p21WAF1/CIP1 RNA Expression in Highly HIV-1 Exposed,Uninfected Individuals

Some individuals remain HIV-1 antibody and PCR negative after repeated exposures to the virus, and are referred to as HIV-exposed seronegatives (HESN). However, the causes of resistance to HIV-1 infection in cases other than those with a homozygous CCR5Δ32 deletion are unclear. We hypothesized that human p21^WAF1/CIP1 (a cyclin-dependent kinase inhibitor) could play a role in resistance to HIV-1 infection in HESN, as p21 expression has been associated with suppression of HIV-1 in elite controllers and reported to block HIV-1 integration in cell culture. We measured p21 RNA expression in PBMC from 40 HESN and 40 low exposure HIV-1 seroconverters (LESC) prior to their infection using a real-time PCR assay. Comparing the 20 HESN with the highest exposure risk (median = 111 partners/2.5 years prior to the 20 LESC with the lowest exposure risk (median = 1 partner/2.5 years prior), p21 expression trended higher in HESN in only one of two experiments (P = 0.11 vs. P = 0.80). Additionally, comparison of p21 expression in the top 40 HESN (median = 73 partners/year) and lowest 40 LESC (median = 2 partners/year) showed no difference between the groups (P = 0.84). There was a weak linear trend between risk of infection after exposure and increasing p21 gene expression (R² = 0.02, P = 0.12), but again only in one experiment. Hence, if p21 expression contributes to the resistance to viral infection in HESN, it likely plays a minor role evident only in those with extremely high levels of exposure to HIV-1.     

Xylem cavitation vulnerability influences tree species’ habitat preferences in miombo woodlands

Although precipitation plays a central role in structuring Africa’s miombo woodlands, remarkably little is known about plant-water relations in this seasonally dry tropical forest. Therefore, in this study, we investigated xylem vulnerability to cavitation for nine principal tree species of miombo woodlands, which differ in habitat preference and leaf phenology. We measured cavitation vulnerability (Ψ₅₀), stem-area specific hydraulic conductivity (K _S), leaf specific conductivity (K _L), seasonal variation in predawn water potential (Ψ_PD) and xylem anatomical properties [mean vessel diameter, mean hydraulic diameter, mean hydraulic diameter accounting for 95 % flow, and maximum vessel length (V _L)]. Results show that tree species with a narrow habitat range (mesic specialists) were more vulnerable to cavitation than species with a wide habitat range (generalists). Ψ₅₀ for mesic specialists ranged between ?1.5 and ?2.2 MPa and that for generalists between ?2.5 and ?3.6 MPa. While mesic specialists exhibited the lowest seasonal variation in Ψ_PD, generalists displayed significant seasonal variations in Ψ_PD suggesting that the two miombo habitat groups differ in their rooting depth. We observed a strong trade-off between K _S and Ψ₅₀ suggesting that tree hydraulic architecture is one of the decisive factors setting ecological boundaries for principal miombo species. While vessel diameters correlated weakly (P > 0.05) with Ψ₅₀, V _L was positively and significantly correlated with Ψ₅₀. Ψ_PD was significantly correlated with Ψ₅₀ further reinforcing the conclusion that tree hydraulic architecture plays a significant role in species’ habitat preference in miombo woodlands.     

Beyond ecosystem modeling: A roadmap to community cyberinfrastructure for ecological data‐model integration

In an era of rapid global change, our ability to understand and predict Earth's natural systems is lagging behind our ability to monitor and measure changes in the biosphere. Bottlenecks to informing models with observations have reduced our capacity to fully exploit the growing volume and variety of available data. Here, we take a critical look at the information infrastructure that connects ecosystem modeling and measurement efforts, and propose a roadmap to community cyberinfrastructure development that can reduce the divisions between empirical research and modeling and accelerate the pace of discovery. A new era of data‐model integration requires investment in accessible, scalable, and transparent tools that integrate the expertise of the whole community, including both modelers and empiricists. This roadmap focuses on five key opportunities for community tools: the underlying foundations of community cyberinfrastructure; data ingest; calibration of models to data; model‐data benchmarking; and data assimilation and ecological forecasting. This community‐driven approach is a key to meeting the pressing needs of science and society in the 21st century.     

Age-related neural dedifferentiation in the motor system

Recent neuroimaging studies using multi-voxel pattern analysis (MVPA) show that distributed patterns of brain activation elicited by different visual stimuli are less distinctive in older adults than in young adults. However, less is known about the effects of aging on the neural representation of movement. The present study used MVPA to compare the distinctiveness of motor representations in young and older adults. We also investigated the contributions of brain structure to age differences in the distinctiveness of motor representations. We found that neural distinctiveness was reduced in older adults throughout the motor control network. Although aging was also associated with decreased gray matter volume in these regions, age differences in motor distinctiveness remained significant after controlling for gray matter volume. Our results suggest that age-related neural dedifferentiation is not restricted to sensory perception and is instead a more general feature of the aging brain.     

