RACER-m leverages structural features for sparse T cell specificity prediction.

Reliable prediction of T cell specificity against antigenic signatures is a formidable task, complicated by the immense diversity of T cell receptor and antigen sequence space and the resulting limited availability of training sets for inferential models. Recent modeling efforts have demonstrated the advantage of incorporating structural information to overcome the need for extensive training sequence data, yet disentangling the heterogeneous TCR-antigen interface to accurately predict MHC-allele-restricted TCR-peptide interactions has remained challenging. Here, we present RACER-m, a coarse-grained structural model leveraging key biophysical information from the diversity of publicly available TCR-antigen crystal structures. Explicit inclusion of structural content substantially reduces the required number of training examples and maintains reliable predictions of TCR-recognition specificity and sensitivity across diverse biological contexts. Our model capably identifies biophysically meaningful point-mutant peptides that affect binding affinity, distinguishing its ability in predicting TCR specificity of point-mutants from alternative sequence-based methods. Its application is broadly applicable to studies involving both closely related and structurally diverse TCR-peptide pairs.

Driving technology factors of carbon emissions: Theoretical framework and its policy implications for China.

Empirical studies have widely examined the driving factors and methods to achieve a carbon peak; however, they seldom construct a theoretical framework and ignore the potential heterogeneity in technology. The most notable controversy is technology's different roles in carbon emissions. This study proposes an integrated theoretical framework considering the evolution of carbon emissions and presents the conditions for achieving a carbon peak. This framework shows that if the positive role of eco-friendly technology in decreasing carbon emissions is larger than the negative role of production-oriented technology in increasing carbon emissions; thus, carbon emissions do not increase (i.e. carbon peak). Additionally, this framework addresses the controversy concerning the effect of technology on carbon emissions. Our empirical results from a city-level panel dataset show that China is still moving towards achieving carbon emission reduction. Analysis of the driving mechanism reveals that production-oriented technology increases carbon emissions by increasing the production scale, consequently demanding more energy and emitting more carbon dioxide.

Chromatin alternates between A and B compartments at kilobase scale for subgenic organization.

Nuclear compartments are prominent features of 3D chromatin organization, but sequencing depth limitations have impeded investigation at ultra fine-scale. CTCF loops are generally studied at a finer scale, but the impact of looping on proximal interactions remains enigmatic. Here, we critically examine nuclear compartments and CTCF loop-proximal interactions using a combination of in situ Hi-C at unparalleled depth, algorithm development, and biophysical modeling. Producing a large Hi-C map with 33 billion contacts in conjunction with an algorithm for performing principal component analysis on sparse, super massive matrices (POSSUMM), we resolve compartments to 500 bp. Our results demonstrate that essentially all active promoters and distal enhancers localize in the A compartment, even when flanking sequences do not. Furthermore, we find that the TSS and TTS of paused genes are often segregated into separate compartments. We then identify diffuse interactions that radiate from CTCF loop anchors, which correlate with strong enhancer-promoter interactions and proximal transcription. We also find that these diffuse interactions depend on CTCF's RNA binding domains. In this work, we demonstrate features of fine-scale chromatin organization consistent with a revised model in which compartments are more precise than commonly thought while CTCF loops are more protracted.

Precise Steric Features Control Aminoacyl-tRNA Accommodation on the Ribosome.

Protein synthesis involves a complex series of large-scale conformational changes in the ribosome. While long-lived intermediate states of these processes can be characterized by experiments, computational methods can be used to identify the interactions that contribute to the rate-limiting free-energy barriers. To this end, we use a simplified energetic model to perform molecular dynamics (MD) simulations of aminoacyl-tRNA (aa-tRNA) accommodation on the ribosome. While numerous studies have probed the energetics of the early stages of accommodation, we focus on the final stage of accommodation, where the 3'-CCA tail of aa-tRNA enters the peptidyl transferase center (PTC). These simulations show how a distinct intermediate is induced by steric confinement of the tail, immediately before it completes accommodation. Multiple pathways for 3'-CCA tail accommodation can be quantitatively distinguished, where the tail enters the PTC by moving past a pocket enclosed by Helix 89, 90, and 92, or through an alternate route formed by Helix 93 and the P-site tRNA. C2573, located within Helix 90, is shown to provide the largest contribution to this late-accommodation steric barrier, such that sub-Å perturbations to this residue can alter the time scale of tail accommodation by nearly an order of magnitude. In terms of biological function, these calculations suggest how this late-stage sterically induced barrier may contribute to tRNA proofreading by the ribosome.

Diffuse Ions Coordinate Dynamics in a Ribonucleoprotein Assembly.

