bluuebunny/crossref_metadata_2025 huggingface dataset:
Cannabinoid Hyperemesis Syndrome and Hypophosphatemia in Adolescents
Authors: Nachnani Rahul , Hushagen Kimberly , Swaffield Thomas , Jhaveri Punit , Vrana Kent E. , Alexander Chandran P.
Published: September 2022

We report 3 adolescents with cannabis hyperemesis syndrome and recurrent hypophosphatemia complicating their clinical course with potential for significant consequences. They serve as reminders for providers to consider the diagnosis of cannabis hyperemesis syndrome and to monitor serum electrolytes closely in the setting of adolescent hyperemesis.
Effects of Initiating Raltegravir-Based Versus Efavirenz-Based Antiretroviral Regimens During Pregnancy on Weight Changes and Perinatal Outcomes: NICHD P1081
Authors: Coutinho Conrado Milani , Warshaw Meredith G. , Duarte Geraldo , Stek Alice , Violari Avy , Hofer Cristina B. , Deville Jaime G. , Ngocho James Samwel , Pilotto José Henrique , Correa Mario Dias , Shapiro David E. , Fuller Trevon L. , Chakhtoura Nahida , Mirochnick Mark , João Esaú C.
Published: September 2022

Background:

Integrase inhibitors have been associated with excess gestational weight gain that may lead to adverse pregnancy outcomes (APOs). This post hoc analysis of NICHD P1081 compared antepartum changes in weight and body mass index (BMI) in pregnant women initiating raltegravir- or efavirenz-based combined antiretroviral therapy (cART) and examined associations between rates of weight gain and APOs.

Setting:

NICHD P1081 enrolled antiretroviral-naive pregnant women living with HIV in the second and third trimester in Brazil, Tanzania, South Africa, Thailand, Argentina, and the United States.

Methods:

Two hundred eighty-one women enrolled between 20 and 31 gestational weeks were randomized to raltegravir- or efavirenz-based cART and followed for ≥4 weeks. A low rate of weight gain was defined as <0.18 kg/wk and high as >0.59 kg/wk. We compared weight gain and BMI increase between treatment arms using Kruskal–Wallis tests. Logistic regression was used to investigate the association between weight gain and APOs.

Results:

Raltegravir-based cART was associated with significantly higher antepartum weight gain (median 0.36 kg/wk versus 0.29 kg/wk, P = 0.01) and BMI increase (median 0.14 kg/m2/wk versus 0.11 kg/m2/wk, P = 0.01) compared with efavirenz-based treatment. Women on raltegravir had less low weight gain (18% versus 36%) and more high weight gain (21% versus 12%) (P = 0.001). Women with low weight gain were more likely than those with normal weight gain to have small for gestational age infants or a composite of APOs.

Conclusions:

A raltegravir-based antiretroviral regimen was associated with significantly higher antepartum rate of weight gain and BMI increase compared with efavirenz-based treatment in antiretroviral-naive pregnant women.
The impacts of anesthetic regimens on the middle cerebral artery occlusion outcomes in male rats
Authors: Mousavi Seyedeh Maryam , Karimi-Haghighi Saeideh , Chavoshinezhad Sara , Pandamooz Sareh , Belém-Filho Ivaldo Jesus Almeida , Keshavarz Somaye , Bayat Mahnaz , Hooshmandi Etrat , Rahimi Jaberi Abbas , Salehi Mohammad Saied , Borhani-Haghighi Afshin
Published: September 2022

The middle cerebral artery occlusion (MCAO) model was introduced more than 3 decades ago to simulate human stroke. Till now, it is the most common platform to investigate stroke-induced pathological changes as well as to discover new drugs and treatments. Induction of general anesthesia is mandatory to induce this model, and different laboratories are using various anesthetic drugs, which might affect MCAO results. Therefore, the present study was designed to compare the impacts of several widely used anesthetic regimens on the MCAO outcomes. Here, adult male rats were anesthetized by isoflurane inhalation, intraperitoneal injection of chloral hydrate (CH), intraperitoneal injection of ketamine-xylazine, or subcutaneous administration of ketamine-xylazine, then subjected to 30 min MCAO. Survival rate, body weight change, infarct size, as well as cognitive and neurological performance were evaluated up to 3 days after the surgery. Our findings revealed CH caused the highest, whereas subcutaneous ketamine-xylazine led to the lowest mortality. Meanwhile, there were no significant differences in the body weight loss, infarct size, cognitive impairments, and neurological deficits among the experimental groups. Based on the current results, we proposed that subcutaneous injection of ketamine-xylazine could be an effective anesthetic regimen in the rat model of MCAO with several advantages such as low mortality, cost-effectiveness, safety, ease of administration, and not requiring specialized equipment.
Coordinated expression of acetyl CoA synthetase and the ace operon enzymes in Escherichia coli in preparation for adaptation to acetate
Authors: El-Mansi Mansi , Afolabi Olumide , Phue Je-Nie , Shiloach Joseph
Published: September 2022

Successful adaptation of

Escherichia coli

to constant environmental challenges demands the operation of a wide range of regulatory control mechanisms, some of which are global, while others are specific. Here, we show that the ability of acetate-negative phenotype strains of

E. coli

devoid of acetate kinase (AK) and phosphotransacetylase (PTA) to assimilate acetate when challenged at the end of growth on acetogenic substrates is explicable by the co-expression of acetyl CoA-synthetase (AcCoA-S) and acetate permease (AP). Furthermore, mRNA transcript measurements for acs and aceA, together with the enzymatic activities of their corresponding enzymes, acetyl CoA synthetase (AcCoA-S) and isocitrate lyase (ICL), clearly demonstrate that the expression of the two enzymes is inextricably linked and triggered in response to growth rate threshold signal (0.4 h−1

