A systematic review of relations between resting-state functional-MRI and treatment response in major depressive disorder

Resting-state functional magnetic resonance imaging (fMRI) is a promising predictor of treatment response in major depressive disorder (MDD)

Differential Regulation of CASZ1 Protein Expression During Cardiac and Skeletal Muscle Development

BACKGROUND: The zinc-finger transcription factor CASZ1 is required for differentiation of a distinct population of cardiomyocytes during development. However, expression of Casz1 mRNA is detected throughout the developing heart, suggesting the spatial regulation of CASZ1 occurs at the protein level. Relatively little is known about posttranscriptional regulation of Casz1 in the heart. RESULTS: We generated antibodies that specifically recognize CASZ1 in developing Xenopus embryos, and performed immunofluorescence analysis of CASZ1 during cardiac development. CASZ1 was detected throughout the developing myocardium. CASZ1 was restricted to terminally differentiated cardiomyocytes, and was down-regulated in cells that re-enter the cell cycle. We determined that CASZ1 expression correlated with terminal differentiation in cardiac muscle cells, skeletal muscle cells, and lymph-heart musculature. CONCLUSIONS: This study indicates that spatially distinct expression of CASZ1 protein may be due to posttranscriptional control of Casz1 mRNA during cardiac development. The results of this study provide insights into the role of Casz1 in cardiac function and in the differentiation of other cell types, including skeletal muscle and lymph heart

Attenuation of Frontostriatal Connectivity During Reward Processing Predicts Response to Psychotherapy in Major Depressive Disorder

There are few reliable predictors of response to antidepressant treatments. In the present investigation, we examined pretreatment functional brain connectivity during reward processing as a potential predictor of response to Behavioral Activation Treatment for Depression (BATD), a validated psychotherapy that promotes engagement with rewarding stimuli and reduces avoidance behaviors. Thirty-three outpatients with major depressive disorder (MDD) and 20 matched controls completed two runs of the monetary incentive delay task during functional magnetic resonance imaging after which participants with MDD received up to 15 sessions of BATD. Seed-based generalized psychophysiological interaction analyses focused on task-based connectivity across task runs, as well as the attenuation of connectivity from the first to the second run of the task. The average change in Beck Depression Inventory-II scores due to treatment was 10.54 points, a clinically meaningful response. Groups differed in seed-based functional connectivity among multiple frontostriatal regions. Hierarchical linear modeling revealed that improved treatment response to BATD was predicted by greater connectivity between the left putamen and paracingulate gyrus during reward anticipation. In addition, MDD participants with greater attenuation of connectivity between several frontostriatal seeds, and midline subcallosal cortex and left paracingulate gyrus demonstrated improved response to BATD. These findings indicate that pretreatment frontostriatal functional connectivity during reward processing is predictive of response to a psychotherapy modality that promotes improving approach-related behaviors in MDD. Furthermore, connectivity attenuation among reward-processing regions may be a particularly powerful endophenotypic predictor of response to BATD in MDD

Sustained anterior cingulate cortex activation during reward processing predicts response to psychotherapy in major depressive disorder

The purpose of the present investigation was to evaluate whether pre-treatment neural activation in response to rewards is a predictor of clinical response to Behavioral Activation Therapy for Depression (BATD), an empirically validated psychotherapy that decreases depressive symptoms by increasing engagement with rewarding stimuli and reducing avoidance behaviors

Congenital heart disease protein 5 associates with CASZ1 to maintain myocardial tissue integrity

The identification and characterization of the cellular and molecular pathways involved in the differentiation and morphogenesis of specific cell types of the developing heart are crucial to understanding the process of cardiac development and the pathology associated with human congenital heart disease. Here, we show that the cardiac transcription factor CASTOR (CASZ1) directly interacts with congenital heart disease 5 protein (CHD5), which is also known as tryptophan-rich basic protein (WRB), a gene located on chromosome 21 in the proposed region responsible for congenital heart disease in individuals with Down's syndrome. We demonstrate that loss of CHD5 in Xenopus leads to compromised myocardial integrity, improper deposition of basement membrane, and a resultant failure of hearts to undergo cell movements associated with cardiac formation. We further report that CHD5 is essential for CASZ1 function and that the CHD5-CASZ1 interaction is necessary for cardiac morphogenesis. Collectively, these results establish a role for CHD5 and CASZ1 in the early stages of vertebrate cardiac development

Resting-State Connectivity Predictors of Response to Psychotherapy in Major Depressive Disorder

