bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold
Authors: Gomes M. Gabriela M. , Ferreira Marcelo U. , Corder Rodrigo M. , King Jessica G. , Souto-Maior Caetano , Penha-Gonçalves Carlos , Gonçalves Guilherme , Chikina Maria , Pegden Wesley , Aguas Ricardo
Published: May 2020

Individual variation in susceptibility and exposure is subject to selection by natural infection, accelerating the acquisition of immunity, and reducing herd immunity thresholds and epidemic final sizes. This is a manifestation of a wider population phenomenon known as “frailty variation”. Despite theoretical understanding, public health policies continue to be guided by mathematical models that leave out considerable variation and as a result inflate projected disease burdens and overestimate the impact of interventions. Here we focus on trajectories of the coronavirus disease (COVID-19) pandemic in England and Scotland until November 2021. We fit models to series of daily deaths and infer relevant epidemiological parameters, including coefficients of variation and effects of non-pharmaceutical interventions which we find in agreement with independent empirical estimates based on contact surveys. Our estimates are robust to whether the analysed data series encompass one or two pandemic waves and enable projections compatible with subsequent dynamics. We conclude that vaccination programmes may have contributed modestly to the acquisition of herd immunity in populations with high levels of pre-existing naturally acquired immunity, while being critical to protect vulnerable individuals from severe outcomes as the virus becomes endemic.

Graphical Abstract

Highlights

Variation in susceptibility/exposure responds to selection by natural infection

Selection on susceptibility/exposure flattens epidemic curves

Models with incomplete heterogeneity overestimate intervention impacts

Individual variation lowered the natural herd immunity threshold for SARS-CoV-2
Latent Blowout of COVID-19 Globally: An Effort to Healthcare Alertness via Medical GIS Approach
Authors: Sharma Laxmi Kant , Verma Rajani Kant
Published: May 2020

Since January 2020, the COVID-19 pandemic has been escalating from North America to Asia. Various studies projected the spread of pandemic globally, using air passenger data from an infected area. But there could be various parameters that can be the basis for the forecasting of the pandemic. Current research adopts the Medical GIS approach and incorporates critical parameters from various domains to create a global alertness scale to combat the pandemic. The finding of the study ranks the countries on a 1 to 9 scale based on the spatial alertness In this context, the study focuses on the role of GIS techniques as an enabler to fight against the global pandemic and could be beneficial for the authorities to adopt timely preventive actions.

One Sentence Summary

Global Alertness Ranking to combat COVID-19
Applications and barriers to use of an mHealth iPhone application for self-management of chronic recurrent medical conditions: A Pilot Study
Authors: Mande Archana , Moore Susan L. , Banaei-Kashani Farnoush , Kaizer Alexander M. , Echalier Benjamin , Bull Sheana , Rosenberg Michael A.
Published: May 2020

Management of chronic recurrent medical conditions (CRMC), such as migraine headaches, chronic pain and anxiety/depression, is a major challenge for modern providers. The fact that often the most effective treatments and/or preventative measures for CRMCs vary from patient to patient lends itself to a platform for self-management by patients. However, to develop such an mHealth app requires an understanding of the various applications, and barriers, to real-world use. In this pilot study with internet-based recruitment, we conducted an assessment of user satisfaction of the iMTracker iOS (iPhone) application for CRMC self-management through a self-administered survey of subjects with CRMCs. From May 15, 2019 until March 27, 2020, we recruited 135 subjects to pilot test the iMTracker application for user-selected CRMCs. The most common age group was 31–45 (48.2%), followed by under 30 (22.2%) and 46–55 (20%). There were no subjects over 75 years old completing the survey. 38.8% of subjects were college graduates, followed by 29.6% with a Master’s degree, and 25.9% with some college. No subjects had not graduated from high school, and only 2 (1.5%) did not attend college after high school. 80.7% of subjects were self-identified as Caucasian, and 90.4% as not Hispanic or Latino. The most common CRMC was pain (other than headaches) in 40% of subjects, followed by mental health in 17.8% and headaches in 15.6%. 39.3% of subjects experienced the condition multiple times in a day, 40.0% experienced the condition daily, and 14.8% experienced the condition weekly, resulting in a total of 94.1% of subjects experiencing the condition at least weekly. Among the concerns about a self-management app, time demands (54.8%) and ineffectiveness (43.7%) were the most prominent, with privacy (24.4%) and data security (25.2%) also noted. In summary, we found internet-based recruitment identified primarily Caucasian population of relatively young patients with CRMCs of relatively high recurrence rate. Future work is needed to examine the use of this application in older, underrepresented minorities, and lower socioeconomic status populations.
Can Nebulised Heparin Reduce Time to Extubation in SARS-CoV-2 (CHARTER Study) – Protocol
Authors: Dixon Barry , Smith Roger J , Artigas Antonio , Laffey John , McNicholas Bairbre , Schmidt Eric , Nunes Quentin , Skidmore Mark , Lima Marcelo Andrade de , Moran John L , VanHaren Frank , Doig Gordon , Ghosh Angajendra , Said Simone , Gupta Sachin , Santamaria John D
Published: May 2020

Introduction

COVID-19 is associated with the development of ARDS displaying the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. The anti-coagulant actions of nebulised heparin limit fibrin deposition and progression of lung injury. Serendipitously, unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents its entry into mammalian cells. Nebulisation of heparin may therefore limit both fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. For these reasons we have initiated a multi-centre international trial of nebulised heparin in patients with COVID-19.

