Cation Permeability of Voltage-Gated Hair Cell Ca2+ Channels of the Vertebrate Labyrinth

Some hearing, vestibular, and vision disorders are imputable to voltage-gated Ca²⁺ channels of the sensory cells. These channels convey a large Ca²⁺ influx despite extracellular Na⁺ being 70-fold more concentrated than Ca²⁺; such high selectivity is lost in low Ca²⁺, and Na⁺ can permeate. Since the permeation properties and molecular identity of sensory Ca²⁺ channels are debated, in this paper, we examine the Na⁺ current flowing through the L- and R-type Ca²⁺ channels of labyrinth hair cells. Ion currents and cytosolic free Ca²⁺ concentrations were simultaneously monitored in whole-cell recording synchronous to fast fluorescence imaging. L-type and R-type channels were present with different densities at selected sites. In 10 nM Ca²⁺, the activation and deactivation time constants of the L-type Na⁺ current were accelerated and its maximal amplitude increased by 6-fold compared to physiological Ca²⁺. The deactivation of the R-type Na⁺ current was not accelerated, and its current amplitude increased by 2.3-fold in low Ca²⁺; moreover, it was partially blocked by nifedipine in a voltage- and time-dependent manner. In conclusion, L channel gating is affected by the ion species permeating the channel, and its selectivity filter binds Ca²⁺ more strongly than that of R channel; furthermore, external Ca²⁺ prevents nifedipine from perturbing the R selectivity filter.     

New Insights in the Control of Fat Homeostasis: The Role of Neurotensin

Neurotensin (NT) is a small peptide with pleiotropic functions, exerting its primary actions by controlling food intake and energy balance. The first evidence of an involvement of NT in metabolism came from studies on the central nervous system and brain circuits, where NT acts as a neurotransmitter, producing different effects in relation to the specific region involved. Moreover, newer interesting chapters on peripheral NT and metabolism have emerged since the first studies on the NT-mediated regulation of gut lipid absorption and fat homeostasis. Intriguingly, NT enhances fat absorption from the gut lumen in the presence of food with a high fat content, and this action may explain the strong association between high circulating levels of pro-NT, the NT stable precursor, and the increased incidence of metabolic disorders, cardiovascular diseases, and cancer observed in large population studies. This review aims to provide a synthetic overview of the main regulatory effects of NT on several biological pathways, particularly those involving energy balance, and will focus on new evidence on the role of NT in controlling fat homeostasis, thus influencing the risk of unfavorable cardio–metabolic outcomes and overall mortality in humans.     

In Vivo Metabolic Responses to Different Formulations of Amino Acid Mixtures for the Treatment of Phenylketonuria (PKU)

Phenylketonuria (PKU) is a rare autosomal recessive inborn error of metabolism where the mainstay of treatment is a Phe restricted diet consisting of a combination of limited amounts of natural protein with supplementation of Phe-free or low-Phe protein substitutes and special low protein foods. Suboptimal outcomes may be related to the different absorption kinetics of free AAs, which have lower biological efficacy than natural proteins. Physiomimic Technology^TM is a technology engineered to prolong AA (AA-PT) release allowing physiological absorption and masking the odor and taste of free AAs. The aim of these studies was to assess the impact of AA-PT formulation on selected functional and metabolic parameters both in acute and long-term experimental studies. Adult rats in fasting conditions were randomized in different groups and treated by oral gavage. Acute AA-PT administration resulted in significantly lower BUN at 90 min versus baseline. Both BUN and glycemia were modulated in the same direction as intact casein protein. Long-term treatment with AA-PT significantly reduces the protein expression of the muscle degradation marker Bnip3L (−46%) while significantly increasing the proliferation of market myostatin (+58%). Animals dosed for 15 days with AA-PT had significantly stronger grip strength (+30%) versus baseline. In conclusion, the results suggest that the AA-PT formulation may have beneficial effects on both AA oxidation and catabolism with a direct impact on muscle as well as on other metabolic pathways.     

Deep Resequencing of 9 Candidate Genes Identifies a Role for ARAP1 and IGF2BP2 in Modulating Insulin Secretion Adjusted for Insulin Resistance in Obese Southern Europeans

Type 2 diabetes is characterized by impairment in insulin secretion, with an established genetic contribution. We aimed to evaluate common and low-frequency (1–5%) variants in nine genes strongly associated with insulin secretion by targeted sequencing in subjects selected from the extremes of insulin release measured by the disposition index. Collapsing data by gene and/or function, the association between disposition index and nonsense variants were significant, also after adjustment for confounding factors (OR = 0.25, 95% CI = 0.11–0.59, p = 0.001). Evaluating variants individually, three novel variants in ARAP1, IGF2BP2 and GCK, out of eight reaching significance singularly, remained associated after adjustment. Constructing a genetic risk model combining the effects of the three variants, only carriers of the ARAP1 and IGF2BP2 variants were significantly associated with a reduced probability to be in the lower, worst, extreme of insulin secretion (OR = 0.223, 95% CI = 0.105–0.473, p < 0.001). Observing a high number of normal glucose tolerance between carriers, a regression posthoc analysis was performed. Carriers of genetic risk model variants had higher probability to be normoglycemic, also after adjustment (OR = 2.411, 95% CI = 1.136–5.116, p = 0.022). Thus, in our southern European cohort, nonsense variants in all nine candidate genes showed association with better insulin secretion adjusted for insulin resistance, and we established the role of ARAP1 and IGF2BP2 in modulating insulin secretion.     

Potent,Metabolically Stable 2‐Alkyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐adenines as Adenosine A2A Receptor Ligands

Inhibition of adenosine A_2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson’s disease (PD). We previously identified the triazolo‐9H‐purine, ST1535, as a potent A_2AR antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω‐1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω‐1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A_2AR was determined. Two compounds, (2‐(3,3‐dimethylbutyl)‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐6‐amine ( 3 b ) and 4‐(6‐amino‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐2‐yl)‐2‐methylbutan‐2‐ol ( 3 c ), exhibited good affinity against A_2AR (K_i=0.4 nM and 2 nM , respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours).     

模拟嵌入式FRP条增强钢筋混凝土梁抗剪的三维力学模型

嵌入式FRP增强钢筋混凝土梁抗剪是进行结构修复的新技术,由于嵌入式FRP所具有的一些优势,使其成为较好的外贴加固技术,越来越受到重视。嵌入式FRP主要优势在于材料开发、对结构完整性的保护以及相对较快的适用性。由于FRP条复杂的几何尺寸,粘结后的非线性力学性能,混凝土受拉性能的离散性,使得嵌入式FRP条加固的性能十分复杂,一般通过试验来获得其性能。为更好地掌握表面嵌贴FRP带的性能,提出三维力学模型,用于模拟在相似加载过程中,嵌入式FRP条体系对钢筋混凝土梁抗剪强度的贡献。模型很好地解释了试验结果,并在模型中考虑了粘结滑移力和混凝土破坏之间的相互作用以及相邻FRP条之间的相互作用等复杂现象。     

Antioxidant activity,color chromaticity coordinates,and chemical characterization of monofloral honeys from Morocco

The bioprospecting of several monofloral Moroccan honeys was carried out. The antiradical activity expressed as mmol Trolox equivalents/kg of honey and evaluated by 2,2-diphenyl-1-picrylhydrazyl assay, ranged from 0.15 for euphorb honey to 1.08 for citrus honey. The antioxidant activity expressed as mmol Fe²⁺/kg and evaluated by ferric ion reducing antioxidant power assay, ranged from 0.96 for euphorb honey to 4.74 for orange honey. The total phenol content was evaluated by colorimetric assay, while the color attributes were evaluated as transmittance data. Significant Pearson correlation factors were found between total polyphenol amount and antioxidant activity and between color attributes and antioxidant activity. Furthermore the chemical composition of volatile organic compounds was determined. The volatile organic compounds chemical composition of the studied honeys was mainly represented by terpene and benzene derivatives, Maillard reaction products, isoprenoids, and hydrocarbons. The volatiles fingerprint, as well as a targeted high-performance liquid chromatography analysis of the polar components, was used to tentatively confirm the declared botanical origin of the samples studied.     

Efficient inclusion for a class of XML types with interleaving and counting

Inclusion between XML types is important but expensive, and is much more expensive when unordered types are considered. We prove here that inclusion for XML types with interleaving and counting can be decided in polynomial time in the presence of two important restrictions: no element appears twice in the same content model, and Kleene star is only applied to disjunctions of single elements.     

Investigation on the non‐quasi‐static effect implementation for millimeter‐wave FET models

The present article analyzes in detail different intrinsic small‐signal models for transistors. Particular attention is devoted to the non‐quasi‐static effects, which play a crucial role at microwave and millimeter‐wave frequencies. The advantages and disadvantages of these different equivalent circuit topologies are analyzed from both theoretical and experimental standpoints. This study clearly proves that best choice among these model representations depends on the specific device technology besides the investigated frequency range. © 2009 Wiley Periodicals, Inc. Int J RF and Microwave CAE, 2010.     

Web accessibility guideline aggregation for older users and its validation

Web site-evaluation methodologies and validation engines take the view that all accessibility guidelines must be met to gain compliance. Problems exist in this regard, as contradictions within the rule set may arise, and the type of impairment or its severity is not isolated. The Barrier Walkthrough (BW) method goes someway to addressing these issues, by enabling barrier types derived from guidelines to be applied to different user categories such as motor or visual impairment, etc. However, the problem remains of combinatorial explosion of possibilities when one has to consider users with multiple disabilities. In this paper, a simple set theory operation is used to create a validation scheme for older users by aggregating barrier types specific to motor impaired and low-vision users, thereby creating a new “older users” category from the results of this set union. To evaluate the feasibility and validity of this aggregation approach, two BW experiments were conducted. The first experiment evaluated the aggregated results by focusing on quality attributes and showed that aggregation generates data whose quality is comparable to the original one. However, this first experiment could not test for validity, as the older users category was not included. To remedy this deficiency, another BW experiment was conducted with expert judges who evaluated a web page in the context of older users. In this second experiment, it was found that there is no significant difference between the aggregated and the manually evaluated (by experts) barrier scores, and that the same barriers are identified using experts and aggregation, even though there are differences in how severity scores are distributed. From these results, it is concluded that the aggregation of barriers is a viable alternative to expert evaluation, when the target of that aggregation could not be evaluated manually or it would not be feasible to do so. It is also argued that aggregation is a technique that can be used in combination with other evaluation methods, like user testing or subjective assessments.