Ubiquitination Increases Parkin Activity to Promote Autophagic α-Synuclein Clearance

Parkinson’s disease (PD) is a movement disorder associated with genetic and age related causes. Although autosomal recessive early onset PD linked to parkin mutations does not exhibit α-Synuclein accumulation, while autosomal dominant and sporadic PD manifest with α-Synuclein inclusions, loss of dopaminergic substantia nigra neurons is a common denominator in PD. Here we show that decreased parkin ubiquitination and loss of parkin stability impair interaction with Beclin-1 and alter α-Synuclein degradation, leading to death of dopaminergic neurons. Tyrosine kinase inhibition increases parkin ubiquitination and interaction with Beclin-1, promoting autophagic α-Synuclein clearance and nigral neuron survival. However, loss of parkin via deletion increases α-Synuclein in the blood compared to the brain, suggesting that functional parkin prevents α-Synuclein release into the blood. These studies demonstrate that parkin ubiquitination affects its protein stability and E3 ligase activity, possibly leading to α-Synuclein sequestration and subsequent clearance.     

Rib lesions in skeletons from early neolithic sites in Central Germany: On the trail of tuberculosis at the onset of agriculture

As an infectious disease, tuberculosis (TB) is one of the major causes of death worldwide. Paleopathological and paleomicrobiological studies indicate a long standing association of the causative agent Mycobacterium tuberculosis and its human host. Since the occurrence and the epidemic spread of this pathogen seem to be closely linked to social and biological factors, it is of particular interest to understand better the role of TB during periods of social and nutritional change such as the Neolithic. In this study, 118 individuals from three sites in Saxony‐Anhalt (Germany) dating to the Linear Pottery Culture (5400–4800 BC) were examined macroscopically to identify TB related bone lesions. In two individuals, Pott's disease was detected. In addition, periosteal reactions of varying degrees and frequency were observed mainly along the neck of the ribs in 6.5% (2/31) of subadults and 35.1% (20/57) of adults, with one site standing out markedly. Rib lesions, however, are not specific indicators of TB as they can also be caused by other diseases; so additional investigations were undertaken using histology and micro‐CT scans to say more about the disease process. Supplementary molecular analyses indicate the presence of pathogens belonging to the Mycobacterium tuberculosis complex in individuals of all sites. Furthermore, we discuss the occurrence and spread of TB during the Neolithic with regard to nutritional aspects and possible risks of infection. The data presented provide important insights into the health status of Early Neolithic populations in Central Germany. Am J Phys Anthropol, 2012. © 2012 Wiley Periodicals, Inc.     

LAP2 Proteins Chaperone GLI1 Movement between the Lamina and Chromatin to Regulate Transcription

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Metabolic and Body Composition Risk Factors Associated with Metabolic Syndrome in a Cohort of Women with a High Prevalence of Cardiometabolic Disease

BackgroundThe aetiology of the metabolic syndrome and the inter-relationship between risk factors for this syndrome are poorly understood. The purpose of this investigation was to determine the risk factors for metabolic syndrome and their interactions in a cohort of women with a high prevalence of metabolic syndrome.ResultsMetabolic syndrome was present in 49.6% of the study cohort. Logistic regression analysis demonstrated that adiponectin (odds ratio [95% CIs]: 0.84 [0.77, 0.92], p<0.0005) and abdominal subcutaneous fat (0.56 [0.39, 0.79], p = 0.001) reduced metabolic syndrome risk whilst insulin resistance (1.31 [1.16, 1.48], p<0.0005) and trunk fat-free soft-tissue mass (1.34 [1.10, 1.61], p = 0.002) increased risk. Within this group of risk factors, the relationship of adiponectin with metabolic syndrome risk, when analysed across adiponectin hexiles, was the least affected by adjustment for the other risk factors.ConclusionsAdiponectin has a significant protective role against metabolic syndrome and is independent of other risk factors. The protective and possible augmentive effects of abdominal subcutaneous fat and lean trunk mass, respectively on metabolic syndrome risk demonstrate the existence of novel interactions between body composition and cardiometabolic disease.     

Effect of Community Engagement Interventions on Patient Safety and Risk Reduction Efforts in Primary Health Facilities: Evidence from Ghana

Background

Patient safety and quality care remain major challenges to Ghana’s healthcare system. Like many health systems in Africa, this is largely because demand for healthcare is outstripping available human and material resource capacity of healthcare facilities and new investment is insufficient. In the light of these demand and supply constraints, systematic community engagement (SCE) in healthcare quality assessment can be a feasible and cost effective option to augment existing quality improvement interventions. SCE entails structured use of existing community groups to assess healthcare quality in health facilities. Identified quality gaps are discussed with healthcare providers, improvements identified and rewards provided if the quality gaps are closed.

Purpose

This paper evaluates whether or not SCE, through the assessment of health service quality, improves patient safety and risk reduction efforts by staff in healthcare facilities.

