bluuebunny/crossref_metadata_2025 huggingface dataset:
A glucagon-like peptide-1 receptor antagonist reduces the insulin response to a glycemic meal in ponies
Authors: de Laat Melody A , Fitzgerald Danielle M , Harris Patricia A , Bailey Simon R
Published: December 2023

High plasma concentrations of insulin can cause acute laminitis. Ponies and horses with insulin dysregulation (ID) exhibit marked hyperinsulinemia in response to dietary hydrolyzable carbohydrates. Glucagon-like peptide-1 (GLP-1), an incretin hormone released from the gastrointestinal tract, enhances insulin release, and is increased postprandially in ponies with ID. The aim of this study was to determine whether blocking the GLP-1 receptor reduces the insulin response to a high glycemic meal. Five adult ponies were adapted to a cereal meal and then given two feed challenges 24 h apart of a meal containing 3 g/kg BW micronized maize. Using a randomized cross-over design all ponies received both treatments, where one of the feeds was preceded by the IV administration of a GLP-1 receptor blocking peptide, Exendin-3 (9-39) amide (80 µg/kg), and the other feed by a sham treatment of peptide diluent only. Blood samples were taken before feeding and peptide administration, and then at 30-min intervals via a jugular catheter for 6 h for the measurement of insulin, glucose, and active GLP-1. The peptide and meal challenge caused no adverse effects, and the change in plasma glucose in response to the meal was not affected (P = 0.36) by treatment: peak concentration 9.24 ± 1.22 and 9.14 ± 1.08 mmol/L without and with the antagonist, respectively. Similarly, there was no effect (P = 0.35) on plasma active GLP-1 concentrations: peak concentration 14.3 ± 1.36 pM and 13.7 ± 1.97 pM without and with the antagonist, respectively. However, the antagonist caused a significant decrease in the area under the curve for insulin (P = 0.04), and weak evidence (P = 0.06) of a reduction in peak insulin concentration (456 ± 147 μIU/mL and 370 ± 146 μIU/mL without and with the antagonist, respectively). The lower overall insulin response to the maize meal after treatment with the antagonist demonstrates that blocking the GLP-1 receptor partially reduced insulin production in response to a high starch, high glycemic index, diet. Using a different methodological approach to published studies, this study also confirmed that GLP-1 does contribute to the excessive insulin production in ponies with ID.
A revised model of energy transactions and body composition in sheep
Authors: Oddy V Hutton , Dougherty James C H , Evered Mark , Clayton Edward H , Oltjen James W
Published: December 2023

A mechanistic, dynamic model was developed to calculate body composition in growing lambs by calculating heat production (HP) internally from energy transactions within the body. The model has a fat pool (f) and three protein pools: visceral (v), non-visceral (m), and wool (w). Heat production is calculated as the sum of fasting heat production (FHP), heat of product formation (HrE) and heat associated with feeding (HAF). Fasting heat production is represented as a function of visceral and non-visceral protein mass. Heat associated with feeding (HAF) calculated as ((1-km) x MEI, where km is partial efficiency of ME use for maintenance, and MEI = metabolizable energy intake) applies at all levels above and below maintenance. The value of km derived from data where lambs were fed above maintenance was 0.7. Protein change (dp/dt) is the sum of change in the m, v, and w pools, and change in fat is equal to net energy available for gain minus dp/dt. Heat associated with change in body composition (HrE) is calculated from change in protein and fat with estimated partial efficiencies of energy use of 0.4 and 0.7 for protein and fat respectively. The model allows for individuals to gain protein while losing fat, or vice versa.

When evaluated with independent data, the model performed better than the current Australian feeding standards (Freer et al., 2007) for predicting protein gain in the empty body but did not perform as well as well for gain of fat and fleece-free empty body weight. Models performed similarly for predicting clean wool growth. By explicit representation of the major energy using processes in the body, and through simplification of the way body composition is computed in growing animals, the model is more transparent than current feeding systems while achieving similar performance. An advantage of this approach is that the model has the potential for wider applicability across different growth trajectories and can explicitly account for the effects systematic changes on energy transactions, such as the effects of selective breeding, growth manipulation, or environmental changes.
Context Matters
Authors: Nuzban Yulia
Published: December 2023

In seven trials to date, the International Criminal Court (ICC) has relied on the expertise of historians, anthropologists and political scientists to provide historical and political context. Overview expert witnesses help the judges appreciate the evidence of charged crimes in a wider context of conflict and violence. In this article, I consider the fundamental purpose and factors militating in favour of engaging an overview expert. In addition, I first review and then reflect on the current use of overview expert evidence — as a subset of expert evidence — in ICC trials, to better understand its legal and practical utility in international crimes cases. I focus on four aspects: relevance in criminal proceedings, timing of engaging an expert, selection of experts and impact on the fairness of proceedings.
Principles-Focused Evaluation: A Promising Practice in the Evaluation of Continuing Professional Development
Authors: Parker Kathryn , Sud Abhimanyu
Published: December 2023

