bluuebunny/crossref_metadata_2025 huggingface dataset:
National Consumption of Antimalarial Drugs and COVID-19 Deaths Dynamics: An Ecological Study
Authors: Izoulet Maxime
Published: April 2020

COVID-19 (Coronavirus Disease-2019) is an international public health problem with a high rate of severe clinical cases. Several treatments are currently being tested worldwide. This paper focuses on anti-malarial drugs such as chloroquine or hydroxychloroquine, which have been currently reviewed by a systematic study as a good potential candidate and that has been reported as the most used treatment by a recent survey of physicians. We compare the dynamics of COVID-19 death rates in countries using anti-malaria drugs as a treatment from the start of the epidemic versus countries that do not, the day of the 3rd death and the following 10 days. We show that the first group have a much slower dynamic in death rates that the second group. This univariate analysis is of course only one additional piece of evidence in the debate regarding the efficiency of anti-malaria drugs, and it is also limited as the two groups certainly have other systemic differences in the way they responded to the pandemic, in the way they report death or in their population that better explain differences in dynamics (systematic differences that may also explain their choice to rely on anti-malaria drugs in the first place). Nevertheless, the difference in dynamics is so striking that we believe that the urgency context commands presenting the univariate analysis before delving into further analysis. In the end, this data might ultimately be either a piece of evidence in favor or anti-malaria drugs or a stepping stone in understanding further what other ecological aspects place a role in the dynamics of COVID-19 deaths.
The impact of current and future control measures on the spread of COVID-19 in Germany
Authors: Barbarossa Maria Vittoria , Fuhrmann Jan , Meinke Jan H. , Krieg Stefan , Varma Hridya Vinod , Castelletti Noemi , Lippert Thomas
Published: April 2020

The novel coronavirus (SARS-CoV-2), identified in China at the end of December 2019 and causing the disease COVID-19, has meanwhile led to outbreaks all over the globe with about 2.2 million confirmed cases and more than 150,000 deaths as of April 17, 2020 [37]. In view of most recent information on testing activity [32], we present here an update of our initial work [4]. In this work, mathematical models have been developed to study the spread of COVID-19 among the population in Germany and to asses the impact of non-pharmaceutical interventions. Systems of differential equations of SEIR type are extended here to account for undetected infections, as well as for stages of infections and age groups. The models are calibrated on data until April 5, data from April 6 to 14 are used for model validation. We simulate different possible strategies for the mitigation of the current outbreak, slowing down the spread of the virus and thus reducing the peak in daily diagnosed cases, the demand for hospitalization or intensive care units admissions, and eventually the number of fatalities. Our results suggest that a partial (and gradual) lifting of introduced control measures could soon be possible if accompanied by further increased testing activity, strict isolation of detected cases and reduced contact to risk groups.
Keynote 48: Is it really for everyone?
Authors: Schoenfeld Jonathan D. , Fell Geoffrey , Haddad Robert I. , Trippa Lorenzo
Published: April 2020

Burtness et al. recently published the landmark Keynote-48 study, demonstrating a survival benefit for pembrolizumab monotherapy and pembrolizumab/chemotherapy, compared with cetuximab/chemotherapy, in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). These data are impactful and practice-changing, and have rapidly been adopted in practice, with increasing numbers of HNSCC patients receiving either pembrolizumab monotherapy, or pembrolizumab / chemotherapy, in the first line recurrent / metastatic setting. Pembrolizumab was approved as a single agent for patients whose tumors express PD□L1 (Combined Positive Score [CPS] ≥1), while pembrolizumab / chemotherapy was approved for use in the United States for all patients irrespective of PD-L1 expression.
Isolate differences in colonization efficiency during experimental human pneumococcal challenge
Authors: Pojar Sherin , Basset Alan , Gritzfeld Jenna F. , Nikolaou Elissavet , van Selm Saskia , Eleveld Marc J. , Gladstone Rebecca A. , Solórzano Carla , Dalia Ankur B. , German Esther , Mitsi Elena , Connor Victoria , Hyder-Wright Angela D. , Hill Helen , Hales Caz , Chen Tao , Camilli Andrew , Collins Andrea M. , Rylance Jamie , Bentley Stephen D. , Jochems Simon P. , de Jonge Marien I. , Weiser Jeffrey N. , Cleary David W. , Clarke Stuart , Malley Richard , Gordon Stephen B. , Ferreira Daniela M.
Published: April 2020

Colonization efficiency varies considerably between Streptococcus pneumoniae (pneumococcus) strains. The microbial characteristics that influence those differences are still largely unknown. Here, we report rates and kinetics of colonization of four pneumococcal strains upon experimental human pneumococcal challenge. Healthy adults were intranasally challenged with one of four pneumococcal strains (serotype/clonal name: 6B/BHN418, 15B/SH8286, 23F/P1121 and 23F/P833) over a range of doses. Maximum colonization achieved was 60%, 31%, 16% and 10%, respectively. Density and duration of colonization did not differ significantly between the tested strains. We further evaluated murine colonization, non-opsonic neutrophil mediated killing, epithelial cell adherence and average chain length of these four pneumococcal strains. Of these, only chain length was found to be associated with colonization efficiency in the human challenge model. Our data demonstrate that colonization rates following experimental challenge vary with the strain used and suggest that efficiency in colonization is related to pneumococcal chain length.
Variational-LSTM Autoencoder to forecast the spread of coronavirus across the globe
Authors: Ibrahim Mohamed R. , Haworth James , Lipani Aldo , Aslam Nilufer , Cheng Tao , Christie Nicola
Published: April 2020

