Short tandem repeat expansions in cortical layer-specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder.

AIM: Short tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD phenotypes. METHODS: We analyzed WGS data of 634 ASD families and performed genome-wide evaluation for 12,929 STR loci. We found rare STR expansions that exceeded normal repeat lengths in autism cases compared to unaffected controls. By integrating single cell RNA and ATAC sequencing datasets of human postmortem brains, we prioritized STR loci in genes specifically expressed in cortical development stages. A deep learning method was used to predict functionality of ASD-associated STR loci. RESULTS: In ASD cases, rare STR expansions predominantly occurred in early cortical layer-specific genes involved in neurodevelopment, highlighting the cellular specificity of STR-associated genes in ASD risk. Leveraging deep learning prediction models, we demonstrated that these STR expansions disrupted the regulatory activity of enhancers and promoters, suggesting a potential mechanism through which they contribute to ASD pathogenesis. We found that individuals with ASD-associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to non-carriers. CONCLUSION: Short tandem repeat expansions in cortical layer-specific genes are associated with ASD and could potentially be a risk genetic factor for ASD. Our study is the first to show evidence of STR expansion associated with ASD in an under-investigated population.

Energy-Balanced Cluster-Routing Protocol Based on Particle Swarm Optimization with Five Mutation Operators for Wireless Sensor Networks.

Prolonging the network lifetime is one of the fundamental requirements in wireless sensor networks (WSNs). Sensor node clustering is a very popular energy conservation strategy in WSNs, allowing to achieve energy efficiency, low latency, and scalability. According to this strategy, sensor nodes are grouped into several clusters, and one sensor node in each cluster is assigned to be a cluster head (CH). The responsibility of each CH is to aggregate data from the other sensor nodes within its cluster and send these data to the sink. However, the distribution of sensor nodes in the sensing region is often non-uniform, which may lead to an unbalanced number of sensor nodes between clusters and thus unbalanced energy consumption between CHs. This, in turn, may result in a reduced network lifetime. Furthermore, a different number of clusters lead to a different quality of service of a WSN system. To address the problems of unbalanced number of sensor nodes between clusters and selecting an optimal number of clusters, this study proposes an energy-balanced cluster-routing protocol (EBCRP) based on particle swarm optimization (PSO) with five mutation operators for WSNs. The five mutation operators are specially proposed to improve the performance of PSO in optimizing sensor node clustering. A rotation CH selection scheme based on the highest residual energy is used to dynamically select a CH for each cluster in each round. Simulation results show that the proposed EBCRP method performs well in balancing energy consumption and prolonging the network lifetime.

The tetraspanin CD81 protein increases melanoma cell motility by up-regulating metalloproteinase MT1-MMP expression through the pro-oncogenic Akt-dependent Sp1 activation signaling pathways.

Despite the importance of multiple tetraspanin proteins in cancer invasion and metastasis, little is known about the role and significance of tetraspanin CD81 in these processes. In the present study, we examined CD81 effects on melanoma cell invasiveness and metastasis. Transfection of CD81 into melanoma cells lacking endogenous CD81 expression significantly enhanced the migrating, invasive, and metastatic abilities of melanoma cells. Interestingly, membrane type 1 matrix metalloproteinase (MT1-MMP) expression was found in CD81-expressing melanoma cells but not in CD81-deficient cells. siRNA knockdown of CD81 in melanoma cells with endogenous CD81 demonstrated decreased MT1-MMP levels and cell motility. Notably, CD81-induced cell migration was abrogated by antibody blocking and siRNA knockdown of MT1-MMP, indicating that MT1-MMP is responsible for CD81-stimulated melanoma cell migration. Promoter analysis revealed an essential role of the Sp1 transcription factor in CD81-induced MT1-MMP transcription. We also demonstrate that the Sp1-activating Akt pathway is involved in adhesion-dependent CD81 signaling to induce MT1-MMP expression and cell motility. Importantly, human skin cancer tissue specimens displayed a positive correlation of CD81 with MT1-MMP expression levels and a close association of CD81 with malignant melanomas. Taken together, these results strongly suggest that CD81 stimulates melanoma cell motility by inducing MT1-MMP expression through the Akt-dependent Sp1 activation signaling pathway, leading to increased melanoma invasion and metastasis.

