bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of Low-Titer O-Positive Whole Blood in Female Trauma Patients: A Literature Review, Qualitative Multidisciplinary Analysis of Risk/Benefit, and Guidelines for Its Use as a Universal Product in Hemorrhagic Shock
Authors: Clements Thomas W , Van Gent Jan-Michael , Menon Neethu , Roberts Aaron , Sherwood Molly , Osborn Lesley , Hartwell Beth , Refuerzo Jerrie , Bai Yu , Cotton Bryan A
Published: November 2023

BACKGROUND:

Whole blood transfusion is associated with benefits including improved survival, coagulopathy, and decreased transfusion requirements. The majority of whole blood transfusion is in the form of low-titer O-positive whole blood (LTOWB). Practice at many trauma centers withholds the use of LTOWB in women of childbearing potential due to concerns of alloimmunization. The purpose of this article is to review the evidence for LTOWB transfusion in female trauma patients and generate guidelines for its application.

STUDY DESIGN:

Literature and evidence for LTOWB transfusion in hemorrhagic shock are reviewed. The rates of alloimmunization and subsequent obstetrical outcomes are compared to the reported outcomes of LTOWB vs other resuscitation media. Literature regarding patient experiences and preferences in regards to the risk of alloimmunization is compared to current trauma practices.

RESULTS:

LTOWB has shown improved outcomes in both military and civilian settings. The overall risk of alloimmunization for Rhesus factor (Rh)− female patients in hemorrhagic shock exposed to Rh+ blood is low (3% to 20%). Fetal outcomes in Rh-sensitized patients are excellent compared to historical standards, and treatment options continue to expand. The majority of female patients surveyed on the risk of alloimmunization favor receiving Rh+ blood products to improve trauma outcomes. Obstetrical transfusion practices have incorporated LTOWB with excellent results.

CONCLUSIONS:

The use of whole blood resuscitation in trauma is associated with benefits in the resuscitation of severely injured patients. The rate at which severely injured, Rh-negative patients develop anti-D antibodies is low. Treatments for alloimmunized pregnancies have advanced, with excellent results. Fears of alloimmunization in female patients are likely overstated and may not warrant the withholding of whole blood resuscitation. The benefits of whole blood resuscitation likely outweigh the risks of alloimmunization.
Stochastic parabolic growth promotes coexistence and a relaxed error threshold in RNA-like replicator populations
Authors: Paczkó Mátyás , Szathmáry Eörs , Szilágyi András
Published: November 2023

The RNA world hypothesis proposes that during the early evolution of life, primordial genomes of the first self-propagating evolutionary units existed in the form of RNA-like polymers. Autonomous, non-enzymatic and sustained replication of such information carriers presents a problem, because product formation and hybridization between template and copy strands reduces replication speed. Kinetics of growth is then parabolic with the benefit of entailing competitive coexistence, thereby maintaining diversity. Here, we test the information-maintaining ability of parabolic growth in stochastic multispecies population models under the constraints of constant total population size and chemostat conditions. We find that large population sizes and small differences in the replication rates favor the stable coexistence of the vast majority of replicator species (“genes”), while the error-threshold problem is alleviated relative to exponential amplification. In addition, sequence properties (GC content) and the strength of resource competition mediated by the rate of resource inflow determine the number of coexisting variants, suggesting that fluctuations in building block availability favored repeated cycles of exploration and exploitation. Stochastic parabolic growth could thus have played a pivotal role in preserving viable sequences generated by random abiotic synthesis and providing diverse genetic raw material to the early evolution of functional ribozymes.
ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines
Authors: Lozinski Mathew , Bowden Nikola A. , Graves Moira C. , Fay Michael , Day Bryan W. , Stringer Brett W. , Tooney Paul A.
Published: November 2023

Glioblastoma cells can restrict the DNA-damaging effects of temozolomide (TMZ) and radiation therapy (RT) using the DNA damage response (DDR) mechanism which activates cell cycle arrest and DNA repair pathways. Ataxia-telangiectasia and Rad3-Related protein (ATR) plays a pivotal role in the recognition of DNA damage induced by chemotherapy and radiation causing downstream DDR activation. Here, we investigated the activity of gartisertib, a potent ATR inhibitor, alone and in combination with TMZ and/or RT in 12 patient-derived glioblastoma cell lines. We showed that gartisertib alone potently reduced the cell viability of glioblastoma cell lines, where sensitivity was associated with the frequency of DDR mutations and higher expression of the G2 cell cycle pathway. ATR inhibition significantly enhanced cell death in combination with TMZ and RT and was shown to have higher synergy than TMZ+RT treatment.MGMTpromoter unmethylated and TMZ+RT resistant glioblastoma cells were also more sensitive to gartisertib. Analysis of gene expression from gartisertib treated glioblastoma cells identified the upregulation of innate immune-related pathways. Overall, this study identifies ATR inhibition as a strategy to enhance the DNA-damaging ability of glioblastoma standard treatment, while providing preliminary evidence that ATR inhibition induces an innate immune gene signature that warrants further investigation.
Working Memory Gating in Obesity is Moderated by Striatal Dopaminergic Gene Variants
Authors: Herzog Nadine , Hartmann Hendrik , Janssen Lieneke Katharina , Kanyamibwa Arsene , Waltmann Maria , Kovacs Peter , Deserno Lorenz , Fallon Sean James , Villringer Arno , Horstmann Annette
Published: November 2023

