bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Regular Screening and Lifestyle Modification on Cardiovascular Disease Risk Factors in South African Women Living With HIV
Authors: Hanley Sherika , Moodley Dhayendre , Naidoo Mergan , Brummel Sean S.
Published: March 2024

Background:

The Integration of cardiovascular disease SCreening and prevention in the HIV MAnagement plan for women of reproductive age study set out to determine the effectiveness of screening and lifestyle modification in modifying cardiovascular disease (CVD) risk factors in women living with HIV (WLHIV).

Methods:

In this prospective, quasiexperimental, intervention study, WLHIV aged 18–<50 years were enrolled from 2 clinics (intervention [I-arm]) and (control arms [C-arm]) in Umlazi, South Africa, between November 2018 and May 2019. Women in the I-arm received lifestyle modification advice on diet, physical activity, alcohol use, and smoking cessation and underwent annual screening for CVD risk. The CVD risk factors were assessed through standardized questionnaires and clinical and laboratory procedures at baseline and at end of 3 years of follow-up. Prevalence of metabolic syndrome and other CVD indices were compared between arms at end-of-study (EOS).

Results:

Total of 269 WLHIV (149 I-arm and 120 C-arm) with a mean ± SD age of 36 ± 1 years were included in the EOS analyses after 32 ± 2 months of follow-up. The metabolic syndrome prevalence at EOS was 16.8% (25/149) in the I-arm and 24% (24/120) in the C-arm (risk ratio 0.9; 95% CI: 0.5 to 1.1; P 0.86). Proportion of women with fasting blood glucose >5.6 mmol/L in the I-arm and C-arm were 2.7% (4/149) and 13.3% (16/120) respectively (risk ratio 0.2; 95% CI: 0.069 to 0.646; P < 0.01). High-density lipoprotein improved with the intervention arm from baseline to EOS (95% CI: −0.157 to −0.034; P < 0.05).

Conclusions:

Although there was no significant difference in the prevalence of metabolic syndrome between study arms, we observed decreased blood glucose levels in the I-arm compared with the C-arm and improved high-density lipoprotein within the I-arm, following lifestyle modification and regular screening for CVD risk factors in WLHIV.
Advanced HIV disease in East Africa and Nigeria, in The African Cohort Study
Authors: Oboho Ikwo K. , Esber Allahna L. , Dear Nicole , Paulin Heather N. , Iroezindu Michael , Bahemana Emmanuel , Kibuuka Hannah , Owuoth John , Maswai Jonah , Shah Neha , Crowell Trevor A. , Ake Julie A. , Polyak Christina S. ,   AFRICOS Study Group
Published: March 2024

Background:

Earlier antiretroviral therapy (ART) may decrease progression to advanced HIV disease (AHD) with CD4 count of <200 cells per cubic millimeter or clinical sequelae. We assessed factors associated with AHD among people living with HIV before and during the “test and treat” era.

Setting:

The African Cohort Study prospectively enrolls adults with and without HIV from 12 clinics in Uganda, Kenya, Tanzania, and Nigeria.

Methods:

Enrollment evaluations included clinical history, physical examination, and laboratory testing. Generalized estimating equations were used to estimate adjusted odds ratios and 95% confidence intervals for factors associated with CD4 count of <200 cells per cubic millimeter at study visits.

Results:

From 2013 to 2021, 3059 people living with HIV with available CD4 at enrollment were included; median age was 38 years [interquartile range: 30–46 years], and 41.3% were men. From 2013 to 2021, the prevalence of CD4 count of <200 cells per cubic millimeter decreased from 10.5% to 3.1%, whereas the percentage on ART increased from 76.6% to 100% (P <0.001). Factors associated with higher odds of CD4 count of <200 cells per cubic millimeter were male sex (adjusted odds ratio 1.56 [confidence interval: 1.29 to 1.89]), being 30–39 years (1.42 [1.11–1.82]) or older (compared with <30), have World Health Organization stage 2 disease (1.91 [1.48–2.49]) or higher (compared with stage 1), and HIV diagnosis eras 2013–2015 (2.19 [1.42–3.37]) or later (compared with <2006). Compared with ART-naive, unsuppressed participants, being viral load suppressed on ART, regardless of ART duration, was associated with lower odds of CD4 count of <200 cells per cubic millimeter (<6 months on ART: 0.45 [0.34–0.58]).

Conclusion:

With ART scale-up, AHD has declined. Efforts targeting timely initiation of suppressive ART may further reduce AHD risk.
Completion of multidose vaccine series in early childhood: current challenges and opportunities
Authors: Michels Sarah Y. , Daley Matthew F. , Newcomer Sophia R.
Published: March 2024

Purpose of review

Completion of all doses in multidose vaccine series provides optimal protection against preventable infectious diseases. In this review, we describe clinical and public health implications of multidose vaccine series noncompletion, including current challenges to ensuring children receive all recommended vaccinations. We then highlight actionable steps toward achieving early childhood immunization goals.

Recent findings

Although coverage levels are high for most early childhood vaccinations, rates of completion are lower for vaccinations that require multiple doses. Recent research has shown that lower family socioeconomic status, a lack of health insurance coverage, having multiple children in the household, and moving across state lines are associated with children failing to complete multidose vaccine series. These findings provide contextual evidence to support that practical challenges to accessing immunization servi

ces are impediments to completion of multidose series. Strategies, including reminder/recall, use of centralized immunization information systems, and clinician prompts, have been shown to increase immunization rates. Re-investing in these effective interventions and modernizing the public health infrastructure can facilitate multidose vaccine series completion.

