bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal deployment of limited vaccine supplies to combat mpox
Authors: Berry Matthew T , MacIntyre C Raina , Cromer Deborah , Hacker Adam , Davenport Miles P , Khoury David S
Published: November 2024

Mpox outbreaks in Central Africa have been declared a public health emergency of international concern by the World Health Organization. Fortunately, real-world effectiveness studies of the MVA-BN vaccine indicate that it has an effectiveness of 74% after one dose, and 82% after two doses against mpox. However, given the very limited supply of vaccines in Central Africa, there remain questions around the optimal deployment of limited MVA-BN doses. In this study, we consider whether more mpox cases might be averted by following the traditional two-dose vaccine regimen (4 week dosing interval), or by giving a single dose of MVA-BN to as many individuals as possible. We find that the optimal strategy depends on both, (i) the degree to which a subpopulation might be at higher risk of mpox, or severe mpox, infections, and (ii) how long ago the first dose was administered to the most at-risk subpopulation.
Site-variable allocation ratios in randomized controlled trials: implications for sample size, recruitment efficiency, and statistical analysis
Authors: Roshanov Pavel S.
Published: November 2024

Introduction

In multicentre randomized trials, some sites face logistical constraints that specifically affect their ability to recruit into one arm of the trial more than other arms. Often these are greater limits on their ability to deliver one of the study interventions. This paper proposes the use of allocation ratios that differ by site to increase recruitment capacity in asymmetrically constrained sites.

Methods

Simulations of randomized trials assessed the impact of several allocation ratios (1:1 to 1:5)—and variation of ratios across sites—on sample size and recruitment capacity, and evaluated several adjustment approaches for time-to-event, binary, and continuous outcomes to prevent bias from site-variable allocation ratios.

Results

Deviating from 1:1 allocation increases recruitment capacity within sites facing asymmetric constraints faster than it increases sample size requirements. For instance, a 1:3 ratio increased sample size by 35% but doubled the hypothetical recruitment capacity with fewer sites. The bias in treatment effect estimates that occurs when the baseline risk or outcome mean differ between sites allocated with different ratios was readily prevented with simple covariate adjustment or stratification by site or allocation ratio.

Conclusions

Site-variable allocation ratios may relieve recruitment bottlenecks caused by asymmetric constraints in trial procedures that affect some of the sites in a trial. Accounting for the variation in allocation ratios during analysis is necessary to ensure unbiased treatment effect estimates. This strategy is particularly relevant for trials with low marginal costs for participant recruitment and follow-up, such as many large pragmatic trials embedded in routine care.
The Causal Nexus of Immune Cells and Vitiligo: A Genetic Perspective
Authors: Lin Ziyi , Wu Zhimin , Duan Xingwu
Published: November 2024

Objective

This study aims to explore the causal relationship between 731 immune cell traits and vitiligo using Mendelian randomization.

Methods

We used a two-sample Mendelian randomization (MR) analysis, employing genetic variations extracted from genome-wide association studies (GWAS) as instrumental variables (IVs). Data sources included immune phenotype data from 3,757 European individuals and data from FinnGen, comprising a total of 385,538 samples (292 cases and 385,509 controls). The study used the inverse-variance weighted (IVW) method as the primary analysis method and conducted various robustness tests through median-based weighted analysis, mode-based weighted analysis, and the MR-Egger method to control for false positive results in multiple hypothesis testing.

Results

Our study found that the pathogenesis of vitiligo may significantly reduce the levels of the following immune cells: TD CD4+ %T cells (b=-0.458, 95% CI=0.17-0.76, PFDR=0.015, P=0.000), CD25 on CD39+ CD4+ cells (b=-0.155, 95% CI=0.78-0.94, PFDR=0.166, P=0.769), and CD4 on HLA DR+ CD4+ cells (b=-0.431, 95% CI=0.50-0.85, PFDR=0.166, P=0.001). Additionally, the causal effect estimate of vitiligo on CCR2 on monocyte is 0.75 (b=-0.290, 95% CI=0.64-0.88, PFDR=0.114, P=0.828), and a negative association was also found on FSC-A on NK cells (b=-0.481, 95% CI=0.47-0.82, PFDR=0.142, P=0.197). On the other hand, our study suggests that the occurrence of vitiligo may increase the levels of CD28 on CD28+ CD45RA+ CD8br cells (b=0.311, 95% CI=1.13-1.65, PFDR=0.166, P=0.393).

Conclusion

The results of this study reveal causal links between vitiligo and multiple immune cell traits, highlighting the important role of the immune system in the pathogenesis of vitiligo. These findings provide new research directions for controlling vitiligo through immune regulation and may pave the way for early intervention and treatment strategies.
Incidence and Progression Patterns of Chronic Pain Disparities Revealed by Analyzing the All of Us Research Program Data
Authors: Baldwin Edwin , Zhou Jin , Luo Wenting , Hooten W. Michael , Fan Jungwei W. , Li Haiquan
Published: November 2024

Disparities in the progression of ten chronic overlapping pain conditions (COPC) and four comorbid mental disorders among traditionally underrepresented populations have rarely been reported in the literature. In this study, we conducted retrospective cohort analyses using All of Us Research Program data from 1981 to 2022 to address this issue. Separate cohorts were created to assess the disparities by sex, race, and ethnicity. Logistic regression models, controlling for demographic variables, were employed to identify significant disparity factors associated with the progression from one COPC or mental condition to another. Among 122 frequent disease pairs, we identified demographic disparities in nine progression pathways. For example, we found an increased likelihood of subsequent depression after irritable bowel syndrome in Hispanics versus non-Hispanic individuals (OR:3.13, p<10−10). To our knowledge, this is the first study to unveil demographic disparities in COPC progression. These findings underscore the importance of examining health disparities among individuals affected by multiple chronic pain conditions.

