bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased mortality associated with uncontrolled diabetes mellitus in patients with Pulmonary Cryptococcosis — a single U.S. cohort study
Authors: Archuleta Solana , Gharamti Amal A. , Sillau Stefan , Castellanos Paula , Chadalawada Sindhu , Mundo William , Bandali Mehdi , Oñate Jose , Martínez Ernesto , Chastain Daniel , DeSanto Kristen , Shapiro Leland , Schwartz Ilan S. , Franco-Paredes Carlos , Henao-Martínez Andrés F.
Published: January 2021

Background

Diabetes mellitus is an established risk factor for bacterial infections, but its role in Cryptococcosis is unclear. The study aimed to determine whether uncontrolled diabetes (HbA1c >7%) was an independent risk factor for mortality in cryptococcosis.

Methods

A retrospective case-control study partially matched by age and gender was performed in patients tested forCryptococcusinfection at the University of Colorado Hospital from 2000-2019. A multivariable logistic regression model was used to identify mortality predictors. Cox proportional hazard model was used for survival analysis.

Results

We identified 96 cases of Cryptococcosis and 125 controls. Among cases, cryptococcal meningitis (49.0%) and pneumonia (36.5%) constituted most infections. Cases with pulmonary cryptococcosis had a higher mortality at 10 weeks (50% vs 7%, p=0.006) and one year (66.7% vs 13.8%, p=0.005). Unadjusted Cox proportional hazard model found an increased rate of death for uncontrolled diabetes at 10-weeks (hazard ratio 8.4, CI: 1.4-50.8, p=0.02), and 1-year (hazard ratio 7.0, CI: 1.7-28.4, p=0.007) among pulmonary cryptococcosis cases. Multivariable analysis showed a significantly increased odds of 10-weeks (OR=4.3, CI: 1.1-16.5, p=0.035) and one-year (OR=5.9, CI: 2.2-15.8, p=0.014) mortality for uncontrolled diabetes among pulmonary cryptococcosis cases. After adjustment for gender, age, and case/control, for every 1% increase in HbA1c levels, the odds of pulmonary cryptococcosis mortality at one-year increased by 11% (OR = 1.6, CI 95%: 1.1-2.3, p= 0.006).

Conclusion

Uncontrolled diabetes is associated with worse outcomes in pulmonary cryptococcosis, including a 4-fold and 6-fold increased odds of death at 10-weeks and 1-year, respectively. Glucose control interventions should be explored to improve clinical outcomes in patients with pulmonary cryptococcosis.
ADAM10- and presenilin 1/γ-secretase-dependent cleavage of PTPRT mitigates neurodegeneration of Alzheimer’s disease
Authors: Liu Siling , Zhang Zhongyu , Li Lianwei , Yao Li , Ma Zhanshan , Li Jiali
Published: January 2021

PTPRT (receptor-type tyrosine-protein phosphatase T), as a brain-specific type 1 transmembrane protein, plays an important function in neurodevelopment and synapse formation. However, whether PTPRT-dependent signaling is involved in Alzheimer’s disease (AD) remains elusive. Here, we identified that PTPRT intracellular domain (PICD), which was released from ADAM10- and presenilin 1-/γ-secretase-dependent cleavage of PTPRT, efficiently translocated to the nucleus via a conserved nuclear localization signal. Inhibition of nuclear localization of PICD via the mutation of its nuclear localization signal (NLS) leads to accumulation of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), which is a substrate of PTPRT and eventually resulted in neuronal cell death. Consistently, RNA sequencing reveals that expression of the PICD alone can profoundly alter the expression of genes associated with synapse function and dephosphorylation, phosphatase and cell adhesion. Unexpectedly, the downregulated levels ofPtprtmRNA and protein were found in both human and mouse AD brains. Finally, overexpression of PICD alone not only significantly decreases the level of phosph-STAT3Y705and Aβ deposition in the hippocampus of APP/PS1 mice, but also improves synaptic function and behavioral deficits in APP/PS1 mice. Our findings suggest that a novel role of the ADAM 10- and presenilin 1-/γ-secretase-dependent cleavage of PTPRT in the events can mitigate neurodegeneration of AD and moderate Alzheimer’s pathogenesis.
VeloSim: Simulating single cell gene-expression and RNA velocity
Authors: Zhang Ziqi , Zhang Xiuwei
Published: January 2021

The availability of high throughput single-cell RNA-Sequencing data allows researchers to study the molecular mechanisms that drive the temporal dynamics of cells during differentiation or development. Recent computational methods that build upon single-cell sequencing technology, such as trajectory inference or RNA-velocity estimation, provide a way for researchers to analyze the state of each cell during a continuous dynamic process. However, with the surge of such computational methods, there is still a lack of simulators that can model the cell temporal dynamics, and provide ground truth data to benchmark the computational methods.

