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Autistic children from heritage-language-speaking homes in the United States are a growing group that would benefit from tailored support that honors their linguistic heritage. Bilingual autistic adults share benefits of their bilingualism abilities and report childhood learning environments as necessary for facilitating language learning or maintenance. Caregivers of young autistic children also report the desire to maintain their heritage languages but sometimes struggle to do so due to misconceptions and a lack of resources such as bilingual personnel. This study was the first to explore U.S.-based bilingual providers' (N = 16) experiences and perceptions of providing bilingual care for autistic children. Data analysis was conducted using reflexive thematic analysis, and resulted in five themes, including (a) You Don't Have to Change Who You Are: Experiences and Beliefs About Bilingualism, (b) Having the "Other" Perspective: Empathy and Intersectionality, (c) Services as a Gateway: Beliefs Rooted in Social Justice, (d) He Was Like a Different Child: Impacts of Receiving Heritage-Language Support, and (e) It Was Just Business: Impacts of Not Receiving Same Language Support. Findings from this study suggest that autistic children and their families benefit from heritage language care, and the recruitment and retention of a linguistically diverse workforce is recommended. Additional implications for research and practice are discussed.

Challenging behavior (CB) is a common occurrence in early childhood and frequently occurs in young children with disabilities. CB is also culturally perceived and includes differences in how caregivers understand and define the topography of CB. Despite the cultural interpretation, CB is known to impact the child and their family but there has been little exploration of what marginalized caregivers perceive as the impact of the CB that their young children with disabilities exhibit. We used semi-structured interviews to explore the perceptions of 24 caregivers, who identified as Black, Mexican American, and White, about the impact of their child's CB. Caregivers shared how the CB impacted themselves, their families, their child, and others. Although much of the impact was similar among caregivers, we discuss nuanced differences across ethnic groups.

Drawing on interviews with 70 college peer socialization agents (PSAs) across 42 U.S.-based institutions of higher education, this study explores how PSAs create "underlives" (Goffman, 1961) in response to their roles and expectations for communicating institutional messages about diversity. Findings from this study illuminate the ways in which institutional scripts produce tension for the PSAs who enact them and the symbolic, behavioral, and discursive ways in which PSAs use distancing strategies to resist. Most of these public-facing students employed "contained" strategies to preserve an underlife away from the surveillance and pressures of the institution. However, some students - especially Students of Color and those from other marginalized groups - also sometimes utilized more "disruptive" forms of underlife, using resistance to attempt systemic change. We illustrate these strategies by presenting two narrative vignettes of participants' experiences that explore and develop the roles of identity, relationships, environment, and expectations in influencing PSAs strategic decisions.

Abstract Quantifying drought tolerance in crops is critical for agriculture management under environmental change, and drought response traits in grape vine have long been the focus of viticultural research. Turgor loss point (π tlp) is gaining attention as an indicator of drought tolerance in plants, though estimating π tlp often requires the construction and analysis of pressure-volume (P-V) curves which are very time consuming. While P-V curves remain a valuable tool for assessing π tlp and related traits, there is considerable interest in developing high-throughput methods for rapidly estimating π tlp, especially in the context of crop screening. We tested the ability of a dewpoint hygrometer to quantify variation in π tlp across and within 12 clones of grape vine (Vitis vinifera subsp. vinifera) and one wild relative (Vitis riparia), and compared these results to those derived from P-V curves. At the leaf-level, methodology explained only 4–5% of the variation in π tlp while clone/species identity accounted for 39% of the variation, indicating that both methods are sensitive to detecting intraspecific π tlp variation in grape vine. Also at the leaf level, π tlp measured using a dewpoint hygrometer approximated π tlp values (r 2 = 0.254) and conserved π tlp rankings from P-V curves (Spearman’s ρ = 0.459). While the leaf-level datasets differed statistically from one another (paired t-test p = 0.01), average difference in π tlp for a given pair of leaves was small (0.1 ± 0.2 MPa (s.d.)). At the species/clone level, estimates of π tlp measured by the two methods were also statistically correlated (r 2 = 0.304), did not deviate statistically from a 1:1 relationship, and conserved π tlp rankings across clones (Spearman’s ρ = 0.692). The dewpoint hygrometer (taking ∼ 10–15 min on average per measurement) captures fine-scale intraspecific variation in π tlp, with results that approximate those from P-V curves (taking 2–3 h on average per measurement). The dewpoint hygrometer represents a viable method for rapidly estimating intraspecific variation in π tlp, and potentially greatly increasing replication when estimating this drought tolerance trait in grape vine and other crops.

Abstract Background Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA-CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA-CN and Alzheimer disease (AD) is unclear. Methods We performed two-sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA-CN and AD to investigate the causal relationship between mtDNA-CN and AD. We estimated mtDNA-CN using whole-genome sequence data from blood and brain samples of 13,799 individuals from the Alzheimer’s Disease Sequencing Project. Linear and Cox proportional hazards models adjusting for age, sex, and study phase were used to assess the association of mtDNA-CN with AD. The association of AD biomarkers and serum metabolites with mtDNA-CN in blood was evaluated in Alzheimer’s Disease Neuroimaging Initiative using linear regression. We conducted a causal mediation analysis to test the natural indirect effects of mtDNA-CN change on AD risk through the significantly associated biomarkers and metabolites. Results MR analysis suggested a causal relationship between decreased blood-derived mtDNA-CN and increased risk of AD (OR = 0.68; P = 0.013). Survival analysis showed that decreased mtDNA-CN was significantly associated with higher risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.002). We also identified significant associations of mtDNA-CN with brain FDG-PET (β = 0.103; P = 0.022), amyloid-PET (β = 0.117; P = 0.034), CSF amyloid-β (Aβ) 42/40 (β=-0.124; P = 0.017), CSF t-Tau (β = 0.128; P = 0.015), p-Tau (β = 0.140; P = 0.008), and plasma NFL (β=-0.124; P = 0.004) in females. Several lipid species, amino acids, biogenic amines in serum were also significantly associated with mtDNA-CN. Causal mediation analyses showed that about a third of the effect of mtDNA-CN on AD risk was mediated by plasma NFL (P = 0.009), and this effect was more significant in females (P

