An in vivo control map for the eukaryotic mRNA translation machinery

Rate control analysis defines the in vivo control map governing yeast protein synthesis and generates an extensively parameterized digital model of the translation pathway. Among other non-intuitive outcomes, translation demonstrates a high degree of functional modularity and comprises a non-stoichiometric combination of proteins manifesting functional convergence on a shared maximal translation rate. In exponentially growing cells, polypeptide elongation (eEF1A, eEF2, and eEF3) exerts the strongest control. The two other strong control points are recruitment of mRNA and tRNAi to the 40S ribosomal subunit (eIF4F and eIF2) and termination (eRF1; Dbp5). In contrast, factors that are found to promote mRNA scanning efficiency on a longer than-average 5′untranslated region (eIF1, eIF1A, Ded1, eIF2B, eIF3, and eIF5) exceed the levels required for maximal control. This is expected to allow the cell to minimize scanning transition times, particularly for longer 5′UTRs. The analysis reveals these and other collective adaptations of control shared across the factors, as well as features that reflect functional modularity and system robustness. Remarkably, gene duplication is implicated in the fine control of cellular protein synthesis

The influence of electromagnetic fields from two commercially available water-treatment devices on calcium carbonate precipitation

CaCO3 precipitation profiles, tracked by absorbance at 350 nm, showing accelerated precipitation upon exposure of the parent solutions to a pulsed electromagnetic field (PEMF) from a commercially available device.</p

Perinatal and sociodemographic factors at birth predicting conduct problems and violence to age 18 years: comparison of Brazilian and British birth cohorts.

This is the final published version. It was first published by Wiley at http://dx.doi.org/10.1111/jcpp.12369BACKGROUND: Many low- and middle-income countries have high levels of violence. Research in high-income countries shows that risk factors in the perinatal period are significant precursors of conduct problems which can develop into violence. It is not known whether the same early influences are important in lower income settings with higher rates of violence. This study compared perinatal and sociodemographic risk factors between Brazil and Britain, and their role in explaining higher rates of conduct problems and violence in Brazil. METHODS: Prospective population-based birth cohort studies were conducted in Pelotas, Brazil (N = 3,618) and Avon, Britain (N = 4,103). Eleven perinatal and sociodemographic risk factors were measured in questionnaires completed by mothers during the perinatal period. Conduct problems were measured in questionnaires completed by mothers at age 11, and violence in self-report questionnaires completed by adolescents at age 18. RESULTS: Conduct problems were predicted by similar risk factors in Brazil and Britain. Female violence was predicted by several of the same risk factors in both countries. However, male violence in Brazil was associated with only one risk factor, and several risk factor associations were weaker in Brazil than in Britain for both females and males. Almost 20% of the higher risk for conduct problems in Brazil compared to Britain was explained by differential exposure to risk factors. The percentage of the cross-national difference in violence explained by early risk factors was 15% for females and 8% for males. CONCLUSIONS: A nontrivial proportion of cross-national differences in antisocial behaviour are related to perinatal and sociodemographic conditions at the start of life. However, risk factor associations are weaker in Brazil than in Britain, and influences in other developmental periods are probably of particular importance for understanding male youth violence in Brazil.The 1993 Pelotas Birth Cohort Study is currently supported by the Wellcome Trust through the programme entitled Major Awards for Latin America on Health Consequences of Population Change (Grant: 086974/Z/08/Z). The European Union, National Support Program for Centers of Excellence (PRONEX), the Brazilian National Research Council (CNPq), and the Brazilian Ministry of Health supported previous phases of the study. The UK Medical Research Council and the Wellcome Trust (Grant: 092731) and the University of Bristol provide core support for ALSPAC. Additional support for the data collected at age 18 in this paper was provided by UK Medical Research Council (Grants G0800612 and G0802736).The research for this specific article was funded by the Wellcome Trust (Grant: 089963/Z/09/Z). The authors are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. Yulia Shenderovich helped prepare the tables. The authors have declared that they have no competing or potential conflicts of interest

S28 peptidases: lessons from a seemingly 'dysfunctional' family of two

<p>Abstract</p> <p>A recent paper in <it>BMC Structural Biology </it>reports the crystal structure of human prolylcarboxypeptidase (PRCP), one of the two members of the S28 peptidase family. Comparison of the substrate-binding site of PRCP with that of its family partner, dipeptidyl dipeptidase 7 (DPP7), helps to explain the different enzymatic activities of these structurally similar proteins, and also reveals a novel apparent charge-relay system in PRCP involving the active-site catalytic histidine.</p> <p>See research article: <url>http://www.biomedcentral.com/1472-6807/10/16/</url></p> <p>Commentary</p> <p>The S28 serine peptidase family is something of an enzymatic odd couple. While showing low sequence similarity to all proteins except each other, the two known family members appear to be at odds functionally; one, prolylcarboxypeptidase (PRCP), is a carboxypeptidase that cleaves single hydrophobic residues from the carboxyl termini of proteins that end with a Pro-X motif (where X is any hydrophobic amino acid), while the other, human dipeptidyl peptidase (DPP7), is an aminopeptidase that cleaves amino-terminal X-Pro dipeptides. The structural basis of this orthogonal specificity would undoubtedly be interesting, and a recent report in <it>BMC Structural Biology </it>from the Merck Global Structural Biology group (Soisson <it>et al</it>. <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>) has now met that expectation. In addition they reveal a new wrinkle to the iconic catalytic triad common to most serine hydrolases.</p> <p>The practical pharmaceutical interest in both these enzymes as potential drug targets is at present speculative. PRCP can inactivate a number of peptide hormones, such as angiotensin II, III and prekallikrein, implicating a role for the enzyme in hypertension, tissue proliferation and smooth-muscle growth. These properties suggest that this enzyme may well be a useful target for hypertension and anti-inflammatory therapy <abbrgrp><abbr bid="B2">2</abbr></abbrgrp>. Another (non-S28 family) dipeptidyl dipeptidase (DPP4) is a major drug target in type 2 diabetes, and Merck has already developed a successful inhibitor of DPP4, the anti-hyperglycemic drug sitagliptin, for the treatment of type 2 diabetes. The DPP enzymes are rich in biological functions and other drug targets emerging from the group are possible <abbrgrp><abbr bid="B3">3</abbr></abbrgrp>.</p

