Biallelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered intrinsic and extrinsic apoptosis and a Perrault syndrome-spectrum phenotype.

The mitoribosome synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders, and frequently show combined oxidative phosphorylation deficiency. Here, we describe five unrelated individuals with biallelic variants in the DAP3 nuclear gene encoding mitoribosomal small subunit 29 (MRPS29), with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein levels, and consequently decreased levels of additional protein components of the mitoribosomal small subunit, associated with a combined complex I and IV deficiency. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression, and partially rescued protein levels of MRPS7, MRPS9 and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants. Protein modelling suggested that DAP3 disease-associated missense variants can impact ADP binding, and in vitro assays demonstrated DAP3 variants can consequently reduce both intrinsic and extrinsic apoptotic sensitivity, DAP3 thermal stability and DAP3 GTPase activity. Our study presents genetic and functional evidence that biallelic variants in DAP3 result in a multisystem disorder of combined oxidative phosphorylation deficiency with pleiotropic presentations, consistent with mitochondrial dysfunction.

Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome.

Primary mitochondrial diseases (PMDs) are among the most common inherited neurological disorders. They are caused by pathogenic variants in mitochondrial or nuclear DNA that disrupt mitochondrial structure and/or function, leading to impaired oxidative phosphorylation (OXPHOS). One emerging subcategory of PMDs involves defective phospholipid (PL) metabolism. Cardiolipin (CL), the signature PL of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesised and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to CL biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human CL-related PMDs are not fully characterised. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1, a mitochondrial tyrosine phosphatase required for de novo CL biosynthesis. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome comprising developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy, and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy, and white matter changes. Using patient-derived fibroblasts and skeletal muscle tissue, combined with cellular rescue experiments, we characterise the molecular defects associated with mutant PTPMT1 and confirm the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterise the functional role of PTPMT1 in CL homeostasis, we established a zebrafish ptpmt1 knockout model associated with abnormalities in body size, developmental alterations, decreased total CL levels, and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired CL metabolism, highlight the contribution of aberrant CL metabolism towards human disease, and emphasise the importance of normal CL homeostasis during neurodevelopment.

Regional variations and drivers of essential and non-essential elements in Steller sea lion pups from the Aleutian Islands, Alaska.

Exposure and resulting tissue concentrations of various elements from natural and anthropogenic sources are influenced by multiple factors, such as geographic location, age, diet, and metabolic rate, that can influence wildlife health. Essential and non-essential elements were assessed in lanugo and whole blood collected in 2019 from 102 Steller sea lion (Eumetopias jubatus) pups from two rookeries from the western and central Aleutian Islands: Agattu (WAI, n = 54) and Ulak Islands (CAI, n = 48). Rookery, sex, dorsal standard length, and trophic ecology (ẟ15N, ẟ13C values) effects on element concentration were evaluated. Significant differences in element concentrations of lanugo were exhibited across rookeries (p < 0.05), except for zinc (Zn). For example, higher mercury (Hg) and selenium (Se) concentrations were observed in WAI than CAI, while other elements were lower in WAI. Whole blood showed higher sulfur (S) and Se concentrations in CAI compared to WAI, while WAI had elevated strontium (Sr) and Hg concentrations relative to CAI. Trophic ecology significantly influenced most element concentrations, possibly due to regional variations in adult female feeding and food web dynamics. Interactions between elements were found in lanugo across both rookeries, with varying strengths. Whole blood displayed less pronounced yet consistent associations, with variable intensities. Essential elements sodium (Na), potassium (K), and calcium (Ca) formed a distinct group whose interaction is crucial for nervous system function and muscle contraction. Another group comprised zinc (Zn), iron (Fe), manganese (Mn), magnesium (Mg), phosphorous (P), S, and Se, which are known for indirectly interacting with enzyme function and metabolic pathways. Hg and Se formed a distinct group probably due to their known chemical interactions and physiological protective interactions.

Rare disease genomic testing in the UK and Ireland: promoting timely and equitable access.

PURPOSE AND SCOPE: The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times. METHODS OF STATEMENT DEVELOPMENT: A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute. RESULTS AND CONCLUSIONS: We identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources.

Inhibiting the Appearance of Green Emission in Mixed Lead Halide Perovskite Nanocrystals for Pure Red Emission.

Mixed halide perovskites exhibit promising optoelectronic properties for next-generation light-emitting diodes due to their tunable emission wavelength that covers the entire visible light spectrum. However, these materials suffer from severe phase segregation under continuous illumination, making long-term stability for pure red emission a significant challenge. In this study, we present a comprehensive analysis of the role of halide oxidation in unbalanced ion migration (I/Br) within CsPbI2Br nanocrystals and thin films. We also introduce a new approach using cyclic olefin copolymer (COC) to encapsulate CsPbI2Br perovskite nanocrystals (PNCs), effectively suppressing ion migration by increasing the corresponding activation energy. Compared with that of unencapsulated samples, we observe a substantial reduction in phase separation under intense illumination in PNCs with a COC coating. Our findings show that COC enhances phase stability by passivating uncoordinated surface defects (Pb2+ and I-), increasing the formation energy of halide vacancies, improving the charge carrier lifetime, and reducing the nonradiative recombination density.

Quantitative proteomics of patient fibroblasts reveal biomarkers and diagnostic signatures of mitochondrial disease.

BACKGROUND: Mitochondrial diseases belong to the group of inborn errors of metabolism (IEM), with a prevalence of 1:2,000-1:5,000. They are the most common form of IEM, but despite advances in next-generation sequencing technologies, almost half of the patients are left genetically undiagnosed. METHODS: We investigated a cohort of 61 patients with defined mitochondrial disease to improve diagnostics, identify biomarkers, and correlate metabolic pathways to specific disease groups. Clinical presentations were structured using human phenotype ontology terms, and mass spectrometry-based proteomics was performed on primary fibroblasts. Additionally, we integrated six patients carrying variants of uncertain significance (VUS) to test proteomics as a diagnostic expansion. RESULTS: Proteomic profiles from patient samples could be classified according to their biochemical and genetic characteristics, with the expression of five proteins (GPX4, MORF4L1, MOXD1, MSRA and TMED9) correlating with the disease cohort, and thus, acting as putative biomarkers. Pathway analysis showed a deregulation of inflammatory and mitochondrial stress responses. This included the upregulation of glycosphingolipid metabolism and mitochondrial protein import, as well as the downregulation of arachidonic acid metabolism. Furthermore, we could assign pathogenicity to a VUS in MRPS23 by demonstrating the loss of associated mitochondrial ribosome subunits. CONCLUSION: We established mass spectrometry-based proteomics on patient fibroblasts as a viable and versatile tool for diagnosing patients with mitochondrial disease. FUNDING: The NovoNordisk Foundation, Knut and Alice Wallenberg Foundation, Wellcome Centre for Mitochondrial Research, UK Medical Research Council, and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children.

The DREAM Implant: A Lightweight, Modular, and Cost-Effective Implant System for Chronic Electrophysiology in Head-Fixed and Freely Behaving Mice.

Chronic electrophysiological recordings in rodents have significantly improved our understanding of neuronal dynamics and their behavioral relevance. However, current methods for chronically implanting probes present steep trade-offs between cost, ease of use, size, adaptability, and long-term stability. This protocol introduces a novel chronic probe implant system for mice called the DREAM (Dynamic, Recoverable, Economical, Adaptable, and Modular), designed to overcome the trade-offs associated with currently available options. The system provides a lightweight, modular and cost-effective solution with standardized hardware elements that can be combined and implanted in straightforward steps and explanted safely for recovery and multiple reuse of probes, significantly reducing experimental costs. The DREAM implant system integrates three hardware modules: (1) a microdrive that can carry all standard silicon probes, allowing experimenters to adjust recording depth across a travel distance of up to 7 mm; (2) a three-dimensional (3D)-printable, open-source design for a wearable Faraday cage covered in copper mesh for electrical shielding, impact protection, and connector placement, and (3) a miniaturized head-fixation system for improved animal welfare and ease of use. The corresponding surgery protocol was optimized for speed (total duration: 2 h), probe safety, and animal welfare. The implants had minimal impact on animals' behavioral repertoire, were easily applicable in freely moving and head-fixed contexts, and delivered clearly identifiable spike waveforms and healthy neuronal responses for weeks of post-implant data collection. Infections and other surgery complications were extremely rare. As such, the DREAM implant system is a versatile, cost-effective solution for chronic electrophysiology in mice, enhancing animal well-being, and enabling more ethologically sound experiments. Its design simplifies experimental procedures across various research needs, increasing accessibility of chronic electrophysiology in rodents to a wide range of research labs.

