Lessons and Untapped Potential of Smartphone-Based Physical Activity Interventions for Mental Health: Narrative Review.

BACKGROUND: Physical activity has well-known and broad health benefits, including antidepressive and anxiolytic effects. However, only approximately half of Americans meet even the minimum exercise recommendations. Individuals with anxiety, depression, or related conditions are even less likely to do so. With the advent of mobile sensors and phones, experts have quickly noted the utility of technology for the enhanced measurement of and intervention for physical activity. In addition to being more accessible than in-person approaches, technology-driven interventions may uniquely engage key mechanisms of behavior change such as self-awareness. OBJECTIVE: This study aims to provide a narrative overview and specific recommendations for future research on smartphone-based physical activity interventions for psychological disorders or concerns. METHODS: In this paper, we summarized early efforts to adapt and test smartphone-based or smartphone-supported physical activity interventions for mental health. The included articles described or reported smartphone-delivered or smartphone-supported interventions intended to increase physical activity or reduce sedentary behavior and included an emotional disorder, concern, or symptom as an outcome measure. We attempted to extract details regarding the intervention designs, trial designs, study populations, outcome measures, and inclusion of adaptations specifically for mental health. In taking a narrative lens, we drew attention to the type of work that has been done and used these exemplars to discuss key directions to build on. RESULTS: To date, most studies have examined mental health outcomes as secondary or exploratory variables largely in the context of managing medical concerns (eg, cancer and diabetes). Few trials have recruited psychiatric populations or explicitly aimed to target psychiatric concerns. Consequently, although there are encouraging signals that smartphone-based physical activity interventions could be feasible, acceptable, and efficacious for individuals with mental illnesses, this remains an underexplored area. CONCLUSIONS: Promising avenues for tailoring validated smartphone-based interventions include adding psychoeducation (eg, the relationship between depression, physical activity, and inactivity), offering psychosocial treatment in parallel (eg, cognitive restructuring), and adding personalized coaching. To conclude, we offer specific recommendations for future research, treatment development, and implementation in this area, which remains open and promising for flexible, highly scalable support.

Prospective examination of psychological risk and maintenance factors for body image distress after mastectomy with immediate breast reconstruction.

Reconstructive breast surgery aims to improve body image following mastectomy, yet many women experience ongoing body image distress (BID). The relationship between the esthetic outcome of reconstructive surgery with BID has been underexplored in mastectomy. This study aimed to assess whether reconstruction outcome following mastectomy is associated with post-surgery BID, and to examine potential psychological risk and maintenance factors for BID above reconstruction outcome. In 49 women undergoing mastectomy with immediate breast reconstruction, we prospectively assessed hypothesized pre-surgery psychological risk factors and post-surgery maintenance factors for post-surgery BID. Reconstruction outcome was assessed via blind surgeon ratings of post-surgery photographs. Surgeon-rated reconstruction outcome was uncorrelated with BID, or with patients' ratings of surgical outcome. Higher pre-surgery depressive symptoms and lower pre-surgery patient expectations for reconstruction predicted greater post-surgery BID, above reconstruction outcome. Post-surgery body checking also predicted greater BID, above reconstruction outcome. Results suggest that the medical team cannot assume their perception of reconstruction outcome matches the patient's view or degree of BID. If replicated, results point to potential psychological risk and maintenance factors that are stronger predictors of post-reconstruction BID, highlighting opportunities for light-touch prevention and intervention to reduce BID after mastectomy with breast reconstruction.

Body Image After Mastectomy Scale: A New Measure of Body Image Behaviors and Beliefs in Women Following Mastectomy.

Background: Body image distress is frequently reported by women after mastectomy and is associated with negative health outcomes, such as reduced quality of life, elevated depression and anxiety symptoms, and impaired sexual functioning. To reduce body image distress after mastectomy, we must first understand the factors that contribute to its development and maintenance. We therefore developed a new measure, the Body Image after Mastectomy Scale (BIMS), to comprehensively assess maladaptive appearance-related beliefs and behaviors (e.g., avoidance and rituals) that may trigger and maintain body image distress after mastectomy. Materials and Methods: Forty-seven female patients undergoing mastectomy with breast reconstruction completed the BIMS and other measures 3 months after breast reconstruction. Results: Evaluation of the BIMS' initial psychometric properties showed that the overall scale has good internal consistency and strong construct validity. Domain-specific subscales ranged in reliability from good to poor. Conclusions: The BIMS can be used clinically to identify cognitive and behavioral psychotherapy targets to reduce body image distress resulting from mastectomy. It can also be used in research to identify factors that contribute to the development and maintenance of body image distress after mastectomy. ClinicalTrials.gov identifier: NCT03428399.