±

0.03: n4). Interestingly, further restriction of carbon supply to the level of starvation led to the repression of acs (AcCoA-S), ackA (AK) and pta (PTA). Further, we provide evidence that the reaction sequence catalysed by PTA, AK and AcCoA-S is not in operation at low growth rates and that the reaction catalysed by AcCoA-S is not merely an ATP-dissipating reaction but rather advantageous, as it elevates the available free energy (ΔG°) in central metabolism. Moreover, the transcriptomic data reinforce the view that the expression of PEP carboxykinase is essential in gluconeogenic phenotypes.
Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture
Authors: Schurz Haiko , Naranbhai Vivek , Yates Tom A. , Gilchrist James J. , Parks Tom , Dodd Peter J. , Möller Marlo , Hoal Eileen G , Morris Andrew P. , Hill Adrian V.S. ,   the International Tuberculosis Host Genetics Consortium
Published: September 2022

The heritability of susceptibility to tuberculosis disease (TB) has been well recognized. Over one-hundred genes have been studied as candidates for TB susceptibility, and several variants were identified by genome-wide association studies (GWAS), but few replicate. We established the International Tuberculosis Host Genetics Consortium (ITHGC) to perform a multi-ancestry meta-analysis of GWAS including 14153 cases and 19536 controls of African, Asian, and European ancestry. Our analyses demonstrate a substantial degree of heritability (pooled polygenic h2=26.3% 95% CI 23.7-29.0%) for susceptibility to TB that is shared across ancestries, highlighting an important host genetic influence on disease. We identified one global host genetic correlate for TB at genome-wide significance (p<5×10−8) in the human leukocyte antigen (HLA)-II region (rs28383206, p-value = 5.2×10−9). These data demonstrate the complex shared genetic architecture of susceptibility to TB and the importance of large scale GWAS analysis across multiple ancestries experiencing different levels of infection pressures.
Comparison of influenza and COVID-19 hospitalizations in British Columbia, Canada: a population-based study
Authors: Setayeshgar Solmaz , Wilton James , Sbihi Hind , Zandy Moe , Janjua Naveed Z , Choi Alexandra , Smolina Kate
Published: September 2022

Objective

To compare the population rate of COVID-19 and influenza hospitalizations by age, COVID-19 vaccine status and pandemic phase.

Design

Observational retrospective study

Setting

Residents of British Columbia (population 5.3 million), Canada

Participants

Hospitalized patients due to COVID-19 or historical influenza

Main outcome measures

This population based study in a setting with universal healthcare coverage, used COVID-19 case and hospital data for COVID-19 and influenza. Admissions were selected from March 2020 to February 2021 for the annual cohort and the first 8 weeks of 2022 for the peak cohort of COVID-19 (Omicron era). Influenza annual and peak cohorts were from three years with varying severity: 2009/10, 2015/16, and 2016/17. We estimated hospitalization rates per 100,000 population by age group.

Results

Similar to COVID-19 with median age 66 (Q1-Q3 44-80), influenza 2016/17 mostly affected older adults, with median age 78 (64-87). COVID-19 and influenza 2016/17 hospitalization rate by age group were “J” shaped. The rates for mostly unvaccinated COVID-19 patients in 2020/21 in the context of public health restrictions were significantly higher than influenza among individuals 30 to 69 years of age, and comparable to a severe influenza year (2016/17) among 70+. In early 2022 (Omicron peak), rates primarily due to COVID-19 among vaccinated adults were comparable with influenza 2016/17 in all age groups while rates among unvaccinated COVID-19 patients were still higher than influenza among 18+. In the pediatric population, COVID-19 hospitalization rates were similar to or lower than influenza.

Conclusions

Our paper highlighted the greater population-level impact of COVID-19 compared with influenza in terms of adult hospitalizations, especially among those unvaccinated. However, influenza had greater impact than COVID-19 among <18 regardless of vaccine status or the circulating variant.
Making the Match or Breaking it? Values, Perceptions, and Obstacles of Trainees Applying into Physician-Scientist Training Programs
Authors: Pepin M.E. , Kamal Y. , Reisman B.J. , Rockman M.E. , Waller J.P.
Published: September 2022

Background

Replenishing the physician-scientist workforce remains a central mission of medical education, but the hemorrhaging of qualified trainees threatens the physician-scientist role. Among the barriers facing physician-scientists is the game-like model of residency matching, which applies several flawed assumptions regarding the comparability of applicant qualifications, cohort size, and the institutional breadth of applicants’ training needs.

Methods

The current report summarizes the collective views and experiences of physician-scientist trainees following the 2021-2022 application cycle of physician-scientist training programs (PSTPs). We obtained survey-based feedback by 27 PSTP applicants from 17 U.S. medical universities, among whom 85% matched into a PSTP.

Results

93% PSTP applicants recognized “scientific community” as the most important feature of postgraduate training, whereas gender-specific worth was assigned to institutional aspects of personal and/or family support. 65% of respondents found “waiting for interviews” as the most stressful aspect of the application cycle. Half of the survey respondents perceived at least one NRMP policy violation by a PSTP, most of which occurred during post-interview communication. 93% of respondents were contacted by a PSTP following interviews, and one-third admitted to feeling pressured into sharing their ranking preferences.

Conclusion

Overall, we believe the values and needs of physician-scientist trainees are poorly represented by the current PSTP selection framework, including inconsistent timelines and communication throughout the process. We propose a series of modifications that, if implemented, would better equip applicants to gauge programs according to the clinical, scientific, and academic communities that we seek to join as academic physician-scientists.
Resilience and resistance to Alzheimer’s disease-associated neuropathological substrates in centenarians: an age-continuous perspective
Authors: Zhang Meng , Ganz Andrea B. , Rohde Susan , Rozemuller Annemieke J. M. ,   Netherlands Brain Bank, Reinders Marcel J.T. , Scheltens Philip , Hulsman Marc , Hoozemans Jeroen J.M. , Holstege Henne
Published: September 2022

INTRODUCTION

With increasing age, neuropathology associated with Alzheimer’s disease (AD) accumulates in brains of cognitively healthy individuals: are they resilient or resistant against AD-associated neuropathologies?

METHODS

In 85 centenarian brains, we correlated NIA-Amyloid stages, Braak-NFT stages and CERAD-NP scores with cognitive performance determined close to death (MMSE). We assessed centenarian brains in context of 2,131 brains from AD patients, non-AD demented and non-demented individuals (age-range 16-100+ years).

RESULTS

With age, brains from non-demented individuals reached NIA-Amyloid and Braak-NFT stages as observed in AD patients, while CERAD-NP scores remained lower. In centenarians, NIA-Amyloid stages varied (22.4% had the highest stage 3), Braak-NFT stages rarely exceeded IV (5.9% had stage V), and CERAD-NP scores rarely exceeded 2 (4.7% had score 3); within these distributions, we observed no correlation with MMSE (NIA-Amyloid: P=0.60; Braak-NFT: P=0.08; CERAD-NP: P=0.16).

DISCUSSION

Cognitive health can be maintained despite the accumulation of high levels of AD-related neuropathological substrates.
Climate Change and Eco-Anxiety in the US: Predictors, Correlates, and Potential Solutions
Authors: Kricorian Katherine , Turner Karin
Published: September 2022

Climate change has many adverse human health effects, including increased anxiety. However, eco-anxiety may also motivate climate action. An online survey was developed and distributed to examine factors associated with eco-anxiety. Logistic regression analysis showed that significant predictors of eco-anxiety include greater media exposure to climate change information, more frequent discussions about climate change with friends and family, the perception that climate change will soon impact one personally, being younger, and being female. Additional analyses suggested that ecoanxiety was associated with a range of both positive and negative emotional impacts including motivation, interest, sadness, and tension. Eco-anxiety was also associated with greater likelihood to engage in environmental behaviors such as recycling. Volunteering for environmental causes and accessing straightforward information with less scientific jargon were found to have particular potential for anxiety reduction among the eco-anxious. The research suggests practical strategies to reduce eco-anxiety while retaining engagement in mitigating climate change.
Rates of osmotic demyelination after rapid correction of sodium in hyponatremia, a multicenter cohort study of patients hospitalized with hyponatremia
Authors: MacMillan Thomas E , Shin Saeha , Topf Joel , Kwan Janice , Weinerman Adina , Tang Terence , Raissi Afsaneh , Koppula Radha , Razak Fahad , Verma Amol A , Fralick Michael
Published: September 2022

Background

Osmotic demyelination syndrome (ODS) is a rare but devastating complication of rapid correction of hyponatremia. Current guidelines recommend limiting the sodium correction rate to no more than 8 mmol/L per 24 hours, but this is based on expert opinion and small observational studies.

Methods

We conducted a multicenter cohort study of patients admitted into hospital with hyponatremia at five academic hospitals in Toronto between April 1, 2010 and December 31, 2019. We identified all adult patients with hyponatremia (sodium <130 mmol/L) based on their initial serum sodium measured on presentation to the emergency department. The primary outcome was the rate of ODS. ODS cases were identified using medical record review and neuroimaging results. The secondary outcome was the rate of rapid correction of sodium (>8 mmol/L in any 24-hour period).

Results

Our cohort included 21182 hospitalizations with hyponatremia. Approximately 50% were women, the average age was 68 years, and mean initial sodium was 124.6 mmol/L (SD 4.6) including 13.1% with sodium <120 mmol/L. Overall, rapid correction of sodium occurred in 3438 (17.9%) admissions. Despite the fact that 3438 experienced rapid correction, there were only 12 cases of ODS among our 21182 hospitalizations with hyponatremia. Cases of ODS had a markedly lower initial serum sodium (110.7 vs. 124.6 mmol/L), were younger (50 years vs 68 years), were more likely to have alcohol use disorder, and were more likely to have hypokalemia (58% vs 14%) compared to those without ODS.

Conclusions

In the large multicenter study of patients with hyponatremia, “rapid” overcorrection was common (N=3438, 17.9%) but ODS was rare (N=12, 0.06%). The initial serum sodium was markedly lower for those with ODS compared to those without. Taken together, these results suggest that the severity of hyponatremia is a more important risk factor for ODS then the rate of correction.
Evaluation of the efficacy of using indocyanine green associated with fluorescence in sentinel lymph node biopsy
Authors: da Silva Sá Rafael , Von Ah Rodrigues Raquel Fujinohara , Antônio Bugalho Luiz , da Silva Suelen Umbelino , Pinto Nazário Afonso Celso
Published: September 2022

Introduction: Sentinel lymph node biopsy is the established technique in the axillary staging of patients with early breast cancer without clinical axillary involvement. Three techniques are widely used globally for the detection of sentinel lymph nodes: patent blue; the radiopharmaceutical technetium 99 with the use of the gamma probe; and the combination of these two techniques. Objectives: To evaluate the sentinel lymph node detection rate with an innovative technique: indocyanine green associated with fluorescence in breast cancer patients, its comparison with the other methods (patent blue and combined patent blue + indocyanine green). Methods: Ninety-nine patients were subdivided into three arms with 33 patients, one arm was submitted to the sentinel lymph node technique using patent blue, the other indocyanine green, and the third a combination of the two dyes. Results: The accuracy rate in the identification of the sentinel lymph node was 78.8% with the use of patent blue, 93.9% with indocyanine green and 100% with patent blue + indocyanine green. The combined group identified mainly two sentinel nodes (48.5%); however, the other groups more commonly identified only one sentinel lymph node. The mean time of sentinel lymph node identification was 20.6 minutes among patients submitted to the traditional dye, 8.6 minutes in the indocyanine green arm and 10 minutes in the combination of the two methods (P<0.001). The mean surgery time was 69.4 minutes with patent blue, 55.1 minutes with indocyanine green and 69.4 minutes with the combination (P<0.001). Conclusions: The sentinel lymph node detection rate by fluorescence with the use of indocyanine green was considered effective. The comparison of the sentinel lymph node detection rate between the use of patent blue, indocyanine green and patent blue + indocyanine green (combined) revealed statistically significant differences (p=0.030), with the combined method being the most effective.
Medial prefrontal transcranial alternating current stimulation for apathy in Huntington’s disease
Authors: Davis Marie-Claire , Hill Aron T. , Fitzgerald Paul B. , Bailey Neil W. , Sullivan Caley , Stout Julie C. , Hoy Kate E.
Published: September 2022

We investigated the effects of transcranial alternating current stimulation (tACS) targeted to the bilateral medial prefrontal cortex (mPFC) and administered at either delta or alpha frequencies, on brain activity and apathy in people with Huntington’s disease (HD) (n = 17). Neurotypical controls (n = 20) were also recruited for comparison. All participants underwent three 20-minute sessions of tACS; one session at alpha frequency (Individualised Alpha Frequency (IAF), or 10Hz when an IAF was not detected); one session at delta frequency (2Hz); and a session of sham tACS. Participants completed the Monetary Incentive Delay (MID) task with simultaneous recording of EEG immediately before and after each tACS condition. The MID task presents participants with cues signalling potential monetary gains or losses that increase activity in key regions of the cortico-basal ganglia-thalamocortical networks, with dysfunction of the latter network being implicated in the pathophysiology of apathy. We used the P300 and Contingent Negative Variation (CNV) event-related potentials elicited during the MID task as markers of mPFC engagement. HD participants’ CNV amplitude significantly increased in response to alpha-tACS, but not delta-tACS or sham. Neurotypical controls’ P300 and CNV were not modulated by any of the tACS conditions, but they did demonstrate a significant decrease in post-target response times following alpha-tACS. We present this as preliminary evidence of the ability of alpha-tACS to modulate brain activity associated with apathy in HD.
Normal values for native T1 at 1.5T in the pericardial fluid of healthy volunteers
Authors: Thalén Simon , Ramos Joao G , Engblom Henrik , Sigfridsson Andreas , Sörensson Peder , Ugander Martin
Published: September 2022

Background

T1 mapping cardiovascular magnetic resonance (CMR) imaging has been used to characterize pericardial effusions. The aim of this study was to measure pericardial fluid native T1 values in healthy volunteers to establish normal values.

Methods

Prospectively recruited volunteers (n=30) underwent CMR at 1.5T and native T1 maps were acquired using a MOLLI 5s(3s)3s acquisition scheme. A volume of pericardial fluid was imaged in a short-axis slice and in a slice perpendicular to the short-axis orientation. A reliable measurement had a region of interest size >10 mm2, coefficient of variation <10 %, and a relative difference <5 % between the two slice orientations.

Results

In 26/30 (87%) of volunteers, there was a sufficient amount of pericardial fluid to enable reliable measurement. Native T1 of pericardial fluid was 3262±163 (95% normal limits 2943–3581ms), and did not differ in the perpendicular slice orientation (3267±173 ms, p=0.75), due to sex (female 3311±177 vs. male 3220±142 ms, p=0.17), or age (R2=0.07, p=0.2)

Conclusions

This study shows that T1 values can be reliably measured in the pericardial fluid of healthy volunteers. It is the first to report normal reference ranges for T1 values at 1.5T in the pericardial fluid of healthy volunteers.
Agricultural land use and lake morphology explain substantial variation in water quality across Canada
Authors: Schacht Joe R. Sánchez , MacKeigan Paul W. , Taranu Zofia E. , Huot Yannick , Gregory-Eaves Irene
Published: September 2022

Despite decades of research and mitigation efforts, declines in freshwater quality resulting from anthropogenic nutrient input remain a persistent issue worldwide. Canada has the greatest number of freshwater lakes in the world, yet we have a limited understanding of the magnitude and scale at which most lakes have been affected by human activities, namely Land Use/Land Cover (LULC) alterations. In response, the NSERC Canadian Lake Pulse Network has compiled the first nationwide systematic database of lake quality metrics by surveying 664 lakes across 12 ecozones over three years. To assess the influence of catchment development on water quality and its spatial variation, we built models quantifying the association between watershed LULC and water quality. We found that agricultural and urban land use explained the greatest proportion of variation in water quality among LULC categories (R2= 0.20–0.29). Overall, our study highlights that drivers of water quality are similar across regions; however, baseline conditions vary, so freshwater ecosystem management strategies must consider their geographic context to better predict where water quality thresholds will be surpassed.
PNuts: Global spatio-temporal database of plant nutritional properties
Authors: Berzaghi Fabio , Bretagnolle Francois , Ratshikombo Zwanga , Abdallah Alya Ben
Published: September 2022