Modelling the spread of coronavirus globally while learning trends at global and country levels remains crucial for tackling the pandemic. We introduce a novel variational LSTM-Autoencoder model to predict the spread of coronavirus for each country across the globe. This deep spatio-temporal model does not only rely on historical data of the virus spread but also includes factors related to urban characteristics represented in locational and demographic data (such as population density, urban population, and fertility rate), an index that represent the governmental measures and response amid toward mitigating the outbreak (includes 13 measures such as: 1) school closing, 2) workplace closing, 3) cancelling public events, 4) close public transport, 5) public information campaigns, 6) restrictions on internal movements, 7) international travel controls, 8) fiscal measures, 9) monetary measures, 10) emergency investment in health care, 11) investment in vaccines, 12) virus testing framework, and 13) contact tracing). In addition, the introduced method learns to generate graph to adjust the spatial dependences among different countries while forecasting the spread. We trained two models for short and long-term forecasts. The first one is trained to output one step in future with three previous timestamps of all features across the globe, whereas the second model is trained to output 10 steps in future. Overall, the trained models show high validation for forecasting the spread for each country for short and long-term forecasts, which makes the introduce method a useful tool to assist decision and policymaking for the different corners of the globe.
Prevalence and Impact of Myocardial Injury in Patients Hospitalized with COVID-19 Infection
Authors: Lala Anuradha , Johnson Kipp W , Januzzi James , Russak Adam J , Paranjpe Ishan , Zhao Shan , Somani Sulaiman , Vaid Akhil , Chaudhry Fayzan , Freitas Jessica K De , Richter Felix , Fayad Zahi A , Pinney Sean P. , Levin Matthew , Charney Alexander , Bagiella Emilia , Narula Jagat , Glicksberg Benjamin S , Nadkarni Girish , Mancini Donna M. , Fuster Valentin
Published: April 2020

STRUCTURED ABSTRACT

Background

The degree of myocardial injury, reflected by troponin elevation, and associated outcomes among hospitalized patients with Coronavirus Disease (COVID-19) in the US are unknown.

Objectives

To describe the degree of myocardial injury and associated outcomes in a large hospitalized cohort with laboratory-confirmed COVID-19.

Methods

Patients with COVID-19 admitted to one of five Mount Sinai Health System hospitals in New York City between February 27th and April 12th, 2020 with troponin-I (normal value <0.03ng/mL) measured within 24 hours of admission were included (n=2,736). Demographics, medical history, admission labs, and outcomes were captured from the hospitals’ EHR.

Results

The median age was 66.4 years, with 59.6% men. Cardiovascular disease (CVD) including coronary artery disease, atrial fibrillation, and heart failure, was more prevalent in patients with higher troponin concentrations, as were hypertension and diabetes. A total of 506 (18.5%) patients died during hospitalization. Even small amounts of myocardial injury (e.g. troponin I 0.03-0.09ng/mL, n=455, 16.6%) were associated with death (adjusted HR: 1.77, 95% CI 1.39-2.26; P<0.001) while greater amounts (e.g. troponin I>0.09 ng/dL, n=530, 19.4%) were associated with more pronounced risk (adjusted HR 3.23, 95% CI 2.59-4.02).

Conclusions

Myocardial injury is prevalent among patients hospitalized with COVID-19, and is associated with higher risk of mortality. Patients with CVD are more likely to have myocardial injury than patients without CVD. Troponin elevation likely reflects non-ischemic or secondary myocardial injury.

Unstructured Abstract

Myocardial injury reflected as elevated troponin in Coronavirus Disease (COVID-19) is not well characterized among patients in the United States. We describe the prevalence and impact of myocardial injury among hospitalized patients with confirmed COVID-19 and troponin-I measurements within 24 hours of admission (N=2,736). Elevated troponin concentrations (normal <0.03ng/mL) were commonly observed in patients hospitalized with COVID-19, most often present at low levels, and associated with increased risk of death. Patients with cardiovascular disease (CVD) or risk factors for CVD were more likely to have myocardial injury. Troponin elevation likely reflects non-ischemic or secondary myocardial injury.
COVID-19 pandemic scenario in India compared to China and rest of the world: a data driven and model analysis
Authors: Mandal Manisha , Mandal Shyamapada
Published: April 2020

