Misregulation of mitochondria-lysosome contact dynamics in Charcot-Marie-Tooth Type 2B disease Rab7 mutant sensory peripheral neurons

Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria-lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot-Marie-Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting peripheral sensory neurons caused by mutations in the GTPase Rab7. Using live super-resolution and confocal time-lapse microscopy, we showed that mitochondria-lysosome contact sites dynamically form in the soma and axons of peripheral sensory neurons. Interestingly, Charcot-Marie-Tooth type 2B mutant Rab7 led to prolonged mitochondria-lysosome contact site tethering preferentially in the axons of peripheral sensory neurons, due to impaired Rab7 GTP hydrolysis-mediated contact site untethering. We further generated a Charcot-Marie-Tooth type 2B mutant Rab7 knock-in mouse model which exhibited prolonged axonal mitochondria-lysosome contact site tethering and defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis as well as fragmented mitochondria in the axon of the sciatic nerve. Importantly, mutant Rab7 mice further demonstrated preferential sensory behavioral abnormalities and neuropathy, highlighting an important role for mutant Rab7 in driving degeneration of peripheral sensory neurons. Together, this study identifies an important role for mitochondria-lysosome contact sites in the pathogenesis of peripheral neuropathy

The effects of training with high-speed interval running on muscle performance are modulated by slope

© 2021 The Authors. Published by Wiley. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.14814/phy2.14656We examined changes in selected muscle performance parameters after 8 weeks of interval training using two opposite running inclinations. We hypothesized that the uphill training will affect endurance muscle performance outcomes, whereas the downhill training will affect power muscle performance outcomes. Fourteen physically active volunteers were randomly assigned into either the Uphill group (UG; n = 7; uphill interval running at +10% incline) or the Downhill group (DG; n = 7; downhill interval running at -10% incline) and completed 16 training sessions. Each session consisted of ten 30 s treadmill runs at 90% of maximum aerobic speed (MAS) with a work to rest ratio of 1:2. Vertical jump performance, isometric (MVC) and isokinetic torque of knee extensors and flexors, and fatigue of knee extensors were evaluated pre and post-training. Moreover, body composition (via bioimpedance) and vastus lateralis muscle architecture (via ultrasonography) were assessed pre and post-training. Relative lean tissue mass, relative fat mass, and squat jump (cm) significantly (p < .05) changed from baseline values by +4.5 ± 4.0%, -11.5 ± 9.6%, and +9.5 ± 11.7%, respectively, only in the DG. Similarly, DG improved absolute values of knee extension rate of torque development and impulse (p < .05), whereas knee flexion peak torque angle significantly decreased in both groups (p < .05). On the other hand, the UG increased the number of repetitions achieved during the fatigue protocol and total work by 21.2 ± 32.6% and 13.8 ± 21.2%, respectively (p < .05). No differences were found between groups in muscle architecture. Introducing variations in slope during HIIT could be used to induce specific improvements toward muscle endurance or power performance characteristics.Published versio

Review of Community Pharmacy Staff Educational Needs for Supporting Mental Health Consumers and Carers

Development of a mental health education package for community pharmacy staff should be informed by mental health consumers/carers’ needs, expectations and experiences, and staff knowledge, skills and attitudes. This review (1) explored research on community pharmacy practice and service provision for mental health consumers/carers, and (2) identified validated methods for assessing staff knowledge, skills and attitudes about mental illness to inform the development of a training questionnaire. A literature scan using key words knowledge, skills, attitudes, and beliefs combined with community pharmacy, pharmacist, and pharmacy support staff, and mental illness, depression, anxiety was conducted. A small number of studies were found that used reliable methods to assess pharmacists’ training needs regarding mental illness and treatment options. There was little published specifically in relation to depression and anxiety in community pharmacy practice. No studies assessed the training needs of pharmacy support staff. A systematic analysis of pharmacy staff learning needs is warranted

Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer

Summary Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886) we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralising antibody titres (NAbT) using a live virus microneutralization assay against wild-type (WT), Delta, Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titres and T cell responses after the fourth vaccine dose increases compared to those after the third vaccine dose. Patients who received B cell-depleting therapies within 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination

Functional antibody and T-cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study (NCT03226886) integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2-positive, 94 were symptomatic and 2 patients died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies, 82% had neutralizing antibodies against WT, whereas neutralizing antibody titers (NAbT) against the Alpha, Beta, and Delta variants were substantially reduced. Whereas S1-reactive antibody levels decreased in 13% of patients, NAbT remained stable up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment-specific, but presented compensatory cellular responses, further supported by clinical. Overall, these findings advance the understanding of the nature and duration of immune response to SARS-CoV-2 in patients with cancer