bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of Persons With COVID-19 in Hospitals With and Without Standard Treatment With (Hydroxy)chloroquine
Authors: Peters EJG , Collard D , Van Assen S , Beudel M , Bomers MK , Buijs J , De Haan LR , De Ruijter W , Douma RA , Elbers PWG , Goorhuis A , Gritters van den Oever NC , Knarren GHH , Moeniralam HS , Mostard RLM , Quanjel MJR , Reidinga AC , Renckens R , Van Den Bergh JPW , Vlasveld IN , Sikkens JJ
Published: August 2020

Objective

To compare survival of subjects with COVID-19 treated in hospitals that either did or did not routinely treat patients with hydroxychloroquine or chloroquine.

Methods

We analysed data of COVID-19 patients treated in 9 hospitals in the Netherlands. Inclusion dates ranged from February 27th 2020, to May 15th, when the Dutch national guidelines no longer supported the use of (hydroxy)chloroquine. Seven hospitals routinely treated subjects with (hydroxy)chloroquine, two hospitals did not. Primary outcome was 21-day all-cause mortality. We performed a survival analysis using log-rank test and Cox-regression with adjustment for age, sex and covariates based on premorbid health, disease severity, and the use of steroids for adult respiratory distress syndrome, including dexamethasone.

Results

Among 1893 included subjects, 21-day mortality was 23.4% in 1552 subjects treated in hospitals that routinely prescribed (hydroxy)chloroquine, and 17.0% in 341 subjects that were treated in hospitals that did not. In the adjusted Cox-regression models this difference disappeared, with an adjusted hazard ratio of 1.17 (95%CI 0.88-1.55). When stratified by actually received treatment in individual subjects, the use of (hydroxy)chloroquine was associated with an increased 21-day mortality (HR 1.58; 95%CI 1.25-2.01) in the full model.

Conclusions

After adjustment for confounders, mortality was not significantly different in hospitals that routinely treated patients with (hydroxy)chloroquine, compared with hospitals that did not. We compared outcomes of hospital strategies rather than outcomes of individual patients to reduce the chance of indication bias. This study adds evidence against the use of (hydroxy)chloroquine in patients with COVID-19.
Impacts of bariatric surgery on costs and health outcomes of patients in Brazil: Interrupted time series analysis of multi-panel data
Authors: Turri José Antonio Orellana , Baraccat Edmund Chada , Soarez José Maria , Santos Lionai Lima dos , Santo Marco Aurélio , Sarti Flavia Mori , Anokye Nana Kwame
Published: August 2020

Study design

Original research

Obesity is one of the most important public health problems worldwide, presenting significant socioeconomic impacts in health systems. Considering the rising costs of health care and the escalating burden of obesity in diverse countries, there has been increasing trends in examination of cost-effectiveness of health interventions towards prevention and treatment of obesity and its effects on comorbidities. Bariatric surgery has been considered an effective intervention for reducing moderate to severe obesity and improvement of obesity-related morbidities.

Methodology

Interrupted Time-Series Analysis (ITSA) on costs and health outcomes from retrospective cohort of 114 patients who had bariatric surgery at the Hospital of Clinics from the University of Sao Paulo. Medical records encompassing complete data on anthropometric, hemodynamic and biochemical parameters, utilization of resources and costs for health care procedures and regular assessments of patients’ health status associated with bariatric surgery at individual level were included in the study. Data on utilization of resources during outpatient and inpatient health care were used for estimation of patient’s direct costs referring to bariatric surgery, and 6-month pre- and post-intervention periods, adopting health system perspective in micro-costing approach.

Results

Mean direct costs of hospitalization (-US$2,762.22; −23.2%), image exams (-US$7.53; −0.8%) and medication (-US$175.37; −25,7%) presented decrease after bariatric surgery, and total direct cost (US$1,375.37; +138%), consultations (US$0.42; +2.4%) and laboratory exams (US$68.96; +63.4%) had increase. Reduction in weight, BMI, LDL, triglycerides, insulin, glucose-linked hemoglobin, and glucose showed improvements in patients’ health status after bariatric surgery. Cholesterol, VLDL, and HDL presenting increase after surgery.

Conclusion

Bariatric surgery represents an effective intervention for treatment of moderate to severe obesity with extensive benefits regarding health promotion and reduction of burden of disease. Trends in direct costs and multiple health outcomes showed post-intervention improvements in patients’ health status and reduction of health care needs of individuals.
Covid-19 related stress and coping strategies among adults with chronic disease in Southwest Ethiopia
Authors: Girma Abel , Ayalew Ermias
Published: August 2020

Background

Coronavirus disease (COVID-19) is an infectious disease caused by a newly discovered coronavirus which are a large family of viruses that are common in people and many different species of animals which can affect people physically and psychologically. The older people and those with underlying medical problems are more likely to develop serious illness and death.

Objective

the aim of this study was to determine Covid-19 related stress and coping strategies among adults with chronic disease in Bench-Sheko,West Omo and Keffa Zones, southwest Ethiopia

Methods

Institutional based cross-sectional study was applied among 613 adults with chronic disease. A simple sampling technique was applied. Correlational analysis was used to determine the relationship between the COVID-19 related stress score and coping strategy types. To measure the strength of association between dependent variables and independent variables and Pearson coefficients (r) with 95% Confidence interval (CI) were calculated. Finally, the variable, which shows statistical significance (p-value < 0.05 cut point) were used to quantify the associations among variables.