Abstract All newborns undergo minor painful procedures (e.g., injections). Despite strong evidence supporting parents' efficacy to reduce procedural pain (e.g., breastfeeding), parents remain an underutilized resource. Limited evidence‐based resources about infant procedural pain management targeting parents in the perinatal period exist. We co‐created Parenting Pain Away, a website to enhance parents' access to information and participation in procedural pain management following birth. This study aimed to conduct iterative usability testing with the perinatal population to refine Parenting Pain Away based on target users' identified needs and satisfaction. In 2020, parents of healthy newborns or expectant parents from an Atlantic Canadian province, participated in two iterative cycles of usability testing of Parenting Pain Away. Through recorded interviews, participants were directed to use the “Think Aloud” approach (e.g., verbalize what they see, think, feel) as they navigated through the website. Participants completed online questionnaires related to demographics and user satisfaction, measured by the Post Study System Usability Questionnaire (PSSUQ). Descriptive statistics and content analysis were conducted to analyze the data. In total, there were 10 participants with an average age of 29.9 years (SD = 3.9). Participants identified as mothers (n = 7) or fathers (n = 3) and were expecting (n = 6) or had a newborn (n = 4). The PSSUQ overall scores were 1.84 (SD = 0.55) and 1.34 (SD = 0.49) in Cycles 1 and 2, respectively, indicating high user satisfaction on the 7‐point scale. When comparing between the two cycles, the average overall score was lower in Cycle 2, suggesting improved satisfaction. Participants provided positive feedback about the website and suggested major refinements to simplify content and site navigation. Findings from usability testing cycles were used to inform refinements of the Parenting Pain Away in response to participant satisfaction and feedback. Engaging target users in the development process enhanced this website in preparation for further effectiveness testing.

Abstract Background Wood carbon fractions (CFs)—the proportion of dry woody biomass comprised of elemental carbon (C)—are a key component of forest C estimation protocols and studies. Traditionally, a wood CF of 50% has been assumed in forest C estimation protocols, but recent studies have specifically quantified differences in wood CFs across several different forest biomes and taxonomic divisions, negating the need for generic wood CF assumptions. The Intergovernmental Panel on Climate Change (IPCC), in its 2006 “Guidelines for National Greenhouse Gas Inventories”, published its own multitiered system of protocols for estimating forest C stocks, which included wood CFs that (1) were based on the best available literature (at the time) and (2) represented a significant improvement over the generic 50% wood CF assumption. However, a considerable number of new studies on wood CFs have been published since 2006, providing more accurate, robust, and spatially- and taxonomically- specific wood CFs for use in forest C estimation. Main text We argue that the IPCC’s recommended wood CFs and those in many other forest C estimation models and protocols (1) differ substantially from, and are less robust than, wood CFs derived from recently published data-rich studies; and (2) may lead to nontrivial errors in forest C estimates, particularly for countries that rely heavily on Tier 1 forest C methods and protocols (e.g., countries of the Global South with large expanses of tropical forests). Based on previous studies on this topic, we propose an alternative set of refined wood CFs for use in multiscale forest C estimation, and propose a novel decision-making framework for integrating species- and location-specific wood CFs into forest C estimation models. Conclusion The refined wood CFs that we present in this commentary may be used by the IPCC to update its recommended wood CFs for use in forest C estimation. Additionally, we propose a novel decision-making framework for integrating data-driven wood CFs into a wider suite of multitiered forest C estimation protocols, models, and studies.

In amniotes, head motions and tilt are detected by two types of vestibular hair cells (HCs) with strikingly different morphology and physiology. Mature type I HCs express a large and very unusual potassium conductance, gK,L, which activates negative to resting potential, confers very negative resting potentials and low input resistances, and enhances an unusual non-quantal transmission from type I cells onto their calyceal afferent terminals. Following clues pointing to KV1.8 (Kcna10) in the Shaker K channel family as a candidate gK,L subunit, we compared whole-cell voltage-dependent currents from utricular HCs of KV1.8-null mice and littermate controls. We found that KV1.8 is necessary not just for gK,L but also for fast-inactivating and delayed rectifier currents in type II HCs, which activate positive to resting potential. The distinct properties of the three KV1.8-dependent conductances may reflect different mixing with other KV subunits that are reported to be differentially expressed in type I and II HCs. In KV1.8-null HCs of both types, residual outwardly rectifying conductances include KV7 (Knq) channels. Current clamp records show that in both HC types, KV1.8-dependent conductances increase the speed and damping of voltage responses. Features that speed up vestibular receptor potentials and non-quantal afferent transmission may have helped stabilize locomotion as tetrapods moved from water to land.

To have the desired therapeutic effect, nanomedicines and macromolecular medications must move from the site of injection to the site of action, without having adverse effects. Transvascular transport is a critical step of this navigation, as exemplified by the Enhanced Permeability and Retention (EPR) effect in solid tumors, not found in normal organs. Numerous studies have concluded that passive, diffusion- and convection-based transport predominates over active, cellular mechanisms in this effect. However, recent work using a new approach reevaluated this principle by comparing tumors with or without fixation and concluded the opposite. Here, we address the controversy generated by this new approach by reporting evidence from experimental investigations and computer simulations that separate the contributions of active and passive transport. Our findings indicate that tissue fixation reduces passive transport as well as active transport, indicating the need for new methods to distinguish the relative contributions of passive and active transport.

Objective There is a growing popularity in the worldwide use of schema therapy (ST) to address a variety of psychological disorders. Yet, research into the cultural suitability of ST is scarce. This study aimed to explore ST clinicians’ experiences of the cultural suitability of ST.Method Eleven clinicians from nine countries were interviewed about their experiences of practising ST. Interviews were analysed using reflexive thematic analysis.Results Two main themes, each with subthemes, were identified. The first theme was considerations for Cultural Context and Content: (i) Incongruence with Cultural Norms of Emotional Expression, (ii) “Maladaptive” or “Adaptive”, But in What Context?, and (iii) Issues Related to Familism when Addressing Parent/Critic Modes. The second theme focused on clinicians’ Cultural Competence: (i) Perceptions of Reduced Confidence and Competence in Providing Culturally Responsive Practice, and (ii) Clinicians’ Cultural Values Impacting ST Delivery. Participants discussed strategies to improve the cultural-responsiveness of ST, suggesting areas for further development.Conclusion Present findings suggest that ST is not a one-size-fits-all approach, underscoring the need to improve the cultural responsiveness of ST, while better supporting clinicians to develop their cultural competence. Future research is needed to establish evidence-based cultural adaptations for ST.

