More than skin deep: Functional genomic basis for resistance to Amphibian Chytridiomycosis

The amphibian-killing chytrid fungus Batrachochytriumdendrobatidis (Bd) is one of themost generalist pathogens known, capable of infecting hundreds of species globally and causing widespread population declines and extinctions. However, some host species are seemingly unaffected by Bd, tolerating or clearing infections without clinical signs of disease. Variation in host immune responses is commonly evoked for these resistant or tolerant species, yet to date,we have nodirect comparisonof amphibian species responses to infection at the level of gene expression. In this study,we challenged four CentralAmerican frog species that vary in Bd susceptibility, with a sympatric virulent strain of the pathogen. We compared skin and spleen orthologous gene expression using differential expression tests and coexpression gene network analyses.Wefound that resistant species have reduced skin inflammatory responses andincreased expressionofgenes involved inskin integrity. Incontrast, onlyhighly susceptible species exhibited suppressionof splenic T-cell genes. We conclude that resistance to chytridiomycosis may be related to a species’ ability to escape the immunosuppressive activity of the fungus. Moreover, our results indicate that within-species differences in splenic proteolytic enzyme gene expression may contribute to intraspecific variation in survival. This first comparison of amphibian functional immunogenomic architecture in response to Bd provides insights into key genetic mechanisms underlying variation in disease outcomes among amphibian species

Non-perturbative Landau gauge and infrared critical exponents in QCD

We discuss Faddeev-Popov quantization at the non-perturbative level and show that Gribov's prescription of cutting off the functional integral at the Gribov horizon does not change the Schwinger-Dyson equations, but rather resolves an ambiguity in the solution of these equations. We note that Gribov's prescription is not exact, and we therefore turn to the method of stochastic quantization in its time-independent formulation, and recall the proof that it is correct at the non-perturbative level. The non-perturbative Landau gauge is derived as a limiting case, and it is found that it yields the Faddeev-Popov method in Landau gauge with a cut-off at the Gribov horizon, plus a novel term that corrects for over-counting of Gribov copies inside the Gribov horizon. Non-perturbative but truncated coupled Schwinger-Dyson equations for the gluon and ghost propagators $D(k)$ and $G(k)$ in Landau gauge are solved asymptotically in the infrared region. The infrared critical exponents or anomalous dimensions, defined by $D(k) \sim 1/(k^2)^{1 + a_D}$ and $G(k) \sim 1/(k^2)^{1 + a_G}$ are obtained in space-time dimensions $d = 2, 3, 4$. Two possible solutions are obtained with the values, in $d = 4$ dimensions, $a_G = 1, a_D = -2$, or $a_G = [93 - (1201)^{1/2}]/98 \approx 0.595353, a_D = - 2a_G$.Comment: 26 pages. Modified 2.25.02 to update references and to clarify Introduction and Conclusio

Alterations of EGFR, p53 and PTEN that mimic changes found in basal-like breast cancer promote transformation of human mammary epithelial cells

Breast cancer can be classified into different molecular subtypes with varying clinical and pathological characteristics. The basal-like breast cancer subtype represents one of the most aggressive and lethal types of breast cancer, and due to poor mechanistic understanding, it lacks targeted therapy. Many basal-like breast cancer patient samples display alterations of established drivers of cancer development, including elevated expression of EGFR, p53 inactivating mutations and loss of expression of the tumor suppressor PTEN; however, their contribution to human basal-like breast cancer pathogenesis remains ill-defined. Using non-transformed human mammary epithelial cells, we set out to determine whether altering EGFR, p53 and PTEN in different combinations could contribute to basal-like breast cancer progression through transformation of cells. Altering PTEN in combination with either p53 or EGFR in contrast to any of the single alterations caused increased growth of transformed colonies in soft agar. Concomitantly modifying all three genes led to the highest rate of cellular proliferation and the greatest degree of anchorage-independent colony formation. Results from our effort to engineer a model of BBC expressing alterations of EGFR, p53 and PTEN suggest that these changes are cooperative and likely play a causal role in basal-like breast cancer pathogenesis. Consideration should be given to targeting EGFR and restoring p53 and PTEN signaling simultaneously as a strategy for treatment of this subtype of breast cancer

