Endocytosis and lysosomal degradation of GluA2/3 AMPARs in response to oxygen/glucose deprivation in hippocampal but not cortical neurons

Abstract Global cerebral ischemia results in oxygen and glucose deprivation (OGD) and consequent delayed cell death of vulnerable neurons, with hippocampal CA1 neurons more vulnerable than cortical neurons. Most AMPA receptors (AMPARs) are heteromeric complexes of subunits GluA1/GluA2 or GluA2/GluA3, and the presence of GluA2 renders AMPARs Ca2+-impermeable. In hippocampal CA1 neurons, OGD causes the synaptic expression of GluA2-lacking Ca2+-permeable AMPARs, contributing to toxic Ca2+ influx. The loss of synaptic GluA2 is caused by rapid trafficking of GluA2-containing AMPARs from the cell surface, followed by a delayed reduction in GluA2 mRNA expression. We show here that OGD causes endocytosis, lysosomal targeting and consequent degradation of GluA2- and GluA3-containing AMPARs, and that PICK1 is required for both OGD-induced GluA2 endocytosis and lysosomal sorting. Our results further suggest that GluA1-containing AMPARs resist OGD-induced endocytosis. OGD does not cause GluA2 endocytosis in cortical neurons, and we show that PICK1 binding to the endocytic adaptor AP2 is enhanced by OGD in hippocampal, but not cortical neurons. We propose that endocytosis of GluA2/3, caused by a hippocampal-specific increase in PICK1-AP2 interactions, followed by PICK1-dependent lysosomal targeting, are critical events in determining changes in AMPAR subunit composition in the response to ischaemia

Gastrointestinal Biopsy Obtained During Cancer Screening, a Biological Marker for alpha-Synucleinopathy?

The hallmark alteration in alpha-synucleinopathies, alpha-synuclein, is observed not only in the brain but also in the peripheral tissues, particularly in the intestine. This suggests that endoscopic biopsies performed for colon cancer screening could facilitate the assessment of alpha-synuclein in the gastrointestinal (GI) tract. Using immunohistochemistry for alpha-synuclein, we assessed whether GI biopsies could be used to confirm an ongoing alpha-synucleinopathy. Seventy-four subjects with cerebral alpha-synucleinopathy in various Braak stages with concomitant GI biopsies were available for study. In 81% of the subjects, alpha-synuclein was seen in the mucosal/submucosal GI biopsies. Two subjects with severe cerebral alpha-synucleinopathy and a long delay between biopsy and death displayed no alpha-synuclein pathology in the gut, and 11 subjects with sparse cerebral alpha-synucleinopathy displayed GI alpha-synuclein up to 36 years prior to death. The finding that there was no GI alpha-synuclein in 19% of the subjects with cerebral alpha-synucleinopathy, and alpha-synuclein was observed in the gut of 11 subjects (15%) with sparse cerebral alpha-synucleinopathy even many years prior to death is unexpected and jeopardizes the use of assessment of alpha-synuclein in the peripheral tissue for confirmation of an ongoing cerebral alpha-synucleinopathy

The Prospects of Secondary Moderate Mitral Regurgitation after Aortic Valve Replacement —Meta-Analysis

Aortic valve replacement for aortic stenosis represents one of the most frequent surgical procedures on heart valves. These patients often have concomitant mitral regurgitation. To reveal whether the moderate mitral regurgitation will improve after aortic valve replacement alone, we performed a systematic review and meta-analysis. We identified 27 studies with 4452 patients that underwent aortic valve replacement for aortic stenosis and had co-existent mitral regurgitation. Primary end point was the impact of aortic valve replacement on the concomitant mitral regurgitation. Secondary end points were the analysis of the left ventricle reverse remodeling and long-term survival. Our results showed that there was significant improvement in mitral regurgitation postoperatively (RR, 1.65; 95% CI 1.36–2.00; p < 0.00001) with the average decrease of 0.46 (WMD; 95% CI 0.35–0.57; p < 0.00001). The effect is more pronounced in the elderly population. Perioperative mortality was higher (p < 0.0001) and long-term survival significantly worse (p < 0.00001) in patients that had moderate/severe mitral regurgitation preoperatively. We conclude that after aortic valve replacement alone there are fair chances but for only slight improvement in concomitant mitral regurgitation. The secondary moderate mitral regurgitation should be addressed at the time of aortic valve replacement. A more conservative approach should be followed for elderly and high-risk patients

King's Sarcoidosis Questionnaire (KSQ) - Validation study in Serbian speaking population of sarcoidosis patients.

IntroductionSarcoidosis is a multiorgan, multisystem chronic disease of unknown etiology and unpredictable course. Health status is reduced in sarcoidosis and assessing it is a difficult multitask effort due to many faces this disease might have. Recently, a new questionnaire for assessing health status in sarcoidosis was developed by a group of authors from England-King's Sarcoidosis Questionnaire (KSQ). The benefit of KSQ is the ability to develop the best care plan for the patient, as well as to differentiate the efficacy of the administered treatment.ObjectiveThe aim of this study was to validate the KSQ in Serbian speaking population of sarcoidosis patients. The test itself is a modular, multi-organ health status measure for patients with sarcoidosis for use in clinic and the evaluation of therapies. The correlation of KSQ with different clinical course of sarcoidosis (acute vs chronic disease) and with the clinical outcome status (COS) in sarcoidosis was also investigated.MethodsA total of 159 biopsy positive sarcoidosis patients participated in this study. The average age of the participants was 49.67, majority was female (67.3%) and majority had only pulmonary form of sarcoidosis (71.7%). KSQ - new disease-specific health status instrument, was compared with 5 other already existing instruments already used and validated in sarcoidosis (Saint George Respiratory Questionnaire- SGRQ, Daily Activity List -DAL, Fatigue Assessment Scale- FAS, Medical Research Council dyspnea scale-MRC, Borg Dyspnea Scale and 15D as general questionnaire.ResultsKSQ has significant correlation with other quality of life questionnaires already used in sarcoidosis. Translated version of KSQ shows significant internal reliability, similar to the original KSQ. Serbian version of KSQ has significant correlation with different clinical course of sarcoidosis and with COS as well. The translated version of KSQ is reliable sarcoidosis specific instrument for assessing health status in these patients

Reinventing Biostatistics Education for Basic Scientists

<div><p>Numerous studies demonstrating that statistical errors are common in basic science publications have led to calls to improve statistical training for basic scientists. In this article, we sought to evaluate statistical requirements for PhD training and to identify opportunities for improving biostatistics education in the basic sciences. We provide recommendations for improving statistics training for basic biomedical scientists, including: 1. Encouraging departments to require statistics training, 2. Tailoring coursework to the students’ fields of research, and 3. Developing tools and strategies to promote education and dissemination of statistical knowledge. We also provide a list of statistical considerations that should be addressed in statistics education for basic scientists.</p></div

Statistics usage and education in physiology.

<p><b>A:</b> A recent systematic review [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002430#pbio.1002430.ref004" target="_blank">4</a>] demonstrated that 97.2% of papers published in the top 25% of physiology journals included statistical analyses. <b>B:</b> Statistics courses are not always required for PhD students in top NIH funded physiology departments. Detailed methodology for panels A and B are described in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002430#pbio.1002430.s003" target="_blank">S1 Text</a>.</p

Changes in student attitudes towards statistics after course completion (n = 90).

<p>Changes in student attitudes towards statistics after course completion (n = 90).</p

Flow of information through the different phases of a systematic review.

<p>Flow of information through the different phases of a systematic review.</p