Warming Up Density Functional Theory

Density functional theory (DFT) has become the most popular approach to electronic structure across disciplines, especially in material and chemical sciences. Last year, at least 30,000 papers used DFT to make useful predictions or give insight into an enormous diversity of scientific problems, ranging from battery development to solar cell efficiency and far beyond. The success of this field has been driven by usefully accurate approximations based on known exact conditions and careful testing and validation. In the last decade, applications of DFT in a new area, warm dense matter, have exploded. DFT is revolutionizing simulations of warm dense matter including applications in controlled fusion, planetary interiors, and other areas of high energy density physics. Over the past decade or so, molecular dynamics calculations driven by modern density functional theory have played a crucial role in bringing chemical realism to these applications, often (but not always) with excellent agreement with experiment. This chapter summarizes recent work from our group on density functional theory at non-zero temperatures, which we call thermal DFT. We explain the relevance of this work in the context of warm dense matter, and the importance of quantum chemistry to this regime. We illustrate many basic concepts on a simple model system, the asymmetric Hubbard dimer

Mass Homozygotes Accumulation in the NCI-60 Cancer Cell Lines As Compared to HapMap Trios, and Relation to Fragile Site Location

Runs of homozygosity (ROH) represents extended length of homozygotes on a long genomic distance. In oncology, it is known as loss of heterozygosity (LOH) if identified exclusively in cancer cell rather than in matched control cell. Studies have identified several genomic regions which show consistent ROH in different kinds of carcinoma. To query whether this consistency can be observed on broader spectrum, both in more cancer types and in wider genomic regions, we investigated ROH patterns in the National Cancer Institute 60 cancer cell line panel (NCI-60) and HapMap Caucasian healthy trio families. Using results from Affymetrix 500 K SNP arrays, we report a genome wide significant association of ROH regions between the NCI-60 and HapMap samples, with much a higher level of ROH (11 fold) in the cancer cell lines. Analysis shows that more severe ROH found in cancer cells appears to be the extension of existing ROH in healthy state. In the HapMap trios, the adult subgroup had a slightly but significantly higher level (1.02 fold) of ROH than did the young subgroup. For several ROH regions we observed the co-occurrence of fragile sites (FRAs). However, FRA on the genome wide level does not show a clear relationship with ROH regions

Tracking Spending Among Commercially Insured Beneficiaries Using a Distributed Data Model

T imely, local data are important to policy-makers, providers, patients, payers, and employers working to slow the growth of healthcare spending, which is a major focus of federal, state, and local healthcare reform initiatives. Community-based multistakeholder coalitions have formed across the country in an effort to influence their local healthcare markets and reduce costs. More than 40 percent of people in the United States live in a community with a multistakeholder coalition aimed at improving health and healthcare, including collaboratives focused on improving the exchange of health information, accelerating engagement by key local opinion leaders and stakeholders, or promoting quality improvement. 1 All of these entities, however, lack the local data needed to determine if their efforts are making a difference. The factors contributing to rising healthcare spending differ across communities and depend on local context; understanding the drivers of local spending growth is complicated by the variety of inputs. Provider culture and supply, various market segments (outpatient, inpatient, long-term care), payer mix, regulation, and the competitiveness of hospital and physician markets all affect pricing, utilization, and ultimately, the total cost of care. Research has shown that the relative contribution of these factors varies across markets and that drivers of commercial spending are not necessarily the same as drivers of Medicare spending. Chernew et al found that commercial spending was not correlated with Medicare spending across hospital referral regions. ABSTRACT Objectives To explore the feasibility of using a distributed data model for ongoing reporting of local healthcare spending, specifically to investigate the contribution of utilization and pricing to geographic variation and trends in reimbursements for commercially insured beneficiaries younger than 65 years. Study Design Retrospective descriptive analysis. Methods Commercial claims were obtained for beneficiaries in 5 states for the years 2008 to 2010 using a distributed data model. Claims were aggregated to the hospital service area (HSA) level and healthcare utilization was quantified using a novel, National Quality Forum-endorsed measure that is independent of price and allows for the calculation of resource use across all services in standardized units. We examined trends in utilization, prices, and reimbursements over time. To examine geographic variation, we mapped resource use by HSA in the 3 states from which we had data from multiple insurers. We calculated the correlation between commercial and Medicare reimbursements and utilization. Medicare claims were obtained from the Dartmouth Atlas