Despite the heterogeneous symptom presentation and complex etiology of major depressive disorder (MDD), functional neuroimaging studies have shown with remarkable consistency that dysfunction in mesocorticolimbic brain systems are central to the disorder. Relatively less research has focused on the identification of biological markers of response to antidepressant treatment that would serve to improve the personalized delivery of empirically supported antidepressant interventions. In the present study, we investigated whether resting-state functional brain connectivity (rs-fcMRI) predicted response to Behavioral Activation Treatment for Depression, an empirically validated psychotherapy modality designed to increase engagement with rewarding stimuli and reduce avoidance behaviors. Twenty-three unmedicated outpatients with MDD and 20 matched nondepressed controls completed rs-fcMRI scans after which the MDD group received an average of 12 sessions of psychotherapy. The mean change in Beck Depression Inventory-II scores after psychotherapy was 12.04 points, a clinically meaningful response. Resting-state neuroimaging data were analyzed with a seed-based approach to investigate functional connectivity with four canonical resting-state networks: the default mode network, the dorsal attention network, the executive control network, and the salience network. At baseline, the MDD group was characterized by relative hyperconnectivity of multiple regions with precuneus, anterior insula, dorsal anterior cingulate cortex (dACC), and left dorsolateral prefrontal cortex seeds and by relative hypoconnectivity with intraparietal sulcus, anterior insula, and dACC seeds. Additionally, connectivity of the precuneus with the left middle temporal gyrus and connectivity of the dACC with the parahippocampal gyrus predicted the magnitude of pretreatment MDD symptoms. Hierarchical linear modeling revealed that response to psychotherapy in the MDD group was predicted by pretreatment connectivity of the right insula with the right middle temporal gyrus and the left intraparietal sulcus with the orbital frontal cortex. These results add to the nascent body of literature investigating pretreatment rs-fcMRI predictors of antidepressant treatment response and is the first study to examine rs-fcMRI predictors of response to psychotherapy

Duchenne muscular dystrophy disease severity impacts skeletal muscle progenitor cells systemic delivery

Duchenne muscular dystrophy (DMD) is caused by an out-of-frame mutation in the DMD gene that results in the absence of a functional dystrophin protein, leading to a devastating progressive lethal muscle-wasting disease. Muscle stem cell-based therapy is a promising avenue for improving muscle regeneration. However, despite the efforts to deliver the optimal cell population to multiple muscles most efforts have failed. Here we describe a detailed optimized method of for the delivery of human skeletal muscle progenitor cells (SMPCs) to multiple hindlimb muscles in healthy, dystrophic and severely dystrophic mouse models. We show that systemic delivery is inefficient and is affected by the microenvironment. We found that significantly less human SMPCs were detected in healthy gastrocnemius muscle cross-sections, compared to both dystrophic and severely dystrophic gastrocnemius muscle. Human SMPCs were found to be detected inside blood vessels distinctly in healthy, dystrophic and severely dystrophic muscles, with prominent clotting identified in severely dystrophic muscles after intra arterial (IA) systemic cell delivery. We propose that muscle microenvironment and the severity of muscular dystrophy to an extent impacts the systemic delivery of SMPCs and that overall systemic stem cell delivery is not currently efficient or safe to be used in cell based therapies for DMD. This work extends our understanding of the severe nature of DMD, which should be taken into account when considering stem cell-based systemic delivery platforms

Duchenne muscular dystrophy disease severity impacts skeletal muscle progenitor cells systemic delivery.

Duchenne muscular dystrophy (DMD) is caused by an out-of-frame mutation in the DMD gene that results in the absence of a functional dystrophin protein, leading to a devastating progressive lethal muscle-wasting disease. Muscle stem cell-based therapy is a promising avenue for improving muscle regeneration. However, despite the efforts to deliver the optimal cell population to multiple muscles most efforts have failed. Here we describe a detailed optimized method of for the delivery of human skeletal muscle progenitor cells (SMPCs) to multiple hindlimb muscles in healthy, dystrophic and severely dystrophic mouse models. We show that systemic delivery is inefficient and is affected by the microenvironment. We found that significantly less human SMPCs were detected in healthy gastrocnemius muscle cross-sections, compared to both dystrophic and severely dystrophic gastrocnemius muscle. Human SMPCs were found to be detected inside blood vessels distinctly in healthy, dystrophic and severely dystrophic muscles, with prominent clotting identified in severely dystrophic muscles after intra arterial (IA) systemic cell delivery. We propose that muscle microenvironment and the severity of muscular dystrophy to an extent impacts the systemic delivery of SMPCs and that overall systemic stem cell delivery is not currently efficient or safe to be used in cell based therapies for DMD. This work extends our understanding of the severe nature of DMD, which should be taken into account when considering stem cell-based systemic delivery platforms

Muscle dysfunction in a zebrafish model of Duchenne muscular dystrophy

Sapje zebrafish lack the protein dystrophin and are the smallest vertebrate model of Duchenne muscular dystrophy (DMD). Their small size makes them ideal for large-scale drug discovery screens. However, the extent that sapje mimic the muscle dysfunction of higher vertebrate models of DMD is unclear. We used an optical birefringence assay to differentiate affected dystrophic sapje larvae from their unaffected siblings and then studied trunk muscle contractility at 4-7 days post fertilization. Preparation cross-sectional area (CSA) was similar for affected and unaffected larvae, yet tetanic forces of affected preparations were only 30-60% of normal. ANCOVA indicated that the linear relationship observed between tetanic force and CSA for unaffected preparations was absent in the affected population. Consequently, the average force/CSA of affected larvae was depressed 30-70%. Disproportionate reductions in twitch vs. tetanic force, and a slowing of twitch tension development and relaxation, indicated that the myofibrillar disorganization evident in the birefringence assay could not explain the entire force loss. Single eccentric contractions, in which activated preparations were lengthened 5-10%, resulted in tetanic force deficits in both groups of larvae. However, deficits of affected preparations were 3 to 5-fold greater at all strains and ages, even after accounting for any recovery. Based on these functional assessments, we conclude that the sapje mutant zebrafish is a phenotypically severe model of DMD. The severe contractile deficits of sapje larvae represent novel physiological endpoints for therapeutic drug screening