The kinesin motor KIF1C is a putative transporter of the exon junction complex in neuronal cells.

Neurons critically depend on regulated RNA localization and tight control of spatio-temporal gene expression to maintain their morphological and functional integrity. Mutations in the kinesin motor protein gene KIF1C cause Hereditary Spastic Paraplegia, an autosomal recessive disease leading to predominant degeneration of the long axons of central motoneurons. In this study we aimed to gain insight into the molecular function of KIF1C and understand how KIF1C dysfunction contributes to motoneuron degeneration.

Synaptotagmin-13 orchestrates pancreatic endocrine cell egression and islet morphogenesis.

During pancreas development endocrine cells leave the ductal epithelium to form the islets of Langerhans, but the morphogenetic mechanisms are incompletely understood. Here, we identify the Ca-independent atypical Synaptotagmin-13 (Syt13) as a key regulator of endocrine cell egression and islet formation. We detect specific upregulation of the Syt13 gene and encoded protein in endocrine precursors and the respective lineage during islet formation.

App-based maintenance treatment for alcohol use disorder after acute inpatient treatment: Study protocol for a multicentre randomized controlled trial.

Background: Alcohol use disorder, a prevalent and disabling mental health problem, is often characterized by a chronic disease course. While effective inpatient and aftercare treatment options exist, the transferal of treatment success into everyday life is challenging and many patients remain without further assistance. App-based interventions with human guidance have great potential to support individuals after inpatient treatment, yet evidence on their efficacy remains scarce.

Adhesion G protein-coupled receptor VLGR1/ADGRV1 regulates cell spreading and migration by mechanosensing at focal adhesions.

VLGR1 (very large G protein-coupled receptor-1) is by far the largest adhesion G protein-coupled receptor in humans. Homozygous pathologic variants of cause hereditary deaf blindness in Usher syndrome 2C and haploinsufficiency of is associated with epilepsy. However, its molecular function remains elusive.

CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module.

Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 (CFAP45) in humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia.

Affinity proteomics identifies novel functional modules related to adhesion GPCRs.

Adhesion G protein-coupled receptors (ADGRs) have recently become a target of intense research. Their unique protein structure, which consists of a G protein-coupled receptor combined with long adhesive extracellular domains, suggests a dual role in cell signaling and adhesion. Despite considerable progress in the understanding of ADGR signaling over the past years, the knowledge about ADGR protein networks is still limited.

CRISPR/Cas9-mediated Genomic Editing of Cluap1/IFT38 Reveals a New Role in Actin Arrangement.

CRISPR/Cas9-mediated gene editing allows manipulation of a gene of interest in its own chromosomal context. When applied to the analysis of protein interactions and in contrast to exogenous expression of a protein, this can be studied maintaining physiological stoichiometry, topology, and context. We have used CRISPR/Cas9-mediated genomic editing to investigate Cluap1/IFT38, a component of the intraflagellar transport complex B (IFT-B).

Liver cyst gene knockout in cholangiocytes inhibits cilium formation and Wnt signaling.

Mutations in the PRKCSH, SEC63 and LRP5 genes cause autosomal dominant polycystic liver disease (ADPLD). The proteins products of PRKCSH (alias GIIB) and SEC63 function in protein quality control and processing in the endoplasmic reticulum (ER), while LRP5 is implicated in Wnt/β-catenin signaling. To identify common denominators in the PLD pathogenesis, we mapped the PLD interactome by affinity proteomics, employing both HEK293T cells and H69 cholangiocytes.

Autophosphorylation on S614 inhibits the activity and the transforming potential of BRAF.

The BRAF proto-oncogene serine/threonine-protein kinase, known as BRAF, belongs to the RAF kinase family. It regulates the MAPK/ERK signalling pathway affecting several cellular processes such as growth, survival, differentiation, and cellular transformation. BRAF is mutated in ~8% of all human cancers with the V600E mutation constituting ~90% of mutations.

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes.

NINL and DZANK1 Co-function in Vesicle Transport and Are Essential for Photoreceptor Development in Zebrafish.

Ciliopathies are Mendelian disorders caused by dysfunction of cilia, ubiquitous organelles involved in fluid propulsion (motile cilia) or signal transduction (primary cilia). Retinal dystrophy is a common phenotypic characteristic of ciliopathies since photoreceptor outer segments are specialized primary cilia. These ciliary structures heavily rely on intracellular minus-end directed transport of cargo, mediated at least in part by the cytoplasmic dynein 1 motor complex, for their formation, maintenance and function.

