bluuebunny/crossref_metadata_2025 huggingface dataset:
Increasing Cardiac Rehabilitation Participation Through a “Nearer to Home” Patient Referral Program
Authors: Bryant Joseph , Rubenfire Melvyn , Katona Aimee M. , Graves Christopher , Fink Samantha , Kline-Rogers Eva , Barber Andrew , Zhang Min , Weinstein David G. , Walden Patrick
Published: December 2020

Purpose:

Time to travel to cardiac rehabilitation (CR) centers is a barrier to participation, and tertiary referral centers often care for patients living at a substantial distance. We sought to determine the impact of referring eligible patients to CR centers closer to home or workplace on overall participation rate.

Methods:

An observational review was conducted in patients from a large cardiovascular program who were referred to CR (January 1, 2015, through December 31, 2016). Those declining participation due to distance from their home were identified and provided coordinated referral to a CR program they chose near their home or workplace.

Results:

Of the 2912 patients referred to CR, 673 (23%) participated and 1900 declined due to distance. Contact was made in 2017 with 1237 of the 1900 of whom 1083 recalled a discussion of distance referral and completed the phone survey. Participants mean age was 64 yr, predominantly White (88%), male (65%), married (66%), and 70% had ≥ comorbidity. Out of the 1083 referred to a local CR program, 78% reported attending. Of those who attended CR, 55% (469/849) would not have attended had they not been referred to a program closer to their home or workplace. Overall participation increased from 23% to >50% of those referred from our institution.

Conclusions:

Coordinating CR referrals from the discharging facility to facilities closer to home or workplace is an effective means for increasing participation. The very low-cost effort has the potential to have a very meaningful impact on the long-term outcome of cardiovascular patients.
A Comparison of Exercise Intensity in Hybrid Versus Standard Phase Two Cardiac Rehabilitation
Authors: Keteyian Steven J. , Grimshaw Crystal , Brawner Clinton A. , Kerrigan Dennis J. , Reasons Lisa , Berry Robert , Peterson Edward L. , Ehrman Jonathon K.
Published: December 2020

Purpose:

To compare exercise training intensity during standard cardiac rehabilitation (S-CR) versus hybrid-CR (combined clinic- and remote home-/community-based).

Methods:

The iATTEND (improving ATTENDance to cardiac rehabilitation) trial is currently enrolling subjects and randomizing patients to S-CR versus hybrid-CR. This substudy involves the first 47 subjects who completed ≥18 CR sessions. Patients in S-CR completed all visits in a typical phase II clinic-based setting and patients in hybrid-CR completed up to 17 of their sessions remotely using telehealth (TH). Exercise training intensity in both CR settings is based on heart rate (HR) data from each CR session, expressed as percent HR reserve.

Results:

Among patients in both study groups, there were no serious adverse events or falls that required hospitalization during or within 3 hr after completing a CR session. Expressed as a percentage of HR reserve, the overall mean exercise training intensities during both the S-CR sessions and the TH-CR sessions from hybrid-CR were not significantly different at 63 ± 12% and 65 ± 10%, respectively (P = .29).

Conclusion:

This study showed that hybrid-CR delivered using remote TH results in exercise training intensities that are not significantly different from S-CR.
Measurement of Natural Radionuclides and Assessment of Radiation Hazard in Coal from Parts of China
Authors: Li Wenhong , Wang Shuo , Yang Baolu , Tuo Fei
Published: December 2020

To study the content of radionuclides in coal and to assess its associated radiological impact on the environment for potential radiological risk assessment, a total of 40 coal samples were collected from various mining areas in eight provinces of China. The specific activities of 226Ra, 232Th, 40K, 210Pb, and 238U were measured in all samples using an HPGe gamma-ray spectrometer, and results were compared with available data from other similar studies. The results reveal that the radium equivalent activity was 74.20 Bq kg−1, external hazard index was 0.20, internal hazard index was 0.27, representative gamma index was 0.52, and indoor and outdoor annual effective dose rates were 0.16 nSv y−1 and 0.04 nSv y−1, respectively. Absorbed gamma dose rate in air was 32.87 nGy h−1. In general, these values are lower than the respective threshold limits recommended by UNSCEAR, and the radiation risk to the public is extremely small.
MLH1 c.199G>A, a Known Mutation for Lynch Syndrome, Is Also Associated with Sebaceous Neoplasm
Authors: Li Wei-Sheng , Li Yan , Zhou Nai-Hui , Liu Jing-Liu , Yang Zi-Liang , Sun Miao , Li Min
Published: December 2020

Introduction:

Muir-Torre syndrome is a phenotypic variant of Lynch syndrome characterized by a predisposition for the development of visceral malignant disease and sebaceous gland neoplasms, and it is caused by germline mutations in the mismatch repair genes MSH2 and MLH1.

Here, we reported a patient with sebaceous neoplasm containing MLH1 c.199G>A mutation.

Case presentation:

The proband was a 42-year-old man who had undergone surgical resection of colorectal adenocarcinoma at 28 years. He presented with macular rashes and red papule. Histological examination of the lesion on his head revealed a sebaceoma at 37 years. Follow-up of the family history revealed that the proband's 65-year-old mother had been highly suspected to have Lynch syndrome with colorectal cancer at 40 years of age. The proband's daughter underwent colonoscopy because of blood in the stool at the age of 13 years, but no abnormalities were found.

Discussion:

We have herein reported a pathogenic missense mutation c.199G>A (p.Gly67Arg) in exon 2 of MLH1 in patients with MTS. This mutation has been reported in patients with Lynch syndrome who have no skin tumors. However, we also found that some patients with MTS had no history of any internal malignancy or skin tumor. Our data support the idea that a hiatus of many years may pass before both elements-a sebaceous neoplasm and an internal cancer-are present in a patient, thus finally allowing the diagnosis of MTS.

Conclusion:

A pathogenic Lynch syndrome mutation c.199G>A in exon 2 of the MLH1 gene was found in a patient with MTS who presented with a sebaceous neoplasm.
Frequency of Falls and Associated Risk Factors in People Living With HIV: A Systematic Review With Meta-Analysis and Meta-Regression
Authors: Tolentino Arthur , Amaral Sávio , S. Souza Lucca , Zeballos Diana , Brites Carlos
Published: December 2020

Background:

Falls are considered as a predictive marker of poorer outcomes for people living with HIV (PLWHIV). However, the available evidences on the predictive value of falls are controversial. Our aim is to summarize the existing data about falls in PLWHIV.

Methods:

A literature search was conducted using electronic databases (MEDLINE, Embase, and LILACS) for original observational studies. The primary outcome was any and recurrent falls' frequency in PLWHIV, and secondary outcomes were factors associated with falls. We conducted a random-effects meta-analysis with meta-regression to obtain a summary frequency of falls and recurrent falls.

Results:

The pooled frequency for any fall was 26% [95% confidence interval (CI): 19% to 34%], compared with 14% for recurrent falls (95% CI: 9% to 22%). In studies comparing PLWHIV and people without HIV, we found no difference for any (pooled odds ratio 1.03, 95% CI: 0.90 to 1.17) or recurrent falls (pooled odds ratio 1.08, 95% CI: 0.92 to 1.27) between groups, but falls in middle-aged PLWHIV might be more associated with subjacent clinical conditions such as cognitive impairment, polypharmacy, use of medications with action in the central nervous system, and frailty, classic risk factors for falls in the elderly.

Conclusions:

The overall frequency of falls in PLWHIV seems to be lower than that presented by some initial studies, and several factors associated with falls are shared with elderly adults. Although both PLWHIV and people without HIV presented similar frequency of falls, we found that these events might be qualitatively different; therefore, an appropriate method to evaluate falls in this population to prevent adverse outcomes is warranted.
Prevalence, Management, and Outcomes Related to Preoperative Medical Orders for Life Sustaining Treatment (MOLST) in an Adult Surgical Population
Authors: Tanious Mariah , Lindvall Charlotta , Cooper Zara , Tukan Natalie , Peters Stephanie , Streid Jocelyn , Fields Kara , Bader Angela
Published: December 2020

Objective:

To determine prevalence of documented preoperative code status discussions and postoperative outcomes (specifically mortality, readmission, and discharge disposition) of patients with completed MOLST forms before surgery.

Summary of Background Data:

A MOLST form documents patient care preference regarding treatment limitations. When considering surgery in these patients, preoperative discussion is necessary to ensure concordance of care. Little is known about prevalence of these discussions and postoperative outcomes.

Methods:

A retrospective cohort study was conducted consisting of all patients having surgery during a 1-year period at a tertiary care academic center in Boston, Massachusetts.

Results:

Among 21,787 surgical patients meeting inclusion criteria, 402 (1.8%) patients had preoperative MOLST. Within the MOLST, 224 (55.7%) patients had chosen to limit cardiopulmonary resuscitation and 214 (53.2%) had chosen to limit intubation and mechanical ventilation. Code status discussion was documented presurgery in 169 (42.0%) patients with MOLST. Surgery was elective or nonurgent for 362 (90%), and median length of stay (Q1, Q3) was 5.1 days (1.9, 9.9). The minority of patients with preoperative MOLST were discharged home [169 (42%), and 103 (25.6%) patients were readmitted within 30 days. Patients with preoperative MOLST had a 30-day mortality of 9.2% (37 patients) and cumulative 90-day mortality of 14.9% (60 patients).

Conclusions:

Fewer than half of surgical patients with preoperative MOLST have documented code status discussions before surgery. Given their high risk of postoperative mortality and the diversity of preferences found in MOLST, thoughtful discussion before surgery is critical to ensure concordant perioperative care.
Gluconacetobacter dulcium sp. nov., a novel Gluconacetobacter species from sugar-rich environments
Authors: Sombolestani Atena Sadat , Cleenwerck Ilse , Cnockaert Margo , Borremans Wim , Wieme Anneleen D. , Moutia Yvan , Spaepen Stijn , De Vuyst Luc , Vandamme Peter
Published: December 2020

A phylogenomic analysis based on 107 single-copy core genes revealed that three strains from sugar-rich environments, i.e. LMG 1728T, LMG 1731 and LMG 22058, represented a single, novel

Gluconacetobacter

lineage with

Gluconacetobacter liquefaciens

as nearest validly named neighbour. OrthoANIu and digital DNA–DNA hybridization analyses among these strains and

Gluconacetobacter

type strains confirmed that the three strains represented a novel

Gluconacetobacter

species. Biochemical characteristics and MALDI-TOF mass spectra allowed differentiation of this novel species from the type strains of

G. liquefaciens

and other closely related

Gluconacetobacter

species. We therefore propose to classify strains LMG 1728T, LMG 1731 and LMG 22058 in the novel species Gluconacetobacter dulcium sp. nov., with LMG 1728T (=CECT 30142T) as the type strain.
QFEA - A Method for Assessing the Filtration Efficiency of Face Mask Materials for Early Design Prototypes and Home Mask Makers
Authors: O’Kelly Eugenia , Arora Anmol , O’Kelly Corinne , Pearson Charlotte , Ward James , Clarkson P John
Published: December 2020

The COVID-19 pandemic has led to a surge in the design and production of fabric face coverings. There are few published methods which enable mask designers, makers and purchasers to assess the relative filtration ability of mask making materials. Those methods which do exist are prohibitively expensive and difficult to conduct. As a result, mask makers, non-profits, and small-scale designers face difficult decisions when designing face coverings for personal and commercial use. In this paper, we propose a novel method, the Qualitative Filtration Efficiency Assessment (QFEA), for easily and inexpensively comparing the filtration efficiency of common materials. This method provides a highly affordable and readily available way to assess potential mask materials.
Development of a Conceptual Model of Childhood Asthma to Inform Asthma Prevention Policies
Authors: Adibi Amin , Turvey Stuart E , Lee Tae Yoon , Sears Malcolm R , Becker Allen B , Mandhane Piush J , Moraes Theo J , Subbarao Padmaja , Sadatsafavi Mohsen
Published: December 2020

Background

There is no definitive cure for asthma; as such, prevention remains a major goal. Decision-analytic models are routinely used to evaluate the value-for-money proposition of interventions. Following best practice standards in decision-analytic modeling, the objective of this study was to solicit expert opinion to develop a concept map for a policy model for primary prevention of asthma.

Methods

We reviewed currently available decision-analytic models for asthma prevention. A steering committee of economic modelers, allergists, and respirologists was then convened to draft a conceptual model of pediatric asthma. A modified Delphi method was followed to define the context of the problem at hand (evaluation of asthma prevention strategies) and develop the concept map of the model.

Results

Consensus was achieved after three rounds of discussions, followed by concealed voting. In the final conceptual model, asthma diagnosis was based on three domains of lung function, atopy, and their symptoms. The panel recommended several markers for each domain. These domains were in turn affected by several risk factors. The panel clustered all risk factors under three groups of ‘patient characteristic’, ‘family history’, and ‘environmental factors’. To be capable of modeling the interplay among risk factors, the panel recommended the use of microsimulation, with an open-population approach that would enable modeling phased implementation and gradual and incomplete uptake of the intervention.

Conclusions

Economic evaluation of childhood interventions for preventing asthma will require modeling of several co-dependent risk factors and multiple domains that affect the diagnosis. The conceptual model can inform the development and validation of a policy model for childhood asthma prevention.

Funding

Genome Canada Large-Scale Applied Research Project
A standardized non-visual behavioral event is broadcasted homogeneously across cortical visual areas without modulating visual responses
Authors: Ramadan Mahdi , Lee Eric Kenji , de Vries Saskia , Caldejon Shiella , Kato India , Roll Kate , Griffin Fiona , Nguyen Thuyanh V. , Larkin Josh , Rhoads Paul , Mace Kyla , Kriedberg Ali , Howard Robert , Berbesque Nathan , Lecoq Jérôme
Published: December 2020

Multiple recent studies have shown that motor activity greatly impacts the activity of primary sensory areas like V1. Yet, the role of this motor related activity in sensory processing is still unclear.

Here we dissect how these behavior signals are broadcast to different layers and areas of the visual cortex. To do so, we leveraged a standardized and spontaneous behavioral fidget event in passively viewing mice. Importantly, this behavior event had no relevance to any ongoing task allowing us to compare its neuronal correlate with visually relevant behavior like running.

A large two-photon Ca2+ imaging database of neuronal responses uncovered four neural response types during fidgets that were surprisingly consistent in their proportion and response patterns across all visual areas and layers of the visual cortex. Indeed, the layer and area identity could not be decoded above chance level based only on neuronal recordings. In contrast to running behavior, fidget evoked neural responses were independent to visual processing.

The broad availability of visually orthogonal standardized behavior signals could be a key component in how the cortex selects, learns and binds local sensory information with motor outputs. Contrary to relevant motor outputs, irrelevant motor signals would use a separate neural subspaces.

Significance Statement

Recent studies have shown contextual and behavioral variables to dominate brain-wide activity, but yet it is unknown how this information is broadcast across cortical layers and areas. Using a large two-photon dataset collected in mice passively viewing a battery of visual stimuli, we characterized the neuronal response of neurons of the visual cortex to a standardized fidget behavior. We found that as much as 47% of excitatory neurons show significant co-activity with fidgets. Throughout all areas and layers we recorded from, those responses were distributed across surprisingly consistent three neural response types. Further analysis showed no interaction between fidget neural events and cells’ visual stimulus responses, contrasting with feedback neural signals induced by running. These contrasting response distribution patterns suggest that behavioral neuronal correlates are broadly available but will modulate sensory responses depending on their relevance to local sensory inputs.
The Persistence of Vaccine Hesitancy: COVID-19 Vaccination Intention
Authors: Thaker Jagadish
Published: December 2020

