Memory of cell shape biases stochastic fate decision-making despite mitotic rounding

Nature Communications 7, (2016). doi:10.1038/ncomms11963Number theory, Algebra and Geometr

Potential Role of Protein Kinase B in Insulin-induced Glucose Transport, Glycogen Synthesis, and Protein Synthesis

Various biological responses stimulated by insulin have been thought to be regulated by phosphatidylinosi-tol 3-kinase, including glucose transport, glycogen syn-thesis, and protein synthesis. However, the molecular link between phosphatidylinositol 3-kinase and these biological responses has been poorly understood. Re-cently, it has been shown that protein kinase B (PKB/c-Akt/ Rac) lies immediately downstream from phosphati-dylinositol 3-kinase. Here, we show that expression of a constitutively active form of PKB induced glucose up-take, glycogen synthesis, and protein synthesis in L6 myotubes downstream of phosphatidylinositol 3-kinase and independent of Ras and mitogen-activated protein kinase activation. Introduction of constitutively active PKB induced glucose uptake and protein synthesis but not glycogen synthesis in 3T3L-1 adipocytes, which lack expression of glycogen synthase kinase 3 different from L6 myotubes. Furthermore, we show that deactivation of glycogen synthase kinase 3 and activation of rapamy-cin- sensitive serine/threonine kinase by PKB in L6 myo-tubes might be involved in the enhancement of glycogen synthesis and protein synthesis, respectively. These re-sults suggest that PKB acts as a key enzyme linking phosphatidylinositol 3-kinase activation to multiple bi-ological functions of insulin through regulation of downstream kinases in skeletal muscle, a major target tissue of insulin

False friends in the Fanfanyu

In the present article, a remarkable phenomenon is brought to the attention of those interested in early Chinese translations of Buddhist texts: false friends in the Fanfanyu (T54n2130). Baochang's Sanskrit-Chinese lexicon that was compiled as early as 517 AD reveals some curious examples of faux amis. In the present contribution, this case will be illustrated with references from the Shanjian lü piposha (T24n1462), a fifth century Chinese translation of the Samantapāsādikā, Buddhaghosa's commentary on the Pāli Vinaya. The fact that Baochang did not realise that this text was not translated from Sanskrit, inadvertently gave rise to some interesting jeux de mots

The Effect of Enzymatically Polymerised Polyphenols on CD4 Binding and Cytokine Production in Murine Splenocytes

High-molecular weight polymerised polyphenols have been shown to exhibit anti-influenza virus, anti-HIV, and anti-cancer activities. The purpose of this study was to evaluate the immunomodulating activities of enzymatically polymerised polyphenols, and to clarify the underlying mechanisms of their effects. The cytokine-inducing activity of the enzymatically polymerised polyphenols derived from caffeic acid (CA), ferulic acid (FA), and p-coumaric acid (CoA) was investigated using murine splenocytes. Polymerised polyphenols, but not non-polymerised polyphenols, induced cytokine synthesis in murine splenocytes. Polymerised polyphenols induced several cytokines in murine splenocytes, with interferon-γ (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) being the most prominent. The underlying mechanisms of the effects of the polymerised polyphenols were then studied using neutralising antibodies and fluorescent-activated cell sorting (FACS) analysis. Our results show that polymerised polyphenols increased IFN-γ and GM-CSF production in splenocytes. In addition, the anti-CD4 neutralised monoclonal antibody (mAb) inhibited polymerised polyphenol-induced IFN-γ and GM-CSF secretion. Moreover, polymerised polyphenols bound directly to a recombinant CD4 protein, and FACS analysis confirmed that interaction occurs between polymerised polyphenols and CD4 molecules expressed on the cell surface. In this study, we clearly demonstrated that enzymatic polymerisation confers immunoactivating potential to phenylpropanoic acids, and CD4 plays a key role in their cytokine-inducing activity

Somatostatin receptor expression, tumour response, and quality of life in patients with advanced hepatocellular carcinoma treated with long-acting octreotide

Octreotide may extend survival in hepatocellular carcinoma (HCC). Forty-one per cent of HCCs have high-affinity somatostatin receptors. We aimed to determine the feasibility, safety, and activity of long-acting octreotide in advanced HCC; to identify the best method for assessing somatostatin receptor expression; to relate receptor expression to clinical outcomes; and to evaluate toxicity. Sixty-three patients with advanced HCC received intramuscular long-acting octreotide 20 mg monthly until progression or toxicity. Median age was 67 years (range 28–81 years), male 81%, Child–Pugh A 83%, and B 17%. The aetiologies of chronic liver disease were alcohol (22%), viral hepatitis (44%), and haemochromatosis (6%). Prior treatments for HCC included surgery (8%), chemotherapy (2%), local ablation (11%), and chemoembolisation (6%). One patient had an objective partial tumour response (2%, 95% CI 0–9%). Serum alpha-fetoprotein levels decreased more than 50% in four (6%). Median survival was 8 months. Thirty four of 61 patients (56%) had receptor expression detected by scintigraphy; no clear relationship with clinical outcomes was identified. There were few grade 3 or 4 toxicities: hyperglycaemia (8%), hypoglycaemia (2%), diarrhoea (5%), and anorexia (2%). Patients reported improvements in some symptoms, but no major changes in quality of life were detected. Long-acting octreotide is safe in advanced HCC. We found little evidence of anticancer activity. A definitive randomised trial would identify whether patients benefit from this treatment in other ways

