AUTS2 Governs Cerebellar Development, Purkinje Cell Maturation, Motor Function and Social Communication.

Autism susceptibility candidate 2 (AUTS2), a risk gene for autism spectrum disorders (ASDs), is implicated in telencephalon development. Because AUTS2 is also expressed in the cerebellum where defects have been linked to ASDs, we investigated AUTS2 functions in the cerebellum. AUTS2 is specifically localized in Purkinje cells (PCs) and Golgi cells during postnatal development. Auts2 conditional knockout (cKO) mice exhibited smaller and deformed cerebella containing immature-shaped PCs with reduced expression of Cacna1a. Auts2 cKO and knock-down experiments implicated AUTS2 participation in elimination and translocation of climbing fiber synapses and restriction of parallel fiber synapse numbers. Auts2 cKO mice exhibited behavioral impairments in motor learning and vocal communications. Because Cacna1a is known to regulate synapse development in PCs, it suggests that AUTS2 is required for PC maturation to elicit normal development of PC synapses and thus the impairment of AUTS2 may cause cerebellar dysfunction related to psychiatric illnesses such as ASDs.

AUTS2 Regulation of Synapses for Proper Synaptic Inputs and Social Communication.

Impairments in synapse development are thought to cause numerous psychiatric disorders. Autism susceptibility candidate 2 (AUTS2) gene has been associated with various psychiatric disorders, such as autism and intellectual disabilities. Although roles for AUTS2 in neuronal migration and neuritogenesis have been reported, its involvement in synapse regulation remains unclear. In this study, we found that excitatory synapses were specifically increased in the Auts2-deficient primary cultured neurons as well as Auts2 mutant forebrains. Electrophysiological recordings and immunostaining showed increases in excitatory synaptic inputs as well as c-fos expression in Auts2 mutant brains, suggesting that an altered balance of excitatory and inhibitory inputs enhances brain excitability. Auts2 mutant mice exhibited autistic-like behaviors including impairments in social interaction and altered vocal communication. Together, these findings suggest that AUTS2 regulates excitatory synapse number to coordinate E/I balance in the brain, whose impairment may underlie the pathology of psychiatric disorders in individuals with AUTS2 mutations.

Prevalence of endocrine disorders and their associated factors in transfusion-dependent thalassemia patients: a historical cohort study in Southern Iran.

PURPOSE: Transfusion-dependent beta-thalassemia (TDT) patients suffer from various endocrinopathies. The main contributing factor associated with these complications is iron overload, secondary to frequent blood transfusions. To improve patients' quality of life, we evaluated the prevalence of endocrine disorders while considering the associated factors for further assessment. METHODS: Seven hundred thirteen transfusion-dependent thalassemia patients with age range 10-62 years were enrolled in this study. Serum calcium, phosphorous, fast blood sugar, ferritin, 25-OH vitamin D, free thyroxin, thyroid-stimulating hormone and parathyroid hormone were assessed. Bone mineral density was measured by dual-energy X-ray absorptiometry. RESULTS: In total, 86.8% of the TDT patients suffered from at least one endocrinopathy. The prevalence of endocrinopathies in descending order of frequency was low bone mass (72.6%), hypogonadism (44.5%), diabetes mellitus (15.9%), hypoparathyroidism (13.2%), and hypothyroidism (10.7%). Age, body mass index and splenectomy were significantly associated with most of the endocrine disorders. CONCLUSION: Endocrine complications are frequently observed in TDT patients. Splenectomy is a major risk factor and should be generally avoided unless it is highly indicated. Periodic surveillance of endocrine function and proper management of iron overload are advised.

Building an ark: creating a vessel for the education of MBSR teachers.

This paper is a response to an invitation by the editors of this special issue to write a first person account about mindfulness-based stress reduction (MBSR) teacher education as it developed within the Stress Reduction Clinic (SRC) and Center for Mindfulness in Medicine, Health Care, and Society (CFM) at the University of Massachusetts Medical School. As the founder of Oasis Institute, I have attempted to describe, in very personal terms, the ground out of which Oasis emerged and the ways this ground shaped the intention, educational trajectory, pedagogy, and infrastructure of Oasis Institute.

The beauty we love: MBSR teacher education going forward.

The paper begins with a brief overview of the current field of mindfulness and MBSR. Following this, the paper identifies and details nine domains of MBSR teacher education to consider going forward.

Investigating the effect of testosterone by itself and in combination with letrozole on 1,25-dihydroxy vitamin D and FGF23 in male rats.

BACKGROUND: Testosterone deficiency might be associated with vitamin D levels in hypogonadal men, but it is not clear whether testosterone can affect vitamin D and fibroblast growth factor-23 (FGF23), either directly or indirectly via aromatization to estradiol. We aimed to investigate the role of testosterone on vitamin D metabolism and serum FGF23 in male rats. METHODS: A total of 48 male rats were divided into 4 equal groups: sham; O, orchiectomy; O + T, orchiectomized rats treated with testosterone; and O + T + L, orchiectomized rats treated with combination of testosterone and letrozole. We compare the vitamin D metabolism biochemical parameters in these four groups, before and after the study. RESULTS: We detected a significant reduction in 25-hydroxyvitamin D (25(OH)D), vitamin D binding protein (DBP), FGF23, and 1,25-dihydroxyvitamin D (1,25(OH)2D) serum level in O group compared to sham group (p = 0.004, p = 0.009, p < 0.001 and p < 0.001, respectively), and a significant increase in serum phosphorus, parathyroid hormone (PTH), and alkaline phosphatase (ALP) levels in orchiectomized rats in comparison to sham group (p < 0.001, p = 0.022, and p = 0.006, respectively). However, these changes were corrected by testosterone replacement in O + T and O + T + L groups. In addition, we found that DBP and 1,25(OH)2D serum levels were significantly higher in O + T group in comparison to O + T + L group (p = 0.030 and p = 0.026, respectively). CONCLUSIONS: Testosterone plays a significant role on regulating 25(OH)D, DBP, FGF23, phosphate (Phos), PTH, and 1,25(OH)2D serum levels in male rats. Also, testosterone has a potent effect on 1,25(OH)2D and DBP by its conversion to estradiol.

Effect of Cholecalciferol therapy on serum FGF23 in vitamin D deficient patients: a randomized clinical trial.

INTRODUCTION: Fibroblast growth factor-23 plays an important role in regulating systemic phosphate homeostasis, and vitamin D metabolism. However, the effect of Cholecalciferol therapy on FGF23 serum level in patients with vitamin D deficiency has not been studied, yet. MATERIALS AND METHODS: This is a double-blind, randomized clinical trial on 119 vitamin D deficient patients in 2016. Biochemical variables of treatment and placebo groups were analyzed after 12 weeks of 50,000 IU of Cholecalciferol vs. placebo therapy once a week, by SPSS18. RESULTS: After Cholecalciferol therapy, delta of serum PTH in treatment group was less than the controls (P < 0.001). However, delta values of serum 25(OH)D3, 1,25(OH)2D3 and FGF23 in vitamin D treated group were more than the placebo-treated ones (P < 0.001, P = 0.002, and P = 0.04, respectively). Moreover, FGF23 serum level in treatment group was associated with serum calcium (P = 0.005, r = -0.256), and serum 1,25(OH)2D3 (P < 0.001, r = 0.529). CONCLUSIONS: We propose that in these patients 1,25(OH)2D3 has a positive association with serum FGF23, and hypostasized that serum calcium might be a down regulator of serum FGF23.

Classic cadherin expressions balance postnatal neuronal positioning and dendrite dynamics to elaborate the specific cytoarchitecture of the mouse cortical area.

A unique feature of the mammalian cerebral cortex is in its tangential parcellation via anatomical and functional differences. However, the cellular and/or molecular machinery involved in cortical arealization remain largely unknown. Here we map expression profiles of classic cadherins in the postnatal mouse barrel field of the primary somatosensory area (S1BF) and generate a novel bacterial artificial chromosome transgenic (BAC-Tg) mouse line selectively illuminating nuclei of cadherin-6 (Cdh6)-expressing layer IV barrel neurons to confirm that tangential cellular assemblage of S1BF is established by postnatal day 5 (P5). When we electroporate the cadherins expressed in both barrel neurons and thalamo-cortical axon (TCA) terminals limited to the postnatal layer IV neurons, S1BF cytoarchitecture is disorganized with excess elongation of dendrites at P7. Upon delivery of dominant negative molecules for all classic cadherins, tangential cellular positioning and biased dendritic arborization of barrel neurons are significantly altered. These results underscore the value of classic cadherin-mediated sorting among neuronal cell bodies, dendrites and TCA terminals in postnatally elaborating the S1BF-specific tangential cytoarchitecture. Additionally, how the "protocortex" machinery affects classic cadherin expression profiles in the process of cortical arealization is examined and discussed.

Skin manifestation of methylmalonic acidemia: case report and review of the literature.

Skin manifestations, including scalded skin, desquamation, and chronic periorificial dermatitis, are rare clinical signs in patients with methylmalonic acidemia. This condition may be due to enzyme deficiency or multi-nutrient deficiency because of nutritional restriction. Bullous skin lesion is very rare in these patients and consequently, this type of skin lesion can be the presenting sign of methylmalonic acidemia.