Completion of multidose vaccine series is a challenge for immunization service delivery. Increased efforts are needed to address remaining barriers and improve vaccination coverage in the United States.
Prediction of Treatment Effect of SLE-ITP Patients Based on Cost-Sensitive Neural Network and Variational Autoencoder
Authors: Xie Qiaoqiao , Li Na , Lu Youbei , Chen Jiaqi , Qu Wenqiang , Geng Linyu , Sun Lingyun
Published: March 2024

Objective

The aim of the study was to examine the factors influencing the therapeutic effect of patients with systemic lupus erythematosus combined with immune thrombocytopenia (SLE-ITP) and develop a prediction model to predict the therapeutic effect of SLE-ITP.

Methods

Three hundred twenty-four SLE-ITP patients were retrieved from the electronic health record database of SLE patients in Jiangsu Province according to the latest treatment response criteria for ITP. We adopted the Cox model based on the least absolute shrinkage and selection operator to explore the impact factors affecting patient therapeutic effect, and we developed neural network model to predict therapeutic effect, and in prediction model, cost-sensitivity was introduced to address data category imbalance, and variational autoencoder was used to achieve data augmentation. The performance of each model was evaluated by accuracy and the area under the receiver operator curve.

Results

The results showed that B-lymphocyte count, H-cholesterol level, complement-3 level, anticardiolipin antibody, and so on could be used as predictors of SLE-ITP curative effect, and abnormal levels of alanine transaminase, immunoglobulin A, and apolipoprotein B predicted adverse treatment response. The neural network treatment effect prediction model based on cost-sensitivity and variational autoencoder was better than the traditional classifiers, with an overall accuracy rate closed to 0.9 and a specificity of more than 0.9, which was useful for clinical practice to identify patients at risk of ineffective treatment response and to achieve better individualized management.

Conclusions

By predicting the curative effect of SLE-ITP, the severity of patients can be determined, and then the best treatment strategy can be planned to avoid ineffective treatment.
Clinical Safety of Gadobutrol: Review of Over 25 Years of Use Exceeding 100 Million Administrations
Authors: Endrikat Jan , Gutberlet Matthias , Hoffmann Karl-Titus , Schöckel Laura , Bhatti Aasia , Harz Cornelia , Barkhausen Jörg
Published: March 2024

Background

The macrocyclic gadolinium-based contrast agent gadobutrol was introduced to the market in February 1998. Over the last 25 years, gadobutrol has been administered more than 100 million times worldwide providing a wealth of data related to safety.

Objective

The aim of this study was to perform a thorough review and status update on gadobutrol's safety.

Materials and Methods

Safety data from the clinical phase II–IV program and postmarketing surveillance were descriptively analyzed from February 1998 until December 31, 2022. Literature on special at-risk populations and specific safety aspects was critically summarized.

Results

Forty-five clinical phase II–IV studies recruited 7856 patients receiving gadobutrol. Drug-related adverse events (AEs) were reported in 3.4% and serious AEs in <0.1% of patients. Nausea (0.7%) and dysgeusia (0.4%) were the most reported AEs. All other drug-related AEs occurred ≤0.3%. After more than 100 million gadobutrol administrations, overall adverse drug reactions (ADRs) from postmarketing surveillance (including clinical trials) were rare with an overall reporting rate of 0.0356%, hypersensitivity reactions (0.0147%), nausea (0.0032%), vomiting (0.0025%), and dyspnea (0.0010%). All other ADRs were <0.001%. No trend for higher rates of AEs was found in patients with reduced renal or liver function. Seven clinical studies reported safety findings in 7292 children ≤18 years, thereof 112 newborns/toddlers younger than 2 years. Overall, 61 ADRs (0.84%) were reported, including 3 serious ones. Adverse events in patients ≥65 years of age (“elderly”) were significantly less frequent than in younger patients. A total of 4 reports diagnostic of or consistent with nephrogenic systemic fibrosis have been received. No causal relationship has been established between clinical signs and symptoms and the presence of small amounts of gadolinium in the body in patients with normal renal function after use of gadobutrol.

Conclusions

More than 100 million administrations worldwide have shown gadobutrol's well-established benefit-risk profile in any approved indication and populations.
Neoadjuvant Peptide Receptor Radionuclide Therapy in a Rare Case of Pediatric Primary Hepatic Gastrinoma
Authors: Mahato Sougata , Aggarwal Piyush , Thunga Chennakeshava , Sood Ashwani , Kanojia Ravi P. , Nada Ritambhra , Lal Sadhna B.
Published: March 2024

Gastrinomas with predilection for the adult male population are located in the gastrinoma triangle (>90%). Primary hepatic gastrinoma especially in pediatric population is very rare. Peptide receptor radionuclide therapy has shown benefit in metastatic gastroenteropancreatic neuroendocrine tumors (NETs) with an increasing interest in expanding its role as neoadjuvant treatment modality to improve the surgical candidature in inoperable NETs. There is currently no literature supporting its role in the pediatric NET patients. We present a rare case of a young boy with primary hepatic gastrinoma where 177Lu-based peptide receptor radionuclide therapy in the neoadjuvant setting contributed to his final disease-free status.
Discovering Genetic Modulators of the Protein Homeostasis System through Multilevel Analysis
Authors: Sarsani Vishal , Aldikacti Berent , Zhao Tingting , He Shai , Chien Peter , Flaherty Patrick
Published: March 2024

