Search

GDF15 (growth differentiation factor 15) is a marker of cellular and mitochondrial energetic stress linked to physical-mental illness, aging, and mortality. Here, we describe the psychobiological regulation of plasma and saliva GDF15 in four human studies including 3,599 samples from 148 healthy individuals. We report two main observations establishing GDF15 as a novel tractable biomarker of psychosocial stress. 1) In two experimental laboratory studies, socio-evaluative stress rapidly elevates GDF15 and lactate, two molecular markers of energetic/reductive stress. 2) Similar to other stress-related metabolic hormones, we also find that saliva GDF15 exhibit a robust awakening response, being highest at the time of waking up and declining by ~42-92% within 30-45 minutes. These data position GDF15 as a dynamic biomarker of psychosocial stress accessible in human blood and saliva, pointing towards a shared psychobiological pathway linking mental and mitochondrial energetic stress. These foundational observations open the door to large-scale studies using GDF15 to non-invasively probe how acute psychosocial factors promote cellular and mitochondrial and energetic stress contributing to the stress-disease cascade across the lifespan., Competing Interests: Financial competing interests The authors have no competing interests to declare.

Health emerges from coordinated psychobiological processes powered by mitochondrial energy transformation. But how do mitochondria regulate the multisystem responses that shape resilience and disease risk across the lifespan? The Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study was established to address this question and determine how mitochondria influence the interconnected neuroendocrine, immune, metabolic, cardiovascular, cognitive, and emotional systems among individuals spanning the spectrum of mitochondrial energy transformation capacity, including participants with rare mitochondrial DNA (mtDNA) lesions causing mitochondrial diseases (MitoDs). This interdisciplinary effort is expected to generate new insights into the pathophysiology of MitoDs, provide a foundation to develop novel biomarkers of human health, and integrate our fragmented knowledge of bioenergetic, brain-body, and mind-mitochondria processes relevant to medicine and public health., Competing Interests: Declaration of interests The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Metastable compounds have greatly expanded the synthesizable compositions of solid-state materials and have attracted enormous amounts of attention in recent years. Especially, mechanochemically enabled metastable materials synthesis has been very successful in realizing cation-disordered materials with highly simple crystal structures, such as rock salts. Application of the same strategy for other structural types, especially for non-close-packed structures, is peculiarly underexplored. Niobium tungsten oxides (NbWOs), a class of materials that have been under the spotlight because of their diverse structural varieties and promising electrochemical and thermoelectric properties, are ideally suited to fill such a knowledge gap. In this work, we develop a new series of metastable NbWOs and realize one with a fully cation-disordered structure. Furthermore, we find that metastable NbWOs transform to a cation-disordered cubic structure when applied as a Li-ion battery anode, highlighting an intriguing non-close-packed-close-packed conversion process, as evidenced in various physicochemical characterizations, in terms of diffraction, electronic, and vibrational structures. Finally, by comparing the cation-disordered NbWO with other trending cation-disordered oxides, we raise a few key structural features for cation disorder and suggest a few possible research opportunities for this field.

Background: Adult Polyglucosan Body Disease (APBD) is an ultra-rare, genetic neurodegenerative disorder caused by autosomal recessive mutations in the glycogen branching enzyme gene. Knowledge of the demographic and clinical characteristics of APBD patients and the natural history of the disease is lacking. We report here initial results from a patient-reported registry of APBD patients., Objectives: (1) Maximize the quality of the APBD Registry survey data; (2) provide an initial report on APBD disease progression and natural history using these data; and (3) specify next steps in the process for testing potential new therapies., Design: Data are from members of the APBD Research Foundation (New York), surveyed from 2014 by the Columbia APBD Patient/Family (CAP) Registry. Inclusion criteria are: disease onset at age 18+ and progressive clinical triad of peripheral neuropathy, spasticity, and neurogenic bladder., Methods: Genetic testing results were used when available. Respondents found to not have APBD in clinical records were excluded. All changes and exclusions were recorded in a database edit log. Results are reported in frequency tables, bar graphs, time plots, and heat maps., Results: The 96 respondents meeting inclusion criteria were predominantly (96.8%) White, highly educated (89.3% at least some college education), and mostly (85.1%) of Ashkenazi Jewish descent. 57.1% had at least one parent born in the United States, with at least one grandparent from Europe (excluding Russia; 75.4%), the United States (42.1%), or Russia (33.3%). 37.2% reported a family history of APBD, and 33.3% had an affected sibling. Median APBD onset age was 51 [Interquartile range (IQR) 11], and median age of diagnosis 57 (IQR 10.5). The 75 reported prior misdiagnoses were mainly peripheral neuropathy (43, 60.6%) and spinal stenosis (11, 15.1%)., Conclusion: Although from a demographically constricted survey, the results provide basic clinical information for future studies to develop treatments for APBD., Competing Interests: There are no competing interests., (© The Author(s) 2024.)

