Dynamic expedition of leading mutations in SARS-CoV-2 spike glycoproteins.

The continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the recent pandemic, has generated countless new variants with varying fitness. Mutations of the spike glycoprotein play a particularly vital role in shaping its evolutionary trajectory, as they have the capability to alter its infectivity and antigenicity. We present a time-resolved statistical method, Dynamic Expedition of Leading Mutations (deLemus), to analyze the evolutionary dynamics of the SARS-CoV-2 spike glycoprotein. The proposed L -index of the deLemus method is effective in quantifying the mutation strength of each amino acid site and outlining evolutionarily significant sites, allowing the comprehensive characterization of the evolutionary mutation pattern of the spike glycoprotein.

Research and Development of Self-Waterproofing Concrete for Tunnel Lining Structure and Its Impermeability and Crack Resistance Characteristics.

This research paper systematically investigates the combined influence of fly ash, cementitious capillary crystalline waterproofing (CCCW) materials, and polypropylene fibers on the mechanical properties and impermeability of concrete through comprehensive orthogonal tests. Microscopic morphological changes in the concrete induced by different composite materials are examined via scanning electron microscopy (SEM) and X-ray diffraction (XRD) testing. The objective is to facilitate a beneficial synergetic interaction among these materials to develop highly permeable, crack-resistant concrete. Key findings of this study are: (1) The study unveils the impact of the concentration of three additive materials on the concrete's compressive strength, tensile strength, and penetration height, thereby outlining their significant influence on the mechanical properties and impermeability of the concrete; (2) An integrated scoring method determined the optimal composite dosage of three materials: 15% fly ash, 2% CCCW, and polypropylene fibers at 1.5 kg/m3. This combination increased the concrete's compressive strength by 12.5%, tensile strength by 48.4%, and decreased the average permeability height by 63.6%; (3) The collective introduction of these three materials notably augments the hydration reaction of the cement, resulting in denser concrete microstructure, enhanced bonding between fibers and matrix, and improved concrete strength and durability.

Accelerating finite-energy generalized Olver beams.

We propose a new, to the best of our knowledge, and very general finite power beam solution to the paraxial wave equation (PWE) in Cartesian coordinates by introducing an exponential differential operator on the existing PWE solution and term it as the "finite-energy generalized Olver beam." Applying the analytical expressions for the field distributions, we study the evolution of intensity, centroid, and variance of these beams during free-space propagation. Our findings demonstrate that these new beams exhibit a diffraction-resistant profile along a curved trajectory when specific beam conditions are met. Using numerical methods, we further demonstrate the ability to adjust the self-accelerating degree, sidelobe profile, and stability of the central mainlobe by manipulating the transforming parameters. This research presents a versatile approach to controlling beam properties and holds promise for advancing applications in various fields.

Traversing the nucleation-growth landscape through heterogeneous random walks.

The nucleation-growth process is a crucial component of crystallization. While previous theoretical models have focused on nucleation events and postnucleation growth, such as the classical nucleation theory and Lifshitz-Slyozov-Wagner model, recent advancements in experiments and simulations have highlighted the inability of classical models to explain the transient dynamics during the early development of nanocrystals. To address these shortcomings, we present a model that describes the nucleation-growth dynamics of individual nanocrystals as a series of reversible chain reactions, with the free energy landscape extended to include activation-adsorption-relaxation reaction pathways. By using the Monte Carlo method based on the transition state theory, we simulate the crystallization dynamics. We derive a Fokker-Planck formalism from the master equation to describe the nucleation-growth process as a heterogeneous random walk on the extended free energy landscape with activated states. Our results reveal the transient quasiequilibrium of the prenucleation stage before nucleation starts, and we identify a postnucleation crossover regime where the dynamic growth exponents asymptotically converge towards classical limits. Additionally, we generalize the power laws to address the dimension and scale effects for the growth of large crystals.

Topology induced crossover between Langevin, subdiffusion, and Brownian diffusion regimes in supercooled water.