Outcome-based evaluations still dominate in continuing professional development (CPD) despite the availability of evaluation approaches that address program processes and contexts. Our continued reliance on outcomes-based evaluation fails to respect the importance of complexity and the human element of program planning and implementation. Therefore, it is time that the field of CPD embrace complementary approaches to program evaluation that consider the complexity and maturity of programs and their contexts, while providing credible and relevant information to inform strategic decisions regarding the future of a program. Principles-focused evaluation provides a complement to traditional evaluation approaches through the articulation of a program's values that can be actioned. These “actionable values,” known as principles, become the focus of the evaluation for the purposes of program decision-making. This paper describes how one CPD program, designed as a response to growing opioid-related harms, adopted a principles-focused evaluation to inform ongoing iteration of the program. The process used to design the principles, how the principles are informing the transportability of the program, and implications for CPD evaluation are discussed.
Deep learning quantification reveals a fundamental prognostic role for ductular reaction in biliary atresia
Authors: Nyholm Iiris , Sjöblom Nelli , Pihlajoki Marjut , Hukkinen Maria , Lohi Jouko , Heikkilä Päivi , Mutka Aino , Jahnukainen Timo , Davenport Mark , Heikinheimo Markku , Arola Johanna , Pakarinen Mikko P.
Published: December 2023

Background:

We aimed to quantify ductular reaction (DR) in biliary atresia using a neural network in relation to underlying pathophysiology and prognosis.

Methods:

Image-processing neural network model was applied to 259 cytokeratin-7–stained native liver biopsies of patients with biliary atresia and 43 controls. The model quantified total proportional DR (DR%) composed of portal biliary epithelium (BE%) and parenchymal intermediate hepatocytes (PIH%). The results were related to clinical data, Sirius Red–quantified liver fibrosis, serum biomarkers, and bile acids.

Results:

In total, 2 biliary atresia biopsies were obtained preoperatively, 116 at Kasai portoenterostomy (KPE) and 141 during post-KPE follow-up. DR% (8.3% vs. 5.9%, p=0.045) and PIH% (1.3% vs. 0.6%, p=0.004) were increased at KPE in patients remaining cholestatic postoperatively. After KPE, patients with subsequent liver transplantation or death showed an increase in DR% (7.9%–9.9%, p = 0.04) and PIH% (1.6%–2.4%, p = 0.009), whereas patients with native liver survival (NLS) showed decreasing BE% (5.5%–3.0%, p = 0.03) and persistently low PIH% (0.9% vs. 1.3%, p = 0.11). In Cox regression, high DR predicted inferior NLS both at KPE [DR% (HR = 1.05, p = 0.01), BE% (HR = 1.05, p = 0.03), and PIH% (HR = 1.13, p = 0.005)] and during follow-up [DR% (HR = 1.08, p<0.0001), BE% (HR = 1.58, p = 0.001), and PIH% (HR = 1.04, p = 0.008)]. DR% correlated with Sirius red–quantified liver fibrosis at KPE (R = 0.47, p<0.0001) and follow-up (R = 0.27, p = 0.004). A close association between DR% and serum bile acids was observed at follow-up (R = 0.61, p<0.001). Liver fibrosis was not prognostic for NLS at KPE (HR = 1.00, p = 0.96) or follow-up (HR = 1.01, p = 0.29).

Conclusions:

DR predicted NLS in different disease stages before transplantation while associating with serum bile acids after KPE.
Age-specific and sex-specific risks for HCC in African-born persons with chronic hepatitis B without cirrhosis
Authors: Kamal Habiba , Ingre Michael , Stål Per , Westman Gabriel , Bruce Daniel , Wedemeyer Heiner , Duberg Ann-Sofi , Aleman Soo
Published: December 2023

Background:

The international recommendations of HCC surveillance for African-born persons with chronic hepatitis B (CHB) without cirrhosis are divergent, probably due to scarce data on incidence rate (IR) for HCC.

Methods:

We assembled a cohort with prospectively collected data of Swedish residents of African origin with diagnosed CHB without cirrhosis at baseline from 1990 to 2015. Data from nationwide registers were used to calculate the sex-specific IR and IR ratio (incidence rate ratios) in relation to age, comorbidities, and birth region, using a generalized linear model with a log-link function and Poisson distribution.

Results:

Among 3865 African-born persons with CHB without cirrhosis at baseline, 31 (0.8%; 77.4% men) developed HCC during a median of 11.1 years of follow-up, with poor survival after HCC diagnosis. The mean age at HCC diagnosis was 46.8 (SD±14.7; range 23–79) in men. HCC IR exceeded the recommended surveillance threshold of 0.2%/year at ages 54 and 59 years in men and women, respectively, and at ages 20–40 years if HCV or HDV co-infection was present. African-born men with CHB had an incidence rate ratios of 10.6 (95% CI 4.4–31.5) for HCC compared to matched African-born peers without CHB, and an incidence rate ratios of 35.3 (95% CI 16.0–88.7) compared to a matched general population.

