Biology subjects

Miller, M. E.

Publications and source records attributed to Miller, M. E..

9 recordsLinked to original sources

bioRxiv2026

Molecular Transducers of Physical Activity Consortium (MoTrPAC): Initial Insights into the Dynamic Human Responses to Exercise

The goal of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) is to examine the physiological and molecular basis for health benefits in response to acute and chronic exercise. Prior to COVID-19 suspension, healthy, sedentary participants (N=206, 18-74y) were randomized to endurance exercise (N=80), resistance exercise (N=81), or non-exercise control (N=45) interventions. The prescribed vigorous acute endurance and resistance exercise bouts induced physiological and metabolic perturbations relative to resting homeostasis. The supervised chronic (3d/wk, 12wk) endurance or resistance training programs robustly improved several physiological parameters (i.e., VO2peak, muscular strength). Temporal biospecimen (blood, muscle, and adipose) collections and processing coupled to the acute exercise bouts were highly successful. In most cases, over 90% success was achieved for blood, muscle, and adipose samples. Endurance and resistance exercise induced distinct acute and chronic physiological responses, which provide a framework to interrogate the molecular basis for health adaptations to these two popular exercise modalities. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/705347v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@554ee9org.highwire.dtl.DTLVardef@afb28dorg.highwire.dtl.DTLVardef@f381cdorg.highwire.dtl.DTLVardef@cef19c_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2026

Multi-Omic, Multi-Tissue Responses to Acute Exercise in Sedentary Adults: Findings from the Molecular Transducers of Physical Activity Consortium

Regular physical activity represents one of the greatest mechanisms for maintaining human health, yet the underlying molecular transducers of these benefits remain incompletely understood. Multi-omic assays now provide new opportunities to study the coordinated molecular responses of body tissues to different exercise modalities. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this need by creating a molecular map of the response to physical activity. Described here is the first human cohort of MoTrPAC: sedentary adults enrolled prior to study suspension during the COVID-19 pandemic (N=175) randomized to either endurance or resistance exercise, or non-exercise control. From these participants, we detail their global acute molecular response in skeletal muscle, adipose tissue, and blood, integrated at multiple levels: tissue, exercise modality, timepoint, and omic category. These analyses characterize key molecular pathways, identify central regulators, and implicate novel candidate exerkines in mediating multi-organ exercise effects.

systems biology↗

bioRxiv2024

Resting-state connectivity modifies the effects of amyloid on cognitive and physical function: evidence for network-based cognitive reserve

Cognitive and physical function are interrelated in aging co-occurring impairments in both domains can be debilitating and lead to increased risk of developing dementia. Amyloid beta (A{beta}) deposition in the brain is linked to cognitive decline and is also associated with poorer physical function in older adults. However, significant inter-individual variability exists with respect to the influence of increased brain A{beta} concentrations on cognitive and physical outcomes. Identifying factors that explain inter-individual variability in associations between A{beta} and clinical outcomes could inform interventions designed to delay declines in both cognitive and physical function. Cognitive reserve (CR) is considered a buffer that allows for cognitive performance that is better than expected for a given level of brain injury or pathology. Although the neural mechanisms underlying CR remain unknown, there is growing evidence that resting-state brain networks may serve as a neural surrogate for CR. The currently study evaluated whether functional brain networks modified associations between brain A{beta} and cognitive and physical function in community-dwelling older adults from the Brain Networks and Mobility (B-NET) study. We found that the integrity of the central executive and basal ganglia networks modified associations of A{beta} with cognitive and physical performance. Associations between brain A{beta} and cognitive and physical function were less pronounced when brain network integrity was high. The current study introduces novel evidence for brain networks underlying CR as a buffer against the influence of A{beta} accumulation on cognitive and physical function. Significance StatementThere is a growing number of medications targeting beta amyloid for the treatment of Alzheimers disease. The treatments effectively lower brain amyloid but do not have as robust of an effect on clinical outcomes. The current study introduces novel evidence for brain networks as a buffer against the influence of A{beta} accumulation on cognitive and physical function in older adults with normal cognition. Future studies should examine if brain network integrity underlies the variability in treatment response to amyloid-lowering drugs in patients with cognitive decline.

neuroscience↗

bioRxiv2023

Genome-enabled analysis of population dynamics and virulence associated loci in the oat crown rust fungus Puccinia coronata f. sp. avenae

