Additive Manufacturing In-situ and Ex-Situ Geometric Data Registration.

Recently, The number and types of measurement devices that collect data that is used to monitor Laser-Based Powder Bed Fusion of Metals processes and inspect Additive Manufacturing (AM) metal parts have increased rapidly. Each measurement device generates data in a unique coordinate system and in a unique format. Data alignment is the process of spatially aligning different datasets to a single coordinate system. It is part of a broader process called "Data Registration". This paper provides a data-registration procedure and includes an example of aligning data to a single, reference, coordinate system. Such a reference coordinate system is needed for downstream applications, including data analytic, artificial intelligence, and part qualification.

Emerging Therapeutic Strategies to Restore Regulatory T Cell Control of Islet Autoimmunity in Type 1 Diabetes.

Despite many decades of investigation uncovering the autoimmune mechanisms underlying Type 1 Diabetes (T1D), translating these findings into effective therapeutics has proven extremely challenging. T1D is caused by autoreactive T cells that become inappropriately activated and kill the ß cells in the pancreas, resulting in insulin insufficiency and hyperglycemia. A large body of evidence supports the idea that the unchecked activation and expansion of autoreactive T cells in T1D is due to defects in immunosuppressive regulatory T cells (Tregs) that are critical for maintaining peripheral tolerance to islet autoantigens. Hence, repairing these Treg deficiencies is a much sought-after strategy to treat the disease. To accomplish this goal in the most precise, effective and safest way possible, restored Treg functions will need to be targeted towards suppressing the autoantigen-specific immune responses only and/or be localized in the pancreas. Here we review the most recent developments in designing Treg therapies that go beyond broad activation or expansion of non-specific polyclonal Treg populations. We focus on two cutting-edge strategies namely ex vivo generation of optimized Tregs for re-introduction in T1D patients vs direct in situ stimulation and restoration of endogenous Treg function.

Standard Connections for IIoT Empowered Smart Manufacturing.

The use of Industrial Internet-of-Things (IIoT) and related technology is propelling manufacturing into a new era in the fourth industry revolution characterized by ubiquitous connectivity. IIoT allows new and unprecedented interactions amongst hardware, software, and humans. Adopting the capability of IIoT with artificial intelligence tools, manufacturing systems become smart - with unprecedented gains in production agility, quality, and efficiency. One of the key enablers of the IIoT empowered smart manufacturing is connectivity and integration standards. In this paper we review the current IIoT standards used in manufacturing, present a new IIoT standards landscape for the smart manufacturing paradigm, and describe some of IIoT standards gaps.

Fatty Acid Metabolites Combine with Reduced ß Oxidation to Activate Th17 Inflammation in Human Type 2 Diabetes.

Mechanisms that regulate metabolites and downstream energy generation are key determinants of T cell cytokine production, but the processes underlying the Th17 profile that predicts the metabolic status of people with obesity are untested. Th17 function requires fatty acid uptake, and our new data show that blockade of CPT1A inhibits Th17-associated cytokine production by cells from people with type 2 diabetes (T2D). A low CACT:CPT1A ratio in immune cells from T2D subjects indicates altered mitochondrial function and coincides with the preference of these cells to generate ATP through glycolysis rather than fatty acid oxidation. However, glycolysis was not critical for Th17 cytokines. Instead, ß oxidation blockade or CACT knockdown in T cells from lean subjects to mimic characteristics of T2D causes cells to utilize 16C-fatty acylcarnitine to support Th17 cytokines. These data show long-chain acylcarnitine combines with compromised ß oxidation to promote disease-predictive inflammation in human T2D.

Categorical models for process planning.

Process plans provide a structure for 1) identifying the tasks involved in a given process, 2) the resources needed to accomplish them, and 3) a variety of relationships and constraints between these. This information guides important operational decisions across various organizational levels, from the factory floor to the global supply chain. Efficient use of this information requires a concrete analytical model that can be easily represented in digital form. In this paper we present a modeling framework for process plans based on a branch of mathematics called category theory (CT). Specifically, string diagrams provide an intuitive yet precise graphical syntax for describing symmetric monoidal categories (SMCs), mathematical structures which support serial and parallel composition. Ideal for process representation, these structures also support a powerful mathematical toolkit. Here we use these tools to analyze the relationship between different levels of abstraction in process planning hierarchy. Our goal in this paper is to provide a precise mathematical account of similarities across levels of process hierarchy; to relate high-level axiomatization of the relationships across levels and to provide sound theoretical foundations for manipulations across levels.