Methods and intervention

Mechanically ventilated patients with confirmed or strongly suspected SARS-CoV-2 infection, hypoxaemia and an acute pulmonary opacity in at least one lung quadrant on chest X-ray, will be randomised to nebulised heparin 25,000 Units every 6 hours or standard care for up to 10 days while mechanically ventilated. The primary outcome is the time to separation from invasive ventilation to day 28, where non-survivors to day 28 are treated as though not separated from invasive ventilation.

Ethics and dissemination

The study protocol has been submitted to the human research and ethics committee of St Vincent’s Hospital, Melbourne, Australia. Submission is pending in other jurisdictions. Results of this study will be published in scientific journals and presented at scientific meetings.

Trial Registration

ACTRN: 12620000517976
Regulation of bacterial cell cycle progression by redundant phosphatases
Authors: Coppine Jérôme , Kaczmarczyk Andreas , Petit Kenny , Brochier Thomas , Jenal Urs , Hallez Régis
Published: May 2020

In the model organismCaulobacter crescentus, a network of two-component systems involving the response regulators CtrA, DivK and PleD coordinate cell cycle progression with differentiation. Active phosphorylated CtrA prevents chromosome replication in G1 cells while simultaneously regulating expression of genes required for morphogenesis and development. At the G1-S transition, phosphorylated DivK (DivK~P) and PleD (PleD~P) accumulate to indirectly inactivate CtrA, which triggers DNA replication initiation and concomitant cellular differentiation. The phosphatase PleC plays a pivotal role in this developmental program by keeping DivK and PleD phosphorylation levels low during G1, thereby preventing premature CtrA inactivation. Here, we describe CckN as a second phosphatase akin to PleC that dephosphorylates DivK~P and PleD~P in G1 cells. However, in contrast to PleC, we do not detect kinase activity with CckN. The effects of CckN inactivation are largely masked when PleC is present, but become evident when PleC and DivJ, the major kinase for DivK and PleD, are absent. Accordingly, mild overexpression ofcckNrestores most phenotypic defects of apleCnull mutant. We also show that CckN and PleC are proteolytically degraded in a ClpXP-dependent way well before the onset of the S phase. Surprisingly, known ClpX adaptors are dispensable for PleC and CckN proteolysis, suggesting the existence of adaptors specifically involved in proteolytic removal of cell cycle regulators. SincecckNexpression is induced in stationary phase, depending on the stress alarmone (p)ppGpp, we propose that CckN acts as an auxiliary factor responding to environmental stimuli to modulate CtrA activity under suboptimal conditions.

Importance

Two-component signal transduction systems are widely used by bacteria to sense environmental signals and respond accordingly by modulating various cellular processes, such as cell cycle progression. InCaulobacter crescentus, PleC acts as a phosphatase that indirectly protects the response regulator CtrA from premature inactivation during the G1 phase of the cell cycle. Here, we provide genetic and biochemical evidence that PleC is seconded by another phosphatase, CckN. The activity of PleC and CckN phosphatases is restricted to G1 phase since both proteins are timely degraded by proteolysis just before the G1-S transition. This degradation requires new proteolytic adaptors as well as an unsuspected N-terminal motif for CckN. Our work illustrates a typical example of redundant functions between two-component proteins.
Rapidly fatal pneumonitis from immunotherapy and concurrent SARS-CoV-2 infection in a patient with newly diagnosed lung cancer
Authors: Lovly Christine M. , Boyd Kelli L. , Gonzalez-Ericsson Paula I. , Lowe Cindy L. , Brown Hunter M. , Hoffman Robert D. , Sterling Brent C. , Kapp Meghan E. , Johnson Douglas B. , Kopparapu Prasad R. , Iams Wade T. , Warren Melissa A. , Noto Michael J. , Rini Brian I. , Jagasia Madan , Das Suman R. , Balko Justin M.
Published: May 2020

Immune checkpoint inhibitors (ICIs) are used for the treatment of numerous cancers, but risks associated with ICI-therapy during the COVID-19 pandemic are poorly understood. We report a case of acute lung injury in a lung cancer patient initially treated for ICI-pneumonitis and later found to have concurrent SARS-CoV-2 infection. Post-mortem analyses revealed diffuse alveolar damage in both the acute and organizing phases, with a predominantly CD68+ inflammatory infiltrate. Serum was positive for anti-SARS-CoV-2 IgG, suggesting that viral infection predated administration of ICI-therapy and may have contributed to a more fulminant clinical presentation. These data suggest the need for routine SARS-CoV-2 testing in cancer patients, where clinical and radiographic evaluations may be non-specific.
Reproductive biology of wild and domesticated Ensete ventricosum: Further evidence for maintenance of sexual reproductive capacity in a vegetatively propagated perennial crop
Authors: Tamrat Solomon , Borrell James S. , Shiferaw Eleni , Wondimu Tigist , Kallow Simon , Davies Rachael M. , Dickie John B. , Nuraga Gizachew W. , White Oliver , Woldeyes Feleke , Demissew Sebsebe , Wilkin Paul
Published: May 2020

Loss of sexual reproductive capacity has been proposed as a syndrome of domestication in vegetatively propagated crops, but there are relatively few examples from agricultural systems. In this study we compare sexual reproductive capacity in wild (sexual) and domesticated (vegetative) populations of enset (Ensete ventricosum (Welw.) Cheesman), a tropical banana relative and Ethiopian food security crop.

