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PubMed2006

SAD: a presynaptic kinase associated with synaptic vesicles and the active zone cytomatrix that regulates neurotransmitter release.

A serine/threonine kinase SAD-1 in C. elegans regulates synapse development. We report here the isolation and characterization of mammalian orthologs of SAD-1, named SAD-A and SAD-B, which are specifically expressed in the brain. SAD-B is associated with synaptic vesicles and, like the active zone proteins CAST and Bassoon, is tightly associated with the presynaptic cytomatrix in nerve terminals. A short conserved region (SCR) in the COOH-terminus is required for the synaptic localization of SAD-B. Overexpression of SAD-B in cultured rat hippocampal neurons significantly increases the frequency of miniature excitatory postsynaptic current but not its amplitude. Introduction of SCR into presynaptic superior cervical ganglion neurons in culture significantly inhibits evoked synaptic transmission. Moreover, SCR decreases the size of the readily releasable pool measured by applying hypertonic sucrose. Furthermore, SAD-B phosphorylates the active zone protein RIM1 but not Munc13-1. These results suggest that mammalian SAD kinase presynaptically regulates neurotransmitter release.

Animals↗
PubMed2001

SADS: A new component of Fas-DISC is the accelerator for cell death signaling and is downregulated in patients with colon carcinoma.

Fas is the death receptor, transducing cell death signaling upon stimulation by Fas ligand. During Fas-initiated cell death signaling, the formation of Fas-death inducing signaling complex (Fas-DISC) is the first step. Here we have identified a new component of Fas-DISC which we call 'small-accelerator for death signaling' (SADS). SADS cDNA encodes a 150 amino acid polypeptide (Mr = 16,700). During Fas-mediated cell death, SADS enhances the interaction of Fas-death domain-interactive factors (FADD) and procaspase-8, and deletion mutant analysis has identified FADD- and caspase-8-interactive domains in SADS. Inhibition or removal of SADS delays Fas-mediated cell death. In addition, we demonstrate the deletion or mutation of SADS in patients with colon carcinoma and that exogenous SADS expression in human colon carcinoma SW480 cells that lack SADS leads to re-acquisition of Fas-mediated cell death. Here, we propose that SADS is one of the cell death-associated factors and enhances Fas-DISC formation, especially FADD and procaspase-8 recruitment.

Apoptosis↗
PubMed1995

Sulfhydryl oxidation and activation of red cell K(+)-Cl- cotransport in the transgenic SAD mouse.

The SAD mouse is characterized by the expression of human SAD hemoglobin (Hb), a super S Hb with a higher tendency to polymerize than HbS due to the presence of two additional mutations, Antilles beta 23Ile and D Punjab beta 121Glu. Monovalent cation transport was studied in erythrocytes from SAD-1 (Hb SAD = 19%) and beta-thal/SAD-1 (Hb SAD = 26%) mice. Erythrocytes containing Hb SAD exhibited dehydration, increased maximal rate of Na(+)-K+ pump, unchanged Rb+ flux via the Gardos channel, and increased K(+)-Cl- cotransport. K(+)-Cl- cotransport was defined as Cl(-)-dependent (substitution with sulfamate or methanesulfonate) okadaic acid-sensitive K+ efflux. Volume regulatory decrease via K(+)-Cl- cotransport was also increased in swollen SAD erythrocytes compared with controls. K(+)-Cl- cotransport was stimulated by staurosporine in all mouse strains, but the extent of stimulation was reduced in beta-thal/SAD-1 mice. Treatment with dithiothreitol reduced K(+)-Cl- cotransport activity in SAD-1 and beta-thal/SAD-1 mice to levels similar to that of control strains, indicating that reversible sulfhydryl oxidation contributes to the activated state of K(+)-Cl- cotransport in mouse erythrocytes that express transgenic human Hb SAD.

Animals↗
PubMed2004

The reliability and validity of Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version- Korean version (K-SADS-PL-K).

