bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of Research Quality and Transparency in Neurosurgery Through the Utilization of Open Science Practices
Authors: Alam Zahin , Desai Kush , Maddali Anirudh , Sivan Vijay , Prem Kumar Rohit , O’Malley Geoffrey R. , Patel Nitesh
Published: August 2024

Background and Objective

Neurosurgical research is a rapidly evolving field, with numerous studies continuously published. As the body of research grows, upholding high-quality standards becomes increasingly essential. Open science practices offer tools to ensure quality and transparency. However, the prevalence of these practices remains unclear. This study investigated the extent to which neurosurgical publications have implemented open science practices.

Methods

Five open science practices (preprint, equator guidelines, published peer review comments, preregistration, and open accessibility to data and methods) were measured from five top-ranked neurosurgical journals (Neurosurgery, Journal of Neurosurgery, World Neurosurgery, Neurosurgical Review, andActa Neurochirurgica), according to Google Scholar. One hundred fifty articles were randomly sampled from January 1, 2022, to December 31, 2023. Two reviewers analyzed these articles for their utilization of open science practices. A third reviewer settled disagreements.

Results

One journal required (20%) and three journals (60%) recommended utilizing EQUATOR guidelines. Three journals (60%) allowed preprints, and all five journals (100%) recommended or required preregistration of clinical trials, but only two (40%) recommended preregistration for systematic reviews (Figure 1). All five journals (100%) recommended or required methods to be publicly available, but none (0%) published peer-review comments.Neurosurgical Reviewutilized the most open science practices, with a mean utilization of 1.4 open science practices per publication versus 0.9 across the other four journals (p < 0.001). Moreover,Neurosurgical Reviewsignificantly utilized more open science practices versusJournal of Neurosurgery(p < .05) andWorld Neurosurgery(p < .05). Both randomized controlled trials (p < .001) and systematic reviews (p < .001) significantly utilized more open science practices compared to observational studies.

Conclusions

Despite advocacy from neurosurgical journals, the adoption of open science practices still needs improvement. Implementing incentives and clearer requirements may prove beneficial. Promoting these practices is crucial to enhancing transparency and research quality in neurosurgery.
A modular self-assembling and self-adjuvanting multiepitope peptide nanoparticle vaccine platform to improve the efficacy and immunogenicity of BCG
Authors: Zhao Guangzu , Sathkumara Harindra D. , Miranda-Hernandez Socorro , Seifert Julia , Valencia-Hernandez Ana Maria , Puri Munish , Huang Wenbin , Toth Istvan , Daly Norelle , Skwarczynski Mariusz , Kupz Andreas
Published: August 2024

After more than a century since its initial development, Bacille Calmette-Guérin (BCG) remains the only licensed vaccine against tuberculosis (TB). Subunit boosters are considered a viable strategy to enhance BCG efficacy, which often wanes in adolescence. While many studies on booster subunit vaccines have concentrated on recombinant proteins, here we developed a novel modular peptide-based subunit vaccine platform that is flexible, cold-chain independent and customizable to diverse circumstances and populations. Each individual peptide building block consists of a linear arrangement comprising a 15-leucine self-assembly inducer moiety, aMycobacterium tuberculosis(Mtb) target epitope and an HLA-E binding moiety, with each moiety separated by a triple lysine spacer. The building blocks, in any combination, were able to form a multiepitope nanoparticle. Six Mtb epitopes were selected to produce the self-assembling and self-adjuvanting peptide-based TB nano-vaccine candidate PNx6.In vivovaccination-challenge experiments demonstrated that subcutaneous boost of parenteral BCG immunization with PNx6 significantly enhanced its immunogenicity and improved its protective efficacy in a murine model of TB by more than 5-fold. Our study present evidence that purely amphiphilic peptides self-assemble into self-adjuvanting nanoparticles with appropriate size and morphology for TB vaccination with great potential for a multitude of other diseases.
Increased vowel contrast and intelligibility in connected speech induced by sensorimotor adaptation
Authors: Beach Sara D. , Johnson Sophie A. , Parrell Benjamin , Niziolek Caroline A.
Published: August 2024

Alterations to sensory feedback can drive robust adaptive changes to the production of consonants and vowels, but these changes often have no behavioral relevance or benefit to communication (e.g., making “head” more like “had”). This work aims to align the outcomes of adaptation with changes known to increase speech intelligibility – specifically, adaptations that increase the acoustic contrast between vowels in running speech. To this end, we implemented a vowel centralization feedback perturbation paradigm that pushes all vowels towards the center of vowel space, making them sound less distinct from one another. Speakers across the adult lifespan adapted to the centralization perturbation during sentence production, increasing the global acoustic contrast among vowels and the articulatory excursions for individual vowels. These changes persisted after the perturbation was removed, including after a silent delay, and showed robust transfer to words that were not present in the sentences. Control analyses demonstrated that these effects were unlikely to be due to explicit pronunciation strategies and occurred in the face of increasingly more rapid and less distinct production of familiar sentences. Finally, sentence transcription by crowd-sourced listeners showed that speakers’ vowel contrast predicted their baseline intelligibility and that experimentally-induced increases in contrast predicted intelligibility gains. These findings establish the validity of a sensorimotor adaptation paradigm to implicitly increase vowel contrast and intelligibility in connected speech, an outcome that has the potential to enhance rehabilitation in individuals who present with a reduced vowel space due to motor speech disorders, such as the hypokinetic dysarthria associated with Parkinson’s disease.

