Structured inference networks using high-dimensional sensors for surveillance purposes

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Connective neck evolution and conductance steps in hot point contacts

Dynamic evolution of the connective neck in Al and Pb mechanically controllable break junctions was studied during continuous approach of electrodes at bias voltages V_b up to a few hundred mV. A high level of power dissipation (10^-4 - 10^-3 W) and high current density (j > 10^10 A/cm^2) in the constriction lead to overheating of the contact area, electromigration and current-enhanced diffusion of atoms out of the "hot spot". At a low electrode approach rate (10 - 50 pm/s) the transverse dimension of the neck and the conductance of the junction depend on V_b and remain nearly constant over the approach distance of 10 - 30 nm. For V_b > 300 mV the connective neck consists of a few atoms only and the quantum nature of conductance manifests itself in abrupt steps and reversible jumps between two or more levels. These features are related to an ever changing number of individual conductance channels due to the continuous rearrangement in atomic configuration of the neck, the recurring motion of atoms between metastable states, the formation and breaking of isolated one-atom contacts and the switching between energetically preferable neck geometries.Comment: 21 pages 10 figure

Hsp90 governs dispersion and drug resistance of fungal biofilms

Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections

PPAR? Downregulation by TGF in Fibroblast and Impaired Expression and Function in Systemic Sclerosis: A Novel Mechanism for Progressive Fibrogenesis

The nuclear orphan receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) is expressed in multiple cell types in addition to adipocytes. Upon its activation by natural ligands such as fatty acids and eicosanoids, or by synthetic agonists such as rosiglitazone, PPAR-γ regulates adipogenesis, glucose uptake and inflammatory responses. Recent studies establish a novel role for PPAR-γ signaling as an endogenous mechanism for regulating transforming growth factor-ß (TGF-ß)- dependent fibrogenesis. Here, we sought to characterize PPAR-γ function in the prototypic fibrosing disorder systemic sclerosis (SSc), and delineate the factors governing PPAR-γ expression. We report that PPAR-γ levels were markedly diminished in skin and lung biopsies from patients with SSc, and in fibroblasts explanted from the lesional skin. In normal fibroblasts, treatment with TGF-ß resulted in a time- and dose-dependent down-regulation of PPAR-γ expression. Inhibition occurred at the transcriptional level and was mediated via canonical Smad signal transduction. Genome-wide expression profiling of SSc skin biopsies revealed a marked attenuation of PPAR-γ levels and transcriptional activity in a subset of patients with diffuse cutaneous SSc, which was correlated with the presence of a ''TGF-ß responsive gene signature'' in these biopsies. Together, these results demonstrate that the expression and function of PPAR-γ are impaired in SSc, and reveal the existence of a reciprocal inhibitory cross-talk between TGF-ß activation and PPAR-γ signaling in the context of fibrogenesis. In light of the potent anti-fibrotic effects attributed to PPAR-γ, these observations lead us to propose that excessive TGF-ß activity in SSc accounts for impaired PPAR-γ function, which in turn contributes to unchecked fibroblast activation and progressive fibrosis. © 2010 Wei et al

Predictors of Occurrence and Severity of First Time Low Back Pain Episodes: Findings from a Military Inception Cohort

Primary prevention studies suggest that additional research on identifying risk factors predictive of low back pain (LBP) is necessary before additional interventions can be developed. In the current study we assembled a large military cohort that was initially free of LBP and followed over 2 years. The purposes of this study were to identify baseline variables from demographic, socioeconomic, general health, and psychological domains that were predictive of a) occurrence; b) time; and c) severity for first episode of self-reported LBP. Baseline and outcome measures were collected via web-based surveillance system or phone to capture monthly information over 2 years. The assembled cohort consisted of 1230 Soldiers who provided self-report data with 518 (42.1%) reporting at least one episode of LBP over 2 years. Multivariate logistic regression analysis indicated that gender, active duty status, mental and physical health scores were significant predictors of LBP. Cox regression revealed that the time to first episode of LBP was significantly shorter for Soldiers that were female, active duty, reported previous injury, and had increased BMI. Multivariate linear regression analysis investigated severity of the first episode by identifying baseline predictors of pain intensity, disability, and psychological distress. Education level and physical fitness were consistent predictors of pain intensity, while gender, smoking status, and previous injury status were predictors of disability. Gender, smoking status, physical health scores, and beliefs of back pain were consistent predictors of psychological distress. These results provide additional data to confirm the multi-factorial nature of LBP and suggest future preventative interventions focus on multi-modal approaches that target modifiable risk factors specific to the population of interest