Building public trust and willingness to vaccinate against COVID-19 is as important as developing an effective vaccine. However, a significant minority of the public are unwilling or hesitant to take a COVID-19 vaccine, when available. A nationally representative sample survey (N=1040) was conducted in July 2020 in New Zealand to identify factors associated with COVID-19 vaccine intention. Trust in experts and general vaccine hesitancy were significantly associated with COVID-19 vaccine intention. A communication campaign from trusted scientific experts, with information that addresses prevailing concerns about vaccines, is likely to help increase COVID-19 vaccine uptake.
Potential Relationship Between eGFRcystatin C/eGFRcreatinine-ratio and Glomerular Basement Membrane Thickness in Diabetic Kidney Disease
Authors: Öberg Carl M. , Lindström Martin , Grubb Anders , Christensson Anders
Published: December 2020

Background

Diabetic nephropathy (DN) is a leading cause of end stage renal disease and renal replacement therapy worldwide. A pathophysiological hallmark of DN is glomerular basal membrane (GBM) thickening, whereas this feature is absent in minimal change disease. Theoretically, a thicker GBM will impede the diffusion of middle-molecules such as cystatin C, potentially leading to a lower estimated GFR (eGFR) from cystatin C compared to that of creatinine. Here we test the hypothesis that thickening of the glomerular filter leads to an increased diffusion length, and lower clearance, of cystatin C.

Methods

Twenty-nine patients with a kidney biopsy diagnosis of either DN (n=17) or minimal change disease (MCD) (n=12) were retrospectively included in the study. GBM thickness was measured at 20 separate locations in the biopsy specimen and plasma levels of cystatin C and creatinine were retrieved from health records. A modified two-pore model was used to simulate the effects of a thicker GBM on glomerular water and solute transport.

Results

The mean age of the patients was 52 years, and 38% were women. The mean eGFRcystatin C/eGFRcreatinine-ratio was 74% in DKD compared to 98% in MCD (P < 0.001). Average GBM thickness was strongly inversely correlated to the eGFRcystatin C/eGFRcreatinine-ratio (Pearson’s r=-0.61, P < 0.01). Two-pore modeling predicted a eGFRcystatin C/eGFRcreatinine-ratio of 78% in DN.

Conclusions

We provide clinical and theoretical evidence suggesting that thickening of the glomerular filter, increasing the diffusion length of cystatin C, lowers the eGFRcystatin C/eGFRcreatinine-ratio in DN.

Significance statement

Increased thickness of the glomerular basement membrane (GBM) is an early structural abnormality in diabetes, and has been identified as an independent risk factor for progression to diabetic nephropathy (DN). Increased GBM thickness will increase the diffusion length of mid-sized molecules like cystatin C across the renal filter, potentially leading to increased plasma concentrations and lower estimated GFR from cystatin C. The authors show theoretically that estimated GFR from cystatin C (eGFRcystatin C) is lower than that of creatinine (eGFRcreatinine) in DN to a degree directly depending on GBM thickness. In line with theory, they provide clinical data showing a lower eGFRcystatin Cin diabetic patients with the eGFRcystatin C/eGFRcreatinine-ratio being inversely correlated to GBM thickness assessed from electron micrographs.
Seroprevalence of anti-SARS-CoV-2 IgG antibodies, risk factors for infection and associated symptoms in Geneva, Switzerland: a population-based study
Authors: Richard Aude , Wisniak Ania , Perez-Saez Javier , Garrison-Desany Henri , Petrovic Dusan , Piumatti Giovanni , Baysson Hélène , Picazio Attilio , Pennacchio Francesco , De Ridder David , Chappuis François , Vuilleumier Nicolas , Low Nicola , Hurst Samia , Eckerle Isabella , Flahault Antoine , Kaiser Laurent , Azman Andrew S , Guessous Idris , Stringhini Silvia ,   For the SEROCOV-POP study group
Published: December 2020

Background

Population-based serological surveys provide a means for assessing the immunologic landscape of a community, without the biases related to health-seeking behaviors and testing practices typically associated with rt-PCR testing. This study assesses SARS-CoV-2 seroprevalence over the first epidemic wave in Canton Geneva, Switzerland, as well as biological and socio-economic risk factors for infection and symptoms associated with IgG seropositivity.

Methods and findings

Between April 6 and June 30, 2020, former participants of a yearly representative cross-sectional survey of the 20-75-year-old population of the canton of Geneva were invited to participate in a seroprevalence study, along with household members five years and older. We collected blood and tested it for anti-SARS-CoV-2 immunoglobulins G (IgG). Questionnaires were self-administered. We estimated seroprevalence with a Bayesian model accounting for test performance and sampling design. We included 8344 participants (53.5% women, mean age 46.9 years). The population-level seroprevalence over the 12-week study period was 7.8 % (95% Credible Interval (CrI) 6.8-8.9), accounting for sex, age and household random effects. Seroprevalence was highest among 18-49 year olds (9.5%, 95%CrI 8.1-10.9), with young children (5-9 years) and those >65 years having significantly lower seroprevalence (4.3% and 4.7-5.4% respectively). Men were more likely to be seropositive than women (relative risk 1.2, 95%CrI 1.1-1.4). Odds of seropositivity were reduced for female retirees (0.46, 95%CI 0.23-0.93) and unemployed men (0.35, 95%CI 0.13-1.0) compared to employed individuals, and for current smokers (0.36, 95%CI 0.23-0.55) compared to never-smokers. We found no significant association between occupation, level of education, neighborhood income and the risk of being seropositive. Symptoms most strongly associated with seropositivity were anosmia/dysgeusia, loss of appetite, fever, fatigue and myalgia and/or arthralgia. Thirteen percent of seropositive participants reported no symptoms.

Conclusions

Our results confirm a low population seroprevalence of anti-SARS-CoV-2 antibodies after the first wave in Geneva, a region hard hit by the COVID-19 pandemic. Socioeconomic factors were not associated with seropositivity in this sample. The elderly and young children were less frequently seropositive, though it is not clear how biology and behaviors shape these differences. These specificities should be considered when assessing the need for targeted public health measures.
Length–length and length–weight relationships for four small pelagic fishes in the Kuroshio–Oyashio current system
Authors: Furuichi Sho , Kamimura Yasuhiro , Yukami Ryuji
Published: December 2020

Length–length relationships and length–weight relationships were estimated for four small pelagic fishes (Japanese sardineSardinops melanostictus, Japanese anchovyEngraulis japonicus, chub mackerelScomber japonicus, and spotted mackerelScomber australasicus) in the Kuroshio–Oyashio current system. Fish samples were collected from surface–midwater trawl surveys and commercial purse-seine fisheries between September and October of 2020 in the western North Pacific. Total length (TL), fork length (FL), and standard length (SL) were measured to 0.01 cm, and whole body weight (W) was measured to the nearest 0.01 g for each individual. All length–length relationships (TL–FL, TL–SL, and FL–SL) were highly significant (p< 0.0001), withr2> 0.98 in all species. Length–weight relationships (W–TL, W–FL, and W–SL) were also highly significant (p< 0.0001), withr2> 0.98 in all species. This study provides a useful reference for biological studies and stock assessments of these small pelagic fishes.
Activity flow underlying abnormalities in brain activations and cognition in schizophrenia
Authors: Hearne Luke J. , Mill Ravi D. , Keane Brian P. , Repovš Grega , Anticevic Alan , Cole Michael W.
Published: December 2020

Cognitive dysfunction is a core feature of many brain disorders such as schizophrenia (SZ), and has been linked to both aberrant brain functional connectivity (FC) and aberrant cognitive brain activations. We propose that aberrant network activity flow over FC pathways leads to altered cognitive activations that produce cognitive dysfunction in SZ. We tested this hypothesis using activity flow mapping – an approach that models the movement of task-related activity between brain regions as a function of FC. Using fMRI data from SZ individuals and healthy controls during a working memory task, we found that activity flow models accurately predict aberrant cognitive activations across multiple brain networks. Within the same framework, we simulated a connectivity-based clinical intervention, predicting specific treatments that normalized brain activations and behavior in independent patients. Our results suggest that dysfunctional task-evoked activity flow is a large-scale network mechanism contributing to the emergence of cognitive dysfunction in SZ.
Monitoring Reactivation of Latent HIV by Label-Free Gradient Light Interference Microscopy
Authors: Goswami Neha , Lu Yiyang , Kandel Mikhail E. , Fanous Michael J. , Bohn-Wippert Kathrin , Tevonian Erin N. , Dar Roy D. , Popescu Gabriel
Published: December 2020

Latent human immunodeficiency virus (HIV) reservoirs in infected individuals present the largest barrier to a cure. The first step towards overcoming this challenge is to understand the science behind latency-reactivation interplay. Fluorescence imaging of GFP-tagged HIV has been the main method for studying reactivation of latent HIV in individually infected cells. In this paper, we report insights provided by label-free, gradient light interference microscopy (GLIM) about the changes in measures including dry mass, diameter, and dry mass density associated with infected cells that occur upon reactivation. We discovered that mean cell dry mass and mean diameter of latently infected cells treated with reactivating drug, TNF-α, are higher for cells with reactivated HIV as compared to those with latent disease. Results also indicate that cells with mean dry mass and diameter less than 10pg and 8µm, respectively, remain exclusively in the latent state. Also, cells with mean dry mass greater than 23pg and mean diameter greater than 11µm have a higher probability of reactivating. This study is significant as it presents a new label-free approach to quantify latent reactivation of a virus in single cells based on changes in cell morphology.
Error Rates in SARS-CoV-2 Testing Examined with Bayesian Inference
Authors: Bentley P. M.
Published: December 2020

A literature review on SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) is used to construct a clinical test confusion matrix. A simple correction method for bulk test results is then demonstrated with examples. The required sensitivity and specificity of a test are explored for societal needs and use cases, before a sequential analysis of common example scenarios is explored. The analysis suggests that many of the people with mild symptoms and positive test results are unlikely to be infected with SARS-CoV-2 in some regions. It is concluded that current and foreseen alternative tests can not be used to “clear” people as being non-infected. Recommendations are given that regional authorities must establish a programme to monitor operational test characteristics before launching large scale testing; and that large scale testing for tracing infection networks in some regions is not viable, but may be possible in a focused way that does not exceed the working capacity of the laboratories staffed by competent experts. RT-PCR tests can not be solely relied upon as the gold standard for SARS-CoV-2 diagnosis at scale, instead clinical assessment supported by a range of expert diagnostic tests should be used.
Classification of the infection status of COVID-19 in 190 countries
Authors: Odagaki Takashi , Suda Reiji
Published: December 2020

