Protective effects of agomelatine on testicular damage caused by bortezomib

Bortezomib is a chemotherapeutic agent used to treat several cancers; however, it exhibits severe side effects in testicular tissue. We investigated the use of agomelatine to prevent testicular tissue damage caused by bortezomib. We used 36 male Sprague-Dawley rats divided randomly into six equal groups: group 1, no treatment control; group 2, agomelatine treatment only; group 3, bortezomib treatment only for 48 h; group 4, bortezomib + agomelatine treatment for 48 h; group 5, bortezomib treatment only for 72 h; and group 6, bortezomib + agomelatine treatment for 72 h. After treatments, the rats were sacrificed and testicular tissue was harvested. Lipid oxidation (LPO) and superoxide dismutase (SOD) levels in the tissues were determined using biochemical methods. Tissue samples also were examined using histopathological and immunohistochemical techniques. The LPO level was increased, while the SOD level was decreased in the bortezomib treated groups. We found that agomelatine treatment normalized LPO and SOD activities in the bortezomib treated groups. In the spermatogonia and Sertoli cells, the staining density of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and caspase 3 were decreased in the bortezomib + agomelatine groups at both 48 and 72 h compared to bortezomib only treated groups. We observed maturation arrest, basal membrane thickening, increase in inflammatory cells and connective tissue, and edema between germ cells in the bortezomib only treated groups. By contrast, normal basal membrane, less edema and more normal maturation were observed in the bortezomib + agomelatine groups at 48 and 72 h. We found that agomelatine reduced the damaging effects of bortezomib. The use of agomelatine to prevent bortezomib induced testicular tissue damage in human patients should be investigated further.     

Effectiveness of the International Phytosanitary Standard ISPM No. 15 on Reducing Wood Borer Infestation Rates in Wood Packaging Material Entering the United States

Numerous bark- and wood-infesting insects have been introduced to new countries by international trade where some have caused severe environmental and economic damage. Wood packaging material (WPM), such as pallets, is one of the high risk pathways for the introduction of wood pests. International recognition of this risk resulted in adoption of International Standards for Phytosanitary Measures No. 15 (ISPM15) in 2002, which provides treatment standards for WPM used in international trade. ISPM15 was originally developed by members of the International Plant Protection Convention to “practically eliminate” the risk of international transport of most bark and wood pests via WPM. The United States (US) implemented ISPM15 in three phases during 2005–2006. We compared pest interception rates of WPM inspected at US ports before and after US implementation of ISPM15 using the US Department of Agriculture AQIM (Agriculture Quarantine Inspection Monitoring) database. Analyses of records from 2003–2009 indicated that WPM infestation rates declined 36–52% following ISPM15 implementation, with results varying in statistical significance depending on the selected starting parameters. Power analyses of the AQIM data indicated there was at least a 95% chance of detecting a statistically significant reduction in infestation rates if they dropped by 90% post-ISPM15, but the probability fell as the impact of ISPM15 lessened. We discuss several factors that could have reduced the apparent impact of ISPM15 on lowering WPM infestation levels, and suggest ways that ISPM15 could be improved. The paucity of international interception data impeded our ability to conduct more thorough analyses of the impact of ISPM15, and demonstrates the need for well-planned sampling programs before and after implementation of major phytosanitary policies so that their effectiveness can be assessed. We also present summary data for bark- and wood-boring insects intercepted on WPM at US ports during 1984–2008.     

D-Amino acids in protein de novo design. II. Protein-diastereomerism versus protein-enantiomerism

Summary With a few exceptions, proteins in our biosphere are based exclusively onl-amino acids. The inversion of configuration of all the stereogenic centers in a protein leads to anall-d compound with ‘mirror image’ properties and ‘mirror image’ structure. We propose to use the termprotein-enantiomerism to describe the relationship between two proteins that have the same sequence but whose amino acids have opposite configuration. We will use the termprotein-diastereomerism to define the relationship between two proteins that have the same sequence in which some amino acids have opposite configurations. A classification of type I, II, III, and IV protein-diastereomerism is proposed. By extension, a diastereoprotein is a protein where some amino acids have the same configuration (l ord) while others have the opposite one (d orl). A particular case of diastereoproteins aremesoproteins, also analyzed in this article. In addition to the goal of making proteins resistant to protease degradation, the use ofd-amino acids in protein de novo design may give rise to proteins with structures, and perhaps properties, very different to those of nativeall-l-proteins.     