We examined floral and seed morphology and germination ecology across 35 wild and domesticated enset. We surveyed variation in floral and seed traits, including seed weight, viability and internal morphology, and germinated seeds across a range of constant and alternating temperature regimes to characterise optimum germination requirements.

We report highly consistent floral allometry, seed viability, internal morphology and days to germination in wild and domesticated enset. However, seeds from domesticated plants responded to cooler temperatures with greater diurnal range. Shifts in germination behaviour appear concordant with a climatic envelope shift in the domesticated distribution.

Our findings provide evidence that sexual reproductive capacity has been maintained despite long-term near-exclusive vegetative propagation in domesticated enset. Furthermore, certain traits such as germination behaviour and floral morphology, may be under continued selection, presumably through rare sexually reproductive events. Compared to sexually propagated crops banked as seeds, vegetative crop diversity is typically conserved in living collections that are more costly and insecure. Improved understanding of sexual propagation in vegetative crops may have applications in germplasm conservation and plant breeding.
Measuring Sequences of Representations with Temporally Delayed Linear Modelling
Authors: Liu Yunzhe , Dolan Raymond J , Penagos-Vargas Hector Luis , Kurth-Nelson Zeb , Behrens Timothy
Published: May 2020

There are rich structures in off-task neural activity. For example, task related neural codes are thought to be reactivated in a systematic way during rest. This reactivation is hypothesised to reflect a fundamental computation that supports a variety of cognitive functions. Here, we introduce an analysis toolkit (TDLM) for analysing this activity. TDLM combines nonlinear classification and linear temporal modelling to testing for statistical regularities in sequences of neural representations. It is developed using non-invasive neuroimaging data and is designed to take care of confounds and maximize sequence detection ability. The method can be extended to rodent electrophysiological recordings. We outline how TDLM can successfully reveal human replay during rest, based upon non-invasive magnetoencephalography (MEG) measurements, with strong parallels to rodent hippocampal replay. TDLM can therefore advance our understanding of sequential computation and promote a richer convergence between animal and human neuroscience research.
Priming of MSCs with inflammation-relevant signals affects extracellular vesicle biogenesis, surface markers, and modulation of T cell subsets
Authors: Andrews Seth , Maughon Ty , Marklein Ross , Stice Steven
Published: May 2020

Although considerable evidence exists supporting the use of mesenchymal stromal cells (MSCs) for treating immune diseases, successful clinical translation has been challenging and has led researchers to investigate cell-free alternatives. MSC-derived extracellular vesicles (MSC-EVs) have been shown to mediate a significant portion of the observed therapeutic effect, including immunosuppression. MSCs have been shown to respond to different aspects of the injury microenvironment such as inflammatory cytokines and hypoxia, although acidosis has not been investigated and different conditions have not been assessed in terms of their effects on MSC-EV function. This study investigated the effects of acidosis, hypoxia, and inflammatory cytokine priming on MSCs and MSC-EVs. We cultured MSCs in the presence of acidosis, hypoxia, or inflammatory cytokines (Interferon-gamma and Tumor Necrosis Factor-alpha) and compared the characteristics of their EVs as well as their uptake by and suppression of different T cell subsets. MSCs showed a greater effect on suppressing activated CD4+and CD8+T cells than MSC-EVs. However, MSC-EVs from MSCs primed with acidosis increased CD4+and CD8+regulatory T cell frequency in vitro. This functional response was reflected by MSC-EV uptake. MSC-EVs from acidosis-primed MSCs were taken up by CD4+and CD8+regulatory T cells at a significantly higher level than MSC-EVs from control, hypoxic, and inflammatory cytokine groups. These data suggest that a simple low-cost alteration in MSC culture conditions, acidosis, can generate extracelluar vesicles that have a desirable influence on anti inflammatory T cell subtypes.
Decision making in auditory externalization perception: model predictions for static conditions
Authors: Baumgartner Robert , Majdak Piotr
Published: May 2020

Under natural conditions, listeners perceptually attribute sounds to external objects in their environment. This core function of perceptual inference is often distorted when sounds are produced via hearing devices such as headphones or hearing aids, resulting in sources being perceived unrealistically close or even inside the head. Psychoacoustic studies suggest a mixed role of various monaural and interaural cues contributing to the externalization process. We developed a model framework for perceptual externalization able to probe the contribution of cue-specific expectation errors and to contrast dynamic versus static strategies for combining those errors within static listening environments. Effects of reverberation and visual information were not considered. The model was applied to various acoustic distortions as tested under various spatially static conditions in five previous experiments. Most accurate predictions were obtained for the combination of monaural and interaural spectral cues with a fixed relative weighting (approximately 60% of monaural and 40% of interaural). That model version was able to reproduce the externalization rating of the five experiments with an average error of 12% (relative to the full rating scale). Further, our results suggest that auditory externalization in spatially static listening situations underlie a fixed weighting of monaural and interaural spectral cues, rather than a dynamic selection of those auditory cues.
Transcriptional control of DNA repair networks by CDK7 regulates sensitivity to radiation in Myc-driven Medulloblastoma
Authors: Veo Bethany , Danis Etienne , Pierce Angela , Wang Dong , Fosmire Susan , Sullivan Kelly D. , Joshi Molishree , Khanal Santosh , Dahl Nathan , Karam Sana , Serkova Natalie , Venkataraman Sujatha , Vibhakar Rajeev
Published: May 2020

