Innovation, design and CAE in new product development

There seems to be a need for clarification on a number of issues that are seminal for the design community: for example, the constructs of invention, of creativity and of innovation (or innovative) appear to be used interchangeably. They are all a vital interest for design but they are different things. Furthermore there is a failure to distinguish between what design has a legitimate interest in or should contribute to and that which is its direct responsibility. The authors of this paper will seek to clarify these and other issues. One of these interests is the increasing demand for sustainable practice: design has a crucial role here and this paper will explore how computer aids can be a powerful tool in this area and also more generally in both design and manufacture

Multicopy Crystallographic & Biophysical Analyses of the N-terminal Domain of NBCe1-A: Illumination of the Human R298S Mutation

Background: NBCe1-A membrane-embedded macromolecules cotransport sodium and bicarbonate ions across the bilayers that serve to maintain acid-base homeostasis throughout the body. Defects are linked to a number of disorders, including proximal renal tubule acidosis, mental retardation, dental defects, and cataracts. Previously, we demonstrated the N-terminal domain of NBCe1-A (Nt) is in pH-sensitive monomer-dimer equilibrium. At neutral pH, bicarbonate ions bind the Nt, stabilizing dimerization and intermolecular self-associations of dimers. Methods: We determine and analyze the X-ray crystal structure of the Nt as a dimer at 2.4-A resolution using molecular-replacement methods, and a multicopy crystallographic structure of the monomer using 5 atomic models and strict 4-fold NCS constraints in refinement procedures. We measure the pH-sensitivity of a truncated Nt mutant by light-scattering techniques, and bicarbonate, bisulfite, mutant self-association bindings by surface plasmon resonance techniques. Results: The structures reveal that R298 implicated in the disorders is part of a putative conduit that transverses the Nt. The conduit opens to the transmembrane domain (TMD) on one end and an apparent foyer entrance on the opposite end. The naturally occurring mutation R298S disrupts an electrostatic pocket within the conduit that disables substrate binding. We also report similar conducts in family member AE1 (Band 3) when exploring its crystal structure. Further, we identify by biophysical analyses on a truncated Nt that the autoregulatory domain (ARD) at the N-terminus of the Nt is responsible for self-associations. Conclusions: The Nt responds to changes in pH or bicarbonate fluctuations. In proximal tubule cells, we propose a model where the ARD is a gate for the foyer. When self-associated, the foyer entrance is accessible, allowing substrate entry into the conduit. During acid loads, the gates close entry into the foyer, preventing bicarbonate from leaving the cell. The R298S defect similarly prevents bicarbonate ions from being transported to blood, giving rise to metabolic acidosis that results from the renal tubule acidosis

Lip, a Human Gene Detected by Transfection of DNA From a Human Liposarcoma Encodes a Protein With Homology to Regulators of Small G Proteins

Purpose/Method. Transfection experiments have been used to identify activated oncogenes in a wide variety of tumour types. Here we describe the use of transfection experiments utilizing DNA from a human pleomorphic liposarcoma to identify a novel gene, designated lip which maps to chromosome 19

NAA10 p.(N101K) disrupts N-terminal acetyltransferase complex NatA and is associated with developmental delay and hemihypertrophy

Nearly half of all human proteins are acetylated at their N-termini by the NatA N-terminal acetyltransferase complex. NAA10 is evolutionarily conserved as the catalytic subunit of NatA in complex with NAA15, but may also have NatA-independent functions. Several NAA10 variants are associated with genetic disorders. The phenotypic spectrum includes developmental delay, intellectual disability, and cardiac abnormalities. Here, we have identified the previously undescribed NAA10 c.303C>A and c.303C>G p.(N101K) variants in two unrelated girls. These girls have developmental delay, but they both also display hemihypertrophy a feature normally not observed or registered among these cases. Functional studies revealed that NAA10 p.(N101K) is completely impaired in its ability to bind NAA15 and to form an enzymatically active NatA complex. In contrast, the integrity of NAA10 p.(N101K) as a monomeric acetyltransferase is intact. Thus, this NAA10 variant may represent the best example of the impact of NatA mediated N-terminal acetylation, isolated from other potential NAA10-mediated cellular functions and may provide important insights into the phenotypes observed in individuals expressing pathogenic NAA10 variants.publishedVersio

"You don’t get side effects from social prescribing”— a qualitative study exploring community pharmacists’ attitudes to social prescribing

Objectives: Social prescribing is an approach that enables the referral of patients to non-clinical support and places a focus on holistic care. This study explored views of community pharmacists regarding social prescribing in pharmacies. Study design: A qualitative phenomenological approach was used. Methods: A convenience sample of eleven community pharmacists from Northern England were recruited via social media (Twitter, Facebook) and took part in a semi-structured, one-to-one qualitative interviews that asked about their knowledge of social prescribing, the advantages of community pharmacist involvement and any barriers they predicted to its implementation. Interviews were transcribed verbatim and thematically analysed. Results: The sample included largely male pharmacists (63.3%) with less than five years’ experience (45.5%) and included pharmacists working as employees (63.6%), locums (27.3%) and owners (9%) in both chain (36%) and independent stores (54.5%). The main findings indicate an enthusiasm for but limited understanding of social prescribing. Factors which appeared to influence involvement were training requirements and time available to complete an additional service in busy pharmacies. Opportunities centred on the broader pharmacy team’s role to optimise health outcomes. Conclusions: The findings indicate pharmacists may be an underused resource due to a poor understanding of the full scale and scope of social prescribing beyond health promotion, lifestyle interventions. Further work is needed to explore the transferability of the findings to the broader pharmacy workforce to understand how social prescribing can be positioned within pharmacy practice

Identifying businesses and entrepreneurs in the Censuses 1851-1881

This paper describes how individual entrepreneurs can be identified and extracted from the original Census Enumerators Books (CEBs) for 1851-81. It describes the early censuses and the method through which different groups of entrepreneurs can be identified, extracted and parsed, particularly focusing on identifying employee numbers of the businesses. It distinguishes between: employers with employees; own account proprietors; and people owning certain business assets. Constraints in the data are summarized and how information was infilled from other sources to correct for the substantial gaps and truncations in the I-CeM electronic records of the census, especially for 1851, 1861 and 1871

Business sectors, occupations and aggregations of census data 1851-1911

This paper discusses alternative aggregations that can be used to code business sectors using the census information on different occupations and employment status categories of entrepreneurs and workers. The paper discusses how sector aggregations can be constructed that classify business proprietors by the type of economic activity in which they were engaged, and also the sector of activity for those that were clearly not entrepreneurs. It defines two classifications at two levels of aggregation that are used in subsequent analysis: ID18 and ID50 used for sector/entrepreneurship coding; and EA17 and EA51 used for sector/whole economically active coding. It compares this coding with the more detailed coding in I-CeM, that used for the PST occupational classification system devised by Wrigley, and with the codes used in modern mainstream industrial classifications of sectors and occupational groups

Sweet Syndrome due to Myelodysplastic Syndrome: Possible Therapeutic Role of Intravenous Immunoglobulin in Addition to Standard Treatment

We report an 82-year-old lady who developed sudden onset nodular and erythematous lesions and neutrophilia following an episode of urinary tract infection. Skin biopsy confirmed the diagnosis of Sweet syndrome. Response to the use of prednisolone alone was not satisfactory. The skin lesions however showed a sustained response to the regular use of intravenous immunoglobulin (IVIG) and prednisolone was slowly weaned off. Our case highlights the possible therapeutic role of IVIG in managing this condition

Drivers of Entrepreneurship and Small Businesses: Project overview and database design

The census 1851-1911 provides a resource of information on employers and small firms that allows 200,000 – 2m individual entrepreneurs per year to be identified and the population of businesses to be estimated. This information has not been previous systematically available or researched. This paper outlines how information can be extracted from the population census, the way in which gaps and truncations in the I-CeM electronic records of the census of businesses can be overcome, and how the data can be enriched. The paper outlines how entrepreneurship is defined from the census and other records, how entrepreneurship rates can be calculated, and how database has been created that is as complete and consistent as possible to be deposited at UKDA

Morphology of the medial collateral ligament of the knee

<p>Abstract</p> <p>Background</p> <p>Quantitative knowledge on the anatomy of the medial collateral ligament (MCL) is important for treatment of MCL injury and for MCL release during total knee arthroplasty (TKA). The objective of this study was to quantitatively determine the morphology of the MCL of human knees.</p> <p>Methods</p> <p>10 cadaveric human knees were dissected to investigate the MCL anatomy. The specimens were fixed in full extension and this position was maintained during the dissection and morphometric measurements. The outlines of the insertion sites of the superficial MCL (sMCL) and deep MCL (dMCL) were digitized using a 3D digitizing system.</p> <p>Results</p> <p>The insertion areas of the superficial MCL (sMCL) were 348.6 ± 42.8 mm²and 79.7 ± 17.6 mm²on the tibia and femur, respectively. The insertion areas of the deep MCL (dMCL) were 63.6 ± 13.4 mm²and 71.9 ± 14.8 mm²on the tibia and femur, respectively. The distances from the centroids of the tibial and femoral insertions of the sMCL to the tibial and femoral joint line were 62.4 ± 5.5 mm and 31.1 ± 4.6 mm, respectively. The distances from the centroids of dMCL in the tibial insertion and the femoral insertion to the tibial and femoral joint line were 6.5 ± 1.3 mm and 20.5 ± 4.2 mm, respectively. The distal portion of the dMCL (meniscotibial ligament - MTL) was approximately 1.7 times wider than the proximal portion of the dMCL (meniscofemoral ligament - MFL), whereas the MFL was approximately 3 times longer than the MTL.</p> <p>Conclusions</p> <p>The morphologic data on the MCL may provide useful information for improving treatments of MCL-related pathology and performing MCL release during TKA.</p