Prairie Dogs, Persistent Plague, Flocking Fleas, and Pernicious Positive Feedback

Plague (caused by the bacterium Yersinia pestis) is a deadly flea-borne disease that remains a threat to public health nearly worldwide and is particularly disruptive ecologically where it has been introduced. We review hypotheses regarding maintenance and transmission of Y. pestis, emphasizing recent data from North America supporting maintenance by persistent transmission that results in sustained non-epizootic (but variable) rates of mortality in hosts. This maintenance mechanism may facilitate periodic epizootic eruptions “in place” because the need for repeated reinvasion from disjunct sources is eliminated. Resulting explosive outbreaks that spread rapidly in time and space are likely enhanced by synergistic positive feedback (PFB) cycles involving flea vectors, hosts, and the plague bacterium itself. Although PFB has been implied in plague literature for at least 50 years, we propose this mechanism, particularly with regard to flea responses, as central to epizootic plague rather than a phenomenon worthy of just peripheral mention. We also present new data on increases in flea:host ratios resulting from recreational shooting and poisoning as possible triggers for the transition from enzootic maintenance to PFB cycles and epizootic explosions. Although plague outbreaks have received much historic attention, PFB cycles that result in decimation of host populations lead to speculation that epizootic eruptions might not be part of the adaptive evolutionary strategy of Y. pestis but might instead be a tolerated intermittent cost of its modus operandi. We also speculate that there may be mammal communities where epizootics, as we define them, are rare or absent. Absence of plague epizootics might translate into reduced public health risk but does not necessarily equate to inconsequential ecologic impact

Development of in-vessel reflood instrumentation at ORNL. [PWR]

A program under the sponsorship of the United States Nuclear Regulatory Commission was intiated at the Oak Ridge National Laboratory (ORNL) in late 1977. The program, Advanced Instrumentation for Reflood Studies (AIRS), is charged with developing instrumentation for measurement of in-vessel fluid phenomena in pressurized water reactor reflood facilities. The goal of the ORNL program is to develop techniques and systems for measuring fluid flow in-core, deentrainment in the upper plenum and liquid fallback from the upper plenum into the core. A large portion of the development at ORNL is devoted to the impedance probes for measurement of two-phase flow velocities and void fractions. Film probe development at ORNL is limited to adapting the present techniques to the environment of a reflood facility. As the development progresses on all the measurement techniques, ORNL will fabricate and supply instrument systems to the reflood facilities included in the 2D/3D Program

Z' Coupling Information from the LHeC

If the LHC discovers a $Z'$-like state the extraction of its couplings to the particles of the Standard Model becomes mandatory in order to determine the nature of the underlying new physics theory. It has been well-known for some time that the direct measurements performed at the LHC in the Drell-Yan channel cannot determine these parameters uniquely in a model-independent manner even if large integrated luminosities, $\sim 100 fb^{-1}$, become available and the $Z'$ is relatively light \lsim 1.5 TeV. Here we examine the possibility that a proposed $e_{L,R}^\pm p$ collider upgrade at the LHC, the LHeC, with $\sqrt s=1.5-2$ TeV could be helpful with such coupling determinations in the years before a Linear Collider is constructed. We show that the polarization and charge asymmetries constructed from the cross sections for these processes can be useful in this regard depending upon the specific values of the particular $Z'$ model parameters.Comment: 16 pages, 9 figs, minor modification

Eigenstate–Specific Temperatures in Two–Level Paramagnetic Spin Lattices

Increasing interest in the thermodynamics of small and/or isolated systems, in combination with recent observations of negative temperatures of atoms in ultracold optical lattices, has stimulated the need for estimating the conventional, canonical temperature Tconvc of systems in equilibrium with heat baths using eigenstate-specific temperatures (ESTs). Four distinct ESTs—continuous canonical, discrete canonical, continuous microcanonical, and discrete microcanonical—are accordingly derived for two-level paramagnetic spin lattices (PSLs) in external magnetic fields. At large N, the four ESTs are intensive, equal to Tconvc, and obey all four laws of thermodynamics. In contrast, for N \u3c 1000, the ESTs of most PSL eigenstates are non-intensive, differ from Tconvc, and violate each of the thermodynamic laws. Hence, in spite of their similarities to Tconvc at large N, the ESTs are not true thermodynamic temperatures. Even so, each of the ESTs manifests a unique functional dependence on energy which clearly specifies the magnitude and direction of their deviation from Tconvc; the ESTs are thus good temperature estimators for small PSLs. The thermodynamic uncertainty relation is obeyed only by the ESTs of small canonical PSLs; it is violated by large canonical PSLs and by microcanonical PSLs of any size. The ESTs of population-inverted eigenstates are negative (positive) when calculated using Boltzmann (Gibbs) entropies; the thermodynamic implications of these entropically induced differences in sign are discussed in light of adiabatic invariance of the entropies. Potential applications of the four ESTs to nanothermometers and to systems with long-range interactions are discussed

Potential diagnostic and prognostic values of detecting promoter hypermethylation in the serum of patients with gastric cancer