Despite extensive studies of supercooled water, it remains challenging to understand its peculiar dynamic anomalous properties. In this work, we integrated full atomistic simulations of supercooled water over the temperature range of room temperature to 200 K using a quantum-mechanics-based polarizable force field with the dressed dynamics method that couples fast collision events and slow reorganization dynamics of hydrogen-bond networks. Our analysis unveils the salient multiscale features in the transient relaxation dynamics of supercooled water. A classical Langevin behavior dominates at fast timescales, while long-time relaxations unveil two different activation barriers in two temperature regions: below and above 230 K. The modulation of the entropy spectrum by temperature is elucidated in terms of a three-state model underlined by the complexity of the water dynamics associated with a topological transition of a strong hydrogen-bond network. This state-dependent network topology is quantitatively characterized by power-law exponents of inverse network connectivity from 200 to 298 K. This work provides valuable guidance for further studies on the transient relaxation dynamics of supercooled water.

Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss.

The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.

Bridging ribosomal synthesis to cell growth through the lens of kinetics.

Understanding prokaryotic cell growth requires a multiscale modeling framework from the kinetics perspective. The detailed kinetics pathway of ribosomes exhibits features beyond the scope of the classical Hopfield kinetics model. The complexity of the molecular responses to various nutrient conditions poses additional challenge to elucidate the cell growth. Herein, a kinetics framework is developed to bridge ribosomal synthesis to cell growth. For the ribosomal synthesis kinetics, the competitive binding between cognate and near-cognate tRNAs for ribosomes can be modulated by Mg2+. This results in distinct patterns of the speed - accuracy relation comprising "trade-off" and "competition" regimes. Furthermore, the cell growth rate is optimized by varying the characteristics of ribosomal synthesis through cellular responses to different nutrient conditions. In this scenario, cellular responses to nutrient conditions manifest by two quadratic scaling relations: one for nutrient flux versus cell mass, the other for ribosomal number versus growth rate. Both are in quantitative agreement with experimental measurements.

Complex source point theory of paraxial and nonparaxial elliptical Gaussian beams.

Using the operator transformation technology, we extend the circular Gaussian beam based virtual (complex) sources method to investigate the paraxial and nonparaxial propagation properties of the elliptical Gaussian beams (EGBs) with planar or cylindrical wavefronts travelling in free space. The paraxial approximation analysis reveals the self-reappearance and self-focusing propagation features for the EGBs with cylindrical wavefront under proper parameter conditions. We further introduce the nonparaxial theory to derive the analytical expressions for the field distribution of an EGB in free space, and confirm that these intriguing propagation features can still be observed with added nonparaxial correction. Comparing with the paraxial approximation results, it is worth noting that there is a clear deviation of the on-axial intensity and phase distributions near the self-focusing position on the basis of nonparaxial correction solution. Our results reveal that the anisotropic diffraction of light propagating through homogeneous medium or free space is possible. The approach in this work can easily be generalized to other beam models with elliptical geometry, which allows us to correctly predict some important information about their near field propagation characteristics for various applications.

Decoupling engineering of formamidinium-cesium perovskites for efficient photovoltaics.

Although pure formamidinium iodide perovskite (FAPbI3) possesses an optimal gap for photovoltaics, their poor phase stability limits the long-term operational stability of the devices. A promising approach to enhance their phase stability is to incorporate cesium into FAPbI3. However, state-of-the-art formamidinium-cesium (FA-Cs) iodide perovskites demonstrate much worse efficiency compared with FAPbI3, limited by the different crystallization dynamics of formamidinium and cesium, which result in poor composition homogeneity and high trap densities. We develop a novel strategy of crystallization decoupling processes of formamidinium and cesium via a sequential cesium incorporation approach. As such, we obtain highly reproducible, highly efficient and stable solar cells based on FA1 - x Cs x PbI3 (x = 0.05-0.16) films with uniform composition distribution in the nanoscale and low defect densities. We also revealed a new stabilization mechanism for Cs doping to stabilize FAPbI3, i.e. the incorporation of Cs into FAPbI3 significantly reduces the electron-phonon coupling strength to suppress ionic migration, thereby improving the stability of FA-Cs-based devices.