In order to develop a structured and objective diagnostic instrument, authors completed: (1) the translation and back translation of the Korean version of the Kiddie-Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version (K-SADS-PL) and (2) the examination of its validity and reliability of the K-SADS-PL-Korean version (K-SADS- PL) when used with Korean children. A total of 91 study subjects were recruited from child and adolescent psychiatry outpatient clinics. Clinical diagnoses were used as a gold standard for the examination of validity of K-SADS-PL-K. Consensual validity of threshold and sub-threshold diagnoses were good to excellent for attention-deficit/hyperactivity disorder (ADHD), fair for tic and oppositional defiant disorders, and poor to fair for anxiety and depressive disorders. Inter-rater and test-retest reliabilities were fair to excellent for ADHD and tic disorder. The significant correlations between the K-SADS-PL-K and Korean Child Behavior Checklist (K-CBCL) were found, which provided additional support for the concurrent validity of the K-SADS-PL-K. Sensitivities varied according to the diagnostic categories, but specificities remained high over all diagnoses, suggesting that the K-SADS-PL-K is a desirable confirmatory diagnostic tool. The results of this study suggest that the K-SADS-PL-K is an effective instrument for diagnosing major child psychiatric disorders, including ADHD, behavioral disorders and tic disorders in Korean children. Future studies will examine the validity and reliability of the K-SADS-PL-K in larger samples, including adolescents and community samples on a variety of child and adolescent psychiatric disorders.

Adolescent↗
PubMed2000

[Alleviation of sadness by pleasant imagery: analyses of subjective and physiological responses].

This study examined whether elicitation of joy or relaxation would reduce intensity of formerly induced sadness by using imagery tasks. Participants (N = 10) imaged a series of four sad scenes successively in the preliminary experiment. Dependent variables were subjective emotional ratings, heart rate, and facial electromyography of the corrugator and the zygomatic muscles. The result indicated that the sadness-imageries increased heart rate, corrugator activity, and zygomatic activity, as well as sad feeling. The procedure of the main experiment (N = 19) was almost the same as that of the preliminary experiment except that the sadness-imageries were followed by one of the 3 emotional imageries, that is, relaxation, neutrality, and joy. The result indicated that the relaxation-imagery marginally significantly decreased the heart rate that had been increased by the sadness-imageries. The joy-imagery reduced sad feeling but increased the zygomatic activity more than the relaxation-imagery. No effect was found on the heart rate. These results suggested that positive emotions alleviate sadness, and that joy and relaxation alleviate different aspects of sadness.

Adult↗
PubMed2005

[Relationship between the adult attachment styles of social anxiety disorder (SAD) and its cognitive mode and behavior mode].

OBJECTIVE: The adult interpersonal relationship is related to individual's early attachment experience. Insecure attachment relationship may lead to dysfunction of interpersonal relationship. This study was carried out to disclose the relationship of SAD-based adult attachment styles with cognitive mode and personality traits. METHODS: A comparison was made between the SAD group and normal control (NC) group by using the psychohygiene measures: Adult attachment scale (AAS), Social avoidance and distress scale (SADS), Fear of negative evaluation scale (FNE), Texas social behaviour inventory (TSBI), and Status trait anxiety inventory (STAI). Statistically, T test, ANOVA, and Scheffe multiple comparison were used. RESULTS: Chi-square test revealed a significant adult attachment-style difference between SAD group and NC group; T test revealed significant FNE, SADS, TSBI and STAI differences between SAD group and NC group. One-way ANOVA revealed significant difference of FNE, SADS, TSBI and STA on the adult attachment styles within SAD group. CONCLUSION: The internal working models of fearful and preoccupied styles in adult attachment are the pathopsychological basis of SAD.

Adolescent↗
PubMed1994

Sickle cell disease of transgenic SAD mice.