Author Summary

Understanding the disparities in chronic overlapping pain conditions (COPC) can aid patients and clinicians in managing and optimizing therapy. Although disparities have been extensively reported for individual COPCs, progression disparity between conditions has been rarely studied. This study addresses this gap by identifying multiple disparities related to sex, race, and ethnicity in COPC progression, providing valuable insights for patients and clinicians to help prevent the exacerbation of other COPCs.
Machine learning engineered PoLixNano nanoparticles overcome delivery barriers for nebulized mRNA therapeutics
Authors: Zhang Dandan , Xiao Qin , Tang Jie , Xiao Kai , Chen Tingting , Chen Yang , Liu Yuheng , Xu Lifeng , Li Chao , Cai Larry , Huang Shouyuan , Wang Ying , Peng Liusheng , Rosenecker Joseph , Shao Dan , Zou Quanming , Guan Shan
Published: November 2024

There continues to be a dearth of competent inhalable mRNA delivery although it holds great potential for addressing a wide variety of refractory diseases. The huge advances seen with parenteral-administered lipid nanoparticle (LNP) have not been translated into nebulized mRNA delivery due to the aggressive nebulization process and insurmountable barriers inherent to respiratory mucosa. Here, we show amphiphilic block copolymers revealed by machine learning (ML) can spontaneously form stabilized nanoparticles (PoLixNano) with the lipids components of LNP and simultaneously impart the PoLixNano with "shield" (shear force-resistant) and "spear" (pulmonary barriers-penetrating abilities) capabilities. We present a ML approach that leverages physicochemical properties and inhaled mRNA transfection profiles of a chemically diverse library of polymeric components to validate the integration of "shield" and "spear" properties as highly predictive indicators of transfection efficiency. This quantitative structure-mRNA transfection prediction (QSMTP) model identifies top-performing amphiphilic-copolymers from more than 10000 candidates and suggests their mucus-penetrating ability outweights the shear force-resistant property in contributing to efficient mRNA transfection. The optimized PoLixNano substantially outperforms the LNP counterpart and mediates up to 1114-times higher levels of mRNA transfection in animal models with negligible toxicities. The PoLixNano promotes overwhelming SARS-CoV-2 antigen-specific sIgA antibody secretion and expansion of TRM cells which collectively confers 100% protection in mice against lethal SARS-CoV-2 challenges and blocks the transmission of Omicron variant between hamsters. PoLixNano also displays versatile therapeutic potential in lung carcinoma and cystic fibrosis models. Our study provides new insights for designing delivery platforms of aerosol-inhaled mRNA therapeutics with clinical translation potential.
Circulating Levels of HMGB-1 and NPM/B23 proteins and Clinical Significance in Debut NSCLC patients
Authors: Hui Tan , Liu Lu , Yi Ying , Valenzuela Carmen , Zhao Qiang , Zhang Zhiwei , Li Wen , Perea Silvio E. , Perera Yasser
Published: November 2024

Alarmins are endogenous molecules that alert the immune system to circumvent the invading antigens in the host. They are basically sensed by specific cellular receptors, leading to recruitment and activation of dendritic cells to mount innate and adaptive immune responses. However, a dual role of alarmins as mediators in either antitumor immunity or tumor progression has been also reported. Here, we investigated the status of the HMGB-1 alarmin and the alarmin-like NPM/B23 in 162 debut NSCLC patients and 60 age-matched healthy individuals as control. NSCLC patients exhibited lower median values of circulating HMGB-1 compared to control (30.04versus37.30 ng/ml, p=0.02), but higher levels of HMGB-1 were positively correlated with tumor size > 2.0 cm (p=0.004) irrespectively of tumor histology. Otherwise, circulating NPM/B23 levels were significantly increased in NSCLC patients respect to control (812versus551 pg/ml, p=0.00027). Likewise, patients with tumors > 2 cm exhibited higher levels NPM/B23. Strong association was observed between HMGB-1 and NPM/B23 in serum of NSCLC patients (r=0.679 p=0.0001) compared to healthy individuals who exhibited a weaker correlation (r=0.278 p=0.031). However, the strongest correlation between both alarmins was observed in patients with STAS and tumors ≤ 2 cm (r=0.900 p=0.0001). Co-expression of HMGB-1 and NPM/B23 was also observed in tumor tissues although to a lesser extent. Our data unveil that concomitant circulating HMGB-1 and NPM/B23 could serve as a putative alarmin-based biomarker of NSCLC disease progression.
Genealogy based trait association with LOCATER boosts power at loci with allelic heterogeneity
Authors: Wang Xinxin , Christ Ryan , Young Erica , Kang Chul Joo , Das Indraniel , Belter Edward A. , Laakso Markku , Aslett Louis J.M. , Steinsaltz David , Stitziel Nathan O. , Hall Ira M.
Published: November 2024

