bluuebunny/crossref_metadata_2025 huggingface dataset:
The magnitude and cross reactivity of SARS-CoV-2 specific antibody responses in vaccinated and unvaccinated Sri Lankan children and association with nutrition status
Authors: Jeewandara Chandima , Karunananda Maneshka Vindesh , Fernando Suranga , Danasekara Saubhagya , Jayakody Gamini , Arulkumaran S. , Samaraweera N.Y. , Kumarawansha Sarathchandra , Sivaganesh Subramaniyam , Amarasinghe P. Geethika , Jayasinghe Chintha , Wijesekara Dilini , Marasinghe Manonath Bandara , Mambulage Udari , Wijayatilake Helanka , Senevirathne Kasun , Bandara A.D.P , Gallage C.P. , Colambage N.R. , Udayasiri A.A. Thilak , Lokumarambage Tharaka , Upasena Y. , Weerasooriya W.P.K.P. ,   seroprevalence study group, Tan Tiong Kit , Townsend Alain , Ogg Graham S. , Malavige Gathsaurie Neelika ,   Study groups, Perera Lahiru , Pushpakumara Pradeep , Gomes Laksiri , Jayamali Jeewantha , Aberathna Inoka Sepali , Nimasha Thashmi , Dissanayake Madushika , Ramu Shyrar , Peranantharajah Deneshan , Colambage Hashini , Wickramanayake Rivindu , Chathurangika Harshani , Bary Farha , Yatiwelle Sathsara , Harvie Michael , Deheragoda Maheli , Jayadas Tibutius , Ishara Shashini , Ariyaratne Dinuka , Dayarathna Shashika , Wijekulasuriya Ruwanthi , Ranathunga Chathura
Published: December 2023

Background

We investigated the seropositivity rates of Sri Lankan children in a large island wide serosurvey, to determine the magnitude and breadth of antibody responses to SARS-CoV-2 variants and the association with the vaccination and nutritional status to understand the likely impact of newer variants in Sri Lanka.

Methods

Using the WHO UNITY protocol, we recruited 5207 children, aged 10 to 20 years, representative of the 9 provinces of Sri Lanka, and assessed seropositive rates, ACE2 blocking antibodies and antibodies to BA.2.75 and XBB.1.5, in vaccinated and unvaccinated children. Anthropometric measurements were taken to determine the association between nutrition status and antibody levels.

Results

3111/3119 (99.7%) vaccinated and 2008/2088 (96.2%) of unvaccinated children, were seropositive for SARS-CoV-2. 2984/3111 (95.9%) of vaccinated children had ACE2 blocking antibodies above the cut-off threshold, compared to 1346/2008 (67.0%) of unvaccinated children. 27.2 % unvaccinated children had positive antibody responses to BA.2.75 and 30.7% to XBB.1.5, while 64.3% of vaccinated had a positive response to BA.2.75 and 43.1% to XBB.1.5. Vaccinated children had significantly higher titres of total antibodies, ACE2 blocking antibodies and antibodies to XBB.1.5 and BA.2.75 than unvaccinated children. However, the vaccinated had significantly higher responses to BA.2.75 (p<0.0001), than XBB.1.5. Unvaccinated children, with <3rd BMI centile had significantly lower ACE2 blocking antibodies than other groups.

Discussion

The high seropositivity rates and antibody titres to SARS-CoV-2 variants in unvaccinated children, suggests that they are likely to have been infected more than once with SARS-CoV-2. The implications of lower antibody levels in undernourished children should be further investigated.
Clinical Uncertainty In Large Vessel Occlusion Ischemic Stroke (CULVO): An Intrarater And Interrater Agreement Study
Authors: Diestro Jose Danilo B. , Fahed Robert , Omar Abdelsimar T. , Hawkes Christine , Hendriks Eef J. , Enriquez Clare Angeli , Eesa Muneer , Stotts Grant , Lee Hubert , Nagendra Shashank , Poppe Alexandre , Ducroux Célina , Lim Timothy , Narvacan Karl , Rizutto Michael , Alfalahi Afra , Nishi Hidehisa , Sarma Pragyan , Itsekzon-Hayosh Vladislav Ze’ev , Ignacio Katrina , Boisseau William , Pimenta Ribeiro Pontes Almeida Eduardo , Benomar Anass , Almekhlafi Mohammed A. , Milot Genvieve , Deshmukh Aviraj Satish , Kishore Kislay , Tampieri Donatella , Wang Jeffrey Z. , Srivastava Abhilekh , Roy Daniel , Carpani Federico , Kashani Nima , Candale-Radu Claudia , Singh Nishita , Bres Bullrich Maria , Sarmiento Robert , Muir Ryan , Parra-Farinas Carmen , Reiter Stephanie D. , Deschaintre Yan , Singh Ravinder-Jeet , Bodani Vivel , Katsanos Aristeidis , Agid Ronit , Zafar Atif , Mendes Pereira Vitor , Spears Julian , Marotta Thomas R. , Djiadeu Pascal , Sharma Sunjay , Farrokhyar Forough
Published: December 2023

Background

Limited research exists regarding the impact of neuroimaging modality on endovascular thrombectomy (EVT) decisions for late window large vessel occlusion (LVO) stroke cases.

Purpose

This study assesses whether perfusion CT imaging: 1) alters the proportion of recommendations for EVT, and 2) enhances the reliability of EVT decision-making compared to non-contrast CT and CT angiography.

