bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Microvascular Complications and Associated Risk Factors among Diabetes Mellitus Patients attending Nyeri County Referral Hospital, Kenya: a cross-sectional Study
Authors: Ireri Rachael , Kikuvi Gideon , Mambo susan , cheriro besty
Published: February 2024

Microvascular complications are one of the major causes of morbidity and mortality worldwide among patients with diabetes mellitus (DM). In Kenya, Nyeri County has the highest prevalence of diabetes mellitus compared to other counties. More than 50% of Nyeri County Referral Hospital (NCRH) admissions result from non-communicable diseases (NCDs) and over 55% of hospital deaths are attributable to NCDs. This study therefore sought to assess the prevalence of microvascular complications and the associated risk factors among patients attending Nyeri County Referral Hospital in Kenya. A hospital-based cross-sectional study was conducted on 314 DM patients on follow-up at NCRH from August 2022 to October 2022. The socio-demographic, anthropometric, biochemical, and clinical data were recorded using a structured survey. All the recruited patients underwent an extensive examination for the presence of Microvascular complications like neuropathy, retinopathy, and nephropathy. Data were analyzed using STATA version 17. Univariate and multivariate logistic regression analyses are used to determine the risk factors associated with Microvascular complications of DM.  Among the 314 patients with DM, 58% were women. The overall prevalence of Microvascular complications (MVCs) is 36.62%. Diabetic peripheral neuropathy was the most frequent complication (27.4%), followed by retinopathy (10.8%) and nephropathy (8%). Inadequate physical exercise was a risk factor for all MVCs. Age, marital status, and level of education were risk factors for neuropathy while smoking and alcohol intake were risk factors for nephropathy. Additionally marital status was a risk factor for retinopathy. Further, the analysis revealed the risk of non-smokers getting neuropathy reduced by 98% compared to smokers (P-0.0001; CI 0.003058-0.191502). lack of regular physical exercise was significantly associated with retinopathy (P 0.012; CI 0.046816-0.690638). One in ten patients with DM had a microvascular complication.  The benefits of microvascular complications prevention should thus be factored into the management of patients with diabetes mellitus.
Multivariate genome-wide association analysis of quantitative reading skill and dyslexia improves gene discovery
Authors: Mountford Hayley S. , Eising Else , Fontanillas Pierre , Auton Adam ,   23andMe Research Team, Irving-Pease Evan K. , Doust Catherine , Bates Timothy C. , Martin Nicholas G. , Fisher Simon E. , Luciano Michelle
Published: February 2024

The ability to read is an important life skill and a major route to education. Individual differences in reading ability are influenced by genetic variation, with a heritability of 0.66 for word reading, estimated by twin studies. Until recently, genomic investigations were limited by modest sample size. Here we use a multivariate genome-wide association study (GWAS) method, MTAG, to leverage summary statistics from two independent GWAS efforts, boosting power for analyses of reading ability; GenLang meta-analysis of word reading (N = 27 180) and the 23andMe, Inc., study of dyslexia (Ncases= 51 800, Ncontrols= 1 087 070). We increase effective sample size to N = 102 082, representing the largest genetic study of reading ability, to date. We identified 35 independent genome-wide significant loci, including 7 regions not previously reported. Single-nucleotide polymorphism (SNP) based heritability was estimated at 24%. We observed clear positive genetic correlations with cognitive and educational measures. Gene-set analyses implicated neuronal synapses and proneural glioblastoma pathways, further supported by enrichment of neuronally expressed genes in the developing embryonic brain. Polygenic scores of our multivariate results predicted between 2.29-3.50% of variance in reading ability in an independent sample, the National Child Development Study cohort (N = 6 410). Polygenic adaptation was examined using a large panel of ancient genomes spanning the last ∼15k years. We did not find evidence of selection, suggesting that reading ability may not have been subject to recent selection pressure in Europeans. By combining existing datasets to improve statistical power, these results provide novel insights into the biology of reading.
Artificial intelligence to facilitate clinical trial recruitment in age-related macular degeneration
Authors: Williamson Dominic J. , Struyven Robbert R. , Antaki Fares , Chia Mark A. , Wagner Siegfried K. , Jhingan Mahima , Wu Zhichao , Guymer Robyn , Skene Simon S. , Tammuz Naaman , Thomson Blaise , Chopra Reena , Keane Pearse A.
Published: February 2024

Background

Recent developments in artificial intelligence (AI) have positioned it to transform several stages of the clinical trial process. In this study, we explore the role of AI in clinical trial recruitment of individuals with geographic atrophy (GA), an advanced stage of age-related macular degeneration, amidst numerous ongoing clinical trials for this condition.

Methods

Using a diverse retrospective dataset from Moorfields Eye Hospital (London, United Kingdom) between 2008 and 2023 (602,826 eyes from 306,651 patients), we deployed a deep learning system trained on optical coherence tomography (OCT) scans to generate segmentations of the retinal tissue. AI outputs were used to identify a shortlist of patients with the highest likelihood of being eligible for GA clinical trials, and were compared to patients identified using a keyword-based electronic health record (EHR) search. A clinical validation with fundus autofluorescence (FAF) images was performed to calculate the positive predictive value (PPV) of this approach, by comparing AI predictions to expert assessments.

