Nitric Oxide Destabilizes Pias3 and Regulates Sumoylation

Small ubiquitin-related protein modifiers (SUMO) modification is an important mechanism for posttranslational regulation of protein function. However, it is largely unknown how the sumoylation pathway is regulated. Here, we report that nitric oxide (NO) causes global hyposumoylation in mammalian cells. Both SUMO E2 conjugating enzyme Ubc9 and E3 ligase protein inhibitor of activated STAT3 (Pias3) were targets for S-nitrosation. S-nitrosation did not interfere with the SUMO conjugating activity of Ubc9, but promoted Pias3 degradation by facilitating its interaction with tripartite motif-containing 32 (Trim32), a ubiquitin E3 ligase. On the one hand, NO promoted Trim32-mediated Pias3 ubiquitination. On the other hand, NO enhanced the stimulatory effect of Pias3 on Trim32 autoubiquitination. The residue Cys459 of Pias3 was identified as a target site for S-nitrosation. Mutation of Cys459 abolished the stimulatory effect of NO on the Pias3-Trim32 interaction, indicating a requirement of S-nitrosation at Cys459 for positive regulation of the Pias3-Trim32 interplay. This study reveals a novel crosstalk between S-nitrosation, ubiquitination, and sumoylation, which may be crucial for NO-related physiological and pathological processes

Comparing Common Data Environment Platforms for Student Collaborative Working: A Case Study from Ulster University

PAS1192-2 (2013) outlines the “fundamental principles of Level 2 information modeling”, one of these principles is the use of what is commonly referred to as a Common Data Environment (CDE). A CDE could be described as an internet-enabled cloudhosting platform, accessible to all construction team members to access shared project information. For the construction sector to achieve increased productivity goals, the next generation of industry professionals will need to be educated in a way that provides them with an appreciation of Building Information Modelling (BIM) working methods, at all levels, including an understanding of how data in a CDE should be structured, managed, shared and published. This presents a challenge for educational institutions in terms of providing a CDE that addresses the requirements set out in PAS1192-2, and mirrors organisational and professional working practices without causing confusion due to over complexity. This paper presents the findings of a two-year study undertaken at Ulster University comparing the use of a leading industry CDE platform with one derived from the in-house Virtual Learning Environment (VLE), for the delivery of a student BIM project. The research methodology employed was a qualitative case study analysis, focusing on observations from the academics involved and feedback from students. The results of the study show advantages for both CDE platforms depending on the learning outcomes required

Comparing Common Data Environment Platforms for Student Collaborative Working: A Case Study from Ulster University

PAS1192-2 (2013) outlines the “fundamental principles of Level 2 information modeling”, one of these principles is the use of what is commonly referred to as a Common Data Environment (CDE). A CDE could be described as an internet-enabled cloudhosting platform, accessible to all construction team members to access shared project information. For the construction sector to achieve increased productivity goals, the next generation of industry professionals will need to be educated in a way that provides them with an appreciation of Building Information Modelling (BIM) working methods, at all levels, including an understanding of how data in a CDE should be structured, managed, shared and published. This presents a challenge for educational institutions in terms of providing a CDE that addresses the requirements set out in PAS1192-2, and mirrors organisational and professional working practices without causing confusion due to over complexity. This paper presents the findings of a two-year study undertaken at Ulster University comparing the use of a leading industry CDE platform with one derived from the in-house Virtual Learning Environment (VLE), for the delivery of a student BIM project. The research methodology employed was a qualitative case study analysis, focusing on observations from the academics involved and feedback from students. The results of the study show advantages for both CDE platforms depending on the learning outcomes required

Does foot pitch at ground contact affect parachute landing technique?

The Australian Defence Force Parachute Training School instructs trainees to make initial ground contact using a fl at foot whereas United States paratroopers are taught to contact the ground with the ball of the foot fi rst. This study aimed to determine whether differences in foot pitch affected parachute landing technique. Kinematic, ground reaction force and electromyographic data were analyzed for 28 parachutists who performed parachute landings (vertical descent velocity = 3.4 m·s −1 ) from a monorail apparatus. Independent t -tests were used to determine signifi cant ( p \u3c 0.05) differences between variables characterizing foot pitch. Subjects who landed fl at-footed displayed less knee and ankle fl exion, sustained higher peak ground reaction forces, and took less time to reach peak force than those who landed on the balls of their feet. Although forefoot landings lowered ground reaction forces compared to landing fl at-footed, further research is required to confi rm whether this is a safer parachute landing strategy

Parachute landing fall characteristics at three realistic vertical descent velocities

Introduction: Although parachute landing injuries are thought to be due in part to a lack of exposure of trainees to realistic descent velocities during parachute landing fall (PLF) training, no research has systematically investigated whether PLF technique is affected by different vertical descent conditions, with standardized and realistic conditions of horizontal drift. This study was designed to determine the effects of variations in vertical descent velocity on PLF technique. Methods: Kinematic, ground reaction force, and electromyographic data were collected and analyzed for 20 paratroopers while they performed parachute landings, using a custom-designed monorail apparatus, with a constant horizontal drift velocity (2.3 m · s−1) and at three realistic vertical descent velocities: slow (2.1 m · s−1), medium (3.3 m · s−1), and fast (4.6 m · s−1). Results: Most biomechanical variables characterizing PLF technique were significantly affected by descent velocity. For example, at the fast velocity, the subjects impacted the ground with 123° of plantar flexion and generated ground reaction forces averaging 13.7 times body weight, compared to 106° and 6.1 body weight, respectively, at the slow velocity. Furthermore, the subjects activated their antigravity extensor muscles earlier during the fast velocity condition to eccentrically control the impact absorption. Discussion: As vertical descent rates increased, the paratroopers displayed a significantly different strategy when performing the PLF. It is therefore recommended that PLF training programs include ground training activities with realistic vertical descent velocities to better prepare trainees to withstand the impact forces associated with initial aerial descents onto the Drop Zone and, ultimately, minimize the potential for injury

Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance.

Recent evidence has highlighted the role of N 6-methyladenosine (m6A) in the regulation of mRNA expression, stability, and translation, supporting a potential role for posttranscriptional regulation mediated by m6A in cancer. Here, we explore prostate cancer as an exemplar and demonstrate that low levels of N 6-adenosine-methyltransferase (METTL3) is associated with advanced metastatic disease. To investigate this relationship, we generated the first prostate m6A maps, and further examined how METTL3 regulates expression at the level of transcription, translation, and protein. Significantly, transcripts encoding extracellular matrix proteins are consistently upregulated with METTL3 knockdown. We also examined the relationship between METTL3 and androgen signaling and discovered the upregulation of a hepatocyte nuclear factor-driven gene signature that is associated with therapy resistance in prostate cancer. Significantly, METTL3 knockdown rendered the cells resistant to androgen receptor antagonists via an androgen receptor-independent mechanism driven by the upregulation of nuclear receptor NR5A2/LRH-1. IMPLICATIONS: These findings implicate changes in m6A as a mechanism for therapy resistance in metastatic prostate cancer