Synthesis of L-fucose in thyroid tissue

A de novo pathway for L-fucose synthesis has been detected in porcine thyroid tissue. This system uses guanosine diphospho-alpha-D mannose as a precursor and forms guanosine diphospho-beta-L-fucose as product. The system seems similar to those reported by others to exist in microorganisms and plants in that the first step of the pathway involves a 4-keto sugar nucleotide intermediate. The first enzyme of the pathway, guanosine diphospho-alpha-D-mannose oxidoreductase has been purified 57-fold from crude extracts by virtue of its affinity for Blue Sepharose.     

A Unique Carboxyl-terminal Insert Domain in the Hematopoietic-specific,GTPase-deficient Rho GTPase RhoH Regulates Post-translational Processing

RhoH is a hematopoietic-specific, GTPase-deficient member of the Rho GTPase family that was first identified as a hypermutable gene in human B lineage lymphomas. RhoH remains in a constitutively active state and thus its effects are regulated by expression levels or post-translational modifications. Similar to other small GTPases, intracellular localization of RhoH is dependent upon the conserved “CAAX” box and surrounding sequences within the carboxyl (C) terminus. However, RhoH also contains a unique C-terminal “insert” domain of yet undetermined function. RhoH serves as adaptor molecule in T cell receptor signaling and RhoH expression correlates with the unfavorable prognostic marker ZAP70 in human chronic lymphocytic leukemia. Disease progression is attenuated in a Rhoh^−/− mouse model of chronic lymphocytic leukemia and treatment of primary human chronic lymphocytic leukemia cells with Lenalidomide results in reduced RhoH protein levels. Thus, RhoH is a potential therapeutic target in B cell malignancies. In the current studies, we demonstrate that deletion of the insert domain (LFSINE) results in significant cytoplasmic protein accumulation. Using inhibitors of degradation pathways, we show that LFSINE regulates lysosomal RhoH uptake and degradation via chaperone-mediated autophagy. Whereas the C-terminal prenylation site is critical for ZAP70 interaction, subcellular localization and rescue of the Rhoh^−/− T cell defect in vivo, the insert domain appears dispensable for these functions. Taken together, our findings suggest that the insert domain regulates protein stability and activity without otherwise affecting RhoH function.     

Discovering novel carbonic anhydrase type IX (CA IX) inhibitors from seven million compounds using virtual screening and in vitro analysis

Carbonic anhydrase type IX (CA IX) enzyme is mostly over expressed in different cancer cell lines and tumor tissues. Potent CA IX inhibitors can be effective for adjusting the pH imbalance in tumor cells. In the present work, we represented the successful application of high throughput virtual screening (HTVS) of large dataset from ZINC database included of ～7 million compounds to discover novel inhibitors of CA IX. HTVS and molecular docking were performed using consequence Glide/standard precision (SP), extra precision (XP) and induced fit docking (IFD) molecular docking protocols. For each compound, docking code calculates a set of low-energy poses and then exhaustively scans the binding pocket of the target with small compounds. Novel CA IX inhibitor candidates were suggested based on molecular modeling studies and a few of them were tested using in vitro analysis. These compounds were determined as good inhibitors against human CA IX target with K_i in the range of 0.85–1.58?μM. In order to predict the pharmaceutical properties of the selected compounds, ADME (absorption, distribution, metabolism and excretion) analysis was also carried out.     

Levels of superoxide dismutase and malondialdehyde in primary spontaneous pneumothorax

The aim of the present study is to determine whether patients with primary spontaneous pneumothorax (PSP) are subject to oxidative stress. For this purpose, we measured the activities of red blood cell superoxide dismutase, which is an antioxidant enzyme, and the level of plasma malondialdehyde, which is one of the lipid peroxidation markers, in a group of patients with PSP. The study was carried out with 16 patients with PSP and 24 healthy individuals. The two groups were similar to each other in terms of sex, age and smoking attitudes. Erythrocyte superoxide dismutase activity was found to be significantly lower in patients with PSP than in the control group (p < 0.01). The plasma malondialdehyde levels were significantly high in patients with PSP (p < 0.01). Our results suggest that oxidative stress may contribute to the pathogenesis of PSP.     