Everyday life requires an adaptive balance between distraction-resistant maintenance of information and the flexibility to update this information when needed. These opposing mechanisms are proposed to be balanced through a working memory gating mechanism. Prior research indicates that obesity may elevate the risk of working memory deficits, yet the underlying mechanisms remain elusive. Dopaminergic alterations have emerged as a potential mediator. However, current models suggest these alterations should only shift the balance in working memory tasks, not produce overall deficits. The empirical support for this notion is currently lacking, however. To address this gap, we pooled data from three studies (N = 320) where participants performed a working memory gating task. Higher BMI was associated with overall poorer working memory, irrespective of whether there was a need to maintain or update information. However, when participants, in addition to BMI level, were categorized based on certain putative dopamine-signaling characteristics (Single Nucleotide Polymorphisms; specifically, Taq1A and DARPP-32), distinct working memory gating effects emerged. These SNPs, primarily associated with striatal dopamine transmission, appear to be linked with differences in updating, specifically, among high-BMI individuals. Moreover, blood amino acid ratio, which indicates central dopamine synthesis capacity, combined with BMI, shifted the balance between distractor-resistant maintenance and updating. These findings suggest that both dopamine-dependent and dopamine-independent cognitive effects exist in obesity. Understanding these effects is crucial if we aim to modify maladaptive cognitive profiles in individuals with obesity.
Loss of ninein interferes with osteoclast formation and causes premature ossification
Authors: Gilbert Thierry , Barbier Merlin , Duployer Benjamin , Dufrançais Ophélie , Martet Laure-Elene , Dalbard Elisa , Segot Loelia , Tenailleau Christophe , Vérollet Christel , Bierkamp Christiane , Merdes Andreas
Published: November 2023

Ninein is a centrosome protein that has been implicated in microtubule anchorage and centrosome cohesion. Mutations in the humannineingene have been linked to Seckel syndrome and to a rare form of skeletal dysplasia. However, the role of ninein in skeletal development remains unknown. Here, we describe a ninein knockout mouse with advanced endochondral ossification during embryonic development. Although the long bones maintain a regular size, the absence of ninein delays the formation of the bone marrow cavity in the prenatal tibia. Likewise, intramembranous ossification in the skull is more developed, leading to a premature closure of the interfrontal suture. We demonstrate that ninein is strongly expressed in osteoclasts of control mice, and that its absence reduces the fusion of precursor cells into syncytial osteoclasts. As a consequence, ninein-deficient osteoclasts have a reduced capacity to resorb bone. At the cellular level, the absence of ninein interferes with centrosomal microtubule organization, reduces centrosome cohesion, and provokes the loss of centrosome clustering in multinucleated mature osteoclasts. We propose that centrosomal ninein is important for osteoclast fusion, to enable a functional balance between bone-forming osteoblasts and bone-resorbing osteoclasts during skeletal development.
In silicoStudy of the Uncertainly SignificantVCPVariants reveal major Structural, Functional fluctuations leading to potential Disease-Based Associations
Authors: Das Tathagata , Roychowdhury Saileyee , Das Parimal
Published: November 2023

Valosin containing protein is involved in a plethora of crucial functions from proteostasis, stress granule clearance to genome maintenance and ubiquitination. Hence, mutations inVCPcan lead to a plethora of fatal diseases like Amyotrophic Lateral Sclerosis, Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1, Spastic paraplegia, Charcot-Marie-Tooth disease type 2Y, Dementia, and Osteitis Deformans to name a few. Studies onVCP’s disease phenotype relationship, structural, and functional modifications of the protein’s stability, conservation, molecular dynamics, and post-translational modifications haven’t been performed. Thisin silicostudy investigated the variants ofVCP(R95C, R95G, A160P, R191P, R191Q) which have conflicting interpretations of pathogenicity which are often depreciated and lack data. Additionally, this study screens the study cohort and the fatal diseases linked to all these variants. Interestingly through various computational tools and disease-based population studies, it was found that these variants are often found in patients linked with fatal diseases. The protein-protein interaction showedUFD1has a direct association withVCP. The physicochemical parameters showed that A160P had the highest fluctuations of all the variants.VCP’s protein secondary structure, molecular dynamics simulations of RMSD, RMSF, RoG, hydrogen bonds, and solvent accessibility were all comparatively impacted due to the changes caused by the variants. Box-plot and Principal component analysis of the MD simulations visualized the changes in the wild type of the protein. Research in wet labs and screening of patient cohorts is necessary to further characterize the diseases linked with these variants. This can potentially lead to the identification of biomarkers for fatal rare diseases.
Electric fields determine carbapenemase activity in class A β-lactamases
Authors: Jabeen Hira , Beer Michael , Spencer James , van der Kamp Marc W. , Bunzel H. Adrian , Mulholland Adrian J.
Published: November 2023

Antimicrobial resistance is a public health crisis. Limited understanding of the catalytic drivers in resistance-mediating enzymes such as β-lactamases hinders our ability to combat this crisis. Here, we dissect the catalytic contributions of active-site electric fields in class A β-lactamases. We studied the enzymatic hydrolysis of a carbapenem antibiotic by QM/MM molecular dynamics simulations and quantified active-site fields with a custom-made script. We discovered that the fields correlate well with activity and identified seven positions, some distal, that distinguish efficient carbapenemases. Electric-field analysis may help predict the activity of β-lactamases and guide antibiotic and enzyme design.

