Involvement of gut microbiota in schizophrenia and treatment resistance to antipsychotics

The gut microbiota is constituted by more than 40, 000 bacterial species involved in key processes including high order brain functions. Altered composition of gut microbiota has been implicated in psychiatric disorders and in modulating the efficacy and safety of psychotropic medications. In this work we characterized the composition of the gut microbiota in 38 patients with schizophrenia (SCZ) and 20 healthy controls (HC), and tested if SCZ patients with different response to antipsychotics (18 patients with treatment resistant schizophrenia (TRS), and 20 responders (R)) had specific patterns of gut microbiota composition associated with different response to antipsychotics. Moreover, we also tested if patients treated with typical antipsychotics (n=20) presented significant differences when compared to patients treated with atypical antipsychotics (n=31). Our findings showed the presence of distinct composition of gut microbiota in SCZ versus HC, with several bacteria at the different taxonomic levels only present in either one group or the other. Similar findings were observed also depending on treatment response and exposure to diverse classes of antipsychotics. Our results suggest that composition of gut microbiota could constitute a biosignatures of SCZ and TRS

Exploring the role of gut microbiota in major depressive disorder and in treatment resistance to antidepressants

Major depressive disorder (MDD) is a common severe psychiatric illness, exhibiting suboptimal response to existing pharmacological treatments. Although its etiopathogenesis is still not completely understood, recent findings suggest that an altered composition of the gut microbiota might play a role. Here we aimed to explore potential differences in the composition of the gut microbiota between patients with MDD and healthy controls (HC) and to identify possible signatures of treatment response by analyzing two groups of MDD patients characterized as treatment-resistant (TR) or responders (R) to antidepressants. Stool samples were collected from 34 MDD patients (8 TR, 19 R and 7 untreated) and 20 HC. Microbiota was characterized using the 16S metagenomic approach. A penalized logistic regression analysis algorithm was applied to identify bacterial populations that best discriminate the diagnostic groups. Statistically significant differences were identified for the families of Paenibacillaceae and Flavobacteriaceaea, for the genus Fenollaria, and the species Flintibacter butyricus, Christensenella timonensis, and Eisenbergiella massiliensis among others. The phyla Proteobacteria, Tenericutes and the family Peptostreptococcaceae were more abundant in TR, whereas the phylum Actinobacteria was enriched in R patients. Moreover, a number of bacteria only characterized the microbiota of TR patients, and many others were only detected in R. Our results confirm that dysbiosis is a hallmark of MDD and suggest that microbiota of TR patients significantly differs from responders to antidepressants. This finding further supports the relevance of an altered composition of the gut microbiota in the etiopathogenesis of MDD, suggesting a role in response to antidepressants

The intergalactic medium thermal history at redshift z=1.7--3.2 from the Lyman alpha forest: a comparison of measurements using wavelets and the flux distribution

We investigate the thermal history of the intergalactic medium (IGM) in the redshift interval z=1.7--3.2 by studying the small-scale fluctuations in the Lyman alpha forest transmitted flux. We apply a wavelet filtering technique to eighteen high resolution quasar spectra obtained with the Ultraviolet and Visual Echelle Spectrograph (UVES), and compare these data to synthetic spectra drawn from a suite of hydrodynamical simulations in which the IGM thermal state and cosmological parameters are varied. From the wavelet analysis we obtain estimates of the IGM thermal state that are in good agreement with other recent, independent wavelet-based measurements. We also perform a reanalysis of the same data set using the Lyman alpha forest flux probability distribution function (PDF), which has previously been used to measure the IGM temperature-density relation. This provides an important consistency test for measurements of the IGM thermal state, as it enables a direct comparison of the constraints obtained using these two different methodologies. We find the constraints obtained from wavelets and the flux PDF are formally consistent with each other, although in agreement with previous studies, the flux PDF constraints favour an isothermal or inverted IGM temperature-density relation. We also perform a joint analysis by combining our wavelet and flux PDF measurements, constraining the IGM thermal state at z=2.1 to have a temperature at mean density of T0/[10^3 K]=17.3 +/- 1.9 and a power-law temperature-density relation exponent gamma=1.1 +/- 0.1 (1 sigma). Our results are consistent with previous observations that indicate there may be additional sources of heating in the IGM at z<4.Comment: 15 pages, 14 figures, matches version accepted for publication on MNRA

The impact of feedback from galaxy formation on the Lyman-alpha transmitted flux

The forest of Lyman-alpha absorption lines seen in the spectra of distant quasars has become an important probe of the distribution of matter in the Universe. We use large, hydrodynamical simulations from the OWLS project to investigate the effect of feedback from galaxy formation on the probability distribution function and the power spectrum of the Lyman-alpha transmitted flux. While metal-line cooling is unimportant, both galactic outflows from massive galaxies driven by active galactic nuclei and winds from low-mass galaxies driven by supernovae have a substantial impact on the flux statistics. At redshift z=2.25, the effects on the flux statistics are of a similar magnitude as the statistical uncertainties of published data sets. The changes in the flux statistics are not due to differences in the temperature-density relation of the photo-ionised gas. Instead, they are caused by changes in the density distribution and in the fraction of hot, collisionally ionised gas. It may be possible to disentangle astrophysical and cosmological effects by taking advantage of the fact that they induce different redshift dependencies. In particular, the magnitude of the feedback effects appears to decrease rapidly with increasing redshift. Analyses of Lyman-alpha forest data from surveys that are currently in process, such as BOSS/SDSS-III and X-Shooter/VLT, must take galactic winds into account.Comment: 15 pages, 11 figures. MNRAS in pres

Construction and Modelling of an Inducible Positive Feedback Loop Stably Integrated in a Mammalian Cell-Line

Understanding the relationship between topology and dynamics of transcriptional regulatory networks in mammalian cells is essential to elucidate the biology of complex regulatory and signaling pathways. Here, we characterised, via a synthetic biology approach, a transcriptional positive feedback loop (PFL) by generating a clonal population of mammalian cells (CHO) carrying a stable integration of the construct. The PFL network consists of the Tetracycline-controlled transactivator (tTA), whose expression is regulated by a tTA responsive promoter (CMV-TET), thus giving rise to a positive feedback. The same CMV-TET promoter drives also the expression of a destabilised yellow fluorescent protein (d2EYFP), thus the dynamic behaviour can be followed by time-lapse microscopy. The PFL network was compared to an engineered version of the network lacking the positive feedback loop (NOPFL), by expressing the tTA mRNA from a constitutive promoter. Doxycycline was used to repress tTA activation (switch off), and the resulting changes in fluorescence intensity for both the PFL and NOPFL networks were followed for up to 43 h. We observed a striking difference in the dynamics of the PFL and NOPFL networks. Using non-linear dynamical models, able to recapitulate experimental observations, we demonstrated a link between network topology and network dynamics. Namely, transcriptional positive autoregulation can significantly slow down the “switch off” times, as comparared to the nonautoregulatated system. Doxycycline concentration can modulate the response times of the PFL, whereas the NOPFL always switches off with the same dynamics. Moreover, the PFL can exhibit bistability for a range of Doxycycline concentrations. Since the PFL motif is often found in naturally occurring transcriptional and signaling pathways, we believe our work can be instrumental to characterise their behaviour

A White Paper on keV Sterile Neutrino Dark Matter

We present a comprehensive review of keV-scale sterile neutrino Dark Matter,collecting views and insights from all disciplines involved - cosmology,astrophysics, nuclear, and particle physics - in each case viewed from boththeoretical and experimental/observational perspectives. After reviewing therole of active neutrinos in particle physics, astrophysics, and cosmology, wefocus on sterile neutrinos in the context of the Dark Matter puzzle. Here, wefirst review the physics motivation for sterile neutrino Dark Matter, based onchallenges and tensions in purely cold Dark Matter scenarios. We then round outthe discussion by critically summarizing all known constraints on sterileneutrino Dark Matter arising from astrophysical observations, laboratoryexperiments, and theoretical considerations. In this context, we provide abalanced discourse on the possibly positive signal from X-ray observations.Another focus of the paper concerns the construction of particle physicsmodels, aiming to explain how sterile neutrinos of keV-scale masses could arisein concrete settings beyond the Standard Model of elementary particle physics.The paper ends with an extensive review of current and future astrophysical andlaboratory searches, highlighting new ideas and their experimental challenges,as well as future perspectives for the discovery of sterile neutrinos

A White Paper on keV sterile neutrino Dark Matter

We present a comprehensive review of keV-scale sterile neutrino Dark Matter, collecting views and insights from all disciplines involved—cosmology, astrophysics, nuclear, and particle physics—in each case viewed from both theoretical and experimental/observational perspectives. After reviewing the role of active neutrinos in particle physics, astrophysics, and cosmology, we focus on sterile neutrinos in the context of the Dark Matter puzzle. Here, we first review the physics motivation for sterile neutrino Dark Matter, based on challenges and tensions in purely cold Dark Matter scenarios. We then round out the discussion by critically summarizing all known constraints on sterile neutrino Dark Matter arising from astrophysical observations, laboratory experiments, and theoretical considerations. In this context, we provide a balanced discourse on the possibly positive signal from X-ray observations. Another focus of the paper concerns the construction of particle physics models, aiming to explain how sterile neutrinos of keV-scale masses could arise in concrete settings beyond the Standard Model of elementary particle physics. The paper ends with an extensive review of current and future astrophysical and laboratory searches, highlighting new ideas and their experimental challenges, as well as future perspectives for the discovery of sterile neutrinos