Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant.

Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the gene. One mutation results in an in frame stop codon (Rstop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (GR) that, surprisingly, does not affect the Ca permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 GR and Rstop mutants and combinations with wild type TRPV6.

Hypothalamic Pomc Neurons Innervate the Spinal Cord and Modulate the Excitability of Premotor Circuits.

Locomotion requires energy, yet animals need to increase locomotion in order to find and consume food in energy-deprived states. While such energy homeostatic coordination suggests brain origin, whether the central melanocortin 4 receptor (Mc4r) system directly modulates locomotion through motor circuits is unknown. Here, we report that hypothalamic Pomc neurons in zebrafish and mice have long-range projections into spinal cord regions harboring Mc4r-expressing V2a interneurons, crucial components of the premotor networks.

Ascl1 Balances Neuronal versus Ependymal Fate in the Spinal Cord Central Canal.

Generation of neuronal types at the right time, location, and number is essential for building a functional nervous system. Significant progress has been reached in understanding the mechanisms that govern neuronal diversity. Cerebrospinal fluid-contacting neurons (CSF-cNs), an intriguing spinal cord central canal population, are produced during advanced developmental stages, simultaneous with glial and ependymal cells.

Stimulation-induced ictal vocalisation of left frontal lobe origin.

Pure ictal non-speech vocalisation occurs in frontal and temporal lobe epilepsies. Electrical stimulation of supplementary motor areas is reported to evoke vocalisation in selected patients. Here, we report a patient with focal epilepsy of the left anterior insula who had isolated monotonous vocalisation elicited by electrical stimulation of the left superior frontal gyrus.

Diet-Induced Growth Is Regulated via Acquired Leptin Resistance and Engages a Pomc-Somatostatin-Growth Hormone Circuit.

Anorexigenic pro-opiomelanocortin (Pomc)/alpha-melanocyte stimulating hormone (αMSH) neurons of the hypothalamic melanocortin system function as key regulators of energy homeostasis, also controlling somatic growth across different species. However, the mechanisms of melanocortin-dependent growth control still remain ill-defined. Here, we reveal a thus-far-unrecognized structural and functional connection between Pomc neurons and the somatotropic hypothalamo-pituitary axis.

Direct activation of chordoblasts by retinoic acid is required for segmented centra mineralization during zebrafish spine development.

Zebrafish mutants with increased retinoic acid (RA) signaling due to the loss of the RA-inactivating enzyme Cyp26b1 develop a hyper-mineralized spine with gradually fusing vertebral body precursors (centra). However, the underlying cellular mechanisms remain incompletely understood. Here, we show that cells of the notochord epithelium named chordoblasts are sensitive to RA signaling.

Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function.

Objective: To ascertain the genetic and functional basis of complex autosomal recessive cerebellar ataxia (ARCA) presented by 2 siblings of a consanguineous family characterized by motor neuropathy, cerebellar atrophy, spastic paraparesis, intellectual disability, and slow ocular saccades.

Methods: Combined whole-genome linkage analysis, whole-exome sequencing, and focused screening for identification of potential causative genes were performed. Assessment of the functional consequences of the mutation on protein function via subcellular fractionation, size-exclusion chromatography, and fluorescence microscopy were done.

Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis.

Homozygous SMN1 loss causes spinal muscular atrophy (SMA), the most common lethal genetic childhood motor neuron disease. SMN1 encodes SMN, a ubiquitous housekeeping protein, which makes the primarily motor neuron-specific phenotype rather unexpected. SMA-affected individuals harbor low SMN expression from one to six SMN2 copies, which is insufficient to functionally compensate for SMN1 loss.

An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility.

Background: Genetic factors predispose individuals to attention-deficit/hyperactivity disorder (ADHD). Previous studies have reported linkage and association to ADHD of gene variants within ADGRL3. In this study, we functionally analyzed noncoding variants in this gene as likely pathological contributors.

A mutation in cnot8, component of the Ccr4-not complex regulating transcript stability, affects expression levels of developmental regulators and reveals a role of Fgf3 in development of caudal hypothalamic dopaminergic neurons.

While regulation of the activity of developmental control genes at the transcriptional level as well as by specific miRNA-based degradation are intensively studied, little is known whether general cellular mechanisms controlling mRNA decay may contribute to differential stability of mRNAs of developmental control genes. Here, we investigate whether a mutation in the deadenylation dependent mRNA decay pathway may reveal differential effects on developmental mechanisms, using dopaminergic differentiation in the zebrafish brain as model system. In a zebrafish genetic screen aimed at identifying genes controlling dopaminergic neuron development we isolated the m1061 mutation that selectively caused increased dopaminergic differentiation in the caudal hypothalamus, while other dopaminergic groups were not affected.

RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8(+) T cells.

Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction.

Direct and indirect roles of Fgf3 and Fgf10 in innervation and vascularisation of the vertebrate hypothalamic neurohypophysis.

The neurohypophysis is a crucial component of the hypothalamo-pituitary axis, serving as the site of release of hypothalamic neurohormones into a plexus of hypophyseal capillaries. The growth of hypothalamic axons and capillaries to the forming neurohypophysis in embryogenesis is therefore crucial to future adult homeostasis. Using ex vivo analyses in chick and in vivo analyses in mutant and transgenic zebrafish, we show that Fgf10 and Fgf3 secreted from the forming neurohypophysis exert direct guidance effects on hypothalamic neurosecretory axons.