The COVID-19 is a rapidly spreading respiratory illness caused with the infection of SARS-CoV-2. The COVID-19 data from India was compared with China and rest of the world. The average values of daily growth rate (DGR), case recovery rate (CRR), case fatality rate (CFR), serial interval (SI) of COVID-19 in India was 17%, 8.25%, and 1.87%, and 5.76 days respectively, as of April 9, 2020. The data driven estimates of basic reproduction number (R0), average reproduction number (R) and effective reproduction number (Re) were 1.03, 1.73, and 1.35, respectively. The results of exponential and SIR model showed higher estimates of R0, R and Re. The data driven as well as estimated COVID-19 cases reflect the growing nature of the epidemic in India and world excluding China, whereas the same in China reveal the involved population became infected with the disease and moved into the recovered stage. The epidemic size of India was estimated to be ∼30,284 (as of April 15, 2020 with 12,370 infectious cases) with an estimated end of the epidemic on June 9, 2020. The Re values in India before and after lockdown were 1.62 and 1.37 respectively, with SI 5.52 days and 5.98 days, respectively, as of April 17, 2020, reflecting the effectiveness of lockdown strategies. Beyond April 17, 2020, our estimate of 24,431 COVID-19 infected cases with lockdown is 78% lower compared to the 112,042 case estimates in absence of lockdown, on April 27, 2020. To early end of the COVID-19 epidemic, strong social distancing is important.
The Association of Lymphocyte count and levels of CRP, D-Dimer, and LDH with severe coronavirus disease 2019 (COVID-19): A Meta-Analysis
Authors: Ali Almigdad H. M. , Mohamed Sagad Omer Obeid , Elkhidir Ibrahim H. E. , Elbathani Mohamed Elata Hassan , Ibrahim Abazr A. H. , Elhassan Almutasim B. E. , Salman Mohammed Suliman Tawer , Elhassan Mazin A.M. , Elnil Mahmoud , Abuzied Abdelhamid Ibrahim Hassan
Published: April 2020

The rapid progression of Coronavirus disease 2019 (COVID-19) and its increasing burden on health systems necessitate the identification of parameters of severe infection to help in monitoring, prognoses and development of treatment algorithms. This review aims to investigate the association of lymphocyte count, CRP, LDH, and D-Dimer with the severe form of COVID-19. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases of MEDLINE/PubMed, WHO-Virtual Health Library (VHL), and ScienceDirect were used for the systematic search. Random effects model was used to estimate the pooled standardized mean differences (SMD) with the corresponding 95% confidence interval (CI), using OpenMeta Analyst software. A total of 11 studies, with 2437 COVID-19 patients, which fulfilled the eligibility criteria were included in the meta-analysis. The analysis revealed that lymphocyte count was significantly lower in patients with the severe form of COVID-19 (SMD = - 1.025, P value <.001). Also, the analysis of SMD showed that patients with severe COVID-19 have a significantly higher serum levels of CRP (SMD = 3.363, P value <.001), D-Dimer (SMD = 1.073, P value <.001), and LDH (SMD = 3.345, P value <.001). Low lymphocyte count and high levels of CRP, LDH, and D-Dimer are associated with severe COVID-19. These laboratory markers could be used as clinical indicators of worsening illness and poor prognosis of COVID-19.
African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer
Authors: Karunamuni Roshan , Huynh-Le Minh-Phuong , Fan Chun , Thompson Wesley , Eeles Rosalind , Kote-Jarai Zsofia , Muir Kenneth ,   UKGPCS collaborators, Lophatananon Artitaya , Tangen Catherine , Goodman Phyllis , Thompson Ian , Blot William , Zheng Wei , Kibel Adam , Drake Bettina , Cussenot Olivier , Cancel-Tassin Geraldine , Menegaux Florence , Truong Therese , Park Jong , Lin Hui-Yi , Bensen Jeannette , Fontham Elizabeth , Mohler James , Taylor Jack , Multigner Luc , Blanchet Pascal , Brureau Laurent , Romana Marc , Leach Robin , John Esther , Fowke Jay , Bush William , Aldrich Melinda , Crawford Dana , Srivastava Shiv , Cullen Jennifer , Petrovics Gyorgy , Parent Marie-Elise , Hu Jennifer , Sanderson Maureen , Mills Ian , Andreassen Ole , Dale Anders , Seibert Tyler M ,   The PRACTICAL Consortium
Published: April 2020

Introduction

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46), showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify SNPs that might improve performance in this population.

Material and Methods

Anonymized genotypic data were obtained from the PRACTICAL consortium for 6,253 men with African genetic ancestry. Ten iterations of a ten-fold cross-validation search were conducted, to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African were compared using the same cross-validated approach.

Results

Three SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53).

Conclusions

We identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans and Asians. A strategy of building on established statistical models might benefit ancestral groups generally under-represented in genome-wide association studies.
Evolution of reproductive traits have no apparent life-history associated cost in populations ofDrosophila melanogasterselected for cold shock resistance
Authors: Singh Karan , Prasad Nagaraj Guru
Published: April 2020