Methods

A randomized control trail was conducted in 64 primary healthcare facilities in the Greater Accra and Western regions of Ghana. Patient risk assessments were conducted in 32 randomly assigned intervention and control facilities. Multivariate multiple regression test was used to determine effect of the SCE interventions on staff efforts towards reducing patient risk. Spearman correlation test was used to ascertain associations between types of community groups engaged and risk assessment scores of healthcare facilities.

Findings

Clinic staff efforts towards increasing patient safety and reducing risk improved significantly in intervention facilities especially in the areas of leadership/accountability (Coef. = 10.4, p<0.05) and staff competencies (Coef. = 7.1, p<0.05). Improvement in service utilization and health resources could not be attributed to the interventions because these were outside the control of the study and might have been influenced by institutional or national level developments between the baseline and follow-up period. Community groups that were gender balanced, religious/faith-based, and had structured leadership appeared to be better options for effective SCE in healthcare quality assessment.

Conclusion

Community engagement in healthcare quality assessment is a feasible client-centered quality improvement option that should be discussed for possible scale-up in Ghana and other resource poor countries in Africa.     

Polysialylation of the neural cell adhesion molecule: interfering with polysialylation and migration in neuroblastoma cells

Polysialic acid represents a unique posttranslational modification of the neural cell adhesion molecule (NCAM). It is built as a homopolymer of up to 150 molecules of alpha 2-8-linked sialic acids on N-glycans of the fifth immunoglobulin-like domain of NCAM. Besides its role in cell migration and axonal growth during development, polysialic acids are closely related to tumor malignancy as they are linked to the malignant potential of several tumors, such as undifferentiated neuroblastoma. Polysialic acid expression is significantly more frequent in high-grade tumors than in low-grade tumors. It is synthesized in the Golgi apparatus by the activity of two closely related enzymes, the polysialyltransferases ST8SiaII and ST8SiaIV. Interestingly, polysialylation of tumors is not equally synthesized by both polysialyltransferases. It has been shown that especially the ST8SiaII gene is not expressed in some normal tissue, but is strongly expressed in tumor tissue. Here we summarize some knowledge on the role of polysialic acid in cell migration and tumor progression and present novel evidence that interfering with polysialylation using unnatural sialic acid precursors decreases the migration of neuroblastoma cells.     

The β1a Subunit of the Skeletal DHPR Binds to Skeletal RyR1 and Activates the Channel via Its 35-Residue C-Terminal Tail

Although it has been suggested that the C-terminal tail of the β_1a subunit of the skeletal dihyropyridine receptor (DHPR) may contribute to voltage-activated Ca²⁺ release in skeletal muscle by interacting with the skeletal ryanodine receptor (RyR1), a direct functional interaction between the two proteins has not been demonstrated previously. Such an interaction is reported here. A peptide with the sequence of the C-terminal 35 residues of β_1a bound to RyR1 in affinity chromatography. The full-length β_1a subunit and the C-terminal peptide increased [³H]ryanodine binding and RyR1 channel activity with an AC₅₀ of 450–600 pM under optimal conditions. The effect of the peptide was dependent on cytoplasmic Ca²⁺, ATP, and Mg²⁺ concentrations. There was no effect of the peptide when channel activity was very low as a result of Mg²⁺ inhibition or addition of 100 nM Ca²⁺ (without ATP). Maximum increases were seen with 1–10 μM Ca²⁺, in the absence of Mg²⁺ inhibition. A control peptide with the C-terminal 35 residues in a scrambled sequence did not bind to RyR1 or alter [³H]ryanodine binding or channel activity. This high-affinity in vitro functional interaction between the C-terminal 35 residues of the DHPR β_1a subunit and RyR1 may support an in vivo function of β_1a during voltage-activated Ca²⁺ release.     

Relationships between four novel ceratomyxid parasites from the gall bladders of labrid fishes from Heron Island, Queensland, Australia

Ceratomyxid parasites from the gall bladder of fishes from the family Labridae were examined for their taxonomic identity and their relatedness to other species of myxozoans. This paper describes four novel species Ceratomyxa choerodonae n. sp. from Choerodon cyanodus; Ceratomyxa cheilinae n. sp. from Cheilinus chlorourus; Ceratomyxa oxycheilinae n. sp. from Oxycheilinus digramma; and Ceratomyxa thalassomae n. sp. from Thalassoma lunare. Each species is characterised morphologically and small subunit (18 S) rDNA sequences were used in molecular phylogenetic analyses. Comparison of the small subunit rDNA sequences revealed four distinct species even though morphological differences indicated the presence of only two morphologically distinctive spore types. Phylogenetic analyses revealed that the ceratomyxids from labrid fishes did not form a clade to the exclusion of all other myxosporeans and provides evidence that host relatedness is not a good character to discriminate between species within the genus Ceratomyxa.