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

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

HPA axis reactivity to pharmacologic and psychological stressors in euthymic women with histories of postpartum versus major depression

It is unclear whether women with a history of postpartum depression (PPD) have residual, abnormal hypothalamic-pituitary-adrenal (HPA) axis reactivity, as has been reported in major depression (MDD). Further unclear is whether the abnormalities in HPA axis reactivity associated with MDD represent a stable, underlying predisposition or a state-dependent phenomenon. This study sought the following: (1) to determine if euthymic postpartum women with a history of depression have an abnormal HPA axis reactivity to pharmacologic and psychological challenges and (2) to compare HPA reactivity in women with histories of PPD versus MDD. As a secondary objective, we wanted to determine the influence of trauma history on HPA axis function. Forty-five parous (12–24 months postpartum), euthymic women with history of MDD (n = 15), PPD (n = 15), and controls (n = 15) completed pharmacologic (dexamethasone/corticotropin-releasing hormone (CRH) test [DEX/CRH]) and psychological (Trier social stress test [TSST]) challenges during the luteal phase. Outcome measures were cortisol and adrenocorticotropic hormone (ACTH) response after DEX/CRH, and blood pressure, heart rate, epinephrine, norepinephrine, and cortisol response during the TSST. All groups had robust cortisol and ACTH response to DEX/CRH and cortisol response to TSST. Groups did not differ significantly in cortisol or ACTH response to DEX/CRH or in blood pressure, heart rate, epinephrine, norepinephrine, or cortisol response to TSST. Cortisol/ACTH ratio did not differ significantly between groups. Trauma history was associated with decreased cortisol response to DEX/CRH in women with histories of MDD, which was not significant after correction (F8,125, p = 0.02, Greenhouse-Geisser corrected p = 0.11). Currently euthymic women with histories of MDD or PPD did not demonstrate residual abnormal stress responsivity following administration of either a pharmacologic or psychological stressor

Bathymetric and longitudinal distribution analyysis of the rockfish Helicolenus Dactylopterus (Delaroche, 1809) in the southern Tyrrhenian Sea (central Mediterranean)

This study provides information on bathymetric and longitudinal distribution heterogeneity of the rockfish Helicolenus dactylopterus in the southern Tyrrhenian Sea. Data were drawn from experimental bottom trawl (1996-2002) plus bottom trap (2001-02) surveys. The frequency of occurrence and mean relative density (N/km2) and biomass (kg/km2) indexes were calculated for two survey seasons (spring and autumn), four geographic sectors and three depth strata. MANOVA was used to test fish abundance among years, sectors and strata. Analysis of the length-frequency distributions was carried out by two-way (gears and depths) ANOVA, post hoc multiple comparisons for testing differences among depths and Student’s t test for testing differences between gears. Length-weight relationship was also estimated and the allometric coefficient was tested with the Student’s t test. The results showed a significant positive bathymetric gradient of sizes both for trawl and trap surveys; at same depths, fish caught by traps were significantly longer than those caught by trawl. In spring surveys, significant differences were found among strata for both abundance indexes; in autumn surveys, significant differences between depth strata were found only for density indices. The distribution and abundance patterns of H. dactylopterus along the southern Tyrrhenian Sea was homogeneous among sectors. Length-weight relationship showed a significant positive allometric growth

Large-Scale Investment in Science: Economic Impact and Social Justice

Abstract Science is not a free lunch. Worldwide, R&D expenditures per year, from basic research to product development by firms, are about USD1.7 trillion (according to UNESCO estimates for 2017). There are perhaps 7.8 million professional researchers globally, around one researcher out of one thousand inhabitants of the planet. In the OECD area, which includes the most developed economies, government R&D spending is worth about USD 315 billion per year and the share of government of the total R&D expenditures is 28%. Hence, citizens support research in two ways: firstly, as consumers by paying a price for goods and services which in turn include in their production costs such expenditures; secondly, by paying taxes which support government R&D expenditures, mostly for basic science. In this short essay, I discuss two questions: What is the economic impact of basic research? What are the implications for social justice of the interplay between -on one side- government funded science and -on the other side- R&D supported by business? I will argue that the ultimate economic impact of large-scale investment in basic research is often (but not always) positive (i.e. benefits are greater than costs). There is, however, a potential concern for social justice arising from the private appropriation by business of rents arising from knowledge as a public good