bluuebunny/crossref_metadata_2025 huggingface dataset:
A tale of two sites – II. Inferring the properties of minihalo-hosted galaxies with upcoming 21-cm interferometers
Authors: Qin Yuxiang , Mesinger Andrei , Greig Bradley , Park Jaehong
Published: October 2020

The first generation of galaxies is expected to form in minihaloes, accreting gas through H2 cooling, and possessing unique properties. Although unlikely to be directly detected in UV/infrared surveys, the radiation from these molecular-cooling galaxies (MCGs) could leave an imprint in the 21-cm signal from the Cosmic Dawn. Here, we quantify their detectability with upcoming radio interferometers. We generate mock 21-cm power spectra using a model for both MCGs as well as more massive, atomic-cooling galaxies, allowing both populations to have different properties and scaling relations. The galaxy parameters are chosen so as to be consistent with: (i) high-redshift UV luminosity functions; (ii) the upper limit on the neutral fraction from QSO spectra; (iii) the Thomson scattering optical depth to the CMB; and (iv) the timing of the recent putative EDGES detection. The latter implies a significant contribution of MCGs to the Cosmic Dawn, if confirmed to be cosmological. We then perform Bayesian inference on two models including and ignoring MCG contributions. Comparing their Bayesian evidences, we find a strong preference for the model including MCGs, despite the fact that it has more free parameters. This suggests that if MCGs indeed play a significant role in the Cosmic Dawn, it should be possible to infer their properties from upcoming 21-cm power spectra. Our study illustrates how these observations can discriminate among uncertain galaxy formation models with varying complexities, by maximizing the Bayesian evidence.
G4-iM Grinder: when size and frequency matter. G-Quadruplex, i-Motif and higher order structure search and analysis tool
Authors: Belmonte-Reche Efres , Morales Juan Carlos
Published: October 2020

We present G4-iM Grinder, a system for the localization, characterization and selection of potential G4s, i-Motifs and higher order structures. A robust and highly adaptable search engine identifies all structures that fit the user’s quadruplex definitions. Their biological relevance, in vitro formation probability and presence of known-to-form structures are then used as filters. The outcome is an efficient methodology that helps select the best candidates for a subsequent in vitro analysis or a macroscopic genomic quadruplex assessment. As proof of the analytical capabilities of G4-iM Grinder, the human genome was analyzed for potential G4s and i-Motifs. Many known-to-form structures were identified. New candidates were selected considering their score and appearance frequency. We also focused on locating Potential Higher Order Quadruplex Sequences (PHOQS). We developed a new methodology to predict the most probable subunits of these assemblies and applied it to a PHOQS candidate. Taking the human average density as reference, we examined the genomes of several etiological causes of disease. This first of its class comparative study found many organisms to be very dense in these potential quadruplexes. Many presented already known-to-form-G4s and i-Motifs. These findings suggest the potential quadruplexes have as therapeutic targets for these diseases that currently kill millions worldwide.
Novel in vitro assays to detect circulating permeability factor(s) in idiopathic focal segmental glomerulosclerosis
Authors: den Braanker Dirk J W , Maas Rutger J , Deegens Jeroen K , Yanginlar Cansu , Wetzels Jack F M , van der Vlag Johan , Nijenhuis Tom
Published: October 2020

Background

Many patients with idiopathic focal segmental glomerulosclerosis (FSGS) develop recurrence of proteinuria after kidney transplantation (TX). Although several circulating permeability factors (CPFs) responsible for recurrence have been suggested, there is no consensus. To facilitate CPF identification and predict recurrence after TX, there is a need for robust methods that demonstrate the presence of CPFs.

Methods

Cultured human podocytes (hPods) and human and mouse glomerular endothelial cells (ciGEnC, mGEnC) were exposed to plasmas of FSGS patients with presumed CPFs, and of (disease) controls. A visual scoring assay and flow cytometry analysis of side scatter were used to measured changes in cellular granularity after exposure to plasma.

Results

Nine out of 13 active disease plasmas of 10 FSGS patients with presumed CPFs induced granularity in hPod in a dose- and time-dependent manner. Corresponding remission plasmas induced no or less granularity in hPod. Similar results were obtained with ciGEnC and mGEnC, although induced granularity was less compared with hPod. Notably, foetal calf serum, healthy plasma and a remission plasma partially blocked FSGS plasma-induced hPod granularity.

Conclusions

We developed a novel assay in which active disease, presumably CPF-containing, FSGS plasmas induced granularity in cultured hPod. Our results may indicate the presence of CPF inhibitor(s) in healthy and remission plasma. We suggest the presence of a delicate balance between CPF and a CPF inhibitory factor, which is disturbed in patients with active disease. Our novel assays can be applied in future research to identify CPF and CPF inhibitors, and possibly to predict recurrence after TX.
Temporal controls on crown nonstructural carbohydrates in southwestern US tree species
Authors: Peltier Drew M P , Guo Jessica , Nguyen Phiyen , Bangs Michael , Gear Linnea , Wilson Michelle , Jefferys Stacy , Samuels-Crow Kimberly , Yocom Larissa L , Liu Yao , Fell Michael K , Auty David , Schwalm Christopher , Anderegg William R L , Koch George W , Litvak Marcy E , Ogle Kiona
Published: October 2020