The E3 ubiquitin ligase TRIM25 regulates adipocyte differentiation via proteasomemediated degradation of PPAR gamma

Peroxisome proliferator-activated receptor gamma (PPAR??) is a ligand-dependent transcription factor that regulates adipocyte differentiation and glucose homeostasis. The transcriptional activity of PPAR?? is regulated not only by ligands but also by post-translational modifications (PTMs). In this study, we demonstrate that a novel E3 ligase of PPAR??, tripartite motif-containing 25 (TRIM25), directly induced the ubiquitination of PPAR??, leading to its proteasome-dependent degradation. During adipocyte differentiation, both TRIM25 mRNA and protein expression significantly decreased and negatively correlated with the expression of PPAR??. The stable expression of TRIM25 reduced PPAR?? protein levels and suppressed adipocyte differentiation in 3T3-L1 cells. In contrast, the specific knockdown of TRIM25 increased PPAR?? protein levels and stimulated adipocyte differentiation. Furthermore, TRIM25-knockout mouse embryonic fibroblasts (MEFs) exhibited an increased adipocyte differentiation capability compared with wild-type MEFs. Taken together, these data indicate that TRIM25 is a novel E3 ubiquitin ligase of PPAR?? and that TRIM25 is a novel target for PPAR??-associated metabolic diseases

SS18 Together with Animal-Specific Factors Defines Human BAF-Type SWI/SNF Complexes

Contains fulltext : 94049.pdf (publisher's version ) (Open Access

Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy

Estrogen receptor (ER) has a crucial role in normal breast development and is expressed in the most common breast cancer subtypes. Importantly, its expression is very highly predictive for response to endocrine therapy. Current endocrine therapies for ER-positive breast cancers target ER function at multiple levels. These include targeting the level of estrogen, blocking estrogen action at the ER, and decreasing ER levels. However, the ultimate effectiveness of therapy is limited by either intrinsic or acquired resistance. Identifying the factors and pathways responsible for sensitivity and resistance remains a challenge in improving the treatment of breast cancer. With a better understanding of coordinated action of ER, its coregulatory factors, and the influence of other intracellular signaling cascades, improvements in breast cancer therapy are emerging

Who is a Bully Anyway?: Examining Perceptions of Bullying among Parents and Children

Bullying is a common problem among youth, whether they have been a bully, victim, or both. The concern with bullying among youth is that it does not just start and stop at school and will impact a child’s interactions in a variety of settings, including out-of-school time activities. Therefore, as youth workers in the field of parks and recreation, we must seek ways to help children address issues related to bullying. Additionally, like with many aspects of children’s lives, we have to consider and foster ways to engage parents, noting that they play a key role in guiding young people’s behavior. Based on this understanding, we felt it was imperative to explore the perspectives of youth and their parents regarding approaches to addressing bullying among youth. To this end, we conducted a study to examine personal experiences and strategies guided by the following three goals: a) to understand how youth and their parents conceptualize bullying, b) to examine how youth and parents address bullying, and c) to explore the types of bullying issues that youth experience. We examined these goals by conducting individual interviews with eight children and eight parents in a rural community in the northeastern United States. Grounding the analysis in Social Cognitive Theory (Bandura, 1986), we found that due to a lack of knowledge and understanding of bullying, parents and youth frequently blur the lines between bully, victim, and friend. Additionally, both parents and youth had reactions toward incidents of bullying that varied from ignoring to directly acknowledging the situation through confrontation with the presumed bully. Children attempted a variety of strategies to combat personal experiences with bullying and often found parental advice to be ineffective. We concluded that youth workers in the field of parks and recreation must continue to provide spaces and programs for young people to develop strategies to address negative peer interactions in a positive and proactive way. Additionally, we suggest that youth workers should take a lead role in facilitating communication between parents, youth, and themselves in order to proactively address issues of bullying in advance of escalation