Results

Around 613 participants of 96% response rate were participated. About 68.4% were moderately stressed; low stress was 17.8% and severe stress was 13.9 %. Covid-19 related perceived stress score were positively associated with coping strategies types of like sell-distraction, active coping, denial, emotional support, behavioral disengagement, venting, and use of instrument, positive reframing, self-blaming, planning, humoring and religion. The most preferable types of coping strategies were religious, instrumental and active coping strategies and while the least used were substance used.

Conclusion

Significant numbers of participants were suffered from severe perceived stress due to covid-19 outbreak in this study area. Both adaptive and maladaptive Coping strategy types were significantly associated with stress. Substance use and self-blaming were the types coping strategies which were not associated with perceived stress.
Detection, prevalence, and duration of humoral responses to SARS-CoV-2 under conditions of limited population exposure
Authors: Ripperger Tyler J. , Uhrlaub Jennifer L. , Watanabe Makiko , Wong Rachel , Castaneda Yvonne , Pizzato Hannah A. , Thompson Mallory R. , Bradshaw Christine , Weinkauf Craig C. , Bime Christian , Erickson Heidi L. , Knox Kenneth , Bixby Billie , Parthasarathy Sairam , Chaudhary Sachin , Natt Bhupinder , Cristan Elaine , Aini Tammer El , Rischard Franz , Campion Janet , Chopra Madhav , Insel Michael , Sam Afshin , Knepler James L. , Capaldi Andrew P. , Spier Catherine M. , Dake Michael D. , Edwards Taylor , Kaplan Matthew E. , Scott Serena Jain , Hypes Cameron , Mosier Jarrod , Harris David T. , LaFleur Bonnie J. , Sprissler Ryan , Nikolich-Žugich Janko , Bhattacharya Deepta
Published: August 2020

We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.
Widespread testing, case isolation and contact tracing may allow safe school reopening with continued moderate physical distancing: a modeling analysis of King County, WA data
Authors: Bracis Chloe , Burns Eileen , Moore Mia , Swan David , Reeves Daniel B , Schiffer Joshua T. , Dimitrov Dobromir
Published: August 2020

Background

In late March 2020, a “Stay Home, Stay Healthy” order was issued in Washington State in response to the COVID-19 pandemic. On May 1, a 4-phase reopening plan began. If implemented without interruptions, all types of public interactions were planned to resume by July 15. We investigated whether adjunctive prevention strategies would allow less restrictive physical distancing to avoid second epidemic waves and secure safe school reopening.

Methods

We developed a mathematical model, stratifying the population by age (0-19 years, 20-49 years, 50-69 years, and 70+ years), infection status (susceptible, exposed, asymptomatic, pre-symptomatic, symptomatic, recovered) and treatment status (undiagnosed, diagnosed, hospitalized) to project SARS-CoV-2 transmission during and after the reopening period. The model was parameterized with demographic and contact data from King County, WA and calibrated to confirmed cases, deaths (overall and by age) and epidemic peak timing. Adjunctive prevention interventions were simulated assuming different levels of pre-COVID physical interactions (pC_PI) restored. We made several predictions related to adjunctive interventions or changes in pC_PI.

Results

The best model fit estimated ~35% pC_PI under lockdown. Gradually restoring 75% pC_PI for all age groups between May 15-July 15 resulted in ~350 daily deaths by early September 2020. Maintaining less than 45% pC_PI was required with current testing practices to ensure low levels of daily infections and deaths. If widespread community transmission persisted, isolating the elderly does not lower daily death rates significantly. Increased testing, isolation of symptomatic infections, and contact tracing permitted 60% pC_PI without significant increases in daily deaths before September, although this strategy may not be sufficient to eliminate community transmission. This combination strategy also allowed opening of schools with <15 daily deaths. Inpatient antiviral treatment reduces deaths significantly without lowering cases or hospitalizations.

Conclusions

We predict that widespread implementation of “test and isolate” policy alone is insufficient to prevent the rapid re-emergence of SARS CoV-2 without moderate physical distancing. However, widespread testing, contact tracing and case isolation would allow relaxation of physical distancing, as well as opening of schools, without a surge in local cases and deaths.
Integrative transcriptome analysis of malignant pleural mesothelioma reveals a clinically relevant immune-based classification
Authors: Alay Ania , Cordero David , Hijazo-Pechero Sara , Aliagas Elisabet , Lopez-Doriga Adriana , Marín Raúl , Palmero Ramón , Llatjós Roger , Escobar Ignacio , Ramos Ricard , Padrones Susana , Moreno Víctor , Nadal Ernest , Solé Xavier
Published: August 2020

Background

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lung mesothelium. Immune checkpoint inhibitors (ICI) in MPM have not been extremely successful, likely due to poor identification of suitable candidate patients for the therapy. We aimed to identify cellular immune fractions associated with clinical outcome and classify MPM patients based on their immune contexture. For each defined group, we sought for molecular specificities that could help further define our MPM classification at the genomic and transcriptomic level, as well as identify differential therapeutic strategies based on transcriptional signatures predictive of drug response.

Methods

The abundance of 20 immune cell fractions in 516 MPM samples from 7 gene expression datasets was inferred using Gene Set Variation Analysis. Identification of clinically relevant fractions was performed with Cox Proportional-Hazards Models adjusted for age, stage, sex, and tumor histology. Immune-based groups were identified using unsupervised classification.

Results

T-Helper 2 (TH2) and cytotoxic T (TC) cells were found to be consistently associated with overall survival. Three immune clusters (IG) were subsequently defined based on TH2 and TC immune infiltration levels: IG1 (54.5%) was characterized by high TH2 and low TC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high TC levels. IG1 and IG3 groups were associated with worse and better overall survival, respectively. The three groups showed differential molecular profiles, with IG1 enriched for CDKN2A and IFN-related genes deletions. At the transcriptional level, IG1 samples showed upregulation of proliferation signatures, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, the integration of gene expression with functional signatures of drug response showed that IG3 patients might be more likely to respond to ICI, while IG1 patients could be more sensitive to PARP inhibitors.

Conclusions

This study identifies a novel immune-based signature with potential clinical relevance based on TH2 and TC levels, unveiling a fraction of MPM patients with better prognosis and who might benefit from immune-based therapies. Genomic and transcriptomic specificities of the different groups could be used to tailor potential therapies in the future.
The clinical and prognostic significance of Protein Arginine Deiminase 2 and 4 (PADI2 & PADI4) in colorectal cancer
Authors: Gijon Mohamed , Metheringham Rachael L , Toss Michael S , Paston Samantha J , Durrant Lindy G
Published: August 2020

Aims

Protein arginine deiminase (PADs) are a family of enzymes that catalyse the post translational modification (PTM) of proteins. Association between PAD expression with clinicopathology, protein expression and outcome was determined.

Methods

PADI2 and PADI4 expression was assessed immunohistochemically in a cohort of CRC patients.

Results

CRC tissues expressed variable levels of PADI2 which was mainly localised in the cytoplasm and correlated with patient survival (p=0.005); high expression increased survival time from 43.5 to 67.6 months. Expression of cytoplasmic PADI2 correlated with expression of nuclear β catenin, PADI4 and alpha-enolase. In contrast expression of nuclear PADI2 correlated with a decrease in survival (p=0.010), with high expression decreasing survival from 76.4 to 42.9 months. CRC tissues expressed variable levels of PADI4 in both the nucleus and cytoplasm. Expression of cytoplasmic PADI4 correlated with survival (p=0.001) with high expression increasing survival time from 48.1 to 71.8 months. Expression of cytoplasmic PADI4 correlated with expression of, nuclear β catenin, alpha-enolase (p≤0.0001,p=0.002) and the apoptotic related protein, Bcl-2. Expression of nuclear PADI4 also correlated with survival (p=0.011) with high expression of nuclear PADI4 increasing survival time from 55.4 to 74 months. Expression of nuclear PADI4 correlated with p53, alpha-enolase and Bcl-2. Multivariate analysis showed that TNM stage, cytoplasmic PADI2 and PADI4 remained independent prognostic factors in CRC. Both PADI2 and PADI4 are good prognostic factors in CRC.

Conclusions

High expression of cytoplasmic PADI2, PADI4 and nuclear PADI4 were associated with an increase in overall survival.
An Analysis of Self-reported Longcovid Symptoms on Twitter
Authors: Singh Shubh Mohan , Reddy Chaitanya
Published: August 2020

Objectives

A majority of patients suffering from acute COVID-19 are expected to recover symptomatically and functionally. However there are reports that some people continue to experience symptoms even beyond the stage of acute infection. This phenomenon has been called longcovid.

Study design

This study attempted to analyse symptoms reported by users on twitter self-identifying as longcovid.

Methods

The search was carried out using the twitter public streaming application programming interface using a relevant search term.

Results

We could identify 89 users with usable data in the tweets posted by them. A majority of users described multiple symptoms the most common of which were fatigue, shortness of breath, pain and brainfog/concentration difficulties. The most common course of symptoms was episodic.

Conclusions

Given the public health importance of this issue, the study suggests that there is a need to better study post acute-COVID symptoms.
The Prevalence of Non-Adherence in Patients with Resistant Hypertension: a Systematic Review and Meta-Analysis
Authors: Bourque Gabrielle , Ilin Julius Vladimir , Ruzicka Marcel , Davis Alexandra , Hundemer Gregory , Hiremath Swapnil
Published: August 2020

Background

Resistant hypertension is quite prevalent and a risk factor for cardiovascular events. Patients with suspected resistant hypertension undergo more screening intensity for secondary hypertension, despite some of them being non-adherent to prescribed pharmacotherapy. The prevalence of non-adherence in this setting varies from about 5 to 80% in the published literature. Apart from the wide range, the relation between method of assessment and prevalence is not well established. Our objective was to establish the overall prevalence of non-adherence in the apparent treatment resistant hypertension population, explore causes of heterogeneity, and evaluate the effect of the method of assessment on the estimate of non-adherence.

