The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease

Studies have shown that alpha-synuclein (alpha-syn) deposited in Lewy bodies in brain tissue from patients with Parkinson disease (PD) is extensively phosphorylated at Ser-129. We used recombinant Adeno-associated virus (rAAV) to overexpress human wild-type (wt) alpha-syn and two human alpha-syn mutants with site-directed replacement of Ser-129 to alanine (S129A) or to aspartate (S129D) in the nigrostriatal tract of the rat to investigate the effect of Ser-129 phosphorylation state on dopaminergic neuron pathology. Rats were injected with rAAV2/5 vectors in the substantia nigra pars compacta (SNc) on one side of the brain; the other side remained as a nontransduced control. The level of human wt or mutant alpha-syn expressed on the injected side was about four times the endogenous rat alpha-syn. There was a significant reduction of dopaminergic neurons in the SNc and dopamine (DA) and tyrosine hydroxylase (TH) levels in the striatum of all S129A-treated rats as early as 4 wk postinjection. Nigral DA pathology occurred more slowly in the wt-injected animals, but by 26 wk the wt alpha-syn group lost nigral TH neurons equivalent to the mutated S129A group at 8 wk. In stark contrast, we did not observe any pathological changes in S129D-treated animals. Therefore, the nonphosphorylated form of S129 exacerbates alpha-syn-induced nigral pathology, whereas Ser-129 phosphorylation eliminates alpha-syn-induced nigrostriatal degeneration. This suggests possible new therapeutic targets for Parkinson Disease.     

Improving the representativeness of influenza viruses shared within the WHO Global Influenza Surveillance and Response System

Background

Sharing influenza viruses within the WHO Global Influenza Surveillance and Response System is crucial for monitoring evolution of influenza viruses.

Objectives

Analysis of timeliness and geographic representativeness of viruses shared by National Influenza Centres (NICs) in the WHO European Region with the London WHO Collaborating Centre for Reference and Research on Influenza for the Northern Hemisphere''s 2010–2011 and 2011–2012 influenza seasons.

Materials and methods

Data from NICs on influenza‐positive specimens shared with WHO CC London for the above‐mentioned influenza seasons were analyzed for timeliness of sharing with respect to the February deadline (31 January) for inclusion in the WHO consultations on the composition of influenza virus vaccines for the Northern Hemisphere and geographic representativeness.

Results

The 2010–2011 and 2011–2012 seasons were different in terms of the seasonal pattern, the timing of the epidemic, and the dominant virus. Consistent patterns of virus sharing across the seasons were observed. Approximately half the viruses collected before the deadline were not shared within the deadline; the average delay between date of specimen collection and shipment receipt was 3 and 1·5 months for the first and second season, respectively.

Conclusion

A baseline was provided for future work on enhancement of specimen sharing in the WHO European Region and improving the vaccine virus selection process. Greater insight into virus selection criteria applied by countries and the causes of delays in shipment are needed to understand the representativeness of viruses shared and to assess the importance of this for vaccine strain selection.     

Comparative Analysis of African Swine Fever Virus Genotypes and Serogroups

African swine fever virus (ASFV) causes highly lethal hemorrhagic disease among pigs, and ASFV’s extreme antigenic diversity hinders vaccine development. We show that p72 ASFV phylogenetic analysis does not accurately define ASFV hemadsorption inhibition assay serogroups. Thus, conventional ASFV genotyping cannot discriminate between viruses of different virulence or predict efficacy of a specific ASFV vaccine.     

Integrating Patient Reported Outcomes With Clinical Cancer Registry Data: A Feasibility Study of the Electronic Patient-Reported Outcomes From Cancer Survivors (ePOCS) System

Background

Routine measurement of Patient Reported Outcomes (PROs) linked with clinical data across the patient pathway is increasingly important for informing future care planning. The innovative electronic Patient-reported Outcomes from Cancer Survivors (ePOCS) system was developed to integrate PROs, collected online at specified post-diagnostic time-points, with clinical and treatment data in cancer registries.

Objective

This study tested the technical and clinical feasibility of ePOCS by running the system with a sample of potentially curable breast, colorectal, and prostate cancer patients in their first 15 months post diagnosis.

Methods

Patients completed questionnaires comprising multiple Patient Reported Outcome Measures (PROMs) via ePOCS within 6 months (T1), and at 9 (T2) and 15 (T3) months, post diagnosis. Feasibility outcomes included system informatics performance, patient recruitment, retention, representativeness and questionnaire completion (response rate), patient feedback, and administration burden involved in running the system.

Results

ePOCS ran efficiently with few technical problems. Patient participation was 55.21% (636/1152) overall, although varied by approach mode, and was considerably higher among patients approached face-to-face (61.4%, 490/798) than by telephone (48.8%, 21/43) or letter (41.0%, 125/305). Older and less affluent patients were less likely to join (both P<.001). Most non-consenters (71.1%, 234/329) cited information technology reasons (ie, difficulty using a computer). Questionnaires were fully or partially completed by 85.1% (541/636) of invited participants at T1 (80 questions total), 70.0% (442/631) at T2 (102-108 questions), and 66.3% (414/624) at T3 (148-154 questions), and fully completed at all three time-points by 57.6% (344/597) of participants. Reminders (mainly via email) effectively prompted responses. The PROs were successfully linked with cancer registry data for 100% of patients (N=636). Participant feedback was encouraging and positive, with most patients reporting that they found ePOCS easy to use and that, if asked, they would continue using the system long-term (86.2%, 361/419). ePOCS was not administratively burdensome to run day-to-day, and patient-initiated inquiries averaged just 11 inquiries per month.

