Analysis of chain length,substitution patterns,and unsaturation of AM-404 derivatives as 20S proteasome stimulators

Proteasome-mediated degradation of proteins is a vital cellular process and is performed by the ubiquitin-dependent proteasome system (UPS) and the ubiquitin-independent proteasome system (UIPS). While both systems are necessary to maintain healthy cell function, many disease states are characterized by reduced activity of the UPS, and the UIPS cannot by itself maintain proper protein levels. It has been suggested that the 20S core particle (20S CP), the isoform of the proteasome in the UIPS that can degrade proteins without a ubiquitin tag, can be stimulated with a small molecule to assist the 20S CP to accept and hydrolyze substrates more rapidly. Several small molecule stimulators of the 20S CP have since been discovered, including AM-404, an arachidonic acid derivative. AM-404 has previously been shown to inhibit fatty acid amide hydrolase activity. We wished to evaluate what structural components of AM-404 are required to stimulate the 20S CP with the long-term goal of using this information to design a stimulator with better drug-like qualities. We synthesized numerous derivatives of AM-404, varying the chain length, substitutions, and degree of unsaturation. Through this endeavor, we obtained several molecules capable of stimulating the 20S CP to various degrees. We discovered that though chain length is important, the presence of a cis-alkene in a specific location in the aliphatic chain has the greatest impact on the ability to stimulate the 20S CP. Two of the derivatives maintain modest stimulatory activity, and have improved toxicity over AM-404.     

The benthic macrofauna community of Kenyan waters of Lake Victoria

The benthic macroinvertebrates in the Kenya waters of Lake Victoria (ca. 1400 km²) were surveyed during four 10 day sampling periods in February, April, August and November 1984. Fourty three taxonomic groups were recorded. Oligochaetes, molluscs and dipteran larvae were the most abundant and widely distributed groups. The dominant oligochaetes were Branchiura sowerbyii Beddard and the swamp worm Alma emini Michaelsen, which were abundant in all silty and soft mud areas in both littoral and open water zones. Melanoides tuberculata Müller, Bellamya unicolor Olivier and Caelatura spp. were the most abundant molluscs. Different patterns were observed between near-littoral stations (<8 m deep) and deep water stations (8–40 m deep). After 10 years (1994), the macroinvertebrates of Lake Victoria were examined again. No evidence was found of seasonal changes in the composition or benthos density, although local changes occurred in some species which were attributed to swarming behaviour or larval settlement patterns. The spatial distribution of the fauna may be influenced primarily by oxygen availability and industrial effluent discharged from paper mill and agro-based industries in the catchment of the lake. There has been a shift in abundance, from an Oligochaeta and Insecta dominated community in 1984, to the present community dominated by Mollusca and Oligochaeta. The ecological role of the benthic community and its recent changes to fisheries production in the lake is discussed.     

Etiology, risks factors, therapy of nosocomial cerebrovascular infections

Nosocomial cerebrovacsular infections are substantial cause of mortality and morbidity in patients after neurosurgery. Risk factors, etiology, treatment strategies and outcome of nosocomial meningitis and brain abscess are briefly reviewed.     

Meningitis in diabetic patients

Community acquired bacterial (CBM) meningitis in diabetic patients was analyzed for risk factors and outcome in a cohort of 201 cases of meningitis within last 17 years: 15 patients with diabetes mellitus and meningitis were identified and compared for etiology and mortality as well as for neurologic sequellae with all CBM cases.     

