Relevant States Research Articles

Second-Shell Residues Contribute to Catalysis by Predominately Preorganizing the Apo State in PafA.

Residues beyond the first coordination shell are often observed to make considerable cumulative contributions in enzymes. Due to typically indirect perturbations of multiple physicochemical properties of the active site, however, their individual and specific roles in enzyme catalysis and disease-causing mutations remain difficult to predict and understand at the molecular level. Here we analyze the contributions of several second-shell residues in phosphate-irrepressible alkaline phosphatase of flavobacterium (PafA), a representative system as one of the most efficient enzymes. By adopting a multifaceted approach that integrates quantum-mechanical/molecular-mechanical free energy computations, molecular-mechanical molecular dynamics simulations, and density functional theory cluster model calculations, we probe the rate-limiting phosphoryl transfer step and structural properties of all relevant enzyme states. In combination with available experimental data, our computational results show that mutations of the studied second-shell residues impact catalytic efficiency mainly by perturbation of the apo state and therefore substrate binding, while they do not affect the ground state or alter the nature of phosphoryl transfer transition state significantly. Several second-shell mutations also modulate the active site hydration level, which in turn influences the energetics of phosphoryl transfer. These mechanistic insights also help inform strategies that may improve the efficiency of enzyme design and engineering by going beyond the current focus on the first coordination shell.

Management of male stress urinary incontinence in high-risk patients: a narrative review.

The artificial urinary sphincter (AUS) remains the gold standard for treatment of stress urinary incontinence (SUI). However, highly complex patients such as those with bulbar urethral compromise, bladder pathology, and lower urinary complications pose a particular challenge for the surgeon. In this article, we will address critical risk factors and synthesize existent data across relevant disease states to support surgeons in successful management of SUI in high-risk patients. A comprehensive review of current literature was performed utilizing the search term "artificial urinary sphincter" in conjunction with any of the following additional terms: "radiation", "urethral stricture", "posterior urethral stenosis", "vesicourethral anastomotic stenosis", "bladder neck contracture", "pelvic fracture urethral injury", "penile revascularization", "inflatable penile prosthesis", and "erosion". Guidance is provided based upon expert opinion where existing literature was sparse or nonexistent. Several known patient risk factors are associated with AUS failure and can ultimately lead to device explantation. Each risk factor requires careful consideration and investigation, or intervention as appropriate, prior to device placement. Optimization of urethral health, confirmation of anatomic and functional stability of the lower urinary tract, and thorough patient counseling are a necessity for these high-risk patients. Several surgical strategies to decrease device complications can be considered: optimization of testosterone, avoidance of 3.5 cm AUS cuff, transcorporal AUS cuff placement, relocation of AUS cuff site, use of lower pressure-regulating balloon, penile revascularization, and intermittent nocturnal deactivation. A number of patient risk factors are associated with AUS failure and can ultimately lead to device explantation. We present an algorithm for management of high-risk patients. Optimization of urethral health, confirmation of anatomic and functional stability of the lower urinary tract, and thorough patient counseling are a necessity for these high-risk patients.

Conformational Plasticity in α-Synuclein and How Crowded Environment Modulates It.

A 140-residue intrinsically disordered protein (IDP), α-synuclein (αS), is known to adopt conformations that are vastly plastic and susceptible to environmental cues and crowders. However, the inherently heterogeneous nature of αS has precluded a clear demarcation of its monomeric precursor between aggregation-prone and functionally relevant aggregation-resistant states and how a crowded environment could modulate their mutual dynamic equilibrium. Here, we identify an optimal set of distinct metastable states of αS in aqueous media by dissecting a 73 μs-long molecular dynamics ensemble via building a comprehensive Markov state model (MSM). Notably, the most populated metastable state corroborates with the dimension obtained from PRE-NMR studies of αS monomer, and it undergoes kinetic transition at diverse time scales with a weakly populated random-coil-like ensemble and a globular protein-like state. However, subjecting αS to a crowded environment results in a nonmonotonic compaction of these metastable conformations, thereby skewing the ensemble by either introducing new tertiary contacts or by reinforcing the innate contacts. The early stage of dimerization process is found to be considerably expedited in the presence of crowders, albeit promoting nonspecific interactions. Together with this, using an extensively sampled ensemble of αS, this exposition demonstrates that crowded environments can potentially modulate the conformational preferences of IDP that can either promote or inhibit aggregation events.

