Phenotypic and functional analysis of positive selection in the gamma/delta T cell lineage.

Recent evidence suggests that T cells expressing gamma/delta antigen receptors (T cell receptor [TCR]) are subject to positive selection during development. We have shown that T cells expressing a class I major histocompatibility complex (MHC)-specific gamma/delta TCR transgene (tg) are not positively selected in class I MHC-deficient, beta 2-microglobulin (beta 2m) gene knockout mice (tg+ beta 2m-). In this report, we examine phenotypic and functional parameters of gamma/delta positive selection in this transgenic model system. TCR-gamma/delta tg+ thymocytes of mature surface phenotype (heat stable antigen-, CD5hi) were found in beta 2m+ but not in beta 2m- mice. Moreover, subsets of tg+ thymocytes with the phenotype of activated T cells (interleukin [IL]2R+, CD44hi, or Mel-14lo) were also present only in the beta 2m+ mice. Cyclosporine A, which blocks positive selection of TCR-alpha/beta T cells, also inhibited gamma/delta tg+ T cell development. These results support the idea that positive selection of TCR-gamma/delta requires active TCR-mediated signal transduction. Whereas tg+ beta 2m+ thymocytes produced IL-2 and proliferated when stimulated by alloantigen, TCR engagement of tg+ beta 2m- thymocytes by antigen induced IL-2R expression but was uncoupled from the signal transduction pathway leading to IL-2 production and autocrine proliferation. Overall, these results demonstrate significant parallels between gamma/delta and alpha/beta lineage development, and suggest a general role for TCR signaling in thymic maturation

Wandering behaviour prevents inter and intra oceanic speciation in a coastal pelagic fish

Small pelagic fishes have the ability to disperse over long distances and may present complex evolutionary histories. Here, Old World Anchovies (OWA) were used as a model system to understand genetic patterns and connectivity of fish between the Atlantic and Pacific basins. We surveyed 16 locations worldwide using mtDNA and 8 microsatellite loci for genetic parameters, and mtDNA (cyt b; 16S) and nuclear (RAG1; RAG2) regions for dating major lineage-splitting events within Engraulidae family. The OWA genetic divergences (0-0.4%) are compatible with intra-specific divergence, showing evidence of both ancient and contemporary admixture between the Pacific and Atlantic populations, enhanced by high asymmetrical migration from the Pacific to the Atlantic. The estimated divergence between Atlantic and Pacific anchovies (0.67 [0.53-0.80] Ma) matches a severe drop of sea temperature during the Gunz glacial stage of the Pleistocene. Our results support an alternative evolutionary scenario for the OWA, suggesting a coastal migration along south Asia, Middle East and eastern Africa continental platforms, followed by the colonization of the Atlantic via the Cape of the Good Hope.Portuguese Foundation for Science & Technology (FCT) [SFRH/BD/36600/2007]; FCT [UID/MAR/04292/2013, SFRH/BPD/65830/2009]; FCT strategic plan [UID/Multi/04326/2013]info:eu-repo/semantics/publishedVersio

Safety Profile of Good Manufacturing Practice Manufactured Interferon \u3b3-Primed Mesenchymal Stem/Stromal Cells for Clinical Trials

Mesenchymal stem/stromal cells (MSCs) are widely studied by both academia and industry for a broad array of clinical indications. The collective body of data provides compelling evidence of the clinical safety of MSC therapy. However, generally accepted proof of therapeutic efficacy has not yet been reported. In an effort to generate a more effective therapeutic cell product, investigators are focused on modifying MSC processing protocols to enhance the intrinsic biologic activity. Here, we report a Good Manufacturing Practice-compliant two-step MSC manufacturing protocol to generate MSCs or interferon \u3b3 (IFN\u3b3) primed MSCs which allows freshly expanded cells to be infused in patients on a predetermined schedule. This protocol eliminates the need to infuse cryopreserved, just thawed cells which may reduce the immune modulatory activity. Moreover, using (IFN\u3b3) as a prototypic cytokine, we demonstrate the feasibility of priming the cells with any biologic agent. We then characterized MSCs and IFN\u3b3 primed MSCs prepared with our protocol, by karyotype, in vitro potential for malignant transformation, biodistribution, effect on engraftment of transplanted hematopoietic cells, and in vivo toxicity in immune deficient mice including a complete post-mortem examination. We found no evidence of toxicity attributable to the MSC or IFN\u3b3 primed MSCs. Our data suggest that the clinical risk of infusing MSCs or IFN\u3b3 primed MSCs produced by our two-step protocol is not greater than MSCs currently in practice. While actual proof of safety requires phase I clinical trials, our data support the use of either cell product in new clinical studies

Vital Rates from the Action of Mutation Accumulation

New models for evolutionary processes of mutation accumulation allow hypotheses about the age-specificity of mutational effects to be translated into predictions of heterogeneous population hazard functions. We apply these models to questions in the biodemography of longevity, including proposed explanations of Gompertz hazards and mortality plateaus

Hybridization in parasites: consequences for adaptive evolution, pathogenesis and public health in a changing world

[No abstract available

A promoter SNP rs4073T>A in the common allele of the interleukin 8 gene is associated with the development of idiopathic pulmonary fibrosis via the IL-8 protein enhancing mode

