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Serum Metabolome Profiling in Patients With Mild Cognitive Impairment Reveals Sex Differences in Lipid Metabolism
Get PDFAlzheimer\u27s disease (AD) affects more women than men. Although women live longer than men, it is not longevity alone, but other factors, including metabolic changes, that contribute to the higher risk of AD in women. Metabolic pathways have been implicated in AD progression, but studies to date examined targeted pathways, leaving many metabolites unmeasured. Sex is often a neglected biological variable, and most metabolomic studies were not designed to investigate sex differences in metabolomic profiles. Here, we performed untargeted metabolomic profiling of sera from male and female patients with mild cognitive impairment (MCI), a common precursor to AD, and matched controls. We discovered significant metabolic changes in individuals with MCI, and found several pathways that were strongly associated with sex. Peptide energy metabolism demonstrated sexual dimorphism. Lipid pathways exhibited the strongest differences between female and male MCI patients, including specific phosphatidylcholine lipids, lysophospholipids, long-chain fatty acids, and monoacylglycerols. 1-palmitoleoyl glycerol and 1-arachidonoyl glycerol were higher in female MCI subjects than in male MCI subjects with no differences between control males and females. Conversely, specific dicarboxylic fatty acids were lower in female MCI subjects than male MCI subjects. In cultured astrocytes, 1-arachidonoyl glycerol promoted phosphorylation of the transcriptional regulator sphingosine kinase 2, which was inhibited by the transient receptor potential vanilloid 1 receptor antagonists, as well as chromatin remodelling. Overall, we identified novel sex-specific metabolites in MCI patients that could serve as biomarkers of MCI in both sexes, help further define AD etiology, and reveal new potential prevention strategies for AD
Preliminary Investigation of the Association Between Epigenetic Aging Acceleration and Amyloid Biomarkers in Bipolar Disorder
Get PDFObjectives: Bipolar disorder (BD) has been associated with an elevated risk of Alzheimer\u27s Disease (AD). We assessed AD biomarkers in BD and tested whether epigenetic aging (EA) acceleration is associated with changes in these markers.
Design, setting, participants: Cross-sectional study of n = 58 living individuals with BD and n = 20 age- and sex-matched control participants, as well as analyses of postmortem brain samples (Brodmann area 9/46) from n = 46 individuals with BD.
Measurements: Amyloid beta (Aβ)40, Aβ42, and total Tau levels were measured in plasma from individuals with BD and controls, and Aβ42 levels were measured in brains. EA and its acceleration (blood: GrimAge and DunedinPACE; brains: DNAmClockCortical) were estimated for all samples. Individuals with BD were split into quartiles with slower or accelerated EA if they were in the first or fourth quartiles for GrimAge acceleration (AgeAccelGrim), DunedinPACE, or DNAmClockCortical acceleration (DNAmClockCorticalAccel).
Results: Individuals with BD showed a decrease in the Aβ42/40 ratio (p = 0.048) compared to controls, and a significant decrease in the Aβ42/40 ratio was also found in individuals with BD with high versus low AgeAccelGrim (p = 0.048). Brain Aβ42 levels significantly correlated with DNAmClockCorticalAccel (r2 = 0.270, p = 0.007), with those with high EA acceleration showing higher brain Aβ42 after controlling for confounders (p = 0.008).
