Optimal detection of homogeneous segment of observations in stochastic sequence

A Markov process is registered. At random moment $\theta$ the distribution of observed sequence changes. Using probability maximizing approach the optimal stopping rule for detecting the change is identified. Some explicit solution is obtained.Comment: 13 page

Evaluation of the role of downregulation of SNF5/INI1 core subunit of SWI/SNF complex in clear cell renal cell carcinoma development

Clear cell renal cell carcinoma (ccRCC) is characterized by stabilization of hypoxia-inducible factor (HIF1), and mutations in von Hippel-Lindau (VHL) gene. Additionally, in about 40% of ccRCC cases the mutation in PBRM1 (POLYBROMO1) gene coding for a non-core subunit of SWI/SNF chromatin remodeling complex was found suggesting potential impairment of this complex function in ccRCC. In this study we assessed the extent to which the core SWI/SNF complex subunit - INI1 (hSNF5/SMARCB1) is affected in ccRCC and whether it has any consequences on the development of this type of cancer. The evaluation of INI1 protein level in samples from 50 patients with diagnosed ccRCC, including three displaying rhabdoid features, showed the INI1 positive staining in rhabdoid cells while the conventional ccRCC cells exhibited reduced INI1 level. This indicated the rhabdoid component of ccRCC as distinct from other known rhabdoid tumors. The reduced INI1 protein level observed in all conventional ccRCC cases used in this study correlated with decreased SMARCB1 gene expression at the transcript level. Consistently, the overexpression of INI1 protein in A498 ccRCC cell line resulted in the elevation of endogenous SMARCB1 transcript level indicating that the INI1-dependent regulatory feedback loop controlling expression of this gene is affected in ccRCC Moreover, the set of INI1 target genes including i.e. CXCL12/CXCR7/CXCR4 chemokine axis was identified to be affected in ccRCC. In summary, we demonstrated that the inactivation of INI1 may be of high importance for ccRCC development and aggressiveness

BRAHMA ATPase of the SWI/SNF Chromatin Remodeling Complex Acts as a Positive Regulator of Gibberellin-Mediated Responses in Arabidopsis

SWI/SNF chromatin remodeling complexes perform a pivotal function in the regulation of eukaryotic gene expression. Arabidopsis (Arabidopsis thaliana) mutants in major SWI/SNF subunits display embryo-lethal or dwarf phenotypes, indicating their critical role in molecular pathways controlling development and growth. As gibberellins (GA) are major positive regulators of plant growth, we wanted to establish whether there is a link between SWI/SNF and GA signaling in Arabidopsis. This study revealed that in brm-1 plants, depleted in SWI/SNF BRAHMA (BRM) ATPase, a number of GA-related phenotypic traits are GA-sensitive and that the loss of BRM results in markedly decreased level of endogenous bioactive GA. Transcriptional profiling of brm-1 and the GA biosynthesis mutant ga1-3, as well as the ga1-3/brm-1 double mutant demonstrated that BRM affects the expression of a large set of GA-responsive genes including genes responsible for GA biosynthesis and signaling. Furthermore, we found that BRM acts as an activator and directly associates with promoters of GA3ox1, a GA biosynthetic gene, and SCL3, implicated in positive regulation of the GA pathway. Many GA-responsive gene expression alterations in the brm-1 mutant are likely due to depleted levels of active GAs. However, the analysis of genetic interactions between BRM and the DELLA GA pathway repressors, revealed that BRM also acts on GA-responsive genes independently of its effect on GA level. Given the central position occupied by SWI/SNF complexes within regulatory networks controlling fundamental biological processes, the identification of diverse functional intersections of BRM with GA-dependent processes in this study suggests a role for SWI/SNF in facilitating crosstalk between GA-mediated regulation and other cellular pathways

The pancreaticoduodenal arteries in human foetal development

Knowledge of the course of the pancreaticoduodenal arteries is of great importance in pancreatic surgery. Lack of care in the preparation of these vessels may lead to ischaemia or necrosis of the duodenum, the first loop of the jejunum, the head of the pancreas and even the liver, bile ducts and transverse colon. In such events, the surgeon would need to diagnose the course of the vessels and their anastomoses intraoperatively. Anatomical dissection in this special area diminishes the risk of early complications in the form of bleeding and late complications in the form of narrowing of the anastomoses, fistulas, necrosis and intestinal ileus after surgical resection or drainage. The aim of the present study was to determine the variability of the pancreaticoduodenal arteries in human foetuses. The material examined consisted of 60 human foetuses of both sexes (33 male, 27 female) from spontaneous abortion or stillbirth and ranging in age from the 16th to 38th week of prenatal life. White latex solution to of volume between 15 ml and 30 ml was injected into the thoracic aorta. The results of this were that a typical pancreatic supply from the coeliac trunk and superior mesenteric artery was observed in all cases. The coeliac trunk, splenic artery and gastroduodenal artery also appeared invariably. However, variability was observed in further generations of branches. The gastroduodenal artery with its branches, the anterior and posterior pancreaticoduodenal arteries, was constantly present. Irrespective of the sex of the foetus, in 10% of cases a large vessel was observed which ran horizontally on the anterior surface of the pancreas from head to tail and which originated in the anterior superior pancreaticoduodenal artery. We termed this vessel the "anterior pancreatic artery". In all cases there were anterior and posterior pancreaticoduodenal arcades, but in two cases (3.3%) a double anterior pancreaticoduodenal arcade was observed

Application of Novel and Existing Methods to Identify Genes with Evidence of Epigenetic Association: Results from GAW20

Background: The rise in popularity and accessibility of DNA methylation data to evaluate epigenetic associations with disease has led to numerous methodological questions. As part of GAW20, our working group of 8 research groups focused on gene searching methods. Results: Although the methods were varied, we identified 3 main themes within our group. First, many groups tackled the question of how best to use pedigree information in downstream analyses, finding that (a) the use of kinship matrices is common practice, (b) ascertainment corrections may be necessary, and (c) pedigree information may be useful for identifying parent-of-origin effects. Second, many groups also considered multimarker versus single-marker tests. Multimarker tests had modestly improved power versus single-marker methods on simulated data, and on real data identified additional associations that were not identified with single-marker methods, including identification of a gene with a strong biological interpretation. Finally, some of the groups explored methods to combine single-nucleotide polymorphism (SNP) and DNA methylation into a single association analysis. Conclusions: A causal inference method showed promise at discovering new mechanisms of SNP activity; gene-based methods of summarizing SNP and DNA methylation data also showed promise. Even though numerous questions still remain in the analysis of DNA methylation data, our discussions at GAW20 suggest some emerging best practices

Inter- and intra-observer variability analysis of completely automated cIMT measurement software (AtheroEdge™) and its benchmarking against commercial ultrasound scanner and expert Readers

The purpose of this study was to evaluate the measurement error and inter- and intra-observer variability of completely off-line automated and semi-automated carotid intima-media thickness (cIMT) measurement software (AtheroEdge™).Two hundred carotid ultrasound images from 50 asymptomatic women were analyzed. AtheroEdge™ was benchmarked against a commercial system (Syngo, Siemens) using automated and semi-automated modes. The measurement error and inter- and intra-observer variability of AtheroEdge™ were tested using three readings.The measurement error of AtheroEdge™ compared to the commercial software was 0.002±0.019. mm (r=0.99) in the automated mode and -0.001±0.004. mm in the semi-automated mode (r=0.99). The measurement error of AtheroEdge™ compared to the mean value of the three expert Readers (cIMT bias) for the automated and semi-automated methods was -0.0004±0.158. mm and -0.008±0.157. mm, respectively. The Figure-of-Merit was 99.8% and 99.9% when compared to the commercial ultrasound scanner (using the automated and semi-automated method, respectively) and was 99.9% and 98.9% when compared to the mean value of the three expert Readers. Regarding inter- and intra-observer variability, the intra-class correlation coefficient of the three independent users using the semi-automated AtheroEdge™ was 0.98.AtheroEdge™ showed a measurement performance comparable to the commercial ultrasound scanner software and the expert Readers' tracings. AtheroEdge™ belongs to a class of automated systems that could find application in processing large datasets for common carotid arteries, avoiding subjectivity in cIMT measurement

Morphometry of the pancreas in human foetuses

With the use of conventional anatomical dissection, radiography, digital and statistical analysis, morphometry and skeletopy of the pancreas was carried out in 60 human foetuses of both sexes (28 female, 32 male) between the 17th and 40th week of intrauterine life. The material was fixed in a 10% formalin solution. The age of the foetuses was determined by crown-rump (CR) lenght measurement on the basis of the Iffy et al. tables. Photographic documentation was made and then digitally processed in the Computer Image Digital Analysis System. The following parameters were taken into account: the length and width of 3 parts of the pancreas, namely the head, corpus and tail. Additionally, radiograms were made to obtain a projection of the gland on the vertebral column. Development of the pancreas was correlated with the age of the foetuses calculated on the basis of crown-rump (CR) lenght measurements. The correlation coefficient with CR was 0.998 for the pancreas length, 0.709 for the width of the head, 0.703 for the width of the corpus and 0.712 for the width of tail. Gender dimorphism was not found (p > 0.05) with regard to the morphometry of the pancreas. In the material under examination the pancreas did not change its position in relation to the vertebral column. The head projected on the vertebral column in the range Th12–L2 (most frequently L1–L2), the corpus on Th12–L2 and the tail on Th11

Constrained snake vs. conventional snake for carotid ultrasound automated IMT measurements on multi-center data sets

Accurate intima-media thickness (IMT) measurement of the carotid artery from minimal plaque ultrasound images is a relevant clinical need, since IMT increase is related to the progression of atherosclerosis. In this paper, we describe a novel dual snake-based model for the high-performance carotid IMT measurement, called Carotid Measurement Using Dual Snakes (CMUDS). Snakes (which are deformable contours) adapt to the lumen-intima (LI) and media-adventitia (MA) interfaces, thus enabling the IMT computation as distance between the LI and MA snakes. However, traditional snakes might be unable to maintain a correct distance and in some spatial location along the artery, it might even collapse between them or diverge. The technical improvement of this work is the definition of a dual snake-based constrained system, which prevents the LI and MA snakes from collapsing or bleeding, thus optimizing the IMT estimation. The CMUDS system consists of two parametric models automatically initialized using the far adventitia border which we automatically traced by using a previously developed multi-resolution approach. The dual snakes evolve simultaneously and are constrained by the distances between them, ensuring the regularization of LI/MA topology. We benchmarked our automated CMUDS with the previous conventional semi-automated snake system called Carotid Measurement Using Single Snake (CMUSS). Two independent readers manually traced the LIMA boundaries of a multi-institutional, multi-ethnic, and multi-scanner database of 665 CCA longitudinal 2D images. We evaluated our system performance by comparing it with the gold standard as traced by clinical readers. CMUDS and CMUSS correctly processed 100% of the 665 images. Comparing the performance with respect to the two readers, our automatically measured IMT was on average very close to that of the two readers (IMT measurement biases for CMUSS was equal to −0.011 ± 0.329 mm and −0.045 ± 0.317 mm, respectively, while for CMUDS, it was 0.030 ± 0.284 mm and −0.004 ± 0.273 mm, respectively). The Figure-of-Merit of the system was 98.5% and 94.4% for CMUSS, while 96.0% and 99.6% for CMUDS, respectively. Results showed that the dual-snake system CMUDS reduced the IMT measurement error accuracy (Wilcoxon, p < 0.02) and the IMT error variability (Fisher, p < 3 × 10−2). We propose the CMUDS technique for use in large multi-centric studies, where the need for a standard, accurate, and automated IMT measurement technique is require

Neuronavigated repetitive transcranial magnetic stimulation as novel mapping technique provides insights into language function in primary progressive aphasia

Navigated repetitive transcranial magnetic stimulation (nrTMS) is an innovative technique that provides insight into language function with high accuracy in time and space. So far, nrTMS has mainly been applied in presurgical language mapping of patients with intracranial neoplasms. For the present study, nrTMS was used for language mapping in primary progressive aphasia (PPA). Seven patients (median age: 70 years, 4 males) with the non-fluent variant of PPA (nfvPPA) were included in this pilot study. Trains of nrTMS (5 Hz, 100% resting motor threshold) caused virtual lesions at 46 standardized cortical stimulation targets per hemisphere. Patients’ errors in a naming task during stimulation were counted. The majority of errors induced occurred during frontal lobe stimulation (34.3%). Timing errors and non-responses were most frequent. More errors were induced in the right hemisphere (58%) than in the left hemisphere (42%). Mapping was tolerated by all patients, however, discomfort or pain was reported for stimulation of frontal areas. The elevated right-hemispheric error rate in our study could be due to a partial shift of language function to the right hemisphere in neurodegenerative aphasia during the course of disease and therefore points to the existence of neuronal plasticity in nfvPPA. While this is an interesting finding for neurodegenerative disorders per se, its promotion might also harbor future therapeutic targets