bluuebunny/crossref_metadata_2025 huggingface dataset:
Scaling COVID-19 against inequalities: should the policy response consistently match the mortality challenge?
Authors: McCartney Gerry , Leyland Alastair H. , Walsh David , Dundas Ruth
Published: May 2020

Background

The mortality impact of COVID-19 has thus far been described in terms of crude death counts. We aimed to calibrate the scale of the modelled mortality impact of COVID-19 using age-standardised mortality rates and life expectancy contribution against other, socially-determined, causes of death in order to inform governments and the public.

Methods

We compared mortality attributable to suicide, drug poisoning and socioeconomic inequality with estimates of mortality from an infectious disease model of COVID-19. We calculated age-standardised mortality rates and life expectancy contributions for the UK and its constituent nations.

Results

Mortality from a fully unmitigated COVID-19 pandemic is estimated to be responsible for a negative life expectancy contribution of −5.96 years for the UK. This is reduced to −0.33 years in the fully mitigated scenario. The equivalent annual life expectancy contributions of suicide, drug poisoning and socioeconomic inequality-related deaths are −0.25, −0.20 and −3.51 years respectively. The negative impact of fully unmitigated COVID-19 on life expectancy is therefore equivalent to 24 years of suicide deaths, 30 years of drug poisoning deaths, and 1.7 years of inequality-related deaths for the UK.

Conclusion

Fully mitigating COVID-19 is estimated to prevent a loss of 5.63 years of life expectancy for the UK. Over 10 years there is a greater negative life expectancy contribution from inequality than around six unmitigated COVID-19 pandemics. To achieve long-term population health improvements it is therefore important to take this opportunity to introduce post-pandemic economic policies to ‘build back better’.

Summary box

What is already known on this subject?

COVID-19 has been modelled to create a substantial excess mortality in the UK, depending on the degree to which this is mitigated by social distancing measures. Best estimates of 510,000 and 20,000 crude deaths are predicted in unmitigated and fully mitigated scenarios respectively.

What does this study add?

We scale the mortality impact of the modelled COVID-19 on age-standardised mortality and life expectancy against suicide, drug poisonings and inequalities. The impact of COVID-19 on life expectancy is substantial (−5.96 years) if unmitigated, but over a decade the life expectancy impact of inequalities is around six times greater than even an unmitigated pandemic.
Assessment of medication Dosage Adjustment in Hospitalized Patients with Chronic Kidney Disease
Authors: Hassan Zair , Ali Iftikhar , Ullah Arslan Rahat , Ahmed Raheel , Rehman Shakeel , Khan Azizullah
Published: May 2020

Background

Inappropriate medication dosing can develop adverse drug reactions (ADRs) or ineffective therapy due to declined renal function in patients with renal insufficiency. This necessitates proper renal dose adjustment. Using a retrospective analysis of medical records, this study was proposed to evaluate medication dosage adjustment in hospitalized chronic kidney disease (CKD) patients.

Methods

This retrospective review of medical records was conducted at the Institute of Kidney Disease (IKD), Peshawar. It included all CKD patients hospitalized between May 01, 2019 and April 25, 2020. Glomerular filtration rate was calculated using Modification of Diet in Renal Disease (MDRD) formula and dose appropriateness was established by evaluating practice with relevant reference books.

Results

Of the total 1537 CKD patients, 231(15.03%) had evidence of dosing error, which were considered for final analysis. Overall, 1549 drugs were prescribed, 480(30.99%) drugs required dose adjustment of which 196(40.42%) were adjusted properly and the remaining 286(59.58%) were unadjusted. The most common unadjusted drugs were meropenem, cefepime, ciprofloxacin and rosuvastatin, whereas captopril, aspirin, bisoprolol, pregabalin and levofloxacin had the highest percentage of adjusted drugs. On multivariate logistic regression, the number of drugs requiring dosing adjustments and obstructive nephropathy were found to be statistically significant factors that increased the likelihood of the medication dosing errors: A unit increase in the number of drugs requiring dose adjustment increases 5.241 times the likelihood of dosing error. Similarly the presence of obstructive nephropathy (OR 0.383, 95% Cl [0.153-0.960] P= 0.041) was found to be significantly associated with dosing error after adjustment for potential confounding factors.

Conclusion

The dosing of more than half of the prescribed drugs that required adjustment in CKD patients were not adjusted which showed that medication dosing errors were high. This highlights the importance of medication prescription according to guidelines in these patients to improve the outcomes of pharmacotherapy and patients’ quality of life.
Does Ventricular Substrate Play a Role in Incident Stroke? The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Johnson John A. , Haq Kazi T. , Lutz Katherine J. , Peters Kyle K. , Paternostro Kevin A. , Craig Natalie E. , Stencel Nathan , Hawkinson Lila , Khayyat-Kholghi Maedeh , Tereshchenko Larisa G.
Published: May 2020

Background

—The goal of the study was to determine an association of ventricular substrate with thrombotic, cardioembolic, and hemorrhagic stroke.

Methods

—Participants from the Atherosclerosis Risk in Communities study with analyzable ECGs and no history of stroke were included (n=14,479; age 54±6 y; 55% female; 24% black). Ventricular substrate was characterized by cardiac memory [spatial QRS-T angle (QRS-Ta), sum absolute QRST integral (SAIQRST), spatial ventricular gradient magnitude (SVGmag)], premature ventricular contractions (PVC) and tachycardia-dependent intermittent bundle branch block (TD-IBBB) on 12-lead ECG recorded at visits 1-5. Incident strokes were adjudicated by physician reviewers. Cox proportional hazard risk models were constructed.

