Biology and Regulatory Roles of Nuclear Lamins in Cellular Function and Dysfunction.

Nuclear lamins, namely lamins A, B and C, surround the nucleoplasmic contents in a meshlike network called the nuclear lamina. These intermediate filaments provide a structural framework to the nuclear envelope (NE), play a role in arrangement of the chromatin within the nucleus, in DNA replication and also participate in DNA damage repair. In order for lamins to be involved in these important nuclear processes and to be functionally active, they undergo a series of post-translational modifications (farnesylation, endoproteolytic cleavage, carboxylmethylation etc.), of which farnesylation is the most studied. Improper farnesylation of lamin proteins, especially lamin A, leads to a number of diseases affecting the striated muscle (e.g. Emery- Dreifuss Muscular Dystrophy, Dilated Cardiomyopathy), adipose tissue (e.g. Dunnigan-type familial partial lipodystrophy) and could result in abnormal senescence and growth deformities (e.g. Progeria syndrome); these are referred to as laminopathies. Despite the existing literature and evidence regarding functions of lamins and diseases associated with abnormal lamin processing, a lot remains to be understood in regards to lamin biology and their role as potential therapeutic targets. In this brief review, we have attempted to summarize the roles of lamins in physiology and pathology of the cell and in type 2 diabetes mellitus [T2DM] and also enlisted patents on methods, systems and devices developed for improving pancreatic beta cell function in diabetes mellitus.

The effects of texting on driving performance in a driving simulator: the influence of driver age.

Distracted driving is a significant contributor to motor vehicle accidents and fatalities, and texting is a particularly significant form of driver distraction that continues to be on the rise. The present study examined the influence of driver age (18-59 years old) and other factors on the disruptive effects of texting on simulated driving behavior. While 'driving' the simulator, subjects were engaged in a series of brief text conversations with a member of the research team. The primary dependent variable was the occurrence of Lane Excursions (defined as any time the center of the vehicle moved outside the directed driving lane, e.g., into the lane for oncoming traffic or onto the shoulder of the road), measured as (1) the percent of subjects that exhibited Lane Excursions, (2) the number of Lane Excursions occurring and (3) the percent of the texting time in Lane Excursions. Multiple Regression analyses were used to assess the influence of several factors on driving performance while texting, including text task duration, texting skill level (subject-reported), texting history (#texts/week), driver gender and driver age. Lane Excursions were not observed in the absence of texting, but 66% of subjects overall exhibited Lane Excursions while texting. Multiple Regression analysis for all subjects (N=50) revealed that text task duration was significantly correlated with the number of Lane Excursions, and texting skill level and driver age were significantly correlated with the percent of subjects exhibiting Lane Excursions. Driver gender was not significantly correlated with Lane Excursions during texting. Multiple Regression analysis of only highly skilled texters (N=27) revealed that driver age was significantly correlated with the number of Lane Excursions, the percent of subjects exhibiting Lane Excursions and the percent of texting time in Lane Excursions. In contrast, Multiple Regression analysis of those drivers who self-identified as not highly skilled texters (N=23) revealed that text task duration was significantly correlated with the number of Lane Excursions. The present studies confirm past reports that texting impairs driving simulator performance. Moreover, the present study demonstrates that for highly skilled texters, the effects of texting on driving are actually worse for older drivers. Given the increasing frequency of texting while driving within virtually all age groups, these data suggest that 'no texting while driving' education and public service messages need to be continued, and they should be expanded to target older drivers as well.

Gamma butyrolactone (GBL) and gamma valerolactone (GVL): similarities and differences in their effects on the acoustic startle reflex and the conditioned enhancement of startle in the rat.

Gamma butyrolactone (GBL) is metabolized to gamma hydroxybutyrate (GHB) in the body. GHB is a DEA Schedule 1 compound; GBL is a DEA List 1 chemical. Gamma valerolactone (GVL) is the 4-methyl analog of GBL; GVL is metabolized to 4-methyl-GHB; GVL is NOT metabolized to GBL or GHB. The effects of GBL (18.75-150 mg/kg), GVL (200-1600 mg/kg) or vehicle on the acoustic startle reflex (ASR), and the classically-conditioned enhancement of startle, the Startle Anticipated Potentiation of Startle (SAPS) response were studied in male rats. Both compounds produced a dose-dependent reduction of ASR, with GBL 5-7 times more potent than GVL. In contrast, GBL treatment significantly reduced SAPS at doses that exerted only moderate effects on ASR, whereas GVL exerted little or no effect on the SAPS, except at doses that produced pronounced reductions in Noise Alone ASR. In a second experiment, rats were tested for Noise Alone ASR behavior following treatment with a single mid-range dose of GBL (75 mg/kg), GVL (400mg/kg) or vehicle; immediately following startle testing the animals were sacrificed and their brains and blood were collected for determination of GHB, 4-methyl-GHB, GBL and GVL. GHB was found in measurable concentrations in all of the blood specimens and 6 (of 8) of the brain specimens from the GBL-treated subjects. 4-Methyl-GHB was found in measurable concentrations in all of the blood and brain specimens of the GVL-treated subjects; the change in startle amplitude was inversely correlated to the brain concentrations of these compounds. These findings confirm the differences in the metabolic fate of GBL and GVL as pro-drugs for the formation of GHB and 4-methyl-GHB, respectively. Moreover, the dissimilarity in effect profile for GBL and GVL on ASR versus SAPS behaviors suggests that different receptor(s) may be involved in mediating these behavioral effects.

Effect of administration time of exenatide on satiety responses, blood glucose, and adverse events in healthy volunteers.

The objective was to investigate whether varying administration time of exenatide affects the magnitude of satiety responses, blood glucose, and adverse events in healthy volunteers. In this randomized, single-blind, placebo-controlled, 4-period crossover, single-dose study, the authors measured satiety responses, blood glucose, and adverse events in 20 participants receiving exenatide (10 µg) at either -60 minutes, -30 minutes, or -15 minutes or placebo at -30 minutes relative to a standardized test meal. Compared with placebo, exenatide reduced caloric intake (P = .0059), food intake (P = .0032), and glucose concentrations at 60 (P < .001) and 120 minutes after meals (P = .015). Nausea (63% vs 20%), reduced appetite (43% vs 10%), and vomiting (18% vs 0%) occurred more frequently in exenatide-treated subjects compared with placebo (P < .05). Significant differences were noted in caloric intake (P = .0149) and food intake (P = .0205) based on the administration time of exenatide, with doses given further from meals producing reduced feeding responses. No such difference was found in postprandial glucose concentrations or adverse events based on timing of exenatide administration. Single-dose exenatide administered further from mealtime had an increased magnitude on satiety responses in healthy volunteers. Postprandial glucose concentrations and the frequency of adverse events did not differ by the administration time of exenatide.

Differential effects of hypocretins on noise-alone versus potentiated startle responses.

Hypocretins are recently discovered neuropeptides, synthesized exclusively in the hypothalamus with excitatory efferents to noradrenergic, serotonergic, and GABAergic (gamma-aminobutyric acid) neurons. Hypocretins also increase corticotropin releasing hormone (CRH) secretion. These actions suggest a possible role for hypocretins in the neurobiology of anxiety, fear, or startle mechanisms. We examined the effects of intracerebroventricular (ICV) administration of hypocretin-A and hypocretin-B on behavior in the Startle Potentiated Startle (SPS) paradigm, a repeated measures, non-shock animal model for studying the classically conditioned enhancement of acoustic startle in the rat. SPS has been used to study effects of anxiolytic treatments. Male Sprague-Dawley rats were tested using the SPS paradigm for 3 days (M-W-F). Following training, rats were anesthetized and 26 gauge stainless cannulae were permanently implanted into the lateral ventricle for intracerebroventricular (ICV) infusions. Following 6-9 days of recovery period, the M-W-F SPS testing was resumed. ICV infusion of both Hypocretin-A (1 and 3 nM) and Hypocretin-B (3 and 10 nM) produced significant reduction in Noise Alone Startle amplitude compared to pre-infusion baseline, whereas infusion with vehicle did not affect Noise Alone Startle. The effect of Hypocretin-B was brief (first 10 min post-infusion), whereas the effect of Hypocretin-A persisted across much of the 50 min post-infusion period. Neither Hypocretin-A nor Hypocretin-B significantly altered the magnitude of the SPS response. Contrary to our expectations, hypocretins seems to possess anxiolytic rather than pro-anxiogenic properties, as indicated by decrease in Noise Alone Startle.

Effects of buspirone and alprazolam treatment on the startle-potentiated startle response.

The startle potentiated startle (SPS) paradigm has been reported to be an effective procedure for studying the conditioned enhancement of acoustic startle in the absence of electric shocks or extinction. This study examines the effects of two anxiolytic treatments, buspirone and alprazolam, on this SPS effect. Subjects were tested in the SPS paradigm 2 days a week (Monday and Thursday) for 10 weeks. Each startle test session consisted of 10 Noise Alone trials (115 dB acoustic noise burst presented for 40 ms) and 10 Light+Noise trials (115 dB acoustic stimuli presented during the latter 40 ms of a 3,540 ms period in which a 15-watt light was illuminated). Although there was no difference in startle amplitude on Noise Alone trials when compared to Light+Noise trials initially, by the end of the first test session and continuing throughout the duration of the experiment, startle amplitude on Light+Noise trials was significantly (approximately 50-75%) greater than on Noise Alone trials. After five control (i.e., no injection) SPS test sessions, once-weekly drug challenges were conducted over the course of 7 weeks. In these weekly drug challenges, subjects received acute treatment with various doses of the benzodiazepine anxiolytic alprazolam (0.25, 0.5, 1.0 mg/kg) or the novel anxiolytic buspirone (1.0, 2.0, 4.0 mg/kg); subjects also received vehicle treatment (0.5% methylcellulose) on one treatment day. All treatments were administered intraperitoneally (i.p.), 15 min before the start of startle testing. Consistent with previous reports, buspirone increased and alprazolam decreased startle amplitude on the Noise Alone trials; these effects were dose-related. Both agents reduced the magnitude of the SPS effect when it was expressed as the Light+Noise startle amplitude minus the Noise Alone startle amplitude. These findings are similar to the effects of these treatments in the traditional shock-based fear-potentiated startle paradigm.

Involvement of 5-HT1A receptors in animal tests of anxiety and depression: evidence from genetic models.

Clinical studies have suggested the involvement of 5-HT1A receptors in anxiety and depressive disorders because partial 5-HT1A receptor agonists such as buspirone are therapeutic. The present review considers evidence from genetic animal models that support a role for 5-HT1A receptors in anxiety-like and depressed-like behavior in animals. Selective breeding for differential hypothermic responses to a selective 5-HT1A receptor agonist led to the development of the high DPAT sensitive (HDS) and low DPAT sensitive (LDS) lines of rats. The HDS rats differ from the LDS rats on several behavioral measures reflective of anxiety or depression, including reduced social interaction, reduced responding in a conflict task and exaggerated immobility in the forced swim test. However, they do not differ from the LDS rats in the elevated plus maze task, which is a commonly used test of anxiety. Nor do the HDS rats exhibit a typical anxiogenic response to the hippocampal administration of the 5-HT1A agonist. Although the HDS rats do exhibit elevations in 5-HT1A receptors in regions of the limbic cortex, it is not clear whether these increases account for the behavioral differences. Paradoxically, 5-HT1A receptor knockout mice also exhibit anxiety-like behavior in the plus maze, open field and conflict tests compared to wild type mice. However, the knockouts exhibited less immobility in the forced swim test than wild type control mice. Recent studies using selective regional reinstatement of the receptor have implicated the postsynaptic 5-HT1A receptors in these changes in anxiety-like behavior. Thus, preliminary evidence from two different types of genetic animal models suggests that anxiety-like behavior can arise if the 5-HT1A receptor function is eliminated or overexpressed. Further study with additional tests of anxiety are needed to confirm this intriguing relationship.