Conclusions:

African-born men with CHB without cirrhosis reached an IR of 0.2%/year between 50 and 60 years, and at younger ages if HCV or HDV co-infection was present. Our findings need further confirmation, and new cost-effectiveness analyses specific for young populations are needed, to provide personalized and cost-effective HCC surveillance.
Hyperinsulinemia, an overlooked clue and potential way forward in metabolic dysfunction–associated steatotic liver disease
Authors: Harrison Stephen A. , Dubourg Julie , Knott Maddie , Colca Jerry
Published: December 2023

Metabolic dysfunction–associated steatotic liver disease is closely associated with other features of the metabolic syndrome such as type 2 diabetes. The progression of the disease may lead to liver fibrosis, which is the main predictor of major adverse liver outcomes. Insulin resistance plays a major role in the pathogenesis of the disease. A component of fasting hyperinsulinemia is a failure of the liver to adjust the peripheral level of insulin due to reduced clearance. The associated fasting hyperinsulinemia has been independently associated as a predictor of major adverse liver outcomes and major adverse cardiovascular events. In this review, we discuss the potential mechanism and entanglement between liver fibrosis and hyperinsulinemia, and we hypothesize that the measure of fasting insulin could become a hepatic functional test within the armamentarium of noninvasive tests for the assessment of Metabolic dysfunction–associated steatotic liver disease.
Design of dot-blot hybridization assay for simultaneous detection of Campylobacter jejuni and Campylobacter coli: a preliminary study
Authors: Bakhshi Bita , Shams Saeed , Rezaie Niloofar , Ameri Shah Reza Mahdieh
Published: December 2023

Objectives:

Campylobacters are a major cause of gastroenteritis worldwide. These are fastidious in culture and false negative results are seen in many clinical laboratories. Among molecular methods, the dot-blot technique is widely used for a variety of purposes, especially diagnostics. So, the authors aimed to detect C. jejuni and C. coli simultaneously using a dot-blot assay.

Methods:

After evaluating the bioinformatics studies, a cadF-conserved fragment was selected for the design of primers and probe. DNAs from standard strains and a recombinant plasmid, prepared in this study, were used to assess the technique. The specificity of the method was also surveyed using DNAs from other enteric bacteria. The limit of detection was evaluated by recombinant plasmid and different concentrations of the designed probe.

Results:

A 95-bp fragment of cadF was selected, and in silico analysis studies showed that it is conserved between both species. Also, the non-specific annealing of the primers and probe with other bacteria was not seen theoretically. The technique with recombinant plasmid as well as DNAs of standard strains created black spots on the membrane, confirming that the probe was correctly synthesized. No non-specific reactions with other bacterial species were observed (specificity=100%). The limit of detection of the test was determined to be 50 µg/ml.

Conclusions:

This is the first study to simultaneously detect two important pathogens in the Campylobacter genus and was able to detect C. jejuni and C. coli with acceptable sensitivity and specificity.
Exploring Health Care Access Among Lesbian, Gay, Bisexual, and Transgender Populations in Orange County, California
Authors: Nation Austin , Pelayo Jonathan , Trevino Mathew , Ambalada Aleiza Mae , Hojilla J. Carlo , Raynor Phyllis , Outlaw Frieda
Published: December 2023

There are approximately 90 000 lesbian, gay, bisexual, and transgender (LGBT) individuals in Orange County, California. LGBT individuals have significant health disparities, particularly if they are from racial or ethnic minority groups and/or have a disability. There are structural and access barriers in the health care system that increase these health disparities. These individuals experience discriminatory situations when accessing health care and mental health services, which may affect their health-seeking behaviors. The purpose of this pilot quantitative cross-sectional study was to gather information about the current health care experiences and needs of this LGBT population including priority health issues, physical and mental health care utilization, and perceived adequacy of LGBT-friendly physical and mental health care providers. These findings will inform organizational strategies for nursing administrators and other health care leaders when tailoring, planning, and redesigning structures that meaningfully address the service needs of this at-risk group. Seventy-five participants were recruited from 2 organizations serving the LGBT community to complete an online survey. Findings include trouble finding an LGBT competent provider, delays or being unable to access care, and worried about losing insurance. Most participants needed to visit multiple different locations to receive care and preferred a 1-stop shop.
Efficacy, Safety, and Cost-effectiveness Analysis of Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation Recipients
Authors: Qiu Yulan , Zhang Yijing , Teng Mengmeng , Cheng Shiqi , Du Qian , Yang Luting , Wang Quanfang , Wang Taotao , Wang Yan , Dong Yalin , Dong Haiyan
Published: December 2023

Background.

Cytomegalovirus (CMV) infection is associated with higher non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). But the preferred drug for preventing cytomegalovirus infection is still controversial. We evaluate the efficacy, safety, and cost-effectiveness of antiviral agents based on the most recent studies.

Methods.

A pairwise and network meta-analysis was conducted to obtain direct and indirect evidence of antivirals. The cost of allo-HSCT recipients in a teaching hospital was collected, and a cost-effectiveness analysis using a decision tree combined with Markov model was completed from the perspective of allo-HSCT recipients over a lifetime horizon.

Results.

A total of 19 RCTs involving 3565 patients (8 antivirals) were included. In the network meta-analysis, relative to placebo, letermovir, valacyclovir, and ganciclovir significantly reduced CMV infection incidence; ganciclovir significantly reduced CMV disease incidence; ganciclovir significantly increased the incidence of serious adverse event; none of antivirals significantly reduced all-cause mortality. Based on meta-analysis and Chinese medical data, the incremental cost-effectiveness ratios (ICER) per quality-adjusted life year (QALY) saved for maribavir, acyclovir, valacyclovir, ganciclovir, and letermovir relative to placebo corresponded to US$216 635.70, US$11 590.20, US$11 816.40, US$13 049.90, and US$12 189.40, respectively. One-way sensitivity analysis showed the most influential parameter was discount rate. The probabilistic sensitivity analysis indicated a 53.0% probability of letermovir producing an ICER below the willingness-to-pay threshold of US$38 824.23/QALY. The scenario analysis demonstrated prophylaxis with letermovir is considered cost-effective in the United States.