Significance statement

During speech production, humans learn from perceived errors by adjusting their speech to compensate, a process known as sensorimotor adaptation. Here we leveraged sensorimotor adaptation to cause an increase in the distinctiveness of speech sounds. Specifically, speakers rapidly and implicitly learned vowel-specific articulation changes during sentence production, with positive effects on their intelligibility. This study is important for models of sensorimotor integration across all motor domains, as it demonstrates the simultaneous learning of multiple opposing transformations in the course of continuous movement. Our findings show that sensorimotor adaptation can be successfully applied to drive changes relevant to a vital ecological behavior: intelligible communication.
Enforced specificity of an animal symbiosis
Authors: Wagner Julian M , Wong Jason H , Millar Jocelyn G , Haxhimali Enes , Bruckner Adrian , Naragon Thomas H , Boedicker James Q , Parker Joseph
Published: August 2024

Insect diversification has been catalyzed by widespread specialization on novel hosts - a process underlying exceptional radiations of phytophagous beetles, lepidopterans, parasitoid wasps, and inordinate lineages of symbionts, predators and other trophic specialists. The strict fidelity of many such interspecies associations is posited to hinge on sensory tuning to host-derived cues, a model supported by studies of neural function in host-specific model species. Here, we investigated the sensory basis of symbiotic interactions between a myrmecophile rove beetle and its single, natural host ant species. We show that host cues trigger analogous behaviors in both ant and symbiont. Cuticular hydrocarbons - the ant's nestmate recognition pheromones - elicit partner recognition by the beetle and execution of ant grooming behavior, integrating the beetle into the colony via chemical mimicry. The beetle also follows host trail pheromones, permitting inter-colony dispersal. Remarkably, the rove beetle also performs its symbiotic behaviors with ant species separated by ~95 million years, and shows minimal preference for its natural host over non-host ants. Experimentally validated agent-based modeling supports a scenario in which specificity is enforced by physiological constraints on symbiont dispersal, and negative fitness interactions with alternative hosts, rather than via sensory tuning. Enforced specificity may be a pervasive mechanism of host range restriction of specialists embedded within host niches. Chance realization of latent compatibilities with alternative hosts may facilitate host switching, enabling deep-time persistence of obligately symbiotic lineages.
Somatic development of Wilms tumour via normal kidneys in predisposed children
Authors: Treger Taryn D. , Wegert Jenny , Wenger Anna , Coorens Tim H. H. , Al-Saadi Reem , Kemps Paul , Kennedy Jonathan , Parks Conor , Anderson Nathaniel D. , Hodder Angus , Letunovska Aleksandra , Jung Hyunchul , Ogbonnah Toochi , Trinh Mi K. , Lee-Six Henry , Morcrette Guillaume , van den Heuvel-Eibrink J. Marry M , Drost Jarno , van Boxtel Ruben , Bertrums Eline J.M. , Goemans Bianca F. , Antoniou Evangelia , Reinhardt Dirk , Streitenberger Heike , Ziegler Barbara , Bartram Jack , Hutchinson J. Ciaran , Vujanic Gordan , Vokuhl Christian , Chowdhury Tanzina , Furtwängler Rhoikos , Graf Norbert , Pritchard-Jones Kathy , Gessler Manfred , Behjati Sam
Published: August 2024

Ten percent of children with cancer harbour a predisposition mutation. In children with the kidney cancer, Wilms tumour, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumour genetic development. To investigate this, we assembled a cohort of 137 children with Wilms tumour, of whom 71 had a pathogenic germline or mosaic predisposition. We examined 237 neoplasms (including two secondary leukaemias), utilising whole genome sequencing, RNA sequencing and genome wide methylation, validating our findings in an independent cohort. Tumour development differed between predisposed and sporadic cases, and amongst predisposed children according to specific mutations and their developmental timing. Differences pervaded the repertoire of driver events, including high risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Predisposition constrains the development of Wilms tumour, suggesting that a variant specific approach to the management of these children merits consideration.

STATEMENT OF SIGNIFICANCE

Tumours that arise in children with a cancer predisposition may, or may not, develop through the same mutational pathways as sporadic tumours. We examined this question in the childhood kidney cancer, Wilms tumour. We found that some predispositions strongly constrain the genetic development of tumours, which may have clinical implications.
White matter microstructural changes in post-traumatic headache: A diffusion tensor imaging (DTI) study
Authors: Yang Ho-Ching , Nguyen Tyler , Naugle Kelly M. , White Fletcher A. , Wu Yu-Chien
Published: August 2024

Introduction

Post-traumatic headache (PTH) is a common consequence of mild traumatic brain injury (mTBI) that can severely impact an individual’s quality of life and rehabilitation. However, the underlying neuropathogenesis mechanisms contributing to PTH are still poorly understood. This study utilized diffusion tensor imaging (DTI) to detect microstructural alterations in the brains of mTBI participants with or at risk of developing PTH.

Method

This study investigated associations between DTI metrics 1-month postinjury and pain sensitivity, as well as psychological assessments 6-months postinjury to identify differences between mTBI (n = 12) and healthy controls (HC; n = 10). MRI scans, including T1-weighted anatomical imaging and DTI were acquired at 1-month postinjury. Pain sensitivity assays included quantitative sensory testing and psychological assessment questionnaires at 1-month and 6-months postinjury.