Flexural Toughness Test and Inversion Research on a Thermal Conductivity Formula on Steel Fiber-Reinforced Concrete Components Post-Fire.

Steel fibers are widely used because they can effectively improve the tensile, compressive and flexural properties of concrete structures. The selection of steel fiber dosage and aspect ratio at high temperature has an important impact on the flexural toughness of concrete components post-fire. In this paper, discussions are made on the simulated fire test in compliance with the ISO 834 standard to study the steel fiber-reinforced concrete (SFRC) components post-fire. The research reveals the influence of two commonly used steel fiber aspect ratios (50, 70) and steel fiber dosages (30 kg/m3, 40 kg/m3, 45 kg/m3) on the changes of the internal temperature field, the initial crack flexural strength and the flexural toughness of the SFRC components under a single-side fire. Moreover, combined with the four-point flexural test of the SFRC components post fire, the research also describes the damage of high temperatures to the flexural toughness of SFRC components, and suggests a calculation formula for SFRC thermal conductivity by way of the numerical inversion method. The results of this study have verified that the incorporation of steel fiber into concrete helps to reduce its internal thermal stress difference and improve the crack resistance and fire resistance of the concrete. Moreover, under high temperature conditions, the concrete component added with the steel fiber in an aspect ratio of 70 and a dosage of 45 kg/m3 increased their initial crack flexural strength by 56.8%, higher than that of plain concrete components, and the loss of equivalent flexural strength and flexural toughness of SFRC post fire was only 45.2% and 13.6%, respectively. The proposed calculation formula of thermal conductivity can provide a reference for a numerical simulation study of the temperature field of SFRC components in a high temperature environment.

Synthesis of Substituted 2-Pyridones via 6π-Electrocyclization of Dienyl Isocyanates.

A one-pot Curtius rearrangement of dienyl carboxylic acids followed by a 6π-electrocyclization process to form substituted 2-pyridone products has been developed. Dienyl isocyanates generated from aliphatic acids were more reactive than their aromatic counterparts. Additionally, substitution patterns of the carboxylic acids had an impact on the efficiency of the cyclization.

Anomalous Photoinduced Reconstructing and Dark Self-Healing Processes on Bi2O2S Nanoplates.

We report an anomalous photoinduced reconstructing and dark self-healing process on Bi2O2S nanoplates by monitoring the time profile of open-circuit potential (OCP). When the light was switched on and off on the nanoplates, we observed pronounced and repeatable decrement-recovery cycles of the OCP signal, which are inexplicable by a rapid electron-hole separation-recombination process only as in a conventional semiconductor. It is proposed that upon irradiation, accumulation of photogenerated holes at the electrode surface caused oxidation of the S layers of Bi2O2S nanoplates into certain intermediates, which, when the light was turned off, were then reduced back to the original state by the electron back flow. Raman scattering spectroscopy provided te S-S vibrational signature of the intermediate, evidencing the hole oxidative dimerization of the S2- species and the inverse reductive S-S dissociation process. The photophysics and photochemistry of semiconductor nanoplates reported here may inspire the development of energy devices, switches, and memristors.

Generalization of Langevin Dynamics from Spatio-Temporal Dressed Dynamics Perspective.

Understanding multiscale dynamics characteristics has been the holy grail in a broad range of scientific disciplines from physics, chemistry, to biology, and beyond. The seminal Langevin equation successfully unravels remarkable details of Brownian motion dynamics involving stochastic collisions from the fluidic medium. However, extraordinary phenomena beyond the scope of Langevin dynamics were observed to exhibit a series of multiscale dynamic features in recent years. Here, an explicit spatio-temporal coupled kernel is developed to provide the microscopic account for delicate dynamic coupling between particle and medium in the dressed dynamics perspective. This methodology is applied to investigate an aqueous solvation shell model with an explicit spatial boundary to illustrate the significance of spatial and temporal coupling, leading to a general temporal profile of dressed dynamics over 12 orders of magnitude in time In particular, the time-resolved viscosity is formulated to address the remarkable enhancement of viscosity measured by the liquid cell electron microscopy. The understanding of dressed dynamics processes will be greatly enriched by further studies on the detailed dynamics that manifests the microscopic inhomogeneity of medium.

Unraveling Dynamic Transitions in Time-Resolved Biomolecular Motions by A Dressed Diffusion Model.

Recent experimental data reveal the complexity of diffusion dynamics beyond the scope of classical Brownian dynamics. The particles exhibit diverse diffusive motions from the anomalous toward classical diffusion over a wide range of temporal scales. Here a dressed diffusion model is developed to account for non-Brownian phenomena. By coupling the particle dynamics with a local field, the dressed diffusion model generalizes the Langevin equation through coupled damping kernels and generates the salient feature of time-dependent diffusion dynamics reported in the experimental measurements of biomolecules. The dressed diffusion model provides one quantitative aspect for future endeavors in this rapid-growing field.

Method to extract multiple states in F1-ATPase rotation experiments from jump distributions.

A method is proposed for analyzing fast (10 µs) single-molecule rotation trajectories in F1 adenosinetriphosphatase ([Formula: see text]-ATPase). This method is based on the distribution of jumps in the rotation angle that occur in the transitions during the steps between subsequent catalytic dwells. The method is complementary to the "stalling" technique devised by H. Noji et al. [Biophys. Rev. 9, 103-118, 2017], and can reveal multiple states not directly detectable as steps. A bimodal distribution of jumps is observed at certain angles, due to the system being in either of 2 states at the same rotation angle. In this method, a multistate theory is used that takes into account a viscoelastic fluctuation of the imaging probe. Using an established sequence of 3 specific states, a theoretical profile of angular jumps is predicted, without adjustable parameters, that agrees with experiment for most of the angular range. Agreement can be achieved at all angles by assuming a fourth state with an ∼10 µs lifetime and a dwell angle about 40° after the adenosine 5'-triphosphate (ATP) binding dwell. The latter result suggests that the ATP binding in one ß subunit and the adenosine 5'-diphosphate (ADP) release from another ß subunit occur via a transient whose lifetime is ∼10 µs and is about 6 orders of magnitude smaller than the lifetime for ADP release from a singly occupied [Formula: see text]-ATPase. An internal consistency test is given by comparing 2 independent ways of obtaining the relaxation time of the probe. They agree and are ∼15 µs.

Stratification Modelling of Key Bacterial Taxa Driven by Metabolic Dynamics in Meromictic Lakes.

In meromictic lakes, the water column is stratified into distinguishable steady layers with different physico-chemical properties. The bottom portion, known as monimolimnion, has been studied for the functional stratification of microbial populations. Recent experiments have reported the profiles of bacterial and nutrient spatial distributions, but quantitative understanding is invoked to unravel the underlying mechanism of maintaining the discrete spatial organization. Here a reaction-diffusion model is developed to highlight the spatial pattern coupled with the light-driven metabolism of bacteria, which is resilient to a wide range of dynamical correlation between bacterial and nutrient species at the molecular level. Particularly, exact analytical solutions of the system are presented together with numerical results, in a good agreement with measurements in Ace lake and Rogoznica lake. Furthermore, one quantitative prediction is reported here on the dynamics of the seasonal stratification patterns in Ace lake. The active role played by the bacterial metabolism at microscale clearly shapes the biogeochemistry landscape of lake-wide ecology at macroscale.

Propagation of multi-cosine-Laguerre-Gaussian correlated Schell-model beams in free space and atmospheric turbulence.