Proper ionic concentrations are required for the functional dynamics of RNA and ribonucleoprotein (RNP) assemblies. While experimental and computational techniques have provided many insights into the properties of chelated ions, less is known about the energetic contributions of diffuse ions to large-scale conformational rearrangements. To address this, we present a model that is designed to quantify the influence of diffuse monovalent and divalent ions on the dynamics of biomolecular assemblies. This model employs all-atom (non-H) resolution and explicit ions, where effective potentials account for hydration effects. We first show that the model accurately predicts the number of excess Mg2+ ions for prototypical RNA systems, at a level comparable to modern coarse-grained models. We then apply the model to a complete ribosome and show how the balance between diffuse Mg2+ and K+ ions can control the dynamics of tRNA molecules during translation. The model predicts differential effects of diffuse ions on the free-energy barrier associated with tRNA entry and the energy of tRNA binding to the ribosome. Together, this analysis reveals the direct impact of diffuse ions on the dynamics of an RNP assembly.

SMOG 2 and OpenSMOG: Extending the limits of structure-based models.

Applying simulations with structure-based Go¯-like models has proven to be an effective strategy for investigating the factors that control biomolecular dynamics. The common element of these models is that some (or all) of the intra/inter-molecular interactions are explicitly defined to stabilize an experimentally determined structure. To facilitate the development and application of this broad class of models, we previously released the SMOG 2 software package. This suite allows one to easily customize and distribute structure-based (i.e., SMOG) models for any type of polymer-ligand system. The force fields generated by SMOG 2 may then be used to perform simulations in highly optimized MD packages, such as Gromacs, NAMD, LAMMPS, and OpenMM. Here, we describe extensions to the software and demonstrate the capabilities of the most recent version (SMOG v2.4.2). Changes include new tools that aid user-defined customization of force fields, as well as an interface with the OpenMM simulation libraries (OpenSMOG v1.1.0). The OpenSMOG module allows for arbitrary user-defined contact potentials and non-bonded potentials to be employed in SMOG models, without source-code modifications. To illustrate the utility of these advances, we present applications to systems with millions of atoms, long polymers and explicit ions, as well as models that include non-structure-based (e.g., AMBER-based) energetic terms. Examples include large-scale rearrangements of the SARS-CoV-2 Spike protein, the HIV-1 capsid with explicit ions, and crystallographic lattices of ribosomes and proteins. In summary, SMOG 2 and OpenSMOG provide robust support for researchers who seek to develop and apply structure-based models to large and/or intricate biomolecular systems.

Size-segregated physicochemical properties of inhalable particulate matter in a tunnel-ventilated layer house in China.

This study investigated the physicochemical properties of the particles in a typical commercial laying hen barn in Southeast China. Mass concentrations and size distributions of the particulate matter (PM) and the key components (incl. organic carbon (OC), element carbon (EC), and the water-soluble inorganic ions (WSIIs)) were analyzed. The result shows that the mass concentrations of PM accumulated along with the airflow inside the house, with the total mass of the sampling particles increasing from 843.66 ± 160.74 µg/m3 at the center of the house to 1264.93 ± 285.70 µg/m3 at the place close to exhaust fans. The particles with the aerodynamic equivalent diameter, Dp > 9 µm, coarse particles (2.1 µm < Dp ≤ 9 µm), fine particles (Dp ≤ 2.1 µm) accounted for around 50%, 40%, and 10% of the total mass of the sampling particles, respectively. Mass closure analysis shows secondary inorganic ions (NH4+, SO42- and NO3-) were abundant in the fine-mode fraction and OC accounted for more than 40% of the coarse particles. Size distribution analysis shows that the three secondary inorganic ions were bimodally distributed, and the rest tested components were unimodally distributed. The ratios of OC/EC in fine particles were smaller than those in the coarse particles. The equivalent concentration of WSIIs indicated that fine particles were slightly acidic, and the large size particles were slightly alkaline. Knowledge gained from this study will lead to a better understanding of physicochemical properties, sources, and formation of PM.

Molecular-Level Insights into Selective Transport of Mg2+ in Metal-Organic Frameworks.

Metal-organic frameworks (MOF) are promising media for achieving solid-state Mg2+ conduction and developing a magnesium-based battery. To this end, the chemical behavior and transport properties of an Mg(TFSI)2/DME electrolyte system inside Mg-MOF-74 were studied by density functional theory (DFT). We found that inside the MOF chemical environment, solvent and anion molecules occupy the coordinatively unsaturated open metal sites of Mg-MOF-74, while Mg2+ ions adsorb directly onto the carboxylate group of the MOF organic linker. These predicted binding geometries were further corroborated by IR spectroscopy. We computed the free energies of desolvation of Mg2+ ions inside MOF to investigate the capacity of Mg-MOF-74 thin film to act as a separator for selective Mg2+ transport. We showed that Mg-MOF-74 could facilitate partial, but not full, desolvation of Mg2+. We found that the dominant minimum-energy pathway (MEP) for Mg2+ conduction inside Mg-MOF-74 corresponds to a "solvent hopping" mechanism, with an energy barrier of 4.4 kcal/mol. The molar conductivity of Mg2+ associated with the idealized solvent hopping mechanism along the MOF one-dimensional channel was predicted to be 2.4 × 10-3 S cm-1 M-1, which is one to two orders of magnitude greater than the experimentally measured value of 1.2 × 10-4 S cm-1 M-1 (with an estimated Mg2+ concentration). We have discussed several possible factors contributing to this apparent discrepancy. The current work demonstrates the validity of the computational strategies applied and the structural models constructed for the understanding of fast and selective Mg2+ transport in Mg-MOF-74, which serves as a cornerstone for studying transport of multivalent ions in MOFs. Furthermore, it provides detailed molecular-level insights that are not yet accessible experimentally.

A steric gate controls P/E hybrid-state formation of tRNA on the ribosome.

The ribosome is a biomolecular machine that undergoes multiple large-scale structural rearrangements during protein elongation. Here, we focus on a conformational rearrangement during translocation, known as P/E hybrid-state formation. Using a model that explicitly represents all non-hydrogen atoms, we simulated more than 120 spontaneous transitions, where the tRNA molecule is displaced between the P and E sites of the large subunit. In addition to predicting a free-energy landscape that is consistent with previous experimental observations, the simulations reveal how a six-residue gate-like region can limit P/E formation, where sub-angstrom structural perturbations lead to an order-of-magnitude change in kinetics. Thus, this precisely defined set of residues represents a novel target that may be used to control functional dynamics in bacterial ribosomes. This theoretical analysis establishes a direct relationship between ribosome structure and large-scale dynamics, and it suggests how next-generation experiments may precisely dissect the energetics of hybrid formation on the ribosome.

Micro Magnetic Field Produced by Fe3O4 Nanoparticles in Bone Scaffold for Enhancing Cellular Activity.

The low cellular activity of poly-l-lactic acid (PLLA) limits its application in bone scaffold, although PLLA has advantages in terms of good biocompatibility and easy processing. In this study, superparamagnetic Fe3O4 nanoparticles were incorporated into the PLLA bone scaffold prepared by selective laser sintering (SLS) for continuously and steadily enhancing cellular activity. In the scaffold, each Fe3O4 nanoparticle was a single magnetic domain without a domain wall, providing a micro-magnetic source to generate a tiny magnetic field, thereby continuously and steadily generating magnetic stimulation to cells. The results showed that the magnetic scaffold exhibited superparamagnetism and its saturation magnetization reached a maximum value of 6.1 emu/g. It promoted the attachment, diffusion, and interaction of MG63 cells, and increased the activity of alkaline phosphatase, thus promoting the cell proliferation and differentiation. Meanwhile, the scaffold with 7% Fe3O4 presented increased compressive strength, modulus, and Vickers hardness by 63.4%, 78.9%, and 19.1% compared with the PLLA scaffold, respectively, due to the addition of Fe3O4 nanoparticles, which act as a nanoscale reinforcement in the polymer matrix. All these positive results suggested that the PLLA/Fe3O4 scaffold with good magnetic properties is of great potential for bone tissue engineering applications.

A Metal-Organic Framework Thin Film for Selective Mg2+ Transport.

The incompatibility between the anode and the cathode chemistry limits the used of Mg as an anode. This issue may be addressed by separating the anolyte and the catholyte with a membrane that only allows for Mg2+ transport. Mg-MOF-74 thin films were used as the separator for this purpose. It was shown to meet the needs of low-resistance, selective Mg2+ transport. The uniform MOF thin films supported on Au substrate with thicknesses down to ca. 202 nm showed an intrinsic resistance as low as 6.4â€…Ω cm2 , with the normalized room-temperature ionic conductivity of ca. 3.17×10-6  S cm-1 . When synthesized directly onto a porous anodized aluminum oxide (AAO) support, the resulting films were used as a standalone membrane to permit stable, low-overpotential Mg striping and plating for over 100 cycles at a current density of 0.05 mA cm-2 . The film was effective in blocking solvent molecules and counterions from crossing over for extended period of time.

Fluctuation Effects in the Adam-Gibbs Model of Cooperative Relaxation.

