22 research outputs found
Thin chalcogenide capillaries as efficient waveguides in the mid-IR - THz spectral range
We present chalcogenide glass As2Se3 capillaries as efficient waveguides in
the mid-IR and THz spectral ranges. The capillaries are fabricated using a
double crucible glass drawing technique. The wall thickness of the glass
capillary is properly designed and controlled during drawing, and we are able
to produce capillaries with different wall thickness, starting from 12 \mum and
up to 130 \mum. Such capillaries show low loss properties in the whole target
wavelength region. In the mid-IR range guidance is governed by Fresnel
reflection and antiguidance mechanisms (ARROWs), while in the THz spectral
range thin walls capillaries guide via total internal reflection
Histidine Hydrogen-Deuterium Exchange Mass Spectrometry for Probing the Microenvironment of Histidine Residues in Dihydrofolate Reductase
Histidine Hydrogen-Deuterium Exchange Mass Spectrometry (His-HDX-MS) determines the HDX rates at the imidazole C(2)-hydrogen of histidine residues. This method provides not only the HDX rates but also the pK(a) values of histidine imidazole rings. His-HDX-MS was used to probe the microenvironment of histidine residues of E. coli dihydrofolate reductase (DHFR), an enzyme proposed to undergo multiple conformational changes during catalysis.Using His-HDX-MS, the pK(a) values and the half-lives (t(1/2)) of HDX reactions of five histidine residues of apo-DHFR, DHFR in complex with methotrexate (DHFR-MTX), DHFR in complex with MTX and NADPH (DHFR-MTX-NADPH), and DHFR in complex with folate and NADP+ (DHFR-folate-NADP+) were determined. The results showed that the two parameters (pK(a) and t(1/2)) are sensitive to the changes of the microenvironment around the histidine residues. Although four of the five histidine residues are located far from the active site, ligand binding affected their pK(a), t(1/2) or both. This is consistent with previous observations of ligand binding-induced distal conformational changes on DHFR. Most of the observed pK(a) and t(1/2) changes could be rationalized using the X-ray structures of apo-DHFR, DHFR-MTX-NADPH, and DHFR-folate-NADP+. The availability of the neutron diffraction structure of DHFR-MTX enabled us to compare the protonation states of histidine imidazole rings.Our results demonstrate the usefulness of His-HDX-MS in probing the microenvironments of histidine residues within proteins
Dimethyl fumarate ameliorates chemotherapy agent-induced neurotoxicity in vitro
Chemotherapy agents such as oxaliplatin, cisplatin, paclitaxel, and bortezomib frequently cause severe peripheral neuropathy and there is currently no effective strategy to prevent this. Dimethyl fumarate (DMF) is a new oral drug for the treatment of multiple sclerosis, and has neuroprotective effects via up-regulation of the nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent antioxidant response. In this study, we investigated the effect of DMF on chemotherapy agent-induced neurodegenerations in cultured cells. We found that DMF and its metabolite monomethyl fumarate (MMF) attenuated oxaliplatin-, cisplatin-, and bortezomib- (but not paclitaxel-) induced inhibition of neurite outgrowth, but had no effect on cell death as a result of these agents in cultured PC12Â cells and primary cultured rat dorsal root ganglion (DRG) neurons. Furthermore, Nrf2 DNA binding activity was increased by DMF and MMF in PC12Â cells. These findings suggest that DMF, which activates Nrf2 pathway, has a potential protective action against chemotherapy-induced neurotoxicity, particularly neurite impairments. Keywords: Dimethyl fumarate, Neurotoxicity, Oxaliplatin, Chemotherapy agents, Nuclear factor-erythroid-2-related factor 2 (Nrf2
Genetic diversity of the KIR/HLA system and susceptibility to hepatitis C virus-related diseases
Background
The variability in the association of host innate immune response to Hepatitis C virus (HCV)
infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related
disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes
and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma
(HCC) or lymphoproliferative disease progression.
Methods and Findings
We analyzed data from 396 HCV-positive patients with CHC (n = 125), HCC (118), and lymphoproliferative
diseases (153), and 501 HCV-negative patients. All were HIV and HBV
negative. KIR-SSO was used to determine the KIR typing. KIR2DL5 and KIR2DS4 variants
were performed using PCR and GeneScan analysis. HLA/class-I genotyping was performed
using PCR-sequence-based typing. The interaction between the KIR gene and
ligand HLA molecules was investigated. Differences in frequencies were estimated using
Fisher’s exact test, and Cochran-Armitage trend test. The non-random association of KIR
alleles was estimated using the linkage disequilibrium test. We found an association of
KIR2DS2/KIR2DL2 genes, with the HCV-related lymphoproliferative disorders. Furthermore,
individuals with a HLA-Bw6 KIR3DL1+ combination of genes showed higher risk of developing lymphoma than cryoglobulinemia. KIR2DS3 gene was found to be the principal gene associated with chronic HCV infection, while a reduction of HLA-Bw4 + KIR3DS1+ was associated with an increased risk of developing HCC.
Conclusions
Our data highlight a role of the innate-systemin developing HCV-related disorders and specifically
KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression,
and mainly towards lymphoproliferative disorders.Moreover the determination of KIR3D/HLA
combination of genes direct the HCV progression towards a lymphoma rather than an hepatic
disease. In this contest IFN-α therapy, a standard therapy for HCV-infection and lymphoproliferative
diseases, known to be able to transiently enhance the cytotoxicity of NK-cells support
the role of NK cells to counterstain HCV-related and lymphoproliferative diseases