bluuebunny/crossref_metadata_2025_split huggingface dataset:
QTNet: Predicting Drug-Induced QT prolongation with Deep Neural Networks
Authors: Jethani Neil , Zhang Hao , Chinitz Larry , Aphinyanaphongs Yindalon , Ranganath Rajesh , Jankelson Lior 
Published: March 2021

AbstractBackgroundDrug-induced QTc prolongation (diQTP) is frequent and associated with a risk of sudden cardiac death. Identifying patients at risk of diQTP can enhance monitoring and treatment plans.ObjectiveTo develop a machine learning architecture for prediction of extreme diQTP (QTc >500ms OR ΔQTc >60ms) at the onset of treatment with a QTc prolonging drug.MethodsWe included 4,628 adult patients who received a baseline ECG within 6 months prior to treatment onset with a QTc prolonging drug and a follow-up ECG after the fifth dose. We collected known clinical QTc prolongation risk factors (CF). We developed a novel neural network architecture (QTNet) to predict diQTP from both the CF and baseline ECG data (ECGD), composed of both the ECG waveform and measurements (i.e. QTc),by fusing a state-of-the-art convolution neural network to process raw ECG waveforms with the CF using amulti-layer perceptron. We fit a logistic regression model using the CF, replicating RISQ-PATH as Baseline. We further compared the performance of QTNet (CF+ECGD) to neural network models trained using three variable subsets: a) baseline QTc (QTC-NN), b) CF-NN, and c) ECGD-NN.ResultsdiQTP was present in 1030 patients (22.3%), of which baseline QTc was normal (QTc<450ms:Male/<470ms:Female) in 405 patients (39.3%). QTNet achieved the best performance (Figure 1)(AUROC, 0.802 [95% CI, 0.782-0.820]), outperforming predictions based on the Baseline (AUROC, 0.738 [95%CI, 0.716-0.757]), QTC-NN (AUROC, 0.735 [95% CI, 0.710-0.757]), CF-NN (AUROC, 0.778 [95% CI, 0.757-0.799]), and ECGD-NN (AUROC, 0.774 [95% CI, 0.750-0.794]).ConclusionWe developed QTNet, the first deep learning model for predicting extreme diQTP, outperforming models trained on known clinical risk factors.
Acute and longer-term psychological distress associated with testing positive for COVID-19: longitudinal evidence from a population-based study of US adults
Authors: Daly Michael , Robinson Eric 
Published: March 2021

AbstractBackgroundThe novel coronavirus (SARS-CoV-2) has produced a considerable public health burden but the impact that contracting the disease has on mental health is unclear. In this observational population-based cohort study, we examined longitudinal changes in psychological distress associated with testing positive for COVID-19.MethodsParticipants (N = 8,002; Observations = 139,035) were drawn from 23 waves of the Understanding America Study, a nationally representative survey of American adults followed-up every two weeks from April 1 2020 to February 15 2021. Psychological distress was assessed using the standardized total score on the Patient Health Questionnaire-4 (PHQ-4).ResultsOver the course of the study 576 participants reported testing positive for COVID-19. Using regression analysis including individual and time fixed effects we found that psychological distress increased by 0.29 standard deviations (p<.001) during the two-week period when participants first tested positive for COVID-19. Distress levels remained significantly elevated (d= 0.16, p <.01) for a further two weeks, before returning to baseline levels. Coronavirus symptom severity explained changes in distress attributable to COVID-19, whereby distress was more pronounced among those whose symptoms were more severe and were slower to subside.ConclusionsThis study indicates that testing positive for COVID-19 is associated with an initial increase in psychological distress that diminishes quickly as symptoms subside. While COVID-19 may not produce lasting psychological distress among the majority of the general population it remains possible that a minority may suffer longer-term mental health consequences.
Molecular beacons allow specific RT-LAMP detection of B.1.1.7 variant SARS-CoV-2
Authors: Sherrill-Mix Scott , Duyne Gregory D. Van , Bushman Frederic D. 
Published: March 2021

AbstractOver the course of the COVID-19 pandemic, several SARS-CoV-2 genetic variants of concern have appeared and spread throughout the world. Detection and identification of these variants is important to understanding and controlling their rapid spread. Current detection methods for a particularly concerning variant, B.1.1.7, require expensive qPCR machines and depend on the absence of a signal rather than a positive indicator of variant presence. Here we report an assay using a pair of molecular beacons paired with reverse transcription loop mediated amplification to allow isothermal amplification from saliva to specifically detect B.1.1.7 and other variants which contain a characteristic deletion in the gene encoding the viral spike protein. This assay is specific, affordable and allows multiplexing with other SARS-CoV-2 LAMP primer sets.
The Ophthalmic Surgical Backlog caused by the COVID-19 Pandemic: A population-based and microsimulation modelling study
Authors: Felfeli Tina , Ximenes Raphael , Naimark David MJ , Hooper Philip L , Campbell Robert J , El-Defrawy Sherif R , Sander Beate 
Published: March 2021

AbstractBackgroundJurisdictions worldwide ramped down ophthalmic surgeries to mitigate the effects of coronavirus disease 2019 (COVID-19), creating a global surgical backlog. We sought to predict the long-term impact of COVID-19 on ophthalmology surgical care delivery.MethodsThis is a population-based and a microsimulation modelling study. Provincial administrative data from January 2019 to May 2021 was used to estimate the backlog size and wait-times following the COVID-19 pandemic. For the post-pandemic recovery phase, we estimated the resources required to clear the backlog of patients accumulated on the waitlist during the pandemic.ResultsA total of 56,923 patients were on the waitlist in the province of Ontario awaiting non-emergency ophthalmic surgery as of March 15, 2020. The number of non-emergency surgeries performed in the province decreased by 45-98% from March to May 2020, and 48-80% from April to May 2021 compared to the same months in 2019. By 2 years and 3 years, the overall estimated number of patients awaiting surgery grew by 129% and 150%, respectively. The estimated mean wait-time for patients for all subspecialty surgeries increased to 282 (SD 91) in March 2023 compared to 94 days (SD 97) in 2019. The provincial monthly additional resources required to clear the backlog by March 2023 was estimated to be a 34% escalation from the pre-pandemic volumes (4,626 additional surgeries).InterpretationThe magnitude of the ophthalmic surgical backlog from COVID-19 has important implications for the recovery phase. The estimates from this microsimulation modelling can be adapted to other jurisdictions to assist with recovery planning for vision saving surgeries.
Characterisation of FADD interactome reveals novel insights into FADD recruitment and signalling at the Death Inducing Signalling Complex (DISC)
Authors: Fox Joanna L , Dickens Laura S , Jukes-Jones Rebekah , Miles Gareth J , Langlais Claudia , Cain Kelvin , MacFarlane Marion 
Published: March 2021

AbstractFas-associated death domain protein (FADD) plays a vital role in the extrinsic apoptotic pathway, where it forms an essential component of the death-inducing signaling complex (DISC). However, the precise early molecular events that facilitate recruitment of FADD to the DISC remain poorly defined. Using affinity purification and mass spectrometry we investigated the FADD interactome in untreated cells and following death receptor stimulation to identify novel FADD-interacting proteins. As expected, in death receptor-stimulated samples our analysis identified key components of the DISC such as Caspase-8. In addition, we identified novel binding partners including Transferrin Receptor 1 (TfR1) and Myosin Light Chain Kinase 2 (MYLK2) that are able to modulate FADD recruitment to the DISC and consequently downstream apoptotic signaling. TfR1 is pre-associated with FADD and recruited into the DISC; moreover, our data reveal that TfR1 is also pre-associated with the death receptors, TRAIL-R1 and TRAIL-R2, thereby functioning as a key regulator of DISC formation. In the case of MYLK2, specific binding of FADD to MYLK2 in non-apoptotic cells sequesters FADD from other DISC components ensuring aberrant apoptosis is not initiated. Furthermore, MYLK2 enzymatic activity is required to for it to translocate, in complex with FADD, to sites of DISC-mediated death receptor oligimerization. Taken together, our study highlights the important role that additional novel FADD binding partners play in the regulation of death receptor-mediated apoptotic cell death, in part by modulating FADD recruitment to the DISC.
SINEultaneous profiling of epigenetic heterogeneity and transcriptome in single cells
Authors: Hunt Kooper V , Burnard Sean M , Roper Ellise A , Bond Danielle R , Dun Matthew D , Verrills Nicole M , Enjeti Anoop K , Lee Heather J 
Published: March 2021

ABSTRACTGlobal changes in DNA methylation are observed in developmental and disease contexts, and singlecell analyses are highlighting the heterogeneous regulation of these processes. However, technical challenges associated with single-cell analysis of DNA methylation limit these studies. We present single-cell transposable element methylation sequencing (scTEM-seq) for cost-effective estimation of global DNA methylation levels. By targeting high-copy LINE-1 and SINE Alu elements, we achieve amplicon bisulphite sequencing with thousands of loci covered in each library. Parallel transcriptome analysis is also performed to link global DNA methylation heterogeneity with gene expression. We apply scTEM-seq to KG1a acute myeloid leukaemia (AML) cells, and primary AML cells. Decitabine treatment of KG1a cells induces global DNA methylation heterogeneity associated with altered expression of immune process genes. We also compare global levels of DNA methylation to expression of transposable elements and find a predominance of negative correlations in both the KG1a and patient cells. Finally, we observe co-ordinated upregulation of many transposable elements in a sub-set of decitabine treated cells. By linking global DNA methylation heterogeneity with transcription, scTEM-seq will refine our understanding of epigenetic regulation in cancer and beyond.
Cockayne Syndrome B protein selectively interacts and resolves intermolecular DNA G-quadruplex structures
Authors: Liano Denise , Antonio Marco Di 
Published: March 2021

AbstractGuanine-rich DNA can fold into secondary structures known as G-quadruplexes (G4s). G4s can form from a single DNA-strand (intramolecular) or from multiple DNA-strands (intermolecular), but studies on their biological functions have been often limited to intramolecular G4s, owing to the low probability of intermolecular G4s to form within genomic DNA. Herein, we report that the endogenous protein Cockayne Syndrome B (CSB) binds with picomolar affinity to intermolecular G4s, whilst displaying negligible binding towards intramolecular structures. We also observed that CSB can selectively resolve intermolecular G4s in an ATP independent fashion. Our study demonstrates that intermolecular G4s formed within ribosomal DNA are natural substrates for CSB, strongly suggesting that these structures might be formed in the nucleolus of living cells. Given that CSB loss of function elicits premature ageing phenotypes, our findings indicate that the interaction between CSB and ribosomal DNA intermolecular G4s is essential to maintain cellular homeostasis.
Conserved hormonal and molecular mechanisms underlying behavioural maturation in open- and cavity-nesting honey bees
Authors: Unnikrishnan Sruthi , Shah Aridni , Bais Deepika , Suryanarayanan Ashwin , Brockmann Axel 
Published: March 2021

AbstractDivision of labour in honey bees is based on a process of behavioural development where the worker bee successively performs different tasks at different ages. Workers start with tasks related to brood care and nest maintenance and move on to become foragers. This process of worker behavioural maturation is well studied inApis mellifera. Juvenile hormone is one of the major drivers of this behavioural maturation, which is also accompanied by changes in brain physiology and anatomy including changes in neuronal gene expression and connections of neurons. Recent studies have identified whole networks of genes associated with specific tasks like nursing, guarding and foraging. Based on this detailed knowledge inA. mellifera, we ask whether major characteristics of the behavioural maturation process and the underlying hormonal and molecular changes are similar or different in two other honey bee species, the phylogenetically ancestral open-nestingA. floreaand the more derived cavity-nestingA. cerana. Our behavioural studies show that workers ofA. floreaexhibit a slower pace of behavioural maturation and on average start foraging at a later age. However, the basic hormonal and molecular changes associated with onset of foraging are similar between both species. Based on our findings, we propose that evolution of accelerated behavioural maturation in cavity-nesting species is likely attributed to changes in the temporal dynamics of juvenile hormone titres.
Structural basis for HCMV Pentamer recognition by antibodies and neuropilin 2
Authors: Wrapp Daniel , Ye Xiaohua , Ku Zhiqiang , Su Hang , Jones Harrison G. , Wang Nianshuang , Mishra Akaash K. , Freed Daniel C. , Li Fengsheng , Tang Aimin , Li Leike , Jaijyan Dabbu Kumar , Zhu Hua , Wang Dai , Fu Tong-Ming , Zhang Ningyan , An Zhiqiang , McLellan Jason S. 
Published: March 2021

