A genetic basis for human susceptibility to West Nile virus

West Nile virus (WNV) infects thousands of humans annually and causes a spectrum of disease ranging from an acute febrile illness to lethal encephalitis. A new study suggests a link between CCR5Delta32 (a common mutant allele of the chemokine and HIV receptor CCR5) and fatal WNV infection. The study highlights a possible risk in targeting this receptor for the prevention and/or treatment of infectious diseases.     

Discovery, SAR, and X-ray structure of novel biaryl-based dipeptidyl peptidase IV inhibitors

The discovery, SAR, and X-ray crystal structure of novel biarylaminoacyl-(S)-2-cyano-pyrrolidines and biarylaminoacylthiazolidines as potent inhibitors of dipeptidyl peptidase IV (DPP IV) are reported.     

Identification and characterization of two families of F420H2‐dependent reductases from Mycobacteria that catalyse aflatoxin degradation

Aflatoxins are polyaromatic mycotoxins that contaminate a range of food crops as a result of fungal growth and contribute to serious health problems in the developing world because of their toxicity and mutagenicity. Although relatively resistant to biotic degradation, aflatoxins can be metabolized by certain species of Actinomycetales. However, the enzymatic basis for their breakdown has not been reported until now. We have identified nine Mycobacterium smegmatis enzymes that utilize the deazaflavin cofactor F₄₂₀H₂ to catalyse the reduction of the α,β‐unsaturated ester moiety of aflatoxins, activating the molecules for spontaneous hydrolysis and detoxification. These enzymes belong to two previously uncharacterized F₄₂₀H₂ dependent reductase (FDR‐A and ‐B) families that are distantly related to the flavin mononucleotide (FMN) dependent pyridoxamine 5′‐phosphate oxidases (PNPOxs). We have solved crystal structures of an enzyme from each FDR family and show that they, like the PNPOxs, adopt a split barrel protein fold, although the FDRs also possess an extended and highly charged F₄₂₀H₂ binding groove. A general role for these enzymes in xenobiotic metabolism is discussed, including the observation that the nitro‐reductase Rv3547 from Mycobacterium tuberculosis that is responsible for the activation of bicyclic nitroimidazole prodrugs belongs to the FDR‐A family.     

The interpretation of abdominal wall muscle recruitment strategies change when the electrocardiogram (ECG) is removed from the electromyogram (EMG)

The purpose of this study was to determine the effect of the ECG artifact on low-level trunk muscle activation amplitudes and assess the effectiveness of two methods used to remove the ECG. Simulations were performed and percent error in root mean square (RMS) amplitudes were calculated from uncontaminated and contaminated EMG signals at various ECG to EMG ratios. Two methods were used to remove the ECG: (1) filtering by adaptive sampling (FAS) and (2) Butterworth high pass filter at 30 Hz (BW-30 Hz HPF). The percent error was also calculated between the ECG removed and the uncontaminated EMG RMS amplitudes. Next, the BW-30 Hz HPF method was used to remove the ECG from 3-bilateral external oblique (EO) muscle sites collected from 30 healthy subjects performing a one handed lift and replace task. Two separate ANOVA models assessed the effects of ECG on the statistical interpretation of EO recruitment strategies. One model included EMG data that contained the ECG and the other model included EMG data after the ECG was removed. Large percent errors were observed when the ECG was not removed. These errors increased with larger ECG to EMG ratios. Both removal methods reduced the errors to below 10%, but the BW-30 Hz HPF method was more time efficient in removing the ECG artifact. Different statistical findings were observed among the muscle sites for the ECG contaminated model compared to the ECG removed model, which resulted in different conclusions concerning neuromuscular control.     

Containment of simian immunodeficiency virus infection in vaccinated macaques: correlation with the magnitude of virus-specific pre- and postchallenge CD4+ and CD8+ T cell responses

Macaques infected with the SIV strain SIVmac251 develop a disease closely resembling human AIDS characterized by high viremia, progressive loss of CD4(+) T cells, occurrence of opportunistic infection, cachexia, and lymphomas. We report in this study that vaccination with the genetically attenuated poxvirus vector expressing the structural Ags of SIVmac (NYVAC-SIV-gag, pol, env) in combination with priming with DNA-SIV-gag, env resulted in significant suppression of viremia within 2 mo after mucosal exposure to the highly pathogenic SIVmac251 in the majority of vaccinated macaques. The control of viremia in these macaques was long lasting and inversely correlated to the level of both pre- and postchallenge Gag-specific lymphoproliferative responses, as well as to the level of total SIV-specific CD4(+) T lymphocyte responses at the peak of acute viremia as detected by intracellular cytokine-staining assay. Viremia containment also correlated with the frequency of the immunodominant Gag(181-189)CM9 epitope-specific CD8(+) T cells present before the challenge or expanded during acute infection. These data indicate, for the first time, the importance of vaccine-induced CD4(+) Th cell responses as an immune correlate of viremia containment. The results presented in this work also further demonstrate the potential of a DNA-prime/attenuated poxvirus-boost vaccine regimen in an animal model that well mirrors human AIDS.     

Overexpressed esterases in a fenvalerate resistant strain of the cotton bollworm, Helicoverpa armigera

Enhanced detoxification is the major mechanism responsible for pyrethroid resistance in Chinese populations of Helicoverpa armigera. Previous work has shown that enhanced oxidation contributes to resistance in the fenvalerate-selected Chinese strain, YGF. The current study provides evidence that enhanced hydrolysis by esterase isozymes also contributes to the resistance in this strain. The average esterase activity of third instar YGF larvae was 1.9-fold compared with that of a susceptible SCD strain. Much of this difference was attributed to isozymes at two zones which hydrolysed the model carboxylester substrate 1-naphthyl acetate and also a 1-naphthyl analogue of fenvalerate. A preparation enriched for enzymes migrating to one of these zones from YGF was shown to hydrolyse fenvalerate with a specific activity of about 2.9 nmol/min/mg. This material was also matched by mass spectrometry with four putative carboxylesterase genes, all of which clustered within a phylogenetic clade of secreted midgut esterases. Quantitative PCR on these four genes showed several-fold greater expression in tissues of YGF compared to SCD but no differences was found in the number of copies of the genes between the strains.