Propagation properties of a partially coherent Laguerre-Gaussian beam with multiple off-axis vortex phases.

In this paper, a new theoretical model of a partially coherent Laguerre-Gaussian (LG) beam carrying multiple off-axis vortex phases was established. The evolution properties of the focused intensity of the beam after passing through a thin lens were theoretically studied, and then the modulation effect of multiple off-axis vortex phases on the beam with multiring structured intensity was explored. The results indicate that the multiple off-axis vortex phases can reconstruct the multiring structured intensity within the LG beam, thus generating a structured intensity with multilobe and multiring patterns.

Non-Markovian Dynamic Models Identify Non-Canonical KRAS-VHL Encounter Complex Conformations for Novel PROTAC Design.

Targeted protein degradation (TPD) is emerging as a promising therapeutic approach for cancer and other diseases, with an increasing number of programs demonstrating its efficacy in human clinical trials. One notable method for TPD is Proteolysis Targeting Chimeras (PROTACs) that selectively degrade a protein of interest (POI) through E3-ligase induced ubiquitination followed by proteasomal degradation. PROTACs utilize a warhead-linker-ligand architecture to bring the POI (bound to the warhead) and the E3 ligase (bound to the ligand) into proximity.

Evaluation of clinical and imaging features for differentiating rhabdomyosarcoma from neuroblastoma in pediatric soft tissue.

Background: In this study, we developed a nomogram predictive model based on clinical, CT, and MRI parameters to differentiate soft tissue rhabdomyosarcoma (RMS) from neuroblastoma (NB) in children preoperatively.

Materials And Methods: A total of 103 children with RMS (n=37) and NB (n=66) were enrolled in the study from December 2012 to July 2023. The clinical and imaging data (assessed by two experienced radiologists) were analyzed using univariate analysis, and significant factors were further analyzed by multivariable logistic regression using the forward LR method to develop the clinical model, radiological model, and integrated nomogram model, respectively.

Performance and Analysis of the Alchemical Transfer Method for Binding-Free-Energy Predictions of Diverse Ligands.

The Alchemical Transfer Method (ATM) is herein validated against the relative binding-free energies (RBFEs) of a diverse set of protein-ligand complexes. We employed a streamlined setup workflow, a bespoke force field, and AToM-OpenMM software to compute the RBFEs of the benchmark set prepared by Schindler and collaborators at Merck KGaA. This benchmark set includes examples of standard small R-group ligand modifications as well as more challenging scenarios, such as large R-group changes, scaffold hopping, formal charge changes, and charge-shifting transformations.

Taming multiple binding poses in alchemical binding free energy prediction: the β-cyclodextrin host-guest SAMPL9 blinded challenge.

We apply the Alchemical Transfer Method (ATM) and a bespoke fixed partial charge force field to the SAMPL9 bCD host-guest binding free energy prediction challenge that comprises a combination of complexes formed between five phenothiazine guests and two cyclodextrin hosts. Multiple chemical forms, competing binding poses, and computational modeling challenges pose significant obstacles to obtaining reliable computational predictions for these systems. The phenothiazine guests exist in solution as racemic mixtures of enantiomers related by nitrogen inversions that bind the hosts in various binding poses, each requiring an individual free energy analysis.

Molecular Latent Space Simulators for Distributed and Multimolecular Trajectories.

All atom molecular dynamics (MD) simulations offer a powerful tool for molecular modeling, but the short time steps required for numerical stability of the integrator place many interesting molecular events out of reach of unbiased simulations. The popular and powerful Markov state modeling (MSM) approach can extend these time scales by stitching together multiple short discontinuous trajectories into a single long-time kinetic model but necessitates a configurational coarse-graining of the phase space that entails a loss of spatial and temporal resolution and an exponential increase in complexity for multimolecular systems. Latent space simulators (LSS) present an alternative formalism that employs a dynamical, as opposed to configurational, coarse graining comprising three back-to-back learning problems to (i) identify the molecular system's slowest dynamical processes, (ii) propagate the microscopic system dynamics within this slow subspace, and (iii) generatively reconstruct the trajectory of the system within the molecular phase space.

Modeling the Effect of Cooperativity in Ternary Complex Formation and Targeted Protein Degradation Mediated by Heterobifunctional Degraders.

Chemically induced proximity between certain endogenous enzymes and a protein of interest (POI) inside cells may cause post-translational modifications to the POI with biological consequences and potential therapeutic effects. Heterobifunctional (HBF) molecules that bind with one functional part to a target POI and with the other to an E3 ligase induce the formation of a target-HBF-E3 ternary complex, which can lead to ubiquitination and proteasomal degradation of the POI. Targeted protein degradation (TPD) by HBFs offers a promising approach to modulate disease-associated proteins, especially those that are intractable using other therapeutic approaches, such as enzymatic inhibition.