Conclusions: Our results provide preliminary evidence that accelerated EA is associated with markers of AD in individuals with BD, suggesting it as a potential target in efforts to prevent dementia and AD in BD
Information Theory Optimization of Signals From Small-Angle Scattering Measurements
No full textSmall-angle X-ray scattering (SAXS) of particles in solution informs on the conformational states and assemblies of biological macromolecules (bioSAXS) outside of cryo- and solid-state conditions. In bioSAXS, the SAXS measurement under dilute conditions is resolution limited, and through an inverse Fourier transform, the measured SAXS intensities directly relate to the physical space occupied by the particles via the P(r)-distribution. Yet, this inverse transform of SAXS data has been historically cast as an ill-posed, ill-conditioned problem requiring an indirect approach. Here, we show that through the applications of matrix and information theories, the inverse transform of SAXS intensity data is a well-conditioned problem. The so-called ill-conditioning of the inverse problem is directly related to the Shannon number. By exploiting the oversampling enabled by modern detectors, a direct inverse Fourier transform of the SAXS data is possible, provided the recovered information does not exceed the Shannon number. The Shannon limit corresponds to the maximum number of significant singular values that can be recovered in a SAXS experiment, suggesting this relationship is a fundamental property of band-limited inverse integral transform problems. This correspondence reduces the complexity of the inverse problem to the Shannon limit and maximum dimension. We propose a hybrid scoring function using an information theory framework that assesses both the quality of the model-data fit as well as the quality of the recovered P(r)-distribution. The hybrid score utilizes the Akaike information criteria and Durbin-Watson statistic that considers parameter-model complexity, i.e., degrees of freedom, and the randomness of the model-data residuals. The described tests and findings extend the boundaries for bioSAXS by completing the information theory formalism initiated by Peter B. Moore to enable a quantitative measure of resolution in SAXS, robustly determine maximum dimension, and more precisely define the best parameter model appropriately representing the observed scattering data
RNA Sculpting by the Primordial Helix-Clasp-Helix-Strand-Loop (HcH-SL) Motif Enforces Chemical Recognition Enabling Diverse KH Domain Functions
No full textIn all domains of life, the ancient K homology (KH) domain superfamily is central to RNA processes including splicing, transcription, posttranscriptional gene regulation, signaling, and translation. Proteins with 1 to 15 KH domains bind single-strand (ss) RNA or DNA with base sequence specificity. Here, we examine over 40 KH domain experimental structures in complex with nucleic acid (NA) and define a novel Helix-clasp-Helix-Strand-Loop (HcH-SL) NA recognition motif binding 4 to 5 nucleotides using 10 to 18 residues. HcH-SL includes and extends the Gly-X-X-Gly (GXXG) signature sequence clasp that brings together two helices as an ∼90° helical corner. The first helix primarily provides side chain interactions to unstack and sculpt 2 to 3 bases on the 5\u27 end for recognition of sequence and chemistry. The clasp and second helix amino dipole recognize a central phosphodiester. Following the helical corner, a beta strand and its loop extension recognize the two 3\u27 nucleotides, primarily through main chain interactions. The HcH-SL structural motif forms a right-handed triangle and concave functional interface for NA interaction that unexpectedly splays four bound nucleotides into conformations matching RNA recognition motif (RRM) bound RNA structures. Evolutionary analyses and its ability to recognize base sequence and chemistry make HcH-SL a primordial NA binding motif distinguished by its binding mode from other NA structural recognition motifs: helix-turn-helix, helix-hairpin-helix, and beta strand RRM motifs. Combined results explain its vulnerability as a viral hijacking target and how mutations and expression defects lead to diverse diseases spanning cancer, cardiovascular, fragile X syndrome, neurodevelopmental disorders, and paraneoplastic disease
Emerging Technologies of Single-Cell Multi-Omics
No full textThe heterogeneity of the hematopoietic system was largely veiled by traditional bulk sequencing methods, which measure the averaged signals from mixed cellular populations. In contrast, single-cell sequencing has enabled the direct measurement of individual signals from each cell, significantly enhancing our ability to unveil such heterogeneity. Building on these advances, numerous single-cell multi-omics techniques have been developed into high-throughput, routinely accessible platforms, delineating the precise relationships among different layers of the central dogma in molecular biology. These technologies have uncovered the intricate landscape of genetic clonality and transcriptional heterogeneity in both normal and malignant hematopoietic systems, highlighting their roles in differentiation, disease progression, and therapy resistance. This review aims to provide a brief overview of the principles of single-cell technologies, their historical development, and a subset of ever-expanding multi-omics tools, emphasizing the specific research questions that inspired their creation. Amidst the evolving landscape of single-cell multi-omics technologies, our main objective is to guide investigators in selecting the most suitable platforms for their research needs
Houston’s Changing Skyline: Herman Hospital 1947-1976
No full textHermann Hospital, as it was originally known, has been a cornerstone of Houston’s medical community for more than a century. Over the years, the institution experienced major expansions, several name changes, and even a few scandals, all while shaping the growth of the Texas Medical Center. The photographs featured in this exhibit, taken between 1947 and 1976, highlight both the hospital’s transformation and the evolving Houston skyline. They also capture milestones such as the launch of Life Flight, which forever changed emergency medical care
The Eleventh Annual Meeting of the Southeastern Association of Shared Resources (SEASR) Nashville, TN, USA June 12-14, 2024
No full textTiming of Cardiac Resynchronization Therapy Following Stable Medical Therapy in Patients With Heart Failure
Get PDFBackground: Guidelines\u27 recommendations for cardiac resynchronization therapy (CRT) implantation in selected patients with heart failure (HF) exist. However, data on the best timing for CRT implantation after the achievement of stable medical therapy (SMT) and its association with outcomes are currently lacking.
Objectives: The aim of this study was to investigate the timing of CRT implantation after the achievement of SMT, associated patient profiles, and clinical outcomes in a real-world HF population.
Methods: Patients with HF treated with SMT derived from the Swedish ICD and Pacemaker Registry who received CRT between 2007 and 2020 were included in the study. Patient characteristics associated with a shorter or longer time to CRT implantation were assessed using multivariable logistic regression, and associations between the time from SMT to CRT implantation and clinical outcomes (mortality and morbidity) were analyzed using multivariable Cox regression.
Results: Of the 9,409 patients, 43.8% received CRT at \u3c 3 months of achieving SMT, 34.9% between 3 and 9 months, and 21.3% after 9 months. The time from SMT to CRT implantation decreased significantly over the study period. Independent determinants of shorter time to implantation included recent HF hospitalization, previous implantation of a defibrillator, and greater use of guideline-directed medical therapy, whereas a history of HF \u3e6 months and ischemic heart disease were associated with a longer time. After adjustments, there was a 9% lower risk of cardiovascular death with a shorter time from SMT to CRT implantation of \u3c 3 months vs 3-9 months (P = 0.045). A delayed time of \u3e9 months vs 3-9 months was associated with a 13% higher risk of cardiovascular death/HF hospitalization, a 12% higher risk of cardiovascular death (P = 0.040), and an 11% higher risk of first HF hospitalization (P = 0.013).
Conclusions: Time from the achievement of SMT to CRT implantation decreased over the study period. Delayed CRT implantation beyond 3 months was associated with higher cardiovascular mortality compared with earlier implantation after GDMT optimization
Translational Genomics of Osteoarthritis in 1,962,069 Individuals
Get PDFOsteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes1. By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide2. As no disease-modifying treatments exist for osteoarthritis, a better understanding of disease aetiopathology is urgently needed. Here we perform a genome-wide association study meta-analyses across up to 489,975 cases and 1,472,094 controls, establishing 962 independent associations, 513 of which have not been previously reported. Using single-cell multiomics data, we identify signal enrichment in embryonic skeletal development pathways. We integrate orthogonal lines of evidence, including transcriptome, proteome and epigenome profiles of primary joint tissues, and implicate 700 effector genes. Within these, we find rare coding-variant burden associations with effect sizes that are consistently higher than common frequency variant associations. We highlight eight biological processes in which we find convergent involvement of multiple effector genes, including the circadian clock, glial-cell-related processes and pathways with an established role in osteoarthritis (TGFβ, FGF, WNT, BMP and retinoic acid signalling, and extracellular matrix organization). We find that 10% of the effector genes express a protein that is the target of approved drugs, offering repurposing opportunities, which can accelerate translation
