Mapping the journey of patients and care partners living with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: developing a framework for improvements in care.

Aim: To identify and raise awareness of healthcare service gaps for individuals with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).Materials & methods: An ALSP patient journey map from symptom onset throughout disease course was developed using existing literature, patient and clinician feedback from a structured workshop and community survey data regarding attitudes toward genetic testing.Results: ALSP diagnosis is frequently delayed due to low awareness of this rare condition and symptom overlap with more common neurological conditions. Multiple factors impact patients' decision-making regarding genetic testing for ALSP, symptom management and participation in research studies.Conclusion: These results highlight the challenges faced by individuals with ALSP and should support program development to improve patient care.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare and fatal neurological disease. Symptoms generally appear between the ages of 40 and 50 years and worsen rapidly. Many patients have changes in memory, personality, behavior, and movement.A patient journey map shows important events that patients experience over the course of a disease. The map can be used to identify challenges that patients face and where the quality of medical care can be improved. This patient journey map for ALSP is based on published scientific articles, a workshop where patients and others who have experience with ALSP talked about their challenges, and answers to questions from a survey on genetic testing for ALSP.The map shows that diagnosis of ALSP is often delayed. Because ALSP is a rare disease, few medical providers have experience managing it. Medical providers may not suspect it because many ALSP symptoms overlap with symptoms of other common neurologic diseases. Genetic testing is needed to be sure that a person has ALSP, but it can be hard for patients to get tested since it is expensive and there may not be a testing center nearby. Finally, some people might not want to get tested if they are fearful of getting a diagnosis.This patient journey map should be used to raise awareness of ALSP and the challenges faced by patients and those who care for them. It may also help researchers and medical providers know how to better support patients who have ALSP.

Climate-Smart Siting for renewable energy expansion.

A massive expansion of renewable energy (RE) is underway to meet the world's climate goals. Although RE serves to reduce threats from climate change, it can also pose threats to species whose current and future ranges intersect with RE installations. Here, we propose a "Climate-Smart Siting" framework for addressing potential conflicts between RE expansion and biodiversity conservation. The framework engenders authentic consultation with affected and disadvantaged communities throughout and uses overlay and optimization routines to identify focal areas now and in the future where RE development poses promise and peril as species' ranges shift in response to climate change. We use this framework to demonstrate methods, identify decision outcomes, and discuss market-based levers for aligning RE expansion with the United Nations Global Biodiversity Framework now and as climate change progresses. In the face of the climate crisis, a Climate-Smart Siting strategy could help create solutions without causing further harm to biodiversity and human communities..

Characterizing the underwater soundscape at the site of a proposed port in northeast Iceland.

Finnafjörður is a small fjord in northeast Iceland, where the planned construction of a large port has the potential to meaningfully change the marine soundscape and ecosystem. In this study, we used one year (2021/22) of passive acoustic recordings to characterize the pre-construction soundscape, including broadband and decidecade sound pressure levels (SPL), frequency-weighted sound exposure levels, seasonal and diel variability and identified regular types of sound. Finnafjörður is relatively quiet with median decidecade levels centered between 25 Hz and 50 kHz of 74.5 to 86.3 dB re 1 µPa. Wind and rain dominate ambient SPL, while anthropogenic sources only occasionally contributed to the soundscape. Regular biological sound sources include humpback whales, toothed whales, and fish. This baseline soundscape description can be used for noise management during port construction, to monitor future changes in the region, and to act as a framework for comprehensive impact assessments as ports are developed globally.

pyRforest: a comprehensive R package for genomic data analysis featuring scikit-learn Random Forests in R.

