Miro1 Regulates Activity-Driven Positioning of Mitochondria within Astrocytic Processes Apposed to Synapses to Regulate Intracellular Calcium Signaling

It is fast emerging that maintaining mitochondrial function is important for regulating astrocyte function, although the specific mechanisms that govern astrocyte mitochondrial trafficking and positioning remain poorly understood. The mitochondrial Rho-GTPase 1 protein (Miro1) regulates mitochondrial trafficking and detachment from the microtubule transport network to control activity-dependent mitochondrial positioning in neurons. However, whether Miro proteins are important for regulating signaling-dependent mitochondrial dynamics in astrocytic processes remains unclear. Using live-cell confocal microscopy of rat organotypic hippocampal slices, we find that enhancing neuronal activity induces transient mitochondrial remodeling in astrocytes, with a concomitant, transient reduction in mitochondrial trafficking, mediated by elevations in intracellular Ca(2+). Stimulating neuronal activity also induced mitochondrial confinement within astrocytic processes in close proximity to synapses. Furthermore, we show that the Ca(2+)-sensing EF-hand domains of Miro1 are important for regulating mitochondrial trafficking in astrocytes and required for activity-driven mitochondrial confinement near synapses. Additionally, activity-dependent mitochondrial positioning by Miro1 reciprocally regulates the levels of intracellular Ca(2+) in astrocytic processes. Thus, the regulation of intracellular Ca(2+) signaling, dependent on Miro1-mediated mitochondrial positioning, could have important consequences for astrocyte Ca(2+) wave propagation, gliotransmission, and ultimately neuronal function

The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.

Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the individual roles for genes at this locus in nervous system development, function and connectivity remain poorly understood. Haploinsufficiency of one gene in this region, Cyfip1, may provide a model for 15q11.2 CNV-associated neuropsychiatric phenotypes. Here we show that altering CYFIP1 expression levels in neurons both in vitro and in vivo influences dendritic complexity, spine morphology, spine actin dynamics and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion. CYFIP1 is highly enriched at synapses and its overexpression in vitro leads to increased dendritic complexity. Neurons derived from Cyfip1 heterozygous animals on the other hand, possess reduced dendritic complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor mobility at synapses. Interestingly, Cyfip1 overexpression or haploinsufficiency increased immature spine number, whereas activity-dependent changes in spine volume were occluded in Cyfip1 haploinsufficient neurons. In vivo, Cyfip1 heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In summary, we provide evidence that dysregulation of CYFIP1 expression levels leads to pathological changes in CNS maturation and neuronal connectivity, both of which may contribute to the development of the neurological symptoms seen in ASD and SCZ

Internet-based cognitive behavior therapy for obsessive compulsive disorder: A pilot study

<p>Abstract</p> <p>Background</p> <p>Cognitive behavior therapy (CBT) is widely regarded as an effective treatment for obsessive compulsive disorder (OCD), but access to CBT therapists is limited. Internet-based CBT (ICBT) with therapist support is a way to increase access to CBT but has not been developed or tested for OCD. The aim of this study was to evaluate ICBT for OCD.</p> <p>Method</p> <p>An open trial where patients (N = 23) received a 15-week ICBT program with therapist support consisting of psychoeducation, cognitive restructuring and exposure with response prevention. The primary outcome was the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), which was assessed by a psychiatrist before and immediately after treatment. Secondary outcomes were self-rated measures of OCD symptoms, depressive symptoms, general functioning, anxiety and quality of life. All assessments were made at baseline and post-treatment.</p> <p>Results</p> <p>All participants completed the primary outcome measure at all assessment points. There were reductions in OCD symptoms with a large within-group effect size (Cohen's <it>d </it>= 1.56). At post-treatment, 61% of participants had a clinically significant improvement and 43% no longer fulfilled the diagnostic criteria of OCD. The treatment also resulted in statistically significant improvements in self-rated OCD symptoms, general functioning and depression.</p> <p>Conclusions</p> <p>ICBT with therapist support reduces OCD symptoms, depressive symptoms and improves general functioning. Randomized trials are needed to confirm the effectiveness of this new treatment format.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01348529">NCT01348529</a></p

Functionalized Positive Nanoparticles Reduce Mucin Swelling and Dispersion

Multi-functionalized nanoparticles (NPs) have been extensively investigated for their potential in household and commercial products, and biomedical applications. Previous reports have confirmed the cellular nanotoxicity and adverse inflammatory effects on pulmonary systems induced by NPs. However, possible health hazards resulting from mucus rheological disturbances induced by NPs are underexplored. Accumulation of viscous, poorly dispersed, and less transportable mucus leading to improper mucus rheology and dysfunctional mucociliary clearance are typically found to associate with many respiratory diseases such as asthma, cystic fibrosis (CF), and COPD (Chronic Obstructive Pulmonary Disease). Whether functionalized NPs can alter mucus rheology and its operational mechanisms have not been resolved. Herein, we report that positively charged functionalized NPs can hinder mucin gel hydration and effectively induce mucin aggregation. The positively charged NPs can significantly reduce the rate of mucin matrix swelling by a maximum of 7.5 folds. These NPs significantly increase the size of aggregated mucin by approximately 30 times within 24 hrs. EGTA chelation of indigenous mucin crosslinkers (Ca2+ ions) was unable to effectively disperse NP-induced aggregated mucins. Our results have demonstrated that positively charged functionalized NPs can impede mucin gel swelling by crosslinking the matrix. This report also highlights the unexpected health risk of NP-induced change in mucus rheological properties resulting in possible mucociliary transport impairment on epithelial mucosa and related health problems. In addition, our data can serve as a prospective guideline for designing nanocarriers for airway drug delivery applications

In Vivo Evaluation of the Biocompatibility of Surface Modified Hemodialysis Polysulfone Hollow Fibers in Rat

Polysulfone (Psf) hollow fiber membranes (HFMs) have been widely used in blood purification but their biocompatibility remains a concern. To enhance their biocompatibility, Psf/TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate) composite HFMs and 2-methacryloyloxyethyl phosphorylcholine (MPC) coated Psf HFMs have been prepared. They have been evaluated for in vivo biocompatibility and graft acceptance and compared with sham and commercial membranes by intra-peritoneal implantation in rats at day 7 and 21. Normal body weights, tissue formation and angiogenesis indicate acceptance of implants by the animals. Hematological observations show presence of post-surgical stress which subsides over time. Serum biochemistry results reveal normal organ function and elevated liver ALP levels at day 21. Histological studies exhibit fibroblast recruitment cells, angiogenesis and collagen deposition at the implant surface indicating new tissue formation. Immuno-histochemistry studies show non-activation of MHC molecules signifying biocompatibilty. Additionally, Psf/TPGS exhibit most favorable tissue response as compared with other HFMs making them the material of choice for HFM preparation for hemodialysis applications

Childhood adversity, mental ill-health and aggressive behavior in an African orphanage: Changes in response to trauma-focused therapy and the implementation of a new instructional system

<p>Abstract</p> <p>Background</p> <p>The number of orphans in Sub-Saharan Africa is constantly rising. While it is known that family or community care is preferable over institutional care of African orphans, little is known about the quality of care in orphanages and possibilities of improvement.</p> <p>Study 1</p> <p>Methods</p> <p>Exposure to traumatic stress, experiences of violence in the home, school and orphanage, as well as mental ill-health and aggression of 38 children (mean age of <it>M </it>= 8.64 years) living in an orphanage in rural Tanzania were assessed at two time points. The severity of post-traumatic stress disorder symptoms (PTSD), depressive symptoms, and internalizing and externalizing problems were used as indicators of mental ill-health.</p> <p>Results</p> <p>Violence experienced in the orphanage correlated more strongly with all indicators of mental ill-health than violence in the former home, school or neighborhood at time point 1. Additionally, violence experienced in the orphanage had a positive relationship with the aggressive behavior of the children at time point 2.</p> <p>Study 2</p> <p>Methods</p> <p>With the help of the pre-post assessment of Study 1, the implementation of a new instructional system and psychotherapeutic treatment (KIDNET) for trauma-related illness were evaluated.</p> <p>Results</p> <p>In response to both, a change in the instructional system and psychotherapeutic treatment of PTSD, a massive decline in experienced violence and in the severity of PTSD-symptoms was found, whereas depressive symptoms and internalizing and externalizing problems exhibited little change.</p> <p>Conclusions</p> <p>These studies show that violence, especially in the orphanage, can severely contribute to mental ill-health in orphans and that mental health can be improved by implementing a new instructional system and psychotherapeutic treatment in an orphanage. Moreover, the results indicate that the experience of violence in an orphanage also plays a crucial role in aggressive behavior of the orphans.</p

