Evidence for cooperative interactions between the two motor domains of cytoplasmic dynein

AbstractCytoplasmic dynein is a force-transducing ATPase that powers the movement of cellular cargoes along microtubules. Two identical heavy chain polypeptides (> 500 kDa) of the cytoplasmic dynein complex contain motor domains that possess the ATPase and microtubule-binding activities required for force production [1]. It is of great interest to determine whether both heavy chains (DHCs) in the dynein complex are required for progression of the mechanochemical cycle and motility, as observed for other dimeric motors. We have used transgenic constructs to investigate cooperative interactions between the two motor domains of the Drosophila cytoplasmic dynein complex. We show that 138 kDa and 180 kDa amino-terminal fragments of DHC can assemble with full-length DHC to form heterodimeric complexes containing only a single motor domain. The single-headed dynein complexes can bind and hydrolyze ATP, yet do not show the ATP-induced detachment from microtubules that is characteristic of wild-type homodimeric dynein. These results suggest that cooperative interactions between the monomeric units of the dimer are required for efficient ATP-induced detachment of dynein and unidirectional movement along the microtubule

Neuromuscular and Neuromuscular Junction Manifestations of the PURA-NDD: A Systematic Review of the Reported Symptoms and Potential Treatment Options

PURA-related neurodevelopmental disorders (PURA-NDDs) are a rare genetic disease caused by pathogenic autosomal dominant variants in the PURA gene or a deletion encompassing the PURA gene. PURA-NDD is clinically characterized by neurodevelopmental delay, learning disability, neonatal hypotonia, feeding difficulties, abnormal movements, and epilepsy. It is generally considered to be central nervous system disorders, with generalized weakness, associated hypotonia, cognitive and development deficits in early development, and seizures in late stages. Although it is classified predominantly as a central nervous syndrome disorder, some phenotypic features, such as myopathic facies, respiratory insufficiency of muscle origin, and myopathic features on muscle biopsy and electrodiagnostic evaluation, point to a peripheral (neuromuscular) source of weakness. Patients with PURA-NDD have been increasingly identified in exome-sequenced cohorts of patients with neuromuscular- and congenital myasthenic syndrome-like phenotypes. Recently, fluctuating weakness noted in a PURA-NDD patient, accompanied by repetitive nerve stimulation abnormalities, suggested the disease to be a channelopathy and, more specifically, a neuromuscular junction disorder. Treatment with pyridostigmine or salbutamol led to clinical improvement of neuromuscular function in two reported cases. The goal of this systematic retrospective review is to highlight the motor symptoms of PURA-NDD, to further describe the neuromuscular phenotype, and to emphasize the role of potential treatment opportunities of the neuromuscular phenotype in the setting of the potential role of PURA protein in the neuromuscular junction and the muscles

Neuromuscular and Neuromuscular Junction Manifestations of the PURA-NDD: A Systematic Review of the Reported Symptoms and Potential Treatment Options

PURA-related neurodevelopmental disorders (PURA-NDDs) are a rare genetic disease caused by pathogenic autosomal dominant variants in the PURA gene or a deletion encompassing the PURA gene. PURA-NDD is clinically characterized by neurodevelopmental delay, learning disability, neonatal hypotonia, feeding difficulties, abnormal movements, and epilepsy. It is generally considered to be central nervous system disorders, with generalized weakness, associated hypotonia, cognitive and development deficits in early development, and seizures in late stages. Although it is classified predominantly as a central nervous syndrome disorder, some phenotypic features, such as myopathic facies, respiratory insufficiency of muscle origin, and myopathic features on muscle biopsy and electrodiagnostic evaluation, point to a peripheral (neuromuscular) source of weakness. Patients with PURA-NDD have been increasingly identified in exome-sequenced cohorts of patients with neuromuscular- and congenital myasthenic syndrome-like phenotypes. Recently, fluctuating weakness noted in a PURA-NDD patient, accompanied by repetitive nerve stimulation abnormalities, suggested the disease to be a channelopathy and, more specifically, a neuromuscular junction disorder. Treatment with pyridostigmine or salbutamol led to clinical improvement of neuromuscular function in two reported cases. The goal of this systematic retrospective review is to highlight the motor symptoms of PURA-NDD, to further describe the neuromuscular phenotype, and to emphasize the role of potential treatment opportunities of the neuromuscular phenotype in the setting of the potential role of PURA protein in the neuromuscular junction and the muscles