Random Forest models are widely used in genomic data analysis and can offer insights into complex biological mechanisms, particularly when features influence the target in interactive, nonlinear, or nonadditive ways. Currently, some of the most efficient Random Forest methods in terms of computational speed are implemented in Python. However, many biologists use R for genomic data analysis, as R offers a unified platform for performing additional statistical analysis and visualization. Here, we present an R package, pyRforest, which integrates Python scikit-learn "RandomForestClassifier" algorithms into the R environment. pyRforest inherits the efficient memory management and parallelization of Python, and is optimized for classification tasks on large genomic datasets, such as those from RNA-seq. pyRforest offers several additional capabilities, including a novel rank-based permutation method for biomarker identification. This method can be used to estimate and visualize P-values for individual features, allowing the researcher to identify a subset of features for which there is robust statistical evidence of an effect. In addition, pyRforest includes methods for the calculation and visualization of SHapley Additive exPlanations values. Finally, pyRforest includes support for comprehensive downstream analysis for gene ontology and pathway enrichment. pyRforest thus improves the implementation and interpretability of Random Forest models for genomic data analysis by merging the strengths of Python with R. pyRforest can be downloaded at: https://www.github.com/tkolisnik/pyRforest with an associated vignette at https://github.com/tkolisnik/pyRforest/blob/main/vignettes/pyRforest-vignette.pdf.

Impact of early continuous positive airway pressure in the delivery room (DR-CPAP) on neonates < 1500 g in a low-resource setting: a protocol for a pilot feasibility and acceptability randomized controlled trial.

BACKGROUND: Preterm birth is the leading cause of childhood mortality, and respiratory distress syndrome is the predominant cause of these deaths. Early continuous positive airway pressure is effective in high-resource settings, reducing the rate of continuous positive airway pressure failure, and the need for mechanical ventilation and surfactant. However, most deaths in preterm infants occur in low-resource settings without access to mechanical ventilation or surfactant. We hypothesize that in such settings, early continuous positive airway pressure will reduce the rate of failure and therefore preterm mortality. METHODS: This is a mixed methods feasibility and acceptability, single-center pilot randomized control trial of early continuous positive airway pressure among infants with birthweight 800-1500 g. There are two parallel arms: (i) application of continuous positive airway pressure; with optional oxygen when indicated; applied in the delivery room within 15 min of birth; transitioning to bubble continuous positive airway pressure after admission to the neonatal unit if Downes Score ≥ 4 (intervention), (ii) supplementary oxygen at delivery when indicated; transitioning to bubble continuous positive airways pressure after admission to the neonatal unit if Downes Score ≥ 4 (control). A two-stage consent process (verbal consent during labor, followed by full written consent within 24 h of birth) and a low-cost third-party allocation process for randomization will be piloted. We will use focus group discussions and key informant interviews to explore the acceptability of the intervention, two-stage consent process, and trial design. We will interview healthcare workers, mothers, and caregivers of preterm infants. Feasibility will be assessed by the proportion of infants randomized within 15 min of delivery; the proportion of infants in the intervention arm receiving CPAP within 15 min of delivery; and the proportion of infants with primary and secondary outcomes measured successfully. DISCUSSION: This pilot trial will enhance our understanding of methods and techniques that can enable emergency neonatal research to be carried out effectively, affordably, and acceptably in low-resource settings. This mixed-methods approach will allow a comprehensive exploration of parental and healthcare worker perceptions, experiences, and acceptance of the intervention and trial design. TRIAL REGISTRATION: The study is registered on the Pan African Clinical Trials Registry (PACTR) PACTR202208462613789. Registered 08 August 2022.  https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=23888 .

Standardised and hierarchically classified heart failure and complementary disease monitoring outcome measures: european Unified Registries for heart Care evaluation and randomised trials (EuroHeart).