Abstract Figure

Electric field script:www.github.com/bunzela/FieldTools
DeepVASP-S: a deep-learning tool for explaining steric mechanism that controls binding specificity
Authors: Liu Yangying , Zhou Houliang , Chen Brian Y.
Published: November 2023

DeepVASP-S is a computational tool that leverages the capabilities of convolutional neural networks (CNNs) to analyze steric aspects of protein-ligand interactions and predict amino acid contributions to binding specificity. This tool combines structural bioinformatics with machine learning to address the complex problem of understanding how specific amino acids contribute to the specificity of binding. Here, we use this tool to predict subclasses for Enolase and Serine Protease according to their binding specificity, and explain it through the underlying steric mechanism. The strength of DeepVASP-S lies in its ability to identify and highlight these specific regions, providing researchers with insights into the molecular determinants of protein function and interaction. Such information is extremely valuable for the field of drug design, as it enables the creation of more targeted and effective therapeutics with minimized side effects. The approach taken by DeepVASP-S represents a significant step forward in computational biochemistry, merging high-resolution 3D structural data with the predictive power of machine learning to unlock a deeper understanding of protein-ligand interactions.
The smooth-walled human RVOT contains trabeculations that cause conduction delay
Authors: Jensen Bjarke , Bosada Fernanda M. , Blok Michiel , Scholman Koen T , Efimov Igor R , Boukens Bastiaan J
Published: November 2023

Aims

The right ventricular outflow tract (RVOT) is the outlet from the right ventricle and is the initiating substrate of life-threatening arrhythmias. While the luminal wall of the RVOT is often assumed to be without the complex trabecular meshwork that characterizes the right ventricular free wall, the anatomy of the RVOT is an understudied subject. Our aim was to investigate whether trabeculations occur in the RVOT and to assess whether this impacts electrical propagation.

Methods & Results

We used high-resolution MRI and serial sectioning to reconstruct the macroscopic details of the human RVOT and identified cases exhibiting much trabeculation. The smooth lumen of the RVOT varied between 9% and 23% of the total RV anterior surface (N=11). Histological analysis on additional six hearts indicated that the RVOT compact layer is thinner when trabeculations are present. RNA sequencing of four human donor hearts revealed enrichment in the subendocardial region of 88 genes associated with cardiac conduction and trabeculations (P adjusted<0.05). Finally, we selected two human donor hearts showing trabeculations in the RVOT from which we generated wedge preparation and performed optical and electrical mapping. The trabecular regions demonstrated high degree of fractionation when compared to non-trabeculated regions, which coincided with delayed activation.

Conclusion

Trabeculations are found in the RVOT, and their extent varies among individuals. This impacts on the thickness of the compact wall in the RVOT, restricting the depth of tissue at which clinical interventions can be performed, as well as influencing electrical propagation and possible arrhythmogenicity.
Towards Choice Engineering
Authors: Dan Ohad , Plonsky Ori , Loewnestein Yonatan
Published: November 2023

Effectively shaping human and animal behavior has been of great practical and theoretical importance for millennia. Here we ask whether quantitative models of choice can be used to achieve this goal more effectively than qualitative psychological principles. We term this approach, which is motivated by the effectiveness of engineering in the natural sciences, ‘choice engineering’. To address this question, we launched an academic competition, in which the academic participants were instructed to use either quantitative models or qualitative principles to design reward schedules that maximally bias choice in a repeated, two-alternative task. We found that a choice engineering approach was the most successful method for shaping behavior in our task. This is a proof of concept that quantitative models are ripe to be used in order to engineer behavior. Finally, we show that choice engineering can be effectively used to compare models in the cognitive sciences, thus providing an alternative to the standard statistical methods of model comparison that are based on likelihood or explained variance.
Myeloid Drp1 Deficiency Limits Revascularization in Ischemic Muscles via Inflammatory Macrophage Polarization and Metabolic Reprograming
Authors: Yadav Shikha , Ganta Vijay , Sudhahar Varadarajan , Ash Dipankar , Nagarkoti Sheela , Das Archita , McMenamin Margorzata , Kelley Stephanie , Fukai Tohru , Ushio-Fukai Masuko
Published: November 2023