Sim1a and Arnt2 contribute to hypothalamo-spinal axon guidance by regulating Robo2 activity via a Robo3-dependent mechanism.

Precise spatiotemporal control of axon guidance factor expression is a prerequisite for formation of functional neuronal connections. Although Netrin/Dcc- and Robo/Slit-mediated attractive and repulsive guidance of commissural axons have been extensively studied, little is known about mechanisms controlling mediolateral positioning of longitudinal axons in vertebrates. Here, we use a genetic approach in zebrafish embryos to study pathfinding mechanisms of dopaminergic and neuroendocrine longitudinal axons projecting from the hypothalamus into hindbrain and spinal cord.

Integrating psychoeducation in a basic computer skills course for people suffering from social anxiety: participants' experiences.

We describe a psychoeducational program integrated in a basic computer skills course for participants suffering from social anxiety. The two main aims of the course were: that the participants learn basic computer skills, and that the participants learn to cope better with social anxiety. Computer skills were taught by a qualified teacher.

Dopaminergic and noradrenergic circuit development in zebrafish.

Dopaminergic and noradrenergic neurons constitute some of the major far projecting systems in the vertebrate brain and spinal cord that modulate the activity of circuits controlling a broad range of behaviors. Degeneration or dysfunction of dopaminergic neurons has also been linked to a number of neurological and psychiatric disorders, including Parkinson's disease.Zebrafish (Danio rerio) have emerged over the past two decades into a major genetic vertebrate model system,and thus contributed to a better understanding of developmental mechanisms controlling dopaminergic neuron specification and axonogenesis.

Zebrafish in endocrine systems: recent advances and implications for human disease.

Since its introduction as a genetic vertebrate model system approximately 30 years ago, the focus of zebrafish research has increasingly shifted to questions that are also relevant for human development and disease. Here, we review the potential of the zebrafish as a model for human endocrine systems. A recent review compared the functions of the different endocrine systems and glands in zebrafish with those in other vertebrates, including humans, coming to the conclusion that major aspects are conserved.

Budesonide 9 mg is at least as effective as mesalamine 4.5 g in patients with mildly to moderately active Crohn's disease.

Background & Aims: Comparative data on budesonide vs mesalamine for the treatment of mild-to-moderately active Crohn's disease (CD) are sparse. We assessed the efficacy and safety of each therapy in patients with mildly to moderately active CD.

Methods: We performed a randomized, double-blind, double-dummy, 8-week, multicenter study in which 309 patients with mildly to moderately active CD received pH-modified-release oral budesonide (9 mg/day once daily or 3 mg/day 3 times daily) or Eudragit-L-coated oral mesalamine (4.

Zebrafish diencephalic A11-related dopaminergic neurons share a conserved transcriptional network with neuroendocrine cell lineages.

Vertebrate dopaminergic neurons develop in distinct neural territories to constitute one of the major neuromodulatory systems. We have identified a zebrafish mutation in the bHLH-PAS family member arnt2, based on a strong reduction in cell number of specific dopaminergic neuron groups in the hypothalamus and posterior tuberculum. Knockdown of sim1 causes a dopaminergic phenotype similar to arnt2 mutants, suggesting that Sim1 acts as a binding partner of Arnt2, similar to their role in hypothalamic neuroendocrine cell specification.

Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-alpha therapy.

Background: The efficacy of consensus interferon (CIFN), a synthetic IFN with optimised in vitro activity, was assessed in chronic hepatitis C virus (HCV) patients who had failed the pretreatment with interferon-alpha (IFNalpha) and ribavirin.

Methods: One hundred and three patients after non-response (n=69) or relapse (n=34) to IFNalpha+/-ribavirin were randomly assigned to high-dose induction (CIFN 27-->9 microg daily for 24 weeks, 9 microg t.i.

Cone opsin mislocalization in Rpe65-/- mice: a defect that can be corrected by 11-cis retinal.

Purpose: In retinal degenerative diseases, rod photoreceptors typically deteriorate more rapidly than cone photoreceptors. In the Rpe65(-/-) mouse, a model for Leber's congenital amaurosis, cones degenerate much more rapidly than rods. In this model, the retinoid processing pathway in the retinal pigment epithelium is disrupted, and 11-cis retinal is not generated.

Downregulation of cone-specific gene expression and degeneration of cone photoreceptors in the Rpe65-/- mouse at early ages.

Purpose: RPE65 is essential for the generation of 11-cis retinal. Rod photoreceptors in the RPE65-knockout (Rpe65(-/-)) mouse are known to degenerate slowly with age. This study was designed to examine cone photoreceptors and the expression of cone-specific genes in the Rpe65(-/-) mouse.

Phenotype and function of monocyte derived dendritic cells in chronic hepatitis B virus infection.

The antiviral T cell failure of patients with chronic hepatitis B virus (HBV) infection was suggested to be caused by a T cell stimulation defect of dendritic cells (DC). To address this hypothesis, monocyte derived DC (MDDC) of patients with chronic or resolved acute HBV infection and healthy controls were studied phenotypically by FACS analyses and functionally by mixed lymphocyte reaction, ELISA, ELISpot and proliferation assays of MDDC cultures or co-cultures with an allogeneic HBc-specific Th cell clone. HBV infection of MDDC was studied by quantitative PCR.