Hereby we presentVeloSim, a simulation software that can simulate the gene-expression kinetics in cells along continuous trajectories.VeloSimis able to take any trajectory structure composed of basic elements including “linear” and “cycle” as input, and outputs unspliced mRNA count matrix, spliced mRNA count matrix, cell pseudo-time and true RNA velocity of the cells. We demonstrate howVeloSimcan be used to benchmark trajectory inference and RNA-velocity estimation methods with different amounts of biological and technical variation within the datasets.VeloSimis implemented into an R package available athttps://github.com/PeterZZQ/VeloSim.
Generalized Euler-Lotka equation for correlated cell divisions
Authors: Pigolotti Simone
Published: January 2021

Cell division times in microbial populations display significant fluctuations. These fluctuations impact the population growth rate in a non-trivial way. If fluctuations are uncorrelated among different cells, the population growth rate is predicted by the Euler-Lotka equation, which is a classic result in mathematical biology. However, cell division times can present significant correlations, due to physical properties of cells that are passed from mothers to daughters. In this paper, we derive an equation remarkably similar to the Euler-Lotka equation which is valid in the presence of correlations. Our exact result is based on large deviation theory and does not require particularly strong assumptions on the underlying dynamics. We apply our theory to a phenomenological model of bacterial cell division. We find that the discrepancy between the growth rate predicted by the Euler-Lotka equation and our generalized version is relatively small, but large enough to be measurable in experiments.
Cutibacterium acnesclonal complexes display various growth rates in blood-culture bottles used for diagnosing orthopedic device-related infections
Authors: Sayed Faten El , Camernik Petra , Roux Anne-Laure , Papst Lea , Bauer Thomas , Nkam Lionelle , Sivadon-Tardy Valérie , Noussair Latifa , Herrmann Jean-Louis , Gaillard Jean-Louis , Jeverica Samo , Rottman Martin
Published: January 2021

Blood-culture bottles (BCBs) are widely used to improve the diagnosis of orthopedic device-related infections. Data is scarce on the growth ofCutibacterium acnesand its genotypes in BCBs under real-life clinical conditions.

We studied 39 cases of revision arthroplasty for which at least one intraoperative sample yielded a pureC. acnesculture from anaerobic BCBs (BD Bactec Lytic/10 Anaerobic/F [Lytic Ana]) and/or solid media. Genotyping ofC. acnesisolates from the 39 cases allowed: i) the identification of 49 non-redundant isolates belonging to four clonal complexes (CCs): CC18, CC28, CC36, and CC53 and ii) the determination of infectant and contaminant strains. Under real-life clinical conditions, Lytic Ana alone was more often positive for contaminants than infectant strains (18/36 [50%]versus2/13 [15.4%]; p = 0.047). The time to detection (TTD) values in Lytic Ana were shorter for CC53 than other CCs (mean [SD] TTD: 77 [15]versus165 [71] hours; p = 0.02). CC53 was confirmed to grow faster than other CCs by studying an enlarged panel of 70 genotypedC. acnesstrains inoculatedin vitrointo Lytic Ana vials (mean [SD] TTD: 73 [13]versus122 [50] hours; p < 0.001).

The use of Lytic Ana BCBs in orthopedics increases the recovery rate ofC. acnesbut leads to the isolation of proportionally more contaminants than true infectant strains. TTD values are much shorter for CC53 strains, irrespective of their being infectant or contaminant. TTD does not solely reflect the bacterial load of samples but also clonal complex-related traits.
Changes in the Health of Adolescent Athletes: A Comparison of Health Measures Collected Before and During the CoVID-19 Pandemic
Authors: McGuine Timothy A. , Biese Kevin , Hetzel Scott J. , Petrovska Labina , Kliethermes Stephanie , Reardon Claudia L. , Bell David R. , Brooks M. Alison , Watson Andrew M.
Published: January 2021

Context

In the spring of 2020, schools closed to in-person teaching and sports were cancelled to control the transmission of CoVID-19. The changes that took place to the physical and mental health among young athletes during this time remain unknown, however.

Objective

Identify changes in the health (mental health, physical activity and quality of life) of athletes that occurred during the CoVID-19 pandemic.

Design

Cross sectional study.

Setting

Sample recruited via social media.

Patients or Other Participants

3243 Wisconsin adolescent athletes (age=16.2±1.2 yrs., female=58% female) completed an online survey in May 2020 (DuringCoVID-19). Health measures for this cohort were compared with previously reported data for Wisconsin adolescent athletes (n=5231, age=15.7±1.2, 47% female) collected in 2016–2018 (PreCoVID-19).

Main Outcome Measure(s)

Demographic information included: sex, grade and sports played. Health assessments included the Patient Health Questionnaire-9 Item (PHQ-9) to identify depression symptoms, the Pediatric Functional Activity Brief Scale (PFABS) for physical activity, and the Pediatric Quality of Life Inventory 4.0 (PedsQL) for health related quality of life (HRQoL). Univariable comparisons of these variables between groups were made via t-tests or chi-square tests. Means and 95% confidence intervals (CI) for each group were estimated by survey weighted ANOVA models.

RESULTS

Compared to PreCoVID-19, a larger proportion of the During-CoVID-19 participants reported rates of moderate to severe levels of depression (9.7% vs 32.9%, p<0.001). During-CoVID-19 participants reported 50% lower (worse) PFABS scores (mean:12.2 [95%CI: 11.9, 12.5] vs 24.7 [24.5, 24.9] p<0.001) and lower (worse) PedsQL total scores compared to the PreCoVID-19 participants (78.4 [78.0, 78.8] vs. 90.9 [90.5, 91.3] p<0.001).

CONCLUSIONS

During the CoVID-19 pandemic, adolescent athletes reported increased symptoms of depression, decreased physical activity and decreased quality of life compared to adolescent athletes in previous years.

Key points

Adolescent athletes during CoVID-19 were three times more likely to report moderate to severe symptoms of depression compared to data collected prior to CoVID-19.

