Nonadaptive Amino Acid Convergence Rates Decrease over Time.

Convergence is a central concept in evolutionary studies because it provides strong evidence for adaptation. It also provides information about the nature of the fitness landscape and the repeatability of evolution, and can mislead phylogenetic inference. To understand the role of adaptive convergence, we need to understand the patterns of nonadaptive convergence. Here, we consider the relationship between nonadaptive convergence and divergence in mitochondrial and model proteins. Surprisingly, nonadaptive convergence is much more common than expected in closely related organisms, falling off as organisms diverge. The extent of the convergent drop-off in mitochondrial proteins is well predicted by epistatic or coevolutionary effects in our "evolutionary Stokes shift" models and poorly predicted by conventional evolutionary models. Convergence probabilities decrease dramatically if the ancestral amino acids of branches being compared have diverged, but also drop slowly over evolutionary time even if the ancestral amino acids have not substituted. Convergence probabilities drop-off rapidly for quickly evolving sites, but much more slowly for slowly evolving sites. Furthermore, once sites have diverged their convergence probabilities are extremely low and indistinguishable from convergence levels at randomized sites. These results indicate that we cannot assume that excessive convergence early on is necessarily adaptive. This new understanding should help us to better discriminate adaptive from nonadaptive convergence and develop more relevant evolutionary models with improved validity for phylogenetic inference

Intrachromosomal recombination mediated by the polyomavirus large T antigen

AbstractWe used a spleen necrosis virus-based retroviral vector to introduce the polyomavirus replication origin into rat cells and developed a system to analyze homologous recombination events that do not reconstitute a selectable marker. Introduction of the gene coding for the polyomavirus large T antigen into the cell lines by DNA transfection promoted high-frequency recombination between the two retroviral LTRs, leading to amplification and excision of DNA sequences. To analyze homology requirements, we constructed cell lines carrying only the replication origin without exogenous repeats. Most of the cell lines sustained high-frequency recombination, presumably by undergoing homologous recombination between repetitive DNA lying in the vicinity of the integrated origin. Our results indicate that homologous recombination promoted by large T antigen does not require recombination hot spots in the viral genome other than the replication origin and they explain the cytotoxicity observed in some cell types when large T antigen is expressed in the presence of a functional origin

Diwali Dinner

Join SALSA for an evening of networking, food and entertainment.https://larc.cardozo.yu.edu/flyers-2017-2018/1010/thumbnail.jp

Trend of transfusion transmitted infections frequency in blood donors: provide a road map for its prevention and control

<p>Abstract</p> <p>Background</p> <p>Transfusion transmitted infections create significant burden on health care system. Donor selection is of paramount importance because infected individuals serve as an asymptomatic reservoir and a potential source of transmission.</p> <p>Methods</p> <p>A retrospective study was carried out in healthy blood donors in the Lady Reading Hospital Peshawar, Pakistan over a period of three and a half years i.e., from January 2008 to June 2011, to determine the prevalence of HBV, HCV, HIV and syphilis in order to provide information for relevant polices.</p> <p>Results</p> <p>Out of 1,27,828 sample of blood donors, recorded mean prevalence for HBs Ag, anti-HCV, anti-HIV and syphilis was 2.68%, 2.46%, 0.06% and 0.43%, respectively, with an increasing trend in frequencies of transfusion transmitted infections (TTIs).</p> <p>Conclusions</p> <p>This study reflects that blood transfusion is one of the leading risk factor of spread of the TTIs, which showed the need and importance of the mandatory screening of these infectious markers in blood donations.</p

Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cellconditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment

IRES-Mediated Translation of Utrophin A Is Enhanced by Glucocorticoid Treatment in Skeletal Muscle Cells

Glucocorticoids are currently the only drug treatment recognized to benefit Duchenne muscular dystrophy (DMD) patients. The nature of the mechanisms underlying the beneficial effects remains incompletely understood but may involve an increase in the expression of utrophin. Here, we show that treatment of myotubes with 6α−methylprednisolone-21 sodium succinate (PDN) results in enhanced expression of utrophin A without concomitant increases in mRNA levels thereby suggesting that translational regulation contributes to the increase. In agreement with this, we show that PDN treatment of cells transfected with monocistronic reporter constructs harbouring the utrophin A 5′UTR, causes an increase in reporter protein expression while leaving levels of reporter mRNAs unchanged. Using bicistronic reporter assays, we further demonstrate that PDN enhances activity of an Internal Ribosome Entry Site (IRES) located within the utrophin A 5′UTR. Analysis of polysomes demonstrate that PDN causes an overall reduction in polysome-associated mRNAs indicating that global translation rates are depressed under these conditions. Importantly, PDN causes an increase in the polysome association of endogenous utrophin A mRNAs and reporter mRNAs harbouring the utrophin A 5′UTR. Additional experiments identified a distinct region within the utrophin A 5′UTR that contains the inducible IRES activity. Together, these studies demonstrate that a translational regulatory mechanism involving increased IRES activation mediates, at least partially, the enhanced expression of utrophin A in muscle cells treated with glucocorticoids. Targeting the utrophin A IRES may thus offer an important and novel therapeutic avenue for developing drugs appropriate for DMD patients