Long-term follow-up of beryllium sensitized workers from a single employer

<p>Abstract</p> <p>Background</p> <p>Up to 12% of beryllium-exposed American workers would test positive on beryllium lymphocyte proliferation test (BeLPT) screening, but the implications of sensitization remain uncertain.</p> <p>Methods</p> <p>Seventy two current and former employees of a beryllium manufacturer, including 22 with pathologic changes of chronic beryllium disease (CBD), and 50 without, with a confirmed positive test were followed-up for 7.4 +/-3.1 years.</p> <p>Results</p> <p>Beyond predicted effects of aging, flow rates and lung volumes changed little from baseline, while D_LCO dropped 17.4% of predicted on average. Despite this group decline, only 8 subjects (11.1%) demonstrated physiologic or radiologic abnormalities typical of CBD. Other than baseline status, no clinical or laboratory feature distinguished those who clinically manifested CBD at follow-up from those who did not.</p> <p>Conclusions</p> <p>The clinical outlook remains favorable for beryllium-sensitized individuals over the first 5-12 years. However, declines in D_LCO may presage further and more serious clinical manifestations in the future. These conclusions are tempered by the possibility of selection bias and other study limitations.</p

Perturbation of adhesion molecule-mediated chondrocyte-matrix interactions by 4-hydroxynonenal binding: implication in osteoarthritis pathogenesis

ABSTRACT: INTRODUCTION: Objectives were to investigate whether interactions between human osteoarthritic chondrocytes and 4-hydroxynonenal (HNE)-modified type II collagen (Col II) affect cell phenotype and functions and to determine the protective role of carnosine (CAR) treatment in preventing these effects. METHODS: Human Col II was treated with HNE at different molar ratios (MR) (1:20 to 1:200; Col II:HNE). Articular chondrocytes were seeded in HNE/Col II adduct-coated plates and incubated for 48 hours. Cell morphology was studied by phase-contrast and confocal microscopy. Adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and alpha1beta1 integrin at protein and mRNA levels were quantified by Western blotting, flow cytometry and real-time reverse transcription-polymerase chain reaction. Cell death, caspases activity, prostaglandin E2 (PGE2), metalloproteinase-13 (MMP-13), mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-kappaB) were assessed by commercial kits. Col II, cyclooxygenase-2 (COX-2), MAPK, NF-kappaB-p65 levels were analyzed by Western blotting. The formation of alpha1beta1 integrin-focal adhesion kinase (FAK) complex was revealed by immunoprecipitation. RESULTS: Col II modification by HNE at MR approximately 1:20, strongly induced ICAM-1, alpha1beta1 integrin and MMP-13 expression as well as extracellular signal-regulated kinases 1 and 2 (ERK1/2) and NF-kappaB-p65 phosphorylation without impacting cell adhesion and viability or Col II expression. However, Col II modification with HNE at MR approximately 1:200, altered chondrocyte adhesion by evoking cell death and caspase-3 activity. It inhibited alpha1beta1 integrin and Col II expression as well as ERK1/2 and NF-kappaB-p65 phosphorylation, but, in contrast, markedly elicited PGE2 release, COX-2 expression and p38 MAPK phosphorylation. Immunoprecipitation assay revealed the involvement of FAK in cell-matrix interactions through the formation of alpha1beta1 integrin-FAK complex. Moreover, the modification of Col II by HNE at a 1:20 or approximately 1:200 MR affects parameters of the cell shape. All these effects were prevented by CAR, an HNE-trapping drug. CONCLUSIONS: Our novel findings indicate that HNE-binding to Col II results in multiple abnormalities of chondrocyte phenotype and function, suggesting its contribution in osteoarthritis development. CAR was shown to be an efficient HNE-snaring agent capable of counteracting these outcomes

HIT family genes: FHIT but not PKCI-1/HINT produces altered transcripts in colorectal cancer

Forty-five colorectal adenocarcinomas were examined for alterations in the HIT family genes FHIT and PKCI-1/HINT by a combination of reverse transcriptase polymerase chain reaction and DNA sequencing. In all cases a single transcript corresponding to the reported sequence was detected using primers specific for the PKCI-1/HINT gene. In contrast multiple transcripts were detected using primers specific for the FHIT gene transcript. 6% (3/45) of tumours evinced no detectable expression of any FHIT transcript and a further 12% (6/45) produced only the normal full length transcripts. Ninety-six aberrant transcripts were characterized from the remaining tumours. Deviations from the normal full length sequence characterized included deletions, insertions of novel sequences, a point mutation as well as the usage of a putative alternate splice site in exon 10. Message variants were detected with approximately equal frequency in all tumour stages with the exception that templates with insertions were found solely in Dukes’ stage B tumours (P < 0.001). With the exception of the putative alternate splice site, aberrant transcripts were not detected in matched normal mucosa. These results suggest that members of the HIT family of genes are only selectively involved in tumorigenesis and that perturbation of FHIT gene expression is an early event in colorectal tumorigenesis. © 1999 Cancer Research Campaig

Fuzzy Tandem Repeats Containing p53 Response Elements May Define Species-Specific p53 Target Genes

