Clustering polymorphs of tau and IAPP fibrils with the CHEP algorithm.

Recent steps towards automation have improved the quality and efficiency of the entire cryo-electron microscopy workflow, from sample preparation to image processing. Most of the image processing steps are now quite automated, but there are still a few steps which need the specific intervention of researchers. One such step is the identification and separation of helical protein polymorphs at early stages of image processing.

Interaction of Fear Conditioning with Eyeblink Conditioning Supports the Sensory Gating Hypothesis of the Amygdala in Men.

Inhibition of the amygdala slows down acquisition of conditioned eyeblink responses (CRs). Based on the two-stage or two-factor theory of aversive conditioning, amygdala-dependent conditioned fear is a necessary prerequisite to acquire eyeblink CRs but is no longer needed after eyeblink CRs are attained. According to the sensory gating hypothesis of the amygdala, on the other hand, the amygdala modulates the salience of unconditioned stimuli (USs) and conditioned stimuli (CSs) in eyeblink conditioning.

Alterations in expression of p11 and SERT in mucosal biopsy specimens of patients with irritable bowel syndrome.

Background & Aims: The pathophysiology of irritable bowel syndrome (IBS) remains enigmatic; abnormalities in serotonin metabolism have been implicated. Two proteins that influence the function of serotonin and serotonergic receptors are serotonin transporter protein (SERT or soluble carrier protein, SLC6A4) and p11 (S-100A10, or calpactin I light chain). Both proteins are reported to be associated with depression-like states, a frequent comorbid condition in IBS.

Effect of a cannabinoid agonist on gastrointestinal transit and postprandial satiation in healthy human subjects: a randomized, placebo-controlled study.

Cannabinoid receptor (CBR) stimulation inhibits motility and increases food intake in rodents. Effects of CBR stimulation in human gastrointestinal (GI) tract are unclear. We compared effects of dronabinol (DRO) and placebo (PLA) on GI transit, gastric volume and satiation in humans.

Effect of atilmotin on gastrointestinal transit in healthy subjects: a randomized, placebo-controlled study.

We studied effects of i.v. atilmotin (BAX-ACC-1638, a novel motilin agonist, circulating t(1/2) < 10 min) on gastrointestinal transit in humans using a randomized, parallel-group, dose-response double-blind study of i.

Barostat testing of rectal sensation and compliance in humans: comparison of results across two centres and overall reproducibility.

We assessed reproducibility of measurements of rectal compliance and sensation in health in studies conducted at two centres. We estimated samples size necessary to show clinically meaningful changes in future studies. We performed rectal barostat tests three times (day 1, day 1 after 4 h and 14-17 days later) in 34 healthy participants.

Effect of gastric volume or emptying on meal-related symptoms after liquid nutrients in obesity: a pharmacologic study.

Background & Aims: Altered postprandial satiation influences food intake in obesity. The aim of this study was to evaluate the contribution of gastric motor functions to intra- and postprandial symptoms in obese, otherwise healthy, people.

Methods: In a randomized, parallel-group, double-blind design, 40 obese (body mass index>30 kg/m2) healthy volunteers (n=10/group) received intravenous saline (placebo), atropine (.

Effect of alvimopan and codeine on gastrointestinal transit: a randomized controlled study.

Unlabelled: background & aims: Opiate bowel dysfunction is a significant clinical problem. Our aim was to evaluate the ability of a peripheral mu-opioid antagonist, alvimopan, to reverse the effect of codeine on gastric, small-bowel, and colonic transit time in healthy volunteers.

Methods: Seventy-four healthy participants (43 women) were randomized in a double-blind, placebo-controlled manner to 1 of 4 groups: alvimopan 12 mg twice daily in the presence and absence of codeine sulfate 30 mg 4 times/day, or codeine or placebo alone.

Contributions of gastric volumes and gastric emptying to meal size and postmeal symptoms in functional dyspepsia.

Background & Aims: The aim was to assess relative contributions of gastric volumes (GV) and gastric emptying (GE) to meal size and postprandial symptoms in patients with functional dyspepsia.

