Sex Differences in the Association of Thigh Fat and Metabolic Risk in Older Adults

We have previously shown a favorable association of subcutaneous leg fat with markers of insulin resistance and dyslipidemia in postmenopausal women. It is not known whether there is a sex dimorphism in the association of lower‐body adiposity with reduced metabolic risk. Thus, our primary aim was to determine whether the favorable association of thigh subcutaneous fat, independent of abdominal fat, is also observed in older men. Mid‐thigh and abdominal fat areas were measured by computed tomography (CT) in 108 older men and postmenopausal women (mean ± s.d.; 69 ± 7 years). Additionally, trunk and leg fat mass (FM) were measured by dual‐energy X‐ray absorptiometry (DXA). Markers of insulin resistance and dyslipidemia were determined from oral glucose tolerance tests and lipid and lipoprotein measurements, respectively. Outcomes were fasted and postchallenge (area under the curve, AUC) insulin (INS_AUC) and glucose (GLU_AUC), product of the insulin and glucose AUC (INS_AUC × GLU_AUC), triglycerides (TG), and high‐density lipoprotein (HDL)‐cholesterol. Consistent with our previous findings in postmenopausal women, adjusting for DXA trunk FM revealed a favorable association of DXA leg FM with the metabolic risk outcomes in both older men and postmenopausal women. Likewise, adjusting for CT abdominal visceral fat generally revealed a favorable association of CT thigh fat with metabolic risk outcomes in women, but not men. The discordance between the DXA and CT results in men is unclear but may be due to sex differences in visceral fat accrual. The mechanisms underlying the protective effect of thigh fat on metabolic risk factors need to be elucidated.     

Expression of the human atypical kinase ADCK3 rescues coenzyme Q biosynthesis and phosphorylation of Coq polypeptides in yeast coq8 mutants

Coenzyme Q (ubiquinone or Q) is a lipid electron and proton carrier in the electron transport chain. In yeast Saccharomyces cerevisiae eleven genes, designated COQ1 through COQ9, YAH1 and ARH1, have been identified as being required for Q biosynthesis. One of these genes, COQ8 (ABC1), encodes an atypical protein kinase, containing six (I, II, III, VIB, VII, and VIII) of the twelve motifs characteristically present in canonical protein kinases. Here we characterize seven distinct Q-less coq8 yeast mutants and show that unlike the coq8 null mutant, each maintained normal steady-state levels of the Coq8 polypeptide. The phosphorylation states of Coq polypeptides were determined with two-dimensional gel analyses. Coq3p, Coq5p, and Coq7p were phosphorylated in a Coq8p-dependent manner. Expression of a human homolog of Coq8p, ADCK3(CABC1) bearing an amino-terminal yeast mitochondrial leader sequence, rescued growth of yeast coq8 mutants on medium containing a nonfermentable carbon source and partially restored biosynthesis of Q(6). The phosphorylation state of several of the yeast Coq polypeptides was also rescued, indicating a profound conservation of yeast Coq8p and human ADCK3 protein kinase function in Q biosynthesis.     

The growth-hormone inducible transmembrane protein (Ghitm) belongs to the Bax inhibitory protein-like family

The conserved protein domain UPF0005 is a protein family signature distributed among many species including fungi and bacteria. Although of unknown functionality this motif has been found in newly identified antiapoptotic proteins comprising the BI-1 family, namely Bax-inhibitory Protein-1 (BI-1), Lifeguard (LFG), and h-GAAP. In a search for vertebrate proteins presumably belonging to the BI-1 family, we found that Growth-hormone inducible transmembrane protein (Ghitm) is another prospective member of the BI-1 family. Here we characterise Ghitm in a first analysis regarding its phylogeny, expression in cancer cell lines, and proteomical properties.     

Structure-based functional inference in structural genomics

The dramatically increasing number of new protein sequences arising from genomics 4 proteomics requires the need for methods to rapidly and reliably infer the molecular and cellular functions of these proteins. One such approach, structural genomics, aims to delineate the total repertoire of protein folds in nature, thereby providing three-dimensional folding patterns for all proteins and to infer molecular functions of the proteins based on the combined information of structures and sequences. The goal of obtaining protein structures on a genomic scale has motivated the development of high throughput technologies and protocols for macromolecular structure determination that have begun to produce structures at a greater rate than previously possible. These new structures have revealed many unexpected functional inferences and evolutionary relationships that were hidden at the sequence level. Here, we present samples of structures determined at Berkeley Structural Genomics Center and collaborators laboratories to illustrate how structural information provides and complements sequence information to deduce the functional inferences of proteins with unknown molecular functions.Two of the major premises of structural genomics are to discover a complete repertoire of protein folds in nature and to find molecular functions of the proteins whose functions are not predicted from sequence comparison alone. To achieve these objectives on a genomic scale, new methods, protocols, and technologies need to be developed by multi-institutional collaborations worldwide. As part of this effort, the Protein Structure Initiative has been launched in the United States (PSI; www.nigms.nih.gov/funding/psi.html). Although infrastructure building and technology development are still the main focus of structural genomics programs [1–6], a considerable number of protein structures have already been produced, some of them coming directly out of semi-automated structure determination pipelines [6–10]. The Berkeley Structural Genomics Center (BSGC) has focused on the proteins of Mycoplasma or their homologues from other organisms as its structural genomics targets because of the minimal genome size of the Mycoplasmas as well as their relevance to human and animal pathogenicity (http://www.strgen.org). Here we present several protein examples encompassing a spectrum of functional inferences obtainable from their three-dimensional structures in five situations, where the inferences are new and testable, and are not predictable from protein sequence information alone.     

