Fighting a losing battle: Vigorous immune response countered by pathogen suppression of host defenses in the chytridiomycosis-susceptible frog Atelopus zeteki

The emergence of the disease chytridiomycosis caused by the chytrid fungus Batrachochytrium dendrobatidis (Bd) has been implicated in dramatic global amphibian declines. Although many species have undergone catastrophic declines and/or extinctions, others appear to be unaffected or persist at reduced frequencies after Bd outbreaks. The reasons behind this variance in disease outcomes are poorly understood: differences in host immune responses have been proposed, yet previous studies suggest a lack of robust immune responses to Bd in susceptible species. Here, we sequenced transcriptomes from clutchmates of a highly susceptible amphibian, Atelopus zeteki, with different infection histories. We found significant changes in expression of numerous genes involved in innate and inflammatory responses in infected frogs despite high susceptibility to chytridiomycosis. We show evidence of acquired immune responses generated against Bd, including increased expression of immunoglobulins and major histocompatibility complex genes. In addition, fungal-killing genes had significantly greater expression in frogs previously exposed to Bd compared with Bd-naïve frogs, including chitinase and serine-type proteases. However, our results appear to confirm recent in vitro evidence of immune suppression by Bd, demonstrated by decreased expression of lymphocyte genes in the spleen of infected compared with control frogs. We propose susceptibility to chytridiomycosis is not due to lack of Bd-specific immune responses but instead is caused by failure of those responses to be effective. Ineffective immune pathway activation and timing of antibody production are discussed as potential mechanisms. However, in light of our findings,suppression of key immune responses by Bd is likely an important factor in the lethality of this fungus

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

Determination of ΛMS‾\Lambda_{\overline{MS}} from quenched and Nf=2N_f = 2 dynamical QCD

The scale parameter $\Lambda_{\overline{MS}}$ is computed on the lattice in the quenched approximation and for $N_f = 2$ flavors of light dynamical quarks. The dynamical calculation is done with non-perturbatively $O(a)$ improved Wilson fermions. In the continuum limit we obtain $\Lambda_{\overline{MS}}^{N_f=0} = 243(1)(10)$ MeV and $\Lambda_{\overline{MS}}^{N_f=2} = 217(16)(11)$ MeV, respectively.Comment: 16 pages, 6 figures. Minor changes. Final version to be published in Phys. Lett.

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

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

Obstetric and perinatal care units functioning during the COVID-19 pandemic

The rapid spread of COVID-19 and the large number of cases put a significant burden on the health systems of any developed country. Specialists in natural disasters and military medicine should be involved in the provision of medical care and observance of anti-epidemic measures. In some countries, including Italy, they were involved only after the situation was dramatically worsening with many clinical units and hospitals overloaded by infected patients. To curb the spread of COVID-19, most countries declared a state of emergency, and unprecedented measures have been taken to strengthen quarantine in suspected or positive symptomatic subjects. Nevertheless, the crisis associated with the unexpectedly global scale and tragedy of the pandemic and the inconsistency of actions of both society and individuals and specialized medical services, lead to insufficient effectiveness of the measures taken in a number of regions. In the present day, it is vital for every person to change its mindset ― relying on personal responsibility to comply with all recommendations of quarantine and anti-epidemic measures, and to reorganize departments and resources of medical institutions at all levels in order to withstand the spread of infection and at the same time provide all those in need with the necessary and appropriate medical care. Particular attention should be paid to the obstetric care service, given that even in “normal” times, the obstetric hospital is an area of increased responsibility for the life and health of mother and child and future mankind. Fulfillment of existing orders, instructions of national and regional committees, international and national protocols and clinical protocols should undoubtedly lead to a positive result, but this requires additional training of medical personnel at all levels. The purpose of this review is to propose quick key strategies for reassessing the maternity and neonatal wards/ hospitals based on the experience of health systems and organizations which faced the spread of this new coronavirus; this advice may be applied along with binding tight instructions in obstetric hospitals in order to proactively respond to a likely wave of growth in COVID-19