Adolescent athletes during CoVID-19 reported significantly lower physical activity and quality of life scores compared to high school athletes prior to the CoVID-19 pandemic

Post CoVID-19 policies should be implemented to improve the health of adolescent athletes in the US.
Genomic surveillance at scale is required to detect newly emerging strains at an early timepoint
Authors: Vavrek Darcy , Speroni Lucia , Curnow Kirsten J. , Oberholzer Michael , Moeder Vanessa , Febbo Phillip G.
Published: January 2021

Genomic surveillance in the setting of the coronavirus disease 2019 (COVID-19) pandemic has the potential to identify emerging SARS-CoV-2 strains that may be more transmissible, virulent, evade detection by standard diagnostic tests, or vaccine escapes. The rapid spread of the SARS-CoV-2 B.1.1.7 strain from southern England to other parts of the country and globe is a clear example of the impact of such strains. Early discovery of the B.1.1.7 strain was enabled through the proactive COVID-19 Genomics UK (COG-UK) program and the UK’s commitment to genomic surveillance, sequencing about 10% of positive samples.1 In order to enact more aggressive public health measures to minimize the spread of such strains, genomic surveillance needs to be of sufficient scale to detect early emergence and expansion in the broader virus population. By modeling common performance characteristics of available diagnostic and sequencing tests, we developed a model that assesses the sampling required to detect emerging strains when they are less than 1% of all strains in a population. This model demonstrates that 5% sampling of all positive tests allows the detection of emerging strains when they are a prevalence of 0.1% to 1.0%. While each country will determine their risk tolerance for the emergence of novel strains, as vaccines are distributed and we work to end the pandemic and prevent future SARS-CoV-2 outbreaks, genomic surveillance will be an integral part of success.
Using Mendelian randomisation to explore the gateway hypothesis: Possible causal effects of smoking initiation and alcohol consumption on substance use outcomes
Authors: Reed Zoe E. , Wootton Robyn E. , Munafò Marcus R.
Published: January 2021

Background and Aims

Initial use of drugs such as tobacco and alcohol may lead to subsequent more problematic drug use – the ‘gateway’ hypothesis. However, observed associations may be due to a shared underlying risk factor, such as trait impulsivity. We used bidirectional Mendelian Randomisation (MR) to test the gateway hypothesis.

Design

Our main method was inverse-variance weighted (IVW) MR, with other methods included as sensitivity analyses (where consistent results across methods would raise confidence in our primary results). MR is a genetic instrumental variable approach used to support stronger causal inference in observational studies.

Setting

European ancestry individuals.

Participants

Genome-wide association summary data for smoking initiation, alcoholic drinks per week, cannabis use and dependence, cocaine and opioid dependence (N=1,749 to 1,232,091).

Measurements

Genetic variants for exposure.

Findings

We found evidence of causal effects from smoking initiation to increased drinks per week (IVW: β=0.06; 95% CI=0.03 to 0.09; p=9.44×10−06), cannabis use (IVW: OR=1.34; 95% CI=1.24 to 1.44; p=1.95×10−14), and cannabis dependence (IVW: OR=1.68; 95% CI=1.12 to 2.51; p=0.01). We also found evidence of an effect of cannabis use on increased likelihood of smoking initiation (IVW: OR=1.39; 95% CI=1.08 to 1.80; p=0.01). We did not find evidence of an effect of drinks per week on other substance use outcomes, except weak evidence of an effect on cannabis use. We found weak evidence of an effect of opioid dependence on increased drinks per week (IVW: β=0.002; 95% CI=0.0005 to 0.003; p=8.61×10−03).

Conclusions

Smoking initiation may lead to increased alcohol consumption, cannabis use and dependence. Cannabis use may also lead to smoking initiation, and opioid dependence to alcohol consumption. However, given tobacco and alcohol use typically begin before other drug use, these results may reflect a shared risk factor, or a bidirectional effect for cannabis use. Further research should explore potentially shared risk factors.
Characteristics and outcomes of 118,155 COVID-19 individuals with a history of cancer in the United States and Spain
Authors: Roel Elena , Pistillo Andrea , Recalde Martina , Sena Anthony G. , Fernández-Bertolín Sergio , Aragón María , Puente Diana , Ahmed Waheed-Ul-Rahman , Alghoul Heba , Alser Osaid , Alshammari Thamir M. , Areia Carlos , Blacketer Clair , Carter William , Casajust Paula , Culhane Aedin C. , Dawoud Dalia , DeFalco Frank , Duvall Scott L. , Falconer Thomas , Golozar Asieh , Gong Mengchun , Hester Laura , Hripcsak George , Tan Eng Hooi , Jeon Hokyun , Jonnagaddala Jitendra , Lai Lana Y.H. , Lynch Kristine E. , Matheny Michael E. , Morales Daniel R. , Natarajan Karthik , Nyberg Fredrik , Ostropolets Anna , Posada José D. , Prats-Uribe Albert , Reich Christian G. , Rivera Donna , Schilling Lisa M. , Soerjomataram Isabelle , Shah Karishma , Shah Nigam , Shen Yang , Spotniz Matthew , Subbian Vignesh , Suchard Marc A. , Trama Annalisa , Zhang Lin , Zhang Ying , Ryan Patrick , Prieto-Alhambra Daniel , Kostka Kristin , Duarte-Salles Talita
Published: January 2021

Purpose

We aimed to describe the demographics, cancer subtypes, comorbidities and outcomes of patients with a history of cancer with COVID-19 from March to June 2020. Secondly, we compared patients hospitalized with COVID-19 to patients diagnosed with COVID-19 and patients hospitalized with influenza.

Methods

We conducted a cohort study using eight routinely-collected healthcare databases from Spain and the US, standardized to the Observational Medical Outcome Partnership common data model. Three cohorts of patients with a history of cancer were included: i) diagnosed with COVID-19, ii) hospitalized with COVID-19, and iii) hospitalized with influenza in 2017-2018. Patients were followed from index date to 30 days or death. We reported demographics, cancer subtypes, comorbidities, and 30-day outcomes.

Results

We included 118,155 patients with a cancer history in the COVID-19 diagnosed and 41,939 in the COVID-19 hospitalized cohorts. The most frequent cancer subtypes were prostate and breast cancer (range: 5-19% and 1-14% in the diagnosed cohort, respectively). Hematological malignancies were also frequent, with non-Hodgkin’s lymphoma being among the 5 most common cancer subtypes in the diagnosed cohort. Overall, patients were more frequently aged above 65 years and had multiple comorbidities. Occurrence of death ranged from 8% to 14% and from 18% to 26% in the diagnosed and hospitalized COVID-19 cohorts, respectively. Patients hospitalized with influenza (n=242,960) had a similar distribution of cancer subtypes, sex, age and comorbidities but lower occurrence of adverse events.

Conclusion

Patients with a history of cancer and COVID-19 have advanced age, multiple comorbidities, and a high occurence of COVID-19-related events. Additionaly, hematological malignancies were frequent in these patients.This observational study provides epidemiologic characteristics that can inform clinical care and future etiological studies.
Differential T cell reactivity to seasonal coronaviruses and SARS-CoV-2 in community and health care workers
Authors: da Silva Antunes Ricardo , Pallikkuth Suresh , Williams Erin , Yu Esther Dawen , Mateus Jose , Quiambao Lorenzo , Wang Eric , Rawlings Stephen A. , Stadlbauer Daniel , Jiang Kaijun , Amanat Fatima , Arnold David , Andrews David , Fuego Irma , Dan Jennifer M. , Grifoni Alba , Weiskopf Daniela , Krammer Florian , Crotty Shane , Hoffer Michael E. , Pahwa Savita G. , Sette Alessandro
Published: January 2021

Herein we measured CD4+ T cell responses against common cold corona (CCC) viruses and SARS-CoV-2 in high-risk health care workers (HCW) and community controls. We observed higher levels of CCC reactive T cells in SARS-CoV-2 seronegative HCW compared to community donors, consistent with potential higher occupational exposure of HCW to CCC. We further show that SARS-CoV-2 reactivity of seronegative HCW was higher than community controls and correlation between CCC and SARS-CoV-2 responses is consistent with cross-reactivity and not associated with recent in vivo activation. Surprisingly, CCC reactivity was decreased in SARS-CoV-2 infected HCW, suggesting that exposure to SARS-CoV-2 might interfere with CCC responses, either directly or indirectly. This result was unexpected, but consistently detected in independent cohorts derived from Miami and San Diego.
Towards a platform for robot-assisted minimally-supervised therapy of hand function: design and pilot usability evaluation
Authors: Ranzani Raffaele , Eicher Lucas , Viggiano Federica , Engelbrecht Bernadette , Held Jeremia P.O. , Lambercy Olivier , Gassert Roger
Published: January 2021

Background

Robot-assisted therapy can increase therapy dose after stroke, which is often considered insufficient in clinical practice and after discharge, especially with respect to hand function. Thus far, there has been a focus on rather complex systems that require therapist supervision. To better exploit the potential of robot-assisted therapy, we propose a platform designed for minimal therapist supervision, and present the preliminary evaluation of its immediate usability, one of the main and frequently neglected challenges for real-world application. Such an approach could help increase therapy dose by allowing the training of multiple patients in parallel by a single therapist, as well as independent training in the clinic or at home.

Methods

We implemented design changes on a hand rehabilitation robot, considering aspects relevant to enabling minimally-supervised therapy, such as new physical/graphical user interfaces and two functional therapy exercises to train hand motor coordination, somatosensation and memory. Ten participants with chronic stroke assessed the usability of the platform and reported the perceived workload during a single therapy session with minimal supervision. The ability to independently use the platform was evaluated with a checklist.

Results

Participants were able to independently perform the therapy session after a short familiarization period, requiring assistance in only 13.46(7.69-19.23)% of the tasks. They assigned good-to-excellent scores on the SUS to the user-interface and the exercises (85.00(75.63-86.88) and 73.75(63.13-83.75) out of 100, respectively). Nine participants stated that they would use the platform frequently. Perceived workloads lay within desired workload bands. Object grasping with simultaneous control of forearm pronosupination and stiffness discrimination were identified as the most difficult tasks.

Discussion

Our findings demonstrate that a robot-assisted therapy device can be rendered safely and intuitively usable upon first exposure with minimal supervision through compliance with usability and perceived workload requirements. The preliminary usability evaluation identified usability challenges that should be solved to allow real-world minimally-supervised use. Such a platformcould complement conventional therapy, allowing to provide increased dose with the available resources, and establish a continuum of care that progressively increases therapy lead of the patient from the clinic to the home.
Optimal SARS-CoV-2 vaccine allocation using real-time seroprevalence estimates in Rhode Island and Massachusetts
Authors: Tran Thu Nguyen-Anh , Wikle Nathan , Albert Joseph , Inam Haider , Strong Emily , Brinda Karel , Leighow Scott M , Yang Fuhan , Hossain Sajid , Pritchard Justin R , Chan Philip , Hanage William P , Hanks Ephraim M , Boni Maciej F
Published: January 2021

As three SARS-CoV-2 vaccines come to market in Europe and North America in the winter of 2020-2021, distribution networks will be in a race against a major epidemiological wave of SARS-CoV-2 that began in autumn 2020. Rapid and optimized vaccine allocation is critical during this time. With 95% efficacy reported for two of the vaccines, near-term public health needs require that distribution is prioritized to the elderly, health-care workers, teachers, essential workers, and individuals with co-morbidities putting them at risk of severe clinical progression. Here, we evaluate various age-based vaccine distributions using a validated mathematical model based on current epidemic trends in Rhode Island and Massachusetts. We allow for varying waning efficacy of vaccine-induced immunity, as this has not yet been measured. We account for the fact that known COVID-positive cases may not be included in the first round of vaccination. And, we account for current age-specific immune patterns in both states. We find that allocating a substantial proportion (> 75%) of vaccine supply to individuals over the age of 70 is optimal in terms of reducing total cumulative deaths through mid-2021. As we do not explicitly model other high mortality groups, this result on vaccine allocation applies to all groups at high risk of mortality if infected. Our analysis confirms that for an easily transmissible respiratory virus, allocating a large majority of vaccinations to groups with the highest mortality risk is optimal. Our analysis assumes that health systems during winter 2020-2021 have equal staffing and capacity to previous phases of the SARS-CoV-2 epidemic; we do not consider the effects of understaffed hospitals or unvaccinated medical staff. Vaccinating only seronegative individuals avoids redundancy in vaccine use on individuals that may already be immune, and will result in 1% to 2% reductions in cumulative hospitalizations and deaths by mid-2021. Assuming high vaccination coverage (> 28%) and no major relaxations in distancing, masking, gathering size, or hygiene guidelines between now and spring 2021, our model predicts that a combination of vaccination and population immunity will lead to low or near-zero transmission levels by the second quarter of 2021.
Impact of COVID-19 on the indigenous population of Brazil: A geo-epidemiological study
Authors: Alves Josilene D , Abade André S , Peres Wigis P , Borges Jonatas E , Santos Sandra M , Scholze Alessandro R
Published: January 2021

This study aimed to analyze the geographical distribution of COVID-19 and to identify highrisk areas for the occurrence of cases and deaths from the disease in the indigenous population of Brazil. This is an ecological study whose units of analysis were the Special Indigenous Sanitary Districts. Cases and deaths by COVID-19 notified by the Special Secretariat for Indigenous Health between March and October 2020 were included. To verify the spatial association, the Getis-Ord General G and Getis-Ord Gi * techniques were used. High spatial risk clusters have been identified by the scan statistics technique. 32,041 cases of COVID-19 and 471 deaths were reported. The incidence and mortality rates were between 758.14 and 18530.56 cases and 5.96 and 265.37 deaths per 100 thousand inhabitants, respectively. The non-randomness of cases (z-score = 5.40; p <0.001) and deaths (z-score = 3.83; p <0.001) was confirmed. Hotspots were evidenced for both events with confidence levels of 90, 95 and 99% concentrated in the North and Midwest regions of the country. Eight high-risk spatial clusters for cases with a relative risk (RR) between 1.08 and 4.11 (p <0.05) and two risk clusters for deaths with RR between 3.08 and 3.97 (p <0.05) were identified. The results indicate critical areas in the indigenous territories of Brazil and contribute to better targeting the control actions of COVID-19 in this population.
MiDAS - Meaningful Immunogenetic Data at Scale
Authors: Migdal Maciej , Ruan Dan Fu , Forrest William F. , Horowitz Amir , Hammer Christian
Published: January 2021

Human immunogenetic variation in the form of HLA and KIR types has been shown to be strongly associated with a multitude of immune-related phenotypes. We present MiDAS, an R package enabling statistical association analysis and using immunogenetic data transformation functions for HLA amino acid fine mapping, analysis of HLA evolutionary divergence as well as HLA-KIR interactions. MiDAS closes the gap between inference of immunogenetic variation and its efficient utilization to make meaningful discoveries.
The influence of positive emotion and negative emotion on false memory based on EEG signal analysis
Authors: Li Ying , Ni Zhaobing , He Renjie , Zhang Junyu , Zhang Zhimou , Yang Shuo , Yin Ning
Published: January 2021

Analyzing the influence of emotion on false memory through electroencephalogram is helpful to further explore the cognition function of brain. In this study, we improved the Deese-Roediger-McDermott paradigm experiment to study the false memory. The memory materials are combined with mixed emotions, which are closer to real life. Twenty-eight participants were randomly divided into positive group and negative group. We used music to induce the participants in the positive group and the negative group to generate corresponding emotions. Finally, we analyzed the difference between the positive group and the negative group from the behavior data, source location and cortex functional network of event related potential. The results of behavioral data analysis show that the false memory rate of positive group (85%) is significantly higher than that of negative group (72%). The results of source localization show that the brain of the positive group is more active than that of the negative group, and the difference of brain activation location between the two groups is mainly manifested in the BA24 and BA45 brain regions. The results of cortex functional network show that the node degree, clustering coefficient, global efficiency and small-world property of the positive group are significantly higher than those of the negative group. It can be found from the three aspects that participants’ emotional state and brain’s understanding of semantic are the main reasons for the difference in the incidence of false memory between the two groups.
The joint role of coevolutionary selection and network structure in shaping trait complementarity in mutualisms
Authors: Pedraza Fernando , Bascompte Jordi
Published: January 2021

Coevolution can sculpt remarkable trait similarity between mutualistic partners. Yet, it remains unclear which network topologies and selection regimes enhance such trait complementarity. To address this, we simulate coevolution in topologically-distinct net-works under a gradient of mutualistic selection strength. We describe three main insights. First, trait matching is jointly influenced by the strength of mutualistic selection and the structural properties of the network where coevolution is unfolding. Second, the strength of mutualistic selection determines the network descriptors better correlated with higher trait matching. When coevolution is weak, network modularity enhances trait matching, but when it is strong, network connectance amplifies trait matching. Third, the structural properties of networks outrank those of modules or species in determining the evolved degree of trait matching. Our findings suggest networks can both enhance or constrain trait complementary, depending on the strength of mutualistic selection.
Establishment of a closed artificial ecosystem to ensure human long-term survival on the moon
Authors: Fu Yuming , Yi Zhihao , Du Yao , Liu Hui , Xie Beizhen , Liu Hong
Published: January 2021

Bioregenerative life support system (BLSS) is a critical technology maintaining long-term human survival on the Moon or other extraterrestrial bodies. In the current study, we carried out a 370-day integrated high-closure experiment (“Lunar Palace 365” experiment) on the Earth in an upgraded ground-based BLSS experimental facility called “Lunar Palace 1”. This experiment was designed to develop techniques to run and adjust system stability under long-term operation and crew shift change conditions. Eight volunteering crew members were divided into two groups with three time phases: Group I stayed in the cabin for the initial 60-day phase; Group II inhabited the cabin instead for a record-breaking duration of 200 days as the second phase; Group I re-entered the cabin, replaced Group II and stayed for the last 105 days. Our results demonstrated the BLSS had excellent stability with a material closure degree of 98.2%. Levels of O2, CO2and trace harmful gases were well controlled within ranges optimal for crew health and plant production. The system exhibited a strong robustness and could quickly minimize effects of disturbances through self-feedback adjustments. The efficiency of plant production completely met the crew’s need of plant-based food. The purification efficiency of domestic and sanitary wastewater was up to irrigation standards, and the recovery rate of urine and solid waste achieved 99.7% and 67%, respectively. These results are valuable for further optimization of the BLSS in a lunar base and computer simulations of similar systems.
Biomaterials direct functional B cell response in a material specific manner
Authors: Moore Erika M. , Maestas David R. , Cherry Chris C. , Garcia Jordan A. , Comeau Hannah Y. , Huyer Locke Davenport , Blosser Richard L. , Rosson Gedge D. , Elisseeff Jennifer H.
Published: January 2021

B cells are an adaptive immune target of biomaterials development in vaccine research but despite their role in wound healing have not been studied in tissue engineering and regenerative medicine. We evaluated the B cell response to biomaterial scaffold materials implanted in a muscle wound; a biological extracellular matrix (ECM) and synthetic polyester polycaprolactone. In the local muscle tissue, small numbers of B cells are recruited in response to tissue injury and biomaterial implantation. ECM materials induced plasmablasts in lymph nodes and antigen presentation in the spleen while the synthetic PCL implants delayed B cell migration and induced an antigen presenting phenotype. In muMt−mice lacking B cells, the fibrotic response to the synthetic biomaterials decreased. Immunofluorescence confirmed antigen presenting B cells in fibrotic tissue surrounding silicone breast implants. In sum, the adaptive B cell immune response to biomaterial depends on composition and induces local, regional and systemic immunological changes.
Chicken peripheral blood lymphocyte response to ALV-J infection assessed by single-cell RNA sequencing
Authors: Dai Manman , Feng Min , Li Ziwei , Chen Weisan , Liao Ming
Published: January 2021

Chicken peripheral blood lymphocytes (PBLs) exhibit wide-ranging cell types, but current understanding of their subclasses, immune cell classification, and function is limited and incomplete. Previously, we found that viremia caused by avian leukosis virus subgroup J (ALV‐J) was eliminated by 21 days post infection (DPI), accompanied by increased CD8+T cell ratio in PBLs and low antibody levels. Here we performed single-cell RNA sequencing (scRNA-seq) of PBLs in ALV-J infected and control chickens at 21 DPI to determine chicken PBL subsets and their specific molecular and cellular characteristics, before and after viral infection. Eight cell clusters and their potential marker genes were identified in chicken PBLs. T cell populations (clusters 6 and 7) had the strongest response to ALV-J infection at 21 DPI, based on detection of the largest number of differentially expressed genes (DEGs). T cell populations of clusters 6 and 7 could be further divided into four subsets: activated CD4+T cells (cluster A0), Th1-like cells (cluster A2), Th2-like cells (cluster A1), and cytotoxic CD8+T cells. Hallmark genes for each T cell subset response to viral infection were initially identified. Furthermore, pseudotime analysis results suggested that chicken CD4+T cells could potentially differentiate into Th1-like and Th2-like cells. Moreover, ALV-J infection probably induced CD4+T cell differentiation into Th1-like cells in which the most immune related DEGs were detected. With respect to the control group, ALV-J infection also had an obvious impact on PBL cell composition. B cells showed inconspicuous response and their numbers decreased in PBLs of the ALV-J infected chickens at 21 DPI. Percentages of cytotoxic Th1-like cells and CD8+T cells were increased in the T cell population of PBLs from ALV-J infected chicken, which were potentially key mitigating factors against ALV-J infection. More importantly, our results provided a rich resource of gene expression profiles of chicken PBL subsets for a systems-level understanding of their function in homeostatic condition as well as in response to viral infection.
Ecosystem engineering alters density-dependent feedbacks in an aquatic insect population
Authors: Phillips Joseph S. , McCormick Amanda R. , Botsch Jamieson C. , Ives Anthony R.
Published: January 2021

Ecosystem engineers have large impacts on the communities in which they live, and these impacts may feed back to populations of engineers themselves. In this study, we assessed the effect of ecosystem engineering on density-dependent feedbacks for midges in Lake Mývatn, Iceland. The midge larvae reside in the sediment and build silk tubes that provide a substrate for algal growth, thereby elevating benthic primary production. Benthic algae are in turn the primary food source for the midge larvae, setting the stage for the effects of engineering to feed back to the midges themselves. Using a field mesocosm experiment manipulating larval midge densities, we found a generally positive but nonlinear relationship between density and benthic production. Furthermore, adult emergence increased with the primary production per midge larva. By combining these two relationships in a simple model, we found that the positive effect of midges on benthic production weakened the negative density dependence at low to intermediate larval densities. However, this benefit disappeared at high densities when midge consumption of primary producers exceeded their positive effects on primary production through ecosystem engineering. Our results illustrate how ecosystem engineering can alter density-dependent feedbacks for engineer populations.
The contribution of astrocyte and neuronal Panx1 to seizures is model and brain region dependent
Authors: Obot Price , Velíšek Libor , Velíšková Jana , Scemes Eliana
Published: January 2021

Pannexin1 (Panx1) is an ATP release channel expressed in neurons and astrocytes that plays important roles in CNS physiology and pathology. Evidence for the involvement of Panx1 in seizures includes the reduction of epileptiform activity and ictal discharges following Panx1 channel blockade or deletion. However, very little is known about the relative contribution of astrocyte and neuronal Panx1 channels to hyperexcitability. To this end, mice with global and cell type specific deletion of Panx1 were used in onein vivoand twoin vitroseizure models. In the low-Mg2+in vitromodel, global deletion but not cell-type specific deletion of Panx1 reduced the frequency of epileptiform discharges. This reduced frequency of discharges did not impact the overall power spectra obtained from local field potentials. In thein vitroKA model, in contrast, global or cell type specific deletion of Panx1 did not affect the frequency of discharges, but reduced the overall power spectra. EEG recordings following KA-injectionin vivorevealed that although global deletion of Panx1 did not affect the onset of status epilepticus (SE), SE onset was delayed in mice lacking neuronal Panx1 and accelerated in mice lacking astrocyte Panx1. EEG power spectral analysis disclosed a Panx1-dependent cortical region effect; while in the occipital region, overall spectral power was reduced in all three Panx1 genotypes; in the frontal cortex, the overall power was not affected by deletion of Panx1. Together, our results show that the contribution of Panx1 to ictal activity is model, cell-type and brain region dependent.
Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice
Authors: Kay Jennifer E. , Corrigan Joshua J. , Armijo Amanda L. , Nazari Ilana S. , Kohale Ishwar N. , Torous Dorothea K. , Avlasevich Svetlana L. , Croy Robert G. , Wadduwage Dushan N. , Carrasco Sebastian E. , Dertinger Stephen D. , White Forest M. , Essigmann John M. , Samson Leona D. , Engelward Bevin P.
Published: January 2021

N-nitrosodimethylamine (NDMA) is a DNA methylating agent that has been discovered to contaminate water, food and drugs. The alkyladenine glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we studiedAag−/−andAag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine, or 3MeA) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switched from cancer to lethality simply by changing AAG levels. To understand the underlying basis for this observation, we integrated a suite of molecular, cellular and physiological analyses. We found that unrepaired 3MeA is somewhat toxic but highly mutagenic (promoting cancer), whereas excess strand breaks are poorly mutagenic and highly toxic (suppressing cancer and promoting lethality). We demonstrate that the levels of a single DNA repair protein tips the balance between blocks and breaks, and thus dictates the disease consequences of DNA damage.
TCF11 Has a Potent Tumor-Repressing Effect than Its Prototypic Nrf1α by Definition of both Similar yet Different Regulatory Profiles, with a Striking Disparity from Nrf2
Authors: Wang Meng , Ren Yonggang , Hu Shaofan , Liu Keli , Qiu Lu , Zhang Yiguo
Published: January 2021

Nrf1 and Nrf2, as two principal CNC-bZIP transcription factors, regulate similar but different targets involved in a variety of biological functions for maintaining cell homeostasis and organ integrity. Of note, the unique topobiological behavior of Nrf1 makes its functions more complicated than Nrf2, because it is allowed for alternatively transcribing and selectively splicing to yield multiple isoforms (e.g., TCF11, Nrf1α). In order to gain a better understanding of their similarities and differences in distinct regulatory profiles, all four distinct cell models for stably expressingTCF11,TCF11ΔN,Nrf1αorNrf2have been herein established by an Flp-In™ T-REx™-293 system and then identified by transcriptomic sequencing. Further analysis revealed that Nrf1α and TCF11 have similar yet different regulatory profiles, although both contribute basically to positive regulation of their co-targets, which are disparate from those regulated by Nrf2. Such disparity in those gene regulation by Nrf1 and Nrf2 was further corroborated by scrutinizing comprehensive functional annotation of their specific and/or common target genes. Conversely, the mutant TCF11ΔN, resulting from a deletion of the N-terminal amino acids 2-156 from TCF11, resembles Nrf2 with the largely consistent structure and function. Interestingly, our further experimental evidence demonstrates that TCF11 acts as a potent tumor-repressor relative to Nrf1α, albeit both isoforms possess a congruous capability to prevent malignant growth of tumor and upregulate those genes critical for improving the survival of patients with hepatocellular carcinoma.
Comparing utility functions between risky and riskless choice in rhesus monkeys
Authors: Bujold Philipe M. , Ferrari-Toniolo Simone , Seak Leo Chi U , Schultz Wolfram
Published: January 2021

Decisions can be risky or riskless, depending on the outcomes of the choice. Expected Utility Theory describes risky choices as a utility maximization process: we choose the option with the highest subjective value (utility), which we compute considering both the option’s value and its associated risk. According to the random utility maximization framework, riskless choices could also be based on a utility measure. Neuronal mechanisms of utility-based choice may thus be common to both risky and riskless choices. This assumption would require the existence of a utility function that accounts for both risky and riskless decisions. Here, we investigated whether the choice behavior of macaque monkeys in riskless and risky decisions could be described by a common underlying utility function. We found that the utility functions elicited in the two choice scenarios were different from each other, even after taking into account the contribution of subjective probability weighting. Our results suggest that distinct utility representations exist for riskless and risky choices, which could reflect distinct neuronal representations of the utility quantities, or distinct brain mechanisms for risky and riskless choices. The different utility functions should be taken into account in neuronal investigations of utility-based choice.
Apolipoprotein M attenuates anthracycline cardiotoxicity and lysosomal injury
Authors: Guo Zhen , Ripoll Carla Valenzuela , Picataggi Antonino , Rawnsley David R. , Ozcan Mualla , Chirinos Julio A. , Chendamarai Ezhilarasi , Girardi Amanda , Riehl Terrence , Evie Hosannah , Diab Ahmed , Kovacs Attila , Hyrc Krzysztof , Ma Xiucui , Asnani Aarti , Shewale Swapnil V. , Scherrer-Crosbie Marielle , Cowart Lauren Ashley , Parks John S. , Zhao Lei , Gordon David , Ramirez-Valle Francisco , Margulies Kenneth B. , Cappola Thomas P. , Desai Ankit A. , Pederson Lauren N. , Bergom Carmen , Stitziel Nathan O. , Rettig Michael P. , DiPersio John F. , Hajny Stefan , Christoffersen Christina , Diwan Abhinav , Javaheri Ali
Published: January 2021

Objectives

Determine the role of apolipoprotein M (ApoM) in anthracycline (Dox) cardiotoxicity.

Background

ApoM binds the cardioprotective sphingolipid sphingosine-1-phosphate (S1P). Circulating ApoM is inversely associated with mortality in human heart failure (HF).

Methods

In the Penn HF Study (PHFS), we tested the relationship between ApoM and mortality in a subset with anthracycline-induced cardiomyopathy. We measured ApoM in humans and mice treated with Dox and utilized hepatic ApoM transgenic (ApomTG), ApoM knockout (ApomKO), ApoM knock-in mice with impaired S1P binding, and S1P receptor 3 (S1PR3) knockout mice in Dox cardiotoxicity. We assayed autophagy in left ventricular tissue from anthracycline-induced HF patients versus donor controls.

Results

ApoM was inversely associated with mortality in PHFS, and Dox reduced circulating ApoM in mice and breast cancer patients.ApomTGmice were protected from Dox-induced cardiac dysfunction and loss of left ventricular mass.ApomTGattenuated Dox-induced impairment in autophagic flux in vivo and accumulation of insoluble p62, which was also observed in the myocardium of patients with anthracycline-induced HF. In vehicle-treated mice, ApoM negatively regulated transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. The effect of ApoM on TFEB required both S1P binding and S1PR3. In the presence of Dox, ApoM preserved TFEB and cardiomyocyte lysosomal abundance assessed as lysosomal associated membrane protein 1 positive structures in vivo, while S1P mimetic pretreatment of cardiomyocytes prevented Dox-induced changes in lysosomal pH.

Conclusions

ApoM attenuates Dox cardiotoxicity via the autophagy-lysosome pathway. The association between ApoM and reduced mortality may be explained by its role in sustaining autophagy.

Highlights

Circulating ApoM is inversely associated with survival in human anthracycline-induced cardiomyopathy

Anthracycline treatment reduces circulating ApoM in humans and mice

Increasing ApoM attenuates doxorubicin cardiotoxicity, lysosomal injury and preserves myocardial autophagic flux, but does not impact doxorubicin anti-neoplastic efficacy

Autophagic impairment is characteristic of human anthracycline cardiomyopathy