Myc-driven Medulloblastoma remains a major therapeutic challenge due to frequent metastasis and a poor 5-year survival rate. Myc gene amplification results in transcriptional dysregulation, proliferation, and survival of malignant cells. To identify therapeutic targets in Myc-amplified medulloblastoma we performed a CRISPR-Cas9 essentiality screen targeting 1140 genes annotated as the druggable genome. CDK7 was identified as a mediator of medulloblastoma tumorigenesis. Using covalent inhibitors and genetic depletion of CDK7 we observe the cessation of tumor growth in xenograft mouse models and increase in apoptotic mechanisms. The results are attributed to repression of a core set of Myc-driven transcriptional programs mediating DNA repair. We further establish that blocking CDK7 activity sensitizes cells to ionizing radiation leading to accrual of DNA damage and extended survival and tumor latency in medulloblastoma xenograft mouse models. Our studies establish a mechanism for selective inhibition of Myc-driven MB by CDK7 inhibition combined with radiation as a viable therapeutic strategy for Myc-amplified medulloblastoma.
Trait-based responses to land use and canopy dynamics modify long-term diversity changes in forest understories
Authors: Happonen Konsta , Muurinen Lauralotta , Virtanen Risto , Kaakinen Eero , Grytnes John-Arvid , Kaarlejärvi Elina , Parisot Philippe , Wolff Matias , Maliniemi Tuija
Published: May 2020

Aim

Land use is the foremost cause of global biodiversity decline, but species do not respond equally to land-use practices. Instead, it is suggested that responses vary with species traits, but long-term data on the trait-mediated effects of land-use on communities is scarce. Here we study how forest understory communities have been affected by two land-use practices during 4–5 decades, and whether changes in plant diversity are related to changes in functional composition.

Location

Finland

Time period

1968–2019

Major taxa studied

Vascular plants

Methods

We resurveyed 245 vegetation plots in boreal herb-rich forest understories, and used hierarchical Bayesian linear models to relate changes in diversity, species composition, average plant size, and leaf economic traits to reindeer abundance, forest management intensity, and changes in climate, canopy cover and composition.

Results

Intensively managed forests decreased in species richness and had increased turnover, but management did not affect functional composition. Increased reindeer densities corresponded with increased leaf dry matter content, evenness and diversity, and decreased height and specific leaf area. Successional development in the canopy was associated with increased specific leaf area and decreased leaf dry matter content and height in the understory over the study period. Effects of reindeer abundance and canopy density on diversity were partially mediated by vegetation height, which had a negative relationship with evenness. Observed changes in climate had no discernible effect on any variable.

Main conclusions

Functional traits are useful in connecting vegetation changes to the mechanisms that drive them, and provide unique information compared to turnover and diversity metrics. These trait-dependent selection effects could inform whether species benefit or suffer from land use changes and explain observed biodiversity changes under global change.
Estimating Movement Smoothness from Inertial Measurement Units
Authors: Melendez-Calderon Alejandro , Shirota Camila , Balasubramanian Sivakumar
Published: May 2020

Abstract

There is an increasing trend in using inertial measurement units (IMUs) to estimate movement quality and quantity, and infer the nature of motor behavior. The current literature contains several attempts to estimate movement smoothness using data from IMUs, most of which assume that the translational and rotational kinematics measured by IMUs can be directly used with existing smoothness measures - spectral arc length (SPARC) and log dimensionless jerk (LDLJ-V). However, there has been no investigation of the validity of these approaches. In this paper, we systematically evaluate the appropriateness of the using these measures on the kinematics measured by an IMU. We show that: (a) current measures (SPARC and LDLJ-V) are inappropriate for translational movements; and (b) SPARC and LDLJ-V can be used rotational kinematics measured by an IMU. For discrete translational movements, we propose a modified version of the LDLJ-V measure, which can be applied to acceleration data (LDLJ-A), while roughly maintaining the properties of the original measure. However, accuracy of LDLJ-A depends on the IMU orientation estimation error. We evaluate the performance of these measures using simulated and experimental data. We then provide recommendations for how to appropriately apply these measures in practice, and the various factors to be aware of when performing smoothness analysis using IMU data.
Intra-saccadic motion streaks jump-start gaze correction
Authors: Schweitzer Richard , Rolfs Martin
Published: May 2020

Rapid eye movements (saccades) incessantly shift objects across the retina. To establish object correspondence, the visual system is thought to match surface features of objects across saccades. Here we show that an object’s intra-saccadic retinal trace – a signal previously considered unavailable to visual processing – facilitates this match-making. Human observers made saccades to a cued target in a circular stimulus array. Using high-speed visual projection, we swiftly rotated this array during the eyes’ flight, displaying continuous intra-saccadic target motion. Observers’ saccades landed between the target and a distractor, prompting secondary saccades. Independently of the availability of object features, which we controlled tightly, target motion increased the rate and reduced the latency of gaze-correcting saccades to the initial pre-saccadic target, in particular when the target’s stimulus features incidentally gave rise to efficient motion streaks. These results suggest that intra-saccadic visual information informs the establishment of object correspondence and jump-starts gaze correction.
Platinum-Induced Ubiquitination of Phosphorylated H2AX by RING1A is Mediated by Replication Protein A in Ovarian Cancer
Authors: Sriramkumar Shruthi , Matthews Timothy D. , Ghobashi Ahmed H. , Miller Samuel A. , VanderVere-Carozza Pamela S. , Pawelczak Katherine S. , Nephew Kenneth P. , Turchi John J. , O’Hagan Heather M.
Published: May 2020

