The three ‘P’s of mitophagy: PARKIN,PINK1, and post-translational modifications

Two Parkinson''s disease (PD)-associated proteins, the mitochondrial kinase PINK1 and the E3-ubiquitin (Ub) ligase PARKIN, are central to mitochondrial quality control. In this pathway, PINK1 accumulates on defective mitochondria, eliciting the translocation of PARKIN from the cytosol to mediate the clearance of damaged mitochondria via autophagy (mitophagy). Throughout the different stages of mitophagy, post-translational modifications (PTMs) are critical for the regulation of PINK1 and PARKIN activity and function. Indeed, activation and recruitment of PARKIN onto damaged mitochondria involves PINK1-mediated phosphorylation of both PARKIN and Ub. Through a stepwise cascade, PARKIN is converted from an autoinhibited enzyme into an active phospho-Ub-dependent E3 ligase. Upon activation, PARKIN ubiquitinates itself in concert with many different mitochondrial substrates. The Ub conjugates attached to these substrates can in turn be phosphorylated by PINK1, which triggers further cycles of PARKIN recruitment and activation. This feed-forward amplification loop regulates both PARKIN activity and mitophagy. However, the precise steps and sequence of PTMs in this cascade are only now being uncovered. For instance, the Ub conjugates assembled by PARKIN consist predominantly of noncanonical K6-linked Ub chains. Moreover, these modifications are reversible and can be disassembled by deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, and USP30. However, PINK1-mediated phosphorylation of Ub can impede the activity of these DUBs, adding a new layer of complexity to the regulation of PARKIN-mediated mitophagy by PTMs. It is therefore evident that further insight into how PTMs regulate the PINK1–PARKIN pathway will be critical for our understanding of mitochondrial quality control.     

Caregiver burden and related factors in caregivers of patients with childhood-onset systemic lupus erythematosus

Clinical Rheumatology - Having a child with a chronic illness is a source of stress for the whole family, especially the primary caregiver. The aim of this study was to evaluate the associations...     

Discrimination between non-functioning pituitary adenomas and hypophysitis using machine learning methods based on magnetic resonance imaging‑derived texture features

Purpose

Hypophysitis is a heterogeneous condition that includes inflammation of the pituitary gland and infundibulum, and it can cause symptoms related to mass effects and hormonal deficiencies. We aimed to evaluate the potential role of machine learning methods in differentiating hypophysitis from non-functioning pituitary adenomas.

Methods

The radiomic parameters obtained from T1A-C images were used. Among the radiomic parameters, parameters capable of distinguishing between hypophysitis and non-functioning pituitary adenomas were selected. In order to avoid the effects of confounding factors and to improve the performance of the classifiers, parameters with high correlation with each other were eliminated. Machine learning algorithms were performed with the combination of gray-level run-length matrix-low gray level run emphasis, gray-level co-occurrence matrix-correlation, and gray-level co-occurrence entropy.

Results

A total of 34 patients were included, 17 of whom had hypophysitis and 17 had non-functioning pituitary adenomas. Among the 38 radiomics parameters obtained from post-contrast T1-weighted images, 10 tissue features that could differentiate the lesions were selected. Machine learning algorithms were performed using three selected parameters; gray level run length matrix-low gray level run emphasis, gray-level co-occurrence matrix-correlation, and gray level co-occurrence entropy. Error matrices were calculated by using the machine learning algorithm and it was seen that support vector machines showed the best performance in distinguishing the two lesion types.

Conclusions

Our analysis reported that support vector machines showed the best performance in distinguishing hypophysitis from non-functioning pituitary adenomas, emphasizing the importance of machine learning in differentiating the two lesions.

     

Acromegaly is associated with a distinct oral and gut microbiota

Pituitary - Our aim was to investigate the changes in the composition of oral and gut microbiota in patients with newly diagnosed acromegaly and their relationship with IGF-1 levels. Oral and fecal...     

The current status of two sublines of the Roman High and Low Avoidance strains

Experiments are described which assess the behavioral status of two sublines of the Roman High and Low Avoidance strains which have been maintained by brother x sister mating without selection at the Institute of Psychiatry, University of London. The strains demonstrate significant differences in the avoidance behavior for which they were originally selected. However, the Low Avoiding strain did show some high-scoring individuals and a degree of selection pressure was consequently applied to this line. The results of this selection and the performance of these strains in an open field are reported. The data are discussed in the light of a recent report that other sublines no longer display differences in avoidance conditioning.This work was supported by Grant RF7038 from the Bethlem/Maudsley Research Fund.     