In trees, large uncertainties remain in how nonstructural carbohydrates (NSCs) respond to variation in water availability in natural, intact ecosystems. Variation in NSC pools reflects temporal fluctuations in supply and demand, as well as physiological coordination across tree organs in ways that differ across species and NSC fractions (e.g., soluble sugars vs starch). Using landscape-scale crown (leaves and twigs) NSC concentration measurements in three foundation tree species (Populus tremuloides, Pinus edulis, Juniperus osteosperma), we evaluated in situ, seasonal variation in NSC responses to moisture stress on three timescales: short-term (via predawn water potential), seasonal (via leaf δ13C) and annual (via current year’s ring width index). Crown NSC responses to moisture stress appeared to depend on hydraulic strategy, where J. osteosperma appears to regulate osmotic potentials (via higher sugar concentrations), P. edulis NSC responses suggest respiratory depletion and P. tremuloides responses were consistent with direct sink limitations. We also show that overly simplistic models can mask seasonal and tissue variation in NSC responses, as well as strong interactions among moisture stress at different timescales. In general, our results suggest large seasonal variation in crown NSC concentrations reflecting the multiple cofunctions of NSCs in plant tissues, including storage, growth and osmotic regulation of hydraulically vulnerable leaves. We emphasize that crown NSC pool size cannot be viewed as a simple physiological metric of stress; in situ NSC dynamics are complex, varying temporally, across species, among NSC fractions and among tissue types.
Risk factors and clinical course of children with cystic fibrosis colonized with Staphylococcus aureus
Authors: Ghimire Jagat Jeevan , Gulla Krishna Mohan , Jat Kana Ram , Sankar Jhuma , Lodha Rakesh , Kabra S K
Published: October 2020

Background

The literature is limited on staphylococcal infection in children with cystic fibrosis (CF) from tropical countries. We aimed to study the risk factors and clinical course of children with CF infected with Staphylococcus aureus.

Methods

In this chart review we compared demographic, clinical and spirometry characteristics in CF children with S. aureus alone (group A), both S. aureus and Pseudomonas aeruginosa (group B) and P. aeruginosa alone (group C) colonization.

Results

We included 79 cases (group A, 22; group B, 19; group C, 38). There was no difference in age of onset of symptoms, age of diagnosis, age of first isolation and spirometry parameters before colonization between the groups. The median duration of follow-up was shorter in group A. After colonization, children in group A and group B had significantly lower mean Shwachman and Kulczycki (SK) scores (44.7±5.4 and 40.8±5.8, respectively) compared with group C (49.9±6.8). Pulmonary exacerbations and hospitalizations were significantly greater in the combined group. After colonization, group A had a significant deterioration in SK score and forced vital capacity (FVC).

Conclusions

S. aureus colonization, especially in combination with P. aeruginosa, in children with CF was associated with worsening of FVC and clinical severity score and increased pulmonary exacerbations.
Aerosol Retention Characteristics of Barrier Devices
Authors: Fidler Richard L. , Niedek Christopher R. , Teng Justin J. , Sturgeon Mary E. , Zhang Qi , Robinowitz David L. , Hirsch Jan
Published: October 2020

Background

Disease severity in coronavirus disease 2019 (COVID-19) may be associated with inoculation dose. This has triggered interest in intubation barrier devices to block droplet exposure; however, aerosol protection with these devices is not known. This study hypothesized that barrier devices reduce aerosol outside of the barrier.

Methods

Aerosol containment in closed, semiclosed, semiopen, and open barrier devices was investigated: (1) “glove box” sealed with gloves and caudal drape, (2) “drape tent” with a drape placed over a frame, (3) “slit box” with armholes and caudal end covered by vinyl slit diaphragms, (4) original “aerosol box,” (5) collapsible “interlocking box,” (6) “simple drape” over the patient, and (7) “no barrier.” Containment was investigated by (1) vapor instillation at manikin’s right arm with video-assisted visual evaluation and (2) submicrometer ammonium sulfate aerosol particles ejected through the manikin’s mouth with ventilation and coughs. Samples were taken from standardized locations inside and around the barriers using a particle counter and a mass spectrometer. Aerosol evacuation from the devices was measured using standard hospital suction, a surgical smoke evacuator, and a Shop-Vac.

Results

Vapor experiments demonstrated leakage via arm holes and edges. Only closed and semiclosed devices and the aerosol box reduced aerosol particle counts (median [25th, 75th percentile]) at the operator’s mouth compared to no barrier (combined median 29 [−11, 56], n = 5 vs. 157 [151, 166], n = 5). The other barrier devices provided less reduction in particle counts (133 [128, 137], n = 5). Aerosol evacuation to baseline required 15 min with standard suction and the Shop-Vac and 5 min with a smoke evacuator.

Conclusions

Barrier devices may reduce exposure to droplets and aerosol. With meticulous tucking, the glove box and drape tent can retain aerosol during airway management. Devices that are not fully enclosed may direct aerosol toward the laryngoscopist. Aerosol evacuation reduces aerosol content inside fully enclosed devices. Barrier devices must be used in conjunction with body-worn personal protective equipment.

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Examining the burden of opioid prescribing for non-cancer pain considering socio-economic differences, in Wales. A retrospective database study examining trends between 2005 – 2015
Authors: Davies Emma , Sewell Bernadette , Jones Mari , Phillips Ceri , Rance Jaynie
Published: October 2020

Objectives

To use a proxy-measure of oral morphine equivalent dose (OMED) to determine trends in opioid burden in people with non-cancer pain and explore differences related to deprivation status.