Results

—Over a median 24.5 y follow-up, there were 899 thrombotic, 400 cardioembolic, and 187 hemorrhagic strokes. After adjustment for cardiovascular disease (CVD) and its risk factors, atrial fibrillation / atrial substrate, and ECG-left ventricular hypertrophy, PVC (HR 1.72; 95%CI 1.02-2.92), QRS-Ta (HR 1.15; 95%CI 1.03-1.28), SAIQRST (HR 1.20; 95%CI 1.07-1.34) and time-updated SVGmag (HR 1.19; 95%CI 1.08-1.32) associated with cardioembolic stroke. After adjustment for CVD and its risk factors, PVC (HR 1.53; 95%CI 1.03-2.26), QRS-Ta (HR 1.08; 95%CI 1.01-1.16), SAIQRST (HR 1.07; 95%CI 1.01-1.14), and time-updated SVGmag (HR 1.11; 95%CI 1.04-1.19) associated with thrombotic stroke. In fully adjusted time-updated Cox model QRS-Ta (HR 1.20; 95%CI 1.04-1.38), SAI QRST (HR 1.23; 95%CI 1.06-1.43), SVGmag (HR 1.23; 95%CI 1.06-1.43) associated with hemorrhagic stroke, whereas TD-IBBB trended (HR 1.84; 95%CI 0.25-13.33).

Conclusions

—PVC burden reflected by cardiac memory is associated with ischemic stroke. Transient cardiac memory (likely through TD-IBBB) precedes hemorrhagic stroke.
Quantitative proteomics of coeliac gut during 14-day gluten challenge: low-level baseline inflammation despite clinical and histological normality predicts subsequent response
Authors: Stamnaes Jorunn , Stray Daniel , Stensland Maria , Sarna Vikas K. , Nyman Tuula A. , Lundin Knut E. A. , Sollid Ludvig M.
Published: May 2020

Objective

To shed light on gut mucosa processes provoked by gluten exposure in coeliac disease, we performed a quantitative proteomic analysis of duodenal tissue from well-treated coeliac patients before and after gluten challenge.

Design

We extracted and digested proteins from formalin-fixed paraffin-embedded tissue of 19 coeliac disease patients who had been challenged orally with gluten for 14 days. Protein identification and quantification was done by label-free quantitative mass spectrometry-based proteomics from total tissue and from laser capture microdissected epithelial cell layer. Proteomics data were compared with clinical, serological and histological data.

Results

At baseline, all patients were in clinical and mucosal remission (Marsh 0-1) except one (Marsh 3). After challenge, five patients reached Marsh 3 scores. Proteome analysis categorised these five and additionally two patients as responders. Already at baseline, responder patients differed from the remaining patients in their gut tissue protein composition with altered levels of inflammatory and enterocyte function proteins – the same proteins that changed upon gluten challenge. Patients classified as responders from the proteomic analysis also differed from the remaining patients at baseline, with mild crypt hyperplasia and a slight increase in blood inflammatory parameters and gluten specific CD4+ T-cell frequencies.

Conclusion

Despite clinical and histological remission, coeliac disease patients that develop a mucosal response after 14-day gluten challenge have already at baseline altered protein compositions of their gut tissue with signs of ongoing inflammation. Thus, apparently well-treated coeliac disease is frequently not fully quiescent with presence of low-grade anti-gluten immunity in gut mucosa.
A prospective cohort study of prodromal Alzheimer’s disease: Prospective Imaging Study of Ageing: Genes, Brain and Behaviour (PISA)
Authors: Lupton Michelle K , Robinson Gail A , Adam Robert J , Rose Stephen , Byrne Gerard J , Salvado Olivier , Pachana Nancy A , Almeida Osvaldo P , McAloney Kerrie , Gordon Scott D , Raniga Parnesh , Fazlollahi Amir , Xia Ying , Ceslis Amelia , Sonkusare Saurabh , Zhang Qing , Kholghi Mahnoosh , Karunanithi Mohan , Mosley Philip E , Lv Jinglei , Adsett Jessica , Garden Natalie , Fripp Jurgen , Martin Nicholas G , Guo Christine C , Breakspear Michael
Published: May 2020

This prospective cohort study, “Prospective Imaging Study of Ageing: Genes, Brain and Behaviour” (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer’s disease (AD). In particular, we are recruiting mid-life Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease onset. PISA utilises genetic prediction to recruit and enrich a prospective cohort and follow them longitudinally. Online surveys and cognitive testing are used to characterise an Australia-wide sample currently totalling nearly 3,000 participants. Participants from a defined at-risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment or early AD) are invited for onsite visits for lifestyle monitoring, detailed neurocognitive testing, blood sample donation, plus functional, structural and molecular neuroimaging. This paper describes recruitment of the PISA cohort, study methodology and baseline demographics.

