Measuring microsatellite conservation in mammalian evolution with a phylogenetic birth-death model.

Microsatellites make up ∼3% of the human genome, and there is increasing evidence that some microsatellites can have important functions and can be conserved by selection. To investigate this conservation, we performed a genome-wide analysis of human microsatellites and measured their conservation using a binary character birth--death model on a mammalian phylogeny. Using a maximum likelihood method to estimate birth and death rates for different types of microsatellites, we show that the rates at which microsatellites are gained and lost in mammals depend on their sequence composition, length, and position in the genome. Additionally, we use a mixture model to account for unequal death rates among microsatellites across the human genome. We use this model to assign a probability-based conservation score to each microsatellite. We found that microsatellites near the transcription start sites of genes are often highly conserved, and that distance from a microsatellite to the nearest transcription start site is a good predictor of the microsatellite conservation score. An analysis of gene ontology terms for genes that contain microsatellites near their transcription start site reveals that regulatory genes involved in growth and development are highly enriched with conserved microsatellites

The development of a HAMstring InjuRy (HAMIR) index to mitigate injury risk through innovative imaging, biomechanics, and data analytics : Protocol for an observational cohort study

Background The etiology of hamstring strain injury (HSI) in American football is multi-factorial and understanding these risk factors is paramount to developing predictive models and guiding prevention and rehabilitation strategies. Many player-games are lost due to the lack of a clear understanding of risk factors and the absence of effective methods to minimize re-injury. This paper describes the protocol that will be followed to develop the HAMstring InjuRy (HAMIR) index risk prediction models for HSI and re-injury based on morphological, architectural, biomechanical and clinical factors in National Collegiate Athletic Association Division I collegiate football players. Methods A 3-year, prospective study will be conducted involving collegiate football student-athletes at four institutions. Enrolled participants will complete preseason assessments of eccentric hamstring strength, on-field sprinting biomechanics and muscle–tendon volumes using magnetic-resonance imaging (MRI). Athletic trainers will monitor injuries and exposure for the duration of the study. Participants who sustain an HSI will undergo a clinical assessment at the time of injury along with MRI examinations. Following completion of structured rehabilitation and return to unrestricted sport participation, clinical assessments, MRI examinations and sprinting biomechanics will be repeated. Injury recurrence will be monitored through a 6-month follow-up period. HAMIR index prediction models for index HSI injury and re-injury will be constructed. Discussion The most appropriate strategies for reducing risk of HSI are likely multi-factorial and depend on risk factors unique to each athlete. This study will be the largest-of-its-kind (1200 player-years) to gather detailed information on index and recurrent HSI, and will be the first study to simultaneously investigate the effect of morphological, biomechanical and clinical variables on risk of HSI in collegiate football athletes. The quantitative HAMIR index will be formulated to identify an athlete’s propensity for HSI, and more importantly, identify targets for injury mitigation, thereby reducing the global burden of HSI in high-level American football players. Trial Registration The trial is prospectively registered on ClinicalTrials.gov (NCT05343052; April 22, 2022)

Measuring Microsatellite Conservation in Mammalian Evolution with a Phylogenetic Birth–Death Model

Microsatellites make up ∼3% of the human genome, and there is increasing evidence that some microsatellites can have important functions and can be conserved by selection. To investigate this conservation, we performed a genome-wide analysis of human microsatellites and measured their conservation using a binary character birth--death model on a mammalian phylogeny. Using a maximum likelihood method to estimate birth and death rates for different types of microsatellites, we show that the rates at which microsatellites are gained and lost in mammals depend on their sequence composition, length, and position in the genome. Additionally, we use a mixture model to account for unequal death rates among microsatellites across the human genome. We use this model to assign a probability-based conservation score to each microsatellite. We found that microsatellites near the transcription start sites of genes are often highly conserved, and that distance from a microsatellite to the nearest transcription start site is a good predictor of the microsatellite conservation score. An analysis of gene ontology terms for genes that contain microsatellites near their transcription start site reveals that regulatory genes involved in growth and development are highly enriched with conserved microsatellites

Memory T-cell trafficking: new directions for busy commuters

The immune system is unique in representing a network of interacting cells of enormous complexity and yet being based on single cells travelling around the body. The development of effective and regulated immunity relies upon co-ordinated migration of each cellular component, which is regulated by diverse signals provided by the tissue. Co-ordinated migration is particularly relevant to the recirculation of primed T cells, which, while performing continuous immune surveillance, need to promptly localize to antigenic sites, reside for a time sufficient to carry out their effector function and then efficiently leave the tissue to avoid bystander damage. Recent advances that have helped to clarify a number of key molecular mechanisms underlying the complexity and efficiency of memory T-cell trafficking, including antigen-dependent T-cell trafficking, the regulation of T-cell motility by costimulatory molecules, T-cell migration out of target tissue and fugetaxis, are reviewed in this article

Post-translational modification-regulated leukocyte adhesion and migration

Leukocytes undergo frequent phenotypic changes and rapidly infiltrate peripheral and lymphoid tissues in order to carry out immune responses. The recruitment of circulating leukocytes into inflamed tissues depends on integrin-mediated tethering and rolling of these cells on the vascular endothelium, followed by transmigration into the tissues. This dynamic process of migration requires the coordination of large numbers of cytosolic and transmembrane proteins whose functional activities are typically regulated by post-translational modifications (PTMs). Our recent studies have shown that the lysine methyltransferase, Ezh2, critically regulates integrin signalling and governs the adhesion dynamics of leukocytes via direct methylation of talin, a key molecule that controls these processes by linking integrins to the actin cytoskeleton. In this review, we will discuss the various modes of leukocyte migration and examine how PTMs of cytoskeletal/adhesion associated proteins play fundamental roles in the dynamic regulation of leukocyte migration. Furthermore, we will discuss molecular details of the adhesion dynamics controlled by Ezh2-mediated talin methylation and the potential implications of this novel regulatory mechanism for leukocyte migration, immune responses, and pathogenic processes, such as allergic contact dermatitis and tumorigenesis.ASTAR (Agency for Sci., Tech. and Research, S’pore)NMRC (Natl Medical Research Council, S’pore)Published versio