The slow but steady rise of binding free energy calculations in drug discovery.

Binding free energy calculations are increasingly used in drug discovery research to predict protein-ligand binding affinities and to prioritize candidate drug molecules accordingly. It has taken decades of collective effort to transform this academic concept into a technology adopted by the pharmaceutical and biotech industry. Having personally witnessed and taken part in this transformation, here I recount the (incomplete) list of problems that had to be solved to make this computational tool practical and suggest areas of future development.

Twisted Gaussian Schell-model breathers and solitons in strongly nonlocal nonlinear media.

Based on the Snyder-Mitchell linear model and the cross-spectral density (CSD) function, the analytical propagation formula of twisted Gaussian Schell-model (TGSM) beams in strongly nonlocal nonlinear medium (SNNM) is derived. Then the propagation characteristics of TGSM beam are studied. It is found that the soliton radius is jointly determined by the initial power, coherence length, and twist factor; the degree of spatial coherence is adjusted by changing the twist factor without affecting the soliton intensity.

Superimposed Hermite-Gaussian-correlated Schell-model beam with multiple off-axis vortices.

We first introduce a class of a superimposed Hermite-Gaussian-correlated Schell model with a multiple off-axis vortices beam, with the side lobe of the beam carrying one to four vortex singularities at the source plane. Subsequently, the variation laws of this beam after being focused by a thin lens are studied theoretically to obtain the optimal beam parameters. The numerical simulation results show that the beam possesses a unique multiple vortex structure, phase structure, and orbital angular momentum.

Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry.

Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated in diseases. A key step in this process is the formation of a ternary complex where a heterobifunctional molecule induces proximity of an E3 ligase to a protein of interest (POI), thus facilitating ubiquitin transfer to the POI. In this work, we characterize 3 steps in the TPD process.

Whole-volume ADC histogram of the brain as an image biomarker in evaluating disease severity of neonatal hypoxic-ischemic encephalopathy.

Purpose: To examine the diagnostic significance of the apparent diffusion coefficient (ADC) histogram in quantifying neonatal hypoxic ischemic encephalopathy (HIE).

Methods: An analysis was conducted on the MRI data of 90 HIE patients, 49 in the moderate-to-severe group, and the other in the mild group. The 3D Slicer software was adopted to delineate the whole brain region as the region of interest, and 22 ADC histogram parameters were obtained.

Characterizing Receptor Flexibility to Predict Mutations That Lead to Human Adaptation of Influenza Hemagglutinin.

A key step in the emergence of human pandemic influenza strains has been a switch in binding preference of the viral glycoprotein hemagglutinin (HA) from avian to human sialic acid (SA) receptors. The conformation of the bound SA varies substantially with HA sequence, and crystallographic evidence suggests that the bound SA is flexible, making it difficult to predict which mutations are responsible for changing HA-binding preference. We performed molecular dynamics (MD) simulations of SA analogues binding to various HAs and observed a dynamic equilibrium among structurally diverse receptor conformations, including conformations that have not been experimentally observed.

IL-31 expression in HIV-infected patients with different routes of disease transmission.

Acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV). AIDS is characterized by an impaired immune system and low cellular immunity. The main manifestation of AIDS is a reduction in the number of CD4+ T cells and alteration in cytokine concentration.

Non-Equilibrium Protein Folding and Activation by ATP-Driven Chaperones.

Recent experimental studies suggest that ATP-driven molecular chaperones can stabilize protein substrates in their native structures out of thermal equilibrium. The mechanism of such non-equilibrium protein folding is an open question. Based on available structural and biochemical evidence, I propose here a unifying principle that underlies the conversion of chemical energy from ATP hydrolysis to the conformational free energy associated with protein folding and activation.

Evolution properties of twisted Hermite Gaussian Schell-model beams in non-Kolmogorov turbulence.

A general form of twisted Hermite Gaussian Schell-model (THGSM) beams is introduced; analytical expressionsare obtained for cross-spectral density and M-factor using the extended Huygens-Fresnel principle and Wigner function. The evolution of THGSM beams during propagation in non-Kolmogorov turbulence is shown numerically; the beams exhibit self-splitting and twist into two lobes. The intensity distribution evolves into a Gaussian shape and beam quality worsens with increasing distance; the intensity distribution and M-factor are determined by the twist factor, beam orders, and other beam parameters.

Precise Binding Free Energy Calculations for Multiple Molecules Using an Optimal Measurement Network of Pairwise Differences.