Parenting stress and child behavior problems among clinic-referred youth: cross-cultural differences across the US and Korea.

Due to increased multiculturalism in the US and abroad, there is a need for increased understanding of the different ways in which parenting stress is related to child problems across cultures. In the present study, we investigated (a) differences in reported parenting stress and childhood problem behaviors across a Korean (n = 71) and US (n = 71) sample, as well as (b) differences in the ways in which parenting stress and childhood problems were related across Korean and US children based on mothers' reports. Results revealed that Korean mothers reported significantly higher parenting stress yet significantly lower childhood problem behaviors compared to US mothers. In addition, mother-based reports of child problems were significantly associated with parenting stress in the US sample, but not in the Korean sample. Clinical implications and culturally-relevant issues relevant to these findings are addressed, including a potential under-reporting bias of child problems among Asian parents.

The cancer/testis antigen CAGE with oncogenic potential stimulates cell proliferation by up-regulating cyclins D1 and E in an AP-1- and E2F-dependent manner.

A cancer/testis antigen, CAGE, is widely expressed in various cancer tissues and cancer cell lines but not in normal tissues except the testis. In the present study, ectopic expression of CAGE in fibroblast cells resulted in foci formation, suggesting its cell-transforming ability. Using stable HeLa transfectant clones with the tetracycline-inducible CAGE gene, we found that CAGE overexpression stimulated both anchorage-dependent and -independent cell growth in vitro and promoted tumor growth in a xenograft mouse model. Cell cycle analysis showed that CAGE augments the levels of cyclin D1 and E, thereby activating cyclin-associated cyclin-dependent kinases and subsequently accelerating the G(1) to S progression. Moreover, increased cyclin D1 and E levels in CAGE-overexpressing cells were observed even in a growth arrested state, indicating a direct effect of CAGE on G(1) cyclin expression. CAGE-induced expression of cyclins D1 and E was found to be mediated by AP-1 and E2F-1 transcription factors, and among the AP-1 members, c-Jun and JunD appeared to participate in CAGE-mediated up-regulation of cyclin D1. CAGE overexpression also enhanced retinoblastoma phosphorylation and subsequent E2F-1 nuclear translocation. In contrast, small interfering RNA-mediated knockdown of CAGE suppressed the expression of G(1) cyclins, activation of AP-1 and E2F-1, and cell proliferation in both HeLa cervical cancer cells and Malme-3M melanoma cells. These results suggest that the cancer/testis antigen CAGE possesses oncogenic potential and promotes cell cycle progression by inducing AP-1- and E2F-dependent expression of cyclins D1 and E.

Metastasis suppressor KAI1/CD82 attenuates the matrix adhesion of human prostate cancer cells by suppressing fibronectin expression and ß1 integrin activation.

KAI1/CD82, a tetraspanin membrane protein functions as a metastasis suppressor in many types of human cancers and has been shown to regulate cell adhesion properties. In the present study, we investigated the underlying mechanism of KAI1/CD82-mediated changes in cell adhesion to the extracellular matrix using human prostate cancer cells. We found that high KAI1/CD82 expression attenuated short-term cell adhesion to uncoated- or fibronectin-coated plates. Moreover, high KAI1/CD82 expression generated an extracellular environment unfavorable for cell adhesion as compared to low KAI1/CD82 expression, suggesting KAI1/CD82-dependent regulation of extracellular matrix (ECM) molecule(s) expression and/or secretion. Among ECM components examined, fibronectin exhibited decreased expression and secretion in high KAI1/CD82-expressing cells. Furthermore, high KAI1/CD82 expression interfered with the activation of ß (1) integrin at the cell surface while total ß (1) integrin levels remained unchanged, concomitant with reduced formation of focal adhesion complex and decreased bundling of actin filaments. Finally, high KAI1/CD82 expression significantly retarded cell motility in a scratch wound assay. Taken together, our results strongly suggest that KAI1/CD82 attenuates the activation of ß (1) integrin, and thereby down-regulates outside-in signaling of ß (1) integrin, leading to the reduction of focal adhesion formation and fibronectin expression/secretion, which subsequently interferes with cell adhesion properties and motility.

Relationship between subjective experiences and psychopathological dimensions in schizophrenia.

OBJECTIVE: Subjective experiences are subtle, self-experienced disturbances, a thorough description of which is provided within the framework of the concept of basic symptoms. Recent studies have shown that subjective experiences have important diagnostic implications for schizophrenia and related disorders. The purpose of the present study was to examine the relationship between subjective experiences and psychopathological dimensions in schizophrenia. METHOD: Sixty-seven outpatients with schizophrenia were evaluated. Subjective experiences were comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). Symptoms of schizophrenia were evaluated using the Manchester Scale (MS). Pearson's partial correlation analysis was performed between the FCQ and the MS scores, controlling for the influence of extrapyramidal adverse effects. RESULTS: The analysis revealed that the MS positive symptom score had significant positive correlations with the FCQ total score and subscales scores. The MS negative symptom score did not have significant correlations with the FCQ scores. CONCLUSIONS: The results of our study suggest that subjective experiences are significantly associated with positive symptomatology in schizophrenia, suggesting that they may share a common underlying neural basis. Future prospective studies are necessary to confirm the stability of these relationships and to explore the diagnostic and therapeutic implications of subjective experiences in a diverse group of patients at different stages of illness.

The relationship between akathisia and subjective tolerability in patients with schizophrenia.

Akathisia remains a significant issue even in the era of atypical antipsychotics. The purpose of the present study was to examine the association of akathisia with various domains of subjective tolerability in order to contribute to the renewed interest in akathisia and the subjective experience of antipsychotic treatment. Fifty schizophrenic outpatients receiving stable doses of risperidone were evaluated for akathisia, schizophrenic symptoms, and subjective tolerability. Subjective tolerability was comprehensively assessed using the Liverpool University Neuroleptic Side Effect Rating Scale. Analysis of covariance revealed that the akathisia group had a significantly higher total score as well as higher subscale scores of extrapyramidal side effect, psychic side effect, and autonomic side effect on the Liverpool University Neuroleptic Side Effect Rating Scale. Further analysis using binary logistic regression analysis revealed that these variables were significantly associated with akathisia. The results of our study suggest that akathisia is significantly associated with a wide range of subjective tolerability profiles, implying the necessity to effectively manage akathisia even its mild forms considering its strong association with subjective tolerability in general.

Non-motor cognitive-perceptual dysfunction associated with drug-induced parkinsonism.

OBJECTIVE: The purpose of the present study was to examine the relationship between drug-induced parkinsonism (DIP) and subjective non-motor cognitive impairments in schizophrenia by performing comprehensive assessments of extrapyramidal side effects (EPS) and the subjective cognitive-perceptual functioning. METHODS: Ninety-one outpatients with schizophrenia were evaluated for DIP and other EPS. Subjective cognitive-perceptual dysfunction was comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). To examine the association between DIP and non-motor cognitive-perceptual dysfunction, Pearson's partial correlation analysis was performed between the FCQ scores and the severity of DIP, controlling for relevant variables. RESULTS: The analysis revealed that the severity of DIP had a significant correlation with the total FCQ score (p < 0.05). In phenomenological subscales, the severity of DIP showed significant correlations with "deterioration of discrimination," "psychomotor disorder," "perceptual disorder," "cognitive floating," and "automatic behavior disorder" (p < 0.05). CONCLUSIONS: The results of our study suggest that DIP is significantly associated with a wide range of subjective non-motor cognitive impairments. Clinicians should be careful of the appearance of DIP and the associated non-motor cognitive-perceptual symptoms, which may cause considerable distress and reduce the quality of life in an already vulnerable group of patients.

Subjective cognitive dysfunction associated with drug-induced parkinsonism in schizophrenia.