Precise measurement of K-shell fluorescence yield in iridium: An improved test of internal-conversion theory

Journals published by the American Physical Society can be found at http://publish.aps.org/We have measured the total intensity of K x rays relative to 129.4-keV gamma rays from decay of the second excited state in Ir-191. This (M1+E2) transition was observed following the beta decay of 15.4-d Os-191. Our measured ratio yields the result alpha(K)omega(K)=2.044(11). When combined with a recent measurement of the same ratio for the 80.2-keV M4 transition from Ir-193(m), this result strongly confirms the need for the K-shell hole to be included in calculations of internal-conversion coefficients alpha(K). Since the alpha(K) value calculated for the Ir-191 transition is virtually independent of the hole treatment, our result also yields a model-independent value for the iridium fluorescence yield, omega(K)=0.954(9)

Cross-species gene expression analysis of species specific differences in the preclinical assessment of pharmaceutical compounds

Animals are frequently used as model systems for determination of safety and efficacy in pharmaceutical research and development. However, significant quantitative and qualitative differences exist between humans and the animal models used in research. This is as a result of genetic variation between human and the laboratory animal. Therefore the development of a system that would allow the assessment of all molecular differences between species after drug exposure would have a significant impact on drug evaluation for toxicity and efficacy. Here we describe a cross-species microarray methodology that identifies and selects orthologous probes after cross-species sequence comparison to develop an orthologous cross-species gene expression analysis tool. The assumptions made by the use of this orthologous gene expression strategy for cross-species extrapolation is that; conserved changes in gene expression equate to conserved pharmacodynamic endpoints. This assumption is supported by the fact that evolution and selection have maintained the structure and function of many biochemical pathways over time, resulting in the conservation of many important processes. We demonstrate this cross-species methodology by investigating species specific differences of the peroxisome proliferatoractivator receptor (PPAR) a response in rat and human

Molecular Valves for Controlling Gas Phase Transport Made from Discrete Angstrom-Sized Pores in Graphene

An ability to precisely regulate the quantity and location of molecular flux is of value in applications such as nanoscale 3D printing, catalysis, and sensor design. Barrier materials containing pores with molecular dimensions have previously been used to manipulate molecular compositions in the gas phase, but have so far been unable to offer controlled gas transport through individual pores. Here, we show that gas flux through discrete angstrom-sized pores in monolayer graphene can be detected and then controlled using nanometer-sized gold clusters, which are formed on the surface of the graphene and can migrate and partially block a pore. In samples without gold clusters, we observe stochastic switching of the magnitude of the gas permeance, which we attribute to molecular rearrangements of the pore. Our molecular valves could be used, for example, to develop unique approaches to molecular synthesis that are based on the controllable switching of a molecular gas flux, reminiscent of ion channels in biological cell membranes and solid state nanopores.Comment: to appear in Nature Nanotechnolog

Rapidly Decaying Supernova 2010X: A Candidate ".Ia" Explosion

We present the discovery, photometric and spectroscopic follow-up observations of SN 2010X (PTF 10bhp). This supernova decays exponentially with tau_d=5 days, and rivals the current recordholder in speed, SN 2002bj. SN 2010X peaks at M_r=-17mag and has mean velocities of 10,000 km/s. Our light curve modeling suggests a radioactivity powered event and an ejecta mass of 0.16 Msun. If powered by Nickel, we show that the Nickel mass must be very small (0.02 Msun) and that the supernova quickly becomes optically thin to gamma-rays. Our spectral modeling suggests that SN 2010X and SN 2002bj have similar chemical compositions and that one of Aluminum or Helium is present. If Aluminum is present, we speculate that this may be an accretion induced collapse of an O-Ne-Mg white dwarf. If Helium is present, all observables of SN 2010X are consistent with being a thermonuclear Helium shell detonation on a white dwarf, a ".Ia" explosion. With the 1-day dynamic-cadence experiment on the Palomar Transient Factory, we expect to annually discover a few such events.Comment: 6 pages, 5 figures; Minor Changes; Note correction in Fig 4 caption; published by ApJ

A comprehensive evaluation of colonic mucosal isolates of Sutterella wadsworthensis from inflammatory bowel disease

Peer reviewedPublisher PD