Demographic history of the Tibetan antelope Pantholops hodgsoni(chiru)

The Tibetan antelope(chiru,Pantholops hodgsoni),a heavily poached species and symbol of the QinghaiTibetan Plateau(QTP),is noted worldwide for its special calving migration.This species originated in the early Quaternary and it is interesting to know how the following climatic oscillations affected its demographic dynamics in the climate-sensitive QTP.In this study,we analyzed the mitochondrial D-loop region from 312 individuals sampled in all of the six major populations.We found high rates of gene flow and little genetic differentiation between populations,suggesting that the calving migration may have homogenized the genetic pool of this species.Both mismatch distribution analyses and coalescent simulations suggested that this species experienced a demographic expansion approximately 600-200 Kyt following the retreat of the large glaciers developed in the QTP at 800-600 Kyr,rather than at the end of the last glacial age,as previously suggested based on a limited sample size.In addition,we found evidence of a chiru population decrease probably related to the human settings at the QTP during the middle Holocene.     

Design of potent and selective GSK3β inhibitors with acceptable safety profile and pharmacokinetics

From potent and selective inhibitors of GSK3β displaying CYP1A2 inhibition and poor PK properties, mostly linked to metabolic instability and in vivo hydrolysis of the amide bond, we were able to obtain safe and orally available inhibitors with good half lives.     

Determination of total antibiotic resistance in waterborne bacteria in rivers and streams in Northern Ireland: Can antibiotic-resistant bacteria be an indicator of ecological change?

Antibiotic resistance (ABR) has now become a major public health issue. Relatively little studies have been published on the incidence of ABR in environmental isolates circulating within the community. A study was performed to determine the diversity of total ABR (intrinsic + acquired resistance) in waterborne bacteria. Surface water from 12 waterways, including 11 rivers/steams and 1 lake, were examined for the presence of ABR phenotypes, using a direct antibiotic susceptibility assay and demonstrated the presence of ABR (in increasing order of resistance), to the following 19 agents: amikacin (17%), gentamicin (17%), ciprofloxacin (33%), colistin (42%), linezolid (42%), tobramycin (42%), vancomycin (42%), ertapenem (67%), erythromycin (75%), meropenem (75%), rifampin (75%), teichoplanin (75%), tetracycline (75%), trimethoprim (75%), fusidic acid (83%), aztreonam (92%), clindamycin (92%), penicillin (92%) and cefoxitin (100%). Multiple resistance to the major classes of antibiotics was noted, which varied from one to six classes, with a mean resistance to 3.7 major antibiotics classes, with diminishing antibacterial effectiveness in the following order: aminoglycosides > fluoroquinolones > glycopeptides > macrolides > tetracyclines > β-lactams. Overall, these data indicate that waterborne bacteria are an important source of ABR determinants and contribute to the mass balance of ABR in the environment, and may be used as an indicator of ecological change in water ecosystems. The waterborne ABR organisms may potentially act as donors in pathogens, which may acquire these through horizontal gene transfer or other genetic exchange events, thus leading to clinically significant cases in both animal and human health. Therefore, environmental bacteria should not be regarded as being devoid of ABR determinants, simply because they are physically removed from clinical settings. Such bacteria have natural intrinsic resistance, as well as having the ability to acquire determinants from agricultural run-off and human wastewater discharge, which may contain ABR organisms, as well as sublethal concentrations of metabolically active antibiotic. The tracking of such organisms to their source may help determine the source of fecal pollution in aquatic ecosystems.     

Developments in clinical cell therapy

Immunotherapy has become an important part of hematopoietic stem cell (HSC) transplantation and cancer therapy. Regenerative and reparative properties of somatic cell-based therapies hold tremendous promise for repairing injured tissue, preventing and reversing damage to organs, and restoring balance to compromised immune systems. The principles and practices of the diverse aspects of immune therapy for cancer, HSC transplantation and regenerative medicine have many commonalities. This meeting report summarizes a workshop sponsored by the National Heart, Lung and Blood Institute (NHLBI) and Production Assistance for Cellular Therapies (PACT), held on 23–24 April 2009 at the National Institutes of Health (NIH, USA). A series of scientific sessions and speakers highlighted key aspects of the latest scientific, clinical and technologic developments in cell therapy, involving a unique set of cell products with a special emphasis on converging concepts in these fields.     

广义估计方程在CT显示方法研究数据分析中的应用

目的:探讨广义估计方程在CT显示方法研究中的应用.方法:采用SAS软件的GENMOD过程,应用广义估计方程方法分析CT显示方法研究实例.结果:给出了广义估计方程SAS程序,并对参数估计和两两比较结果进行解释.结论:广义估计方程能有效的分析CT显示方法研究中反应变量为两分类或多分类的非独立数据.     