AIMS: The lack of standardised definitions for heart failure outcome measures limits the ability to reliably assess effectiveness of heart failure therapies. The European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart) aimed to produce a catalogue of internationally endorsed data definitions for heart failure outcome measures. METHODS: Following the EuroHeart methods for the development of cardiovascular data standards, a working group was formed of representatives from the European Society of Cardiology Heart Failure Association and other leading heart failure experts. A systematic review of observational and randomised clinical trials identified current outcome measures, which was supplemented by clinical practice guidelines and existing registries for contemporary definitions. A modified Delphi process was employed to gain consensus for variable inclusion and whether collection should be mandatory (Level 1) or optional (Level 2) within EuroHeart. In addition, a set of complementary outcome measures were identified by the Working Group as of scientific and clinical importance for longitudinal monitoring for people with heart failure. RESULTS: Five Level 1 and two Level 2 outcome measures were selected and defined, alongside five complementary monitoring outcomes for patients with heart failure. CONCLUSION: We present a structured, hierarchical catalogue of internationally endorsed heart failure outcome measures. This will facilitate quality improvement, high quality observational research, registry-based trials, and post market surveillance of medical devices.

HER4 is a high-affinity dimerization partner for all EGFR/HER/ErbB family proteins.

Human epidermal growth factor receptors (HER)-also known as EGFR or ErbB receptors-are a subfamily of receptor tyrosine kinases (RTKs) that play crucial roles in cell growth, division, and differentiation. HER4 (ErbB4) is the least studied member of this family, partly because its expression is lower in later stages of development. Recent work has suggested that HER4 can play a role in metastasis by regulating cell migration and invasiveness; however, unlike EGFR and HER2, the precise role that HER4 plays in tumorigenesis is still unresolved. Early work on HER family proteins suggested that there are direct interactions between the four members, but to date, there has been no single study of all four receptors in the same cell line with the same biophysical method. Here, we quantitatively measure the degree of association between HER4 and the other HER family proteins in live cells with a time-resolved fluorescence technique called pulsed interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS). PIE-FCCS is sensitive to the oligomerization state of membrane proteins in live cells, while simultaneously measuring single-cell protein expression levels and diffusion coefficients. Our PIE-FCCS results demonstrate that HER4 interacts directly with all HER family members in the cell plasma membrane. The interaction between HER4 and other HER family members intensified in the presence of a HER4-specific ligand. Our work suggests that HER4 is a preferred dimerization partner for all HER family proteins, even in the absence of ligands.

Genome-wide association studies of Down syndrome associated congenital heart defects.

Congenital heart defects (CHDs) are the most common structural birth defect and are present in 40-50% of children born with Down syndrome (DS). To characterize the genetic architecture of DS-associated CHD, we sequenced genomes of a multiethnic group of children with DS and a CHD (n=886: atrioventricular septal defects (AVSD), n=438; atrial septal defects (ASD), n=122; ventricular septal defects (VSD), n=170; other types of CHD, n=156) and DS with a structurally normal heart (DS+NH, n=572). We performed four GWAS for common variants (MAF>0.05) comparing DS with CHD, stratified by CHD-subtype, to DS+NH controls. Although no SNP achieved genome-wide significance, multiple loci in each analysis achieved suggestive significance (p<2×10-6). Of these, the 1p35.1 locus (near RBBP4) was specifically associated with ASD risk and the 5q35.2 locus (near MSX2) was associated with any type of CHD. Each of the suggestive loci contained one or more plausible candidate genes expressed in the developing heart. While no SNP replicated (p<2×10-6) in an independent cohort of DS+CHD (DS+CHD: n=229; DS+NH: n=197), most SNPs that were suggestive in our GWASs remained suggestive when meta-analyzed with the GWASs from the replication cohort. These results build on previous work to identify genetic modifiers of DS-associated CHD.

Backtracking childhood leukaemia to birth: A battle of addition.

Paediatric leukaemia has a long tail of driver mutations each of which must be 'backtracked' to samples taken at birth to identify the prenatal origin of a subtype. Presently, Bardini et al. describe the first successful backtracking of an NUTM1 rearrangement, which sheds light on the biology of this particular alteration. Continued backtracking of NUTM1 rearrangements, and all leukaemia-typical somatic alterations, is necessary to fully understand the prenatal origin of these diseases. Commentary on: Bardini et al. Prenatal origin of NUTM1 gene rearrangement in infant B-cell precursor acute lymphoblastic leukaemia. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19685.