Supernumerary proteins of the human mitochondrial ribosomal small subunit are integral for assembly and translation.

Mitochondrial ribosomes (mitoribosomes) have undergone substantial evolutionary structural remodeling accompanied by loss of ribosomal RNA, while acquiring unique protein subunits located on the periphery. We generated CRISPR-mediated knockouts of all 14 unique (mitochondria-specific/supernumerary) human mitoribosomal proteins (snMRPs) in the small subunit to study the effect on mitoribosome assembly and protein synthesis, each leading to a unique mitoribosome assembly defect with variable impact on mitochondrial protein synthesis. Surprisingly, the stability of mS37 was reduced in all our snMRP knockouts of the small and large ribosomal subunits and patient-derived lines with mitoribosome assembly defects. A redox-regulated CX9C motif in mS37 was essential for protein stability, suggesting a potential mechanism to regulate mitochondrial protein synthesis. Together, our findings support a modular assembly of the human mitochondrial small ribosomal subunit mediated by essential supernumerary subunits and identify a redox regulatory role involving mS37 in mitochondrial protein synthesis in health and disease.

Fit for purpose: Selecting the best mitochondrial DNA for the job.

The factors determining levels of pathogenic mitochondrial DNA in cells and tissues are critical to disease pathology but remain poorly understood and contentious. In Nature, Kotrys et al. published a single-cell-based analysis casting fresh light on this thorny problem and introduced a powerful new investigative tool.

Selection for high and low antibody responses to sheep red blood cells influences cytokine and chemokine expression in chicken peripheral blood leukocytes and splenic tissue.

White Leghorn chickens from a common founder population have been divergently selected for high (HAS) or low (LAS) antibody responses to sheep red blood cells (SRBC) for 49 generations resulting in 2 diverse lines for this trait. Much has been studied in these two lines; however, the impact of these selection pressures on cytokine and chemokine expression is not fully understood. The purpose of this study is to determine if selection for antibody response to SRBC impacts cytokine and chemokine expression in peripheral blood leukocytes (PBL) and spleen from HAS and LAS chickens. Total RNA was isolated from PBL and spleen after which mRNA expression of cytokines (IL4, IL6, IL10, TGF-ß4) and chemokines (CXCL8, CCL4) were determined by quantitative real-time RT-PCR (qRT-PCR). The data were analyzed using Student's t test comparing HAS and LAS (P < 0.05) and are reported as corrected 40-CT. PBL and spleen samples were analyzed separately. With respect to PBL, expression of IL6 was higher (P < 0.05) in PBL isolated from LAS chickens compared to those from the HAS line whereas there were no differences (P > 0.05) in IL4, IL10, CXCL8, CCL4, or TGF-ß4. The cytokine and chemokine mRNA expression profiles were different in the spleen between the two lines. IL4 and CXCL8 expression were higher (P < 0.05) in spleen samples from HAS chickens than LAS. The expression of IL6, IL10, CCL4, or TGF-ß4 in the spleens did not differ (P > 0.05) between the lines. The data indicate that selection for specific antibody responses to SRBC impacts the cytokine and chemokine expression profile in PBL and spleens but in different ways in HAS and LAS. These studies provide insight into the influence that selection pressures for antibody responses have on different immune response components, specifically cytokines and chemokines typically involved in the innate response.

The RHCE gene encodes the chicken blood system I.