Materials and Methods

We conducted an online survey using 30 patients drawn from an institutional database of 3144 acute stroke cranial CT scans. These cases were presented to 29 stroke or neurointerventional physicians from Canada across two sessions. Physicians evaluated each patient both with and without perfusion imaging and gave EVT recommendations. We used non-overlapping 95% confidence intervals and difference in agreement classification as criteria to suggest a difference between the Gwet AC1 statistics (κG). Our outcomes were: 1) the proportion of EVT recommendations, and 2) interrater and intrarater agreement, with or without perfusion imaging.

Results

In the first round, 29 raters completed the assessment, with 28 finishing the second round. The percentage of EVT recommendations differed by 1.1% with or without perfusion imaging. However, individual decisions changed in 21.4% of cases, with 11.3% against EVT and 10.1% in favor. Interrater agreement (κG) among the 29 raters was similar between non-perfusion CT neuroimaging and perfusion CT neuroimaging (κG = 0.487; 95% CI 0.327, 0.647 and κG = 0.552; 95% CI 0.430, 0.675). The 95% CIs overlapped with moderate agreement in both. Intrarater agreement exhibited overlapping 95% CIs for all 28 raters. κG was either substantial or excellent (0.81-1) for 71.4% (20/28) of raters in both groups.

Conclusion

The difference in EVT recommendations is minimal with either neuroimaing protocol. Regarding agreement we found that use of automated CT perfusion images does not significantly impact the reliability of EVT decisions for late window LVO patients.
Mathematical assessment of the role of intervention programs for malaria control
Authors: Korsah Maame Akua , Johnston Stuart T. , Tiedje Kathryn E. , Day Karen P. , Flegg Jennifer A. , Walker Camelia R.
Published: December 2023

Malaria remains a global health problem despite the many attempts to control and eradicate it. There is an urgent need to understand the current transmission dynamics of malaria and to determine the interventions necessary to control malaria. In this paper, we seek to develop a fit-for-purpose mathematical model to assess the interventions needed to control malaria in an endemic setting. To achieve this, we formulate a malaria transmission model to analyse the spread of malaria in the presence of interventions. A sensitivity analysis of the model is performed to determine the relative impact of the model parameters on disease transmission. We explore how existing variations in the recruitment and management of intervention strategies affect malaria transmission. Results obtained from the study imply that the discontinuation of existing interventions has a significant effect on malaria prevalence. Thus, the maintenance of interventions is imperative for malaria elimination and eradication. In a scenario study aimed at assessing the impact of long-lasting insecticidal nets (LLINs), indoor residual spraying (IRS), and localized individual measures, our findings indicate that increased LLINs utilization and extended IRS coverage (with longer-lasting insecticides) cause a more pronounced reduction in symptomatic malaria prevalence compared to a reduced LLINs utilization and shorter IRS coverage. Additionally, our study demonstrates the impact of localized preventive measures in mitigating the spread of malaria when compared to the absence of interventions.
The Status of Indian Cancer Record Keeping and Study of Mesothelioma Cases to Ascertain Asbestos Exposure in India
Authors: Singh Raja , Frank Arthur L.
Published: December 2023

Setting

Asbestos exposure causes mesothelioma which is classified as a malignancy and recorded by cancer registries which currently covers only16% of the population in India. The accurate number of mesothelioma cases may not be available for decision making as India still uses asbestos and it is important to ascertain its health impact, especially mesothelioma.

Objective

This study aims to find the cases of mesothelioma from 83 hospitals across India from 2012 onwards till 2022-2023. The study also compares the national registry reported cases to the ones found in this study.

Design

The study uses the Right to Information Act 2005 to find data from various hospitals and reporting the same. The data from the voluntary national registry was also collected. This was compiled and compared.

Results

Overall, the study shows 2213 cases of mesothelioma 2012 onwards in India from 83 hospitals. In the comparison period of 2012-2016, the registry reported cases were 54, while the study shows 1126 cases. Only 21% of hospitals in this study were part of the national registry programme.

Conclusion

Mesothelioma cases in India are more frequent than reported and the current recordkeeping for all cancers does not fully cover the expanse of India and needs to be revamped.
Integrative proteogenomic analyses provide novel interpretations of type 1 diabetes risk loci through circulating proteins
Authors: Lu Tianyuan , Manousaki Despoina , Sun Lei , Paterson Andrew D.
Published: December 2023

Type 1 diabetes (T1D) requires new preventive measures and interventions. Circulating proteins are promising biomarkers and drug targets. Leveraging genome-wide association studies (GWASs) of T1D (18,942 cases and 501,638 controls) and circulating protein abundances (10,708 individuals), the associations between 1,565 circulating proteins and T1D risk were assessed through Mendelian randomization, followed by multiple sensitivity and colocalization analyses, examinations of horizontal pleiotropy, and replications. Genetically increased circulating abundances of CTSH, IL27RA, SIRPG, and PGM1 were associated with an increased risk of T1D, consistently replicated in other cohorts. Bulk tissue and single-cell gene expression profiles revealed strong enrichment ofCTSH, IL27RA, and SIRPG in immune system-related tissues, andPGM1in muscle and liver tissues. Among immune cells,CTSHwas enriched in B cells and myeloid cells, whileSIRPGwas enriched in T cells and natural killer cells. These proteins warrant exploration as T1D biomarkers or drug targets in relevant tissues.
Effectivity and Safety Profile of Tenapanor, a Sodium-Hydrogen Exchanger Isoform 3 Inhibitor, as an Innovative Treatment for Hyperphosphatemia in Chronic Kidney Disease, a Systematic Review of Clinical Studies
Authors: Suciangto William , Rasyid Haerani , Vicente Anastasya Angelica , Suciangto Winny
Published: December 2023