Results

Significant aberrations of mean axial diffusivity in the forceps major were observed in mTBI relative to HCs at 1-month postinjury (p =0.02). Within the mTBI group, DTI metrics at 1-month postinjury were significantly associated (p’s < 0.05) with pain-related measures and psychological outcomes at 6-month postinjury in several white matter tracts (right sagittal stratum, left anterior thalamic radiation, left corticospinal tract, left insula, left superior longitudinal fasciculus). Notably, the associations between DTI metrics at 1-month postinjury and pain-related measures at 6-month postinjury showed significant group differences in the right sagittal stratum (p’s < 0.01), white matter tract in left insula (p < 0.04), and left superior longitudinal fasciculus (p’s < 0.05).

Conclusion

This study suggests that “Post-Traumatic Stress Disorder for DSM-5” and “Center for Epidemiological Studies-Depression Scale” are the most sensitive psychological measures to early microstructural changes after mTBI, and that the DTI metrics are predictive of pain and psychological measures in mTBI. Together, these results suggest that white matter microstructure plays an important role in the PTH following mTBI.
A SIMULATION MODEL TO QUANTIFY THE EFFICACY OF DRY CLEANING INTERVENTIONS ON A CONTAMINATED MILK POWDER LINE
Authors: Daeschel Devin , Chen Long , Zoellner Claire , Snyder Abigail B.
Published: August 2024

Outbreaks ofSalmonellaand other pathogens associated with low moisture foods have been caused by cross-contamination from the processing environment into product. We used Monte Carlo simulations to model the impact of hypothetical cross-contamination scenarios ofSalmonellafrom production equipment into milk powder. Model outputs include the quantity and extent of contaminated product from a production line, which can be useful for comparing the efficacy of different cleaning interventions. We also modeled the cross-contamination of potential dry cleaning surrogates to see how they responded to cleaning interventions in comparison toSalmonella. Input parameters for the model included log reductions from wiping an inoculated surface with a dry towel and transfer coefficients from an inoculated surface into milk powder that were measured experimentally and fitted to probability distributions. After a 2 log CFU contamination breach, the number of consumer size milk powder units (300 g) contaminated withSalmonellawas 72 [24, 96] (median [p5, p95] across 1000 simulation iterations). The average concentration ofSalmonellawithin contaminated units was -2.33 log CFU/g [-2.46, -1.86]. Wiping with a dry towel reduced the number of contaminated units to 26 [12, 64]. After product flushing with 150 kg of milk powder, the number of contaminated units dropped to 0 [0, 41].E. faeciumwas the most appropriate surrogate forSalmonellatransfer from surface to milk powder, whileL. innocuawas a more appropriate surrogate for the dry towel wiping intervention. These results suggest that product flushing, and to a lesser degree dry wiping, may be effective interventions in reducing contaminated milk powder product after a contamination breach. Further, simulation modeling is a useful tool for evaluatingSalmonelladry transfer surrogates for their use in dry cleaning validation and modeling applications.

IMPORTANCE

This work demonstrates the utility ofin silicomodeling as a decision support tool that can 1) estimate the cross-contamination ofSalmonellainto milk powder under different processing scenarios, 2) compare the efficacy of different cleaning interventions and 3) help inform surrogate selection for the dry transfer ofSalmonellain modeling and cleaning validation applications. The model presented here contributes to the risk-benefit analysis of tradeoffs associated with dry cleaning in low moisture food environments. For example, the model can be applied to estimate the efficacy of cleaning interventions like product flushing at a lower resource cost than experimental trials in a processing line. The model presented here also provides a more interpretable metric for choosing appropriateSalmonellasurrogates for dry cleaning validation.
Associations between work characteristics and large joint osteoarthritis: a cross-sectional study of 285,947 UK Biobank participants
Authors: Hashmi A , Scott S , Jung M , Meng Q-J , Tobias JH , Beynon RA , Faber BG
Published: August 2024

Objectives

Shift work-induced circadian rhythm disruption has been identified as a risk factor for specific diseases. Additionally, physically demanding work has been linked to osteoarthritis. This study investigated the independent associations of shift work and physical work with risk of large joint osteoarthritis.

Design

UK Biobank participants completed questionnaires detailing their employment status, including shift work, night shifts, heavy manual work and prolonged non-sedentary work. Responses were categorised into binary and categorical variables. Knee and hip osteoarthritis diagnoses were extracted from hospital records and osteoarthritis (any site) was self-reported. Logistic regression models, adjusted for age, sex, BMI, Townsend Deprivation Index and other work factors, were used to investigate the relationships between work characteristics and osteoarthritis outcomes.

Results

This study included 285,947 participants (mean age 52.7 years; males 48.0%). Shift work and night shifts were associated with knee osteoarthritis (fully adjusted OR: 1.12 [95% CI:1.07-1.17] and 1.12 [1.04-1.20], respectively), and self-reported osteoarthritis but there was little evidence of an association with hip osteoarthritis (1.01 [0.95-1.08] and 1.03 [0.93-1.14]). Heavy manual work and prolonged non-sedentary work were associated with increased risk of all osteoarthritis outcomes.