Platinum resistance is a common occurrence in high grade serous ovarian cancer (HGSOC) and a major cause of OC deaths. Platinum agents form DNA crosslinks, which activate nucleotide excision repair (NER), fanconi anemia (FA) and homologous recombination repair (HRR) pathways. Chromatin modifications occur in the vicinity of DNA damage and play an integral role in the DNA damage response (DDR). Chromatin modifiers, including polycomb repressive complex 1 (PRC1) members, and chromatin structure are frequently dysregulated in OC and can potentially contribute to platinum resistance. However, the role of chromatin modifiers in the repair of platinum DNA damage in OC is not well understood. We demonstrate that the PRC1 complex member RING1A mediates monoubiquitination of lysine 119 of phosphorylated H2AX (γH2AXub1) at sites of platinum DNA damage in OC cells. After platinum treatment, our results reveal that NER and HRR both contribute to RING1A localization and γH2AX monoubiquitination. Importantly, replication protein A (RPA), involved in both NER and HRR, mediates RING1A localization to sites of damage. Furthermore, RING1A deficiency impaired the activation of the G2/M DNA damage checkpoint and reduced the ability of OC cells to repair platinum DNA damage. Elucidating the role of RING1A in the DDR to platinum agents will allow for the identification of therapeutic targets to improve the response of OC to standard chemotherapy regimens.
Chemical patterns of colony membership and mother-offspring similarity in Antarctic fur seals are reproducible over time
Authors: Tebbe Jonas , Humble Emily , Stoffel Martin A. , Tewes Lisa J. , Müller Caroline , Forcada Jaume , Caspers Barbara , Hoffman Joseph I.
Published: May 2020

Replication studies are essential for assessing the validity of previous research findings and for probing their generality. However, it has proven challenging to reproduce the results of ecological and evolutionary studies, partly because of the complexity and lability of many of the phenomena being investigated, but also due to small sample sizes, low statistical power and publication bias. Additionally, replication is often considered too difficult in field settings where many factors are beyond the investigator’s control and where spatial and temporal dependencies may be strong. We investigated the feasibility of reproducing original research findings in the field of chemical ecology by attempting to replicate a previous study by our team on Antarctic fur seals (Arctocephalus gazella). In the original study, skin swabs from 41 mother-offspring pairs from two adjacent breeding colonies on Bird Island, South Georgia, were analysed using gas chromatography-mass spectrometry. Seals from the two colonies differed significantly in their chemical fingerprints, suggesting that colony membership may be chemically encoded, and mothers were also chemically similar to their pups, implying that phenotype matching may be involved in mother-offspring recognition. Here, we generated and analysed comparable chemical data from a non-overlapping sample of 50 mother-offspring pairs from the same two colonies five years later. The original results were corroborated in both hypothesis testing and estimation contexts, withp-values remaining highly significant and effect sizes, standardized between studies by bootstrapping the chemical data over individuals, being of comparable magnitude. We furthermore expanded the geographic coverage of our study to include pups from a total of six colonies around Bird Island. Significant chemical differences were observed in the majority of pairwise comparisons, indicating not only that patterns of colony membership persist over time, but also that chemical signatures are colony-specific in general. Our study systematically confirms and extends our previous findings, while also implying that temporal and spatial heterogeneity need not necessarily negate the reproduction and generalization of ecological research findings.
Dysregulation in mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells
Authors: Appelberg Sofia , Gupta Soham , Ambikan Anoop T , Mikaeloff Flora , Végvári Ákos , Akusjärvi Sara Svensson , Benfeitas Rui , Sperk Maike , Ståhlberg Marie , Krishnan Shuba , Singh Kamal , Penninger Josef M. , Mirazimi Ali , Neogi Ujjwal
Published: May 2020

How Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remain largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected HuH7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infectionin vitro. Western blot validation of the downstream effector molecules of these pathways revealed a significant reduction in activated S6K1 and 4E-BP1 at 72 hours post infection. Unlike other human respiratory viruses, we found a significant inhibition of HIF-1α through the entire time course of the infection, suggesting a crosstalk between the SARS-CoV-2 and the mTOR/HIF-1 signaling. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe COVID-19 patients.
Detecting Early Response to Immune Checkpoint Blockade by Multimodal Molecular Imaging
Authors: Saida Yu , Brender Jeffery R. , Yamamoto Kazutoshi , Mitchell James B. , Krishna Murali C. , Kishimoto Shun
Published: May 2020