Design, setting and participants

Retrospective cohort study using cross-sectional and longitudinal trend analyses of opioid prescribing data from 78% of Welsh Primary Care General Practices, whose data is shared with the Secure Anonymised Information Linkage (SAIL) databank. Anonymised data for the period 2005 to 2015, for people aged 18 or over, without a recorded cancer diagnosis and who received at least one prescription for an opioid medicine was included.

Primary and Secondary outcomes

A proxy-measure of oral morphine equivalence dose (OMED) was used to describe trends in opioid burden over the study period. OMED burden was stratified by 8 drug groups and deprivation, based on the quintile measures of the Welsh Index of Multiple Deprivation 2011 (WIMD2011).

Results

In the 11 years examined, 22 641 424 prescriptions for opioids were issued from 345 primary care general practices in Wales. Daily OMED per 1000 population increased by 94.7% (from 16 266 mg to 31 665 mg). Twenty-eight percent of opioid prescribing occurred in the most deprived quintile. More than 100 000 000mg more OMED was prescribed in the most deprived areas of Wales, compared to the least deprived. Codeine prescribing accounted for 35% of the OMED burden in Wales over the study period.

Conclusions

Whilst opioid prescription numbers increased 44% between 2005 and 2015, the OMED burden nearly doubled, with a disproportionate OMED load in the most deprived communities in Wales. Using OMED provides an insightful representation of opioid burden, more so than prescription numbers alone. Socio-economic differences are likely to affect pain presentation, access to support services and increase the likelihood of receiving an opioid prescription.

Strengths and limitations of this study

This study forms part of the first large-scale examination of opioid prescribing in Wales and is the first to use oral morphine equivalent dose as an outcome measure.

Access to anonymously linked data allows more detailed examination of demographic influences on opioid prescribing.

The study used a proxy-measure for oral morphine equivalent dose due to unavailability of anonymously linked prescription dispensing data.

Disproportionate levels of prescribing in particular populations have been reported in many countries; further research should seek to understand the reasons for the differences and develop means to address any inequality noted.
Digital Imaging and Vision Analysis in Science Project improves the self-efficacy and skill of undergraduate students in computational work
Authors: Brooks Tessa Durham , Burks Raychelle , Doyle Erin , Meysenburg Mark , Frey Tim
Published: October 2020

In many areas of science, the ability to use computers to process, analyze, and visualize large data sets has become essential. The mismatch between the ability to generate large data sets and the computing skill to analyze them is arguably the most striking within the life sciences. The Digital Image and Vision Applications in Science (DIVAS) project describes a scaffolded series of interventions implemented over the span of a year to build the coding and computing skill of undergraduate students majoring primarily in the natural sciences. The program is designed as a community of practice, providing support within a network of learners. The program focus, images as data, provides a compelling ‘hook’ for participating scholars. Scholars begin the program with a one-credit spring semester seminar where they are exposed to image analysis. The program continues in the summer with a one-week, intensive Python and image processing workshop. From there, scholars tackle image analysis problems using a pair programming approach and finish the summer with independent research. Finally, scholars participate in a follow-up seminar the following spring and help onramp the next cohort of incoming scholars. We observed promising growth in participant self-efficacy in computing that was maintained throughout the project as well as significant growth in key computational skills. DIVAS program funding was able to support seventeen DIVAS over three years, with 76% of DIVAS scholars identifying as women and 14% of scholars being members of an underrepresented minority group. Most scholars (82%) entered the program as freshmen, with 89% of DIVAS scholars retained for the duration of the program and 100% of scholars remaining a STEM major one year after completing the program. The outcomes of the DIVAS project support the efficacy of building computational skill through repeated exposure of scholars to relevant applications over an extended period within a community of practice.
Retrospective assessment of SARS-COV2 circulation in two hospital nurseries hosting healthcare workers’ children during lockdown in one of the most affected French areas
Authors: Penot Pauline , Delaval Anne , L’Hour Fabienne , Grenier Angélique , Harich Raya
Published: October 2020

Background

Evidence as to whether childcare and school closure limits the spread of SARS-CoV-2 virus is limited, especially because the role of children in SARS-CoV2 transmission remains unclear.

Methods

Between May 29 and July 2, 2020, a retrospective cohort study was conducted among two populations: requisitioned health-care workers and requisitioned staff from hospitals childcare centers, to investigate the virus circulation during lockdown, in a French area of high transmission.

Results

The infection attack rate was 6/52 (11.6%) and 8/46 (17.4%) among health-care workers and childcare staff, respectively. An early epidemic occurred among Montreuil s hospital childcare staff, but the parents were not affected (p=0.029). Among Aulnay-sous-bois childcare center, three staff members were infected but none of them was in charge of a child whose parents were infected. Also among the parents of the children they cared for, none developed antibodies. Out of 14 infections, 12 were reliable to a source of transmission, mostly among colleagues.

