Selective influence of Sox2 on POU transcription factor binding in embryonic and neural stem cells

Embryonic stem cell (ESC) identity is orchestrated by co-operativity between the transcription factors (TFs) Sox2 and the class V POU-TF Oct4 at composite Sox/Oct motifs. Neural stem cells (NSCs) lack Oct4 but express Sox2 and class III POU-TFs Oct6, Brn1 and Brn2. This raises the question of how Sox2 interacts with POU-TFs to transcriptionally specify ESCs versus NSCs. Here, we show that Oct4 alone binds the Sox/Oct motif and the octamer-containing palindromic MORE equally well. Sox2 binding selectively increases the affinity of Oct4 for the Sox/Oct motif. In contrast, Oct6 binds preferentially to MORE and is unaffected by Sox2. ChIP-Seq in NSCs shows the MORE to be the most enriched motif for class III POU-TFs, including MORE subtypes, and that the Sox/Oct motif is not enriched. These results suggest that in NSCs, co-operativity between Sox2 and class III POU-TFs may not occur and that POU-TF-driven transcription uses predominantly the MORE cis architecture. Thus, distinct interactions between Sox2 and POU-TF subclasses distinguish pluripotent ESCs from multipotent NSCs, providing molecular insight into how Oct4 alone can convert NSCs to pluripotency. EMBO Rep 2015 Sep; 16(9):1177-91

Surgical revascularization of bilateral renal artery stenosis due to fibromuscular dysplasia

Fibromuscular dysplasia (FMD) is a noninflammatory disease affecting small- and medium-sized arteries of the renal and the carotids. It affects the renal arteries in nearly 60%–75% cases. The primary clinical manifestation of renal FMD is hypertension. Medial fibroplasia represents the most common dysplastic lesion. We report two cases who presented with hypertension and renal insufficiency and on evaluation was found to have bilateral renal artery stenosis. Stenting of the renal vessels was not possible due to the narrowed caliber of the vessel and inability to cannulate the renal arteries. They underwent renal artery revascularization with a splenorenal end to end anastomosis. The renal parameters and blood pressure of both the patients stabilized subsequently. Renal revascularization can be a good option for patient having failed angioplasty with stenting

Urethral duplication with unusual cause of bladder outlet obstruction

A 12-year-old boy presented with poor flow and recurrent urinary tract infections following hypospadias repair at the age of 3 years. The evaluation revealed urethral duplication with a hypoplastic dorsal urethra and patent ventral urethra. He also had duplication of the bladder neck, and on voiding cystourethrogram the ventral bladder neck appeared hypoplastic and compressed by the dorsal bladder neck during voiding. The possibility of functional obstruction of the ventral urethra by the occluded dorsal urethra was suspected, and he underwent a successful urethro-urethrostomy

Time-dependent specific molecular signatures of inflammation and remodelling are associated with trimethylamine-N-oxide (TMAO)-induced endothelial cell dysfunction

Abstract Endothelial dysfunction is a critical initiating factor contributing to cardiovascular diseases, involving the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO). This study aims to clarify the time-dependent molecular pathways by which TMAO mediates endothelial dysfunction through transcriptomics and metabolomics analyses in human microvascular endothelial cells (HMEC-1). Cell viability and reactive oxygen species (ROS) generation were also evaluated. TMAO treatment for either 24H or 48H induces reduced cell viability and enhanced oxidative stress. Interestingly, the molecular signatures were distinct between the two time-points. Specifically, few Gene Ontology biological processes (BPs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were modulated after a short (24H) compared to a long (48H) treatment. However, the KEGG signalling pathways namely “tumour necrosis factor (TNF)” and “cytokine-cytokine receptor interaction” were downregulated at 24H but activated at 48H. In addition, at 48H, BPs linked to inflammatory phenotypes were activated (confirming KEGG results), while BPs linked to extracellular matrix (ECM) structural organisation, endothelial cell proliferation, and collagen metabolism were repressed. Lastly, metabolic profiling showed that arachidonic acid, prostaglandins, and palmitic acid were enriched at 48H. This study demonstrates that TMAO induces distinct time-dependent molecular signatures involving inflammation and remodelling pathways, while pathways such as oxidative stress are also modulated, but in a non-time-dependent manner

Point mutations and gene fusions organized into functional categories.

<p>Protein altering mutations and INDELs, alternative splicing events and validated fusions are shown. Red boxes indicate protein-altering mutations (i.e. nonsense, missense and splice site mutations); purple boxes indicate frame-shift INDELs whereas blue, green and orange boxes represent fusion events resulting in over-expression of the partner gene, inactivation of the partner gene or generation of a chimeric protein, respectively, and finally black boxes indicating alternative splicing events.</p

Comparison between RNA-seq and exome-seq.

<p>Variant Allele Frequency plots for evaluating two RNA-seq mapping strategies for two example samples, namely the RPMI8402 cell line (<b>A</b>, <b>B</b>) and the TLE79 patient sample (<b>C</b>, <b>D</b>). On the left are the results of mapping with TopHat 1.3.3. (<b>A</b>,<b>C</b>), while on the right are the results of mapping with TopHat 2.0.5 with forced re-mapping of all reads to the genome. The SNVs that have at least 20 reads in exome-seq and RNA-seq are plotted. Red and green dots represent the SNVs that are detected only in RNA-seq and only in exome-seq, respectively, while black dots represent the SNVs that are called in both. Venn diagrams are produced from the points represented in the graphs.</p