Irritable bowel syndrome (IBS) is a common disorder characterized by altered gut function and often is accompanied by comorbid anxiety. Although changes in the gut microbiota have been documented, ...their relevance to the clinical expression of IBS is unknown. To evaluate a functional role for commensal gut bacteria in IBS, we colonized germ-free mice with the fecal microbiota from healthy control individuals or IBS patients with diarrhea (IBS-D), with or without anxiety, and monitored gut function and behavior in the transplanted mice. Microbiota profiles in recipient mice clustered according to the microbiota profiles of the human donors. Mice receiving the IBS-D fecal microbiota showed a taxonomically similar microbial composition to that of mice receiving the healthy control fecal microbiota. However, IBS-D mice showed different serum metabolomic profiles. Mice receiving the IBS-D fecal microbiota, but not the healthy control fecal microbiota, exhibited faster gastrointestinal transit, intestinal barrier dysfunction, innate immune activation, and anxiety-like behavior. These results indicate the potential of the gut microbiota to contribute to both intestinal and behavioral manifestations of IBS-D and suggest the potential value of microbiota-directed therapies in IBS patients.
Although intercellular bridges resulting from incomplete cytokinesis were discovered in somatic Drosophila tissues decades ago, the impact of these structures on intercellular communication and ...tissue biology is largely unknown. In this work, we demonstrate that the ~250-nanometer-diameter somatic ring canals permit diffusion of cytoplasmic contents between connected cells and across mitotic clone boundaries and enable the equilibration of protein between transcriptionally mosaic follicle cells in the Drosophila ovary. We obtained similar, although more restricted, results in the larval imaginai discs. Our work illustrates the lack of cytoplasmic autonomy in these tissues and suggests a role for somatic ring canals in promoting homogeneous protein expression within the tissue.
G protein-coupled receptors (GPCRs) are considered to function primarily at the plasma membrane, where they interact with extracellular ligands and couple to G proteins that transmit intracellular ...signals. Consequently, therapeutic drugs are designed to target GPCRs at the plasma membrane. Activated GPCRs undergo clathrin-dependent endocytosis. Whether GPCRs in endosomes control pathophysiological processes in vivo and are therapeutic targets remains uncertain. We investigated the contribution of endosomal signaling of the calcitonin receptor-like receptor (CLR) to pain transmission. Calcitonin gene-related peptide (CGRP) stimulated CLR endocytosis and activated protein kinase C (PKC) in the cytosol and extracellular signal regulated kinase (ERK) in the cytosol and nucleus. Inhibitors of clathrin and dynamin prevented CLR endocytosis and activation of cytosolic PKC and nuclear ERK, which derive from endosomal CLR. A cholestanol-conjugated antagonist, CGRP8–37, accumulated in CLR-containing endosomes and selectively inhibited CLR signaling in endosomes. CGRP caused sustained excitation of neurons in slices of rat spinal cord. Inhibitors of dynamin, ERK, and PKC suppressed persistent neuronal excitation. CGRP8–37–cholestanol, but not unconjugated CGRP8–37, prevented sustained neuronal excitation. When injected intrathecally to mice, CGRP8–37–cholestanol inhibited nociceptive responses to intraplantar injection of capsaicin, formalin, or complete Freund’s adjuvant more effectively than unconjugated CGRP8–37. Our results show that CLR signals from endosomes to control pain transmission and identify CLR in endosomes as a therapeutic target for pain. Thus, GPCRs function not only at the plasma membrane but also in endosomes to control complex processes in vivo. Endosomal GPCRs are a drug target that deserve further attention.