Discussion-conclusion

The assessment of viral circulation among healthcare workers and childcare staff suggests that the children did not contribute to SARS-CoV-2 spread in our setting.
Major new lineages of SARS-CoV-2 emerge and spread in South Africa during lockdown
Authors: Tegally Houriiyah , Wilkinson Eduan , Lessells Richard R , Giandhari Jennifer , Pillay Sureshnee , Msomi Nokukhanya , Mlisana Koleka , Bhiman Jinal , Allam Mushal , Ismail Arshad , Engelbrecht Susan , Van Zyl Gert , Preiser Wolfgang , Williamson Carolyn , Pettruccione Francesco , Sigal Alex , Gazy Inbal , Hardie Diana , Hsiao Marvin , Martin Darren , York Denis , Goedhals Dominique , San Emmanuel James , Giovanetti Marta , Lourenco Jose , Alcantara Luiz Carlos Junior , de Oliveira Tulio
Published: October 2020

In March 2020, the first cases of COVID-19 were reported in South Africa. The epidemic spread very fast despite an early and extreme lockdown and infected over 600,000 people, by far the highest number of infections in an African country. To rapidly understand the spread of SARS-CoV-2 in South Africa, we formed the Network for Genomics Surveillance in South Africa (NGS-SA). Here, we analyze 1,365 high quality whole genomes and identify 16 new lineages of SARS-CoV-2. Most of these unique lineages have mutations that are found hardly anywhere else in the world. We also show that three lineages spread widely in South Africa and contributed to ∼42% of all of the infections in the country. This included the first identified C lineage of SARS-CoV-2, C.1, which has 16 mutations as compared with the original Wuhan sequence. C.1 was the most geographically widespread lineage in South Africa, causing infections in multiple provinces and in all of the eleven districts in KwaZulu-Natal (KZN), the most sampled province. Interestingly, the first South-African specific lineage, B.1.106, which was identified in April 2020, became extinct after nosocomial outbreaks were controlled. Our findings show that genomic surveillance can be implemented on a large scale in Africa to identify and control the spread of SARS-CoV-2.
Symptom based and transmission-prevention based testing in long-term care facilities: Symptomatology, clinical course and mortality for residents with COVID-19
Authors: Paap Kelly C. , van Loon Anouk M. , van Rijs Sarian M. , Helmich Esther , Buurman Bianca M. , Smalbrugge Martin , Hertogh Cees M.P.M.
Published: October 2020

Objectives

Initially, for preventing COVID-19 transmission in long-term care facilities (LTCF) primarily rely on presence of core symptoms (fever, cough, dyspnea), but LTCF residents may also show an atypical course of a SARS-CoV-2 infection. We described the clinical presentation and course of COVID-19 in LTCF residents who were tested either because of presence of core symptoms (S-based) or because of transmission prevention (TP-based)

Design

Retrospective cohort study.

Setting and participants

Amsta (Amsterdam, The Netherlands), is a 1185-bed LTCF. All LTCF residents who underwent SARS-CoV-2 RT-PCR testing between March 16, 2020 and May 31, 2020 were included (n = 380).

Measures

Clinical symptoms, temperature and oxygen saturation were extracted from medical records, 7 days before testing up to 14 days after testing.

Results

SARS-CoV-2 was confirmed in 81 (21%) residents. Of these 81, 36 (44%) residents were tested S-based and 45 (56%) residents were tested TP-based. Yet, CT-values did not differ between the groups. In the 7 days prior to the test the most common symptoms in both groups were: falling (32%), somnolence (25%) and fatigue (21%). Two days before the test, we observed a stronger decrease in oxygen saturation and an increase in temperature for the S-based group compared to the T-based group that remained up to 10 days after testing. Residents with in the S-based group were 2.5 times more likely to decease within 30 days than residents in the TP-based group (HR, 2.56; 95% 1.3 to 5.2). Even though, 73% of the T-based group did eventually developed core symptoms.

Conclusion and implications

Many LTCF residents with a positive PCR did not have core symptoms when tested but had other signs/symptoms in the week before the positive test. Testing policies should therefore be adjusted to prevent transmission. Daily measures of temperature and oxygen saturation can contribute to earlier detection.
A distributed learning strategy improves performance and retention of skills in neonatal resuscitation: A simulation-based randomized controlled trial
Authors: Nambyiah Pratheeban , Boet Sylvain , Moore Gregory , Boyle Riley , Aylward Deborah , Jakubow Andre , Lam Sandy , Abdulla Karim , Bould M. Dylan
Published: October 2020

Skill retention after neonatal resuscitation training is poor. A distributed learning strategy – where learning is spread over multiple sessions – can improve retention of declarative memory (facts & knowledge). Session timings are critical – maximal retention occurs when a refresher session is scheduled at 10-30% of the time between initial training and test. We hypothesized this also holds true for neonatal resuscitation, a complex skill set requiring both declarative and procedural memory. We conducted a prospective, single-blinded randomized-controlled trial. University of Ottawa residents were recruited to training in neonatal resuscitation, with a high-fidelity simulated pre-test, immediate post-tests, and a retention test at 4 months. After training, they were randomized to either a refresher session at 3 weeks (18% of interval) or at 2 months (50%). Technical and non-technical skills were scored using validated checklists, knowledge with standardized questions. There was no difference between groups prior to the retention test. The early refresher group demonstrated significantly improved technical (mean ± 95% CI: 22.4 ± 1.3 v 18.2 ± 2.5, p = 0.02) and non-technical (31.0 ± 0.9 v 25.6 ± 3.1, p = 0.03) skill scores in the retention post-test compared to the late group. No difference was seen with knowledge scores. We conclude that both technical and non-technical aspects of neonatal resuscitation performance can benefit from an early refresher session. Session timings are critical and should be tailored to the desired length of skill retention. Findings may be generalizable to other interventions that depend on mixed types of memory.
Health-related quality of life of patients presenting to the emergency department with a musculoskeletal disorder
Authors: Gagnon Rose , Perreault Kadija , Robert-Guertin Jason , Berthelot Simon , Achou Bertrand , Hébert Luc J.
Published: October 2020

Objectives

The purpose of this study was to assess utility scores of patients presenting to the emergency department (ED) with a musculoskeletal disorder and to explore the influence of diverse factors on health-related quality of life.

Design

Secondary analysis of data obtained before randomization during a pragmatic randomized controlled trial

Setting

Academic ED in Quebec City (Canada)

Participants

Participants aged 18-80 years old presenting with a minor MSKD.

Main Outcome Measures

Health-related quality of life (five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and utility scores (0 – dead, 100 – perfect health), measured with the EQ-5D-5L, were compared between subgroups and with reference values using descriptive statistics (mean, median), rankFD ANOVAs, and χ2 tests.

Results

Sixty-nine participants completed the EQ-5D-5L. Mean and median utility scores were respectively 0.536 (95% CI: 0.479-0.594) and 0.531 (IQR: 0.356-0.760). Participants with higher levels of pain (<4/10: 0.741; 4-7/10: 0.572; >7/10: 0.433) or pain interference on function (<4/10: 0.685; 4-7/10: 0.463; >7/10: 0.294) presented significantly lower utility scores. No significant differences were found for other socio-demographic characteristics. The mean overall VAS score was 58.1 (95% CI: 52.2-64.0).

Conclusions

In patients with MSKDs presenting to the ED, higher levels of pain and pain interference on function may influence perceived health-related QoL. These findings need to be confirmed on a larger scale.

Trial Registration

This trial was registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT04009369 on July 5, 2019
Global Absence and Targeting of Protective Immune States in Severe COVID-19
Authors: Combes Alexis J. , Courau Tristan , Kuhn Nicholas F. , Hu Kenneth H. , Ray Arja , Chen William S. , Cleary Simon J. , Chew Nayvin W. , Kushnoor Divyashree , Reeder Gabriella C. , Shen Alan , Tsui Jessica , Hiam-Galvez Kamir J. , Muñoz-Sandoval Priscila , Zhu Wandi S , Lee David S. , Sun Yang , You Ran , Magnen Mélia , Rodriguez Lauren , Leligdowicz Aleksandra , Zamecnik Colin R. , Loudermilk Rita P. , Wilson Michael R. , Ye Chun J. , Fragiadakis Gabriela K. , Looney Mark R. , Chan Vincent , Ward Alyssa , Carrillo Sidney ,   The UCSF COMET Consortium, Matthay Michael , Erle David J. , Woodruff Prescott G. , Langelier Charles , Kangelaris Kirsten , Hendrickson Carolyn M. , Calfee Carolyn , Rao Arjun Arkal , Krummel Matthew F.
Published: October 2020

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.

One Sentence Summary

In severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.
Analysis of the early Covid-19 epidemic curve in Germany by regression models with change points
Authors: Küchenhoff Helmut , Günther Felix , Höhle Michael , Bender Andreas
Published: October 2020

We analyze the Covid-19 epidemic curve from March to end of April 2020 in Germany. We use statistical models to estimate the number of cases with disease onset on a given day and use back-projection techniques to obtain the number of new infections per day. The respective time series are analyzed by a trend regression model with change points. The change points are estimated directly from the data. We carry out the analysis for the whole of Germany and the federal state of Bavaria, where we have more detailed data. Both analyses show a major change between March 9th and 13th for the time series of infections: from a strong increase to a decrease. Another change was found between March 25th and March 29th, where the decline intensified. Furthermore, we perform an analysis stratified by age. A main result is a delayed course of the epidemic for the age group 80+ resulting in a turning point at the end of March.

Our results differ from those by other authors as we take into account the reporting delay, which turned out to be time dependent and therefore changes the structure of the epidemic curve compared to the curve of newly reported cases.
The COVID-19 Healthcare Personnel Study (CHPS): Overview, Methods and Preliminary Findings
Authors: DiMaggio Charles , Abramson David , Susser Ezra S. , Hoven Christina W. , Chen Qixuan , Andrews Howard F , Herman Daniel , Kreniske Jonah , Ryan Megan , Susser Ida , Thorpe Lorna E. , Li Guohua
Published: October 2020

Introduction

The onslaught of the COVID-19 pandemic has placed severe demands on US health systems and the health care workforce. In New York State (NYS) and New York City (NYC), the early American epicenter, hospitals ran the risk of exhausting supplies of ventilators, ICU beds, and personal protective equipment (PPE); the capacity of the healthcare workforce to meet the added demand was equally strained. The COVID-19 Healthcare Personnel Study (CHPS) was designed to assess adverse short and long-term physical and mental health impacts of the COVID-19 pandemic on New York’s physicians, nurse practitioners, and physician assistants.