Objective: The goal of this study is to demonstrate the utility of a growth assay to quantify the functional impact of single nucleotide variants (SNVs) in SLC2A1, the gene responsible for Glut1DS., Methods: The functional impact of 40 SNVs in SLC2A1 was quantitatively determined in HAP1 cells in which SLC2A1 is required for growth. Donor libraries were introduced into the endogenous SLC2A1 gene in HAP1-Lig4KO cells using CRISPR/Cas9. Cell populations were harvested and sequenced to quantify the effect of variants on growth and generate a functional score. Quantitative functional scores were compared to 3-OMG uptake, SLC2A1 cell surface expression, CADD score, and clinical data, including CSF/blood glucose ratio., Results: Nonsense variants (N = 3) were reduced in cell culture over time resulting in negative scores (mean score: -1.15 ± 0.17), whereas synonymous variants (N = 10) were not depleted (mean score: 0.25 ± 0.12) (P < 2e-16). Missense variants (N = 27) yielded a range of functional scores including slightly negative scores, supporting a partial function and intermediate phenotype. Several variants with normal results on either cell surface expression (p.N34S and p.W65R) or 3-OMG uptake (p.W65R) had negative functional scores. There is a moderate but significant correlation between our functional scores and CADD scores., Interpretation: Cell growth is useful to quantitatively determine the functional effects of SLC2A1 variants. Nonsense variants were reliably distinguished from benign variants in this in vitro functional assay. For facilitating early diagnosis and therapeutic intervention, future work is needed to determine the functional effect of every possible variant in SLC2A1., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Objectives: Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel in July 2018 largely on the basis of the availability and efficacy of newly approved disease-modifying therapies. New York State (NYS) started universal newborn screening for SMA in October 2018. The authors report the findings from the first 3 years of screening., Methods: Statewide neonatal screening was conducted using DNA extracted from dried blood spots using a real-time quantitative PCR assay. Retrospective follow-up data were collected from 9 referral centers across the state on 34 infants., Results: In the first 3 years since statewide implementation, nearly 650,000 infants have been screened for SMA. Thirty-four babies screened positive and were referred to a neuromuscular specialty care center. The incidence remains lower than previously predicted. The majority (94%), including all infants with 2-3 copies of survival motor neuron ( SMN) 2, have received treatment. Among treated infants, the overwhelming majority (94%; 30/32) have received gene replacement. All infants in this cohort with 3 copies of SMN2 are clinically asymptomatic posttreatment based on early clinical follow-up data. Infants with 2 copies of SMN2 are more variable in their outcomes. Electrodiagnostic outcomes data obtained from a subgroup of patients (n = 11) demonstrated either improvement or no change in compound muscle action potential (CMAP) amplitude at last clinical follow-up compared with pretreatment baseline. Most infants were treated before 6 weeks of age (median = 34.5 days of life; range 11-180 days). Delays and barriers to treatment identified by treating clinicians followed 2 broad themes: medical and nonmedical. Medical delays most commonly reported were the presence of AAV9 antibodies and elevated troponin I levels. Nonmedical barriers included delays in obtaining insurance and insurance policies regarding specific treatment modalities., Discussion: The findings from the NYS cohort of newborn screen-identified infants are consistent with other reports of improved outcomes from early diagnosis and treatment. Additional biomarkers of motor neuron health including EMG can potentially be helpful in detecting preclinical decline., (© 2022 American Academy of Neurology.)

Objective: To examine the correlation between verbal and visual memory function and correlation with brain metabolites (lactate and N-Acetylaspartate, NAA) in individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)., Methods: Memory performance and brain metabolites (ventricular lactate, occipital lactate, and occipital NAA) were examined in 18 MELAS, 58 m.3243A > G carriers, and 20 familial controls. Measures included the Selective Reminding Test (verbal memory), Benton Visuospatial Retention Test (visual memory), and MR Spectroscopy (NAA, Lactate). ANOVA, chi-squared/Fisher's exact tests, paired t-tests, Pearson correlations, and Spearman correlations were used., Results: When compared to carriers and controls, MELAS patients had the: (1) most impaired memory functions (Visual: p = 0.0003; Verbal: p = 0.02), (2) greatest visual than verbal memory impairment, (3) highest brain lactate levels (p < 0.0001), and (4) lowest brain NAA levels (p = 0.0003). Occipital and ventricular lactate to NAA ratios correlated significantly with visual memory performance (p ≤ 0.001). Higher lactate levels (p ≤ 0.01) and lower NAA levels (p = 0.0009) correlated specifically with greater visual memory dysfunction in MELAS. There was little or no correlation with verbal memory., Interpretation: Individuals with MELAS are at increased risk for impaired memory. Although verbal and visual memory are both affected, visual memory is preferentially affected and more clearly associated with brain metabolite levels. Preferential involvement of posterior brain regions is a distinctive clinical signature of MELAS. We now report a distinctive cognitive phenotype that targets visual memory more prominently and earlier than verbal memory. We speculate that this finding in carriers presages a conversion to the MELAS phenotype., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)