Grapevine is an economically-important culture worldwide but is currently the target of decline, especially caused by grapevine trunk diseases (GTD). One of the major grapevine trunk disease is Botryosphaeria dieback, which is associated with Botryosphaeriaceae fungi. Among the different methods that could contribute to increase grapevine fitness under stresses, viticulture could take advantage of symbiosis with arbuscular mycorrhizal fungi. Within this context, we investigated the effect of V. vinifera cv. Gewurztraminer colonization with the arbuscular mycorrhizal fungus Rhizophagus irregularis on plant tolerance to wood inoculation with Neofusicoccum parvum Bt67, one of the most aggressive fungus associated with Botryosphaeria dieback. We showed that grapevine mycorrhization resulted in a small but significant reduction of wood necrosis size and less intense necrosis symptoms on the leaves. We further characterized the response of grapevine leaves and roots to both arbuscular mycorrhizal fungus (AMF) symbiosis and GTD fungus inoculation, especially the interaction between these two conditions, with a non-targeted metabolomic approach. In the roots, both mycorrhization and N. parvum infection triggered metabolite reprogramming, especially sugars and stilbenes, which were downregulated by both AMF symbiosis and pathogen infection. Furthermore, N. parvum infection triggered a significant decrease in fatty acids and oxylipins in leaves of non-mycorrhized plants, whereas contents were maintained or increased in Rhizophagus irregularis-colonized plants. In conclusion, AMF symbiosis may be an interesting tool to improve health of young grapevines and help sustaining infection by trunk disease fungi, by harnessing lipid metabolism.

Entamoeba histolytica, the causative agent of amebiasis, is one of the top three parasitic causes of mortality worldwide. However, no vaccine exists against amebiasis. Using a lead candidate vaccine containing the LecA fragment of Gal-lectin and GLA-3M-052 liposome adjuvant, we immunized rhesus macaques via intranasal or intramuscular routes. The vaccine elicited high-avidity functional humoral responses as seen by the inhibition of amebic attachment to mammalian target cells by plasma and stool antibodies. Importantly, antigen-specific IFN-γ-secreting peripheral blood mononuclear cells (PBMCs) and IgG/IgA memory B cells (BMEM) were detected in immunized animals. Furthermore, antigen-specific antibody and cellular responses were maintained for at least 8 months after the final immunization as observed by robust LecA-specific BMEM as well as IFN-γ+ PBMC responses. Overall, both intranasal and intramuscular immunizations elicited a durable and functional response in systemic and mucosal compartments, which supports advancing the LecA+GLA-3M-052 liposome vaccine candidate to clinical testing.

DNA methylation (DNAm) plays a crucial role in a number of complex diseases. However, the reliability of DNAm levels measured using Illumina arrays varies across different probes. Previous research primarily assessed probe reliability by comparing duplicate samples between the 450k-450k or 450k-EPIC platforms, with limited investigations on Illumina EPIC v1.0 arrays. We conducted a comprehensive assessment of the EPIC v1.0 array probe reliability using 69 blood DNA samples, each measured twice, generated by the Alzheimer’s Disease Neuroimaging Initiative study. We observed higher reliability in probes with average methylation beta values of 0.2 to 0.8, and lower reliability in type I probes or those within the promoter and CpG island regions. Importantly, we found that probe reliability has significant implications in the analyses of Epigenome-wide Association Studies (EWAS). Higher reliability is associated with more consistent effect sizes in different studies, the identification of differentially methylated regions (DMRs) and methylation quantitative trait locus (mQTLs), and significant correlations with downstream gene expression. Moreover, blood DNAm measurements obtained from probes with higher reliability are more likely to show concordance with brain DNAm measurements. Our findings, which provide crucial reliability information for probes on the EPIC v1.0 array, will serve as a valuable resource for future DNAm studies.

Aims: Patient dissatisfaction is not uncommon following primary total knee arthroplasty. One proposed method to alleviate this is by improving knee kinematics. Therefore, we aimed to answer the following research question: are there significant differences in knee kinematics based on the design of the tibial insert (cruciate-retaining (CR), ultra-congruent (UC), or medial congruent (MC))? Methods: Overall, 15 cadaveric knee joints were examined with a CR implant with three different tibial inserts (CR, UC, and MC) using an established knee joint simulator. The effects on coronal alignment, medial and lateral femoral roll back, femorotibial rotation, bony rotations (femur, tibia, and patella), and patellofemoral length ratios were determined. Results: No statistically significant differences were found regarding coronal alignment (p = 0.087 to p = 0.832). The medial congruent insert demonstrated restricted femoral roll back (mean medial 37.57 mm; lateral 36.34 mm), while the CR insert demonstrated the greatest roll back (medial 42.21 mm; lateral 37.88 mm; p < 0.001, respectively). Femorotibial rotation was greatest with the CR insert with 2.45° (SD 4.75°), then the UC insert with 1.31° (SD 4.15°; p < 0.001), and lowest with the medial congruent insert with 0.8° (SD 4.24°; p < 0.001). The most pronounced patella shift, but lowest patellar rotation, was noted with the CR insert. Conclusion: The MC insert demonstrated the highest level of constraint of these inserts. Femoral roll back, femorotibial rotation, and single bony rotations were lowest with the MC insert. The patella showed less shifting with the MC insert, but there was significantly increased rotation. While the medial congruent insert was found to have highest constraint, it remains uncertain if this implant recreates native knee kinematics or if this will result in improved patient satisfaction. Cite this article: Bone Jt Open 2024;5(7):592–600.