Plant nutritional properties (crude protein, fibers, minerals, and carbohydrates) and chemical defenses (tannins and phenols) are key traits determining food quality and feeding preferences of animals and humans. Plant nutritional properties are also relevant to crop production and livestock. Here we present PNuts, a global database containing > 1000 species and > 13,000 records of nutritional properties of different plant organs complete with location and time of collection (year/month/season). Species include crops and wild plants and are classified in six functional groups: legumes, herbs, grasses, lianas, shrubs and trees. Plant organs include leaf, fruit, seed, stem, twigs, flower, root, and bark. PNuts data can be used as inputs for ecological analyses and model parametrization requiring large amounts of data. PNuts provides an important tool to better understand the importance of nutritional properties in plant eco-physiology and the implications for humans and animals’ food quality and plant-animal interactions in a context of global changes.
Environmentally robustcis-regulatory changes underlie rapid climatic adaptation
Authors: Ballinger Mallory A. , Mack Katya L. , Durkin Sylvia M. , Riddell Eric A. , Nachman Michael W.
Published: September 2022

Changes in gene expression are proposed to play a major role in adaptive evolution. While it is known that gene expression is highly sensitive to the environment, very few studies have determined the influence of genetic and environmental effects on adaptive gene regulation in natural populations. Here, we utilize allele-specific expression to characterizecisandtransgene regulatory divergence in temperate and tropical house mice in two metabolic tissues under two thermal conditions. First, we show that gene expression divergence is pervasive between populations and across thermal conditions, with roughly 5-10% of genes exhibiting genotype-by-environment interactions. Second, we found that most expression divergence was due tocis-regulatory changes that were stable across temperatures. In contrast, patterns of expression plasticity were largely attributable totrans-effects, which showed greater sensitivity to temperature. Nonetheless, we discovered a small subset of temperature-dependentcis-regulatory changes, thereby identifying loci underlying expression plasticity. Finally, we performed scans for selection in wild house mice to identify genomic signatures of rapid adaptation. Genomic outliers were enriched in genes with evidence forcis-regulatory divergence. Notably, these genes were associated with phenotypes that affected body weight and metabolism, suggesting thatcis-regulatory changes are a possible mechanism for adaptive body size evolution between populations. Our results show that gene expression plasticity, largely controlled intrans, may facilitate the colonization of new environments, but that evolved changes in gene expression are largely controlled incis, illustrating the genetic and non-genetic mechanisms underlying the establishment of populations in new environments.

Significance Statement

Gene expression variation is shaped by both genetic and environmental effects, yet these two factors are rarely considered together in the context of adaptive evolution. We studied environmental influences on gene regulatory evolution in temperate and tropical house mice in cold and warm laboratory environments. We discovered that genetic effects in the form ofcis-regulatory divergence were pervasive and largely insensitive to the environment. Many of these genetic effects are under selection and are associated with genes that affect body size, suggestingcis-regulatory changes as a possible mechanism for adaptive body size evolution. We also discovered manytrans-effects controlling expression plasticity, demonstrating the importance of both genetic and non-genetic changes associated with adaptation over short timescales (a few hundred generations).
Chromosomal and gonadal sex drive sex differences in lipids and hepatic gene expression in response to hypercholesterolemia and statin treatment
Authors: Wiese Carrie B. , Agle Zoey W. , Zhang Peixiang , Reue Karen
Published: September 2022

Background

Biological sex impacts susceptibility and presentation of cardiovascular disease, which remains the leading cause of death for both sexes. To reduce cardiovascular disease risk, statin drugs are commonly prescribed to reduce circulating cholesterol levels through inhibition of cholesterol synthesis. The effectiveness of statin therapy differs between individuals with a sex bias in the frequency of adverse effects. Limited information is available regarding the mechanisms driving sex-specific responses to hypercholesterolemia or statin treatment.

Methods

Four core genotypes mice (XX and XY mice with ovaries and XX and XY mice with testes) on a hypercholesteremic Apoe−/− background were fed a chow diet without or with simvastatin for 8 weeks. Plasma lipid levels were quantified and hepatic differential gene expression was evaluated with RNA-sequencing to identify the independent effects of gonadal and chromosomal sex.

Results

In a hypercholesterolemic state, gonadal sex influenced the expression levels of more than 3000 genes, and chromosomal sex impacted expression of nearly 1400 genes, which were distributed across all autosomes as well as the sex chromosomes. Gonadal sex uniquely influenced the expression of ER stress response genes, whereas chromosomal and gonadal sex influenced fatty acid metabolism gene expression in hypercholesterolemic mice. Sex-specific effects on gene regulation in response to statin treatment included a compensatory upregulation of cholesterol biosynthetic gene expression on mice with XY chromosome complement, regardless of presence of ovaries or testes.