Immune checkpoint inhibitors have become a standard therapy for several cancers; however, the response is inconsistent and a method for non-invasive assessment has not been established to date. To investigate the capability of multi-modal imaging to evaluate treatment response to immune checkpoint blockade therapy, we employed hyperpolarized13C MRI on tumor bearing mice using [1-13C] pyruvate and [1,4-13C2] fumarate to detect early changes in tumor glycolysis and necrosis, respectively. Following αPD-L1 Ab + αCTLA-4 Ab dual immune checkpoint blockade (ICB) therapy, dynamic contrast enhanced (DCE) MRI was used to determine the treatment effect on intratumor perfusion/permeability. Mice bearing MC38 colon adenocarcinoma and B16.F10 melanoma were used as sensitive and less sensitive models, respectively to immune checkpoint dual blockade of PD-L1 and CTLA-4. Glycolytic flux significantly decreased upon treatment in the less ICB sensitive B16.F10 model but remained essentially unchanged in MC38 tumors. Imaging [1,4-13C] fumarate conversion to [1,4-13C] malate showed a significant increase in necrosis in the treatment group for the ICB sensitive MC38 tumor (p= 0.0003), with essentially no change in ICB sensitive B16.F10 tumors. Histological assessment showed increased necrotic tissue with enhanced lymphocyte infiltration in the MC38 treatment group, suggesting immunogenic tumor cell death. Dynamic contrast enhanced MRI showed significantly increased perfusion/permeability of Gd-DTPA in MC38 treated tumor, while a similar trend but statistically non-significant change was observed in B16.F10 treated tumor. These results provide imaging biomarkers to detect early response to cancer immunotherapy, allowing qualitative assessment of tumors treated with immune checkpoint blockade therapy.
A systematic mutational analysis identifies a 5-residue proline tag that enhances thein vivoimmunogenicity of a non-immunogenic model protein 240 folds
Authors: Rahman Nafsoon , Islam Mohammad Monirul , Kibria Md Golam , Unzai Satoru , Kuroda Yutaka
Published: May 2020

Small proteins are generally non-immunogenic, which can be a major hurdle in developing protein and peptide vaccines or producing antibodies for biopharmaceutical usage. For improving a protein’s immunogenicity, we previously proposed to use short Solubility Controlling Peptide (SCP) tags that oligomerize proteins into soluble aggregates. Here, we systematically analyzed the effect of SCP-tags that do not induce oligomerization on the immunogenicity of a small, non-immunogenic, model protein, Bovine Pancreatic Trypsin Inhibitor (BPTI-19A; 6 kDa). We assessed the effect of the following ten SCP-tags: Six tags made of five consecutive Arg, Lys, His, Asp, Asn, Pro; one made of seven Pro; two tags made of consecutive Arg-lle and Asn-Ile, all attached at the C-terminus of BPTI-19A; and a 5-proline tag attached at the N-terminus. Circular dichroism, fluorescence, dynamic light scattering measurements, and analytical ultra-centrifugation indicated that the addition of the SCP-tags did not change the secondary structure content nor the tertiary structures of the protein nor its monomeric state. On the other hand, the C-terminus 5-proline (C5P) tag unexpectedly increased the immunogenicity (IgG level) of BPTI-19A by up to 240 fold as assessed by ELISA. Additionally, the 5-arginine tag (C5R) increased the titer by up to 73 fold. The titer increase lasted for several weeks, and the effect was cumulative to that of the Freund’s adjuvant, which is commonly used to boost a protein’s immunogenicity. Altogether, SCP-tags that do not oligomerize proteins substantially increased the immunogenicity of a non-immunogenic protein, suggesting that the 5-proline and the 5-arginine SCP-tags may provide a novel tool for facilitating the production of antibodies or improving the effectiveness of protein-based vaccines.
Human and mouse transcriptome profiling identifies cross-species homology in pulmonary and lymph node mononuclear phagocytes
Authors: Leach Sonia M. , Gibbings Sophie L. , Tewari Anita D. , Atif Shaikh M. , Vestal Brian , Danhorn Thomas , Janssen William J. , Wager Tor D. , Jakubzick Claudia V.
Published: May 2020

The mononuclear phagocyte (MP) system consists of macrophages, monocytes, and dendritic cells (DCs). MP subtypes play distinct functional roles in steady state and inflammatory conditions. Though murine MPs are well characterized, their pulmonary and lymph node (LN) human homologs remain poorly understood. To address this gap, we created a gene expression compendium across 15 distinct human and 9 distinct murine MPs from lung, LN, blood, and spleen. Human blood MPs and murine spleen MPs served as validation datasets, as the human-mouse MP homologs are relatively well-defined in these tissues. In-depth RNA sequencing identified corresponding human-mouse MP subtypes and determined marker genes shared and divergent across between species counterparts. Unexpectedly, at the gene expression level, only 13-23% of the top 1000 marker genes (i.e., genes not shared across species-specific MP subtypes) overlapped in corresponding human-mouse MP counterparts, indicating a need for caution when translating mouse studies to human gene targets and functions. Lastly, CD88 was useful in both species to distinguish macrophage and tissue monocytes from DCs. Our cross-species gene expression compendium serves as a resource for future translational studies to investigate beforehand whether pursuing specific MP subtypes, or genes will prove fruitful.
Thermal sensitivity of theSpiroplasma-Drosophila hydeiprotective symbiosis: The best of climes, the worst of climes
Authors: Corbin Chris , Jones Jordan E. , Chrostek Ewa , Fenton Andy , Hurst Gregory D. D.
Published: May 2020

