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التمهيد في وراثة المحافظة
يركز هذا الكتاب على القضايا الرئيسية في مجال المحافظة على الحياة البرية وإدارتها، كالتنوع الوراثي في العشائر الطبيعية وقياسه، والأسباب المؤدية لفقدانه، والتناسل الداخلي وكيفية قياسه، وتأثيره على اللياقة، وحل القضايا المتعلقة بالشكوك التصنيفية، والإدارة الوراثية للأنواع المهددة. لقد صمم هذا الكتاب ونسق بطريقة جذابة تسهل على القارئ فهم محتواه، مع طرح بعض الأمثلة لأنواع منقرضة، وأنواع مهددة، وأنواع تميت استعادتها من حافة الانقراض. لقد صمم هذا الكتاب ليكون مرجعا للمقررات الجامعية التي تعنى بوراثة العشائر، ووراثة وبيولوجيا المحافظة، والإنتاج النباتي والحيواني. كما أنه مناسب للعاملين في حقل المحافظة على الحياة البرية، وحدائق الحيوان، والعاملين في مزارع تربية الحيوان الذين يحتاجون إلى مرجع يسهل الوصول فيه إلى المعلومات ذات العلاقة.
BOOK
Microfluidic platform for the quantitative analysis of leukocyte migration signatures
Leukocyte migration into tissues is characteristic of inflammation. It is usually measured
in vitro
as the average displacement of populations of cells towards a chemokine gradient, not acknowledging other patterns of cell migration. Here, we designed and validated a microfluidic migration platform to simultaneously analyse four qualitative migration patterns: chemoattraction, -repulsion, -kinesis and -inhibition, using single-cell quantitative metrics of direction, speed, persistence and fraction of cells responding. We find that established chemokines, complement component 5a and IL-8 induce chemoattraction and repulsion in equal proportions, resulting in the dispersal of cells. These migration signatures are characterized by high persistence and speed and are independent of the chemokine dose or receptor expression. Furthermore, we find that twice as many T lymphocytes migrate away than towards stromal cell-derived factor 1 and their directional migration patterns are not persistent. Overall, our platform helps discover migratory signature responses and uncovers an avenue for precise characterization of leukocyte migration and therapeutic modulators.
Current leukocyte migration assays usually report bulk attractive behaviour of cells within a chemokine gradient. Here, the authors develop a microfluidic device to simultaneously measure several migration responses on exposure to commonly used leukocyte chemokines, and report previously unrecognized cell behaviour.
Journal Article
Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction
Pulse-like expression of VEGF-A from modified RNA extends survival in a mouse model of myocardial infarction.
In a cell-free approach to regenerative therapeutics, transient application of paracrine factors
in vivo
could be used to alter the behavior and fate of progenitor cells to achieve sustained clinical benefits. Here we show that intramyocardial injection of synthetic modified RNA (modRNA) encoding human vascular endothelial growth factor-A (VEGF-A) results in the expansion and directed differentiation of endogenous heart progenitors in a mouse myocardial infarction model. VEGF-A modRNA markedly improved heart function and enhanced long-term survival of recipients. This improvement was in part due to mobilization of epicardial progenitor cells and redirection of their differentiation toward cardiovascular cell types. Direct
in vivo
comparison with DNA vectors and temporal control with VEGF inhibitors revealed the greatly increased efficacy of pulse-like delivery of VEGF-A. Our results suggest that modRNA is a versatile approach for expressing paracrine factors as cell fate switches to control progenitor cell fate and thereby enhance long-term organ repair.
Journal Article
Neuropilin-2 functions as a coinhibitory receptor to regulate antigen-induced inflammation and allograft rejection
Coinhibitory receptors function as central modulators of the immune response to resolve T effector activation and/or to sustain immune homeostasis. Here, using humanized SCID mice, we found that neuropilin-2 (NRP2) is inducible on late effector and exhausted subsets of human CD4+ T cells and that it is coexpressed with established coinhibitory molecules including PD-1, CTLA4, TIGIT, LAG3, and TIM3. In murine models, we also found that NRP2 is expressed on effector memory CD4+ T cells with an exhausted phenotype and that it functions as a key coinhibitory molecule. Knockout (KO) of NRP2 resulted in hyperactive CD4+ T cell responses and enhanced inflammation in delayed-type hypersensitivity and transplantation models. After cardiac transplantation, allograft rejection and graft failure were accelerated in global as well as CD4+ T cell-specific KO recipients, and enhanced alloimmunity was dependent on NRP2 expression on CD4+ T effectors but not on CD4+Foxp3+ Tregs. Also, KO Tregs were found to be as efficient as WT cells in the suppression of effector responses in vitro and in vivo. These collective findings identify NRP2 as a potentially novel coinhibitory receptor and demonstrate that its expression on CD4+ T effector cells is of great functional importance in immunity.