Methods

Population-based online survey of physicians, nurse practitioners and physician assistants registered with the New York State Department of Health. Survey-weighted descriptive results were analyzed using frequencies, proportions, and means, with 95% confidence intervals. Odds ratios were calculated for association using survey-weighted logistic regression.

Results

Over half (51.5%; 95% CI 49.1, 54.0) of respondents worked directly with COVID-19 patients. Among those tested, 27.3% (95% CI 22.5, 32.2) were positive. The majority (57.6%; 95% CI 55.2, 60.0) of respondents reported that the COVID-19 pandemic had a negative impact on their mental health. Negative mental health was associated with experiencing symptoms of COVID-19 (OR=1.7, 95% CI 1.3, 2.1) and redeployment to unfamiliar functions. (OR=1.3, 95% CI 1.1, 1.6).

Conclusions

A majority of New York healthcare providers were involved in treating COVID-19 patients and reported that the pandemic had a negative impact on their mental health.
The FLI portion of EWS/FLI contributes a transcriptional regulatory function that is distinct and separable from its DNA-binding function in Ewing sarcoma
Authors: Boone Megann A. , Taslim Cenny , Crow Jesse C. , Selich-Anderson Julia , Showpnil Iftekhar A. , Sunkel Benjamin D. , Wang Meng , Stanton Benjamin Z. , Theisen Emily R. , Lessnick Stephen L.
Published: October 2020

Background

Ewing sarcoma is an aggressive bone cancer in children and young adults that contains a pathognomonic chromosomal translocation: t(11;22)(q24;q12). The encoded protein, EWS/FLI, fuses the low-complexity amino-terminal portion of EWS to the carboxyl-terminus of FLI. The FLI portion contains an ETS DNA-binding domain and adjacent amino- and carboxyl-regions. Early studies using non-Ewing sarcoma cellular models provided conflicting information on the role of these adjacent regions in the oncogenic function of EWS/FLI. We therefore sought to define the specific contributions of each FLI region to EWS/FLI activity in an appropriate Ewing model, and in doing so, to better understand Ewing sarcoma development mediated by the fusion protein.

Methods

We used a “knock-down/rescue” system to replace endogenous EWS/FLI expression with mutant forms of the protein in Ewing sarcoma cells and tested these for oncogenic transformation using soft-agar colony forming assays. These data were complemented by DNA-binding assays using fluorescence anisotropy, genomic localization assays using CUT&RUN, transcriptional regulation studies using luciferase reporter assays and RNA-sequencing, as well as chromatin accessibility assays using ATAC-sequencing.

Results

We found that the DNA-binding domain and short flanking regions of FLI were required for oncogenic transformation, gene expression, genomic localization and chromatin accessibility when fused to the amino-terminal EWS-portion from EWS/FLI, but that the remaining regions of FLI were dispensable for these functions. Removal of a carboxyl-terminal alpha-helix from the short flanking regions of the DNA-binding domain of FLI created a hypomorphic EWS/FLI that retained normal DNA binding, genomic localization, and chromatin accessibility, but had significantly restricted transcriptional activity and a near total loss of oncogenic transformational capacity.

Conclusions

The DNA-binding domain and carboxyl-terminal short flanking region of FLI are the only portions of FLI required for EWS/FLI-mediated oncogenic transformation in a Ewing sarcoma cellular context. In addition to the well-defined DNA-binding function of FLI, this additional alpha-helix immediately downstream of the DNA-binding domain contributes a previously-undescribed function in gene regulation and oncogenic transformation. Understanding the function of this critical region could provide new therapeutic opportunities to target EWS/FLI in Ewing sarcoma.
Degenerated virulence and irregular development ofFusarium oxysporumf. sp.niveuminduced by successive subculture
Authors: Chang Tao-Ho , Lin Ying-Hong , Wan Yu-Ling , Chen Kan-Shu , Huang Jenn-Wen , Chang Pi-Fang Linda
Published: October 2020

Successive cultivation of fungus has been reported to cause the sectorization, which leads to degeneration of developmental phenotype, and virulence.Fusarium oxysporumf. sp.niveum(Fon), the causal agent of watermelon Fusarium wilt, demonstrated that successive cultivation formed the degenerated sectors. In the present research, we demonstrated that subculture with aged mycelium increased the incidence of degenerations. To further investigate the differences between the Fon wild type (sporodochial type, ST) and variants (MT: mycelium type and PT: pionnotal type), developmental phenotypes and pathogenicity to watermelon were examined. Results have shown that degeneration variants (PT2, PT3, PT11 and MT6) were different from ST with mycelium growth, conidia production and chlamydospore formation. Virulence of degenerated variants on susceptible watermelon Grand Baby (GB) cultivar was determined after inoculated with Fon variants and Fon ST. In root dipping methods, all Fon variants showed slightly increased disease severity than ST. Conversely, all Fon variants showed a significant decrease in disease progression compared with ST through infested soil inoculation. The contrary results of two inoculation methods suggest that the changes of successive cultural degeneration may lead to the loss of pathogen virulence-related factors of the early stage of Fon infection process. Therefore, Cell wall-degrading enzymes (CWDEs; cellulase, pectinase, and xylanase) activities of different variants were analysed. All Fon degenerated variants demonstrated significantly decreased of CWDEs activities compared with ST. Additionally, transcripts level of 9 virulence-related genes (fmk1,fgb1,pacC,xlnR,pl1,rho1,gas1,wc1 and fow1) were assessed in normal state. The degenerated variants demonstrated a significantly low level of tested virulence-related genes transcripts except forfmk1,xlnRandfow1. In summary, the degeneration of Fon is triggered with successive subculture through aged mycelium. The degeneration showed significant impacts on virulence to watermelon, which caused by the reduction of CWDEs activities and declining expression of a set of virulence-related genes.
The adaptive benefit of evolved increases in hemoglobin-O2affinity is contingent on tissue O2diffusing capacity in high-altitude deer mice
Authors: Wearing Oliver H. , Ivy Catherine M. , Gutiérrez-Pinto Natalia , Velotta Jonathan P. , Campbell-Staton Shane C. , Natarajan Chandrasekhar , Cheviron Zachary A. , Storz Jay F. , Scott Graham R.
Published: October 2020

Background

Complex organismal traits are often the result of multiple interacting genes and sub-organismal phenotypes, but how these interactions shape the evolutionary trajectories of adaptive traits is poorly understood. We examined how functional interactions between cardiorespiratory traits contribute to adaptive increases in the capacity for aerobic thermogenesis (maximal O2consumption, V◻O2max, during acute cold exposure) in high-altitude deer mice (Peromyscus maniculatus). We crossed highland and lowland deer mice to produce F2inter-population hybrids, which expressed genetically based variation in hemoglobin (Hb) O2affinity on a mixed genetic background. We then combined physiological experiments and mathematical modeling of the O2transport pathway to examine links between cardiorespiratory traits and V◻O2max.

Results

Physiological experiments revealed that increases in Hb-O2affinity of red blood cells improved blood oxygenation in hypoxia, but were not associated with an enhancement in V◻O2max. Sensitivity analyses performed using mathematical modeling showed that the influence of Hb-O2affinity on V◻O2max in hypoxia was contingent on the capacity for O2diffusion in active tissues.

Conclusions

These results suggest that increases in Hb-O2affinity would only have adaptive value in hypoxic conditions if concurrent with or preceded by increases in tissue O2diffusing capacity. In high-altitude deer mice, the adaptive benefit of increasing Hb-O2affinity is contingent on the capacity to extract O2from the blood, which helps resolve controversies about the general role of hemoglobin function in hypoxia tolerance.
Early invasion of uropathogenicEscherichia coliinto the bladder wall by solitary bacteria that are protected from antibiotics and neutrophil swarms in an organoid model
Authors: Sharma Kunal , Thacker Vivek V. , Dhar Neeraj , Signorino-Gelo François , Cabrer Maria Clapés , Dubois Anaëlle , Mullenders Jasper , Knott Graham , Clevers Hans , McKinney John D.
Published: October 2020

UropathogenicEscherichia coli(UPEC) is the most common cause of urinary tract infections (UTIs) requiring antibiotic therapy. Recurrent infections, which occur in a quarter of treated individuals, may arise from “quiescent intracellular reservoirs” of bacteria that invade deeper layers of the bladder wall following infection and exfoliation of superficial umbrella cells. Here, we present a novel bladder organoid model of UPEC infection that recapitulates the stratified bladder architecture within a small volume suitable for live-cell imaging of host-pathogen dynamics with high spatiotemporal resolution. We confirm that bacteria injected into the organoid lumen rapidly enter superficial cells that resemble umbrella cells and proliferate to generate tightly packed colonies that resemble intracellular bacterial communities (IBCs), a hallmark of UPEC pathogenesis. Unexpectedly, at early stages of infection we detect individual “solitary” bacteria that penetrate deeper layers of the organoid wall, where they evade killing by antibiotics and neutrophils. Volumetric serial block face scanning electron microscopy of infected organoids reveals that solitary bacteria can be found throughout the bladder wall and may be intracellular or pericellular (sandwiched between uroepithelial cells). Unlike bacteria within IBCs, which are coccoid-shaped and non-flagellated, solitary bacteria within the bladder wall are rod-shaped and flagellated. We conclude that early invasion of deeper layers of the bladder wall, independent of IBC formation, results in the establishment of reservoirs of solitary bacteria that resist elimination by antibiotics and the host innate immune response.
Boosting the MS1-only proteomics with machine learning allows 2000 protein identifications in 5-minute proteome analysis
Authors: Ivanov Mark V. , Bubis Julia A. , Gorshkov Vladimir , Abdrakhimov Daniil A. , Kjeldsen Frank , Gorshkov Mikhail V.
Published: October 2020

Proteome-wide analyses most often rely on tandem mass spectrometry imposing considerable instrumental time consumption that is one of the main obstacles in a broader acceptance of proteomics in biomedical and clinical research. Recently, we presented a fast proteomic method termed DirectMS1 based on MS1-only mass spectra acquisition and data processing. The method allowed significant squeezing of the proteome-wide analysis to a few minute time frame at the depth of quantitative proteome coverage of 1000 proteins at 1% FDR. In this work, to further increase the capabilities of the DirectMS1 method, we explored the opportunities presented by the recent progress in the machine learning area and applied the LightGBM tree-based learning algorithm into the scoring of peptide-feature matches when processing MS1 spectra. Further, we integrated the peptide feature identification algorithm of DirectMS1 with the recently introduced peptide retention time prediction utility, DeepLC. Additional approaches to improve performance of the DirectMS1 method are discussed and demonstrated, such as FAIMS coupled to the Orbitrap mass analyzer. As a result of all improvements to DirectMS1, we succeeded in identifying more than 2000 proteins at 1% FDR from the HeLa cell line in a 5 minute LC-MS1 analysis.
DNA methylation directs nucleosome positioning in RNA-mediated transcriptional silencing
Authors: Rothi M. Hafiz , Sethuraman Shriya , Dolata Jakub , Boyle Alan P , Wierzbicki Andrzej T
Published: October 2020

Repressive chromatin modifications are instrumental in regulation of gene expression and transposon silencing. InArabidopsis thaliana, transcriptional silencing is performed by the RNA-directed DNA methylation (RdDM) pathway. In this process, two specialized RNA polymerases, Pol IV and Pol V, produce non-coding RNAs, which recruit several RNA-binding proteins and lead to the establishment of repressive chromatin marks. An important feature of chromatin is nucleosome positioning, which has also been implicated in RdDM. We show that RdDM affects nucleosomes via the SWI/SNF chromatin remodeling complex. This leads to the establishment of nucleosomes on methylated regions, which counteracts the general depletion of DNA methylation on nucleosomal regions. Nucleosome placement by RdDM has no detectable effects on the pattern of DNA methylation. Instead, DNA methylation by RdDM and other pathways affects nucleosome positioning. We propose a model where DNA methylation serves as one of the determinants of nucleosome positioning.
Sclerostin directly stimulates osteocyte synthesis of fibroblast growth factor-23
Authors: Ito Nobuaki , Prideaux Matthew , Wijenayaka Asiri R. , Yang Dongqing , Ormsby Renee T. , Bonewald Lynda F. , Atkins Gerald J.
Published: October 2020

Osteocyte produced fibroblast growth factor 23 (FGF23) is the key regulator of serum phosphate (Pi) homeostasis. The interplay between parathyroid hormone (PTH), FGF23 and other proteins that regulate FGF23 production and serum Pi levels is complex and incompletely characterised. Evidence suggests that the protein product of theSOSTgene, sclerostin (SCL), also a PTH target and also produced by osteocytes, plays a role in FGF23 expression, however the mechanism for this effect is unclear. Part of the problem of understanding the interplay of these mediators is the complex multi-organ system that achieves Pi homeostasisin vivo. In the current study, we sought to address this using a unique cell line model of the osteocyte, IDG-SW3, known to express FGF23 at both the mRNA and protein levels. In cultures of differentiated IDG-SW3 cells, both PTH1-34and recombinant human (rh) SCL remarkably inducedFgf23mRNA expression dose-dependently within 3 hours. Both rhPTH1-34and rhSCL also strongly induced C-terminal FGF23 protein secretion. Secreted intact FGF23 levels remained unchanged, consistent with constitutive post-translational cleavage of FGF23 in this cell model. Both rhPTH1-34and rhSCL treatments significantly suppressed mRNA levels ofPhex, Dmp1andEnpp1mRNA, encoding putative negative regulators of FGF23 levels, and inducedGalnt3mRNA expression, encoding N-acetylgalactosaminyl-transferase 3 (GalNAc-T3), which protects FGF23 from furin-like proprotein convertase-mediated cleavage. The effect of both rhPTH1-34and rhSCL was antagonised by pre-treatment with the NF-κβ signalling inhibitors, BAY11 and TPCK. RhSCL also stimulatedFGF23mRNA expression inex vivocultures of human bone. These findings provide evidence for the direct regulation of FGF23 expression by sclerostin. Locally expressed sclerostin via the induction of FGF23 in osteocytes thus has the potential to contribute to the regulation of Pi homeostasis.
Ethanol’s interaction with BK channel α subunit residue K361 does not mediate behavioral responses to alcohol in mice
Authors: Okhuarobo Agbonlahor , Kreifeldt Max , Gandhi Pauravi J , Lopez Catherine , Martinez Briana , Bajo Michal , Bhattacharyya Pushpita , Dopico Alex M , Roberto Marisa , Roberts Amanda J , Homanics Gregg E , Contet Candice
Published: October 2020

Large conductance potassium (BK) channels are among the most sensitive molecular targets of ethanol and genetic variations in the channel-forming α subunit have been nominally associated with alcohol use disorders. However, whether the direct action of ethanol at BK α influences the motivation to drink alcohol remains to be determined. In the present study, we sought to investigate the behavioral relevance of this molecular interaction by introducing in the mouse genome a point mutation known to render BK channels insensitive to ethanol while preserving their physiological function. The BK α K361N substitution prevented ethanol from reducing spike threshold in medial habenula neurons. However, it did not alter acute responses to ethanolin vivo, including ataxia, sedation, hypothermia, analgesia, and conditioned place preference.

Furthermore, the mutation did not have reproducible effects on alcohol consumption in limited, continuous, or intermittent access home cage two-bottle choice paradigms conducted in both males and females. Notably, in contrast to previous observations made in mice missing BK channel auxiliary β subunits, the BK α K361N substitution had no significant impact on ethanol intake escalation induced by chronic intermittent alcohol vapor inhalation. It also did not affect the metabolic and locomotor consequences of chronic alcohol exposure. Altogether, these data suggest that the direct interaction of ethanol with BK α does not mediate the alcohol-related phenotypes examined here in mice.