While there is no reliable serum biomarker for the diagnosis and monitoring of patients with gastric cancer, we tested the potential diagnostic and prognostic values of detecting methylation changes in the serum of gastric cancer patients. DNA was extracted from the pretherapeutic serum of 60 patients with confirmed gastric adenocarcinoma and 22 age-matched noncancer controls. Promoter hypermethylation in 10 tumour-related genes (APC, E-cadherin, GSTP1, hMLH1, MGMT, p15, p16, SOCS1, TIMP3 and TGF-beta RII) was determined by quantitative methylation-specific PCR (MethyLight). Preferential methylation in the serum DNA of gastric cancer patients was noted in APC (17%), E-cadherin (13%), hMLH1 (41%) and TIMP3 (17%) genes. Moreover, patients with stages III/IV diseases tended to have higher concentrations of methylated APC (P=0.08), TIMP3 (P=0.005) and hMLH1 (P=0.03) in the serum. In all, 33 cancers (55%) had methylation detected in the serum in at least one of these four markers, while three normal subjects had methylation detected in the serum (specificity 86%). The combined use of APC and E-cadherin methylation markers identified a subgroup of cancer patients with worse prognosis (median survival 3.3 vs 16.1 months, P=0.006). These results suggest that the detection of DNA methylation in the serum may carry both diagnostic and therapeutic values in gastric cancer patients

Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance

Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors

<p>Abstract</p> <p>Background</p> <p>Aberrant promoter hypermethylation of cancer-associated genes occurs frequently during carcinogenesis and may serve as a cancer biomarker. In this study we aimed at defining a quantitative gene promoter methylation panel that might identify the most prevalent types of renal cell tumors.</p> <p>Methods</p> <p>A panel of 18 gene promoters was assessed by quantitative methylation-specific PCR (QMSP) in 85 primarily resected renal tumors representing the four major histologic subtypes (52 clear cell (ccRCC), 13 papillary (pRCC), 10 chromophobe (chRCC), and 10 oncocytomas) and 62 paired normal tissue samples. After genomic DNA isolation and sodium bisulfite modification, methylation levels were determined and correlated with standard clinicopathological parameters.</p> <p>Results</p> <p>Significant differences in methylation levels among the four subtypes of renal tumors were found for <it>CDH1 </it>(<it>p </it>= 0.0007), <it>PTGS2 </it>(<it>p </it>= 0.002), and <it>RASSF1A </it>(<it>p </it>= 0.0001). <it>CDH1 </it>hypermethylation levels were significantly higher in ccRCC compared to chRCC and oncocytoma (<it>p </it>= 0.00016 and <it>p </it>= 0.0034, respectively), whereas <it>PTGS2 </it>methylation levels were significantly higher in ccRCC compared to pRCC (<it>p </it>= 0.004). <it>RASSF1A </it>methylation levels were significantly higher in pRCC than in normal tissue (<it>p </it>= 0.035). In pRCC, <it>CDH1 </it>and <it>RASSF1A </it>methylation levels were inversely correlated with tumor stage (<it>p </it>= 0.031) and nuclear grade (<it>p </it>= 0.022), respectively.</p> <p>Conclusion</p> <p>The major subtypes of renal epithelial neoplasms display differential aberrant <it>CDH1</it>, <it>PTGS2</it>, and <it>RASSF1A </it>promoter methylation levels. This gene panel might contribute to a more accurate discrimination among common renal tumors, improving preoperative assessment and therapeutic decision-making in patients harboring suspicious renal masses.</p

Both SEPT2 and MLL are down-regulated in MLL-SEPT2 therapy-related myeloid neoplasia

<p>Abstract</p> <p>Background</p> <p>A relevant role of septins in leukemogenesis has been uncovered by their involvement as fusion partners in <it>MLL</it>-related leukemia. Recently, we have established the <it>MLL-SEPT2 </it>gene fusion as the molecular abnormality subjacent to the translocation t(2;11)(q37;q23) in therapy-related acute myeloid leukemia. In this work we quantified <it>MLL </it>and <it>SEPT2 </it>gene expression in 58 acute myeloid leukemia patients selected to represent the major AML genetic subgroups, as well as in all three cases of <it>MLL-SEPT2</it>-associated myeloid neoplasms so far described in the literature.</p> <p>Methods</p> <p>Cytogenetics, fluorescence in situ hybridization (FISH) and molecular studies (RT-PCR, qRT-PCR and qMSP) were used to characterize 58 acute myeloid leukemia patients (AML) at diagnosis selected to represent the major AML genetic subgroups: <it>CBFB-MYH11 </it>(n = 13), <it>PML-RARA </it>(n = 12); <it>RUNX1-RUNX1T1 </it>(n = 12), normal karyotype (n = 11), and <it>MLL </it>gene fusions other than <it>MLL-SEPT2 </it>(n = 10). We also studied all three <it>MLL-SEPT2 </it>myeloid neoplasia cases reported in the literature, namely two AML patients and a t-MDS patient.</p> <p>Results</p> <p>When compared with normal controls, we found a 12.8-fold reduction of wild-type <it>SEPT2 </it>and <it>MLL-SEPT2 </it>combined expression in cases with the <it>MLL-SEPT2 </it>gene fusion (p = 0.007), which is accompanied by a 12.4-fold down-regulation of wild-type <it>MLL </it>and <it>MLL-SEPT2 </it>combined expression (p = 0.028). The down-regulation of <it>SEPT2 </it>in <it>MLL-SEPT2 </it>myeloid neoplasias was statistically significant when compared with all other leukemia genetic subgroups (including those with other <it>MLL </it>gene fusions). In addition, <it>MLL </it>expression was also down-regulated in the group of <it>MLL </it>fusions other than <it>MLL-SEPT2</it>, when compared with the normal control group (p = 0.023)</p> <p>Conclusion</p> <p>We found a significant down-regulation of both <it>SEPT2 </it>and <it>MLL </it>in <it>MLL-SEPT2 </it>myeloid neoplasias. In addition, we also found that <it>MLL </it>is under-expressed in AML patients with <it>MLL </it>fusions other than <it>MLL-SEPT2</it>.</p