Every protein progresses through a natural lifecycle from birth to maturation to death; this process is coordinated by the protein homeostasis system. Environmental or physiological conditions trigger pathways that maintain the homeostasis of the proteome. An open question is how these pathways are modulated to respond to the many stresses that an organism encounters during its lifetime. To address this question, we tested how the fitness landscape changes in response to environmental and genetic perturbations using directed and massively parallel transposon mutagenesis inCaulobacter crescentus. We developed a general computational pipeline for the analysis of gene-by-environment interactions in transposon mutagenesis experiments. This pipeline uses a combination of general linear models (GLMs), statistical knockoffs, and a nonparametric Bayesian statistical model to identify essential genetic network components that are shared across environmental perturbations. This analysis allows us to quantify the similarity of proteotoxic environmental perturbations from the perspective of the fitness landscape. We find that essential genes vary more by genetic background than by environmental conditions, with limited overlap among mutant strains targeting different facets of the protein homeostasis system. We also identified 146 unique fitness determinants across different strains, with 19 genes common to at least two strains, showing varying resilience to proteotoxic stresses. Experiments exposing cells to a combination of genetic perturbations and dual environmental stressors show that perturbations that are quantitatively dissimilar from the perspective of the fitness landscape are likely to have a synergistic effect on the growth defect.

Significance Statement

This study provides critical insights into how cells adapt to environmental and genetic challenges affecting protein homeostasis. Using multilevel statistical analysis and transposon mutagenesis, we find that a model organism,Caulobacter crescentus, lacks a universal redundancy mechanism for coping with stress, as evidenced by the limited overlap in essential genes across different environmental and genetic perturbations. Our methods also pinpoint key fitness determinants and enable the prediction of perturbation combinations that synergistically affect cell growth.
The effect of enriched versus depleted housing on eucalyptus smoke-induced cardiovascular dysfunction in mice
Authors: Harmon Molly E. , Fiamingo Michelle , Toler Sydnie , Lee Kaleb , Kim Yongho , Martin Brandi , Gilmour Ian , Farraj Aimen K. , Hazari Mehdi S.
Published: March 2024

Living conditions play a major role in health and well-being, particularly for the cardiovascular and pulmonary systems. Depleted housing contributes to impairment and development of disease, but how it impacts body resiliency during exposure to environmental stressors is unknown. This study examined the effect of depleted (DH) versus enriched housing (EH) on cardiopulmonary function and subsequent responses to wildfire smoke. Two cohorts of healthy female mice, one of them surgically implanted with radiotelemeters for the measurement of electrocardiogram, body temperature (Tco) and activity, were housed in either DH or EH for 7 weeks. Telemetered mice were exposed for 1 hour to filtered air (FA) and then flaming eucalyptus wildfire smoke (WS) while untelemetered mice, which were used for ventilatory assessment and tissue collection, were exposed to either FA or WS. Animals were continuously monitored for 5-7 days after exposure. EH prevented a decrease in Tco after radiotelemetry surgery. EH mice also had significantly higher activity levels and lower heart rate during and after FA and WS. Moreover, EH caused a decreased number of cardiac arrhythmias during WS. WS caused ventilatory depression in DH mice but not EH mice. Housing enrichment also upregulated the expression of cardioprotective genes in the heart. The results of this study indicate that housing conditions impact overall health and cardiopulmonary function. More importantly, depleted housing appears to worsen the response to air pollution. Thus, non-chemical factors should be considered when assessing the susceptibility of populations, especially when it comes to extreme environmental events.
Mispacking of the F87 sidechain drives aggregation-promoting conformational fluctuations in the subunit interfaces of the transthyretin tetramer
Authors: Sun Xun , Ferguson James A , Yang Ke , Stanfield Robyn L , Dyson Jane , Wright Peter
Published: March 2024

Aberrant formation and deposition of human transthyretin (TTR) aggregates causes transthyretin amyloidosis. To initialize aggregation, transthyretin tetramers must first dissociate into monomers that partially unfold to promote entry into the aggregation pathway. The native TTR tetramer (T) is stabilized by docking of the F87 sidechain into an interfacial cavity enclosed by several hydrophobic residues including A120. We have previously shown that an alternative tetramer (T*) with mispacked F87 sidechains is more prone to dissociation and aggregation than the native T state. However, the molecular basis for the reduced stability in T* remains unclear. Here we report characterization of the A120L mutant, where steric hindrance is introduced into the F87 binding site. The X-ray structure of A120L shows that the F87 sidechain is displaced from its docking site across the subunit interface. In A120S, a naturally occurring pathogenic mutant that is less aggregation-prone than A120L, the F87 sidechain is correctly docked, as in the native TTR tetramer. Nevertheless,19F-NMR aggregation assays show an elevated population of a monomeric aggregation intermediate in A120S relative to a control containing the native A120, due to accelerated tetramer dissociation and slowed monomer tetramerization. The mispacking of the F87 sidechain is associated with enhanced exchange dynamics for interfacial residues. At 298 K, the T* populations of various naturally occurring mutants fall between 4-7% (ΔG ~ 1.5-1.9 kcal/mol), consistent with the free energy change expected for undocking and solvent exposure of one of the four F87 sidechains in the tetramer (ΔG ~ 1.6 kcal/mol). Our data provide a molecular-level picture of the likely universal F87 sidechain mispacking in tetrameric TTR that promotes interfacial conformational dynamics and increases aggregation propensity.
Deep learning modeling of ribosome profiling reveals regulatory underpinnings of translatome and interprets disease variants
Authors: He Jialin , Xiong Lei , Shi Shaohui , Li Chengyu , Chen Kexuan , Fang Qianchen , Nan Jiuhong , Ding Ke , Li Jingyun , Mao Yuanhui , Boix Carles A. , Hu Xinyang , Kellis Manolis , Xiong Xushen
Published: March 2024