The design and discovery of novel amide CCR5 antagonists

The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR’s which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.     

Importance of data structure in comparing two dimension reduction methods for classification of microarray gene expression data

Background  

With the advance of microarray technology, several methods for gene classification and prognosis have been already designed. However, under various denominations, some of these methods have similar approaches. This study evaluates the influence of gene expression variance structure on the performance of methods that describe the relationship between gene expression levels and a given phenotype through projection of data onto discriminant axes.     

Effect of indomethacin on prostaglandin content of several rabbit tissues

The prostaglandin (PG) content of several tissues and fluids from 6 day pregnant rabbits was evaluated following treatment with indomethacin or vehicle . PGE and PGF were measured by radioimmunoassay. More complete depletion of PGE and PGF was accomplished by 3 injections of indomethacin (s.c.) given during the 18 h before sacrifice at a dose of 10 mg indomethacin per kg body weight than was accomplished by 1 injection of the same amount of indomethacin (i.v.) 1.5 h before sacrifice. Levels of PGF were more easily depressed by indomethacin than were those of PGE. PG levels in the kidney and blastocysts were depressed to a greater extent by indomethacin than were those in the uterus, uterine fluid or peritoneal fluid. Evaluation of the effect of indomethacin on a particular physiological function should be interpreted with caution unless the extent of PG depletion in that tissue is also measured.     

Heparan sulfate 2-O-sulfotransferase (Hs2st) and mouse development

Heparan sulphate 2-O-sulphotransferase (Hs2st) acts at an intermediate stage in the pathway of biosynthesis of heparan sulphate (HS), catalysing the transfer of sulphate from 3-phosphoadenosine-5-phosphosulfate (PAPS) to the C2-position of selected hexuronic acid residues within the maturing HS chain. It is well established that 2-O-sulphation within HS, particularly of iduronate residues, is essential for HS to participate in a variety of high-affinity ligand-binding interactions. HS plays a central role in embryonic development and cellular function, modulating the activities of an extensive range of growth factors. Interestingly, in contrast to the early failure of embryos entirely lacking HS, Hs2st ^–/– mice survive until birth, but die perinatally due to a complete failure of kidney formation. The phenotype of Hs2st ^–/– mutant kidneys suggests that signalling between two tissues, ureteric bud and metanephric mesenchyme, is disrupted. We discuss candidate signalling molecules that may mediate this interaction. The HS generated by these mice lacks 2-O-sulphate groups but is extensively modified above wild type levels by O-sulphation at C-6 of glucosamine-N-sulfate (GlcNS) residues. We will discuss the potentially altered role of this atypical HS in growth factor signalling. Published in 2003.     

Risk Assessment of the Abandoned Jukjeon Metal Mine in South Korea Following the Korean Guidelines

Toxic metal contamination in the vicinity of Korean abandoned metal mines has been reported. A risk assessment for these metals was performed for the inhabitants in the area of the abandoned Jukjeon metal mine. Soil, groundwater, and crop samples were collected around the mine. After pretreatment of these samples, metal concentrations were measured and then a risk assessment was performed using the Korean soil-contamination risk assessment guidelines. Phytoaccumulation of metals in crops was observed in soybeans (As and Zn), red peppers (Zn), sweet potatoes (As and Zn), and cabbage (Cu), which had higher metal concentrations than soils in the area. The metal intake rate was highest for inhalation of soil. Cancer risk was highest from ingestion of As-contaminated crops. The sum of carcinogenic risks was 6.29 × 10^–3. The non-carcinogenic risk was highest for ingestion of As-contaminated crops (8.17). Most of the risks were attributable to As, Pb, and Hg contamination, therefore these three metals must be considered as the principal metals toxic to human health in the sampled area. In particular, the inhalation of metal-contaminated soil should be considered for risk assessment along with ingestion of water and crops in abandoned mine areas.