Limiting optimal discounted-cost control of a class of time-varying stochastic systems

We consider a class of time-varying -valued control models, and with possibly unbounded costs. The processes evolve according to the system equation x_n+1=G_n(x_n,a_n)+ξ_n ( ), where {ξ_n} are i.i.d. random vectors and {G_n} a sequence of known functions converging to some function G_∞. Under suitable hypotheses, we show the existence of an α-discount optimal policy for the limiting system x_n+1=G_∞(x_n,a_n)+ξ_n.     

Nanoparticle‐embedded polymer‐dispersed liquid crystal for paper‐like displays

Abstract— A polymer‐dispersed liquid‐crystal (PDLC) matrix template embedded with nano/microparticles can be backfilled/infiltrated with a dye‐doped liquid crystal for a paper‐like reflective display. In this way, a desirable degree of diffusion can be realized to reduce the viewing‐angle dependency of a gain reflector and metallic glare without changing other electro‐optical properties.     

Flight deck disturbance management: a simulator study of diagnosis and recovery from breakdowns in pilot-automation coordination

OBJECTIVE: To examine operator strategies for diagnosing and recovering from errors and disturbances as well as the impact of automation design and time pressure on these processes. BACKGROUND: Considerable efforts have been directed at error prevention through training and design. However, because errors cannot be eliminated completely, their detection, diagnosis, and recovery must also be supported. Research has focused almost exclusively on error detection. Little is known about error diagnosis and recovery, especially in the context of event-driven tasks and domains. METHOD: With a confederate pilot, 12 airline pilots flew a 1-hr simulator scenario that involved three challenging automation-related tasks and events that were likely to produce erroneous actions or assessments. Behavioral data were compared with a canonical path to examine pilots' error and disturbance management strategies. Debriefings were conducted to probe pilots' system knowledge. RESULTS: Pilots seldom followed the canonical path to cope with the scenario events. Detection of a disturbance was often delayed. Diagnostic episodes were rare because of pilots' knowledge gaps and time criticality. In many cases, generic inefficient recovery strategies were observed, and pilots relied on high levels of automation to manage the consequences of an error. CONCLUSION: Our findings describe and explain the nature and shortcomings of pilots' error management activities. They highlight the need for improved automation training and design to achieve more timely detection, accurate explanation, and effective recovery from errors and disturbances. APPLICATION: Our findings can inform the design of tools and techniques that support disturbance management in various complex, event-driven environments.     

Stability ball versus office chair: comparison of muscle activation and lumbar spine posture during prolonged sitting

OBJECTIVE: The objective of the study was to evaluate the differences between sitting on a stability ball and in an office chair in terms of trunk muscle activation and lumbar spine posture. BACKGROUND: Stability balls have become increasingly popular as an alternative to office chairs to help reduce the prevalence of low back pain; however, little research has been conducted on their use as office chairs. METHODS: The 14 participants (7 men, 7 women) were required to sit on both a stability ball and an office chair for 1 hour each while performing various computer workstation tasks throughout the sitting periods. The activation of eight muscles and lumbar spine posture were measured and analyzed. RESULTS: Increased muscle activation in thoracic erector spinae (p = .0352), decreased pelvic tilt (p = .0114), and increased perceived discomfort (p < .0001) while sitting on the stability ball were observed. CONCLUSIONS: The small changes in biological responses when sitting on a stability ball as compared with an office chair, combined with the increased reported discomfort while on the ball, suggests its use for prolonged sitting may not be advantageous. APPLICATION: Prolonged sitting on a stability ball does not greatly alter the manner in which an individual sits, yet it appears to increase the level of discomfort. Therefore, it is important to fully explore a new chair design and consult scientific research before implementing its use.     

Activity-rest schedules in physically demanding work and the variation of responses with age

Workers in physically demanding occupations require work breaks to recover from exertion. In a laboratory setting, we investigated the impact of ergometer cycling for 7 h in two conditions with an identical total break time but with two different activity-rest schedules. We hypothesised that more frequent but shorter breaks lead to less psychophysical strain and its effects than do less frequent but longer breaks, particularly for older workers. Twenty-nine participants representing three different age groups were tested in both conditions. Heart rate, perceived exertion/tension and feelings of fatigue were assessed and used as dependent variables. Results indicate no general activity-rest differences as well as no age-related differences of break effects under the condition of subjectively equal straining load. However, heart rate was found to be lower at some measurement points in the frequent-short-break condition and perceived exertion was lower in the infrequent-long-break condition. PRACTITIONER SUMMARY: Design of activity-rest schedules in physically demanding occupations is a key issue in the prevention of strain and hence of interest to ergonomists. Our study suggests that breaks during physically demanding work have the same effect if they are frequent and short or infrequent and long, regardless of age.     