Conclusions

The informatics underlying the ePOCS system demonstrated successful proof-of-concept – the system successfully linked PROs with registry data for 100% of the patients. The majority of patients were keen to engage. Participation rates are likely to improve as the Internet becomes more universally adopted. ePOCS can help overcome the challenges of routinely collecting PROs and linking with clinical data, which is integral for treatment and supportive care planning and for targeting service provision.     

Enzymatic synthesis and electrochemical characterization of sodium 1,2-naphthoquinone-4-sulfonate-doped PEDOT/MWCNT composite

The development of novel materials with improved functional characteristics for supercapacitor electrodes is of current concern and calls for elaboration of innovative approaches. We report on an eco-friendly enzymatic synthesis of a composite based on poly(3,4-ethylenedioxythiophene) (PEDOT) and multi-walled carbon nanotubes (MWCNTs). The redox active compound, sodium 1,2-naphthoquinone-4-sulfonate (NQS), was used as a dopant for the backbone of the polymer. Oxidative polymerization of 3,4-ethylenedioxythiophene (EDOT) was catalyzed by a high redox potential laccase from the fungus Trametes hirsuta. Atmospheric oxygen served as an oxidant. A uniform thin layer of NQS-doped PEDOT formed on the surface of MWCNTs as a result of the enzymatic polymerization. The PEDOT–NQS/MWCNT composite showed a high specific capacitance of ca. 575 F g⁻¹ at a potential scan rate of 5 mV s⁻¹ and an excellent cycling stability within a potential window between −0.5 and 1.0 V, which makes it a promising electrode material for high-performance supercapacitors.

The use of redox active NSQ as a dopant of PEDOT dramatically increases the specific capacitance and cyclic stability of enzymatically synthesized PEDOT–NSQ/MWCNT composite.     

Cystatin C deficiency increases elastic lamina degradation and aortic dilatation in apolipoprotein E-null mice

The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves substantial proteolysis of the arterial extracellular matrix. The lysosomal cysteine proteases can exert potent elastolytic and collagenolytic activity. Human atherosclerotic plaques have increased cysteine protease content and decreased levels of the endogenous inhibitor cystatin C, suggesting an imbalance that would favor matrix degradation in the arterial wall. This study tested directly the hypothesis that impaired expression of cystatin C alters arterial structure. Cystatin C-deficient mice (Cyst C-/-) were crossbred with apolipoprotein E-deficient mice (ApoE-/-) to generate cystatin C and apolipoprotein E-double deficient mice (Cyst C-/-ApoE-/-). After 12 weeks on an atherogenic diet, cystatin C deficiency yielded significantly increased tunica media elastic lamina fragmentation, decreased medial size, and increased smooth muscle cell and collagen content in aortic lesions of ApoE-/- mice. Cyst C-/-ApoE-/- mice also showed dilated thoracic and abdominal aortae compared with control ApoE-/- mice, although atheroma lesion size, intimal macrophage accumulation, and lipid core size did not differ between these mice. These findings demonstrate directly the importance of cysteine protease/protease inhibitor balance in dysregulated arterial integrity and remodeling during experimental atherogenesis.     

Pathology of the endometrium in women with chronic hepatitis C and HIV infection as a cause of unsuccessful in vitro fertilization attempts

Abstract

Aim: The purpose of the study is to detect endometrial pathology in individuals with blood-borne infections (hepatitis C virus [HCV] and HIV) and to assess the impact of quality of the endometrium on the efficiency of assisted reproductive technologies (ART).

Materials and methods of research: The study involved 56 women of reproductive age, 33 women with HCV, 22 with HIV infection (stages 3 and 4A) and 1 patient with co-infection of HCV and HIV, which was excluded from the further study. Ultrasound investigation of the small pelvic organs, hysteroscopy with biopsy of the mucosa of the uterine cavity, histological examination of the endometrium, determination of HCV RNA and HIV RNA in serum and endometrial tissue by PCR method were conducted.

Results: Ultrasound and histological studies of the endometrium revealed a high incidence of development of hyperplastic and inflammatory processes of the endometrium in women with HCV (86% and 100%) and HIV (51% and 99%). When molecular biological examination of endometrial tissue of these patients was performed with the use of a set of reagents “AmpliSens HCV/HBV/HIV-FL” produced by Federal Budgetary Institution of Science (FBUN) Central Research Institute of Epidemiology of Rospotrebnadzor of Russia, HCV was detected in 16.7% and HIV in 14.3% of cases. In 5% of patients with HCV infection and 7% with HIV, pathogens were detected in the endometrium under the non-detectable viral load in the blood plasma. Lower effectiveness of IVF in women with HIV and HCV is defined compared to the women without blood-borne infections.

Conclusion: Detected HIV and HCV replications in the endometrium is the likely cause of hyperplastic and inflammatory processes of the endometrium leading to reduced efficiency of the ART programs in patients with chronic hepatitis C and HIV.