the heat stress induced hypogalactia. Heat exposure during middle to late gestation suppressed food intake, which was fully responsible for the lowered mammary gland weight of dams at parturition. However, the impaired mammary gland function in heat exposed dams measured by metabolic rate and lactogenesis could not be explained by depressed food consumption. In conclusion, mice recapitulate the depressed milk production and mammary gland development observed in dairy species while providing insight regarding the role of food intake. This opens the potential to apply genetic, experimental and pharmacological models unique to mice to identify the mechanism by which heat is limiting animal production.Summary StatementsThis study demonstrates that heat stress decreases lactation and mammary development through food intake dependent and independent mechanisms.
Virologic and clinical characteristics for prognosis of severe COVID-19: a retrospective observational study in Wuhan, China
Authors: Fu Sha , Fu Xiao-yu , Song Yang , Li Min , Pan Pin-hua , Tang Tao , Zhang Chun-hu , Jiang Tie-jian , Tan De-ming , Fan Xue-gong , Sha Xin-ping , Ma Jing-dong , Huang Yan , Li Sha-ling , Zheng Yi-xiang , Qian Zhao-xin , Xiong Zeng , Xiao Li-zhi , Long Hui-bao , Chen Jiang-hai , Ouyang Yi 
Published: April 2020

ABSTRACTBackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has progressed to a pandemic associated with substantial morbidity and mortality. The WHO and the United States Center for Disease Control and Prevention (CDC) have issued interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19), but there is limited data on the virologic and clinical characteristics for prognosis of severe COVID-19.MethodsA total of 50 patients with severe COVID-19 were divided into good and poor recovery groups. The dynamic viral shedding and serological characteristics of SARS-CoV-2 were explored. The risk factors associated with poor recovery and lung lesion resolutions were identified. In addition, the potential relationships among the viral shedding, the pro-inflammatory response, and lung lesion evolutions were characterized.ResultsA total of 58% of the patients had poor recovery and were more likely to have a prolonged interval of viral shedding. The longest viral shedding was 57 days after symptom onset. Older age, hyperlipemia, hypoproteinemia, corticosteroid therapy, consolidation on chest computed-tomography (CT), and prolonged SARS-CoV-2 IgM positive were all associated with poor recovery. Additionally, the odds of impaired lung lesion resolutions were higher in patients with hypoproteinemia, hyperlipemia, and elevated levels of IL-4 and ferritin. Finally, viral shedding and proinflammatory responses were closely correlated with lung lesion evolutions on chest CT.ConclusionsPatients with severe COVID-19 have prolonged SARS-CoV-2 infection and delayed intermittent viral shedding. Older age, hyperlipemia, hypoproteinemia, corticosteroid usage, and prolonged SARS-CoV-2 IgM positive might be utilized as predicative factors for the patients with poor recovery.
A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease
Authors: Hendrickx Diana M , Garcia Pierre , Ashrafi Amer , Sciortino Alessia , Schmit Kristopher J , Kollmus Heike , Nicot Nathalie , Kaoma Tony , Vallar Laurent , Buttini Manuel , Glaab Enrico 
Published: April 2020

AbstractUnderstanding Parkinson’s disease (PD) in particular in its earliest phases is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful to investigate PD progression. Here, we compare ventral midbrain transcriptomics profiles fromα-synuclein transgenic mice with a progressive, early PD-like striatum neurodegeneration across different ages using pathway, gene set and network analysis methods. Our study uncovers statistically significant altered genes across ages and between genotypes with known, suspected or unknown function in PD pathogenesis and key pathways associated with disease progression. Among those are genotype-dependent alterations associated with synaptic plasticity, neurotransmission, as well as mitochondria-related genes and dysregulation of lipid metabolism. Age-dependent changes were among others observed in neuronal and synaptic activity, calcium homeostasis, and membrane receptor signaling pathways, many of which linked to G-protein coupled receptors. Most importantly, most changes occurred before neurodegeneration was detected in this model, which points to a sequence of gene expression events that may be relevant for disease initiation and progression. It is tempting to speculate that molecular changes similar to those changes observed in our model happen in midbrain dopaminergic neurons before they start to degenerate. In other words, we believe we have uncovered molecular changes that accompany the progression from preclinical to early PD.