Gene expression involves transcription and translation. Despite large datasets and increasingly powerful methods devoted to calculating genetic variants' effects on transcription, discrepancy between mRNA and protein levels hinders the systematic interpretation of the regulatory effects of disease-associated variants. Accurate models of the sequence determinants of translation are needed to close this gap and to interpret disease-associated variants that act on translation. Here, we present Translatomer, a multimodal transformer framework that predicts cell-type-specific translation from mRNA expression and gene sequence. We train Translatomer on 33 tissues and cell lines, and show that the inclusion of sequence substantially improves the prediction of ribosome profiling signal, indicating that Translatomer captures sequence-dependent translational regulatory information. Translatomer achieves accuracies of 0.72 to 0.80 for de novo prediction of cell-type-specific ribosome profiling. We develop an in silico mutagenesis tool to estimate mutational effects on translation and demonstrate that variants associated with translation regulation are evolutionarily constrained, both within the human population and across species. Notably, we identify cell-type-specific translational regulatory mechanisms independent of eQTLs for 3,041 non-coding and synonymous variants associated with complex diseases, including Alzheimer's disease, schizophrenia, and congenital heart disease. Translatomer accurately models the genetic underpinnings of translation, bridging the gap between mRNA and protein levels, and providing valuable mechanistic insights toward mapping "missing regulation" in disease genetics.
Eligibility to COAPT trial in the daily practice: a real-world experience
Authors: Zancanaro Edoardo , Buzzatti Nicola , Denti Paolo , Guicciardi Nicolò Azzola , Melillo Enrico , Monaco Fabrizio , Agricola Eustachio , Ancona Francesco , Alfieri Ottavio , De Bonis Michele , Maisano Francesco
Published: March 2024

Background

The COAPT Trial was the first ever to demonstrate a survival benefit in treating functional mitral regurgitation (FMR). That was achieved through transcatheter mitral repair in selected patient. The exact proportion of patients fulfilling COAPT selection criteria in the real-world is unknown.

Objectives

to assess the applicability of COAPT criteria in real-world and its impact on patients’ survival.

Methods

We assessed the clinical data and follow-up results of all consecutive patients admitted for FMR at our Department between January 2016 and May 2021 according to COAPT eligibility. COAPT eligibility was retrospectively assessed by a cardiac surgeon and a cardiologist.

Results

Among 394 patients, 56 (14%) were COAPT eligible. The most frequent reasons for exclusion were MR<=2 (22%), LVEF <20% or >50% (19%), and non-optimized GDMT (21.3%). Among NON-COAPT patients, weighted 4-year survival was higher in patients who received MitraClip compared to those who were left in optimized medical therapy (91.5% (CI: [0.864, 0.96] vs 71.8 % (CI = [0.509, 0.926]) respectively, p=0.027)

Conclusions

Only a minority (14%) of real-world patients with FMR referred to a tertiary hospital fulfilled the COAPT selection criteria. Among NON-COAPT patients, weighted 4-year survival was higher in patients who received MitraClip compared to those who were left in optimized medical therapy (91.5% (CI: [0.864, 0.96] vs 71.8 % (CI = [0.509, 0.926]) respectively, p=0.027)

Condensed Abstract

In the present real-life single center experience, only a small proportion of patients with functional mitral regurgitation were COAPT-like. Non-COAPT like patients treated with MitraClip experienced improved survival compared to those left in medical therapy and similar survival compared to patients treated with MitraClip fulfilling COAPT criteria. While these findings require further validation, the numerous patients currently referred to percutaneous repair outside the COAPT criteria should not be denied intervention but should receive a tailored Heart-Team evaluation. Further refinement of patients selection for transcatheter mitral valve repair and longer follow-up remain necessary.

Key messages

What is already known about this subject?It is established the efficacy of TEER in case of FMR and the results form the highly selective COAPT trial.

What does this study add?This is the first article that prove the applicability of COAPT in real practice and shows the good outcomes also in patients excluded by the trial.

How might this impact on clinical practice?This may help the operator not to exclude patients with anatomy and clinical features considered not fit from one of the most important trials in the last 10 years on TEER and medical therapy.
Genome-Wide Association Study Reveals Influence of Cell-specific Gene Networks on Soybean Root System Architecture
Authors: Sun Ying , Miller Charlotte , Rajurkar Ashish B. , Lynch Ryan C. , Alyward Anthony , Zhang Ling , Shaner Marieken , Copeland Charles D. , Ye Heng , Nguyen Henry T. , Busch Wolfgang , Michael Todd P.
Published: March 2024

Root system architecture (RSA) describes the shape and arrangement of a plant’s roots in the soil including the angle, rate of growth, and type of individual roots, which facilitates the uptake of nutrients and water. In crop improvement efforts, RSA has been less well studied due to the technical challenges associated with phenotyping roots as well as a focus on above-ground traits such as yield. We developed a gel-based root phenotyping system calledRADICYL(Root Architecture 3D Cylinder), which is a non-invasive, high-throughput approach that enabled us to measure 15 RSA traits. We leveragedRADICYLto perform a comprehensive genome-wide association study (GWAS) with a panel of 371 diverse soybean elite lines, cultivars, landraces, and closely related species to identify gene networks underlying RSA. We identified 54 significant single nucleotide polymorphisms (SNPs) in our GWAS, some of which were shared across multiple RSA traits while others were specific to a given trait. We generated a single cell atlas of the soybean root using single nuclei RNA sequencing (snRNAseq) to explore the associated genes in the context of root tissues. Using gene co-expression network (GCN) analyses applied to RNA-seq of soybean root tissues, we identified network-level associations of genes predominantly expressed in endodermis with root width, and of those expressed in metaphloem with lateral root length. Our results suggest that pathways active in the endodermis and metaphloem cell-types influence soybean root system architecture.
Insights into post-translational regulation of skeletal muscle contractile function by the acetyltransferases, p300 and CBP
Authors: Meyer Gretchen A. , Ferey Jeremie L.A. , Sanford James A. , Fitzgerald Liam S. , Greenberg Akiva E. , Svensson Kristoffer , Greenberg Michael J. , Schenk Simon
Published: March 2024

Mice with skeletal muscle-specific inducible double knockout of the lysine acetyltransferases, p300 (E1A binding protein p300) and CBP (cAMP-response element-binding protein binding protein), referred to as i-mPCKO, demonstrate a dramatic loss of contractile function in skeletal muscle and ultimately die within 7 days. Given that many proteins involved in ATP generation and cross-bridge cycling are acetylated, we investigated whether these processes are dysregulated in skeletal muscle from i-mPCKO mice and thus could underlie the rapid loss of muscle contractile function. Just 4-5 days after inducing knockout of p300 and CBP in skeletal muscle from adult i-mPCKO mice, there was ∼90% reduction inex vivocontractile function in the extensor digitorum longus (EDL) and a ∼65% reduction inin vivoankle dorsiflexion torque, as compared to wildtype (WT; i.e. Cre negative) littermates. Despite the profound loss of contractile force in i-mPCKO mice, there were no genotype-driven differences in fatigability during repeated contractions, nor were there genotype differences in mitochondrial specific pathway enrichment of the proteome, intermyofibrillar mitochondrial volume or mitochondrial respiratory function. As it relates to cross-bridge cycling, remarkably, the overt loss of contractile function in i-mPCKO muscle was reversed in permeabilized fibers supplied with exogenous Ca2+and ATP, with active tension being similar between i-mPCKO and WT mice, regardless of Ca2+concentration. Actin-myosin motility was also similar in skeletal muscle from i-mPCKO and WT mice. In conclusion, neither mitochondrial abundance/function, nor actomyosin cross-bridge cycling, are the underlying driver of contractile dysfunction in i-mPCKO mice.

New & Noteworthy

The mechanism underlying dramatic loss of muscle contractile function with inducible deletion of both p300 and CBP in skeletal muscle remains unknown. Here we find that impairments in mitochondrial function or cross-bridge cycling are not the underlying mechanism of action. Future work will investigate other aspects of excitation-contraction coupling, such as Ca2+handling and membrane excitability, as contractile function could be rescued by permeabilizing skeletal muscle, which provides exogenous Ca2+and bypasses membrane depolarization.
Bioinformatic analysis of human ZPR1 gene pathogenic exome mutations
Authors: Abok Jeremiah I. , Garver William S. , Edwards Jeremy S.
Published: March 2024

Advanced sequencing technologies enable rapid detection of sequence variants, aiming to uncover the molecular foundations of human genetic disorders. The challenge lies in interpreting the influence of new exome variants that lead to diverse phenotypes. Our study introduces a detailed, multi-tiered method for assessing the impact of novel variants, particularly focusing on the zinc finger protein 1 (ZPR1) gene. Herein, we employed a combination of variant effect predictors, protein stability analyses, and the American College of Medical Genetics and Association of Molecular Pathology (ACMG/AMP) guidelines. Our structural analysis pinpoints specific amino acid residues in the ZPR1 zinc finger domains that are sensitive to changes, distinguishing between benign and disease-causing coding variants using rigorousin silicotools. We examined 223 germline ZPR1 exome variants, uncovering significant ethnic disparities in the frequency of heterozygous harmful ZPR1 variants, ranging from 0.04% in the Ashkenazi Jewish population to 0.34% in African/African Americans. Additionally, the discovery of three homozygous carriers in European and South Asian groups suggests a higher occurrence of ZPR1 variants in these demographics, meriting further exploration. This research provides insights into the prevalence and implications of amino acid substitutions in the ZPR1 protein.
Hydroxysteroid 17-beta dehydrogenase 13(Hsd17b13)knockdown attenuates liver steatosis in high-fat diet obese mice
Authors: Mahmood Shehroz , Morrice Nicola , Thompson Dawn , Milanizadeh Sara , Wilson Sophie , Whitfield Philip D. , Mcilroy George D. , Rochford Justin J. , Mody Nimesh
Published: March 2024

Hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) loss-of-function gene variants are associated with decreased risk of ‘metabolic dysfunction-associated steatotic liver disease’ (MASLD). Our RNA-seq analysis of steatotic liver from obese mice -/+ Fenretinide treatment identified major beneficial effects of Fenretinide on hepatic gene expression includingHsd17b13. We sought to determine the relationship between Hsd17b13 expression and MASLD and to validate it as a therapeutic target by liver-specific knockdown. Hsd17b13 expression, which is unique to hepatocytes and associated with the lipid-droplet, was elevated in multiple models of MASLD and normalised with prevention of obesity and steatotic liver. Direct, liver- specific, shRNA-mediated knockdown ofHsd17b13(shHsd17b13) in high-fat diet (HFD)-obese mice, markedly improved hepatic steatosis with no effect on body weight, adiposity or glycaemia.shHsd17b13decreased elevated serum ALT, serum FGF21 levels and markers of liver fibrosis e.g.Timp2.shHsd17b13knockdown in HFD-obese mice and Hsd17b13 overexpression in cells reciprocally regulated expression of lipid metabolism genes e.g.Cd36. Global lipidomic analysis of liver tissue revealed a major decrease in diacylglycerols (e.g. DAG 34:3) withshHsd17b13and an increase in phosphatidylcholines containing polyunsaturated fatty acids (PUFA) e.g. PC 34:3 and PC 42:10. Expression of key genes involved in phospholipid and PUFA metabolism e.g.Cept1, were also reciprocally regulated suggesting a potential mechanism of Hsd17b13 biological function and role in MASLD. In conclusion,Hsd17b13knockdown in HFD-obese adult mice was able to alleviate MASLD via regulation of fatty acid and phospholipid metabolism, thereby confirming HSD17B13 as a genuine therapeutic target for MASLD and development of liver fibrosis.

