Role of PINCH and Its Partner Tumor Suppressor Rsu-1 in Regulating Liver Size and Tumorigenesis

Particularly interesting new cysteine-histidine-rich protein (PINCH) protein is part of the ternary complex known as the IPP (integrin linked kinase (ILK)-PINCH-Parvin-α) complex. PINCH itself binds to ILK and to another protein known as Rsu-1 (Ras suppressor 1). We generated PINCH 1 and PINCH 2 Double knockout mice (referred as PINCH DKO mice). PINCH2 elimination was systemic whereas PINCH1 elimination was targeted to hepatocytes. The genetically modified mice were born normal. The mice were sacrificed at different ages after birth. Soon after birth, they developed abnormal hepatic histology characterized by disorderly hepatic plates, increased proliferation of hepatocytes and biliary cells and increased deposition of extracellular matrix. After a sustained and prolonged proliferation of all epithelial components, proliferation subsided and final liver weight by the end of 30 weeks in livers with PINCH DKO deficient hepatocytes was 40% larger than the control mice. The livers of the PINCH DKO mice were also very stiff due to increased ECM deposition throughout the liver, with no observed nodularity. Mice developed liver cancer by one year. These mice regenerated normally when subjected to 70% partial hepatectomy and did not show any termination defect. Ras suppressor 1 (Rsu-1) protein, the binding partner of PINCH is frequently deleted in human liver cancers. Rsu-1 expression is dramatically decreased in PINCH DKO mouse livers. Increased expression of Rsu-1 suppressed cell proliferation and migration in HCC cell lines. These changes were brought about not by affecting activation of Ras (as its name suggests) but by suppression of Ras downstream signaling via RhoGTPase proteins. In conclusion, our studies suggest that removal of PINCH results in enlargement of liver and tumorigenesis. Decreased levels of Rsu-1, a partner for PINCH and a protein often deleted in human liver cancer, may play an important role in the development of the observed phenotype. © 2013 Donthamsetty et al

Light Scalar Mesons as Manifestation of Spontaneously Broken Chiral Symmetry

Attention is paid to the production mechanisms of light scalars that reveal their nature. We reveal the chiral shielding of the \sigma(600) meson. We show that the kaon loop mechanism of the \phi radiative decays, ratified by experiment, points to the four-quark nature of light scalars. We show also that the light scalars are produced in the two photon collisions via four-quark transitions in contrast to the classic P wave tensor q\bar q mesons that are produced via two-quark transitions $\gamma\gamma\to q\bar q$. The history of spontaneous breaking of symmetry in quantum physics is discussed in Appendix.Comment: Talk at The International Bogolyubov Conference "Problems of Theoretical and Mathematical Physics" devoted to the 100th anniversary of N.N.Bogolyubov's birth that was held from August 21 to August 22,2009 in Moscow at the Russian Academy of Sciences (RAS) and from August 23 to August 27, 2009 in Dubna at the Joint Institute for Nuclear Research (JINR

Consequences of intrauterine growth restriction for the kidney

Low birth weight due to intrauterine growth restriction is associated with various diseases in adulthood, such as hypertension, cardiovascular disease, insulin resistance and end-stage renal disease. The purpose of this review is to describe the effects of intrauterine growth restriction on the kidney. Nephrogenesis requires a fine balance of many factors that can be disturbed by intrauterine growth restriction, leading to a low nephron endowment. The compensatory hyperfiltration in the remaining nephrons results in glomerular and systemic hypertension. Hyperfiltration is attributed to several factors, including the renin-angiotensin system (RAS), insulin-like growth factor (IGF-I) and nitric oxide. Data from human and animal studies are presented, and suggest a faltering IGF-I and an inhibited RAS in intrauterine growth restriction. Hyperfiltration makes the kidney more vulnerable during additional kidney disease, and is associated with glomerular damage and kidney failure in the long run. Animal studies have provided a possible therapy with blockage of the RAS at an early stage in order to prevent the compensatory glomerular hyperfiltration, but this is far from being applicable to humans. Research is needed to further unravel the effect of intrauterine growth restriction on the kidney

Russian solar on Baikal

The major summer event in the Russian semiconductor community was a July workshop ‘Silicon-2004’ organised and hosted by the Institute of Geochemistry of the Siberian Branch of the Russian Academy of Sciences (IG SB RAS) in Irkutsk (Fig 1).Some 150 participants from all corners of Russia and abroad (Belarus, Ukraine, Kazakhstan, Germany, Hungary, India) gathered in the beautiful Pribaikalskii hotel - at the birth place of the Angara river - to discuss all aspects of science and technology of the element No 14, the emphasis being placed on ‘solar’ silicon

New e-health services for the European Network for Rare and Congenital Anaemias (e-ENERCA)

Rare Anaemias (RA) are a group of Rare Diseases (RD) with prevalence, in Europe, less than 5 per 10.000 individuals. Major forms of RAs require red blood cell transfusions, iron chelation, splenectomy, and/or in very severe cases, bone marrow transplantation, as main therapeutic options. Beta-thalassaemia major is predominant in Italy and Cyprus, and sickle cell disease (SCD) in African population. During the last 30 years, SCD is increasing in Europe due to African immigration, leading to an important impact on health care burden in several countries. Preventive programs, aiming to epidemiological control, and improvement of diagnosis and clinical management of major RA, are crucial for decreasing the affected birth rate and achieving an efficient balance between morbidity and patient’s life expectancy. Since 2003, the European Network for Rare and Congenital Anaemias (ENERCA) has taken an active role for improving this situation by the following actions: a) the identification of Centres of Expertise on RAs in Europe according to the recommendations of ENERCA White Book b) the promotion of best clinical and laboratory practices by the publication of ENERCA recommendations c) the improving of continuous medical education, by organising topic-specific training courses, workshops and symposia, e) the empowerment of patients, by cooperation with Patient’s Associations, and co-organizing a bi-annual European Symposium on RAs with interactive patients-health professionals sessions. In September 2013, a new phase of the project called e-ENERCA has started with the aim to provide, patients and professionals with e-Health tools for assure the same access to health services in RAs across Europe, independently from the country of practise and origin of the patients. e-Health services will be developed through the set-up of three different e-platforms endorsed by ENERCA website (http://www.enerca.org) : 1) e-Registry, a Pan European registry of RAs for gathering patient’s data necessary to achieve the required sample size for epidemiological surveillance and clinical research 2) e-Learning , a teaching platform for the dissemination of knowledge, continuous medical education, and best practices awareness and promotion through Internet, and 3) e-Medicine , a platform to provide, at distance, expertise (telexpertise) and diagnostic facilities (telediagnosis), avoiding, when possible, the need of travelling. Finally, e-ENERCA will also promote the recognition of the previously identified Centres of Expertise in RAs (White Book) by the national health authorities, a mandatory condition for ENERCA final recognition as European Reference Network in Rare Anaemias (RA-ERN)

Formation rates of core collapse SNe and GRBs

We study the evolution of stars that may be the progenitors of long-soft gamma-ray burst (GRBs) -- rotating naked helium stars presumed to have lost their envelopes to winds or companions. Our aim is to investigate the formation and development of single and binary systems and from this population evaluate the rates of interesting individual species. Using a rapid binary evolution algorithm, that enables us to model the most complex binary systems and to explore the effect of metallicity on GRB production, we draw the following conclusions. First we find that, if we include an approximate treatment of angular momentum transport by mass loss, the resulting spin rates for single stars become too low to form a centrifugally supported disc that can drive a GRB engine. Second massive stars in binaries result in enough angular momentum -- due to spin-orbit tidal interactions -- to form a centrifugally supported disc and are thus capable of supplying a sufficient number of progenitors. This holds true even if only a small fraction of bursts are visible to a given observer and the GRB rate is several hundred times larger than the observed rate. Third low-metallicity stars aid the formation of a rapidly rotating, massive helium cores at collapse and so their evolution is likely to be affected by the local properties of the ISM. This effect could increase the GRB formation rate by a factor of 5-7 at Z=Z_solar/200. Finally we quantify the effects of mass loss, common-envelope evolution and black-hole formation and show that more stringent constraints to many of these evolution parameters are needed in order to draw quantitative conclusions from population synthesis work.Comment: 37 pages, 14 figures, MNRAS in pres

Yolk sac erythromyeloid progenitors expressing gain of function PTPN11 have functional features of JMML but are not sufficient to cause disease in mice

Background: Accumulating evidence suggests the origin of juvenile myelomonocytic leukemia (JMML) is closely associated with fetal development. Nevertheless, the contribution of embryonic progenitors to JMML pathogenesis remains unexplored. We hypothesized that expression of JMML-initiating PTPN11 mutations in HSC-independent yolk sac erythromyeloid progenitors (YS EMPs) would result in a mouse model of pediatric myeloproliferative neoplasm (MPN). Results: E9.5 YS EMPs from VavCre+;PTPN11D61Y embryos demonstrated growth hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and hyperactive RAS-ERK signaling. Mutant EMPs engrafted the spleens of neonatal recipients, but did not cause disease. To assess MPN development during unperturbed hematopoiesis we generated CSF1R-MCM+;PTPN11E76K;ROSAYFP mice in which oncogene expression was restricted to EMPs. Yellow fluorescent protein-positive progeny of mutant EMPs persisted in tissues one year after birth and demonstrated hyperactive RAS-ERK signaling. Nevertheless, these mice had normal survival and did not demonstrate features of MPN. Conclusions: YS EMPs expressing mutant PTPN11 demonstrate functional and molecular features of JMML but do not cause disease following transplantation nor following unperturbed development

Star formation history, double degenerates and type Ia supernovae in the thin disc

We investigate the relation between the star formation history and the evolution of the double-degenerate (DD) population in the thin disc of the Galaxy, which we assume to have formed 10 Gyr before the present. We introduce the use of star-formation contribution functions as a device for evaluating the birth rates, total number and merger rates of DDs. These contribution functions help to demonstrate the relation between star-formation history and the current DD population and, in particular, show how the numbers of different types of DD are sensitive to different epochs of star formation. We have compared the impact of different star-formation models on the rates and numbers of DDs and on the rates of type Ia (SNIa) and core-collapse supernovae (ccSN). In addition to a quasi-exponential decline model, we considered an instantaneous (or initial starburst) model, a constant-rate model, and an enhanced-rate model. All were normalised to produce the present observed star density in the local thin disc. The evolution of the rates and numbers of both DDs and SNIa are different in all four models, but are most markedly different in the instantaneous star-formation model, which produces a much higher rate than the other three models in the past, primarily as a consequence of the normalisation. Predictions of the current SNIa rate range from ~2 to 5\times10^{-4} yr^{-1} in the four models, and are slightly below the observed rate because we only consider the DD merger channel. The predicted ccSN rate ranges from 1.5 to 3 century^{-1}, and is consistent with observations.Comment: 11 pages, 16 figures, accepted for publication in MNRA