Prions and the proteasome

Prion diseases are fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in animals. They are unique in terms of their biology because they are caused by the conformational re-arrangement of a normal host-encoded prion protein, PrPC, to an abnormal infectious isoform, PrPSc. Currently the precise mechanism behind prion-mediated neurodegeneration remains unclear. It is hypothesised than an unknown toxic gain of function of PrPSc, or an intermediate oligomeric form, underlies neuronal death. Increasing evidence suggests a role for the ubiquitin proteasome system (UPS) in prion disease. Both wild-type PrPC and disease-associated PrP isoforms accumulate in cells after proteasome inhibition leading to increased cell death, and abnormal beta-sheet-rich PrP isoforms have been shown to inhibit the catalytic activity of the proteasome. Here we review potential interactions between prions and the proteasome outlining how the UPS may be implicated in prion-mediated neurodegeneration.     

Synthesis and crystal structures of cobalt(II), cadmium(II), and zinc(II) complexes of 4-nitro phenylcyanamide: enhancing the biological properties through bound to human serum albumin

Metal complexes of the type [Co(phen)₂(4-NO₂pcyd)₂].CH₃OH, 1, [Zn(phen)₂(4-NO₂pcyd)₂].CH₃OH, 2, [Cd(phen)₂(4-NO₂pcyd)₂], and 3, (phen?=?1,10-phenanthroline, 4-NO₂pcyd?=?4-nitro phenylcyanamide) have been studied. The synthesis, characterization, and the biological activities of complexes 1-3 have been investigated. The geometries of complexes 1-3 were confirmed by single-crystal X-ray crystallography. The interactions of complexes 1-3 with human serum albumin (HSA) were studied using fluorescence and circular dichroism spectroscopy. The thermodynamic studies have showed the reaction for the binding of complexes 1-3 with HSA is hydrophobic (ΔH_0???0 and ΔS₀ > 0). The in vitro cytotoxic potential of complexes 1-3 and their complexes with HSA were examined. The complexes 1-3 with HSA enhance about 3-fold cytotoxicity in cancer cells lines.     

G209A mutant alpha synuclein expression specifically enhances dopamine induced oxidative damage

Alpha synuclein protein may play an important role in familial and sporadic Parkinson's disease pathology. We have induced G209A mutant or wild-type alpha-synuclein expression in stable HEK293 cell models to determine if this influences markers of oxidative stress and damage under normal conditions or in the presence of dopamine or paraquat. Induced wild-type or mutant alpha-synuclein expression alone had no effect upon levels of oxidative stress or damage, as measured by glutathione levels or aconitase activity. Both wild-type and mutant alpha-synuclein expression decreased the oxidative damage induced by paraquat, although the protection was less marked with mutant alpha-synuclein expression. This suggests that alpha-synuclein expression may either have anti-oxidant properties or may upregulate cellular antioxidant levels, a function that was diminished by the G209A mutation. However, mutant but not wild-type alpha-synuclein expression specifically enhanced dopamine associated oxidative damage. Non-expressing cells treated with reserpine to inhibit the vesicular monoamine compartmentalisation produced similar results. However, consistent with the hypothesis that mutant alpha-synuclein disrupts vesicular dopamine compartmentalization, this effect was diminished in cells expressing mutant alpha-synuclein. This may result in increased dopamine metabolism and cause selective oxidative damage to dopaminergic cells.     

Deconvolution of the three components of the photoacoustic signal by curve fitting and the relationship of CO2 uptake to proton fluxes

The photoacoustic response of the photosynthetic apparatus to a short light pulse consists of three components: heat evolution, O₂ evolution and CO₂ uptake. Recent attempts of deconvoluting the individual components by curve-fitting by means of model curves [Kolbowski et al. (1990) Photosynth Res 25: 309–316] suffered from the fact that the model curve for CO₂ uptake changed its curve shape with CO₂ concentration. Here, it is shown that good fits can be obtained if a stretching factor is incorporated into the fitting routine which adjusts the shape of the uptake model curve. The relationship between CO₂ uptake und H⁺ transport across the thylakoid membrane was investigated by experiments in different CO₂ concentrations from 0 to 7%. It was found that under limiting conditions (7% CO₂) the flux ratio CO₂: O₂ was close to 4. This was compared with the value expected from the stoichiometries of the linear electron transport chain.     

The morphospace of Late Permian coiled nautiloids

Occurrences of Late Permian coiled nautiloids are widespread but they have never been analysed in terms of spatial and temporal disparity changes. Morphometric analyses using the cardinal Raupian conch parameters: conch width index, umbilical width index and whorl expansion rate with subsequent analysis by using principal components analysis and non-metric multidimensional scaling, allow the construction of a nautiloid morphospace. The analyses show that there is a stable disparity in the coiled nautiloids from the Wuchiapingian to the Changhsingian. Differences between the three major Late Permian nautiloid occurrences (Salt Range, South China and Transcaucasus-NW Iran) are considerably small; the South Chinese occurrences, however, are characterized by many endemic genera. The most important variation in morphospace occupation is caused by environmental differences such as water depth.     

Human Papillomavirus Type 6 and 11 Genetic Variants Found in 71 Oral and Anogenital Epithelial Samples from Australia

Genetic variation of 49 human papillomavirus (HPV) 6 and 22 HPV11 isolates from recurrent respiratory papillomatosis (RRP) (n = 17), genital warts (n = 43), anal cancer (n = 6) and cervical neoplasia cells (n = 5), was determined by sequencing the long control region (LCR) and the E6 and E7 genes. Comparative analysis of genetic variability was examined to determine whether different disease states resulting from HPV6 or HPV11 infection cluster into distinct variant groups. Sequence variation analysis of HPV6 revealed that isolates cluster into variants within previously described HPV6 lineages, with the majority (65%) clustering to HPV6 sublineage B1 across the three genomic regions examined. Overall 72 HPV6 and 25 HPV11 single nucleotide variations, insertions and deletions were observed within samples examined. In addition, missense alterations were observed in the E6/E7 genes for 6 HPV6 and 5 HPV11 variants. No nucleotide variations were identified in any isolates at the four E2 binding sites for HPV6 or HPV11, nor were any isolates found to be identical to the HPV6 lineage A or HPV11 sublineage A1 reference genomes. Overall, a high degree of sequence conservation was observed between isolates across each of the regions investigated for both HPV6 and HPV11. Genetic variants identified a slight association with HPV6 and anogenital lesions (p = 0.04). This study provides important information on the genetic diversity of circulating HPV 6 and HPV11 variants within the Australian population and supports the observation that the majority of HPV6 isolates cluster to the HPV6 sublineage B1 with anogenital lesions demonstrating an association with this sublineage (p = 0.02). Comparative analysis of Australian isolates for both HPV6 and HPV11 to those from other geographical regions based on the LCR revealed a high degree of sequence similarity throughout the world, confirming previous observations that there are no geographically specific variants for these HPV types.     

Detection of Oral Human Papillomavirus in HIV-Positive Men Who Have Sex with Men 3 Years after Baseline: A Follow Up Cross-Sectional Study

Background

Human papillomavirus (HPV) is a causative agent in oropharyngeal squamous cell carcinoma. The natural history of oral HPV in HIV-positive men who have sex with men (MSM) is unclear.

Methods

Detection of oral human papillomavirus in 173 HIV-positive MSM using oral rinse samples 3 years apart was investigated. HPV DNA was detected by polymerase chain reaction, and genotyped by Roche Linear Array.

Results

Of 173 men tested in 2010, 30 had at least one HPV genotype (17%, 95% CI: 12–23), 15 at least one hr-HPV (9%, 95% CI: 5–14) and 8 had HPV 16 (5%, 95% CI: 2–9) detected. In 2013, 33 had at least one HPV genotype (19%, 95% CI: 14–26), 20 had at least one hr-HPV (12%, 95% CI: 7–17) and 7 had HPV 16 (4%, 95% CI: 2–8) detected. Of 30 men at baseline (2010) with any HPV detected, 14 (47%, 95% CI: 28–66) had at least one persistent genotype. Of the 15 men in 2010 with high risk (hr-) HPV, 6 men (40%, 95% CI: 16–68) had at least one persistent hr-HPV genotype. The incidence rate of detection of at least one new HPV genotype was 4.8 per 100 person years (95% CI: 3.1–7.0), of at least one hr-HPV genotype was 3.2 per 100 person years (95% CI: 1.8–5.1) and of HPV 16 was 0.8 per 100 person years (95% CI: 0.2–2.0). The clearance rate was 14.9 per 100 person years (95% CI: 8.2–24.2) for any HPV, 18.2 per 100 person years (95% CI: 8.2–32.7) for hr-HPV and 17.4 per 100 person years (95% CI: 5.0–38.8) for HPV-16. Persistent HPV detection was associated with duration of HIV (OR 1.13 (per additional year), 95% CI: 1.00–1.26) and tonsillectomy (OR 8.17, 95% CI: 1.30–51.40).

Conclusion

The same oral HPV genotype was detected again after 3 years in nearly half of HIV-positive men who have sex with men.     

Oral Human Papillomavirus in Men Having Sex with Men: Risk-Factors and Sampling

Background

Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma is becoming more common. We examined prevalence and risk factors for oral HPV among men who have sex with men (MSM) and compared sampling and transport methods.

Methods

In 2010, 500 MSM (249 HIV-positive) attending Melbourne Sexual Health Centre answered a questionnaire, swabbed their mouth and throat and collected a gargled oral rinse sample. Half the oral rinse was transported absorbed in a tampon (to enable postage). HPV was detected by polymerase chain reaction, and genotyped by Roche Linear Array®. Men with HPV 16 or 18 were retested after six months.

Results

Any HPV genotype was detected in 19% (95% confidence intervals (CI) 15–25%) of HIV-infected men and 7% (95% CI 4–11%) of HIV-negative men (p<0.001), and HPV 16 was detected in 4.4% (95% CI 2–8%) of HIV-infected men and 0.8% (0.1–2.8%) of HIV-negative men. Oral HPV was associated with: current smoking (adjusted odds ratio (aOR) 2.2 (95%CI: 1.2–3.9)), time since tooth-brushing (aOR per hour 0.87, 95%CI: 0.8–0.96) and number of lifetime tongue-kissing partners aOR 3.2 95%CI: (1.2–8.4) for 26–100 partners and 4.9 95%CI: (1.9–12.5) for>100 partners. Lifetime oral-penile sex partner numbers were significantly associated in a separate model: aOR 2.8(1.2–6.3) for 26–100 partners and 3.2(1.4–7.2) for>100 partners. HPV 16 and 18 persisted in 10 of 12 men after a median six months. Sensitivities of sampling methods compared to all methods combined were: oral rinse 97%, tampon-absorbed oral rinse 69%, swab 32%.

Conclusions

Oral HPV was associated with HIV infection, smoking, recent tooth-brushing, and more lifetime tongue-kissing and oral sex partners. The liquid oral rinse sample was more sensitive than a tampon-absorbed oral rinse or a self-collected swab.