Nonequilibrium Response for Markov Jump Processes: Exact Results and Tight Bounds.

Generalizing response theory of open systems far from equilibrium is a central quest of nonequilibrium statistical physics. Using stochastic thermodynamics, we develop an algebraic method to study the static response of nonequilibrium steady state to arbitrary perturbations. This allows us to derive explicit expressions for the response of edge currents as well as traffic to perturbations in kinetic barriers and driving forces. We also show that these responses satisfy very simple bounds. For the response to energy perturbations, we straightforwardly recover results obtained using nontrivial graph-theoretical methods.

Thermodynamics of Growth in Open Chemical Reaction Networks.

We identify the thermodynamic conditions necessary to observe indefinite growth in homogeneous open chemical reaction networks (CRNs) satisfying mass action kinetics. We also characterize the thermodynamic efficiency of growth by considering the fraction of the chemical work supplied from the surroundings that is converted into CRN free energy. We find that indefinite growth cannot arise in CRNs chemostatted by fixing the concentration of some species at constant values, or in continuous-flow stirred tank reactors. Indefinite growth requires a constant net influx from the surroundings of at least one species. In this case, unimolecular CRNs always generate equilibrium linear growth, i.e., a continuous linear accumulation of species with equilibrium concentrations and efficiency one. Multimolecular CRNs are necessary to generate nonequilibrium growth, i.e., the continuous accumulation of species with nonequilibrium concentrations. Pseudounimolecular CRNs-a subclass of multimolecular CRNs-always generate asymptotic linear growth with zero efficiency. Our findings demonstrate the importance of the CRN topology and the chemostatting procedure in determining the dynamics and thermodynamics of growth.

Congenital heart diseases (CHDs) and forensic investigations: Searching for the cause of death.

Congenital Heart Diseases (CHDs) are a group of structural abnormalities or defects of the heart that are present at birth. CHDs could be connected to sudden death (SD), defined by the WHO (World Health Organization) as "death occurring within 24 h after the onset of the symptoms" in an apparently "healthy" subject. These conditions can range from relatively mild defects to severe, life-threatening anomalies. The prevalence of CHDs varies across populations, but they affect millions of individuals worldwide. This article aims to discuss the post-mortem investigation of death related to CHDs, exploring the forensic approach, current methodologies, challenges, and potential advancements in this challenging field. A further goal of this article is to provide a guide for understanding these complex diseases, highlighting the pivotal role of autopsy, histopathology, and genetic investigations in defining the cause of death, and providing evidence about the translational use of autopsy reports. Forensic investigations play a crucial role in understanding the complexities of CHDs and determining the cause of death accurately. Through collaboration between medical professionals and forensic experts, meticulous examinations, and analysis of evidence, valuable insights can be gained. These insights not only provide closure to the families affected but also contribute to the prevention of future tragedies.

Sudden unexpected postnatal collapse and BUB1B mutation: first forensic case report.

Sudden unexpected postnatal collapse (SUPC) is a sudden collapse of the clinical conditions of a full-term or near-term newborn, within the first 7 days of life, that requires resuscitation with positive ventilation and who either dies, has hypoxic-ischemic encephalopathy, or requires intensive care. The incidence of SUPC is very low, and most often presents a negative prognosis. The BUB1B gene is a mitotic checkpoint of serine/threonine kinase B that encodes a protein crucial for maintaining the correct number of chromosomes during cell division. Mutations in the BUB1B gene are linked to mosaic variegated aneuploidy syndrome 1 (MVA1), a rare autosomal recessive disorder characterized by diffuse mosaic aneuploidies involving several chromosomes and tissues. This paper discusses a case of a newborn who had a spontaneous delivery. After 2 h and 10 min, the infant showed generalized hypotonia and cyanosis, and his doctors performed orotracheal intubation, cardiac massage, pharmacological hemodynamic therapy, mechanical ventilation, antibiotic therapy, and hypothermic treatment. The newborn was discharged after 5 months with the diagnosis of hypoxic-ischemic encephalopathy. Suspecting an SUPC, a complete genetic analysis was performed demonstrating a compound heterozygous mutations in the BUB1B gene. The newborn died at 6 months of life, 1 month after discharge. A complete autopsy was performed, determining that the cause of death was due to sepsis starting from a brocopneumonic process, with outcomes of hypoxic-ischemic encephalopathy (HIE). In this scenario, it is not possible to demonstrate the causal effect of this mutation, considering that it could play a causal or concausal role in the onset of SUPC. Further research based on multicenter studies, as well as on animal models, could be very useful to clarify the pathological effect of this mutation.

