Insulin And Non-Insulin Dependent Glut4 Trafficking: Regulation By The Tug Protein

The body tightly regulates glucose production and disposal despite changing metabolic demands, including large post-prandial and fasting fluctuations. Specifically, under the action of insulin, muscle contraction, ischemia, and poor nutrient availability, cells increase the amount of the glucose transporter type 4 (GLUT4) at the plasma membrane by mobilizing a sequestered pool of transporters. In this work, we demonstrate that the TUG (tether containing a UBX domain for GLUT4) protein mediates both insulin-dependent and insulin-independent pathways to increase GLUT4 at the plasma membrane. In mice fed a high fat diet to induce insulin resistance, the regulation of the endoproteolytic cleavage of the TUG protein was disrupted. We also present evidence that helps to identify the key protease, Usp25m, that cleaves the tethering protein TUG in both an insulin-dependent and insulin-independent manner, releasing GLUT4 from its storage location in the basal state to the plasma membrane in an activated state. Finally, our results also suggest that in the adipocytes and myocytes, activated AMPK leads to cleavage of the TUG protein

04. Experiential Integrative Approaches to Heart Health

Focus Areas: Integrative Approaches to Care, Experiential Workshop This session will highlight two of the most important, yet frequently overlooked, determinants of heart health: mind-body interactions and nutrition. These areas will be explored through didactic and experiential learning. The session will begin with a short presentation by Dr Adi Haramati on the physiology of stress and the scientific basis for mind-body approaches to de-stress, followed by an experiential autogenic exercise that will allow participants to track their own vascular response to a relaxation exercise (using skin thermistors). Dr David Eisenberg will then provide a short presentation on national and global trends in the areas of nutrition, obesity, and diabetes and will discuss the relationship between health professionals’ personal self-care behaviors and the frequency with which they advise their patients about these same behaviors. A cooking demonstration will showcase simple techniques that healthcare professionals can use and share with their patients to convey the fact that healthy foods can also be easy to make, convenient, affordable, and “craveably” delicious. Dr Stephen Devries will complete the presentation with a review of recent clinical studies highlighting the efficacy of nutrition and mind-body interventions on heart health. Practical recommendations for incorporating integrative strategies into heart care will be emphasized

Violence against children perpetrated by peers: A cross-sectional school-based survey in Uganda.

Violence against children by peers is a global public health problem. We aimed to assess factors associated with peer violence victimization among primary school children in Uganda. We conducted multilevel multivariable logistic regression analyses of cross-sectional data from 3706 primary students in 42 Ugandan primary schools. Among primary school students, 29% and 34% had ever experienced physical and emotional violence perpetrated by their peers, respectively. Factors strongly associated with both physical and emotional violence were similar and overlapping, and included exposure to interparental violence, having an attitude supportive of violence against children from school staff, not living with biological parents, working for payment, and higher SDQ score. However, we found that younger age, sharing sleeping area with an adult and achieving a higher educational performance score, were specifically associated with physical violence. On the other hand, being female, walking to school, reporting disability and eating one meal on the previous day, were particularly associated with emotional violence. Interventions to reduce peer violence should focus on family contexts, school environments and those with poor socio-economic status may need extra support

Computation in Classical Mechanics

There is a growing consensus that physics majors need to learn computational skills, but many departments are still devoid of computation in their physics curriculum. Some departments may lack the resources or commitment to create a dedicated course or program in computational physics. One way around this difficulty is to include computation in a standard upper-level physics course. An intermediate classical mechanics course is particularly well suited for including computation. We discuss the ways we have used computation in our classical mechanics courses, focusing on how computational work can improve students' understanding of physics as well as their computational skills. We present examples of computational problems that serve these two purposes. In addition, we provide information about resources for instructors who would like to include computation in their courses.Comment: 6 pages, 3 figures, submitted to American Journal of Physic

Brine release based on structural calculations of damage around an excavation at the Waste Isolation Pilot Plant (WIPP)

In a large in situ experimntal circular room, brine inflow was measured over 5 years. After correcting for evaporation losses into mine ventilation air, the measurements gave data for a period of nearly 3 years. Predicted brine accumulation based on a mechanical ``snow plow`` model of the volume swept by creep-induced damage as calculated with the Multimechanism Deformation Coupled Fracture model was found to agree with experiment. Calculation suggests the damage zone at 5 years effectively exends only some 0.7 m into the salt around the room. Also, because the mecahnical model of brine release gives an adequate explanation of the measured data, the hydrological process of brine flow appears to be rapid compared to the mechanical process of brine release

