Investigation of linezolid resistance in staphylococci and enterococci

The objective of this study was to investigate an apparent increase in linezolid-nonsusceptible staphylococci and enterococci following a laboratory change in antimicrobial susceptibility testing from disk diffusion to an automated susceptibility testing system. Isolates with nonsusceptible results (n = 27) from Vitek2 were subjected to a battery of confirmatory testing which included disk diffusion, Microscan broth microdilution, Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution, gradient diffusion (Etest), 23S rRNA gene sequencing, and cfr PCR. Our results show that there is poor correlation between methods and that only 70 to 75% of isolates were confirmed as linezolid resistant with alternative phenotypic testing methods (disk diffusion, Microscan broth microdilution, CLSI broth microdilution, and Etest). 23S rRNA gene sequencing identified mutations previously associated with linezolid resistance in 16 (59.3%) isolates, and the cfr gene was detected in 3 (11.1%) isolates. Mutations located at positions 2576 and 2534 of the 23S rRNA gene were most common. In addition, two previously undescribed variants (at positions 2083 and 2345 of the 23S rRNA gene) were also identified and may contribute to linezolid resistance

DISC1–ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1

Disrupted-In-Schizophrenia 1 (DISC1), a risk factor for major mental illnesses, has been studied extensively in the context of neurodevelopment. However, the role of DISC1 in neuronal signaling, particularly in conjunction with intracellular cascades that occur in response to dopamine, a neurotransmitter implicated in numerous psychiatric disorders, remains elusive. Previous data suggest that DISC1 interacts with numerous proteins that impact neuronal function, including activating transcription factor 4 (ATF4). In this study, we identify a novel DISC1 and ATF4 binding region in the genomic locus of phosphodiesterase 4D (PDE4D), a gene implicated in psychiatric disorders. We found that the loss of function of either DISC1 or ATF4 increases PDE4D9 transcription, and that the association of DISC1 with the PDE4D9 locus requires ATF4. We also show that PDE4D9 is increased by D1-type dopamine receptor dopaminergic stimulation. We demonstrate that the mechanism for this increase is due to DISC1 dissociation from the PDE4D locus in mouse brain. We further characterize the interaction of DISC1 with ATF4 to show that it is regulated via protein kinase A-mediated phosphorylation of DISC1 serine-58. Our results suggest that the release of DISC1-mediated transcriptional repression of PDE4D9 acts as feedback inhibition to regulate dopaminergic signaling. Furthermore, as DISC1 loss-of-function leads to a specific increase in PDE4D9, PDE4D9 itself may represent an attractive target for therapeutic approaches in psychiatric disorders.National Institute of General Medical Sciences (U.S.) (Award T32GM07753)National Institutes of Health (U.S.) (R01 MH091115

Supplemental Brief for Appellees

Supplemental brief for appellees, written by appellees in support of plaintiffs-appellees in AMP v. Myriad Genetics (No. 2010-1406)

Plaintiffs-Appellees' Petition for Panel Rehearing

Petitioners-appelles' petition for panel rehearing, submitted after the CAFC's July 29, 2011 ruling

Transgenic expression of the dicotyledonous pattern recognition receptor EFR in rice leads to ligand-dependent activation of defense responses

Plant plasma membrane localized pattern recognition receptors (PRRs) detect extracellular pathogen-associated molecules. PRRs such as Arabidopsis EFR and rice XA21 are taxonomically restricted and are absent from most plant genomes. Here we show that rice plants expressing EFR or the chimeric receptor EFR::XA21, containing the EFR ectodomain and the XA21 intracellular domain, sense both Escherichia coli- and Xanthomonas oryzae pv. oryzae (Xoo)-derived elf18 peptides at sub-nanomolar concentrations. Treatment of EFR and EFR::XA21 rice leaf tissue with elf18 leads to MAP kinase activation, reactive oxygen production and defense gene expression. Although expression of EFR does not lead to robust enhanced resistance to fully virulent Xoo isolates, it does lead to quantitatively enhanced resistance to weakly virulent Xoo isolates. EFR interacts with OsSERK2 and the XA21 binding protein 24 (XB24), two key components of the rice XA21-mediated immune response. Rice-EFR plants silenced for OsSERK2, or overexpressing rice XB24 are compromised in elf18-induced reactive oxygen production and defense gene expression indicating that these proteins are also important for EFR-mediated signaling in transgenic rice. Taken together, our results demonstrate the potential feasibility of enhancing disease resistance in rice and possibly other monocotyledonous crop species by expression of dicotyledonous PRRs. Our results also suggest that Arabidopsis EFR utilizes at least a subset of the known endogenous rice XA21 signaling components

Brief for Petitioners

Petitioners Brief written by ACLU and Public Patent Foundation in support of petitioners in AMP v. Myriad Genetics (Supreme Court Case Docket No. 12-398)

Petition for a Writ of Certiorari

Petition for a Writ of Certiorari submitted by petitioners Public Patent Foundation and American Civil Liberties Union (No. 11-725

Superconducting Phase with Fractional Vortices in the Frustrated Kagome Wire Network at f=1/2

In classical XY kagome antiferromagnets, there can be a novel low temperature phase where $\psi^3=e^{i3\theta}$ has quasi-long-range order but $\psi$ is disordered, as well as more conventional antiferromagnetic phases where $\psi$ is ordered in various possible patterns ($\theta$ is the angle of orientation of the spin). To investigate when these phases exist in a physical system, we study superconducting kagome wire networks in a transverse magnetic field when the magnetic flux through an elementary triangle is a half of a flux quantum. Within Ginzburg-Landau theory, we calculate the helicity moduli of each phase to estimate the Kosterlitz-Thouless (KT) transition temperatures. Then at the KT temperatures, we estimate the barriers to move vortices and effects that lift the large degeneracy in the possible $\psi$ patterns. The effects we have considered are inductive couplings, non-zero wire width, and the order-by-disorder effect due to thermal fluctuations. The first two effects prefer $q=0$ patterns while the last one selects a $\sqrt{3}\times\sqrt{3}$ pattern of supercurrents. Using the parameters of recent experiments, we conclude that at the KT temperature, the non-zero wire width effect dominates, which stabilizes a conventional superconducting phase with a $q=0$ current pattern. However, by adjusting the experimental parameters, for example by bending the wires a little, it appears that the novel $\psi^3$ superconducting phase can instead be stabilized. The barriers to vortex motion are low enough that the system can equilibrate into this phase.Comment: 30 pages including figure

Robotic right ventricle is a biohybrid platform that simulates right ventricular function in (patho)physiological conditions and intervention

The increasing recognition of the right ventricle (RV) necessitates the development of RV-focused interventions, devices and testbeds. In this study, we developed a soft robotic model of the right heart that accurately mimics RV biomechanics and hemodynamics, including free wall, septal and valve motion. This model uses a biohybrid approach, combining a chemically treated endocardial scaffold with a soft robotic synthetic myocardium. When connected to a circulatory flow loop, the robotic right ventricle (RRV) replicates real-time hemodynamic changes in healthy and pathological conditions, including volume overload, RV systolic failure and pressure overload. The RRV also mimics clinical markers of RV dysfunction and is validated using an in vivo porcine model. Additionally, the RRV recreates chordae tension, simulating papillary muscle motion, and shows the potential for tricuspid valve repair and replacement in vitro. This work aims to provide a platform for developing tools for research and treatment for RV pathophysiology.</p