Biology subjects

Henderson, J.

Publications and source records attributed to Henderson, J..

24 records · Page 2Linked to original sources

bioRxiv2020

Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, while the Alzheimer's R47H mutant does the opposite

Missense mutations (e.g. R47H) of the microglial receptor TREM2 increase risk of Alzheimers disease (AD), and the soluble ectodomain of wild-type TREM2 (sTREM2) appears to protect in vivo, but the underlying mechanisms are unclear. We show that A{beta} oligomers bind to TREM2, inducing shedding of sTREM2. Wild-type sTREM2 inhibits A{beta} oligomerization, fibrillization and neurotoxicity, and disaggregates preformed A{beta} oligomers and protofibrils. In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric A{beta}, but rather promotes A{beta} protofibril formation and neurotoxicity. Thus, in addition to mediating phagocytosis, wild-type TREM2 may protect against amyloid pathology by A{beta}-induced release of sTREM2 that blocks A{beta} aggregation and neurotoxicity; while R47H sTREM2 promotes A{beta} aggregation into neurotoxic forms, which may explain why the R47H variant gene increases AD risk several fold.

biochemistry↗

bioRxiv2019

Hand Knob Area of Motor Cortex in People with Tetraplegia Represents the Whole Body in a Modular Way

Decades after the motor homunculus was first proposed, it is still unknown how different body parts are intermixed and interrelated in human motor cortex at single-neuron resolution. Using microelectrode arrays, we studied how face, head, arm and leg movements on both sides of the body are represented in hand knob area of precentral gyrus in people with tetraplegia. Contrary to the traditional somatotopy, we found strong representation of all movements. Probing further, we found that ipsilateral and contralateral movements, and homologous arm and leg movements (e.g. wrist and ankle), had a correlated representation. Additionally, there were neural dimensions where the limb was represented independently of the movement. Together, these patterns formed a \"modular\" code that might facilitate skill transfer across limbs. We also investigated dual-effector movement, finding that more strongly represented effectors suppressed the activity of weaker effectors. Finally, we leveraged these results to improve discrete brain-computer interfaces by spreading targets across all limbs.

neuroscience↗

bioRxiv2018

Food web interaction strength distributions are conserved by greater variation between than within predator-prey pairs

Species interactions in food webs are usually recognized as dynamic, varying across species, space and time due to biotic and abiotic drivers. Yet food webs also show emergent properties that appear consistent, such as a skewed frequency distribution of interaction strengths (many weak, few strong). Reconciling these two properties requires an understanding of the variation in pairwise interaction strengths and its underlying mechanisms. We estimated stream sculpin feeding rates in three seasons at nine sites in Oregon to examine variation in trophic interaction strengths both across and within predator-prey pairs. We considered predator and prey densities, prey body mass, and abiotic factors as putative drivers of within-pair variation over space and time. We hypothesized that consistently skewed interaction strength distributions could result if individual interaction strengths show relatively little variation, or alternatively, if interaction strengths vary but shift in ways that conserve their overall frequency distribution. We show that feeding rate distributions remained consistently and positively skewed across all sites and seasons. The mean coefficient of variation in feeding rates within each of 25 focal species pairs across surveys was less than half the mean coefficient of variation seen across species pairs within a given survey. The rank order of feeding rates also remained relatively conserved across streams, seasons and individual surveys. On average, feeding rates on each prey taxon nonetheless varied by a hundredfold across surveys, with some feeding rates showing more variation in space and others in time. For most species pairs, feeding rates increased with prey density and decreased with high stream flows and low water temperatures. For nearly half of all species pairs, factors other than prey density explained the most variation, indicating that the strength of density dependence in feeding rates can vary greatly among a generalist predators prey species. Our findings show that although individual interaction strengths exhibit considerable variation in space and time, they can nonetheless remain relatively consistent, and thus predictable, compared to the even larger variation that occurs across species pairs. These insights help reconcile how the skewed nature of interaction strength distributions can persist in highly dynamic food webs.

ecology↗

bioRxiv2018

Deformation microscopy for dynamic intracellular and intranuclear mapping of mechanics with high spatiotemporal resolution

Structural heterogeneity is a hallmark of living cells and nuclei that drives local mechanical properties and dynamic cellular responses, including adhesion, gene expression, and differentiation. However, robust quantification of intracellular or intranuclear mechanics are lacking from conventional methods. Here, we describe new development of deformation microscopy that leverages conventional imaging and an automated hyperelastic warping algorithm to investigate strain history, deformation dynamics, and changes in structural heterogeneity within the interior of cells and nuclei. Using deformation microscopy, we found that tensile loading modes dominated intranuclear architectural dynamics in cardiomyocytes in vitro or myocytes in vivo, which was compromised by disruption of LINC complex molecule nesprin-3 or Lamin A/C, respectively. We also found that cells cultured on stiff substrates or in hyperosmotic conditions displayed abnormal strain burden and asymmetries compared to controls at interchromatin regions where active translation was expected. Deformation microscopy represents a foundational approach toward intracellular elastography, with potential utility to provide new mechanistic and quantitative insights in diverse mechanobiological applications.

biophysics↗

bioRxiv2018

What drives interaction strengths in complex food webs? A test with feeding rates of a generalist stream predator

Describing the mechanisms that drive variation in species interaction strengths is central to understanding, predicting, and managing community dynamics. Multiple factors have been linked to trophic interaction strength variation, including species densities, species traits, and abiotic factors. Yet most empirical tests of the relative roles of multiple mechanisms that drive variation have been limited to simplified experiments that may diverge from the dynamics of natural food webs. Here, we used a field-based observational approach to quantify the roles of prey density, predator density, predator-prey body-mass ratios, prey identity, and abiotic factors in driving variation in feeding rates of reticulate sculpin (Cottus perplexus). We combined data on over 6,000 predator-prey observations with prey identification time functions to estimate 289 prey-specific feeding rates at nine stream sites in Oregon. Feeding rates on 57 prey types showed an approximately log-normal distribution, with few strong and many weak interactions. Model selection indicated that prey density, followed by prey identity, were the two most important predictors of prey-specific sculpin feeding rates. Feeding rates showed a positive, accelerating relationship with prey density that was inconsistent with predator saturation predicted by current functional response models. Feeding rates also exhibited four orders-of-magnitude in variation across prey taxonomic orders, with the lowest feeding rates observed on prey with significant anti-predator defenses. Body-mass ratios were the third most important predictor variable, showing a hump-shaped relationship with the highest feeding rates at intermediate ratios. Sculpin density was negatively correlated with feeding rates, consistent with the presence of intraspecific predator interference. Our results highlight how multiple co-occurring drivers shape trophic interactions in nature and underscore ways in which simplified experiments or reliance on scaling laws alone may lead to biased inferences about the structure and dynamics of species-rich food webs.

ecology↗

bioRxiv2017

Epigenome-Wide Association Study Of Asthma And Wheeze In Childhood And Adolescence

Asthma heritability has only been partially explained by genetic variants and is known to be sensitive to environmental factors, implicating epigenetic modifications such as DNA methylation in its pathogenesis.\n\nUsing data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC), we assessed associations of asthma and wheeze with DNA methylation at 7.5 years and 16.5 years, at over 450,000 CpG sites in DNA from the peripheral blood of approx. 1000 participants. We used Mendelian randomization (MR), a method of causal inference that uses genetic variants as instrumental variables, to infer the direction of association between DNA methylation and asthma.\n\nWe identified 302 CpGs associated with current asthma status (FDR-adjusted P-value <0.05) and 445 with current wheeze status at 7.5 years, with substantial overlap between the two. Genes annotated to the 302 associated CpGs were enriched for pathways related to movement of cellular/subcellular components, locomotion, interleukin-4 production and eosinophil migration. All associations attenuated when adjusted for eosinophil and neutrophil cell count estimates. At 16.5 years, two sites were associated with current asthma after adjustment for cell counts. The CpGs mapped to the AP2A2 and IL5RA genes, with a -2.32 [95% CI -1.47,-3.18] and -2.49 [95% CI -1.56,-3.43] change in percentage methylation in asthma cases respectively. Two-sample bi-directional MR indicated a causal effect of asthma on DNA methylation at several CpG sites at 7.5 years. However, associations did not persist after adjustment for multiple testing. There was no evidence of a causal effect of asthma on DNA methylation at either of the two CpG sites at 16.5 years.\n\nThe majority of observed associations are driven by higher eosinophil cell counts in asthma cases, acting as an intermediate phenotype, with important implications for future studies of DNA methylation in atopic diseases.

epidemiology↗