Investigation of osteopontin levels and genomic variation of osteopontin and its receptors in Type 1 diabetes mellitus.

BACKGROUND: Failure in self-tolerance towards ß-cells in diabetes mellitus (DM) pathogenesis involves a series of complex events that are governed by environmental and genetic factors. Considering the importance of osteopontin (OPN) in T-helper-1 (Th1) cells development, the aim of this study was to evaluate the serum level and gene polymorphism of OPN in Iranian Type 1 diabetic (T1DM) children. METHODS: In this case-control study, 87 T1DM children and 86 healthy ones were enrolled. Blood samples of both groups were checked for OPN level. The single nucleotide polymorphisms (SNP) were genotyped by RFLP analysis for OPN rs1126772, its receptor integrin α4 (ITGA4) rs 1449263, and CD44 rs8193. RESULTS: Serum levels of OPN in diabetic children were significantly higher in cases compared to the control group (p=0.023), but there was no significant relationship between OPN rs1126772 (p=0.79), its receptor integrin α4 (p=0.31), and CD44 rs8193 (p=0.45), and T1DM. CONCLUSION: Higher amounts of OPN were seen in T1DM children. It is assumed that OPN might have inducing effects on T1DM development, particularly when genetically susceptible individuals are predisposed by an environmental insult. However, the 3 SNPs of OPN and its receptors did not show noticeable association with T1DM. The power of our study (~19%) was insufficient to observe any significant statistical difference between the groups; moreover, this study does not exclude the possibility of association of other SNPs of OPN and its receptors with this disease, and more studies are needed to clarify the issue.

Cadherin-6 mediates axon-target matching in a non-image-forming visual circuit.

Neural circuits consist of highly precise connections among specific types of neurons that serve a common functional goal. How neurons distinguish among different synaptic targets to form functionally precise circuits remains largely unknown. Here, we show that during development, the adhesion molecule cadherin-6 (Cdh6) is expressed by a subset of retinal ganglion cells (RGCs) and also by their targets in the brain. All of the Cdh6-expressing retinorecipient nuclei mediate non-image-forming visual functions. A screen of mice expressing GFP in specific subsets of RGCs revealed that Cdh3-RGCs which also express Cdh6 selectively innervate Cdh6-expressing retinorecipient targets. Moreover, in Cdh6-deficient mice, the axons of Cdh3-RGCs fail to properly innervate their targets and instead project to other visual nuclei. These findings provide functional evidence that classical cadherins promote mammalian CNS circuit development by ensuring that axons of specific cell types connect to their appropriate synaptic targets.

Bacterial artificial chromosomes as analytical basis for gene transcriptional machineries.

Bacterial Artificial Chromosomes (BACs) had been minimal components of various genome-sequencing projects, constituting perfect analytical basis for functional genomics. Here we describe an enhancer screening strategy in which BAC clones that cover any genomic segments of interest are modified to harbor a reporter cassette by transposon tagging, then processed to carry selected combinations of gene regulatory modules by homologous recombination mediated systematic deletions. Such engineered BAC-reporter constructs in bacterial cells are ready for efficient transgenesis in mice to evaluate activities of gene regulatory modules intact or absent in the constructs. By utilizing the strategy, we could speedily identify a critical genomic fragment for spatio-temporally regulated expression of a mouse cadherin gene whose structure is extraordinarily huge and intricate. This BAC-based methodology would hence provide a novel screening platform for gene transcriptional machineries that dynamically fluctuate during development, pathogenesis and/or evolution.

Alterations in brain and immune function produced by mindfulness meditation.

OBJECTIVE: The underlying changes in biological processes that are associated with reported changes in mental and physical health in response to meditation have not been systematically explored. We performed a randomized, controlled study on the effects on brain and immune function of a well-known and widely used 8-week clinical training program in mindfulness meditation applied in a work environment with healthy employees. METHODS: We measured brain electrical activity before and immediately after, and then 4 months after an 8-week training program in mindfulness meditation. Twenty-five subjects were tested in the meditation group. A wait-list control group (N = 16) was tested at the same points in time as the meditators. At the end of the 8-week period, subjects in both groups were vaccinated with influenza vaccine. RESULTS: We report for the first time significant increases in left-sided anterior activation, a pattern previously associated with positive affect, in the meditators compared with the nonmeditators. We also found significant increases in antibody titers to influenza vaccine among subjects in the meditation compared with those in the wait-list control group. Finally, the magnitude of increase in left-sided activation predicted the magnitude of antibody titer rise to the vaccine. CONCLUSIONS: These findings demonstrate that a short program in mindfulness meditation produces demonstrable effects on brain and immune function. These findings suggest that meditation may change brain and immune function in positive ways and underscore the need for additional research.