Conclusions

Shift work showed independent associations with knee osteoarthritis and self-reported osteoarthritis but not hip osteoarthritis, suggesting circadian rhythm dysfunction may play a role in knee osteoarthritis pathogenesis. Heavy manual work and prolonged non-sedentary work were associated with all outcomes, with stronger associations in knee osteoarthritis, possibly reflecting the knee’s higher susceptibility to biomechanical stress. Further research is needed to explore workplace interventions for reducing these risks.
Secular trends in the incidence, prevalence, and survival of primary liver cancer in the United Kingdom from 2000-2021: a population-based cohort study
Authors: Cuyàs Berta , Alvarado-Tapias Edilmar , Tan Eng Hooi , Golozar Asieh , Duarte-Salles Talita , Delmestri Antonella , Ballbé Josep Maria Argemí , Man Wai Yi , Burn Edward , Guarner-Argente Carlos , Prieto Alhambra Daniel , Newby Danielle
Published: August 2024

Background

Primary liver cancer (PLC) remains a global health challenge. Understanding trends in the disease burden and survival is crucial to inform decisions regarding screening, prevention and treatment.

Methods

Population-based cohort study using UK primary care data from the Clinical Practice Research Datalink (CPRD) GOLD (2000 to 2021), replicated in CPRD Aurum. PLC incidence rates (IR), period prevalence (PP) and survival at one, five and ten years over the study period were calculated, and stratified by age, sex and diagnosis year.

Results

The crude IR of PLC was 4.56 (95%CI 4.42-4.70) per 100,000 person-years between 2000 and 2021, with an increase over time across age and sex strata. Sex-specific IR for males was higher than females, 6.60 (95%CI 6.36-6.85) vs. 2.58 (95%CI 2.44-2.74) per 100,000 person-years. Crude PP showed a 7-fold increase over the study period, with PP 0.02% (95%CI 0.019%-0.022%) in 2021, and a 2.8-fold higher PP in males. Survival at one, five and ten years after diagnosis was 41.7%, 13.2% and 7.1%, respectively, for both sexes. One-year survival increased only in men, from 33.2% in 2005-2009 to 49.3% in 2015-2019.

Conclusion

Over the past two decades, there has been a significant increase in the number of patients diagnosed with PLC. Despite a slight improvement in median and one-year survival in men, prognosis remains poor. To improve the survival of PLC patients, it is necessary to understand the epidemiological changes and address the preventable risk factors associated with liver disease and promote early detection and access to care.

LAY SUMMARY

This population-based cohort study shows that the incidence and prevalence of primary liver cancer in the UK has increased in the last 20 years across both sexes and age groups, with a 7-fold increase in crude period prevalence over the study period. One-year survival has improved only in males over the study period and, regrettably, no increases in long-term survival were observed. Our findings are a call for awareness to stimulate further research and public health actions on liver cancer.
Triaging clients at risk of disengagement from HIV care: Application of a predictive model to clinical trial data in South Africa
Authors: Maskew Mhairi , Smith Shantelle , De Voux Lucien , Sharpey-Schafer Kieran , Crompton Thomas , Govender Ashley , Pisa Pedro , Rosen Sydney
Published: August 2024

Background

To reach South Africa’s targets for HIV treatment and viral suppression, retention on antiretroviral therapy (ART) must increase. Much effort and resources have been invested in tracing those already disengaged and returning them to care programs with mixed success. Here we aim to successfully identify ART clients at risk of loss from care prior to disengagement.

Methods and Findings

We applied a previously developed machine learning and predictive modelling algorithm (PREDICT) to routinely collected ART client data from the SLATE I and SLATE II trials, which evaluated same-day ART initiation in 2017-18. Using a primary outcome of an interruption in treatment (IIT), defined as missing the next scheduled clinic visit by >28 days, we investigated the reproducibility of PREDICT in SLATE datasets. We also tested two risk triaging approaches: 1) threshold approach classifying individuals into low, moderate, or high risk of IIT; and 2) archetype approach identifying subgroups with characteristics associated with risk of ITT. We report associations between risk category groups and subsequent IIT at the next scheduled visit using crude risk differences and relative risks with 95% confidence intervals. SLATE datasets included 7,199 client visits for 1,193 clients over ≤14 months of follow-up. The algorithm achieved 63% accuracy, 89% negative predictive value, and an area under the curve of 0.61 for attendance at next scheduled visit, similar to previous results using only medical record data. The threshold approach consistently and accurately assigned levels of IIT risk for multiple stages of the care cascade. The archetype approach identified several subgroups at increased risk of IIT, including those late to previous appointments, those returning after a period of disengagement, those living alone or without a treatment supporter. Behavioural elements of the archetypes tended to drive risk of treatment interruption more consistently than demographics; e.g. adolescent boys/young men who attended visits on time experienced lowest rates of treatment interruption (10%, PREDICT datasets and 7% SLATE datasets), while adolescent boys/young men returning after previously disengaging from care had highest rates of subsequent treatment interruption (31%, PREDICT datasets and 40% SLATE datasets).