Ring canals connecting Drosophila germline, follicle and imaginal disc cells provide direct contact of cytoplasm between cells. To date, little is known about the formation, structure, or function of ...the somatic ring canals present in follicle and imaginal disc cells. Here, we show by confocal and electron microscopy that Pavarotti kinesin-like protein and Visgun are stable components of somatic ring canals. Using live-cell confocal microscopy, we show that somatic ring canals form from the stabilization of mitotic cleavage furrows. In contrast to germline cells, syncytial follicle cells do not divide synchronously, are not maximally branched and their ring canals do not increase in size during egg chamber development. We show for the first time that somatic ring canals permit exchange of cytoplasmic proteins between follicle cells. These results provide insight into the composition and function of ring canals in somatic cells, implying a broader functional significance for syncytial organization of cells outside the germline.
Objective: We explored the dynamic relationship between cognition and obsession severity during 2 different treatments for primary obsessions, examining evidence for the hypothesis that symptom ...reduction would be mediated by appraisals about the meaning of unwanted intrusive thoughts. Method: Data from a recent randomized controlled trial were analyzed with traditional mediation analyses and latent difference scores. The trial had compared cognitive behavioral therapy and stress management training among 73 patients with primary obsessions. Mediation analyses were conducted with pre-, post-, and follow-up scores on the Obsessions subscale of the Yale-Brown Obsessive Compulsive Scale and 2 self-report measures of cognitions related to obsessive-compulsive disorder. Bivariate dual change score (BDCS) analyses were conducted with weekly assessments of obsession severity and appraisals of personal significance. Results: Change in most cognitions related to obsessive-compulsive disorder accounted for reduction in obsession severity during the course of treatment and follow-up. BDCS analyses of the longitudinal data, however, indicated prior obsession severity is a leading indicator of subsequent change in appraisals, rather than the reverse. Analyses also suggested cognitive behavioral therapy is more effective than stress management training when symptoms are severe and that stress management training is more advantageous in the context of mild-to-moderate obsessions. Conclusions: The traditional mediation analysis indicated that appraisal change is a tenable mediator of obsession reduction, but the BDCS results raise doubts about the causal direction. The results highlight the importance of examining the dynamic relationship between putative mediators and outcome variables, and they suggest interesting hypotheses about mechanisms in treatment of obsessions.
The efficacy of contemporary cognitive therapy for obsessive–compulsive disorder (OCD) has only recently been investigated. The current study compares exposure and response prevention (ERP) and ...cognitive behavior therapy (CBT) delivered in an individual format. Participants were randomly assigned to the 12 consecutive-week CBT or ERP treatment. Based on 59 treatment completers, there was no significant difference in YBOCS scores between CBT and ERP at post-treatment or at 3-month follow-up. A higher percentage of CBT participants obtained recovered status at post-treatment (67%) and at follow-up (76%), compared to ERP participants (59% and 58%, respectively), but the difference was not significant. Effect sizes (ESs) were used to compare the results of the current study with a previous study conducted at our center that utilized group CBT and ERP treatments, as well as other controlled trials that have compared CBT and ERP. The significance of these results is discussed and a comparison is made with the existing literature.
Nitric oxide (NO) production by the vascular endothelium maintains an essential antiinflammatory, cytoprotective influence on the blood vessel wall. A key component of this activity is attributed to ...prevention of leukocyte-endothelial cell interactions, yet the underlying mechanisms remain unclear. The NO receptor, soluble guanylate cyclase (sGC), is expressed in endothelial cells but fulfils an unknown function. Therefore, we used intravital microscopy in mesenteric postcapillary venules from WT and endothelial nitric oxide synthase (eNOS) knockout (eNOS-/-) mice, and an sGC activator (BAY 41-2272), to investigate a potential role for sGC in the regulation of adhesion molecule expression and leukocyte recruitment. Leukocyte rolling and adhesion was 6-fold greater in eNOS-/-than WT animals. BAY 41-2272 and the NO-donor, diethylamine-NONOate, reduced leukocyte rolling and adhesion in eNOS-/-mice to levels observed in WT animals. These effects were blocked by the sGC inhibitor ODQ 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one, which itself caused a 6-fold increase in leukocyte rolling and adhesion in WT mice. Increased leukocyte rolling and adhesion in IL-1β-treated mice was also inhibited by BAY 41-2272. Fluorescence-activated cell sorting analysis in vitro and a specific P-selectin neutralizing antibody in vivo revealed that selective down-regulation of P-selectin expression accounted for the anti-adhesive effects of sGC activation. These data demonstrate that sGC plays a key antiinflammatory role by inhibiting P-selectin expression and leukocyte recruitment.