Respect for bioethical principles and human rights in prisons: a systematic review on the state of the art.

BACKGROUND: Respect for human rights and bioethical principles in prisons is a crucial aspect of society and is proportional to the well-being of the general population. To date, these ethical principles have been lacking in prisons and prisoners are victims of abuse with strong repercussions on their physical and mental health. METHODS: A systematic review was performed, through a MESH of the following words (bioethics) AND (prison), (ethics) AND (prison), (bioethics) AND (jail), (ethics) AND (jail), (bioethics) AND (penitentiary), (ethics) AND (penitentiary), (prison) AND (human rights). Inclusion and exclusion criteria were defined and after PRISMA, 17 articles were included in the systematic review. RESULTS: Of the 17 articles, most were prevalence studies (n.5) or surveys (n.4), followed by cross-sectional studies (n.3), qualitative studies (n.1), retrospective (n.1) and an explanatory sequential mixed-methods study design (n.1). In most cases, the studies associated bioethics with prisoners' access to treatment for various pathologies such as vaccinations, tuberculosis, hepatitis, HIV, it was also found that bioethics in prisons was related to the mental health of prisoners, disability, ageing, the condition of women, the risk of suicide or with the request for end-of-life by prisoners. The results showed shortcomings in the system of maintaining bioethical principles and respect for human rights. CONCLUSIONS: Prisoners, in fact, find it difficult to access care, and have an increased risk of suicide and disability. Furthermore, they are often used as improper organ donors and have constrained autonomy that also compromises their willingness to have end-of-life treatments. In conclusion, prison staff (doctors, nurses, warders, managers) must undergo continuous refresher courses to ensure compliance with ethical principles and human rights in prisons.

Fermionic One-Body Entanglement as a Thermodynamic Resource.

There is ongoing controversy about whether a coherent superposition of the occupied states of two fermionic modes should be regarded entangled or not, that is, whether its intrinsic quantum correlations are operationally accessible and useful as a resource. This has been questioned on the basis that such an entanglement cannot be accessed by local operations on individual modes due to the parity superselection rule which constrains the set of physical observables. In other words, one cannot observe violations of Bell's inequality. Here, we show, however, that entanglement of a two-mode fermionic state can be used as a genuine quantum resource in open-system thermodynamic processes, enabling one to perform tasks forbidden for separable states. We thus demonstrate that quantum thermodynamics can shed light on the nature of fermionic entanglement and the operational meaning of the different notions used to define it.

Nonideal Reaction-Diffusion Systems: Multiple Routes to Instability.

We develop a general classification of the nature of the instabilities yielding spatial organization in open nonideal reaction-diffusion systems, based on linear stability analysis. This encompasses dynamics where chemical species diffuse, interact with each other, and undergo chemical reactions driven out of equilibrium by external chemostats. We find analytically that these instabilities can be of two types: instabilities caused by intermolecular energetic interactions (E type), and instabilities caused by multimolecular out-of-equilibrium chemical reactions (R type). Furthermore, we identify a class of chemical reaction networks, containing unimolecular networks but also extending beyond them, that can only undergo E-type instabilities. We illustrate our analytical findings with numerical simulations on two reaction-diffusion models, each displaying one of the two types of instability and generating stable patterns.

Thermalization and Dephasing in Collisional Reservoirs.

We introduce a wide class of quantum maps that arise in collisional reservoirs and are able to thermalize a system if they operate in conjunction with an additional dephasing mechanism. These maps describe the effect of collisions and induce transitions between populations that obey detailed balance, but also create coherences that prevent the system from thermalizing. We combine these maps with a unitary evolution acting during random Poissonian times between collisions and causing dephasing. We find that, at a low collision rate, the nontrivial combination of these two effects causes thermalization in the system. This scenario is suitable for modeling collisional reservoirs at equilibrium. We justify this claim by identifying the conditions for such maps to arise within a scattering theory approach and provide a thorough characterization of the resulting thermalization process.