Abstract Background HIV-1 produces Tat, a crucial protein for transcription, viral replication, and CNS neurotoxicity. Tat interacts with TAR, enhancing HIV reverse transcription. Subtype C Tat variants (C31S, R57S, Q63E) are associated with reduced transactivation and neurovirulence compared to subtype B. However, their precise impact on Tat-TAR binding is unclear. This study investigates how these substitutions affect Tat-TAR interaction. Methods We utilized molecular modelling techniques, including MODELLER, to produce precise three-dimensional structures of HIV-1 Tat protein variants. We utilized Tat subtype B as the reference or wild type, and generated Tat variants to mirror those amino acid variants found in Tat subtype C. Subtype C-specific amino acid substitutions were selected based on their role in the neuropathogenesis of HIV-1. Subsequently, we conducted molecular docking of each Tat protein variant to TAR using HDOCK, followed by molecular dynamic simulations. Results Molecular docking results indicated that Tat subtype B (TatWt) showed the highest affinity for the TAR element (-262.07), followed by TatC31S (-261.61), TatQ63E (-256.43), TatC31S/R57S/Q63E (-238.92), and TatR57S (-222.24). However, binding free energy analysis showed higher affinities for single variants TatQ63E (-349.2 ± 10.4 kcal/mol) and TatR57S (-290.0 ± 9.6 kcal/mol) compared to TatWt (-247.9 ± 27.7 kcal/mol), while TatC31S and TatC31S/R57SQ/63E showed lower values. Interactions over the protein trajectory were also higher for TatQ63E and TatR57S compared to TatWt, TatC31S, and TatC31S/R57SQ/63E, suggesting that modifying amino acids within the Arginine/Glutamine-rich region notably affects TAR interaction. Single amino acid mutations TatR57S and TatQ63E had a significant impact, while TatC31S had minimal effect. Introducing single amino acid variants from TatWt to a more representative Tat subtype C (TatC31S/R57SQ/63E) resulted in lower predicted binding affinity, consistent with previous findings. Conclusions These identified amino acid positions likely contribute significantly to Tat-TAR interaction and the differential pathogenesis and neuropathogenesis observed between subtype B and subtype C. Additional experimental investigations should prioritize exploring the influence of these amino acid signatures on TAR binding to gain a comprehensive understanding of their impact on viral transactivation, potentially identifying them as therapeutic targets.

Abstract Acoustic waves generated by seismic waves contain information on the internal structure of planets, and can be sensed by pressure sensors onboard high-altitude balloons. To identify the various contributions (infrasound signal, noise, balloon response, etc.) in such pressure records, a full waveform modeling is implemented and completed by infrasound ray tracing and additional data analysis. Here, we analyze the Stratéole-2 pressure data associated with two earthquakes (Garcia et al. Geophys. Res. Lett. 49(15):e98844, 2022) and compared these to full waveform simulations by SPECFEM2D-DG-LNS software. Even if our simulations do not precisely reproduce the waveform observed in the frequency range [0.05, 0.3] Hz, we show that the waveform presents more sensitivity to quake and internal structure parameters than to atmospheric structure, and that seismic surface wave dispersion is observed in balloon pressure records. The long-duration pressure oscillations observed after the main infrasonic signal cannot be fully reproduced by our one-dimensional input model even when source time function complexity and aftershocks are considered. These features are ascribed mainly to the complex vertical ground movements below the balloon and partly to late secondary infrasound arrivals excited by the interactions of seismic waves with the topography. These results enhance the advantages and limitations of quake-related infrasound observations on board terrestrial and planetary balloon platforms. Graphical Abstract

Abstract Polygenic scores (PGSs) offer the ability to predict genetic risk for complex diseases across the life course; a key benefit over short-term prediction models. To produce risk estimates relevant to clinical and public health decision-making, it is important to account for varying effects due to age and sex. Here, we develop a novel framework to estimate country-, age-, and sex-specific estimates of cumulative incidence stratified by PGS for 18 high-burden diseases. We integrate PGS associations from seven studies in four countries (N = 1,197,129) with disease incidences from the Global Burden of Disease. PGS has a significant sex-specific effect for asthma, hip osteoarthritis, gout, coronary heart disease and type 2 diabetes (T2D), with all but T2D exhibiting a larger effect in men. PGS has a larger effect in younger individuals for 13 diseases, with effects decreasing linearly with age. We show for breast cancer that, relative to individuals in the bottom 20% of polygenic risk, the top 5% attain an absolute risk for screening eligibility 16.3 years earlier. Our framework increases the generalizability of results from biobank studies and the accuracy of absolute risk estimates by appropriately accounting for age- and sex-specific PGS effects. Our results highlight the potential of PGS as a screening tool which may assist in the early prevention of common diseases.

Abstract Evidence for adaptation of human skin color to regional ultraviolet radiation suggests shared and distinct genetic variants across populations. However, skin color evolution and genetics in East Asians are understudied. We quantified skin color in 48,433 East Asians using image analysis and identified associated genetic variants and potential causal genes for skin color as well as their polygenic interplay with sun exposure. This genome-wide association study (GWAS) identified 12 known and 11 previously unreported loci and SNP-based heritability was 23–24%. Potential causal genes were determined through the identification of nonsynonymous variants, colocalization with gene expression in skin tissues, and expression levels in melanocytes. Genomic loci associated with pigmentation in East Asians substantially diverged from European populations, and we detected signatures of polygenic adaptation. This large GWAS for objectively quantified skin color in an East Asian population improves understanding of the genetic architecture and polygenic adaptation of skin color and prioritizes potential causal genes.

Aim: The aim of the research was to find significant factors that influence womenʼs satisfaction with childbirth. Design: A cross-sectional study design was chosen. Methods: The Czech version of the Birth Satisfaction Scale - Revised, supplemented with demographic questions and questions related to the process of childbirth, was used for data collection. The online questionnaire was completed by 870 women who met the inclusion criteria for the study. Results: Several statistically significant results were found: womenʼs satisfaction with childbirth increases with increasing age (p

Abstract Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators – Caspase-8, RIPK1, RIPK3 and MLKL – in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo.