We introduce a class of random stationary, scalar source named as multi-cosine-Laguerre-Gaussian-correlated Schell-model (McLGCSM) source whose spectral degree of coherence (SDOC) is a combination of the Laguerre-Gaussian correlated Schell-model (LGCSM) and multi-cosine-Gaussian correlated Schell-model (McGCSM) sources. The analytical expressions for the spectral density function and the propagation factor of a McLGCSM beam propagating in turbulent atmosphere are derived. The statistical properties, such as the spectral intensity and the propagation factor, of a McLGCSM beam are illustrated numerically. It is shown that a McLGCSM beam exhibits a robust ring-shaped beam array with adjustable number and positions in the far field by directly modulating the spatial structure of its SDOC in the source plane. Moreover, we provide a detailed insight into the theoretical origin and characteristics of such a ring-shaped beam array. It is demonstrated that these peculiar shaping properties are the concentrated manifestation of the individual merits respectively associated with the Laguerre- and multi-cosine-related factors of the whole SDOC. Our results provide a novel scheme to generate robust and controllable ring-shaped beam arrays over large distances, and will widen the potentials for manipulation of multiple particles, free-space optical communications and imaging in the atmosphere.

Direct Synthesis of ß-Aminoenals through Reaction of 1,2,3-Triazine with Secondary Amines.

Simple and direct nucleophilic addition of secondary amines, including imidazole, to 1,2,3-triazine under mild reaction conditions (THF, 25-65 °C, 12-48 h), requiring no additives, cleanly provides ß-aminoenals 4 in good yields (21 examples, 31-79%). The reaction proceeds by amine nucleophilic addition to C4 of the 1,2,3-triazine, in situ loss of N2, and subsequent imine hydrolysis to provide 4.

Evaluation of multifunctional synthetic tetralone derivatives for treatment of Alzheimer's disease.

Neurodegeneration, a complex disease state, comprises several pathways that contribute to cell death. Conventional approach of targeting only one of these pathways has not been proven to be entirely successful and has demanded a hypothetical change as to how researchers design and develop new drugs. In this study, effects of a series of α, ß-unsaturated carbonyl-based tetralone derivatives against Alzheimer's disease (AD) were investigated. Moreover, their activity toward amyloid ß-induced cytotoxicity was also studied. Six compounds including 3f, 3o, 3u, 3ae, 3af, and 3ag were discovered to be most protective against Aß-induced neuronal cell death in PC12 cells. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against MAO-B, AChE, and self-induced Aß1-42 aggregation. The compound 3f exhibited best AChE (IC50  = 0.045 ± 0.02 µm) inhibitory potential in addition to potent inhibition of MAO-B (IC50  = 0.88 ± 0.12 µm). Furthermore, compound 3f disassembled the Aß fibrils produced by self-induced Aß aggregation by 78.2 ± 4.8%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment.

Theranostic applications of carbon nanomaterials in cancer: Focus on imaging and cargo delivery.

Carbon based nanomaterials have attracted significant attention over the past decades due to their unique physical properties, versatile functionalization chemistry, and biological compatibility. In this review, we will summarize the current state-of-the-art applications of carbon nanomaterials in cancer imaging and drug delivery/therapy. The carbon nanomaterials will be categorized into fullerenes, nanotubes, nanohorns, nanodiamonds, nanodots and graphene derivatives based on their morphologies. The chemical conjugation/functionalization strategies of each category will be introduced before focusing on their applications in cancer imaging (fluorescence/bioluminescence, magnetic resonance (MR), positron emission tomography (PET), single-photon emission computed tomography (SPECT), photoacoustic, Raman imaging, etc.) and cargo (chemo/gene/therapy) delivery. The advantages and limitations of each category and the potential clinical utilization of these carbon nanomaterials will be discussed. Multifunctional carbon nanoplatforms have the potential to serve as optimal candidates for image-guided delivery vectors for cancer.