Mitogen-activated protein (MAP) kinases, also known as extracellular signal-regulated kinases (ERKs), are thought to act at an integration point for multiple biochemical signals because they are ...activated by a wide variety of extracellular signals, rapidly phosphorylated on threonine and tyrosine, and highly conserved. A critical protein kinase lies upstream of MAP kinase and stimulates the enzymatic activity of MAP kinase. The structure of this protein kinase, denoted MEK1, for $\underline{M}$AP kinase or $\underline{E}$RK $\underline{k}$inase, was elucidated from a complementary DNA sequence and shown to be a protein of 393 amino acids (43,500 daltons) that is related most closely in size and sequence to the product encoded by the Schizosaccharomyces pombe byr1 gene. The MEK gene was highly expressed in murine brain, and the product expressed in bacteria phosphorylated the ERK gene product.
The inhibition of new blood vessel formation (angiogenesis) is an effective means of limiting both the size and metastasis of solid tumors. The leading anti-angiogenic compound, TNP-470, has proven ...to be effective in in vitro and in animal model studies, and is currently being tested in phase III antitumor clinical trials. Despite many detailed pharmacological studies, little is known of the molecular mode of action of TNP-470. Using a derivative of the TNP-470 parent compound, the fungal metabolite, fumagillin, we have purified a mammalian protein that is selectively and covalently bound by this natural product. This fumagillin binding protein was found to be a metalloprotease, methionine aminopeptidase (MetAP-2), that is highly conserved between human and Saccharomyces cerevisiae. In the absence of MetAP-1, a distantly related methionine aminopeptidase, MetAP-2 function is essential for vegetative growth in yeast. We demonstrate that fumagillin selectively inhibits the S. cerevisiae MetAP-2 protein in vivo. The binding is highly specific as judged by the failure of fumagillin to inhibit MetAP-1 in vivo. Hence, these results identify MetAP-2 as an important target of study in the analysis of the potent biological activities of fumagillin.
Energy expenditure is a physiological process that may be closely associated with residual feed intake (RFI). The maintenance energy (ME(M)) EPD was developed by the Red Angus Association of America ...(RAAA) and is used as an indicator of energy expenditure. The objectives of this study were to evaluate and quantify the following relationships using progeny of Red Angus (RA) sires divergent for ME(M) EPD: 1) postweaning RFI and finishing phase feed efficiency (FE), 2) postweaning RFI and end-product quality, and 3) postweaning RFI and sire ME(M) EPD. A total of 12 RA sires divergent for ME(M) EPD were chosen using the RAAA-generated ME(M) EPD values and were partitioned into 2 groups: high ME(M) EPD (≥4 Mcal/mo) and low ME(M) EPD (<4 Mcal/mo), based on the breed average of 4 Mcal/mo. Commercial crossbred cows were inseminated to produce 3 cohorts of progeny, which were tested for postweaning RFI (cohorts 1, 2, and 3) and finishing phase FE (cohorts 1 and 3). Results indicate that postweaning RFI and finishing phase FE of steer progeny tended to be positively correlated (r = 0.38; P = 0.06) in cohort 1 and were positively correlated (r = 0.50; P = 0.001) in cohort 3. In addition, postweaning RFI was not phenotypically correlated (P > 0.05) with any carcass traits or end-product quality measurements. Sire ME(M) EPD was phenotypically correlated (P < 0.05) with carcass traits in cohort 1 (HCW, LM area, KPH, fat thickness, and yield grade) and cohort 2 (KPH and fat thickness). Since variation in measured LM area was not explained by the genetic potential of rib eye area EPD, and therefore, the observed correlation between sire ME(M) EPD and measured LM area may suggest an association between ME(M) EPD and LM area. A correlation (r = 0.24; P = 0.02) was observed between postweaning RFI and ultrasound intramuscular fat percentage in cohort 2 but was not detected in cohorts 1 or 3. In addition, no phenotypic relationship was observed (P > 0.05) between progeny postweaning RFI and sire ME(M) EPD. Therefore, results suggest 1) RFI measured during the postweaning growth phase is indicative of FE status in the finishing phase, 2) neither RFI nor sire ME(M) EPD negatively affected carcass or end-product quality, and 3) RFI and sire ME(M) EPD are not phenotypically associated.
Epoxomicin (
1), a peptide α',β'-epoxyketone isolated from the actinomycete strain No.Q996-17, possesses potent
in vivo anti-tumor and anti-inflammatory activities. In this paper, we report the first ...syntheses of epoxomicin,
3H-epoxomicin, and a biotinylated epoxomicin analog as well as the absolute configuration of the epoxide stereocenter. The natural product and derivatives have permitted the first identification of the proteasome as the specific cellular target of epoxomicin.
The first syntheses of epoxomicin,
3H-epoxomicin, and a biotinylated epoxomicin affinity analog were accomplished. These reagents permitted the identification of the 20S proteasome as the target of epoxomicin's mode of action. In addition, the absolute configuration of the epoxide stereocenter is reported.
