M1 muscarinic receptors inhibit L-type Ca2+ current and M-current by divergent signal transduction cascades

Ion channels reside in a sea of phospholipids. During normal fluctuations in membrane potential and periods of modulation, lipids that directly associate with channel proteins influence gating by incompletely understood mechanisms. In one model, M(1)-muscarinic receptors (M(1)Rs) may inhibit both Ca(2+) (L- and N-) and K(+) (M-) currents by losing a putative interaction between channels and phosphatidylinositol-4,5-bisphosphate (PIP(2)). However, we found previously that M(1)R inhibition of N-current in superior cervical ganglion (SCG) neurons requires loss of PIP(2) and generation of a free fatty acid, probably arachidonic acid (AA) by phospholipase A(2) (PLA(2)). It is not known whether PLA(2) activity and AA also participate in L- and M-current modulation in SCG neurons. To test whether PLA(2) plays a similar role in M(1)R inhibition of L- and M-currents, we used several experimental approaches and found unanticipated divergent signaling. First, blocking resynthesis of PIP(2) minimized M-current recovery from inhibition, whereas L-current recovered normally. Second, L-current inhibition required group IVa PLA(2) [cytoplasmic PLA(2) (cPLA(2))], whereas M-current did not. Western blot and imaging studies confirmed acute activation of cPLA(2) by muscarinic stimulation. Third, in type IIa PLA(2) [secreted (sPLA(2))](-/-)/cPLA(2)(-/-) double-knock-out SCG neurons, muscarinic inhibition of L-current decreased. In contrast, M-current inhibition remained unaffected but recovery was impaired. Our results indicate that L-current is inhibited by a pathway previously shown to control M-current over-recovery after washout of muscarinic agonist. Our findings support a model of M(1)R-meditated channel modulation that broadens rather than restricts the roles of phospholipids and fatty acids in regulating ion channel activity

Walk well:a randomised controlled trial of a walking intervention for adults with intellectual disabilities: study protocol

Background - Walking interventions have been shown to have a positive impact on physical activity (PA) levels, health and wellbeing for adult and older adult populations. There has been very little work carried out to explore the effectiveness of walking interventions for adults with intellectual disabilities. This paper will provide details of the Walk Well intervention, designed for adults with intellectual disabilities, and a randomised controlled trial (RCT) to test its effectiveness. Methods/design - This study will adopt a RCT design, with participants allocated to the walking intervention group or a waiting list control group. The intervention consists of three PA consultations (baseline, six weeks and 12 weeks) and an individualised 12 week walking programme. A range of measures will be completed by participants at baseline, post intervention (three months from baseline) and at follow up (three months post intervention and six months from baseline). All outcome measures will be collected by a researcher who will be blinded to the study groups. The primary outcome will be steps walked per day, measured using accelerometers. Secondary outcome measures will include time spent in PA per day (across various intensity levels), time spent in sedentary behaviour per day, quality of life, self-efficacy and anthropometric measures to monitor weight change. Discussion - Since there are currently no published RCTs of walking interventions for adults with intellectual disabilities, this RCT will examine if a walking intervention can successfully increase PA, health and wellbeing of adults with intellectual disabilities

Pre-Flight Calibration of the Mars 2020 Rover Mastcam Zoom (Mastcam-Z) Multispectral, Stereoscopic Imager

The NASA Perseverance rover Mast Camera Zoom (Mastcam-Z) system is a pair of zoomable, focusable, multi-spectral, and color charge-coupled device (CCD) cameras mounted on top of a 1.7 m Remote Sensing Mast, along with associated electronics and two calibration targets. The cameras contain identical optical assemblies that can range in focal length from 26 mm (25.5∘×19.1∘ FOV) to 110 mm (6.2∘×4.2∘ FOV) and will acquire data at pixel scales of 148-540 μm at a range of 2 m and 7.4-27 cm at 1 km. The cameras are mounted on the rover’s mast with a stereo baseline of 24.3±0.1 cm and a toe-in angle of 1.17±0.03∘ (per camera). Each camera uses a Kodak KAI-2020 CCD with 1600×1200 active pixels and an 8 position filter wheel that contains an IR-cutoff filter for color imaging through the detectors’ Bayer-pattern filters, a neutral density (ND) solar filter for imaging the sun, and 6 narrow-band geology filters (16 total filters). An associated Digital Electronics Assembly provides command data interfaces to the rover, 11-to-8 bit companding, and JPEG compression capabilities. Herein, we describe pre-flight calibration of the Mastcam-Z instrument and characterize its radiometric and geometric behavior. Between April 26thth and May 9thth, 2019, ∼45,000 images were acquired during stand-alone calibration at Malin Space Science Systems (MSSS) in San Diego, CA. Additional data were acquired during Assembly Test and Launch Operations (ATLO) at the Jet Propulsion Laboratory and Kennedy Space Center. Results of the radiometric calibration validate a 5% absolute radiometric accuracy when using camera state parameters investigated during testing. When observing using camera state parameters not interrogated during calibration (e.g., non-canonical zoom positions), we conservatively estimate the absolute uncertainty to be 0.2 design requirement. We discuss lessons learned from calibration and suggest tactical strategies that will optimize the quality of science data acquired during operation at Mars. While most results matched expectations, some surprises were discovered, such as a strong wavelength and temperature dependence on the radiometric coefficients and a scene-dependent dynamic component to the zero-exposure bias frames. Calibration results and derived accuracies were validated using a Geoboard target consisting of well-characterized geologic samples

