bluuebunny/crossref_metadata_2025 huggingface dataset:
Analog reducibility
Authors: Hanson James
Published: May 2021

In this paper we introduce and characterize two ‘analog reducibility’ notions for $[0,1]$-valued oracles on $\omega $ obtained by applying the syntactic characterizations of Turing and enumeration reducibility in terms of (positive) relatively $\varSigma _1$ and $\varPi _1$ formulas to formulas in continuous logic (Ben Yaacov, Berenstein, Henson and Usvyatsov, 2008, Model Theory for Metric Structures, vol. 2 of London Mathematical Society Lecture Note Series, pp. 315–427. Cambridge University Press.). The resulting analog and analog enumeration degree structures, $\mathscr {D}_a$ and $\mathscr {D}_{ae}$, naturally extend $\mathscr {D}_T$ and $\mathscr {D}_e$ in a compatible way. To show that these extensions are proper we prove that a sufficiently generic total $[0,1]$-valued oracle does not ‘analog enumerate’ any non-c.e. discrete set and that a sufficiently generic positive $[0,1]$-valued oracle neither ‘analog enumerates’ a non-c.e. discrete set nor ‘analog computes’ a non-trivial total $[0,1]$-valued oracle. We also provide a characterization of the continuous degrees among $\mathscr {D}_{ae}$ as precisely $\mathscr {D}_e \cap \mathscr {D}_a$. Finally we characterize a generalization of r.i.c.e. relations to metric structures via $\varSigma _1$ formulas in the ‘hereditarily compact superstructure’, which was the original motivation for the concepts in this paper.
Extracellular signal-regulated kinase signaling pathway and silicosis
Authors: Xie Yujia , Ma Jixuan , Yang Meng , Fan Lieyang , Chen Weihong
Published: May 2021

Silicosis is a scarring lung disease caused by inhaling fine particles of crystalline silica in the workplace of many industries. Due to the lack of effective treatment and management, the continued high incidence of silicosis remains a major public health concern worldwide, especially in the developing countries. Till now, related molecular mechanisms underlying silicosis are still not completely understood. Multiple pathways have been reported to be participated in the pathological process of silicosis, and more complex signaling pathways are receiving attention. The activated extracellular signal-regulated kinase (ERK) signaling pathway has been recognized to control some functions in the cell. Recent studies have identified that the ERK signaling pathway contributes to the formation and development of silicosis through regulating the processes of oxidative stress, inflammatory response, proliferation and activation of fibroblasts, epithelial–mesenchymal transformation, autophagy, and apoptosis of cells. In this review article, we summarize the latest findings on the role of ERK signaling pathway in silica-induced experimental models of silicosis, as well as clinical perspectives.
Genetic architecture of the metabolic pathway of salicylic acid biosynthesis in Populus
Authors: Xiao Liang , Du Qingzhang , Fang Yuanyuan , Quan Mingyang , Lu Wenjie , Wang Dan , Si Jingna , El-Kassaby Yousry A , Zhang Deqiang
Published: May 2021

Salicylic acid (SA) is a vital hormone for adaptive responses to biotic and abiotic stresses, which facilitates growth-immunity trade-offs in plants. However, the genetic regulatory networks underlying the metabolic pathway of SA biosynthesis in perennial species remain unclear. Here, we integrated genome-wide association study (GWAS) with metabolite and expression profiling methodologies to dissect the genetic architecture of SA biosynthesis in Populus. First, we quantified nine intermediate metabolites of SA biosynthesis in 300 unrelated Populus tomentosa Carr. individuals. Then, we used a systematic genetic strategy to identify candidate genes for constructing the genetic regulatory network of SA biosynthesis. We focused on WRKY70, an efficient transcription factor, as the key causal gene in the regulatory network, and combined the novel genes coordinating the accumulation of SA. Finally, we identified eight GWAS signals and eight expression quantitative trait loci situated in a selective sweep, and showed the presence of large allele frequency differences among the three geographic populations, revealing that candidate genes subject to selection were involved in SA biosynthesis. This study provides an integrated strategy for dissecting the genetic architecture of the metabolic pathway of SA biosynthesis in Populus, thereby enhancing our understanding of genetic regulation of SA biosynthesis in trees, and accelerating marker-assisted breeding efforts toward high-resistance elite varieties of Populus.
Hearing Aid Noise Reduction Lowers the Sustained Listening Effort During Continuous Speech in Noise—A Combined Pupillometry and EEG Study
Authors: Fiedler Lorenz , Seifi Ala Tirdad , Graversen Carina , Alickovic Emina , Lunner Thomas , Wendt Dorothea
Published: May 2021

Objectives:

The investigation of auditory cognitive processes recently moved from strictly controlled, trial-based paradigms toward the presentation of continuous speech. This also allows the investigation of listening effort on larger time scales (i.e., sustained listening effort). Here, we investigated the modulation of sustained listening effort by a noise reduction algorithm as applied in hearing aids in a listening scenario with noisy continuous speech. The investigated directional noise reduction algorithm mainly suppresses noise from the background.

Design:

We recorded the pupil size and the EEG in 22 participants with hearing loss who listened to audio news clips in the presence of background multi-talker babble noise. We estimated how noise reduction (off, on) and signal-to-noise ratio (SNR; +3 dB, +8 dB) affect pupil size and the power in the parietal EEG alpha band (i.e., parietal alpha power) as well as the behavioral performance.