Journal Article
Convergent and Divergent Migratory Patterns of Human Neutrophils inside Microfluidic Mazes
Neutrophils are key cellular components of the innate immune response and characteristically migrate from the blood towards and throughout tissues. Their migratory process is complex, guided by multiple chemoattractants released from injured tissues and microbes. How neutrophils integrate the various signals in the tissue microenvironment and mount effective responses is not fully understood. Here, we employed microfluidic mazes that replicate features of interstitial spaces and chemoattractant gradients within tissues to analyze the migration patterns of human neutrophils. We find that neutrophils respond to LTB4 and fMLF gradients with highly directional migration patterns and converge towards the source of chemoattractant. We named this directed migration pattern
convergent
. Moreover, neutrophils respond to gradients of C5a and IL-8 with a low-directionality migration pattern and disperse within mazes. We named this alternative migration pattern
divergent
. Inhibitors of MAP kinase and PI-3 kinase signaling pathways do not alter either convergent or divergent migration patterns, but reduce the number of responding neutrophils. Overlapping gradients of chemoattractants conserve the convergent and divergent migration patterns corresponding to each chemoattractant and have additive effects on the number of neutrophils migrating. These results suggest that convergent and divergent neutrophil migration-patterns are the result of simultaneous activation of multiple signaling pathways.
Journal Article
Regulation of mTOR Signaling by Semaphorin 3F-Neuropilin 2 Interactions In Vitro and In Vivo
Semaphorin 3F (SEMA3F) provides neuronal guidance cues via its ability to bind neuropilin 2 (NRP2) and Plexin A family molecules. Recent studies indicate that SEMA3F has biological effects in other cell types, however its mechanism(s) of function is poorly understood. Here, we analyze SEMA3F-NRP2 signaling responses in human endothelial, T cell and tumor cells using phosphokinase arrays, immunoprecipitation and Western blot analyses. Consistently, SEMA3F inhibits PI-3K and Akt activity and responses are associated with the disruption of mTOR/rictor assembly and mTOR-dependent activation of the RhoA GTPase. We also find that the expression of vascular endothelial growth factor, as well as mTOR-inducible cellular activation responses and cytoskeleton stability are inhibited by SEMA3F-NRP2 interactions
in vitro
.
In vivo
, local and systemic overproduction of SEMA3F reduces tumor growth in NRP2-expressing xenografts. Taken together, SEMA3F regulates mTOR signaling in diverse human cell types, suggesting that it has broad therapeutic implications.
Journal Article
Environmental Complexity and Biodiversity: The Multi-Layered Evolutionary History of a Log-Dwelling Velvet Worm in Montane Temperate Australia
Phylogeographic studies provide a framework for understanding the importance of intrinsic versus extrinsic factors in shaping patterns of biodiversity through identifying past and present microevolutionary processes that contributed to lineage divergence. Here we investigate population structure and diversity of the Onychophoran (velvet worm) Euperipatoides rowelli in southeastern Australian montane forests that were not subject to Pleistocene glaciations, and thus likely retained more forest cover than systems under glaciation. Over a ~100 km transect of structurally-connected forest, we found marked nuclear and mitochondrial (mt) DNA genetic structuring, with spatially-localised groups. Patterns from mtDNA and nuclear data broadly corresponded with previously defined geographic regions, consistent with repeated isolation in refuges during Pleistocene climatic cycling. Nevertheless, some E. rowelli genetic contact zones were displaced relative to hypothesized influential landscape structures, implying more recent processes overlying impacts of past environmental history. Major impacts at different timescales were seen in the phylogenetic relationships among mtDNA sequences, which matched geographic relationships and nuclear data only at recent timescales, indicating historical gene flow and/or incomplete lineage sorting. Five major E. rowelli phylogeographic groups were identified, showing substantial but incomplete reproductive isolation despite continuous habitat. Regional distinctiveness, in the face of lineages abutting within forest habitat, could indicate pre- and/or postzygotic gene flow limitation. A potentially functional phenotypic character, colour pattern variation, reflected the geographic patterns in the molecular data. Spatial-genetic patterns broadly match those in previously-studied, co-occurring low-mobility organisms, despite a variety of life histories. We suggest that for E. rowelli, the complex topography and history of the region has led to interplay among limited dispersal ability, historical responses to environmental change, local adaptation, and some resistance to free admixture at geographic secondary contact, leading to strong genetic structuring at fine spatial scale.
