The Gemin2 Complex: An Evolving View Of Smn Mediated Snrnp Assembly

Assembly of spliceosome snRNPs requires a megadalton molecular machine called the survival of motor neuron (SMN) complex. In higher eukaryotes, this complex consists of SMN, Gemins2-8 and unrip. Deficiency in SMN causes spinal muscular atrophy (SMA), a leading cause of heritable mortality in infants and children. The mechanism of precisely how seven Sm proteins are arranged in a ring around an snRNA, to form a snRNP was not well understood, due in part to the large number of components and heterogeneity of the SMN complex. Through use of several techniques including: RNA gel-shifts, pull-downs, F�rster resonance energy transfer, ultracentrifugation, electron microscopy, molecular modeling and genetic manipulation in simple model organisms and human cells, this area was illuminated. Here I will present evidence for Sm5 dependent association of Gemin2 with SMN. Through a series of hydrophobic interactions between amino and carboxy termini, binding of Sm protein to Gemin2 opens a binding site for SMN on its distal side, in both human and S. pombe. I will prove that human SMN complexes in cells require Gemin8 to form large oligomers. I will demonstrate that the oligomerization state of S. pombe SMN is a tetramer, and visualize its complete SMN complex. I will show that both S. pombe and S. cerevisiae SMN-Gemin2 and Brr1 are sufficient for snRNP assembly from recombinant sources. I will further show that S. cerevisiae Brr1 is capable of binding all substrates of the SMN complex. Through genetics I demonstrate a toxicity from Gemin2, when its levels exceed SMN capacity in S. pombe. Finally, I will suggest that the imbalance of Gemin2 and SMN occurs in the devastating childhood disease, SMA, and is a contributing factor. These results amount to a paradigm shift wherein Gemin2 usurps SMN as the most important member of the now SMN-Gemin2 complex for snRNP. Furthermore, with toxicity of excess Gemin2 relative to SMN and the likelihood of this occurring in SMA patients, Gemin2’s position of importance as a potential therapeutic target in SMA has been revealed

Determining the engergy expenditure and relative intensity of two crossfit workouts

This study was designed to determine the energy expenditure and relative intensity of two Crossfit workouts. Fifteen subjects (7 males, 8 females) performed a VO2max test before participating in the CrossFit workouts. Additionally, subjects completed two different CrossFit workouts, which included a similar number of sets and repetitions. Each workout included a 5-minute warm-up, a skill phase, a workout of the day (WOD), and a 5-minute cool-down phase. During the CrossFit workouts heart rate was measured every minute using radiotelemetry. Subjects reported rating of perceived exertion (RPE) after each set of exercises and upon completion of the workout using the 6-20 Borg scale. Males had a significantly higher VO2, session RPE, and energy expenditure during both workouts compared to females. Heart rates were elevated to 90% of HRmax, and VO2 reached 80% VO2max in both workouts. Both values fall within the training range recommended by ACSM for improving cardiorespiratory endurance

Combined spinal-epidural anesthetic management of delivery for marfan syndrome: Case report

Pregnancy in a patient with Marfan syndrome is associated with risks, including cardiovascular complications. The hemodynamic changes of pregnancy during delivery are deleterious to Marfan syndrome patients. This case describes a Marfan syndrome parturient with dilated aortic root >45 mm who underwent neuraxial anesthesia and cesarean delivery. Anesthetic management focused on reducing hypertension and shear forces on the ascending aorta. A combined spinal-epidural with a reduced dose of hyperbaric bupivacaine was utilized for cesarean delivery. Multidisciplinary approaches are vital in the management of Marfan syndrome pregnancy and cardiovascular complications must be considered when planning for delivery and postpartum management. Anesthetic management must consider the hemodynamic changes in pregnancy and severity of Marfan syndrome cardiovascular involvement in the parturient as well as neonatal risks. Guideline development concerning anesthetic management for both the timing of delivery and aortic repair postpartum would be beneficial to Marfan syndrome parturients