Type 1 diabetes alters lipid handling and metabolism in human fibroblasts and peripheral blood mononuclear cells.

Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca2+ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis factor α (TNFα). These data indicate that metabolic and signal transduction defects present in T1D can be elicited ex vivo in isolated cells. Changes that precede T1D, including inflammation, may activate atypical responses in people that are genetically predisposed to T1D. To identify such cellular differences in T1D, we quantified a panel of metabolic responses in fibroblasts and peripheral blood cells (PBMCs) from age-matched T1D and non-T1D subjects, as models for non-immune and immune cells, respectively. Fibroblasts from T1D subjects accumulated more lipid, had higher LC-CoA levels and converted more FA to CO2, with less mitochondrial proton leak in response to oleate alone or with TNFα, using the latter as a model of inflammation. T1D-PBMCs contained and also accumulated more lipid following FA exposure. In addition, they formed more peroxidized lipid than controls following FA exposure. We conclude that both immune and non-immune cells in T1D subjects differ from controls in terms of responses to FA and TNFα. Our results suggest a differential sensitivity to inflammatory insults and FA that may precede and contribute to T1D by priming both immune cells and their targets for autoimmune reactions.

Extracellular Redox Regulation of Intracellular Reactive Oxygen Generation, Mitochondrial Function and Lipid Turnover in Cultured Human Adipocytes.

BACKGROUND: Many tissues play an important role in metabolic homeostasis and the development of diabetes and obesity. We hypothesized that the circulating redox metabolome is a master metabolic regulatory system that impacts all organs and modulates reactive oxygen species (ROS) production, lipid peroxidation, energy production and changes in lipid turnover in many cells including adipocytes. METHODS: Differentiated human preadipocytes were exposed to the redox couples, lactate (L) and pyruvate (P), ß-hydroxybutyrate (ßOHB) and acetoacetate (Acoc), and the thiol-disulfides cysteine/ cystine (Cys/CySS) and GSH/GSSG for 1.5-4 hours. ROS measurements were done with CM-H2DCFDA. Lipid peroxidation (LPO) was assessed by a modification of the thiobarbituric acid method. Lipolysis was measured as glycerol release. Lipid synthesis was measured as 14C-glucose incorporated into lipid. Respiration was assessed using the SeaHorse XF24 analyzer and the proton leak was determined from the difference in respiration with oligomycin and antimycin A. RESULTS: Metabolites with increasing oxidation potentials (GSSG, CySS, Acoc) increased adipocyte ROS. In contrast, P caused a decrease in ROS compared with L. Acoc also induced a significant increase in both LPO and lipid synthesis. L and Acoc increased lipolysis. ßOHB increased respiration, mainly due to an increased proton leak. GSSG, when present throughout 14 days of differentiation significantly increased fat accumulation, but not when added later. CONCLUSIONS: We demonstrated that in human adipocytes changes in the external redox state impacted ROS production, LPO, energy efficiency, lipid handling, and differentiation. A more oxidized state generally led to increased ROS, LPO and lipid turnover and more reduction led to increased respiration and a proton leak. However, not all of the redox couples were the same suggesting compartmentalization. These data are consistent with the concept of the circulating redox metabolome as a master metabolic regulatory system.

Inborn Errors of Long-Chain Fatty Acid ß-Oxidation Link Neural Stem Cell Self-Renewal to Autism.