Body dysmorphic disorder and self-esteem: a meta-analysis.

OBJECTIVE: Body dysmorphic disorder (BDD) is associated with low self-esteem. The aim of this meta-analysis was to examine the strength of the cross-sectional relationship between BDD symptom severity and global self-esteem in individuals with BDD, mentally healthy controls, community or student samples, and cosmetic surgery patients. Moreover, the role of depressive symptom severity in this relationship and other moderating factors were investigated. METHODS: A keyword-based literature search was performed to identify studies in which BDD symptoms and global self-esteem were assessed. Random effects meta-analysis of Fisher's z-transformed correlations and partial correlations controlling for the influence of depressive symptom severity was conducted. In addition to meta-analysis of the observed effects, we corrected the individual correlations for variance restrictions to address varying ranges of BDD symptom severity across samples. RESULTS: Twenty-five studies with a total of 6278 participants were included. A moderately negative relationship between BDD symptom severity and global self-esteem was found (r = -.42, CI = [-.48, -.35] for uncorrected correlations, r = -.45, CI = [-.51, -.39] for artifact-corrected correlations). A meta-analysis of partial correlations revealed that depressive symptom severity could partly account for the aforementioned relationship (pr = -.20, CI = [-.25, -.15] for uncorrected partial correlations, pr = -.23, CI = [-.28, -.17] for artifact-corrected partial correlations). The sample type (e.g., individuals with BDD, mentally healthy controls, or community samples) and diagnosis of BDD appeared to moderate the relationship only before artifact correction of effect sizes, whereas all moderators were non-significant in the meta-analysis of artifact-corrected correlations. CONCLUSIONS: The findings demonstrate that low self-esteem is an important hallmark of BDD beyond the influence of depressive symptoms. It appears that negative evaluation in BDD is not limited to appearance but also extends to other domains of the self. Altogether, our findings emphasize the importance of addressing self-esteem and corresponding core beliefs in prevention and treatment of BDD.

TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation.

The TSC complex is a critical negative regulator of the small GTPase Rheb and mTORC1 in cellular stress signaling. The TSC2 subunit contains a catalytic GTPase activating protein domain and interacts with multiple regulators, while the precise function of TSC1 is unknown. Here we provide a structural characterization of TSC1 and define three domains: a C-terminal coiled-coil that interacts with TSC2, a central helical domain that mediates TSC1 oligomerization, and an N-terminal HEAT repeat domain that interacts with membrane phosphatidylinositol phosphates (PIPs). TSC1 architecture, oligomerization, and membrane binding are conserved in fungi and humans. We show that lysosomal recruitment of the TSC complex and subsequent inactivation of mTORC1 upon starvation depend on the marker lipid PI3,5P2, demonstrating a role for lysosomal PIPs in regulating TSC complex and mTORC1 activity via TSC1. Our study thus identifies a vital role of TSC1 in TSC complex function and mTORC1 signaling.

Treatment utilization and treatment barriers in individuals with body dysmorphic disorder.

BACKGROUND: Although effective treatments are available, most individuals with body dysmorphic disorder (BDD) do not receive an appropriate diagnosis or treatment. We aimed to examine treatment utilization and barriers to treatment, and to identify associated socio-demographic and clinical characteristics. METHODS: German individuals completed an online self-report survey of appearance concerns. A sample of N = 429 individuals met criteria for BDD. We examined the frequency of treatment utilization and barriers, analyzed comparisons between treated and untreated individuals and assessed the relationships of socio-demographic and clinical features with mental health treatment utilization and treatment barriers, respectively. RESULTS: Only 15.2% of the individuals with BDD had been diagnosed with BDD, and lifetime rates of mental health treatment were low (39.9%). Individuals endorsed multiple barriers to mental health treatment, especially shame, low perceived need and a preference for cosmetic and medical treatments. Associated features were identified, including age, a BDD diagnosis, body dysmorphic symptom severity, a likely major depressive disorder, prior cosmetic surgery, and insight. CONCLUSIONS: The results of this largest study to date highlight that BDD is still underrecognized and undertreated even in a country with extensive mental health care and few financial barriers. We discuss modifiable factors and strategies to foster awareness of BDD in sufferers and professionals to improve treatment dissemination and to reduce treatment barriers.

Inhibitor of Apoptosis Protein-1 Regulates Tumor Necrosis Factor-Mediated Destruction of Intestinal Epithelial Cells.

BACKGROUND AND AIMS: Tumor necrosis factor (TNF) is a cytokine that promotes inflammation and contributes to pathogenesis of inflammatory bowel diseases. Unlike other cells and tissues, intestinal epithelial cells undergo rapid cell death upon exposure to TNF, by unclear mechanisms. We investigated the roles of inhibitor of apoptosis proteins (IAPs) in the regulation of TNF-induced cell death in the intestinal epithelium of mice and intestinal organoids. METHODS: RNA from cell lines and tissues was analyzed by quantitative polymerase chain reaction, protein levels were analyzed by immunoblot assays. BIRC2 (also called cIAP1) was expressed upon induction from lentiviral vectors in young adult mouse colon (YAMC) cells. YAMC cells, the mouse colon carcinoma cell line MC38, the mouse macrophage cell line RAW 264.7, or mouse and human organoids were incubated with second mitochondrial activator of caspases (Smac)-mimetic compound LCL161 or recombinant TNF-like weak inducer of apoptosis (TNFSF12) along with TNF, and cell death was quantified. C57BL/6 mice with disruption of Xiap, Birc2 (encodes cIAP1), Birc3 (encodes cIAP2), Tnfrsf1a, or Tnfrsf1b (Tnfrsf1a and b encode TNF receptors) were injected with TNF or saline (control); liver and intestinal tissues were collected and analyzed for apoptosis induction by cleaved caspase 3 immunohistochemistry. We also measured levels of TNF and alanine aminotransferase in serum from mice. RESULTS: YAMC cells, and mouse and human intestinal organoids, died rapidly in response to TNF. YAMC and intestinal crypts expressed lower levels of XIAP, cIAP1, cIAP2, and cFLIP than liver tissue. Smac-mimetics reduced levels of cIAP1 and XIAP in MC38 and YAMC cells, and Smac-mimetics and TNF-related weak inducer of apoptosis increased TNF-induced cell death in YAMC cells and organoids-most likely by sequestering and degrading cIAP1. Injection of TNF greatly increased levels of cell death in intestinal tissue of cIAP1-null mice, compared with wild-type C57BL/6 mice, cIAP2-null mice, or XIAP-null mice. Excessive TNF-induced cell death in the intestinal epithelium was mediated TNF receptor 1. CONCLUSIONS: In a study of mouse and human cell lines, organoids, and tissues, we found cIAP1 to be required for regulation of TNF-induced intestinal epithelial cell death and survival. These findings have important implications for the pathogenesis of TNF-mediated enteropathies and chronic inflammatory diseases of the intestine.

Cigarette smoking in obsessive-compulsive disorder and unaffected parents of OCD patients.

BACKGROUND: Cigarette smoking is more prevalent among individuals with psychiatric disorders than the general population. Obsessive-compulsive disorder (OCD) may be an intriguing exception, although no recent study has investigated this hypothesis in OCD patients. Moreover, it is unknown whether reduced smoking rates are present in unaffected first-degree relatives of OCD patients. METHODS: We assessed smoking prevalence in adults with OCD and unaffected parents of youth with OCD (PYOCD). To this end, 113 adults with OCD completed online questionnaires assessing symptom severity and smoking status. Smoking status was obtained from an independent sample of 210 PYOCD assessed for psychiatric diagnoses. RESULTS: Smoking prevalence rates in adults with OCD (13.3%; n=15) and PYOCD (9.5%; n=20) samples were significantly lower than those found in representative samples of the general population (19-24%, all P<.001) and Axis I disorders (36-64%; all P<.001). There were no smokers in the adult OCD subset without clinically significant depressive symptoms (n=54). CONCLUSION: Low prevalence of smoking in OCD may be familial and unique among psychiatric disorders, and might represent a possible state-independent OCD marker. Hypotheses concerning the uncharacteristically low prevalence rates are discussed with relation to OCD phenomenology and pathophysiology.

Modular cognitive-behavioral therapy for body dysmorphic disorder: a randomized controlled trial.

There are few effective treatments for body dysmorphic disorder (BDD) and a pressing need to develop such treatments. We examined the feasibility, acceptability, and efficacy of a manualized modular cognitive-behavioral therapy for BDD (CBT-BDD). CBT-BDD utilizes core elements relevant to all BDD patients (e.g., exposure, response prevention, perceptual retraining) and optional modules to address specific symptoms (e.g., surgery seeking). Thirty-six adults with BDD were randomized to 22 sessions of immediate individual CBT-BDD over 24 weeks (n=17) or to a 12-week waitlist (n=19). The Yale-Brown Obsessive-Compulsive Scale Modified for BDD (BDD-YBOCS), Brown Assessment of Beliefs Scale, and Beck Depression Inventory-II were completed pretreatment, monthly, posttreatment, and at 3- and 6-month follow-up. The Sheehan Disability Scale and Client Satisfaction Inventory (CSI) were also administered. Response to treatment was defined as ≥30% reduction in BDD-YBOCS total from baseline. By week 12, 50% of participants receiving immediate CBT-BDD achieved response versus 12% of waitlisted participants (p=0.026). By posttreatment, 81% of all participants (immediate CBT-BDD plus waitlisted patients subsequently treated with CBT-BDD) met responder criteria. While no significant group differences in BDD symptom reduction emerged by Week 12, by posttreatment CBT-BDD resulted in significant decreases in BDD-YBOCS total over time (d=2.1, p<0.0001), with gains maintained during follow-up. Depression, insight, and disability also significantly improved. Patient satisfaction was high, with a mean CSI score of 87.3% (SD=12.8%) at posttreatment. CBT-BDD appears to be a feasible, acceptable, and efficacious treatment that warrants more rigorous investigation.

Anhedonia in obsessive-compulsive disorder: beyond comorbid depression.

Obsessive-compulsive disorder (OCD) has been linked to reward dysfunctions, highlighting a possible role of anhedonia in OCD. Surprisingly, anhedonia in OCD has never been evaluated. Moreover, although nicotine typically has anti-anhedonic effects, anecdotal reports suggest low prevalence rates of smoking in OCD. To address these two phenomena, 113 individuals with OCD completed a battery of questionnaires assessing symptom severity, anhedonia, and smoking. 28.3% of the sample met criteria for clinically significant anhedonia, which correlated with Y-BOCS scores (r=0.44), even when controlling for depressive symptoms. 13.3% of the sample endorsed current smoking, a lower rate than seen in psychiatric disorders (40-90%) and the general adult population (19%). Results highlight high rates of anhedonia and yet reduced prevalence of smoking in OCD. In contrast to the known positive association between anhedonia and smoking, a negative association emerged. Future research is needed to address the unique interface between anhedonia and reward responsiveness in OCD. Potential clinical implications are discussed.

The relationship between perceived social support and severity of body dysmorphic disorder symptoms: the role of gender / O efeito do gênero sobre a relação entre suporte social apreendido e gravidade dos sintomas do transtorno dismórfico corporal

OBJECTIVE: Whether social support is associated with severity of body dysmorphic symptoms is unknown. To address this gap in the literature, the present study aims to examine the association between three domains of perceived social support (i.e., family, friends, and significant others) and severity of body dysmorphic disorder symptoms. METHOD: Participants (N = 400) with symptoms consistent with diagnosis of body dysmorphic disorder completed measures of symptomatology and social support via the internet. RESULTS: More perceived social support from friends and significant others was associated with less severe body dysmorphic disorder symptoms for males, and more perceived social support from family and friends was associated with less severe body dysmorphic disorder symptoms among females. Additionally, gender moderated the association between perceived social support from significant others and symptom severity, such that perceived social support from a significant other was significantly negatively associated with body dysmorphic symptom severity in males, but not females. CONCLUSION: The present study implicates social support as an important area of future body dysmorphic disorder research.

OBJETIVO: Não há informação sobre o impacto do suporte social apreendido sobre a gravidade dos sintomas do transtorno dismórfico corporal. A fim de investigar essa relação, este estudo visa avaliar a associação entre três domínios do suporte social apreendido (familiares, amigos, e relacionamentos amorosos significativos) e a gravidade dos sintomas do transtorno dismórfico corporal. MÉTODO: Os participantes (N = 400) com sintomas compatíveis com o diagnóstico de transtorno dismórfico corporal preencheram questionários sobre seus sintomas e suporte social via internet. RESULTADOS: Foi encontrada correlação inversa estatisticamente significativa entre a apreensão do suporte social por parte de amigos e relacionamentos amorosos e a gravidade dos sintomas de transtorno dismórfico corporal em homens. Do mesmo modo, foi encontrada correlação inversa e estatisticamente significativa entre a apreensão do suporte social por parte de familiares e amigos e gravidade dos sintomas de transtorno dismórfico corporal em mulheres. Além disso, gênero foi um moderador da associação entre apreensão do suporte social por parte de relacionamentos amorosos e gravidade dos sintomas de transtorno dismórfico corporal. A apreensão de suporte social por parte de relacionamentos amorosos mostrou-se inversamente associada à gravidade dos sintomas de transtorno dismórfico corporal em homens, mas não em mulheres. CONCLUSÃO: Este estudo demonstra a importância da avaliação do suporte social apreendido em estudos futuros envolvendo pacientes com transtorno dismórfico corporal.

Treatment utilization and barriers to treatment engagement among people with body dysmorphic symptoms.

OBJECTIVES: Body dysmorphic disorder (BDD) is characterized by an excessive preoccupation with an imagined or minor appearance flaw. Many aspects of BDD remain unknown, such as rates of treatment utilization, types of treatment sought, and barriers to treatment. The present study sought to examine rates and patterns of treatment utilization as well as barriers to treatment among individuals with body dysmorphic symptoms. METHODS: The present study consists of 401 individuals with symptoms consistent with a diagnosis of BDD who completed self-reported measures of treatment utilization and barriers to treatment in an internet survey. RESULTS: Consistent with past research, results showed that individuals with probable BDD reported seeking non-mental health treatments for BDD (e.g., plastic surgery). Additionally, an examination of treatment barriers demonstrated significant barriers for the sample for the three domains examined: logistic and financial; stigma, shame, and discrimination; and treatment skepticism. Secondary analyses revealed a differential endorsement of treatment barriers across ethnic groups for all three barrier domains. CONCLUSION: These data suggest that BDD is still an underrecognized disorder with marked barriers to treatment. Increased education and dissemination efforts are warranted.

Updates on the prevalence of body dysmorphic disorder: a population-based survey.

Body dysmorphic disorder (BDD) is characterised by a preoccupation with perceived defects in one's appearance, which leads to significant distress and/or impairment. Although several studies have investigated the prevalence of BDD, many studies have methodological limitations (e.g., small sample sizes and student populations), and studies on the prevalence of BDD in the general population are limited. In the current study, 2510 individuals participated in a representative German nationwide survey. Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for BDD and associated characteristics such as suicidality and the prevalence of plastic surgeries were examined using self-report questionnaires. The prevalence of current BDD was 1.8% (N=45). Further, individuals with BDD, relative to individuals without BDD, reported significantly more often a history of cosmetic surgery (15.6% vs. 3.0%), higher rates of suicidal ideation (31.0% vs. 3.5%) and suicide attempts due to appearance concerns (22.2% vs. 2.1%). The current findings are consistent with previous findings, indicating that self-reported BDD is a common disorder associated with significant morbidity.

Chemical crosslinking studies with the mouse Kcc1 K-Cl cotransporter.

Oligomerization, function, and regulation of unmodified mouse Kcc1 K-Cl cotransporter were studied by chemical crosslinking. Treatment of Xenopus oocytes and 293T cells expressing K-Cl cotransporter Kcc1 with several types of chemical cross-linkers shifted Kcc1 polypeptide to higher molecular weight forms. More extensive studies were performed with the amine-reactive disuccinyl suberate (DSS) and with the sulfhydryl-reactive bis-maleimidohexane (BMH). Kcc1 cross-linking was time-dependent in intact oocytes, and was independent of protein concentration in detergent lysates from oocytes or 293T cells. Kcc1 cross-linking by the cleavable cross-linker DTME was reversible. The N-terminal and C-terminal cytoplasmic tails of Kcc1 were not essential for Kcc1 crosslinking. PFO-PAGE and gel filtration revealed oligomeric states of uncrosslinked KCC1 corresponding in mobility to that of cross-linked protein. DSS and BMH each inhibited KCC1-mediated (86)Rb(+) uptake stimulated by hypotonicity or by N-ethylmaleimide (NEM) without reduction in nominal surface abundance of KCC1. These data add to evidence supporting the oligomeric state of KCC polypeptides.

Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition.

Multiple myeloma is an incurable plasma cell neoplasia characterized by the production of large amounts of monoclonal immunoglobulins. The proteasome inhibitor bortezomib (PS-341, Velcade) induces apoptosis in various malignant cells and has been approved for treatment of refractory multiple myeloma. Inhibition of the antiapoptotic transcription factor nuclear factor-kappaB (NF-kappaB) apparently contributes to the antitumor effects of bortezomib; however, this mechanism cannot fully explain the exceptional sensitivity of myeloma cells. Extensive protein synthesis as in myeloma cells is inherently accompanied by unfolded proteins, including defective ribosomal products (DRiPs), which need to be degraded by the ubiquitin-proteasome system. Therefore, we hypothesized that the proapoptotic effect of bortezomib in multiple myeloma is mainly due to the accumulation of unfolded proteins in cells with high protein biosynthesis. Using the IgG-secreting human myeloma cell line JK-6L and murine muH-chain-transfected Ag8.H myeloma cells, apoptosis induction upon proteasome inhibition was clearly correlated with the amount of immunoglobulin production. Preferentially in immunoglobulin-high myeloma cells, bortezomib triggered activation of caspases and induction of proapoptotic CHOP, a component of the terminal unfolded protein response induced by endoplasmic reticulum (ER) stress. In immunoglobulin-high cells, bortezomib increased the levels of proapoptotic Bax while reducing antiapoptotic Bcl-2. Finally, IgG-DRiPs were detected in proteasome inhibitor-treated cells. Hence, proteasome inhibitors induce apoptosis preferentially in cells with high synthesis rate of immunoglobulin associated with accumulation of unfolded proteins/DRiPs inducing ER stress. These findings further elucidate the antitumor activities of proteasome inhibitors and have important implications for optimizing clinical applications.

The prevalence of body dysmorphic disorder: a population-based survey.

BACKGROUND: Body dysmorphic disorder (BDD) is a highly distressing and impairing disorder characterized by a preoccupation with imagined or slight physical defects in appearance. Well designed studies on its prevalence and on base rates for diagnostic criteria are rare. Therefore this study aimed to reveal prevalence rates of BDD in the general population and to examine clinical features associated with BDD. METHOD: Of 4152 selected participants 2552, aged 14-99 years, participated in this German nationwide survey. Participants were carefully selected to ensure that the sample was representative; they were visited by a study assistant who provided instructions and help if needed. Participation rate was 62.3%. DSM-IV criteria for BDD, as well as subthreshold features (e.g. individuals who consider some part(s) of their body as ugly or disfigured, but do not fulfill all BDD criteria) were examined. We also assessed suicidal ideation associated with the belief of having an ugly body part, as well as the desire for cosmetic surgery. Furthermore, somatization symptoms were assessed. RESULTS: The prevalence of current BDD was 1.7% (CI 1.2-2.1%). Individuals with BDD reported higher rates of suicidal ideation (19% v. 3%) and suicide attempts due to appearance concerns (7% v. 1%) than individuals who did not meet criteria for BDD. Somatization scores were also increased in individuals with BDD, relative to those without. BDD was associated with lower financial income, lower rates of living with a partner, and higher rates of unemployment. CONCLUSIONS: Our study shows that self-reported BDD is relatively common and associated with significant morbidity.

