Axonal transport deficit in a KIF5A–/– mouse model

Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder preferentially affecting the longest corticospinal axons. More than 40 HSP genetic loci have been identified, among them SPG10, an autosomal dominant HSP caused by point mutations in the neuronal kinesin heavy chain protein KIF5A. Constitutive KIF5A knockout (KIF5A–/–) mice die early after birth. In these mice, lungs were unexpanded, and cell bodies of lower motor neurons in the spinal cord swollen, but the pathomechanism remained unclear. To gain insights into the pathophysiology, we characterized survival, outgrowth, and function in primary motor and sensory neuron cultures from KIF5A–/– mice. Absence of KIF5A reduced survival in motor neurons, but not in sensory neurons. Outgrowth of axons and dendrites was remarkably diminished in KIF5A–/– motor neurons. The number of axonal branches was reduced, whereas the number of dendrites was not altered. In KIF5A–/– sensory neurons, neurite outgrowth was decreased but the number of neurites remained unchanged. In motor neurons maximum and average velocity of mitochondrial transport was reduced both in anterograde and retrograde direction. Our results point out a role of KIF5A in process outgrowth and axonal transport of mitochondria, affecting motor neurons more severely than sensory neurons. This gives pathophysiological insights into KIF5A associated HSP, and matches the clinical findings of predominant degeneration of the longest axons of the corticospinal tract

Role of Kinesin Heavy Chain in Crumbs Localization along the Rhabdomere Elongation in Drosophila Photoreceptor

BACKGROUND:Crumbs (Crb), a cell polarity gene, has been shown to provide a positional cue for the extension of the apical membrane domain, adherens junction (AJ), and rhabdomere along the growing proximal-distal axis during Drosophila photoreceptor morphogenesis. In developing Drosophila photoreceptors, a stabilized microtubule structure was discovered and its presence was linked to polarity protein localization. It was therefore hypothesized that the microtubules may provide trafficking routes for the polarity proteins during photoreceptor morphogenesis. This study has examined whether Kinesin heavy chain (Khc), a subunit of the microtubule-based motor Kinesin-1, is essential in polarity protein localization in developing photoreceptors. METHODOLOGY/PRINCIPAL FINDINGS:Because a genetic interaction was found between crb and khc, Crb localization was examined in the developing photoreceptors of khc mutants. khc was dispensable during early eye differentiation and development. However, khc mutant photoreceptors showed a range of abnormalities in the apical membrane domain depending on the position along the proximal-distal axis in pupal photoreceptors. The khc mutant showed a progressive mislocalization in the apical domain along the distal-proximal axis during rhabdomere elongation. The khc mutation also led to a similar progressive defect in the stabilized microtubule structures, strongly suggesting that Khc is essential for microtubule structure and Crb localization during distal to proximal rhabdomere elongation in pupal morphogenesis. This role of Khc in apical domain control was further supported by khc's gain-of-function phenotype. Khc overexpression in photoreceptors caused disruption of the apical membrane domain and the stabilized microtubules in the developing photoreceptors. CONCLUSIONS/SIGNIFICANCE:In summary, we examined the role of khc in the regulation of the apical Crb domain in developing photoreceptors. Since the rhabdomeres in developing pupal eyes grow along the distal-proximal axis, these phenotypes suggest that Khc is essential for the microtubule structures and apical membrane domains during the distal-proximal elongation of photoreceptors, but is dispensable for early eye development

The role of the mitochondria and the endoplasmic reticulum contact sites in the development of the immune responses