Conclusions.

Currently, letermovir is an effective and well-tolerated treatment for preventing CMV infection, and it might be a cost-effective choice in allo-HSCT recipients in China.
A Pilot Study of the Convergent and Discriminant Validity of the Dutch Version of the Parametric Go/No-Go Task
Authors: van Horn Joan E. , van der Schoot Anna , Wilpert Julia , Engelbregt Hessel J. , Brand Nico
Published: December 2023

Background:

The parametric go/no-go (PGNG) task is a computerized task that is designed to measure cognitive flexibility, response inhibition, and working memory. The PGNG task has been shown to measure core executive functions (EFs) in a psychometrically sound, brief, and ecologically valid manner.

Objective:

To analyze the psychometric properties of the Dutch version of the PGNG task in a convenience sample of nonclinical adults.

Method:

The sample consisted of 74 highly educated adults, with an average age of 36 years. Forty-two participants completed test battery A to investigate the task’s convergent validity; 36 participants completed test battery B to investigate the task’s discriminant validity. The results were analyzed using a repeated-measures ANOVA, Friedman’s test, paired-samples t test, and correlation analyses.

Results:

Level 3 of the PGNG task places increased demands on sustained attention, response inhibition, and set-shifting. Several moderate correlations between level 3 and a complex EFs measure supported the convergent validity of this level of the PGNG task. The convergent validity of levels 1 and 2 was not supported. No significant correlations were found between PGNG levels and non-EF tests, supporting discriminant validity.

Conclusion:

Our study included a rather homogenous sample of highly educated participants, which might explain the convergent validity of level 3 of the Dutch version of the PGNG task. Hence, to overcome these potentially confounding factors, the Dutch version of the PGNG task should be investigated in a larger and more heterogeneous population in terms of age and educational level.
Antimicrobial and quorum sensing inhibitory activity of epiphytic bacteria isolated from the red alga Halymenia durvillei
Authors: Padayao Mary Hannah Rose , Padayao Francis Reuben Paul , Patalinghug Jenny Marie , Raña Gem Stephen , Yee Jonie , Geraldino Paul John , Quilantang Norman
Published: December 2023

Halymenia durvillei is a red alga that is commonly utilized in the Philippines as food and as a source of high-value natural products for industrial applications. However, there are no studies regarding the microbial community associated with H. durvillei and its potential applications. This study aimed to isolate and identify the epiphytic bacteria of H. durvillei and determine their antimicrobial and quorum sensing inhibitory (QSI) effects. The thalli of H. durvillei were collected at the shores of Santa Fe, Bantayan, Cebu, Philippines. Bacterial isolates were identified using 16S rRNA, and their ethyl acetate (EtOAc) extracts were subjected to antimicrobial susceptibility tests against representative species of yeast and Gram-negative and Gram-positive bacteria. Their QSI activity against

Chromobacterium violaceum

was also determined. Fourteen distinct bacterial colonies belonging to four genera, namely

Alteromonas

(3),

Bacillus

(5),

Oceanobacillus

(1) and

Vibrio

(5), were successfully isolated and identified. All 14 bacterial isolates exhibited antibacterial effects. EPB9, identified as

Bacillus safensis

, consistently showed the strongest inhibition against

Escherichia coli

,

Staphylococcus aureus

and

Staphylococcus epidermidis

, with minimum inhibitory concentrations (MICs) ranging from 0.0625 to 1.0 mg ml−1. In contrast, all 14 isolates showed weak antifungal effects. Both

B. safensis

(EPB9) and

Bacillus australimaris

(EPB15) exhibited QSI effects at 100 mg ml−1, showing opaque zones of 3.1±0.9 and 3.8±0.4 mm, respectively. This study is the first to isolate and identify the distinct microbial epiphytic bacterial community of H. durvillei and its potential as an abundant resource for new antibacterial and QSI bioactives.
Regional Genetic Architecture of the Corpus Callosum and its Overlap with Psychiatric and Substance Use Phenotypes
Authors: Campbell Megan L. , Shadrin Alexey , van der Meer Dennis , Tesfaye Markos , Smeland Olav B. , O’Connell Kevin S. , Parker Nadine , Frei Oleksandr , Andreassen Ole , Stein Dan J. , Dalvie Shareefa , Rokicki Jaroslav
Published: December 2023

Background

The corpus callosum (CC) is a brain structure with a high heritability and a potential role in psychiatric and substance use traits. However, the genetic relationship of the CC, and its subregions, with psychiatric phenotypes remains largely unclear. We aimed to investigate the genetic architecture of the CC and its subregions and its overlap with psychiatric phenotypes using causal mixture model analysis.

Methods

We employed summary statistics from genome-wide association studies (GWAS) of the CC (n=35,592), psychiatric- (attention deficit hyperactivity disorder, ADHD; autism spectrum disorder, ASD; bipolar disorder, BD; major depressive disorder, MDD; schizophrenia, SCZ) and substance use- phenotypes (drinks per week, smoking cessation, smoking initialization, number of cigarettes per day and cannabis use) phenotypes, and performed bivariate casual mixture model analyses with MiXeR to investigate the genetic overlap between these phenotypes. Conjunctional false discovery rate (conjFDR) was used to identify genetic loci that exhibit joint associations with the CC and psychiatric or substance use phenotypes. Open Targets was used to annotate significant, independent variants and MAGMA was used to conduct gene-set enrichment analyses.