A glycoconjugate of Haemophilus influenzae Type b capsular polysaccharide with tetanus toxoid protein: hydrodynamic properties mainly influenced by the carbohydrate

Three important physical properties which may affect the performance of glycoconjugate vaccines against serious disease are molar mass (molecular weight), heterogeneity (polydispersity), and conformational flexibility in solution. The dilute solution behaviour of native and activated capsular polyribosylribitol (PRP) polysaccharides extracted from Haemophilus influenzae type b (Hib), and the corresponding glycoconjugate made by conjugating this with the tetanus toxoid (TT) protein have been characterized and compared using a combination of sedimentation equilibrium and sedimentation velocity in the analytical ultracentrifuge with viscometry. The weight average molar mass of the activated material was considerably reduced (Mw ~ 0.24 × 106 g.mol−1) compared to the native (Mw ~ 1.2 × 106 g.mol−1). Conjugation with the TT protein yielded large polydisperse structures (of Mw ~ 7.4 × 106 g.mol−1), but which retained the high degree of flexibility of the native and activated polysaccharide, with frictional ratio, intrinsic viscosity, sedimentation conformation zoning behaviour and persistence length all commensurate with highly flexible coil behaviour and unlike the previously characterised tetanus toxoid protein (slightly extended and hydrodynamically compact structure with an aspect ratio of ~3). This non-protein like behaviour clearly indicates that it is the carbohydrate component which mainly influences the physical behaviour of the glycoconjugate in solution

Mass extinctions drove increased global faunal cosmopolitanism on the supercontinent Pangaea

Mass extinctions have profoundly impacted the evolution of life through not only reducing taxonomic diversity but also reshaping ecosystems and biogeographic patterns. In particular, they are considered to have driven increased biogeographic cosmopolitanism, but quantitative tests of this hypothesis are rare and have not explicitly incorporated information on evolutionary relationships. Here we quantify faunal cosmopolitanism using a phylogenetic network approach for 891 terrestrial vertebrate species spanning the late Permian through Early Jurassic. This key interval witnessed the Permian–Triassic and Triassic–Jurassic mass extinctions, the onset of fragmentation of the supercontinent Pangaea, and the origins of dinosaurs and many modern vertebrate groups. Our results recover significant increases in global faunal cosmopolitanism following both mass extinctions, driven mainly by new, widespread taxa, leading to homogenous ‘disaster faunas’. Cosmopolitanism subsequently declines in post-recovery communities. These shared patterns in both biotic crises suggest that mass extinctions have predictable influences on animal distribution and may shed light on biodiversity loss in extant ecosystems

Demographic and Clinical Features and Prescribing Patterns of Psychotropic Medications in Patients with the Melancholic Subtype of Major Depressive Disorder in China

BACKGROUND: Little has been known about the demographic and clinical features of the melancholic subtype of major depressive disorder (MDD) in Chinese patients. This study examined the frequency of melancholia in Chinese MDD patients and explored its demographic and clinical correlates and prescribing patterns of psychotropic drugs. METHODS: A consecutively collected sample of 1,178 patients with MDD were examined in 13 psychiatric hospitals or psychiatric units of general hospitals in China nationwide. The cross-sectional data of patients' demographic and clinical characteristics and prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. The diagnosis of the melancholic subtype was established using the Mini International Neuropsychiatric Interview (MINI). Medications ascertained included antidepressants, mood stabilizers, antipsychotics and benzodiazepines. RESULTS: Six hundred and twenty nine (53.4%) of the 1,178 patients fulfilled criteria for melancholia. In multiple logistic regression analyses, compared to non-melancholic counterparts, melancholic MDD patients were more likely to be male and receive benzodiazepines, had more frequent suicide ideations and attempts and seasonal depressive episodes, while they were less likely to be employed and receive antidepressants and had less family history of psychiatric disorders and lifetime depressive episodes. CONCLUSIONS: The demographic and clinical features of melancholic MDD in Chinese patients were not entirely consistent with those found in Western populations. Compared to non-melancholic MDD patients, melancholic patients presented with different demographic and clinical features, which have implications for treatment decisions