A Dual Read-Out Assay to Evaluate the Potency of Compounds Active against Mycobacterium tuberculosis

PMCID: PMC3617142This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The APC/C Coordinates Retinal Differentiation with G1 Arrest through the Nek2-Dependent Modulation of Wingless Signaling

The cell cycle is coordinated with differentiation during animal development. Here we report a cell-cycle-independent developmental role for a master cell-cycle regulator, the anaphase-promoting complex or cyclosome (APC/C), in the regulation of cell fate through modulation of Wingless (Wg) signaling. The APC/C controls both cell-cycle progression and postmitotic processes through ubiquitin-dependent proteolysis. Through an RNAi screen in the developing $\textit{Drosophila}$eye, we found that partial APC/C inactivation severely inhibits retinal differentiation independently of cell-cycle defects. The differentiation inhibition coincides with hyperactivation of Wg signaling caused by the accumulation of a Wg modulator, $\textit{Drosophila}$ Nek2 (dNek2). The APC/C degrades dNek2 upon synchronous G1 arrest prior to differentiation, which allows retinal differentiation through local suppression of Wg signaling. We also provide evidence that decapentaplegic signaling may posttranslationally regulate this APC/C function. Thus, the APC/C coordinates cell-fate determination with the cell cycle through the modulation of developmental signaling pathways.T.M. and F.M. were partly supported by a CRUK Fellowship to Y.K. T.M. thanks the European Commission for a Marie Curie fellowship

Predictors and outcomes of recognition of intellectual disability for adults during hospital admissions: A retrospective data linkage study in NSW, Australia

Adults with intellectual disability have high health care needs. Despite frequent contact with health services, they often receive inadequate health care. One method to improve health care delivery is reasonable adjustments, that is, the adaptation of health care delivery such that barriers to participation are removed for the person with disability. A starting point for the provision of reasonable adjustments is recognition of intellectual disability during the health care contact. To determine rates and predictors of the recognition of intellectual disability during hospital admissions, and its impact on admission metrics, we examined a population of adults with intellectual disability identified from disability services datasets from New South Wales, Australia between 2005 and 2014. Recognition of intellectual disability was determined by the recording of an International Classification of Diseases 10th revision (ICD-10) diagnostic code for intellectual disability during a given hospital admission. We examined how recognition of intellectual disability related to length of hospital episodes. We found an overall low rate of recognition of intellectual disability (23.79%) across all hospital episodes, with the proportion of hospital episodes recognising intellectual disability decreasing from 2005-2015. Admissions for adults with complex health profiles (e.g., those with many comorbidities, those with Autism Spectrum Disorder, and those admitted for urgent treatment) were more likely to recognise intellectual disability, but admissions for adults with complexity in other domains (i.e., for those in custody, or those with drug and alcohol disorders) were less likely to recognise intellectual disability. Recognition of intellectual disability was associated with longer episodes of care, possibly indicating the greater provision of reasonable adjustments. To improve the recognition of intellectual disability for adults during health service contacts, we advocate for the implementation of targeted initiatives (such as a nationwide disability flag to be included in health service records) to improve the provision of reasonable adjustments

Lattice simulations of non-minimally coupled scalar fields in the Jordan frame

The presence of scalar fields with non-minimal gravitational interactions of the form ξ|φ|2R may have important implications for the physics of the early universe. We propose a procedure to solve the dynamics of non-minimally coupled scalar fields directly in the Jordan frame, where the non-minimal couplings are maintained explicitly. Our algorithm can be applied to lattice simulations that include minimally coupled fields and an arbitrary number of non-minimally coupled scalars, with the expansion of the universe sourced by all fields present. This includes situations when the dynamics become fully inhomogeneous, fully non-linear (due to e.g. backreaction or mode rescattering effects), and/or when the expansion of the universe is dominated by non-minimally coupled species. As an example, we study geometric preheating with a non-minimally coupled scalar spectator field when the inflaton oscillates following the end of inflation

Immune Checkpoint Blockade in Lung Carcinoids with Aggressive Behaviour: One More Arrow in Our Quiver?

Lung carcinoids are well-differentiated and low-/intermediate-grade neuroendocrine neoplasms of the lung. Given their relative rarity, and the paucity of data available from prospective studies, no global consensus exists on the systemic treatment of these tumours. In recent years, immune checkpoint inhibitors have revolutionized cancer management and are under evaluation in patients with diverse types of neuroendocrine neoplasms. The aim of this narrative review is to analyse all available data for the use of approved immune checkpoint inhibitors in patients with lung carcinoids. We performed an extensive search for relevant data sources and found five published articles, one meeting abstract, and nine registered clinical trials indicating a growing interest of researchers in this field, and providing preliminary evidence of efficacy for combined nivolumab plus ipilimumab and durvalumab plus tremelimumab regimens in the treatment of advanced and/or metastatic lung carcinoids

Characterization of Volatile Organic Compounds (VOC) in wet-white and metal-free leathers

Content: As it is known in the tanning sector, in recent times, the so-called wet-white and/or metal-free concepts have had a certain increase. For example, in the automotive sector, the wet-white tanning system, carried out with glutaraldehyde and tannins, has been widely diffused. In fact, car manufacturers offer, for interior furnishings, leather not only for high-end cars but increasingly also in the lower segments. The components on which the leather upholstery is applied are mainly steering wheel, seats, dashboard and panels. Therefore, the use of leather also in this context must be able to meet both the aesthetic/performance criteria and the environmental ones; environmental criteria should also consider the air quality of the interior of a motor vehicle. In practice, the interior furniture consisting of finished leather must be able to release a few volatile substances and, at the same time, provide a typical smell of leather. Considering, therefore, the diffusion of alternative chrome tanning systems for the different uses, in this work, wet-white (glutaraldehyde and tannins) will be investigated, both from the point of view of the performance characteristics and from the ecotoxicological ones. and leathers deriving from the latest generation of metal-free tanning. For the characterization of Volatile Organic Compounds (VOC) the GC-MS will be used coupled with the 'Purge and Trap' technique with the aim of obtaining information on the new substances used in the wetwhite / metal free production process and then avoiding undesired effects during use (eg bad smell, SVHC substances, etc.) Take-Away: metal-free automotive VO

Depletion of density of states near Fermi energy induced by disorder and electron correlation in alloys

We have performed high resolution photoemission study of substitutionally disordered alloys Cu-Pt, Cu-Pd, Cu-Ni, and Pd-Pt. The ratios between alloy spectra and pure metal spectra are found to have dips at the Fermi level when the residual resistivity is high and when rather strong repulsive electron-electron interaction is expected. This is in accordance with Altshuler and Aronov's model which predicts depletion of density of states at the Fermi level when both disorder and electron correlation are present.Comment: 1 tex file and 4 ps file

A novel integrated Sachs-Wolfe effect from Early Dark Energy

We study the nonlinear effects of minimally coupled, massless, cosmological scalar fields on the cosmic microwave background (CMB). These fields can exhibit post-recombination parametric resonance and subsequent nonlinear evolution leading to novel contributions to the gravitational potential. We compute the resulting contributions to the CMB temperature anisotropies through the time-variation of the gravitational potential (i.e., the integrated Sachs-Wolfe (ISW) effect). We find that fields that constitute 5% of the total energy density and become dynamical at $z_c \simeq 10^{4}$ can produce marginally observable ISW signals at multipoles $\ell \simeq 2000$. Fields that become dynamical at earlier times and/or have initial displacements at a flatter part of their potential, produce ISW contributions that are significantly larger and at higher multipoles. We calculate these dynamics and the resulting evolution of gravitational perturbations using analytic estimates alongside detailed nonlinear lattice simulations, which couple scalar fields and cosmological fluids to a perturbed metric. Finally, we discuss the possibility of detecting these features with future high-resolution CMB observations.Comment: 12 pages, 6 figures, comments welcom

Novel Integrated Sachs-Wolfe Effect From Early Dark Energy

We study the nonlinear effects of minimally coupled, massless, cosmological scalar fields on the cosmic microwave background (CMB). These fields can exhibit postrecombination parametric resonance and subsequent nonlinear evolution leading to novel contributions to the gravitational potential. We compute the resulting contributions to the CMB temperature anisotropies through the time variation of the gravitational potential (i.e., the integrated Sachs-Wolfe (ISW) effect). We find that fields that constitute 5% of the total energy density and become dynamical at zc ≃ 104 can produce marginally observable ISW signals at multipoles ℓ ≃ 2000. Fields that become dynamical at earlier times and/or have initial displacements at a flatter part of their potential, produce ISW contributions that are significantly larger and at higher multipoles. We calculate these dynamics and the resulting evolution of gravitational perturbations using analytic estimates alongside detailed nonlinear lattice simulations, which couple scalar fields and cosmological fluids to a perturbed metric. Finally, we discuss the possibility of detecting these features with future high-resolution CMB observations