Results

The polygenicity of the CC subregions ranges from 1.4k variants in the posterior subregion to 1.8k variants in the mid posterior subregion, with approximately 1.8k variants influencing total CC volume. The extent of genetic overlap between CC and psychiatric and substance use phenotypes varied across CC subregion; loci contributing to anterior regions showing almost complete overlap with those involved in BD and SCZ (96% and 98%, respectively), while a distinct pattern emerged for MDD indicating fewer variants overlapping with central and mid anterior subregions (47% and 38%, respectively), loci contributing to the central region exhibited substantial overlap with drinks per week (87%). Loci contributing to the CC subregions exhibited lower overlap with ASD and ADHD (26% to 48%). The conjunctional analysis of CC subregions and psychiatric phenotypes revealed a total of 138 significant independent variants, with gene-set enrichment analyses implicating antigen processing, regulation of the extracellular matrix and hyaluronan metabolism.

Conclusion

We observed significant genetic overlap between the CC and SCZ, BD, and drinks per week, identifying loci linked to brain-related traits with specific overlap patterns found across conditions. Overlapping genetic architectures suggest shared biological pathways, and the potential value of targeting such pathways for the purposes of treatment.
Assessment of the impact of the Vaccine Pass Policy on COVID-19 vaccine hesitancy and uptake among Chinese adults in Hong Kong
Authors: Wong Irene O. L. , Wong Cherry , Mak Nelly , Dai Alan , Xiao Jingyi , Wu Peng , Ni Michael Y. , Liao Qiuyan , Cowling Benjamin J.
Published: December 2023

Background

Recognising the importance of attaining high vaccine coverage to mitigate the COVID-19 impact, a Vaccine Pass scheme was implemented during and after the first large Omicron wave in Hong Kong in early 2022 requiring three doses by June 2022. We evaluated the impact of the Vaccine Pass policy on vaccine uptake in adults.

Methods

We analyzed patterns in vaccine uptake and hesitancy using local data from the population vaccine registry and 32 cross-sectional surveys conducted from October 2021 to December 2022. We examined the association of Vaccine Pass phases with vaccine uptake, taking into account covariables including self-risk perception, perceived self-efficacy in preventing COVID-19 and trust in government in pandemic control as well as physical distancing measures and demographics.

Findings

The uptake of primary series and third doses was significantly associated with stages of Vaccine Pass implementation, and other statistically significant drivers included age group, chronic condition, higher perceived personal susceptibility to COVID-19, higher trust in government, and higher educational attainment. Older adults (≥65y) were less likely to be vaccinated against COVID-19, compared to adults aged 18-44 years.

Interpretation

Vaccine uptake in older adults was observed to have increased by a greater extent after the policy announcement and implementation, which occurred during and after a large Omicron wave with high mortality in older ages in early 2022. Since the policy withdrawal the uptake of further booster doses has been very low in all ages. Improving voluntary booster uptake in older adults should be prioritized.

Funding

Health and Medical Research Fund, Hong Kong.
Spatial niche separation of an invasive and a native mesopredator
Authors: Jansen Jeroen , Moseby Katherine E , Comte Sebastien , Dean Abbey T , Axford Geoff , Peacock David E , Brandle Robert , Jones Menna E
Published: December 2023

Re-introduced native animals face major challenges to re-establish themselves in their previous range of distribution when invasive alien predators are present. We study the interactions between a native and an invasive mesopredator across an ecological gradient in the Ikara-Flinders Ranges National Park in South Australia. We placed VHF/ GPS-collars on feral cats (Felis catus) and re-introduced western quolls (Dasyurus geoffroyi) and analysed their movement patterns, both utilisation distributions and behavioural states, and habitat selection. Despite being able to move anywhere in this open landscape, there is a clear interspecific difference between the two species in their use and preference for landscape elements. Cats prefer grassland and occupy flat areas where rabbit densities are high. Quolls prefer forests and avoid areas of high rabbit and therefore areas of high cat density. The almost complete spatial separation of cats and quolls may reflect different habitat requirements, but the historically broad distribution of quolls suggests that cats may limit quolls continuously to a restricted niche in the Flinders Ranges. This raises the possibility of management interventions that could support a further expansion of quoll occupancy.
Coevolution of longevity and female germline maintenance
Authors: Baur Julian , Koppik Mareike , Savkovic Uros , Dordevic Mirko , Stojkovic Biljana , Berger David
Published: December 2023

An often-overlooked aspect of life-history optimization is the allocation of resources to protect the germline and secure safe transmission of genetic information. While failure to do so renders significant fitness consequences in future generations, germline maintenance comes with substantial costs. Thus, germline allocation should trade-off with other life history decisions and be optimized in accordance with an organism’s reproductive schedule. Here we tested this hypothesis by studying germline maintenance in lines of seed beetle, selected for early (E) or late (L) reproduction for 350 and 240 generations, respectively. Female animals provide maintenance and screening of male gametes in their reproductive tract and oocytes. Here, we revealed the ability of young and aged E and L-females to provide this form of germline maintenance by mating them to males with ejaculates with artificially elevated levels of protein and DNA damage. We find that germline maintenance in E-females peaks at young age and then declines, while the opposite is true for L-females, in accordance with the age of reproduction in respective regime. These findings identify the central role of allocation to secure germline integrity in life history evolution and highlight how females can play a crucial role in mitigating effects of male germline decisions on mutation rate and offspring quality.
simona:a comprehensive R package for semantic similarity analysis on bio-ontologies
Authors: Gu Zuguang
Published: December 2023

Background

Bio-ontologies are keys in structuring complex biological information for effective data integration and knowledge representation. Semantic similarity analysis on bio-ontologies quantitatively assesses the degree of similarity between biological concepts based on the semantics encoded in ontologies. It plays an important role in structured and meaningful interpretations and integration of complex data from multiple biological domains.

Results

We presentsimona, a novel R package for semantic similarity analysis on general bioontologies.Simonaimplements infrastructures for ontology analysis by offering efficient data structures, fast ontology traversal methods, and elegant visualizations. Moreover, it provides a robust toolbox supporting over 70 methods for semantic similarity analysis. Withsimona, we conducted a benchmark against current semantic similarity methods. The results demonstrate methods are clustered based on their mathematical methodologies, thus guiding researchers in the selection of appropriate methods. Additionally, we explored annotation-based versus topology-based methods, revealing that semantic similarities solely based on ontology topology can efficiently reveal semantic similarity structures, facilitating analysis on less-studied organisms and other ontologies.

Conclusions

Simonaoffers a versatile interface and efficient implementation for processing, visualization, and semantic similarity analysis on bio-ontologies. We believe thatsimonawill serve as a robust tool for uncovering relationships and enhancing the interoperability of biological knowledge systems.
Msx genes delineate a novel molecular map of the developing cerebellar neuroepithelium
Authors: Gupta Ishita , Yeung Joanna , Rahimi-Balaei Maryam , Wu Sih-Rong , Goldowitz Daniel
Published: December 2023

In the early cerebellar primordium, there are two progenitor zones, the ventricular zone (VZ) residing atop the IVthventricle and the rhombic lip (RL) at the lateral edges of the developing cerebellum. These zones give rise to the several cell types that form the GABAergic and glutamatergic populations of the adult cerebellum, respectively. Recently, an understanding of the molecular compartmentation of these zones has emerged. TheMsxgenes are a family of three transcription factors that are expressed downstream of Bone Morphogenetic Protein (BMP) signaling in these zones. Using fluorescent RNAin situhybridization, we have characterized theMsx(Msh Homeobox) genes and demonstrated that their spatiotemporal pattern segregates specific regions in the progenitor regions.Msx1andMsx2are compartmentalized within the rhombic lip (RL), whileMsx3is localized within the ventricular zone (VZ). The relationship of theMsxgenes with an early marker of the glutamatergic lineage,Atoh1, was examined inAtoh1-null mice and it was found that the expression ofMsxgenes persisted. Importantly,Msx1andMsx3expressions expanded in response to the elimination ofAtoh1. These results point to early markers of cerebellar progenitor zones and more importantly to an updated view of the molecular parcellation of the RL with respect to the canonical marker of the RL,Atoh1.
Electrochemical DNA-based sensors for measuring cell-generated forces
Authors: Tabrizi Mahmoud Amouzadeh , Bhattacharyya Priyanka , Zheng Ru , You Mingxu
Published: December 2023

Mechanical forces play an important role in cellular communication and signaling. We developed in this study novel electrochemical DNA-based force sensors for measuring cell-generated adhesion forces. Two types of DNA probes, i.e., tension gauge tether and DNA hairpin, were constructed on the surface of a smartphone-based electrochemical device to detect piconewton-scale cellular forces at tunable levels. Upon experiencing cellular tension, the unfolding of DNA probes induces the separation of redox reporters from the surface of the electrode, which results in detectable electrochemical signals. Using integrin-mediated cell adhesion as an example, our results indicated that these electrochemical sensors can be used for highly sensitive, robust, simple, and portable measurement of cell-generated forces.
Calcitriol impairs the secretion of IL-4 and IL-13 in Th2 cells via modulating VDR-Gata3-Gfi1 axis
Authors: Biswas Biswajit , Chattopadhyay Shagnik , Hazra Sayantee , Goswami Ritobrata
Published: December 2023

Calcitriol, the bioactive form of vitamin D, exerts its biological functions by binding to its cognate receptor VDR. The indicators of the severity of allergies and asthma have been linked to low vitamin D levels. However, the role of calcitriol in regulating IL-4 and IL-13; two cytokines pivotal to allergic inflammation, remained unclear. Our study observed a decrease in IL-4 and IL-13 secretion in murine and human Th2 cells, treated with calcitriol. In murine Th2 cells, Gata3 expression was attenuated by calcitriol. However, the expression of the transcriptional repressor Gfi1, that prevents Th1 fate of activated CD4+ T cells, too was attenuated in the presence of calcitriol. Ectopic expression of either Gfi1 or VDR impaired the secretion of IL-13 in Th2 cells. Gfi1 significantly impairedIl13promoter activation; which calcitriol failed to restore. Ecr, a conserved region between the two genes, which enhanced the transactivation ofIl4andIl13promoters; is essential for calcitriol-mediated suppression of both the genes. In murine Th2 cells, VDR interacted with Gata3 but not Gfi1. Calcitriol augmented the recruitment of VDR to theIl13promoter and Ecr regions. Gata3 recruitment was significantly impaired atIl13and Ecr locus in the presence of calcitriol but increased atIl4promoter. However, in the presence of calcitriol, the overall recruitment of Gfi1 remained unchanged atIl4but increased atIl13locus in Th2 cells. Together, our study clearly elucidates that calcitriol modulates VDR, Gata3, and Gfi1 to suppress IL-4 and IL-13 production in Th2 cells.

Abstract Figure
The impact of perioperative diagnostic tools on clinical outcomes and cost-effectiveness in parathyroid surgery: a health economic evaluation
Authors: Bátora Daniel , Iskandar Rowan , Gertsch Jürg , Kaderli Reto M.
Published: December 2023

Objectives

Pre- and intraoperative diagnostic tools influence the surgical management of primary hyperparathyroidism (PHPT), whereby their performance of classification varies considerably for the two common causes of PHPT: solitary adenomas and multiglandular disease. A consensus on the use of such diagnostic tools for optimal perioperative management of all PHPT patients has not been reached.

Design

A decision tree model was constructed to estimate and compare the clinical outcomes and the cost-effectiveness of preoperative imaging modalities and intraoperative parathyroid hormone (ioPTH) monitoring criteria in a 14-year time horizon. The robustness of the model was assessed by conducting a one-way sensitivity analysis and probabilistic uncertainty analysis.

Setting

The United States healthcare system.

Population

A hypothetical population consisting of 5,000 patients with sporadic, symptomatic, or asymptomatic PHPT.

Interventions

Pre- and intraoperative diagnostic modalities for parathyroidectomy

Main outcome measures

Costs, quality-adjusted life years (QALYs), net monetary benefits (NMB), clinical outcomes

Results

In the base-case analysis, four-dimensional (4D)-computed tomography (CT) was the least expensive strategy with $10,289 and 13.93 QALYs. Ultrasound and99mTc-Sestamibi single-photon-emission computed tomography/CT were both dominated strategies, while18F-fluorocholine positron emission tomography was cost-effective with a net monetary benefit of $264 considering a willingness to pay threshold of $95,958. The application of ioPTH monitoring with the Vienna criterion decreased the rate of reoperations from 10.50 to 0.58 per 1,000 patients. Due to an increased rate of bilateral neck explorations from 257.45 to 347.45 per 1,000 patients, it was not cost-effective.

Conclusions

4D-CT is the most cost-effective instrument for the preoperative localization of parathyroid adenomas. Due to an excessive increase of bilateral neck explorations, the use of ioPTH monitoring is not cost-effective in PHPT but leads to a significant reduction of reoperations.

Strengths and limitations of the study

Our decision tree model is the most complete for parathyroidectomy; incorporating both solitary adenomas and multiglandular disease and ioPTH monitoring.

In addition to cost-effectiveness, we present the impact of the interventions on the major clinical outcomes.

Our study is limited to the United States and does not include a societal perspective.

The model did not consider the potential institutional variations in the prevelance of multiglandular disease

There remains uncertainty for certain parameters for the model as they were derived from a limited number of single-institution studies
Comparative Clinical Evaluation of the Alinity m STI Multiplex PCR Assay for Diagnosis and Surveillance ofChlamydia trachomatis,Neisseria gonorrhea,Trichomonas vaginalis, andMycoplasma genitalium
Authors: Lima Amorce , Uy Dominic , Kostera Joshua , Silbert Suzane
Published: December 2023

Background

Chlamydia trachomatis(CT) andNeisseria gonorrhoeae(NG) are routinely tested and reported; however,Trichomonas vaginalis(TV) is the most common STI in the US and the prevalence ofMycoplasma genitalium(MG) infections is likely higher than estimated. We examined the clinical performance of the Alinity m STI assay for detection and surveillance of CT/NG/TV/MG in urine specimens from patients at a large academic medical center.

Methods

Prevalence of mono- and co-infections on Alinity m STI pathogens and predictors of a positive result were identified. Alinity m STI and Aptima Combo 2 CT/NG and TV assay (Panther System) results were compared, with discrepant results run on the cobas 6800 CT/NG, TV and MG assays. Analyzer turnaround times (TAT) were determined for Alinity m and Panther systems.

Results

199 urine specimens were included. Age ≥25 years, collection outside the emergency department (ED), and asymptomatic status were predictive of TV or MG infection; symptomatic status was the only predictor of CT or NG infection. Overall agreement rates for the Alinity m, Aptima, and cobas assays ranged from 86.4% to 99.5% for the four pathogens. TV and MG infections comprised 54% of the positive samples and were more often asymptomatic than CT and NG infections. Analyzer TAT (onboard to result reporting) was 4 hours 45 minutes for the Aptima CT/NG, 3 hours 25 minutes for Aptima TV, and 1 hour 55 minutes for Alinity m STI assay.

Conclusions

The Alinity m STI assay allows for fast and simultaneous detection of the four major STI pathogens, which can facilitate surveillance and provide accurate results to help clinicians diagnose for initiation of appropriate treatment.
Pervasive correlations between causal disease effects of proximal SNPs vary with functional annotations and implicate stabilizing selection
Authors: Zhang Martin Jinye , Durvasula Arun , Chiang Colby , Koch Evan M. , Strober Benjamin J. , Shi Huwenbo , Barton Alison R. , Kim Samuel S. , Weissbrod Omer , Loh Po-Ru , Gazal Steven , Sunyaev Shamil , Price Alkes L.
Published: December 2023

The genetic architecture of human diseases and complex traits has been extensively studied, but little is known about the relationship of causal disease effect sizes between proximal SNPs, which have largely been assumed to be independent. We introduce a new method, LD SNP-pair effect correlation regression (LDSPEC), to estimate the correlation of causal disease effect sizes of derived alleles between proximal SNPs, depending on their allele frequencies, LD, and functional annotations; LDSPEC produced robust estimates in simulations across various genetic architectures. We applied LDSPEC to 70 diseases and complex traits from the UK Biobank (averageN=306K), meta-analyzing results across diseases/traits. We detected significantly nonzero effect correlations for proximal SNP pairs (e.g., −0.37±0.09 for low-frequency positive-LD 0-100bp SNP pairs) that decayed with distance (e.g., −0.07±0.01 for low-frequency positive-LD 1-10kb), varied with allele frequency (e.g., −0.15±0.04 for common positive-LD 0-100bp), and varied with LD between SNPs (e.g., +0.12±0.05 for common negative-LD 0-100bp) (because we consider derived alleles, positive-LD and negative-LD SNP pairs may yield very different results). We further determined that SNP pairs with shared functions had stronger effect correlations that spanned longer genomic distances, e.g., −0.37±0.08 for low-frequency positive-LD same-gene promoter SNP pairs (average genomic distance of 47kb (due to alternative splicing)) and −0.32±0.04 for low-frequency positive-LD H3K27ac 0-1kb SNP pairs. Consequently, SNP-heritability estimates were substantially smaller than estimates of the sum of causal effect size variances across all SNPs (ratio of 0.87±0.02 across diseases/traits), particularly for certain functional annotations (e.g., 0.78±0.01 for common Super enhancer SNPs)—even though these quantities are widely assumed to be equal. We recapitulated our findings via forward simulations with an evolutionary model involving stabilizing selection, implicating the action of linkage masking, whereby haplotypes containing linked SNPs with opposite effects on disease have reduced effects on fitness and escape negative selection.
Understanding the key determinants of an HPV therapeutic vaccine: a modeling analysis
Authors: Cohen Jamie A. , Stuart Robyn M. , Lee Serin , Klein Daniel J. , Kerr Cliff C. , Rao Darcy W. , Shin Haina , Achilles Sharon L.
Published: December 2023

Despite incredibly effective tools to prevent HPV infection and treat precancerous lesions, the scale-up of existing interventions in most low and middle-income countries has been slow, leaving a residual burden of invasive cervical cancer that will persist for decades. An HPV therapeutic vaccine may overcome some of the scalability and infrastructure challenges of traditional screening and treatment programs, though its potential public health value depends upon its characteristics, delivery strategy, and the underlying immunity of the population on which it would act. This analysis uses HPVsim, an open-access agent-based simulation framework, to evaluate the impact of a range of potential HPV therapeutic vaccines with varying scale-up of existing preventive interventions in nine high-burden low- and middle-income countries (LMICs). For each setting, the model is populated with context-specific demographic and behavioral data, and calibrated to fit estimates of HPV and cervical disease by age. We find that an HPV therapeutic vaccine that clears 90% of virus and regresses 50% of high-grade lesions, reaching 70 percent of 35-45 year old women starting in 2030, could avert 1.2-2.2 million incident cases of cervical cancer, 500,000-1.2 million cervical cancer deaths and 20-40 million disability adjusted life years (DALYs) in the modeled high-burden LMICs over 30 years. The size of the impact is sensitive to rates of background intervention scale-up and the characteristics of the vaccine, including ability to establish long-lasting immune memory.
STIL overexpression shortens lifespan and reduces tumor formation in mice
Authors: Moussa Amira-Talaat , Cosenza Marco R. , Wohlfromm Timothy , Brobeil Katharina , Hill Anthony , Patrizi Annarita , Müller-Decker Karin , Holland-Letz Tim , Jauch Anna , Kraft Bianca , Krämer Alwin
Published: December 2023

Centrosomes are the major microtubule organizing centers of animal cells. Supernumerary centrosomes are a common feature of human tumors and associated with karyotype abnormalities and aggressive disease, but whether they are cause or consequence of cancer remains controversial. Here, we analyzed the consequences of centrosome amplification by generating transgenic mice in which centrosome numbers can be increased by overexpression of the structural centrosome protein STIL. We show that STIL overexpression induces centrosome amplification and aneuploidy, leading to senescence, apoptosis, and impaired proliferation in mouse embryonic fibroblasts, and microcephaly with increased perinatal lethality and shortened lifespan in mice. Importantly, both overall tumor formation in mice with constitutive, global STIL overexpression and chemical skin carcinogenesis in animals with inducible, skin-specific STIL overexpression were reduced, an effect that was not rescued by concomitant p53 inactivation. These results suggest that supernumerary centrosomes impair proliferationin vitroas well asin vivo, resulting in reduced lifespan and spontaneous as well as carcinogen-induced tumor formation.