Space dependent Fermi velocity in strained graphene

We resolve some apparent discrepancies between two different models for curved graphene: the one based on tight binding and elasticity theory, and the covariant approach based on quantum field theory in curved space. We demonstrate that strained or corrugated samples will have a space dependent Fermi velocity in either approach that can affect the interpretation of some experiments.Comment: Revised version as will appear in Phys. Rev. Let

Low energy electron-phonon effective action from symmetry analysis

Based on a detailed symmetry analysis, we state the general rules to build up the effective low energy field theory describing a system of electrons weakly interacting with the lattice degrees of freedom. The basic elements in our construction are what we call the "memory tensors", that keep track of the microscopic discrete symmetries into the coarse-grained action. The present approach can be applied to lattice systems in arbitrary dimensions and in a systematic way to any desired order in derivatives. We apply the method to the honeycomb lattice and re-obtain the by now well-known effective action of Dirac fermions coupled to fictitious gauge fields. As a second example, we derive the effective action for electrons in the kagom\'e lattice, where our approach allows to obtain in a simple way the low energy electron-phonon coupling terms.Comment: 18 pages, one figur

General practitioners' experiences with sickness certification: a comparison of survey data from Sweden and Norway

<p>Abstract</p> <p>Background</p> <p>In most countries with sickness insurance systems, general practitioners (GPs) play a key role in the sickness-absence process. Previous studies have indicated that GPs experience several tasks and situations related to sickness certification consultations as problematic. The fact that the organization of primary health care and social insurance systems differ between countries may influence both GPs' experiences and certification. The aim of the present study was to gain more knowledge of GPs' experiences of sickness certification, by comparing data from Sweden and Norway, regarding frequencies and aspects of sickness certification found to be problematic.</p> <p>Methods</p> <p>Statistical analyses of cross-sectional survey data of sickness certification by GPs in Sweden and Norway. In Sweden, all GPs were included, with 3949 (60.6%) responding. In Norway, a representative sample of GPs was included, with 221 (66.5%) responding.</p> <p>Results</p> <p>Most GPs reported having consultations involving sickness certification at least once a week; 95% of the GPs in Sweden and 99% of the GPs in Norway. A majority found such tasks problematic; 60% of the GPs in Sweden and 53% in Norway. In a logistic regression, having a higher frequency of sickness certification consultations was associated with a higher risk of experiencing them as problematic, in both countries. A higher rate of GPs in Sweden than in Norway reported meeting patients wanting a sickness certification without a medical reason. GPs in Sweden found it more problematic to discuss the advantages and disadvantages of sick leave with patients and to issue a prolongation of a sick-leave period initiated by another physician. GPs in Norway more often worried that patients would go to another physician if they did not issue a certificate, and a higher proportion of Norwegian GPs found it problematic to handle situations where they and their patient disagreed on the need for sick leave.</p> <p>Conclusions</p> <p>The study confirms that many GPs experience sickness absence consultations as problematic. However, there were differences between the two countries in GPs' experiences, which may be linked to differences in social security regulations and the organization of GP services. Possible causes and consequences of national differences should be addressed in future studies.</p

An update on treatment options for interstitial cystitis

Interstitial cystitis or bladder pain syndrome (IC/BPS) is a chronic pelvic pain syndrome related to the urinary bladder. The ideal treatment should match as much as possible with the pathophysiologic causes of the IC/BPS, but the scarcely available evidence limits this approach, with the majority of available treatments that are primarily targeted to the control of symptoms. The treatment strategies have traditionally focused on the bladder, which is considered the primary end-organ and source of pain. Nevertheless, the growing body of evidence suggests a multifaceted nature of the disease with systemic components. In general, guidelines recommend the personalized and progressive approach, that starts from the more conservative options and then advances toward more invasive and combined treatments. The behavioral changes represent the first and most conservative steps. They can be combined with oral medications or progressively with intravesical instillation of drugs, up to more invasive techniques in a combined way. Despite the multiple available options, the optimal treatment is not easy to be found. Only further investigation on the etiopathogenetic mechanisms, taking into account the differences among subgroups, and the interaction between central and peripherical factors may allow providing a real improvement in the treatment and management of these patients

Dr. Harold C. Smith Fund of Ursinus College Official Prospectus, April 24, 2018

This prospectus contains investment strategy and performance for the following stocks in the managed fund: Garmin Ltd., Masimo, Micron Technologies, SEI Investments, Waste Management and Stamps.com

Is it possible to assess the best mitral valve repair in the individual patient? Preliminary results of a finite element study from magnetic resonance imaging data

ObjectivesFinite element modeling was adopted to quantitatively compare, for the first time and on a patient-specific basis, the biomechanical effects of a broad spectrum of different neochordal implantation techniques for the repair of isolated posterior mitral leaflet prolapse.MethodsCardiac magnetic resonance images were acquired from 4 patients undergoing surgery. A patient-specific 3-dimensional model of the mitral apparatus and the motion of the annulus and papillary muscles were reconstructed. The location and extent of the prolapsing region were confirmed by intraoperative findings, and the mechanical properties of the mitral leaflets, chordae tendineae and expanded polytetrafluoroethylene neochordae were included. Mitral systolic biomechanics was simulated under preoperative conditions and after 5 different neochordal procedures: single neochorda, double neochorda, standard neochordal loop with 3 neochordae of the same length and 2 premeasured loops with 1 common neochordal loop and 3 different branched neochordae arising from it, alternatively one third and two thirds of the entire length.ResultsThe best repair in terms of biomechanics was achieved with a specific neochordal technique in the single patient, according to the location of the prolapsing region. However, all techniques achieved a slight reduction in papillary muscle forces and tension relief in intact native chordae proximal to the prolapsing region. Multiple neochordae implantation improved the repositioning of the prolapsing region below the annular plane and better redistributed mechanical stresses on the leaflet.ConclusionsAlthough applied on a small cohort of patients, systematic biomechanical differences were noticed between neochordal techniques, potentially affecting their short- to long-term clinical outcomes. This study opens the way to patient-specific optimization of neochordal techniques

LANCL1 binds abscisic acid and stimulates glucose transport and mitochondrial respiration in muscle cells via the AMPK/PGC-1α/Sirt1 pathway

Objective: Abscisic acid (ABA) is a plant hormone also present and active in animals. In mammals, ABA regulates blood glucose levels by stimulating insulin-independent glucose uptake and metabolism in adipocytes and myocytes through its receptor LANCL2. The objective of this study was to investigate whether another member of the LANCL protein family, LANCL1, also behaves as an ABA receptor and, if so, which functional effects are mediated by LANCL1. Methods: ABA binding to human recombinant LANCL1 was explored by equilibrium-binding experiments with [3H]ABA, circular dichroism, and surface plasmon resonance. Rat L6 myoblasts overexpressing either LANCL1 or LANCL2, or silenced for the expression of both proteins, were used to investigate the basal and ABA-stimulated transport of a fluorescent glucose analog (NBDG) and the signaling pathway downstream of the LANCL proteins using Western blot and qPCR analysis. Finally, glucose tolerance and sensitivity to ABA were compared in LANCL2−/− and wild-type (WT) siblings. Results: Human recombinant LANCL1 binds ABA with a Kd between 1 and 10 μM, depending on the assay (i.e., in a concentration range that lies between the low and high-affinity ABA binding sites of LANCL2). In L6 myoblasts, LANCL1 and LANCL2 similarly, i) stimulate both basal and ABA-triggered NBDG uptake (4-fold), ii) activate the transcription and protein expression of the glucose transporters GLUT4 and GLUT1 (4-6-fold) and the signaling proteins AMPK/PGC-1α/Sirt1 (2-fold), iii) stimulate mitochondrial respiration (5-fold) and the expression of the skeletal muscle (SM) uncoupling proteins sarcolipin (3-fold) and UCP3 (12-fold). LANCL2−/− mice have a reduced glucose tolerance compared to WT. They spontaneously overexpress LANCL1 in the SM and respond to chronic ABA treatment (1 μg/kg body weight/day) with an improved glycemia response to glucose load and an increased SM transcription of GLUT4 and GLUT1 (20-fold) of the AMPK/PGC-1α/Sirt1 pathway and sarcolipin, UCP3, and NAMPT (4- to 6-fold). Conclusions: LANCL1 behaves as an ABA receptor with a somewhat lower affinity for ABA than LANCL2 but with overlapping effector functions: stimulating glucose uptake and the expression of muscle glucose transporters and mitochondrial uncoupling and respiration via the AMPK/PGC-1α/Sirt1 pathway. Receptor redundancy may have been advantageous in animal evolution, given the role of the ABA/LANCL system in the insulin-independent stimulation of cell glucose uptake and energy metabolism

Immunological and mass spectrometry-based approaches to determine thresholds of the mutagenic DNA adduct O 6 -methylguanine in vivo

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. N-nitroso compounds are alkylating agents, which are widespread in our diet and the environment. They induce DNA alkylation adducts such as O 6 -methylguanine (O 6 -MeG), which is repaired by O 6 -methylguanine-DNA methyltransferase (MGMT). Persistent O 6 -MeG lesions have detrimental biological consequences like mutagenicity and cytotoxicity. Due to its pivotal role in the etiology of cancer and in cytotoxic cancer therapy, it is important to detect and quantify O 6 -MeG in biological specimens in a sensitive and accurate manner. Here, we used immunological approaches and established an ultra performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) to monitor O 6 -MeG adducts. First, colorectal cancer (CRC) cells were treated with the methylating anticancer drug temozolomide (TMZ). Immunofluorescence microscopy and an immuno-slot blot assay, both based on an adduct-specific antibody, allowed for the semi-quantitative, dose-dependent assessment of O 6 -MeG in CRC cells. Using the highly sensitive and specific UPLC–MS/MS, TMZ-induced O 6 -MeG adducts were quantified in CRC cells and even in peripheral blood mononuclear cells exposed to clinically relevant TMZ doses. Furthermore, all methodologies were used to detect O 6 -MeG in wildtype (WT) and MGMT-deficient mice challenged with the carcinogen azoxymethane. UPLC–MS/MS measurements and dose–response modeling revealed a non-linear formation of hepatic and colonic O 6 -MeG adducts in WT, whereas linear O 6 -MeG formation without a threshold was observed in MGMT-deficient mice. Collectively, the UPLC–MS/MS analysis is highly sensitive and specific for O 6 -MeG, thereby allowing for the first time for the determination of a genotoxic threshold upon exposure to O 6 -methylating agents. We envision that this method will be instrumental to monitor the efficacy of methylating chemotherapy and to assess dietary exposures

Bypass of mutagenic O 6 -Carboxymethylguanine DNA Adducts by Human Y- and B-Family Polymerases

The generation of chemical alkylating agents from nitrosation of glycine and bile acid conjugates in the gastrointestinal tract is hypothesized to initiate carcinogenesis. O6-carboxymethylguanine (O6-CMG) is a product of DNA alkylation derived from nitrosated glycine. Although the tendency of the structurally related adduct O6-methylguanine to code for the misincoporation of TTP during DNA replication is well-established, the impact of the presence of the O6-CMG adduct in a DNA template on the efficiency and fidelity of translesion DNA synthesis (TLS) by human DNA polymerases (Pols) has hitherto not been described. Herein, we characterize the ability of the four human TLS Pols η, ι, κ, and ζ and the replicative Pol δ to bypass O6-CMG in a prevalent mutational hot-spot for colon cancer. The results indicate that Pol η replicates past O6-CMG, incorporating dCMP or dAMP, whereas Pol κ incorporates dCMP only, and Pol ι incorporates primarily dTMP. Additionally, the subsequent extension step was carried out with high efficiency by TLS Pols η, κ, and ζ, while Pol ι was unable to extend from a terminal mismatch. These results provide a first basis of O6-CMG-promoted base misincorporation by Y- and B-family polymerases potentially leading to mutational signatures associated with colon cancer

Structural and biochemical impact of C8-aryl-guanine adducts within the NarI recognition DNA sequence: influence of aryl ring size on targeted and semi-targeted mutagenicity

Chemical mutagens with an aromatic ring system may be enzymatically transformed to afford aryl radical species that preferentially react at the C8-site of 2′-deoxyguanosine (dG). The resulting carbon-linked C8-aryl-dG adduct possesses altered biophysical and genetic coding properties compared to the precursor nucleoside. Described herein are structural and in vitro mutagenicity studies of a series of fluorescent C8-aryl-dG analogues that differ in aryl ring size and are representative of authentic DNA adducts. These structural mimics have been inserted into a hotspot sequence for frameshift mutations, namely, the reiterated G3-position of the NarI sequence within 12mer (NarI(12)) and 22mer (NarI(22)) oligonucleotides. In the NarI(12) duplexes, the C8-aryl-dG adducts display a preference for adopting an anti-conformation opposite C, despite the strong syn preference of the free nucleoside. Using the NarI(22) sequence as a template for DNA synthesis in vitro, mutagenicity of the C8-aryl-dG adducts was assayed with representative high-fidelity replicative versus lesion bypass Y-family DNA polymerases, namely, Escherichia coli pol I Klenow fragment exo− (Kf−) and Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4). Our experiments provide a basis for a model involving a two-base slippage and subsequent realignment process to relate the miscoding properties of C-linked C8-aryl-dG adducts with their chemical structure