BACKGROUND: There are 13 known chicken blood systems, which were originally detected by agglutination of red blood cells by specific alloantisera. The genomic region or specific gene responsible has been identified for four of these systems (A, B, D and E). We determined the identity of the gene responsible for the chicken blood system I, using DNA from multiple birds with known chicken I blood system serology, 600K and 54K single nucleotide polymorphism (SNP) data, and lowpass sequence information. RESULTS: The gene responsible for the chicken I blood system was identified as RHCE, which is also one of the genes responsible for the highly polymorphic human Rh blood group locus, for which maternal/fetal antigenic differences can result in fetal hemolytic anemia with fetal mortality. We identified 17 unique RHCE haplotypes in the chicken, with six haplotypes corresponding to known I system serological alleles. We also detected deletions in the RHCE gene that encompass more than 6000 bp and that are predicted to remove its last seven exons. CONCLUSIONS: RHCE is the gene responsible for the chicken I blood system. This is the fifth chicken blood system for which the responsible gene and gene variants are known. With rapid DNA-based testing now available, the impact of I blood system variation on response against disease, general immune function, and animal production can be investigated in greater detail.

Interleukin-1ß induces and accelerates human endometrial stromal cell senescence and impairs decidualization via the c-Jun N-terminal kinase pathway.

As the mean age of first-time mothers increases in the industrialized world, inquiries into causes of human reproductive senescence have followed. Rates of ovulatory dysfunction and oocyte aneuploidy parallel chronological age, but poor reproductive outcomes in women older than 35 years are also attributed to endometrial senescence. The current studies, using primary human endometrial stromal cell (ESC) cultures as an in vitro model for endometrial aging, characterize the proinflammatory cytokine, IL-1ß-mediated and passage number-dependent effects on ESC phenotype. ESC senescence was accelerated by incubation with IL-1ß, which was monitored by RNA sequencing, ELISA, immunocytochemistry and Western blotting. Senescence associated secreted phenotype (SASP) proteins, IL-1ß, IL-6, IL-8, TNF-α, MMP3, CCL2, CCL5, and other senescence-associated biomarkers of DNA damage (p16, p21, HMGB1, phospho-γ-histone 2 A.X) were noted to increase directly in response to 0.1 nM IL-1ß stimulation. Production of the corresponding SASP proteins increased further following extended cell passage. Using enzyme inhibitors and siRNA interference, these effects of IL-1ß were found to be mediated via the c-Jun N-terminal kinase (JNK) signaling pathway. Hormone-induced ESC decidualization, classical morphological and biochemical endocrine responses to estradiol, progesterone and cAMP stimulation (prolactin, IGFBP-1, IL-11 and VEGF), were attenuated pari passu with prolonged ESC passaging. The kinetics of differentiation responses varied in a biomarker-specific manner, with IGFBP-1 and VEGF secretion showing the largest and smallest reductions, with respect to cell passage number. ESC hormone responsiveness was most robust when limited to the first six cell passages. Hence, investigation of ESC cultures as a decidualization model should respect this limitation of cell aging. The results support the hypotheses that "inflammaging" contributes to endometrial senescence, disruption of decidualization and impairment of fecundity. IL-1ß and the JNK signaling pathway are pathogenetic targets amenable to pharmacological correction or mitigation with the potential to reduce endometrial stromal senescence and enhance uterine receptivity.

Growth of White Leghorn Chicken Immune Organs after Long-Term Divergent Selection for High or Low Antibody Response to Sheep Red Blood Cells.

Long-term divergent selection from a common founder population for a single trait-antibody response to sheep erythrocytes 5 days post-injection-has resulted in two distinct lines of White Leghorn chickens with a well-documented difference in antibody titers: high (HAS)- and low (LAS)-antibody selected lines. Subpopulations-high (HAR)- and low (LAR)-antibody relaxed-were developed from generation 24 of the selected lines to relax selection. The objective of the current experiment was to determine if this long-term selection and relaxation of selection impacted the growth of two organs important to chicken immunity: the spleen and the bursa of Fabricius. Spleens and bursae were obtained from ten chickens per line at nine timepoints (E18, D0, D6, D13, D20, D35, D49, D63, and D91) throughout their rapid growth phase and presented as a percent of body weight. Significance was set at p ≤ 0.05. For the spleen, all lines consistently increased in size relative to body weight to D49, followed by a consistent decline. All lines had a similar growth pattern, but HAS spleens grew faster than LAS spleens. For the bursa, LAS was smaller than the other three lines as an embryo and also smaller than HAS through D63. In the selected lines, bursa weight peaked at D35, whereas the relaxed lines peaked at D49. By D91, there was no difference between lines. Artificial and natural selection, represented by the long-term selected and relaxed antibody lines, resulted in differences in the growth patterns and relative weights of the spleen and bursa of Fabricius.

Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.

Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. A substantial proportion of CI deficiencies are believed to arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of these CIAFs is poorly defined, making their role in CI assembly unclear, and confounding interpretation of potential disease-causing genetic variants. To address these challenges, we devised a deep mutational scanning approach to systematically assess the function of thousands of NDUFAF6 genetic variants. Guided by these data, biochemical analyses and cross-linking mass spectrometry, we discovered that the CIAF NDUFAF6 facilitates incorporation of NDUFS8 into CI and reveal that NDUFS8 overexpression rectifies NDUFAF6 deficiency. Our data further provide experimental support of pathogenicity for seven novel NDUFAF6 variants associated with human pathology and introduce functional evidence for over 5,000 additional variants. Overall, our work defines the molecular function of NDUFAF6 and provides a clinical resource for aiding diagnosis of NDUFAF6-related diseases.

Clarity tubes as effective citizen science tools for monitoring wastewater treatment works and rivers.

Improved freshwater resource management requires the implementation of widespread, effective, and timely water quality monitoring. Conventional monitoring methods are often inhibited by financial, infrastructural, and human capacity limitations, especially in developing regions. This study aimed to validate the citizen-scientist-operated transparency or clarity tube (hereafter "clarity tube") for measuring water clarity as a proxy for total suspended solids (TSS) concentration, a critical quality metric in river systems and wastewater treatment works (WWTW) effluent in Southern Africa. Clarity tubes provided a relatively accurate and precise proxy for TSS in riverine lotic systems and WWTW effluent, revealing significant inverse log-linear relationships between clarity and TSS with r2 = 0.715 and 0.503, respectively. We demonstrate that clarity-derived estimates of TSS concentration (TSScde) can be used to estimate WWTW compliance with WWTW effluent TSS concentration regulations. The measurements can then be used to engage with WWTW management, potentially affecting WWTW performance. Overall, these findings demonstrate the usefulness of clarity tubes as low-cost, accessible, and easy-to-use citizen science tools for high spatial and temporal resolution water quality monitoring, not only in rivers in Southern Africa but also in WWTW effluent for estimating compliance, with strong global relevance to the sustainable development goals (SDGs). Integr Environ Assess Manag 2024;20:1463-1472. © 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Social Isolation, Self-Rated Health, and Self-Rated Oral Health among African Americans.

Social isolation is associated with worse health; however, few studies have examined the health effects of isolation among African Americans. The purpose of this study is to evaluate associations between social isolation and self-rated physical and oral health from the National Survey of American Life, a nationally representative sample of African Americans. Social isolation was operationalized to reflect both objective isolation (lack of contact) and subjective isolation (lack of emotional closeness). Self-rated physical and oral health were regressed on objective and subjective isolation while controlling for marital status, gender, age, family income, education, and health behaviors. Poorer self-rated physical health was associated with objective isolation, while poorer self-rated oral health was associated with subjective isolation. This study contributes to the small literature of the impact of social isolation on health among African Americans; furthermore, it is the first to examine the relationship between isolation and self-rated oral health in this population.

Association between maternal cigarette smoking cessation and risk of preterm birth in Western New York.