Results

The AI system shortlisted a larger number of eligible patients with greater precision (1,139, PPV: 63%; 95% CI: 54–71%) compared to the EHR search (693, PPV: 40%; 95% CI: 39– 42%). A combined AI-EHR approach identified 604 eligible patients with a PPV of 86% (95% CI: 79–92%). Intraclass correlation of GA area segmented on FAF versus AI-segmented area on OCT was 0.77 (95% CI: 0.68–0.84) for cases meeting trial criteria. The AI also adjusts to the distinct imaging criteria from several clinical trials, generating tailored shortlists ranging from 438 to 1,817 patients.

Conclusions

We demonstrate the potential for AI in facilitating automated pre-screening for clinical trials in GA, enabling site feasibility assessments, data-driven protocol design, and cost reduction. Once treatments are available, similar AI systems could also be used to identify individuals who may benefit from treatment.
Sufficient reproduction numbers to prevent recurrent epidemics
Authors: Mari Lorenzo , Trevisin Cristiano , Rinaldo Andrea , Gatto Marino
Published: February 2024

Current practice in the design and evaluation of epidemic control measures, including vaccination, is largely based on reproduction numbers (RNs), which represent prognostic indexes of long-term disease transmission, both in naive populations (basic RN) and in the presence of prior exposure or interventions (effective RN). A standard control objective is to establish herd immunity, e.g., by immunizing enough susceptible individuals to achieve RN<1. However, attaining this goal is not sufficient to avoid transient outbreaks that, in the short term, might revamp epidemics by coalescence of subthreshold flare-ups. Using reactivity analysis applied to a discrete SIR model with age-of-infection structure, we determine sufficient conditions to prevent transient epidemic dynamics and recurrent, non-periodic outbreaks due to imported cases. These conditions are based on fundamental infection characteristics, namely the average infectiousness clearance rate, the generation time distribution, and the RN. We show that preventing subthreshold epidemicity requires stricter RN thresholds than simply maintaining RN<1. Taking into account a wide spectrum of respiratory viral infections, epidemicity-curbing RN thresholds vary between 0.10 (rubella) and 0.51 (MERS), with a median of 0.26 close to the estimate of 0.24 for the ancestral SARS-CoV-2 virus. The portion of the population that needs to be included in containment efforts to avoid short-term outbreaks is considerably higher than herd immunity thresholds (HITs) based solely on the basic RN (e.g., 93% vs. 72% for ancestral SARS-CoV-2). We also find that subthreshold epidemicity is harder to prevent for pathogens with a longer mean generation time, smaller standard deviation of the generation time distribution, longer duration of infection, and higher RN. Determining sufficient RN thresholds to prevent transient outbreaks is a key challenge in disease ecology, with practical consequences for the design of control measures, as the weaker RN reductions and HITs associated with customary control targets may prove ineffective in preventing potentially recurrent flare-ups. Due to its modest data requirements, our modeling framework may also have important implications for human and non-human diseases caused by emerging pathogens.
Value sets and the problem of redundancy in value set repositories
Authors: Gold Sigfried , Lehmann Harold P. , Schilling Lisa M. , Lutters Wayne G.
Published: February 2024

Objective

Crafting high-quality value sets is time-consuming and requires a range of clinical, terminological, and informatics expertise. Despite widespread agreement on the importance of reusing value sets, value set repositories suffer from clutter and redundancy, greatly complicating efforts at reuse. When users encounter multiple value sets with the same name or ostensibly representing the same clinical condition, it can be difficult to choose amongst them or determine if any differences among them are due to error or intentional decision.

Methods

This paper offers a view of value set development and reuse based on a field study of researchers and informaticists. The results emerge from an analysis of relevant literature, reflective practice, and the field research data.

Results

Qualitative analysis of our study data, the relevant literature, and our own professional experience led us to three dichotomous concepts that frame an understanding of diverse practices and perspectives surrounding value set development:

Permissible values versus analytic value sets;

Prescriptive versus descriptive approaches to controlled medical vocabulary use; and

Semantic and empirical types of value set development and evaluation practices and the data they rely on.

This three-fold framework opens up the redundancy problem, explaining why multiple value sets may or may not be needed and advancing academic understanding of value set development.

Conclusion

The paper catalogues the methods and practices used and provides practical aid in managing the value set development process. It offers recommendations for improving that process and for software innovation in to support. In order for value set repositories to become more rather than less useful over time, software must channel user efforts into either improving existing value sets or making new ones only when absolutely necessary.
Dietary diversity and the risk of metabolic syndrome in a Japanese population: An analysis of baseline cross-sectional data from the J-MICC study
Authors: Htay Zin Wai , Michihata Nobuyuki , Nakamura Yohko , Hippo Yoshitaka , Otonari Jun , Ikezaki Hiroaki , Nishida Yuichiro , Shimanoe Chisato , Tamura Takashi , Nagayoshi Mako , Kato Yasufumi , Tamada Yudai , Hishida Asahi , Tanoue Shiroh , Nishimoto Daisaku , Koyama Teruhide , Ozaki Etsuko , Kuriki Kiyonori , Takashima Naoyuki , Miyagawa Naoko , Katsuura-Kamano Sakurako , Watanabe Takeshi , Wakai Kenji , Matsuo Keitaro
Published: February 2024