Author Approval

All authors have seen and approved this manuscript.
Initial Model for the Impact of Social Distancing on CoVID-19 Spread
Authors: Eng Genghmun
Published: May 2020

The initial stages of the CoVID-19 coronavirus pandemic all around the world exhibit a nearly exponential rise in the number of infections with time. Planners, governments, and agencies are scrambling to figure out “How much? How bad?” and how to effectively treat the potentially large numbers of simultaneously sick people. Modeling the CoVID-19 pandemic using an exponential rise implicitly assumes a nearly unlimited population of uninfected persons (“dilute pandemic”). Once a significant fraction of the population is infected (“saturated pandemic”), an exponential growth no longer applies. A new model is developed here, which modifies the standard exponential growth function to account for factors such as Social Distancing. A Social Mitigation Parameter [SMP] αS is introduced to account for these types of society-wide changes, which can modify the standard exponential growth function, as follows:

The doubling-time tdbl = (In 2)/Ko can also be used to substitute for Ko, giving a {tdbl, αS} parameter pair for comparing to actual CoVID-19 data. This model shows how the number of CoVID-19 infections can self-limit before reaching a saturated pandemic level. It also provides estimates for: (a) the timing of the pandemic peak, (b) the maximum number of new daily cases that would be expected, and (c) the expected total number of CoVID-19 cases. This model shows fairly good agreement with the presently available CoVID-19 pandemic data for several individual States, and the for the USA as a whole (6 Figures), as well as for various countries around the World (9 Figures). An augmented model with two Mitigation Parameters, αS and βS, is also developed, which can give better agreement with the daily new CoVID-19 data. Data-to-model comparisons also indicate that using αS by itself likely provides a worst-case estimate, while using both αS and βS likely provides a best-case estimate for the CoVID-19 spread.
Point-of-care testing for COVID-19 using SHERLOCK diagnostics
Authors: Joung Julia , Ladha Alim , Saito Makoto , Segel Michael , Bruneau Robert , Huang Mee-li W. , Kim Nam-Gyun , Yu Xu , Li Jonathan , Walker Bruce D. , Greninger Alexander L. , Jerome Keith R. , Gootenberg Jonathan S. , Abudayyeh Omar O. , Zhang Feng
Published: May 2020

The recent outbreak of the novel coronavirus SARS-CoV-2, which causes COVID-19, can be diagnosed using RT-qPCR, but inadequate access to reagents and equipment has slowed disease detection and impeded efforts to mitigate viral spread. Alternative approaches based on combinations of isothermal amplification and CRISPR-mediated detection, such as the SHERLOCK (SpecificHighSensitivityEnzymaticReporter UnLOCKing) technique, offer reduced dependence on RT-qPCR equipment, but previously reported methods required multiple fluid handling steps, complicating their deployment outside clinical labs. Here we developed a simple test chemistry called STOP (SHERLOCK Testing in One Pot) for detecting SARS-CoV-2 in one hour that is suitable for point-of-care use. This simplified test, STOPCovid, provides sensitivity comparable to RT-qPCR-based SARS-CoV-2 tests and has a limit of detection of 100 copies of viral genome input in saliva or nasopharyngeal swabs per reaction. Using lateral flow readout, the test returns result in 70 minutes, and using fluorescence readout, the test returns result in 40 minutes. Moreover, we validated STOPCovid using nasopharyngeal swabs from COVID-19 patients and were able to correctly diagnose 12 positive and 5 negative patients out of 3 replicates. We envision that implementation of STOPCovid will significantly aid “test-trace-isolate” efforts, especially in low-resource settings, which will be critical for long-term public health safety and effective reopening of the society.
Omics BioAnalytics: Reproducible Research using R Shiny and Alexa
Authors: Singh Amrit , Tebbutt Scott J. , McManus Bruce M.
Published: May 2020

High-throughput technologies produce complex high-dimensional datasets which are analyzed using a variety of ever-evolving bioinformatics tools. Well-designed web frameworks enable more intuitive and efficient analysis such that less time is spent on coding and more time is spent on interpretation of results and addressing insightful biological questions aided by interactive visualizations. Here, we present Omics BioAnalytics, a full-service Web framework that enables comprehensive, multi-level characterization, analysis, and integration of omics datasets. Blending web-based (R Shiny) and voice-based (Amazon’s Alexa) analytics, Omics BioAnalytics can be used both by expert computational biologists and non-coding biological domain experts, alike. Our web framework can be utilized to explore complex datasets and identify biosignatures and discriminative biomarkers of health and disease processes, and generate testable hypotheses relating to underlying molecular mechanisms.

Availability

Omics BioAnalytics is freely available athttps://github.com/singha53/omicsBioAnalyticsand the web app is deployed athttps://amritsingh.shinyapps.io/omicsBioAnalytics/. The source code for the companion Alexa Skill can be found athttps://github.com/singha53/omics-bioanalytics-alexa-skill.
Multidimensional plasticity in the Glanville fritillary butterfly: larval performance curves are temperature, host and family specific
Authors: Verspagen Nadja , Ikonen Suvi , Saastamoinen Marjo , Bergen Erik van
Published: May 2020

Variation in environmental conditions during development can lead to changes in life-history traits with long-lasting effects. Here, we study environmentally induced variation, i.e. the consequences of potential maternal oviposition choices, in a suite of life-history traits in pre-diapause larvae of the Glanville fritillary butterfly. We focus on offspring survival, early growth rates and relative fat reserves, and pay specific attention to intraspecific variation in the responses (GxExE). Globally, we found that thermal performance and survival curves varied between diets of two host plants, suggesting that host modifies the temperature impact, orvice versa. Additionally, we show that the relative fat content has a host-dependent, discontinuous response to developmental temperature. This implies that a potential switch in resource allocation, from more investment in growth at lower temperatures to storage at higher temperatures, is dependent on other environmental variables. Interestingly, we find that a large proportion of the variance in larval performance is explained by differences among families, or interactions with this variable. Finally, we demonstrate that these family-specific responses to the host plant remain largely consistent across thermal environments. Altogether, the results of our study underscore the importance of paying attention to intraspecific trait variation in the field of evolutionary ecology.
Single cell resolution landscape of equine peripheral blood mononuclear cells reveals diverse immune cell subtypes including T-bet+B cells
Authors: Patel Roosheel S. , Tomlinson Joy E. , Divers Thomas J. , Van de Walle Gerlinde R. , Rosenberg Brad R.
Published: May 2020

Traditional laboratory model organisms represent a small fraction of the diversity of multicellular life, and findings in any given experimental model often do not translate to other species. Immunology research in non-traditional model organisms can be advantageous or even necessary (e.g. for host-pathogen interaction studies), but presents multiple challenges, many stemming from an incomplete understanding of potentially species-specific immune cell types, frequencies and phenotypes. Identifying and characterizing immune cells in such organisms is frequently limited by the availability of species-reactive immunophenotyping reagents for flow cytometry, and insufficient prior knowledge of cell type-defining markers. Here, we demonstrate the utility of single cell RNA sequencing (scRNA-Seq) to characterize immune cells for which traditional experimental tools are limited. Specifically, we used scRNA-Seq to comprehensively define the cellular diversity of equine peripheral blood mononuclear cells (PBMCs) from healthy horses across different breeds, ages, and sexes. We identified 30 cell type clusters partitioned into five major populations: Monocytes/Dendritic Cells, B cells, CD3+PRF1+lymphocytes, CD3+PRF1-lymphocytes, and Basophils. Comparative analyses revealed many cell populations analogous to human PBMC, including transcriptionally heterogeneous monocytes and distinct dendritic cell subsets (cDC1, cDC2, plasmacytoid DC). Unexpectedly, we found that a majority of the equine peripheral B cell compartment is comprised of T-bet+B cells; an immune cell subpopulation typically associated with chronic infection and inflammation in human and mouse. Taken together, our results demonstrate the potential of scRNA-Seq for cellular analyses in non-traditional model organisms, and form the basis for an immune cell atlas of horse peripheral blood.
Repeated genomic signatures of adaptation to urbanisation in a songbird across Europe
Authors: Salmón Pablo , Jacobs Arne , Ahrén Dag , Biard Clotilde , Dingemanse Niels J. , Dominoni Davide M. , Helm Barbara , Lundberg Max , Senar Juan Carlos , Sprau Philipp , Visser Marcel E. , Isaksson Caroline
Published: May 2020

Urbanisation is currently increasing worldwide, and there is now ample evidence of phenotypic changes in wild organisms in response to this novel environment, but the extent to which this adaptation is due to genetic changes is poorly understood. Current evidence for evolution is based on localised studies, and thus lacking replicability. Here, we genotyped great tits (Parus major) from nine cities across Europe, each paired with a rural site, and provide evidence of repeated polygenic responses to urban habitats. In addition, we show that selective sweeps occurred in response to urbanisation within the same genes across multiple cities. These genetic responses were mostly associated with genes related to neural function and development, demonstrating that genetic adaptation to urbanisation occurred around the same pathways in wildlife populations across a large geographical scale.
RNA and DNA G-quadruplexes bind to human Dicer and inhibit its activity
Authors: Koralewska Natalia , Szczepanska Agnieszka , Ciechanowska Kinga , Wojnicka Marta , Pokornowska Maria , Milewski Marek C. , Gudanis Dorota , Baranowski Daniel , Nithin Chandran , Bujnicki Janusz M. , Gdaniec Zofia , Figlerowicz Marek , Kurzynska-Kokorniak Anna
Published: May 2020

Guanine (G)-rich single-stranded nucleic acids can adopt G-quadruplex structures. Accumulating evidence indicates that G-quadruplexes serve important regulatory roles in fundamental biological processes such as DNA replication, transcription, and translation, while aberrant G-quadruplex formation is linked to genome instability and cancer. Understanding the biological functions played by G-quadruplexes requires detailed knowledge of their protein interactome. Here, we report that both RNA and DNA G-quadruplexes are bound by human Dicerin vitro. Usingin vitrobinding assays, mutation studies, and computational modeling we demonstrate that G-quadruplexes can interact with the Platform-PAZ-Connector helix cassette of Dicer, the region responsible for anchoring microRNA precursors (pre-miRNAs). Consequently, we show that G-quadruplexes efficiently and stably inhibit the cleavage of pre-miRNA by Dicer. Our data highlight the potential of human Dicer for binding of G-quadruplexes and allow us to propose a G-quadruplex-driven sequestration mechanism of Dicer regulation.
Predicting dynamic cellular protein-RNA interactions using deep learning andin vivoRNA structure
Authors: Sun Lei , Xu Kui , Huang Wenze , Yang Yucheng T. , Tang Lei , Xiong Tuanlin , Zhang Qiangfeng Cliff
Published: May 2020

Interactions with RNA-binding proteins (RBPs) are crucial for RNA regulation and function. While both RNA sequence and structure are critical determinants, RNA structure is dependent on cellular environment and especially important in regulating dynamic RBP bindings across various conditions. However, how distinct it contributes to RBP bindingin vivoremains poorly understood. To address this issue, we obtained transcriptome-wide RNA secondary structure profiles in multiple cell-types, and established a deep neural network, PrismNet, that uses invivoRNA structures to accurately predict cellular protein-RNA interactions. With a deep learning “attention” strategy, PrismNet discovers the exact binding nucleotides and their mutational effect. The predicted binding sites are highly conserved and enriched for rare, deleterious genetic variants. Remarkably, dynamic RBP binding sites are enriched for structure-changing variants (riboSNitches), which are often associated with disease, reflecting dysregulated RBP bindings. Our resource enables the analysis of cell-type-specific RNA regulation, with applications in human disease.

Highlights

1, A big data resource of transcriptome-wide RNA secondary structure profiles in multiple cell types

2, PrismNet, a deep neural network, accurately models the sequence and structural combined patterns of protein-RNA interactionsin vivo

3, RNA structural informationin vivois critical for the accurate prediction of dynamic RBP binding in various cellular conditions

4, PrismNet can dissect and predict how mutations affect RBP binding via RNA sequence or structure changes

5, RNA structure-changing RiboSNitches are enriched in dynamic RBP binding sites and often associated with disease, likely disrupting RBP-based regulation
Genetic structure and molecular diversity of Brazilian grapevine germplasm: management and use in breeding programs
Authors: de Oliveira Geovani Luciano , de Souza Anete Pereira , de Oliveira Fernanda Ancelmo , Zucchi Maria Imaculada , de Souza Lívia Moura , Moura Mara Fernandes
Published: May 2020

The management of germplasm banks is complex, especially when many accessions are involved. Microsatellite markers are an efficient tool for assessing the genetic diversity of germplasm collections, optimizing their use in breeding programs. This study genetically characterizes a large collection of 410 grapevine accessions maintained at the Agronomic Institute of Campinas (IAC) (Brazil). The accessions were genotyped with 17 highly polymorphic microsatellite markers. Genetic data were analyzed to determine the genetic structure of the germplasm, quantify its allelic diversity, suggest the composition of a core collection, and discover cases of synonymy, duplication, and misnaming. A total of 304 alleles were obtained, and 334 unique genotypes were identified. The molecular profiles of 145 accessions were confirmed according to the literature and databases, and the molecular profiles of more than 100 genotypes were reported for the first time. The analysis of the genetic structure revealed different levels of stratification. The primary division was between accessions related toVitis viniferaandV. labrusca, followed by their separation from wild grapevine. A core collection of 120 genotypes captured 100% of all detected alleles. The accessions selected for the core collection may be used in future phenotyping efforts, in genome association studies, and for conservation purposes. Genetic divergence among accessions has practical applications in grape breeding programs, as the choice of relatively divergent parents will maximize the frequency of progeny with superior characteristics. Together, our results can enhance the management of grapevine germplasm and guide the efficient exploitation of genetic diversity to facilitate the development of new grape cultivars for fresh fruits, wine, and rootstock.
Validity of the Lumen®hand-held metabolic device to measure fuel utilization in healthy young adults
Authors: Lorenz Kent A. , Yeshurun Shlomo , Aziz Richard , Ortiz-Delatorre Julissa , Bagley James R. , Mor Merav , Kern Marialice
Published: May 2020

Background

Metabolic carts measure the carbon dioxide produced and oxygen consumed from the breath in order to assess metabolic fuel usage (carbohydrates vs. fats). However, these systems are expensive, time-consuming, and only available in the clinic. A small hand-held device capable of measuring metabolic fuel via CO2from exhaled air has been developed

Objective

To evaluate the validity of a novel hand-held device (Lumen®) for measuring metabolic fuel utilization in healthy young adults

Methods

Metabolic fuel usage was assessed in healthy participants (n = 33; age: 23.1 ± 3.9 y) via respiratory exchange ratio (RER) values from the “gold-standard” metabolic cart as well as %CO2from the Lumen device. Measurements were performed at rest in two conditions, fasting, and after consuming 150 grams of glucose in order to determine changes in metabolic fuel. Reduced major axis regression was performed as well as Bland-Altman plots and linear regressions to test for agreement between RER and Lumen %CO2.

Results

Both RER and Lumen %CO2significantly increased after glucose intake compared with fasting conditions (P< .0001). Regression analyses and Bland-Altman plots revealed an agreement between the two measurements with a systematic bias resulting from the nature of the different units.

Conclusions

This study shows the validity of Lumen®to estimate metabolic fuel utilization in a comparable manner with the “gold-standard” metabolic cart, providing the ability for real-time metabolic information for users under any circumstances.
Where in the leaf is intercellular CO2(Ci)? Considerations and recommendations for assessing gaseous diffusion in leaves
Authors: Stinziano Joseph R. , Tominaga Jun , Hanson David T.
Published: May 2020

The assumptions that water vapor exchange occurs exclusively through stomata, that the intercellular airspace is fully saturated with water vapor, and that CO2gradients are negligible between stomata and the intercellular airspace have enabled significant advancements in photosynthetic gas exchange research for nearly 60 years via calculation of intercellular CO2(Ci). However, available evidence suggests that these assumptions may be overused. Here we review the literature surrounding evidence for and against the assumptions made by Moss & Rawlins (1963). We reinterpret data from the literature by propagating different rates of cuticular water loss, CO2gradients, and unsaturation through the data. We find that in general, when cuticle conductance is less than 1% of stomatal conductance, the assumption that water vapor exchange occurs exclusively through stomata has a marginal effect on gas exchange calculations, but this is not true when cuticle conductance exceeds 5% of stomatal conductance. Our analyses further suggest that CO2and water vapor gradients have stronger impacts at higher stomatal conductance, while cuticle conductance has a greater impact at lower stomatal conductance. Therefore, we recommend directly measuring Ciwhenever possible, measuring apoplastic water potentials to estimate humidity inside the leaf, and exercising caution when interpreting data under conditions of high temperature and/or low stomatal conductance, and when a species is known to have high cuticular conductance.

Highlight

Leaf water vapor and CO2exchange have been successfully used to model photosynthetic biochemistry. We review critical assumptions in these models and make recommendations about which need to be re-assessed.
Phenotype Heritability in holobionts: An Evolutionary Model
Authors: Huitzil Saúl , Sandoval-Motta Santiago , Frank Alejandro , Aldana Maximino
Published: May 2020

Many complex diseases are expressed with high incidence only in certain populations. Genealogy studies determine that these diseases are inherited with a high probability. However, genetic studies have been unable to identify the genomic signatures responsible for such heritability, as identifying the genetic variants that make a population prone to a given disease is not enough to explain its high occurrence within the population. This gap is known as the missing heritability problem. We know that the microbiota plays a very important role in determining many important phenotypic characteristics of its host, in particular, the complex diseases for which the missing heritability occurs. Therefore, when computing the heritability of a phenotype it is important to consider not only the genetic variation in the host but also in its microbiota. Here we test this hypothesis by studying an evolutionary model based on gene regulatory networks. Our results show that the holobiont (the host plus its microbiota) is capable of generating a much larger variability than the host alone, greatly reducing the missing heritability of the phenotype. This result strongly suggests that a considerably large part of the missing heritability can be attributed to the microbiome.
Chromatin profiling reveals reorganization of lysine specific demethylase 1 by an oncogenic fusion protein
Authors: Theisen Emily R. , Selich-Anderson Julia , Miller Kyle R. , Tanner Jason M. , Taslim Cenny , Pishas Kathleen I. , Sharma Sunil , Lessnick Stephen L.
Published: May 2020

Pediatric cancers commonly harbor quiet mutational landscapes and are instead characterized by single driver events such as the mutation of critical chromatin regulators, expression of oncohistones, or expression of oncogenic fusion proteins. These events ultimately promote malignancy through disruption of normal gene regulation and development. The driver protein in Ewing sarcoma, EWS/FLI, is an oncogenic fusion and transcription factor that reshapes the enhancer landscape, resulting in widespread transcriptional dysregulation. Lysine-specific demethylase 1 (LSD1) is a critical functional partner for EWS/FLI as inhibition of LSD1 reverses the transcriptional activity of EWS/FLI. However, how LSD1 participates in fusion-directed epigenomic regulation and aberrant gene activation is unknown. We now show EWS/FLI causes dynamic rearrangement of LSD1 and we uncover a role for LSD1 in gene activation through colocalization at EWS/FLI binding sites throughout the genome. LSD1 is integral to the establishment of Ewing sarcoma super-enhancers at GGAA-microsatellites, which ubiquitously overlap non-microsatellite loci bound by EWS/FLI. Together, we show that EWS/FLI induces widespread changes to LSD1 distribution in a process that impacts the enhancer landscape throughout the genome.
Rare variant enriched identity-by-descent enables the detection of distant relatedness and older divergence between populations
Authors: Shetty Amol C. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,   TOPMed Population Genetics Working Group, O’Connell Jeffrey , Mitchell Braxton D. , O’Connor Timothy D.
Published: May 2020

Motivation

The global human population has experienced an explosive growth from a few million to roughly 7 billion people in the last 10,000 years. Accompanying this growth has been the accumulation of rare variants that can inform our understanding of human evolutionary history. Common variants have primarily been used to infer the structure of the human population and relatedness between two individuals. However, with the increasing abundance of rare variants observed in large-scale projects, such as Trans-Omics for Precision Medicine (TOPMed), the use of rare variants to decipher cryptic relatedness and fine-scale population structure can be beneficial to the study of population demographics and association studies. Identity-by-descent (IBD) is an important framework used for identifying these relationships. IBD segments are broken down by recombination over time, such that longer shared haplotypes give strong evidence of recent relatedness while shorter shared haplotypes are indicative of more distant relationships. Current methods to identify IBD accurately detect only long segments (> 2cM) found in related individuals.

Algorithm

We describe a metric that leverages rare-variants shared between individuals to improve the detection of short IBD segments. We computed IBD segments using existing methods implemented inRefined IBDwhere we enrich the signal using our metric that facilitates the detection of short IBD segments (<2cM) by explicitly incorporating rare variants.

Results

To test our new metric, we simulated datasets involving populations with varying divergent time-scales. We show that rare-variant IBD identifies shorter segments with greater confidence and enables the detection of older divergence between populations. As an example, we applied our metric to the Old-Order Amish cohort with known genealogies dating 14 generations back to validate its ability to detect genetic relatedness between distant relatives. This analysis shows that our method increases the accuracy of identifying shorter segments that in turn capture distant relationships.

Conclusions

We describe a method to enrich the detection of short IBD segments using rare-variant sharing within IBD segments. Leveraging rare-variant sharing improves the information content of short IBD segments better than common variants alone. We validated the method in both simulated and empirical datasets. This method can benefit association analyses, IBD mapping analyses, and demographic inferences.
Comprehensive mapping of the human cytokine gene regulatory network
Authors: Santoso CS , Li Z , Lal S , Yuan S , Gan KA , Agosto LM , Liu X , Carrasco Pro S , Sewell JA , Henderson A , Atianand MK , Fuxman Bass JI
Published: May 2020

Proper cytokine gene expression is essential in development, homeostasis, and immune responses. Studies on the transcriptional control of cytokine genes have mostly focused on highly researched transcription factors (TFs) and cytokines, resulting in an incomplete portrait of cytokine gene regulation. Here, we use enhanced yeast one-hybrid (eY1H) assays to derive a comprehensive network comprising 1,380 interactions between 265 TFs and 108 cytokine gene promoters, greatly expanding the known repertoire of TF-cytokine gene interactions. We found an enrichment of nuclear receptors and confirmed their role in cytokine regulation in primary macrophages. Additionally, we used the eY1H-derived network as a framework to identify pairs of TFs that synergistically modulate cytokine gene expression, and to identify novel TF-cytokine regulatory axes in immune diseases and immune cell lineage development. Overall, the eY1H data provides a rich resource to study cytokine regulation in a variety of physiological and disease contexts.
Programmable gene regulation for metabolic engineering using decoy transcription factor binding sites
Authors: Wang Tiebin , Tague Nathan , Whelan Stephen , Dunlop Mary J.
Published: May 2020

Transcription factor decoy binding sites are short DNA sequences that can serve as “sponges” to titrate a transcription factor away from its natural binding site, therefore regulating gene expression. In this study, we harness decoy sites to develop synthetic transcription factor sponge systems to regulate gene expression for metabolic pathways inEscherichia coli.We show that transcription factor sponges can effectively regulate expression of native and heterologous genes. Tunability of the sponge can be engineered via changes in copy number or modifications to the DNA decoy site sequence. Using arginine biosynthesis as a showcase, we observe a 16-fold increase in arginine production when we introduce the sponge system to steer metabolic flux towards increased arginine biosynthesis, with negligible growth differences compared to the wild type strain. The sponge-based production strain shows high genetic stability; in contrast to a gene knock-out approach where mutations were common, we detected no mutations in the production system using the sponge-based strain. We further show that transcription factor sponges are amenable to multiplexed library screening by demonstrating enhanced tolerance to pinene with a combinatorial sponge library. Our study shows that transcription factor sponges are a powerful and compact tool for metabolic engineering.
Optimal protocols for sequence-based characterization of the human vaginal microbiome
Authors: Hugerth Luisa W. , Pereira Marcela , Zha Yinghua , Seifert Maike , Kaldhusdal Vilde , Boulund Fredrik , Krog Maria C , Bashir Zahra , Hamsten Marica , Fransson Emma , Svarre-Nielsen Henriette , Schuppe-Koistinen Ina , Engstrand Lars
Published: May 2020

The vaginal microbiome has been connected to a wide range of health outcomes. This has led to a thriving research environment, but also to the use of conflicting methodologies to study its microbial composition. Here we systematically assess best practices for the sequencing-based characterization of the human vaginal microbiome. As far as 16S rRNA gene sequencing is concerned, the V1-V3 region has the best theoretical properties, but limitations of current sequencing technologies mean that the V3-V4 region performs equally well. Both of these approaches present very good agreement with qPCR quantification of key taxa, provided an appropriate bioinformatic pipeline is used. Shotgun metagenomic sequencing presents an interesting alternative to 16S amplification and sequencing, but it is not without its challenges. We have assessed different tools for the removal of host reads and the taxonomic annotation of metagenomic reads, including a new, easy-to-build and – use, reference database of vaginal taxa. This strategy performed as well as the best performing previously published strategies. Despite the many advantages of shotgun sequencing none of the shotgun approaches assessed here had as good agreement with the qPCR data as 16S rRNA gene sequencing.

Importance

The vaginal microbiome has been connected to a wide range of health outcomes, from susceptibility to sexually transmitted infections to gynecological cancers and pregnancy outcomes. This has led to a thriving research environment, but also to conflicting available methodologies, including many studies that do not report their molecular biological and bioinformatic methods in sufficient detail for them to be considered reproducible. This can lead to conflicting messages and delay progress from descriptive to intervention studies. By systematically assessing best practices for the characterization of the human vaginal microbiome, this study will enable past studies to be assessed more critically and assist future studies in the selection of appropriate methods for their specific research questions.
The spatial percept of tinnitus is associated with hearing asymmetry: subgroup comparisons
Authors: Genitsaridi Eleni , Kypraios Theodore , Edvall Niklas K. , Trpchevska Natalia , Canlon Barbara , Hoare Derek J. , Cederroth Christopher R. , Hall Deborah A.
Published: May 2020

The spatial percept of tinnitus is hypothesized as an important variable for tinnitus subtyping. Hearing asymmetry often associates with tinnitus laterality, but not always. One of the methodological limitations for cross-study comparisons is how the variables for hearing asymmetry and tinnitus spatial perception are defined. In this study, data from two independent datasets were combined (n= 833 adults, age ranging from 20 to 91 years, 404 males, 429 females) to investigate characteristics of subgroups with different tinnitus spatial perception focusing on hearing asymmetry. Three principle findings emerged. First, a hearing asymmetry variable emphasizing the maximum interaural difference most strongly discriminated unilateral from bilateral tinnitus. Merging lateralized bilateral tinnitus (perceived in both ears but worse in one side) with unilateral tinnitus weakened this relationship. Second, there was an association between unilateral tinnitus and ipsilateral asymmetric hearing. Third, unilateral and bilateral tinnitus were phenotypically distinct, with unilateral tinnitus being characterized by older age, asymmetric hearing, more often wearing one hearing aid, older age at tinnitus onset, shorter tinnitus duration, and higher percentage of time being annoyed by tinnitus. We recommend that careful consideration is given to the definitions of hearing asymmetry and tinnitus spatial perception in order to improve the comparability of findings across studies.
Extending A Chronological and Geographical Analysis of Personal Reports of COVID-19 on Twitter to England, UK
Authors: Golder S , Klein Ari Z. , Magge Arjun , O’Connor Karen , Cai Haitao , Weissenbacher Davy , Gonzalez-Hernandez Graciela
Published: May 2020

The rapidly evolving COVID-19 pandemic presents challenges for actively monitoring its transmission. In this study, we extend a social media mining approach used in the US to automatically identify personal reports of COVID-19 on Twitter in England, UK. The findings indicate that natural language processing and machine learning framework could help provide an early indication of the chronological and geographical distribution of COVID-19 in England.
Sensitivity of Nasopharyngeal, Nasal and Throat Swab for the Detection of SARS-CoV-2
Authors: Berenger Byron Michael , Fonseca Kevin , Schneider Angela R , Hu Jia , Zelyas Nathan
Published: May 2020

Nasopharyngeal (NP), nasal and throat swabs are the most practical specimen sources to test for upper respiratory pathogens. We compared the sensitivity of NP, nasal and throat swabs to detect SARS-CoV-2 in community patients. Using detection at any site as the standard, the sensitivities were 90%, 80% and 87% for NP, nasal and throat respectively (n=30 positive at any site). Throat swabs are likely a suitable alternative to NP swabs for the detection of COVID-19 infections.
CoVID-19 prediction for India from the existing data and SIR(D) model study
Authors: Rajesh Aditya , Pai Haidas , Roy Victor , Samanta Subhasis , Ghosh Sabyasachi
Published: May 2020

CoVID-19 is spreading throughout the world at an alarming rate. So far it has spread over 200 countries in the whole world. Mathematical modelling of an epidemic like CoVID-19 is always useful for strategic decision making, especially it is very useful to gain some understanding of the future of the epidemic in densely populous countries like India. We use a simple yet effective mathematical model SIR(D) to predict the future of the epidemic in India by using the existing data. We also estimate the effect of lock-down/social isolation via a time-dependent coefficient of the model. The model study with realistic parameters set shows that the epidemic will be at its peak around the end of June or the first week of July with almost 108 Indians most likely being infected if the lock-down relaxed after May 3, 2020. However, the total number of infected population will become one-third of what predicted here if we consider that people only in the red zones (approximately one-third of India's population) are susceptible to the infection. Even in a very optimistic scenario we expect that at least the infected numbers of people will be of the order of 107.
Longitudinal peripheral blood transcriptional analysis of COVID-19 patients captures disease progression and reveals potential biomarkers
Authors: Yan Qihong , Li Pingchao , Ye Xianmiao , Huang Xiaohan , Mo Xiaoneng , Wang Qian , Zhang Yudi , Luo Kun , Chen Zhaoming , Luo Jia , Niu Xuefeng , Feng Ying , Ji Tianxing , Feng Bo , Wang Jinlin , Li Feng , Zhang Fuchun , Li Fang , Wang Jianhua , Feng Liqiang , Chen Zhilong , Lei Chunliang , Qu Linbing , Chen Ling
Published: May 2020

COVID-19, caused by SARS-CoV-2, is an acute self-resolving disease in most of the patients, but some patients can develop a severe illness or even death. To characterize the host responses and identify potential biomarkers during disease progression, we performed a longitudinal transcriptome analysis for peripheral blood mononuclear cells (PBMCs) collected from 4 COVID-19 patients at 4 different time points from symptom onset to recovery. We found that PBMCs at different COVID-19 disease stages exhibited unique transcriptome characteristics. SARS-CoV-2 infection dysregulated innate immunity especially type I interferon response as well as the disturbed release of inflammatory cytokines and lipid mediators, and an aberrant increase of low-density neutrophils may cause tissue damage. Activation of cell death, exhaustion and migratory pathways may lead to the reduction of lymphocytes and dysfunction of adaptive immunity. COVID-19 induced hypoxia may exacerbate disorders in blood coagulation. Based on our analysis, we proposed a set of potential biomarkers for monitoring disease progression and predicting the risk of severity.