In insect species likeDrosophila melanogaster, the ability to evolve greater resistance or evolution of certain traits under specific environmental conditions leads to energy trade-offs with other important life-history traits. A number of studies from multiple fields have documented the life-history associated cost. However, no known studies have assessed the life-history associated cost with evolved reproductive traits and increase egg viability in cold shock selected population. To explore this, we used replicate populations ofD. melanogasterthat have evolved reproductive traits and egg viability in response to increased resistance to non lethal cold shock. To assess life-history cost; we measured longevity, life time fecundity, Larvae to adults development time, and larvae to adults survival. We found that there were no significant differences in longevity, life time fecundity, larvae to adults survival, and male body weight between the selected and control populations. However, selected populations have significantly longer pre adults developmental time compared to their control population. Females from the selected populations were bigger in size compared to the control populations. These findings suggest that there is no life-history cost associated with the evolution of greater resistance in the aspect of faster recovery of egg viability and reproductive traits post cold-shock. It quite possible the cost of the evolution of reproductive traits and egg viability in response to cold shock resistant is paid in terms of reduced resistance to other stresses
Bidirectional pharmacological perturbations of the noradrenergic system differentially affect tactile detection
Authors: McBurney-Lin Jim , Sun Yina , Tortorelli Lucas S. , Nguyen Quynh Anh , Haga-Yamanaka Sachiko , Yang Hongdian
Published: April 2020

The brain neuromodulatory systems heavily influence behavioral and cognitive processes. Previous work has shown that norepinephrine (NE), a classic neuromodulator mainly derived from the locus coeruleus (LC), enhances neuronal responses to sensory stimuli. However, the role of the LC-NE system in modulating perceptual task performance is not well understood. In addition, systemic perturbation of NE signaling has often been proposed to specifically target the LC in functional studies, yet the assumption that localized (specific) and systemic (nonspecific) perturbations of LC-NE have the same behavioral impact remains largely untested. In this study, we trained mice to perform a head-fixed, quantitative tactile detection task, and administered an α2 adrenergic receptor agonist or antagonist to pharmacologically down- or up-regulate LC-NE activity, respectively. We addressed the outstanding question of how bidirectional perturbations of LC-NE activity affect tactile detection, and tested whether localized and systemic drug treatments exert the same behavioral effects. We found that both localized and systemic suppression of LC-NE impaired tactile detection by reducing motivation. Surprisingly, while locally activating LC-NE enabled mice to perform in a near-optimal regime, systemic activation impaired behavior by promoting impulsivity. Our results demonstrate that localized silencing and activation of LC-NE differentially affect tactile detection, and that localized and systemic NE activation induce distinct behavioral changes.
Unifying the mechanism of mitotic exit control in a spatio-temporal logical model
Authors: Howell R. S. M. , Klemm C. , Thorpe P. H. , Csikász-Nagy A.
Published: April 2020

1

The transition from mitosis into the first gap phase of the cell cycle in budding yeast is controlled by the Mitotic Exit Network (MEN). The network interprets spatio-temporal cues about the progression of mitosis and ensures that release of Cdc14 phosphatase occurs only after completion of key mitotic events. The MEN has been studied intensively however a unified understanding of how localization and protein activity function together as a system is lacking. In this paper we present a compartmental, logical model of the MEN that is capable of representing spatial aspects of regulation in parallel to control of enzymatic activity. Through optimization of the model, we reveal insights into role of Cdc5 in Cdc15 localization and the importance of Lte1 regulation in control of Bfa1. We show that our model is capable of correctly predicting the phenotype of∼80% of mutants we tested, including mutants representing mislocalizing proteins. We use a continuous time implementation of the model to demonstrate the role of Cdc14 Early Anaphase Release (FEAR) to ensure robust timing of anaphase and verify our findings in living cells. We show that our model can represent measured cell-cell variation in Spindle Position Checkpoint (SPoC) mutants. Finally, we use the model to predict the impact of forced localization of MEN proteins and validate these predictions experimentally. This model represents a unified view of the mechanism of mitotic exit control.
Combining eye tracking with EEG: Effects of filter settings on EEG for trials containing task relevant eye-movements
Authors: Kulke Louisa , Kulke Vincent
Published: April 2020

Co-registration of electroencephalography (EEG) and eye movements is becoming increasingly popular, as technology advances. This new method has several advantages, including the possibility of testing non-verbal populations and infants. However, eye movements can create artefacts in EEG data. Previous methods to remove eye-movement artefacts, have used high-pass filters before data processing. However, the role of filter settings for eye-artefact exclusion has not directly been investigated. The current study examined the effect of filter settings on EEG recorded in a dataset containing task-relevant eye movements. Part 1 models the effects of filters on eye-movement artifacts and part 2 demonstrates this effect on an EEG dataset containing task-relevant eye-movements. It shows that high-pass filters can lead to significant distortions and create artificial responses that are unrelated to the target. In conclusion, high-pass filter settings of 0.1 or lower can be recommended for EEG studies involving task-relevant eye movements.

Highlights

Co-registration of EEG and eye-tracking is gaining popularity

However, eye movements can create artifacts in the EEG signal

The current paper models the effect of high pass filters on eye-movement artifacts

High pass filters can induce large distortions in EEG data containing regular eye-movements

The distortion is affected by fixation duration and filter frequency
Lipid specificity of the immune effector perforin
Authors: Hodel Adrian W. , Rudd-Schmidt Jesse A. , Trapani Joseph A. , Voskoboinik Ilia , Hoogenboom Bart W.
Published: April 2020

