The PDK1-Rsk signaling pathway controls Langerhans cell proliferation and patterning

Langerhans cells (LC), the dendritic cells of the epidermis, are distributed in a distinctive regularly spaced array. In the mouse, the LC array is established in the first few days of life from proliferating local precursors, but the regulating signaling pathways are not fully understood. We found that mice lacking the kinase phosphoinositide-dependent kinase 1 selectively lack LC. Deletion of the phosphoinositide-dependent kinase 1 target kinases, ribosomal S6 kinase 1 (Rsk1) and Rsk2, produced a striking perturbation in the LC network: LC density was reduced 2-fold, but LC size was increased by the same magnitude. Reduced LC numbers in Rsk1/2?/? mice was not due to accelerated emigration from the skin but rather to reduced proliferation at least in adults. Rsk1/2 were required for normal LC patterning in neonates, but not when LC were ablated in adults and replaced by bone marrow–derived cells. Increased LC size was an intrinsic response to reduced LC numbers, reversible on LC emigration, and could be observed in wild type epidermis where LC size also correlated inversely with LC density. Our results identify a key signaling pathway needed to establish a normal LC network and suggest that LC might maintain epidermal surveillance by increasing their “footprint” when their numbers are limite

Amplifier spurious input current components in electrode-electrolyte interface impedance measurements

BACKGROUND: In Impedance Microbiology, the time during which the measuring equipment is connected to the bipolar cells is rather long, usually between 6 to 24 hrs for microorganisms with duplication times in the order of less than one hour and concentrations ranging from 10(1 )to 10(7 )[CFU/ml]. Under these conditions, the electrode-electrolyte interface impedance may show a slow drift of about 2%/hr. By and large, growth curves superimposed on such drift do not stabilize, are less reproducible, and keep on distorting all over the measurement of the temporal reactive or resistive records due to interface changes, in turn originated in bacterial activity. This problem has been found when growth curves were obtained by means of impedance analyzers or with impedance bridges using different types of operational amplifiers. METHODS: Suspecting that the input circuitry was the culprit of the deleterious effect, we used for that matter (a) ultra-low bias current amplifiers, (b) isolating relays for the selection of cells, and (c) a shorter connection time, so that the relays were maintained opened after the readings, to bring down such spurious drift to a negligible value. Bacterial growth curves were obtained in order to test their quality. RESULTS: It was demonstrated that the drift decreases ten fold when the circuit remained connected to the cell for a short time between measurements, so that the distortion became truly negligible. Improvement due to better-input amplifiers was not as good as by reducing the connection time. Moreover, temperature effects were insignificant with a regulation of ± 0.2 [°C]. Frequency did not influence either. CONCLUSION: The drift originated either at the dc input bias offset current (I(os)) of the integrated circuits, or in discrete transistors connected directly to the electrodes immersed in the cells, depending on the particular circuit arrangement. Reduction of the connection time was the best countermeasure

The clustering of the SDSS-IV extended Baryon Oscillation Spectroscopic Survey DR14 quasar sample : anisotropic Baryon Acoustic Oscillations measurements in Fourier-space with optimal redshift weights

We present a measurement of the anisotropic and isotropic Baryon Acoustic Oscillations (BAO) from the extended Baryon Oscillation Spectroscopic Survey Data Release 14 quasar sample with optimal redshift weights. Applying the redshift weights improves the constraint on the BAO dilation parameter α(zeff) by 17%. We reconstruct the evolution history of the BAO distance indicators in the redshift rangeof 0.8 < z < 2.2. This paper is part of a set that analyses the eBOSS DR14 quasar sample.PostprintPeer reviewe

Application of a stochastic modeling to evaluate tuberculosis onset in patients treated with tumor necrosis factor inhibitors

In this manuscript we apply stochastic modeling to investigate the risk of reactivation of latent mycobacterial infections in patients undergoing treatment with tumor necrosis factor inhibitors. First, we review the perspective proposed by one of the authors in a previous work and which consists in predicting the occurrence of reactivation of latent tuberculosis infection or newly acquired tuberculosis during treatment; this is based on variational procedures on a simple set of parameters (e.g. rate of reactivation of a latent infection). Then, we develop a full analytical study of this approach through a Markov chain analysis and we find an exact solution for the temporal evolution of the number of cases of tuberculosis infection (re)activation. The analytical solution is compared with Monte Carlo simulations and with experimental data, showing overall excellent agreement. The generality of this theoretical framework allows to investigate also the case of non-tuberculous mycobacteria infections; in particular, we show that reactivation in that context plays a minor role. This may suggest that, while the screening for tuberculous is necessary prior to initiating biologics, when considering non-tuberculous mycobacteria only a watchful monitoring during the treatment is recommended. The framework outlined in this paper is quite general and could be extremely promising in further researches on drug-related adverse events.Comment: 26 pages, 7 figure

The clustering of the SDSS-IV extended Baryon Oscillation Spectroscopic Survey DR14 quasar sample : measuring the evolution of the growth rate using redshift-space distortions between redshift 0.8 and 2.2

Funding: RR and WJP acknowledge support from the European Research Council through the Darksurvey grant 614030. WJP also acknowledges support from the UK Science and Technology Facilities Council grant ST/N000668/1, and the UK Space Agency grant ST/N00180X/1. Funding for SDSS-III and SDSS-IV has been provided by the Alfred P. Sloan Foundation and Participating Institutions. Additional funding for SDSS-III comes from the National Science Foundationa nd the U.S. Department of Energy Office of Science.We measure the growth rate and its evolution using the anisotropic clustering of the extended Baryon Oscillation Spectroscopic Survey (eBOSS) Data Release 14 (DR14) quasar sample, which includes 148 659 quasars covering the wide redshift range of 0.8 < z < 2.2 and a sky area of 2112.90 deg2. To optimize measurements we deploy a redshift-dependent weighting scheme, which allows us to avoid binning and perform the data analysis consistently including the redshift evolution across the sample. We perform the analysis in Fourier space, and use the redshift evolving power spectrum multipoles to measure the redshift-space distortion parameter fσ8 and parameters controlling the anisotropic projection of the cosmological perturbations. We measure fσ8(z = 1.52) = 0.43 ± 0.05 and dfσ8/dz(z = 1.52) = -0.16 ± 0.08, consistent with the expectation for a lambda cold dark matter cosmology as constrained by the Planck experiment.Publisher PDFPeer reviewe

The clustering of the SDSS-IV extended Baryon Oscillation Spectroscopic Survey DR14 quasar sample: Anisotropic Baryon Acoustic Oscillations measurements in Fourier-space with optimal redshift weights

We present a measurement of the anisotropic and isotropic Baryon Acoustic Oscillations (BAO) from the extended Baryon Oscillation Spectroscopic Survey Data Release 14 quasar sample with optimal redshift weights. Applying the redshift weights improves the constraint on the BAO dilation parameter $\alpha(z_{\rm eff})$ by 17\%. We reconstruct the evolution history of the BAO distance indicators in the redshift range of $0.8<z<2.2$. This paper is part of a set that analyses the eBOSS DR14 quasar sample.Comment: 8 pages, 6 figures, 3 tables; This paper is part of a set that analyses the eBOSS DR14 quasar sample; MNRAS submitte

Intellectual Property, Open Science and Research Biobanks

In biomedical research and translational medicine, the ancient war between exclusivity (private control over information) and access to information is proposing again on a new battlefield: research biobanks. The latter are becoming increasingly important (one of the ten ideas changing the world, according to Time magazine) since they allow to collect, store and distribute in a secure and professional way a critical mass of human biological samples for research purposes. Tissues and related data are fundamental for the development of the biomedical research and the emerging field of translational medicine: they represent the “raw material” for every kind of biomedical study. For this reason, it is crucial to understand the boundaries of Intellectual Property (IP) in this prickly context. In fact, both data sharing and collaborative research have become an imperative in contemporary open science, whose development depends inextricably on: the opportunities to access and use data, the possibility of sharing practices between communities, the cross-checking of information and results and, chiefly, interactions with experts in different fields of knowledge. Data sharing allows both to spread the costs of analytical results that researchers cannot achieve working individually and, if properly managed, to avoid the duplication of research. These advantages are crucial: access to a common pool of pre-competitive data and the possibility to endorse follow-on research projects are fundamental for the progress of biomedicine. This is why the "open movement" is also spreading in the biobank's field. After an overview of the complex interactions among the different stakeholders involved in the process of information and data production, as well as of the main obstacles to the promotion of data sharing (i.e., the appropriability of biological samples and information, the privacy of participants, the lack of interoperability), we will firstly clarify some blurring in language, in particular concerning concepts often mixed up, such as “open source” and “open access”. The aim is to understand whether and to what extent we can apply these concepts to the biomedical field. Afterwards, adopting a comparative perspective, we will analyze the main features of the open models – in particular, the Open Research Data model – which have been proposed in literature for the promotion of data sharing in the field of research biobanks. After such an analysis, we will suggest some recommendations in order to rebalance the clash between exclusivity - the paradigm characterizing the evolution of intellectual property over the last three centuries - and the actual needs for access to knowledge. We argue that the key factor in this balance may come from the right interaction between IP, social norms and contracts. In particular, we need to combine the incentives and the reward mechanisms characterizing scientific communities with data sharing imperative

Early rise in central venous pressure during a spontaneous breathing trial: A promising test to identify patients at high risk of weaning failure?

Background The spontaneous breathing trial (SBT) assesses the risk of weaning failure by evaluating some physiological responses to the massive venous return increase imposed by discontinuing positive pressure ventilation. This trial can be very demanding for some critically ill patients, inducing excessive physical and cardiovascular stress, including muscle fatigue, heart ischemia and eventually cardiac dysfunction. Extubation failure with emergency reintubation is a serious adverse consequence of a failed weaning process. Some data suggest that as many as 50% of patients that fail weaning do so because of cardiac dysfunction. Unfortunately, monitoring cardiovascular function at the time of the SBT is complex. The aim of our study was to explore if central venous pressure (CVP) changes were related to weaning failure after starting an SBT. We hypothesized that an early rise on CVP could signal a cardiac failure when handling a massive increase on venous return following a discontinuation of positive pressure ventilation. This CVP rise could identify a subset of patients at high risk for extubation failure. Methods Two-hundred and four mechanically ventilated patients in whom an SBT wa