ABSTRACTHuman cytomegalovirus (HCMV) encodes for multiple surface glycoproteins and glycoprotein complexes1, 2. One of these complexes, the HCMV Pentamer (gH, gL, UL128, UL130 and UL131), mediates tropism to both epithelial and endothelial cells by interacting with the cell surface receptor neuropilin 2 (NRP2)3, 4. Despite the critical nature of this interaction, the molecular determinants that govern NRP2 recognition remain unclear. Here we describe the cryo-EM structure of NRP2 bound to the HCMV Pentamer. The high-affinity interaction between these proteins is calcium-dependent and differs from the canonical C-terminal arginine (CendR) binding that NRP2 typically utilizes5, 6. The interaction is primarily mediated by NRP2 domains a2 and b2, which interact with UL128 and UL131. We also determine the structures of four human-derived neutralizing antibodies in complex with the HCMV Pentamer to define susceptible epitopes. The two most potent antibodies recognize a novel epitope yet do not compete with NRP2 binding. Collectively, these findings provide a structural basis for HCMV tropism and antibody-mediated neutralization, and serve as a guide for the development of HCMV treatments and vaccines.
Performance of generalist hemiparasiticEuphrasiaacross a phylogenetically diverse host spectrum
Authors: Brown Max R. , Moore Paloma G.P. , Twyford Alex D. 
Published: March 2021

SummaryGeneralist hemiparasites may attach to many different host species and experience complex parasite-host interactions. How these parasite-host interactions impact on the fitness of hemiparasitic plants remain largely unknown.We used experimentally tractable eyebrights(Euphrasia,Orobanchaceae) to understand parasite-host interactions affecting the performance of a generalist hemiparasitic plant. Common garden experiments were carried out measuringEuphrasiaperformance across 45 diverse hosts and in different parasite-host combinations.We showed that variation in hemiparasite performance could be attributed mainly to host species and host phylogenetic relationships (λ = 0.82; 0.17-1.00 Cl). When this variation in performance is broken down temporally, annual host species cause earlier flowering, and lead to poorer performance late in the season. WhileEuphrasiaspecies typically perform similarly on a given host species, some eyebrights show more specialised parasite-host interactions.Our results show that generalist hemiparasites only benefit from attaching to a limited, but phylogenetically divergent, subset of hosts. The conserved responses of divergentEuphrasiaspecies suggest hemiparasite performance is affected by common host attributes. However, evidence for more complex parasite-host interactions show that a generalist hemiparasite can potentially respond to individual host selection pressures and may adapt to local host communities.
Modelling The Effect of MUC1 on Influenza Virus Infection Kinetics and Macrophage Dynamics
Authors: Li Ke , Cao Pengxing , McCaw James M. 
Published: March 2021

AbstractMUC1 belongs to the family of cell surface (cs-) mucins. Experimental evidence indicates that its presence reducesin vivoinfluenza viral infection severity. However, the mechanisms by which MUC1 influences viral dynamics and the host immune response are not yet well understood, limiting our ability to predict the efficacy of potential treatments that target MUC1. To address this limitation, we utilize availablein vivokinetic data for both virus and macrophage populations in wildtype and MUC1 knockout mice. We apply two mathematical models of within-host influenza dynamics to this data. The models differ in how they categorise the mechanisms of viral control. Both models provide evidence that MUC1 reduces the susceptibility of epithelial cells to influenza virus and regulates macrophage recruitment. Furthermore, we predict and compare some key infection-related quantities between the two mice groups. We find that MUC1 significantly reduces the basic reproduction number of viral replication as well as the number of cumulative macrophages but has little impact on the cumulative viral load. Our analyses suggest that the viral replication rate in the early stages of infection influences the kinetics of the host immune response, with consequences for infection outcomes, such as severity. We also show that MUC1 plays a strong anti-inflammatory role in the regulation of the host immune response. This study improves our understanding of the dynamic role of MUC1 against influenza infection and may support the development of novel antiviral treatments and immunomodulators that target MUC1.
Integrated population genomic analysis and numerical simulation to estimate larval dispersal of Acanthaster cf. solaris between Ogasawara and other Japanese regions
Authors: Horoiwa Mizuki , Nakamura Takashi , Yuasa Hideaki , Kajitani Rei , Ameda Yosuke , Sasaki Tetsuro , Taninaka Hiroki , Kikuchi Taisei , Yamakita Takehisa , Toyoda Atsushi , Itoh Takehiko , Yasuda Nina 
Published: March 2021