Perforin is a pore forming protein used by cytotoxic T lymphocytes to remove cancerous or virus-infected cells during immune response. During the response, the lymphocyte membrane becomes refractory to perforin function by accumulating densely ordered lipid rafts and externalizing negatively charged lipid species. The dense membrane packing lowers the capacity of perforin to bind, and negatively charged lipids scavenge any residual protein before pore formation. Using atomic force microscopy on model membrane systems, we here provide insight into the molecular basis of perforin lipid specificity.
Fused in sarcoma regulates DNA replication timing and progression
Authors: Jia Weiyan , Scalf Mark A. , Tonzi Peter , Millikin Robert J. , Kim Sang Hwa , Guns William M. , Liu Lu , Mastrocola Adam S. , Smith Lloyd M. , Huang Tony T. , Tibbetts Randal S.
Published: April 2020

Fused in sarcoma (FUS) encodes a low complexity RNA-binding protein with diverse roles in transcriptional activation and RNA processing. While oncogenic fusions of FUS and transcription factor DNA-binding domains are associated with soft tissue sarcomas, dominant mutations in FUS cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). FUS has also been implicated in DNA double-strand break repair (DSBR) and genome maintenance. However, the underlying mechanisms are unknown. Here we employed quantitative proteomics, transcriptomics, and DNA copy number analysis (Sort-Seq), in conjunction withFUS-/-cells to ascertain roles of FUS in genome protection.FUS-/-cells exhibited alterations in the recruitment and retention of DSBR factors BRCA1 and 53BP1 but were not overtly sensitive to genotoxins. By contrast, FUS-deficient cells had reduced proliferative potential that correlated with reduced replication fork speed, diminished loading of pre-replication complexes, and attenuated expression of S-phase associated genes. FUS interacted with lagging strand DNA synthesis factors and other replisome components, but did not translocate with active replication forks. Using a Sort-Seq workflow, we show that FUS contributes to genome-wide control of DNA replication timing and is essential for the early replication of transcriptionally active DNA. These findings illuminate new roles for FUS in DNA replication initiation and timing that may contribute to genome instability and functional defects in cells harboring disease-associated FUS fusions.
Sequence-dependent correlated segments in the intrinsically disordered region of ChiZ
Authors: Hicks Alan , Escobar Cristian A. , Cross Timothy A. , Zhou Huan-Xiang
Published: April 2020

Intrinsically disordered proteins (IDPs) account for a significant fraction of any proteome and are central to numerous cellular functions. Yet how sequences of IDPs code for their conformational dynamics is poorly understood. Here we combined NMR spectroscopy, small-angle X-ray scattering (SAXS), and molecular dynamics (MD) simulations to characterize the conformations and dynamics of ChiZ1-64. This IDP is the N-terminal fragment (residues 1-64) of the transmembrane protein ChiZ, a component of the cell division machinery inMycobacterium tuberculosis. Its N-half contains most of the prolines and all of the anionic residues while the C-half most of the glycines and cationic residues. MD simulations, first validated by SAXS and secondary chemical shift data, found scant α-helices or β-strands but considerable propensity for polyproline II (PPII) torsion angles. Importantly, several blocks of residues (e.g., 11-29) emerge as “correlated segments”, identified by frequent formation of PPII stretches, salt bridges, cation-π interactions, and sidechain-backbone hydrogen bonds. NMR relaxation experiments showed non-uniform transverse relaxation rates (R2s) and nuclear Overhauser enhancements (NOEs) along the sequence (e.g., highR2s and NOEs for residues 11-14 and 23-28). MD simulations further revealed that the extent of segmental correlation is sequence-dependent: segments where internal interactions are more prevalent manifest elevated “collective” motions on the 5-10 ns timescale and suppressed local motions on the sub-ns timescale. Amide proton exchange rates provides corroboration, with residues in the most correlated segment exhibiting the highest protection factors. We propose correlated segment as a defining feature for the conformation and dynamics of IDPs.
Tumor secreted extracellular vesicles regulate T-cell costimulation and can be manipulated to induce tumor specific T-cell responses
Authors: Zhao Xianda , Yuan Ce , Wangmo Dechen , Subramanian Subbaya
Published: April 2020

Tumor intrinsic factors negatively regulate tumor immune cell infiltration and function. Deciphering the underlying mechanisms is critical to improving immunotherapy in cancers. Our analyses of human colorectal cancer (CRC) immune profiles and tumor-immune cell interactions revealed that tumor cell secreted extracellular vesicles (TEVs) induced immunosuppression in CRC. Specifically, TEVs containing microRNA miR-424 suppressed the CD28-CD80/86 costimulatory pathway in tumor infiltrating T cells and dendritic cells. Modified TEVs with miR-424 knocked down enhanced T-cell mediated antitumor immune response in CRC tumor models and increased the response to immune checkpoint blockade therapies (ICBT). Intravenous injections of modified TEVs induced tumor antigen specific immune responses. Moreover, injections of modified TEVs boosted the ICBT efficacy in CRC models that mimic treatment refractory late-stage disease. Collectively, we demonstrate a critical role for TEVs in antitumor immune regulation and immunotherapy response, which could be developed as a novel treatment for ICBT resistant human CRC.
Side-Impact Collision: Mechanics of Obstacle Negotiation in Sidewinding Snakes
Authors: Astley Henry C. , Rieser Jennifer M. , Kaba Abdul , Paez Veronica M. , Tomkinson Ian , Mendelson Joseph R. , Goldman Daniel I.
Published: April 2020