Puccinia coronata f. sp. avenae (Pca) is an important fungal pathogen causing crown rust that impacts oat production worldwide. Genetic resistance for crop protection against Pca is often overcome by the rapid virulence evolution of the pathogen. This study investigated the factors shaping adaptive evolution of Pca using pathogen populations from distinct geographic regions within the USA and South Africa (SA). Phenotypic and genome-wide sequencing data of these diverse Pca collections, including 217 isolates, uncovered phylogenetic relationships and established distinct genetic composition between populations from northern and southern regions from the USA and SA. The population dynamics of Pca involve a bidirectional movement of inoculum between northern and southern regions of the USA and contributions from clonality and sexuality. The population from SA is solely clonal. A genome-wide association study (GWAS) employing a haplotype-resolved Pca reference genome was used to define eleven virulence-associated loci corresponding to twenty-five oat differential lines. These regions were screened to determine candidate Avr effector genes. Overall, the GWAS results allowed us to identify the underlying genetic traits controlling pathogen recognition in an oat differential set used in the USA to assign pathogen races (pathotypes). Key GWAS findings support complex genetic interactions in several oat lines suggesting allelism among resistance genes or redundancy of genes included in the differential set, multiple resistance genes recognising genetically linked Avr effector genes, or potentially epistatic relationships. A careful evaluation of the composition of the oat differential set accompanied by the development or implementation of molecular markers is recommended.

genomics↗

bioRxiv2023

Costs of resistance limit the effectiveness of cooperation enforcement

Cooperative groups are susceptible to invasion by cheaters that reap the benefits but fail to pay the costs. Both theory and experimental work have shown that cheating can select for counter-adaptations to resist cheating. But then why is cheating so common? One key hypothesis is that trade-offs prevent resistors from taking over, but evidence to support the trade-off model is lacking. Here we evolved resistance to different cheaters and tested for trade-offs. Improvements against one cheater frequently entailed correlated improvements against novel cheaters. However, direct responses to selection were typically stronger than correlated responses to selection, resulting in a pattern of local adaptation of resistance. Control populations, evolved in the absence of a cheater, showed improvements in spore germination, whereas cheater-evolved populations did not, suggesting that the evolution of resistance retards or prevents other fitness improvements. Taken together, our findings suggest that, although cheater resistance can evolve rapidly, it may also involve subtle trade-offs that can help to explain the maintenance of polymorphism in cheating and resistance in nature.

evolutionary biology↗

bioRxiv2022

Temporal dynamics of the multi-omic response to endurance exercise training across tissues

Regular exercise promotes whole-body health and prevents disease, yet the underlying molecular mechanisms throughout a whole organism are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome, and immunome in whole blood, plasma, and 18 solid tissues in Rattus norvegicus over 8 weeks of endurance exercise training. The resulting data compendium encompasses 9466 assays across 19 tissues, 25 molecular platforms, and 4 training time points in young adult male and female rats. We identified thousands of shared and tissue- and sex-specific molecular alterations. Temporal multi-omic and multi-tissue analyses demonstrated distinct patterns of tissue remodeling, with widespread regulation of immune, metabolism, heat shock stress response, and mitochondrial pathways. These patterns provide biological insights into the adaptive responses to endurance training over time. For example, exercise training induced heart remodeling via altered activity of the Mef2 family of transcription factors and tyrosine kinases. Translational analyses revealed changes that are consistent with human endurance training data and negatively correlated with disease, including increased phospholipids and decreased triacylglycerols in the liver. Sex differences in training adaptation were widespread, including those in the brain, adrenal gland, lung, and adipose tissue. Integrative analyses generated novel hypotheses of disease relevance, including candidate mechanisms that link training adaptation to non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health, and tissue injury and recovery. The data and analysis results presented in this study will serve as valuable resources for the broader community and are provided in an easily accessible public repository (https://motrpac-data.org/). HighlightsO_LIMulti-tissue resource identifies 35,439 analytes regulated by endurance exercise training at 5% FDR across 211 combinations of tissues and molecular platforms. C_LIO_LIInterpretation of systemic and tissue-specific molecular adaptations produced hypotheses to help describe the health benefits induced by exercise. C_LIO_LIRobust sex-specific responses to endurance exercise training are observed across multiple organs at the molecular level. C_LIO_LIDeep multi-omic profiling of six tissues defines regulatory signals for tissue adaptation to endurance exercise training. C_LIO_LIAll data are available in a public repository, and processed data, analysis results, and code to reproduce major analyses are additionally available in convenient R packages. C_LI

molecular biology↗

bioRxiv2022

Physical resilience in the brain: The effect of white matter disease on brain networks in cognitively normal older adults