Methods: Patients with chronic upper gastrointestinal symptoms were prospectively evaluated. GV during fasting and after 300 mL Ensure was measured with 99m Tc-single-photon emission computed tomography imaging and solid GE (99m Tc-egg) by scintigraphy.

Human embryonic stem cells possess immune-privileged properties.

Human embryonic stem cells (hESCs) are envisioned to be a major source for cell-based therapies. Efforts to overcome rejection of hESCs include nuclear transfer and collection of hESC banks representing the broadest diversity of major histocompatability complex (MHC) polymorphorisms. Surprisingly, immune responses to hESCs have yet to be experimentally evaluated.

Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders.

Background: The role of genetics in the phenotypic manifestations of irritable bowel syndrome (IBS) is unclear. Our aims were: (1) to compare the prevalence of polymorphisms of alpha 2 (alpha(2)) adrenoceptors, norepinephrine transporter, and serotonin transporter protein (soluble carrier protein member 4 (SLC6A4)) promoter in patients with lower functional gastrointestinal disorders (FGID) and in healthy controls; and (2) to test associations of these genetic variations with symptoms of IBS and high somatic symptom scores.

Methods: Validated bowel and somatic symptom questionnaires characterised the phenotype: 90 with IBS constipation (IBS-C), 128 IBS diarrhoea, 38 IBS alternating bowel function, and 20 chronic abdominal pain.

Effects of venlafaxine, buspirone, and placebo on colonic sensorimotor functions in healthy humans.

Background & Aims: We have shown that venlafaxine-XR, a serotonin (5-HT) and norepinephrine reuptake inhibitor, enhanced gastric accommodation, whereas buspirone, a 5-HT(1A) receptor agonist, reduced postprandial symptoms after a fully satiating meal. Our aim was to compare the effects of venlafaxine, buspirone, and placebo on colonic sensorimotor functions in healthy adults.

Methods: In this randomized, double-blind, parallel-group, placebo-controlled trial of 60 healthy adults, we assessed the effects of oral venlafaxine, 150 mg; buspirone, 20 mg; and placebo on colonic sensorimotor functions.

Independent influences of body mass and gastric volumes on satiation in humans.

Background & Aims: We assessed the association of body mass and gastric volumes (fasting and postprandial) with satiation and postprandial symptoms.

Methods: Healthy obese and nonobese subjects underwent measurement of caloric intake at maximum satiation; postprandial symptoms were measured with visual analogue scales 30 minutes after a meal. Gastric volume during fasting and after 300 mL of Ensure was measured with technetium-99m single-photon emission computed tomography imaging.

Effects of asimadoline, a kappa-opioid agonist, on satiation and postprandial symptoms in health.

Aim: To evaluate the effect of single administrations of asimadoline, a kappa-opioid agonist, on satiation volume, postprandial symptoms and gastric volumes.

Methods: Healthy subjects received oral placebo, or 0.5 or 1.

Effects of a kappa-opioid agonist, asimadoline, on satiation and GI motor and sensory functions in humans.

To compare the effects of the kappa-opioid agonist asimadoline and placebo on visceral sensation and gastrointestinal (GI) motor functions in humans, 91 healthy participants were randomized in a double-blind fashion to 0.15, 0.5, or 1.

In vitro chemo- and radio-resistance in small cell lung cancer correlates with cell adhesion and constitutive activation of AKT and MAP kinase pathways.

Most small cell lung cancer (SCLC) patients relapse within 12 months of starting combination chemotherapy plus radio-therapy, due to the development of acquired chemo- and radio-resistance. This phenomenon relates to the induction of tumour differentiation, resulting in apoptosis-resistant, morphologically variant (v-SCLC) cells, which lack the neuroendocrine expression of classic (c-) SCLC cells. In this study spontaneously adherent SCLC sublines were shown by differential gene expression analysis to provide an in vitro model of variant differentiation in SCLC, with down-regulation of neuroendocrine markers and up-regulation of epithelial differentiation markers cyclin D1, endothelin, the cell adhesion molecules CD 44 and integrin subunits alpha2, beta3 and beta4.