Genetic rescue often leads to higher fitness as a result of increased heterozygosity across animal taxa.

Biodiversity loss has reached critical levels partly due to anthropogenic habitat loss and degradation. These landscape changes are damaging as they can fragment species distributions into small, isolated populations, resulting in limited gene flow, population declines and reduced adaptive potential. Genetic rescue, the translocation of individuals to increase genetic diversity and ultimately fitness, has produced promising results for fragmented populations but remains underutilized due to a lack of long-term data and monitoring. To promote a better understanding of genetic rescue and its potential risks and benefits over the short-term, we reviewed and analysed published genetic rescue attempts to identify whether genetic diversity increases following translocation, and if this change is associated with increased fitness. Our review identified 19 studies that provided genetic and fitness data from before and after the translocation; the majority of these were on mammals, and included experimental, natural and conservation-motivated translocations. Using a Bayesian meta-analytical approach, we found that on average, genetic diversity and fitness increased in populations post translocations, although there were some exceptions to this trend. Overall, genetic diversity was a positive predictor of population fitness, and in some cases this relationship extended three generations post-rescue. These data suggest a single translocation can have lasting fitness benefits, and support translocation as another tool to facilitate conservation success. Given the limited number of studies with long-term data, we echo the need for genetic monitoring of populations post-translocation to understand whether genetic rescue can also limit the loss of adaptive potential in the long-term.

Analysis of EGFR binding hotspots for design of new EGFR inhibitory biologics.

The epidermal growth factor (EGF) receptor (EGFR) is activated by the binding of one of seven EGF-like ligands to its ectodomain. Ligand binding results in EGFR dimerization and stabilization of the active receptor conformation subsequently leading to activation of downstream signaling. Aberrant activation of EGFR contributes to cancer progression through EGFR overexpression/amplification, modulation of its positive and negative regulators, and/or activating mutations within EGFR. EGFR targeted therapeutic antibodies prevent dimerization and interaction with endogenous ligands by binding the ectodomain of EGFR. However, these antibodies have had limited success in the clinic, partially due to EGFR ectodomain resistance mutations, and are only applicable to a subset of patients with EGFR-driven cancers. These limitations suggest that alternative EGFR targeted biologics need to be explored for EGFR-driven cancer therapy. To this end, we analyze the EGFR interfaces of known inhibitory biologics with determined structures in the context of endogenous ligands, using the Rosetta macromolecular modeling software to highlight the most important interactions on a per-residue basis. We use this analysis to identify the structural determinants of EGFR targeted biologics. We suggest that commonly observed binding motifs serve as the basis for rational design of new EGFR targeted biologics, such as peptides, antibodies, and nanobodies.

Phenotypic characterisation of people at risk of atrial fibrillation: Protocol for the FIND-AF longitudinal cohort study.

AIMS: The Future Innovations in Novel Detection of Atrial Fibrillation (FIND-AF) longitudinal cohort study is a multi-centre prospective cohort study of patients identified at risk of atrial fibrillation (AF). The aim of the FIND-AF longitudinal cohort study is to provide multi-modal phenotypic characterisation of these patients. METHODS AND RESULTS: 1955 participants identified as at risk of AF by the FIND-AF algorithm from primary care electronic health (EHR) data, aged 30 years and above and eligible for oral anticoagulation, will be be recruited between October 2023 and November 2024 to receive home-based intermittent ECG monitoring. About 500 participants without diagnosed AF will then undergo cross-sectional phenotypic characterisation including physical examination, symptoms assessment, serum blood biomarkers and echocardiography, and non-stress cardiac magnetic resonance imaging. Longitudinal information about cardio-renal-metabolic-pulmonary outcomes will be ascertained from linkages to EHR data. The study is funded by the British Heart Foundation (CC/22/250026). The study has ethical approval (North West - Greater Manchester South Research Ethics Committee reference 23/NW/0180). Findings will be announced at relevant conferences and published in peer-reviewed journals in line with the Funder's open access policy. CONCLUSIONS: The FIND-AF multi-centre prospective longitudinal cohort study aims to (i) provide evidence for the impact of comorbidities on AF genesis (ii) uncover actionable targets to prevent AF, and (iii) act as a platform for cohort randomised clinical trials that investigate enhanced detection and prevention of AF.