A key methodological challenge for genome wide association studies is how to leverage haplotype diversity and allelic heterogeneity to improve trait association power, especially in noncoding regions where it is difficult to predict variant impacts and define functional units for variant aggregation. Genealogy-based association methods have the potential to bridge this gap by testing combinations of common and rare haplotypes based purely on their ancestral relationships. In parallel work we developed an efficient local ancestry inference engine and a novel statistical method (LOCATER) for combining signals present on different branches of a locus specific haplotype tree. Here, we developed a genome-wide LOCATER analysis pipeline and applied it to a genome sequencing study of 6,795 Finnish individuals with 101 cardiometabolic traits and 18.9 million autosomal variants. We identified 351 significant trait associations at 47 genomic loci and found that LOCATER boosted single marker test (SMT) association power at 5 loci by combining independent signals from distinct alleles. LOCATER successfully recovered known quantitative trait loci not found by SMT, includingLIPG, recovered known allelic heterogeneity at theAPOE/C1/C4/C2gene cluster, and suggested one novel association. We find that confounders have a more pronounced effect on genealogy-based methods than SMT; we propose a new randomization approach and a general method for genomic control to eliminate their effects. This study demonstrates that genealogy-based methods such as LOCATER excel when multiple causal variants are present and suggests that their application to larger and more diverse cohorts will be fruitful.
Design and Methods of the “Understanding pre-exposure prophylaxis modalities for HIV prevention in European communities” (PROTECT) Survey
Authors: Kolstee Johann , Wang Haoyi , Zimmermann Hanne , Schroeder Melanie , Appiah Ama , Brown Carolyn , Milinkovic Ana , Jonas Kai J.
Published: November 2024

Background

Despite the increasing availability of oral PrEP in Europe, gaps remain in the coverage of HIV prevention strategies at a population level. Long-acting injectable PrEP (LA PrEP) has the potential to help provide greater HIV prevention coverage to increasing proportions of men who have sex with men (MSM) and trans people, communities still disproportionately affected by HIV.

Methods

An online cross-sectional survey was conducted across 20 European countries from October 2023 to April 2024. The survey was translated into 22 local and migrant languages. The main aim of the survey was to understand which MSM and trans* people in Europe are interested and intend to use LA-PrEP if it becomes available.

Results

A total of 15,458 MSM and trans* individuals participated in the survey. Participants were recruited mainly from gay dating apps and through a social media campaign. Overall, the sample was sexually active (96.4%), engaged in condomless anal intercourse in the past 6 months (83.4%), had more than 10 partners in the past 6 months (57.6%) and was PrEP naïve (51.4%).

Conclusions

MSM and trans people in Europe can be engaged effectively to participate in research about LA PrEP.
The effect of long-term adherence to physical activity recommendations in midlife on plasma proteins associated with frailty in the Atherosclerosis Risk in Communities (ARIC) study
Authors: Liu Fangyu , Schrack Jennifer A. , Walker Keenan A. , Walston Jeremy , Mathias Rasika A. , Griswold Michael E. , Palta Priya , Windham B. Gwen , Jackson John W.
Published: November 2024

Clinical trials have shown favorable effects of exercise on frailty, supporting physical activity (PA) as a treatment and prevention strategy. Proteomics studies suggest that PA alters levels of many proteins, some of which may function as molecules in the biological processes underlying frailty. However, these studies have focused on structured exercise programs or cross-sectional PA-protein associations. Therefore, the effects of long-term PA on frailty-associated proteins remain unknown. Among 14,898 middle-aged adults, we emulated a target trial that assigned individuals to either (i) achieve and maintain the recommended PA level (≥150 minutes/week of moderate-to-vigorous physical activity [MVPA]) through 6 (±0.3) years of follow-up or (ii) follow a "natural course" strategy, where all individuals engage in various amounts of habitual MVPA. We estimated the effects of long-term adherence to recommended MVPA versus the natural course strategy on 45 previously identified frailty-associated proteins (log 2 transformed and standardized) at the end of the follow-up using inverse probability of weighting (IPW) and iterative conditional expectations (ICE). We found that long-term adherence to recommended MVPA improved the population levels of many frailty-associated proteins (ranged from 0.04 to 0.11 standard deviation); the greatest benefits were seen in proteins involved in the nervous system (e.g., voltage-dependent calcium channel subunit alpha-2/delta-3 [CACNA2D3], contactin-1 [CNTN1], neural cell adhesion molecule 1 [NCAM1], and transmembrane protein 132D [TMEM132D]) and inflammation (e.g., high-temperature requirement serine protease A1 [HTRA1] and C-reactive protein [CRP]). Our findings suggest long-term engagement in adequate habitual PA may reduce frailty risk through specific nervous systems and inflammatory proteins.
Synchronization of the segmentation clock using synthetic cell-cell signaling
Authors: Isomura Akihiro , Asanuma Daisuke , Kageyama Ryoichiro
Published: November 2024