Snakes excel at moving through cluttered environments, and heterogeneities can be used as propulsive contacts for snakes performing lateral undulation. However, sidewinding, often associated with sandy deserts, cuts a broad path through the environment that may increase the vulnerability to obstacles. Our prior work demonstrated that sidewinding can be represented as a pair of orthogonal body waves (vertical and horizontal) that can be independently modulated to achieve high maneuverability and incline ascent, suggesting that sidewinders may also use template modulations to negotiate obstacles. To test this hypothesis, we recorded overhead video of four sidewinder rattlesnakes(Crotalus cerastes)crossing a line of vertical pegs placed in the substrate. Snakes used three methods to traverse the obstacles: a Propagate Through behavior in which the lifted moving portion of the snake was deformed around the peg and dragged through as the snake continued sidewinding (115/160 runs), Reversal turns that reorient the snake entirely (35/160), or switching to Concertina locomotion (10/160). The Propagate-Through response was only used if the anterior-most region of static contact would propagate along a path anterior to the peg, or if a new region of static contact could be formed near the head to satisfy this condition; otherwise, snakes could only use Reversal Turns or switch to Concertina locomotion. Reversal Turns allowed the snake to re-orient and either escape without further peg contact or resorting to Propagate Through. We developed an algorithm to reproduce the Propagate Through behavior in a robotic model using a modulation of the two-wave template. This range of behavioral strategies provides sidewinders with a versatile range of options for effectively negotiating obstacles in their natural habitat, as well as provide insights into the design and control of robotic systems dealing with heterogeneous habitats.
Item recognition and lure discrimination in younger and older adults are supported by alpha/beta desynchronization
Authors: Karlsson Anna E. , Wehrspaun Claudia C. , Sander Myriam C.
Published: April 2020

Our episodic memories vary in their specificity, ranging from a mere sense of familiarity to detailed recollection of the initial experience. Recent work suggests that alpha/beta desynchronization promotes information flow through the cortex, tracking the richness in detail of recovered memory representations. At the same time, as we age, memories become less vivid and detailed, which may be reflected in age-related reductions in alpha/beta desynchronization during retrieval. To understand age differences in the specificity of episodic memories, we investigated differences in alpha/beta desynchronization between younger (18–26 years,n= 31) and older (65–76 years,n= 27) adults during item recognition and lure discrimination.

Alpha/beta desynchronization increased linearly with the demand for memory specificity, i.e., the requirement to retrieve details for an accurate response, across retrieval situations (correct rejections < item recognition < lure discrimination). Stronger alpha/beta desynchronization was related to memory success, as indicated by reliable activation differences between correct and incorrect memory responses. In line with the assumption of a loss of mnemonic detail in older age, older adults had more difficulties than younger adults to discriminate lures from targets. Importantly, they also showed a reduced modulation of alpha/beta desynchronization across retrieval demands. Together, these results extend previous findings by demonstrating that alpha/beta desynchronization dissociates between item recognition and the retrieval of highly detailed memories as required in lure discrimination, and that age-related impairments in episodic retrieval are accompanied by attenuated modulations in the alpha/beta band. Thus, we provide novel findings suggesting that alpha/beta desynchronization tracks mnemonic specificity and that changes in these oscillatory mechanisms may underlie age-related declines in episodic memory.
Deconvolution of Cell Type-Specific Drug Responses in Human Tumor Tissue with Single-Cell RNA-seq
Authors: Zhao Wenting , Dovas Athanassios , Spinazzi Eleonora Francesca , Levitin Hanna Mendes , Upadhyayula Pavan , Sudhakar Tejaswi , Marie Tamara , Otten Marc L. , Sisti Michael , Bruce Jeffrey N. , Canoll Peter , Sims Peter A.
Published: April 2020

Precision oncology requires the timely selection of effective drugs for individual patients. An ideal platform would enable rapid screening of cell type-specific drug sensitivities directly in patient tumor tissue and reveal strategies to overcome intratumoral heterogeneity. Here we combine multiplexed drug perturbation in acute slice culture from freshly resected tumors with single-cell RNA sequencing (scRNA-seq) to profile transcriptome-wide drug responses. We applied this approach to glioblastoma (GBM) and demonstrated that acute slice cultures from individual patients recapitulate the cellular and molecular features of the originating tumor tissue. Detailed investigation of etoposide, a topoisomerase poison, and the histone deacetylase (HDAC) inhibitor panobinostat in acute slice cultures revealed cell type-specific responses across multiple patients, including unexpected effects on the immune microenvironment. We anticipate that this approach will facilitate rapid, personalized drug screening to identify effective therapies for solid tumors.
Obtaining leaner deep neural networks for decoding brain functional connectome in a single shot
Authors: Gupta Sukrit , Chan Yi Hao , Rajapakse Jagath C. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: April 2020

Neuroscientific knowledge points to the presence of redundancy in the correlations of brain’s functional activity. These redundancies can be removed to mitigate the problem of overfitting when deep neural network (DNN) models are used to classify neuroimaging datasets. We propose an algorithm that removes insignificant nodes of DNNs in a layerwise manner and then adds a subset of correlated features in a single shot. When performing experiments with functional MRI datasets for classifying patients from healthy controls, we were able to obtain simpler and more generalizable DNNs. The obtained DNNs maintained a similar performance as the full network with only around 2% of the initial trainable parameters. Further, we used the trained network to identify salient brain regions and connections from functional connectome for multiple brain disorders. The identified biomarkers were found to closely correspond to previously known disease biomarkers. The proposed methods have cross-modal applications in obtaining leaner DNNs that seem to fit the data better. The corresponding code is available athttps://github.com/SCSE-Biomedical-Computing-Group/LEAN_CLIP.
Common brain networks between major depressive disorder and symptoms of depression that are validated for independent cohorts
Authors: Yamashita Ayumu , Sakai Yuki , Yamada Takashi , Yahata Noriaki , Kunimatsu Akira , Okada Naohiro , Itahashi Takashi , Hashimoto Ryuichiro , Mizuta Hiroto , Ichikawa Naho , Takamura Masahiro , Okada Go , Yamagata Hirotaka , Harada Kenichiro , Matsuo Koji , Tanaka Saori C , Kawato Mitsuo , Kasai Kiyoto , Kato Nobumasa , Takahashi Hidehiko , Okamoto Yasumasa , Yamashita Okito , Imamizu Hiroshi
Published: April 2020

Many studies have highlighted the difficulty inherent to the clinical application of fundamental neuroscience knowledge based on machine learning techniques. It is difficult to generalize machine learning brain markers to the data acquired from independent imaging sites, mainly due to large site differences in functional magnetic resonance imaging. We address the difficulty of finding a generalizable major depressive disorder (MDD) brain network markers which would distinguish patients from healthy controls (a classifier) or would predict symptom severity (a prediction model) based on resting state functional connectivity patterns. For the discovery dataset with 713 participants from 4 imaging sites, we removed site differences using our recently developed harmonization method and developed a machine learning MDD brain network markers. The classifier achieved 70% generalization accuracy, and the prediction model moderately well predicted symptom severity for an independent validation dataset with 449 participants from 4 different imaging sites. Finally, we found common 2 functional connections between those related to MDD diagnosis and those related to depression symptoms. The successful generalization to the perfectly independent dataset acquired from multiple imaging sites is novel and ensures scientific reproducibility and clinical applicability.
Mechanism of NanR gene repression and allosteric induction of bacterial sialic acid metabolism
Authors: Horne Christopher R. , Venugopal Hariprasad , Panjikar Santosh , Henrickson Amy , Brookes Emre , North Rachel A. , Murphy James M. , Friemann Rosmarie , Griffin Michael D.W. , Ramm Georg , Demeler Borries , Dobson Renwick C.J.
Published: April 2020

Bacteria respond to environmental changes by inducing transcription of some genes and repressing others. Sialic acids, which coat human cell surfaces, are a nutrient source for pathogenic and commensal bacteria. TheEscherichia coliGntR-type transcriptional repressor, NanR, regulates sialic acid metabolism, but the mechanism is unclear. Here, we demonstrate that three NanR dimers bind a (GGTATA)3-repeat operator cooperatively and with high affinity. Truncation of an N-terminal extension abolishes cooperative binding. The effector,N-acetylneuraminate, binds NanR and attenuates DNA binding. Crystal structure data show thatN-acetylneuraminate binding to NanR causes a domain rearrangement that locks the protein in a conformation that prevents DNA binding. Single-particle cryo-electron microscopy structures of NanR bound to DNA reveal the DNA binding domain is reorganized to engage DNA, while the three dimers assemble in close proximity across the (GGTATA)3-repeat operator allowing protein-protein interactions to formviathe N-terminal extensions. Our data provides a molecular basis for the regulation of bacterial sialic acid metabolism.
scConsensus: combining supervised and unsupervised clustering for cell type identification in single-cell RNA sequencing data
Authors: Ranjan Bobby , Schmidt Florian , Sun Wenjie , Park Jinyu , Honardoost Mohammad Amin , Tan Joanna , Rayan Nirmala Arul , Prabhakar Shyam
Published: April 2020

Clustering is a crucial step in the analysis of single-cell data. Clusters identified using unsupervised clustering are typically annotated to cell types based on differentially expressed genes. In contrast, supervised methods use a reference panel of labelled transcriptomes to guide both clustering and cell type identification. Supervised and unsupervised clustering strategies have their distinct advantages and limitations. Therefore, they can lead to different but often complementary clustering results. Hence, a consensus approach leveraging the merits of both clustering paradigms could result in a more accurate clustering and a more precise cell type annotation. We present scConsensus, an R framework for generating a consensus clustering by (i) integrating the results from both unsupervised and supervised approaches and (ii) refining the consensus clusters using differentially expressed (DE) genes. The value of our approach is demonstrated on several existing single-cell RNA sequencing datasets, including data from sorted PBMC sub-populations. scConsensus is freely available on GitHub at https://github.com/prabhakarlab/scConsensus.
Autonomic activity during a daytime nap facilitates working memory improvement
Authors: Chen Pin-Chun , Whitehurst Lauren N. , Mednick Sara C.
Published: April 2020