Results:

Our results show that noise reduction reduces pupil size, while there was no significant effect of the SNR. It is important to note that we found interactions of SNR and noise reduction, which suggested that noise reduction reduces pupil size predominantly under the lower SNR. Parietal alpha power showed a similar yet nonsignificant pattern, with increased power under easier conditions. In line with the participants’ reports that one of the two presented talkers was more intelligible, we found a reduced pupil size, increased parietal alpha power, and better performance when people listened to the more intelligible talker.

Conclusions:

We show that the modulation of sustained listening effort (e.g., by hearing aid noise reduction) as indicated by pupil size and parietal alpha power can be studied under more ecologically valid conditions. Mainly concluded from pupil size, we demonstrate that hearing aid noise reduction lowers sustained listening effort. Our study approximates to real-world listening scenarios and evaluates the benefit of the signal processing as can be found in a modern hearing aid.
Associations of long-term exposure to environmental noise and outdoor light at night with age at natural menopause in a US women cohort
Authors: Li Huichu , Hart Jaime E. , Mahalingaiah Shruthi , Nethery Rachel C. , James Peter , Bertone-Johnson Elizabeth , Schernhammer Eva , Laden Francine
Published: May 2021

Background:

Previous studies have suggested noise, especially at night time, and light at night (LAN) could cause neuroendocrine disturbance and circadian disruption, which may lead to ovarian follicle atresia and earlier onset of menopause. However, no study to date has directly investigated the associations of exposure to these factors and menopausal age.

Methods:

Premenopausal women from the Nurses’ Health Study II (NHS II) were followed from age 40 through 2015. Median daytime and nighttime anthropogenic noise and outdoor LAN exposure were measured from a geospatial prediction model and satellite images, respectively, at residential addresses throughout the follow-up. Time-varying Cox proportional hazard models were used to calculate the hazard ratios and 95% confidence intervals, adjusting for individual lifestyle, reproductive history, and neighborhood socioeconomic factors. Possible effect modification by region, smoking status, body mass index, race/ethnicity, history of rotating shift work, and census tract population density and median income was examined.

Results:

A total of 63,380 of 105,326 women self-reported natural menopause during 1,043,298 person-years of follow-up. No associations were found for noise (both daytime and nighttime) and outdoor LAN exposure with age at natural menopause (hazard ratios = 0.99–1.00) in the fully adjusted models. Sensitivity analyses showed similar null associations. No meaningful effect modification was found for region, smoking status, body mass index, race/ethnicity, history of rotating shift work, and census tract socioeconomic measures in stratified analyses.

Conclusion:

No associations were found between environmental noise and outdoor LAN exposure in mid-adulthood and menopausal age in this cohort of US women.
Nontraumatic In-Custody Homicidal Deaths in Harris County, Texas (2015–2019)
Authors: Wolf Dwayne A.
Published: May 2021

A subset of in-custody deaths, typically occurring in the precustody phase, arise from a combination of mechanisms, rather than a single anatomically or circumstantially demonstrable cause. This case series examined nontraumatic in-custody deaths that occurred over a 5-year period (2015–2019) in Harris County, Texas. Cases were identified as “in custody” or “during police intervention,” with a homicide manner; traumatic causes of death (eg, police shootings) were excluded.

Sixteen cases were identified. The median age was 40 years, with an interquartile range of 35 to 50.5 years. All but one were male, and there were 8 (50%) Black, 5 (31%) White, and 1 (6%) Hispanic cases. Intoxicants were detected in all except 1 death that occurred after a prolonged hospitalization; stimulants were identified in 12 (75%). The cause of death for each was descriptive, representing the complex interplay of external forces with physiologic/toxicologic and disease-related mechanisms.

This series is used as a backdrop for a discussion regarding the inadequacy of the current 5-category manner of death classification scheme and to suggest an alternative category of manner. This alternative category, specifically “legal intervention,” would be most useful for this subset of nontraumatic in-custody deaths but may have applicability for other types of in-custody deaths.
Isolated Atrial Neutrophilic Myocarditis
Authors: Duffy Michael , O'Connor Kate , Milne David , Ondruschka Benjamin , Tse Rexson , Garland Jack
Published: May 2021

Myocarditis can focally or diffusely involve the myocardium and is associated with arrhythmia, cardiac failure, and sudden death. The majority of cases of myocarditis are lymphocytic in etiology, and neutrophilic myocarditis is relatively uncommon. Although reported in lymphocytic myocarditis, isolated/focal neutrophilic myocarditis of the atrium causing death is not reported in the postmortem literature, and its postmortem computed tomography correlation is not documented. We report a fatal case of isolated neutrophilic atrial myocarditis affecting only the left atrium in a 33-year-old woman presenting as a sudden unexpected death. Microscopy of the left atrium, a not commonly sampled area of the heart, showed florid neutrophilic myocarditis with the remaining right atrium, conduction system, and both ventricles uninvolved. Similar to previously reported fatal isolated atrial lymphocytic myocarditis, postmortem computed tomography was unable to detect any atrial abnormalities. This case highlights a potential “blind spot” for both routine postmortem imaging and examination.
Development of the mammalian cortical hem and its derivatives: the choroid plexus, Cajal–Retzius cells and hippocampus
Authors: Moore Samantha A. , Iulianella Angelo
Published: May 2021

The dorsal medial region of the developing mammalian telencephalon plays a central role in the patterning of the adjacent brain regions. This review describes the development of this specialized region of the vertebrate brain, called thecortical hem, and the formation of the various cells and structures it gives rise to, including the choroid plexus, Cajal–Retzius cells and the hippocampus. We highlight the ontogenic processes that create these different forebrain derivatives from their shared embryonic origin and discuss the key signalling pathways and molecules that influence the patterning of the cortical hem. These include BMP, Wnt, FGF and Shh signalling pathways acting with Homeobox factors to carve the medial telencephalon into district progenitor regions, which in turn give rise to the choroid plexus, dentate gyrus and hippocampus. We then link the formation of the lateral ventricle choroid plexus with embryonic and postnatal neurogenesis in the hippocampus.
Mutational signatures in esophageal squamous cell carcinoma from eight countries of varying incidence
Authors: Moody Sarah , Senkin Sergey , Islam S M Ashiqul , Wang Jingwei , Nasrollahzadeh Dariush , Penha Ricardo Cortez Cardoso , Fitzgerald Stephen , Bergstrom Erik N , Atkins Joshua , He Yudou , Khandekar Azhar , Smith-Byrne Karl , Carreira Christine , Gaborieau Valerie , Latimer Calli , Thomas Emily , Abnizova Irina , Bucciarelli Pauline E , Jones David , Teague Jon W , Abedi-Ardekani Behnoush , Serra Stefano , Scoazec Jean-Yves , Saffar Hiva , Azmoudeh-Ardelan Farid , Sotoudeh Masoud , Nikmanesh Arash , Eden Michael , Richman Paul , Campos Lia S , Fitzgerald Rebecca C , Ribeiro Luis Felipe , Dzamalala Charles , Mmbaga Blandina Theophil , Shibata Tatsuhiro , Menya Diana , Goldstein Alisa M , Hu Nan , Malekzadeh Reza , Fazel Abdolreza , McCormack Valerie , McKay James , Perdomo Sandra , Scelo Ghislaine , Chanudet Estelle , Humphreys Laura , Alexandrov Ludmil B , Brennan Paul , Stratton Michael R
Published: May 2021

Esophageal squamous cell carcinoma (ESCC) shows a remarkable variation in incidence which is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. The mutational profiles of ESCC were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining the differences in ESCC incidence. APOBEC associated mutational signatures SBS2 and SBS13 were present in 88% and 91% of cases respectively and accounted for a quarter of the mutation burden on average, indicating that activation of APOBEC is a crucial step in ESCC tumor development.
Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient: a source of immune escape variants
Authors: Weigang Sebastian , Fuchs Jonas , Zimmer Gert , Schnepf Daniel , Kern Lisa , Beer Julius , Luxenburger Hendrik , Ankerhold Jakob , Falcone Valeria , Kemming Janine , Hofmann Maike , Thimme Robert , Neumann-Haefelin Christoph , Ulferts Svenja , Grosse Robert , Hornuss Daniel , Tanriver Yakup , Rieg Siegbert , Wagner Dirk , Huzly Daniela , Schwemmle Martin , Panning Marcus , Kochs Georg
Published: May 2021

The recent emergence of SARS-CoV-2 variants showing increased transmissibility and immune escape is a matter of global concern. Their origin remains unclear, but intra-host virus evolution during persistent infections could be a contributing factor. Here, we studied the long-term SARS-CoV-2 infection in an immunosuppressed organ transplant recipient. Frequent respiratory specimens were tested for variant viral genomes by RT-qPCR, next-generation sequencing (NGS), and virus isolation. Late in infection, several virus variants emerged which escaped neutralization by COVID-19 convalescent and vaccine-induced antisera and had acquired genome mutations similar to those found in variants of concern first identified in UK, South Africa, and Brazil. Importantly, infection of susceptible hACE2-transgenic mice with one of the patient’s escape variants elicited protective immunity against re-infection with either the parental virus, the escape variant or the South African variant of concern, demonstrating broad immune control. Upon lowering immunosuppressive treatment, the patient generated spike-specific neutralizing antibodies and resolved the infection. Our results indicate that immunocompromised patients are an alarming source of potentially harmful SARS-CoV-2 variants and open up new avenues for the updating of COVID-19 vaccines.
Investigating the relationship between serum ACE 2 level and COVID-19 patients’ prognosis: a cross-sectional study
Authors: Mohammadi Parsa , Varpaei Hesam Aldin , Seifi Arash , Miandoab Sepideh Zahak , Beiranvand Saba , Mobaraki Sahar , Mohammadi Mostafa
Published: May 2021

Background

The only known receptor for this virus in the human body is ACE2, the same known receptor for the SARS virus.

Material and Method

In this single-center cross-sectional study, 38 hospitalized adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the infectious disease ward in Imam Khomeini hospital complex. The study also has been approved in ethics committee of Tehran University of medical sciences with ethic code: 99/11/101/16529. Data were analyzed using SPSS 25. p < 0.05 was considered statistically significant when a two-tailed test was performed.

Result

Among the 38 patients, the mean age was 64.13 years, 52.6% were male, 42% were PCR test positive and 39.5% was expired. The most common presenting symptoms were cough (80%), fever (75.5%), dyspnea (60.5%), myalgias (35.8%), diarrhea (20%), and nausea and vomiting (15%). There were not any significant differences between expired and discharged group in terms of serum ACE2 level. Results were similar between discharged and expired patients in the subgroup analysis of 38 patients.

Conclusion

It seems that serum ACE 2 level is not correlated with COVID-19 patients’ prognosis. However, it seems that more researches are required to confirm supposed association between serum ACE2 level and inflammatory biomarkers, clinical outcome, and patient’s survival.
An Audit of Use and Monitoring of ACE-inhibitors in General Practice
Authors: Coffey Fíona , Bradley Colin , Curran Tadhg-Iarla
Published: May 2021

Introduction

ACE-inhibitors are one of the most widely prescribed drugs in general practice for the treatment of hypertension. They are also one of the most frequent drugs associated with preventable drug-related morbidity incidents and guidelines are in place regarding the monitoring of renal function during treatment with these drugs.

Aim

To assess the pattern of prescribing and monitoring of ACE-inhibitors in a general practice setting.

Methods

A retrospective medical records review was undertaken in a general practice in the Kerry region. Data collected included the indication for the ACE-inhibitor and whether blood pressure, electrolytes, renal function and glomerular filtration rate were measured within three months after initiation and in the period from January 2010 to June 2011. Data was entered into Microsoft Excel and analysed using SPSS.

Results

Data on 285 patients was analysed and showed that 78.2% of patients were on ACE-inhibitors for treatment of blood pressure. Following initiation of the ACE-inhibitor, 94.8% of patients had their blood pressure checked within 3 months, while 37.1% of patients had electrolytes checked, 51% of patients had their renal function checked and 31% of people had their glomerular filtration rate checked in the same time period. In the months from January 2010 to June 2011, 91.2% of patients had their blood pressure checked with 73% having electrolytes checked, 80.4% having their renal function checked and 54.7% had their glomerular filtration rate checked. Of those who had their renal function checked 26.1% had an abnormal creatinine level.

Conclusion

Follow up of monitoring blood pressure, renal function, electrolytes and glomerular filtration rate within 3 months initiation of the ACE-inhibitor was poor but annual check up scored highly. Having a recall system in place within the practice for reminding patients to get their blood levels checked may help to increase all percentages to 100%.
Non-neutralizing secretory IgA and T cells targeting SARS-CoV-2 spike protein are transferred to the breastmilk upon BNT162b2 vaccination
Authors: Gonçalves Juliana , Juliano A. Margarida , Charepe Nádia , Alenquer Marta , Athayde Diogo , Ferreira Filipe , Archer Margarida , João Amorim Maria , Serrano Fátima , Soares Helena
Published: May 2021

In view of data scarcity to guide decision-making in breastfeeding women, we evaluated how mRNA vaccines impact immune response of lactating health care workers (HCW) and the effector profile of breast milk transferred immune protection. We show that upon BNT162b2 vaccination, immune transfer via milk to suckling infants occurs through secretory IgA (SIgA) and T cells. Functionally, spike-SIgA was non-neutralizing and its titers were unaffected by vaccine boosting, indicating that spike-SIgA is produced in a T-cell independent manner by mammary gland. Even though their milk was devoid of neutralizing antibodies, we found that lactating women had higher frequencies of RBD-reactive circulating memory B cells and more RBD-IgG antibodies, when compared to controls. Nonetheless, blood neutralization titers in lactating and non-lactating HCW were similar. Further studies are required to determine transferred antibodies and spike-T cells complete functional profile and whether they can mediate protection in the suckling infant.

Highlights

Milk and blood responses to BNT162b2 vaccine are initially isotype discordant

Immune transfer via milk to suckling infants occurs by spike-reactive SIgA and T cells

Spike-reactive SIgA in the breastmilk is non-neutralizing and T-cell independent

Lactating vs non-lactating HCW had distinct cellular responses, despite similar NT50
Association between high serum favipiravir concentrations and drug-induced liver injury
Authors: Kawasuji Hitoshi , Tsuji Yasuhiro , Ogami Chika , Takegoshi Yusuke , Kaneda Makito , Murai Yushi , Kimoto Kou , Ueno Akitoshi , Miyajima Yuki , Fukui Yasutaka , Nagaoka Kentaro , Sakamaki Ippei , Morinaga Yoshitomo , Yamamoto Yoshihiro
Published: May 2021

Objectives

This study aimed to evaluate the incidence and pattern of favipiravir-induced liver injury and the potential association between serum concentrations in hospitalized COVID-19 patients.

Patients and methods

We retrospectively reviewed laboratory-confirmed patients with COVID-19 for whom serum favipiravir trough concentration (Cmin) was measured under steady-state conditions during treatment. All patients were administered 1800 mg of favipiravir twice daily on the first day and 800 mg twice daily from the second day.

Results

Thirty observed favipiravir concentrations were collected from nine patients. Of these, favipiravir-induced liver injury developed in three patients after 13 (11–14) days from the initiation of therapy, with two classified as cholestatic and one hepatocellular injury, with a score of four (possible), seven (probable), and three (possible) based on the CIMOS/RUCAM scoring system. Median (range) favipiravir Cmin at steady state was found to be significantly higher in patients with liver injury at 66.4 (47.8–72.4) mg/L than in those without injury at 12.8 (9.4–21.8) mg/L (P = 0.028).