Journal Article
Spatial scaling of microbial eukaryote diversity
Patterns in the spatial distribution of organisms provide important information about mechanisms that regulate the diversity of life and the complexity of ecosystems
1
,
2
. Although microorganisms may comprise much of the Earth's biodiversity
3
,
4
and have critical roles in biogeochemistry and ecosystem functioning
5
,
6
,
7
, little is known about their spatial diversification. Here we present quantitative estimates of microbial community turnover at local and regional scales using the largest spatially explicit microbial diversity data set available (> 10
6
sample pairs). Turnover rates were small across large geographical distances, of similar magnitude when measured within distinct habitats, and did not increase going from one vegetation type to another. The taxa–area relationship of these terrestrial microbial eukaryotes was relatively flat (slope
z
= 0.074) and consistent with those reported in aquatic habitats
8
,
9
. This suggests that despite high local diversity, microorganisms may have only moderate regional diversity. We show how turnover patterns can be used to project taxa–area relationships up to whole continents. Taxa dissimilarities across continents and between them would strengthen these projections. Such data do not yet exist, but would be feasible to collect.
Journal Article
Does Inbreeding and Loss of Genetic Diversity Decrease Disease Resistance?
Inbreeding and loss of genetic diversity are predicted to decrease the resistance of species to disease. However, this issue is controversial and there is limited rigorous scientific evidence available. To test whether inbreeding and loss of genetic diversity affect a host's resistance to disease, Drosophila melanogasterpopulations with different levels of inbreeding and genetic diversity were exposed separately to (a) thuringiensin, an insecticidal toxin produced by some strains of Bacillus thuringiensis, and (b) live Serratia marcescensbacteria. Inbreeding and loss of genetic diversity significantly reduced resistance of D. melanogasterto both the thuringiensin toxin and live Serratia marcescens. For both, the best fitting relationships between resistance and inbreeding were curvilinear. As expected, there was wide variation among replicate inbred populations in disease resistance. Lowered resistances to both the toxin and the pathogen in inbred populations were due to specific resistance alleles, rather than generalized inbreeding effects, as correlations between resistance and population fitness were low or negative. Wildlife managers should strive to minimise inbreeding and loss of genetic diversity within threatened populations and to minimise exposure of inbred populations to disease.[PUBLICATION ABSTRACT]
Journal Article
Proinflammatory functions of vascular endothelial growth factor in alloimmunity
Vascular endothelial growth factor (VEGF), an established angiogenesis factor, is expressed in allografts undergoing rejection, but its function in the rejection process has not been defined. Here, we initially determined that VEGF is functional in the trafficking of human T cells into skin allografts in vivo in the humanized SCID mouse. In vitro, we found that VEGF enhanced endothelial cell expression of the chemokines monocyte chemoattractant protein 1 and IL-8, and in combination with IFN-gamma synergistically induced endothelial cell production of the potent T cell chemoattractant IFN-inducible protein-10 (IP-10). Treatment of BALB/c (H-2d) recipients of fully MHC-mismatched C57BL/6 (H-2b) donor hearts with anti-VEGF markedly inhibited T cell infiltration of allografts and acute rejection. Anti-VEGF failed to inhibit T cell activation responses in vivo, but inhibited intragraft expression of several endothelial cell adhesion molecules and chemokines, including IP-10. In addition, whereas VEGF expression was increased, neovascularization was not associated with acute rejection, and treatment of allograft recipients with the angiogenesis inhibitor endostatin failed to inhibit leukocyte infiltration of the grafts. Thus, VEGF appears to be functional in acute allograft rejection via its effects on leukocyte trafficking. Together, these observations provide mechanistic insight into the proinflammatory function of VEGF in immunity.
Journal Article