A law of large numbers approximation for Markov population processes with countably many types

When modelling metapopulation dynamics, the influence of a single patch on the metapopulation depends on the number of individuals in the patch. Since the population size has no natural upper limit, this leads to systems in which there are countably infinitely many possible types of individual. Analogous considerations apply in the transmission of parasitic diseases. In this paper, we prove a law of large numbers for rather general systems of this kind, together with a rather sharp bound on the rate of convergence in an appropriately chosen weighted $\ell_1$ norm.Comment: revised version in response to referee comments, 34 page

Evolutionary action and structural basis of the allosteric switch controlling β(2)AR functional selectivity

Functional selectivity of G-protein-coupled receptors is believed to originate from ligand-specific conformations that activate only subsets of signaling effectors. In this study, to identify molecular motifs playing important roles in transducing ligand binding into distinct signaling responses, we combined in silico evolutionary lineage analysis and structure-guided site-directed mutagenesis with large-scale functional signaling characterization and non-negative matrix factorization clustering of signaling profiles. Clustering based on the signaling profiles of 28 variants of the β(2)-adrenergic receptor reveals three clearly distinct phenotypical clusters, showing selective impairments of either the Gi or βarrestin/endocytosis pathways with no effect on Gs activation. Robustness of the results is confirmed using simulation-based error propagation. The structural changes resulting from functionally biasing mutations centered around the DRY, NPxxY, and PIF motifs, selectively linking these micro-switches to unique signaling profiles. Our data identify different receptor regions that are important for the stabilization of distinct conformations underlying functional selectivity

Structural barriers to comprehensive, coordinated HIV care: Geographic accessibility in the US South

Structural barriers to HIV care are particularly challenging in the US South, which has higher HIV diagnosis rates, poverty, uninsurance, HIV stigma, and rurality, and fewer comprehensive public health programs versus other US regions. Focusing on one structural barrier, we examined geographic accessibility to comprehensive, coordinated HIV care (HIVCCC) in the US South. We integrated publicly available data to study travel time to HIVCCC in 16 Southern states and District of Columbia. We geocoded HIVCCC service locations and estimated drive time between the population-weighted county centroid and closest HIVCCC facility. We evaluated drive time in aggregate, and by county-level HIV prevalence quintile, urbanicity, and race/ethnicity. Optimal drive time was ≤30 min, a common primary care accessibility threshold. We identified 228 service locations providing HIVCCC across 1422 Southern counties, with median drive time to care of 70 min (IQR 64 min). For 368 counties in the top HIV prevalence quintile, median drive time is 50 min (IQR 61 min), exceeding 60 min in over one-third of these counties. Among counties in the top HIV prevalence quintile, drive time to care is six-folder higher for rural versus super-urban counties. Counties in the top HIV prevalence quintiles for non-Hispanic Blacks and for Hispanics have >50% longer drive time to care versus for non-Hispanic Whites. Including another potential care source—publicly-funded health centers serving low-income populations— could double the number of high-HIV burden counties with drive time ≤30 min, representing nearly 35,000 additional people living with HIV with accessible HIVCCC. Geographic accessibility to HIVCCC is inadequate in the US South, even in high HIV burden areas, and geographic and racial/ethnic disparities exist. Structural factors, such as geographic accessibility to care, may drive disparities in health outcomes. Further research on programmatic policies, and evidence-based alternative HIV care delivery models improving access to care, is critical

Molecular structure and developmental expression of zebrafish atp2a genes

[[abstract]]We isolated two atp2a genes, atp2a1 and atp2a2a, from embryonic zebrafish. Amino acid sequences deduced from zebrafish atp2a genes are aligned with orthologue proteins from other species, the results showed that they share high percentage of identities (82%–94%) and acidic pIs (5.03–5.33). Whole mount in situ hybridization experiments showed that atp2a1 and atp2a2a are maternal inherited genes which can be detected at 1-cell stage embryos and express in the entire animal pole from 6 hours post-fertilization (hpf) to 12 hpf. At the later stages (48–96 hpf), expression of atp2a1 was restricted in head and trunk muscles as well as in some neurons. In contrast to the strongly expression of atp2a1 in head muscle, expression of atp2a2a was detected in head muscle in a fainter manner. In addition, transcripts of atp2a2a were observed in the developing heart during early cardiogenesis. The present studies not only help us to comparatively analyze atp2a genes across species, but also provide useful information about expressions during early embryogenesis that will help in further investigations of functional studies of Atp2a in the future.[[incitationindex]]SCI[[booktype]]紙

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe