Genetic Variant in HK1 Is Associated With a Proanemic State and A1C but Not Other Glycemic Control–Related Traits

OBJECTIVE A1C is widely considered the gold standard for monitoring effective blood glucose levels. Recently, a genome-wide association study reported an association between A1C and rs7072268 within HK1 (encoding hexokinase 1), which catalyzes the first step of glycolysis. HK1 deficiency in erythrocytes (red blood cells [RBCs]) causes severe nonspherocytic hemolytic anemia in both humans and mice. RESEARCH DESIGN AND METHODS The contribution of rs7072268 to A1C and the RBC-related traits was assessed in 6,953 nondiabetic European participants. We additionally analyzed the association with hematologic traits in 5,229 nondiabetic European individuals (in whom A1C was not measured) and 1,924 diabetic patients. Glucose control–related markers other than A1C were analyzed in 18,694 nondiabetic European individuals. A type 2 diabetes case-control study included 7,447 French diabetic patients. RESULTS Our study confirms a strong association between the rs7072268–T allele and increased A1C (β = 0.029%; P = 2.22 × 10−7). Surprisingly, despite adequate study power, rs7072268 showed no association with any other markers of glucose control (fasting- and 2-h post-OGTT–related parameters, n = 18,694). In contrast, rs7072268–T allele decreases hemoglobin levels (n = 13,416; β = −0.054 g/dl; P = 3.74 × 10−6) and hematocrit (n = 11,492; β = −0.13%; P = 2.26 × 10−4), suggesting a proanemic effect. The T allele also increases risk for anemia (836 cases; odds ratio 1.13; P = 0.018). CONCLUSIONS HK1 variation, although strongly associated with A1C, does not seem to be involved in blood glucose control. Since HK1 rs7072268 is associated with reduced hemoglobin levels and favors anemia, we propose that HK1 may influence A1C levels through its anemic effect or its effect on glucose metabolism in RBCs. These findings may have implications for type 2 diabetes diagnosis and clinical management because anemia is a frequent complication of the diabetes state

A multi-layered view of chemical and biochemical engineering

The contents of this article are based on the results of discussions the corresponding author has had since 2015 with the co-authors, who are members of academia and industry in Europe, on the scope and significance of chemical and biochemical engineering as a discipline. The result is a multi-layered view of chemical and biochemical engineering where the inner-layer deals with the fundamental principles and their application; the middle-layer deals with consolidation and expansion of the principles through a combination of science and engineering, leading to the development of sustainable technologies; and the outer-layer deals with integration of knowledge and collaboration with other disciplines to achieve a more sustainable society. Through this multi-layered view several important issues with respect to education, research and practice are highlighted together with current and future challenges and opportunities

Pathogenic Bacteria Target NEDD8-Conjugated Cullins to Hijack Host-Cell Signaling Pathways

The cycle inhibiting factors (Cif), produced by pathogenic bacteria isolated from vertebrates and invertebrates, belong to a family of molecules called cyclomodulins that interfere with the eukaryotic cell cycle. Cif blocks the cell cycle at both the G1/S and G2/M transitions by inducing the stabilization of cyclin-dependent kinase inhibitors p21waf1 and p27kip1. Using yeast two-hybrid screens, we identified the ubiquitin-like protein NEDD8 as a target of Cif. Cif co-compartmentalized with NEDD8 in the host cell nucleus and induced accumulation of NEDD8-conjugated cullins. This accumulation occurred early after cell infection and correlated with that of p21 and p27. Co-immunoprecipitation revealed that Cif interacted with cullin-RING ubiquitin ligase complexes (CRLs) through binding with the neddylated forms of cullins 1, 2, 3, 4A and 4B subunits of CRL. Using an in vitro ubiquitylation assay, we demonstrate that Cif directly inhibits the neddylated CUL1-associated ubiquitin ligase activity. Consistent with this inhibition and the interaction of Cif with several neddylated cullins, we further observed that Cif modulates the cellular half-lives of various CRL targets, which might contribute to the pathogenic potential of diverse bacteria

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

The Future of Chemical Engineering: Did You Say The Triplet 'Processus-Product-Process' Engineering?

One key to survival in globalization of trade and competition, including needs and challenges, is the ability of chemical engineering to cope with the society and economic problems encountered in the chemical and related process industries. It appears that the necessary progress will be achieved via a multidisciplinary and time and length multiscale integrated approach to satisfy both the market requirements for specific end-use properties and the environmental and society constraints of the industrial processes and the associated services. This concerns four main objectives for engineers and researchers: (a) total multiscale control of the process (or procedure) to increase selectivity and productivity, (b) design of novel equipment based on scientific principles and new methods of production: process intensification, (c) manufacturing end-use properties for product design: the triplet 'processus-product-process' engineering, (d) implementation of multiscale application of computational modeling and simulation to real-life situations: from the molecular scale to the overall complex production scale

In the Framework of Global Trade, Sustainability and Industry Demand for Innovative Process and Technologies, what kind of Modern “Green” Chemical Engineering is Required for the Design of “the Factory of the Future”?

 The chemical, petroleum, gas, energy and related industries are today confronted with the globalization of the markets, acceleration of partnerships and demand for innovative process and technologies for economic growth, and they are required to offer a contribution to the fight against environmental destruction and not always sustainable behavior of the today world production. This militates for the evolution of chemical engineering in favor of a modern green process engineering voluntarily concerned by sustainability that will face new challenges and stakes bearing on complex length and time multiscale systems at the molecular scale, at the product scale and at the process scale. Indeed, the existing and the future industry processes are progressively adapted to the principles of the « green (bio) chemistry ». This involves a modern approach of chemical engineering that satisfies both the market requirements for specific nano and microscale end-use properties of competitive targeted green (sustainable) products, and the social and environmental constraints of sustainable industrial meso and macroscale production processes at the scales of the units and sites of production. These multiscale constraints require an integrated system approach of complex multidisciplinary, non-linear, non equilibrium processes and transport phenomena occurring on the different time and length scales of the chemical supply chain. This means a good understanding of how phenomena at a smaller length-scale relates to properties and behavior at a longer length-scale, from the molecular and active aggregates-scales up to the production-scales (i.e. the design of a refinery from the Schrödinger’s equations...). It will be seen that the success of this integrated multiscale approach for process innovation (the 3rd paradigm of chemical engineering) is mainly due to the considerable developments in the analytical scientific techniques coupled with image processing, in the powerful computational tools and capabilities (clusters, supercomputers, cloud computers, graphic processing units, numerical codes parallelization etc.) and in the development and application of descriptive models of steady state and dynamic behavior of the objects at the scale of interest. This modern scientific multiscale approach of chemical engineering « the green approach of process engineering » that combines both market pull and technology push is strongly oriented on process intensification and on the couple green products/green processes “to produce much more and better in using much less”, i.e. to sustainabily produce molecules and products responding to environmental and economic challenges. It will be pointed out that process intensification due to innovative continuous flow process processes (novel process windows) and innovative technologies and new equipment construction technologies (additive manufacturing) will contribute to the design of the eco-efficient “factory of the future ”:i.e. a plant in a shoe box for polymer production or in a mobile banana container platform for small-scale production of specialty chemicals, or more generally modular plants leading to flexible chemical production by modularization and standardization in the pharmaceutical and specialty chemical industries and in a great number of other fields such as materials, petroleum and gas, water treatment and desalination and environmental management, among others

Did you Ask for the Importance of Investigations Concerning the Chain of a Sustainable Petroleum and Oil Exploration, Production, Flow, and Fast Optimal Refining Technology?

EDITORIA