New investigations into the stability of Mesna using LC-MS/MS and NMR

Both LC-MS/MS and NMR analyses confirmed the instability of Mesna and its conversion into Dimesna

Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation

BACKGROUND: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. OBJECTIVES: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. METHODS: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. RESULTS: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. CONCLUSIONS: Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial

Acceptability of Implantable Continuous Glucose Monitoring Sensor

Real-time continuous glucose monitoring is associated with significant benefits for diabetes management. Implantable sensors could overcome some challenges reportedly associated with device visibility, psychosocial functioning and sensor durability. A psychosocial assessment was conducted to determine acceptability and impact of an implantable continuous glucose monitoring (CGM) sensor as part of the PRECISE trial. Questionnaires were administered to participants comprising the Diabetes Distress Scale, the CGM impact scale, and bespoke device satisfaction. Fifty-one participants across the United Kingdom (n = 10) and Germany (n = 41) completed the questionnaires. Of these, 90% had T1D, 50% followed an insulin pump therapy regimen, and 45% of the participants were previous CGM users. CGM Impact Scale results show 86% (n = 44) of participants reported feeling better (14% neutral) about their diabetes control with 90% CGM naïve participants and 81% previous CGM users reporting increased confidence about their diabetes management. Furthermore, 73% (n = 37) felt more safe (27% neutral) while sleeping and 78% (n = 39) more confident (22% neutral) about avoiding serious hypoglycemia. Responses correspond with an average improvement in HbA1c from 7.51 to 7.05 ( P < .0001) over the 90 days use of the CGM. Overall, the system was rated highly on ease of use, convenience and comfort. 84% would choose to be inserted again with 93% of CGM naïve participants (86% previous CGM users) reporting minimized burden of diabetes. Implantable CGM devices are acceptable to users and are evaluated favorably. The considerable majority of participants (93% of first time users and 77% previous CGM users) would like to continue using the system to help manage their diabetes more effectivel

Space allowance and the behaviour of captive southern hairy-nosed wombats (Lasiorhinus latifrons)

Captive southern hairy-nosed wombats (Lasiorhinus latifrons) often display indicators of substandard welfare, including aggression and stereotypical pacing. To determine if space availability influences the welfare of wombats, the behaviour of three groups of L. latifrons (n = 3) was studied in three different sized enclosures: small (S) (75.5 m2; the minimum space requirement for three wombats in Queensland, Australia), medium (M) (151 m2, twice the minimum space) and large (L) (224 m2, three times the minimum space) in a Latin Square design. Compared to wombats in larger enclosures, those in the small enclosure were observed to display more biting (S: 1.96; M: 0.42; L: 0.28, SED &plusmn; 0.56 counts / day, P = 0.01), retreat from conspecifics (S: 15.0; M: 9.9; L: 7.1 SED &plusmn; 2.66 counts / day, P = 0.03), and visual scanning (S: 52.8; M: 33.9; L: 28.8, SED &plusmn; 4.62 counts / day, P &lt; 0.001); they also spent more time fenceline digging, which may represent attempts to escape (S: 0.78; M: 0.16; L: 0.24, SED &plusmn; 0.07 min / m / day, P &lt; 0.0001). Those in the largest enclosure showed less self-directed grooming behaviour than those in the two smaller enclosures (S: 23.80; M: 24.08; L: 14.42, SED &plusmn; 3.22 counts / day, P = 0.02). It is concluded that small 2 enclosure size had a negative impact on the behaviour of wombat, and as a consequence, current 30 minimum space requirements for wombats in captivity should be reassessed

A Synaptic Mechanism for Temporal Filtering of Visual Signals

The visual system transmits information about fast and slow changes in light intensity through separate neural pathways. We used in vivo imaging to investigate how bipolar cells transmit these signals to the inner retina. We found that the volume of the synaptic terminal is an intrinsic property that contributes to different temporal filters. Individual cells transmit through multiple terminals varying in size, but smaller terminals generate faster and larger calcium transients to trigger vesicle release with higher initial gain, followed by more profound adaptation. Smaller terminals transmitted higher stimulus frequencies more effectively. Modeling global calcium dynamics triggering vesicle release indicated that variations in the volume of presynaptic compartments contribute directly to all these differences in response dynamics. These results indicate how one neuron can transmit different temporal components in the visual signal through synaptic terminals of varying geometries with different adaptational properties