Erythrocyte sickling on deoxygenation in vitro occurs in transgenic SAD mice, hemizygous for a modified human sickle hemoglobin, HbSAD [alpha 2 beta 2S(beta 6val)Antilles (beta 23 lle)D- Punjab (beta 121Gln)] (SAD-1, 19% HbSAD; beta-thal/SAD-1, 26% HbSAD). The present study examines the cellular defects in vivo and pathologic changes observed in SAD-1 mice at atmospheric oxygenation as well as the effect of acute hypoxia. The transgenic mice showed generalized congestion and microvascular occlusions, occasionally with thrombosis and infarctions of lung, kidneys, penis, and myocardium. The most prevalent chronic organ lesions were congestive splenomegaly (83% of animals) and renal glomerulopathy, which affected 75% of animals by 10 months of age. Further, SAD mice have a mean lifespan that was reduced by 40% when compared with nontransgenic littermates. Premature death of SAD mice was associated with acute vasoocclusive events or severe renal disease. SAD mice developed lethal vasoocclusive processes when exposed to reduced pO2 conditions, whereas control mice survived normally. The sensitivity to hypoxia appears to depend on the cellular level of HbSAD, because death occurred at pO2 of 42 mmHg for SAD mice and 49 mmHg for beta-thal/SAD. Administration of an antisickling agent that increases oxygen affinity (BW12C79) protected SAD and beta-thal/SAD mice from the lethal hypoxic stress. In conclusion, the transgenic SAD and beta-thal/SAD mice developed a pathophysiology that strongly resembles human sickle cell disease. Moreover, this animal model allows studies on the effect of antisickling agents.

Anemia, Sickle Cell↗
PubMed2003

Neural circuitry underlying voluntary suppression of sadness.

BACKGROUND: The ability to voluntarily self-regulate negative emotion is essential to a healthy psyche. Indeed, a chronic incapacity to suppress negative emotion might be a key factor in the genesis of depression and anxiety. Regarding the neural underpinnings of emotional self-regulation, a recent functional neuroimaging study carried out by our group has revealed that the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex are involved in voluntary suppression of sexual arousal. As few things are known, still, with respect to the neural substrate underlying volitional self-regulation of basic emotions, here we used functional magnetic resonance imaging to identify the neural circuitry associated with the voluntary suppression of sadness. METHODS: Twenty healthy female subjects were scanned during a Sad condition and a Suppression condition. In the Sad condition, subjects were instructed to react normally to sad film excerpts whereas, in the Suppression condition, they were asked to voluntarily suppress any emotional reaction in response to comparable stimuli. RESULTS: Transient sadness was associated with significant loci of activation in the anterior temporal pole and the midbrain, bilaterally, as well as in the left amygdala, left insula, and right ventrolateral prefrontal cortex (VLPFC) (Brodmann area [BA] 47). Correlational analyses carried out between self-report ratings of sadness and regional blood oxygen level dependent (BOLD) signal changes revealed the existence of positive correlations in the right VLPFC (BA 47), bilaterally, as well as in the left insula and the affective division of the left anterior cingulate gyrus (BA 24/32). In the Suppression condition, significant loci of activation were noted in the right DLPFC (BA 9) and the right orbitofrontal cortex (OFC) (BA 11), and positive correlations were found between the self-report ratings of sadness and BOLD signal changes in the right OFC (BA 11) and right DLPFC (BA 9). CONCLUSIONS: These results confirm the key role played by the DLPFC in emotional self-regulation. They also indicate that the right DLPFC and right OFC are components of a neural circuit implicated in voluntary suppression of sadness.

Adult↗
PubMed2002

Assessing the performance of a new depression screener for primary care (PC-SAD).

As many as 50% of patients with major depression seen in primary care settings are not diagnosed. To facilitate efficient identification of primary care patients with depression, we developed a new patient-administered depression screening instrument (PC-SAD) that produces a DSM-IV diagnosis, and compared its performance to other screeners that yield DSM-IV diagnoses. To assess validity, the diagnostic accuracy of the PC-SAD was compared with the Inventory to Diagnose Depression (IDD) and the PRIME-MD-PHQ (PHQ) in a convenience sample (N = 312) of health plan members, primary care outpatients, and psychiatric patients (with diagnoses). The screeners were compared with each other and with psychiatric diagnoses to assess their relative performance. Disagreement among the three screeners was formally tested using a triangulation approach that incorporates a statistical likelihood model. Of patients diagnosed as depressed using the IDD, 84.2% were also depressed by the PC-SAD (sensitivity). Of patients not diagnosed as depressed by the IDD, 94.7% were not depressed by the PC-SAD (specificity). Using the triangulation method the sensitivities were 87.2% (PC-SAD), 88.4% (IDD), and 60.7% (PHQ). The specificities were 95.0% (PC-SAD), 92.7% (IDD), and 98.3% (PHQ). The performance of the PC-SAD and the IDD was comparable. The PHQ was less sensitive than either of those. The PC-SAD respondent burden strikes a balance between the very short PHQ, and the longer IDD, and has the lowest (easiest) Flesch-Kincaid reading level. Investigators, clinicians, and health plans that want a DSM-IV-based depression screener can choose from among these three instruments, with known tradeoffs in sensitivity, respondent burden, and readability.

Adult↗
PubMed2001

The SAD-1 kinase regulates presynaptic vesicle clustering and axon termination.

During synapse formation, presynaptic axon outgrowth is terminated, presynaptic clusters of vesicles are associated with active zone proteins, and active zones are aligned with postsynaptic neurotransmitter receptors. We report here the identification of a novel serine/threonine kinase, SAD-1, that regulates several aspects of presynaptic differentiation in C. elegans. In sad-1 mutant animals presynaptic vesicle clusters in sensory neurons and motor neurons are diffuse and disorganized. Sensory axons fail to terminate in sad-1 mutants, whereas overexpression of SAD-1 causes sensory axons to terminate prematurely. SAD-1 protein is expressed in the nervous system and localizes to synapse-rich regions of the axons. SAD-1 is related to PAR-1, a kinase that regulates cell polarity during asymmetric cell division. Overexpression of SAD-1 causes mislocalization of vesicle proteins to dendrites, suggesting that sad-1 affects axonal-dendritic polarity as well as synaptic development.

Animals↗
PubMed2003

SAD: a new DOF protein from barley that activates transcription of a cathepsin B-like thiol protease gene in the aleurone of germinating seeds.

Functional analysis of hydrolase gene promoters, induced by gibberellin (GA) in aleurone cells following germination, has identified a GA-responsive complex (GARC) as a tripartite element containing a pyrimidine-box motif 5'-CCTTTT-3'. We describe here the characterization of a new barley gene (Sad gene) encoding a transcription factor (SAD) of the DNA binding with One Finger (DOF) class that binds to the pyrimidine box in vitro and activates transcription of a GA-induced protease promoter in bombarded aleurone layers. RT-PCR and in situ hybridization analyses showed that the Sad transcripts accumulated in all tissues analysed, being especially abundant in the scutellum and aleurone cells upon seed germination. The SAD protein, expressed in bacteria, binds in a specific manner to two oligonucleotides containing the sequence 5'-G/CCTTTT/C-3', derived from the promoter region of the Al21 gene encoding a cathepsin B-like cysteine protease. Although the Sad transcript accumulation did not respond to external GA-incubation in aleurone cells, in transient expression experiments in co-bombarded aleurone layers, SAD trans-activated transcription from the Al21 promoter in a similar manner as did GAMYB, a MYB protein previously shown to respond to GA and to activate several hydrolase gene promoters in barley aleurone cells. In vivo interaction between the GAMYB and SAD proteins was shown in the yeast two-hybrid system, where GAMYB potentiates the SAD trans-activation capacity through interaction with its C-terminal domain.

Amino Acid Sequence↗
PubMed1988

Phototherapy in subsyndromal seasonal affective disorder (S-SAD) and "diagnosed" controls.

Antidepressant and energizing effects of bright light exposure have been widely reported to occur in patients with seasonal affective disorder (SAD). In order to evaluate whether other segments of the population might also benefit from this treatment, we studied 20 normal individuals with mild SAD-like symptoms (subsyndromal SAD, S-SAD) and 20 with no reported seasonal difficulties (non-S-SAD). Whereas S-SAD individuals benefited from phototherapy, non-S-SAD normals did not. This finding raises the questions of whether a history of seasonal problems might be a marker of vulnerability to affective episodes and if S-SAD individuals might be considered as a high risk population in this regard.

Adult↗
PubMed2000

The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain.

Transforming growth factor-beta (TGF-beta) family members signal through a unique set of intracellular proteins called Smads. Smad4, previously identified as the tumor suppressor DPC4, is functionally distinct among the Smad family, and is required for the assembly and transcriptional activation of diverse, Smad-DNA complexes. We previously identified a 48-amino acid proline-rich regulatory element within the middle linker domain of this molecule, the Smad4 activation domain (SAD), which is essential for mediating these signaling activities. We now characterize the functional activity of the SAD. Mutants lacking the SAD are still able to form complexes with other Smad family members and associated transcription factors, but cannot activate transcription in these complexes. Furthermore, the SAD itself is able to activate transcription in heterologous reporter assays, identifying it as a proline-rich transcriptional activation domain, and indicating that the SAD is both necessary and sufficient to activate Smad-dependent transcriptional responses. We show that transcriptional activation by the SAD is p300-dependent, and demonstrate that this activity is associated with a physical interaction of the SAD with the amino terminus of p300. These data identify a novel function of the middle linker region of Smad4, and define the role of the SAD as an important locus determining the transcriptional activation of the Smad complex.

Amino Acid Sequence↗
PubMed2006

Neuronal polarity is regulated by a direct interaction between a scaffolding protein, Neurabin, and a presynaptic SAD-1 kinase in Caenorhabditis elegans.

The establishment of axon-dendrite identity in developing neurites is essential for the development of a functional nervous system. The SAD serine-threonine kinases have been implicated in regulating neuronal polarization and synapse formation. Here, we show that the C. elegans SAD-1 kinase regulates axonal identity and synapse formation through distinct mechanisms. We identified a scaffolding protein, Neurabin (NAB-1), as a physiological binding partner of SAD-1. Both sad-1 and nab-1 loss-of-function mutants display polarity defects in which synaptic vesicles accumulate in both axons and dendrites. We show that sad-1 and nab-1 function in the same genetic pathway to restrict axonal fate. Unlike sad-1, nab-1 mutants display normal morphology of vesicle clusters. Strikingly, although the physical interaction of NAB-1 with SAD-1 is necessary for polarity, it is dispensable for synapse morphology. We propose that Neurabin functions as a scaffold to facilitate SAD-1-mediated phosphorylation for substrates specific for restricting axonal fate during neuronal polarization.

Animals↗
PubMed2003

Neural correlates of sad feelings in healthy girls.

Emotional development is indisputably one of the cornerstones of personality development during infancy. According to the differential emotions theory (DET), primary emotions are constituted of three distinct components: the neural-evaluative, the expressive, and the experiential. The DET further assumes that these three components are biologically based and functional nearly from birth. Such a view entails that the neural substrate of primary emotions must be similar in children and adults. Guided by this assumption of the DET, the present functional magnetic resonance imaging study was conducted to identify the neural correlates of sad feelings in healthy children. Fourteen healthy girls (aged 8-10) were scanned while they watched sad film excerpts aimed at externally inducing a transient state of sadness (activation task). Emotionally neutral film excerpts were also presented to the subjects (reference task). The subtraction of the brain activity measured during the viewing of the emotionally neutral film excerpts from that noted during the viewing of the sad film excerpts revealed that sad feelings were associated with significant bilateral activations of the midbrain, the medial prefrontal cortex (Brodmann area [BA] 10), and the anterior temporal pole (BA 21). A significant locus of activation was also noted in the right ventrolateral prefrontal cortex (BA 47). These results are compatible with those of previous functional neuroimaging studies of sadness in adults. They suggest that the neural substrate underlying the subjective experience of sadness is comparable in children and adults. Such a similitude provides empirical support to the DET assumption that the neural substrate of primary emotions is biologically based.

