Inhibition of multiple phases of human immunodeficiency virus type 1 replication by a dithiane compound that attacks the conserved zinc fingers of retroviral nucleocapsid proteins

The human immunodeficiency virus type 1 (HIV-1) nucleocapsid p7 protein contains two retrovirus-type zinc finger domains that are required for multiple phases of viral replication. Chelating residues (three Cys residues and one His residue) of the domains are absolutely conserved among all strains of HIV-1 and other retroviruses, and mutations in these residues in noninfectious virions. These properties establish the zinc finger domains as logical targets for antiviral chemotherapy. Selected dithiobis benzamide (R-SS-R) compounds were previously found to inhibit HIV-1 replication by mediating an electrophilic attack on the zinc fingers. Unfortunately, reaction of these disulfide-based benzamides with reducing agents yields two monomeric structures (two R-SH structures) that can dissociated and no longer react with the zinc fingers, suggesting that in vivo reduction would inactivate the compounds. Through an extensive drug discovery program of the National Cancer Institute, a nondissociable tethered dithiane compound (1,2-dithiane-4,5-diol, 1,1-dioxide, cis; NSC 624151) has been identified. This compound specifically attacks the retroviral zinc fingers, but not other antiviral targets. The lead compound demonstrated broad antiretroviral activity, ranging from field isolates and drug-resistant strains of HIV-1 to HIV-2 and simian immunodeficiency virus. The compound directly inactivated HIV-1 virions and blocked production of infectious virus from cells harboring integrated proviral DNA. NSC 624151 provides a scaffold from which medicinal chemists can develop novel compounds for the therapeutic treatment of HIV infection.     

Hemolysis and schizocytosis, malabsorption and the "folate trap": unusual semiological peculiarities associated with vitamin B12 deficiency

INTRODUCTION: Hemolysis and red cell fragmentation accompanying vitamin B12 deficiency may misdirect the diagnosis. Signs of malabsorption and abnormalities related to folic acid metabolism characterized by discrepancies between folic acid normal serum levels and erythrocytic folic acid levels may also exist. EXEGESIS: We report the occurrence of hemolysis and red cell fragmentation mimicking microangiopathic hemolytic anemia, malabsorption and folic acid deficiency in the course of vitamin B12 deficiency. Appropriate replacement therapy corrected all abnormalities. CONCLUSION: An association between hemolysis, malabsorption and folic acid deficiency should lead physicians to search for signs of vitamin B12 deficiency.     

Rejoinder to Kurtz.

Kurtz (1971; see record 1990-56874-001) is, of course, quite correct in noting that my comment (Schaeffer, 1970; see record 1990-56809-001) does not really answer my question; but this appears clearly indicated in the conclusions I draw in the final paragraph of my paper. His plea for the use of Psychometrika as a touchstone for the investigation of "favoritism" is also reasonable, but my data should be sufficient to answer his question here. In fact, for 1967, Psychometrika ranked second in terms of printing editors' contributions, and lowest (among the journals reviewed) in terms of printing outside contributions. Further, the correlation between my measure of "favoritism" and the Jakobovits and Osgood measure of "Rigor" (on which Psychometrika ranks second) also suggests this journal would be high on the measure of "favoritism." While it might then be possible to argue from these data (and Kurtz's premises) that almost all journals considered in this study are prejudiced in favor of outside contributors, such an argument would seem somewhat forced, and would minimally require more extensive sampling of this and related journals than I felt the question really deserved. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Desensitization of beta3-adrenergic receptor-stimulated adenylyl cyclase activity and lipolysis in rats

The beta3-adrenergic receptor is an integral membrane protein consisting of seven transmembrane domains. Unlike the beta1 and beta2 receptors, this subtype lacks the consensus phosphorylation sites required for desensitization by serine kinases. Using the rodent specific beta3 agonist BRL 35135, our initial data indicated that beta3 receptor-mediated glycerol levels progressively decreased following daily oral doses of 5 mg/kg. Therefore, we initiated studies designed to delineate the possible mechanism(s) for this decreased response. Within 3 hours following a single oral dose of BRL 35135, serum glycerol levels and UCP (uncoupling protein) RNA levels were significantly increased whereas beta3 RNA levels were significantly decreased. Rats were dosed daily for 5 days with either vehicle or BRL 35135 (5 mg/kg, p.o.) and blood samples were collected for glycerol analysis. Adipose tissue was excised for lipolysis and adenyl cyclase measurements. In addition, UCP and beta3 receptor RNA levels were assessed. No effect on adipocyte BRL 37344-stimulated adenylyl cyclase activity was observed 3 hours following the initial dose of BRL 35135. Although a slight decrease (approximately 25%) in adenylyl cyclase activity could be observed 24 hours following the initial dose, it wasn't until day 4 of dosing that a significant decrease (50%) was observed. In contrast, beta3- stimulated lipolysis in adipocytes from BRL 35135-treated rats was decreased 85% within 24 hours and this decrease persisted through four days of treatment. These data indicate that the lipolytic response to beta3 receptor activation is decreased after only a single oral dose of BRL 35135, whereas receptor-mediated adenylyl cyclase activation, although initially unaffected, also desensitizes by day four of treatment.     

Threshold models applied to Holstein conformation traits.

Threshold animal models were applied to five conformation traits of Canadian Holsteins. The estimated breeding values for sires from the threshold model allowed the calculation of predicted percentages of daughters in the desirable categories. Results were compared with those from a linear animal model in terms of their ability to predict future percentages of daughters in the desirable categories using an independent set of data. There was no advantage in a threshold model compared with a conventional linear animal model in its ability to predict future daughter performance. This was likely due to the 18 categories used in the classification of major type traits in Canada and the nearly normal distribution of observations across categories.     

Description of a new DRB1*11 allele (DRB1*1132)

We describe a new DRB1*11 allele which is similar to DRB1*11011 except at codon 74, where a GCG is changed for a GTG leading to an alanine/valine substitution. This new allele was carried by a Caucasian patient suffering from rheumatoid arthritis and by her healthy daughter. The motif at codon 74 of the new DRB1*11 is not found in any other known DRB alleles, nor among the published DQA1, DQB1, DPA1 or DPB1 alleles, and therefore suggests a mechanism of point mutation.     

Development and Characterization of Microcalorimeters for a Next Generation 187Re Beta-Decay Experiment

It has been demonstrated in the past that observing the β-decay spectrum of ¹⁸⁷Re with microbolometers provides a suitable method to determine the mass of the electron anti-neutrino from β-endpoint measurements. In a first step, with the experiment MIBETA a sensitivity of m _νe≤15 eV/c² was achieved. To compete with the sensitivity of m _νe≤2.2 eV/c² established by the Mainz/Troitsk tritium β-decay experiment and the limit of m _νe≤0.2 eV/c² aimed at with KATRIN, a new experiment MARE has been initiated. As a first stage (MARE-1), 300 detectors consisting of silicon implanted thermistors, produced by NASA/GSFC, and absorbers of AgReO₄ crystals will be mounted. To optimize the experimental setup, a test array was equipped with 10 AgReO₄ crystals of various size and shape. The influence of the crystal quality as well as of different types of resin on rise time and energy resolution was investigated.      

Design of the Cryogen-Free Cryogenic System for the CUORE Experiment

We present here the final design of the cryogenic system where the CUORE detector will be installed in 2010. It is a large cryogen-free cryostat cooled by pulse tubes and by a high-power dilution refrigerator. To avoid radioactive background, about 15000 kg of lead will be cooled to below 1 K and only few construction materials are acceptable. The detector assembly will have a total mass of about 1500 kg and must be cooled to less than 10 mK in a vibration-free environment. We discuss the adopted technical solutions, the results of the preliminary thermal analysis of the system, and its expected performance.      

Design and Sizing Electric Micro Generator Using Thermoelectric Modules

This paper presents the development of a methodology for calculating sizing electric micro sources of power generation using TEG （thermoelectric modules） to capture energy industrial process waste. Since the thermoelectric modules are able to convert a temperature gradient directly into electricity and still occupy a small space, and have no vibration or noise during operation. Furthermore, the cogeneration using thermoelectric modules is totally clean and reuses part of the residual thermal energy to generate power, or improve the overall yield of the process and avoid the emission of gases to the environment. Therefore, this research contributes to the development of a green energy to numerical modeling for the design and dimensioning of micro-sources of electric power generation from performance curves and predetermined temperature gradients industrial processes. The result is an effective methodology for the design and conditioning the voltage level and power of micro allowing the size of the electrical quickly and securely for many industrial applications, varying the types of modules used area, voltage and power generated.     

Our own translation box: exploring proximity antecedents and performance implications of customer co-design in manufacturing

Customer involvement with design activity is one of the principal components of mass customisation. Whereas many studies proposed methods to enable customer co-design, more research needs to determine co-design predictors and its associations with operations improvements. This study tests relationships between proximity, co-design, and performance, and whether co-design mediates proximity-performance relationships. Following on recent technology and collaborative trends, the study uses a three-dimensional operationalisation of customer proximity that includes physical, virtual, and affinity proximity measures. Regression analyses of data from 698 manufacturers from metal-mechanic industries suggest that virtual and affinity proximity related positively with customer co-design, that co-design explained quality and delivery improvements, and that co-design mediated the relationship between virtual proximity and quality improvements.