Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.     

The ontogeny ofa-foetoprotein in the chicken

Summary The ontogeny ofa-foetoprotein (AFP) has been studied in the chicken using polyacrylamide gel gradient electrophoresis and electroimmunoassay from 7 days of incubation until after hatching. The results are discussed in the light of previous on the ontogeny of AFP in mammals.     

Microwave devices: carbon nanotubes as cold cathodes

To communicate, spacecraft and satellites rely on microwave devices, which at present are based on relatively inefficient thermionic electron sources that require heating and cannot be switched on instantaneously. Here we describe a microwave diode that uses a cold-cathode electron source consisting of carbon nanotubes and that operates at high frequency and at high current densities. Because it weighs little, responds instantaneously and has no need of heating, this miniaturized electron source should prove valuable for microwave devices used in telecommunications.     

Advanced Credit-Assignment CMAC Algorithm for Robust Self-Learning and Self-Maintenance Machine

Smart machine necessitates self-learning capabilities to assess its own performance and predict its behavior. To achieve self-maintenance intelligence, robust and fast learning algorithms need to be embedded in machine for real-time decision. This paper presents a credit-assignment cerebellar model articulation controller (CA-CMAC) algorithm to reduce learning interference in machine learning. The developed algorithms on credit matrix and the credit correlation matrix are presented. The error of the training sample distributed to the activated memory cell is proportional to the cell‘s credibility, which is determined by its activated times. The convergence processes of CA-CMAC in cyclic learning are further analyzed with two convergence theorems. In addition, simulation results on the inverse kinematics of 2degree-of-freedom planar robot arm are used to prove the convergence theorems and show that CA-CMAC converges faster than conventional machine learning.     

Recent mass balance of polar ice sheets inferred from patterns of global sea-level change

Global sea level is an indicator of climate change, as it is sensitive to both thermal expansion of the oceans and a reduction of land-based glaciers. Global sea-level rise has been estimated by correcting observations from tide gauges for glacial isostatic adjustment--the continuing sea-level response due to melting of Late Pleistocene ice--and by computing the global mean of these residual trends. In such analyses, spatial patterns of sea-level rise are assumed to be signals that will average out over geographically distributed tide-gauge data. But a long history of modelling studies has demonstrated that non-uniform--that is, non-eustatic--sea-level redistributions can be produced by variations in the volume of the polar ice sheets. Here we present numerical predictions of gravitationally consistent patterns of sea-level change following variations in either the Antarctic or Greenland ice sheets or the melting of a suite of small mountain glaciers. These predictions are characterized by geometrically distinct patterns that reconcile spatial variations in previously published sea-level records. Under the--albeit coarse--assumption of a globally uniform thermal expansion of the oceans, our approach suggests melting of the Greenland ice complex over the last century equivalent to -0.6 mm yr(-1) of sea-level rise.     

Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins

Plasma high density lipoproteins (HDL) are a negative risk factor for atherosclerosis. Increased HDL is sometimes clustered in families, but a genetic basis has never been clearly documented. The plasma cholesteryl ester transfer protein (CETP) catalyses the transfer of cholesteryl ester from HDL to other lipoproteins and therefore might influence HDL levels. Using monoclonal antibodies, we show that CETP is absent in two Japanese siblings who have markedly increased and enlarged HDL. Furthermore, they are homozygous for a point mutation in the 5'-splice donor site of intron 14 of the gene for CETP, a change that is incompatible with normal splicing of pre-messenger RNA. The results indicate that the family has an inherited deficiency of CETP due to a gene splicing defect, and illustrate the key role that CETP has in human HDL metabolism.     

Initial sequencing and analysis of the human genome

The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.