Background: With the increasing burden of metabolic syndrome, it is crucial to focus on lifestyle interventions to reduce the risk. Diet is a modifiable factor that can reduce the risk of metabolic syndrome. Methods: We examined the association between the dietary diversity score (DDS) and risk of metabolic syndrome using baseline data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. In total, 75,332 participants were included in this study. A multiple logistic regression analysis was conducted to analyze the association between the DDS and metabolic syndrome. Results: Inverse associations were observed between a high DDS and metabolic syndrome (adjusted odds ratio, 0.83 [95% confidential interval 0.76-0.92]). Likewise, a high DDS was associated with reduced odds of a high body mass index and hypertension. No significant associations were observed between the DDS and serum triglyceride, fasting blood glucose, or high-density lipoprotein cholesterol values. Conclusion: To reduce the risk of metabolic syndrome, public health interventions should focus on promoting a diverse and balanced diet.
Contemporary burden of atrial fibrillation in mechanical thrombectomy stroke patients in the United States
Authors: Otite Fadar Oliver , Patel Smit D. , Hoffman Haydn , Aneni Ehimen , Anikpezie Nnabuchi , Akano Emmanuel Oladele , Wee Claribel , Burke Devin , Albright Karen , Beutler Timothy , Latorre Julius Gene , Singla Amit , Morris Nicholas , Chaturvedi Seemant , Khandelwal Priyank
Published: February 2024

Background

How the prevalence of atrial fibrillation (AF) differs between various demographic subgroups of acute ischemic stroke (AIS) patients undergoing mechanical thrombectomy (MT) in the United States (US) is unknown. Data on whether AF prevalence in MT admissions changed over the last decade are sparse.

Methods

We conducted a serial cross-sectional study using all primary AIS discharges in the 2010-2020 National Inpatient Sample. Discharges with MT codes were identified (n=155,277) and the proportion with AF in various age, sex and racial subgroups were computed. We used multivariable-adjusted negative binomial regression to compare AF prevalence between demographic subgroups and Joinpoint regression to evaluate trends over time. Multivariable-adjusted generalized linear models were used to evaluate the association of AF with in-hospital outcomes.

Results

Across the study period, 45.0% of AIS discharges with MT had AF but marked disparity existed by age, sex and race. After multivariable adjustment, AF prevalence was 4% higher in women vs. men (prevalence rate ratio [PRR] 1.04, 95%CI 1.01-1.07), was lower in Black vs White (PRR 0.80, 95%CI 0.77-0.84) but higher in Asian compared to White discharges (PRR 1.11, 95%CI 1.05-1.18). Prevalence increased with age (PRR for ≥80 years vs 18-39 years: 5.23, 95%CI 4.28-6.39). Following joinpoint regression, prevalence increased by 3.2% (95%CI 1.3 to 5.2%) annually across the period 2010-2015 but declined by -2.2% (95%CI -2.9% to -1.4%) from 2015-2020. AF was associated with 27% lower odds of in-hospital mortality (Odds ratio 0.72, 95%CI 0.62-0.84) and 31% greater odds of routine home discharge (Odds ratio, 95%CI 1.17 to 1.47) compared to no AF.

Conclusion

AF prevalence in MT patients in the US is approximately twice that of the general AIS population but marked disparity exists by age, sex and race. AF Prevalence in MT increased from 2010-2015 but declined in the period 2015-2020.

Clinical Perspective

What is new?

Approximately 45% of mechanical thrombectomy acute ischemic stroke hospitalizations have comorbid atrial fibrillation (AF) and this proportion increases with age with 70% of patients >=80 years having AF.

In contrast to all AIS patients, in the subset of AF patients undergoing MT, AF is associated with reduced in-hospital mortality and better odds of routine home discharge.

What are the clinical implications?

Given the post-stroke CHA2DS2-VASc score of at least 2, almost half of all MT patients in the US may be potential candidates for therapeutic anticoagulation.
Population genomics of the rice landrace Acuce reveals exceptional dynamics of immune receptors
Authors: De Mita Stéphane , Duan Shengchang , Li Xiang , Pélissier Rémi , Mathieu Laura , Li Jingyu , Ma Linna , Li Zihang , Liao Jingjing , He Xiahong , Zhu Youyong , Li Chengyun , Dong Yang , Morel Jean-benoit , Huang Huichuan
Published: February 2024

Landraces are important resources for breeding programs. However, the diversity harbored at the genomic level by landraces is yet to be analyzed. Here we sequenced more than 200 individual plants from the long-lasting and durably resistant rice landrace Acuce (Oryza sativa subsp. indica). We found that Acuce exhibits diversity levels as high as 38% of the entire indica sub-species. We pinpoint signatures of selection in favor of polymorphism associated with resistance, but not other agronomic trait genes. Furthermore, we provide evidences that emerging properties upon mixing genomic diversity also increase Acuce's performances.
Tissue Tension and Strain as Indicators of Suction-mediated Cutaneous DNA Transfection: A Parametric Study
Authors: Jhumur Nandita Chakrabarty , Lallow Emran O. , Nachtigal Catherine , Yeo Dahee , Kwon Ijoo , Park Young K. , Roberts Christine C. , Zahn Jeffrey D. , Shreiber David I. , Shan Jerry W. , Singer Jonathan P. , Maslow Joel N. , Lin Hao
Published: February 2024