AbstractThe estimation of larval dispersal of marine species occurring on an ecological timescale is significant for conservation. In 2018, a semi-population outbreak of crown of thorns starfish, Acanthaster cf. solaris was observed on a relatively isolated oceanic island, Ogasawara. The aim of this study was to assess whether this population outbreak was caused by large-scale larval recruitment (termed secondary outbreak) from the Kuroshio region. We estimated larval dispersal of the coral predator A. cf. solaris between the Kuroshio and Ogasawara regions using both population genomic analysis and oceanographic dispersal simulation. Population genomic analysis revealed overall genetically homogenized patterns among Ogasawara and other Japanese populations, suggesting that the origin of the populations in the two regions is the same. In contrast, a simulation of 26-year oceanographic dispersal indicated that larvae are mostly self-seeded in Ogasawara populations and have difficulty reaching Ogasawara from the Kuroshio region within one generation. However, a connectivity matrix produced by the larval dispersal simulation assuming a Markov chain indicated gradual larval dispersal migration from the Kuroshio region to Ogasawara in a stepping-stone manner over multiple years. These results suggest that, while large-scale larval dispersal from an outbreak of the Kuroshio population spreading to the Ogasawara population within one generation is unlikely. This study also highlighted the importance of using both genomic and oceanographic methods to estimate larval dispersal, which provides significant insight into larval dispersal that occurs on ecological and evolutionary timescales.
A pipelining mechanism supporting previewing during visual exploration and reading
Authors: Jensen Ole , Pan Yali , Frisson Steven , Wang Lin 
Published: March 2021

AbstractHumans have a remarkable ability to efficiently explore visual scenes and text by means of eye-movements. Humans typically make eye-movements (saccades) every ~250ms. Since the saccadic motor planning and execution takes 100ms this leaves only ~150ms to recognize the fixated object (or word), while simultaneously previewing candidates for the next saccade goal. We propose apipelining mechanismthat efficiently can coordinate visual exploration and reading. The mechanism is timed by alpha oscillations that coordinate the saccades, visual recognition and previewing in the cortical hierarchy. Consequently, the neuronal mechanism supporting visual processing and saccades must be studied in unison to uncover the brain mechanism supporting visual exploration and reading.HighlightsHumans have a remarkable ability to efficiently acquire information from visual scenes and pages of text by means of saccadic exploration.Visual exploration is surprisingly efficient given the temporal and spatial constraints imposed by the visual system. As such, both information from current fixations as well as upcoming locations must be processed within a 150 ms time window.New data recording in humans and non-human primates points to a link between the timing of saccades and alpha oscillations.We present a framework in which visual exploration and reading are supported by similar neuronal mechanisms.We propose a novel mechanism in which visual exploration and reading is supported by a pipelining mechanism organized by alpha oscillations.According to the pipelining mechanism, fixated and previewed objects/words are represented at different phases of an alpha cycle.
Genomic surveillance and phylodynamic analyses reveal emergence of novel mutation and co-mutation patterns within SARS-CoV2 variants prevalent in India
Authors: Biswas Nupur , Mallick Priyanka , Maity Sujay Krishna , Bhowmik Debaleena , Mitra Arpita Ghosh , Saha Soumen , Roy Aviral , Chakrabarti Partha , Paul Sandip , Chakrabarti Saikat 
Published: March 2021

AbstractEmergence of distinct viral clades has been observed in SARS-CoV2 variants across the world and India. Identification of the genomic diversity and the phylodynamic profiles of the prevalent strains of the country are critical to understand the evolution and spread of the variants. We performed whole-genome sequencing of 54 SARS-CoV2 strains collected from COVID-19 patients in Kolkata, West Bengal during August to October 2020. Phylogeographic and phylodynamic analyses were performed using these 54 and other sequences from India and abroad available in GISAID database. Spatio-temporal evolutionary dynamics of the pathogen across various regions and states of India over three different time periods in the year 2020 were analyzed. We estimated the clade dynamics of the Indian strains and compared the clade specific mutations and the co-mutation patterns across states and union territories of India over the time course. We observed that GR, GH and G (GISAID) or 20B and 20A (Nextstrain) clades were the prevalent clades in India during middle and later half of the year 2020. However, frequent mutations and co-mutations observed within the major clades across time periods do not show much overlap, indicating emergence of newer mutations in the viral population prevailing in the country. Further, we explored the possible association of specific mutations and co-mutations with the infection outcomes manifested within the Indian patients.