bluuebunny/crossref_metadata_2025_split huggingface dataset:
Covasim: an agent-based model of COVID-19 dynamics and interventions
Authors: Kerr Cliff C. , Stuart Robyn M. , Mistry Dina , Abeysuriya Romesh G. , Rosenfeld Katherine , Hart Gregory R. , Núñez Rafael C. , Cohen Jamie A. , Selvaraj Prashanth , Hagedorn Brittany , George Lauren , Jastrzębski Michał , Izzo Amanda , Fowler Greer , Palmer Anna , Delport Dominic , Scott Nick , Kelly Sherrie , Bennette Caroline S. , Wagner Bradley , Chang Stewart , Oron Assaf P. , Wenger Edward , Panovska-Griffiths Jasmina , Famulare Michael , Klein Daniel J. 
Published: May 2020

AbstractThe COVID-19 pandemic has created an urgent need for models that can project epidemic trends, explore intervention scenarios, and estimate resource needs. Here we describe the methodology of Covasim (COVID-19 Agent-based Simulator), an open-source model developed to help address these questions. Covasim includes country-specific demographic information on age structure and population size; realistic transmission networks in different social layers, including households, schools, workplaces, long-term care facilities, and communities; age-specific disease outcomes; and intrahost viral dynamics, including viral-load-based transmissibility. Covasim also supports an extensive set of interventions, including non-pharmaceutical interventions, such as physical distancing and protective equipment; pharmaceutical interventions, including vaccination; and testing interventions, such as symptomatic and asymptomatic testing, isolation, contact tracing, and quarantine. These interventions can incorporate the effects of delays, loss-to-follow-up, micro-targeting, and other factors. Implemented in pure Python, Covasim has been designed with equal emphasis on performance, ease of use, and flexibility: realistic and highly customized scenarios can be run on a standard laptop in under a minute. In collaboration with local health agencies and policymakers, Covasim has already been applied to examine epidemic dynamics and inform policy decisions in more than a dozen countries in Africa, Asia-Pacific, Europe, and North America.
De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy
Authors: Klöckner Chiara , Sticht Heinrich , Zacher Pia , Popp Bernt , Bakker Dewi P. , Barwick Katy , Bonfert Michaela V. , Brilstra Eva H. ,   Care4Rare Canada Consortium, Chung Wendy K. , Clarke Angus J. , Devine Patrick , Friedman Jennifer , Gates Alyssa , Horvath Gabriella , Keller-Ramey Jennifer , Keren Boris , Kurian Manju A. , Lee Virgina , Leppig Kathleen A. , Lundgren Johan , McDonald Marie T. , McTague Amy , Mefford Heather C. , Mignot Cyril , Mikati Mohamad A. , Nava Caroline , Raymond F. Lucy , Sampson Julian R. , Sanchis-Juan Alba , Shashi Vandana , Shieh Joseph T.C. , Shinawi Marwan , Slavotinek Anne , Stödberg Tommy , Stong Nicholas , Sullivan Jennifer A. , Taylor Ashley C. , Toler Tomi L. , van den Bogaard Marie-José , van der Crabben Saskia N. , van Gassen Koen , van Jaarsveld Richard H. , Van Ziffle Jessica , Wadley Alexandrea F. , Wagner Matias , Wortmann Saskia B. , Møller Rikke S. , Lemke Johannes R. , Platzer Konrad 
Published: May 2020

ABSTRACTPurposeThis study aims to provide the first comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25- DEE) by reviewing newly identified and previously reported individuals.MethodsIndividuals harboring heterozygous missense or truncating variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms and literature review. For each individual, detailed phenotyping, classification and structural modeling of the identified variant was performed.ResultsThe cohort comprises 20 individuals with (likely) pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cortical visual impairment and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.ConclusionWe provide a first comprehensive description of SNAP25-DEE with intellectual disability and early onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1 or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed “SNAREopathies”.
Prevalence of Hospital PCR Confirmed COVID-19 Cases in Patients with Chronic Inflammatory and Autoimmune Rheumatic Diseases
Authors: Pablos José L. , Abasolo-Alcázar Lydia , Álvaro-Gracia José M. , Blanco Francisco J. , Blanco Ricardo , Castrejón Isabel , Fernández-Fernández David , Fernández-Gutierrez Benjamín , Galindo María , González-Gay Miguel A. , Manrique-Arija Sara , Mena-Vázquez Natalia , Mera-Varela Antonio , Retuerto Miriam , Seijas-Lopez Álvaro ,   RIER investigators group
Published: May 2020