Alkaline-shifted pHo sensitivity of AE2c1-mediated anion exchange reveals novel regulatory determinants in the AE2 N-terminal cytoplasmic domain.

The mouse anion exchanger AE2/SLC4A2 Cl(-)/HCO(-)(3) exchanger is essential to post-weaning life. AE2 polypeptides regulate pH(i), chloride concentration, cell volume, and transepithelial ion transport in many tissues. Although the AE2a isoform has been extensively studied, the function and regulation of the other AE2 N-terminal variant mRNAs of mouse (AE2b1, AE2b2, AE2c1, and AE2c2) have not been examined. We now present an extended analysis of AE2 variant mRNA tissue distribution and function. We show in Xenopus oocytes that all AE2 variant polypeptides except AE2c2 mediated Cl(-) transport are subject to inhibition by acidic pH(i) and to activation by hypertonicity and NH(+)(4). However, AE2c1 differs from AE2a, AE2b1, and AE2b2 in its alkaline-shifted pH(o)((50)) (7.70 +/- 0.11 versus 6.80 +/- 0.05), suggesting the presence of a novel AE2a pH-sensitive regulatory site between amino acids 99 and 198. Initial N-terminal deletion mutagenesis restricted this site to the region between amino acids 120 and 150. Further analysis identified AE2a residues 127-129, 130-134, and 145-149 as jointly responsible for the difference in pH(o)((50)) between AE2c1 and the longer AE2a, AE2b1, and AE2b2 polypeptides. Thus, AE2c1 exhibits a unique pH(o) sensitivity among the murine AE2 variant polypeptides, in addition to a unique tissue distribution. Physiological coexpression of AE2c1 with other AE2 variant polypeptides in the same cell should extend the range over which changing pH(o) can regulate AE2 transport activity.

Essential role of BCL9-2 in the switch between beta-catenin's adhesive and transcriptional functions.

beta-Catenin controls both cadherin-mediated cell adhesion and activation of Wnt target genes. We demonstrate here that the beta-catenin-binding protein BCL9-2, a homolog of the human proto-oncogene product BCL9, induces epithelial-mesenchymal transitions of nontransformed cells and increases beta-catenin-dependent transcription. RNA interference of BCL9-2 in carcinoma cells induces an epithelial phenotype and translocates beta-catenin from the nucleus to the cell membrane. The switch between beta-catenin's adhesive and transcriptional functions is modulated by phosphorylation of Tyr 142 of beta-catenin, which favors BCL9-2 binding and precludes interaction with alpha-catenin. During zebrafish embryogenesis, BCL9-2 acts in the Wnt8-signaling pathway and regulates mesoderm patterning.

Immunolocalization of potassium-chloride cotransporter polypeptides in rat exocrine glands.

Potassium-chloride cotransporters (KCCs) encoded by at least four homologous genes are believed to contribute to cell volume regulation and transepithelial ion transport. We have studied KCC polypeptide expression and immunolocalization of KCCs in rat salivary glands and pancreas. Immunoblot analysis of submandibular, parotid, and pancreas plasma membrane fractions with immunospecific antibodies raised against mouse KCC1 revealed protein bands at ca 135 kDa and ca 150 kDa. Immunocytochemical analysis of fixed salivary and pancreas tissue revealed basolateral KCC1 distribution in rat parotid and pancreatic acinar cells, as well as in parotid, submandibular, and pancreatic duct cells. KCC1 or the polypeptide product(s) of one or more additional KCC genes was also expressed in the basolateral membranes of submandibular acinar cells. Both immunoblot and immunofluorescence signals were abolished in the presence of the peptide antigen. These results establish the presence in rat exocrine glands of KCC1 and likely other KCC polypeptides, and suggest a contribution of KCC polypeptides to transepithelial Cl(-) transport.