Towards Parsimonious Generative Modeling of RNA Families

Generative probabilistic models emerge as a new paradigm in data-driven, evolution-informed design of biomolecular sequences. This paper introduces a novel approach, called Edge Activation Direct Coupling Analysis (eaDCA), tailored to the characteristics of RNA sequences, with a strong emphasis on simplicity, efficiency, and interpretability. eaDCA explicitly constructs sparse coevolutionary models for RNA families, achieving performance levels comparable to more complex methods while utilizing a significantly lower number of parameters. Our approach demonstrates efficiency in generating artificial RNA sequences that closely resemble their natural counterparts in both statistical analyses and SHAPE-MaP experiments, and in predicting the effect of mutations. Notably, eaDCA provides a unique feature: estimating the number of potential functional sequences within a given RNA family. For example, in the case of cyclic di-AMP riboswitches (RF00379), our analysis suggests the existence of approximately $\mathbf{10^{39}}$ functional nucleotide sequences. While huge compared to the known $< \mathbf{4,000}$ natural sequences, this number represents only a tiny fraction of the vast pool of nearly $\mathbf{10^{82}}$ possible nucleotide sequences of the same length (136 nucleotides). These results underscore the promise of sparse and interpretable generative models, such as eaDCA, in enhancing our understanding of the expansive RNA sequence space.Comment: 33 pages (including SI

Fluctuation theorems for harmonic oscillators

We study experimentally the thermal fluctuations of energy input and dissipation in a harmonic oscillator driven out of equilibrium, and search for Fluctuation Relations. We study transient evolution from the equilibrium state, together with non equilibrium steady states. Fluctuations Relations are obtained experimentally for both the work and the heat, for the stationary and transient evolutions. A Stationary State Fluctuation Theorem is verified for the two time prescriptions of the torque. But a Transient Fluctuation Theorem is satisfied for the work given to the system but not for the heat dissipated by the system in the case of linear forcing. Experimental observations on the statistical and dynamical properties of the fluctuation of the angle, we derive analytical expressions for the probability density function of the work and the heat. We obtain for the first time an analytic expression of the probability density function of the heat. Agreement between experiments and our modeling is excellent

La fauna asociada a Tubularia crocea (Agassiz, 1862) (anthomedusae; tubulariidae) y la aplicación de un método de cartificación

A systematic list of the organisms found on the polyps of T. crocea is presented. Monthly samples from the coast of Mar del Plata (38°03'S ; 57°31'W) allowed the analysis of the dynamic of the associations, specially with picnogonids, amphipods, annelids and nematodes, which varied in composition and abundance along of year. We present a modification of a mapping model of Marfenin (1980) and its use to present the different stages of the polyps and the localization of the associated organisms.Se presenta un listado sistemático de los organismos hallados sobre los pólipos de T. creocea. Muestras mensuales obtenidas en la costa de Mar del Plata (38°O8'S ; 57°31'W) permitieron el análisis de la dinámica de las asociaciones, especialmente con picnogónidos, anfípodos, anélidos y nemátodos, las cuales variaron en composición y abundancia a través del año. Nosotros presentamos una modificación del modelo de cartificación de Marfenin (1980) y su uso para representar distintos estados de los pólipos y la localización de los organismos asociados

Fluctuation relations and coarse-graining

We consider the application of fluctuation relations to the dynamics of coarse-grained systems, as might arise in a hypothetical experiment in which a system is monitored with a low-resolution measuring apparatus. We analyze a stochastic, Markovian jump process with a specific structure that lends itself naturally to coarse-graining. A perturbative analysis yields a reduced stochastic jump process that approximates the coarse-grained dynamics of the original system. This leads to a non-trivial fluctuation relation that is approximately satisfied by the coarse-grained dynamics. We illustrate our results by computing the large deviations of a particular stochastic jump process. Our results highlight the possibility that observed deviations from fluctuation relations might be due to the presence of unobserved degrees of freedom.Comment: 19 pages, 6 figures, very minor change

Replica analysis of the generalized p-spin interaction glass model

We investigate stability of replica symmetry breaking solutions in generalized $p$-spin models. It is shown that the kind of the transition to the one-step replica symmetry breaking state depends not only on the presence or absence of the reflection symmetry of the generalized "spin"-operators $\hat{U}$ but on the number of interacting operators and their individual characteristics.Comment: 14 pages, 1 figur

Environmental impacts and risk assessment in the re-use of Cr-bearing pyrolyzed tannery wastes: A case study in a residential area

Increasing concern has been raised on the environmental impacts of chromium -tanning wastes recycling. In particular, the pyrolytic conversion of leather industry sludges into Cr(VI)-free carbonized residues is believed to represent a viable route for a sustainable re -use of this type of wastes. The aim of this study was to determine the impact of recycled Cr-bearing pyrolyzed char (named KEU) as backfilling material for road construction in an urban area in Tuscany (Italy). Geochemical and chromium -isotope data, together with microstructural analyses (HR-TEM and XAS), indicate that the presence of KEU results in a significant enhancement of the natural Cr background. The results support the hypothesis that, in environmental conditions, the Cr (III) hosted in KEU is converted into Cr(VI), which is leached out by rainwater. Indeed, Cr(VI) is dispersed in surface water, reaching concentrations up to 18 mg/L and it also occurs in coatings on the surface gravel of unpaved roads. The 53 Cr/ 52 Cr ratio measured in KEU, reported in delta 53 Cr notation, was in the restricted range delta 53 Cr = - 0.031 +/- 0.057 %o ; on the contrary, the delta 53 Cr in water varied between + 1.581 +/- 0.038 %o and + 3.261 +/- 0.191 %o , indicating the reduction of Cr(VI) after the pristine oxidative mobilization. The risk -based soil screening levels (SSLs) for total Cr are well above the concentration measured in soil for all the exposure pathways. On the contrary, the SSL for Cr(VI)indicates that soil contamination poses health hazards for residents

Analgesic Effect of a Mixed T-Type Channel Inhibitor/CB2 Receptor Agonist

Background: Cannabinoid receptors and T-type calcium channels are potential targets for treating pain. Here we report on the design, synthesis and analgesic properties of a new mixed cannabinoid/T-type channel ligand, NMP-181. Results: NMP-181 action on CB1 and CB2 receptors was characterized in radioligand binding and in vitro GTP gamma[S-35] functional assays, and block of transiently expressed human Cav3.2 T-type channels by NMP-181 was analyzed by patch clamp. The analgesic effects and in vivo mechanism of action of NMP-181 delivered spinally or systemically were analyzed in formalin and CFA mouse models of pain. NMP-181 inhibited peak Ca(V)3.2 currents with IC50 values in the low micromolar range and acted as a CB2 agonist. Inactivated state dependence further augmented the inhibitory action of NMP-181. NMP-181 produced a dose-dependent antinociceptive effect when administered either spinally or systemically in both phases of the formalin test. Both i.t. and i.p. treatment of mice with NMP-181 reversed the mechanical hyperalgesia induced by CFA injection. NMP-181 showed no antinocieptive effect in Ca(V)3.2 null mice. The antinociceptive effect of intrathecally delivered NMP-181 in the formalin test was reversed by i.t. treatment of mice with AM-630 (CB2 antagonist). In contrast, the NMP-181-induced antinociception was not affected by treatment of mice with AM-281 (CB1 antagonist). Conclusions: Our work shows that both T-type channels as well as CB2 receptors play a role in the antinociceptive action of NMP-181, and also provides a novel avenue for suppressing chronic pain through novel mixed T-type/cannabinoid receptor ligands

NMP-7 inhibits chronic inflammatory and neuropathic pain via block of Cab3.2 T-type calcium channels and activation of CB2 receptors

Background: T-type calcium channels and cannabinoid receptors are known to play important roles in chronic pain, making them attractive therapeutic targets. We recently reported on the design, synthesis and analgesic properties of a novel T-type channel inhibitor (NMP-7), which also shows mixed agonist activity on CB1 and CB2 receptors in vitro. Here, we analyzed the analgesic effect of systemically delivered NMP-7 (intraperitoneal (i.p.) or intragstric (i.g.) routes) on mechanical hypersensitivity in inflammatory pain induced by Complete Freund’s Adjuvant (CFA) and neuropathic pain induced by sciatic nerve injury. Results: NMP-7 delivered by either i.p. or i.g. routes produced dose-dependent inhibition of mechanical hyperalgesia in mouse models of inflammatory and neuropathic pain, without altering spontaneous locomotor activity in the open-field test at the highest active dose. Neither i.p. nor i.g. treatment reduced peripheral inflammation per se, as evaluated by examining paw edema and myeloperoxidase activity. The antinociception produced by NMP-7 in the CFA test was completely abolished in CaV3.2-null mice, confirming CaV3.2 as a key target. The analgesic action of intraperitoneally delivered NMP-7 was not affected by pretreatment of mice with the CB1 antagonist AM281, but was significantly attenuated by pretreatment with the CB2 antagonist AM630, suggesting that CB2 receptors, but not CB1 receptors are involved in the action of NMP-7 in vivo. Conclusions: Overall, our work shows that NMP-7 mediates a significant analgesic effect in a model of persistent inflammatory and chronic neuropathic pain by way of T-type channel modulation and CB2 receptor activation. Thus, this study provides a novel therapeutic avenue for managing chronic pain conditions via mixed CB ligands/ T-type channel blockers

Chaotic Hypothesis, Fluctuation Theorem and singularities

The chaotic hypothesis has several implications which have generated interest in the literature because of their generality and because a few exact predictions are among them. However its application to Physics problems requires attention and can lead to apparent inconsistencies. In particular there are several cases that have been considered in the literature in which singularities are built in the models: for instance when among the forces there are Lennard-Jones potentials (which are infinite in the origin) and the constraints imposed on the system do not forbid arbitrarily close approach to the singularity even though the average kinetic energy is bounded. The situation is well understood in certain special cases in which the system is subject to Gaussian noise; here the treatment of rather general singular systems is considered and the predictions of the chaotic hypothesis for such situations are derived. The main conclusion is that the chaotic hypothesis is perfectly adequate to describe the singular physical systems we consider, i.e. deterministic systems with thermostat forces acting according to Gauss' principle for the constraint of constant total kinetic energy (``isokinetic Gaussian thermostats''), close and far from equilibrium. Near equilibrium it even predicts a fluctuation relation which, in deterministic cases with more general thermostat forces (i.e. not necessarily of Gaussian isokinetic nature), extends recent relations obtained in situations in which the thermostatting forces satisfy Gauss' principle. This relation agrees, where expected, with the fluctuation theorem for perfectly chaotic systems. The results are compared with some recent works in the literature.Comment: 7 pages, 1 figure; updated to take into account comments received on the first versio

Z-Drugs and their use in drug-facilitated crimes: a review of the literature

Background: Z-Drugs are a category of non-benzodiazepine sedative-hypnotic drugs that include Zolpidem, Zopiclone and Zaleplon. They are all rapidly adsorbed and have a very short half- life, features that make them first-line treatment of insomnia and, in the meantime, first-choice drugs in cases of poisoning for criminal purposes. Z-drugs are frequently use in Drug Facilitated Crime cases (DFC) and Drug Facilitated Sexual Assault (DFSA), namely crimes, robberies, extortion and sexual violence committed after administration of incapacitating substances able to induce sedative-hypnotic effects. In these circumstances, the psychoactive substance is considered as a weapon and constitutes an aggravating circumstance in the criminal act: accordingly, judicial authority legitimates the analytical determination of these substances. Currently, few tests able to detect such drugs are available in daily clinical practice. Aim: The aim of this work is to evaluate the effective utilization of Z-Drugs. Methods: We have analyzed the literature, focusing on cases in which the criminal use of such incapacitating substances has been demonstrated. Relevant scientific articles were identified from PubMed, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE up to December 2022 using the following keywords: "z-drugs", "drug facilitated crime", "forensic toxicology". The resulting references were screened to exclude duplicates. In addition, non-English papers were excluded. This evaluation left 10 articles (8 case reports and 2 original studies) divided as follows: 1 case report of a DFC (robbery), 6 cases of confirmed DFSA, 3 cases of suspected DFSA, 2 original studies about DFC. Results: The totality of the selected cases showed positive toxicological tests for a single intake of z-drugs. Conclusions: This work has shown the limitations of screening tests currently in use in the emergency rooms. Forensic toxicology tests should be introduced in daily clinical practice