KEY POINTS

HSD17B13loss-of-function gene variants are associated with decreased risk of metabolic dysfunction-associated (MA) steatotic liver disease and steatohepatitis (MASLD and MASH).

RNA-seq analysis of steatotic liver identified beneficial effects of Fenretinide on hepatic gene expression including downregulation ofHsd17b13.

Liver-specific shRNA knockdown ofHsd17b13in obese mice markedly improved hepatic steatosis and markers of liver health e.g. serum ALT, serum Fgf21 levels.

Hsd17b13 influenced expression of lipid/phospholipid metabolism genes e.g. Cd36 and Cept1 and phosphatidylcholines PC 34:3 and PC 42:10.

Our study suggests a mechanism of HSD17B13’s biological function and the strong rationale behind targeting HSD17B13 for MASLD/MASH.
Premeiotic endoreplication is the mechanism of obligate parthenogenesis in rock lizards of the genusDarevskia
Authors: Dedukh Dmitrij , Altmanová Marie , Petrosyan Ruzanna , Arakelyan Marine , Galoyan Eduard , Kratochvíl Lukáš
Published: March 2024

Among vertebrates, obligate parthenogenesis occurs exclusively in squamate reptiles. Premeiotic endoreplication in a small subset of developing oocytes has been documented as the mechanism of production of unreduced eggs in minutely explored obligate parthenogenetic lineages, namely in teiids and geckos. The situation in the lacertid genusDarevskiahas been discussed for decades. Certain observations suggested that ploidy level is restored during egg formation through a fusion of egg and polar body nuclei inD. unisexualisandD. armeniaca. In this study, we re-evaluated the fusion hypothesis by studying diplotene chromosomes in adult females of sexual speciesD. raddei nairensisand obligate parthenogensD. armeniaca, D. dahliandD. unisexualis. We revealed 19 bivalents in the sexual species and 38 bivalents in the diploid obligate parthenogens, which uncovers premeiotic endoreplication as the mechanism of the production of non-reduced eggs in parthenogenetic females. The earlier contradicting reports can be likely attributed to the difficulty in identifying mispairing of chromosomes in pachytene, and the fact that in parthenogenetic reptiles relying on premeiotic endoreplication only a small subset of developing oocytes undergo genome doubling and overcome the pachytene checkpoint. This study highlights co-option of premeiotic endoreplication for escape from sexual reproduction in all independent hybrid origins of obligate parthenogenesis in vertebrates studied to date.
Taste evolution in an herbivorous drosophilid
Authors: Peláez Julianne N. , Bernstein Susan , Okoro Judith , Rodas Esteban , Liang Irene , Leipertz Anna , Marion-Poll Frédéric , Whiteman Noah K.
Published: March 2024

Plant secondary metabolites pose a challenge for generalist herbivorous insects because they are not only potentially toxic, they also may trigger aversion. On the contrary, some highly specialized herbivorous insects evolved to use these same compounds as ‘token stimuli’ for unambiguous determination of their host plants. Two questions that emerge from these observations are how recently derived herbivores evolve to overcome this aversion to plant secondary metabolites and the extent to which they evolve increased attraction to these same compounds. In this study, we addressed these questions by focusing on the evolution of bitter taste preferences in the herbivorous drosophilidScaptomyza flava, which is phylogenetically nested deep in the paraphyleticDrosophila. We measured behavioral and neural responses ofS. flavaand a set of non-herbivorous species representing a phylogenetic gradient (S. pallida, S. hsui, andD. melanogaster) towards host- and non-host derived bitter plant compounds. We observed thatS. flavaevolved a shift in bitter detection, rather than a narrow shift towards glucosinolates, the precursors of mustard-specific defense compounds. In a dye-based consumption assay,S. flavaexhibited shifts in aversion toward the non-mustard bitter, plant-produced alkaloids caffeine and lobeline, and reduced aversion towards glucosinolates, whereas the non-herbivorous species each showed strong aversion to all bitter compounds tested. We then examined whether these changes in bitter preferences ofS. flavacould be explained by changes in sensitivity in the peripheral nervous system and compared electrophysiological responses from the labellar sensilla ofS. flava,S. pallida, andD. melanogaster. Using scanning electron microscopy, we also created a map of labellar sensilla inS. flavaandS. pallida. We assigned each sensillum to a functional sensilla class based on their morphology and initial response profiles to bitter and sweet compounds. Despite a high degree of conservation in the morphology and spatial placement of sensilla betweenS. flavaandS. pallida, electrophysiological studies revealed thatS. flavahad reduced sensitivity to glucosinolates to varying degrees. We found this reduction only in I type sensilla. Finally, we speculate on the potential role that evolutionary genetic changes in gustatory receptors betweenS. pallidaandS. flavamay play in driving these patterns. Specifically, we hypothesize that the evolution of bitter receptors expressed in I type sensilla may have driven the reduced sensitivity observed inS. flava, and ultimately, its reduced bitter aversion. TheS. flavasystem showcases the importance of reduced aversion to bitter defense compounds in relatively young herbivorous lineages, and how this may be achieved at the molecular and physiological level.
FLYNC: A Machine Learning-Driven Framework for Discovering Long Non-Coding RNAs inDrosophila melanogaster
Authors: dos Santos Ricardo F. , Baptista Tiago , Marques Graça S. , Homem Catarina C. F.
Published: March 2024

Non-coding RNAs have increasingly recognized roles in critical molecular mechanisms of disease. However, the non-coding genome ofDrosophila melanogaster, one of the most powerful disease model organisms, has been understudied. Here, we present FLYNC – FLY Non-Coding discovery and classification – a novel machine learning-based model that predicts the probability of a newly identified RNA transcript being a long non-coding RNA (lncRNA). Integrated into an end-to-end bioinformatics pipeline capable of processing single-cell or bulk RNA sequencing data, FLYNC outputs potential new non-coding RNA genes. FLYNC leverages large-scale genomic and transcriptomic datasets to identify patterns and features that distinguish non-coding genes from protein-coding genes, thereby facilitating lncRNA prediction. We demonstrate the application of FLYNC to publicly availableDrosophilaadult head bulk transcriptome and single-cell transcriptomic data fromDrosophilaneural stem cell lineages and identify several novel tissue- and cell-specific lncRNAs. We have further experimentally validated the existence of a set of FLYNC positive hits by qPCR. Overall, our findings demonstrate that FLYNC serves as a robust tool for identifying lncRNAs inDrosophila melanogaster, transcending current limitations in ncRNA identification and harnessing the potential of machine learning.
Resting natural killer cells promote the progress of colon cancer liver metastasis by elevating tumor-derived sSCF
Authors: Mao Chenchen , Chen Yanyu , xing dong , zhang teming , Lin Yangxuan , Long Cong , yu jiaye , Luo Yunhui , Ming Tao , Mei Dianfeng , xie wangkai , han zheng , Xiang Dan , Lu Mingdong , shen xian , xue xiangyang
Published: March 2024

Purpose: The abundance and biological contribution of Natural killer (NK) cells in cancer are controversial. Here, we aim to uncover clinical relevance and cellular roles of NK cells in colon cancer liver metastasis (CCLM) Methods: We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-sequencing datasets to investigate NK cells' biological properties and functions in the microenvironment of primary and liver metastatic tumors. Results were validated through an in vitro co-culture experiment based on bioinformatics analysis. Results: We used single-cell RNA sequencing and spatial transcriptomics to map the immune cellular landscape of colon cancer and well-matched liver metastatic cancer. We discovered that GZMK+ resting NK cells increased significantly in tumor tissues and were enriched in the tumor regions of both diseases. After combining bulk RNA and clinical data, we observed that these NK cell subsets contributed to a worse prognosis. Meanwhile, KIR2DL4+ activated NK cells exhibited the opposite position and relevance. Pseudotime cell trajectory analysis revealed the evolution of activated to resting NK cells. In vitro experiments further confirmed that tumor-cell-co-cultured NK cells exhibited a decidual-like status, as evidenced by remarkable increasing CD9 expression. Functional experiments finally revealed that NK cells exhibited tumor-activating characteristics by promoting the dissociation of SCF (stem cell factor) on the tumor cells membrane depending on cell-to-cell interaction, as the supernatant of the co-culture system enhanced tumor progression. Conclusion: Together, our findings revealed a population of protumorigenic NK cells that may be exploited for novel therapeutic strategies to improve therapeutic outcomes for patients with CCLM.
Evidence for the independent evolution of a rectal complex within the beetle superfamily Scarabaeoidea
Authors: Beaven Robin , Denholm Barry , Fremlin Maria , Scaccini Davide
Published: March 2024

Rectal or cryptonephridial complexes have evolved repeatedly in arthropods, including in beetles where they occur in ∼190,000 species of Cucujiformia and Bostrichoidea, and Lepidoptera where they occur in ∼160,000 species. Sections of the Malpighian/renal tubules coat the outer surface of the rectum, acting as powerful recycling systems of the gut contents, recovering water and specific solutes. There are hints that a rectal complex evolved independently within another beetle group, Scarabaeoidea. Here we report our observations of rectal complexes in Scarabaeoidea, which support this view. We did not find a rectal complex in the related group, Staphylinoidea, or in Lucanidae, a basal group of Scarabaeoidea. We did observe rectal complexes inMelolontha melolontha(Melolonthini),Pachnoda marginataandCetonia aurata(Cetoniinae), consistent with previous reports from these groups. Intriguingly we found that rectal complexes occur in adult, but notM. melolonthalarvae, and larvae but not adults within Cetoniinae, indicating dramatic pupal remodelling of these organ systems. Insights into the structure of the rectal complexes of Scarabaeoidea are compared with the well-studied rectal complexes of Cucujiformia. Finally we discuss possible functions of the rectal complexes of beetles within Scarabaeoidea, and future approaches to address this question.
Nextflow vs. plain Bash: Different Approaches to the Parallelisation of SNP Calling from the Whole Genome Sequence Data
Authors: Sztuka Marek , Kotlarz Krzysztof , Mielczarek Magda , Hajduk Piotr , Liu Jakub , Szyda Joanna
Published: March 2024

This study compared computational approaches to parallelisation of an SNP calling workflow. Data comprised DNA from five Holstein-Friesian cows sequenced with the Illumina platform. The pipeline consisted of quality control, alignment to the reference genome, post-alignment, and SNP calling. Three approaches to parallelisation were compared: (i) a plain Bash script in which a pipeline for each cow was executed as separate processes invoked at the same time, (ii) a Bash script wrapped in a single Nextflow process, and (iii) a Nextflow script with each component of the pipeline defined as a separate process. The results demonstrated that on average, the multi-process Nextflow script performed 15% to 27% faster depending on the number of assigned threads, with the biggest execution time advantage over the plain Bash approach observed with 10 threads. In terms of RAM usage, the most substantial variation was observed for the multi-process Nextflow, for which it increased with the number of assigned threads, while RAM consumption of the other setups did not depend much on the numbers of threads assigned for computations. Due to intermediate and log files generated, disk usage was markedly higher for the multi-process Nextflow than for the plain Bash and for the single-process Nextflow.
Multi-COBRA hemagglutinin formulated with cGAMP microparticles elicit protective immune responses against influenza viruses
Authors: Zhang Xiaojian , Shi Hua , Hendy Dylan A. , Bachelder Eric M. , Ainslie Kristy M. , Ross Ted M.
Published: March 2024

Influenza viruses cause a common respiratory disease known as influenza. In humans, seasonal influenza viruses can lead to epidemics, with avian influenza viruses of particular concern because they can infect multiple species and lead to unpredictable and severe disease. Therefore, there is an urgent need for a universal influenza vaccine that provides protection against seasonal and pre-pandemic influenza virus strains. The cyclic GMP-AMP (cGAMP) is a promising adjuvant for subunit vaccines that promotes type I interferons production through the stimulator of interferon genes (STING) pathway. The encapsulation of cGAMP in acetalated dextran (Ace-DEX) microparticles (MPs) enhances its intracellular delivery. In this study, the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology was used to generate H1, H3, and H5 vaccine candidates. Monovalent and multivalent COBRA HA vaccines formulated with cGAMP Ace-DEX MPs were evaluated in a mouse model for antibody responses and protection against viral challenge. Serological analysis showed that cGAMP MPs adjuvanted monovalent and multivalent COBRA vaccines elicited robust antigen-specific antibody responses after a prime-boost vaccination and antibody titers were further enhanced after second boost. Compared to COBRA vaccine groups with no adjuvant or blank MPs, the cGAMP MPs enhanced HAI antibody responses against COBRA vaccination. The HAI antibody titers were not significantly different between cGAMP MPs adjuvanted monovalent and multivalent COBRA vaccine groups for most of the viruses tested in panels. The cGAMP MPs adjuvanted COBRA vaccines groups had higher antigen-specific IgG2a binding titers than the COBRA vaccine groups with no adjuvant or blank MPs. The COBRA vaccines formulated with cGAMP MPs mitigated disease caused by influenza viral challenge and decreased pulmonary viral titers in mice. Therefore, the formulation of COBRA vaccines plus cGAMP MPs is a promising universal influenza vaccine that elicits protective immune responses against human seasonal and pre-pandemic strains.
Erectile Dysfunction in Men with and without Type 2 Diabetes Mellitus at Livingstone University Teaching Hospital, Zambia: A cross-sectional study
Authors: Muchaili Lweendo , Mweene Bislom C. , Hamooya Benson M. , Masenga Sepiso Kenias
Published: March 2024

Background

Erectile dysfunction (ED) is frequently undiagnosed in males with type 2 diabetes mellitus (T2DM), despite its high prevalence. Early detection of ED in T2DM is crucial for effective treatment and prevention of severe complications such as cardiovascular events. This study explores the prevalence of ED and its associated factors in males with and without T2DM at Livingstone University Teaching Hospital (LUTH), Zambia.

Methodology

We conducted a cross-sectional study at LUTH among 42 males aged ≥18 years (22 with and 20 without T2DM). T2DM diagnosis was confirmed through medical records, and erectile dysfunction was assessed using the International Index of Erectile Function (IIEF-5) questionnaire. Logistic regression identified factors associated with ED, with significance set at a p-value less than 0.05

Results

The overall prevalence of ED was 74% (31/42). Among T2DM participants, the prevalence of ED was 91% (20/22; 95% confidence interval (CI) 70.8-98.9) whereas among the non-diabetic participants, the prevalence was 55% (11/20; 95%CI 31.5-76.9). The majority [40% (8/20)] of the T2DM participants with ED had mild ED, 35% (7/20) had mild to moderate ED, 15% (3/20) had moderate ED and 10% (2/20) had severe ED. 54.5% (6/11)] of the non-T2DM participants with ED had mild ED, 36.4% (4/11) had mild to moderate ED, 9.1% (1/11) had moderate ED, and none had severe ED. In the multivariable analysis, employed individuals had lower odds of erectile dysfunction compared to the unemployed (OR 0.01, 95% CI 0.00 - 0.84, p = 0.041); while elevated plasma creatinine levels were associated with an increased risk of erectile dysfunction (OR 1.22, 95% CI 1.03 - 1.45, p = 0.021).

Conclusion

This study underscores a significant prevalence of ED, particularly heightened in T2DM participants; and significantly associated with plasma creatinine levels and employment status. The findings highlight the need for comprehensive assessment and management of ED in T2DM individuals. There is a need for further research with larger sample sizes to validate the findings and for a clearer understanding of associated factors and identification of effective targeted interventions.