In the preclinical model of peripheral arterial disease (PAD), M2-like anti-inflammatory macrophage polarization and angiogenesis are required for revascularization. The regulation of cell metabolism and inflammation in macrophages is tightly linked to mitochondrial dynamics. Drp1, a mitochondrial fission protein, has shown context-dependent macrophage phenotypes with both pro- and anti-inflammatory characteristics. However, the role of macrophage Drp1 in reparative neovascularization remains unexplored. Here we show that Drp1 expression was significantly increased in F4/80+macrophages within ischemic muscle at day 3 after hindlimb ischemia (HLI), an animal model of PAD. Myeloid-specific Drp1-/-mice exhibited reduced limb perfusion recovery, angiogenesis and muscle regeneration after HLI. These effects were associated with an increase in pro-inflammatory M1-like macrophages, p-NFkB and TNFα, and reduced anti-inflammatory M2-like macrophages and p-AMPK in ischemic muscle of myeloid Drp1-/-mice.In vitro, Drp1-/-macrophages under hypoxia serum starvation (HSS), an in vitro PAD model, demonstrated enhanced glycolysis via reducing p-AMPK as well as mitochondrial dysfunction and excessive mitochondrial ROS, resulting in increased M1-gene and reduced M2-gene expression. Conditioned media from HSS-treated Drp1-/-macrophages exhibited increased secretion of pro-inflammatory cytokines and suppressed angiogenic responses in cultured endothelial cells. Thus, Drp1 deficiency in macrophages under ischemia drives inflammatory metabolic reprogramming and macrophage polarization, thereby limiting revascularization in experimental PAD.
Characterisation of post-fundoplication gastric dysfunction using Gastric Alimetry
Authors: Xu William , Wang Tim , Foong Daphne , Schamberg Gabe , Evennett Nicholas , Beban Grant , Gharibans Armen , Calder Stefan , Daker Charlotte , Ho Vincent , O’Grady Greg
Published: November 2023

Background

Adverse gastric symptoms persist in up to 20% of fundoplication surgeries completed for gastroesophageal reflux disease, causing significant morbidity, and driving the need for revisional procedures. Non-invasive techniques to assess the mechanisms of persistent postoperative symptoms are lacking. We aimed to investigate gastric myoelectrical abnormalities and symptoms in patients after fundoplication using a novel non-invasive body surface gastric mapping (BSGM) device.

Methods

Patients with previous fundoplication surgery and ongoing significant gastroduodenal symptoms, and matched controls were included. BSGM using Gastric Alimetry (Alimetry, New Zealand) was employed, consisting of a high resolution 64-channel array, validated symptom-logging App, and wearable reader.

Results

16 patients with significant chronic symptoms post-fundoplication were recruited, with 16 matched controls. Overall, 6/16 (37.5%) patients showed significant spectral abnormalities defined by unstable gastric myoelectrical activity (n = 2), abnormally high gastric frequencies (n = 3) or high gastric amplitudes (n = 1). Those with spectral abnormalities had higher Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index scores (3.2 [2.8 to 3.6] vs 2.3 [2.2 to 2.8]; p =0.024). 7/16 patients (43.8%) had Gastric Alimetry tests suggestive of gut-brain axis contributions, and without myoelectrical dysfunction. Increasing Principal Gastric Frequency deviation, and decreasing Rhythm Index were associated with symptom severity (r>0.40, p<0.05).

Conclusion

A significant number of patients with persistent post-fundoplication symptoms display abnormal gastric function on Gastric Alimetry testing, which correlates with symptom severity. These findings advance the pathophysiological understanding of post-fundoplication disorders which may inform diagnosis and patient selection for medical therapy and revisional surgery.
Usual-Paced 400m Long Distance Corridor Walk Estimates Cardiorespiratory Fitness among Older Adults: The Study of Muscle, Mobility and Aging (SOMMA)
Authors: Moffit Reagan E. , Cawthon Peggy M. , Nicklas Barbara J. , Goodpaster Bret H. , Coen Paul M. , Forman Daniel E. , Cummings Steven R. , Newman Anne B. , Glynn Nancy W.
Published: November 2023

Background

Cardiopulmonary exercise testing (CPET), the gold-standard method to quantify cardiorespiratory fitness (CRF), is not always feasible due to cost, access, and burden. The usual-paced 400m long-distance corridor walk (LDCW), a measure of mobility among older adults, may provide an alternate method to assess CRF among populations unable to complete maximal intensity testing. The purpose of this study was to develop and validate an estimating equation to estimate VO2peak from average 400m walking speed (WS) among participants in the Study of Muscle, Mobility and Aging (SOMMA).

Methods

At baseline, participants (N=820, 76.2±4.9 years, 58% Women, 86% Non-Hispanic White) completed a 400m LDCW (400m WS=400m/completion time in seconds) and symptom-limited maximal CPET (Modified Balke Protocol). VO2peak (mL/kg/min) was considered the highest 30-second average oxygen consumption during CPET. Other covariates included: age, sex, race, physical activity (7-day wrist-worn accelerometer), physical function (Short Physical Performance Battery, range 0-12), perceived physical fatigability (Pittsburgh Fatigability Scale, range 0-50), and Borg Rating of Perceived Exertion (RPE, range 6-20) at completion of the 400m LDCW. Stepwise linear regression was used. Internal validation was completed using data-splitting method (70%; 30%).

Results

Mean VO2peak was 20.2±4.8 mL/kg/min and mean 400m WS was 1.06±0.2 m/s. Each 0.05 m/s increment in 400m WS was associated with a 0.40 mL/kg/min higher VO2peak after adjustment for covariates. An estimating equation including 400m WS, age, sex, race, and RPE was developed. Internal validation showed low overall bias (-0.26) and strong correlation (r = 0.71) between predicted and measured VO2peak values. Bland-Altman plot and regression analyses indicated predicted VO2peak was an acceptable alternative, despite mean underestimation of 4.53 mL/kg/min among those with CPET VO2peak ≥25 mL/kg/min.

