Tihonov theory and center manifolds for inhibitory mechanisms in enzyme kinetics

Abstract In this paper we study the chemical reaction of inhibition, determine the appropriate parameter ε for the application of Tihonov's Theorem, compute explicitly the equations of the center manifold of the system and find sufficient conditions to guarantee that in the phase space the curves which relate the behavior of the complexes to the substrates by means of the tQSSA are asymptotically equivalent to the center manifold of the system. Some numerical results are discussed

Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia

Treatment-resistant schizophrenia (TRS) or suboptimal response to antipsychotics affects almost 30% of schizophrenia (SCZ) patients, and it is a relevant clinical issue with significant impact on the functional outcome and on the global burden of disease. Among putative novel treatments, glycine-centered therapeutics (i.e. sarcosine, glycine itself, D-Serine, and bitopertin) have been proposed, based on a strong preclinical rationale with, however, mixed clinical results. Therefore, a better appraisal of glycine interaction with the other major players of SCZ pathophysiology and specifically in the framework of dopamine – glutamate interactions is warranted. New methodological approaches at cutting edge of technology and drug discovery have been applied to study the role of glycine in glutamate signaling, both at presynaptic and post-synaptic level and have been instrumental for unveiling the role of glycine in dopamine-glutamate interaction. Glycine is a non-essential amino acid that plays a critical role in both inhibitory and excitatory neurotransmission. In caudal areas of central nervous system (CNS), such as spinal cord and brainstem, glycine acts as a powerful inhibitory neurotransmitter through binding to its receptor, i.e. the Glycine Receptor (GlyR). However, glycine also works as a co-agonist of the N-Methyl-D-Aspartate receptor (NMDAR) in excitatory glutamatergic neurotransmission. Glycine concentration in the synaptic cleft is finely tuned by glycine transporters, i.e. GlyT1 and GlyT2, that regulate the neurotransmitter's reuptake, with the first considered a highly potential target for psychosis therapy. Reciprocal regulation of dopamine and glycine in forebrain, glycine modulation of glutamate, glycine signaling interaction with postsynaptic density proteins at glutamatergic synapse, and human genetics of glycinergic pathways in SCZ are tackled in order to highlight the exploitation of this neurotransmitters and related molecules in SCZ and TRS

Long-term efficacy and tolerability of intranasal fentanyl in the treatment of breakthrough cancer pain

Purpose: The aim of the present study was to assess the long-term tolerability and efficacy of intranasal fentanyl (INFS) in opioid-tolerant patients with breakthrough cancer pain (BTP).Patients and methods: A 6 months, observational, prospective, cohort study design was employed to follow advanced cancer patients with BTP receiving INFS under routine clinical practice. Eligible adult cancer patients suffering from BTP had been prescribed INFS at effective doses. Data were collected at T0 and at month intervals for six months. The principal outcomes were the evaluation of possible serious adverse effects with prolonged use of INFS, the efficacy of BTP treatment with INFS, the quality of sleep, the rate of INFS discontinuation, and reasons for that.Results: Seventy-five patients were surveyed. Thirty-four patients (45.3 %) had a follow-up at 3 months, and twelve patients (16 %) were followed up at 6 months. The mean opioid doses, expressed as oral morphine equivalents, ranged 111\u2013180 mg/day, while the mean INFS doses were 87\u2013119 \u3bcg. Adverse effects were reported in a minority of patients and were considered to be associated with opioid therapy used for background pain. The quality of sleep significantly improved during the first 3\u20134 months. Finally, efficacy based on a general impression regarding the efficacy of INFS was good-excellent in most patients and statistically improved in time up to the third month.Conclusion: The long-term use of INFS in advanced cancer patients is effective and safe. No serious adverse effects were found up to six months of assessment. The level of quality of sleep and patients\u2019 satisfaction was relatively good, considering the advanced stage of disease

Statistical analysis of probability density functions for photometric redshifts through the KiDS-ESO-DR3 galaxies

Despite the high accuracy of photometric redshifts (zphot) derived using Machine Learning (ML) methods, the quantification of errors through reliable and accurate Probability Density Functions (PDFs) is still an open problem. First, because it is difficult to accurately assess the contribution from different sources of errors, namely internal to the method itself and from the photometric features defining the available parameter space. Second, because the problem of defining a robust statistical method, always able to quantify and qualify the PDF estimation validity, is still an open issue. We present a comparison among PDFs obtained using three different methods on the same data set: two ML techniques, METAPHOR (Machine-learning Estimation Tool for Accurate PHOtometric Redshifts) and ANNz2, plus the spectral energy distribution template fitting method, BPZ. The photometric data were extracted from the KiDS (Kilo Degree Survey) ESO Data Release 3, while the spectroscopy was obtained from the GAMA (Galaxy and Mass Assembly) Data Release 2. The statistical evaluation of both individual and stacked PDFs was done through quantitative and qualitative estimators, including a dummy PDF, useful to verify whether different statistical estimators can correctly assess PDF quality. We conclude that, in order to quantify the reliability and accuracy of any zphot PDF method, a combined set of statistical estimators is required.Comment: Accepted for publication by MNRAS, 20 pages, 14 figure

Metasurface dome for above-the-horizon grating lobes reduction in 5G-NR systems

The use of fifth-generation (5G) new radio (NR) spectrum around 26 GHz is currently raising the quest on its compatibility with the well-established Earth exploration-satellite service, which may be blinded by the spurious radiation emitted above the horizon (AtH) by base station (BS) antennas. Indeed, AtH grating lobes are often present during cell scanning due to the large interelement spacing in BS array antennas for achieving higher gains with a reduced number of RF chains. In this letter, we propose an approach based on an electrically thin metasurface-based dome for the reduction of AtH grating lobes in 5G-NR BS antennas. The proposed scanning range shifting approach exploits the natural lower amplitude of the grating lobes when the antenna array scans in an angular region closer to the broadside direction. The grating lobe reduction is here demonstrated considering a 1x4 phased linear antenna array operating under dual-liner +/- 45 degrees-slant polarization. A simple design procedure for designing the metasurface dome is reported, together with the antenna performances, evaluated through a proper set of numerical experiments. It is shown that the grating lobe radiation toward the satellite region is significantly reduced, whereas the overall insertion loss is moderate

Guselkumab for treatment of moderate-to-severe plaque psoriasis: real-life effectiveness and drug-survival for up to 148 weeks

Background: Real-world data are useful to guide the management of psoriasis. Here, we present data on the effectiveness and survival of guselkumab in moderate-to-severe chronic plaque psoriasis for up to 148 weeks. Research design and methods: Cross-sectional study of 122 patients receiving guselkumab (100 mg at weeks 0 and 4, and then every 8 weeks thereafter) for>12 weeks, from November 2018 to April 2022. Main outcome measures: Clinical features and drug survival were analyzed up to 148 weeks. Results: Obese patients (32.8%) and those receiving prior biologics (64.8%) were included. Guselkumab treatment was associated with a rapid decrease in PASI, from 16.2 to 3.2 at week 12, and long-term improvements in all subgroups (97.6%, 82.9%, and 63.4% of patients, respectively, achieved PASI 75, 90, and 100 after 148 weeks). More non-obese than obese patients achieved PASI 100 at week 148 (86.4% vs 38.9%), as did bio-naïve vs bio-experienced patients (86.7% vs 50.0%). Previous biologic therapy was a negative prognostic factor for achieving PASI 100 over the long-term by multivariate analysis (p = 0.005). Overall, 96% of patients were on treatment after 2 years. Conclusions: Real-world data confirm the long-term effectiveness of guselkumab in patients with psoriasis

Enhanced epidemiological surveillance of influenza A(H1N1)v in Italy.

As of 7 July 2009, a total of 158 laboratory-confirmed cases of influenza A(H1N1)v were reported in Italy, from half of the 21 Italian regions. To date all cases have had symptoms consistent with seasonal influenza and no severe or fatal cases have been reported. An active surveillance of cases has been set up in Italy in order to undertake appropriate measures to slow down the spread of the new virus. This report describes the routine and enhanced surveillance currently ongoing in Italy

DAMEWARE - Data Mining & Exploration Web Application Resource

Astronomy is undergoing through a methodological revolution triggered by an unprecedented wealth of complex and accurate data. DAMEWARE (DAta Mining & Exploration Web Application and REsource) is a general purpose, Web-based, Virtual Observatory compliant, distributed data mining framework specialized in massive data sets exploration with machine learning methods. We present the DAMEWARE (DAta Mining & Exploration Web Application REsource) which allows the scientific community to perform data mining and exploratory experiments on massive data sets, by using a simple web browser. DAMEWARE offers several tools which can be seen as working environments where to choose data analysis functionalities such as clustering, classification, regression, feature extraction etc., together with models and algorithms

Hierarchical large-scale elastic metamaterials for passive seismic wave mitigation

Large scale elastic metamaterials have recently attracted increasing interest in the scientific community for their potential as passive isolation structures for seismic waves. In particular, so-called "seismic shields"have been proposed for the protection of large areas where other isolation strategies (e.g. dampers) are not workable solutions. In this work, we investigate the feasibility of an innovative design based on hierarchical design of the unit cell, i.e. a structure with a self-similar geometry repeated at different scales. Results show how the introduction of hierarchy allows the conception of unit cells exhibiting reduced size with respect to the wavelength while maintaining the same or improved isolation efficiency at frequencies of interest for earthquake engineering. This allows to move closer to the practical realization of such seismic shields, where low-frequency operation and acceptable size are both essential characteristics for feasibility

Efficient photochemical synthesis of peptide-α-phenylthioesters

Low yields and substantial epimerization of peptide-α-thioesters often compromise the overall efficiency of native chemical ligation (NCL). Peptide arylthioesters are more reactive than peptide alkylthioesters in NCL, but are also more difficult to handle due to their propensity to hydrolyze, and are therefore often generated in situ. However, pre-prepared peptide arylthioesters are required for some NCL applications. Here we present a 7-nitroindoline-based photochemical method that generates protected peptide phenylthioesters under neutral reaction conditions via their activated esters from photoreactive peptide precursors in high isolated yields, and with low levels of epimerization. This method is fully compatible with Fmoc-strategy solid-phase peptide synthesis. Global deprotection with trifluoroacetic acid furnishes peptide phenylthioesters for NCL. Photoreactive peptide precursors can also be converted into their hydrazides in two steps by this method