Cutaneous suction-based transfection is a recently developed technique that is painless and simple-to-use for the delivery of DNA for nucleic-acid-based vaccines. The technique promises high efficiency for both antigen expression and immunogenicity as demonstrated in both animal studies and human clinical trials. To realize this promise, a parametric study and systematic evaluation on the efficacy of cutaneous suction as a transfection method was performed. Using Green Fluorescent Protein (GFP) plasmid expression as a transfection reporter in a rat model, the expression level as a function of both suction nozzle size and suction pressure was quantified. A numerical model was employed to compute skin deformation in terms of strain, which was used to correlate with GFP expression. Based on these results, two quantities, total integrated strain and tissue tension, are proposed as indicators of expression level that can be used to guide protocol development and optimization. These indicators are also discussed in relation to possible cellular uptake mechanisms.
Phasing Diploid Genome Assembly Graphs with Single-Cell Strand Sequencing
Authors: Henglin Mir , Ghareghani Maryam , Harvey William , Porubsky David , Koren Sergey , Eichler Evan E. , Ebert Peter , Marschall Tobias
Published: February 2024

Haplotype information is crucial for biomedical and population genetics research. However, current strategies to producede-novohaplotype-resolved assemblies often require either difficult-to-acquire parental data or an intermediate haplotype-collapsed assembly. Here, we present Graphasing, a workflow which synthesizes the global phase signal of Strand-seq with assembly graph topology to produce chromosome-scalede-novohaplotypes for diploid genomes. Graphasing readily integrates with any assembly workflow that both outputs an assembly graph and has a haplotype assembly mode. Graphasing performs comparably to trio-phasing in contiguity, phasing accuracy, and assembly quality, outperforms Hi-C in phasing accuracy, and generates human assemblies with over 18 chromosome-spanning haplotypes.
Sex-specific fear acquisition following early life stress is linked to amygdala glutamate metabolism
Authors: Bordes Joeri , Bajaj Thomas , Miranda Lucas , van Doeselaar Lotte , Brix Lea Maria , Narayan Sowmya , Yang Huanqing , Mitra Shiladitya , Kovarova Veronika , Springer Margherita , Kleigrewe Karin , Mueller-Myhsok Bertram , Gassen Nils C , Schmidt Mathias V.
Published: February 2024

Early life stress (ELS) adversely affects physiological and behavioral outcomes, increasing the vulnerability to stress-related disorders, such as post-traumatic stress disorder (PTSD). PTSD prevalence is significantly higher in women and is partially mediated by genetic risk variants. Understanding how sex influences the interaction of PTSD risk genes, such as FKBP5, with trauma-related behaviors is crucial for uncovering PTSD's neurobiological pathways. The development of in-depth behavioral analysis tools using unsupervised behavioral classification is thereby a crucial tool to increase the understanding of the behavioral outcomes related to stress-induced fear memory formation. The current study investigates the sex-specific effects of ELS exposure by using the limited bedding and nesting (LBN) paradigm. The LBN exposure disrupted different facets of the hypothalamic-pituitary-adrenal (HPA) axis in a sex-specific manner directly after stress and at adult age. Moreover, freezing was altered by LBN exposure in both the acquisition and the retrieval of fear in a sex-dependent manner. Unsupervised behavioral analysis revealed a higher active fear response after LBN exposure during fear acquisition in females, but not in males. The regulation of the HPA axis is closely intertwined with cellular metabolism and core regulatory cascades. To investigate the impact of LBN exposure on tissue-specific metabolism, a metabolomic pathway analysis in the basolateral amygdala revealed a specific sex- and stress-dependent effect on purine, pyrimidine, and glutamate metabolism. The present study highlights the intricate interplay between metabolic pathways and the neurobiological substrates implicated in fear memory formation and stress regulation. Overall, these findings highlight the importance of considering sex-specific metabolic alterations in understanding the neurobiological mechanisms underlying stress-related disorders and offer potential avenues for targeted interventions.
A critical reexamination of recovered SARS-CoV-2 sequencing data
Authors: Débarre F. , Hensel Z.
Published: February 2024

SARS-CoV-2 genomes collected at the onset of the Covid-19 pandemic are valuable because they could help understand how the virus entered the human population. In 2021, Jesse Bloom reported on the recovery of a dataset of raw sequencing reads that had been removed from the NCBI SRA database at the request of the data generators, a scientific team at Wuhan University (Wanget al., 2020b). Bloom concluded that the data deletion had obfuscated the origin of SARS-CoV-2 and suggested that deletion may have been requested to comply with a government order; further, he questioned reported sample collection dates on and after January 30, 2020. Here, we show that sample collection dates were published in 2020 by Wanget al. together with the sequencing reads, and match the dates given by the authors in 2021. Collection dates of January 30, 2020 were manually removed by Bloom during his analysis of the data. We examine mutations in these sequences and confirm that they are entirely consistent with the previously known genetic diversity of SARS-CoV-2 of late January 2020. Finally, we explain how an apparent phylogenetic rooting paradox described by Bloom was resolved by subsequent analysis. Our reanalysis demonstrates that there was no basis to question the sample collection dates published by Wanget al..

Note for bioRxiv readers

The automatically generated Full Text version of our manuscript is missing footnotes; they are available in the PDF version.
The metabolome of individuals with knee osteoarthritis is influenced by 18-months of an exercise and weight loss intervention and sex: the IDEA trial
Authors: Welhaven Hope , Welfley Avery , Bothner Brian , Messier Stephen , Loeser Richard , June Ronald
Published: February 2024

Objective: The Intensive Diet and Exercise for Arthritis (IDEA) trial was conducted to evaluate the effects of diet and exercise on osteoarthritis (OA), the most prevalent form of arthritis. Various risk factors, such as obesity and sex, contribute to the debilitating nature of OA. While diet and exercise are known to improve OA symptoms, cellular and molecular mechanisms underlying these interventions, as well as effects of participant sex, remain elusive. Methods: Serum was obtained at three timepoints from IDEA participants assigned to groups of diet, exercise, or combined diet and exercise (n=10 per group). All serum metabolites were extracted and analyzed via liquid chromatography-mass spectrometry combined with metabolomic profiling. Extracted serum was pooled and fragmentation patterns were analyzed to identify metabolites that statistically differentially regulated between groups. Results: Changes in metabolism across male and female IDEA participants after 18-months of diet, exercise, and combined diet and excise intervention mapped to lipid, amino acid, carbohydrate, vitamin, and matrix metabolism. The diverse metabolic landscape detected across IDEA participants shows that intervention type impacts the serum metabolome of individuals with OA in distinct patterns. Moreover, differences in the serum metabolome corresponded with participant sex. Conclusions: These findings suggest that intensive weight loss among male and female subjects offers potential metabolic benefits for individuals with knee OA. This provides a deeper understanding of dysregulation occurring during OA development that may pave the way for improved interventions, treatments, and quality of life of those impacted by this disease.
The polysaccharide capsule ofAcinetobacter baumanniiaffects bacterial adhesion and natural transformation
Authors: Whiteway Clemence , de Pillecyn Victor , Maure Alexandra , Breine Anke , Valcek Adam , Buylaere Juliette Van , Van der Henst Charles
Published: February 2024

Acinetobacter baumanniiis an important threat worldwide due to its ability to acquire antibiotic resistance and survive harsh conditions. The polysaccharide capsule represents a major virulence and resistance asset. How the capsular polysaccharides barrier impacts bacterial adhesion remains to be investigated inA. baumannii.We characterized capsule mutants of the commonly used AB5075 strain. We assessed how these different capsule mutants adhere to biotic (bacterial and eukaryotic cells) and abiotic surfaces (polystyrene). We confirmed our observations using modern and relevant clinical isolates characterized by different capsule types and capsulation levels. Strains with low capsulation levels systematically depicted increased adhesion compared to capsulated strains, and mucoid isolates showed minimal adhesion. These results show capsule production inA. baumanniiaffects adhesion to various surfaces. We also determined that the presence/absence ofA. baumanniicapsule influences its natural transformability. This illustrates the importance of the trade-off of capsule production inA. baumannii.
Gender/Sex Disparities in the COVID-19 Cascade from Testing to Mortality: An Intersectional Analysis of Swiss Surveillance Data
Authors: Auderset Diane , Amiguet Michaël , Clair Carole , Pittet Valérie , Riou Julien , Schwarz Joëlle , Mueller Yolanda
Published: February 2024

Objectives

This study investigates gender and sex disparities in COVID-19 epidemiology in the Canton of Vaud, Switzerland, focusing on the interplay with socioeconomic position (SEP) and age.

Methods

We analyzed COVID-19 surveillance data from March 2020 to June 2021, using an intersectional approach. Negative binomial regression models assessed disparities between women and men, across SEP quintiles and age groups, in testing, positivity, hospitalizations, ICU admissions, and mortality (Incidence Rate Ratios [IRR], with 95% Confidence Intervals [CI]).

Results

Women had higher testing and positivity rates than men, while men experienced more hospitalizations, ICU admissions, and deaths. The higher positivity in women under 50 was mitigated when accounting for their higher testing rates. Within SEP quintiles, gender/sex differences in testing and positivity were not significant. In the lowest quintile, women’s mortality risk was 68% lower (Q1: IRR 0.32, CI 0.20-0.52), with decreasing disparities with increasing SEP quintiles (Q5: IRR 0.66, CI 0.41-1.06).

Conclusion

Our findings underscore the complex epidemiological patterns of COVID-19, shaped by the interactions of gender/sex, SEP, and age, highlighting the need for intersectional perspectives in both epidemiological research and public health strategy development.
Immunological Drivers and Potential Novel Drug Targets for Major Psychiatric, Neurodevelopmental, and Neurodegenerative Conditions
Authors: Dardani Christina , Robinson Jamie W. , Jones Hannah J. , Rai Dheeraj , Stergiakouli Evie , Grove Jakob , Gardner Renee , McIntosh Andrew M. , Havdahl Alexandra , Hemani Gibran , Smith George Davey , Richardson Tom G. , Gaunt Tom R. , Khandaker Golam M.
Published: February 2024

Immune dysfunction is implicated in the aetiology of psychiatric, neurodevelopmental, and neurodegenerative conditions, but the issue of causality remains unclear impeding attempts to develop new interventions. We have tested evidence for causality for 735 immune response-related biomarkers on 7 neuropsychiatric conditions, using cutting-edge genomic causal inference methods (Mendelian randomization and genetic colocalization) applied to genomic data on protein and gene expression across blood and brain. We provide robust evidence of causality for 21 biomarkers, including two previously unreported (LATS1, andFCN1), confirming a role of both brain specific and systemic immune response in the pathogenesis of several neuropsychiatric conditions especially schizophrenia, Alzheimer’s disease, depression, and bipolar disorder. Furthermore, 18 of the identified biomarkers are therapeutically tractable, includingACE,TNFRSF17, andCD40,with drugs approved or in advanced clinical trials, offering an opportunity for repurposing existing drugs for neuropsychiatric indications.
Spatial and Temporal Distribution of Visceral Leishmaniasis in Karamoja Region, Uganda: Analysis of surveillance data, 2015–2022
Authors: Wanyana Mercy Wendy , Migisha Richard , King Patrick , Kwesiga Benon , Kadobera Daniel , Bulage Lilian , Ario Alex Riolexus
Published: February 2024

Background

Uganda targets to control leishmaniasis and eliminate visceral leishmaniasis as a public health problem by 2030, with 85% of the cases detected, 95% treated, and visceral leishmaniasis eliminated (<1% case fatality rate [CFR]). However, little is documented on the country’s progress towards achieving these targets. We examined the temporal trends and spatial distribution of leishmaniasis in the endemic Karamoja Region of Uganda, 2015–2022.

Methods

We analysed aggregate secondary data on clinically diagnosed leishmaniasis laboratory-confirmed cases, visceral leishmaniasis cases, hospital admissions, and deaths from the District Health Information System 2. We used population-based calculations to determine the annual prevalence of leishmaniasis and quarterly prevalence of visceral leishmaniasis per 1,000,000 persons, while the prevalence of leishmaniasis admissions and CFRs were calculated per 100 cases. We used the Mann-Kendall test to assess the significance of the trend.

Results

Overall, 4,008 cases of clinically diagnosed leishmaniasis were reported, and of these, 11% were laboratory-confirmed. The average annual prevalence of leishmaniasis was 4 per 1,000,000 population. From 2020 to 2022, there was an increasing trend in quarterly prevalence of visceral leishmaniasis (Kendall’s score=36, p=0.016), averaging 3 cases per 1,000,000 population. Leishmaniasis admissions increased annually to 55 per 100 cases (Kendall’s score=23, p=0.006). The average annual CFR was 5%, with no deaths reported in 2018, 2019, and 2021. Amudat District had the highest prevalence rates of leishmaniasis (477 per 1,000,000 population) and visceral leishmaniasis (139 per 100,000 population).

Conclusion

The increasing trend of visceral leishmaniasis, and CFR >1% threaten the goal of controlling leishmaniasis as a public health problem by 2030. Gaps in case detection may further prevent the achievement of targets. Strengthening existing interventions, such as vector control and rapid diagnostic kits for early detection and treatment, may be crucial to sustain progress toward elimination targets.
Molecular switching of a DNA-sliding clamp to a repressor mediates long-range gene silencing
Authors: McLean Thomas C , Balaguer-Perez Francisco , Chandanani Joshua , Thomas Christopher M , Aicart-Ramos Clara , Burick Sophia , Olinares Paul Dominic B , Gobbato Giulia , Mundy Julia E A , Chait Brian T , Lawson David M , Darst Seth A , Campbell Elizabeth A , Moreno-Herrero Fernando , Le Tung B K
Published: February 2024

Long-range gene regulation is rare in bacteria and is confined to the classical DNA looping model. Here, we use a combination of biophysical approaches, including X-ray crystallography and single-molecule analysis, to show that long-range gene silencing on the plasmid RK2, a source of multidrug resistance across diverse Gram-negative bacteria, is achieved cooperatively by a DNA-sliding clamp, KorB, and a clamp-locking protein, KorA. We find that KorB is a CTPase clamp that can entrap and slide along DNA to reach distal target promoters. We resolved the tripartite crystal structure of a KorB-KorA-DNA co-complex, revealing that KorA latches KorB into a closed-clamp state. KorA thus stimulates repression by stalling KorB sliding at target promoters to occlude RNA polymerase holoenzymes. Altogether, our findings explain the mechanistic basis for KorB role-switching from a DNA-sliding clamp to a co-repressor, and provide a new paradigm for the long-range regulation of gene expression.
The far extracellular CUB domain of the adhesion GPCR ADGRG6/GPR126 is a key regulator of receptor signaling
Authors: Dintzner Ethan , Bandekar Sumit J. , Leon Katherine , Cechova Kristina , Vafabakhsh Reza , Araç Demet
Published: February 2024

Adhesion G Protein–coupled receptors (aGPCRs) transduce extracellular adhesion signals into cytoplasmic signaling pathways. ADGRG6/GPR126 is an aGPCR critical for axon myelination, heart development and ear development; and is associated with developmental diseases and cancers. ADGRG6 has a large, alternatively-spliced, five-domain extracellular region (ECR) that samples different conformations and regulates receptor signaling. However, the molecular details of how the ECR regulates signaling are unclear. Herein, we studied the conformational dynamics of the conserved CUB domain which is located at the distal N-terminus of the ECR and is deleted in an alternatively-spliced isoform (ΔCUB). We showed that theΔCUB isoform has decreased signaling. Molecular dynamics simulations suggest that the CUB domain is involved in interdomain contacts to maintain a compact ECR conformation. A cancer-associated CUB domain mutant, C94Y, drastically perturbs the ECR conformation and results in elevated signaling, whereas another CUB mutant, Y96A, located near a conserved Ca2+-binding site, decreases signaling. Our results suggest an ECR-mediated mechanism for ADGRG6 regulation in which the CUB domain instructs conformational changes within the ECR to regulate receptor signaling.
High density genomic surveillance and risk profiling of clinical Listeria monocytogenes subtypes in Germany, 2018-2021
Authors: Halbedel Sven , Wamp Sabrina , Lachmann Raskit , Holzer Alexandra , Pietzka Ariane , Ruppitsch Werner , Wilking Hendrik , Flieger Antje
Published: February 2024