Development of a panel of genome-wide ancestry informative markers to study admixture throughout the Americas

Most individuals throughout the Americas are admixed descendants of Native American, European, and African ancestors. Complex historical factors have resulted in varying proportions of ancestral contributions between individuals within and among ethnic groups. We developed a panel of 446 ancestry informative markers (AIMs) optimized to estimate ancestral proportions in individuals and populations throughout Latin America. We used genome-wide data from 953 individuals from diverse African, European, and Native American populations to select AIMs optimized for each of the three main continental populations that form the basis of modern Latin American populations. We selected markers on the basis of locus-specific branch length to be informative, well distributed throughout the genome, capable of being genotyped on widely available commercial platforms, and applicable throughout the Americas by minimizing within-continent heterogeneity. We then validated the panel in samples from four admixed populations by comparing ancestry estimates based on the AIMs panel to estimates based on genome-wide association study (GWAS) data. The panel provided balanced discriminatory power among the three ancestral populations and accurate estimates of individual ancestry proportions (R2 > 0.9 for ancestral components with significant between-subject variance). Finally, we genotyped samples from 18 populations from Latin America using the AIMs panel and estimated variability in ancestry within and between these populations. This panel and its reference genotype information will be useful resources to explore population history of admixture in Latin America and to correct for the potential effects of population stratification in admixed samples in the region.     

Population genetic simulation: Benchmarking frameworks for non-standard models of natural selection

Population genetic simulation has emerged as a common tool for investigating increasingly complex evolutionary and demographic models. Software capable of handling high-level model complexity has recently been developed, and the advancement of tree sequence recording now allows simulations to merge the efficiency and genealogical insight of coalescent simulations with the flexibility of forward simulations. However, frameworks utilizing these features have not yet been compared and benchmarked. Here, we evaluate various simulation workflows using the coalescent simulator msprime and the forward simulator SLiM, to assess resource efficiency and determine an optimal simulation framework. Three aspects were evaluated: (1) the burn-in, to establish an equilibrium level of neutral diversity in the population; (2) the forward simulation, in which temporally fluctuating selection is acting; and (3) the final computation of summary statistics. We provide typical memory and computation time requirements for each step. We find that the fastest framework, a combination of coalescent and forward simulation with tree sequence recording, increases simulation speed by over twenty times compared to classical forward simulations without tree sequence recording, although it does require six times more memory. Overall, using efficient simulation workflows can lead to a substantial improvement when modelling complex evolutionary scenarios—although the optimal framework ultimately depends on the available computational resources.     

Centrosomal enrichment and proteasomal degradation of SYS-1/β-catenin requires the microtubule motor dynein

The Caenorhabditis elegans Wnt/β-catenin asymmetry (WβA) pathway utilizes asymmetric regulation of SYS-1/β-catenin and POP-1/TCF coactivators. WβA differentially regulates gene expression during cell fate decisions, specifically by asymmetric localization of determinants in mother cells to produce daughters biased toward their appropriate cell fate. Despite the induction of asymmetry, β-catenin localizes symmetrically to mitotic centrosomes in both mammals and C. elegans. Owing to the mitosis-specific localization of SYS-1 to centrosomes and enrichment of SYS-1 at kinetochore microtubules when SYS-1 centrosomal loading is disrupted, we investigated active trafficking in SYS-1 centrosomal localization. Here, we demonstrate that trafficking by microtubule motor dynein is required to maintain SYS-1 centrosomal enrichment, by dynein RNA interference (RNAi)-mediated decreases in SYS-1 centrosomal enrichment and by temperature-sensitive allele of the dynein heavy chain. Conversely, we observe depletion of microtubules by nocodazole treatment or RNAi of dynein-proteasome adapter ECPS-1 exhibits increased centrosomal enrichment of SYS-1. Moreover, disruptions to SYS-1 or negative regulator microtubule trafficking are sufficient to significantly exacerbate SYS-1 dependent cell fate misspecifications. We propose a model whereby retrograde microtubule-mediated trafficking enables SYS-1 enrichment at centrosomes, enhancing its eventual proteasomal degradation. These studies support the link between centrosomal localization and enhancement of proteasomal degradation, particularly for proteins not generally considered “centrosomal.”     

NK cells and monocytes modulate primary HTLV-1 infection

We investigated the impact of monocytes, NK cells, and CD8⁺ T-cells in primary HTLV-1 infection by depleting cell subsets and exposing macaques to either HTLV-1 wild type (HTLV-1_WT) or to the HTLV-1_p12KO mutant unable to infect replete animals due to a single point mutation in orf-I that inhibits its expression. The orf-I encoded p8/p12 proteins counteract cytotoxic NK and CD8⁺ T-cells and favor viral DNA persistence in monocytes. Double NK and CD8⁺ T-cells or CD8 depletion alone accelerated seroconversion in all animals exposed to HTLV-1_WT. In contrast, HTLV-1_p12KO infectivity was fully restored only when NK cells were also depleted, demonstrating a critical role of NK cells in primary infection. Monocyte/macrophage depletion resulted in accelerated seroconversion in all animals exposed to HTLV-1_WT, but antibody titers to the virus were low and not sustained. Seroconversion did not occur in most animals exposed to HTLV-1_p12KO. In vitro experiments in human primary monocytes or THP-1 cells comparing HTLV-1_WT and HTLV-1_p12KO demonstrated that orf-I expression is associated with inhibition of inflammasome activation in primary cells, with increased CD47 “don’t-eat-me” signal surface expression in virus infected cells and decreased monocyte engulfment of infected cells. Collectively, our data demonstrate a critical role for innate NK cells in primary infection and suggest a dual role of monocytes in primary infection. On one hand, orf-I expression increases the chances of viral transmission by sparing infected cells from efferocytosis, and on the other may protect the engulfed infected cells by modulating inflammasome activation. These data also suggest that, once infection is established, the stoichiometry of orf-I expression may contribute to the chronic inflammation observed in HTLV-1 infection by modulating monocyte efferocytosis.