Conclusion

Routinely collected medical record data can be combined with basic demographic and socioeconomic data to assess individual risk of future treatment disengagement using machine learning and predictive modelling. This approach offers an opportunity to intervene prior to and potentially prevent disengagement from HIV care, rather than responding only after it has occurred.
Resilience and Protective Factors for Mental Health among Indigenous Youth in Canada: A Scoping Review
Authors: Shin Hwayeon Danielle , Carrier Leah , Dame Jessy , Padley Michelle , Daclan Anika , Wong Helen , Dass Ronessa , Dorey Rachel Anne , Stirling-Cameron Emma , Langley Jodi , Curran Janet A.
Published: August 2024

Indigenous youth’s inherent strength and resilience play a vital role in their well-being and mental health. Protective factors, closely linked to resilience, spanning individual, family, and community levels reinforce positive mental health outcomes. The purpose of the present scoping review was to summarize the available literature that describes resilience and/or protective factors promoting mental health and well-being among Indigenous youth in Canada. As a secondary objective, this review investigated community involvement reported in the identified sources. JBI scoping review methodology was followed, and the search of PubMed, EMBASE, CINHAL, PsycINFO, ERIC, and Scopus commenced in August 2021, and was updated in February 2023. A targeted Google search was also conducted to identify eligible grey literature. A total of 61 papers were included in data extraction. The types of sources identified were observational (n=22), participatory action research (n=11), mixed/multi-methods (n=10), qualitative (n=9), case study (n=4), quasi-experimental (n=1), experimental (=1), and other designs such as quality improvement and program evaluation (n=3). Additionally, only a handful of included studies reported use of an Indigenous-specific approach, such as Two-Eyed seeing. Protective and resilience factors were identified across various levels such as individual (n=52), interpersonal (n=37), and wider environmental beyond social systems (n=37) levels. Forty studies described community involvement, which included non-specified community members, like friends or citizens (n=21), youth (n=19), Indigenous community members such as leaders and workers (n=14), and Elders (n=11). These groups were engaged to varying degrees, functioning either as equal collaborators, consultants, or, in some instances, as decision-makers.
Reduced Risk of Cardiovascular Diseases after Bariatric Surgery Based on the New PREVENT Equations
Authors: Wang Lei , Zhang Xinmeng , Chen You , Flynn Charles R. , English Wayne J. , Samuels Jason M. , Williams Brandon , Spann Matthew , Albaugh Vance L. , Shu Xiao-Ou , Yu Danxia
Published: August 2024

Background

We applied the novel Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) equations to evaluate cardiovascular-kidney-metabolic (CKM) health and estimated CVD risk, including heart failure (HF), after bariatric surgery.

Methods

Among 7804 patients (20–79 years) undergoing bariatric surgery at Vanderbilt University Medical Center during 1999–2022, CVD risk factors at pre-surgery, 1-year, and 2-year post-surgery were extracted from electronic health records. The 10- and 30-year risks of total CVD, atherosclerotic CVD (ASCVD), coronary heart disease (CHD), stroke, and HF were estimated for patients without a history of CVD or its subtypes at each time point, using the social deprivation index-enhanced PREVENT equations. Paired t-tests or McNemar tests were used to compare pre- with post-surgery CKM health and CVD risk. Two-sample t-tests were used to compare CVD risk reduction between patient subgroups defined by age, sex, race, operation type, weight loss, and history of diabetes, hypertension, and dyslipidemia.

Results

CKM health was significantly improved after surgery with lower systolic blood pressure, non-high-density-lipoprotein cholesterol (non-HDL), and diabetes prevalence, but higher HDL and estimated glomerular filtration rate (eGFR). The 10-year total CVD risk decreased from 6.51% at pre-surgery to 4.81% and 5.08% at 1- and 2-year post-surgery (relative reduction: 25.9% and 16.8%), respectively. Significant risk reductions were seen for all CVD subtypes (i.e., ASCVD, CHD, stroke, and HF), with the largest reduction for HF (relative reduction: 55.7% and 44.8% at 1- and 2-year post-surgery, respectively). Younger age, White race, >30% weight loss, diabetes history, and no dyslipidemia history were associated with greater HF risk reductions. Similar results were found for the 30-year risk estimates.

Conclusions

Bariatric surgery significantly improves CKM health and reduces estimated CVD risk, particularly HF, by 45-56% within 1-2 years post-surgery. HF risk reduction may vary by patient’s demographics, weight loss, and disease history, which warrants further research.
A spatial atlas of mitochondrial gene expression reveals dynamic translation hubs and remodeling in stress
Authors: Begeman Adam , Smolka John A. , Shami Ahmad , Waingankar Tejashree Pradip , Lewis Samantha C.
Published: August 2024

Mitochondrial genome expression is important for cellular bioenergetics. How mitochondrial RNA processing and translation are spatially organized across dynamic mitochondrial networks is not well understood. Here, we report that processed mitochondrial RNAs are consolidated with mitoribosome components into translation hubs distal to either nucleoids or processing granules in human cells. During stress, these hubs are remodeled into translationally repressed mesoscale bodies containing messenger, ribosomal, and double-stranded RNA. We show that the highly conserved helicase SUV3 contributes to the distribution of processed RNA within mitochondrial networks, and that stress bodies form downstream of proteostatic stress in cells lacking SUV3 unwinding activity. We propose that the spatial organization of nascent chain synthesis into discrete domains serves to throttle the flow of genetic information in stress to ensure mitochondrial quality control.
Snapshots of acetyl-CoA synthesis, the final step of CO2fixation in the Wood-Ljungdahl pathway
Authors: Yin Max Dongsheng , Lemaire Olivier N. , Rosas Jiménez José Guadalupe , Belhamri Mélissa , Shevchenko Anna , Hummer Gerhard , Wagner Tristan , Murphy Bonnie J.
Published: August 2024

In the ancient microbial Wood-Ljungdahl pathway, CO2is fixed in a multi-step process ending with acetyl-CoA synthesis at the bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase complex (CODH/ACS). Here, we present catalytic snapshots of the CODH/ACS from the gas-converting acetogenClostridium autoethanogenum, characterizing the molecular choreography of the overall reaction including electron transfer to the CODH for CO2reduction, methyl transfer from the corrinoid iron-sulfur protein (CoFeSP) partner to the ACS active site and acetyl-CoA production. Unlike CODH, the multidomain ACS undergoes large conformational changes to form an internal connection to the CODH active site, accommodate the CoFeSP for methyl transfer and protect the reaction intermediates. Altogether, the structures allow us to draw a detailed reaction mechanism of this enzyme crucial for CO2fixation in anaerobic organisms.