Measurement of Exclusive B Decays to Final States Containing a Charmed Baryon

Using data collected by the CLEO detector in the Upsilon(4S) region, we report new measurements of the exclusive decays of B mesons into final states of the type Lambda_c^+ p-bar n(pi), where n=0,1,2,3. We find signals in modes with one, two and three pions and an upper limit for the two body decay Lambda_c^+ pbar. We also make the first measurements of exclusive decays of B mesons to Sigma_c p-bar n(pi), where n=0,1,2. We find signals in modes with one and two pions and an upper limit for the two body decay Sigma_c p-bar. Measurements of these modes shed light on the mechanisms involved in B decays to baryons.Comment: 11 pages postscript, also available through http://w4.lns.cornell.edu/public/CLNS, submitted to PR

Measurement of the Masses and Widths of the Sigma_c^++ and Sigma_c^0 Charmed Baryons

Using data recorded by the CLEO II and CLEO II.V detector configurations at CESR, we report new measurements of the masses of the Sigma_c^{++} and Sigma_c^0 charmed baryons, and the first measurements of their intrinsic widths. We find M(Sigma_c^{++}) - M(Lambda_c^+) = 167.4 +- 0.1 +- 0.2 MeV, Gamma(Sigma_c^{++}) = 2.3 +- 0.2 +- 0.3 MeV, and M(Sigma_c^0) - M(Lambda_c^+) = 167.2 +- 0.1 +- 0.2 MeV, Gamma(Sigma_c^0) = 2.5 +- 0.2 +- 0.3 MeV, where the uncertainties are statistical and systematic, respectively.Comment: 9 pages postscript, also available through http://w4.lns.cornell.edu/public/CLNS, submitted to PRD, Rapid Communications. Reference [13] correcte

Observation of Exclusive barB --> D(*) K*- Decays

We report the first observation of the exclusive decays \bar B\to D^{(*)}K^{*-}, using 9.66 x 10^{6} B\bar{B} pairs collected at the \Upsilon(4S) with the CLEO detector. We measure the following branching fractions: {\cal B}(B^- -> D^0 K^{*-})=(6.1 +- 1.6 +-1.7)x10^{-4}, {\cal B}(\bar{B^0} -> D^+K^{*-})=(3.7 +- 1.5 +- 1.0) x 10^{-4}, {\cal B}(\bar{B^0} -> D^{*+}K^{*-})=(3.8 +- 1.3 +- 0.8) x 10^{-4} and {\cal B}(B^- --> D^{*0} K^{*-})=(7.7 +- 2.2 +- 2.6) x 10^{-4}. The \bar B ->D^*K^{*-} branching ratios are the averages of those corresponding to the 00 and 11 helicity states. The errors shown are statistical and systematic, respectively.Comment: 9 pages postscript, also available through http://w4.lns.cornell.edu/public/CLNS, Published in Phys.Rev.Lett.88:101803,200

Transient receptor potential canonical 4 and 5 proteins as targets in cancer therapeutics

Novel approaches towards cancer therapy are urgently needed. One approach might be to target ion channels mediating Ca²+ entry because of the critical roles played by Ca²+ in many cell types, including cancer cells. There are several types of these ion channels, but here we address those formed by assembly of transient receptor potential canonical (TRPC) proteins, particularly those which involve two closely related members of the family: TRPC4 and TRPC5. We focus on these proteins because recent studies point to roles in important aspects of cancer: drug resistance, transmission of drug resistance through extracellular vesicles, tumour vascularisation, and evoked cancer cell death by the TRPC4/5 channel activator (−)-englerin A. We conclude that further research is both justified and necessary before these proteins can be considered as strong targets for anti-cancer cell drug discovery programmes. It is nevertheless already apparent that inhibitors of the channels would be unlikely to cause significant adverse effects, but, rather, have other effects which may be beneficial in the context of cancer and chemotherapy, potentially including suppression of innate fear, visceral pain and pathological cardiac remodelling