Modeling epidemics dynamics on heterogenous networks

The dynamics of the SIS process on heterogenous networks, where different local communities are connected by airlines, is studied. We suggest a new modeling technique for travelers movement, in which the movement does not affect the demographic parameters characterizing the metapopulation. A solution to the deterministic reaction-diffusion equations that emerges from this model on a general network is presented. A typical example of a heterogenous network, the star structure, is studied in detail both analytically and using agent-based simulations. The interplay between demographic stochasticity, spatial heterogeneity and the infection dynamics is shown to produce some counterintuitive effects. In particular it was found that, while movement always increases the chance of an outbreak, it may decrease the steady-state fraction of sick individuals. The importance of the modeling technique in estimating the outcomes of a vaccination campaign is demonstrated.     

The penetration of a dinucleoside monophosphate into rabbit blood cells in vitro

Uridylyl 3′-5′[¹⁴C] adenosine and uridylyl 2′-5′[¹⁴C] adenosine penetrate into rabbit blood cell sap at the same rate. No enzymatic or chemical hydrolysis of the dinucleoside monophosphates was observed.     

Spatial Distribution and Temporal Patterns of Cassin’s Auklet Foraging and Their Euphausiid Prey in a Variable Ocean Environment

Krill (Euphausiids) play a vital ecosystem role in many of the world’s most productive marine regions, providing an important trophic linkage. We introduce a robust modeling approach to link Cassin’s auklet (Ptychoramphus aleuticus) abundance and distribution to large-scale and local oceanic and atmospheric conditions and relate these patterns to similarly modeled distributions of an important prey resource, krill. We carried out at-sea strip transect bird surveys and hydroacoustic assessments of euphausiids (2004–2013). Data informed separate, spatially-explicit predictive models of Cassin’s auklet abundance (zero-inflated negative binomial regression) and krill biomass (two-part model) based on these surveys. We established the type of prey responsible for acoustic backscatter by conducting net tows of the upper 50 m during surveys. We determined the types of prey fed to Cassin’s auklet chicks by collecting diet samples from provisioning adults. Using time-depth-recorders, we found Cassin’s auklets utilized consistent areas in the upper water column, less than 30 m, where krill could be found (99.5% of dives were less than 30 m). Birds primarily preyed upon two species of euphausiids, Euphausia pacifica and Thysanoessa spinifera, which were available in the upper water column. Cassin’s auklet abundance was best predicted by both large scale and localized oceanic processes (upwelling) while krill biomass was best predicted by local factors (temperature, salinity, and fluorescence) and both large scale and localized oceanic processes (upwelling). Models predicted varying krill and bird distribution by month and year. Our work informs the use of Cassin’s auklet as a valuable indicator or krill abundance and distribution and strengthens our understanding of the link between Cassin’s auklet and its primary prey. We expect future increases in frequency and magnitude of anomalous ocean conditions will result in decreased availability of krill leading to declines in the Farallon Islands population of Cassin’s auklets.     

Genetic Association Study of Adiposity and Melanocortin-4 Receptor (MC4R) Common Variants: Replication and Functional Characterization of Non-Coding Regions

Common genetic variants 3′ of MC4R within two large linkage disequilibrium (LD) blocks spanning 288 kb have been associated with common and rare forms of obesity. This large association region has not been refined and the relevant DNA segments within the association region have not been identified. In this study, we investigated whether common variants in the MC4R gene region were associated with adiposity-related traits in a biracial population-based study. Single nucleotide polymorphisms (SNPs) in the MC4R region were genotyped with a custom array and a genome-wide array and associations between SNPs and five adiposity-related traits were determined using race-stratified linear regression. Previously reported associations between lower BMI and the minor alleles of rs2229616/Val103Ile and rs52820871/Ile251Leu were replicated in white female participants. Among white participants, rs11152221 in a proximal 3′ LD block (closer to MC4R) was significantly associated with multiple adiposity traits, but SNPs in a distal 3′ LD block (farther from MC4R) were not. In a case-control study of severe obesity, rs11152221 was significantly associated. The association results directed our follow-up studies to the proximal LD block downstream of MC4R. By considering nucleotide conservation, the significance of association, and proximity to the MC4R gene, we identified a candidate MC4R regulatory region. This candidate region was sequenced in 20 individuals from a study of severe obesity in an attempt to identify additional variants, and the candidate region was tested for enhancer activity using in vivo enhancer assays in zebrafish and mice. Novel variants were not identified by sequencing and the candidate region did not drive reporter gene expression in zebrafish or mice. The identification of a putative insulator in this region could help to explain the challenges faced in this study and others to link SNPs associated with adiposity to altered MC4R expression.     

Effects of stimuli shape and polarization in evoking deimatic patterns in the European cuttlefish, Sepia officinalis, under varying turbidity conditions

Cuttlefish possess the complex ability to identify approaching threats and then to selectively express the appropriate defense. We examined the visual cues used by Sepia officinalis cuttlefish during predator detection and the responses they selected. Using computer-generated stimuli, we set out to quantitate the deimatic responses to artificial looming stimuli of different shapes and contrasts. Defensive behavior gradually intensified as geometrical shapes resembled an image of a fish. Therefore, in addition to an object’s size or its sudden increase in size, cuttlefish use form recognition to identify a threat. Cuttlefish demonstrated equal performance in predator detection trough clear water when presented with intensity versus polarization contrasts. However, when the water turbidity increased, the cuttlefish still detected looming fish shapes based on polarization contrast even when intensity information alone did not suffice. These results demonstrate the interplay between intensity and polarization information transmission and processing in the spatial domain. As nectobenthic organisms, cuttlefish probably experience low visibility conditions on a regular basis. The ability to see further into turbid water and to better detect an approaching object would be beneficial for their survival.     

Recovering population parameters from a single gene genealogy: an unbiased estimator of the growth rate

We show that the number of lineages ancestral to a sample, as a function of time back into the past, which we call the number of lineages as a function of time (NLFT), is a nearly deterministic property of large-sample gene genealogies. We obtain analytic expressions for the NLFT for both constant-sized and exponentially growing populations. The low level of stochastic variation associated with the NLFT of a large sample suggests using the NLFT to make estimates of population parameters. Based on this, we develop a new computational method of inferring the size and growth rate of a population from a large sample of DNA sequences at a single locus. We apply our method first to a sample of 1,212 mitochondrial DNA (mtDNA) sequences from China, confirming a pattern of recent population growth previously identified using other techniques, but with much smaller confidence intervals for past population sizes due to the low variation of the NLFT. We further analyze a set of 63 mtDNA sequences from blue whales (BWs), concluding that the population grew in the past. This calls for reevaluation of previous studies that were based on the assumption that the BW population was fixed.     

Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration

Krabbe disease is caused by a deficiency of the lysosomal galactosylceramidase (GALC) enzyme, which results in the accumulation of galactosylceramide (GalCer) and psychosine. In Krabbe disease, the brunt of demyelination and neurodegeneration is believed to result from the dysfunction of myelinating glia. Recent studies have shown that neuronal axons are both structurally and functionally compromised in Krabbe disease, even before demyelination, suggesting a possible neuron-autonomous role of GALC. Using a novel neuron-specific Galc knockout (CKO) model, we show that neuronal Galc deletion is sufficient to cause growth and motor coordination defects and inflammatory gliosis in mice. Furthermore, psychosine accumulates significantly in the nervous system of neuron-specific Galc-CKO. Confocal and electron microscopic analyses show profound neuro-axonal degeneration with a mild effect on myelin structure. Thus, we prove for the first time that neuronal GALC is essential to maintain and protect neuronal function independently of myelin and may directly contribute to the pathogenesis of Krabbe disease.

Krabbe disease is a demyelinating neurodegenerative disorder caused by a deficiency of the enzyme lysosomal galactosylceramidase (GALC), which results in the accumulation of galactosylceramide and psychosine. This study uses a novel neuron-specific knockout model in the first in vivo attempt to investigate the role of neuronal GALC in neuronal function and the etiology of Krabbe disease.     

Medical sequencing at the extremes of human body mass

Body weight is a quantitative trait with significant heritability in humans. To identify potential genetic contributors to this phenotype, we resequenced the coding exons and splice junctions of 58 genes in 379 obese and 378 lean individuals. Our 96-Mb survey included 21 genes associated with monogenic forms of obesity in humans or mice, as well as 37 genes that function in body weight-related pathways. We found that the monogenic obesity-associated gene group was enriched for rare nonsynonymous variants unique to the obese population compared with the lean population. In addition, computational analysis predicted a greater fraction of deleterious variants within the obese cohort. Together, these data suggest that multiple rare alleles contribute to obesity in the population and provide a medical sequencing-based approach to detect them.