Methods

We performed a systematic review and meta-analysis. MEDLINE, EMBASE Classic+EMBASE, Cochrane, CINAHL, and Web of Science were searched for relevant articles. Details about the method of adherence assessment were extracted from each included article and grouped into direct and indirect. Pooled analysis was performed using the random effects model and heterogeneity was explored with metaregression and subgroup analyses.

Results

The literature search yielded 1428 studies, of which 36 were included. The pooled prevalence of non-adherence was 35% (95% confidence interval 25 – 46 %). For indirect methods of adherence assessment, it was 25% (95% CI 15 – 39 %), whereas for direct methods of assessment, it was 44% (95% CI 32 – 57 %). Metaregression suggested gender, age, and time of publication as potential factors contributing to the heterogeneity.

Conclusions

Non-adherence to pharmacotherapy is quite common in resistant hypertension, with the prevalence varying with the methods of assessment.

Brief Summary

Resistant hypertension is known to be a risk factor for cardiovascular events. These patients also undergo higher screening intensity for secondary hypertension. However, not all patients with apparent treatment resistant hypertension have true resistant hypertension, with some of them being non-adherent to prescribed pharmacotherapy. This systematic review aims to establish the overall prevalence of non-adherence in the apparent treatment resistant hypertension population and assess the relative contributions of non-adherence assessed with direct and indirect measures.
Bidirectional associations between COVID-19 and psychiatric disorder: a study of 62,354 COVID-19 cases
Authors: Taquet Maxime , Luciano Sierra , R Geddes John , J Harrison Paul
Published: August 2020

Background

Adverse mental health consequences of COVID-19, including anxiety and depression, have been widely predicted but not yet accurately measured. There are a range of physical health risk factors for COVID-19, but it is not known if there are also psychiatric risk factors.

Methods

We addressed both questions using cohort studies derived from an electronic health records (EHR) network of 69 million patients including over 62,000 cases of COVID-19. Propensity score matching was used to control for confounding by risk factors for COVID-19 and for more severe illness.

Findings

In patients with no prior psychiatric history, COVID-19 was associated with an increased incidence of psychiatric diagnoses in the three months after infection compared to 6 other health events (hazard ratio [95% CI] 2.1 [1.8–2.5] compared to influenza; 1.7 [1.5–1.9] compared to other respiratory tract infections; 1.6 [1.4–1.9] compared to skin infection; 1.6 [1.3–1.9] compared to cholelithiasis; 2.2 [1.9–2.6] compared to urolithiasis, and 2.1 [1.9–2.5] compared to fracture of a large bone; all p< 0.0001). The increase was greatest for anxiety disorders but also present for depression, insomnia, and dementia. The results were robust to several sensitivity analyses. There was a ∼30% reduction in psychiatric diagnoses in the total EHR population over the same period. A psychiatric diagnosis in the previous year was associated with a 65% higher incidence of COVID-19 (relative risk 1.65, 95% CI: 1.59–1.71, p< 0.0001). This was independent of known physical health risk factors for COVID-19.

Interpretation

COVID-19 infection has both psychiatric sequelae and psychiatric antecedents. Survivors have an increased rate of new onset psychiatric disorders, and prior psychiatric disorders are associated with a higher risk of COVID-19. The findings have implications for research into aetiology and highlight the need for clinical services to provide multidisciplinary follow-up, and prompt detection and treatment.
Assessment of physiological signs associated with COVID-19 measured using wearable devices
Authors: Natarajan Aravind , Su Hao-Wei , Heneghan Conor
Published: August 2020

Respiration rate, heart rate, and heart rate variability are some health metrics that are easily measured by consumer devices and which can potentially provide early signs of illness. Furthermore, mobile applications which accompany wearable devices can be used to collect relevant self-reported symptoms and demographic data. This makes consumer devices a valuable tool in the fight against the COVID-19 pandemic. We considered two approaches to assessing COVID-19 – a symptom-based approach, and a physiological signs based technique. Firstly, we trained a Logistic Regression classifier to predict the need for hospitalization of COVID-19 patients given the symptoms experienced, age, sex, and BMI. Secondly, we trained a neural network classifier to predict whether a person is sick on any specific day given respiration rate, heart rate, and heart rate variability data for that day and and for the four preceding days. Data on 1,181 subjects diagnosed with COVID-19 (active infection, PCR test) were collected from May 21 – July 14, 2020. 11.0% of COVID-19 subjects were asymptomatic, 47.2% of subjects recovered at home by themselves, 33.2% recovered at home with the help of someone else, 8.16% of subjects required hospitalization without ventilation support, and 0.448% required ventilation. Fever was present in 54.8% of subjects. Based on self-reported symptoms alone, we obtained an AUC of 0.77±0.05 for the prediction of the need for hospitalization. Based on physiological signs, we obtained an AUC of 0.77±0.03 for the prediction of illness on a specific day with 4 previous days of history. Respiration rate and heart rate are typically elevated by illness, while heart rate variability is decreased. Measuring these metrics can help in early diagnosis, and in monitoring the progress of the disease.
Newborn dried blood spots for serological surveys of COVID-19
Authors: Liu Feimei , Nguyen Mytien , Vijayakumar Pavithra , Kaplan Alanna , Meir Amit , Dai Yile , Wang Eric , Walsh Hannah , Ring Aaron M. , Omer Saad B. , Farhadian Shelli F.
Published: August 2020

There is an urgent need for inexpensive, population-wide surveillance testing for COVID-19. We tested newborn dried blood spots (DBS) anti-SARS-COV-2 antibodies for all infants born at Yale from March-May 2020, and found that newborn DBS serologies reflect maternal and population-wide infection rates during the study period. This suggests a role for DBS in COVID-19 surveillance in areas where viral testing is limited.
Detection of Prenatal Alcohol Exposure Using Machine Learning Classification of Resting-State Functional Network Connectivity Data
Authors: Rodriguez Carlos I. , Vergara Victor , Davies Suzy , Calhoun Vince , Savage Daniel D. , Hamilton Derek A.
Published: August 2020

Introduction

Previous work utilizing resting state fMRI to measure functional network connectivity in rodents with moderate prenatal alcohol exposure (PAE) revealed several sex- and region-dependent alterations in FNC implicating FNC as potential biomarker for PAE. Given that FNC is sensitive to neurological and psychiatric conditions in humans, here, we explore the use of previously acquired FNC data and machine learning methods to detect PAE among a sample of rodents exposed to moderate PAE and controls exposed to a saccharin solution.

Materials & Methods

We utilized previously acquired fMRI data from 48 adult rats 24 PAE (12 male 12 female) and 24 saccharin exposed (SAC) controls (12 male and 12 female) for classification. The entire data sample was utilized to perform binary classification (SAC or PAE) of FNC data with multiple support vector machine (SVM) kernels and out-of-sample cross-validation to evaluate classification performance.

Results

Results revealed accuracy rates of 62.5% for all samples, 58.3% for males, and 79.2% for females using a quadratic SVM kernel to classify moderate PAE from FNC data. In addition, brain networks localized to hippocampal and cortical regions contributed strongly to QSVM classifications.

Conclusion

Our results suggest overall modest classification performance of a QSVM to detect moderate PAE from FNC data gathered from adult rats, yet good performance among females. Further developments and refinement of the technique hold promise for the detection of PAE in earlier developmental time periods that potentially offer additional tools for the non-invasive detection of PAE from FNC data.

IMPACT STATEMENT

The diagnosis of fetal alcohol spectrum disorders (FASDs) can be challenging in individuals who lack the hallmark facial dysmorphologies associated with heavy prenatal alcohol exposure (PAE). The absence of a diagnosis prevents individuals with PAE from receiving the treatment and services that improves quality of life outcomes. This research explores the use of preclinical functional network connectivity data and machine learning techniques as a novel and non-invasive means of detecting PAE. Our aim is to contribute basic science towards improving diagnostic strategies that can lead to securing timely and appropriate support for individuals with FASD and their caregivers.
Regulation of early growth response-1 (Egr-1) gene expression by Stat1-independent type I interferon signaling and respiratory viruses
Authors: Ramana Chilakamarti V.
Published: August 2020

Respiratory virus infection is one of the leading causes of death in the world. Activation of the Jak-Stat pathway by Interferon-alpha/beta (IFN-α/β) in lung epithelial cells is critical for innate immunity to respiratory viruses. Genetic and biochemical studies have shown that transcriptional regulation by IFN-α/βrequired the formation of Interferon-stimulated gene factor-3 (ISGF-3) complex consisting of Stat1, Stat2, and Irf9 transcription factors. Furthermore, IFNα/βreceptor activates multiple signal transduction pathways in parallel to the Jak-Stat pathway and induces several transcription factors at mRNA levels resulting in the secondary and tertiary rounds of transcription. Transcriptional factor profiling in the transcriptome and RNA analysis revealed that Early growth response-1 (Egr-1) was rapidly induced by IFN-α/βand Toll-like receptor (TLR) ligands in multiple cell types. Studies in mutant cell lines lacking components of the ISGF-3 complex revealed that IFN-βinduction of Egr-1 was independent of Stat1, Stat2, or Irf9. Activation of the Mek/Erk-1/2 pathway was implicated in the rapid induction of Egr-1 by IFN-βin serum-starved mouse lung epithelial cells. Interrogation of multiple microarray datasets revealed that respiratory viruses including coronaviruses regulated Egr-1 expression in human lung cell lines. Furthermore, Egr-1 inducible genes including transcription factors, mediators of cell growth, and chemokines were differentially regulated in the human lung cell lines after coronavirus infection, and in the lung biopsies of COVID-19 patients. Rapid induction by interferons, TLR ligands, and respiratory viruses suggests a critical role for Egr-1 in antiviral response and inflammation with potential implications for human health and disease.
Designing Sub-20 nm Nanocarriers for Small Molecule Delivery: Interplay among Structural Geometry, Assembly Energetics, and Cargo Release Kinetics
Authors: Jung Benson T. , Lim Marc , Jung Katherine , Li Michael , Dong He , Dube Nikhil , Xu Ting
Published: August 2020