We propose a simple method to determine the infection rate from the time dependence of the daily confirmed new cases, in which the logarithm of the rate is fitted by piece-wise quadratic functions. Exploiting this method, we analyze the time dependence of the outbreak of COVID-19 in 190 countries around the world and determine the status of the outbreak in each country by the dependence of the infection rate on the number of new cases. We show that the infection status of each country can be completely classified into nine different states and that the infection status of countries succeeded in controlling COVID-19 implies the importance of the quarantine and/or self-isolation measure.
Capturing Human Trophoblast Development with Naïve Pluripotent Stem Cells In Vitro
Authors: Io Shingo , Kabata Mio , Iemura Yoshiki , Semi Katsunori , Morone Nobuhiro , Okamoto Ikuhiro , Nakamura Tomonori , Kojima Yoji , Iwatani Chizuru , Tsuchiya Hideaki , Kaswandy Belinda , Kondoh Eiji , Saitou Mitinori , Yamamoto Takuya , Mandai Masaki , Takashima Yasuhiro
Published: December 2020

Trophoblast are extra-embryonic cells that are essential to maintain pregnancy. Human trophoblasts arise from the morula as trophectoderm (TE), which, after implantation, differentiates into cytotrophoblast (CT), syncytiotrophoblast (ST), and extravillous trophoblast (EVT) composing the placenta. Here we show that naïve, but not primed, human pluripotent stem cells (PSCs) recapitulate trophoblast development. Naïve PSC-derived TE and CT (nCT) recreated the human and monkey TE-to-CT transition. nCT self-renewed as CT stem cells and had the characteristics of proliferating villous CT and CT in the cell column of the first trimester. Notably, although primed PSCs differentiated into trophoblast-like cells (pBAP), pBAP were distinct from nCT and human placenta-derived CT stem cells, exhibiting properties consistent of the amnion. Our findings establish an authentic paradigm for human trophoblast development, demonstrating the invaluable properties of naïve human PSCs. Our system will provide a platform to study the molecular mechanisms underlying trophoblast development and related diseases.
Deregulation of epigenetic marks is correlated to differential exon usage of developmental genes
Authors: Trang Do Hoang Thu , Shanak Siba , Barghash Ahmad , Helms Volkhard
Published: December 2020

Alternative exon usage is known to affect a large portion of genes in mammalian genomes. Importantly, different splice forms sometimes lead to distinctly different protein functions. We analyzed data from the Human Epigenome Atlas (version 9) whereby we connected the differential usage of exons in various developmental stages of human cells/tissues to differential epigenetic modifications at the exon level. In total, we analyzed 19 human tissues, adult cells, and cultured cells that mimic early developmental stages. We found that the differential occurrence of protein isoforms across developmental stages was often associated with changes in histone marks at exon boundary regions. Many of the genes that are differentially regulated at the exon level were found to be functionally associated with development and metabolism.
Asymmetric chromatin capture and nuclear envelopes separate chromosomes in fused cells during mitosis
Authors: Sunchu Bharath , Lee Nicole , Segura Roberto Carlos , Roubinet Chantal , Cabernard Clemens
Published: December 2020

Hybrid cells derived through fertilization or somatic cell fusion recognize and separate chromosomes of different origin. The underlying mechanisms are unknown but could prevent aneuploidy and tumor formation. Here, we acutely induce fusion betweenDrosophilaneural stem cells (neuroblasts; Nbs) and differentiating ganglion mother cells (GMCs)in vivoto define how epigenetically distinct chromatin is recognized and segregated. We find that Nb-GMC hybrid cells align both endogenous (neuroblast-origin) and ectopic (GMC-origin) chromosomes at the metaphase plate through centrosome derived dual-spindles. Mixing of endogenous and ectopic chromatin is prevented through an asymmetric, microtubule-dependent chromatin capture mechanism during interphase and physical boundaries imposed by nuclear envelopes. Although hybrid cells fail to accurately segregate ectopic chromatin, hybrid cells neither reduce the lifespan nor form visible tumors in host flies. We propose that Nb-GMC derived hybrid cells utilize asymmetric centrosome activity in interphase and nuclear envelopes to physically separate epigenetically distinct chromatin.
Towards a unified theory of plant photosynthesis and hydraulics
Authors: Joshi Jaideep , Stocker Benjamin D. , Hofhansl Florian , Zhou Shuangxi , Dieckmann Ulf , Prentice Iain Colin
Published: December 2020

The global carbon and water cycles are governed by the coupling of CO2and water vapour exchanges through the leaves of terrestrial plants, controlled by plant adaptations to balance carbon gains and hydraulic risks. We introduce a trait-based optimality theory that unifies the treatment of stomatal responses and biochemical acclimation of plants to environments changing on multiple timescales. Tested with experimental data from 18 species, our model successfully predicts the simultaneous decline in carbon assimilation rate, stomatal conductance, and photosynthetic capacity during progressive soil drought. It also correctly predicts the dependencies of gas exchange on atmospheric vapour pressure deficit, temperature, and CO2. Model predictions are also consistent with widely observed empirical patterns, such as the distribution of hydraulic strategies. Our unified theory opens new avenues for reliably modelling the interactive effects of drying soil and rising atmospheric CO2on global photosynthesis and transpiration.
Divergent molecular signatures of regeneration and fibrosis during wound repair
Authors: Mascharak Shamik , desJardins-Park Heather E. , Januszyk Michael , Chen Kellen , Davitt Michael F. , Demeter Janos , Henn Dominic , Griffin Michelle , Bonham Clark A. , Foster Deshka S. , Mooney Nancie , Cheng Ran , Jackson Peter K. , Wan Derrick C. , Gurtner Geoffrey C. , Longaker Michael T.
Published: December 2020

