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In the version of this article initially published, NIAMS grant R01AR061445 was not included in the Acknowledgements. The error has been corrected in the HTML and PDF versions of the article.

The gut microbiome has important effects on human health, yet its importance in human ageing remains unclear. In the present study, we demonstrate that, starting in mid-to-late adulthood, gut microbiomes become increasingly unique to individuals with age. We leverage three independent cohorts comprising over 9,000 individuals and find that compositional uniqueness is strongly associated with microbially produced amino acid derivatives circulating in the bloodstream. In older age (over ~80 years), healthy individuals show continued microbial drift towards a unique compositional state, whereas this drift is absent in less healthy individuals. The identified microbiome pattern of healthy ageing is characterized by a depletion of core genera found across most humans, primarily Bacteroides. Retaining a high Bacteroides dominance into older age, or having a low gut microbiome uniqueness measure, predicts decreased survival in a 4-year follow-up. Our analysis identifies increasing compositional uniqueness of the gut microbiome as a component of healthy ageing, which is characterized by distinct microbial metabolic outputs in the blood.

The global distribution of primary production and consumption by humans (fisheries) is well-documented, but we have no map linking the central ecological process of consumption within food webs to temperature and other ecological drivers. Using standardized assays that span 105° of latitude on four continents, we show that rates of bait consumption by generalist predators in shallow marine ecosystems are tightly linked to both temperature and the composition of consumer assemblages. Unexpectedly, rates of consumption peaked at midlatitudes (25 to 35°) in both Northern and Southern Hemispheres across both seagrass and unvegetated sediment habitats. This pattern contrasts with terrestrial systems, where biotic interactions reportedly weaken away from the equator, but it parallels an emerging pattern of a subtropical peak in marine biodiversity. The higher consumption at midlatitudes was closely related to the type of consumers present, which explained rates of consumption better than consumer density, biomass, species diversity, or habitat. Indeed, the apparent effect of temperature on consumption was mostly driven by temperature-associated turnover in consumer community composition. Our findings reinforce the key influence of climate warming on altered species composition and highlight its implications for the functioning of Earth's ecosystems.

The identification of microglia subtypes is important for understanding the role of innate immunity in neurodegenerative diseases. Current methods of unsupervised cell type identification assume a small noise-to-signal ratio of transcriptome measurements to produce well-separated cell clusters. However, identification of subtypes can be obscured by gene expression noise, which diminishes the distances in transcriptome space between distinct cell types, blurs boundaries, and reduces reproducibility. Here we use Fokker-Planck (FP) diffusion maps to model cellular differentiation as a stochastic process whereby cells settle into local minima that correspond to cell subtypes, in a potential landscape constructed from transcriptome data using a nearest neighbor graph approach. By applying critical transition fields, we identify individual cells on the verge of transitioning between subtypes, revealing microglial cells in an inactivated, homeostatic state before radially transitioning into various specialized subtypes. Specifically, we show that cells from Alzheimer's disease patients are enriched in a microglia subtype associated to antigen presentation and T-cell recruitment, and are depleted in an anti-inflammatory subtype. Combining a novel, biophysically plausible clustering scheme with statistics and interpretable machine learning yields insights into microglia dysfunction in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer death globally, with newly diagnosed oropharyngeal squamous cell carcinoma (OPSCC) cases rising to 54,000 in the US alone in the year 2022. Recently, human papilloma virus (HPV) infection was more prevalent in OPSCC patients than the traditionally known carcinogens such as tobacco or alcohol. HPV 16 is the most common causative HPV strain, which is found in 5–10% of HNSCC patients. HPV 16's E6 and E7 oncoproteins bind and inactivate p53 and retinoblastoma (Rb) tumor-suppressing genes. This causes aberrant over-expression of the cell cycle inhibitor gene, p16, leading to tumorigenesis. Leica Biosystems (LBS) has developed a p16 antibody (6H12 clone) for qualitatively identifying the p16 protein in formalin-fixed paraffin-embedded (FFPE) tissue by immunohistochemical staining. This method comparison study tested the concordance rates between ready-to-use (RTU) LBS p16/LBS RTU p16 antibody and Roche Tissue Diagnostics (RTD) CINtec p16 Histology immunohistochemical (IHC) assays by measuring overall agreement (OA), average positive agreement (APA), and average negative agreement (ANA) rates in 170 OPSCC FFPE cases. Interobserver agreement of the 2 assays and LBS RTU p16 comparison with the standard HPV molecular assays (DNA ISH and PCR) were also assessed. Methods: One hundred and seventy (170) unique oropharyngeal cancer cases were stained for qualitative analysis by the LBS p16 antibody on BOND III. This assay was compared to Ventana's RTD E6H4 (CINtec) clone on Benchmark XT. A stained core was considered p16 positive if the Histoscore (H score) was ≥ 140 and negative if H < 140. Results: Across the pathologists, the agreement rate between the 2 assays ranged from OA, 98.7 – 98.8%, ANA, 98.8 -98.9%, and APA, 98.6%. For LBS RTU p16, the interobserver agreement was OA, 98.7%, ANA, 98.8%, and APA, 98.6%; while for RTD CINtec p16 assay, the concordance was OA, 98.7%, ANA, 98.8% and APA, 98.6%. In comparison to the HPV molecular testing, DNA ISH, and PCR, across pathologists, LBS p16 clone (LBS RTU p16) showed a concordance rate of 85.8-86.9% and 87.6-88.8%, respectively. Conclusion: LBS p16 monoclonal antibody demonstrated high concordance with CINtec p16 IHC assay across all the endpoints, suggesting a potential use of LBS RTU p16 clone in detecting p16 protein in oropharyngeal cancer cases. [ABSTRACT FROM AUTHOR]

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10-8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10-9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10-6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.

Background: The immerging role of CD8+T cells, interferon and the adaptive immune response in AD is consistent with previous observations of the putative role of neurotrophic herpesvirus family infections contributing to Alzheimer's Disease pathophysiology. An outstanding question is how chronic viral infections over decades may contribute to AD pathogenesis. Our HSV‐1 reactivation model aims to provide insights to this question. Method: We infected 2 month old C57B6/J mice containing humanized APP and APOE4 with 106 PFU HSV‐1 strain 17 via corneal scarification. We reactivated the virus with the bromo‐domain compound JQ1 at 4, 7 and 10 months, with 1x, 3x and 6x reactivations respectively and harvested the brainstem, hippocampus, entorhinal cortex and dural sinuses, for RNAseq. To identify common changes in gene expression between our HSV‐1 reactivation model and AD, we compared the gene expression profiles of our mice to both human and mouse model gene profiles using 19 AD‐specific categories (BioDomains). Result: We found reactivation by JQ1 resulted in increased HSV‐1 detection by qPCR in a progressive manner, emanating outward from the trigeminal ganglion, towards more distal brain regions. We observed changes in RNAseq expression profiles in a time‐dependent manner, with the greatest number of differentially expressed genes at 7 months. We observed changes in synaptic and immune genes in both the entorhinal cortex and hippocampus. We also saw decreases in gene expression in lipid metabolism, myelination, and the endolysosomal pathways. Conclusion: Our HSV‐1 reactivation mouse model identifies changes in gene expression that are similar to those observed in humans and mouse AD models, with observed, distinct changes in synaptic‐ and immune‐associated genes in multiple brain regions. Activation of immune genes was highest in the brain stem, where detection of HSV‐1 was highest. The greatest changes in gene expression occurred at 7 months, with fewer changes following at 10 months. These changes are most similar to changes in early disease and support the role of HSV‐1 contributing to AD pathophysiology. [ABSTRACT FROM AUTHOR]