Background

Chronic kidney disease (CKD) is a major global health problem. Hyperphosphatemia is frequent in CKD and a reason for increased morbidity and mortality as it generates hyperparathyroidism, high fibroblast growth factor 23 (FGF23), and hypocalcemia. Available hyperphosphatemia therapies still have limitations, including risk of metal overload, cardiovascular calcification, and systemic adverse effects (AEs). Tenapanor is a new hyperphosphatemia treatment in CKD with sodium-hydrogen exchanger isoform 3 (NHE3) inhibition mechanism and low systemic AEs.

Objectives

Discovering the effectivity and safety of tenapanor as hyperphosphatemia management in CKD.

Method

Literature searching is performed by using “pubmed” and “science direct” with “tenapanor”, “chronic kidney disease”, and “hyperphosphatemia” as keywords. The literatures were selected using PRISMA algorithm version 2020. Literature was screened based on Population, Intervention, Comparison, and Outcome (PICO) criteria which are: CKD patients requiring dialysis as population, tenapanor or its combination with dialysis or phosphate binders as intervention, placebo or other phosphate binders without tenapanor as comparison, and serum phosphate, safety profile, and other pleiotropic benefits related to hyperphosphatemia management as the outcome. The included studies then assessed for risk of bias and qualitatively reviewed.

Outcome

Tenapanor was able to reduce serum phosphate, generally in a dose-dependent manner. Tenapanor also suppressed FGF23 and parathyroid hormone, probably due to decreased serum phosphate. The frequent AEs was transient mild-to-moderate diarrhea in a dose-dependent manner. Tenapanor was generally well-tolerated with low systemic AEs due to its non-calcium, metal-free, and low-absorbed properties.

Conclusion

Tenapanor is an effective and safe option for hyperphosphatemia management in CKD.
Patients with Type 2 Diabetes and aGCKvariant are still at risk for T2D-related secondary complications
Authors: Schiabor Barrett Kelly M. , Telis Natalie , McEwen Lisa M. , Burrows Evanette K. , Judge Daniel P. , Pawloski Pamala A. , Grzymski Joseph J. , Washington Nicole L. , Bolze Alexandre , Cirulli Elizabeth T.
Published: December 2023

Natural HbA1c levels inGCK-MODY patients often sit above the diagnostic threshold for type 2 diabetes (T2D). Standard treatments to lower HbA1c levels are ineffective in these individuals, yet in case studies to date,GCK-MODY patients often evade secondary T2D complications. Given these deviations from a more typical T2D disease course, genetic screening ofGCKmay be clinically useful, but population studies are needed to more precisely quantify T2D-related outcomes inGCKvariant carriers. Using a state-of-the-art variant interpretation strategy based on glucose elevations, we genotyped all individuals in two real-world cohorts (n~535,000) forGCKrisk variants and examined rates of T2D and T2D-complications from seven disease categories.

We identified 439 individuals withGCKvariants predicted to increase glucose (~1/1200). Aligning with their glucose elevations,GCK-MODY variant carriers were 12x as likely, and all otherGCKrisk carriers 4x as likely, to receive a T2D diagnosis, compared to non-GCKcarriers. Surprisingly,GCKrisk carriers with T2D develop a range of T2D-related complications at rates comparable to non-GCKT2D patients. Although the penetrance for secondary complications is lower than that for glucose elevations,GCKrisk carriers remain at elevated risk of T2D and secondary complications.
Challenges in the case-based surveillance of infectious diseases
Authors: Eales Oliver , McCaw James M. , Shearer Freya M.
Published: December 2023

To effectively inform infectious disease control strategies, accurate knowledge of the pathogen’s transmission dynamics is required. The infection incidence, which describes the number of new infections in a given time interval (e.g., per day or per week), is fundamental to understanding transmission dynamics, and can be used to estimate the time-varying reproduction number and the severity (e.g., the infection fatality ratio) of a disease. The timings of infections are rarely known and so estimates of the infection incidence often rely on measurements of other quantities amenable to surveillance. Case-based surveillance, in which infected individuals are identified by a positive test, is the pre-dominant form of surveillance for many pathogens, and was used extensively during the COVID-19 pandemic. However, there can be many biases present in case-based surveillance indicators due to, for example, test sensitivity and specificity, changing testing behaviours, and the co-circulation of pathogens with similar symptom profiles. Without a full understanding of the process by which surveillance systems generate data, robust estimates of the infection incidence, time-varying reproduction number, and severity based on these data cannot be made. Here we develop a mathematical description of case-based surveillance of infectious diseases. By considering realistic epidemiological parameters and situations, we demonstrate potential biases in common surveillance indicators based on case-based surveillance data. The description is highly general and could be applied to a diverse set of pathogens and situations. The mathematical description could be used to inform inference of infection incidence using existing data, with a full understanding of where bias and uncertainty will be present in any such analysis. Future surveillance strategies could be designed to minimise these sources of bias and uncertainty, providing more accurate estimates of a pathogen’s transmission dynamics and, ultimately, more targeted application of public health measures.
Epigenetic scores indicate differences in the proteome of preterm infants
Authors: Mckinnon Katie , Conole Eleanor L.S. , Vaher Kadi , Hillary Robert F. , Gadd Danni A. , Binkowska Justyna , Sullivan Gemma , Stevenson Anna J. , Corrigan Amy , Murphy Lee , Whalley Heather C. , Richardson Hilary , Marioni Riccardo E. , Cox Simon R. , Boardman James P.
Published: December 2023