Regeneration is the “holy grail” of tissue repair, but skin injury typically yields fibrotic, non-functional scars. Developing pro-regenerative therapies requires rigorous understanding of the molecular progression from injury to fibrosis or regeneration. Here, we report the divergent molecular events driving skin wound cells toward either scarring or regenerative fates. We profile scarring versus YAP inhibition-induced wound regeneration at the transcriptional (single-cell RNA-sequencing), protein (timsTOF proteomics), and tissue (extracellular matrix ultrastructural analysis) levels. Using cell surface barcoding, we integrate these data to reveal fibrotic and regenerative “molecular trajectories” of healing. We show that disrupting YAP mechanical signaling yields regenerative repair orchestrated by fibroblasts with activated Trps1 and Wnt signaling. Our findings serve as a multimodal map of wound regeneration and could have therapeutic implications for pathologic fibroses.
ZIKV disrupts placental ultrastructure and drug transporter expression in mice
Authors: de Andrade Cherley Borba Vieira , de Siqueira Monteiro Victoria Regina , Coelho Sharton Vinicius Antunes , Gomes Hanailly Ribeiro , de Sousa Ronny Paiva Campos , de Oliveira Nascimento Veronica Muller , Bloise Flavia Fonseca , Matthews Stephen , Bloise Enrrico , de Arruda Luciana Barros , Ortiga-Carvalho Tania Maria
Published: December 2020

Congenital Zika virus (ZIKV) infection can induce fetal brain abnormalities. Here, we investigated whether maternal ZIKV infection affects placental physiology and metabolic transport potential and impacts the fetal outcome, regardless of viral presence in the fetus at term. Low (103PFU-ZIKVPE243; low ZIKV) and high (5×107PFU-ZIKVPE243; high ZIKV) virus titers were injected into immunocompetent (ICompetent C57BL/6) and immunocompromised (ICompromised A129) mice at gestational day (GD) 12.5 for tissue collection at GD18.5 (term). High ZIKV elicited fetal death rates of 66% and 100%, whereas low ZIKV induced fetal death rates of 0% and 60% in C57BL/6 and A129 dams, respectively. All surviving fetuses exhibited intrauterine growth restriction (IUGR) and decreased placental efficiency. High-ZIKV infection in C57BL/6 and A129 mice resulted in virus detection in maternal spleens and placenta, but only A129 fetuses presented virus RNA in the brain. Nevertheless, pregnancies in both strains produced fetuses with decreased head sizes (p<0.05). Low-ZIKV-A129 dams had higher IL-6 and CXCL1 levels (p<0.05), and their placentas showed increased CCL-2 and CXCL-1 contents (p<0.05). In contrast, low-ZIKV-C57BL/6 dams had an elevated CCL2 serum level and increased type I and II IFN expression in the placenta. Notably, less abundant microvilli and mitochondrial degeneration were evidenced in the placental labyrinth zone (Lz) of ICompromised and high-ZIKV-ICompetent mice but not in low-ZIKV-C57BL/6 mice. In addition, decreased placental expression of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) and the lipid transporter Abca1 was detected in all ZIKV-infected groups, but Bcrp and Abca1 were only reduced in ICompromised and high-ZIKV ICompetent mice. Our data indicate that gestational ZIKV infection triggers specific proinflammatory responses and affects placental turnover and transporter expression in a manner dependent on virus concentration and maternal immune status. Placental damage may impair proper fetal-maternal exchange function and fetal growth/survival, likely contributing to congenital Zika syndrome.
Exosomal miR-224 contributes to hemolymph microbiota homeostasis during bacterial infection in crustacean
Authors: Gong Yi , Wei Xiaoyuan , Sun Wanwei , Ren Xin , Chen Jiao , Aweya Jude Juventus , Ma Hongyu , Chan Kok-Gan , Zhang Yueling , Li Shengkang
Published: December 2020

The modulation of hemolymph microbiota homeostasis is vital for the marine invertebrate innate immunity, while growing evidence shows that exosomes could serves as anti-bacterial immune factors, however, the relationship between exosomes and hemolymph microbiota homeostasis during pathogenic bacteria infection has not been addressed. Here, we determined that exosomes released fromVibrio parahaemolyticus-infectedScylla paramamosain(mud crabs) could reduce the mortality of the host during the infection by maintaining the homeostasis of hemolymph microbiota. We further confirmed that miR-224 was densely packaged in these exosomes and targeting to HSP70, which resulted in disruption of the HSP70-TRAF6 complex to release TRAF6 that allows it to interact with Ecsit. The interaction of TRAF6 with Ecsit regulates the production of mitochondrial ROS (mROS) and Anti-lipopolysaccharide factors (ALFs) expression in recipient hemocytes, which affects homeostasis of hemolymph microbiota in response to the pathogenic bacteria infection in mud crab. To the best of our knowledge, this is the first document that reports the role of exosome in the homeostasis of hemolymph microbiota during pathogen infection and a novel regulatory mechanism and crosstalk between exosomal miRNAs and innate immune response in crustaceans.

