Designing a robust production system for erratic demand environments.

Production systems must have the right type of material in the right quantities when required for production. They must minimize the work in progress while ensuring no stock-outstock-out occurs. While these twin opposing goals are achievable when demand is stable, they are difficult to realize under an erratic demand pattern. This dissertation aims to develop a production system that can meet erratic demands with minimal costs or errors. After a detailed introduction to the problem considered, we review the relevant literature. We then conduct a numerical analysis of current production systems, identify their deficiencies, and then present our solution to address these deficiencies via the ARK (Automated Replenishment System) technique. This technique is applied to a real-world problem at Methode Engineering ©. We conclude by detailing the scientific benefit of our technique and proposing ideas for future research

Microglial Scavenger Receptors and Their Roles in the Pathogenesis of Alzheimer's Disease

Alzheimer's disease (AD) is increasing in prevalence with the aging population. Deposition of amyloid-β (Aβ) in the brain of AD patients is a hallmark of the disease and is associated with increased microglial numbers and activation state. The interaction of microglia with Aβ appears to play a dichotomous role in AD pathogenesis. On one hand, microglia can phagocytose and clear Aβ, but binding of microglia to Aβ also increases their ability to produce inflammatory cytokines, chemokines, and neurotoxic reactive oxygen species (ROS). Scavenger receptors, a group of evolutionally conserved proteins expressed on the surface of microglia act as receptors for Aβ. Of particular interest are SCARA-1 (scavenger receptor A-1), CD36, and RAGE (receptor for advanced glycation end products). SCARA-1 appears to be involved in the clearance of Aβ, while CD36 and RAGE are involved in activation of microglia by Aβ. In this review, we discuss the roles of various scavenger receptors in the interaction of microglia with Aβ and propose that these receptors play complementary, nonredundant functions in the development of AD pathology. We also discuss potential therapeutic applications for these receptors in AD

Fibrils from Designed Non-Amyloid-Related Synthetic Peptides Induce AA-Amyloidosis during Inflammation in an Animal Model

Background: Mouse AA-amyloidosis is a transmissible disease by a prion-like mechanism where amyloid fibrils act by seeding. Synthetic peptides with no amyloid relationship can assemble into amyloid-like fibrils and these may have seeding capacity for amyloid proteins. Principal Findings: Several synthetic peptides, designed for nanotechnology, have been examined for their ability to produce fibrils with Congo red affinity and concomitant green birefringence, affinity for thioflavin S and to accelerate AAamyloidosis in mice. It is shown that some amphiphilic fibril-forming peptides not only produced Congo red birefringence and showed affinity for thioflavin S, but they also shortened the lag phase for systemic AA-amyloidosis in mice when they were given intravenously at the time of inflammatory induction with silver nitride. Peptides, not forming amyloid-like fibrils, did not have such properties. Conclusions: These observations should caution researchers and those who work with synthetic peptides and thei

Combining several thermal indices to generate a unique heat comfort assessment methodology

Purpose: The proposed methodology hopes to provide a systematic multi-disciplinary approach to assess the thermal environment while minimizing unneeded efforts. Design/methodology/approach: Different factors affect the perception of the human thermal experience: metabolic rate (biology), surrounding temperatures (heat balance and environmental factors) and cognitive treatment (physiology).This paper proposes a combination of different multidisciplinary variables to generate a unique heat comfort assessment methodology. The variables at stake are physiological, biological, and environmental. Our own heat analysis is thoroughly presented and all relevant equations are described. Findings: Most companies are oblivious about potential dangers of heat stress accidents and thus about methods to monitor and prevent them. This methodology enables the company or the concerned individual to conduct a preliminary assessment with minimal wasted resources and time in unnecessary steps whilst providing a guideline for a detailed study with minimal error rates if needed. More so, thermal comfort is an integral part of sound ergonomics practices, which in turn are decisive for the success of any lean six sigma initiative. Research limitations/implications: This methodology requires several full implementations to finalize its design. Originality/value: Most used heat comfort models are inherently uncertain and tiresome to apply. An extensive literature review confirms the need for a uniform assessment methodology that combines the different thermal comfort models such as the Fanger comfort model (PMV, PPD) and WGBT since high error rates coupled with tiresome calculations often hinder the thermal assessment process.Peer Reviewe

Experimental Diabetes Mellitus Exacerbates Tau Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Diabetes mellitus (DM) is characterized by hyperglycemia caused by a lack of insulin, insulin resistance, or both. There is increasing evidence that insulin also plays a role in Alzheimer's disease (AD) as it is involved in the metabolism of β-amyloid (Aβ) and tau, two proteins that form Aβ plaques and neurofibrillary tangles (NFTs), respectively, the hallmark lesions in AD. Here, we examined the effects of experimental DM on a pre-existing tau pathology in the pR5 transgenic mouse strain that is characterized by NFTs. pR5 mice express P301L mutant human tau that is associated with dementia. Experimental DM was induced by administration of streptozotocin (STZ), which causes insulin deficiency. We determined phosphorylation of tau, using immunohistochemistry and Western blotting. Solubility of tau was determined upon extraction with sarkosyl and formic acid, and Gallyas silver staining was employed to reveal NFTs. Insulin depletion by STZ administration in six months-old non-transgenic mice causes increased tau phosphorylation, without its deposition or NFT formation. In contrast, in pR5 mice this results in massive deposition of hyperphosphorylated, insoluble tau. Furthermore, they develop a pronounced tau-histopathology, including NFTs at this early age, while the pathology in sham-treated pR5 mice is moderate. Whereas experimental DM did not result in deposition of hyperphosphorylated tau in non-transgenic mice, a predisposition to develop a tau pathology in young pR5 mice was both sufficient and necessary to exacerbate tau deposition and NFT formation. Hence, DM can accelerate onset and increase severity of disease in individuals with a predisposition to developing tau pathology

Probing Vibrationally Mediated Ultrafast Excited-state Reaction Dynamics With Multireference (caspt2) Trajectories

Excited-state trajectories computed at the complete active space second-order perturbation theory (CASPT2) reveal how vibrational excitation controls the molecular approach to the intersection space that drives the photodissociation of a prototypical halogenated methyl radical, namely CF2I. Translating the Franck-Condon structure along the ground-state CASPT2 vibrational modes in this system followed by propagating the displaced structures in the first excited doublet state simulates specific vibrational excitations and vibrationally mediated dynamics, respectively. Three distinct situations are encountered: the trajectories (i) converge to an energetically flat segment of the intersection space, (ii) locate a segment of the intersection space, and (iii) access a region where the intersection space degeneracy is lifted to form a ridge of avoided crossings. The computational protocol documented herein can be used as a tool to design control strategies based on selective excitation of vibrational modes, including adaptive feedback schemes using coherent light sources

Roles of Microglial and Monocyte Chemokines and Their Receptors in Regulating Alzheimer's Disease-Associated Amyloid-β and Tau Pathologies

Chemokines and their receptors have been shown to affect amyloid-β (Aβ) and tau pathologies in mouse models of Alzheimer's disease (AD) by regulating microglia and monocyte-associated neuroinflammation, microglial movement and monocyte recruitment into the brain. These cells in turn can promote and mediate Aβ phagocytosis and degradation and tau phosphorylation. In this review we discuss published work in this field in mouse models of AD and review what is known about the contributions of microglial and monocyte chemokines and their receptors to amyloid and tau pathologies. We focus on the roles of the chemokine/chemokine receptor pairs CCL2/CCR2, CX3CL1/CX3CR1, CCL5/CCR5, CXCL10/CXCR3 and CXCL1/CXCR2, highlighting important knowledge gaps in this field. A full understanding of the functions of chemokines and their receptors in AD may guide the development of novel immunotherapies for this devastating disease