Conclusions

Usual-paced 400m LDCW strongly correlates with direct measures of cardiorespiratory fitness during CPET in older adults with lower fitness and can be used to test both fitness and function.
Generalizability Assessment of AI Models Across Hospitals: A Comparative Study in Low-Middle Income and High Income Countries
Authors: Yang Jenny , Dung Nguyen Thanh , Thach Pham Ngoc , Phong Nguyen Thanh , Phu Vu Dinh , Phu Khiem Dong , Yen Lam Minh , Xuan Thy Doan Bui , Soltan Andrew A. S. , Thwaites Louise , Clifton David A.
Published: November 2023

The integration of artificial intelligence (AI) into healthcare systems within low-middle income countries (LMICs) has emerged as a central focus for various initiatives aiming to improve healthcare access and delivery quality. In contrast to high-income countries (HICs), which often possess the resources and infrastructure to adopt innovative healthcare technologies, LMICs confront resource limitations such as insufficient funding, outdated infrastructure, limited digital data, and a shortage of technical expertise. Consequently, many algorithms initially trained on data from non-LMIC settings are now being employed in LMIC contexts. However, the effectiveness of these systems in LMICs can be compromised when the unique local contexts and requirements are not adequately considered. In this study, we evaluate the feasibility of utilizing models developed in the United Kingdom (a HIC) within hospitals in Vietnam (a LMIC). Consequently, we present and discuss practical methodologies aimed at improving model performance, emphasizing the critical importance of tailoring solutions to the distinct healthcare systems found in LMICs. Our findings emphasize the necessity for collaborative initiatives and solutions that are sensitive to the local context in order to effectively tackle the healthcare challenges that are unique to these regions.
Lexical Markers of Disordered Speech in Primary Progressive Aphasia and ‘Parkinson-plus’ Disorders
Authors: Henderson Shalom K. , Ramanan Siddharth , Patterson Karalyn E. , Garrard Peter , Patel Nikil , Peterson Katie A. , Halai Ajay , Cappa Stefano F. , Rowe James B. , Lambon Ralph Matthew A.
Published: November 2023

Connected speech samples elicited by a picture description task are widely used in the assessment of aphasias, but it is not clear what their interpretation should focus on. Although such samples are easy to collect, analyses of them tend to be time-consuming, inconsistently conducted, and impractical for non-specialist settings. Here, we analysed connected speech samples from patients with the three variants of primary progressive aphasia (semantic, svPPA N = 9; logopenic, lvPPA N = 9; non-fluent, nfvPPA N = 9), progressive supranuclear palsy (PSP Richardson’s syndrome N = 10), corticobasal syndrome (CBS N = 13), and age-matched healthy controls. There were three principal aims: (i) to determine the differences in quantitative language output and psycholinguistic properties of words produced by patients and controls; (ii) to identify the neural correlates of connected speech measures; and (iii) to develop a simple clinical measurement tool. Using data-driven methods, we optimised a 15-word checklist for use with the Boston Diagnostic Aphasia Examination ‘cookie theft’ and Mini Linguistic State Examination ‘beach scene’ pictures and tested the predictive validity of outputs fromLeast Absolute Shrinkage and Selection Operator(LASSO) models using an independent clinical sample from a second site. The total language output was significantly reduced in patients with nfvPPA, PSP and CBS relative to those with svPPA and controls. The speech of patients with lvPPA and svPPA contained a disproportionately greater number of words of both high frequency and high semantic diversity. Results from our exploratory voxel-based morphometry analyses across the whole group revealed correlations between grey matter volume in (i) bilateral frontal lobes with overall language output, (ii) the left frontal and superior temporal regions with speech complexity, (iii) bilateral frontotemporal regions with phonology, and (iv) bilateral cingulate and subcortical regions with age of acquisition. With the 15-word checklists, the LASSO models showed excellent accuracy for within-samplek-fold classification (over 93%) and out-of-sample validation between patients and controls (over 90%), and moderately good (59% - 74%) differentiation between the motor disorders (nfvPPA, PSP, CBS) and lexico-semantic groups (svPPA, lvPPA). In conclusion, we propose that a simple 15-word checklist provides a suitable screening test to identify people with progressive aphasia, while further specialist assessment is needed to differentiate accurately some groups (e.g., svPPA versus lvPPA and PSP versus nfvPPA).
Confirmation of male well-being indicators in Malaysia
Authors: Mohd Ajis Siti Zaiton , Mohamad Emma , Azlan Arina Anis
Published: November 2023

Background

Assessing well-being can be tricky due to its subjective nature which may result in inaccurate or incomplete evaluations. This is particularly challenging in measuring male well-being, as traditional gender roles and expectations often discourage normalising discussions about men’s health concerns. Studies reveal notable obstacles in the way men perceive, behave, and hold beliefs about their health and well-being which may result in underreporting of health issues among men. A gender-specific measurement of well-being for men is therefore essential and merits further examination.

Methods

This study aims to validate a male well-being instrument in the context of Malaysian men using confirmatory factor analysis (CFA). An online cross-sectional survey involving a total of 651 Malaysian men aged 18 and above was conducted utilising a 33-item male well-being instrument developed in a preliminary study.

Results

The analysis resulted in a satisfactory 24-item model with six dimensions: self-confidence (4 items); family/close relationships adaptation (5 items); physical health (3 items); living environment adaptation (4 items); autonomy and agency (4 items); and economic stability (4 items). There were high correlations among the 24 items. The internal consistency reliability was robust, with no floor or ceiling effects. These results represented equivalence and consistency among the responses to items, suggesting that the items were homogenous in measuring Malaysian male well-being.

Conclusions

This study confirms the suitability of a 24-item instrument measuring male well-being in Malaysia. The instrument may possibly be used in similar Asian cultures as it achieved strong reliability, structural validity and construct validity that fulfilled goodness-of-fit criteria.
Deciphering the Metabolic Shifts in The Hippocampus of Mice Subjected to Near Low Dose Radiation: Insights from Metabolomics and Integrated Multi-omics
Authors: Narasimhamurthy Rekha Koravadi , Venkidesh Babu Santhi , Joshi M B , Satish Rao Bola Sadashiva , Sharan Krishna , Mumbrekar Kamalesh Dattaram
Published: November 2023

Recent years have witnessed a drastic upsurge in neurological disorders, with sporadic cases contributing more than ever to their cause. Radiation exposure through diagnostic or therapeutic routes often results in neurological injuries indicative of neurodegenerative pathogenesis. Nevertheless, the impact of low doses of radiation on the brain remains a subject of extensive discussion, as research findings have presented conflicting evidence regarding potential harm and benefits. In the present study, C57/BL mice were exposed to a whole-body single dose of 0.5 Gy X-ray. Fourteen days after treatment, the animals were euthanized, and the hippocampus was isolated and processed for metabolomic analysis. Statistical and bioinformatic analysis revealed 115 metabolites altered in the radiation-exposed group, while pathway enrichment analysis unveiled alterations in tyrosine, phenylalanine, aminoacyl-tRNA metabolism, arginine biosynthesis, glutathione, arginine, proline metabolism, etc. Furthermore, a multiomics interaction network of the genes and the metabolites was constructed to gather an overview of their interaction with the neighboring genes and metabolites in different pathways. These metabolic pathways correlate with synthesizing neurotransmitters such as dopamine and neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and dementia. The present study findings unveiled metabolomic level regulation of low-dose radiation-induced neurotoxicity and its implication in the pathogenesis of neurological disorders.
An intronic copy number variation inSyntaxin 17determines speed of greying and melanoma incidence in Grey horses
Authors: Rubin Carl-Johan , Hodge McKaela , Naboulsi Rakan , Beckman Madeleine , Bellone Rebecca R. , Kallenberg Angelica , J’Usrey Stephanie , Ohmura Hajime , Seki Kazuhiro , Ohnuma Aoi , Davis Brian W. , Tozaki Teruaki , Lindgren Gabriella , Andersson Leif
Published: November 2023

The Greying with age phenotype involves loss of hair pigmentation whereas skin pigmentation is not reduced and a predisposition to melanoma. The causal mutation was initially reported as a duplication of a 4.6 kb intronic sequence inSyntaxin 17. The speed of greying varies considerably among Grey horses. Here we demonstrate the presence of two differentGreyalleles,G2carrying two tandem copies of the duplicated sequence andG3carrying three. The latter is by far the most common allele, probably due to strong selection for the striking white phenotype. Our results reveal a remarkable dosage effect where theG3allele is associated with fast greying and high incidence of melanoma whereasG2is associated with slow greying and low incidence of melanoma. Epigenetic analysis, based on nanopore sequencing of genomic DNA, reveals a drastic reduction in DNA methylation in part of the duplicated sequence harboring MITF binding sites. The copy number expansion transforms a weak enhancer to a strong melanocyte-specific enhancer that underlies hair greying (G2andG3) and a drastically elevated risk of melanoma (G3only).
Swimming with the current improves juvenile survival in southern elephant seals
Authors: Foo Dahlia , McMahon Clive R. , Hindell Mark A. , Fedak Michael , Biuw Martin , McConnell Bernie , Raymond Ben
Published: November 2023

Understanding juvenile survival is crucial for the population ecology of long-lived species, where parental guidance can significantly influence survival rates of completely naive juveniles. In southern elephant seals (Mirounga leonina), however, offspring receive no knowledge from their parents, only fat reserves. This research focuses on how dispersal direction on their maiden foraging trip and physical traits influence the survival of naïve southern elephant seal pups at Macquarie Island. We tracked 44 pups with satellite tags during their post-weaning migration and compared their movements to the post-moult winter migrations of 58 adult females. We found that most pups (61.2%) travelled southeast, in line with the Antarctic Circumpolar Current. Pups travelling with the predominant east-southeast current had a 1.5 times higher survival rate for their first trip than those swimming westward against it. Those that swam with the current and were heavier were more likely to survive their first year. Adult females showed different dispersal patterns, where they travelled southwards towards Antarctic waters, implying that learning from experience influences their direction. Future investigations into the role of the primary eastward current in the sub-Antarctic on circumpolar movement patterns of top marine predators could expand our understanding of Southern Ocean ecology.
The changing morphology of the ventricular walls of mouse and human with increasing gestation
Authors: Jensen Bjarke , Chang Yun Hee , Bamforth Simon D. , Mohun Timothy , Sedmera David , Bartos Martin , Anderson Robert H.
Published: November 2023