Extreme elevation of serum alpha fetoprotein in decompensated cirrhosis without HCC: an ominous sign

Three cases of extreme elevation of serum alpha fetoprotein (>10,000 ng/mL) with decompensated cirrhosis without demonstrable hepatocellular carcinoma are reported. While 2 patients died of liver failure, 1 survived after liver transplantation. Extreme elevation of alpha fetoprotein not associated with hepatocellular carcinoma in liver cirrhosis heralds an ominous prognosis necessitating urgent liver transplantation.     

Metabolite control of L-fucose utilization.

Thyroid fucokinase is responsive to a number of metabolites which might serve in a regulatory capacity. In addition to inhibition by ADP and stimulation by GMP, fucokinase responds selectively to a series of nucleotide sugars. Of those studied, only guanine nucleotide sugars moderate the activity of the enzyme. GDP-alpha-D-mannose, GDP-alpha-D-glucose, GDP-alpha-D-rhamnose, and GDP-alpha-L-fucose on the other hand is strongly inhibitory. In the case of GDP-alpha-D-mannose stimulation, a physiological role seems possible, but the rationale is not entirely clear. The effects of GDP-beta-L-fucose, on the other hand may represent physiological control effected through feedback inhibition by and end product.     

Dispersal and field progeny production of Trichogramma species released in an olive orchard in Egypt

Dispersal ability and field progeny production of augmentative released biological control agents depend on ecological adaptations of the particular species or strains used. Four species of the egg parasitoid genus Trichogramma were compared aiming to select suitable candidates for control of lepidopteran olive pests. Three of them (T. bourarachae Pintureau and Babault, T. cordubensis Vargas and Cabello, T. euproctidis Girault) had been previously collected from olive groves, whereas the commercially available strain used (T. evanescens Westwood) was originally isolated from sugarcane fields. During five consecutive field releases in an olive orchard near Cairo, dispersal and/or progeny production of these species was monitored using sentinel eggs placed at different heights in the release tree canopies as well as in neighboring trees (“distance effect”). The cardinal direction of dispersal was random for T. euproctidis and T. evanescens. Significant higher parasitism occurred on sentinel eggs placed on the middle part of tree canopy and highest parasitism was observed in trees where wasps had been released. Field progeny production was highest for T. bourarachae, followed by T. euproctidis and T. cordubensis. T. evanescens propagated less under field conditions. Inter-tree dispersal of all species except T. bourarachae was limited and, for biological control, releasing material should therefore be distributed on each olive tree, preferably also at different levels of the canopy.     

Syncope: Assessment of risk and an approach to evaluation in the emergency department and urgent care clinic

Syncope is among the most frequent forms of transient loss of consciousness (TLOC), and is characterized by a relatively brief and self-limited loss of consciousness that by definition is triggered by transient cerebral hypoperfusion. Most often, syncope is caused by a temporary drop of systemic arterial pressure below that required to maintain cerebral function, but brief enough not to cause permanent structural brain injury. Currently, approximately one-third of syncope/collapse patients seen in the emergency department (ED) or urgent care clinic are admitted to hospital for evaluation. The primary objective of developing syncope/TLOC risk stratification schemes is to provide guidance regarding the immediate prognostic risk of syncope patients presenting to the ED or clinic; thereafter, based on that risk assessment physicians may be better equipped to determine which patients can be safely evaluated as outpatients, and which require hospital care. In general, the need for hospitalization is determined by several key issues: i) the patient''s immediate (usually considered 1 week to 1 month) mortality risk and risk for physical injury (e.g., falls risk), ii) the patient''s ability to care for him/herself, and iii) whether certain treatments inherently require in-hospital initiation (e.g., pacemaker implantation). However, at present no single risk assessment protocol appears to be satisfactory for universal application, and development of a consensus recommendation is an essential next step.