24-Hour profiles of circulating ghrelin and peptide YY are inversely associated in normal weight premenopausal women

Peptide YY (PYY) and ghrelin (GHR) may modulate one another's actions within the hypothalamus. Peripheral infusion of PYY in humans acutely suppresses circulating concentrations of GHR. Whether an association between PYY and GHR exists in the peripheral circulation of humans over 24 h is unknown. The purpose of this study was to determine if circulating concentrations of PYY and GHR were significantly associated over 24 h in humans. Participants (n = 13) were normal weight, moderately active, women ages 18–24 yr. Blood samples were obtained q10 min for 24 h and assayed using RIA for total PYY and total GHR hourly from 0800 to 1000 h and 2000 to 0800 h and q20 min from 1000 to 2000 h. Dietary intake during the 24 h procedure was comprised of 55% carbohydrates, 30% fat, and 15% protein (three meals and a snack). Statistical analyses included linear mixed-effects modeling to test whether PYY predicted GHR concentrations over 24 h. Participants weighed 57.0 ± 1.5 kg and had 26.1 ± 1.5% body fat (15.0 ± 1.1 kg), 42.1 ± 1.1 kg fat free mass, a BMI of 21.3 ± 0.5 kg/m² and RMR of 1072 ± 28 kcal/24 h. Visually, PYY and GHR exhibited an inverse association over nearly the entire 24 h period. Statistically, circulating concentrations of 24 h PYY predicted 24 h GHR (ghrelin = 1860.51–2.14*PYY; p = 0.04). Circulating concentrations of PYY are inversely associated with GHR over 24 h. These data provide evidence that PYY may contribute to the modulation of the secretion of GHR in normal weight, premenopausal women over a 24 h period and supports similar inferences from experimental studies in animals and humans.     

Isolation and characterization of a novel conus peptide with apparent antinociceptive activity

Cone snails are tropical marine mollusks that envenomate prey with a complex mixture of neuropharmacologically active compounds. We report the discovery and biochemical characterization of a structurally unique peptide isolated from the venom of Conus marmoreus. The new peptide, mr10a, potently increased withdrawal latency in a hot plate assay (a test of analgesia) at intrathecal doses that do not produce motor impairment as measured by rotarod test. The sequence of mr10a is NGVCCGYKLCHOC, where O is 4-trans-hydroxyproline. This sequence is highly divergent from all other known conotoxins. Analysis of a cDNA clone encoding the toxin, however, indicates that it is a member of the recently described T-superfamily. Total chemical synthesis of the three possible disulfide arrangements of mr10a was achieved, and elution studies indicate that the native form has a disulfide connectivity of Cys1-Cys4 and Cys2-Cys3. This disulfide linkage is unprecedented among conotoxins and defines a new family of Conus peptides.     

Angelman syndrome associated with an inversion of chromosome 15q11.2q24.3.

Angelman syndrome (AS) most frequently results from large (> or = 5 Mb) de novo deletions of chromosome 15q11-q13. The deletions are exclusively of maternal origin, and a few cases of paternal uniparental disomy of chromosome 15 have been reported. The latter finding indicates that AS is caused by the absence of a maternal contribution to the imprinted 15q11-q13 region. Failure to inherit a paternal 15q11-q13 contribution results in the clinically distinct disorder of Prader-Willi syndrome. Cases of AS resulting from translocations or pericentric inversions have been observed to be associated with deletions, and there have been no confirmed reports of balanced rearrangements in AS. We report the first such case involving a paracentric inversion with a breakpoint located approximately 25 kb proximal to the reference marker D15S10. This inversion has been inherited from a phenotypically normal mother. No deletion is evident by molecular analysis in this case, by use of cloned fragments mapped to within approximately 1 kb of the inversion breakpoint. Several hypotheses are discussed to explain the relationship between the inversion and the AS phenotype.     

