A Comprehensive Assessment of Qualitative and Quantitative Prodromal Parkinsonian Features in Carriers of Gaucher Disease—Identifying Those at the Greatest Risk

Carriers of GBA1 gene variants have a significant risk of developing Parkinson’s disease (PD). A cohort study of GBA carriers between 40–75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains of PD. Ninety-eight unrelated GBA carriers were enrolled (43 males) at a median age (range) of 51 (40–74) years; 71 carried the N370S variant (c.1226A > G) and 25 had a positive family history of PD. The Montreal Cognitive Assessment (MoCA) was the most frequently abnormal (23.7%, 95% CI 15.7–33.4%), followed by the ultrasound hyperechogenicity (22%, 95% CI 14–32%), Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) (17.2%, 95% CI 10.2–26.4%), smell assessment (12.4%, 95% CI 6.6–20.6%) and abnormalities in sleep questionnaires (11%, 95% CI 5.7–19.4%). Significant correlations were found between tests from different domains. To define the risk for PD, we assessed the bottom 10th percentile of each prodromal test, defining this level as “abnormal”. Then we calculated the percentage of “abnormal” tests for each subject; the median (range) was 4.55 (0–43.5%). Twenty-two subjects had more than 15% “abnormal” tests. The limitations of the study included ascertainment bias of individuals with GBA-related PD in relatives, some incomplete data due to technical issues, and a lack of well-characterized normal value ranges in some tests. We plan to enroll additional participants and conduct longitudinal follow-up assessments to build a model for identifying individuals at risk for PD and investigate interventions aiming to delay the onset or perhaps to prevent full-blown PD.     

Nicotinamide Mononucleotide Protects against Retinal Dysfunction in a Murine Model of Carotid Artery Occlusion

Cardiovascular abnormality-mediated retinal ischemia causes severe visual impairment. Retinal ischemia is involved in enormous pathological processes including oxidative stress, reactive gliosis, and retinal functional deficits. Thus, maintaining retinal function by modulating those pathological processes may prevent or protect against vision loss. Over the decades, nicotinamide mononucleotide (NMN), a crucial nicotinamide adenine dinucleotide (NAD⁺) intermediate, has been nominated as a promising therapeutic target in retinal diseases. Nonetheless, a protective effect of NMN has not been examined in cardiovascular diseases-induced retinal ischemia. In our study, we aimed to investigate its promising effect of NMN in the ischemic retina of a murine model of carotid artery occlusion. After surgical unilateral common carotid artery occlusion (UCCAO) in adult male C57BL/6 mice, NMN (500 mg/kg/day) was intraperitoneally injected to mice every day until the end of experiments. Electroretinography and biomolecular assays were utilized to measure ocular functional and further molecular alterations in the retina. We found that UCCAO-induced retinal dysfunction was suppressed, pathological gliosis was reduced, retinal NAD⁺ levels were preserved, and the expression of an antioxidant molecule (nuclear factor erythroid-2-related factor 2; Nrf2) was upregulated by consecutive administration of NMN. Our present outcomes first suggest a promising NMN therapy for the suppression of cardiovascular diseases-mediated retinal ischemic dysfunction.     

A new view of anti‐windup design for uncertain linear systems in the frequency domain

This paper presents a new perspective on the stability problem for uncertain LTI feedback systems with actuator input amplitude saturation. The solution is obtained using the quantitative feedback theory and a 3 DoF non‐interfering control structure. Describing function (DF) analysis is used as a criterion for closed loop stability and limit cycle avoidance, but the circle or Popov criteria could also be employed. The novelty is the combination of a controller parameterization from the literature and describing function‐based limit cycle avoidance with margins for uncertain plants. Two examples are given. The first is a benchmark problem and a comparison is made with other proposed solutions. The second is an example that was implemented and tested on an X‐Y linear stage used for nano‐positioning applications. Design and implementation considerations are given. An example is given on how the method can be extended to amplitude and rate saturation with the help of the generalized describing function, and a novel anti‐windup compensation structure inspired by previous contributions. Copyright © 2015 John Wiley & Sons, Ltd.     

Approximating the Advertisement Placement Problem

The advertisement placement problem deals with space and time sharing by advertisements on the Internet. Consider a Web page containing a rectangular display area (e.g., a banner) in which advertisements may appear. The display area can be utilized efficiently by allowing several small ads to appear simultaneously side by side, as well as by cycling through a schedule of ads, allowing different ads to be displayed at different times. A customer wishing to purchase advertising space specifies an ad size and a display count, which is the number of times their ad should appear during each cycle. The scheduler may accept or reject any given advertisement, but must be able to schedule all accepted ads within the given time and space constraints. Each advertisement has a non-negative profit associated with it, and the objective is to schedule a maximum-profit subset of ads. We present a (3 + )-approximation algorithm for the general problem, as well as (2 + )-approximation algorithms for two special cases.     

Optimal structure for heat and cold protection under transient heat conduction

A suitable combination of materials for sheltering a system from a sudden change of environmental temperature has been theoretically studied. The protective composite wall consists of two materials. An insulating material is placed on the outer surface, while, for the inner surface, materials that have good heat storage properties but negligible heat transfer resistance are chosen. The results show that by replacing some of the insulation material with a heat storage material, the temperature of the protected system can be maintained at a considerably lower level. Although the optimal thickness ratio X depends on the Biot number, Fourier number, and on the heat capacity ratio K _C, for a large number of thermal protection cases, the approximation X = 0.45 yields practically the minimum progress of the transient. If the Biot number is sufficiently small, it is better to replace all of the insulation material with a good heat storage material.     