Biological constraints in diseased tissues have motivated the need for small nanocarriers (10-30 nm) to achieve sufficient vascular extravasation and pervasive tumor penetration. This particle size limit is only an order of magnitude larger than small molecules, such that cargo loading is better described by co-assembly processes rather than simple encapsulation. Understanding the structural, kinetic, and energetic contributions of carrier-cargo co-assembly is thus critical to achieve molecular-level control and predictablein vivobehavior. These interconnected set of properties were systematically examined using sub-20 nm self-assembled nanocarriers known as three-helix micelles (3HM). Both hydrophobicity and the “geometric packing parameter” dictate small molecule compatibility with 3HM’s alkyl tail core. Planar obelisk-like apomorphine and doxorubicin (DOX) molecules intercalated well within the 3HM core and near the core-shell interface, forming an integral component to the co-assembly, as corroborated by small angle X-ray and neutron-scattering structural studies. DOX promoted crystalline alkyl tail ordering, which significantly increased (+63%) the activation energy of 3HM subunit exchange. Subsequently, 3HM-DOX displayed slow-release kinetics (t1/2=40 h) at physiological temperatures, with ~50x greater cargo preference for the micelle core as described by two drug partitioning coefficients (micellar core/shell Kp1~24, and shell/bulk solvent Kp2~2). The geometric and energetic insights between nanocarrier and their small molecule cargos developed here will aid in broader efforts to deconvolute the interconnected properties of carrier-drug co-assemblies, and to understand nanomedicine behavior throughout all the physical andin vivoprocesses they are intended to encounter.
Identification and characterization of phlorizin transporter fromArabidopsis thalianaand its application for phlorizin production inSaccharomyces cerevisiae
Authors: Belew Zeinu Mussa , Crocoll Christoph , Møller-Hansen Iben , Naesby Michael , Borodina Irina , Nour-Eldin Hussam Hassan
Published: August 2020

Bioengineering aimed at producing complex and valuable plant specialized metabolites in microbial hosts requires efficient uptake of precursor molecules and export of final products to alleviate toxicity and feedback inhibition. Plant genomes encode a vast repository of transporters of specialized metabolites that— due to lack of molecular knowledge—remains largely unexplored in bioengineering. Using phlorizin as a case study—an anti-diabetic and anti-cancerous flavonoid from apple—we demonstrate that brute-force functional screening of plant transporter libraries inXenopusoocytes is a viable approach to identify transporters for bioengineering. By screening 600Arabidopsistransporters, we identified and characterizedpurinepermease 8 (AtPUP8) as a bidirectional phlorizin transporter. Functional expression in the plasma membrane of a phlorizin-producing yeast strain increased phlorizin titer by more than 80 %. This study provides a generic approach for identifying plant exporters of specialized metabolites and demonstrates the potential of transport-engineering for improving yield in bioengineering approaches.
A fetal wave of human type-3 γδ T cells with restricted TCR diversity persists into adulthood
Authors: Tan Likai , Fichtner Alina Suzann , Bubke Anja , Odak Ivan , Schultze-Florey Christian , Koenecke Christian , Förster Reinhold , Jarek Michael , von Kaisenberg Constantin , Borchers Alina , Panzer Ulf , Krebs Christian , Ravens Sarina , Prinz Immo
Published: August 2020

Accumulating evidence suggests that the human embryonic thymus produces distinct waves of innate effector γδ T cells. However, it is unclear whether this process comprises a dedicated subset of IL-17-producing γδ T (γδT17) cells, like reported in mice. Here we present a novel protocol for high-throughput paired γδ TCR-sequencing, which in combination with single-cell RNA-sequencing revealed a high heterogeneity of effector γδ T cell clusters. While immature γδ T cell clusters displayed mixed and diverse TCR, effector cell types in neonatal and adult blood segregated according to γδTCR usage. In adult samples, mature Vδ1+T cells segregated into exhausted PD-1hiand active PD-1lowclusters. Among Vγ9Vδ2+T cell subsets, we identified distinct PLZF-positive effector γδ T cell clusters with innate type-1 and type-3 T cell signatures that were already detectable in a public dataset of early embryonic thymus organogenesis. Together, this suggests that functionally distinct waves of human innate effector γδ T cells including CCR6+γδT17 cells develop in the early fetal thymus and persist into adulthood.
Alpha-1-antitrypsin and its variant-dependent role in COVID-19 pathogenesis
Authors: Stevens Christian S , Oguntuyo Kasopefoluwa Y , Kowdle Shreyas , Brambilla Luca , Haas Griffin , Gowlikar Aditya , Siddiquey Mohammed NA , Schilke Robert M , Woolard Matthew D , Zhang Hongbo , Acklin Joshua A , Ikegame Satoshi , Huang Chuan-Tien , Lim Jean K , Cross Robert W , Geisbert Thomas W , Ivanov Stanimir S , Kamil Jeremy P ,   the Alpha-1 Foundation, Lee Benhur
Published: August 2020

Rationale

SARS-CoV-2 entry into host cells is facilitated by endogenous and exogenous proteases that proteolytically activate the spike glycoprotein and antiproteases inhibiting this process. Understanding the key actors in viral entry is crucial for advancing knowledge of virus tropism, pathogenesis, and potential therapeutic targets.

Objectives

We aimed to investigate the role of naïve serum and alpha-1-antitrypsin (AAT) in inhibiting protease-mediated SARS-CoV-2 entry and explore the implications of AAT deficiency on susceptibility to different SARS-CoV-2 variants.

Findings

Our study demonstrates that naïve serum exhibits significant inhibition of SARS-CoV-2 entry, with AAT identified as the major serum protease inhibitor potently restricting entry. Using pseudoparticles, replication-competent pseudoviruses, and authentic SARS-CoV-2, we show that AAT inhibition occurs at low concentrations compared with those in serum and bronchoalveolar tissues, suggesting physiological relevance. Furthermore, sera from subjects with an AAT-deficient genotype show reduced ability to inhibit entry of both Wuhan-Hu-1 (WT) and B.1.617.2 (Delta) but exhibit no difference in inhibiting B.1.1.529 (Omicron) entry.

Conclusions

AAT may have a variant-dependent therapeutic potential against SARS-CoV-2. Our findings highlight the importance of further investigating the complex interplay between proteases, antiproteases, and spike glycoprotein activation in SARS-CoV-2 and other respiratory viruses to identify potential therapeutic targets and improve understanding of disease pathogenesis.
Contribution of resident and circulating precursors to tumor-infiltrating CD8+T cell populations in non-small cell lung cancer patients
Authors: Gueguen Paul , Metoikidou Christina , Dupic Thomas , Lawand Myriam , Goudot Christel , Baulande Sylvain , Lameiras Sonia , Lantz Olivier , Girard Nicolas , Seguin-Givelet Agathe , Lefevre Marine , Mora Thierry , Walczak Aleksandra M. , Waterfall Joshua J , Amigorena Sebastian
Published: August 2020

Tumor-infiltrating lymphocytes (TILs) in general, and CD8+TILs in particular, represent a favorable prognostic factor in non-small cell lung cancer (NSCLC). The tissue origin, regenerative capacities, and differentiation pathways of TIL subpopulations, however, remain poorly understood. Using a combination of single cell RNA and T cell receptor (TCR) sequencing, we investigate the functional organization of TIL populations in primary NSCLC. We identify two CD8+TIL subpopulations expressing memory-like gene modules: one is also present in blood (circulating precursors) and the other one in juxta-tumor tissue (tissue resident precursors). In tumors, these two precursor populations converge through a unique transitional state into terminally differentiated cells, often referred to as dysfunctional or exhausted. Differentiation is associated with TCR expansion, and transition from precursor to late differentiated states correlates with intratumor T cell cycling. These results provide a coherent working model for TIL origin, filiation and functional organization in primary NSCLC.
The immune response is a critical regulator of zebrafish retinal pigment epithelium regeneration
Authors: Leach Lyndsay L. , Hanovice Nicholas J. , George Stephanie M. , Gabriel Ana E. , Gross Jeffrey M.
Published: August 2020

Loss of the retinal pigment epithelium (RPE) due to dysfunction or disease can lead to blindness in humans. Harnessing the intrinsic ability of the RPE to self-repair is an attractive therapeutic strategy; however, mammalian RPE is limited in its regenerative capacity. Zebrafish possess tremendous intrinsic regenerative potential in ocular tissues, including the RPE, but little is known about the mechanisms that drive RPE regeneration. Here, utilizing zebrafish, we identified elements of the immune response as critical mediators of intrinsic RPE regeneration. Macrophages/microglia are responsive to RPE damage and are required for the timely progression of the regenerative response and our data highlight that inflammation post-RPE injury is also critical for normal RPE regeneration. To our knowledge, these data are the first to identify the molecular and cellular underpinnings of RPE regeneration in any system and hold significant potential for translational approaches aimed towards promoting a pro-regenerative environment in mammalian RPE.
Regular aerobic exercise is positively associated with hippocampal structure and function in young and middle-aged adults
Authors: Hendrikse Joshua , Chye Yann , Thompson Sarah , Rogasch Nigel C. , Suo Chao , Coxon James , Yücel Murat
Published: August 2020

Regular exercise has numerous benefits for brain health, including the structure and function of the hippocampus. The hippocampus plays a critical role in memory function, and is altered in a number of psychiatric disorders associated with memory impairments (e.g. depression and schizophrenia), as well as healthy ageing. While many studies have focussed on how regular exercise may improve hippocampal integrity in older individuals, less is known about these effects in young to middle-aged adults. Therefore, we assessed the associations of regular exercise and cardiorespiratory fitness with hippocampal structure and function in these age groups. We recruited 40 healthy young to middle-aged adults, comprised of two groups (n = 20) who self-reported either high or low levels of exercise, according to World Health Organisation guidelines. We assessed cardiorespiratory fitness using a graded exercise test (VO2max) and hippocampal structure via manual tracing of T1-weighted magnetic resonance images. We also assessed hippocampal function using magnetic resonance spectroscopy to derive estimates of NAA concentration and hippocampal-dependent associative memory and pattern separation tasks. We observed evidence of increased N-acetyl-aspartate concentration and associative memory performance in individuals engaging in high levels of exercise. However, no differences in hippocampal volume or pattern separation capacity were observed between groups. Cardiorespiratory fitness was positively associated with hippocampal volume (left, right, and bilateral), N-acetyl-aspartate concentration, and pattern separation. However, no association was observed between cardiorespiratory fitness and associative memory. Therefore, we provide evidence that higher levels of exercise and cardiorespiratory fitness are associated with improved hippocampal structure and function. Exercise may provide a low-risk, effective method of improving hippocampal integrity in an early-to-mid-life stage.
Non-epigenetic mechanisms enable short memories of the environment for cell cycle commitment
Authors: Qu Yimiao , Jiang Jun , Liu Xiang , Yang Xiaojing , Tang Chao
Published: August 2020

