Approaching criticality via the zero dissipation limit in the abelian avalanche model

The discrete height abelian sandpile model was introduced by Bak, Tang & Wiesenfeld and Dhar as an example for the concept of self-organized criticality. When the model is modified to allow grains to disappear on each toppling, it is called bulk-dissipative. We provide a detailed study of a continuous height version of the abelian sandpile model, called the abelian avalanche model, which allows an arbitrarily small amount of dissipation to take place on every toppling. We prove that for non-zero dissipation, the infinite volume limit of the stationary measure of the abelian avalanche model exists and can be obtained via a weighted spanning tree measure. We show that in the whole non-zero dissipation regime, the model is not critical, i.e., spatial covariances of local observables decay exponentially. We then study the zero dissipation limit and prove that the self-organized critical model is recovered, both for the stationary measure and for the dynamics. We obtain rigorous bounds on toppling probabilities and introduce an exponent describing their scaling at criticality. We rigorously establish the mean-field value of this exponent for $d > 4$.Comment: 46 pages, substantially revised 4th version, title has been changed. The main new material is Section 6 on toppling probabilities and the toppling probability exponen

A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development

Cell lineages of the early human gonad commit to one of the two mutually antagonistic organogenetic fates, the testis or the ovary. Some individuals with a 46,XX karyotype develop testes or ovotestes (testicular or ovotesticular disorder of sex development; TDSD/OTDSD), due to the presence of the testis-determining gene, SRY Other rare complex syndromic forms of TDSD/OTDSD are associated with mutations in pro-ovarian genes that repress testis development (e.g. WNT4); however, the genetic cause of the more common non-syndromic forms is unknown. Steroidogenic factor-1 (known as NR5A1) is a key regulator of reproductive development and function. Loss-of-function changes in NR5A1 in 46,XY individuals are associated with a spectrum of phenotypes in humans ranging from a lack of testis formation to male infertility. Mutations in NR5A1 in 46,XX women are associated with primary ovarian insufficiency, which includes a lack of ovary formation, primary and secondary amenorrhoea as well as early menopause. Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families. Remarkably, in one family a sibling raised as a girl and carrying this NR5A1 mutation was found to have a 46,XY karyotype with partial testicular dysgenesis. These unique findings highlight how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represents the first missense mutation causing isolated, non-syndromic 46,XX testicular/ovotesticular DSD in humans

Impact on arsenic exposure of a growing proportion of untested wells in Bangladesh

In many areas of Bangladesh, it has been more than six years since a national campaign to test tubewells for arsenic (As) was conducted. Many households therefore draw their water for drinking and cooking from untested wells. A household drinking water survey of 6646 households was conducted in Singair upazilla of Bangladesh. A subset of 795 untested wells used by 1000 randomly selected households was tested in the field by trained village workers with the Hach EZ kit, using an extended reaction time of 40 min, and in the laboratory by high-resolution inductively-coupled plasma-mass spectrometry (HR ICP-MS). The household survey shows that more than 80% of the wells installed since the national testing campaign in this area were untested. Less than 13% of the households with untested wells knew where a low-As well was located near their home. Village workers using the Hach EZ kit underestimated the As content of only 4 out of 795 wells relative to the Bangladesh standard. However, the As content of 168 wells was overestimated relative to the same threshold. There is a growing need for testing tubewells in areas of Bangladesh where As concentrations in groundwater are elevated. This could be achieved by village workers trained to use a reliable field kit. Such an effort would result in a considerable drop in As exposure as it increases the opportunities for well switching by households

Understanding Crowd-Powered Search Groups: A Social Network Perspective

Background: Crowd-powered search is a new form of search and problem solving scheme that involves collaboration among a potentially large number of voluntary Web users. Human flesh search (HFS), a particular form of crowd-powered search originated in China, has seen tremendous growth since its inception in 2001. HFS presents a valuable test-bed for scientists to validate existing and new theories in social computing, sociology, behavioral sciences, and so forth. Methodology: In this research, we construct an aggregated HFS group, consisting of the participants and their relationships in a comprehensive set of identified HFS episodes. We study the topological properties and the evolution of the aggregated network and different sub-groups in the network. We also identify the key HFS participants according to a variety of measures. Conclusions: We found that, as compared with other online social networks, HFS participant network shares the power-law degree distribution and small-world property, but with a looser and more distributed organizational structure, leading to the diversity, decentralization, and independence of HFS participants. In addition, the HFS group has been becoming increasingly decentralized. The comparisons of different HFS sub-groups reveal that HFS participants collaborated more often when they conducted the searches in local platforms or the searches requiring a certain level of professional knowledge background. On the contrary, HFS participants did not collaborate much when they performed the search tas

Delimiting the Origin of a B Chromosome by FISH Mapping, Chromosome Painting and DNA Sequence Analysis in Astyanax paranae (Teleostei, Characiformes)

Supernumerary (B) chromosomes have been shown to contain a wide variety of repetitive sequences. For this reason, fluorescent in situ hybridisation (FISH) is a useful tool for ascertaining the origin of these genomic elements, especially when combined with painting from microdissected B chromosomes. In order to investigate the origin of B chromosomes in the fish species Astyanax paranae, these two approaches were used along with PCR amplification of specific DNA sequences obtained from the B chromosomes and its comparison with those residing in the A chromosomes. Remarkably, chromosome painting with the one-arm metacentric B chromosome probe showed hybridization signals on entire B chromosome, while FISH mapping revealed the presence of H1 histone and 18S rDNA genes symmetrically placed in both arms of the B chromosome. These results support the hypothesis that the B chromosome of A. paranae is an isochromosome. Additionally, the chromosome pairs Nos. 2 or 23 are considered the possible B chromosome ancestors since both contain syntenic H1 and 18S rRNA sequences. The analysis of DNA sequence fragments of the histone and rRNA genes obtained from the microdissected B chromosomes showed high similarity with those obtained from 0B individuals, which supports the intraspecific origin of B chromosomes in A. paranae. Finally, the population hereby analysed showed a female-biased B chromosome presence suggesting that B chromosomes in this species could influence sex determinism.This research was funded by grants from the State of São Paulo Research Foundation (FAPESP) to DMZAS (2011/16825-3) and CO (2010/17009-2), grants from National Council for Research and Development (CNPq) to FF and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Although the <it>high mobility group A1 </it>(<it>HMGA1</it>) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. <it>HMGA1 </it>functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, <it>HMGA1 </it>is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells from <it>HMGA1a </it>transgenic mice at different stages in tumorigenesis.</p> <p>Results</p> <p>RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors.</p> <p>Conclusions</p> <p>We found that <it>HMGA1 </it>induces inflammatory pathways early in lymphoid tumorigenesis and pathways involved in stem cells, cell cycle progression, and cancer in established tumors. <it>HMGA1 </it>also dyregulates genes and pathways involved in stem cells, cellular development and hematopoiesis at both early and late stages of tumorigenesis. These results provide insight into <it>HMGA1 </it>function during tumor development and point to cellular pathways that could serve as therapeutic targets in lymphoid and other human cancers with aberrant <it>HMGA1 </it>expression.</p

Crackling Noise

Crackling noise arises when a system responds to changing external conditions through discrete, impulsive events spanning a broad range of sizes. A wide variety of physical systems exhibiting crackling noise have been studied, from earthquakes on faults to paper crumpling. Because these systems exhibit regular behavior over many decades of sizes, their behavior is likely independent of microscopic and macroscopic details, and progress can be made by the use of very simple models. The fact that simple models and real systems can share the same behavior on a wide range of scales is called universality. We illustrate these ideas using results for our model of crackling noise in magnets, explaining the use of the renormalization group and scaling collapses. This field is still developing: we describe a number of continuing challenges

HMGA1 Reprograms Somatic Cells into Pluripotent Stem Cells by Inducing Stem Cell Transcriptional Networks

PMC3499526BACKGROUND: Although recent studies have identified genes expressed in human embryonic stem cells (hESCs) that induce pluripotency, the molecular underpinnings of normal stem cell function remain poorly understood. The high mobility group A1 (HMGA1) gene is highly expressed in hESCs and poorly differentiated, stem-like cancers; however, its role in these settings has been unclear. METHODS/PRINCIPAL FINDINGS: We show that HMGA1 is highly expressed in fully reprogrammed iPSCs and hESCs, with intermediate levels in ECCs and low levels in fibroblasts. When hESCs are induced to differentiate, HMGA1 decreases and parallels that of other pluripotency factors. Conversely, forced expression of HMGA1 blocks differentiation of hESCs. We also discovered that HMGA1 enhances cellular reprogramming of somatic cells to iPSCs together with the Yamanaka factors (OCT4, SOX2, KLF4, cMYC - OSKM). HMGA1 increases the number and size of iPSC colonies compared to OSKM controls. Surprisingly, there was normal differentiation in vitro and benign teratoma formation in vivo of the HMGA1-derived iPSCs. During the reprogramming process, HMGA1 induces the expression of pluripotency genes, including SOX2, LIN28, and cMYC, while knockdown of HMGA1 in hESCs results in the repression of these genes. Chromatin immunoprecipitation shows that HMGA1 binds to the promoters of these pluripotency genes in vivo. In addition, interfering with HMGA1 function using a short hairpin RNA or a dominant-negative construct blocks cellular reprogramming to a pluripotent state. CONCLUSIONS: Our findings demonstrate for the first time that HMGA1 enhances cellular reprogramming from a somatic cell to a fully pluripotent stem cell. These findings identify a novel role for HMGA1 as a key regulator of the stem cell state by inducing transcriptional networks that drive pluripotency. Although further studies are needed, these HMGA1 pathways could be exploited in regenerative medicine or as novel therapeutic targets for poorly differentiated, stem-like cancers.JH Libraries Open Access Fun