Gaucher Disease Diagnosis Using Lyso-Gb1 on Dry Blood Spot Samples: Time to Change the Paradigm?

For years, the gold standard for diagnosing Gaucher disease (GD) has been detecting reduced β-glucocerebrosidase (GCase) activity in peripheral blood cells combined with GBA1 mutation analysis. The use of dried blood spot (DBS) specimens offers many advantages, including easy collection, the need for a small amount of blood, and simpler transportation. However, DBS has limitations for measuring GCase activity. In this paper, we recount our cross-sectional study and publish seven years of experience using DBS samples and levels of the deacylated form of glucocerebroside, glucosylsphingosine (lyso-Gb1), for GD diagnosis. Of 444 screened subjects, 99 (22.3%) were diagnosed with GD at a median (range) age of 21 (1–78) years. Lyso-Gb levels for genetically confirmed GD patients vs. subjects negative to GD diagnosis were 252 (9–1340) ng/mL and 5.4 (1.5–16) ng/mL, respectively. Patients diagnosed with GD1 and mild GBA1 variants had lower median (range) lyso-Gb1, 194 (9–1050), compared to GD1 and severe GBA1 variants, 447 (38–1340) ng/mL, and neuronopathic GD, 325 (116–1270) ng/mL (p = 0.001). Subjects with heterozygous GBA1 variants (carrier) had higher lyso-Gb1 levels, 5.8 (2.5–15.3) ng/mL, compared to wild-type GBA1, 4.9 (1.5–16), ng/mL (p = 0.001). Lyso-Gb1 levels, median (range), were 5 (2.7–10.7) in heterozygous GBA1 carriers with Parkinson’s disease (PD), similar to lyso-Gb1 levels in subjects without PD. We call for a paradigm change for the diagnosis of GD based on lyso-Gb1 measurements and confirmatory GBA1 mutation analyses in DBS. Lyso-Gb1 levels could not be used to differentiate between heterozygous GBA1 carriers and wild type.     

Enhancing the electrical conductivity of carbon black/graphite nanoplatelets: Poly(ethylene‐butyl acrylate) composites by melt extrusion

The influence of processing parameters such as screw geometry, temperature profile, and screw speed on the electrical properties of hybrid composites consisting of graphite nanoplatelets and carbon black in ethyl butyl acrylate was studied. Two different screws were used to compound the hybrid composites at two different temperatures and two different screw speeds. A beneficial effect was noted with regard to the electrical properties when adding nanoplatelets to the filler system. The cause could be a synergistic effect due to the difference in particle shape of the two fillers. Lower percolation thresholds were obtained with the conventional screw due to less breakage of the graphite nanoplatelets compared to the barrier screw. No significant changes of the electrical properties were observed when changing the temperature profiles or the screw speeds. Furthermore, the melt viscosity of the compounds was not appreciably affected at the rather low filler contents used here. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 42897.     

Experimental study of bubbly swirling flow in a vertical tube using ultrasonic velocity profiler (UVP) and wire mesh sensor (WMS)

Two-phase air-water bubbly swirling flow through a pipe is a complex turbulent flow and its prediction is still challenging. The present paper describes the experimental investigation of the air-water bubbly swirling flow in vertical co-current flow. Swirling flow is induced by a twisted tape in a 20 mm inner diameter pipe. The flow is investigated using Ultrasonic velocity profiler (UVP), which allows the measurement of liquid and gas velocities simultaneously. Furthermore, simultaneous measurement of void fraction is performed using Wire mesh sensor (WMS). The experimental results reveal that swirling flow has significant impact on bubbles’ distribution. In low liquid flow rate, the average bubble velocity is fairly uniform along the radial position and void fraction increases in the near wall region. However, increasing liquid flow rate at constant gas flow rate leads to increase in void fraction in the core region, this is mainly due to drift velocity which is affected by centrifugal force. Experimental findings and parametric trends based on the effects of swirling flow are summarized and discussed.     

The use of (green field) biomass pretreatment liquor for fermentative butanol production and the catalytic oxidation of biobutanol

In this study, pretreatment liquor of acid-stored green and yellowish barley silage was used for fermentative acetone–butanol–ethanol (ABE) production. Further, the catalytic oxidation of biobutanol over Pt catalysts was studied to investigate the behaviour of butanol as a fuel in the combustion engine. After the hydrothermal treatment of green and yellowish barley silage followed by enzymatic hydrolysis, approximately 88% and 100% of the available sugars were recovered, respectively. Batch fermentations of pretreatment barley silage liquor, supplemented with gelatinised barley grain, showed good fermentability with total ABE concentrations of 9.0 g/L and 10.9 g/L. Butanol yields of 0.20, 0.17 and ABE yields of 0.28, 0.26 (g/g monosaccharide) were obtained, respectively. In catalytic activity measurements, the conversion of biobutanol became appreciable in the 120–140 °C range, whereas conversions greater than 95% were obtained over 200 °C. Selectivities were also high, although formation of by-products, such as butyraldehyde, was observed.