Factors associated with community ambulation in chronic stroke

Purpose: Loss of independent community ambulation is one of the most disabling consequences of stroke. The aim of this study was to investigate the association of multiple personal and post-stroke factors with community ambulation in persons between 1- and 3-year post-stroke. Methods: This was a cross-sectional study of 40 community-dwelling stroke patients, >18 years, between 1- and 3-year post-stroke. The main outcome measures used were self-report community ambulation questionnaire, demographic information, 10-M Walk Test, Timed Up and Go test, Activities-Specific Balance Confidence Scale, Fatigue Severity Scale, Hospital Anxiety and Depression Scale, Trail-Making Test-Part B, Single Letter Cancellation Test. Results: Age, number of medications and use of a walking aid were found to be significantly associated with community ambulation (p?≤?0.05). Gait speed, walking balance and balance self-efficacy were also found to be significantly associated with community ambulation (p?≤?0.05). Balance self-efficacy was the only factor independently associated with community ambulation post-stroke (p?≤?0.05). Conclusion: Balance self-efficacy may be a significant determinant in the attainment of independent community ambulation post-stroke. This suggests that physical aspects such as gait speed and walking balance should not be considered in isolation when addressing community ambulation post-stroke.

• Implications for Rehabilitation

• Balance self-efficacy may play a significant role in the attainment of independent community ambulation in a chronic stroke population.

• Physiotherapy interventions addressing community ambulation post-stroke should consider methods for improving balance self-efficacy in chronic stroke, such as self management programmes.

     

Fracture liaison service in a non-regional orthopaedic clinic--a cost-effective service

Fracture liaison services (FLS) aim to provide cost-effective targeting of secondary fracture prevention. It is proposed that a dedicated FLS be available in any hospital to which a patient presents with a fracture. An existing orthopaedic clinic nurse was retrained to deliver a FLS. Proformas were used so that different nurses could assume the fracture liaison nurse (FLN) role, as required. Screening consisted of fracture risk estimation, phlebotomy and DXA scanning. 124 (11%) of all patients attending the orthopaedic fracture clinic were reviewed in the FLS. Upper limb fractures accounted for the majority of fragility fractures screened n=69 (55.6%). Two-thirds of patients (n=69) had reduced bone mineral density (BMD). An evidence based approach to both non-pharmacological and pharmacotherapy was used and most patients (76.6%) receiving pharmacotherapy received an oral bisphosphonate (n=46). The FLS has proven to be an effective way of delivering secondary prevention for osteoporotic fracture in a non-regional fracture clinic, without increasing staff costs.     

Evidence for adenosine A2 receptor involvement in the hypomobility effects of adenosine analogues in mice

The hypomobility induced by a series of adenosine analogues was investigated using a holeboard test and their behavioral potencies correlated to their reported adenosine A1 and A2 receptor affinities. All of the adenosine analogues dose dependently inhibited both exploratory behavior (head dipping) and locomotor activity. The rank order of potency 5'-ethylcarboxamido adenosine (NECA) greater than 5'-methylcarboxamido adenosine (MECA) greater than N6-[(R)-1-methyl-2-phenylethyl]adenosine (R-PIA) greater than N6-cyclohexyladenosine (CHA) = N6-cyclopentyladenosine (CPA) greater than N6-[(S)-1-methyl-2-phenylethylladenosine (S-PIA) greater than N6-(2-hydroxyethyl)adenosine (2-OH-ethyl) was observed for inhibiting both activities. The behavioral potency of these adenosine analogues correlates extremely well with their reported A2 receptor affinity (r2 = 0.93, P less than 0.01 and r2 = 0.86, P less than 0.05 for locomotor and head dipping activity respectively), but very poorly with their reported A1 receptor affinity (r2 less than 0.02, P greater than 0.50 for both activities). These results suggest that adenosine A2 receptors, but not A1 receptors, may be involved in the hypomobility induced by adenosine analogues.     

Common breast cancer susceptibility loci are associated with triple-negative breast cancer

Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer.