Just enough inflation: power spectrum modifications at large scales

We show that models of `just enough' inflation, where the slow-roll evolution lasted only $50-60$ e-foldings, feature modifications of the CMB power spectrum at large angular scales. We perform a systematic and model-independent analysis of any possible non-slow-roll background evolution prior to the final stage of slow-roll inflation. We find a high degree of universality since most common backgrounds like fast-roll evolution, matter or radiation-dominance give rise to a power loss at large angular scales and a peak together with an oscillatory behaviour at scales around the value of the Hubble parameter at the beginning of slow-roll inflation. Depending on the value of the equation of state parameter, different pre-inflationary epochs lead instead to an enhancement of power at low-$\ell$, and so seem disfavoured by recent observational hints for a lack of CMB power at $\ell\lesssim 40$. We also comment on the importance of initial conditions and the possibility to have multiple pre-inflationary stages.Comment: 31 pages, 13 figure

Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants.

AbstractAn increasing rate of antidepressant trials fail due to large placebo responses. This analysis aimed to identify variables influencing signal detection in clinical trials of major depressive disorder. Patient-level data of randomized patients with a duloxetine dose ≥60 mg/day were obtained from Lilly. Total scores of the Hamilton Depression Rating scale (HAM-D) were used as efficacy endpoints. In total, 4661 patients from 14 studies were included in the analysis. The overall effect size (ES), based on the HAM-D total score at endpoint, between duloxetine and placebo was −0.272. Although no statistically significant interactions were found, the following results for factors influencing ES were seen: a very low ES (−0.157) in patients in the lowest baseline HAM-D category and in patients recruited in the last category of the recruitment period (−0.122). A higher ES in patients recruited in centers with a site-size at but not more than 2.5 times the average site-size for the study (−0.345). Study characteristics that resulted in low signal detection in our database were: 5 points, a high variability of placebo response (SD > 7 points HAM-D), >6 post baseline visits per study, and use of an active control drug. Simpler trial designs, more homogeneous and mid-sized study sites, a primary analysis based on a higher cutoff blinded to investigators to avoid the influence of score inflation in mild patients and, if possible, studies without an active control group could lead to a better signal detection of antidepressive efficacy

From band insulator to Mott insulator in one dimension

We derive the phase diagram for the one-dimensional model of a ferroelectric perovskite recently introduced by Egami, Ishihara and Tachiki [Science, {\bf 261}, 1307 (1993)]. We show that the interplay between covalency, ionicity and strong correlations results in a spontaneously dimerized phase which separates the weak-coupling band insulator from the strong-coupling Mott insulator. The transition from the band insulator to the dimerized phase is identified as an Ising critical point. The charge gap vanishes at this single point with the optical conductivity diverging as $\sigma(\omega)\sim \omega^{-3/4}$. The spin excitations are gapless above the second transition to the Mott insulator phase.Comment: 4 pages LaTex (RevTex) and 1 postscript figure included by eps

Behind the Mirror: Chirality Tunes the Reactivity and Cytotoxicity of Chloropiperidines as Potential Anticancer Agents

The pressing demand for sustainable antitumor drugs prompted us to investigate 3-chloropiperidines as potential mustard-based anticancer agents. In this study, an explorative set of variously decorated monofunctional 3-chloropiperidines (M-CePs) was efficiently synthesized through a fast and affordable route providing high yields of pure racemates and enantiomers. Consistently with their reactivity, M-CePs were demonstrated to alkylate DNA in vitro. On a panel of carcinoma cell lines, M-CePs exhibited low nanomolar cytotoxicity indexes, which showed their remarkable activity against pancreatic cancer cells and in all cases performed strikingly better than the chlorambucil control. Very interestingly, stereochemistry modulated the activity of M-CePs in unexpected ways, pointing to additional molecular mechanisms of action beyond the direct damage of genomic DNA. This encouraging combination of efficacy and sustainability suggests they are valid candidates for anticancer agent development

Temporal orienting in Parkinson's disease

Temporal orienting of attention can affect multiple stages of processing to guide adaptive behaviour. We tested whether temporal expectation in different task contexts is compromised in individuals with Parkinson's disease (PD). In Experiment 1 two temporal-orienting tasks were used: a speeded task emphasizing motor preparation and a non-speeded task emphasizing perceptual discrimination using rapid serial visual presentation. In both tasks, auditory cues indicated the likelihood of a target appearing after a short or long interval. In the speeded-response task, participants used the cues to anticipate an easily detectable target stimulus. In the non-speeded perceptual-discrimination task, participants used the cues to help discriminate a target letter embedded in a stream of letters. Relative to healthy participants, participants with PD did not show altered temporal orienting effects in the speeded-response task. However, they were impaired in using temporal cues to improve perceptual discrimination. In Experiment 2, we tested whether the temporal-orienting deficits in the perceptual-discrimination task depended on the requirement to ignore temporally distracting stimuli. We replicated the impaired temporal orienting for perceptual discrimination in an independent group of individuals with PD, and showed the impairment was abolished when individuals were on their dopaminergic medication. In a task without any distracting letters, however, patients off or on medication benefited normally from temporal orienting cues. Our findings suggest that deficits in temporal orienting in individuals with PD interact with specific task demands, such as the requirement to select target from temporally competing distractors

Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality

A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor Nuclear Matrix Protein 4 (Nmp4, Zfp384, Ciz, ZNF384) respond to several classes of osteoporosis drugs with enhanced bone formation compared to wild type (WT) animals. Nmp4-/- mesenchymal stem/progenitor cells (MSPCs) exhibit an accelerated and enhanced mineralization during osteoblast differentiation. To address the mechanisms underlying this hyper-anabolic phenotype, we carried out RNA-sequencing and molecular and cellular analyses of WT and Nmp4-/- MSPCs during osteogenesis to define pathways and mechanisms associated with elevated matrix production. We determined that Nmp4 has a broad impact on the transcriptome during osteogenic differentiation, contributing to the expression of over 5,000 genes. Phenotypic anchoring of transcriptional data was performed for the hypothesis-testing arm through analysis of cell metabolism, protein synthesis and secretion, and bone material properties. Mechanistic studies confirmed that Nmp4-/- MSPCs exhibited an enhanced capacity for glycolytic conversion- a key step in bone anabolism. Nmp4-/- cells showed elevated collagen translation and secretion. Expression of matrix genes that contribute to bone material-level mechanical properties were elevated in Nmp4-/- cells, an observation that was supported by biomechanical testing of bone samples from Nmp4-/- and WT mice. We conclude that loss of Nmp4 increases the magnitude of glycolysis upon the metabolic switch, which fuels the conversion of the osteoblast into a super-secretor of matrix resulting in more bone with improvements in intrinsic quality

How typhoons trigger turbidity currents in submarine canyons

Intense turbidity currents occur in the Malaylay Submarine Canyon off the northern coast of Mindoro Island in the Philippines. They start in very shallow waters at the shelf break and reach deeper waters where a gas pipeline is located. The pipeline was displaced by a turbidity current in 2006 and its rock berm damaged by another 10 years later. Here we propose that they are triggered near the mouth of the Malaylay and Baco rivers by direct sediment resuspension in the shallow shelf and transport to the canyon heads by typhoon-induced waves and currents. We show these rivers are unlikely to generate hyperpycnal flows and trigger turbidity currents by themselves. Characteristic signatures of turbidity currents, in the form of bed shear stress obtained by numerical simulations, match observed erosion/deposition and rock berm damage patterns recorded by repeat bathymetric surveys before and after typhoon Nock-ten in December 2016. Our analysis predicts a larger turbidity current triggered by typhoon Durian in 2006; and reveals the reason for the lack of any significant turbidity current associated with typhoon Melor in December 2015. Key factors to assess turbidity current initiation are typhoon proximity, strength, and synchronicity of typhoon induced waves and currents. Using data from a 66-year hindcast we estimate a ~8-year return period of typhoons with capacity to trigger large turbidity currents