Biology subjects

Hammond, T.

Publications and source records attributed to Hammond, T..

5 recordsLinked to original sources

bioRxiv2025

Integration of Multiomic and Multi-phenotypic Data Identifies Biological Pathways Associated with Physical Fitness

Unraveling the complex associations between human phenotypes and molecular pathways can pave the way to improved health and performance, but faces a fundamental challenge: the measurable genes, proteins, and metabolites vastly outnumber the participants in even the largest studies, yielding spurious correlations. To address this imbalance, we have developed a bioinformatic framework and computational approach ("PhenoMol") to discover biological drivers of phenotypic characteristics that integrates all available phenotypic data predictive of outcomes and reduces multi-omic data dimensionality by generating "expression circuits" via graph theory constrained by prior biological knowledge of molecular interactions. We applied PhenoMol to analyze causal patterns and predict elite physical performance in a healthy cohort with deep physiological, physical, behavioral, cognitive, and molecular characterization. PhenoMol outperforms regression models based on equivalent analytic methodologies that do not employ network biology for dimensionality reduction. The PhenoMol software is provided for future studies.

bioinformatics↗

bioRxiv2024

THE FAM53C/DYRK1A axis regulates the G1/S transition of the cell cycle

A growing number of therapies are being developed to target the cell cycle machinery for the treatment of cancer and other human diseases. Consequently, a greater understanding of the factors regulating cell cycle progression becomes essential to help enhance the response to these new therapies. Here, using data from the Cancer Dependency Map, we identified FAM53C as a new regulator of cell cycle progression. We found that FAM53C is critical for this cell cycle transition and that it acts upstream of the CyclinD-CDK4/6-RB axis and of p53 in the regulation of the G1/S transition. By mass spectrometry, biochemical, and cellular assays, we identified and validated DYRK1A as a cell cycle kinase that is inhibited by and directly interacts with FAM53C. Consistent with the role for FAM53C identified in cells in culture, FAM53C knockout human cortical organoids display increased cell cycle arrest and growth defects. Fam53C knockout mice show minor behavioral phenotypes. Because DYRK1A dysregulation contributes to developmental disorders such as Down syndrome as well as tumorigenesis, future strategies aiming at regulating FAM53C activity may benefit a broad range of patients.

cell biology↗

bioRxiv2021

Disrupted microglial iron homeostasis in progressive multiple sclerosis

Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS). Despite therapies that reduce relapses, many patients eventually develop secondary progressive MS (SPMS), characterized by ongoing and irreversible neurodegeneration and worsening clinical symptoms. Microglia are the resident innate immune cells of the CNS. While the cellular and molecular determinants of disability progression in MS remain incompletely understood, they are thought to include non-resolving microglial activation and chronic oxidative injury. In this study, our aim was to better characterize microglia in SPMS tissues to identify disease-related changes at the single cell level. We performed single nucleus RNA-seq (snRNA-seq) on cryopreserved post-mortem brain cortex and identified disease associated changes in multiple cell types and in particular distinct SPMS-enriched microglia subsets. When compared to the cluster most enriched in healthy controls (i.e. homeostatic microglia), we found a number of SPMS-enriched clusters with transcriptional profiles reflecting increased oxidative stress and perturbed iron homeostasis. Using histology and RNA-scope, we confirmed the presence of iron accumulating, ferritin-light chain (FTL)-expressing microglia in situ. Among disease-enriched clusters, we found evidence for divergent responses to iron accumulation and identified the antioxidant enzyme GPX4 as a key fate determinant. These data help elucidate processes that occur in progressive MS brains, and highlight novel nodes for therapeutic intervention.

neuroscience↗

bioRxiv2019

Recombination-independent recognition of DNA homology for meiotic silencing in Neurospora crassa

Pairing of homologous chromosomes represents a critical step of meiosis in nearly all sexually reproducing species. While in some organisms meiotic pairing requires programmed DNA breakage and recombination, in many others it engages homologous chromosomes that remain apparently intact. The mechanistic nature of such recombination-independent pairing represents a fundamental question in molecular genetics. Using meiotic silencing by unpaired DNA (MSUD) in Neurospora crassa as a model process, we demonstrate the existence of a cardinally different approach to DNA homology recognition in meiosis. The main advantage of MSUD over other experimental systems lies in its ability to identify any relatively short DNA fragment lacking a homologous allelic partner. Here we show that MSUD does not rely on the canonical mechanism of meiotic recombination, yet it is promoted by REC8, a conserved component of the meiotic cohesin complex. We also show that certain patterns of interspersed homology are recognized as pairable during MSUD. Such patterns need to be co-linear and must contain short tracts of sequence identity spaced apart with a periodicity of 21 or 22 base-pairs. By using these values as a guiding parameter in all-atom molecular modeling, we discover that homologous double-stranded DNA molecules can associate by forming quadruplex-based contacts with an interval of 2.5 helical turns, which requires right-handed plectonemic coiling and additional conformational changes in the intervening double-helical segments. These results (i) reconcile genetic and biophysical lines of evidence for the existence of direct homologous dsDNA-dsDNA pairing, (ii) identify a role for this process in initiating post-transcriptional silencing, and (iii) suggest that chromosomes are cross-matched in meiosis by a precise mechanism that operates on intact double-stranded DNA molecules.

molecular biology↗

bioRxiv2017

Sexual dimorphism of complement-dependent microglial synaptic pruning in the developing brain

Sexual dimorphism has been reported in the prevalence, onset and progression of neurodevelopmental and neurodegenerative disorders. We hypothesize that immunological signaling in the developing brain, notably the complement cascade underlying microglial synaptic pruning, could be one mechanism for this dimorphism. Here we show that genes differentially expressed between male and female normal cortical development are enriched for pathways associated with the activation of the innate immune system, complement cascade and phagocytic processes. Specifically, the male brain is enriched for the expression of genes associated with phagocytic function of microglia through complement-dependent synaptic pruning especially at the developmental stages before birth. Our results suggest the existence of a common regulatory module involved in both prenatal immune activation in males and postnatal immune activation in females. The activation of immune pruning pathways at different stages of normal male and female development could provide valuable insights about critical periods of plasticity and refinement in the human cortex that could explain the different vulnerabilities of males and females to neurological disorders.

neuroscience↗