ABSTRACTBackgroundThe susceptibility of patients with rheumatic diseases, and the risks or benefits of immunosuppressive therapies for COVID-19 are unknown.MethodsWe performed a retrospective study with patients under follow-up in rheumatology departments from seven hospitals in Spain. We matched updated databases of rheumatology patients with SARS-CoV-2 positive PCR tests performed in the hospital to the same reference populations. Rates of PCR+ confirmed COVID-19 were compared among groups.ResultsPatients with chronic inflammatory diseases had 1.32-fold higher prevalence of hospital PCR+ COVID-19 than the reference population (0.76% vs 0.58%). Systemic autoimmune or immune mediated diseases (AI/IMID) patients showed a significant increase, whereas inflammatory arthritis (IA) or systemic lupus erythematosus (SLE) patients did not. COVID-19 cases in some but not all diagnostic groups had older ages than cases in the reference population. IA patients on targeted-synthetic or biological disease-modifying antirheumatic drugs (ts/bDMARD), but not those on conventional-synthetic (csDMARD), had a greater prevalence despite a similar age distribution.ConclusionPatients with AI/IMID show a variable risk of hospital diagnosed COVID-19. Interplay of aging, therapies, and disease specific factors seem to contribute. These data provide a basis to improve preventive recommendations to rheumatic patients and to analyze the specific factors involved in COVID-19 susceptibility.
COVID-19 Pandemic in Pakistan: Stages and Recommendations
Authors: Saif Farhan 
Published: May 2020

AbstractWe present a real-time forecast of COVID-19 in Pakistan that is important for decision-making to control the spread of the pandemic in the country. The study helps to develop an accurate plan to eradicate the COVID-19 by taking calculated steps at the appropriate time, that are crucial in the absence of a tested medicine. We use four phenomenological mathematical models, namely Discrete Exponential Growth model, the Discrete Generalized Growth model, the Discrete Generalized Logistic Growth, and Discrete Generalize Richards Growth model. Our analysis explains the important characteristics quantitatively. The study leads to understand COVID-19 pandemic in Pakistan in three evolutionary stages, and provides understanding to control its spread in the short time domain and in the long term domain. For the reason the study is helpful in devising the measures to handle the emerging threat of similar outbreaks in other countries.
RTEL1 Influences the Abundance and Localization of TERRA RNA
Authors: Ghisays Fiorella , Garzia Aitor , Wang Hexiao , Canasto-Chibuque Claudia , Hohl Marcel , Savage Sharon A. , Tuschl Thomas , Petrini John H. J. 
Published: May 2020

SummaryTelomere repeat containing RNAs (TERRAs) are a family of long non-coding RNAs transcribed from the sub-telomeric regions of eukaryotic chromosomes. TERRA transcripts can form R-loops at chromosome ends; however the importance of these structures or the regulation of TERRA expression and retention in telomeric R-loops remain unclear. Here, we show that the RTEL1 (Regulator of Telomere Length 1) helicase influences the abundance and localization of TERRA in human cells. Depletion of RTEL1 leads to increased levels of TERRA RNA while reducing TERRA-containing R loops at telomeres. In vitro, RTEL1 shows a strong preference for binding G-quadruplex structures which form in TERRA. This binding is mediated by the C-terminal region of RTEL1, and is independent of the RTEL1 helicase domain. RTEL1 binding to TERRA appears to be essential for cell viability, underscoring the importance of this function. Degradation of TERRA containing R-loops by overexpression of RNAse H1 partially recapitulates the increased TERRA levels and telomeric instability associated with RTEL1 deficiency. Collectively, these data suggest that regulation of TERRA at the telomeres is a key function of the RTEL1 helicase, and that loss of that function may contribute to the disease phenotypes of patients with RTEL1 mutations.
Exploiting KRAS-driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC)
Authors: Jiang Honglin , Muir Ryan K. , Gonciarz Ryan L. , Olshen Adam B. , Yeh Iwei , Hann Byron C. , Zhao Ning , Wang Yung-hua , Behr Spencer C. , Korkola James E. , Evans Michael J. , Collisson Eric A. , Renslo Adam R. 
Published: May 2020

AbstractKRASmutations cause a quarter of cancer mortality and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at dosages required to adequately extinguish RAS/RAF/MAPK signaling. We found that oncogenic KRAS signaling induces ferrous iron (Fe2+) accumulation early in and throughout KRAS-mediated transformation. We used an FDA-approved MEK inhibitor to produce a prototypical Ferrous Iron–Activatable Drug Conjugate (FeADC) which achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor bearing animals, with tumor-selective drug activation producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation and FeADCs hold promise for improving treatment of KRAS-driven solid tumors.
Alleviatory effects of Danshen, Salvianolic acid A and Salvianolic acid B on PC12 neuronal cells andDrosophila melanogastermodel of Alzheimer’s disease
Authors: Tan Florence Hui Ping , Ting Andrew Chung Jie , Najimudin Nazalan , Watanabe Nobumoto , Azzam Ghows 
Published: May 2020

AbstractAlzheimer’s disease (AD) is the most common form of neurodegenerative disorder worldwide. Its pathogenesis involves the hallmark aggregation of amyloid-beta (Aβ). Of all the Aβ oligomers formed in the brain, Aβ42 has been found to be the most toxic and aggressive. Despite this, the mechanism behind this disease remains elusive. With the ability to utilize various genetic manipulations,Drosophila melanogasteris ideal in analysing not only cellular characteristics, but also physiological and behavioural traits of human neurodegenerative diseases. Danshen water extract (DWE), obtained from the root ofSalvia miltiorrhizaBunge, was found to have a vast array of beneficial properties. In this study, DWE, and its major components, Salvianolic acid A (SalA) and Salvianolic acid B (SalB) were tested for their abilities to ameliorate Aβ42’s effects. DWE, SalA and SalB were confirmed to be able to reduce fibrillation of Aβ42. As Aβ42 causes neurodegeneration on neurons, DWE, SalA and SalB were tested on Aβ42-treated PC12 neuronal cells and were shown to increase cell viability. DWE and its components were then tested on theDrosophila melanogasterAD model and their rescue effects were further characterized. When human Aβ42 was expressed, theDrosophilaexhibited degenerated eye structures known as the rough eye phenotype (REP), reduced lifespan and deteriorated locomotor ability. Administration of DWE, SalA and SalB partially reverted the REP, increased the age of ADDrosophilaand improved most of the mobility of ADDrosophila. In conclusion, DWE and its components may have therapeutic potential for AD patients and possibly other forms of brain diseases.
Using local convolutional neural networks for genomic prediction
Authors: Pook Torsten , Freudenthal Jan , Korte Arthur , Simianer Henner 
Published: May 2020

ABSTRACTThe prediction of breeding values and phenotypes is of central importance for both livestock and crop breeding. With increasing computational power and more and more data to potentially utilize, Machine Learning and especially Deep Learning have risen in popularity over the last few years. In this study, we are proposing the use of local convolutional neural networks for genomic prediction, as a region specific filter corresponds much better with our prior genetic knowledge of traits than traditional convolutional neural networks. Model performances are evaluated on a simulated maize data panel (n = 10,000) and real Arabidopsis data (n = 2,039) for a variety of traits with the local convolutional neural network outperforming both multi layer perceptrons and convolutional neural networks for basically all considered traits. Linear models like the genomic best linear unbiased prediction that are often used for genomic prediction are outperformed by up to 24%. Highest gains in predictive ability was obtained in cases of medium trait complexity with high heritability and large training populations. However, for small dataset with 100 or 250 individuals for the training of the models, the local convolutional neural network is performing slightly worse than the linear models. Nonetheless, this is still 15% better than a traditional convolutional neural network, indicating a better performance and robustness of our proposed model architecture for small training populations. In addition to the baseline model, various other architectures with different windows size and stride in the local convolutional layer, as well as different number of nodes in subsequent fully connected layers are compared against each other. Finally, the usefulness of Deep Learning and in particular local convolutional neural networks in practice is critically discussed, in regard to multi dimensional inputs and outputs, computing times and other potential hazards.
RosENet: Improving binding affinity prediction by leveraging molecular mechanics energies with a 3D Convolutional Neural Network
Authors: Hassan-Harrirou Hussein , Zhang Ce , Lemmin Thomas 
Published: May 2020

ABSTRACTThe worldwide increase and proliferation of drug resistant microbes, coupled with the lag in new drug development represents a major threat to human health. In order to reduce the time and cost for exploring the chemical search space, drug discovery increasingly relies on computational biology approaches. One key step in these approaches is the need for the rapid and accurate prediction of the binding affinity for potential leads.Here, we present RosENet (RosettaEnergy NeuralNetwork), a three-dimensional (3D) Convolutional Neural Network (CNN), which combines voxelized molecular mechanics energies and molecular descriptors for predicting the absolute binding affinity of protein – ligand complexes. By leveraging the physico-chemical properties captured by the molecular force field, our model achieved a Root Mean Square Error (RMSE) of 1.26 on the PDBBind v2016core set. We also explored some limitations and the robustness of the PDBBind dataset and our approach, on nearly 500 structures, including structures determined by Nuclear Magnetic Resonance and virtual screening experiments. Our study demonstrated that molecular mechanics energies can be voxelized and used to help improve the predictive power of the CNNs. In the future, our framework can be extended to features extracted from other biophysical and biochemical models, such as molecular dynamics simulations.Availabilityhttps://github.com/DS3Lab/RosENet
Probing the functions of microglial cyclin-dependent kinase 5 under physiological and pathological conditions
Authors: Peng Zhuyu , Huang Wen-Chin , Chen Maggie , Penney Jay , Cam Hugh , Abdurrob Fatema , Akay Leyla , Chen Xiao , Ralvenius William T. , Rubino Lorena Pantano , Tsai Li-Huei 
Published: May 2020

AbstractCyclin dependent kinase 5 (Cdk5) regulates various developmental and physiological processes in the central nervous system. Deregulation of Cdk5 activity in neurons induces severe neurodegeneration and has been implicated in Alzheimer’s disease (AD) and other neurodegenerative conditions. A large fraction of AD risk genes are highly expressed in microglia, highlighting an important role for these cells in AD pathogenesis. While Cdk5 function in neurons is well characterized, our understanding of its roles in microglial function under physiological and neurodegenerative conditions remain rudimentary. Here, we investigate the roles of Cdk5 in microglia using myeloid-specific Cdk5 conditional knockout mice. Using microglia-specific transcriptome profiling, histological analyses, and behavioral assessments, we found that knockout of Cdk5 in microglia for 1 month induced transcriptional changes characterized by upregulation of cell cycle processes and type I interferon signaling genes in both physiological conditions and AD-related amyloidogenesis. In contrast to the robust transcriptional changes, conditional loss of microglial Cdk5 produced minimal effects on the density and morphology of microglia and their phagocytic activity toward myelin debris. Moreover, Cdk5cKO mice exhibited little change in synaptic density and tasks associated with locomotor, anxiety-like, and memory-related behaviors. Our findings indicate that the conditional loss of Cdk5 in microglia induces rapid alterations of microglial transcriptome with minimal or delayed effects on histological and behavioral responses.
Integration of haptics and vision in human multisensory grasping
Authors: Camponogara Ivan , Volcic Robert 
Published: May 2020

AbstractGrasping actions are directed not only toward objects we see but also toward objects we both see and touch (multisensory grasping). In this latter case, the integration of visual and haptic inputs improves movement performance compared to each sense alone. This performance advantage could be due to the integration of all the redundant positional and size cues or to the integration of only a subset of these cues. Here we selectively provided specific cues to tease apart how these different sensory sources contribute to visuo-haptic multisensory grasping. We demonstrate that the availability of the haptic positional cue together with the visual cues is sufficient to achieve the same grasping performance as when all cues are available. These findings provide strong evidence that the human sensorimotor system relies on non-visual sensory inputs and open new perspectives on their role in supporting vision during both development and adulthood.
FFA and OFA encode distinct types of face identity information
Authors: Tsantani Maria , Kriegeskorte Nikolaus , Storrs Katherine , Williams Adrian Lloyd , McGettigan Carolyn , Garrido Lúcia 
Published: May 2020

AbstractFaces of different people elicit distinct functional MRI (fMRI) patterns in several face-selective brain regions. Here we used representational similarity analysis to investigate what type of identity-distinguishing information is encoded in three face-selective regions: fusiform face area (FFA), occipital face area (OFA), and posterior superior temporal sulcus (pSTS). We used fMRI to measure brain activity patterns elicited by naturalistic videos of famous face identities, and compared their representational distances in each region with models of the differences between identities. Models included low-level to high-level image-computable properties and complex human-rated properties. We found that the FFA representation reflected perceived face similarity, social traits, and gender, and was well accounted for by the OpenFace model (deep neural network, trained to cluster faces by identity). The OFA encoded low-level image-based properties (pixel-wise and Gabor-jet dissimilarities). Our results suggest that, although FFA and OFA can both discriminate between identities, the FFA representation is further removed from the image, encoding higher-level perceptual and social face information.
Genome-wide analyses of transcription factors and co-regulators across seven cohorts identified reduced PPARGC1A expression as a driver of prostate cancer progression
Authors: Siddappa Manjunath , Wani Sajad A. , Long Mark D. , Leach Damien A , Mathé Ewy A. , Bevan Charlotte L. , Campbell Moray J. 
Published: May 2020

ABSTRACTDefining altered transcription factor (TF) and coregulators that are oncogenic drivers remains a challenge, in part because of the multitude of TFs and coregulators. We addressed this challenge by using bootstrap approaches to test how expression, copy number alterations or mutation of TFs (n = 2662), coactivators (COA; n= 766); corepressor (COR; n = 599); mixed function coregulators (MIXED; n = 511) varied across seven prostate cancer (PCa) cohorts (three of localized and four advanced disease). COAS, CORS, MIXED and TFs all displayed significant down-regulated expression (q.value < 0.1) and correlated with protein expression (ρ 0.4 to 0.55). Stringent expression filtering identified commonly altered TFs and coregulators including well-established (e.g. ERG) and underexplored (e.g.PPARGC1A, encodes PGC1α) in localized PCa. ReducedPPARGC1Aexpression significantly associated with worse disease-free survival in two cohorts of localized PCa. Stable PGC1α knockdown in LNCaP cells increased growth rates and invasiveness and RNA-Seq revealed a profound basal impact on gene expression (~2300 genes; FDR < 0.05, logFC > 1.5), but only modestly impacted PPARγ responses. GSEA analyses of the PGC1α transcriptome revealed that it significantly altered the AR-dependent transcriptome, and was enriched for epigenetic modifiers. PGC1α-dependent genes were overlapped with PGC1α-ChIP-Seq genes and significantly associated in TCGA with higher grade tumors and worse disease-free survival. Together these data demonstrate an approach to identify cancer-driver coregulators in cancer and that PGC1α expression is clinically significant yet underexplored coregulator in aggressive early stage PCa.
Performance and behavioral flexibility on a complex motor task depend on available sensory inputs in early blind and sighted short-tailed opossums
Authors: Englund Mackenzie , Faridjoo Samaan , Iyer Chris , Krubitzer Leah 
Published: May 2020

ABSTRACTThe early loss of vision results in a reorganized visual cortex that processes tactile and auditory inputs. Recent studies in the short-tailed opossum (Monodelphis domestica)found that the connections and response properties of neurons in somatosensory cortex of early blind animals are also altered. While research in humans and other mammals shows that early vision loss leads to heightened abilities on discrimination tasks involving the spared senses, if and how this superior discrimination leads to adaptive sensorimotor behavior has yet to be determined. Moreover, little is known about the extent to which blind animals rely on the spared senses. Here, we tested early blind opossums on a sensorimotor task involving somatosensation and found that they had increased limb placement accuracy. However, increased reliance on tactile inputs in early blind animals resulted in greater deficits in limb placement and behavioral flexibility when the whiskers were trimmed.