Alchemical binding free energy (BFE) calculations offer an efficient and thermodynamically rigorous approach to in silico binding affinity predictions. As a result of decades of methodological improvements and recent advances in computer technology, alchemical BFE calculations are now widely used in drug discovery research. They help guide the prioritization of candidate drug molecules by predicting their binding affinities for a biomolecular target of interest (and potentially selectivity against undesirable antitargets).

Linc8986 and linc0597 in plasma are novel biomarkers for systemic lupus erythematosus.

Despite increasing evidence that large intergenic non-coding RNAs (lincRNAs) are widely involved in human disease, the role of lincRNAs in the development of systemic lupus erythematosus (SLE) has remained largely elusive. The purpose of the present study was to investigate the expression of three lincRNAs (linc0597, linc8986 and linc7190) in the plasma of patients with SLE and their potential use as biomarkers for the diagnosis and treatment of SLE. Plasma samples were obtained from 54 patients with SLE, 24 patients with rheumatoid arthritis (RA), 24 patients with Sjogren's syndrome (SS) and 22 healthy controls.

The genotype analysis of the hepatitis C virus in Heilongjiang Province, China.

Introduction: Hepatitis C virus (HCV) infection is a major public health issue. HCV genotype identification is clinically important to tailor the dosage and duration of treatment, and recombination in intra-patient populations of HCV may lead to the generation of escape mutants, as previously observed for other RNA viruses. Up to now, there is no study assessing HCV genotypes and subtypes in Heilongjiang Province, China.

Shaping the focal intensity distribution using a partially coherent radially polarized beam with multiple off-axis vortices.

A new kind of partially coherent vector vortex beam, namely, the partially coherent radially polarized (PCRP) beam with multiple off-axis vortices, is introduced, and the average intensity distributions of such vortex beam focused by a thin lens are investigated theoretically. It is novelty that the off-axis vortices will induce the focal intensity redistribution and reconstruction, while this remarkable characteristic will be vanished in the case of a very low coherence. In view of this distinctive feature, a new method has been put forward to shape or modulate the focal intensity distribution by elaborately tailoring the multiple off-axis vortices as well as the coherence length.

ATP-Driven Nonequilibrium Activation of Kinase Clients by the Molecular Chaperone Hsp90.

The molecular chaperone 90-kDa heat-shock protein (Hsp90) assists the late-stage folding and activation of diverse types of protein substrates (called clients), including many kinases. Previous studies have established that the Hsp90 homodimer undergoes an ATP-driven cycle through open and closed conformations. Here, I propose a model of client activation by Hsp90 that predicts that this cycle enables Hsp90 to use ATP energy to drive a client out of thermodynamic equilibrium toward its active conformation.

Alchemical Binding Free Energy Calculations in AMBER20: Advances and Best Practices for Drug Discovery.

Predicting protein-ligand binding affinities and the associated thermodynamics of biomolecular recognition is a primary objective of structure-based drug design. Alchemical free energy simulations offer a highly accurate and computationally efficient route to achieving this goal. While the AMBER molecular dynamics package has successfully been used for alchemical free energy simulations in academic research groups for decades, widespread impact in industrial drug discovery settings has been minimal because of the previous limitations within the AMBER alchemical code, coupled with challenges in system setup and postprocessing workflows.

Evolution properties of the radially polarized Laguerre-Gaussian-correlated Schell-model beams propagating in uniaxial crystals.

In this paper, we discuss, both analytically and numerically, the paraxial propagation of the radially polarized Laguerre-Gaussian-correlated Schell-model (LGCSM) beams orthogonal to the optical axis in uniaxial crystals. The analytical expression for the cross-spectral density function and the second-order moments of the radially polarized LGCSM beams are derived, and the evolution properties of the normalized intensity distribution, the spectral degree of the coherence (SDOC), and the spectral degree of the polarization (SDOP) in uniaxial crystals are elucidated by numerical examples. It is found that the intensity distribution of the radially polarized LGCSM beams evolves from a doughnut shape into a solid shape and finally converts into an elliptical symmetric hollow-ring profile in uniaxial crystals due to the combined effect of special correlation functions and the anisotropy effect of the uniaxial crystals.

Best Practices for Alchemical Free Energy Calculations [Article v1.0].

Alchemical free energy calculations are a useful tool for predicting free energy differences associated with the transfer of molecules from one environment to another. The hallmark of these methods is the use of "bridging" potential energy functions representing intermediate states that cannot exist as real chemical species. The data collected from these bridging alchemical thermodynamic states allows the efficient computation of transfer free energies (or differences in transfer free energies) with orders of magnitude less simulation time than simulating the transfer process directly.