Therapeutic peptides targeting the Ras superfamily

The Ras superfamily of small GTPases are master regulators of numerous essential processes within the cell, so that when they malfunction, cancer and many other diseases can result. For example, activating Ras mutations are present in approximately 20% of human cancers. As such, they are key therapeutic targets, yet more than three decades of intensive research efforts have failed to produce effective Ras inhibitors in the clinic. This is, in part, due to their relatively smooth surfaces which are difficult to target through traditional drug discovery methods using small molecules. Peptides offer a solution to this issue as they occupy larger surface areas on their targets and therefore offer exquisite selectivity and affinity. However, their use in the past has been limited to extracellular targets due to delivery issues. Recent advances in peptide macrocyclization, modifications and delivery methods have ignited increased interest in the use of these highly effective biologics for intracellular targets. This review will cover progress made in the development of peptides targeting small GTPases to treat a wide range of diseases.Cambridge Cancer Centre MRC BBSRC Glover Research Fund. AstraZenec

Testing the thermal limits of Eccritotarsus catarinensis: a case of thermal plasticity

Water hyacinth is considered the most damaging aquatic weed in South Africa. The success of biocontrol initiatives against the weed varies nation-wide, but control remains generally unattainable in higher altitude, temperate regions. Eccritotarsus catarinensis (Hemiptera: Miridae) is a biocontrol agent of water hyacinth that was first released in South Africa in 1996. By 2011, it was established at over 30 sites across the country. These include the Kubusi River, a site with a temperate climate where agent establishment and persistence was unexpected. This study compared the critical thermal limits of the Kubusi River insect population with a laboratory-reared culture to determine whether any physiological plasticity was evident that could account for its unexpected establishment. There were no significant differences in critical thermal maxima (CTmax) or minima (CTmin) between sexes, while the effect of rate of temperature change on the thermal parameters in the experiments had a significant impact in some trials. Both CTmax and CTmin differed significantly between the two populations, with the field individuals tolerating significantly lower temperatures (CTmin: −0.3°C ± 0.063 [SE], CTmax: 42.8°C ± 0.155 [SE]) than those maintained in the laboratory (CTmin: 1.1°C ± 0.054 [SE], CTmax: 44.9°C ± 0.196 [SE]). Acclimation of each population to the environmental conditions typical of the other for a five-day period illustrated that short-term acclimation accounted for some, but not all of the variation between their lower thermal limits. This study provides evidence for the first cold-adapted strain of E. catarinensis in the field, with potential value for introduction into other colder regions where water hyacinth control is currently unattainable

In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine.

Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells. Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a >3-fold and >2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo

BORIS/CTCFL is an RNA-binding protein that associates with polysomes

© 2013 Ogunkolade et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Effect of Silicon Content on Carbide Precipitation and Low-Temperature Toughness of Pressure Vessel Steels

Cr – Mn – Mo – Ni pressure vessel steels containing 0.54 and 1.55% Si are studied. Metallographic and fractographic analyses of the steels after tempering at 650 and 700°C are performed. The impact toughness at – 30°C and the hardness of the steels are determined. The mass fraction of the carbide phase in the steels is computed with the help of the J-MatPro 4.0 software

Spin and orbital states in La1.5 Sr0.5 CoO4 studied by electronic structure calculations

Electronic structure of the layered perovskite La1.5Sr0.5CoO4 with a checkerboard Co2+/Co3+ charge order is studied, using the local-spin-density approximation plus Hubbard U calculations including also the spin-orbit coupling and multiplet effect. Our results show that the Co2+ ion is in a high spin state (HS, t(2g)(5)e(g)(2)) and Co3+ low spin state (LS, t(2g)(6)). Due to a small Co2+ t(2g) crystal field splitting, the spin-orbit interaction produces an orbital moment of 0.26 mu(B) and accounts for the observed easy in-plane magnetism. Moreover, we find that the Co3+ intermediate spin state (IS, t(2g)(5)e(g)(1)) has a multiplet splitting of several tenths of eV and the lowest-lying one is still higher than the LS ground state by 120 meV, and that the Co3+ HS state (t(2g)(4)e(g)(2)) is more unstable by 310 meV. Either the IS or HS Co3+ ions would give rise to a wrong magnetic order and anisotropy

Lactate signalling regulates fungal β-glucan masking and immune evasion

AJPB: This work was supported by the European Research Council (STRIFE, ERC- 2009-AdG-249793), The UK Medical Research Council (MR/M026663/1), the UK Biotechnology and Biological Research Council (BB/K017365/1), the Wellcome Trust (080088; 097377). ERB: This work was supported by the UK Biotechnology and Biological Research Council (BB/M014525/1). GMA: Supported by the CNPq-Brazil (Science without Borders fellowship 202976/2014-9). GDB: Wellcome Trust (102705). CAM: This work was supported by the UK Medical Research Council (G0400284). DMM: This work was supported by UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K000306/1). NARG/JW: Wellcome Trust (086827, 075470,101873) and Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377). ALL: This work was supported by the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).Peer reviewedPostprin

Association of genetic liability for psychiatric disorders with accelerometer-assessed physical activity in the UK Biobank.