Evolutionary forces that shape regulatory networks remain poorly understood. In mammals, the Rb pathway is a classic example of species-specific gene regulation, as a germline mutation in one Rb allele promotes retinoblastoma in humans, but not in mice. Here we show that p53 transactivates the Retinoblastoma-like 2 (Rbl2) gene to produce p130 in murine, but not human, cells. We found intronic fuzzy tandem repeats containing perfect p53 response elements to be important for this regulation. We next identified two other murine genes regulated by p53 via fuzzy tandem repeats: Ncoa1 and Klhl26. The repeats are poorly conserved in evolution, and the p53-dependent regulation of the murine genes is lost in humans. Our results indicate a role for the rapid evolution of tandem repeats in shaping differences in p53 regulatory networks between mammalian species

Replicative Age Induces Mitotic Recombination in the Ribosomal RNA Gene Cluster of Saccharomyces cerevisiae

Somatic mutations contribute to the development of age-associated disease. In earlier work, we found that, at high frequency, aging Saccharomyces cerevisiae diploid cells produce daughters without mitochondrial DNA, leading to loss of respiration competence and increased loss of heterozygosity (LOH) in the nuclear genome. Here we used the recently developed Mother Enrichment Program to ask whether aging cells that maintain the ability to produce respiration-competent daughters also experience increased genomic instability. We discovered that this population exhibits a distinct genomic instability phenotype that primarily affects the repeated ribosomal RNA gene array (rDNA array). As diploid cells passed their median replicative life span, recombination rates between rDNA arrays on homologous chromosomes progressively increased, resulting in mutational events that generated LOH at >300 contiguous open reading frames on the right arm of chromosome XII. We show that, while these recombination events were dependent on the replication fork block protein Fob1, the aging process that underlies this phenotype is Fob1-independent. Furthermore, we provide evidence that this aging process is not driven by mechanisms that modulate rDNA recombination in young cells, including loss of cohesion within the rDNA array or loss of Sir2 function. Instead, we suggest that the age-associated increase in rDNA recombination is a response to increasing DNA replication stress generated in aging cells

Receptors for Hyaluronic Acid and Poliovirus: A Combinatorial Role in Glioma Invasion?

Background: CD44 has long been associated with glioma invasion while, more recently, CD155 has been implicated in playing a similar role. Notably, these two receptors have been shown closely positioned on monocytes. Methods and Findings: In this study, an up-regulation of CD44 and CD155 was demonstrated in established and earlypassage cultures of glioblastoma. Total internal reflected fluorescence (TIRF) microscopy revealed close proximity of CD44 and CD155. CD44 antibody blocking and gene silencing (via siRNA) resulted in greater inhibition of invasion than that for CD155. Combined interference resulted in 86 % inhibition of invasion, although in these investigations no obvious evidence of synergy between CD44 and CD155 in curbing invasion was shown. Both siRNA-CD44 and siRNA-CD155 treated cells lacked processes and were rounder, while live cell imaging showed reduced motility rate compared to wild type cells. Adhesion assay demonstrated that wild type cells adhered most efficiently to laminin, whereas siRNA-treated cells (p,0.0001 for both CD44 and CD155 expression) showed decreased adhesion on several ECMs investigated. BrdU assay showed a higher proliferation of siRNA-CD44 and siRNA-CD155 cells, inversely correlated with reduced invasion. Confocal microscopy revealed overlapping of CD155 and integrins (b1, avb1 and avb3) on glioblastoma cell processes whereas siRNAtransfected cells showed consequent reduction in integrin expression with no specific staining patterns. Reduced expression of Rho GTPases, Cdc42, Rac1/2/3, RhoA and RhoB, was seen in siRNA-CD44 and siRNA-CD155 cells. In contrast t

p16 Mutation Spectrum in the Premalignant Condition Barrett's Esophagus

Background: Mutation, promoter hypermethylation and loss of heterozygosity involving the tumor suppressor gene p16 (CDKN2a/INK4a) have been detected in a wide variety of human cancers, but much less is known concerning the frequency and spectrum of p16 mutations in premalignant conditions. Methods and Findings: We have determined the p16 mutation spectrum for a cohort of 304 patients with Barrett’s esophagus, a premalignant condition that predisposes to the development of esophageal adenocarcinoma. Forty seven mutations were detected by sequencing of p16 exon 2 in 44 BE patients (14.5%) with a mutation spectrum consistent with that caused by oxidative damage and chronic inflammation. The percentage of patients with p16 mutations increased with increasing histologic grade. In addition, samples from 3 out of 19 patients (15.8%) who underwent esophagectomy were found to have mutations. Conclusions: The results of this study suggest the environment of the esophagus in BE patients can both generate an