Abstract Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are dynamic modules enriched in subset of lipids and specialized proteins that determine their structure and functions. The MERCs regulate lipid transfer, autophagosome formation, mitochondrial fission, Ca2+ homeostasis and apoptosis. Since these functions are essential for cell biology, it is therefore not surprising that MERCs also play a critical role in organ physiology among which the immune system stands by its critical host defense function. This defense system must discriminate and tolerate host cells and beneficial commensal microorganisms while eliminating pathogenic ones in order to preserve normal homeostasis. To meet this goal, the immune system has two lines of defense. First, the fast acting but unspecific innate immune system relies on anatomical physical barriers and subsets of hematopoietically derived cells expressing germline-encoded receptors called pattern recognition receptors (PRR) recognizing conserved motifs on the pathogens. Second, the slower but very specific adaptive immune response is added to complement innate immunity. Adaptive immunity relies on another set of specialized cells, the lymphocytes, harboring receptors requiring somatic recombination to be expressed. Both innate and adaptive immune cells must be activated to phagocytose and process pathogens, migrate, proliferate, release soluble factors and destroy infected cells. Some of these functions are strongly dependent on lipid transfer, autophagosome formation, mitochondrial fission, and Ca2+ flux; this indicates that MERCs could regulate immunity

Reverse osmosis membrane sensitivity to ozone and halogen disinfectants. Desalination

SUMMARY The sensitivity of commercial reverse osmosis (RO) membranes toward halogen and ozone disinfectants has been measured at carefully controlled concentration and pH levels. Membrane sensitivity varies with polymer type, disinfectant chemical, and solution pH. Aromatic polyamide membranes are damaged by halogen addition to aromatic rings within the polymer. This process follows predictable reaction kinetics. Polymer viscosity changes with increasing membrane damage have also been followed. Results of this study will be useful in planning disinfection strategies for RO units in the field

Reverse osmosis membrane sensitivity to ozone and halogen disinfectants. Desalination

SUMMARY The sensitivity of commercial reverse osmosis (RO) membranes toward halogen and ozone disinfectants has been measured at carefully controlled concentration and pH levels. Membrane sensitivity varies with polymer type, disinfectant chemical, and solution pH. Aromatic polyamide membranes are damaged by halogen addition to aromatic rings within the polymer. This process follows predictable reaction kinetics. Polymer viscosity changes with increasing membrane damage have also been followed. Results of this study will be useful in planning disinfection strategies for RO units in the field

Cricoid Pressure during Induction for Tracheal Intubation in Critically Ill Children: A Report from National Emergency Airway Registry for Children

© 2018 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. Objectives: Cricoid pressure is often used to prevent regurgitation during induction and mask ventilation prior to high-risk tracheal intubation in critically ill children. Clinical data in children showing benefit are limited. Our objective was to evaluate the association between cricoid pressure use and the occurrence of regurgitation during tracheal intubation for critically ill children in PICU. Design: A retrospective cohort study of a multicenter pediatric airway quality improvement registry. Settings: Thirty-five PICUs within general and children\u27s hospitals (29 in the United States, three in Canada, one in Japan, one in Singapore, and one in New Zealand). Patients: Children (\u3c 18 yr) with initial tracheal intubation using direct laryngoscopy in PICUs between July 2010 and December 2015. Interventions: None. Measurements and Main Results: Multivariable logistic regression analysis was used to evaluate the association between cricoid pressure use and the occurrence of regurgitation while adjusting for underlying differences in patient and clinical care factors. Of 7,825 events, cricoid pressure was used in 1,819 (23%). Regurgitation was reported in 106 of 7,825 (1.4%) and clinical aspiration in 51 of 7,825 (0.7%). Regurgitation was reported in 35 of 1,819 (1.9%) with cricoid pressure, and 71 of 6,006 (1.2%) without cricoid pressure (unadjusted odds ratio, 1.64; 95% CI, 1.09-2.47; p = 0.018). On multivariable analysis, cricoid pressure was not associated with the occurrence of regurgitation after adjusting for patient, practice, and known regurgitation risk factors (adjusted odds ratio, 1.57; 95% CI, 0.99-2.47; p = 0.054). A sensitivity analysis in propensity score-matched cohorts showed cricoid pressure was associated with a higher regurgitation rate (adjusted odds ratio, 1.01; 95% CI, 1.00-1.02; p = 0.036). Conclusions: Cricoid pressure during induction and mask ventilation before tracheal intubation in the current ICU practice was not associated with a lower regurgitation rate after adjusting for previously reported confounders. Further studies are needed to determine whether cricoid pressure for specific indication with proper maneuver would be effective in reducing regurgitation events