Conclusions

Higher favipiravir serum concentrations were observed in patients who developed favipiravir-induced liver injury than in those who did not. As the variations in favipiravir concentrations between patients were large, personalized optimal dosing strategies may be needed for safe use.
Impaired everyday executive functions and cognitive strategy use on the Weekly Calendar Planning Activity in individuals with stroke undergoing acute inpatient rehabilitation
Authors: Jaywant Abhishek , Arora Catherine , Lussier Alexis , Toglia Joan
Published: May 2021

Executive dysfunction is common in stroke patients undergoing acute inpatient rehabilitation. However, comprehensive neuropsychological evaluation of executive functions is often not feasible in this setting. Objective, standardized, and performance-based measures of cognitively-based instrumental activities of daily living (C-IADL) can capture everyday executive functions and inform rehabilitation planning and interventions. The goal of this study was to compare performance of individuals with stroke to healthy age-matched adults in performance on the 10-item Weekly Calendar Planning Activity (WCPA). 77 stroke inpatients undergoing rehabilitation and 77 healthy control participants completed the WCPA, a C-IADL measure involving scheduling appointments that requires planning, working memory, shifting, and inhibitory control. Compared to the control group, stroke patients had significantly worse accuracy, made more errors, used fewer cognitive strategies, followed fewer rules, took more time to complete the task, and were less efficient. 83% of stroke patients were less accurate than predicted by their age, and 64% used less strategies than their age prediction. Among 28 participants who screened as having “normal” cognitive function on the Montreal Cognitive Assessment, the majority had deficits on the WCPA. Our results indicate that the WCPA is sensitive to executive dysfunction in stroke patients undergoing acute inpatient rehabilitation and underscores deficits in C-IADL accuracy, efficiency, and strategy use at this stage of stroke recovery. The WCPA may be a useful measure to ascertain executive dysfunction and to incorporate in cognitive rehabilitation.
Roles of generation-interval distributions in shaping relative epidemic strength, speed, and control of new SARS-CoV-2 variants
Authors: Park Sang Woo , Bolker Benjamin M. , Funk Sebastian , Metcalf C. Jessica E. , Weitz Joshua S. , Grenfell Bryan T. , Dushoff Jonathan
Published: May 2021

Inferring the relative strength (i.e., the ratio of reproduction numbers, ℛvar/ℛwt) and relative speed (i.e., the difference between growth rates,rvar−rwt) of new SARS-CoV-2 variants compared to their wild types is critical to predicting and controlling the course of the current pandemic. Multiple studies have estimated the relative strength of new variants from the observed relative speed, but they typically neglect the possibility that the new variants have different generation intervals (i.e., time between infection and transmission), which determines the relationship between relative strength and speed. Notably, the increasingly predominant B.1.1.7 variant may have a longer infectious period (and therefore, a longer generation interval) than prior dominant lineages. Here, we explore how differences in generation intervals between a new variant and the wild type affect the relationship between relative strength and speed. We use simulations to show how neglecting these differences can lead to biases in estimates of relative strength in practice and to illustrate how such biases can be assessed. Finally, we discuss implications for control: if new variants have longer generation intervals then speed-like interventions such as contact tracing become more effective, whereas strength-like interventions such as social distancing become less effective.
Implementation of SARS-CoV2 Screening in K-12 Schools using In-School Pooled Molecular Testing and Deconvolution by Rapid Antigen Test
Authors: Pollock Nira R. , Berlin David , Smole Sandra C. , Madoff Lawrence C. , Henderson Kelsey , Larsen Elizabeth , Hay Jeremiah , Gabriel Stacey , Gawande Atul A. , Lennon Niall J.
Published: May 2021

What is already known about this topic?

SARS-CoV2 testing is a key component of a multi-layered mitigation strategy to enable safe return to in-person school for the K-12 population. However, costs, logistics, and uncertainty about effectiveness are potential barriers to implementation.

What is added by this report?

Over three months, 259,726 individual swabs were tested across 50,636 pools from 582 schools. Pool positivity rate was 0.8%; 98.1% of pools tested negative and 0.3% inconclusive, and 0.8% of pools submitted could not be tested. In reflex testing, 92.5% of fully deconvoluted pools with N1 or N2 target Ct ≤30 yielded a positive individual using the BinaxNOW antigen rapid diagnostic test (Ag RDT) performed 1-3 days later. With sufficient staffing support and low pool positivity rates, pooled sample collection and reflex testing were feasible for schools.

What are the implications for public health practice?

Screening testing for K-12 students and staff is achievable at scale and at low cost with a scheme that incorporates in-school pooling, RT-PCR primary testing, and Ag RDT reflex/deconvolution testing. Staffing support is a key factor for program success.
Pregnancy pharmacoepidemiology: How often are key methodological elements reported in publications?
Authors: Margulis Andrea V , Kawai Alison T , Anthony Mary S , Rivero-Ferrer Elena
Published: May 2021

Purpose

Publications are an important information source for clinicians, researchers, and patients. Key methodological elements must be reported for maximum transparency. We identified key methodological elements necessary for fully understanding pharmacoepidemiological research in pregnancy and quantified the proportion of studies that report these elements in a sample of publications.

Methods

Key methodological elements were identified from guidelines from regulatory agencies, literature, and subject-matter knowledge: source of information to determine pregnancy start; mother- or father-infant linkages (process, success rate); unit of analysis; and whether non-live births and fetuses with various anomalies were included in the study population.

We conducted a literature review for recent observational studies on medical product utilization or safety during pregnancy and estimated the prevalence of reporting these elements.

Results

Data were extracted from a random sample of 100 publications; 8% were published in epidemiology/pharmacoepidemiology journals; 85% were medical product–safety studies.

Of included publications, 43% reported the source for determining pregnancy start; 57% reported whether the study population included multifetal pregnancies; 39%, whether it included more than 1 pregnancy per woman; 27%, whether it included fetuses with chromosomal abnormalities; 60%, fetuses with major congenital malformations; and 93%, non-live births. Of the 20 studies with mother-infant linkage, 35% described the process; 21% reported the linkage success rate. Among studies with more than one pregnancy/offspring per woman, 22% reported methods addressing sibling correlation.

Conclusions

In this sample of pregnancy-related pharmacoepidemiology publications, completeness of reporting can be improved. A pregnancy-specific checklist would help to increase transparency in the dissemination of study results.

Key points

▪

Publications on the utilization or safety of medical products in pregnancy (pregnancy pharmacoepidemiology) are fully understandable when all key methodological elements are presented to the reader.

▪

We identified 17 methodological elements from guidelines, literature, and subject-matter knowledge that we felt were crucial for understanding publications on pregnancy pharmacoepidemiology.

▪

In a random sample of 100 publications, completeness of reporting varied across elements, with almost perfect reporting on whether non-live births were included in the study population to a 21% completeness on mother-infant linkage success rate.

▪

A pregnancy-specific checklist would help to increase transparency in the dissemination of study results.
The encephalomyocarditis virus Leader promotes the release of virions inside extracellular vesicles via the induction of secretory autophagy
Authors: van der Grein Susanne G. , Defourny Kyra A.Y. , Rabouw Huib H. , Goerdayal Soenita S. , van Herwijnen Martijn J.C. , Wubbolts Richard W. , Altelaar Maarten , van Kuppeveld Frank J.M. , Nolte-‘t Hoen Esther N.M.
Published: May 2021

Naked viruses can escape host cells before the induction of lysis via release in extracellular vesicles (EVs). These nanosized EVs cloak the secreted virus particles in a host-derived membrane, which alters virus-host interactions that affect infection efficiency and antiviral immunity. Currently, little is known about the viral and host factors regulating this form of virus release. Here, we assessed the role of picornavirus security proteins by studying the encephalomyocarditis virus (EMCV) Leader protein. EV release upon infection with wildtype virus or a Leader-deficient mutant was characterized at the single particle level using high-resolution flow cytometry. Inactivation of the Leader abolished EV induction during infection and strongly reduced EV-enclosed virus release. We demonstrate that the Leader promotes the release of virions within EVs by stimulating a secretory arm of autophagy. This newly discovered role of the EMCV Leader adds to the variety of mechanisms via which this protein affects virus-host interactions. Moreover, these data provide first evidence for a crucial role of non-structural viral proteins in the non-lytic release of picornaviruses via packaging in EVs.
BigBrainWarp: Toolbox for integration of BigBrain 3D histology with multimodal neuroimaging
Authors: Paquola Casey , Royer Jessica , Lewis Lindsay B. , Lepage Claude , Glatard Tristan , Wagstyl Konrad , DeKraker Jordan , Toussaint Paule-J , Valk Sofie L , Collins Louis , Khan Ali R. , Amunts Katrin , Evans Alan C. , Dickscheid Timo , Bernhardt Boris
Published: May 2021

Abstract

Neuroimaging stands to benefit from emerging ultrahigh-resolution histological atlases of the human brain; the first of which is “BigBrain”. Ongoing research aims to characterise regional differentiation of cytoarchitecture with BigBrain and to optimise registration of BigBrain with standard neuroimaging templates. Together, this work paves the way for multi-scale investigations of brain organisation. However, working with BigBrain can present new challenges for neuroimagers, including dealing with cellular resolution neuroanatomy and complex transformation procedures. To simplify workflows and support adoption of best practices, we developed BigBrainWarp, a toolbox for integration of BigBrain with multimodal neuroimaging. The primary BigBrainWarp function wraps multiple state-of-the-art deformation matrices into one line of code, allowing users to easily map data between BigBrain and standard MRI spaces. Additionally, the toolbox contains ready-to-use cytoarchitectural features to improve accessibility of histological information. The present article discusses recent contributions to BigBrain-MRI integration and demonstrates the utility of BigBrainWarp for further investigations.
Characterization of the ABC methionine transporter fromNeisseria meningitidisreveals that MetQ is a lipoprotein
Authors: Sharaf Naima G. , Shahgholi Mona , Kim Esther , Lai Jeffrey Y. , VanderVelde David , Lee Allen T. , Rees Douglas C.
Published: May 2021

NmMetQ is a substrate binding protein (SBP) fromNeisseria meningitidisthat has been identified as a surface-exposed candidate antigen for meningococcal vaccines. However, this location for NmMetQ challenges the prevailing view that SBPs in Gram-negative bacteria are localized to the periplasmic space to promote interaction with their cognate ABC transporter embedded in the bacterial inner membrane. To address the roles of NmMetQ, we characterized NmMetQ with and without its cognate ABC transporter (NmMetNI). Here, we show that NmMetQ is a lipoprotein (lipo-NmMetQ) that binds multiple methionine analogs and stimulates the ATPase activity of NmMetNI. Using single-particle electron cryo-microscopy, we determined the structures of NmMetNI in the absence and presence of lipo-NmMetQ. Based on our data, we propose that NmMetQ tethers to membranes via a lipid anchor and has dual function/topology, playing a role in NmMetNI-mediated transport at the inner-membrane in addition to moonlighting functions on the bacterial surface.
Cortical Surface-Informed Volumetric Spatial Smoothing of fMRI Data via Graph Signal Processing
Authors: Behjat Hamid , Westin Carl-Fredrik , Aganj Iman
Published: May 2021

Conventionally, as a preprocessing step, functional MRI (fMRI) data are spatially smoothed before further analysis, be it for activation mapping on task-based fMRI or functional connectivity analysis on resting-state fMRI data. When images are smoothed volumetrically, however, isotropic Gaussian kernels are generally used, which do not adapt to the underlying brain structure. Alternatively, cortical surface smoothing procedures provide the benefit of adapting the smoothing process to the underlying morphology, but require projecting volumetric data on to the surface. In this paper, leveraging principles from graph signal processing, we propose avolumetricspatial smoothing method that takes advantage of the gray-white and pial cortical surfaces, and as such, adapts the filtering process to the underlying morphological details at each point in the cortex.
Comprehensive PAM prediction for CRISPR-Cas systems reveals evidence for spacer sharing, preferred strand targeting and conserved links with CRISPR repeats
Authors: Vink Jochem NA , Baijens Jan HL , Brouns Stan JJ
Published: May 2021

The adaptive CRISPR-Cas immune system stores sequences from past invaders as spacers in CRISPR arrays and thereby provides direct evidence that links invaders to hosts. Mapping CRISPR spacers has revealed many aspects of CRISPR biology, including target requirements such as the protospacer adjacent motif (PAM). However, studies have so far been limited by a low number of mapped spacers in the database. By using vast metagenomic sequence databases, we mapped one third (∼70,000) of more than 200,000 unique CRISPR spacers from a variety of microbes, and derived a catalog of more than one hundred unique PAM sequences associated with specific CRISPR subtypes. These PAMs were further used to correctly assign the orientation of CRISPR arrays, revealing conserved patterns between the last nucleotides of the CRISPR repeat and PAM. From the curated CRISPR arrays dataset we could also deduce CRISPR subtype specific preferences for targeting either template or coding strand of open reading frames. While some DNA-targeting systems (e.g. Type I-E and Type II systems) prefer the template strand and avoid mRNA, other DNA- and RNA-targeting systems (i.e. Type I-A, I-B and Type III systems) prefer the coding strand and mRNA. In addition, we found large scale evidence that both CRISPR adaptation machinery and CRISPR arrays are shared between different CRISPR-Cas systems. This could lead to simultaneous DNA- and RNA targeting of invaders, which may be effective at combating mobile genetic invaders.
Increased mitochondrial activity upon CatSper channel activation is required for sperm capacitation
Authors: Ferreira Juan J. , Cassina Adriana , Irigoyen Pilar , Ford Mariana , Pietroroia Santiago , Radi Rafael , Santi Celia M. , Sapiro Rossana
Published: May 2021

To fertilize an oocyte, sperm must become hyperactive. However, whether they obtain ATP for hyperactivated motility via glycolysis or mitochondrial respiration is unclear. Here, high-resolution respirometry, flow cytometry, and confocal microscopy experiments revealed that mitochondrial respiration and membrane potential increased during mouse sperm capacitation. Treatment with inhibitors of mitochondrial respiration prevented sperm from hyperactivating and fertilizing an oocyte. Mitochondrial respiration was impaired in sperm from mice lacking the calcium channel CatSper. We developed a method to image mitochondrial calcium in sperm and found that CatSper activation led to increased mitochondrial calcium concentration. Finally, treating sperm with an inhibitor of mitochondrial calcium import impaired mitochondrial function and sperm hyperactivation. Together, our results uncover a new role of sperm mitochondria and reveal a new pathway connecting calcium influx through CatSper to mitochondrial activity and the sperm hyperactivation required to fertilize an oocyte.

The source of ATP for sperm hyperactivation is unclear. Ferreira et al. show that mitochondrial activity increases during, and is required for, hyperactivation and fertilization ability. Increased mitochondrial activity depends on calcium influx through the channel CatSper.
Evolution of enzyme levels in metabolic pathways: A theoretical approach
Authors: Coton Charlotte , Talbot Grégoire , Le Louarn Maud , Dillmann Christine , de Vienne Dominique
Published: May 2021

The central role of metabolism in cell functioning and adaptation has given rise to count-less studies on the evolution of enzyme-coding genes and network topology. However, very few studies have addressed the question of how enzyme concentrations change in response to positive selective pressure on the flux, considered a proxy of fitness. In particular, the way cellular constraints, such as resource limitations and co-regulation, affect the adaptive landscape of a pathway under selection has never been analyzed theoretically. To fill this gap, we developed a model of the evolution of enzyme concentrations that combines metabolic control theory and an adaptive dynamics approach, and integrates possible dependencies between enzyme concentrations. We determined the evolutionary equilibria of enzyme concentrations and their range of neutral variation, and showed that they differ with the properties of the enzymes, the constraints applied to the system and the initial enzyme concentrations. Simulations of long-term evolution confirmed all analytical and numerical predictions, even though we relaxed the simplifying assumptions used in the analytical treatment.
Functional and ultrastructural analysis of reafferent mechanosensation in larval zebrafish
Authors: Odstrcil Iris , Petkova Mariela D. , Haesemeyer Martin , Boulanger-Weill Jonathan , Nikitchenko Maxim , Gagnon James A. , Oteiza Pablo , Schalek Richard , Peleg Adi , Portugues Ruben , Lichtman Jeff , Engert Florian
Published: May 2021

All animals need to differentiate between exafferent stimuli, which are caused by the environment, and reafferent stimuli, which are caused by their own movement. In the case of mechanosensation in aquatic animals, the exafferent inputs are water vibrations in the animal’s proximity, which need to be distinguished from the reafferent inputs arising from fluid drag due to locomotion. Both of these inputs are detected by the lateral line, a collection of mechanosensory organs distributed along the surface of the body.

In this study, we characterize in detail how the hair cells, which are the receptor cells of the lateral line, discriminate between such reafferent and exafferent signals in zebrafish larvae. Using dye labeling of the lateral line nerve, we visualize two parallel descending inputs that can influence lateral line sensitivity. We combine functional imaging with ultra-structural EM circuit reconstruction to show that cholinergic signals originating from the hindbrain transmit efference copies that cancel out self-generated reafferent stimulation during locomotion, and that dopaminergic signals from the hypothalamus may have a role in threshold modulation both in response to locomotion and salient stimuli. We further gain direct mechanistic insight into the core components of this circuit by loss-of-function perturbations using targeted ablations and gene knockouts.

We propose that this simple circuit is the core implementation of mechanosensory reafferent suppression in these young animals and that it might form the first instantiation of state-dependent modulation found at later stages in development.
Heme oxygenase limits mycobacterial infection-induced ferroptosis
Authors: Luo Kaiming , Stocker Roland , Britton Warwick J , Kikuchi Kazu , Oehlers Stefan H
Published: May 2021

Iron homeostasis is essential for both sides of the host-pathogen interface. Restricting access of iron slows bacterial growth while iron is also a necessary co-factor for host immunity. Heme oxygenase 1 (HMOX1) is a critical regulator of iron homeostasis that catalyses the liberation of iron during degradation of heme. It is also a stress-responsive protein that can be rapidly upregulated and confers protection to the host. Although a protective role of HMOX1 has been demonstrated in a variety of diseases, the role of HMOX1 inMycobacterium tuberculosisinfection is equivocal across experiments with different host-pathogen combinations. Here we use the natural host-pathogen pairing of the zebrafish-Mycobacterium marinuminfection platform to study the role of zebrafish heme oxygenase in mycobacterial infection. We identify zebrafish Hmox1a as the relevant functional paralog of mammalian HMOX1 and demonstrate a conserved role for Hmox1a in protecting the host from mycobacterial infection. Using genetic and chemical tools, we show zebrafish Hmox1a protects the host against mycobacterial infection by reducing infection-induced iron accumulation and ferroptosis.
The genomic landscape of early stage ovarian high grade serous carcinoma
Authors: Cheng Z. , Mirza H. , Ennis D.P. , Smith P. , Gavarró L. Morrill , Sokota C. , Giannone G. , Goranova T. , Bradley T. , Piskorz A. , Lockley M. ,   the BriTROC-1 Investigators^, Kaur B. , Singh N. , Tookman L.A. , Krell J. , McDermott J. , Macintyre G. , Markowetz F. , Brenton J.D. , McNeish I.A.
Published: May 2021

Purpose

High grade serous carcinoma (HGSC) is the commonest type of ovarian cancer. Nearly all HGSC cases are diagnosed at late stage and it is not clear whether early stage HGSC has unique characteristics compared to late stage tumours.

Experimental Design

We analysed samples from 45 patients with FIGO stage I - IIA HGSC - 40 from the pathology archives of three large UK cancer centres and 5 from the BriTROC-1 study. We performed shallow whole genome sequencing (sWGS) and targeted next generation sequencing to investigate somatic mutations and copy number alterations. We compared results to 51 stage IIIC/IV HGSC patients from the BriTROC-1 study.

Results

There was no difference in median age between the early stage (median 61.3 years, range 40-84) and late stage (median 62.3 years, range 34-76) patients at diagnosis.TP53mutations were near-universal (92% early stage, 100% late stage samples) and there were no significant differences in the rates of other somatic mutations, includingBRCA1andBRCA2, or focal copy number alterations between early- and late-stage cohorts. There were also no unique amplifications or deletions in either cohort. However, median ploidy was greater in late stage (median 3.1) than early stage (median 2.0) samples. In addition, there were higher numbers of breakpoints per 10MB and per chromosome arm and higher absolute copy number in late stage than early stage cohorts; early stage samples had longer segment length. Overall copy number signature exposures were significantly different between early and late stage samples with greater signature 3 exposure in early stage and greater signature 4 in late stage. Both simplex plot and unsupervised hierarchical clustering suggested that a subset of late stage samples retain early stage appearances with high signature 3 and co-clustering with the early stage samples

Conclusions

These data suggest that there are no unique mutations or focal copy number alterations in early stage HGSC. However, whole genome duplication is significantly more common in late-stage disease, suggesting evolution during disease progression. However, a subset of late stage HGSC retains early-stage features, which are associated with improved overall survival.