Ciliary tip actin dynamics regulate photoreceptor outer segment integrity.

As signalling organelles, cilia regulate their G protein-coupled receptor content by ectocytosis, a process requiring localised actin dynamics to alter membrane shape. Photoreceptor outer segments comprise an expanse of folded membranes (discs) at the tip of highly-specialised connecting cilia, into which photosensitive GPCRs are concentrated. Discs are shed and remade daily.

Centriolar satellites expedite mother centriole remodeling to promote ciliogenesis.

Centrosomes are orbited by centriolar satellites, dynamic multiprotein assemblies nucleated by Pericentriolar material 1 (PCM1). To study the requirement for centriolar satellites, we generated mice lacking PCM1, a crucial component of satellites. mice display partially penetrant perinatal lethality with survivors exhibiting hydrocephalus, oligospermia, and cerebellar hypoplasia, and variably expressive phenotypes such as hydronephrosis.

The Mouse Model to Unravel Retinogenesis Misregulation in Patients with Albinism.

We have recently identified encoding dopachrome tautomerase (DCT) as the eighth gene for oculocutaneous albinism (OCA). Patients with loss of function of suffer from eye hypopigmentation and retinal dystrophy. Here we investigate the eye phenotype in mice.

Impacts of Professionalization and Wellbeing Policies on Scottish Prison Workers.

Prison workers occupy a niche role. Balancing the care and welfare of prisoners while simultaneously restricting their freedoms is a stressful job, laced with danger, that occurs entirely within the bounded context of the prison. Here, wellbeing and professionalism are closely linked and articulated through a range of policies.

A mouse model of brittle cornea syndrome caused by mutation in Zfp469.

Brittle cornea syndrome (BCS) is a rare recessive condition characterised by extreme thinning of the cornea and sclera. BCS results from loss-of-function mutations in the poorly understood genes ZNF469 or PRDM5. In order to determine the function of ZNF469 and to elucidate pathogenic mechanisms, we used genome editing to recapitulate a human ZNF469 BCS mutation in the orthologous mouse gene Zfp469.

Dopachrome tautomerase variants in patients with oculocutaneous albinism.

Purpose: Albinism is a clinically and genetically heterogeneous condition. Despite analysis of the 20 known genes, ~30% patients remain unsolved. We aimed to identify new genes involved in albinism.

The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification.

The precise control of eye size is essential for normal vision. TMEM98 is a highly conserved and widely expressed gene which appears to be involved in eye size regulation. Mutations in human TMEM98 are found in patients with nanophthalmos (very small eyes) and variants near the gene are associated in population studies with myopia and increased eye size.

Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse.

Purpose: We previously found a dominant mutation, Rwhs, causing white spots on the retina accompanied by retinal folds. Here we identify the mutant gene to be Tmem98. In humans, mutations in the orthologous gene cause nanophthalmos.

Correction: Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice.

[This corrects the article DOI: 10.1371/journal.pgen.

Mouse mutations cause retinal degeneration and reduced mitochondrial function.

Isocitrate dehydrogenase (IDH) is an enzyme required for the production of α-ketoglutarate from isocitrate. IDH3 generates the NADH used in the mitochondria for ATP production, and is a tetramer made up of two α, one β and one γ subunit. Loss-of-function and missense mutations in both and have previously been implicated in families exhibiting retinal degeneration.

Anomalous biliary and vascular anatomy-Potential pitfalls during cholecystectomy.

Laparoscopic cholecystectomy is usually a low-risk procedure associated with a short stay and a low rate of conversion to open surgery. Complications are sometimes associated with anomalous vascular or biliary anatomy. Outlined below are the variations in vascular and biliary anatomy which may result in complications either due to involvement in the inflammatory process or inadvertent division during dissection.

PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic Proteins.

During neurotransmission, synaptic vesicles undergo multiple rounds of exo-endocytosis, involving recycling and/or degradation of synaptic proteins. While ubiquitin signaling at synapses is essential for neural function, it has been assumed that synaptic proteostasis requires the ubiquitin-proteasome system (UPS). We demonstrate here that turnover of synaptic membrane proteins via the endolysosomal pathway is essential for synaptic function.

A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect.

Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals.