Cells continuously survey their environment in order to make fundamental decisions, including whether to divide, migrate, or differentiate. However, a fascinating phenomenon in biology is that cells often possess memory—they temporally integrate both past and present signals to make a reliable decision. Cellular memory manifests across different biological systems over different timescales, and a variety of underlying molecular mechanisms have been proposed. Here we investigate a non-epigenetic molecular mechanism underpinning how a single yeast cell can remember its recent environmental history to decide whether to enter the cell cycle. This “memories” is encoded by the phosphorylation level of the cell cycle inhibitor Whi5. G1 cyclin Cln3 senses environmental nutrient levels and promotes cell-cycle entry by phosphorylating and thus inactivating Whi5. We developed an optogenetic system whereby the nuclear localization of Cln3 can be rapidly and reversibly controlled by light. By monitoring cellular response to different temporal profiles of Cln3, we found that cell cycle entry requires the time duration of nuclear Cln3, supporting the model of “cellular memories”. Moreover, instead of the memory could last for the entire G1 phase as previously observed in glucose, we found Whi5 re-activates rapidly, with a similar half-time ∼ 12 min, in a variety of nutrient and stress conditions. Our results suggest yeast cell can shortly remember its recent environmental cues to decide whether to enter the cell cycle.
The specific features of the developing T cell compartment of the neonatal lung are a determinant of respiratory syncytial virus immunopathogenesis
Authors: Démoulins Thomas , Brügger Melanie , Zumkehr Beatrice , Oliveira Esteves Blandina I. , Mehinagic Kemal , Fahmi Amal , Borcard Loïc , Taddeo Adriano , Posthaus Horst , Benarafa Charaf , Ruggli Nicolas , Alves Marco P.
Published: August 2020

The human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants, possibly due to the specific features of the immature neonatal pulmonary immune system. Using the newborn lamb, a classical model of human lung development and a state-of-the-art model of RSV infection, we aimed to explore the role of cell-mediated immunity in RSV disease during early life. Remarkably, in healthy conditions, the developing T cell compartment of the neonatal lung showed major differences to that seen in the mature adult lung. The most striking observation being a high baseline frequency of bronchoalveolar IL-4-producing CD4 and CD8 T cells, which declined progressively over developmental age. RSV infection exacerbated this pro-type 2 environment in the bronchoalveolar space, rather than inducing a type 2 responseper se. Moreover, regulatory T cell suppressive functions occurred very early to dampen this pro-type 2 environment, rather than shutting them down afterwards, while γδ T cells dropped and failed to produce IL-17. Importantly, RSV disease severity was related to the magnitude of those unconventional bronchoalveolar T cell responses. These findings provide novel insights in the mechanisms of RSV immunopathogenesis in early life, and constitute a major step for the understanding of RSV disease severity.

AUTHOR SUMMARY

By using a state-of-the-art translational model with full accessibility to the small airways at defined early life periods, we provide an unpreceded characterization of the developing T cell compartment in the distal lungs of healthy and RSV-infected neonates. This process is highly dynamic and tightly regulated, characterized by colonizing T-cell subsets that synergize towards a narrow pro-tolerogenic immunological window. We believe our work constitutes a solid basis to clarify the age dependency of RSV immunopathogenesis, and should be considered in vaccine design, which remains challenging after five decades of effort.
Sub-lethal pyrethroid exposure and ageing lead to pronounced changes in gene expression in insecticide resistanceAnopheles coluzzii
Authors: Ingham V A , Brown F , Ranson H
Published: August 2020

Background

Malaria control is heavily reliant on the use of insecticides that target and kill the adult female Anopheline vector. The intensive use of insecticides of the pyrethroid class has led to widespread resistance in mosquito populations. The intensity of pyrethroid resistance in some settings in Africa means mosquitoes can contact bednets treated with this insecticide class multiple times with minimal mortality effects. However, the sublethal exposure may affect other traits controlling the vectorial capacity or fitness of the mosquito.

Results

Here we show that sublethal exposure of a highly resistantAnopheles coluzziipopulation originally from Burkina Faso to the pyrethroid deltamethrin results in large and sustained changes to transcript expression. We identify five clear patterns in the data showing changes to transcripts relating to: DNA repair, respiration, translation, ion transport and oxioreductase processes. Further, we highlight differential regulation of transcripts from detoxification families previously linked with insecticide resistance, in addition to clear down-regulation of the oxidative phosphorylation pathway both indicative of changes in metabolism post-exposure. Finally, we show that both ageing and diel cycle have major effects on known insecticide resistance related transcripts.

Conclusion

Sub-lethal pyrethroid exposure, ageing and the diel cycle results in large-scale changes in the transcriptome of the major malaria vectorAnopheles coluzzii. Our data strongly supports further phenotypic studies on how transcriptional changes such as reduced expression of the oxidative phosphorylation pathway or pyrethroid induced changes to redox state might impact key mosquito traits, such as vectorial capacity and life history traits.