Biology subjects

Howard, T. D.

Publications and source records attributed to Howard, T. D..

4 recordsLinked to original sources

bioRxiv2026

The Non-Human Primate Sample Size Calculator: a design tool for longitudinal research projects

Nonhuman primates (NHP) are crucial models of human health and disease and offer the opportunity to bridge the gap between basic research and the clinic. Given the ethical considerations, high costs, and logistical constraints associated with NHP studies, careful planning is essential to maximize scientific rigor while minimizing animal use. Statistical power calculations, to determine optimal sample size, require knowing the expected number of animals at each timepoint, a challenge for longitudinal studies that must account for natural deaths or disease during a study. Here, we leveraged data from a recent study detailing NHP life- and healthspans to develop a web-based NHP study design tool, available at midas.wakehealth.edu. For 11 NHP species relevant to biomedical research, users can provide study details to generate estimates of sample counts based on natural healthspan trajectories. We envision this tool being used by colony managers and investigators for both study design and monitoring colony health over the course of a study.

physiology↗

bioRxiv2020

Divergent effects of Western and Mediterranean diets on behavior and monocyte polarization.

Dietary changes associated with industrialization substantially increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease, which are major contributors to the public health burden. The high prevalence of these chronic diseases is often attributed to an "evolutionary mismatch," between human physiology and modern nutritional environments. In support of this idea, Western diets enriched with foods that were scarce throughout human evolutionary history (e.g., simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to hunter-gatherer diets, such as a Mediterranean diet; however, the mechanisms linking dietary mismatch to inflammation and chronic disease are poorly understood. We used a macaque model and whole diet manipulations to evaluate one possible mechanism - inflammatory polarization of monocytes - that potentially leads to this evolutionary mismatch. After consuming a Western- or Mediterranean-like diet for 15 months, monocytes from Western diet consumers exhibited a more proinflammatory phenotype, with 40% of their genes differentially expressed (FDR<0.05). Compared to the Mediterranean diet, the Western diet shifted the co-expression of 445 gene pairs, including small RNAs and transcription factors associated with metabolism and adiposity in humans, and dramatically altered animal behavior. For example, Western-fed individuals were more anxious and less socially integrated compared to the Mediterranean-fed subjects. These behavioral changes were also associated with some of the effects of diet on gene expression, suggesting an interaction between diet, central nervous system activity, and monocyte gene expression. The results of this study provide new insights into evolutionary mismatch at the molecular level and uncover new pathways through which Western diets generate inflammation and disease.

genomics↗

bioRxiv2019

Intrinsic DNA topology as a prioritization metric in genomic fine-mapping studies

In genomic fine-mapping studies, some approaches leverage annotation data to prioritize likely functional polymorphisms. However, existing annotation sources often present challenges as many: lack data for novel variants, offer no context for noncoding regions, and/or are confounded with linkage disequilibrium. We propose a novel annotation source - sequence-dependent DNA topology - as a prioritization metric for fine-mapping. DNA topology and function are well-intertwined, and as an intrinsic DNA property, it is readily applicable to any genomic region. Here, we constructed and applied, Minor Groove Width (MGW), as a prioritization metric. Using an established MGW-prediction method, we generated an MGW census for 199,038,197 SNPs across the human genome. Summarizing a SNPs change in MGW ({Delta}MGW) as a Euclidean distance, {Delta}MGW exhibited a strongly right-skewed distribution, highlighting the infrequency of SNPs that generate dissimilar shape profiles. We hypothesized that phenotypically-associated SNPs can be prioritized by {Delta}MGW. We applied Bayesian and frequentist MGW-prioritization approaches to three non-coding regions associated with System Lupus Erythematosus in multiple ancestries. In two regions, including {Delta}MGW resolved the association to a single, trans-ancestral, SNP, corroborated by external functional data. Together, this study presents the first usage of sequence-dependent DNA topology as a prioritization metric in genomic association studies. Graphical AbstractWe hypothesize that SNPs imposing dissimilar minor groove width profiles ({Delta}MGW) are more likely to alter function. {Delta}MGW was interrogated genome-wide and then used as a weighting metric for fine-mapping associations. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/837245v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@d350adorg.highwire.dtl.DTLVardef@155a2cborg.highwire.dtl.DTLVardef@132e30aorg.highwire.dtl.DTLVardef@1d7b065_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2019

Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B

The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation, loss of which results in severe macrothrombocytopenia and aberrant platelet function in mice and humans. Using a combination of immunohistochemistry, affinity chromatography and proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as a G6b-B binding partner. Subsequent in vitro biochemical studies and a cell-based genetic screen demonstrated that the interaction is specifically mediated by the HS chains of perlecan. Biophysical analysis revealed that heparin forms a high-affinity complex with G6b-B and mediates dimerization. Using platelets from humans and genetically-modified mice, we demonstrate that binding of G6b-B to HS and multivalent heparin inhibits platelet and megakaryocyte function by inducing downstream signaling via the tyrosine phosphatases Shp1 and Shp2. Our findings provide novel insights into how G6b-B is regulated and contribute to our understanding of the interaction of megakaryocytes and platelets with glycans.

biochemistry↗