The Interaction of CCDC104/BARTL1 with Arl3 and Implications for Ciliary Function.

Cilia are small antenna-like cellular protrusions critical for many developmental signaling pathways. The ciliary protein Arl3 has been shown to act as a specific release factor for myristoylated and farnesylated ciliary cargo molecules by binding to the effectors Unc119 and PDE6δ. Here we describe a newly identified Arl3 binding partner, CCDC104/CFAP36.

An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.

Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa.

Elution profile analysis of SDS-induced subcomplexes by quantitative mass spectrometry.

Analyzing the molecular architecture of native multiprotein complexes via biochemical methods has so far been difficult and error prone. Protein complex isolation by affinity purification can define the protein repertoire of a given complex, yet, it remains difficult to gain knowledge of its substructure or modular composition. Here, we introduce SDS concentration gradient induced decomposition of protein complexes coupled to quantitative mass spectrometry and in silico elution profile distance analysis.

Active transport and diffusion barriers restrict Joubert Syndrome-associated ARL13B/ARL-13 to an Inv-like ciliary membrane subdomain.

Cilia are microtubule-based cell appendages, serving motility, chemo-/mechano-/photo- sensation, and developmental signaling functions. Cilia are comprised of distinct structural and functional subregions including the basal body, transition zone (TZ) and inversin (Inv) compartments, and defects in this organelle are associated with an expanding spectrum of inherited disorders including Bardet-Biedl syndrome (BBS), Meckel-Gruber Syndrome (MKS), Joubert Syndrome (JS) and Nephronophthisis (NPHP). Despite major advances in understanding ciliary trafficking pathways such as intraflagellar transport (IFT), how proteins are transported to subciliary membranes remains poorly understood.

ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3.

Nephronophthisis is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. Most NPHP gene products form molecular networks. Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3.

Phosphodiesterase III inhibition affects platelet-monocyte aggregate formation depending on the axis of stimulation.

Objective: The purpose of this study was to investigate the effect of the phosphodiesterase (PDE) type 3 inhibitor milrinone on the adhesion of platelets to monocytes in vitro.

Design: Prospective study.

Setting: University experimental laboratory.

Epinephrine enhances platelet-neutrophil adhesion in whole blood in vitro.

Previous studies showed that alpha- or beta-adrenoceptor stimulation by catecholamines influenced neutrophil function, cytokine liberation, and platelet aggregability. We investigated whether adrenergic stimulation with epinephrine also alters platelet-neutrophil adhesion. This might be of specific interest in the critically ill, because the increased association of platelets and neutrophils has been shown to be of key importance in inflammation and thrombosis.

Minimum anesthetic concentration of sevoflurane with different xenon concentrations in swine.

Unlabelled: In a previous study, we described a partial antagonism of xenon (Xe) in combination with isoflurane. One hypothetical explanation suggested that Xe and isoflurane probably induced anesthesia via different pathways at the neuronal level. This warranted investigating the combination of Xe with other inhaled anesthetics to examine the relationship between Xe and volatile anesthetics in general.

Minimum alveolar anesthetic concentration of isoflurane with different xenon concentrations in Swine.

Unlabelled: For patients requiring a fraction of inspired oxygen more than 0.3, the use of xenon (Xe) as the sole anesthetic is limited because of its large minimum alveolar anesthetic concentration (MAC) of 71%. This warrants investigating the combination of Xe with other inhaled anesthetics.

Xenon preserves neutrophil and monocyte function in human whole blood.

Purpose: Most volatile anesthetics are known to inhibit the oxidative and phagocytic function of neutrophils. In the present study, we investigated the effect of xenon on phagocytosis and respiratory burst activity of neutrophils and monocytes in human whole blood.

Methods: Heparinized whole blood from 22 healthy volunteers was incubated for 60 min in the presence of 65% xenon.

The effect of isoflurane on neutrophil selectin and beta(2)-integrin activation in vitro.

Unlabelled: Isoflurane is reported to reduce ischemia-reperfusion injury. Lower expression of CD11b may be responsible for attenuated postischemic neutrophil adhesion to vascular endothelium. However, neutrophil adhesion to vascular endothelium is a multistep process involving several selectins and beta(2)-integrins.