BACKGROUNDPhysical resilience with age is considered a key feature of healthy aging, but current understanding of the neural contributions to resilience is limited. Additionally, few methods exist to identify physical resilience and observe the mechanisms through which resilience manifests. METHODSTo address these gaps, we used data from 189 participants from the Brain Networks and Mobility (B-NET) study who completed the short physical performance battery (SPPB) as well as its expanded version (eSPPB), magnetic resonance imaging (MRI), and functional MRI (fMRI). Functional brain networks were generated using graph theory methods. We grouped participants based on SPPB scores (<10=unhealthy & 10-12=healthy) and median splits of white matter hyperintensity volumes: Expected Healthy (EH: low WMH, healthy SPPB, n=81), Expected Impaired (EI: high WMH, unhealthy SPPB, n=42), Unexpected Healthy (UH: high WMH, healthy SPPB, n=53), and Unexpected Impaired (UI: low WMH, unhealthy SPPB, n=13). UH is considered the "resilient" group due to their maintained function despite elevated WMH burden. Continuous analyses assessed the relationships between network properties, mobility, and cognition. RESULTSHigher SPPB scores were associated (p<0.01) with greater sensorimotor cortex community structure (SMN-CS) consistency. While no main effect of the resilience interaction term (SPPB*WMH) was found on SMN-CS, UH showed higher numbers of second-order connections between the SMN and anterior cingulate cortex (ACC) than EI (p<0.01). CONCLUSIONSIncreased connectivity between SMN and ACC may be a marker of physical resilience within the brain.

neuroscience↗

bioRxiv2021

Kenyan Traditional Medicine: Exploring Old Solutions to the Modern Antibacterial Crises Through Natural Products Chemistry

Infectious diseases are a major cause of morbidity and mortality around the world, accounting for approximately 50% of all deaths in tropical countries. Despite remarkable progress in the field of microbiology, inability to control or mitigate, epidemics caused by drug-resistant microorganisms pose a serious health hazard to the global population. New therapeutic strategies must be developed as a global initiative for the prevention and control of infectious diseases. This study focuses on Kenyan medicinal plants and their activity against bacteria. Plant extracts obtained from seven Kenyan plants used in traditional medicine, were screened for their antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus cereus, and Mycobacterium smegmatis. Extracts from all these plants showed antibacterial activity against at least one of the tested organisms at a concentration of 2 mg/mL. Chemical screening showed the presence of different classes of phytochemicals such as alkaloids, terpenes, tannins, in some active extracts.

microbiology↗

bioRxiv2017

De novo assembly and phasing of dikaryotic genomes from two isolates of Puccinia coronata f. sp. avenae, the causal agent of oat crown rust

Oat crown rust, caused by the fungus Puccinia coronata f. sp. avenae (Pca), is a devastating disease that impacts worldwide oat production. For much of its life cycle, Pca is dikaryotic, with two separate haploid nuclei that may vary in virulence genotype, highlighting the importance of understanding haplotype diversity in this species. We generated highly contiguous de novo genome assemblies of two Pca isolates, 12SD80 and 12NC29, from long-read sequences. In total, we assembled 603 primary contigs for a total assembly length of 99.16 Mbp for 12SD80 and 777 primary contigs with a total length of 105.25 Mbp for 12NC29, and approximately 52% of each genome was assembled into alternate haplotypes. This revealed structural variation between haplotypes in each isolate equivalent to more than 2% of the genome size, in addition to about 260,000 and 380,000 heterozygous single-nucleotide polymorphisms in 12SD80 and 12NC29, respectively. Transcript-based annotation identified 26,796 and 28,801 coding sequences for isolates 12SD80 and 12NC29, respectively, including about 7,000 allele pairs in haplotype-phased regions. Furthermore, expression profiling revealed clusters of co-expressed secreted effector candidates, and the majority of orthologous effectors between isolates showed conservation of expression patterns. However, a small subset of orthologs showed divergence in expression, which may contribute to differences in virulence between 12SD80 and 12NC29. This study provides the first haplotype-phased reference genome for a dikaryotic rust fungus as a foundation for future studies into virulence mechanisms in Pca.\n\nImportanceDisease management strategies for oat crown rust are challenged by the rapid evolution of Puccinia coronata f. sp. avenae (Pca), which renders resistance genes in oat varieties ineffective. Despite the economic importance of understanding Pca, resources to study the molecular mechanisms underpinning pathogenicity and emergence of new virulence traits are lacking. Such limitations are partly due to the obligate biotrophic lifestyle of Pca as well as the dikaryotic nature of the genome, features that are also shared with other important rust pathogens. This study reports the first release of a haplotype-phased genome assembly for a dikaryotic fungal species and demonstrates the amenability of using emerging technologies to investigate genetic diversity in populations of Pca.

genomics↗