A nutrient drink test to assess maximum tolerated volume and postprandial symptoms: effects of gender, body mass index and age in health.

To assess the effects of age, gender and body mass index on the maximum tolerated volume of a nutrient drink and postprandial symptoms in health. Healthy adolescents (15 M, 15 F, aged 13-17 years) and adults (15 M, 25 F, aged 19-51 years) ingested Ensure (1 kcal mL-1) at a rate of 30 mL min-1. The maximum tolerated volume was recorded.

Viscoelastic properties of the human colon.

Our objectives were to characterize colonic viscoelastic properties of the human descending colon by assessing pressure-volume (P-V) relationships during barostatic balloon distension. In 16 healthy subjects, a balloon was inflated to 44 mmHg and then deflated to 0 mmHg in 4-mmHg steps at 10, 30, and 60 ml/min, allowing volume fluctuations to stabilize at each pressure increment. Thereafter, these "quasi-static" P-V curves were compared with "dynamic" distensions to 300 ml, at 1 and 10 ml/s, before and after intravenous atropine in another five subjects.

Effects of a serotonin 5-HT(4) receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans.

Background: Serotonin 5-HT(4) receptors are located on enteric cholinergic neurones and may regulate peristalsis. 5-HT(4) receptors on primary afferent neurones have been postulated to modulate visceral sensation. While 5-HT(4) agonists are used as prokinetic agents, the physiological role of 5-HT(4) receptors in the human gut is unknown.

GATA-3 significantly downregulates IFN-gamma production from developing Th1 cells in addition to inducing IL-4 and IL-5 levels.

IL-12 and IL-4 are dominant factors driving the development of Th1 and Th2 cells, respectively, by their activation of Stat-4 and Stat-6 signaling molecules. Activation of Stat factors, although specific, is a rapid event; however, differentiation of Th cells takes place over several days. Thus, it is unlikely that the expression of effector cytokines is mediated solely by Stat factors.

Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein.

Following induction of experimental encephalomyelitis with a T-cell clone, L10C1, that is specific for the myelin basic protein epitope p87-99, the inflammatory infiltrate in the central nervous system contains a diverse collection of T cells with heterogeneous receptors. We show here that when clone L10C1 is tolerized in vivo with an analogue of p87-99, established paralysis is reversed, inflammatory infiltrates regress, and the heterogeneous T-cell infiltrate disappears from the brain, with only the T-cell clones that incited disease remaining in the original lesions. We found that antibody raised against interleukin-4 reversed the tolerance induced by the altered peptide ligand.

Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE).

Experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, is an autoimmune disorder seen in mice and rats following immunization with myelin basic protein (MBP) or MBP-derived peptides. IFN-gamma, a cytokine produced by a variety of cells, is involved in many inflammatory and immune regulatory events. Contradictory results concerning exacerbations and the disease course were seen comparing injections of IFN-gamma in humans suffering from multiple sclerosis to studies using anti-IFN-gamma Abs in mice with EAE.

The integrity of the cholecystokinin receptor gene in gallbladder disease and obesity.

Cholesterol gallstone disease and obesity are common and often associated disorders that could be affected by dysfunction of the receptor for cholecystokinin (CCK). Extending earlier studies that identified a defect at the level of receptor-G protein coupling in cholesterol gallstone disease, we characterized the primary structure of the gallbladder CCK receptor in patients undergoing a cholecystectomy. Represented were patients with cholesterol gallstones, as well as controls with pigment gallstones or without gallbladder disease.

Levels of peripheral T cell tolerance induced by different doses of tolerogen.

Antigen-specific immunosuppression requires an understanding of the parameters that control peripheral T cell tolerance. A liver-specific inducible promoter was used to drive the expression of the major histocompatibility complex antigen Kb in transgenic mice. Minute amounts of Kb, expressed exclusively on hepatocytes, induced tolerance by partial down-regulation of the T cell receptor (TCR) on the self-reactive CD8+ cells.