The outcome of natural enemy attack in insects has commonly been found to be influenced by the presence of protective symbionts in the host. The degree to which protection functions in natural populations, however, will depend on the robustness of the phenotype to variation in the abiotic environment. We studied the impact of a key environmental parameter – temperature – on the efficacy of the protective effect of the symbiontSpiroplasmaon its hostDrosophila hydei, against attack by the parasitoid waspLeptopilina heterotoma. In addition, we investigated the thermal sensitivity of the symbiont’s vertical transmission, which may be a key determinant of the ability of the symbiont to persist. We found that vertical transmission was more robust than previously considered, withSpiroplasmabeing maintained at 25 °C, 18 °C and with 18/15 °C diurnal cycles, with rates of segregational loss only increasing at 15 °C. Protection against wasp attack was ablated before symbiont transmission was lost, with the symbiont failing to rescue the fly host at 18 °C. We conclude that the presence of a protective symbiosis in natural populations cannot be simply inferred from presence of a symbiont whose protective capacity has been tested under narrow controlled conditions. More broadly, we argue that the thermal environment is likely to represent an important determinant of the evolutionary ecology of defensive symbioses in natural environments, potentially driving seasonal, latitudinal and altitudinal variation in symbiont frequency, and modulating the strength of selection for symbiotic protective systems compared to defensive systems encoded in the nuclear genomes.
Optimized photochemistry and enzymology enable efficient analysis of RNA structures and interactions in cells and virus infections
Authors: Zhang Minjie , Li Kongpan , Velema Willem A. , Bai Jianhui , Yu Chengqing , van Damme Ryan , Lee Wilson H. , Corpuz Maia L. , Chen Jian-Fu , Lu Zhipeng
Published: May 2020

Direct determination of RNA structures and interactions in living cells is critical for understanding their functions. Current crosslinking and proximity-ligation approaches are fundamentally limited due to inefficient RNA crosslinking, purification and high-level photochemical damages. Here we present PARIS2 (psoralen analysis of RNA interactions and structures, second generation), a re-invented method for capturing RNA duplexes in cells with three orders of magnitude improved efficiency. PARIS2 captures ribosome small subunit (SSU) binding sites on mRNAs, reporting translation status on a transcriptome wide scale, and captures spliceosomal snRNP binding sites on various RNA targets. We determine the RNA genome structure of enterovirus D68, a re-emerging viral pathogen associated with severe neurological symptoms, and discover alternative conformations in the internal ribosome entry site (IRES) that controls translation initiation. Together, these results reveal new aspects of RNA photochemistry and enzymology, and enable highly efficient interrogation of the RNA structurome and interactome in cells.
Comparative transcriptome analysis reveals the intensive early-stage responses of host cells to SARS-CoV-2 infection
Authors: Sun Jiya , Ye Fei , Wu Aiping , Yang Ren , Pan Mei , Sheng Jie , Zhu Wenjie , Mao Longfei , Wang Ming , Huang Baoying , Tan Wenjie , Jiang Taijiao
Published: May 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a widespread outbreak of highly pathogenic COVID-19. It is therefore important and timely to characterize interactions between the virus and host cell at the molecular level to understand its disease pathogenesis. To gain insights, we performed high-throughput sequencing that generated time-series data simultaneously for bioinformatics analysis of virus genomes and host transcriptomes implicated in SARS-CoV-2 infection. Our analysis results showed that the rapid growth of the virus was accompanied by an early intensive response of host genes. We also systematically compared the molecular footprints of the host cells in response to SARS-CoV-2, SARS-CoV and MERS-CoV. Upon infection, SARS-CoV-2 induced hundreds of up-regulated host genes hallmarked by a significant cytokine production followed by virus-specific host antiviral responses. While the cytokine and antiviral responses triggered by SARS-CoV and MERS-CoV were only observed during the late stage of infection, the host antiviral responses during the SARS-CoV-2 infection were gradually enhanced lagging behind the production of cytokine. The early rapid host responses were potentially attributed to the high efficiency of SARS-CoV-2 entry into host cells, underscored by evidence of a remarkably up-regulated gene expression of TPRMSS2 soon after infection. Taken together, our findings provide novel molecular insights into the mechanisms underlying the infectivity and pathogenicity of SARS-CoV-2.
Distinct Inductions of and Responses to Type I and Type III Interferons Promote Infections in Two SARS-CoV-2 Isolates
Authors: Hsin Fu , Chao Tai-Ling , Chan Yun-Rui , Kao Han-Chieh , Liu Wang-Da , Wang Jann-Tay , Pang Yu-Hao , Lin Chih-Hui , Tsai Ya-Min , Lin Jing-Yi , Chang Sui-Yuan , Liu Helene Minyi
Published: May 2020

The recent emerging coronavirus, SARS-CoV-2, has been rapidly and widely spread and causing an ongoing viral pneumonia outbreak worldwide. It has been observed that SARS-CoV-2 patients show a rather long and asymptomatic incubation time. We characterized the abilities to induce and to response to IFNβ/IFNλ1 of two or our clinical isolates, SARS-CoV-2/NTU01/TWN/human/2020 and SARS-CoV-2/NTU02/TWN/human/2020, which exhibit only two amino acid differences over the ∼30kb viral genome. We found that both isolates may infect Huh7, A549 and Calu-3 cells, yet the RIG-I-like receptor-dependent antiviral signaling was poorly induced in these cells in the early infections. Unexpectedly, we found that the intracellular vRNA levels of these isolates were sustained upon to type I/III IFN treatments, and this phenotype was more pronounced in the Taiwan/NTU01/2020 isolate. The type I/III IFN responses are antiviral but partially proviral in the case of SARS-CoV-2 infections. Poor induction and response to innate immunity may contribute to destitute neutralization index of the antibody produced, and indeed we found that the patient serum could not efficiently neutralize SARS-CoV-2 virions. With better understandings of the interplay between SARS-CoV-2 and the host antiviral innate immunity, our report may provide new insights for the regimen of therapies for SARS-CoV-2 infected patients.
Prohibitin protects against cigarette smoke extract-induced cell apoptosis in cultured human pulmonary microvascular endothelial cells
Authors: Peng Yating , Zhou Zijing , Zhou Aiyuan , Duan JiaXi , Peng Hong , Ouyang Ruoyun , Chen Yan , Chen Ping
Published: May 2020

Prohibitin is an evolutionarily conserved and ubiquitously expressed protein in eukaryocyte. It mediate many important roles in cell survival, apoptosis, autophagy and senescence. In the present study, we aimed to explore the role of prohibitin in cigarette smoke extract (CSE)-induced apoptosis of human pulmonary microvascular endothelial cells (HPMECs). For this purpose, HPMECs were trasfected with prohibitin and challenged with CSE. Our results showed that CSE exposure inhibited prohibitin expression in a dose-dependent manner in HPMECs. Overexpression of prohibitin could protect cell from CSE-induced injury by inhibiting CSE-induced cell apoptosis, inhibiting reactive oxygen species (ROS) production, increase mitochondrial membrane potential, increase the content of mitochondrial transcription factor A (mtTFA), IKKα/β phosphorylation and IκB-α degradation. CSE decreases prohibitin expression in endothelial cells and restoration of prohibitin expression in these cells can protect against the deleterious effects of CSE on mitochondrial and cells. We identified prohibitin is a novel regulator of endothelial cell apoptosis and survival in the context of cigarette smoke exposure.
Mutational spectra of SARS-CoV-2 orf1ab polyprotein and Signature mutations in the United States of America
Authors: Banerjee Shuvam , Seal Sohan , Dey Riju , Mondal Kousik Kr. , Bhattacharjee Pritha
Published: May 2020

Pandemic COVID-19 outbreak has been caused due to SARS-COV2 pathogen, resulting millions of infection and death worldwide, USA being on top at the present moment. The long, complex orf1ab polyproteins of SARS-COV2 play an important role in viral RNA synthesis. To assess the impact of mutations in this important domain, we analyzed 1134 complete protein sequences of orf1ab polyprotein from NCBI Virus database from affected patients across various states of USA from December 2019 to 25thApril, 2020. Multiple sequence alignment using Clustal Omega followed by statistical significance was calculated. Four significant mutations T265I (nsp 2), P4715L (nsp 12) and P5828L and Y5865C (both at nsp 13) were identified in important non-structural proteins, which function either as replicase or helicase. A comparative analysis shows 265T>I, 5828P>L and 5865Y>C are unique to USA and not reported from Europe or Asia; while one, 4715P>L is predominant in both Europe and USA. Mutational changes in amino acids are predicted to alter structure and function of corresponding proteins, thereby it is imperative to consider the mutational spectra while designing new antiviral therapeutics targeting viral orf1ab.
On spatial molecular arrangements of SARS-CoV2 genomes of Indian patients
Authors: Hassan Sk. Sarif , Moitra Atanu , Rout Ranjeet Kumar , Choudhury Pabitra Pal , Pramanik Prasanta , Jana Siddhartha Sankar
Published: May 2020

A pandemic caused by the SARS-CoV2 is being experienced by the whole world since December, 2019. A thorough understanding beyond just sequential similarities among the protein coding genes of SARS-CoV2 is important in order to differentiate or relate to the other known CoVs of the same genus. In this study, we compare three genomes namely MT012098 (India-Kerala), MT050493 (India-Kerala), MT358637 (India-Gujrat) from India with NC_045512 (China-Wuhan) to view the spatial as well as molecular arrangements of nucleotide bases of all the genes embedded in these four genomes. Based on different features extracted for each gene embedded in these genomes, corresponding phylogenetic relationships have been built up. Differences in phylogenetic tree arrangement with individual gene suggest that three genomes of Indian origin have come from three different origins or the evolution of viral genome is very fast process. This study would also help to understand the virulence factors, disease pathogenicity, origin and transmission of the SARS-CoV2.
Release sites are positioned to activate NMDA receptors
Authors: Li Shuo , Raychaudhuri Sumana , Alexander Lee Stephen , Wang Jing , Kusick Grant , Prater Christine , Syed Sarah , Falahati Hanieh , Ramos Raul , Bartol Tomas M. , Hosy Eric , Watanabe Shigeki
Published: May 2020

Neurotransmitter is released synchronously and asynchronously following an action potential. The release sites of these two phases are segregated within an active zone, with asynchronous release sites enriched near the center. Here we demonstrate that synchronous and asynchronous release sites are aligned with AMPA receptor and NMDA receptor clusters, respectively. Computational simulations indicate that this spatial and temporal arrangement of release ensures maximal membrane depolarization through AMPA receptors, alleviating the pore-blocking magnesium leading to greater activation of NMDA receptors. Together, these results suggest that release sites are organized to efficiently activate NMDA receptors.