Tight coordination of cell-cell signaling in space and time is vital for self-organization in tissue patterning. During vertebrate development, the segmentation clock drives oscillatory gene expression in the presomitic mesoderm (PSM), leading to the periodic formation of somites. Oscillatory gene expression is synchronized at the cell population level; inhibition of Delta-Notch signaling results in the loss of synchrony and the fusion of somites. However, it remains unclear how cell-cell signaling couples oscillatory gene expression and controls synchronization. Here, we report the reconstitution of synchronized oscillation in PSM organoids by synthetic cell-cell signaling with designed ligand-receptor pairs. Optogenetic assays uncovered that the intracellular domains of synthetic ligands play key roles in dynamic cell-cell communication. Oscillatory coupling using synthetic cell-cell signaling recovered the synchronized oscillation in PSM cells deficient for Delta-Notch signaling; non-oscillatory coupling did not induce recovery. This study reveals the mechanism by which ligand-receptor molecules coordinate the synchronization of the segmentation clock, and provides direct evidence of oscillatory cell-cell communication in the segmentation clock.
Weberviruses are gut-associated phages that infectKlebsiellaspp
Authors: Dawson Samuel J. T. , Shibu Preetha , Garnett Sara , Newberry Fiona , Brook Thomas C. , Tijani Tobi , Kujawska Magdalena , Hall Lindsay J. , McCartney Anne L. , Negus David , Hoyles Lesley
Published: November 2024

Weberviruses are bacteriophages (phages) that have been shown to infect and lyse members of the genusKlebsiella. Due to their antimicrobial properties, phages and their products have emerged as a potential therapeutic option to help tackle increasing rates of antimicrobial resistance amongstKlebsiellaspp. Weberviruses are an attractive option due to their high burst sizes, long shelf life and associated depolymerase enzymes. In this study we isolated and characterized seven new weberviruses and compared their genomes with those of their closest relatives to further our understanding of the genusWebervirus. We show that the seven phages isolated in this study can lyse a range of clinical multidrug-resistantKlebsiellastrains, includingK. variicola. Gene-sharing network-based analysis using vConTACT2 and incorporating all publicly available webervirus genomes (n=67) confirmed the seven phages as members of the genusWebervirusand that weberviruses are affiliated with the familyDrexlerviridae. Using the online resource PhageClouds, we demonstrated that weberviruses can be readily detected in metagenome-derived phage datasets from a diverse range of geographical locations. Using a curated database of 67 isolated phage genomes and 60 metagenome-assembled genomes (n=127 total), we found that weberviruses are primarily associated with samples originating from the gut, with human faeces (61/127, 48 %), sewage (39/127, 31 %) and wastewater (14/127, 11 %) being the most frequent sources of these phages.
Type IV pili-associated secretion of a biofilm matrix protein fromClostridium perfringensthat forms intermolecular isopeptide bonds
Authors: Kivimaki Sarah E. , Dempsey Samantha , Camper Collette , Tani Julia M. , Hicklin Ian K. , Blaby-Haas Crysten E. , Brown Anne M. , Melville Stephen B.
Published: November 2024

Clostridium perfringensis a Gram-positive anaerobic spore-forming bacterial pathogen of humans and animals.C. perfringensalso produces type IV pili (T4P) and has two complete sets of T4P-associated genes, one of which has been shown to produce surface pili needed for cell adherence. One hypothesis about the role of the other set of T4P genes is that they could comprise a system analogous to the type II secretion systems (TTSS) found in Gram-negative bacteria, which is used to export folded proteins from the periplasm through the outer membrane to the extracellular environment. Gram-positive bacteria have a similar secretion barrier in the thick peptidoglycan (PG) layer, which blocks secretion of folded proteins >25 kD. To determine if the T4P-associated genes comprise a Gram-positive TTSS, the secretome of mutants lacking type IV pilins were examined and a single protein, a von Willebrand A domain containing protein BsaC (CPE0517) was identified as being dependent on PilA3 for secretion. BsaC is in an operon with a signal peptidase and two putative biofilm matrix proteins with homology toBacillus subtilisTasA. One of these proteins, BsaA, was shown by another group to produce high mol wt oligomers. We analyzed BsaA monomer interactions withde novomodeling, which projected that the monomers formed isopeptide bonds as part of a donor strand exchange process. Mutations in residues predicted to form the isopeptide bonds led to loss of oligomerization, supporting the predicted bond formation process. Phylogenetic analysis showed the BsaA family of proteins are widespread among bacteria and archaea but only a subset are predicted to form isopeptide bonds.

Importance

For bacteria to secrete folded proteins to the environment, they have to overcome the physical barriers of an outer membrane in Gram-negative bacteria and the thick peptidoglycan layer in Gram-positive bacteria. One mechanism to do this is the use of a Type II secretion system in Gram-negative bacteria, which has a similar structure as type IV pili and is modeled to act as a piston that pumps folded proteins through the outer membrane to the environment.Clostridium perfringens, like all or most all of the clostridia, has type IV pili and, in fact, has two sets of pilus-associated genes. Here we present evidence thatC. perfringensuses one set of pilus genes to secrete a biofilm associated protein and may be responsible for secreting the main biofilm protein BsaA. We show that BsaA monomers are, unlike most other biofilm matrix proteins, linked by intermolecular isopeptide bonds, enhancing the physical strength of BsaA fibers.
Corticonigral projections recruit substantia nigra pars lateralis dopaminergic neurons for auditory threat memories
Authors: Sansalone Lorenzo , Evans Rebekah C. , Twedell Emily , Zhang Renshu , Khaliq Zayd M.
Published: November 2024

Dopaminergic neurons (DANs) in the lateral substantia nigra project to the tail of striatum (TS), which is involved in threat conditioning. Auditory cortex also contributes to threatening behaviors, but whether it directly interacts with midbrain DANs and how these interactions might influence threat conditioning remain unclear. Here, functional mapping revealed robust excitatory input from auditory and temporal association cortexes to substantia nigra pars lateralis (SNL) DANs, but not to pars compacta (SNc) DANs. SNL DANs exhibited unique firing patterns, with irregular pacemaking and higher maximal firing, reflecting different channel complements than SNc DANs. Behaviorally, inhibiting cortex to SNL projections impaired memory retrieval during auditory threat conditioning. Thus, we demonstrate robust corticonigral projections to SNL DANs, contrasting with previous observations of sparse cortical input to substantia nigra DANs. These findings distinguish SNL DANs from other nigral populations, highlighting their role in threatening behaviors and expanding knowledge of cortex to midbrain interactions.
Predicting neuronal firing from calcium imaging using a control theoretic approach
Authors: Rondoni Nicholas , Lu Fan , Turner-Evans Daniel B. , Gomez Marcella
Published: November 2024

Two-photon calcium imaging has become a powerful tool to explore the functions of neurons and the connectivity of their circuitry. Frequently, fluorescent calcium indicators are taken as a direct measure of neuronal activity. These indicators, however, are slow relative to behavior, obscuring functional relationships between an animal's movements and the true neuronal activity. As a consequence, the firing rate of a neuron is a more meaningful metric. Converting calcium imaging data to the firing of a neuron is nontrivial. State of the art methods depend largely on neural networks or non-mechanistic processes, which may yield acceptable correlations between calcium dynamics and the frequency at which a neuron fires, but do not illuminate the underlying chemical exchanges within the neuron or require significant data to be trained on. Leveraging modeling frameworks from chemical reaction networks (CRN) coupled with modern control architectures, a new algorithm is presented based off of fully deterministic ordinary differential equations (ODEs). This framework utilizes model predictive control to challenge state of the art correlation scores while retaining the interpretability that comes inherent with a model. Moreover, these computations can be done in real time, thus enabling online experimentation informed by neuronal firing rates. To demonstrate the use cases of this architecture, it is tested on a ground truth dataset courtesy of the spikefinder challenge. Finally, the predictive power of the methodology put forward here is underscored by demonstrating its ability to aid in the creation of novel indicators utilized in two-photon imaging.
Control of Golgi- V-ATPase through Sac1-dependent co-regulation of PI(4)P and cholesterol
Authors: Zhou Xin , van der Stoel Miesje M. , Kaptan Shreyas , Li Haoran , Li Shiqian , Hölttä Maarit , Vihinen Helena , Jokitalo Eija , Thiele Christoph , Pietiläinen Olli , Morioka Shin , Sasaki Junko , Sasaki Takehiko , Vattulainen Ilpo , Ikonen Elina
Published: November 2024

Sac1 is a conserved phosphoinositide phosphatase, whose loss-of-function compromises cell and organism viability. Here, we employed acute auxin-inducible Sac1 degradation to identify its immediate downstream effectors in human cells. Most of Sac1 was degraded in ∼1 h, paralleled by increased PI(4)P and decreased cholesterol in the trans-Golgi network (TGN) during the following hour, and superseded by Golgi fragmentation, impaired glycosylation, and selective degradation of TGN proteins by ∼4 h. The TGN disintegration resulted from its acute deacidification caused by disassembly of the Golgi V-ATPase. Mechanistically, Sac1 mediated TGN membrane composition maintained an assembly promoting conformation of the V0a2 subunit. Key phenotypes of acute Sac1 degradation were recapitulated in human differentiated trophoblasts, causing processing defects of chorionic gonadotropin, in line with loss-of-function intolerance of the humanSACML1gene. Collectively, our findings reveal that the assembly of the Golgi V-ATPase is controlled by the TGN membrane via Sac1 fuelled lipid exchange.
F2,6BP restores mitochondrial genome integrity in Huntington’s Disease
Authors: Chakraborty Anirban , Mandal Santi M. , Mankevich Mikita , Sreenivasmurthy Sravan Gopalkrishnashetty , Hegde Muralidhar L. , Krishnan Balaji , Ghosh Gourisankar , Hazra Tapas
Published: November 2024

Several reports have indicated that impaired mitochondrial function contributes to the development and progression of Huntington’s disease (HD). Mitochondrial genome damage, particularly DNA strand breaks (SBs), is a potential cause for its compromised functionality. We have recently demonstrated that the activity of polynucleotide kinase 3’-phosphatase (PNKP), a critical DNA end-processing enzyme, is significantly reduced in the nuclear extract of HD patients due to lower level of a metabolite fructose-2,6 bisphosphate (F2,6BP), a biosynthetic product of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3), leading to persistent DNA SBs with 3’-phosphate termini, refractory to subsequent steps for repair completion. PNKP also plays a pivotal role in maintaining mitochondrial genome integrity. In this report, we provide evidence that both PFKFB3 and F2,6BP, an allosteric modulator of glycolysis, are also present in the mitochondria. Notably, the level of F2,6BP, a cofactor of PNKP, is significantly decreased due to the degradation of PFKFB3 in the mitochondrial extract of HD patients’ brain. PNKP activity is thus severely decreased in the mitochondrial extract; however, addition of F2,6BP restored PNKP activity. Moreover, supplementation of F2,6BP in HD mouse striatal neuronal cells restored mitochondrial genome integrity and partially restored mitochondrial membrane potential and prevented pathogenic aggregate formation. We observed similar restoration of mitochondrial genome integrity in HD drosophila supplemented with F2,6BP. Our findings, therefore, suggest that F2,6BP or its structural analog hold promise as a therapeutic for restoring both nuclear and mitochondrial genome integrity and thereby of organismal health.
A modiolar-pillar gradient in auditory-nerve dendritic length: a novel post-synaptic contribution to dynamic range?
Authors: Kostrikov Serhii , Hjortkjaer Jens , Dau Torsten , Corfas Gabriel , Liberman Leslie D. , Liberman M. Charles
Published: November 2024

Auditory-nerve fibers (ANFs) from a given cochlear region can vary in threshold sensitivity by up to 60 dB, corresponding to a 1000-fold difference in stimulus level, although each fiber innervates a single inner hair cell (IHC) via a single synapse. ANFs with high-thresholds also have low spontaneous rates (SRs) and synapse on the side of the IHC closer to the modiolus, whereas the low-threshold, high-SR fibers synapse on the side closer to the pillar cells. Prior biophysical work has identified modiolar-pillar differences in both pre- and post-synaptic properties, but a comprehensive explanation for the wide range of sensitivities remains elusive. Here, in guinea pigs, we used immunostaining for several neuronal markers, including Caspr, a key protein in nodes of Ranvier, to reveal a novel modiolar-pillar gradient in the location of the first ANF heminodes, presumed to be the site of the spike generator, just outside the sensory epithelium. Along the cochlea, from apex to base, the unmyelinated terminal dendrites of modiolar ANFs were 2 - 4 times longer than those of pillar ANFs. This modiolar-pillar gradient in dendritic length, coupled with the 2 - 4 fold smaller caliber of modiolar dendrites seen in prior single-fiber labeling studies, suggests there could be a large difference in the number of length constants between the synapse and the spike initiation zone for low- vs high-SR fibers. The resultant differences in attenuation of post-synaptic potentials propagating along these unmyelinated dendrites could be a key contributor to the observed range of threshold sensitivities among ANFs.
Pharmacological depletion of microglia protects against alcohol-induced corticolimbic neurodegeneration during intoxication in male rats
Authors: Carlson Erika R. , Melbourne Jennifer K. , Nixon Kimberly
Published: November 2024

Excessive alcohol use damages the brain, especially corticolimbic regions such as the hippocampus and rhinal cortices, leading to learning and memory problems. While neuroimmune reactivity is hypothesized to underly alcohol-induced damage, direct evidence of the causative role of microglia, brain-resident immune cells, in this process is lacking. Here, we depleted microglia using PLX5622 (PLX), a CSF1R inhibitor commonly used in mice, but rarely in rats, and assessed cell death following binge-like alcohol exposure in male rats. Eleven days of PLX treatment depleted microglia >90%. Further, PLX treatment prevented alcohol-induced neuronal death in the hippocampus and rhinal cortices, as the number of FluoroJade-B-positive cells (dying neurons) was reduced to control diet levels. This study provides direct evidence that alcohol-induced microglial reactivity is neurotoxic in male rats. Improved understanding of alcohol-microglia interactions is essential for developing therapeutics that suppress pro-cytotoxic and/or amplify protective microglia activity to relieve alcohol-related damage.
Identification of novel thiazole derivatives as flaviviral protease inhibitors against DENV and JEV
Authors: Murtuja Sheikh , Das Sayan , Jana Indrani Das , Shilkar Deepak , Rakshit Gourav , Sarkar Biswatrish , Sinha Barij Nayan , Dewangan Rikeshwar Prasad , Mondal Arindam , Jayaprakash Venkatesan
Published: November 2024

Flaviviruses are the causative agents of viral hemorrhagic fever (VHF) globally and have demonstrated the capacity to result in fatal outcomes if not managed effectively. Among different types of flaviviruses, dengue (DENV) and Japanese encephalitis (JEV) are the most common in tropical and subtropical countries. Given the scarcity of effective vaccines against flaviviral infections, small molecule agents that target crucial viral proteins emerge as the sole feasible option. This study outlines the synthesis of novel thiazole compounds as flavivirus NS2B-NS3 protease inhibitor and characterization of their antiviral activity against DENV and JEV. We synthesized a heterocyclic template derived from a substrate-based retrotripeptide dengue protease inhibitor, leading to forty-eight thiazole derivatives. Two compounds demonstrated significant inhibition of dengue virus protease activityin vitro. Comprehensive characterization of these two compounds was conducted through biochemical assay which revealed an uncompetitive mode of inhibition. Subsequent cell-based assays using Dengue and Japanese encephalitis viruses as representatives Flaviviruses imparted the potential of these compounds to block viral RNA synthesis, and viral replication. Finally time-course experiments unveiled that the two compounds impeded the accumulation of viral genomic RNA primarily at later stages of infection, aligning with their capacity to hinder NS2B-NS3 protease activity, polyprotein processing and viral genomic RNA replication. Together our work presents the development and validation of flavivirus protease inhibitors with therapeutic potential against Dengue and Japanese encephalitis virus.
Identification of Y-chromosome turnover in newts fails to support a sex chromosome origin for theTriturusbalanced lethal system
Authors: France James , Babik Wiesław , Cvijanović Milena , Dudek Katarzyna , Ivanović Ana , Vučić Tijana , Wielstra Ben
Published: November 2024

Non-recombining regions of the genome often have profound effects on evolution, resulting in phenomena such as sex chromosomes and supergenes. Amongst the strangest examples are balanced lethal systems, such as that found in newts of the genusTriturus. These systems halve reproductive output, and the evolution of such a deleterious trait is difficult to explain. ForTriturusan intriguing model proposes that the balanced lethal system evolved from an ancestral Y-chromosome. To test this hypothesis, we identify the Y-chromosome ofTriturusand verify whether it, or the balanced lethal system, is homologous to the Y-chromosome of its sister genusLissotriton, which does not possess the balanced lethal system. We identify a set of candidate Y-linked markers inT. ivanbureschiand place them on a high-density linkage map that we construct with 7,233 RADseq markers. We validate male specificity of the markers across the genus, and then place both theTriturusandLissotritonY-linked regions within previously constructed target capture linkage maps that include genes linked to the balanced lethal system. We observe that neither theTriturusbalanced lethal system, nor theTriturusY-chromosome are homologous to theLissotritonY-chromosome. This is the first molecular evidence of a transition between Y-chromosome systems within salamanders. However, unless additional sex chromosome turnover events are involved, our data does not support a sex chromosome origin of the balanced lethal system.
Placebo and Nocebo Responses in Multiple System Atrophy - a systematic review and meta-analysis of clinical trials
Authors: de Amorim Afonso Pessoa , Rodrigues Filipe B , Castro-Caldas Ana , Ferreira Joaquim J
Published: November 2024

BACKGROUND

Multiple System Atrophy (MSA) is a rapidly progressive and fatal neurodegenerative disease, with no effective treatment. Estimating the placebo and nocebo responses will help better design and interpret clinical trials.

Objective

To estimate the placebo and nocebo responses in MSA and explore their determinants.

METHODS

Electronic databases were searched up to November 2020. Randomized, blinded, placebo- or sham-controlled trials of patients with MSA were included if quantitative data were extractable on the placebo arm. The primary outcomes were: placebo response, defined as the within-group change from baseline, using any scale measuring motor outcomes; and nocebo response, defined as the proportion of patients experiencing adverse effects in the placebo arm. Random-effects meta-analyses were used to pool data. Several predetermined subgroup analyses and metaregressions were performed. PROSPERO registration number: CRD42021222915.

RESULTS

We included 21 randomized controlled trials (614 participants). Pooled placebo response was an increase in the Unified MSA Rating Scale (UMSARS) parts I and II of 9.09 points (95% CI 7.78 to 10.31, I2=94.00%, 9 studies, 304 participants). Pooled nocebo response was 63,88% (CI 95% 41.15 to 84.05, I2=93.03%, 13 studies, 331 participants). Both placebo and nocebo responses were greater in trials with longer duration, whereas nocebo response was also higher in studies testing pharmacological interventions when compared with non-pharmacological interventions.

CONCLUSIONS

There may be a favorable response associated with the placebo, but this data needs to be compared with a “no treatment group” in order to validate its real impact. The nocebo response is high and should be considered in future clinical trial design and interpretation.
Risk Factor Analysis for Cancer and Coronary Heart Disease: A Machine Learning Approach Using National Health and Nutrition Examination Survey Data
Authors: Hakan Şat Bozcuk
Published: November 2024

Objectives

The relative significance of predictive factors for cancer and coronary heart disease (CHD) is still unclear. This study aims to identify and evaluate the risk factors contributing to the development of both conditions using the CatBoost machine learning algorithm.

Methods

Data from twelve datasets of the 2009–2010 National Health and Nutrition Examination Survey (NHANES), incorporating both survey responses and laboratory results, were used. Separate CatBoost models were developed to predict cancer and CHD occurrences, by using Shapley Additive Explanations (SHAP), with the help of Recursive Feature Elimination with Cross-Validation (RFECV), and by adjusting class weights, and model performance was assessed using Receiver Operating Characteristic (ROC) curves.

Results

The datasets were combined to form a cohort of 5,012 participants, each with 24 selected features. The cancer prediction model achieved a ROC Area Under the Curve (AUC) of 0.76, with 13 selected features, yielding an accuracy of 0.70, sensitivity of 0.67, and specificity of 0.70. In contrast, the CHD prediction model achieved a higher ROC AUC of 0.87, with an accuracy of 0.83, sensitivity of 0.78, and specificity of 0.83. Accordingly, top predictive features for each disease have been ranked and selected by the CatBoost algorithm.

Conclusions

This study identifies key demographic and laboratory features significantly associated with cancer and CHD risk in the NHANES dataset. The findings suggest that these factors could be valuable for estimating individual risk and could inform machine learning models aimed at early detection and screening.
Factors impacting target-enriched long-read sequencing of resistomes and mobilomes
Authors: Slizovskiy Ilya B. , Bonin Nathalie , Bravo Jonathan E. , Ferm Peter M. , Singer Jacob , Boucher Christina , Noyes Noelle R.
Published: November 2024