Recent investigations have implicated the parasympathetic branch of the autonomic nervous system (ANS) in higher-order executive functions. These actions are purported to occur through ANS’s modulation of the prefrontal cortex, with parasympathetic activity during wake associated with working memory ability (WM). Compared with wake, sleep is a period with substantially greater parasympathetic tone. Recent work has reported that sleep may also contribute to improvement in WM. Here, we examined the role of cardiac parasympathetic activity during sleep on WM improvement in healthy young adults. Participants were tested in an operation span task (OSpan) in the morning and evening, and during the inter-test period subjects either experienced a nap or wake. We measured high frequency heart rate variability (HF HRV) as an index of cardiac, parasympathetic activity during both wake and sleep. Participants showed the expected boost in parasympathetic activity during nap, compared with wake, as well as greater WM improvement after a nap compared with an equivalent period awake. Furthermore, parasympathetic activity during sleep, but not wake, was significantly correlated with WM improvement. Together these results indicate that the natural boost in parasympathetic activity during sleep has substantial benefits to gains in prefrontal executive function in young adults. We present a conceptual model illustrating the interaction between sleep, autonomic activity, and prefrontal brain function, and highlight open research questions that will facilitate understanding of the factors that contribute to executive abilities in young adults, as well as in cognitive aging.

Significance Statement

Recently, the neurovisceral integration model has implicated activity on the parasympathetic branch of the autonomic nervous system (ANS) during wake in executive functioning. Parasympathetic activity peaks during deep sleep, and sleep has been shown to facilitate executive functioning. Yet, the role of parasympathetic activity during sleep for executive functioning is not known. Herein, participants demonstrated increased parasympathetic activity during deep sleep, sleep-dependent WM improvement, and associations between performance gains and parasympathetic activity in sleep, not wake. Our conceptual model illustrates the interaction between sleep, autonomic activity, and prefrontal brain function that may contribute to executive abilities in young adults and to cognitive aging.
Diurnal metabolic regulation of isoflavones and soyasaponins in soybean roots
Authors: Matsuda Hinako , Nakayasu Masaru , Aoki Yuichi , Yamazaki Shinichi , Nagano Atsushi J. , Yazaki Kazufumi , Sugiyama Akifumi
Published: April 2020

Isoflavones and soyasaponins are major specialized metabolites accumulated in soybean roots and secreted into the rhizosphere. Unlike the biosynthetic pathway, the transporters involved in metabolite secretion remain unknown. The developmental regulation of isoflavone and soyasaponin secretions has been recently reported, but the diurnal regulation of their biosynthesis and secretion still needs to be further studied. To address these challenges, we conducted transcriptome and metabolite analysis using hydroponically grown soybean plants at 6-hour intervals for 48 hours in a 12-h-light/12-h-dark condition. Isoflavone and soyasaponin biosynthetic genes showed opposite patterns in the root tissues; that is, the former genes are highly expressed in daytime, while the latter ones are strongly induced at nighttime.GmMYB176encoding a transcription factor of isoflavone biosynthesis was upregulated from ZT0 (6:00 am) to ZT6 (12:00 am), followed by the induction of isoflavone biosynthetic genes at ZT6. The isoflavone aglycone content in the roots accordingly increased from ZT6 to ZT18 (0:00 am), accompanied by an increase in glucoside levels that peaked at ZT0. The isoflavone aglycone content in root exudates was kept consistent throughout the day, whereas that of glucosides increased at ZT6, which reflected the decreased expression of the gene encoding beta-glucosidase involved in the hydrolysis of apoplast-localized isoflavone conjugates. Co-expression analysis revealed that those isoflavone and soyasaponin biosynthetic genes formed separate clusters, which exhibited a correlation to ABC and MATE transporter genes. As summary, the results in this study indicated the diurnal regulation of isoflavone biosynthesis in soybean roots and the putative transporter genes responsible for isoflavone and soyasaponin transport.
Clinical genetics lacks standard definitions and protocols for the collection and use of diversity measures
Authors: Popejoy Alice B. , Crooks Kristy R. , Fullerton Stephanie M. , Hindorff Lucia A. , Hooker Gillian W. , Koenig Barbara A. , Pino Natalie , Ramos Erin M. , Ritter Deborah I. , Wand Hannah , Wright Matt W. , Yudell Michael , Zou James Y. , Plon Sharon E. , Bustamante Carlos D. , Ormond Kelly E.
Published: April 2020

Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in either setting. Two NIH-funded research consortia, the Clinical Genome Resource (ClinGen) and Clinical Sequencing Evidence-generating Research (CSER), have partnered to address this issue and report how REA are currently collected, conceptualized, and used. Surveying clinical genetics professionals and researchers (N=448), we found heterogeneity in the way REA are perceived, defined, and measured, with variation in the perceived importance of REA in both clinical and research settings. The majority of respondents (>55%) felt that REA are at least somewhat important for clinical variant interpretation, ordering genetic tests, and communicating results to patients. However, there was no consensus on the relevance of REA, including how each of these measures should be used in different scenarios and what information they can convey in the context of human genetics. A lack of common definitions and applications of REA across the precision medicine pipeline may contribute to inconsistencies in data collection, missing or inaccurate classifications, and misleading or inconclusive results. Thus, our findings support the need for standardization and harmonization of REA data collection and use in clinical genetics and precision health research.