Dispersion relations for hadronic light-by-light scattering in triangle kinematics

We present a new strategy for the dispersive evaluation of the hadronic light-by-light contribution to the anomalous magnetic moment of the muon aμ. The new approach directly applies in the kinematic limit relevant for aμ: one of the photons is treated as an external electromagnetic field with vanishing momentum, so that the kinematics corresponds to a triangle. We derive expressions for the relevant single-particle intermediate states, as well as the tensor decompositions of the two-pion sub-processes that appear in addition to those needed in the established dispersive approach. The existing approach is based on a set of dispersion relations for the hadronic light-by-light tensor in four-point kinematics. At present it is not known how to consistently include in this framework resonant intermediate states of spin 2 or larger, due to the appearance of kinematic singularities that can be traced back to the redundancy of the tensor decomposition. We show that our new approach circumvents this problem and enables dispersion relations in the limit of triangle kinematics that are manifestly free from kinematic singularities, paving the way towards a data-driven evaluation of all relevant exclusive hadronic intermediate states.

Reliability analysis of the compressed air supplying system in underground mines

Despite the high cost and low efficiency, compressed air is mostly used in underground mining for ore extraction, hoisting, and mineral processing operations. Failures of compressed air systems not only threaten the health and safety of workers but also contribute to inefficient control of airflow and stopped all equipment that operates by compressed air. In such uncertain conditions, mine managers are faced with the big challenge to supply enough compressed air, and therefore, the reliability evaluation of these systems is essential. This paper aims to analyze the reliability of the compressed air system using the Markov modeling approach as a case study, Qaleh-Zari Copper Mine, Iran. To achieve this, the state space diagram was constructed considering all relevant states for all compressors in the main compressor house of the mine. The failure and repair rate of all main and reserve compressors were calculated for all possible transitions between states to obtain the probability of being of the system in each of the states. Moreover, the probability of failure at any time period was considered to study the reliability behavior. The results of this study show that there is 31.5% probability that the compressed air supplying system is in operating condition with two main and one standby compressors. The system probability that two main compressors are remain in the operation without failure for one months is 92.32%. Furthermore, the lifetime of the system is estimated 33 months when at least one main compressor is active.

Does AlphaFold2 model proteins’ intracellular conformations? An experimental test using cross-linking mass spectrometry of endogenous ciliary proteins

A major goal in structural biology is to understand protein assemblies in their biologically relevant states. Here, we investigate whether AlphaFold2 structure predictions match native protein conformations. We chemically cross-linked proteins in situ within intact Tetrahymena thermophila cilia and native ciliary extracts, identifying 1,225 intramolecular cross-links within the 100 best-sampled proteins, providing a benchmark of distance restraints obeyed by proteins in their native assemblies. The corresponding structure predictions were highly concordant, positioning 86.2% of cross-linked residues within Cɑ-to-Cɑ distances of 30 Å, consistent with the cross-linker length. 43% of proteins showed no violations. Most inconsistencies occurred in low-confidence regions or between domains. Overall, AlphaFold2 predictions with lower predicted aligned error corresponded to more correct native structures. However, we observe cases where rigid body domains are oriented incorrectly, as for ciliary protein BBC118, suggesting that combining structure prediction with experimental information will better reveal biologically relevant conformations.

Toward a Rigorous Theoretical Description of Photocatalysis Using Realistic Models.

This Perspective aims at providing a road map to computational heterogeneous photocatalysis highlighting the knowledge needed to boost the design of efficient photocatalysts. A plausible computational framework is suggested focusing on static and dynamic properties of the relevant excited states as well of the involved chemistry for the reactions of interest. This road map calls for explicitly exploring the nature of the charge carriers, the excited-state potential energy surface, and its time evolution. Excited-state descriptors are introduced to locate and characterize the electrons and holes generated upon excitation. Nonadiabatic molecular dynamics simulations are proposed as a convenient tool to describe the time evolution of the photogenerated species and their propagation through the crystalline structure of photoactive material, ultimately providing information about the charge carrier lifetime. Finally, it is claimed that a detailed understanding of the mechanisms of heterogeneously photocatalyzed reactions demands the analysis of the excited-state potential energy surface.

Kinetic Models for Epidemic Dynamics in the Presence of Opinion Polarization

Understanding the impact of collective social phenomena in epidemic dynamics is a crucial task to effectively contain the disease spread. In this work, we build a mathematical description for assessing the interplay between opinion polarization and the evolution of a disease. The proposed kinetic approach describes the evolution of aggregate quantities characterizing the agents belonging to epidemiologically relevant states and will show that the spread of the disease is closely related to consensus dynamics distribution in which opinion polarization may emerge. In the present modelling framework, microscopic consensus formation dynamics can be linked to macroscopic epidemic trends to trigger the collective adherence to protective measures. We conduct numerical investigations which confirm the ability of the model to describe different phenomena related to the spread of an epidemic.

New constraints on sodium production in globular clusters from theNa23(He3,d)Mg24reaction

The star-to-star anticorrelation of sodium and oxygen is a defining feature of globular clusters, but, to date, the astrophysical site responsible for this unique chemical signature remains unknown. Sodium enrichment within these clusters depends sensitively on reaction rate of the sodium destroying reactions $^{23}\mathrm{Na}(p,\ensuremath{\gamma})$ and $^{23}\mathrm{Na}(p,\ensuremath{\alpha})$. In this paper, we report the results of a $^{23}\mathrm{Na}{(^{3}\mathrm{He},d)}^{24}\mathrm{Mg}$ transfer reaction carried out at Triangle Universities Nuclear Laboratory using a $21\phantom{\rule{0.16em}{0ex}}\mathrm{MeV}\phantom{\rule{0.16em}{0ex}}^{3}\mathrm{He}$ beam. Astrophysically relevant states in $^{24}\mathrm{Mg}$ between $11<{E}_{x}<12\phantom{\rule{0.16em}{0ex}}\mathrm{MeV}$ were studied using high-resolution magnetic spectroscopy, thereby allowing the extraction of excitation energies and spectroscopic factors. Bayesian methods are combined with the distorted wave Born approximation to assign statistically meaningful uncertainties to the extracted spectroscopic factors. For the first time, these uncertainties are propagated through to the estimation of proton partial widths. Our experimental data are used to calculate the reaction rate. The impact of the new rates are investigated using asymptotic giant branch star models. It is found that while the astrophysical conditions still dominate the total uncertainty, intramodel variations on sodium production from the $^{23}\mathrm{Na}(p,\ensuremath{\gamma})$ and $^{23}\mathrm{Na}(p,\ensuremath{\alpha})$ reaction channels are a lingering source of uncertainty.

Path-Based Visibility Graph Kernel and Application for the Borsa Istanbul Stock Network

Using networks to analyze time series has become increasingly popular in recent years. Univariate and multivariate time series can be mapped to networks in order to examine both local and global behaviors. Visibility graph-based time series analysis is proposed herein; in this approach, individual time series are mapped to visibility graphs that characterize relevant states. Companies listed on the emerging market index Borsa Istanbul 100 (BIST 100) had their market visibility graphs collected. To further account for the local extreme values of the underlying time series, we constructed a novel kernel function of the visibility graphs. Via the provided novel measure, sector-level and sector-to-sector analyses are conducted using the kernel function associated with this metric. To examine sectoral trends, the COVID-19 crisis period was included in the study’s data set. The findings indicate that an effective strategy for analyzing financial time series has been devised.

Theory of Dynamical Phase Transitions in Quantum Systems with Symmetry-Breaking Eigenstates.