Synthetic muO-conotoxin MrVIB blocks TTX-resistant sodium channel NaV1.8 and has a long-lasting analgesic activity

MuO-conotoxin MrVIB is a blocker of voltage-gated sodium channels, including TTX-sensitive and -resistant subtypes. A comprehensive characterization of this peptide has been hampered by the lack of sufficient synthetic material. Here, we describe the successful chemical synthesis and oxidative folding of MrVIB that has made an investigation of the pharmacological properties and therapeutic potential of the peptide feasible. We show for the first time that synthetic MrVIB blocks rat NaV1.8 sodium channels and has potent and long-lasting local anesthetic effects when tested in two pain assays in rats. Furthermore, MrVIB can block propagation of action potentials in A- and C-fibers in sciatic nerve as well as skeletal muscle in isolated preparations from rat. Our work provides the first example of analgesia produced by a conotoxin that blocks sodium channels. The emerging diversity of antinociceptive mechanisms targeted by different classes of conotoxins is discussed.     

Increasing cell biomass in <Emphasis Type="Italic">Saccharomyces cerevisiae</Emphasis> increases recombinant protein yield: the use of a respiratory strain as a microbial cell factory

Background  

Recombinant protein production is universally employed as a solution to obtain the milligram to gram quantities of a given protein required for applications as diverse as structural genomics and biopharmaceutical manufacture. Yeast is a well-established recombinant host cell for these purposes. In this study we wanted to investigate whether our respiratory Saccharomyces cerevisiae strain, TM6*, could be used to enhance the productivity of recombinant proteins over that obtained from corresponding wild type, respiro-fermentative strains when cultured under the same laboratory conditions.     

Detection of a glycosylated subunit in human serum ferritin.

Chemical reaction of coenzyme M, sodium 2-mercaptoethanesulphonate (HS-CoM, Na+), and formaldehyde formed sodium 2-(hydroxymethylthio)ethanesulphonate (HOCH2-S-CoM), whereas reaction with the ammonium salt of HS-CoM yielded iminobis-[2-(methylthio)ethanesulphonate], monoammonium salt [NH = (CH2 - S - CoM)2]. In water, NH = (CH2 - S - CoM)2 decomposed to 2-(aminomethylthio)ethanesulphonate (NH2CH2 - S - CoM) and HOCH2-S-CoM. NH-2-CH2 - CoM was degraded further to form more HOCH2-S-CoM. The structures of these coenzyme M derivatives were confirmed by i.r. and n.m.r. spectroscopy and by elemental analysis. When added to cell extracts of Methanobacterium thermoautotrophicum, methane was formed from either HOCH2 - S - CoM or NH = (CH2 - S - CoM)2 at rates comparable with the rate of methane formation from the methanogenic precursor 2-(methylthio)-ethanesulphonate (CH3 - S - CoM). Formaldehyde was reduced to methane at similar rates. In addition, certain hemimercaptals, including thiazolidine and thiazolidine-4-carboxylate, were reduced, although at slower rates. The reduction of formaldehyde, thiazolidine, or thiazolidine-4-carboxylate required catalytic amounts of HS-CoM. ATP was required by cells extracts for reduction of each of these methane precursors.     

Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome.

Monocycline is the most widely prescribed systemic antibiotic for acne largely because it needs to be given only once or twice a day and seems not to induce resistance. Up to April 1994 11 cases of minocycline induced systemic lupus erythematosus and 16 cases of hepatitis had been reported to the Committee on Safety of Medicines. An analysis of these cases together with seven other cases shows the severity of some of these reactions. Two patients died while taking the drug for acne and a further patient needed a liver transplant. Acne itself can induce arthritis and is often seen in association with autoimmine liver disease, but the clinical and biochemical resolution seen after withdrawal of the drug, despite deterioration of the acne, suggests a drug reaction. In five cases re-exposure led to recurrence. Because reactions may be severe early recognition is important to aid recovery and also to avoid invasive investigations and treatments such as corticosteroids and immunosuppresants. Safer alternatives should be considered for treating acne.