Behavior Therapy↗
PubMed1994

The transgenic SAD mouse: a model of human sickle cell glomerulopathy.

The transgenic SAD mouse which expresses a modified sickle hemoglobin, Hb SAD, displays in vivo hemoglobin polymerization and erythrocyte sickling. In the presence study functional and morphological renal analyses were performed in SAD mice in order to compare the renal pathology of SAD mice with the human disease. The SAD mice display renal hemosiderosis, microvascular occlusions, vascular thrombosis, cortical infarcts and papillary necrosis. In the medulla, hemoglobin polymers could be observed with infrequent erythrocyte sickling, which may explain the absence of significant renal concentration defect, whereas in humans, the difference in the vascularization network leads to more extensive sickling. Most animals develop glomerular hypertrophy and mesangial sclerosis which increases in frequency and severity with age. The glomerular damage is associated with functional defects, including increased blood urea nitrogen levels and non-selective proteinuria. The glomerular lesions of SAD mice strikingly mimic sickle cell glomerulosclerosis, the most severe renal complication of sickle cell disease in humans. In summary, the SAD mouse is a valuable model of the thrombotic and glomerulosclerotic complications of human sickle cell glomerulopathy and can serve for pathophysiologic studies, and, eventually, for prevention and therapy investigation.

Anemia, Sickle Cell↗
PubMed1997

Grey glasses: sadness in young women.

Sadness as a developmental phenomenon in young women was discovered in a study designed to identify developmental transitions and the relationship of these transitions to mental health. Sadness is conceptualized as a pervasive feeling of disillusionment and unhappiness that influences the meaning of life events and decision-making. Field research and interpretive analysis techniques were used to observe, describe and analyse the life experiences of 25 volunteer participants. For most women in the study, sadness was found to be time-limited and perhaps had beneficial effects. Some women, however, were unable to resolve sadness and became depressed. Sadness can be an antecedent to depression. Sadness that is recognized and validated may facilitate reshaping of a woman's expectations, a form of cognitive restructuring. The transitional nature of sadness has important implications for women's mental health.

Adaptation, Psychological↗
PubMed2004

Classifying psychiatric disorders after traumatic brain injury and orthopaedic injury in children: adequacy of K-SADS versus CBCL.

PRIMARY OBJECTIVE: [corrected] To evaluate the convergence between the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) for the diagnosis of psychiatric disorders and the Child Behavior Checklist (CBCL). RESEARCH DESIGN: Cross-sectional psychiatric study of 72 children with traumatic brain injuries or orthopaedic injuries aged 5-14. METHODS AND PROCEDURES: Sensitivity, specificity, total predictive value and odds ratio were calculated to evaluate the association between CBCL summary scores and K-SADS diagnosis of at least one psychiatric disorder (K-SADS-1), and of CBCL subscales and K-SADS diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD). Lowered cut-off scores of t > or = 60 were used. MAIN OUTCOMES AND RESULTS: Convergence between the CBCL total problem scale and K-SADS-1 was poor. Convergence between 'at least one elevated CBCL subscale' and K-SADS-1, and between CBCL attention problems and social problems scales and K-SADS diagnosis of ADHD was excellent. CONCLUSIONS: Caution is needed when using the total problem scale of CBCL in predicting global psychological impairment because underestimation of problems is likely. The attention and social problems scales of CBCL can be used to estimate ADHD.

Adolescent↗