BACKGROUND: Although many studies suggested the benefit of smoking cessation among pregnant women in reducing the risk of preterm birth (PTB), the timing of the effect of the cessation remains inconclusive. OBJECTIVES: To examine the association of trimester-specific smoking cessation behaviours with PTB risk. METHODS: We included 199,453 live births in Western New York between 2004 and 2018. Based on self-reported cigarette smoking during preconception and in each trimester, we created six mutually exclusive groups: non-smokers, quitters in each trimester, those who smoked throughout pregnancy, and inconsistent smokers. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated using Poisson regression to examine the association between smoking cessation and PTB. Effect modification by illegal drug use, maternal age, race and ethnicity and pre-pregnancy body mass index (BMI) was investigated multiplicatively by ratio of relative risk and additively by relative excess risk due to interaction (RERI). RESULTS: Overall, 6.7% of women had a PTB; 14.1% smoked throughout pregnancy and 3.4%, 1.8% and 0.8% reported quitting smoking during the first, second and third trimesters, respectively. Compared to non-smokers, third-trimester cessation (RR 1.20, 95% CI 1.01, 1.43) and smoking throughout pregnancy (RR 1.27, 95% CI 1.21, 1.33) were associated with a higher PTB risk, while quitting smoking during the first or second trimester, or inconsistent smoking was not associated with PTB. A positive additive interaction was identified for maternal age and late smoking cessation or smoking throughout pregnancy on PTB risk (RERI 0.17, 95% CI 0.00, 0.36), and a negative interaction was observed for pre-pregnancy BMI ≥30 kg/m2 (ratio of relative risk 0.70, 95% CI 0.63, 0.78; RERI -0.42, 95% CI -0.56, -0.30). CONCLUSION: Compared to non-smokers, smoking throughout pregnancy and third-trimester smoking cessation are associated with an increased risk of PTB, while quitting before the third trimester may not increase PTB risk.

Correlates of Spirituality among African American and Black Caribbean Emerging Adults.

Spirituality is a significant cultural strength and resource for Black emerging adults. Numerous studies show that increasing numbers of emerging adults tend to identify themselves as being spiritual but not religious. However, no studies to date have identified the demographic correlates of spirituality for Black emerging adults from different ethnic groups (i.e., African American vs. Black Caribbean). Data from the National Survey of American Life was used to identify the demographic correlates of 2 indicators of spirituality (e.g., self-rated spirituality and subjective spirituality) for 802 African American and 428 Black Caribbean emerging adults using linear regression. For African Americans, being a woman predicted both greater self-rated spirituality and subjective spirituality. However, among Black Caribbeans men rated spirituality higher in importance than women. African Americans who reported higher educational attainment tended to report higher levels of self-rated spirituality and subjective spirituality. Romantic status for Black Caribbeans, whether they had no romantic involvement or a current romantic partner, was associated with lower self-ratings of spirituality. Unmarried cohabitating individuals in both ethnic groups tended to report lower levels of self-related spirituality. Unemployment for Black Caribbeans was associated with lower subjective spirituality. Findings are of interest to those who serve and work with Black emerging adults.

Fosgonimeton attenuates amyloid-beta toxicity in preclinical models of Alzheimer's disease.

Positive modulation of hepatocyte growth factor (HGF) signaling may represent a promising therapeutic strategy for Alzheimer's disease (AD) based on its multimodal neurotrophic, neuroprotective, and anti-inflammatory effects addressing the complex pathophysiology of neurodegeneration. Fosgonimeton is a small-molecule positive modulator of the HGF system that has demonstrated neurotrophic and pro-cognitive effects in preclinical models of dementia. Herein, we evaluate the neuroprotective potential of fosgonimeton, or its active metabolite, fosgo-AM, in amyloid-beta (Aß)-driven preclinical models of AD, providing mechanistic insight into its mode of action. In primary rat cortical neurons challenged with Aß (Aß1-42), fosgo-AM treatment significantly improved neuronal survival, protected neurite networks, and reduced tau hyperphosphorylation. Interrogation of intracellular events indicated that cortical neurons treated with fosgo-AM exhibited a significant decrease in mitochondrial oxidative stress and cytochrome c release. Following Aß injury, fosgo-AM significantly enhanced activation of pro-survival effectors ERK and AKT, and reduced activity of GSK3ß, one of the main kinases involved in tau hyperphosphorylation. Fosgo-AM also mitigated Aß-induced deficits in Unc-like kinase 1 (ULK1) and Beclin-1, suggesting a potential effect on autophagy. Treatment with fosgo-AM protected cortical neurons from glutamate excitotoxicity, and such effects were abolished in the presence of an AKT or MEK/ERK inhibitor. In vivo, fosgonimeton administration led to functional improvement in an intracerebroventricular Aß25-35 rat model of AD, as it significantly rescued cognitive function in the passive avoidance test. Together, our data demonstrate the ability of fosgonimeton to counteract mechanisms of Aß-induced toxicity. Fosgonimeton is currently in clinical trials for mild-to-moderate AD (NCT04488419; NCT04886063).