Biophysical analysis of a lethal laminin alpha-1 mutation reveals altered self-interaction

Laminins are key basement membrane molecules that influence several biological activities and are linked to a number of diseases. They are secreted as heterotrimeric proteins consisting of one α, one β, and one γ chain, followed by their assembly into a polymer-like sheet at the basement membrane. Using sedimentation velocity, dynamic light scattering, and surface plasmon resonance experiments, we studied self-association of three laminin (LM) N-terminal fragments α-1 (hLM α-1 N), α-5 (hLM α-5 N) and β-3 (hLM β-3 N) originating from the short arms of the human laminin αβγ heterotrimer. Corresponding studies of the hLM α-1 N C49S mutant, equivalent to the larval lethal C56S mutant in zebrafish, have shown that this mutation causes enhanced self-association behavior, an observation that provides a plausible explanation for the inability of laminin bearing this mutation to fulfill functional roles in vivo, and hence for the deleterious pathological consequences of the mutation on lens function

BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription

Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.This article is available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.Wellcome Trust (grant number WT098051)Published (open access

Post-transplant lymphoproliferative disorder as a cause of oesophageal ulceration and stricture: case report and literature review

Post-transplant lymphoproliferative disorder (PTLD) of the oesophagus is a rare complication of solid organ transplant that requires a high index of suspicion to diagnose. A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified. Development of oesophageal strictures related to PTLD has not been reported in the literature. We report a case of oesophageal PTLD following lung transplant, presenting with extensive, circumferential ulceration in the oesophagus. PTLD was successfully treated with chemotherapy but subsequently, this patient developed a severe oesophageal stricture at the site of her PTLD. She presented with an episode of food bolus impaction requiring endoscopic retrieval. In the following years, our patient required multiple endoscopic dilatations of this PTLD-related oesophageal stricture

Does Government Performance Matter? The Effects of Local Government on Urban Outcomes in England

This paper applies an extensive literature that argues that political leadership and local government activity enhance urban performance. Using the State of the Cities Database of 56 Primary Urban Areas in England, it tests for the impact of consolidated governance, political stability, planning performance, average service performance, local government capacity and planning development expenditure on jobs and population growth from 1995 to 2005. The regression analysis finds that the competence of service delivery is weakly associated with full-time jobs growth and that a consolidated governance structure is weakly associated with greater population growth. None of the other tests is statistically significant. Overall, the findings place doubt on the salience of the political determinants of economic performance in English cities for the period in question.

Preoperative Localization of a Gastrin-Secreting Tumour by Total Body Imaging with 111Indium-Labelled Pentatreotide

A 41-year-old female presented with persistent diarrhea, and was diagnosed with Zollinger-Ellison syndrome when her gastrin level was greater than 3000 ng/L. All modalities for preoperative localization of her gastrinoma were unsuccessful, including transabdominal and endoscopic ultrasound, computed tomography, pancreatic angiogram, selective transhepatic portal venous sampling and magnetic resonance imaging. The gastrin-secreting tumour was visualized using the somatostatin analogue pentatreotide labelled with 111Indium, combined with gamma camera imaging. A successful resection of the tumour resulted in the normalization of serum gastrin levels 3.5 years after presentation. A discussion of the merits and sensitivities of these tests for preoperative localization of gastrin-secreting tumours will be presented

A transferable method for the automated grain sizing of river gravels

This article was published in the journal, Water resources research [© American Geophysical Union] and is also available at: http://www.agu.org/journals/wr/The spatial and temporal resolution of surface grain-size characterization is constrained by the limitations of traditional measurement techniques. In this paper we present an extremely rapid image-processing-based procedure for the measurement of exposed fluvial gravels and other coarsegrained sediments, defining the steps required to minimize the errors in the derived grain-size distribution. This procedure differs significantly from those used previously. It is based around a robust object-detection algorithm that produces excellent results on images exhibiting a wide range of sedimentary conditions, crucially, without any user intervention or site-specific parameterization. The procedure is tested using a dataset comprising 39 images from three rivers with contrasting grain lithology, shape, roundness and packing configuration and representing a very wide range of textures. It is shown to perform more consistently than the best existing automated method, achieving a precision equivalent to that obtainable by Wolman sampling, but taking between one sixth and one twentieth of the time. The error in area-by-number grain-size distribution percentiles is typically less than 0.05 Ï