Inborn errors of metabolism (IEMs) occur with high incidence in human populations. Especially prevalent among these are inborn deficiencies in fatty acid ß-oxidation (FAO), which are clinically associated with developmental neuropsychiatric disorders, including autism. We now report that neural stem cell (NSC)-autonomous insufficiencies in the activity of TMLHE (an autism risk factor that supports long-chain FAO by catalyzing carnitine biosynthesis), of CPT1A (an enzyme required for long-chain FAO transport into mitochondria), or of fatty acid mobilization from lipid droplets reduced NSC pools in the mouse embryonic neocortex. Lineage tracing experiments demonstrated that reduced flux through the FAO pathway potentiated NSC symmetric differentiating divisions at the expense of self-renewing stem cell division modes. The collective data reveal a key role for FAO in controlling NSC-to-IPC transition in the mammalian embryonic brain and suggest NSC self renewal as a cellular mechanism underlying the association between IEMs and autism.

Implementing the ISO 15746 Standard for Chemical Process Optimization.

This paper proposes an approach to integrating advanced process control solutions with optimization (APC-O) solutions, within any factory, to enable more efficient production processes. Currently, vendors who provide the software applications that implement control solutions are isolated and relatively independent. Each such solution is designed to implement a specific task such as control, simulation, and optimization - and only that task. It is not uncommon for vendors to use different mathematical formalisms and modeling tools that produce different data representations and formats. Moreover, instead of being modeled uniformly only once, the same knowledge is often modeled multiple times - each time using a different, specialized abstraction. As a result, it is extremely difficult to integrate optimization with advanced process control. We believe that a recent standard, International Organization for Standardization (ISO) 15746, describes a data model that can facilitate that integration. In this paper, we demonstrate a novel method of integrating advanced process control using ISO 15746 with numerical optimization. The demonstration is based on a chemical-process-optimization problem, which resides at level 2 of the International Society of Automation (ISA) 95 architecture. The inputs to that optimization problem, which are captured in the ISO 15746 data model, come in two forms: goals from level 3 and feedback from level 1. We map these inputs, using this data model, to a population of a meta-model of the optimization problem for a chemical process. Serialization of the metamodel population provides input to a numerical optimization code of the optimization problem. The results of this integrated process, which is automated, provide the solution to the originally selected, level 2 optimization problem.

Fibroblasts from type 1 diabetics exhibit enhanced Ca(2+) mobilization after TNF or fat exposure.

The effects of cytokine and fatty acid treatment on signal transduction in dermal fibroblasts from type 1 diabetics and matched controls were compared. Chronic exposure to TNF, accentuated Ca(2+) mobilization in response to bradykinin (BK) in cells from both controls and diabetics; responses were three-fold greater in cells from diabetics than in controls. Similarly, with chronic exposure to IL-1ß, BK-induced Ca(2+) mobilization was accentuated in cells from type 1 diabetics compared to the controls. Pretreatment with the protein synthesis inhibitor cycloheximide or the protein kinase C inhibitor calphostin C prior to the addition of TNF completely abrogated the TNF-induced increment in peak bradykinin response. Ca(2+) transients induced by depleting endoplasmic reticulum (ER) Ca(2+) with thapsigargin were also greater in TNF treated fibroblasts than in untreated cells, with greater increases in cells from diabetics. Exposing fibroblasts for 48 hours to 2 mM oleate also increased both the peak bradykinin response and the TNF-induced increment in peak response, which were significantly greater in diabetics than controls. These data indicate that cells from diabetic patients acquire elevated ER Ca(2+) stores in response to both cytokines and free fatty acids,and thus exhibit greater sensitivity to environmental inflammatory stimuli and elevated lipids.

The Newfoundland population: a unique resource for genetic investigation of complex diseases.

The population of the province of Newfoundland and Labrador is genetically isolated. This isolation is evidenced by an overabundance of several monogenic disorders. The Newfoundland population, like that of other isolates, is now the focus of interest for identification of genes implicated in common diseases. However, the utility of such populations for this purpose remains unproven. In this paper, we review the current genetic architecture of the province, with respect to geographic isolation, homogeneity, founder effect, genetic drift and extended linkage disequilibrium. Based on these factors, we propose that the population of Newfoundland offers many advantages for genetic mapping of common diseases, compared with admixed populations, and even compared with other isolates.

Public sector health insurance trusts.

Public sector associations have successfully developed and run employee health insurance pools for almost 30 years, providing members with savings and flexibility not available from commercial health insurance carriers. This article looks at the models, technical tools and governance philosophy that have contributed to their success in a very challenging business environment.