Background

Epigenetic scores (EpiScores), reflecting DNA methylation (DNAm)-based surrogates for complex traits, have been developed for multiple circulating proteins. EpiScores for pro-inflammatory proteins, such as C-reactive protein (DNAm CRP), are associated with brain health and cognition in adults and with inflammatory comorbidities of preterm birth in neonates. Social disadvantage can become embedded in child development through inflammation, and deprivation is over-represented in preterm infants. We tested the hypotheses that preterm birth and socioeconomic status (SES) are associated with alterations in a set of EpiScores enriched for inflammation-associated proteins.

Results

104 protein EpiScores were derived from saliva samples of 332 neonates born at gestational age (GA) 22.14 to 42.14 weeks. Saliva sampling was between 36.57 and 47.14 weeks. Forty-three (41%) EpiScores were associated with low GA at birth (standardised estimates |0.14 to 0.88|, Bonferroni-adjustedp-value <8.3×10−3). These included EpiScores for chemokines, growth factors, proteins involved in neurogenesis and vascular development, cell membrane proteins and receptors, and other immune proteins. Three EpiScores were associated with SES, or the interaction between birth GA and SES: afamin, intercellular adhesion molecule 5 and hepatocyte growth factor-like protein (standardised estimates |0.06 to 0.13|, Bonferroni-adjustedp-value <8.3×10−3). In a preterm sub-group (n=217, median [range] GA 29.29 weeks [22.14 to 33.0 weeks]), SES-EpiScore associations did not remain statistically significant after adjustment for sepsis, bronchopulmonary dysplasia, necrotising enterocolitis, and histological chorioamnionitis.

Conclusions

Low birth GA is substantially associated with a set of EpiScores. The set was enriched for inflammatory proteins, providing new insights into immune dysregulation in preterm infants. SES had fewer associations with EpiScores; these tended to have small effect sizes and were not statistically significant after adjusting for inflammatory comorbidities. This suggests that inflammation is unlikely to be the primary axis through which SES becomes embedded in the development of preterm infants in the neonatal period.
Future HIV epidemic trajectories in South Africa and long-term consequences of reductions in general HIV testing: a mathematical modelling study
Authors: Rautenbach Stefan P , Whittles Lilith K , Meyer-Rath Gesine , Jamieson Lise , Chidarikire Thato , Johnson Leigh F , Imai-Eaton Jeffrey W
Published: December 2023

Background

Following successful intensive interventions to rapidly increase HIV awareness, antiretroviral therapy (ART) coverage, and viral suppression, HIV programmes in eastern and southern Africa must now consider whether to scale-back certain programmes, such as widespread general population HIV testing services (general HTS), without risking a resurging epidemic or substantially increasing long-term ART need through slowed incidence declines.

Methods

We used a mathematical model (Thembisa) to project the South African HIV epidemic to 2100 under current epidemiologic and programmatic conditions. We assessed the epidemiological impact and cost of implementing general HTS reductions at different times between 2025 and 2050, while maintaining antenatal, symptom-based, and risk-based testing modalities and other HIV prevention. We considered how future uncertainty interacted with testing reductions by assuming positive or negative changes in ART interruption rates and condom usage over 2025–2035.

Findings

Under the status quo scenario, HIV incidence (15-49 years) steadily declined from 4.95/1000 (95% CI: 4.40–5.34) in 2025 to 0.14/1000 (0.05–0.31) in 2100, attaining <1/1000 in 2055 (2051–2060). When general HTS was scaled-back in 2025, incidence continued declining, but time to <1/1000 was delayed by 5, 13, and 35 years for a 25%, 50%, or 75% reduction in general HTS, and not attained by 2100 with full cessation. Reducing general HTS by 25% to 100% from 2025 resulted in 10% (8–12%) to 65% (53–77%) more new HIV infections and 7% (5–8%) to 46% (38–53%) more AIDS-related deaths over 50 years. Delaying general HTS reductions for 5 to 25 years mitigated some impacts. HIV testing accounted for only 5% of total programmatic costs at baseline. Reducing testing modestly reduced short-term total costs, but increased long-term costs. Changes in ART interruption rates and condom usage levels affected incidence decline rates and general HTS levels required to control transmission but did not cause rapid resurgent incidence.

Interpretation

Scaling-back general HTS did not result in resurging HIV infections, but it delayed attainment of incidence reduction targets and increased long-term expected infections, deaths, ART provision, and costs. HIV programmes face decisions balancing near-term health system resource savings by reducing intensive HIV programmes with epidemic control objectives over several decades.

Funding

BMGF, Wellcome, UKRI
Molecular heterogeneity of quiescent melanocyte stem cells revealed by single-cell RNA-sequencing
Authors: Palmer Joseph W. , Kumar Nilesh , An Luye , White Andrew C. , Mukhtar M. Shahid , Harris Melissa L.
Published: December 2023

Melanocyte stem cells (McSCs) of the hair follicle are a rare cell population within the skin and are notably underrepresented in whole-skin, single-cell RNA sequencing (scRNA-seq) datasets. Using a cell enrichment strategy to isolate KIT+/CD45-cells from the telogen skin of adult female C57BL/6J mice, we evaluated the transcriptional landscape of quiescent McSCs (qMcSCs) at high resolution. Through this evaluation, we confirmed existing molecular signatures for qMcCS subpopulations (e.g.,Kit+, Cd34+/-,Plp1+, Cd274+/-, Thy1+, Cdh3+/-) and identified novel qMcSC subpopulations, including two that differentially regulate their immune privilege status. Within qMcSC subpopulations, we also predicted melanocyte differentiation potential, neural crest potential, and quiescence depth. Taken together, the results demonstrate that the qMcSC population is heterogenous and future studies focused on investigating changes in qMcSCs should consider changes in subpopulation composition.

Significance

Single cell transcriptomics has revolutionized our ability to interrogate the dynamic nature of tissues. Here we provide a high-resolution map of the melanocyte stem cell population during quiescence. This map provides one of few examples highlighting broad heterogeneity in stem cells during the quiescent cell state. The map also unifies previous observations using other cell, molecular and functional analyses to define the unique features of the quiescent melanocyte stem cell population. This data provides a valuable resource to individuals interested in further evaluating aspects of cellular quiescence in stem cells broadly or melanocyte stem cells specifically.
Learning of the same task subserved by substantially different mechanisms between patients with Body Dysmorphic Disorder and healthy individuals
Authors: Wang Zhiyan , Tan Qingleng , Frank Sebastian M. , Sasaki Yuka , Sheinberg David , Phillips Katharine A. , Watanabe Takeo
Published: December 2023

It is generally believed that learning of a perceptual task involving low-level neuronal mechanisms is similar between individuals. However, it is unclear whether this assumption also applies to individuals with psychiatric disorders that are known to have altered brain activation during visual processing. We investigated this question in patients with body dysmorphic disorder (BDD), a psychiatric disorder characterized by distressing or impairing preoccupation with nonexistent or slight defects in one’s physical appearance, and in healthy controls. Participants completed six training sessions on separate days on a visual detection task for human faces with low spatial frequency (LSF) components. Brain activation during task performance was measured with functional magnetic resonance imaging (fMRI) on separate days prior to and after training. The behavioral results showed that both groups of participants improved on the visual detection task to a similar extent through training. Despite this similarity in behavioral improvement, neuronal changes in the Fusiform Face Area (FFA), a core cortical region involved in face processing, with training were substantially different between groups. First, activation in the right FFA for LSF faces relative to High Spatial Frequency (HSF) faces that were used as an untrained control increased after training in BDD patients but decreased in controls. Second, resting state functional connectivity between left and right FFAs decreased after training in BDD patients but increased in controls. Contrary to the assumption that learning of a perceptual task is subserved by the same neuronal mechanisms across individuals, our results indicate that the neuronal mechanisms involved in learning of a face detection task differ fundamentally between patients with BDD and healthy individuals. The involvement of different neuronal mechanisms for learning of even simple perceptual tasks in patients with BDD might reflect the brain’s adaptations to altered functions imposed by the psychiatric disorder.
Parkinson’s disease-related Miro1 mutation induces mitochondrial dysfunction and loss of dopaminergic neuronsin vitroandin vivo
Authors: Chemla Axel , Arena Giuseppe , Sacripanti Ginevra , Barmpa Kyriaki , Zagare Alise , Garcia Pierre , Antony Paul , Ohnmacht Jochen , Baron Alexandre , Jung Jaqueline , Marzesco Anne-Marie , Buttini Manuel , Schmidt Thorsten , Grünewald Anne , Schwamborn Jens C. , Krüger Rejko , Saraiva Claudia
Published: December 2023

The complex and heterogeneous nature of Parkinson’s disease (PD) is still not fully understood, however, increasing evidence supports mitochondrial impairments as a major driver of neurodegeneration in PD. Recently, the regulator of mitochondrial homeostasis Miro1 has been linked genetically and pathophysiologically to PD. Using 2D and 3D patient-based induced pluripotent stem cells models, including an isogenic control, showed that the Miro1 p.R272Q mutation leads to mitochondrial impairments including increased oxidative stress, disrupted mitochondrial bioenergetics and altered metabolism. This was accompanied by increased α-synuclein levels in 2D dopaminergic neurons and by a significant reduction of dopaminergic neurons within midbrain organoids. Knock-in mice expressing mutant p.R285Q Miro1 (orthologue of the human p.R272Q mutation) confirmed the PD-specific dopaminergic neuronal loss in the substantia nigra, accumulation of striatal phosphorylated α-synuclein accompanied by behavioral alterations. These findings demonstrate that mutant Miro1 is sufficient to comprehensively model PD-relevant phenotypesin vitroandin vivo, reinforcing its pivotal role in PD pathogenesis.
Characterizing Molecular and Synaptic Signatures in mouse models of Late-Onset Alzheimer’s Disease Independent of Amyloid and Tau Pathology
Authors: Kotredes Kevin P. , Pandey Ravi S. , Persohn Scott , Elderidge Kierra , Burton Charles P , Miner Ethan W. , Haynes Kathryn A. , Santos Diogo Francisco S. , Williams Sean-Paul , Heaton Nicholas , Ingraham Cynthia M. , Lloyd Christopher , Garceau Dylan , O’Rourke Rita , Herrick Sarah , Rangel-Barajas Claudia , Maharjan Surendra , Wang Nian , Sasner Michael , Lamb Bruce T. , Territo Paul R. , Sukoff Rizzo Stacey J. , Carter Gregory W. , Howell Gareth R. , Oblak Adrian L.
Published: December 2023

Structured Abstract

INTRODUCTION

MODEL-AD is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to more accurately mimic LOAD than commonly used transgenic models.