The antioxidant power and level of lipid peroxidation products in the sera of apparently healthy adult males

The aim of this study was to determine the antioxidant potential of the serum and the level of lipid oxidation products in the sera of apparently healthy adult males. The "antioxidant power" of the serum, defined as the ability to reduce ferric ions by antioxidants from the serum (FRAP), was taken as the indicator of total antioxidation potential. The formation of lipid oxidation products was evaluated as thiobarbituric reactive species serum test (TBARS). The ferrous oxidation in xylenol orange version 2 (FOX2) assay coupled with triphenylphosphine was used for measurement of total sera hydroperoxides (ROOHs). The following biochemical variables were determined in the sera: aspartat aminotranspherase (AST), alanine aminotranspherase (ALT), gamma-glutamyl transpherase (GGT), bilirubin, glucose, creatinine, cholesterol, triglycerides and hemoglobin. Blood sera from apparently healthy subjects (166 adult males) were analyzed. Median age of study participants was 36 years (range 25-50 years). The X +/- SD sera FRAP level of the 166 apparently healthy adult males was 1047 +/- 131 micromol/L (779-1410 range). The X +/- SD level of sera TBARS was 1.2 +/- 0.3 micromol/L of the sera (0.5-2.2 range). Compared with the level of TBARS in the sera, the level of FOX2-ROOH was significantly higher The X +/- SD level of lipid hydroperoxides in the fresh sera, determined as FOX2, was 3.9 +/- 1.5 micromol/L of the sera (1.9-6.9 range). Observation of correlation between FRAP and determined biochemical variables in the sera have confirmed a statistically significant linear correlation between sera FRAP and bilirubin, hemoglobine, glucose, ALT and triglycerides (p < 0.05). The results of sera FRAP, TBARS and FOX2 levels can help in estimating the antioxidant status of humans. Significant correlation between the antioxidant power of blood serum and particular biochemical parameters indicates the complexity of defence mechanisms and various molecules involved in increasing the reduction power of the serum.     

Q fever in Croatia: war-induced changes in epidemiological characteristics

The article describes the epidemiological characteristics of Q fever in Croatia, during the period before and after the Homeland War. In the ten years prior to the Homeland War (1983-1992) 1053 cases of Q fever were recorded, 16.2% (171) of which on islands and in coastal areas. In the period after the Homeland War (1995-2008), a total of 654 cases was recorded, 59.9% (392) of which on islands and in coastal areas. In addition to reduced incidence, geographic distribution of the disease also changed. Before the war, the highest morbidity rate was recorded in the Sisak-Moslavina County. After the war, the Split-Dalmatia County recorded the highest morbidity rate because in the post-war period sheep from Bosnia and Herzegovina went to this county for winter grazing. The disease might be relevant to the Croatian Army and other armed forces that stay in Croatia as part of NATO forces.     

Meningitis in tropics--what is the optimal initial therapy?

Risk factors, etiology, epidemiology and initial therapy of community acquired meningitis in tropics is briefly reviewed.     

Meningococcal meningitis is still the commonest neuroinfection in the community in tropics: overview of 62 cases

Within last 17 years we went through all charts of bacterial meningitis within our nationwide survey and among 372 cases we found 62 cases of MM, in 12 cases with meningococcal disease (with shock, petechial effusions or disseminated intravascular coagulation or digital gangrenes). MM was usually observed in young adults without any of investigated risk factors like neoplasia, ENT (ear, nose, throat) focuses, elderly age, sepsis, diabetes, alcoholism, trauma, neonatal VLBW etc. Trauma, diabetes mellitus, alcohol abuse and chronic sinusitis/otitis were significantly less frequently found as a risk factor for MM. Mortality was very low, only 4.8% and was lower than overall mortality in CBM (12.4%, NS). Also the proportion of neurologic sequellae (9.7%) and initial treatment failure (8.1%) were comparable or even lower. This positive outcome results are probably because all N. meningitis strains were susceptible to penicillin, chloramphenicol, cefotaxim, cotrimoxazol or ciprofloxacin. Other reason for low mortality was that most cases received oral antibiotic immediately, even before admission (50 of 62). 95.2% of cases survived, 90.3% without any transient neurological residual symptoms.     

粤东地区野果植物资源

本文报道了粤东地区野生水果植物资源的调查结果,记录到该地区野生水果植物有57科、101属、205种(含变种),分别占全国野生果树73科、173属、1157种(变种)的78．1％、58．4％、17．7％,含15种以上的科有蔷薇科、壳斗科、芸香科、桑科4个科,为该地区野生水果的优势科,这说明粤东地区的野生水果植物资源极为丰富．