SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout

Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.     

A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse

In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Here we show that the Gray phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (syntaxin-17) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 gene are overexpressed in melanomas from Gray horses. Gray horses carrying a loss-of-function mutation in ASIP (agouti signaling protein) had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in Gray horses. The Gray horse provides a notable example of how humans have cherry-picked mutations with favorable phenotypic effects in domestic animals.     

A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration

Epithelial organs, including the lung, are known to possess regenerative abilities through activation of endogenous stem cell populations, but the molecular pathways regulating stem cell expansion and regeneration are not well understood. Here we show that Gata6 regulates the temporal appearance and number of bronchioalveolar stem cells (BASCs) in the lung, its absence in Gata6-null lung epithelium leading to the precocious appearance of BASCs and concurrent loss in epithelial differentiation. This expansion of BASCs was the result of a pronounced increase in canonical Wnt signaling in lung epithelium upon loss of Gata6. Expression of the noncanonical Wnt receptor Fzd2 was downregulated in Gata6 mutants and increased Fzd2 or decreased beta-catenin expression rescued, in part, the lung epithelial defects in Gata6 mutants. During lung epithelial regeneration, canonical Wnt signaling was activated in the niche containing BASCs and forced activation of Wnt signaling led to a large increase in BASC numbers. Moreover, Gata6 was required for proper lung epithelial regeneration, and postnatal loss of Gata6 led to increased BASC expansion and decreased differentiation. Together, these data demonstrate that Gata6-regulated Wnt signaling controls the balance between progenitor expansion and epithelial differentiation required for both lung development and regeneration.     

Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis

We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 x 10(-8) in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18-1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies.     

A partial robust optimization approach to inventory management for the offline-to-online problem under different selling prices

This study examines an optimal inventory strategy when a retailer markets a product at different selling prices through a dual-channel supply chain, comprising an online channel and an offline channel. Using the operating pattern of the offline-to-online (O2O) business model, we develop a partial robust optimization (PRO) model. Then, we provide a closed-form solution when only the mean and standard deviation of the online channel demand distribution is known and the offline channel demand follows a uniform distribution (partial robust). Specifically, owing to the good structural properties of the solution, we obtain a heuristic ordering formula for the general distribution case (i.e., the offline channel demand follows a general distribution). In addition, a series of numerical experiments prove the rationality of our conjecture. Moreover, after comparing our solution with other possible policies, we conclude that the PRO approach improves the performance of incorporating the internet into an existing supply chain and, thus, is able to adjust the level of conservativeness of the solution. Finally, in a degenerated situation, we compare our PRO approach with a combination of information approach. The results show that the PRO approach has more “robust” performance. As a result, a reasonable trade-off between robustness and performance is achieved.     

Systemic Development of Leadership: Action Research in an Indian Manufacturing Organization

This insider action research study differentiates between developing leaders and leadership, evolves a systemic leadership model, and intervenes on the human, social and processes dimensions for developing leadership. This is a real-time study and responds to the organizational reality of fast pace of change and its systemic nature. Consequently, the research too is fast to guide actions and influence positive changes in the organization. As the action research addresses a systemic reality, research and contributions are in multiple aspects, with new techniques having huge implications for theory building as well as improving practice. The study provides a structural solution to perceived lack of commitment in senior colleagues—a syndrome I acronym as HILE (High Intentions and Lukewarm Execution)–by re-designing organizational processes and making time available for its effective utilization in developing leadership. A new technique of triggering major changes in organizations termed “concept sublimation” distils concept from the statements of major stakeholder and sublimates it from lower to higher unit of analysis and to higher levels of positivity. Statistical simplification of a competency framework by applying concepts from Euclidian geometry and making it effective is yet a unique contribution of this action research study. The study adapts the competing values framework in developing a method of assessing cultural congruence of a candidate with the culture of the organization. The uniqueness of the study lies in bridging the gap in the literature by actually and systemically developing leadership in an organization and providing pragmatic insights on developing leadership while also creating knowledge for theory building.     

Operationalising “Double-Loop” Learning in Service Organisations: A Systems Approach for Creating Knowledge

Learning organisation literature has widely discussed the connections between “double-loop” learning and its significance to organisational performance, but paying little attention to tools and systems that can operationalise “double-loop” learning in organisations. This paper investigates the impact of applying a systems approach for service operations design, expressed as the Vanguard Method (Seddon, Freedom from command and control: a better way to make the work work, 2003), in order to activate “double-loop” learning in service organisations. Two case studies were conducted in the banking mortgage operations and adults’ social care services in the UK, using the dimensions of the learning organisation questionnaire (DLOQ), semi-structured interviews, observations, and documents. The findings of the cross-case analysis support the link of applying the Vanguard Method with operationalising “double-loop” learning through three main factors, namely systematic-operations improvement, organisational capacity development, and outside-in mode of work; that are all embedded into the seven dimensions of the DLOQ. The value of this paper is the introduction of a service operations design tool that can activate “double-loop” learning performance in the fast changing knowledge era. It also provides an impetus for service organisations to creatively influence employees’ competencies to effectively improve internal systems.