METHODS

We created the LOAD2 model by combining APOE4, Trem2*R47H, and humanized amyloid-beta. Mice aged up to 24 months were subjected to either a control diet or a high-fat/high-sugar diet (LOAD2+HFD) from two months of age. We assessed disease-relevant outcomes, including in vivo imaging, biomarkers, multi-omics, neuropathology, and behavior.

RESULTS

By 18 months, LOAD2+HFD mice exhibited cortical neuron loss, elevated insoluble brain Aβ42, increased plasma NfL, and altered gene/protein expression related to lipid metabolism and synaptic function. In vivo imaging showed age-dependent reductions in brain region volume and neurovascular uncoupling. LOAD2+HFD mice also displayed deficits in acquiring touchscreen-based cognitive tasks.

DISCUSSION

Collectively the comprehensive characterization of LOAD2+HFD mice reveal this model as important for preclinical studies that target features of LOAD independent of amyloid and tau.
The role of kinesthetic and visuospatial cues in pain-induced movement avoidance
Authors: Fuchs Xaver , Heed Tobias
Published: December 2023

Background

Avoidance of movements is an important factor in chronic pain. Previous experiments have investigated the involved learning mechanisms by pairing movements with painful stimuli but, usually, other visuospatial cues are concurrently presented during learning. Therefore, participants might primarily avoid these visuospatial rather than the movement-related cues, potentially invalidating related interpretations of pain-induced movement avoidance. Here, we separated kinesthetic from visuospatial cues to investigate their respective contribution to avoidance learning.

Methods

Participants used a hand-held robotic manipulandum and, during an acquisition phase, received painful stimuli when performing center-out movements. Pain stimuli could be avoided by choosing a curved rather than direct movement trajectories. To distinguish the contribution of kinesthetic vs. visuospatial cues we used two generalization contexts: either participants executed novel movements passing through the same location at which pain had previously been presented in the acquisition phase; or they executed the same pain-associated movements after having been reseated, so that the hand did not pass through the pain-associated location.

Results

Avoidance generalization was comparable in both contexts, and remarkably, highly correlated between them. Our findings suggest that both visuospatial and kinesthetic cues available during acquisition were associated with pain and led to avoidance.

Conclusions

Our research corroborates the fear-avoidance pain model and previous studies’ findings that pain can become associated with movements. However, our study indicates that visuospatial cues also play a critical role. Future studies should distinguish movement-related and space-related associations in pain learning.

Significance

Chronic pain is a significant health issue typically attributed to maladaptive learning of pain-movement associations and movement avoidance. We demonstrate that visual cues can play a similarly important role as movement cues in pain learning. This aspect has not previously been considered and has likely confounded previous research findings.
Structural basis for human mitochondrial tRNA maturation
Authors: Meynier Vincent , Hardwick Steven W. , Catala Marjorie , Roske Jonas , Oerum Stephanie , Chirgadze Dimitri Y. , Barraud Pierre , Yu Wyatt , Luisi Ben F. , Tisné Carine
Published: December 2023

The human mitochondrial genome is transcribed into two RNAs, containing mRNAs, rRNAs and tRNAs, all dedicated to produce essential proteins of the respiratory chain. The precise excision of tRNAs by the mitochondrial endoribonucleases (mt-RNase), mt-RNase P and Z, releases all RNA species from the two RNA transcripts. The tRNAs then undergo 3’-CCA addition. In metazoan mitochondria, RNase P is a multi-enzyme assembly that comprises the endoribonuclease PRORP and a tRNA methyltransferase subcomplex. The requirement for a tRNA methyltransferase complex in mt-RNase P cleavage activity is not fully understood. Moreover, the mechanisms of pre-tRNA 3’-cleavage and CCA addition have also yet to be uncovered. Here we report cryo-EM structures that visualise these events, revealing the molecular basis for the first steps of RNA-transcript processing in human mitochondria. Altogether, the structures visualise four steps of mitochondrial tRNA maturation: 5’ and 3’ tRNA-end processing, methylation and 3’-CCA addition, and explain the defined sequential order of tRNA processing. The methyltransferase subcomplex recognises the pre-tRNA in a distinct mode that can support tRNA processing and 3’-CCA addition, likely resulting from an evolutionary adaptation of mitochondrial tRNA maturation complexes to the structurally-variable mitochondrial tRNAs. This subcomplex can also ensure a tRNA-folding quality-control checkpoint before the sequential docking of the maturation enzymes.
The last days ofAporia crataegi(L.) in Britain: evaluating genomic erosion in an extirpated butterfly
Authors: Whitla Rebecca , Hens Korneel , Hogan James , Martin Geoff , Breuker Casper , Shreeve Timothy G. , Arif Saad
Published: December 2023

Current rates of habitat degradation and climate change are causing unprecedented declines in global biodiversity. Studies on vertebrates highlight how conservation genomics can be an effective tool to identify and manage threatened populations, but it is unclear how vertebrate derived metrics of genomic erosion translate to invertebrate species, with their markedly different population sizes and life histories. The Black-veined White butterfly (Aporia crataegi)was extirpated from Britain in the 1920s. Here, we sequenced historical DNA from 17 museum specimens collected between 1854-1924 to reconstruct demography and compare levels of genomic erosion between extirpated British and extant European mainland populations. We contrast these results using modern samples of the Common Blue butterfly (Polyommatus icarus); a species with relatively stable demographic trends in Great Britain. We provide evidence for bottlenecks in both these species around the period of post-glacial colonisation of the British Isles. Our results reveal different demographic histories andNefor both species, consistent with their fates in Britain, likely driven by differences in life history, ecology, genome lengths and body size. Despite a difference, by an order of magnitude, in historical effective population sizes (Ne), reduction in genome-wide heterozygosity inA. crataegiwas comparable to that inP. icarus. Symptomatic ofA. crataegi’s disappearance were marked increases in runs-of-homozygosity (RoH), potentially indicative of recent inbreeding, and accumulation of putatively mildly and weakly deleterious variants. Our results support the idea that metrics of inbreeding and accumulation of deleterious mutations could be more informative markers of population or species in decline.
Effect of eye globe and optic nerve morphologies on gaze-induced optic nerve head deformations
Authors: Liu Tingting , Hung Pham Tan , Wang Xiaofei , Girard Michaël J. A.
Published: December 2023

Purpose

To investigate the effect of globe and optic nerve (ON) morphologies and tissue stiffnesses on gaze-induced optic nerve head deformations using parametric finite element modeling and a Design of Experiment (DOE) approach.

Methods

A custom software was developed to generate finite element models of the eye using 10 morphological parameters: dural radius, scleral, choroidal, retinal, pial, peripapillary border tissue thicknesses, prelaminar tissue depth, lamina cribrosa (LC) depth, ON radius, and ON tortuosity. A 10-factor 2-level full-factorial analysis (1,024 models) was used to predict the effects of each morphological factor and their interactions on LC strains induced by 13° adduction. Subsequently, a further DOE analysis (1,024 models) was conducted to study the effects and potential interactions between the top 5 morphological parameters identified from the initial DOE study and 5 critical tissue stiffnesses.

Results

In the DOE analysis of 10 morphological parameters, the five most significant factors were ON tortuosity, dural radius, ON radius, scleral thickness and LC depth. Further DOE analysis incorporating biomechanical parameters highlighted the importance of dural and LC stiffness. A larger dural radius and stiffer dura increased LC strains but the other main factors had the opposite effects. Notably, a significant interaction was found between dural radius and dural stiffness.

Conclusions

This study highlights the significant impact of morphological factors on LC deformations during eye movements, with key morphological effects being more pronounced than tissue stiffnesses.
Apical constriction requires patterned apical surface remodeling to synchronize cellular deformation
Authors: Yamashita Satoshi , Ishihara Shuji , Graner François
Published: December 2023

Apical constriction is a basic mechanism for epithelial morphogenesis, making columnar cells into wedge shape and bending a flat cell sheet. It has long been thought that an apically localized myosin generates a contractile force and drives the cell deformation. However, when we tested the increased apical surface contractility in a cellular Potts model simulation, the constriction increased pressure inside the cell and pushed its lateral surface outward, making the cells adopt a drop shape instead of the expected wedge shape. To keep the lateral surface straight, we considered an alternative model in which the cell shape was determined by cell membrane elasticity and endocytosis, and the increased pressure is balanced among the cells. The cellular Potts model simulation succeeded in reproducing the apical constriction, and it also suggested that a too strong apical surface tension might prevent the tissue invagination.
Reconstitution of autophagosomal membrane tethering reveals that Atg11 can bind and cluster vesicles on cargo mimetics
Authors: Andhare Devika , Katzenell Sarah , Najera Sarah I , Bauer Katherine M , Ragusa Michael J
Published: December 2023

Autophagy is essential for the degradation of mitochondria from yeast to humans. Mitochondrial autophagy in yeast is initiated when the selective autophagy scaffolding protein Atg11 is recruited to mitochondria through its interaction with the selective autophagy receptor Atg32. This also results in the recruitment of small 30 nm vesicles that fuse to generate the initial autophagosomal membrane. We demonstrate that Atg11 can bind to autophagosomal-like membranes in vitro in a curvature dependent manner via a predicted amphipathic helix. Deletion of the amphipathic helix from Atg11 results in a delay in the formation of mitophagy initiation sites in yeast. Furthermore, using a novel biochemical approach we demonstrate that the interaction between Atg11 and Atg32 results in the tethering of autophagosomal-like vesicles in clusters to giant unilamellar vesicles containing a lipid composition designed to mimic the outer mitochondrial membrane. Taken together our results demonstrate an important role for autophagosomal membrane binding by Atg11 in the initiation of mitochondrial autophagy.
SntB triggers the antioxidant pathways to regulate development and aflatoxin biosynthesis inAspergillus flavus
Authors: Wu Dandan , Yang Chi , Yao Yanfang , Ma Dongmei , Lin Hong , Hao Ling , Xin Wenwen , Ye Kangfu , Sun Minghui , Hu Yule , Yang Yanling , Zhuang Zhenhong
Published: December 2023

The epigenetic reader SntB was identified as an important transcriptional regulator of growth, development, and secondary metabolite synthesis inAspergillus flavus. However, the underlying molecular mechanism is still unclear. In this study,sntBgene deletion (ΔsntB), complementary (Com-sntB), and HA tag fused tosntB(sntB-HA) strains were constructed by using the homologous recombination method, respectively. Our results revealed that deletion ofsntBinhibited the processes of mycelia growth, conidial production, sclerotia formation, aflatoxin synthesis, and ability to colonize host, and the defective phenotype of knockout strain ΔsntBcould be restored in its complementary strain Com-sntB. Chromatin immunoprecipitation sequencing (ChIP-seq) ofsntB-HA and WT, and RNA sequencing (RNA-seq) of ΔsntBand WT strains revealed that SntB played key roles in oxidative stress response ofA. flavus. The function ofcatCgene (encode a catalase) was further analyzed based on the integration results of ChIP-seq and RNA-seq. In ΔsntBstrain, the relative expression level ofcatCwas significantly higher than in WT strain, while a secretory lipase encoding gene (G4B84_008359) was down-regulated. Under the stress of oxidant menadione sodium bisulfite (MSB), the deletion ofsntBobvious down-regulated the expression level ofcatC. After deletion ofcatCgene, the mycelia growth, conidial production, and sclerotia formation were inhibited, while ROS level and aflatoxin production were increased compared to the WT strain. Results also showed that the inhibition rate of MSB to ΔcatCstrain was significantly lower than that of WT group and AFB1 yield of the ΔcatCstrain was significantly decreased than that of WT strain under the stress of MSB. Our study revealed the potential machinery that SntB regulated fungal morphogenesis, mycotoxin anabolism, and fungal virulence through the axle of from SntB to fungal virulence and mycotoxin bio-synthesis, i.e. H3K36me3 modification-SntB-Peroxisomes-Lipid hydrolysis-fungal virulence and mycotoxin bio-synthesis. The results of this study shed light into the SntB mediated transcript regulation pathways of fungal mycotoxin anabolism and virulence, which provided potential strategy for control the contamination ofA. flavusand its aflatoxins.
Phase diversity-based wavefront sensing for fluorescence microscopy
Authors: Johnson Courtney , Guo Min , Schneider Magdalena C. , Su Yijun , Khuon Satya , Reiser Nikolaj , Wu Yicong , Riviere Patrick La , Shroff Hari
Published: December 2023

Fluorescence microscopy is an invaluable tool in biology, yet its performance is compromised when the wavefront of light is distorted due to optical imperfections or the refractile nature of the sample. Such optical aberrations can dramatically lower the information content of images by degrading image contrast, resolution, and signal. Adaptive optics (AO) methods can sense and subsequently cancel the aberrated wavefront, but are too complex, inefficient, slow, or expensive for routine adoption by most labs. Here we introduce a rapid, sensitive, and robust wavefront sensing scheme based on phase diversity, a method successfully deployed in astronomy but underused in microscopy. Our method enables accurate wavefront sensing to less than λ/35 root mean square (RMS) error with few measurements, and AO with no additional hardware besides a corrective element. After validating the method with simulations, we demonstrate calibration of a deformable mirror > 100-fold faster than comparable methods (corresponding to wavefront sensing on the ~100 ms scale), and sensing and subsequent correction of severe aberrations (RMS wavefront distortion exceeding λ/2), restoring diffraction-limited imaging on extended biological samples.
Mutations inGPNMBassociated with Amyloid cutis dyschromica alter intracellular trafficking and processing of GPNMB
Authors: Bogacki Erin C. , Lewis Patrick A. , Herbst Susanne
Published: December 2023

Amyloid cutis dyschromica (ACD) is a rare skin condition characterized by focal areas of hyperpigmentation with hypopigmented macules and distinct regions of amyloid deposition. Until recently, the genetic cause of ACD remained unknown. Several studies have since named GPNMB truncation mutations as causal, with protein loss-of-function underlying ACD pathogenesis. GPNMB missense mutations have also been observed in patients, but these are less well characterized; especially on a cellular level. Here, we observed that GPNMB missense mutations implicated in familial ACD show distinct cellular phenotypes that result in impaired protein maturation and processing from the endoplasmic reticulum (ER) to thetrans-Golgi network (TGN), prompting failed trafficking to lysosomes. These missense mutations also show failed secretion of the extracellular fragment of GPNMB, a well-characterized property of the protein. Overall, this work highlights previously undescribed cellular characteristics of GPNMB missense mutations implicated in ACD and helps to better inform the clinically observed phenotypes, as well as underscore GPNMB’s role at melanosomes.
Enzyme Fragment Complementation Driven by Nucleic Acid Hybridization
Authors: Xu Zihan , Zhang Xiaoyu , Pal Chandan , Rozners Eriks , Callahan Brian P.
Published: December 2023

A modified protein fragment complementation assay has been designed and validated as a gain-of-signal biosensor for nucleic acid:nucleic acid interactions. The assay uses fragments of NanoBiT, the split luciferase reporter enzyme, that are esterified at their C-termini to steramers, sterol-modified oligodeoxynucleotides. TheDrosophilahedgehog autoprocessing domain, DHhC, served as a self-cleaving catalyst for these bioconjugations. In the presence of ssDNA or RNA with segments complementary to the steramers and adjacent to one another, the two NanoBiT fragments productively associate, reconstituting NanoBiT enzyme activity. NanoBiT luminescence in samples containing nM ssDNA or RNA template exceeded background by 30-fold and as high as 120-fold depending on assay conditions. A unique feature of this detection system is the absence of a self-labeling domain in the NanoBiT bioconjugates. Eliminating that extraneous bulk broadens the detection range from short oligos to full-length mRNA.

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