Glucose-lowering therapies in type 2 diabetes: Opportunities and challenges for peptides

This overview considers the opportunities and challenges that face the use of gluco-regulatory peptides to treat type 2 diabetes. New insulin analogues and formulations are being developed with pharmacokinetic properties to speed-up or prolong transfer from a subcutaneous injection site to the target tissues, or to selectively favour effects on the liver. Alternative routes of insulin administration continue to attract attention, and advances in the integration of glucose monitoring with insulin pump devices are improving miniaturised ‘closed loop’ artificial pancreas systems. Proof of concept has been established for non-cellular glucose-responsive insulin delivery (‘smart insulins’) to release insulin from implants or circulating depots in proportion to circulating glucose. The many peptides involved in blood glucose control offer diverse therapeutic opportunities. Exploitation of multiple selected receptor targets using constructs of hybrid and chimeric peptides, especially those based on glucagon and gastrointestinal hormones, has gained much credence from initial preclinical studies. Peptide templates identified from comparative endocrine studies have also provided valuable insights in this respect and indicated novel approaches to address associated conditions such as obesity and infections at the same time. Nevertheless, there are many challenges to the use of therapeutic peptides that impose on every step in the complex pathway from design and testing through to making a fully characterised therapeutic product, and optimising administration, tissue targeting and degradation. Stability of peptides and immunological uncertainties of novel structures require particular consideration as well as the need to avoid over-reduction of blood glucose into hypoglycaemia

Report of the Advisory Committee in Seismology

The Advisory Committee in Seismology has pleasure in reporting the continued progress of its study of California earth movements during the year 1924-1925 without essential change of plan. A considerable amount of geologic work in the study of fault zones has been done during the year in the Mojave Desert and in Death Valley, the system of primary triangulation for the detection and measurement of horizontal displacements has progressed rapidly and effectively, and the development of suitable instruments for determining the two horizontal components of local earth movements has progressed to completion. Ground for a new laboratory has been purchased by the California Institute of Technology and the construction of the central station laboratory building upon it has been begun. The laboratory is expected to be occupied by Mr. H. O. Wood, Research Associate in Seismology, and his associates, about January 1, 1926. It is hoped that additional stations will also be occupied before the close of the present calendar year (1925), and that actual work in what has been happily termed the seismologic triangulation of California will be successfully inaugurated

Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia

© 2008 Henry et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Necessary fictions: indigenous claims and the humanity of rights

Indigenous right insistently challenges the surpassing arrogations of sovereign right. In so doing, it affirms dimensions of being-together denied or stunted in sovereign modes of political formation. This force of Indigenous right is amplified here through legal and literary instantiations. These, in turn, uncover the continuously created and fictional quality of rights, revealing them to be necessary fictions

Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency

Human methylmalonyl-CoA epimerase (MCEE) catalyzes the interconversion of d-methylmalonyl-CoA and l-methylmalonyl-CoA in propionate catabolism. Autosomal recessive pathogenic variations in MCEE reportedly cause methylmalonic aciduria (MMAuria) in eleven patients. We investigated a cohort of 150 individuals suffering from MMAuria of unknown origin, identifying ten new patients with pathogenic variations in MCEE. Nine patients were homozygous for the known nonsense variation p.Arg47* (c.139C > T), and one for the novel missense variation p.Ile53Arg (c.158T > G). To understand better the molecular basis of MCEE deficiency, we mapped p.Ile53Arg, and two previously described pathogenic variations p.Lys60Gln and p.Arg143Cys, onto our 1.8 Å structure of wild-type (wt) human MCEE. This revealed potential dimeric assembly disruption by p.Ile53Arg, but no clear defects from p.Lys60Gln or p.Arg143Cys. We solved the structure of MCEE-Arg143Cys to 1.9 Å and found significant disruption of two important loop structures, potentially impacting surface features as well as the active-site pocket. Functional analysis of MCEE-Ile53Arg expressed in a bacterial recombinant system as well as patient-derived fibroblasts revealed nearly undetectable soluble protein levels, defective globular protein behavior, and using a newly developed assay, lack of enzymatic activity - consistent with misfolded protein. By contrast, soluble protein levels, unfolding characteristics and activity of MCEE-Lys60Gln were comparable to wt, leaving unclear how this variation may cause disease. MCEE-Arg143Cys was detectable at comparable levels to wt MCEE, but had slightly altered unfolding kinetics and greatly reduced activity. These studies reveal ten new patients with MCEE deficiency and rationalize misfolding and loss of activity as molecular defects in MCEE-type MMAuria

The space density of cataclysmic variables: constraints from the ROSAT North Ecliptic Pole Survey

We use the ROSAT North Ecliptic Pole (NEP) survey to construct a small, but purely X-ray flux-limited sample of cataclysmic variable stars (CVs). The sample includes only 4 systems, 2 of which (RX J1715.6+6856 and RX J1831.7+6511) are new discoveries. We present time-resolved spectroscopy of the new CVs and measure orbital periods of 1.64 \pm 0.02 h and 4.01\pm 0.03 h for RX 1715.6+6856 and RX J1831.7+6511, respectively. We also estimate distances for all the CVs in our sample, based mainly on their apparent brightness in the infrared. The space density of the CV population represented by our small sample is (1.1 +2.3/-0.7) 10^-5 pc^-3. We can also place upper limits on the space density of any sub-population of CVs too faint to be included in the NEP survey. In particular, we show that if the overall space density of CVs is as high as 2 10^-4 pc^-3 (as has been predicted theoretically), the vast majority of CVs must be fainter than L_X \simeq 2 10^29 erg/s.Comment: 11 pages, 7 figure, accepted for publication in MNRA