Citations

Abstract Introduction Screening individuals with latent tuberculosis infection (LTBI) from regions with varying TB endemicity is critical for global TB control. Immune responses to TB differ due to variations in exposure, immune adaptations, and environmental factors. This study evaluated antigen-specific immune responses in untreated LTBI individuals from low- and high-TB-endemic settings. Methods Peripheral blood mononuclear cells from untreated LTBI individuals from low-endemic (USA) and high-TB-endemic settings (Mexico) were stimulated with PPD, MTB300, ESAT-6/CFP-10 (RD1) peptides, mycobacterial glycopeptidolipids (GPL), and controls. We compare flow cytometric immune responses of T-cell intracellular cytokines and activation markers using non-parametric statistical methods. Results We studied age-matched, untreated LTBI individuals who tested IGRA(+)/TST(+) from low-TB-endemic (n = 18) and 18 healthcare workers from a high-TB-endemic settings. IGRA results showed no statistical differences across groups. The frequency of CD3+CD8+IFN-γ+HLA-DR+ and total CD3+TNF-α+ T cells after RD1 stimulation was significantly higher in the high-TB-endemic group (P < 0.05). Additionally, we observed significant increased frequencies in CD3/CD4+TNF-α+HLA-DR+ and CD8+TNF-α+HLA-DR+ T cells stimulated by GPL in the same group, probably associated with nontuberculous mycobacteria (NTM) exposures. Our findings suggest possible recent TB and NTM exposures in healthcare workers from a high-TB-endemic setting, resulted in increased antigen-specific adaptive TNF-α and IFN-γ producing T cells, which are important for pathogen control and immunity. Conclusion We found significant differences in antigen-specific cell immunity, including HLA-DR activated T-cells, a marker of recent antigen encounter, in individuals from a high-TB-endemic settings. These findings underscore the importance of settings-specific immune biomarkers for improving LTBI diagnostics, clinical management, and vaccination trials. Funding Source National Institute of Allergy and Infectious Diseases at the National Institutes of Health Topic Categories Immune Mechanisms of Human Disease (HUM)

Abstract Frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick’s disease, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.

Abstract Frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick’s disease, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.

Abstract GNE myopathy (GNEM) is a neuromuscular disorder caused by biallelic mutations in the gene GNE , which encodes a bifunctional enzyme essential for the biosynthesis of sialic acid. Despite extensive characterization, no effective therapies or validated biomarkers exist, and the molecular mechanisms driving disease pathology remain poorly understood. This study identifies the proteoglycan serglycin as a preliminary candidate biomarker in GNEM and investigates the mechanisms underlying its dysregulation. Proteomic analysis of serum samples from GNEM patients revealed reduced circulating serglycin levels. In contrast, increased intracellular serglycin was observed in GNE knockout and GNEM patient iPSC-derived myoblasts, suggesting impaired secretion and/or degradation. To investigate the basis of this accumulation, intracellular trafficking and autophagic pathways were examined. Proteomic profiling from HEK GNE knockout cells revealed alterations in pathways involved in membrane trafficking, Golgi function, and glycoprotein processing, consistent with broader disruptions in the secretory system that may impair serglycin export and contribute to its intracellular retention. In GNEM iPSC-derived myoblasts, serglycin overlapped with LAMP1-positive lysosomal compartments and the ER-phagy receptor FAM134B, suggesting association with lysosomal and ER-phagy related pathways. Functional assays further indicated impaired autophagic flux in mutant cells. Together, these findings support a model in which combined defects in secretion and autophagic clearance contribute to intracellular serglycin accumulation and reduced circulating levels. This study identifies serglycin as a potential circulating biomarker for GNEM and highlights dysregulation of secretory and degradative pathways as converging features of disease pathology.

Abstract Objective . Penile vibro-elastography (PVE) is complicated by reverberant shear wavefields from the cylindrical geometry of the corpus cavernosum (CC), which bias shear wave speed (SWS) estimates. This study evaluated local phase velocity imaging with wavefield-based filtering (LPVI-WBF) for CC stiffness assessment in post-prostatectomy erectile dysfunction (ED), compared against phase gradient (PG) and time-of-flight (TOF) methods. Approach . Six patients with post-prostatectomy ED underwent PVE at four longitudinal visits (902 acquisitions). SWS was estimated in flaccid and erect states at 100, 150, and 200 Hz using LPVI-WBF, PG, and TOF. Wavefield composition was quantified via the standing wave index. Simulations evaluated accuracy and frequency stability under clean and reverberant conditions. Main results . Reverberant components dominated penile acquisitions, with traveling wave energy absent in 59% of acquisitions and mean standing wave fraction of 57 ± 17%. LPVI-WBF was the only method producing physiologically consistent estimates, with erect SWS exceeding flaccid (3.59 ± 0.48 vs 3.25 ± 0.58 m s −1 , p < 0.0001). PG and TOF yielded reversed results ( E < F, p < 0.0001). The dispersion exponent was near-zero for LPVI-WBF ( α = 0.048, p = 0.21), consistent with weakly viscoelastic tissue, while PG ( α = 0.184) and TOF ( α = 0.321) showed significant frequency dependence from reverberant contamination. Simulations confirm PG accuracy in clean wavefields but collapse under reverberant ones. Significance . LPVI-WBF produced SWS estimates consistent with expected CC biomechanics across all patients and frequencies, a criterion PG and TOF failed to satisfy. Phantom validation and multi-directional wavefield simulation are needed to establish accuracy.

ABSTRACT Background and Objectives Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm 3 , SE=317.0, p= 0.0046, f 2 =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm 3 , SE=29.9, p= 0.035, f 2 =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.