Electron energy loss spectroscopy for analysis of inhaled ultrafine particles in rat lungs

Epidemiologic studies have associated cardiovascular morbidity and mortality with ambient particulate air pollution. Particles smaller than 100 nm in diameter (ultrafine particles) are present in the urban atmosphere in very high numbers yet at very low mass concentration. Organs beyond the lungs are considered as targets for inhaled ultrafine particles, whereby the route of particle translocation deeper into the lungs is unclear. Five rats were exposed to aerosols of ultrafine titanium dioxide particles of a count median diameter of 22 nm (geometric standard deviation, GSD 1.7) for 1 hour. The lungs were fixed by intravascular perfusion of fixatives immediately thereafter. TiO(2) particles in probes of the aerosol as well as in systematic tissue samples were analyzed with a LEO 912 transmission electron microscope equipped with an energy filter for elemental microanalysis. The characteristic energy loss spectra were obtained by fast spectrum acquisition. Aerosol particles as well as those in the lung tissue were unambiguously identified by electron energy loss spectroscopy. Particles were mainly found as small clusters with a rounded shape. Seven percent of the particles in the lung tissue had a needle-like shape. The size distribution of the cluster profiles in the tissue had a count median diameter of 29 nm (GSD 1.7), which indicates no severe clustering or reshaping of the originally inhaled particles. Electron energy loss spectroscopy and related analytical methods were found to be suitable to identify and localize ultrafine titanium dioxide particles within chemically fixed and resin-embedded lung tissue.     

SK119, a Novel Shikonin Derivative,Leads to Apoptosis in Melanoma Cell Lines and Exhibits Synergistic Effects with Vemurafenib and Cobimetinib

Melanoma is a complex and heterogenous disease, displays the deadliest form of skin cancer, and accounts for approx. 80% of all skin cancer deaths. In this study, we reported on the synthesis and pharmacological effects of a novel shikonin derivative (SK119), which is active in a nano-molar range and exhibits several promising in vitro effects in different human melanoma cells. SK119 was synthesized from shikonin as part of our search for novel, promising shikonin derivatives. It was screened against a panel of melanoma and non-tumorigenic cell lines using XTT viability assays. Moreover, we studied its pharmacological effects using apoptosis and Western blot experiments. Finally, it was combined with current clinically used melanoma therapeutics. SK119 exhibited IC₅₀ values in a nano-molar range, induced apoptosis and led to a dose-dependent increase in the expression and protein phosphorylation of HSP27 and HSP90 in WM9 and MUG-Mel 2 cells. Combinatorial treatment, which is highly recommended in melanoma, revealed the synergistic effects of SK119 with vemurafenib and cobimetinib. SK119 treatment changed the expression levels of apoptosis genes and death receptor expression and exhibited synergistic effects with vemurafenib and cobimetinib in human melanoma cells. Further research indicates a promising potential in melanoma therapy.     

Reg-1α, a New Substrate of Calpain-2 Depending on Its Glycosylation Status

Reg-1α/lithostathine, a protein mainly associated with the digestive system, was previously shown to be overexpressed in the pre-clinical stages of Alzheimer’s disease. In vitro, the glycosylated protein was reported to form fibrils at physiological pH following the proteolytic action of trypsin. However, the nature of the protease able to act in the central nervous system is unknown. In the present study, we showed that Reg-1α can be cleaved in vitro by calpain-2, the calcium activated neutral protease, overexpressed in neurodegenerative diseases. Using chemical crosslinking experiments, we found that the two proteins can interact with each other. Identification of the cleavage site using mass spectrometry, between Gln⁴ and Thr⁵, was found in agreement with the in silico prediction of the calpain cleavage site, in a position different from the one reported for trypsin, i.e., Arg¹¹-Ile¹² peptide bond. We showed that the cleavage was impeded by the presence of the neighboring glycosylation of Thr⁵. Moreover, in vitro studies using electron microscopy showed that calpain-cleaved protein does not form fibrils as observed after trypsin cleavage. Collectively, our results show that calpain-2 cleaves Reg-1α in vitro, and that this action is not associated with fibril formation.     

Hyperinsulinemic Hypoglycemia Associated with a CaV1.2 Variant with Mixed Gain- and Loss-of-Function Effects

The voltage-dependent L-type calcium channel isoform Ca_V1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the Ca_V1.2 α₁-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified Ca_V1.2^L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism.