Butyrylated starch is less susceptible to enzymic hydrolysis and increases large-bowel butyrate more than high-amylose maize starch in the rat

Large-bowel fermentation of resistant starch produces SCFA that are believed to be important in maintaining visceral function. High-amylose maize starch (HAMS) and acylated starches are sources of resistant starch and are an effective means of increasing colonic SCFA. Cooking increases digestibility of starches but its effects on the capacity of these starches to raise large-bowel SCFA are unknown. We have examined the effects of cooking of HAMS and butyrylated HAMS (HAMSB) on amylolysis in vitro and their capacity to raise caeco-colonic SCFA in rats. The starches were boiled in excess water and microwaved, followed by drying at 100°C. Cooking increased in vitro glucose release for both starches but significantly less from HAMSB. Rat growth rates were unaffected when fed cooked resistant starch. Digesta pH was increased in the caecum and proximal colon of rats fed cooked HAMS. Distal colonic pH was highest in rats fed cooked HAMSB. Factorial analyses (2×2) of caecal SCFA pools showed significant differences between HAMS and HAMSB, and that cooking significantly lowered caecal butyrate pools. Portal venous butyrate concentrations were higher in both HAMSB groups than those fed HAMS. The data suggest that HAMSB is less susceptible to in vitro amylolysis than HAMS following cooking and delivers more butyrate to rat caecum than HAMS. This attribute may be useful in food applications for specific delivery of SCFA to the colon. Preparation of carbohydrates to simulate human food in animal experiments may be important to assess nutritional and physiological effects accurately.Balázs H. Bajka, David L. Topping, Lynne Cobiac and Julie M. Clark

Eastern European Modernism: Works on Paper at the Columbia University Libraries and the Cornell University Library

This compendium is more than an extensive register of two of the world’s most consequential institutional holdings of progressive works on paper. Indeed, it is a material affirmation of the extraordinary inventive prowess, the stunning artistic achievements, and the daring visual scope of creative figures from the Baltic north to the Balkan south during almost a half-century of their most audacious ambitions. Thus, the works on paper documented here, and the essays contextualizing them, represent a benchmark of aesthetic accomplishment, of scholarly appraisal, and of academic accessibility. Each of the hundreds of brief bibliographical analyses offers an incisive and lucid introduction to the two universities’ libraries’ rich array of modernist pamphlets, booklets, broadsides, and advertising copy that collectively encompass and define the modern world – from the arts to politics to commerce to sexuality. In its encyclopedic breadth, this compendium reveals the visual potency and inventive aesthetic strategies that shaped not only eastern Europe during the first decades of the twentieth century, but ultimately determined how we have come to see ourselves. (Steven Mansbach, Univ. of Maryland

Impact of Enzalutamide on Skeletal Related Events (Sres), Pain and Quality of Life (Qol) in the Prevail Trial

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Predictive rules of efflux inhibition and avoidance in Pseudomonas aeruginosa

Antibiotic-resistant bacteria rapidly spread in clinical and natural environments and challenge our modern lifestyle. A major component of defense against antibiotics in Gram-negative bacteria is a drug permeation barrier created by active efflux across the outer membrane. We identified molecular determinants defining the propensity of small peptidomimetic molecules to avoid and inhibit efflux pumps in Pseudomonas aeruginosa, a human pathogen notorious for its antibiotic resistance.Combining experimental and computational protocols, we mapped the fate of the compounds from structure-activity relationships through their dynamic behavior in solution, permeation across both the inner and outer membranes, and interaction with MexB, the major efflux transporter of P. aeruginosa. We identified predictors of efflux avoidance and inhibition and demonstrated their power by using a library of traditional antibiotics and compound series and by generating new inhibitors of MexB. The identified predictors will enable the discovery and optimization of anti-bacterial agents suitable for treatment of P. aeruginosa infections

Pharmacological Investigations of the Dissociative ‘Legal Highs’ Diphenidine, Methoxphenidine and Analogues

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as ‘legal highs’ in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many ‘legal highs’, little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine

Effect of Visceral Disease Site on Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide in the PREVAIL Trial.

Background The Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy (PREVAIL) trial was unique as it included patients with visceral disease. This analysis was designed to describe outcomes for the subgroup of men from PREVAIL with specific sites of visceral disease to help clinicians understand how these patients responded to enzalutamide prior to chemotherapy.Patients and methods Prespecified analyses examined the coprimary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) only. All other efficacy analyses were post hoc. The visceral subgroup was divided into liver or lung subsets. Patients with both liver and lung metastases were included in the liver subset.Results Of the 1717 patients in PREVAIL, 204 (12%) had visceral metastases at screening (liver only or liver/lung metastases, n = 74; lung only metastases, n = 130). In patients with liver metastases, enzalutamide was associated with an improvement in rPFS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.22-0.90) but not OS (HR, 1.04; 95% CI, 0.57-1.87). In patients with lung metastases only, the HR for rPFS (0.14; 95% CI, 0.06-0.36) and the HR for OS (0.59; 95% CI, 0.33-1.06) favored enzalutamide over placebo. Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment. Enzalutamide was well tolerated in patients with visceral disease.Conclusions Enzalutamide is an active first-line treatment option for men with asymptomatic or mildly symptomatic chemotherapy-naive metastatic castration-resistant prostate cancer and visceral disease. Patients with lung-only disease fared better than patients with liver disease, regardless of treatment

Modulation of Tcf7l2 Expression Alters Behavior in Mice

The comorbidity of type 2 diabetes (T2D) with several psychiatric diseases is well established. While environmental factors may partially account for these co-occurrences, common genetic susceptibilities could also be implicated in the confluence of these diseases. In support of shared genetic burdens, TCF7L2, the strongest genetic determinant for T2D risk in the human population, has been recently implicated in schizophrenia (SCZ) risk, suggesting that this may be one of many loci that pleiotropically influence both diseases. To investigate whether Tcf7l2 is involved in behavioral phenotypes in addition to its roles in glucose metabolism, we conducted several behavioral tests in mice with null alleles of Tcf7l2 or overexpressing Tcf7l2. We identified a role for Tcf7l2 in anxiety-like behavior and a dose-dependent effect of Tcf7l2 alleles on fear learning. None of the mutant mice showed differences in prepulse inhibition (PPI), which is a well-established endophenotype for SCZ. These results show that Tcf7l2 alters behavior in mice. Importantly, these differences are observed prior to the onset of detectable glucose metabolism abnormalities. Whether these differences are related to human anxiety-disorders or schizophrenia remains to be determined. These animal models have the potential to elucidate the molecular basis of psychiatric comorbidities in diabetes and should therefore be studied further

Circumstellar disks around Herbig Ae/Be stars: polarization, outflows and binary orbits

The geometrical relationship between the distribution of circumstellar matter, observed optical linear polarization, outflows and binary orbital plane in Herbig Ae/Be stars is investigated. Optical linear polarization measurements carried out for a number of Herbig Ae/Be stars that are either known to be in binary systems and/or have bipolar jets are presented in this paper. Available information on the position angles of polarization, outflows and binary companions for Herbig Ae/Be stars is compiled and analysed for any possible correlations. In $\approx 85$ of the sources the outflow position angle is within $30^{\circ}$ of being parallel or perpendicular to the polarization position angle. In $\approx 81$ of the sources the binary position angle is within $30^{\circ}$ of being parallel or perpendicular to the polarization position angle. Out of 15 sources with bipolar outflows, 10 sources have the binary position angle within $30^{\circ}$ of being perpendicular to the outflow position angle. These results favour those binary formation mechanisms in which the binary components and the disks around individual stars or circumbinary disks are coplanar.Comment: 11 pages, 2 figures, accepted by Astronomy & Astrophysic

Overexpression of transmembrane protein 168 in the mouse nucleus accumbens induces anxiety and sensorimotor gating deficit

Transmembrane protein 168 (TMEM168) comprises 697 amino acid residues, including some putative transmembrane domains. It is reported that TMEM168 controls methamphetamine (METH) dependence in the nucleus accumbens (NAc) of mice. Moreover, a strong link between METH dependence-induced adaptive changes in the brain and mood disorders has been evaluated. In the present study, we investigated the effects of accumbal TMEM168 in a battery of behavioral paradigms. The adeno-associated virus (AAV) Tmem168 vector was injected into the NAc of C57BL/6J mice (NAc-TMEM mice). Subsequently, the accumbal TMEM168 mRNA was increased approximately by seven-fold when compared with the NAc-Mock mice (controls). The NAc-TMEM mice reported no change in the locomotor activity, cognitive ability, social interaction, and depression-like behaviors; however, TMEM168 overexpression enhanced anxiety in the elevated-plus maze and light/dark box test. The increased anxiety was reversed by pretreatment with the antianxiety drug diazepam (0.3 mg/kg i.p.). Moreover, the NAc-TMEM mice exhibited decreased prepulse inhibition (PPI) in the startle response test, and the induced schizophrenia-like behavior was reversed by pretreatment with the antipsychotic drug risperidone (0.01 mg/kg i.p.). Furthermore, accumbal TMEM168 overexpression decreased the basal levels of extracellular GABA in the NAc and the high K+ (100 mM)-stimulated GABA elevation; however, the total contents of GABA in the NAc remained unaffected. These results suggest that the TMEM168-regulated GABAergic neuronal system in the NAc might become a novel target while studying the etiology of anxiety and sensorimotor gating deficits