Conclusion

Gonadal and chromosomal sex have independent effects on the hepatic transcriptome to influence different cellular pathways in a hypercholesterolemic environment. Furthermore, chromosomal sex in particular impacted the cellular response to statin treatment. An improved understanding of how gonadal and chromosomal sex influence cellular response to disease conditions and in response to drug treatment is critical to optimize disease management for all individuals.
HUMAN FECAL BILE ACID ANALYSIS AFTER INVESTIGATIONAL MICROBIOTA-BASED LIVE BIOTHERAPEUTIC DELIVERY FOR RECURRENT CLOSTRIDIOIDES DIFFICILE INFECTION
Authors: Papazyan Romeo , Ferdyan Nicky , Srinivasan Karthik , Gonzalez Carlos , Shannon Bill , Blount Ken , Fuchs Bryan C.
Published: September 2022

Intestinal microbiome disruption is associated with recurrent Clostridioides difficile infection (rCDI), which poses a high risk of morbidity and mortality. Microbiome-based therapeutics are increasingly evaluated as a strategy to reduce rCDI, and their proposed mechanisms include restoration of the microbiota and microbiota-mediated functions, including bile acid (BA) metabolism. This study reports the development of a highly quantitative and sensitive assay for targeted metabolomic assessment of bile acids, and the application of the assay to profile bile acid composition in a Phase 2 trial of the investigational microbiota-based live biotherapeutic RBX2660 for reduction of rCDI (PUNCH CD2; NCT02299570). Participants were asked to provide stool samples before and up to 24 months after treatment. A liquid chromatography tandem mass spectrometry method was developed to extract and quantify 35 BAs from a total of 113 participant stool samples from 27 rCDI participants treated with RBX2660 in the double-blinded, placebo-controlled clinical trial. The results demonstrate a high-confidence assay as represented by sensitivity, linearity, accuracy, and precision of the output measurements of BAs. When the assay was utilized to assess stool samples from the clinical trial participants, primary BAs were the dominant BA species at baseline, consistent with the expected loss of commensals after broad-spectrum antibiotic treatment. As early as 7 days after RBX2660 administration, there was a significant drop in primary BAs concurrent with increased secondary BAs, and this profile was sustained through 24 months after RBX2660 administration. Taken together, we describe a robust assay that demonstrates altered BA metabolism associated with RBX2660 administration, shifting towards a profile that is consistent with a healthier BA profile and clinical response.
The effect of variation of individual infectiousness on SARS-CoV-2 transmission in households
Authors: Tsang Tim K. , Huang Xiaotong , Wang Can , Chen Sijie , Yang Bingyi , Cauchemez Simon , Cowling Benjamin J.
Published: September 2022

Quantifying variation of individual infectiousness is critical to inform disease control. Previous studies reported substantial heterogeneity in transmission of many infectious diseases (including SARS-CoV-2). However, those results are difficult to interpret since the number of contacts is rarely considered in such approaches. Here, we analyze data from 17 SARS-CoV-2 household transmission studies conducted in periods dominated by ancestral strains, in which the number of contacts was known. By fitting individual-based household transmission models to these data, accounting for number of contacts and baseline transmission probabilities, the pooled estimate suggests that the 20% most infectious cases have 3.1-fold (95% confidence interval: 2.2-4.2 fold) higher infectiousness than average cases, which is consistent with the observed heterogeneity in viral shedding. Household data can inform the estimation of transmission heterogeneity, which is important for epidemic management.

One Sentence Summary

In this study, variation of individual infectiousness is quantified. Potential sources of such variation, particularly heterogeneity of viral shedding is discussed.
Antibody and memory B cell responses to the dengue virus NS1 antigen in individuals with varying severity of past infection
Authors: Ramu Shyrar Tanussiya , Dissanayake Madushika , Jeewandara Chandima , Bary Farha , Harvie Michael , Gomes Laksiri , Wijesinghe Ayesha , Ogg Graham S. , Malavige Gathsaurie Neelika
Published: September 2022

Background

To further understand the role of NS1 specific antibodies (Abs) in disease pathogenesis, we compared neutralizing antibody levels (Nabs), NS1-Ab levels, IgG antibody sub-class profiles and NS1 specific memory B cell responses (Bmems) in individuals, with varying severity of past dengue.

Methods

Nabs (Neut50 titres) were assessed using Foci Reduction Neutralization Test (FRNT) and in-house ELISAs were used to assess NS1-Abs and NS1-Ab subclasses for all four DENV serotypes in individuals with past DF (n=22), those with past DHF (n=14) and seronegative (SN) individuals (n=7). B cell ELISpot assays were used to assess NS1-specific Bmem responses.

Results

15/22 (68.18%) individuals with past DF and 9/14 (64.29%) individuals with past DHF had heterotypic infections. Neut50 titres were found to be significantly higher for DENV1 than DENV2 (p=0.0006) and DENV4 (p= 0.0127), in those with past DHF, whereas there was no significant difference in titres was seen for different DENV serotypes in those with past DF. Overall NS1-Ab to all serotypes and NS1-specific IgG1 responses for DENV1, 2 and 4 serotypes were significantly higher in those with past DHF than individuals with past DF. Those with past DHF also had higher IgG1 than IgG3 for DENV1 and DENV3, whereas no differences were seen in those with past DF. Over 50% of those with past DF or DHF had NS1-specific Bmem responses to >2 DENV serotypes. There was no difference in the frequency of Bmem responses to any of the DENV serotypes between individuals with past DF and DHF. Although the frequency of Bmem responses to DENV1 corelated with DENV1 specific NS1-Abs levels (Spearman r=0.35, p=0.02), there was no correlation with other DENV serotypes.

Conclusions

We found that those with past DF had broadly cross reactive Nabs, while those with past DHF had higher NS1-Ab responses possibly with a different functionality profile than those with past DF. Therefore, it would be important to further evaluate the functionality of NS1-specific antibody and Bmem responses to find out the type of antibody repertoire that is associated with protection against severe disease.
Longitudinal IgG antibody responses to Plasmodium vivax blood-stage antigens during and after acute vivax malaria in individuals living in the Brazilian Amazon
Authors: Tashi Tenzin , Upadhye Aditi , Kundu Prasun , Wu Chunxiang , Menant Sébastien , Soares Roberta Reis , Ferreira Marcelo Urbano , Longley Rhea J. , Mueller Ivo , Hoang Quyen Q. , Tham Wai-Hong , Rayner Julian C. , KG Scopel Kézia , Lima Junior Josué C. , Tran Tuan M.
Published: September 2022

Background

To make progress towards malaria elimination, a highly effective vaccine targeting Plasmodium vivax is urgently needed. Evaluating the kinetics of natural antibody responses to vaccine candidate antigens after acute vivax malaria can inform the design of serological markers of exposure and vaccines.

Methodology/Principal Findings

The responses of IgG antibodies to 9 P. vivax vaccine candidate antigens were evaluated in longitudinal serum samples from Brazilian individuals collected at the time of acute vivax malaria and 30, 60, and 180 days afterwards. Antigen-specific IgG correlations, seroprevalence, and half-lives were determined for each antigen using the longitudinal data. Antibody reactivity against Pv41 and PVX_081550 strongly correlated within each of the four time points. The analysis identified robust responses in terms of magnitude and seroprevalence against Pv41 and PvGAMA at 30 and 60 days. Among the 8 P. vivax antigens demonstrating >50% seropositivity across all individuals, antibodies specific to PVX_081550 had the longest half-life 100 days (95% CI, 83—130 days), followed by PvRBP2b (91 days; 95% CI, 76—110 days) and Pv12 (82 days; 95% CI, 64—110 days).

Conclusion/Significance

This study provides an in-depth assessment of the kinetics of antibody responses to key vaccine candidate antigens in Brazilians with acute vivax malaria. Follow-up studies are needed to determine whether the longer-lived antibody responses induced by natural infection are effective in controlling blood-stage infection and mediating clinical protection.

AUTHOR SUMMARY

To successfully eliminate malaria, highly effective vaccines against the two major human malaria species, Plasmodium falciparum and Plasmodium vivax, will be needed. Vaccines against the blood form of malaria generate antibodies that target specific proteins on the Plasmodium parasite to reduce its replication within the host. Studying the antibody response after natural malaria infection can help identify blood markers of parasite exposure and also shed light on the magnitude and longevity of antibodies to vaccine candidate proteins. We performed a study to determine the frequency, magnitude, and longevity of natural antibody responses against nine P. vivax vaccine candidate proteins in patients with vivax malaria in Brazil. These proteins were selected based on prior studies demonstrating that antibodies against these proteins were either associated with protection against vivax malaria or have been tested as blood markers of recent infection with vivax malaria. We identify specific vivax proteins that produce more frequent and longer-lived antibody responses in this population.
Characterisation and Genetic Architecture of Major Depressive Disorder Subgroups Defined by Weight and Sleep Changes
Authors: Marshall Sally , Adams Mark J , Evans Kathryn L , Strawbridge Rona J , Campbell Archie , Hayward Caroline , McIntosh Andrew , Thomson Pippa
Published: September 2022

Major depressive disorder, MDD, is highly heterogeneous and thus subgroups with different underlying aetiologies have been postulated. The aim of this work is to further characterise depression subgroups defined using sleep and weight changes. Probable lifetime MDD cases (n = 26,662) from the UK Biobank were stratified into three subgroups defined by self-reported weight and sleep changes during worst episode: (i) increased weight and sleep (↑WS), (ii) decreased weight and sleep (↓WS) and (iii) the remaining uncategorised individuals. Analyses compared the depression characteristics, mental health scores, neurological and inflammatory comorbidities and genetic architecture between subgroups and with 50,147 controls from UK Biobank. In contrast to ↑WS depression, ↓WS depression had a higher age of onset and lower proportion reporting countless or continuous episodes compared to uncategorised individuals. The ↓WS depression also had a higher wellbeing score than the other subgroups. Analyses of subgroup comorbidities identified a novel association between ↑WS depression and epilepsy. Subgroup-specific GWAS identified three genome-wide significant loci associated with ↑WS in genes previously associated with immunometabolic traits and response to anticonvulsants. The effect of BMI adjustment in the genetic analyses of the subgroups and using broader weight-only definitions were also examined. The findings provide further evidence for differences in the characteristics and genetic architecture of depression subgroups defined by sleep and weight change and highlight the importance of dividing non-↑WS individuals into ↓WS and uncategorised subgroups in analyses, as ↓WS symptoms may identify a more acute depression subgroup.
Prognostic association of immunoproteasome expression in solid tumours is governed by the immediate immune environment
Authors: Kumar Rahul , Dhaka Bhavya , Sahoo Sarthak , Jolly Mohit Kumar , Sabarinathan Radhakrishnan
Published: September 2022

Induction of immunoproteasome (IP) expression in tumour cells can enhance antigen presentation and immunogenicity. Recently, overexpression of IP genes has been associated with better prognosis and response to immune checkpoint blockade (ICB) therapies in melanoma. However, the extent of this association in other solid tumour types and how that is influenced by tumour cell-intrinsic and cell-extrinsic factors remains unclear. Here, we address this by exploring the gene expression patterns from available bulk and single-cell transcriptomic data of primary tumours. We find that IP expression positively correlates with the constitutive proteasome (CP) across multiple tumour types. Furthermore, tumours with high IP expression exhibit cytotoxic immune cell infiltration and upregulation of interferon-gamma and TNF-α pathways in tumour cells. However, the association of IP expression with overall survival (in TCGA cohort) and response to ICB therapy (in non-TCGA cohorts) is tumour-type specific and is greatly influenced by immune cell infiltration patterns. This emphasises the need for considering immune cell infiltration patterns, along with IP expression, to be used as a prognostic biomarker to predict overall survival or response to ICB treatment in solid tumours, besides melanoma.
Cryo-EM structures of the Mycobacterium 50S subunit reveal an intrinsic conformational dynamics of 23S rRNA helices
Authors: Baid Priya , Sengupta Jayati
Published: September 2022

Pathogenic organisms encounter a broad range of stress conditions within host micro-environment and adopt variety of mechanisms to stall protein translation and protect translational machinery. Structural investigations of the ribosomes isolated from pathogenic and non-pathogenic Mycobacterium species have identified several mycobacteria-specific structural features of ribosomal RNA and proteins. Here, we report a growth phase-dependent conformational switch of domain III and IV helices (H54a and H67-H71) of the mycobacterium 23S rRNA. Cryo-electron microscopy (cryo-EM) structures (∼3-4 Å) of the M. smegmatis (Msm) 50S ribosomal subunit of log-phase manifested that, while H68 possesses the usual stretched conformation in one of the maps, another one exhibits an unprecedented conformation of H68 curling onto a differently oriented H69, indicating an intrinsic dynamic nature of H68. Remarkably, a 2.8Å cryo-EM map of the Msm stationary-state 50S subunit unveiled that H68 preferably acquires folded conformation in this state (closely mimicking dormant state). Formation of a bulge-out structure by H68 at the inter-subunit surface of the stationary-state 50S subunit due to the rRNA conformational changes prevents association with 30S subunit and keeps an inactive pool of the 50S subunit representing a ribosome-protection mechanism during dormancy. Evidently, this dynamic nature of H68 is an integral part of the cellular functions of mycobacterium ribosome, and irreversibly arresting H68 flexible motion would stall ribosome function. Thus, this conformational change may be exploited to develop anti-mycobacterium drug molecules.

Significant statement

Bacteria utilize several mechanisms to reprogram the protein synthesis machinery so that their metabolism is reduced in the dormant state. Mycobacteria are capable of hiding themselves in a dormant state during physiological stresses. Our study identified a hitherto-unknown folded conformation of the helix 68 (H68) of domain IV of mycobacterial 23S rRNA, which is predominantly present in the stationary state (closely mimicking latency). Our results suggest that this conformational transition is instrumental in keeping an inactive pool of the 50S subunit in the stationary state. Irreversibly arresting such conformational dynamics would lead to protein synthesis shutdown in mycobacteria during dormancy. Thus, this folded conformation of H68 offers an excellent therapeutic intervention site to treat mycobacterial latent infection.

Highlights

Identification of a hitherto-unknown folded conformation of the helix 68 of mycobacterial 23S rRNA

H68 conformation transition represents a new ribosome protection mechanism in dormant mycobacteria

The conformational switch of mycobacterial H68 offers an excellent therapeutic intervention site
The seeker R package: simplified fetching and processing of transcriptome data
Authors: Schoenbachler Joshua L. , Hughey Jacob J.
Published: September 2022

Transcriptome data have become invaluable for interrogating biological systems. Preparing a transcriptome dataset for analysis, particularly an RNA-seq dataset, entails multiple steps and software programs, each with its own command-line interface (CLI). Although these CLIs are powerful, they often require shell scripting for automation and parallelization, which can have a high learning curve, especially when the details of the CLIs vary from one tool to another. However, many individuals working with transcriptome data are already familiar with R due to the plethora and popularity of R-based tools for analyzing biological data. Thus, we developed an R package called seeker for simplified fetching and processing of RNA-seq and microarray data. Seeker is a wrapper around various existing tools, and provides a standard interface, simple parallelization, and detailed logging. Seeker’s primary output—sample metadata and gene expression values based on Entrez or Ensembl Gene IDs—can be directly plugged into a differential expression analysis. To maximize reproducibility, seeker is available as a standalone R package and in a Docker image that includes all dependencies, both of which are accessible at https://seeker.hugheylab.org.
Arsenic induced alteration of neuroregulatory gene expression in Macrobrachium lamarrei: a neurotoxicological approach to grooming behaviour
Authors: Munshi Chayan , Mukhuty Alpana , Bandyopadhyay Arindam , Bhowmik Arpan Dey , Mondal Paritosh , Shaw Pallab , Bhattacharya Shelley
Published: September 2022

Arsenic is a highly active neuromodulator which can induce neurological disorders in invertebrates. The present study is a neurotoxicological approach to assess the toxicity of arsenic trioxide, where grooming behaviour is considered as a behavioural biomarker of arsenic induced stress in the prawns. Non-lethal exposure to arsenic trioxide, manipulates the expression pattern of neuroregulatory marker genes in a freshwater prawn, Macrobrachium lamarrei and induces symptoms of autism spectrum disorders (ASDs) in a short time.