SHORT syndrome due to a novel de novo mutation in PRKCE (Protein Kinase Cɛ) impairing TORC2-dependent AKT activation.

SHORT syndrome is a rare, recognizable syndrome resulting from heterozygous mutations in PIK3R1 encoding a regulatory subunit of phosphoinositide-3-kinase (PI3K). The condition is characterized by short stature, intrauterine growth restriction, lipoatrophy and a facial gestalt involving a triangular face, deep set eyes, low hanging columella and small chin. PIK3R1 mutations in SHORT syndrome result in reduced signaling through the PI3K-AKT-mTOR pathway. We performed whole exome sequencing for an individual with clinical features of SHORT syndrome but negative for PIK3R1 mutation and her parents. A rare de novo variant in PRKCE was identified. The gene encodes PKCε and, as such, the AKT-mTOR pathway function was assessed using phospho-specific antibodies with patient lymphoblasts and following ectopic expression of the mutant in HEK293 cells. Kinase analysis showed that the variant resulted in a partial loss-of-function. Whilst interaction with PDK1 and the mTORC2 complex component SIN1 was preserved in the mutant PKCε, it bound to SIN1 with a higher affinity than wild-type PKCε and the dynamics of mTORC2-dependent priming of mutant PKCε was altered. Further, mutant PKCε caused impaired mTORC2-dependent pAKT-S473 following rapamycin treatment. Reduced pFOXO1-S256 and pS6-S240/244 levels were also observed in the patient LCLs. To date, mutations in PIK3R1 causing impaired PI3K-dependent AKT activation are the only known cause of SHORT syndrome. We identify a SHORT syndrome child with a novel partial loss-of-function defect in PKCε. This variant causes impaired AKT activation via compromised mTORC2 complex function

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201

Structural and mechanistic insights into s-block bimetallic catalysis : sodium magnesiate-catalyzed guanylation of amines

To advance the catalytic applications of s-block mixed-metal complexes, sodium magnesiate [NaMg(CH2SiMe3)3] (1) is reported as an efficient precatalyst for the guanylation of a variety of anilines and secondary amines with carbodiimides. First examples of hydrophosphination of carbodiimides by using a Mg catalyst are also described. The catalytic ability of the mixed-metal system is much greater than that of its homometallic components [NaCH2SiMe3 ] and [Mg(CH2SiMe3)2]. Stoichiometric studies suggest that magnesiate amido and guanidinate complexes are intermediates in these catalytic routes. Reactivity and kinetic studies imply that these guanylation reactions occur via (tris)amide intermediates that react with carbodiiimides in insertion steps. The rate law for the guanylation of N,N'-diisopropylcarbodiimide with 4-tert-butylaniline catalyzed by 1 is first order with respect to [amine], [carbodiimide], and [catalyst], and the reaction shows a large kinetic isotopic effect, which is consistent with an amine-assisted rate-determining carbodiimide insertion transition state. Studies to assess the effect of sodium in these transformations denote a secondary role with little involvement in the catalytic cycle

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Role of natural phenolics in hepatoprotection: A mechanistic review and analysis of regulatory network of associated genes

The liver is not only involved in metabolism and detoxification, but also participate in innate immune function and thus exposed to frequent target Thus, they are the frequent target of physical injury. Interestingly, liver has the unique ability to regenerate and completely recoup from most acute, non-iterative situation. However, multiple conditions, including viral hepatitis, non-alcoholic fatty liver disease, long term alcohol abuse and chronic use of medications can cause persistent injury in which regenerative capacity eventually becomes dysfunctional resulting in hepatic scaring and cirrhosis. Despite the recent therapeutic advances and significant development of modern medicine, hepatic diseases remain a health problem worldwide. Thus, the search for the new therapeutic agents to treat liver disease is still in demand. Many synthetic drugs have been demonstrated to be strong radical scavengers, but they are also carcinogenic and cause liver damage. Present day various hepatic problems are encountered with number of synthetic and plant based drugs. Nexavar (sorafenib) is a chemotherapeutic medication used to treat advanced renal cell carcinoma associated with several side effects. There are a few effective varieties of herbal preparation like Liv-52, silymarin and Stronger neomin phages (SNMC) against hepatic complications. Plants are the huge repository of bioactive secondary metabolites viz; phenol, flavonoid, alkaloid etc. In this review we will try to present exclusive study on phenolics with its mode of action mitigating liver associated complications. And also its future prospects as new drug lead

Testicular Characteristics of Male Angora Goats Consuming Acacia berlandieri (Guajillo)

Last updated: 5/11/201

Cortisol response to acute stressors in male angora goats consuming guajillo

Last updated: 5/23/201

Reproductive characteristics of male angora goats consuming guajillo (Acacia berlandieri)

Last updated: 5/23/201

Cortisol response to acute stressors in male angora goats consuming guajillo

Last updated: 5/23/201

Reproductive characteristics of male angora goats consuming guajillo (Acacia berlandieri)

Last updated: 5/23/201