A [3]-catenane non-autonomous molecular motor model: Geometric phase, no-pumping theorem, and energy transduction.

We study a model of a synthetic molecular motor-a [3]-catenane consisting of two small macrocycles mechanically interlocked with a bigger one-subjected to time-dependent driving using stochastic thermodynamics. The model presents nontrivial features due to the two interacting small macrocycles but is simple enough to be treated analytically in limiting regimes. Among the results obtained, we find a mapping into an equivalent [2]-catenane that reveals the implications of the no-pumping theorem stating that to generate net motion of the small macrocycles, both energies and barriers need to change. In the adiabatic limit (slow driving), we fully characterize the motor's dynamics and show that the net motion of the small macrocycles is expressed as a surface integral in parameter space, which corrects previous erroneous results. We also analyze the performance of the motor subjected to step-wise driving protocols in the absence and presence of an applied load. Optimization strategies for generating large currents and maximizing free energy transduction are proposed. This simple model provides interesting clues into the working principles of non-autonomous molecular motors and their optimization.

A chemical reaction network implementation of a Maxwell demon.

We study an autonomous model of a Maxwell demon that works by rectifying thermal fluctuations of chemical reactions. It constitutes the chemical analog of a recently studied electronic demon. We characterize its scaling behavior in the macroscopic limit, its performances, and the impact of potential internal delays. We obtain analytical expressions for all quantities of interest: the generated reverse chemical current, the output power, the transduction efficiency, and correlation between the number of molecules. Due to a bound on the nonequilibrium response of its chemical reaction network, we find that, contrary to the electronic case, there is no way for the Maxwell demon to generate a finite output in the macroscopic limit. Finally, we analyze the information thermodynamics of the Maxwell demon from a bipartite perspective. In the limit of a fast demon, the information flow is obtained, its pattern in the state space is discussed, and the behavior of partial efficiencies related to the measurement and feedback processes is examined.

Deficiency, kinetic invertibility, and catalysis in stochastic chemical reaction networks.

Stochastic chemical processes are described by the chemical master equation satisfying the law of mass-action. We first ask whether the dual master equation, which has the same steady state as the chemical master equation, but with inverted reaction currents, satisfies the law of mass-action and, hence, still describes a chemical process. We prove that the answer depends on the topological property of the underlying chemical reaction network known as deficiency. The answer is yes only for deficiency-zero networks. It is no for all other networks, implying that their steady-state currents cannot be inverted by controlling the kinetic constants of the reactions. Hence, the network deficiency imposes a form of non-invertibility to the chemical dynamics. We then ask whether catalytic chemical networks are deficiency-zero. We prove that the answer is no when they are driven out of equilibrium due to the exchange of some species with the environment.

miRNA Dysregulation in Cardiovascular Diseases: Current Opinion and Future Perspectives.

MicroRNAs (miRNAs), small noncoding RNAs, are post-transcriptional gene regulators that can promote the degradation or decay of coding mRNAs, regulating protein synthesis. Many experimental studies have contributed to clarifying the functions of several miRNAs involved in regulatory processes at the cardiac level, playing a pivotal role in cardiovascular disease (CVD). This review aims to provide an up-to-date overview, with a focus on the past 5 years, of experimental studies on human samples to present a clear background of the latest advances to summarize the current knowledge and future perspectives. SCOPUS and Web of Science were searched using the following keywords: (miRNA or microRNA) AND (cardiovascular diseases); AND (myocardial infarction); AND (heart damage); AND (heart failure), including studies published from 1 January 2018 to 31 December 2022. After an accurate evaluation, 59 articles were included in the present systematic review. While it is clear that miRNAs are powerful gene regulators, all the underlying mechanisms remain unclear. The need for up-to-date data always justifies the enormous amount of scientific work to increasingly highlight their pathways. Given the importance of CVDs, miRNAs could be important both as diagnostic and therapeutic (theranostic) tools. In this context, the discovery of "TheranoMIRNAs" could be decisive in the near future. The definition of well-setout studies is necessary to provide further evidence in this challenging field.

New Insight into Mechanisms of Cardiovascular Diseases: An Integrative Analysis Approach to Identify TheranoMiRNAs.

MiRNAs regulate both physiological and pathological heart functions. Altered expression of miRNAs is associated with cardiovascular diseases (CVDs), making miRNAs attractive therapeutic strategies for the diagnosis and treatment of heart diseases. A recent publication defined, for the first time, the term theranoMiRNA, meaning the miRNAs that may be used both for diagnosis and treatment. The use of in silico tools may be considered fundamental for these purposes, clarifying several molecular aspects, suggesting future directions for in vivo studies. This study aims to explore different bioinformatic tools in order to clarify miRNA interactions with candidate genes, demonstrating the need to use a computational approach when establishing the most probable associations between miRNAs and target genes. This study focused on the functions of miR-133a-3p, miR-21-5p, miR-499a-5p, miR-1-3p, and miR-126-3p, providing an up-to-date overview, and suggests future lines of research in the identification of theranoMiRNAs related to CVDs. Based on the results of the present study, we elucidated the molecular mechanisms that could be linked between miRNAs and CVDs, confirming that these miRNAs play an active role in the genesis and development of heart damage. Given that CVDs are the leading cause of death in the world, the identification of theranoMiRNAs is crucial, hence the need for a definition of in vivo studies in order to obtain further evidence in this challenging field of research.

Vitality markers in forensic investigations: a literature review.

Determining whether an injury was sustained in life or not is one of the most important topics in forensic medicine. Morphological, cytological, and biological techniques are used to assess wound vitality. Several markers involved in vital and supravital reactions increase the accuracy of wound age estimation. This systematic review aimed to investigate the main vitality markers used in forensic medicine to date. This review was conducted by performing a systematic literature search on online resources (PubMed Central database and Google Scholar) until May 2022. We identified 46 articles published between 1987 and May 2022, analyzing a total of 53 markers. Based on the data of this review, the most studied vitality markers were adhesion molecules (fibronectin, p-selectin, CD 15), pro-inflammatory cytokines (IL-6, IL-1ß, TNF-α), cathepsin D, tryptase, and microRNAs (miRNAs). The most interesting studies were based on animal models: the different markers were investigated through immunohistochemical and qRT-PCR methods. The experimental methods were usually based on skin incisions, ligature marks, and burned skin areas. To date, it has not been possible to identify any gold standard markers based on the criteria of efficacy, specificity, and reliability; however, studies are still in progress. In the future, the use of miRNAs is promising as well as the combination of multiple markers. In this way, it will be possible to increase the sensitivity and specificity to validate systems or models for determining wound vitality in forensic practice.

Using Catalysis to Drive Chemistry Away from Equilibrium: Relating Kinetic Asymmetry, Power Strokes, and the Curtin-Hammett Principle in Brownian Ratchets.

Chemically fueled autonomous molecular machines are catalysis-driven systems governed by Brownian information ratchet mechanisms. One fundamental principle behind their operation is kinetic asymmetry, which quantifies the directionality of molecular motors. However, it is difficult for synthetic chemists to apply this concept to molecular design because kinetic asymmetry is usually introduced in abstract mathematical terms involving experimentally inaccessible parameters. Furthermore, two seemingly contradictory mechanisms have been proposed for chemically driven autonomous molecular machines: Brownian ratchet and power stroke mechanisms. This Perspective addresses both these issues, providing accessible and experimentally useful design principles for catalysis-driven molecular machinery. We relate kinetic asymmetry to the Curtin-Hammett principle using a synthetic rotary motor and a kinesin walker as illustrative examples. Our approach describes these molecular motors in terms of the Brownian ratchet mechanism but pinpoints both chemical gating and power strokes as tunable design elements that can affect kinetic asymmetry. We explain why this approach to kinetic asymmetry is consistent with previous ones and outline conditions where power strokes can be useful design elements. Finally, we discuss the role of information, a concept used with different meanings in the literature. We hope that this Perspective will be accessible to a broad range of chemists, clarifying the parameters that can be usefully controlled in the design and synthesis of molecular machines and related systems. It may also aid a more comprehensive and interdisciplinary understanding of biomolecular machinery.