Relatively little is known about the long-term durability of group treatments for obsessive-compulsive disorder (OCD) and contemporary cognitive treatments. The current study investigated the 2-year ...follow-up results for participants who completed randomized trials of group or individual treatment and received either cognitive therapy (CT) or exposure plus response prevention (ERP). Yale-Brown Obsessive Compulsive Scale (YBOCS) scores for individual ERP and CT were not significantly different over 2 years. However, YBOCS scores were consistently lower over time for group ERP participants than for group CT participants. With a single exception in the group treatment study, secondary cognitive and depression scores were stable, indicating that gains achieved during acute treatment were maintained over 2 years. Less than 10% of treatment completers relapsed in each of the treatment trials. Approximately 50% of the completer sample was rated as recovered at 2 years. Additionally, a tentative cross-study comparison suggests that CT was better tolerated and resulted in less dropout than did ERP. Despite the overall positive results, efficacy of OCD treatments has reached a plateau and may require a fresh perspective to move forward.
In recent times, the perception of functional gastrointestinal disorders such as irritable bowel syndrome (IBS) has shifted fundamentally. Such disorders are now thought of as serious diseases ...characterized by perturbations in the neuronal regulation of gastrointestinal function. The concept of visceral hypersensitivity, the characterization of neuronal networks in the ‘brain–gut axis’ and the identification of several novel 5-HT-mediated mechanisms have contributed to this shift. Here, we review how some of the more promising of these new mechanisms (e.g. those involving 5-HT transporters and the 5-HT2B , 5-HT7 and putative 5-HT1p receptors) might lead to a range of second-generation therapies that could revolutionize the treatment of functional gastrointestinal disorders, particularly IBS.
The European winters of 2017–18 and 2018–19 were not climatically extreme, but both winters had a major sudden stratospheric warming (SSW). In February 2018, an SSW led to an intense cold outbreak ...across Europe and further spells of cold weather in March. The SSW of January 2019, although well predicted and expected to increase the chance of a cold end to winter, apparently produced little impact. In this study, we examine the performance of the Met Office seasonal prediction system in these winters, and the influences that led to these outcomes. To achieve this latter objective, sets of numerical experiments are performed in which the tropical troposphere and the extratropical stratosphere are relaxed towards their observed state, allowing the influence of each on the North Atlantic‐European atmospheric circulation to be identified. Using these experiments, we show that the SSWs had similar impacts in each case, creating a signal of easterly surface wind anomalies in the weeks following the event. In contrast, tropical influences were opposite in the two winters, acting to strengthen the easterly signal at the end of February 2018 and opposing it in January 2019. The different apparent responses to the two events therefore came about largely through tropical tropospheric variability. Furthermore, we highlight the importance of a very strong cycle of the Madden‐Julian Oscillation (MJO) in late January and early February 2018 as an important driver for the February 2018 SSW. MJO teleconnections appear to have been critical in creating the large mid‐latitude wave 2 amplitude that has been identified as the immediate cause of this event.
In February 2018, a strong negative North Atlantic Oscillation brought freezing weather to Europe following a sudden stratospheric warming (SSW). Yet the January 2019 SSW apparently had only a small impact. Here we explain these differences as the result of prevailing tropical influences—aiding cold weather in one case and inhibiting it in the other. Furthermore, we reveal a key role for the Madden‐Julian Oscillation in triggering the February 2018 SSW that led to European cold spell.
PDF