Levels of activity are often affected in psychiatric disorders and can be core symptoms of illness. Advances in technology now allow the accurate assessment of activity levels but it remains unclear whether alterations in activity arise from shared risk factors for developing psychiatric disorders, such as genetics, or are better explained as consequences of the disorders and their associated factors. We aimed to examine objectively-measured physical activity in individuals with psychiatric disorders, and assess the role of genetic liability for psychiatric disorders on physical activity. Accelerometer data were available on 95,529 UK Biobank participants, including measures of overall mean activity and minutes per day of moderate activity, walking, sedentary activity, and sleep. Linear regressions measured associations between psychiatric diagnosis and activity levels, and polygenic risk scores (PRS) for psychiatric disorders and activity levels. Genetic correlations were calculated between psychiatric disorders and different types of activity. Having a diagnosis of schizophrenia, bipolar disorder, depression, or autism spectrum disorders (ASD) was associated with reduced overall activity compared to unaffected controls. In individuals without a psychiatric disorder, reduced overall activity levels were associated with PRS for schizophrenia, depression, and ASD. ADHD PRS was associated with increased overall activity. Genetic correlations were consistent with PRS findings. Variation in physical activity is an important feature across psychiatric disorders. Whilst levels of activity are associated with genetic liability to psychiatric disorders to a very limited extent, the substantial differences in activity levels in those with psychiatric disorders most likely arise as a consequences of disorder-related factors

Removal of ecotoxicity of 17α-ethinylestradiol using TAML/peroxide water treatment

17α -ethinylestradiol (EE2), a synthetic oestrogen in oral contraceptives, is one of many pharmaceuticals found in inland waterways worldwide as a result of human consumption and excretion into wastewater treatment systems. At low parts per trillion (ppt), EE2 induces feminisation of male fish, diminishing reproductive success and causing fish population collapse. Intended water quality standards for EE2 set a much needed global precedent. Ozone and activated carbon provide effective wastewater treatments, but their energy intensities and capital/operating costs are formidable barriers to adoption. Here we describe the technical and environmental performance of a fast- developing contender for mitigation of EE2 contamination of wastewater based upon smallmolecule, full-functional peroxidase enzyme replicas called “TAML activators”. From neutral to basic pH, TAML activators with H2O2 efficiently degrade EE2 in pure lab water, municipal effluents and EE2-spiked synthetic urine. TAML/H2O2 treatment curtails estrogenicity in vitro and substantially diminishes fish feminization in vivo. Our results provide a starting point for a future process in which tens of thousands of tonnes of wastewater could be treated per kilogram of catalyst. We suggest TAML/H2O2 is a worthy candidate for exploration as an environmentally compatible, versatile, method for removing EE2 and other pharmaceuticals from municipal wastewaters.Heinz Endowments, the Swiss National Science Foundation, the Steinbrenner Institute for a Steinbrenner Doctoral Fellowship. NMR instrumentation at CMU was partially supported by NSF (CHE-0130903 and CHE-1039870)

Value of antibodies to free light chains in immunoperoxidase studies of renal biopsies

Aims Because immunoglobulin abnormalities may affect the kidney, investigation of renal biopsies requires immunohistological study of light chains. A problem is that most antibodies to light chains react with whole immunoglobulins as well as free light chains, and there are generally many more whole immunoglobulins than free light chains. The usefulness of antibodies that only detected free light chains was investigated. Methods Antibodies to free light chains were used in an immunoperoxidase method on paraffin sections of 198 renal biopsies, and compared with conventional antibodies against light chains examined by immunofluorescence on 13 frozen sections and by immunoperoxidase on 46 paraffin sections. Results Immunofluorescence and immunoperoxidase were concordant on 10 of 13 biopsies. Immunofluorescence detected slight deposition of light chains in three biopsies not shown by immunoperoxidase, of undetermined clinical significance. Using immunoperoxidase, the free light chain antibodies were more sensitive than conventional antibodies, giving much cleaner staining and better detection of deposits in AL amyloid, light chain deposition disease and cryoglobulinaemic glomerulonephritis. The free light chain antibodies showed discordance or ambiguity between immunohistological and clinical findings in seven (4%) of 185 patients with known immunoglobulin status. These included two of 28 cases of AL amyloid that showed no light chain deposition. The method was not designed for detection of light chain restriction in neoplastic plasma or lymphoplasmacytic cells. Conclusions Polyclonal antibodies to free light chains are an improvement on conventional antibodies in immunoperoxidase study of paraffin sections of renal biopsies and are useful in everyday practice