The authors investigated the subjective cognitive dysfunction associated with drug-induced parkinsonism (DIP) among 58 stabilized schizophrenic outpatients. Subjective cognitive dysfunction was comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). Multivariate analysis revealed that the DIP group scored significantly higher on the total FCQ score than the non-DIP group. In phenomenological subscale scores, the DIP group had significantly higher scores on "deterioration of discrimination", "psychomotor disorder", and "perceptual disorder" than the non-DIP group. These results suggest that DIP is significantly associated with subjective cognitive-perceptual dysfunction, reflecting the complex nature of DIP that includes motor and cognitive aspects.

Tetraspanin CD82 represses Sp1-mediated Snail expression and the resultant E-cadherin expression interrupts nuclear signaling of ß-catenin by increasing its membrane localization.

Tetraspanin membrane proteins form physical complexes with signaling molecules and have been suggested to influence the signaling events of associated molecules. Of the tetraspanin proteins, CD82 has been shown to promote homotypic cell-cell adhesion, which partially accounts for its role in suppressing cancer invasion and metastasis. We found here that CD82-induced cell-cell adhesion is attributed to increased E-cadherin expression through CD82-mediated downregulation of the E-cadherin repressor Snail. The Snail repression by CD82 resulted from the reduced binding of the Sp1 transcription factor to the Snail gene promoter. Notably, high CD82 expression did not allow the fibronectin matrix to induce Sp1 phosphorylation, implicating CD82 inhibition of the fibronectin-integrin signaling-dependent Sp1 activation. Meanwhile, E-cadherin upregulated by CD82 pulled ß-catenin up to the membrane region, and consequently reduced the amount of cytoplasmic ß-catenin that was able to move into to the nucleus. The Wnt signal-induced nuclear translocation of ß-catenin was also inhibited by the CD82 function of upregulating E-cadherin. Overall, high CD82 expression was likely to suppress fibronectin adhesion-induced Sp1 activation signaling for Snail expression, resulting in continuous E-cadherin expression, which contributed not only to the maintenance of strong cell-cell adhesion but also to the blockage of nuclear ß-catenin signaling.

The metastasis suppressor CD82/KAI1 inhibits fibronectin adhesion-induced epithelial-to-mesenchymal transition in prostate cancer cells by repressing the associated integrin signaling.

The transmembrane protein CD82/KAI1 suppresses the metastatic potential of various cancer cell types. Moreover, decrease or loss of CD82 expression is closely associated with malignancy and poor prognosis in many human cancers including prostate cancer. Despite intense scrutiny, the mechanisms underlying the metastasis-suppressing role of CD82 are still not fully understood. Here, we found that a fibronectin matrix induced mesenchymal phenotypes in human prostate cancer cells with no or low CD82 expression levels. However, high CD82 expression rendered prostate cancer cells to have intensified epithelial characteristics upon fibronectin engagement, along with decreased cell motility and invasiveness. The CD82 function of inhibiting fibronectin-induced epithelial-to-mesenchymal transition (EMT) was dependent not only on CD82 interactions with fibronectin-binding α3ß1/α5ß1 integrins but also on the integrin-mediated intracellular signaling events. Notably, CD82 attenuated the FAK-Src and ILK pathways downstream of the fibronectin-receptor integrins. Immunofluorescence staining of human prostate cancer tissue specimens illustrated a negative association of CD82 with EMT-related gene expression as well as prostate malignancy. Altogether, these results suggest that CD82 suppresses EMT in prostate cancer cells adhered to the fibronectin matrix by repressing adhesion signaling through lateral interactions with the associated α3ß1 and α5ß1 integrins, leading to reduced cell migration and invasive capacities.

Psychiatric comorbidity in Korean children and adolescents with attention-deficit hyperactivity disorder: psychopathology according to subtype.