Mouse slc9a8 mutants exhibit retinal defects due to retinal pigmented epithelium dysfunction.

Purpose: As part of a large scale systematic screen to determine the effects of gene knockout mutations in mice, a retinal phenotype was found in mice lacking the Slc9a8 gene, encoding the sodium/hydrogen ion exchange protein NHE8. We aimed to characterize the mutant phenotype and the role of sodium/hydrogen ion exchange in retinal function.

Methods: Detailed histology characterized the pathological consequences of Slc9a8 mutation, and retinal function was assessed by electroretinography (ERG).

A dominant-negative mutation of mouse Lmx1b causes glaucoma and is semi-lethal via LDB1-mediated dimerization [corrected].

Mutations in the LIM-homeodomain transcription factor LMX1B cause nail-patella syndrome, an autosomal dominant pleiotrophic human disorder in which nail, patella and elbow dysplasia is associated with other skeletal abnormalities and variably nephropathy and glaucoma. It is thought to be a haploinsufficient disorder. Studies in the mouse have shown that during development Lmx1b controls limb dorsal-ventral patterning and is also required for kidney and eye development, midbrain-hindbrain boundary establishment and the specification of specific neuronal subtypes.

A novel mouse model of Warburg Micro syndrome reveals roles for RAB18 in eye development and organisation of the neuronal cytoskeleton.

Mutations in RAB18 have been shown to cause the heterogeneous autosomal recessive disorder Warburg Micro syndrome (WARBM). Individuals with WARBM present with a range of clinical symptoms, including ocular and neurological abnormalities. However, the underlying cellular and molecular pathogenesis of the disorder remains unclear, largely owing to the lack of any robust animal models that phenocopy both the ocular and neurological features of the disease.

PET-CT as a predictor of outcome in resectable colorectal liver metastases.

Introduction: PET-computed tomography (PET-CT) is a useful staging imaging modality in colorectal liver metastases (CRLM). This study aimed to determine whether PET-CT parameters, standardized uptake value (SUV) and reconstructed tumour volume (RTV), are predictors of prognosis and survival.

Methods: A study of all resectable CRLM patients in the regional HPB unit from 2007-2009 was performed.

Surgical versus endoscopic treatment of bile duct stones.

Background: Between 10% to 18% of people undergoing cholecystectomy for gallstones have common bile duct stones. Treatment of the bile duct stones can be conducted as open cholecystectomy plus open common bile duct exploration or laparoscopic cholecystectomy plus laparoscopic common bile duct exploration (LC + LCBDE) versus pre- or post-cholecystectomy endoscopic retrograde cholangiopancreatography (ERCP) in two stages, usually combined with either sphincterotomy (commonest) or sphincteroplasty (papillary dilatation) for common bile duct clearance. The benefits and harms of the different approaches are not known.

Surgical versus endoscopic treatment of bile duct stones.

Background: Between 10% to 18% of people undergoing cholecystectomy for gallstones have common bile duct stones. Treatment of the bile duct stones can be conducted as open cholecystectomy plus open common bile duct exploration or laparoscopic cholecystectomy plus laparoscopic common bile duct exploration (LC + LCBDE) versus pre- or post-cholecystectomy endoscopic retrograde cholangiopancreatography (ERCP) in two stages, usually combined with either sphincterotomy (commonest) or sphincteroplasty (papillary dilatation) for common bile duct clearance. The benefits and harms of the different approaches are not known.

Role of carcinoembryonic antigen as a marker for colorectal liver metastases.

Carcinoembryonic antigen (CEA), a marker for colorectal adenocarcinoma, can monitor disease progression and treatment response. This study aims to determine the accuracy of CEA in the detection and resectability of colorectal liver metastases. Patients with primary colorectal cancer were divided into three groups: resectable hepatic metastases (group 1), unresectable metastases (group 2), and disease-free cases (group 3).

Biliary complications during a decade of increased cholecystectomy rate.

Background: Bile duct injury is a rare complication of cholecystectomy. The aims of this study were to analyse the mechanism and outcome of biliary complications and determine the Northern Ireland incidence of bile duct injury over the last decade.

Methods: Annual numbers of cholecystectomies were obtained from the Northern Ireland Hospital Inpatient System database.