Finite-Time Dynamical Phase Transition in Nonequilibrium Relaxation.

We uncover a finite-time dynamical phase transition in the thermal relaxation of a mean-field magnetic model. The phase transition manifests itself as a cusp singularity in the probability distribution of the magnetization that forms at a critical time. The transition is due to a sudden switch in the dynamics, characterized by a dynamical order parameter. We derive a dynamical Landau theory for the transition that applies to a range of systems with scalar, parity-invariant order parameters. Close to criticalilty, our theory reveals an exact mapping between the dynamical and equilibrium phase transitions of the magnetic model, and implies critical exponents of mean-field type. We argue that interactions between nearby saddle points, neglected at the mean-field level, may lead to critical, spatiotemporal fluctuations of the order parameter, and thus give rise to novel, dynamical critical phenomena.

Maxwell Demon that Can Work at Macroscopic Scales.

Maxwell's demons work by rectifying thermal fluctuations. They are not expected to function at macroscopic scales where fluctuations become negligible and dynamics become deterministic. We propose an electronic implementation of an autonomous Maxwell's demon that indeed stops working in the regular macroscopic limit as the dynamics becomes deterministic. However, we find that if the power supplied to the demon is scaled up appropriately, the deterministic limit is avoided and the demon continues to work. The price to pay is a decreasing thermodynamic efficiency. Our Letter suggests that novel strategies may be found in nonequilibrium settings to bring to the macroscale nontrivial effects so far only observed at microscopic scales.

Thermodynamics of concentration vs flux control in chemical reaction networks.

We investigate the thermodynamic implications of two control mechanisms of open chemical reaction networks. The first controls the concentrations of the species that are exchanged with the surroundings, while the other controls the exchange fluxes. We show that the two mechanisms can be mapped one into the other and that the thermodynamic theories usually developed in the framework of concentration control can be applied to flux control as well. This implies that the thermodynamic potential and the fundamental forces driving chemical reaction networks out of equilibrium can be identified in the same way for both mechanisms. By analyzing the dynamics and thermodynamics of a simple enzymatic model, we also show that while the two mechanisms are equivalent at steady state, the flux control may lead to fundamentally different regimes where systems achieve stationary growth.

Information thermodynamics for deterministic chemical reaction networks.

Information thermodynamics relates the rate of change of mutual information between two interacting subsystems to their thermodynamics when the joined system is described by a bipartite stochastic dynamics satisfying local detailed balance. Here, we expand the scope of information thermodynamics to deterministic bipartite chemical reaction networks, namely, composed of two coupled subnetworks sharing species but not reactions. We do so by introducing a meaningful notion of mutual information between different molecular features that we express in terms of deterministic concentrations. This allows us to formulate separate second laws for each subnetwork, which account for their energy and information exchanges, in complete analogy with stochastic systems. We then use our framework to investigate the working mechanisms of a model of chemically driven self-assembly and an experimental light-driven bimolecular motor. We show that both systems are constituted by two coupled subnetworks of chemical reactions. One subnetwork is maintained out of equilibrium by external reservoirs (chemostats or light sources) and powers the other via energy and information flows. In doing so, we clarify that the information flow is precisely the thermodynamic counterpart of an information ratchet mechanism only when no energy flow is involved.

Free-energy transduction in chemical reaction networks: From enzymes to metabolism.

We provide a rigorous definition of free-energy transduction and its efficiency in arbitrary-linear or nonlinear-open chemical reaction networks (CRNs) operating at a steady state. Our method is based on the knowledge of the stoichiometric matrix and the chemostatted species (i.e., the species maintained at a constant concentration by the environment) to identify the fundamental currents and forces contributing to the entropy production. Transduction occurs when the current of a stoichiometrically balanced process is driven against its spontaneous direction (set by its force), thanks to other processes flowing along their spontaneous direction. In these regimes, open CRNs operate as thermodynamic machines. After exemplifying these general ideas using toy models, we analyze central energy metabolism. We relate the fundamental currents to metabolic pathways and discuss the efficiency with which they can transduce free energy.