Purpose: To investigate the impact of smartphone viewing distance and angle on reaction times. Design: A prospective, self-controlled, single-center study. Methods: Participants engaged in a driving simulation facing a large screen with a simulated brake pedal. They were tasked to stop the simulation once recognizing the deceleration of upcoming traffic. Tests were conducted without distraction and with a standardized distraction simulating texting while driving (TWD). Smartphone positions varied at distances of 30 cm and 60 cm, and at angles parallel to and 30° below the road plane. Reaction times were measured from the onset of simulated closure to detection. Stopping distances were extrapolated using data from the National Highway Traffic Safety Administration. Results: Ninety-four participants were included with a mean age of 24 ± 2.7 years. The control reaction time was 11.5 ± 4.1 s. Reaction times significantly decreased with smartphone placement at a closer distance of 30 cm parallel (17.0 ± 3.3 s) vs 60 cm parallel (15.4 ± 3.8 s), P

Abstract Studies in evolution, ecology and conservation are increasingly based on genetic and genomic data. With increased focus on molecular approaches, ethical concerns about destructive or more invasive techniques need to be considered, with a push for minimally invasive sampling to be optimised. Buccal swabs have been increasingly used to collect DNA in a number of taxa, including amphibians. However, DNA yield and purity from swabs are often low, limiting its use. In this study, we compare different types of swabs, preservation method and storage, and DNA extraction techniques in three case studies to assess the optimal approach for recovering DNA in anurans. Out of the five different types of swabs that we tested, Isohelix MS‐02 and Rapidry swabs generated higher DNA yields than other swabs. When comparing storage buffers, ethanol is a better preservative than a non‐alcoholic alternative. Dried samples resulted in similar or better final DNA yields compared to ethanol‐fixed samples if kept cool. DNA extraction via a Qiagen™ DNeasy Blood and Tissue Kit and McHale's salting‐out extraction method resulted in similar DNA yields but the Qiagen™ kit extracts contained less contamination. We also found that samples have better DNA recovery if they are frozen as soon as possible after collection. We provide recommendations for sample collection and extraction under different conditions, including budgetary considerations, size of individual animal sampled, access to cold storage facilities and DNA extraction methodology. Maximising efficacy of all of these factors for better DNA recovery will allow buccal swabs to be used for genetic and genomic studies in a range of vertebrates.

BackgroundDegenerative cervical myelopathy (DCM) is a progressive chronic spinal cord injury estimated to affect 1 in 50 adults. Without standardised guidance, clinical research studies have selected outcomes at their discretion, often underrepresenting the disease and limiting comparability between studies. Utilising a standard minimum data set formed via multi-stakeholder consensus can address these issues. This combines processes to define a core outcome set (COS)-a list of key outcomes-and core data elements (CDEs), a list of key sampling characteristics required to interpret the outcomes. Further "how" these outcomes should be measured and/or reported is then defined in a core measurement set (CMS). This can include a recommendation of a standardised time point at which outcome data should be reported. This study defines a COS, CDE, and CMS for DCM research.Methods and findingsA minimum data set was developed using a series of modified Delphi processes. Phase 1 involved the setup of an international DCM stakeholder group. Phase 2 involved the development of a longlist of outcomes, data elements, and formation into domains. Phase 3 prioritised the outcomes and CDEs using a two-stage Delphi process. Phase 4 determined the final DCM minimal data set using a consensus meeting. Using the COS, Phase 5 finalised definitions of the measurement construct for each outcome. In Phase 6, a systematic review of the literature was performed, to scope and define the psychometric properties of measurement tools. Phase 7 used a modified Delphi process to inform the short-listing of candidate measurement tools. The final measurement set was then formed through a consensus meeting (Phase 8). To support implementation, the data set was then integrated into template clinical research forms (CRFs) for use in future clinical trials (Phase 9). In total, 28 outcomes and 6 domains (Pain, Neurological Function, Life Impact, Radiology, Economic Impact, and Adverse Events) were entered into the final COS. Thirty two outcomes and 4 domains (Individual, Disease, Investigation, and Intervention) were entered into the final CDE. Finally, 4 outcome instruments (mJOA, NDI, SF-36v2, and SAVES2) were identified for the CMS, with a recommendation for trials evaluating outcomes after surgery, to include baseline measurement and at 6 months from surgery.ConclusionsThe AO Spine RECODE-DCM has produced a minimum data set for use in DCM clinical trials today. These are available at https://myelopathy.org/minimum-dataset/. While it is anticipated the CDE and COS have strong and durable relevance, it is acknowledged that new measurement tools, alongside an increasing transition to study patients not undergoing surgery, may necessitate updates and adaptation, particularly with respect to the CMS.

The presented data relates to the investigation of the adsorption properties of carbon dioxide (CO2), methane (CH4), and dihydrogen (H2) within pristine and functionalized carbophene pores. The carbophenes were functionalized with one of the groups carboxyl (COOH), amine (NH2), nitro (NO2), hydroxyl (OH), or an amide (CONH2, NHCOOH, and N(COOH)2) groups. The systems were optimized using the density functional tight-binding theory code DFTB+ (pre-compiled Version 19.1) with the matsci Slater-Koster files on the Mana high performance computing cluster at the University of Hawaiʻi at Mānoa. The dataset consists of the molecular geometries, lattice vectors, and the total energies for each specific system. One possible use of the data is for training or validating force fields for running molecular dynamics simulations.

Abstract Computational approaches for predicting the pathogenicity of genetic variants have advanced in recent years. These methods enable researchers to determine the possible clinical impact of rare and novel variants. Historically these prediction methods used hand-crafted features based on structural, evolutionary, or physiochemical properties of the variant. In this study we propose a novel framework that leverages the power of pre-trained protein language models to predict variant pathogenicity. We show that our approach VariPred (Variant impact Predictor) outperforms current state-of-the-art methods by using an end-to-end model that only requires the protein sequence as input. Using one of the best-performing protein language models (ESM-1b), we establish a robust classifier that requires no calculation of structural features or multiple sequence alignments. We compare the performance of VariPred with other representative models including 3Cnet, Polyphen-2, REVEL, MetaLR, FATHMM and ESM variant. VariPred performs as well as, or in most cases better than these other predictors using six variant impact prediction benchmarks despite requiring only sequence data and no pre-processing of the data.