A generalization of the Adam-Gibbs model of relaxation in glass-forming liquids is formulated that takes into account fluctuation in the number of molecules inside the cooperative region. The configurational fraction links the excess entropy with kinetic properties described in the Adam-Gibbs model. We express the configurational fraction at the glass-transition temperature in terms of the width of the distribution of relaxation times, the nonlinearity parameter that demarcates the variations of the relaxation time with structure and temperature, the steepness index that is proportional to the slope of the logarithm of the relaxation time with respect to temperature, the excess heat capacity under constant pressure, and the number of correlated molecules or structural units. The configurational fraction in the absence of fluctuation effects is also determined for several glass-forming liquids at the glass-transition temperature.

Using SMOG 2 to Simulate Complex Biomolecular Assemblies.

Over the last 20 years, the application of structure-based (Go-like) models has ranged from protein folding with coarse-grained models to all-atom representations of large-scale molecular assemblies. While there are many variants that may be employed, the common feature of these models is that some (or all) of the stabilizing energetic interactions are defined based on the knowledge of a particular experimentally obtained conformation. With the generality of this approach, there was a need for a versatile computational platform for designing and implementing this class of models. To this end, the SMOG 2 software package provides an easy-to-use interface, where the user has full control of the model parameters. This software allows the user to edit XML-formatted files in order to provide definitions of new structure-based models. SMOG 2 reads these "template" files and maps the interactions onto specific structures, which are provided in PDB format. The force field files produced by SMOG 2 may then be used to perform simulations with a variety of popular molecular dynamics suites. In this chapter, we describe some of the key features of the SMOG 2 package, while providing examples and strategies for applying these techniques to complex (often large-scale) molecular assemblies, such as the ribosome.

Convergence analysis of China's energy intensity at the industrial sector level.

China's industrial energy consumption accounted for approximately 70% of national energy demand in the past four decades. Regarding energy demand and environmental pollution, success in controlling energy demand and reducing energy intensity for industrial sectors in China would play a crucial role for the country's sustainable growth problems. To formulate targeted energy plans, the features and characters of China's industrial energy intensity should be carefully evaluated. In this study, a carefully designed econometric model that considers different technological factors including indigenous R&D and technology spillovers from foreign direct investment and trade under a united framework is applied to investigate the ß-convergence characteristics for China's industrial energy intensity by employing a panel dataset covering China's 34 industrial sectors over 2000-2010. The results verify the existence of ß-convergence in industrial energy intensity during the sample period. For the industrial sectors overall and the light industrial sectors, the empirical results indicate that indigenous R&D and technology spillovers from FDI and imports are beneficial in curbing energy intensity. However, technology spillover through exports makes it harder to reduce energy intensity. In addition, not all technological factors have played a significant role in reducing energy intensity for the heavy industrial sectors.

RNA as a Complex Polymer with Coupled Dynamics of Ions and Water in the Outer Solvation Sphere.

We unravel the internal and collective modes of a widely studied 58-nucleotide rRNA fragment in solvent using atomically detailed molecular dynamics simulations. The variation of lifetimes for water hydrogen bonds with nucleotide groups indicates heterogeneity of water dynamics on the RNA surface. The time scales of interactions of the discrete water molecules with RNA nucleotides extend from several hundred picoseconds to a few nanoseconds. We determine all of the association sites and the spatial distribution of residence times for Mg2+, K+, and water molecules in those sites. We provide insights into the population of Mg2+ and K+ ions and water molecules in the outer sphere and how their fluctuations are intricately linked with the kinetics of the 58-mer. We find that many of the long-lived Mg2+ sites identified from the simulations agree with the locations of ions in the X-ray structure. We determine the excess ion atmosphere around the rRNA and compare it with experimental data. We investigate the collective behavior of RNA, ions, and water, by performing a joint principle component analysis for the Cartesian coordinates of the RNA phosphorus atoms and for the occupation counts of the association sites. Our results indicate that the 58-mer system is a complex polymer, composed of RNA that is encased by a fluctuating network of associated counterions, co-ions, and water.

Designing p-type semiconductor-metal hybrid structures for improved photocatalysis.

A practical strategy is proposed to facilitate the migration of holes in semiconductor (the low rate of which limits photocatalytic efficiency) by taking advantage of the Schottky barrier between p-type semiconductor and metal. A high work function is found to serve as an important selection rule for building such desirable Schottky junction between semiconductor surface facets and metal. The intrinsic charge spatial distribution has to be taken into account when selecting the facets, as it results in accumulation of photoexcited electrons and holes on certain semiconductor facets. Importantly, the facets have a high work function, the same characteristic required for the formation of Schottky junction in a p-type semiconductor-metal hybrid structure. As a result, the semiconductor crystals in the hybrid design may be better enclosed by single facets with high work function, so as to synergize the two effects: Schottky barrier versus charge spatial separation.