D-Amino acids in protein de novo design. II. Protein-diastereomerism versus protein-enantiomerism

With a few exceptions, proteins in our biosphereare based exclusively on l-amino acids. The inversionof configuration of all the stereogenic centers in aprotein leads to an all- d compound with mirrorimage properties and mirror image structure. Wepropose to use the term protein-enantiomerism to describe the relationship betweentwo proteins that have the same sequence but whoseamino acids have opposite configuration. We will usethe term protein-diastereomerism todefine the relationship between two proteins that havethe same sequence in which some amino acids haveopposite configurations. A classification of type I,II, III, and IV protein-diastereomerism isproposed. By extension, a diastereoprotein is aprotein where some amino acids have the sameconfiguration (l or d) while others have the oppositeone (d or l). A particular case of diastereoproteinsare mesoproteins, also analyzed in thisarticle. In addition to the goal of making proteinsresistant to protease degradation, the use of d-amino acids in protein de novo design may give riseto proteins with structures, and perhaps properties,very different to those of native all-L-proteins.     

Evaluation of semiochemicals potentially synergistic to α-pinene for trapping the larger European pine shoot beetle, Tomicus piniperda (Col., Scolytidae)

Abstract:  The pine shoot beetle, Tomicus piniperda (L.) (Col., Scolytidae) is an exotic pest of pine, Pinus spp., in North America. It is attracted strongly to host volatiles (±)- α -pinene, (+)-3-carene, and α -terpinolene. Attraction to insect-produced compounds is less clear. Other potential attractants include trans -verbenol, myrtenol, myrtenal, nonanal and α -pinene oxide. We conducted a series of field experiments to determine if any of these compounds would increase attraction of T. piniperda to α -pinene, either individually or in various combinations. None of the individual compounds increased attraction. Although several combinations that included trans -verbenol, nonanal, myrtenol, or myrtenal increased attraction, results were variable between experiments.     

Parallel reverse genetic screening in mutant human cells using transcriptomics

Reverse genetic screens have driven gene annotation and target discovery in model organisms. However, many disease‐relevant genotypes and phenotypes cannot be studied in lower organisms. It is therefore essential to overcome technical hurdles associated with large‐scale reverse genetics in human cells. Here, we establish a reverse genetic approach based on highly robust and sensitive multiplexed RNA sequencing of mutant human cells. We conduct 10 parallel screens using a collection of engineered haploid isogenic cell lines with knockouts covering tyrosine kinases and identify known and unexpected effects on signaling pathways. Our study provides proof of concept for a scalable approach to link genotype to phenotype in human cells, which has broad applications. In particular, it clears the way for systematic phenotyping of still poorly characterized human genes and for systematic study of uncharacterized genomic features associated with human disease.     

Differential effects of 20-trifluoromethyl leukotriene B4 on human neutrophil functions

A leukotriene B₄ (LTB₄) analog, 20-trifluoromethyl LTB₄ (20CF₃−LTB₄), has been synthesized and evaluated with human neutrophils for effects on chemotaxis and degranulation. 20CF₃−LTB₄ was equipotent to LTB₄ as a chemoattractant (EC₅₀, 3 nM), produced 50% of maximal activity of LTB₄, and competed with [H] LTB₄ for binding to intact human neutrophil LTB₄ receptors. In contrast to chemotactic activity, 20CF₃−LTB₄ in nanomolar concentrations exhibited antagonist activity without agonist activity up to 10 μM on LTB₄-induced degranulation. The analog had no significant effect on degranulation induced by the chemoattractant peptide, N-formyl-methionyl-leucyl-phenylalanine (fMLP). Like LTB₄, 20CF₃−LTB₄ induced neutrophil desensitization to degranulation by LTB₄. The results indicate that hydrogen atoms at C-20 of LTB₄ are critical for its intrinsic chemotactic and degranulation activities. The fact that 20CF₃−LTB₄ is a partial agonist for chemotaxis and an antagonist for degranulation syggests that different LTB₄ receptor subtypes are coupled to these neutrophil functions. Desensitization of the neutrophil degranulation response to LTB₄ can result from receptor occupancy by an antagonist, and therefore, the desensitization is not specific for an agonist.