Introducing a new ICRU report: Prescribing, recording and reporting electron beam therapy

The ICRU published several Reports about volumes and doses specifications for radiotherapy, such as the Report 29 (1978), devoted to photon and electron beam therapy. This report 29 becoming absolete, a new Report was published in 1993 for external photon beam radiotherapy, the Report 50, recommending new definitions and more accurate specifications. With electran beams specific problems are raised, and the ICRU considered suitable to prepare a special Report for them, to be published in the near future.The main features of the present draft are as follows:1.Volumes specifications in agreement with the ICRU Report 50,•Volumes to be determined before treatment planning: gross tumour volume (GTV), c1inical target volume (CTV), organs at risk volumes (OR).•Volume to be determined during treatment planning: Planning target volume (PTV).•Volumes resulting fram the treatment plan chosen: treatment volume (TV), irradiated volume (IV).In the future Report on electron beams, an additional volume is defined, the internal target volume (ITV) geometrical concept representing the volume en-compassing the c1inical target volume, taking into consideration margins due to the variations of the clinical target volume in position, shape an size. A similar concept has been extended to organs at risk, the planning organ at risk volume.2.Dose specificationThe general statements for photon beams apply:•dose at a reference point (ICRU point) situated at or near the center of the planning target volume and, when possible, near or on the central axis of the electron beam at the depth of the peak dose.•Minimal and maximal doses in the planning target volume•Dose delivered to the organs at risk•Additional information is recommended, when possible (e.g. DVH).With electron beams, the dose homogeneity expected within the PTV (± 5 to ± 10 %) requires an adaptation of the terapeutic range concept, such that the value of the isodose surface encompassing the PTV be situated between 85 % and 95 % of the reference dose. The peak absorbed dose on the beam axis should always been specified, even if it is different fram the reference dose.At last, as in Report 50, three levels of dose evaluation for reporting are considered, depending on the aim of the treatment and the data available

Analysis of her1 and her7 Mutants Reveals a Spatio Temporal Separation of the Somite Clock Module

Somitogenesis is controlled by a genetic network consisting of an oscillator (clock) and a gradient (wavefront). The “hairy and Enhancer of Split”- related (her) genes act downstream of the Delta/Notch (D/N) signaling pathway, and are crucial components of the segmentation clock. Due to genome duplication events, the zebrafish genome, possesses two gene copies of the mouse Hes7 homologue: her1 and her7. To better understand the functional consequences of this gene duplication, and to determine possible independent roles for these two genes during segmentation, two zebrafish mutants her1hu2124 and her7hu2526 were analyzed. In the course of embryonic development, her1hu2124 mutants exhibit disruption of the three anterior-most somite borders, whereas her7hu2526 mutants display somite border defects restricted to somites 8 (+/−3) to 17 (+/−3) along the anterior-posterior axis. Analysis of the molecular defects in her1hu2124 mutants reveals a her1 auto regulatory feedback loop during early somitogenesis that is crucial for correct patterning and independent of her7 oscillation. This feedback loop appears to be restricted to early segmentation, as cyclic her1 expression is restored in her1hu2124 embryos at later stages of development. Moreover, only the anterior deltaC expression pattern is disrupted in the presomitic mesoderm of her1hu2124 mutants, while the posterior expression pattern of deltaC remains unaltered. Together, this data indicates the existence of an independent and genetically separable anterior and posterior deltaC clock modules in the presomitic mesdorm (PSM)

Role of Active Site Rigidity in Activity: MD Simulation and Fluorescence Study on a Lipase Mutant

Relationship between stability and activity of enzymes is maintained by underlying conformational flexibility. In thermophilic enzymes, a decrease in flexibility causes low enzyme activity while in less stable proteins such as mesophiles and psychrophiles, an increase in flexibility is associated with enhanced enzyme activity. Recently, we identified a mutant of a lipase whose stability and activity were enhanced simultaneously. In this work, we probed the conformational dynamics of the mutant and the wild type lipase, particularly flexibility of their active site using molecular dynamic simulations and time-resolved fluorescence techniques. In contrast to the earlier observations, our data show that active site of the mutant is more rigid than wild type enzyme. Further investigation suggests that this lipase needs minimal reorganization/flexibility of active site residues during its catalytic cycle. Molecular dynamic simulations suggest that catalytically competent active site geometry of the mutant is relatively more preserved than wild type lipase, which might have led to its higher enzyme activity. Our study implies that widely accepted positive correlation between conformation flexibility and enzyme activity need not be stringent and draws attention to the possibility that high enzyme activity can still be accomplished in a rigid active site and stable protein structures. This finding has a significant implication towards better understanding of involvement of dynamic motions in enzyme catalysis and enzyme engineering through mutations in active site