It is well-known that more than 50% of attention-deficit hyperactivity disorder (ADHD) cases also have comorbid psychiatric disorders. We evaluated the comorbid psychopathology of Korean children and adolescents with ADHD using a standardized diagnostic instrument. The Korean Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL-K) was administered and completed in 105 patients who had been referred to the outpatient and inpatient clinics at the Samsung Medical Center from March 2004 to May 2005. All of the cases were diagnosed as ADHD according to DSM-IV criteria. We analyzed their clinical characteristics and psychiatric comorbidities, and assessed the correlation of any comorbidity with gender, age and ADHD subtype. Among our 105 participants, 70 (66.7%) subjects were diagnosed with combined-type ADHD, 22 (21.0%) were the predominantly inattentive type, only 1 (1.0%) was determined to have the predominantly hyperactive-impulsive type of ADHD, and 12 (11.4%) were classified as not otherwise specified (NOS) ADHD. Eighty (76.2%) subjects had at least one comorbid disorder such as oppositional defiant disorder (n = 53, 50.5%), anxiety disorders (n = 35, 33.3%) and affective disorders (n = 15, 14.3%). Our patients ranged in age from five to 16 years. Among the factors including gender, age, and ADHD subtype, ADHD subtype was the only one significant to comorbidity in our study. The results of this study suggest that psychiatric comorbidity in Korean children with ADHD is similar to the results of previous studies in western countries. Out of all the ADHD subtypes, the combined-type group had a significantly higher ratio of comorbid disorders and psychopathologies.

Prevalence and characteristics of subjective akathisia, objective akathisia, and mixed akathisia in chronic schizophrenic subjects.

Akathisia is a complex syndrome that is characterized by subjective inner restlessness and objective motor manifestations, and it can be classified into several subtypes. The purpose of this study was to examine the prevalence of subjective akathisia, objective akathisia, and mixed akathisia, and to evaluate their relationships with other drug-induced movement disorders, in chronic schizophrenic subjects treated with antipsychotics. One hundred and forty-two in-patients were assessed for akathisia, drug-induced parkinsonism, and tardive dyskinesia. The subtypes of akathisia were specified according to the Barnes Akathisia Rating Scale. Drug-induced parkinsonism and tardive dyskinesia were assessed using the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale, respectively. The prevalence of subjective, objective, and mixed akathisia was 11.3%, 6.3%, and 16.9%, respectively. Regarding concurrence rates of akathisia subtypes and other extrapyramidal syndromes, the comorbidity rates of mixed akathisia with parkinsonism and tardive dyskinesia were higher. In conclusion, the present study presented the prevalence of subjective, objective, and mixed akathisia among hospitalized schizophrenic subjects. Mixed akathisia showed an association with parkinsonism and tardive dyskinesia, suggesting a common vulnerability involved in these drug-induced movement disorders. Further studies are required to elucidate more detailed clinical characteristics of each subtype of akathisia.

Fibronectin and vitronectin induce AP-1-mediated matrix metalloproteinase-9 expression through integrin α(5)ß(1)/α(v)ß(3)-dependent Akt, ERK and JNK signaling pathways in human umbilical vein endothelial cells.

The activity of matrix metalloproteinases (MMPs), which selectively degrades the extracellular matrix (ECM), is critical in angiogenesis. Conversely, changes in ECM composition/structure alter the expression and activity of MMPs in various cell types. In the present study, we examined whether changes in ECM composition affect MMPs expression/activity of endothelial cells and thereby alter the surrounding ECM structure. Among the ECM molecules examined, fibronectin (FN) and vitronectin (VN) increased the expression and activity of MMP-9 in human umbilical vein endothelial cells (HUVECs). Both α(5)ß(1) and α(v)ß(3) integrins were involved in FN-induced MMP-9 expression. Also, FN-induced MMP-9 expression was found to be mediated by AP-1 transcription factors, including c-Jun, JunB, and JunD. Inhibitors or siRNAs specific to AP-1 activating signal transducers, including FAK-Src, PI3K/Akt, ERK, and JNK, abolished both FN-induced AP-1 activation and MMP-9 expression. VN-induced AP-1 activation and MMP-9 expression were also mediated by these AP-1 activating signal transducers in addition to p38 MAPK. Moreover, treatment with FN or VN resulted in increased degradation of collagen on HUVEC culture plates. Taken together, our data suggest that both fibronectin and vitronectin induce MMP-9 expression via the AP-1-activating signaling pathways in endothelial cells, and thereby stimulate degradation of surrounding collagen, leading to alterations in ECM structure and potentially the promotion of angiogenesis.