Neonatal exposure to propylthiouracil induces a shift in lymphoid cell sub-populations in the developing postnatal male rat spleen and thymus

Evidence of the connections between the immune system and the thyroid axis is increasingly strong; however, much of the data are focused on immune effects of altered thyroid status in adults or rodents with congenital defects of the pituitary/thyroid axis. The object of the present study was to determine the effects of PTU-induced hypothyroidism on the developing immune system of the rat by focussing on both the spleen and thymus gland. Male Sprague-Dawley rat pups were exposed to PTU through maternal milk by giving the mothers 0.02% PTU in their drinking water starting on the pups' day of birth until day 24 (d24), shortly before weaning on d28. Animals were sampled on days 14, 22, 30, and 91. The mean body weight was decreased in the PTU-treated animals on days 14, 22, and 30. The mean spleen and thymic weights and cellularity were all decreased in the PTU-treated animals on d22 and d30. PTU exposure increased the proportion of NK cells in the spleen on days 14, 22, and 30. The proportion of T-cells was increased on days 22 and 30 with a particular increase in the CD4+ T-cells, resulting in an increase in the ratio of helper T-cells to suppressor/cytotoxic T-cells at d22. PTU also decreased the proportion of splenic B-cells at days 14, 22, and 30 which could explain the increased proportion of both NK and T-cells during these sampling periods. PTU treatment decreased the lytic ability of NK cells at d22, but no functional differences were observed at days 14, 30, 91, despite the increased proportion of NK cells in PTU-exposed animals at days 14, 22, and 30. PTU exposure also increased the proportion of CD4+CD8- cells in the thymus on d22 and caused an increase in both the CD4+CD8- and CD4-CD8+ populations on d30. These data suggest that the effects of temporary, PTU-induced hypothyroidism on the cell populations in the spleen partially result from transient changes in thymic T-cell development, including a shift towards increased CD4+CD8- cells. The data also suggest that temporary hypothyroidism early in development decreases B-cell development in a transient fashion. Temporary hypothyroidism induced from birth to the latter stages of the weaning period induced transitory effects on the spleen, thymus, and immune cell sub-populations--all of which recovered to normal values when the animals matured.     

Linking fungal morphogenesis with virulence

Pathogenic fungi have become an increasingly common cause of systemic disease in healthy people and those with impaired immune systems. Although a vast number of fungal species inhabit our planet, just a small number are pathogens, and one feature that links many of them is the ability to differentiate morphologically from mould to yeast, or yeast to mould. Morphological differentiation between yeast and mould forms has commanded attention for its putative impact on the pathogenesis of invasive fungal infections. This review explores the current body of evidence linking fungal morphogenesis and virulence. The topics addressed cover work on phase-locked fungal cells, expression of phase-specific virulence traits and modulation of host responses by fungal morphotypes. The effect of morphological differentiation on fungal interaction with host cells, immune modulation and the net consequence on pathogenesis of disease in animal model systems are considered. The evidence argues strongly that morphological differentiation plays a vital role in the pathogenesis of fungal infection, suggesting that factors associated with this conversion process represent promising therapeutic targets.     

Agrobacterium tumefaciens integrates transfer DNA into single chromosomal sites of dimorphic fungi and yields homokaryotic progeny from multinucleate yeast

The dimorphic fungi Blastomyces dermatitidis and Histoplasma capsulatum cause systemic mycoses in humans and other animals. Forward genetic approaches to generating and screening mutants for biologically important phenotypes have been underutilized for these pathogens. The plant-transforming bacterium Agrobacterium tumefaciens was tested to determine whether it could transform these fungi and if the fate of transforming DNA was suited for use as an insertional mutagen. Yeast cells from both fungi and germinating conidia from B. dermatitidis were transformed via A. tumefaciens by using hygromycin resistance for selection. Transformation frequencies up to 1 per 100 yeast cells were obtained at high effector-to-target ratios of 3,000:1. B. dermatitidis and H. capsulatum ura5 lines were complemented with transfer DNA vectors expressing URA5 at efficiencies 5 to 10 times greater than those obtained using hygromycin selection. Southern blot analyses indicated that in 80% of transformants the transferred DNA was integrated into chromosomal DNA at single, unique sites in the genome. Progeny of B. dermatitidis transformants unexpectedly showed that a single round of colony growth under hygromycin selection or visible selection of transformants by lacZ expression generated homokaryotic progeny from multinucleate yeast. Theoretical analysis of random organelle sorting suggests that the majority of B. dermatitidis cells would be homokaryons after the ca. 20 generations necessary for colony formation. Taken together, the results demonstrate that A. tumefaciens efficiently transfers DNA into B. dermatitidis and H. capsulatum and has the properties necessary for use as an insertional mutagen in these fungi.     

A common factor regulates both Th1- and Th2-specific cytokine gene expression.

Murine T helper cell clones are classified into two distinct subsets, T helper 1 (Th1) and T helper 2 (Th2), on the basis of cytokine secretion patterns. Th1 clones produce interleukin-2 (IL-2), tumor necrosis factor-beta (TNF-beta) and interferon-gamma (IFN-gamma), while Th2 clones produce IL-4, IL-5, IL-6 and IL-10. These subsets differentially promote delayed-type hypersensitivity or antibody responses, respectively. The nuclear factor NF-AT is induced in Th1 clones stimulated through the T cell receptor-CD3 complex, and is required for IL-2 gene induction. The NF-AT complex consists of two components: NF-ATp, which pre-exists in the cytosol and whose appearance in the nucleus is induced by an increase of intracellular calcium, and a nuclear AP-1 component whose induction is dependent upon activation of protein kinase C (PKC). Here we report that the induction of the Th2-specific IL-4 gene in an activated Th2 clone involves an NF-AT complex that consists only of NF-ATp, and not the AP-1 component. On the basis of binding experiments we show that this 'AP-1-less' NF-AT complex is specific for the IL-4 promoter and does not reflect the inability of activated Th2 cells to induce the AP-1 component. We propose that NF-ATp is a common regulatory factor for both Th1 and Th2 cytokine genes, and that the involvement of PKC-dependent factors, such as AP-1, may help determine Th1-/Th2-specific patterns of gene expression.