We present a major release of the Tomofast-x open-source gravity and magnetic inversion code that incorporates several functionalities enhancing its performance and applicability for both industrial and academic studies. The code has been re-designed with a focus on real-world mineral exploration scenarios, while offering flexibility for applications at regional scale or for crustal studies. This new version includes several major improvements: magnetisation vector inversion, inversion of multi-component magnetic data, wavelet compression, improved handling of topography with support for non-uniform grids, a new and efficient parallelisation scheme, a flexible parameter file, and optimised input–output operations. Extensive testing has been conducted on a large synthetic dataset and field data from a prospective area of the Eastern Goldfields (Western Australia) to explore new functionalities with a focus on inversion for magnetisation vectors and magnetic susceptibility, respectively. Results demonstrate the effectiveness of Tomofast-x 2.0 in real-world studies in terms of both the recovery of subsurface features and performances on shared and distributed memory machines. Overall, with its updated features, improved capabilities, and performances, the new version of Tomofast-x provides a free open-source, validated advanced and versatile tool for constrained gravity and magnetic inversion.

The factors that influence dissipated energy and pore pressure generation patterns with respect to the cycle ratio and dissipated energy ratio were analyzed using the results of cyclic triaxial and cyclic direct simple shear tests. These analyses revealed several interesting differences in pore pressure generation patterns when related to cycle ratio than to dissipated energy ratio. Soils with different pore pressure generation patterns when plotted against the cycle ratio were found to have nearly identical pore pressure generation patterns when plotted against the dissipated energy ratio. The differences exist as the result of the fundamental differences between cycle ratio and dissipated energy ratio. The fundamental difference is that pore pressure generation is directly linked to the process of energy dissipation; it is not inherently linked to cycles of loading. Therefore, to achieve an understanding of the pore pressure response of a soil that is independent of the specifics of the applied loading, one needs to evaluate it in terms of energy dissipation, not in terms of cycles of loading, especially irregular loadings.

Abstract Background Chronic malnutrition is a condition associated with negative impacts on physical and cognitive development. It is multi-causal and can start very early in life, already in utero, thus it is especially challenging to find appropriate interventions to tackle it. The government of Angola is implementing a standard of care program with potential to prevent it, and the provision of cash transfers and the supplementation with small quantity lipid-based nutrients (SQ-LNS) are also promising interventions. We aimed to evaluate the impact of the standard of care program alone and of the standard of care plus a cash transfer intervention in the lineal growth of children less than 2 years old and compare it to the effectiveness of a nutrition supplementation plus standard of care program in Southern Angola. Methods/design The three-arm parallel cluster randomised controlled trial is set in four communes of Huila and Cunene provinces. Clusters are villages or neighbourhoods with a population around 1075 people. A total of twelve clusters were selected per arm and forty pregnant women are expected to be recruited in each cluster. Pregnant women receive the standard of care alone, or the standard of care plus unconditional cash transfer or plus nutritional supplementation during the first 1000 days, from pregnancy to the child reaching 24 months. The primary outcome is the prevalence of stunting measured as height-for-age Z-score (HAZ) < -2 in children below 2 years. Impact will be assessed at 3, 6, 12, 18 and 24 months of children’s age. Secondary outcomes include mortality, morbidity, caring, hygiene and nutrition behaviours and practices, and women and children’s dietary diversity. Quantitative data are also collected on women’s empowerment, household food security, expenditure and relevant clinical and social events at baseline, endline and intermediate time points. Discussion The results will provide valuable information on the impact of the standard of care intervention alone as well as combined with an unconditional cash transfer intervention compared to a nutrition supplementation plus standard of care intervention, carried out during the first 1000 days, in the children´s growth up to 2 years and related outcomes in Southern Angola. Trial registration Clinical Trials NCT05571280. Registered 7 October 2022.

Abstract Obtaining rigorous baseline density estimates of species of conservation interest is key when assisting landowners to achieve management goals on private lands. Northern bobwhite (Colinus virginianus) populations are declining throughout their range and despite being the focus of numerous private land conservation initiatives, baseline density estimates in privately owned pine forests are lacking. We sought to address this knowledge gap across the Southeastern United States by sampling 105 privately owned pine stands throughout 2018 to 2020 using observer point count and autonomous recording unit (ARU) sampling data. Using Bayesian hierarchical models, we investigated the influence of stand management (brush management or applied fire) on bobwhite density, as well as four landscape‐scale environmental variables. These included percentage cover of forest, herbaceous, agricultural or burnt land area across six different spatial scales ranging from 500‐m to 10‐km around each pine stand. Baseline density on sites with no management was estimated to be 2.24 coveys per 100 ha (1.00–5.03, 95% BCI), with little impact of applying brush management, but a trend for a positive effect of fire management (0.19, −0.01 to 0.38 95% BCI). This impact of fire was seen at both the stand‐scale, correlated with an increase in acreage of applied prescribed burn management, and across the greater landscape area, correlated with cover of burnt area within a 2‐km buffer around each site. There were also strong positive influences of herbaceous vegetation and a strong negative influence of forest cover on bobwhite density. Practical implication: our sampling efforts fill an important information gap regarding densities throughout private lands in the Southeastern United States. Our study also highlights the necessity of landscape scale planning for Northern Bobwhite conservation initiatives because the efficacy of conservation practices (i.e. prescribed fire and brush management) could be altered by the landscape surrounding the treated forest stand.

Abstract The objective of this study is to provide a positron emission tomography (PET) imaging modality targeting vascular endothelial growth factor receptors (VEGFR) for the early noninvasive detection and assessment of pulmonary arterial hypertension (PAH) severity. To validate the effectiveness of the [18F]VEGFR PET tracer, we utilized a monocrotaline (MCT)‐induced PAH rat model. Molecular optical imaging, using a Cy5.5‐conjugated VEGFR targeting agent, was employed to demonstrate the uptake of the agent at pulmonary arterioles, correlating with the onset and progression of PAH. Histological examinations of the MCT‐PAH rat lung revealed a significant correlation between VEGFR2 expression and the pathogenesis of PAH. Molecular optical imaging demonstrated heightened uptake of the Cy5.5‐conjugated VEGFR targeting agent at pulmonary arterioles, corresponding with the onset and progression of PAH. [18F]VEGFR PET showed increased lung uptake detectable in early‐stage PAH before increase in pulmonary artery pressures, and this uptake correlated with increased PAH severity. Moreover, when compared to [18F]FDG PET, [18F]VEGFR PET exhibited markedly lower background cardiac signal, enhancing imaging sensitivity for lung abnormalities. Our study provides a compelling evidence for the potential utility of the innovative [18F]VEGFR PET tracer, in non‐invasively detecting early signs of PAH, and monitoring its progression. The observed correlations between VEGFR2 expression, molecular optical imaging results, and [18F]VEGFR PET findings support the use of this tracer for early detection, and assessment of PAH severity. The lower background cardiac signal observed with [18F]VEGFR PET further enhances its imaging sensitivity, emphasizing its potential clinical significance.

Musical absorption is a multi-dimensional phenomenon that has been understood in various ways, but is related to strong, immersive, and transformative musical encounters. For this exploratory article, we used a phenomenologically and psychologically informed questionnaire to measure audience members’ reports of musical absorption and affective experiences at the MusicLab Copenhagen research concert with the Danish String Quartet (DSQ). We aimed to examine the relation between musical absorption and (1) attention, mind-wandering, and senses of transformation; (2) affective phenomena of feeling moved or touched and awe; (3) social context, as determined by technological mediation of a livestream; (4) musical context (Beethoven, Schnittke, and folk music); and (5) motion. There were 91 participants in the live audience and 43 participants in the livestreaming audience, who completed questionnaires after each piece in the concert and who had their motion measured through an application that recorded accelerometer data from their smartphones. Drawing on methods from experimental psychology, we found that (1) being “absorbed in the music” was not related to mind-wandering, but it was related to a sense of positive transformation; (2) musical absorption was related to experiences of feeling moved, awe, connectedness, and enjoyment, and to being an “admirer” of the DSQ, as well as to being familiar with the music; (3) being at the live concert facilitated more musical absorption than watching the livestream; (4) the final concert section, containing a collection of folk tunes, promoted the most musical absorption; and (5) within the restrained movement dynamics of the live audience, motion trended as an indicator of an embodied experience of musical absorption. We use these results to engage in a phenomenologically informed and empirically enriched discussion of musical absorption and related affective and attentional dynamics.

Silicon is a promising material for anodes in future generations of LIBs. However, its volume changes during the lithiation/delithiation process that degrades battery performance, making it an impractical alternative. To mitigate this issue, we have found a viable alternate solution, which is the preparation of adamantane-polyacrylic acid (AdEN-AA) and β-cyclodextrin-polyacrylic acid (βCD6A-AA) polymers as supramolecular binders. The advantage of these binders is that polymers leverage host-guest interactions. To carry out this research, we prepared the anode materials in water and in NMP, and then we studied their capacity to crosslink and gel. Additionally, we examined the extent of the supramolecular interaction vs. hydrogen bond. Thermogravimetric analysis showed that the thermal stability of the mixture of complementary polymer increased in the following order: AdEN-AA/βCD6A-AA in NMP

IntroductionMicrobial population structures within fecal samples are vital for disease screening, diagnosis, and gut microbiome research. The two primary methods for collecting feline fecal samples are: (1) using a fecal loop, which retrieves a rectal sample using a small, looped instrument, and (2) using the litter box, which collects stool directly from the litter. Each method has its own advantages and disadvantages and is suitable for different research objectives.Methods and resultsWhole-genome shotgun metagenomic sequencing were performed on the gut microbiomes of fecal samples collected using these two methods from 10 adult cats housed in the same research facility. We evaluated the influence of collection methods on feline microbiome analysis, particularly their impact on DNA extraction, metagenomic sequencing yield, microbial composition, and diversity in subsequent gut microbiome analyses. Interestingly, fecal sample collection using a fecal loop resulted in a lower yield of microbial DNA compared to the litterbox method (p = 0.004). However, there were no significant differences between the two groups in the proportion of host contamination (p = 0.106), virus contamination (p = 0.232), relative taxonomy abundance of top five phyla (Padj > 0.638), or the number of microbial genes covered (p = 0.770). Furthermore, no significant differences were observed in alpha-diversity, beta-diversity, the number of taxa identified at each taxonomic level, and the relative abundance of taxonomic units.DiscussionThese two sample collection methods do not affect microbial population structures within fecal samples and collecting fecal samples directly from the litterbox within 6 hours after defecation can be considered a reliable approach for microbiome research.

The Argentinian flag sign (AFS) is a feared complication during cataract extraction. Intralenticular pressures, especially excessive posterior pressure, have been identified as potential mechanisms for capsular stress and tearing associated with AFS. Capsular tension is created by positive intralenticular pressures, which cause the irido-lens diaphragm to move anteriorly once the manual capsulorhexis has been initiated. This tension can cause inadvertent tears that self-propagate to the lens equator, causing an AFS, among other intraoperative complications. Thus, this review highlights the importance of identifying intumescent cataracts as well as a combination of techniques to relieve intracapsular pressures needed to prevent AFS. However, some instances of anterior capsular tears are unavoidable. Therefore, focus will also be placed on techniques during cataract extraction used to manage anterior capsular tears, mitigating extension to the posterior capsule.

Abstract Rare-event search experiments located on-surface, such as short-baseline reactor neutrino experiments, are often limited by muon-induced background events. Highly efficient muon vetos are essential to reduce the detector background and to reach the sensitivity goals. We demonstrate the feasibility of deploying organic plastic scintillators at sub-Kelvin temperatures. For the NUCLEUS experiment, we developed a cryogenic muon veto equipped with wavelength shifting fibers and a silicon photo multiplier operating inside a dilution refrigerator. The achievable compactness of cryostat-internal integration is a key factor in keeping the muon rate to a minimum while maximizing coverage. The thermal and light output properties of a plastic scintillation detector were examined. We report first data on the thermal conductivity and heat capacity of the polystyrene-based scintillator UPS-923A over a wide range of temperatures extending below one Kelvin. The light output was measured down to 0.8 K and observed to increase by a factor of 1.61 ± 0.05 compared to 300 K. The development of an organic plastic scintillation muon veto operating in sub-Kelvin temperature environments opens new perspectives for rare-event searches with cryogenic detectors at sites lacking substantial overburden.

Abstract Over the past decade, stereotactically placed electrodes have become the gold standard for deep brain recording and stimulation for a wide variety of neurological and psychiatric diseases. Current electrodes, however, are limited in their spatial resolution and ability to record from small populations of neurons, let alone individual neurons. Here, we report on an innovative, customizable, monolithically integrated human-grade flexible depth electrode capable of recording from up to 128 channels and able to record at a depth of 10 cm in brain tissue. This thin, stylet-guided depth electrode is capable of recording local field potentials and single unit neuronal activity (action potentials), validated across species. This device represents an advance in manufacturing and design approaches which extends the capabilities of a mainstay technology in clinical neurology.

Abstract Smoking is the leading risk factor for chronic obstructive pulmonary disease (COPD) worldwide, yet many people who never smoke develop COPD. We perform a longitudinal analysis of COPD in the UK Biobank to derive and validate the Socioeconomic and Environmental Risk Score which captures additive and cumulative environmental, behavioral, and socioeconomic exposure risks beyond tobacco smoking. The Socioeconomic and Environmental Risk Score is more predictive of COPD than smoking status and pack-years. Individuals in the highest decile of the risk score have a greater risk for incident COPD compared to the remaining population. Never smokers in the highest decile of exposure risk are more likely to develop COPD than previous and current smokers in the lowest decile. In general, the prediction accuracy of the Social and Environmental Risk Score is lower in non-European populations. While smoking status is often considered in screening COPD, our finding highlights the importance of other non-smoking environmental and socioeconomic variables.

Good, satisfying, sleep is a key indicator and determinant of health and wellness. However, there is no consensus about how to define and measure good sleep. The present research aimed to define sleep satisfaction through the extant literature and disentangle it from sleep quality, a conceptually similar construct. Systematic review methods were adapted for a rapid review approach. The entire review was completed in eight weeks. Tabulation coding with content analysis was used to identify key categories and synthesize findings. A systematic process for generating construct definitions was followed. Database search yielded 51 eligible studies (N > 218,788), representing diverse adult populations, in 20 countries. Designs varied in rigour. Sleep satisfaction was defined as a personal, introspective, and global judgment about one’s feelings of contentment with one’s sleep, at a particular point in time. Sleep satisfaction was understood as an indicator of general health, impacted by and varied as a function of one’s sleep environment and individual-level characteristics. This rapid review contributes to the literature by providing the first systematically generated definition of sleep satisfaction, with strong implications for measurement, research, and practice.

Takotsubo syndrome (otherwise known as broken-heart syndrome or left ventricular apical ballooning) is a rare cause of reversible heart failure that predominantly affects postmenopausal women. It was first described by Japanese researchers in the 1990s and has become established as a differential for heart failure following a physically or psychologically stressful event. This was popularised by a spike in cases following natural disasters in Japan. As the recognition of takotsubo syndrome in the differential diagnosis for sudden, onset heart failure in a previously healthy individual has grown, so has the discussion concerning takotsubo in the peripartum period. Peripartum cardiomyopathy is a rare cause of reversible heart failure in the latter weeks of pregnancy and the postpartum period. Morbidity and mortality for both cardiomyopathies can be highly variable, ranging from complete recovery of cardiac function to life threatening arrhythmias and even death. This rapid review highlights the similarities between both cardiomyopathies and challenges the hitherto assumption that both takotsubo and peripartum cardiomyopathies are distinct entities that can easily be distinguished from one another. The implications of this are significant within the context of the behavioural aspects of diagnosis, treatment, and outcome.

Abstract The white sturgeon (Acipenser transmontanus) is the largest freshwater fish in North America. Because of the unique life history characteristics of sturgeon, including longevity, late maturation and long spawning intervals, their aquaculture can be a significant investment of resources. As a result of habitat loss and overharvesting, natural populations of white sturgeon are threatened and there is a growing effort to improve conservation aquaculture programs. Germ cell transplantation is an innovative technology previously demonstrated in a variety of fish species to be able to produce a surrogate broodstock. The technique relies upon optimal donor germ cell recovery and transplantation into a recipient fish. In this study, we developed and optimized the harvest of donor cells for germline transplantation and evaluated methods for ovary cryopreservation for the first time in the white sturgeon. We found that harvesting gonads from juveniles between the ages of 1.5 and 2.5-years resulted in reliably high proportions of pre-meiotic cells regardless of sex, a critical feature for using white sturgeon for transplantation studies since the species shows no distinguishing external sex characteristics. From the viable cells, we identified germline cells using immunolabeling with the antibody DDX4, a marker specific to the germline. For in vivo tracking of donor cells during transplantations, gonadal cells were stained with a long half-life non-toxic cell membrane dye, PKH26, and microinjected into the peritoneal cavity of newly hatched white sturgeon larvae. Larvae were reared until 3 months post-transplantation to monitor for colonization and proliferation of PKH26-labeled cells within the recipient larval gonads. Furthermore, viable cell detection, assessment of germline-specificity, and transplantation was determined for cells recovered from cryopreserved ovarian tissue from sexually immature females. Transplantations using cells cryopreserved with media supplemented with dimethyl sulfoxide (DMSO) rather than ethylene glycol (EG) demonstrated the highest number of PKH26-labeled cells distributed along the gonadal ridges of the larval recipient. Determining optimal methods of tissue cryopreservation, and germ cell recovery and transplantation are foundational to the future development of germ cell transplantation as a strategy to improve the aquaculture and conservation of this species. Our study demonstrates that conservation actions, such as surrogate breeding, could be utilized by hatcheries to retain or improve natural gamete production without genetic modification, and provide an encouraging approach to the management of threatened sturgeon species.

Abstract Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo, Mlkl S131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.