Author summary

Exosomes are small membrane vesicles of endocytic origin which are widely involved in the regulation of a variety of pathological processes in mammals. Yet, although the antibacterial function of exosomes has been discovered for many years, the relationship between exosomes and hemolymph microbiota homeostasis remains unknown. In the present study, we identified the miRNAs packaged by exosomes that were possibly involved inVibrio parahaemolyticusinfection by modulating hemolymph microbiota homeostasis in crustacean mud crabScylla paramamosain. Moreover, it was found that miR-224 was densely packaged in exosomes afterVibrio parahaemolyticuschallenge, resulting in the suppression of HSP70 and disruption of the HSP70-TRAF6 complex in recipient hemocytes, then the released TRAF6 was further interacted with Ecsit to regulate ROS and ALFs levels, which eventually affected hemolymph microbiota homeostasis to cope with pathogenic bacteria infection. Our finding is the first to reveal the relationship between exosomes and hemolymph microbiota homeostasis in animals, which shows a novel molecular mechanism of invertebrate resistance to pathogenic microbial infection.
Identifying mutant-specific multi-drug combinations using Comparative Network Reconstruction
Authors: Bosdriesz Evert , Fernandes Neto João M. , Sieber Anja , Bernards René , Blüthgen Nils , Wessels Lodewyk F.A.
Published: December 2020

Inhibition of aberrant signaling with target inhibitors is an important treatment strategy in cancer, but unfortunately responses are often short-lived. Multi-drug combinations have the potential to mitigate this, but to avoid toxicity such combinations must be selective and the dosage of the individual drugs should be as low as possible. Since the search space of multi-drug combinations is enormous, an efficient approach to identify the most promising drug combinations and dosages is needed.

Here, we present a pipeline to prioritize promising multi-drug combinations. We performed a limited set of drug perturbations in an isogenic cell line pair with and without an activating PI3K mutation, and recorded their signaling states and cell viability. We used these data to reconstruct mutant specific signaling networks and map the short term signaling response to longer term changes in cell viability. The resulting models then allowed us to predict the effect of unseen multi-drug combinations, at arbitrary drug-concentrations, on cell viability. Our initial aim was to find combinations that selectively reduce the viability of the PI3K mutant cells, but our models indicated that such combinations do not exist for this cell line pair. However, we were able to validate 25 of the 30 low-dose multi-drug combinations that we predicted to be anti-selective. Our pipeline thus enables a powerful strategy to rapidly map the efficacy and possible selectivity of drug combinations, hence significantly speeding up the pace at which we can explore the vast space of combination therapies.
Consensus clustering for Bayesian mixture models
Authors: Coleman Stephen , Kirk Paul D.W. , Wallace Chris
Published: December 2020

Abstract

Cluster analysis is an integral part of precision medicine and systems biology, used to define groups of patients or biomolecules. Consensus clustering is an ensemble approach that is widely used in these areas, which combines the output from multiple runs of a non-deterministic clustering algorithm. Here we consider the application of consensus clustering to a broad class of heuristic clustering algorithms that can be derived from Bayesian mixture models (and extensions thereof) by adopting an early stopping criterion when performing sampling-based inference for these models. While the resulting approach is non-Bayesian, it inherits the usual benefits of consensus clustering, particularly in terms of computational scalability and providing assessments of clustering stability/robustness.

In simulation studies, we show that our approach can successfully uncover the target clustering structure, while also exploring different plausible clusterings of the data. We show that, when a parallel computation environment is available, our approach offers significant reductions in runtime compared to performing sampling-based Bayesian inference for the underlying model, while retaining many of the practical benefits of the Bayesian approach, such as exploring different numbers of clusters. We propose a heuristic to decide upon ensemble size and the early stopping criterion, and then apply consensus clustering to a clustering algorithm derived from a Bayesian integrative clustering method. We use the resulting approach to perform an integrative analysis of three ‘omics datasets for budding yeast and find clusters of co-expressed genes with shared regulatory proteins. We validate these clusters using data external to the analysis. These clusters can help assign likely function to understudied genes, for exampleGAS3clusters with histones active in S-phase, suggesting a role in DNA replication.

Our approach can be used as a wrapper for essentially any existing sampling-based Bayesian clustering implementation, and enables meaningful clustering analyses to be performed using such implementations, even when computational Bayesian inference is not feasible, e.g. due to poor exploration of the target density (often as a result of increasing numbers of features) or a limited computational budget that does not along sufficient samples to drawn from a single chain. This enables researchers to straightforwardly extend the applicability of existing software to much larger datasets, including implementations of sophisticated models such as those that jointly model multiple datasets.
Impact of blindness onset on the representation of sound categories in occipital and temporal cortices
Authors: Stefania Mattioni , Mohamed Rezk , Ceren Battal , Jyothirmayi Vadlamudi , Olivier Collignon
Published: December 2020

How does blindness onset impact on the organization of cortical regions coding for the deprived and the remaining senses? We show that the coding of sound categories in the occipital cortex is enhanced and more stable within and across blind individuals when compared to sighted controls, while a reverse group difference is found in the temporal cortex. Importantly, occipital and temporal regions share a more similar representational structure in blind people, suggesting an interplay between the reorganization of occipital and temporal regions following visual deprivation. We suggest that early, and to some extent late blindness, induces network-level reorganization of the neurobiology of auditory categories by concomitantly increasing/decreasing the respective computational load of occipital/temporal regions. These results highlight the interactive nature of regional brain development in case of sensory deprivation.