We investigated the efficiency of target-enriched long-read sequencing (TELSeq) for detecting antimicrobial resistance genes (ARGs) and mobile genetic elements (MGEs) within complex matrices. We aimed to overcome limitations associated with traditional antimicrobial resistance (AMR) detection methods, including short-read shotgun metagenomics, which can lack sensitivity, specificity, and the ability to provide detailed genomic context. By combining biotinylated probe-based enrichment with long-read sequencing, we facilitated the amplification and sequencing of ARGs, eliminating the need for bioinformatic reconstruction. Our experimental design included replicates of human fecal microbiota transplant material, bovine feces, pristine prairie soil, and a mock human gut microbial community, allowing us to examine variables including genomic DNA input and probe set composition. Our findings demonstrated that TELSeq markedly improves the detection rates of ARGs and MGEs compared to traditional sequencing methods, underlining its potential for accurate AMR monitoring. A key insight from our research is the importance of incorporating mobilome profiles to better predict the transferability of ARGs within microbial communities, prompting a recommendation for the use of combined ARG–MGE probe sets for future studies. We also reveal limitations for ARG detection from low-input workflows, and describe the next steps for ongoing protocol refinement to minimize technical variability and expand utility in clinical and public health settings. This effort is part of our broader commitment to advancing methodologies that address the global challenge of AMR.
Measuring cultural friction in cross-border mergers and acquisitions using a microfoundation-based approach
Authors: Durand Muriel , Very Philippe
Published: November 2024

Purpose

Cultural friction (CF) was introduced by researchers to overcome the issues and challenges of cultural distance measurement in the context of cross-border mergers and acquisitions (CBMAs). However, this construct has proved itself to be problematic to operationalize. To address this challenge, this paper aims to elaborate on a CF measurement instrument based on individual perceptions in CBMAs. This study used a microfoundation approach to measure CF, relying on managers’ interactions in CBMA settings.

Design/methodology/approach

To develop and validate a CF measurement in the context of CBMAs, this study followed a classical procedure including items development, lab tests and one field-study and an assessment of the construct validity.

Findings

The final instrument developed for measuring CF is composed of six critical incidents with three associated items each. The factor analysis revealed that the scale used in the field-test measures two factors of CF: internal and external. Reliability and discriminant validity are tested, demonstrating a good discriminant validity of “external” CF. The final measurement can be used as a valid and reliable scale in further studies to assess CF in the context of CBMAs.

Originality/value

This paper’s originality lies in developing and validating a CF measurement instrument that does not rely on cultural distance frameworks. The resulting scale shows the interest in considering micro-individual perceptions – the microfoundation level – for analyzing an organizational phenomenon as culture in CBMA contexts. Using a micro-founded approach, this study offers promising avenues for researchers who wish to study cultural interactions in international settings.
Entropy optimization in a radiative and chemically reactive EMHD flow of a nanofluid coexisting Ohmic dissipation and multiple slips
Authors: US Mohanaphriya , Chakraborty Tanmoy
Published: November 2024

Purpose

This research focuses on the controlling irreversibilities in a radiative, chemically reactive electromagnetohydrodynamics (EMHD) flow of a nanofluid toward a stagnation point. Key considerations include the presence of Ohmic dissipation, linear thermal radiation, second-order chemical reaction with the multiple slips. With these factors, this study aims to provide insights for practical applications where thermal management and energy efficiency are paramount.

Design/methodology/approach

Lie group transformation is used to revert the leading partial differential equations into nonlinear ODE form. Hence, the solutions are attained analytically through differential transformation method-Padé and numerically using the Runge–Kutta–Fehlberg method with shooting procedure, to ensure the precise and reliable determination of the solution. This dual approach highlights the robustness and versatility of the methods.

Findings

The system’s entropy generation is enhanced by incrementing the magnetic field parameter (M), while the electric field (E) and velocity slip parameters (ξ) control its growth. Mass transportation irreversibility and the Bejan number (Be) are significantly increased by the chemical reaction rate (Cr). In addition, there is a boost in the rate of heat transportation by 3.66% while 0.05⩽ξ⩽0.2; meanwhile for 0.2⩽ξ⩽1.1, the rate of mass transportation gets enhanced by 12.87%.

Originality/value

This paper presents a novel approach to analyzing the entropy optimization in a radiative, chemically reactive EMHD nanofluid flow near a stagnation point. Moreover, this research represents a significant advancement in the application of analytical techniques, complemented by numerical approaches to study boundary layer equations.
An emotional learning process? The role of socially induced and regulated emotions for the development of an entrepreneurial mindset
Authors: Zabel Cynthia Maria Katharina , Meister Alexander , Van De Sandt Nicolas , Mauer René
Published: November 2024

Purpose

Although emotional dynamics (EDs) during the entrepreneurial learning (EL) process are acknowledged to promote the growth of an entrepreneurial mindset (EM), while having social causes, empirical research on learning mainly looks at emotions as socially isolated concepts. This study aims to investigate how socially induced and regulated emotions during the EL process affect EM development.

Design/methodology/approach

We applied a qualitative, inductive approach related to interpretative phenomenological analysis to get deeply involved into individuals’ experienced emotions. We conducted semi-structured interviews with participants of two EL programs. Open-ended questions stimulated free narratives and detailed descriptions of experiences that were analyzed following a five-stage process.

Findings

There is a correlation between socially induced and regulated emotions and the development of EM elements. We suggest a framework for the EL process based on EDs, which triggers four main mechanisms that help individuals develop an EM: “re-assessment of individual emotions through EDs”, “EDs affected by facilitator intervention,” “sharing and co-creation of emotions,” and “sensemaking of experiences and emotions.”

Originality/value

This study adds to the knowledge on EDs during the EL process and contributes to the literature on EL and emotions in learning. Therewith, it helps to sensitize practitioners toward the complexity of emotions in the entrepreneurial process, allows to moderate individual emotional reactions and social Eds, and improves existing EE programs. Future research could investigate the interplay of specific personality traits, learning environments, and socioemotional team dynamics in EL.