That the highly trabeculated ventricular walls of the developing embryos transforms to the arrangement during the fetal stages, when the mural architecture is dominated by the thickness of the compact myocardium, has been explained by coalescence of trabeculations, often erroneously described as “compaction”. Recent data, however, supports differential rates of growth of the trabecular and compact layers as the major driver of change. Here, these processes were assessed quantitatively and morphologically using a larger dataset than has previously been available of mouse hearts from embryonic day 10.5 to postnatal day 3, supported by images from human hearts. The volume of the trabecular layer increased throughout development, in contrast to what would be expected had there been “compaction”. During the embryonic-fetal transition, fast growth of the compact layer diminished the proportion of trabeculations. Similarly, great expansion of the central cavity reduced the proportion that intertrabecular recesses make of the total cavity. Using the median value of left ventricular trabeculation, we provided illustrations for each gestational day so as to provide pictorial evidence of the changes. The illustrations confirmed a pronounced growth of the compact wall, and prominence of the central cavity. This corresponds, in morphological terms, to a reduction in the extent of the trabecular layer. Similar observations were made in the human hearts. We conclude that it is a period of comparatively slow growth of the trabecular layer, rather than so-called compaction, that is the major determinant of the changing morphology of the ventricular walls of both mouse and human.
Same principle, but different computations in representing time and space
Authors: Sima Sepehr , Sanayei Mehdi
Published: November 2023

Time and space are two intertwined contexts that frame our cognition of the world and have shared mechanisms. A well-known theory on this case is ‘A Theory of Magnitude (ATOM)’ which states that the perception of these two domains shares common mechanisms. However, evidence regarding shared computations of time and space is intermixed. To investigate this issue, we asked human subjects to reproduce time and distance intervals with saccadic eye movements in similarly designed tasks. We applied an observer model to both modalities and found underlying differences the processing of time and space. While time and space computations are both probabilistic, adding prior to space perception minimally improved model performance, as opposed to time perception which was consistently better explained by Bayesian computations. We also showed that while both measurement and motor variability were smaller in distance than time reproduction, only the motor variability was correlated between them, as both tasks used saccadic eye movements for response. Our results suggest that time and space perception abide by the same algorithm but have different computational properties.
Contexts facilitate dynamic value encoding in the mesolimbic dopamine system
Authors: Fraser Kurt M. , Collins Val L. , Wolff Amy R. , Ottenheimer David J. , Bornhoft Kaisa N. , Pat Fiona , Chen Bridget J. , Janak Patricia H , Saunders Benjamin T.
Published: November 2023

Adaptive behavior in a dynamic environment often requires rapid revaluation of stimuli that deviates from well-learned associations. The divergence between stable value-encoding and appropriate behavioral output remains a critical test to theories of dopamine’s function in learning, motivation, and motor control. Yet how dopamine neurons are involved in the revaluation of cues when the world changes to alter our behavior remains unclear. Here we make use of pharmacology, in vivo electrophysiology, fiber photometry, and optogenetics to resolve the contributions of the mesolimbic dopamine system to the dynamic reorganization of reward-seeking. Male and female rats were trained to discriminate when a conditioned stimulus would be followed by sucrose reward by exploiting the prior, non-overlapping presentation of a separate discrete cue - an occasion setter. Only when the occasion setter’s presentation preceded the conditioned stimulus did the conditioned stimulus predict sucrose delivery. As a result, in this task we were able to dissociate the average value of the conditioned stimulus from its immediate expected value on a trial-to-trial basis. Both the activity of ventral tegmental area dopamine neurons and dopamine signaling in the nucleus accumbens were essential for rats to successfully update behavioral responding in response to the occasion setter. Moreover, dopamine release in the nucleus accumbens following the conditioned stimulus only occurred when the occasion setter indicated it would predict reward. Downstream of dopamine release, we found that single neurons in the nucleus accumbens dynamically tracked the value of the conditioned stimulus. Together these results reveal a novel mechanism within the mesolimbic dopamine system for the rapid revaluation of motivation.
Conserved amino acid residues and gene expression patterns associated with the substrate preferences of the competing enzymes FLS and DFR
Authors: Choudhary Nancy , Pucker Boas
Published: November 2023

Background

Flavonoids, an important class of specialized metabolites, are synthesized from phenylalanine and present in almost all plant species. Different branches of flavonoid biosynthesis lead to products like flavones, flavonols, anthocyanins, and proanthocyanidins. Dihydroflavonols form the branching point towards the production of non-colored flavonols via flavonol synthase (FLS) and colored anthocyanins via dihydroflavonol 4-reductase (DFR). Despite the wealth of publicly accessible data, there remains a gap in understanding the mechanisms that mitigate competition between FLS and DFR for the shared substrate, dihydroflavonols.

Results

An angiosperm-wide comparison of FLS and DFR sequences revealed the amino acids at positions associated with the substrate specificity in both enzymes. A global analysis of the phylogenetic distribution of these amino acid residues revealed that monocots generally possess FLS with Y132 (FLSY) and DFR with N133 (DFRN). In contrast, dicots generally possess FLSHand DFRN, DFRD, and DFRA. DFRA, which restricts substrate preference to dihydrokaempferol, previously believed to be unique to strawberry species, is found to be more widespread in angiosperms and has evolved independently multiple times. Generally, angiosperm FLS appears to prefer dihydrokaempferol, whereas DFR appears to favor dihydroquercetin or dihydromyricetin. Moreover, in the FLS-DFR competition, the dominance of one over the other is observed, with typically only one gene being expressed at any given time.