Association of subjective cognitive dysfunction with akathisia in patients receiving stable doses of risperidone or haloperidol.

BACKGROUND AND OBJECTIVE: Antipsychotic-induced akathisia leads to poor compliance with medication and is still a source of concern in the treatment with antipsychotic drugs. Regarding clinical characteristics, the distinguishing features of akathisia in comparison with other extrapyramidal syndromes are prominent subjective symptoms. The purpose of the present study was to examine the subjective cognitive dysfunction associated with antipsychotic-induced akathisia. METHODS: Sixty-seven outpatients with schizophrenia receiving stable doses of risperidone or haloperidol were evaluated for akathisia and other extrapyramidal side effects. Subjective cognitive dysfunction was comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). The severity of subjective cognitive deficits was compared between the groups with and without akathisia using analysis of covariance with relevant variables as covariates. RESULTS: The akathisia group (n = 25) scored significantly higher on the total FCQ score than the non-akathisia group (n = 42) (P < 0.05). In phenomenological subscale scores, the akathisia group had significantly higher scores on various subscales, i.e. 'anxiety', 'disorder of selective attention', 'deterioration of discrimination', 'perceptual disorder' and 'disorder of coping responses' than the non-akathisia group (P < 0.05). CONCLUSIONS: These results suggest that akathisia is significantly associated with a variety of subjective cognitive-perceptual deficits. Early therapeutic interventions for akathisia should be performed considering its significant association with the subjective cognitive dysfunction and the impairment of coping responses.

The KIDSCREEN-52 quality of life measure for children and adolescents (KIDSCREEN-52-HRQOL): reliability and validity of the Korean version.

The KIDSCREEN-52 quality-of-life (KIDSCREEN-52-HRQOL) is a relevant, worldwide tool used for assessing the health-related quality of life in children and adolescents. The purpose of this study was to define measurement properties of the Korean version of the KIDSCREEN-52 HRQOL. The original questionnaire was translated following international translation guidelines. Analysis regarding psychometric properties showed that the Cronbach-alpha ranged from 0.77 to 0.95. The correlation coefficient between the PedQL and KIDSCREEN-52 dimensions were high for the assessments of similar constructs. Therefore, the Korean version of the KIDSCREEN-52 was found to be suitable for use in Korean adolescents.

Homophilic interactions of Tetraspanin CD151 up-regulate motility and matrix metalloproteinase-9 expression of human melanoma cells through adhesion-dependent c-Jun activation signaling pathways.

The tetraspanin membrane protein CD151 has been suggested to regulate cancer invasion and metastasis by initiating signaling events. The CD151-mediated signaling pathways involved in this regulation remain to be revealed. In this study, we found that stable transfection of CD151 into MelJuSo human melanoma cells lacking CD151 expression significantly increased cell motility, matrix metalloproteinase-9 (MMP-9) expression, and invasiveness. The enhancement of cell motility and MMP-9 expression by CD151 overexpression was abrogated by inhibitors and small interfering RNAs targeted to focal adhesion kinase (FAK), Src, p38 MAPK, and JNK, suggesting an essential role of these signaling components in CD151 signaling pathways. Also, CD151-induced MMP-9 expression was shown to be mediated by c-Jun binding to AP-1 sites in the MMP-9 gene promoter, indicating AP-1 activation by CD151 signaling pathways. Meanwhile, CD151 was found to be associated with alpha(3)beta(1) and alpha(6)beta(1) integrins in MelJuSo cells, and activation of associated integrins was a prerequisite for CD151-stimulated MMP-9 expression and activation of FAK, Src, p38 MAPK, JNK, and c-Jun. Furthermore, CD151 on one cell was shown to bind to neighboring cells expressing CD151, suggesting that CD151 is a homophilic interacting protein. The homophilic interactions of CD151 increased motility and MMP-9 expression of CD151-transfected MelJuSo cells, along with FAK-, Src-, p38 MAPK-, and JNK-mediated activation of c-Jun in an adhesion-dependent manner. Furthermore, C8161 melanoma cells with endogenous CD151 were also shown to respond to homophilic CD151 interactions for the induction of adhesion-dependent activation of FAK, Src, and c-Jun. These results suggest that homophilic interactions of CD151 stimulate integrin-dependent signaling to c-Jun through FAK-Src-MAPKs pathways in human melanoma cells, leading to enhanced cell motility and MMP-9 expression.