We present a theory for the two kinds of dynamical quantum phase transitions, termed DPT-I and DPT-II, based on a minimal set of symmetry assumptions. In the special case of collective systems with infinite-range interactions, both are triggered by excited-state quantum phase transitions. For quenches below the critical energy, the existence of an additional conserved charge, identifying the corresponding phase, allows for a nonzero value of the dynamical order parameter characterizing DPTs-I, and precludes the main mechanism giving rise to nonanalyticities in the return probability, trademark of DPTs-II. We propose a statistical ensemble describing the long-time averages of order parameters in DPTs-I, and provide a theoretical proof for the incompatibility of the main mechanism for DPTs-II with the presence of this additional conserved charge. Our results are numerically illustrated in the fully connected transverse-field Ising model, which exhibits both kinds of dynamical phase transitions. Finally, we discuss the applicability of our theory to systems with finite-range interactions, where the phenomenology of excited-state quantum phase transitions is absent. We illustrate our findings by means of numerical calculations with experimentally relevant initial states.

Deep mining of the protein energy landscape

For over half a century, it has been known that protein molecules naturally undergo extensive structural fluctuations, and that these internal motions are intimately related to their functional properties. The energy landscape view has provided a powerful framework for describing the various physical states that proteins visit during their lifetimes. This Perspective focuses on the commonly neglected and often disparaged axis of the protein energy landscape: entropy. Initially seen largely as a barrier to functionally relevant states of protein molecules, it has recently become clear that proteins retain considerable conformational entropy in the "native" state, and that this entropy can and often does contribute significantly to the free energy of fundamental protein properties, processes, and functions. NMR spectroscopy, molecular dynamics simulations, and emerging crystallographic views have matured in parallel to illuminate dynamic disorder of the "ground state" of proteins and their importance in not only transiting between biologically interesting structures but also greatly influencing their stability, cooperativity, and contribution to critical properties such as allostery.

Contribution to the Knowledge of Pontechium maculatum(Boraginaceae), a Species of High Conservation Concern in the Bulgarian Flora

Pontechium maculatum (Boraginaceae) is a species of high conservation concern in the Bulgarian flora. It is assigned a national IUCN category ‘Vulnerable’, legally protected according to the national Biological Diversity Act, and listed in Annex II of the Habitats Directive (Council Directive 92/43/EEC). Recent studies in one of the largest populations in the country revealed some new data about the species which are reported here. The population studied is situated in Mt Lozenska, Mt Sredna Gora (Western) floristic region. Relevant taxonomic literature states that P. maculatum is a biennial plant, however, our observations revealed the plants in Mt Lozenska are perennial (possibly short-lived). A great variation in the corolla-colour was observed, most plants having bluish to violet corolla and only a few – reddish to dark red. This can be explained by either natural variation in the population, not reported in the taxonomic literature so far, or by hybridisation with Echium vulgare which cooccurs in the same locality. Large fluctuation in the number of flowering plants in two consecutive years was recorded, with some 180 blooming specimens in 2019 and only about 25 in 2020. Studies in the genome size of this population revealed the plants have significantly higher DNA-content (1C-value) than plants from the typical populations of the species in Northeast Bulgaria floristic region, e.g. Kabiyushka Mogila locality. Further biosystematics studies(chromosome number, genome size, genetic studies, etc.) are currently in progress to explain the observed phenomena within the Bulgarian populations of P. maculatum.

Effectiveness and Safety Profiles of Vernakalant for Cardioversion of Acute-onset Atrial Fibrillation: A Systematic Review and Meta-analysis

PurposePharmacologic cardioversion is an effective clinical strategy for fibrillation. Vernakalant is a novel drug used to treat atrial fibrillation (AF). This study aimed to evaluate the efficacy- and tolerability-related data on vernakalant from clinical trials. MethodsLiterature from PubMed and the Cochrane Library was systematically reviewed, and 139 eligible studies were found after specific key words were identified. Twelve randomized clinical trials discussing vernakalant cardioversion in patients with AF were chosen for the meta-analysis after scrutiny. Ten of the 12 trials used placebo while two reported data on active and established drugs to compare the effects of vernakalant. Three of the 12 trials included relevant clinical states in addition to AF. FindingsIn this meta-analysis of data from 12 studies (2365 patients, 887 events), the rate of cardioversion from AF to sinus rhythm (SR) was significantly greater with vernakalant compared with placebo and active comparators (risk ratio = 5.60; 95% CI, 2.83–11.09; I2 test for heterogeneity, 92%). Tolerability-related data revealed that dysgeusia, paresthesia, atrial flutter, and hypotension were major adverse events that occurred with vernakalant use, but the data were not clinically significant compared to placebo and active drug (risk ratio = 1.13; 95% CI, 0.86–1.47). Eleven deaths were reported in 4 trials, with vernakalant directly implicated in two deaths. Vernakalant was well tolerated and effective in patients with rapid-onset AF. ImplicationsVernakalant appears to be a good choice when AF is manifested postoperatively or exists with ischemic heart disease and valvular states. Tolerability-related data are promising, but a specific trial may be required to identify the causes of the deaths considered unrelated to vernakalant use.

Overriding Mandatory Rules Applicable to International Sales of Goods: Evidence from South Africa

In private international law of contract, the law regulating the rights and obligations of contracting parties may (whether objectively determined or chosen by the parties), in some instances, be limited by either public policy considerations or other relevant mandatory rules. In this regard, the public policy and the overriding mandatory rules of three places – that of the forum state, the applicable law (if different from the lex fori) and the law of the place of performance (or a third state with relevant connection to the contract) – have been considered by both jurists and scholars as being important. However, this article is limited to matters concerning choice of law rules on overriding mandatory provisions (but not public policy considerations). This article assesses the various private international law rules utilised by the South African courts in ascertaining which overriding mandatory provisions must apply to international contracts for the sale of goods. The aim is to adopt a general private international law of contract rule that effectively addresses the difficulty in determining the state, whose overriding mandatory provisions may legitimately claim application over certain relevant issues in international sales contracts. To this end, the article considers the general application of the overriding mandatory rules of the forum and that of the applicable law state (lex causae) to determine if these laws may legitimately by applied to contracts as it is practiced by some courts. Thereafter, the article considers the application of the overriding mandatory rules of the place of performance (locus solutionis) or other relevant third states and demonstrate that it is the overriding mandatory provisions of “a relevant state” that may legitimately derogate the application of certain provisions of the proper law of an international contract.

Evaluation of tight-binding DFT performance for the description of organic photochromes properties.

Photochromic molecules are widely studied and developed for their many potential applications. To optimize the required properties through theoretical models, a considerable chemical space is to be explored, and their environment in devices is to be accounted for.. To this end, cheap and reliable computational methods can be powerful tools to steer synthetic developments. As ab initio methods remain costly for extensive studies (in terms of the size of the system and/or number of molecules), semiempirical methods such as density functional tight-binding (TB) could offer a good compromise between accuracy computational cost. However, these approaches necessitate benchmarking on the families of compounds of interest. Thus, the aim of the present study is to evaluate the accuracy of several key features calculated with TB methods (DFTB2, DFTB3, GFN2-xTB, and LC-DFTB2) for three sets of photochromic organic molecules: azobenzene (AZO), norbornadiene/quadricyclane (NBD/QC), and dithienylethene (DTE) derivatives. The features considered here are the optimized geometries, the difference in energy between the two isomers (ΔE), and of the energies of the first relevant excited states. All the TB results are compared to those obtained with DFT methods and state-of-the-art electronic structure calculation methods: DLPNO-CCSD(T) for ground states and DLPNO-STEOM-CCSD for excited states. Our results show that, overall, DFTB3 is the TB method leading to the best results for the geometries and the ΔE values and can be used alone for these purposes for NBD/QC and DTE derivatives. Single point calculations at the r2SCAN-3c level using TB geometries allow circumventing the deficiencies of the TB methods in the AZO series. For electronic transition calculations, the range separated LC-DFTB2 method is the most accurate TB method tested for AZO and NBD/QC derivatives, in close agreement with the reference.

Data-driven framework for input/output lookup tables reduction: Application to hypersonic flows in chemical nonequilibrium

In this paper, we present a novel model-agnostic machine learning technique to extract a reduced thermochemical model for reacting hypersonic flows simulation. A first simulation gathers all relevant thermodynamic states and the corresponding gas properties via a given model. The states are embedded in a low-dimensional space and clustered to identify regions with different levels of thermochemical (non)-equilibrium. Then, a surrogate surface from the reduced cluster-space to the output space is generated using radial-basis-function networks. The method is validated and benchmarked on a simulation of a hypersonic flat-plate boundary layer with finite-rate chemistry. The gas properties of the reactive air mixture are initially modeled using the open-source Mutation++ library. Substituting Mutation++ with the light-weight, machine-learned alternative improves the performance of the solver by 50% while maintaining overall accuracy.

Charge-Transfer and Spin-Flip States: Thriving as Complements.

Transition metal complexes with photoactive charge-transfer excited states are pervasive throughout the literature. In particular, [Ru(bpy)3 ]2+ (bpy=2,2'-bipyridine), with its metal-to-ligand charge-transfer emission, has been established as a key complex. Meanwhile, interest in so-called spin-flip metal-centered states has risen dramatically after the molecular ruby [Cr(ddpd)2 ]3+ (ddpd=N,N'-dimethyl-N,N'-dipyridin-2-yl-pyridine-2,6-diamine) led to design principles to access strong, long-lived emission from photostable chromium(III) complexes. This Review contrasts the properties of emissive charge-transfer and spin-flip states by using [Ru(bpy)3 ]2+ and [Cr(ddpd)2 ]3+ as prototypical examples. We discuss the relevant excited states, the tunability of their energy and lifetimes, and their response to external stimuli. Finally, we identify strengths and weaknesses of charge-transfer and spin-flip states in applications such as photocatalysis and circularly polarized luminescence.

Understanding cell biology using cryo-electron microscopy

In order to fully understand biological processes, and how they fail in disease, it is vital to obtain structural information for the relevant biological machinery. Notably, it is becoming increasingly apparent that proteins, the key biological players in fundamental biology or disease mechanisms, often adopt multiple conformations or act in complexes with other proteins. These large and/or dynamic systems present a challenge to traditional methods of 3D structural determination as X-Ray crystallography or NMR. In recent years, single particle analysis (SPA) through cryo-EM has emerged as a mainstream structural biology technique, which can determine the 3D structure of proteins and protein complexes at near-atomic resolution. SPA allows determination of molecular details of purified and isolated proteins at near native conditions, albeit without the spatial and functional context of these proteins within the cell. Cryo Electron Tomography (Cryo-ET) fills this gap by visualizing proteins within their functional cellular environments. This allows for observation of their relationships and interactions with other cellular components and holds great promise for cell biology. In Cryo-EM, specimens are rapidly frozen (vitrified) so that their biologically relevant native states are preserved. This technique has transformed the field of structural biology, leading to new insight into numerous biological processes. Senior Scientist with Thermo Fisher Scientific, Natalia de Val, will discuss the latest advances in the SPA and cellular Cryo-ET workflows and will present the latest results in SPA and Tomography. These results will show how the field is changing our understanding of fundamental cell biology.

Selectivity through ion modulated changes in pKa values.

In bacterial voltage gated sodium (Nav) channels, the passage of ions through the pore is controlled by a selectivity filter (SF) comprised of four glutamate residues. The mechanism of selectivity has been the subject of intense research, with suggested mechanisms based on steric effects, and ion triggered conformational change. Here we propose a novel mechanism based on ion-triggered shift in pKa values of SF glutamates. We study the NavMs channel for which the open channel structure is available. Our free energy calculations based on molecular dynamics simulations suggest that pKa values of the four glutamates are higher in solution of K+ ions, than in solution of Na+ ions. Since pKa values are close to the physiological pH, this results in predominant population of the fully deprotonated state of glutamates in Na+ solution, while protonated states are predominantly populated in K+ solution. Through molecular dynamics simulations we also calculate the conductances of the relevant protonation states. The deprotonated state is the most conductive, single protonated state is less conductive, and double protonated state has further reduced conductance. Thus, we propose that the selectivity is achieved through ion triggered shift in protonation state which favors more conductive states for Na+ ions and less conductive states for K+ ions. This mechanism would also suggest pH dependence of selectivity, which was experimentally observed in structurally similar NaChBas channels.