Atrial fibrillation (AF) is the most common abnormal heart rhythm encountered in clinical practice but we know little about changes to the heart before AF starts, and whether these can be reversed to reduce the risk of future AF. In this study people we will recruit people who have been identified as higher risk of AF using a decision support tool in their medical records, but who have not been found to have AF at the moment when they have had their ECG checked.We will look at the structure and function of their hearts using ultrasound and MRI, and we will also check their blood tests. We aim to learn if people without AF, but at higher risk of AF, have changes to their heart and then conduct studies to establish if these changes can be reversed.

Membrane Stabilization of Helical Previtamin D Conformers as Possible Enhancement of Vitamin D Photoproduction.

Photoinduced vitamin D formation occurs 10-15-fold faster in phospholipid bilayers (PLB) than in isotropic solution. It has been hypothesized that amphipatic interactions of the PLB with the rotationally flexible previtamin D (Pre) stabilize its helical conformers, enhancing thermal intramolecular [1,7]-hydrogen transfer, forming vitamin D. To test this hypothesis, we carried out molecular dynamics (MD) simulations of Pre in a PLB composed of dipalmitoylphosphatidylcholine (DPPC). We designed a classical force field capable of accurately describing the equilibrium composition of Pre conformers. Using adaptive biasing force MD simulations, we determined the free energy of Pre conformers in isotropic environments (hexane and gas-phase) and in the anisotropic environment of a DPPC PLB. We find a total increase of 25.5% of the population of both helical conformers (+20.5% g+Zg+ and +5% g-Zg-) in DPPC compared to hexane. In view of ab initio simulations, showing that hydrogen transfer occurs in both helical conformers, our study strongly suggests the validity of the initial hypothesis. Regarding the amphipatic interactions of Pre with the PLB, we find that, similar to cholesterol (Chol) and 7-dehydrocholesterol (7-DHC), Pre entertains hydrogen bonds mainly to the carbonyl groups of DPPC and, to a lesser extent, with phosphate oxygen atoms and rarely to water molecules at the interface. We further report order parameters of the Pre/DPPC system, which are slightly smaller than those for Chol/DPPC and 7-DHC/DPPC, but larger than for pure DPPC. This indicates a loss in membrane viscosity upon photochemical ring-opening of 7-DHC to form Pre.

Interrogation of a fluoropolymer dispersion manufactured with a non-fluorinated polymerization aid for targeted and non-targeted fluorinated residuals by liquid chromatography high resolution mass spectrometry.

Recent advances in fluoropolymer polymerization have focused on replacing perfluorinated polymerization aids (PAs) with hydrocarbon-based alternatives. Hydrocarbon PAs are vulnerable to fluorinated radicals during polymerization, leading to the creation of hundreds of process-specific polyfluorinated residuals. These residuals, which include low molecular weight extractable or leachable impurities, are challenging to detect at trace levels. This study investigates a polytetrafluoroethylene (PTFE) dispersion prepared with a hydrocarbon-based surfactant (DOSS) to measure these process-specific fluorinated residues. Liquid chromatography high resolution mass spectrometry is one of the few analytical methods that offers the sensitivity and selectivity required to detect these residuals in complex matrices at concentrations as low as parts per billion. The results indicate that using a hydrocarbon PA during emulsion polymerization produces numerous polyfluorinated residuals. These must be identified and monitored to develop effective abatement strategies, ensuring responsible fluoropolymer manufacturing.

The validity of single-item measures of health-related quality of life across groups differing in acute respiratory symptom severity.

PURPOSE: Practical considerations precluding health-related quality of life (HRQOL) monitoring in population and clinical research have spawned development of improved items for more brief surveys of frequently measured HRQOL outcomes. The aim of this study was to validate the use of the Quality of Life General (QGEN-8), a shorter 8-item alternative to the longer 36-item short form (SF)-36 Health Survey for measuring the same eight HRQOL domains across groups of adults with varying severity of acute respiratory symptoms, such as cough and sore throat. METHODS: National Opinion Research Center (NORC) representative probability (N = 1,648) and supplemental opt-in (N = 5,915) U.S. adult samples were surveyed cross-sectionally online in 2020. Parallel analyses compared QGEN-8 and SF-36 estimates of group means for each of eight matching profile domains and summary physical and mental scores across groups differing in severity of acute symptoms and chronic respiratory conditions using analysis of covariance (ANCOVAs) controlling for socio-demographics and presence of chronic respiratory conditions. RESULTS: In support of discriminant validity, ANCOVA estimates of QGEN-8 means with SF-36 estimates revealed the same patterns of declining HRQOL with the presence and increasing severity of symptoms and chronic condition severity. CONCLUSION: QGEN-8® shows satisfactory validity and warrants further testing in cross-sectional and longitudinal population and clinical survey research as a more practical method for estimating group differences in SF-36 profile and summary component HRQOL scores.

Upper respiratory tract infections (URTI) with symptoms such as cough and sore throat are highly prevalent and negatively impact on health-related quality of life (HRQOL). Existing instruments that comprehensively measure HRQOL are lengthy, potentially increasing respondent burden and restricting their use in clinical studies and research. The aim of this study was to evaluate whether eight newly constructed survey items, the QGEN-8®, measure the same HRQOL outcomes as the 36-item SF-36 Health Survey well enough to serve as a more practical alternative for purposes of detecting the physical and mental HRQOL effects on differing severity of acute URTI symptoms, specifically cough and sore throat. The results showed that the QGEN-8® was psychometrically sound and able to differentiate between different levels of URTI symptoms, even in cases where respondents had chronic respiratory conditions. This indicates that the briefer QGEN-8® with 75% shorter response time is able to provide HRQOL measurements comparable to those derived from lengthier instruments thereby lending itself more readily to use in clinical studies and research of URTI symptoms, such as cough and sore throat.

Corticotropin-releasing factor and GABA in the ventral tegmental area modulate partner preference formation in male and female prairie voles (Microtus ochrogaster).

Introduction: The mesolimbic reward system is associated with the promotion and rewarding benefits of social relationships. In the socially monogamous prairie vole (Microtus ochrogaster), the establishment of a pair bond can be displayed by a robust preference for a breeding partner and aggressive rejection of unfamiliar conspecifics. Mesolimbic dopamine signaling influences bond-related behaviors within the vole through dopamine transmission and receptor activity in the nucleus accumbens. However, only one experiment has examined how the ventral tegmental area (VTA), a region that produces much of the fore- and mid-brain dopamine, regulates these social behaviors. Specifically, inhibition of either glutamate or GABA neurons in the VTA during a brief courtship promoted a partner preference formation in male prairie voles. The VTA is a heterogeneous structure that contains dopamine, GABA, and glutamate neurons as well as receives a variety of projections including corticotropin-releasing factor (CRF) suggested to modulate dopamine release. Methods: We used pharmacological manipulation to examine how GABA and CRF signaling in the VTA modulate partner preference formation in male and female prairie voles. Specifically, we used a 3 h partner preference test, a social choice test, to assess the formation of a partner preference following an infused bicuculline and CRF during a 1 h cohabitation and muscimol and CP154526, a CRFR1 antagonist, during a 24 h cohabitation with an opposite-sex conspecific. Results: Our study demonstrated that bicuculline, a GABA A receptor antagonist, and CRF in the VTA promoted a partner preference, whereas low-dose muscimol, a GABA A receptor agonist, and CP154526, a CRFR1 antagonist, inhibited a partner preference in both male and female prairie voles. Conclusion: This study demonstrated that GABA and CRF inputs into the VTA is necessary for the formation of a partner preference in male and female prairie voles.