Understanding acute ankle ligamentous sprain injury in sports

This paper summarizes the current understanding on acute ankle sprain injury, which is the most common acute sport trauma, accounting for about 14% of all sport-related injuries. Among, 80% are ligamentous sprains caused by explosive inversion or supination. The injury motion often happens at the subtalar joint and tears the anterior talofibular ligament (ATFL) which possesses the lowest ultimate load among the lateral ligaments at the ankle. For extrinsic risk factors to ankle sprain injury, prescribing orthosis decreases the risk while increased exercise intensity in soccer raises the risk. For intrinsic factors, a foot size with increased width, an increased ankle eversion to inversion strength, plantarflexion strength and ratio between dorsiflexion and plantarflexion strength, and limb dominance could increase the ankle sprain injury risk. Players with a previous sprain history, players wearing shoes with air cells, players who do not stretch before exercising, players with inferior single leg balance, and overweight players are 4.9, 4.3, 2.6, 2.4 and 3.9 times more likely to sustain an ankle sprain injury. The aetiology of most ankle sprain injuries is incorrect foot positioning at landing – a medially-deviated vertical ground reaction force causes an explosive supination or inversion moment at the subtalar joint in a short time (about 50 ms). Another aetiology is the delayed reaction time of the peroneal muscles at the lateral aspect of the ankle (60–90 ms). The failure supination or inversion torque is about 41–45 Nm to cause ligamentous rupture in simulated spraining tests on cadaver. A previous case report revealed that the ankle joint reached 48 degrees inversion and 10 degrees internal rotation during an accidental grade I ankle ligamentous sprain injury during a dynamic cutting trial in laboratory. Diagnosis techniques and grading systems vary, but the management of ankle ligamentous sprain injury is mainly conservative. Immobilization should not be used as it results in joint stiffness, muscle atrophy and loss of proprioception. Traditional Chinese medicine such as herbs, massage and acupuncture were well applied in China in managing sports injuries, and was reported to be effective in relieving pain, reducing swelling and edema, and restoring normal ankle function. Finally, the best practice of sports medicine would be to prevent the injury. Different previous approaches, including designing prophylactice devices, introducing functional interventions, as well as change of games rules were highlighted. This paper allows the readers to catch up with the previous researches on ankle sprain injury, and facilitate the future research idea on sport-related ankle sprain injury

Commercial products for osteochondral tissue repair and regeneration

The osteochondral tissue represents a complex structure composed of four interconnected structures, namely hyaline cartilage, a thin layer of calcified cartilage, subchondral bone, and cancellous bone. Due to the several difficulties associated with its repair and regeneration, researchers have developed several studies aiming to restore the native tissue, some of which had led to tissue-engineered commercial products. In this sense, this chapter discusses the good manufacturing practices, regulatory medical conditions and challenges on clinical translations that should be fulfilled regarding the safety and efficacy of the new commercialized products. Furthermore, we review the current osteochondral products that are currently being marketed and applied in the clinical setting, emphasizing the advantages and difficulties of each one.FROnTHERA (NORTE-01-0145- FEDER-000023), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). The authors would also like to acknowledge H2020-MSCA-RISE program, as this work is part of developments carried out in BAMOS project, funded by the European Union’s Horizon 2020 research and innovation program under grant agreement N° 734156. The financial support from the Portuguese Foundation for Science and Technology under the program Investigador FCT 2012 and 2015 (IF/00423/2012 and IF/01285/2015)info:eu-repo/semantics/publishedVersio

Role of biomechanics in the understanding of normal, injured, and healing ligaments and tendons

Ligaments and tendons are soft connective tissues which serve essential roles for biomechanical function of the musculoskeletal system by stabilizing and guiding the motion of diarthrodial joints. Nevertheless, these tissues are frequently injured due to repetition and overuse as well as quick cutting motions that involve acceleration and deceleration. These injuries often upset this balance between mobility and stability of the joint which causes damage to other soft tissues manifested as pain and other morbidity, such as osteoarthritis