Conclusion

This study illustrates how almost mutually exclusive gene expression and substrate-preference determining residues could mitigate competition between FLS and DFR, delineates the evolution of these enzymes, and provides insights into mechanisms directing the metabolic flux of the flavonoid biosynthesis, with potential implications for ornamental plants and molecular breeding strategies.
Physiology of the Weight Loss Plateau after Calorie Restriction, GLP-1 Receptor Agonism, and Bariatric Surgery
Authors: Hall Kevin D.
Published: November 2023

Objective

To investigate why different weight loss interventions result in varying durations of weight loss prior to approaching plateaus.

Methods

A validated mathematical model of energy balance and body composition dynamics was used to simulate mean weight loss trajectories in response to intensive calorie restriction, semaglutide 2.4 mg, tirzepatide 10 mg, and Roux en-Y gastric bypass (RYGB) surgery interventions. Each intervention was simulated by varying two model parameters affecting energy intake to fit the observed mean weight loss data. One parameter represented the persistent magnitude of the intervention to shift the system from baseline equilibrium and the other parameter represented the strength of the feedback control circuit relating weight loss to increased appetite.

Results

RYGB surgery resulted in a persistent intervention magnitude more than 4-fold greater than calorie restriction and about double that of tirzepatide and semaglutide. All interventions except calorie restriction substantially weakened the appetite feedback control circuit resulting in an extended period of weight loss prior to the plateau.

Conclusions

These preliminary mathematical modeling results suggest that both GLP-1 receptor agonism and RYGB surgery interventions act to weaken the appetite feedback control circuit regulating body weight and induce greater persistent effects to shift the body weight equilibrium as compared to intensive calorie restriction.
Molecular basis for dual functions in pilus assembly modulated by the lid of a pilus-specific sortase
Authors: Chang Chungyu , Ton-That HyLam , Osipiuk Jerzy , Joachimiak Andrzej , Das Asis , Ton-That Hung
Published: November 2023

The biphasic assembly of Gram-positive pili begins with the covalent polymerization of distinct pilins catalyzed by a pilus-specific sortase, followed by the cell wall anchoring of the resulting polymers mediated by the housekeeping sortase. InActinomyces oris, the pilus-specific sortase SrtC2 not only polymerizes FimA pilins to assemble type 2 fimbriae with CafA at the tip, but it can also act as the anchoring sortase, linking both FimA polymers and SrtC1-catalyzed FimP polymers (type 1 fimbriae) to peptidoglycan when the housekeeping sortase SrtA is inactive. To date, the structure-function determinants governing the unique substrate specificity and dual enzymatic activity of SrtC2 have not been illuminated. Here, we present the crystal structure of SrtC2 solved to 2.10-Å resolution. SrtC2 harbors a canonical sortase fold and a lid typical for class C sortases and additional features specific to SrtC2. Structural, biochemical, and mutational analyses of SrtC2 reveal that the extended lid of SrtC2 modulates its dual activity. Specifically, we demonstrate that the polymerizing activity of SrtC2 is still maintained by alanine-substitution, partial deletion, and replacement of the SrtC2 lid with the SrtC1 lid. Strikingly, pilus incorporation of CafA is significantly reduced by these mutations, leading to compromised polymicrobial interactions mediated by CafA. In asrtAmutant, the partial deletion of the SrtC2 lid reduces surface anchoring of FimP polymers, and the lid-swapping mutation enhances this process, while both mutations diminish surface anchoring of FimA pili. Evidently, the extended lid of SrtC2 enables the enzyme the cell wall-anchoring activity in a substrate-selective fashion.
Zinc stimulation of phytoplankton in a low carbon dioxide, coastal Antarctic environment
Authors: Kell Riss M , Subhas Adam V , Schanke Nicole L , Lees Lauren E , Chmiel Rebecca J , Rao Deepa , Brisbin Margaret M. Mars , Moran Dawn M , McIlvin Matthew R , Bolinesi Francesco , Mangoni Olga , Casotti Raffaella , Balestra Cecilia , Horner Tristan , Dunbar Robert B , Allen Andrew E. , DiTullio Giacomo R , Saito Mak A
Published: November 2023

Zinc (Zn) is a key micronutrient used by phytoplankton for carbon (C) acquisition, yet there have been few observations of its influence on natural oceanic phytoplankton populations. In this study, we observed Zn limitation of growth in the natural phytoplankton community of Terra Nova Bay, Antarctica, due to low (~220 μatm) pCO2 conditions, in addition to primary iron (Fe) limitation. Shipboard incubation experiments amended with Zn and Fe resulted in significantly higher chlorophyll a content and dissolved inorganic carbon drawdown compared to Fe addition alone. Zn and Fe response proteins detected in incubation and environmental biomass provided independent verification of algal co-stress for these micronutrients. These observations of Zn limitation under low pCO2 conditions demonstrate Zn can influence coastal primary productivity. Yet, as surface ocean pCO2 rises with continued anthropogenic emissions, the occurrence of Zn/C co-limitation will become rarer, impacting the biogeochemical cycling of Zn and other trace metal micronutrients.