A splice variant of CD99 increases motility and MMP-9 expression of human breast cancer cells through the AKT-, ERK-, and JNK-dependent AP-1 activation signaling pathways.

The CD99 gene encodes two distinct transmembrane proteins by alternative splicing of its transcript. To examine the effects of two CD99 isoforms on the invasive phenotypes of breast cancer cells, MDA-MB-231 and MCF-7 human breast cancer cell lines were stably transfected with CD99 cDNAs encoding the major wild-type form (type I) or a minor splice variant (type II). As a result, expression of CD99 type II, but not type I, markedly elevated the motility, binding to fibronectin, MMP-9 expression, and invasiveness of MDA-MB-231 and MCF-7 breast cancer cells. In MDA-MB-435 breast cancer cells expressing both CD99 type I and type II, invasion-related cellular activities were inhibited by the transfection of small interfering RNA (siRNA) targeted to CD99 type II. Meanwhile, CD99 type II-induced MMP-9 expression in MDA-MB-231 cells was shown to be mediated by the binding of AP-1 factors to the MMP-9 gene promoter. Gel shift assay revealed that ligation of CD99 type II with antibody resulted in the binding of JunD to the AP-1 site of the MMP-9 promoter region. Initiation of CD99 type II signaling by antibody ligation increased expression of JunD and FosB AP-1 factors, along with phosphorylation of Src, Akt, p38 MAPK, ERK, and JNK. Knockdown of JunD and FosB by siRNA transfection abolished the positive effects of CD99 type II on the motility and MMP-9 expression of MDA-MB-231 cells. Increased expression of JunD and FosB as well as elevated cell motility and MMP-9 expression by CD99 type II ligation were also abrogated by inhibitors, dominant-negative forms, and siRNAs for Akt1, ERK1/2, and JNK1 but not for p38 MAPK. These results suggest that expression of a splice variant of CD99 contributes to the invasive ability of human breast cancer cells by up-regulating AP-1-mediated gene expression through the Akt-dependent ERK and JNK signaling pathways.

Multidimensional sensory phenomena in antipsychotic-induced akathisia.

The primary distinguishing features of akathisia in comparison with other extrapyramidal syndromes are the prominent subjective manifestations, which include various sensory symptoms. The sensory symptoms are multidimensional in nature and encompass various forms of bodily and mental sensations. The purpose of the present study was to elucidate the multidimensional aspects of the sensory phenomena associated with antipsychotic-induced akathisia. Seventy stable and chronic schizophrenic subjects receiving maintenance antipsychotic treatment were evaluated for akathisia and other extrapyramidal side effects. Subjective sensory phenomena were evaluated in 3 dimensions (ie, bodily sensations, mental sensations, and autonomic sensations). The frequency of each dimension of these sensory phenomena was compared between the groups with and without akathisia using chi test with Bonferroni correction. The akathisia group (n = 29) reported significantly more frequent focal or generalized bodily sensations than the non-akathisia group (n = 41) (P < 0.001). The akathisia group also showed significantly more frequent mental sensations such as mental urge and a feeling of inner tension/pressure (P < 0.001). In autonomic phenomena, there was a trend for the akathisia group to show more frequent autonomic sensations. The most common autonomic phenomena associated with akathisia were palpitation and difficulty breathing. The results of the present study suggest that the sensory phenomena of antipsychotic-induced akathisia are characterized by multidimensional features such as bodily sensations, mental sensations, and several autonomic sensations. The assessment of these multidimensional sensory phenomena would be useful in evaluating the important phenotypic features of akathisia.