<p>Abstract</p> <p>Background</p> <p>Interleukin-8 (IL-8) is a potent chemo-attractant cytokine responsible for neutrophil infiltration in lungs with idiopathic pulmonary fibrosis (IPF). The IL-8 protein and mRNA expression are increased in the lung with IPF. We evaluated the effect of single nucleotide polymorphisms (SNPs) of the IL-8 gene on the risk of IPF.</p> <p>Methods</p> <p>One promoter (rs4073T>A) and two intronic SNPs (rs2227307T>G and rs2227306C>T) of the IL-8 genes were genotyped in 237 subjects with IPF and 456 normal controls. Logistic regression analysis was applied to evaluate the association of these SNPs with IPF. IL-8 in BAL fluids was measured using a quantitative sandwich enzyme immunoassay, and promoter activity was assessed using the luciferase reporter assay.</p> <p>Results</p> <p>The minor allele frequencies of rs4073T>A and rs2227307T>G were significantly lower in the 162 subjects with surgical biopsy-proven IPF and 75 subjects with clinical IPF compared with normal controls in the recessive model (OR = 0.46 and 0.48, <it>p </it>= 0.006 and 0.007, respectively). The IL-8 protein concentration in BAL fluids significantly increased in 24 subjects with IPF compared with 14 controls (<it>p </it>= 0.009). Nine IPF subjects homozygous for the rs4073 T>A common allele exhibited higher levels of the IL-8 protein compared with six subjects homozygous for the minor allele (<it>p </it>= 0.024). The luciferase activity of the rs4073T>A common allele was significantly higher than that of the rs4073T>A minor allele (<it>p </it>= 0.002).</p> <p>Conclusion</p> <p>The common allele of a promoter SNP, rs4073T>A, may increase susceptibility to the development of IPF via up-regulation of IL-8.</p

Find the weakest link. A comparison between demographic, genetic and demo-genetic metapopulation extinction times

<p>Abstract</p> <p>Background</p> <p>While the ultimate causes of most species extinctions are environmental, environmental constraints have various secondary consequences on evolutionary and ecological processes. The roles of demographic, genetic mechanisms and their interactions in limiting the viabilities of species or populations have stirred much debate and remain difficult to evaluate in the absence of demography-genetics conceptual and technical framework. Here, I computed projected times to metapopulation extinction using (1) a model focusing on the effects of species properties, habitat quality, quantity and temporal variability on the time to demographic extinction; (2) a genetic model focusing on the dynamics of the drift and inbreeding loads under the same species and habitat constraints; (3) a demo-genetic model accounting for demographic-genetic processes and feedbacks.</p> <p>Results</p> <p>Results indicate that a given population may have a high demographic, but low genetic viability or vice versa; and whether genetic or demographic aspects will be the most limiting to overall viability depends on the constraints faced by the species (e.g., reduction of habitat quantity or quality). As a consequence, depending on metapopulation or species characteristics, incorporating genetic considerations to demographically-based viability assessments may either moderately or severely reduce the persistence time. On the other hand, purely genetically-based estimates of species viability may either underestimate (by neglecting demo-genetic interactions) or overestimate (by neglecting the demographic resilience) true viability.</p> <p>Conclusion</p> <p>Unbiased assessments of the viabilities of species may only be obtained by identifying and considering the most limiting processes (i.e., demography or genetics), or, preferentially, by integrating them.</p

NINJ2 SNP may affect the onset age of first-ever ischemic stroke without increasing silent cerebrovascular lesions

<p>Abstract</p> <p>Background</p> <p>To investigate if single nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene <it>NINJ2 </it>would be associated with earlier-onset (vs. late-onset) first-ever ischemic stroke and increase silent cerebrovascular lesions prior to the manifestation of the stroke.</p> <p>Methods</p> <p>We prospectively enrolled 164 patients (67.6 ± 12.9 years, 92 men) admitted with first-ever ischemic strokes. All patients underwent genotyping of rs11833579 and rs12425791 as well as systemic investigations including magnetic resonance (MR) imaging and other vascular workup. Stroke-related MR lesions were registered on a brain-template-set using a custom-built software package 'Image_QNA': high-signal-intensity ischemic lesions on diffusion, T2-weighted, or fluid attenuation inversion recovery (FLAIR) MR images, and low signal intensity hemorrhagic lesions on gradient-echo MR images.</p> <p>Results</p> <p>The rs11833579 A/A or G/A genotype was independently associated with the first-ever ischemic stroke before the age 59 vs. 59 or over, after adjusting for cardiovascular risk factors and prior medication of antiplatelet or anticoagulant drugs, increasing the risk by about 2.5 fold. In the quantitative MR lesion maps from age-sex matched subgroups (n = 124 or 126), there was no difference between the patients with the rs11833579 A/A or G/A genotype and those with the G/G genotype. Unexpectedly, the extent of leukoaraiosis on FLAIR-MR images tended to be smaller in the corona radiata and centrum semiovale of the patients with the rs12425791 A/A or G/A genotype than in those with the G/G genotype (<it>P </it>= 0.052). Neither the rs11833579 nor the rs12425791 genotype significantly affected initial stroke severity; however the latter was associated with relatively low modified Rankin scale scores at 1 year after stroke.</p> <p>Conclusions</p> <p>The rs11833579 A/A or G/A genotype may bring forward the onset age of first-ever ischemic stroke without increasing silent cerebrovascular lesions prior to the stroke. Further studies are required to confirm our preliminary findings.</p