Background The quality of patient-physician discussions about chronic kidney disease (CKD) in primary care has not been studied previously. Study Design Cross-sectional study. Settings & Participants ...We audiotaped encounters between 236 patients with hypertension and their primary care physicians (n = 40). Predictors Patient, physician, and encounter characteristics. Outcomes & Measurements We described the occurrence and characteristics (content, use of technical terms, and physician assessment of patient comprehension of new concepts) of CKD discussions. We assessed patient and physician characteristics associated with CKD discussion occurrence. Results Many patients (mean age, 59 years) had uncontrolled hypertension (51%), diabetes (44%), and/or 3 or more comorbid conditions (51%). Most primary care physicians practiced (52%) fewer than 10 years. CKD discussions occurred in few (26%; n = 61) encounters, with content focused on laboratory assessment (89%), risk-factor treatment (28%), and causes (26%) of CKD. In encounters that included a CKD discussion, physicians used technical terms (28%; n = 17) and rarely assessed patients' comprehension (2%; n = 1). CKD discussions were statistically significantly less common in visits of patients with some (vs no) college education (OR, 0.23; 95% CI, 0.09-0.56), with 3 or more (vs fewer) comorbid conditions (OR, 0.49; 95% CI, 0.25-0.96), and who saw physicians with more (vs fewer) than 10 years of practice experience (OR, 0.41; 95% CI, 0.21-0.80). CKD discussions were more common during longer encounters (OR, 1.31; 95% CI, 1.04-1.65) and encounters in which diabetes was (vs was not) discussed (OR, 2.87; 95% CI, 1.22-6.77). Limitations Generalizability of our findings may be limited. Conclusions Patient-physician discussions about CKD in high-risk primary care patients were infrequent. Physicians used technical terms and infrequently assessed patients' understanding of new CKD concepts. Efforts to improve the frequency and content of patient-physician CKD discussions in primary care could improve patients' clinical outcomes.
Despite doubling of yields of major grain crops since the 1950s, more than one in seven people suffer from malnutrition (1). Global population is growing; demand for food, especially meat, is ...increasing; much land most suitable for annual crops is already in use; and production of nonfood goods (e.g., biofuels) increasingly competes with food production for land (2). The best lands have soils at low or moderate risk of degradation under annual grain production but make up only 12.6% of global land area (16.5 million km super(2)) (3). Supporting more than 50% of world population is another 43.7 million km super(2) of marginal lands (33.5% of global land area), at high risk of degradation under annual grain production but otherwise capable of producing crops (3). Global food security depends on annual grains- cereals, oilseeds, and legumes-planted on almost 70% of croplands, which combined supply a similar portion of human calories (4, 5). Annual grain production, though, often compromises essential ecosystem services, pushing some beyond sustainable boundaries (5). To ensure food and ecosystem security, farmers need more options to produce grains under different, generally less favorable circumstances than those under which increases in food security were achieved this past century. Development of perennial versions of important grain crops could expand options.
The new field of chemical biology brings together chemists and biologists who are seeking to understand and mimic the natural world. One research strategy in this new field is the development of ...biologically active small molecules as molecular probes. This approach, which has been called ‘chemical’ genetics, has allowed elucidation of several pathways that have been difficult to study using traditional genetic approaches.
Background A comprehensive assessment of the association of patients' renal replacement therapy (RRT) modality with their participation in life activities (physical function, travel, recreation, ...freedom, and work) is needed. Study Design Systematic review of peer-reviewed published studies. Setting & Population Adults undergoing RRT (hemodialysis, peritoneal dialysis, or transplantation). Selection Criteria for Studies We searched PubMed, Cochrane Library, and EMBASE from January 1980 through April 2012 for English-language articles that compared participation in life activities among patients receiving: (1) hemodialysis compared with peritoneal dialysis, (2) hemodialysis compared with kidney transplantation, or (3) peritoneal dialysis compared with kidney transplantation. Predictor RRT modality. Outcomes Reported rates of physical function, travel, recreation, freedom, and work-related activities by RRT modality. Results 46 studies (6 prospective cohort, 38 cross-sectional, and 2 pre-post transplantation) provided relevant comparisons of life participation activities among patients treated with hemodialysis, peritoneal dialysis, and kidney transplantation. Studies were conducted in 1985-2011 among diverse patient populations in 16 distinct locations. A majority of studies reported greater life participation rates for patients with kidney transplants compared with patients receiving either hemodialysis or peritoneal dialysis. In contrast, a majority of studies reported no differences in outcomes between patients receiving hemodialysis and patients receiving peritoneal dialysis. These results were consistent throughout the study period, across diverse populations, and among the subset of studies that performed appropriate adjustments for potential confounding factors. Limitations Many studies included in the review had significant design weaknesses. Conclusions Evidence suggests that patients with kidney transplants may experience better rates of life participation compared with patients receiving dialysis, whereas patients receiving hemodialysis and patients receiving peritoneal dialysis may experience similar rates of life participation. Rigorously performed studies are needed to better inform patients about the association of RRT with these important patient-reported outcomes.
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