One-Sentence Summary:Structural description of key states of CO2fixation by the carbon monoxide dehydrogenase/acetyl-CoA synthase complex.
Variant-to-function dissection of rare non-coding GWAS loci with high impact on blood traits
Authors: Tardaguila Manuel , Schiller Dominique Von , Colombo Michela , Gori Ilaria , Coomber Eve L. , Vanderstichele Thomas , Benaglio Paola , Chiereghin Chiara , Gerety Sebastian , Vuckovic Dragana , Landini Arianna , Clerici Giuditta , Albers Patrick , Ray-Jones Helen , Burnham Katie L. , Tokolyi Alex , Persyn Elodie , Spivakov Mikhail , Sankaran Vijay G. , Walter Klaudia , Kundu Kousik , Pirastu Nicola , Inouye Michael , Paul Dirk S. , Davenport Emma E. , Sahlén Pelin , Watt Stephen , Soranzo Nicole
Published: August 2024

Two decades of Genome Wide Association Studies (GWAS) have yielded hundreds of thousands of robust genetic associations to human complex traits and diseases. Nevertheless, the dissection of the functional consequences of variants lags behind, especially for non-coding variants (RNVs). Here we have characterised a set of rare, non-coding variants with large effects on haematological traits by integrating (i) a massively parallel reporter assay with (ii) a CRISPR/Cas9 screen and (iii)in vivogene expression and transcript relative abundance analysis of whole blood and immune cells. After extensive manual curation we identify 22 RNVs with robust mechanistic hypotheses and perform an in-depth characterization of one of them, demonstrating its impact on megakaryopoiesis through regulation of theCUX1transcriptional cascade. With this work we advance the understanding of the translational value of GWAS findings for variants implicated in blood and immunity.
Scarless circular mRNA-based CAR-T cell therapy elicits superior anti-tumor efficacy
Authors: Hu Qinchao , Zhao Hui , Zhou Kaicheng , Hua Xianxin , Zhang Xuyao
Published: August 2024

Messenger RNA (mRNA)-based transient expression of CAR shows optimal safety profiles and provides promising opportunities to address existing challenges of viral vector-based CAR-T therapies and to meet emerging medical needs in noncancerous indications. However, linear mRNAs are intrinsically unstable and thus just achieve compromised efficacy. Here, we engineered a permuted intron exon (PIE) platform to synthesize scarless circular mRNA (cmRNA) for potent CAR expression and long-lasting efficacy. cmRNA significantly increased amount and duration of anti-CD19 CAR expression on human T cells. cmRNA-based anti-CD19 CAR-T cells elicit superior anti-tumor efficacy over linear mRNA counterparts, demonstrated by parallel lines of evidence includingin vitrospecific cell-killing, cytokine release, transcriptomics patterns, andin vivotumor elimination and survival benefit. We found that cmRNA-based anti-CD19 CAR-T efficiently eliminated target cellsin vivoand provide long-lasting antitumor efficacy. These results suggested that cmRNA could be a potent platform for unleashing full potential of mRNA technologies in cell therapies.
Exact distributions of threshold crossing times of proteins under post-transcriptional regulation by small RNAs
Authors: Ali Syed Yunus , Prasad Ashok , Das Dibyendu
Published: August 2024

The timings of several cellular events like cell lysis, cell division, or pore formation in endosomes are regulated by the time taken for the relevant proteins to cross a threshold in number or concentration. Since protein synthesis is stochastic, the threshold crossing time is a first passage problem. The exact distributions of these first passage processes have been obtained recently for unregulated and auto-regulated genes. Many proteins are however regulated by post-transcriptional regulation, controlled by small non-coding RNAs (sRNAs). Certain mathematical models of gene expressionwithpost-transcriptional sRNA regulation have been recently exactly mapped to modelswithoutsRNA regulation. Utilizing this mapping and the exact distributions, we calculate exact results on fluctuations (full distribution, all cumulants, and characteristic times) of protein threshold crossing times in the presence of sRNA regulation. We derive two interesting predictions from these exact results. We show that the size of the fluctuation of the threshold crossing times have a non-monotonic U-shaped behavior as a function of the rates of binding and unbinding of the sRNA-mRNA complex. Thus there are optimal parameters that minimize noise. Furthermore, the fluctuations in models with sRNA regulation may be higher or lower compared to the model without regulation, depending on the mean protein burst size.
The molecular basis of Human FN3K mediated phosphorylation of glycated substrate
Authors: Garg Ankur , On Kin Fan , Xiao Yang , Elkayam Elad , Cifani Paolo , David Yael , Joshua-Tor Leemor
Published: August 2024

Glycation, a non-enzymatic post-translational modification occurring on proteins, can be actively reversed via site-specific phosphorylation of the fructose-lysine moiety by FN3K kinase, to impact the cellular function of target protein. A regulatory axis between FN3K and glycated protein targets has been associated with conditions like diabetes and cancer. However the molecular basis of this relationship has not been explored so far. Here, we determined a series of crystal structures of HsFN3K in apo-state, and in complex with different nucleotide analogs together with a sugar substrate mimic to reveal the features important for its kinase activity and substrate recognition. Additionally, the dynamics in sugar substrate binding during the kinase catalytic cycle provide important mechanistic insights into HsFN3K function. Our structural work provides the molecular basis for rationale small molecule design targeting FN3K.
Two structurally mobile regions control the conformation and function of metamorphic meiotic HORMAD proteins
Authors: Barroso Consuelo , Prince Josh P , Rattu Punam , Kundé Daimona , Ferrandiz Nuria , Khalid Syma , Martinez-Perez Enrique
Published: August 2024

Metamorphic HORMA domain proteins (HORMADs) nucleate protein complex formation by refolding their mobile safety belt region to bind short motifs on interactors. Meiotic HORMADs (mHORMADs) bind proteinaceous axial elements to orchestrate complex chromosomal events that underpin fertility, including pairing and recombination between homologous chromosomes. However, the mechanisms supporting the diverse roles of mHORMADs remain unclear. Here, we show that mHORMADs have a second structurally mobile region, the β5-αC loop, which controls mHORMAD conformation and function. Molecular dynamics and in vivo approaches show that functional specialisation ofC. elegansparalogs HTP-1 and HTP-2 depends on the interplay between their β5-αC loop and safety belt. The β5-αC loop can interact with the same HORMA core surface as the safety belt, forming a “loop engaged” conformation. The β5-αC loop HORMA core interaction is essential for axis loading of HTP-1 and its paralog HTP-3, and is also present in yeast, plant, and mammalian mHORMADs, suggesting that it represents a conserved functional feature of mHORMADs. Our study reveals that mHORMADs have expanded the bimodal folding landscape first identified in Mad2, paving the way to elucidate how non-canonical HORMAD conformations control meiotic chromosome function to ensure fertility.
Aversion-induced drug taking and escape behavior involve similar nucleus accumbens core dopamine signaling signatures
Authors: Grafelman Elaine M , Côté Bridgitte E , Vlach Lisa , Geise Ella , Padula G. Nino , Wheeler Daniel S , Hearing Matthew , Mantsch John , Wheeler Robert A
Published: August 2024

Dopamine release in the nucleus accumbens core (NAcC) has long been associated with the promotion of motivated behavior. However, inhibited dopamine signaling can increase behavior in certain settings, such as during drug self-administration. While aversive environmental stimuli can reduce dopamine, it is unclear whether such stimuli reliably engage this mechanism in different contexts. Here we compared the physiological and behavioral responses to the same aversive stimulus in different designs to determine if there is uniformity in the manner that aversive stimuli are encoded and promote behavior. NAcC dopamine was measured using fiber photometry in male and female rats during cocaine self-administration sessions in which an acutely aversive 90 dB white noise was intermittently presented. In a separate group of rats, aversion-induced changes in dopamine were measured in an escape design in which operant responses terminated aversive white noise. Aversive white noise significantly reduced NAcC dopamine and increased cocaine self-administration in both male and female rats. The same relationship was observed in the escape design, in which white noise reduced dopamine and promoted escape attempts. In both designs, the magnitude of the dopamine reduction predicted behavioral performance. While prior research demonstrated that pharmacologically reduced dopamine signaling can promote intake, this report demonstrates that this physiological mechanism is naturally engaged by aversive environmental stimuli and generalizable to non-drug contexts. These findings illustrate a common physiological signature in response to aversion that may promote both adaptive and maladaptive behavior.
EXOSC4 is recruited by histone H3 co-modified with K9me3 and acetylations to surveil non-coding transcription
Authors: Stransky Stephanie , Cutler Ronald , Aguilan Jennifer , DeAngelo Joseph D. , Shechter David , Sidoli Simone
Published: August 2024

Histones are hyper modified proteins that regulate chromatin accessibility and DNA readout. Co-existing post-translational modifications (PTMs) on histones affect interaction affinities of chromatin-associated proteins in ways that are still mostly unexplored. Here, we focus on the biological role of a specific histone code made of two PTMs with supposedly opposing biological functions, i.e. H3K9me3 marker of constitutive heterochromatin and H3K14ac benchmarking accessible chromatin. By applying multi-dimensional mass spectrometry, we demonstrated that EXOSC4 interacts with H3K9me3 + acetyls and affects post-transcriptional regulation. Specifically, EXOSC4 depletion leads to down-regulation of the RNA surveillance machinery and increased expression of non-coding transcripts, including anti-sense RNAs. Together, we elucidate the role of a co-modified histone tail and demonstrate its involvement in the RNA machinery and spurious transcription surveillance.
Mfn2 induces NCLX-mediated calcium release from mitochondria
Authors: Kolitsida Panagiota , Saha Akash , Caliri Andrew , Assali Essam , Riera Alejandro Martorell , Itskanov Samuel , Magana Catalina S. , Stork Björn , Shirihai Orian , Sekler Israel , Koehler Carla M. , van der Bliek Alexander M.
Published: August 2024

Mfn2 is a mitochondrial outer membrane fusion protein with the additional role of tethering mitochondria to the ER. Here, we describe a novel connection between Mfn2 and calcium release from mitochondria. We show that Mfn2 controls the mitochondrial inner membrane sodium-calcium exchange protein NCLX, which is a major source for calcium release from mitochondria. This discovery was made with the fungal toxin Phomoxanthone (PXA), which induces calcium release from mitochondria. PXA-induced calcium release is blocked by a chemical inhibitor of NCLX, while NCLX and Mfn2 deletions both also prevent PXA-induced calcium release. CETSA experiments show that PXA directly targets Mfn2, which likely controls NCLX through physical interactions since co-immunoprecipitation and proximity ligation assays show increased association between Mfn2 and NCLX upon treatment with PXA. Interactions between Mfn2 and NCLX also increase when cells are treated with mitochondrial ROS-inducing conditions, such as oligomycin treatment of respiring cells, while the interactions do not increase in Oma1 -/-cells. It seems likely that opening of cristae by Oma1-mediated cleavage of Opa1 promotes translocation of NCLX from cristae to the rim where it can come into contact with Mfn2 thus promoting PXA-induced calcium release from mitochondria. These results therefore delineate a pathway that connects ROS produced inside mitochondria with calcium release and signaling in the cytosol.
A biodegradable and restorative peripheral neural interface for the interrogation of neuropathic injuries
Authors: Wang Liu , Zhang Tieyuan , Lei Jiaxin , Wang Shirong , Guan Yanjun , Chen Kuntao , Li Chaochao , Song Yahao , Li Weining , Wang Shimeng , Jia Zhibo , Chen Shengfeng , Bai Jun , Yu Bingbing , Yang Can , Sun Pengcheng , Wang Qingyun , Sheng Xing , Peng Jiang , Fan Yubo , Wang Lizhen , Zhang Milin , Wang Yu , Yin Lan
Published: August 2024

Monitoring the early-stage healing of severe traumatic nerve injuries is essential to gather physiological and pathological information for timely interventions and optimal clinical outcomes. While implantable peripheral nerve interfaces provide direct access to nerve fibers for precise interrogation and modulation, conventional non-degradable designs pose limited utilization in nerve injury rehabilitation. Here, we introduce a biodegradable and restorative neural interface for wireless real-time tracking and recovery of long-gap nerve injuries. Leveraging machine learning techniques, this electronic platform deciphers nerve recovery status and identifies traumatic neuroma formation at the early phase, enabling timely intervention and significantly improved therapeutic outcomes. The biodegradable nature of the device eliminates the need for retrieval procedures, reducing infection risks and secondary tissue damage. This research sheds light on bioresorbable multifunctional peripheral nerve interfaces for probing neuropathic injuries, offering vital information for early diagnosis and therapeutic intervention.
Photon-Counting Detector Computed Tomography Angiography to assess intracranial stents and flowdiverters - in vivo study comprising ultra-high resolution spectral reconstructions
Authors: De Beukelaer Frederic , De Beukelaer Sophie , Wuyts Laura L , Nikoubashman Omid , El Halal Mohammed , Kantzeli Iliana , Wiesmann Martin , Ridwan Hani , Weyland Charlotte S.
Published: August 2024

BACKGROUND AND PURPOSE

Neuroimaging of intracranial vessels with implanted stents (ICS) and flowdiverters (FD) is limited by artifacts. Photon-Counting-Detector-Computed Tomography (PCD-CT) is characterized by a higher resolution. The purpose of this study was to assess the image quality of ultra-high-resolution (UHR) PCD-CT-Angiography (PCD-CTA) and spectral reconstructions to define the best imaging parameters for the evaluation of vessel visibility in ICS and FD.

MATERIALS AND METHODS

Retrospective analysis of consecutive patients with implanted ICS or FD, who received a PCD-CTA between April 2023 and March 2024. Polyenergetic (PE), virtual monoenergetic imaging (VMI), pure lumen (PL) and iodine (I) reconstructions with different kiloelectron volt (keV) levels (keV 40, 60 and 80) and reconstruction kernels (Body vascular kernel (Bv) 48, Bv56, Bv64, Bv72, Bv76) were acquired to evaluate image quality and assessed by 2 independent radiologists using a 5-point Likert scale and regions of interest (ROI). The different kernels, keV and the optimized spectral reconstructions were compared in descriptive analysis.

RESULTS

In total, 12 patients with 9 FDs and 6 ICSs were analyzed. In terms of quantitative image quality, sharper kernels as Bv64 and Bv72 yielded increased image noise, and decreased signal to noise (SNR) and contrast to noise ratio (CNR) compared to the smoothest kernel Bv48, (p<0.01). Among the different keV levels and kernels, readers selected the 40 keV level (p<0.01) and sharper kernels (in the majority of cases Bv72) as the best to visualize the in-stent vessel lumen. Assessing the different spectral reconstructions virtual monoenergetic and iodine reconstructions proved to be best to evaluate in-stent vessel lumen (p<0.01).

CONCLUSIONS

Our preliminary study suggests that PCD-CTA and spectral reconstructions with sharper reconstruction kernels and a low keV level of 40 seem to be beneficial to achieve optimal image quality for the evaluation of ICS and FD. Iodine and virtual monoenergetic reconstructions were superior to pure lumen and polyenergetic reconstructions to evaluate in-stent vessel lumen.

Key points

PCD-CTA imaging quality can be advanced by image post processing with spectral reconstructions and certain reconstruction kernels.

Intracranial in-stent vessel lumen visibility significantly improves using sharp reconstruction kernels (Bv72) and low keV level in high-resolution mode in photon-counting detector computed tomography. Regarding the different optimized spectral reconstructions virtual monoenergetic and iodine reconstructions proved to be best to evaluate in-stent vessel lumen.