Foodborne infections represent a significant public health concern, particularly when outbreaks affect many individuals over prolonged time. Systematic collection of pathogen isolates from infected patients, whole genome sequencing and phylogenetic analyses allow recognition and termination of outbreaks after source identification and risk profiling of abundant lineages. We here present a multi-dimensional analysis of >1,800 genome sequences from clinical L. monocytogenes isolates collected in Germany between 2018-2021. These isolates covered 62% of all notified cases and belonged to 188 infection clusters. 42% of these clusters were active for >12 months, 60% generated cases cross-regionally, including 11 multinational clusters. 37% of the clusters were caused by sequence type (ST) ST6, ST8 and ST1 clones and for selected clusters, we provide further epidemiological and genetic information. Frequencies of materno-fetal and brain infections allowed risk profiling of the most abundant STs, differentiating ST1 as hyper- and ST8, ST14, ST29 as well as ST155 as hypovirulent from ST6 with average virulence potential. Hepatocyte infection experiments confirmed these virulence differences. Inactivating mutations were found in several virulence and house-keeping genes, particularly in hypovirulent STs. Our work supports prioritization of clusters for epidemiological investigations and reinforces the need to analyse the mechanisms underlying hyper- and hypovirulence.
The activation chain of the broad-spectrum antiviral bemnifosbuvir at atomic resolution
Authors: Chazot Aurelie , Zimberger Claire , Feracci Mikael , Moussa Adel , Good Steven , Sommadossi Jean-Pierre , ALVAREZ Karine , Ferron Francois , Canard Bruno
Published: February 2024

Bemnifosbuvir (AT-527) and AT-752 are guanosine analogues currently in clinical trials against several RNA viruses. Here we show that these drugs require a minimal set of 5 cellular enzymes for activation to their common 5'-triphosphate AT-9010, with an obligate order of reactions. AT-9010 selectively inhibits essential viral enzymes, accounting for broad spectrum antiviral potency. Functional and structural data at atomic resolution decipher N6-purine deamination compatible with metabolic activation by human ADALP1. Crystal structures of human HINT1, ADALP1, GUK1, and NDPK at 2.09, 2.44, 1.76, and 1.9 A resolution, respectively, with cognate precursors of AT-9010 illuminate the activation pathway from the orally available bemnifosbuvir to AT-9010, pointing to key drug-protein contacts along the activation pathway. Our work provides a framework to integrate the design of antiviral nucleotide analogues, confronting requirements and constraints associated with activation enzymes along the 5'-triphosphate assembly line.
Structural characterization and dynamics of AdhE ultrastructures fromClostridium thermocellum:A containment strategy for toxic intermediates
Authors: Ziegler Samantha J. , Knott Brandon C. , Gruber Josephine N. , Hengge Neal N. , Xu Qi , Olson Daniel G. , Romero Eduardo E. , Joubert Lydia M. , Bomble Yannick J.
Published: February 2024

Clostridium thermocellum, a cellulolytic thermophilic anaerobe, is considered by many to be a prime candidate for the realization of consolidated bioprocessing (CBP) and is known as an industry standard for biofuel production.C. thermocellumis among the best biomass degraders identified to date in nature and produces ethanol as one of its main products. Many studies have helped increase ethanol titers in this microbe, however ethanol production usingC. thermocellumis still not economically viable. Therefore, a better understanding of its ethanol synthesis pathway is required. The main pathway for ethanol production inC. thermocelluminvolves the bifunctional aldehyde-alcohol dehydrogenase (AdhE). To better understand the function of theC. thermocellumAdhE, we used cryo-electron microscopy (cryo-EM) to obtain a 3.28 Å structure of the AdhE complex. This high-resolution structure, in combination with molecular dynamics simulations, provides insight into the substrate channeling of the toxic intermediate acetaldehyde, indicates the potential role ofC. thermocellumAdhE to regulate activity and cofactor pools, and establishes a basis for future engineering studies. The containment strategy found in this enzyme offers a template that could be replicated in other systems where toxic intermediates need to be sequestered to increase the production of valuable biochemicals.
Ultrastructure expansion microscopy (U-ExM) of mouse and human kidneys for analysis of subcellular structures
Authors: Langner Ewa , Puapatanakul Pongpratch , Pudlowski Rachel , Alsabbagh Dema Yaseen , Miner Jeffrey H. , Horani Amjad , Dutcher Susan K. , Brody Steven L. , Wang Jennifer T. , Suleiman Hani Y. , Mahjoub Moe R.
Published: February 2024

Ultrastructure expansion microscopy (U-ExM) involves the physical magnification of specimens embedded in hydrogels, which allows for super-resolution imaging of subcellular structures using a conventional diffraction-limited microscope. Methods for expansion microscopy exist for several organisms, organs, and cell types, and used to analyze cellular organelles and substructures in nanoscale resolution. Here, we describe a simple step-by-step U-ExM protocol for the expansion, immunostaining, imaging, and analysis of cytoskeletal and organellar structures in kidney tissue. We detail the critical modified steps to optimize isotropic kidney tissue expansion, and preservation of the renal cell structures of interest. We demonstrate the utility of the approach using several markers of renal cell types, centrioles, cilia, the extracellular matrix, and other cytoskeletal elements. Finally, we show that the approach works well on mouse and human kidney samples that were preserved using different fixation and storage conditions. Overall, this protocol provides a simple and cost-effective approach to analyze both pre-clinical and clinical renal samples in high detail, using conventional lab supplies and standard widefield or confocal microscopy.
Proteomic analysis uncovers clusterin-mediated disruption of actin-based contractile machinery in the trabecular meshwork to lower intraocular pressure
Authors: Soundararajan Avinash , Wang Ting , Pattabiraman Padmanabhan P
Published: February 2024

Glaucoma, a major cause of blindness, is characterized by elevated intraocular pressure (IOP) due to improper drainage of aqueous humor via the trabecular meshwork (TM) outflow pathway. Our recent work identified that loss of clusterin resulted in elevated IOP. This study delves deeper to elucidate the role of clusterin in IOP regulation. Employing anex vivohuman anterior segment perfusion model, we established that constitutive expression and secretion as well as exogenous addition of clusterin can significantly lower IOP. Interestingly, clusterin significantly lowered transforming growth factor β2 (TGFβ2)-induced IOP elevation. This effect was linked to the suppression of extracellular matrix (ECM) deposition and, highlighting the crucial role of clusterin in maintaining ECM equilibrium. A comprehensive global proteomic approach revealed the broad impact of clusterin on TM cell structure and function by identifying alterations in protein expression related to cytoskeletal organization, protein processing, and cellular mechanics, following clusterin induction. These findings underscore the beneficial modulation of TM cell structure and functionality by clusterin. Specifically, clusterin influences the actin-cytoskeleton and focal adhesion dynamics, which are instrumental in cell contractility and adhesion processes. Additionally, it suppresses the activity of proteins critical in TGFβ2, G-protein, and JAK-STAT signaling pathways, which are vital for the regulation of ocular pressure. By delineating these targeted effects of clusterin within the TM outflow pathway, our findings pave the way for novel treatment strategies aimed at mitigating the progression of ocular hypertension and glaucoma through targeted molecular interventions.
Resistance to Naïve and Formative Pluripotency Conversion in RSeT Human Embryonic Stem Cells
Authors: Chen Kevin G. , Johnson Kory R. , Park Kyeyoon , Maric Dragan , Yang Forest , Liu Wen Fang , Fann Yang C. , Mallon Barbara S. , Robey Pamela G.
Published: February 2024

One of the most important properties of human embryonic stem cells (hESCs) is related to their primed and naïve pluripotent states. Our previous meta-analysis indicates the existence of heterogeneous pluripotent states derived from diverse naïve protocols. In this study, we have characterized a commercial medium (RSeT)-based pluripotent state under various growth conditions. Notably, RSeT hESCs can circumvent hypoxic growth conditions as required by naïve hESCs, in which some RSeT cells (e.g., H1 cells) exhibit much lower single cell plating efficiency, having altered or much retarded cell growth under both normoxia and hypoxia. Evidently, hPSCs lack many transcriptomic hallmarks of naïve and formative pluripotency (a phase between naive and primed states). Integrative transcriptome analysis suggests our primed and RSeT hESCs are close to the early stage of post-implantation embryos, similar to the previously reported primary hESCs and early hESC cultures. Moreover, RSeT hESCs did not express naïve surface markers such as CD75, SUSD2, and CD130 at a significant level. Biochemically, RSeT hESCs exhibit a differential dependency of FGF2 and co-independency of both Janus kinase (JAK) and TGFβ signaling in a cell-line-specific manner. Thus, RSeT hESCs represent a previously unrecognized pluripotent state downstream of formative pluripotency. Our data suggest that human naïve pluripotent potentials may be restricted in RSeT medium. Hence, this study provides new insights into pluripotent state transitionsin vitro.
The gaming concession system in Macao: reform or retain?
Authors: Wang Changbin , Yan Libo
Published: February 2024

Purpose

This study aims to examine the problems of the concession system that Macao has long-term adopted to regulate its gaming industry and discuss alternatives.

Design/methodology/approach

Theoretical reflection was used to provide qualitatively different insights about governmental supervision of the gaming industry.

Findings

Two options for reform are proposed: (1) replace the concession system with a licensing system that does not restrict the number of concessionaires or the period of concession or (2) adopt a modified form of the concession system that changes the number of concessionaires, period of concessions and methods for selecting concessionaires.

Practical implications

This study’s results have implications for the Macao government and other gaming jurisdictions in Asia.

Originality/value

This study provides a comprehensive examination of the concession system for governmental supervision of the gaming industry.
Aligning academic career management in the evolving landscape of Cambodian public universities
Authors: Hum Chan , Choi Tae-Hee , Lo Sing-Kai , Sok Say , Yu Wai Mui Christina
Published: February 2024

Purpose

This study examines the management practices and alignment features needed to develop academic staff’s careers, mainly focusing on teaching competencies in the evolving landscape of Cambodian public universities.

Design/methodology/approach

A multiple-case research design was adopted to collect data from interviews with 11 academic leaders and focus-group discussions (FGDs) with 13 academic teachers at two public universities in provincial Cambodia. A thematic approach was performed to code and analyse data to address the research questions.

Findings

This study found that the management of academic careers in the selected universities was hybrid, deregulating state control to relative institutional autonomy for contracted employees but rather centralised management for civil servants. However, weak institutional leadership and negligence in formulating comprehensive institutional guidelines for strategic human resource management (HRM) have caused misalignments of management practices to develop academic careers in the studied contexts.

Research limitations/implications

This case study limits its findings to two universities in provincial Cambodia. Nevertheless, this study adds to the scarce literature on the research topic in Cambodian public universities and opens a path for cross-institutional and national comparative studies on similar foci.

Originality/value

This is a ground-breaking study set in the evolving space of Cambodian public higher education, where attention to the research area remains limited.