Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease.

The rapid analysis of genomic data is providing effective mutational confirmation in patients with clinical and biochemical hallmarks of a specific disease. This is the case for nonketotic hyperglycinemia (NKH), a Mendelian disorder causing seizures in neonates and early-infants, primarily due to mutations in the GLDC gene. However, understanding the impact of missense variants identified in this gene is a major challenge for the application of genomics into clinical practice. Herein, a comprehensive functional and structural analysis of 19 GLDC missense variants identified in a cohort of 26 NKH patients was performed. Mutant cDNA constructs were expressed in COS7 cells followed by enzymatic assays and Western blot analysis of the GCS P-protein to assess the residual activity and mutant protein stability. Structural analysis, based on molecular modeling of the 3D structure of GCS P-protein, was also performed. We identify hypomorphic variants that produce attenuated phenotypes with improved prognosis of the disease. Structural analysis allows us to interpret the effects of mutations on protein stability and catalytic activity, providing molecular evidence for clinical outcome and disease severity. Moreover, we identify an important number of mutants whose loss-of-functionality is associated with instability and, thus, are potential targets for rescue using folding therapeutic approaches.

Novel ergonomic postural assessment method (NERPA) using product-process computer aided engineering for ergonomic workplace design.

BACKGROUND: Musculoskeletal disorders (MSDs) that result from poor ergonomic design are one of the occupational disorders of greatest concern in the industrial sector. A key advantage in the primary design phase is to focus on a method of assessment that detects and evaluates the potential risks experienced by the operative when faced with these types of physical injuries. The method of assessment will improve the process design identifying potential ergonomic improvements from various design alternatives or activities undertaken as part of the cycle of continuous improvement throughout the differing phases of the product life cycle. METHODOLOGY/PRINCIPAL FINDINGS: This paper presents a novel postural assessment method (NERPA) fit for product-process design, which was developed with the help of a digital human model together with a 3D CAD tool, which is widely used in the aeronautic and automotive industries. The power of 3D visualization and the possibility of studying the actual assembly sequence in a virtual environment can allow the functional performance of the parts to be addressed. Such tools can also provide us with an ergonomic workstation design, together with a competitive advantage in the assembly process. CONCLUSIONS: The method developed was used in the design of six production lines, studying 240 manual assembly operations and improving 21 of them. This study demonstrated the proposed method's usefulness and found statistically significant differences in the evaluations of the proposed method and the widely used Rapid Upper Limb Assessment (RULA) method.