Engineering of RNase P Ribozymes for Therapy against Human Cytomegalovirus Infection.

Nucleic acid-based gene interference and editing strategies, such as antisense oligonucleotides, ribozymes, RNA interference (RNAi), and CRISPR/Cas9 coupled with guide RNAs, are exciting research tools and show great promise for clinical applications in treating various illnesses. RNase P ribozymes have been engineered for therapeutic applications against human viruses such as human cytomegalovirus (HCMV). M1 ribozyme, the catalytic RNA subunit of RNase P from Escherichia coli, can be converted into a sequence-specific endonuclease, M1GS ribozyme, which is capable of hydrolyzing an mRNA target base-pairing with the guide sequence. M1GS RNAs have been shown to hydrolyze essential HCMV mRNAs and block viral progeny production in virus-infected cell cultures. Furthermore, RNase P ribozyme variants with enhanced hydrolyzing activity can be generated by employing in vitro selection procedures and exhibit better ability in suppressing HCMV gene expression and replication in cultured cells. Additional studies have also examined the antiviral activity of RNase P ribozymes in mice in vivo. Using cytomegalovirus infection as an example, this review summarizes the principles underlying RNase P ribozyme-mediated gene inactivation, presents recent progress in engineering RNase P ribozymes for applications in vitro and in mice, and discusses the prospects of using M1GS technology for therapeutic applications against HCMV as well as other pathogenic viruses.

Blood-based multivariate methylation risk score for cognitive impairment and dementia.

INTRODUCTION: The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood-derived DNA methylation as a promising tool for early dementia risk detection. METHODS: In conjunction with an extensive array of machine learning techniques, we employed whole blood genome-wide DNA methylation data as a surrogate for 14 modifiable and non-modifiable factors in the assessment of dementia risk in independent dementia cohorts. RESULTS: We established a multivariate methylation risk score (MMRS) for identifying mild cognitive impairment cross-sectionally, independent of age and sex (P = 2.0 × 10-3). This score significantly predicted the prospective development of cognitive impairments in independent studies of Alzheimer's disease (hazard ratio for Rey's Auditory Verbal Learning Test (RAVLT)-Learning = 2.47) and Parkinson's disease (hazard ratio for MCI/dementia = 2.59). DISCUSSION: Our work shows the potential of employing blood-derived DNA methylation data in the assessment of dementia risk. HIGHLIGHTS: We used whole blood DNA methylation as a surrogate for 14 dementia risk factors. Created a multivariate methylation risk score for predicting cognitive impairment. Emphasized the role of machine learning and omics data in predicting dementia. The score predicts cognitive impairment development at the population level.

Validated 3D finite-element model of the Risso's dolphin (Grampus griseus) head anatomy demonstrates gular sound reception and channelling through the mandibular fats.

Like other odontocetes, Risso's dolphins actively emit clicks and passively listen to the echoes during echolocation. However, the head anatomy of Risso's dolphins differs from that of other odontocetes by a unique vertical cleft along the anterior surface of the forehead and a differently-shaped lower jaw. In this study, 3D finite-element sound reception and production models were constructed based on computed tomography (CT) data of a deceased Risso's dolphin. Our results were verified by finding good agreement with experimental measurements of hearing sensitivity. Moreover, the acoustic pathway for sounds to travel from the seawater into the dolphin's tympanoperiotic complexes (TPCs) was computed. The gular reception mechanism, previously discovered inDelphinus delphisandZiphius cavirostris, was also found in this species. The received sound pressure levels and relative displacement at TPC surfaces were compared between the cases with and without the mandibular fats or mandible. The results demonstrate a pronounced wave-guiding role of the mandibular fats and a limited bone-conductor role of the mandible. For sound production modelling, we digitally filled the cleft with neighbouring soft tissues, creating a hypothetical 'cleftless' head. Comparison between sound travelling through a 'cleftless' head vs. an original head indicates that the distinctive cleft plays a limited role in biosonar sound propagation.