Effect of 3,4-diaminopyridine phosphate in symptomatic SOD1-G93A mice

Objective: To study the effect of 3,4-diaminopyridine phosphate (3,4-DAPP) on body weight, grip strength, neurological score and survival in symptomatic SOD1-G93A mice.   Method: We administered 3,4-diaminopyridine phosphate (3,4-DAPP) at 0, 8, and 16 mg/kg to SOD1-G93A mice 5 days/week beginning at 90 days of age. We measured body weight, grip strength, neurological score and survival in this model of ALS.   Results: 3,4-DAPP had no influence on body weight, grip strength, neurological score or survival in this transgenic mouse model.   Conclusion: Our study showed that 3,4-DAPP administration had no effects on survival, body weight, grip strength and neurological score of mice with SOD1 mutation. Since the results of this study are of limited significance, larger animal studies are required to investigate the utility of 3,4-DAPP

Can clinical parameters at admission predict severity and intensive care unit mortality outcomes in patients with COVID-19?

Background: COVID-19 acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality. Identification of clinical prognostic factors at admission is crucial in the triage and therapeutic selection of patients in resource-poor settings. The study was done to identify clinical parameters at admission to prognosticate patients who required intensive care unit (ICU) admission. Methods: In this retrospective study, the clinical parameters and outcomes of critically ill patients admitted from a single medical unit during the second wave of COVID-19 were studied. Patients were categorized as survivors and nonsurvivors. Factors associated with mortality were explored using Fisher's exact and t-test as appropriate. Results: The study population included 62 patients with a male: female ratio of 43 (69.3%):19 (30.7%) with a mean (standard deviation [SD]) age of 50.97 (±9.9) years. The mean (SD) O2 saturation was 82% (±10%) and median (interquartile range) PaO2/FiO2 ratio was 161 (89–214) on arrival to the emergency department. Forty-two (66%) required mechanical ventilation and the mean (SD) duration of hospital stay was 20 (±15) days. Thirty-six patients died, and the overall mortality was 58.1%. Increasing age, low SpO2 at presentation to the hospital, and need for mechanical ventilation were noted to be independent predictors of mortality with an odds ratio of 5.1 (95% confidence interval) (1.61–16.2) (P = 0.006) and 25 (3.70–180.19) (P = 0.001), respectively. Admission respiratory rate >36/min (P = 0.009) and SpO2 ≤83% (P = 0.001) were predictive of increased mortality among ICU patients. Conclusion: Low SpO2 at presentation (36/min), and requirement of mechanical ventilation were strong predictors of mortality in patients admitted to ICU with COVID-19 ARDS

Home-based gait analysis as an exploratory endpoint during a multicenter phase 1 trial in limb girdle muscular dystrophy type R2 and facioscapulohumeral muscular dystrophy.

INTRODUCTION/AIMS: Limb girdle muscular dystrophy type 2B (LGMDR2) and facioscapulohumeral muscular dystrophy (FSHD) are genetic muscular dystrophies with an increasing number of potential therapeutic approaches. The aim of this study is to report the data of exploratory digital outcomes extracted from wearable magneto-inertial sensors used in a non-controlled environment for ambulant patients with FSHD and LGMDR2 in a short-term, multicenter clinical study. METHODS: Digital outcomes (stride length, stride speed, and walk parameters in a non-controlled environment) were used as exploratory outcomes in the open-label study ATYR1940-C-004 in ambulant patients during the 3 mo of ATYR1940 treatment and 1 mo of follow-up. Activity and gait variables were calculated from the data recorded in 30-day sub-periods using the sensors. For each sub-period, activity and gait parameters were compared between FSHD and LGMDR2 patients. Change from baseline over the 4-mo study period was assessed. RESULTS: Ten patients (5 FSHD, 5 LGMDR2) were ambulant and compliant for analysis. Gait parameters, but not activity variables, were significantly lower in LGMDR2 compared to FSHD patients at baseline. Longitudinal analyses showed a slight but significant decrease in stride speed at month 4 for all subjects. Activity variables such as total number of strides per day were highly variable from month to month in individual patients, and no visit effects were found for this variable. DISCUSSION: The present study suggests that home-recorded stride speed constitutes a precise and sensitive outcome in ambulant patients with FSHD and LGMDR2