Intermediate Structure Research Articles

Mapping the FF domain folding pathway via structures of transiently populated folding intermediates

Despite the tremendous accomplishments of AlpaFold2/3 in predicting biomolecular structure, the protein folding problem remains unsolved in the sense that accurate atomistic models of how protein molecules fold into their native conformations from an unfolded ensemble are still elusive. Here, using chemical exchange saturation transfer (CEST) NMR experiments and a comprehensive four-state kinetic model of the folding trajectory of a 71 residue four-helix bundle FF domain from human HYPA/FBP11 we present an atomic resolution structure of a transiently formed intermediate, I2, that along with the structure of a second intermediate, I1, provides a description of the FF domain folding trajectory. By recording CEST profiles as a function of urea concentration the extent of compaction along the folding pathway is evaluated. Our data establish that unlike the partially disordered I1 state, the I2 intermediate that is also formed before the rate-limiting folding barrier is well ordered and compact like the native conformer, while retaining nonnative interactions similar to those found in I1. The slow-interconversion from I2 to F, involving changes in secondary structure and the breaking of nonnative interactions, proceeds via a compact transition-state. Interestingly, the native state of the FF1 domain from human p190-A Rho GAP resembles the I2 conformation, suggesting that well-ordered folding intermediates can be repurposed by nature in structurally related proteins to assume functional roles. It is anticipated that the strategy for elucidation of sparsely populated and transiently formed structures of intermediates along kinetic pathways described here will be of use in other studies of protein dynamics.

Total Synthesis of Euphorbialoid A.

Euphorbialoid A (1) belongs to the rare diterpenoid family of premyrsinanes and exhibits potent anti-inflammatory effects. The 5/7/6/3-membered carbocycle (ABCD-ring) of 1 contains 11 contiguous stereocenters and seven oxygen-containing functional groups. Moreover, four of the six hydroxy groups of 1 are concentrated in the southern sector and flanked by four structurally different acyl groups. The dense array of various functional groups with disparate reactivities on the tetracyclic ABCD-ring presents a daunting challenge for the chemical synthesis of 1. As a reflection of its formidable complexity, synthesis of 1 or any other premyrsinane diterpenoids has not yet been reported. Here, we devised a novel strategy comprising two stages and achieved the first total synthesis of 1 (35 steps as the longest linear sequence). In the first stage, the ABCD-ring was expeditiously assembled by integrating three powerful transformations: (1) Pt-doped TiO2-catalyzed radical coupling to attach a northern chain to a 6/3-membered CD-ring, (2) Pd-catalyzed decarboxylative asymmetric allylation to construct a quaternary carbon with a southern chain, and (3) a Co-mediated Pauson-Khand reaction to cyclize the two chains into the 5/7-membered AB-ring. In the second stage, three-dimensional structures of the ABCD-ring intermediates were utilized to stereoselectively fabricate the A-ring and site-selectively append the four different acyl groups. In the present total synthesis, we revealed the significance of orchestrating the multistep reaction sequence and incorporating cyclic protective groups. The overall strategy and tactics provide new insights into designing synthetic routes to premyrsinanes and densely oxygenated terpenoids decorated with diverse acyl groups.

Adsorbate Configurations in Ni Single-Atom Catalysts during CO2 Electrocatalytic Reduction Unveiled by Operando XAS, XES, and Machine Learning

Nickel and nitrogen co-doped carbon (Ni-N-C) catalysts are attracting attention due to their exceptionally high performance in the electrocatalytic reduction of CO2(CO2RR) to CO. However, the direct experimental insight into the working mechanism of these catalysts is missing, hindering our fundamental understanding and their further improvement. This work sheds light on the nature of adsorbates forming under CO2RR at singly dispersed Ni sites. In particular, high energy resolution fluorescence detected x-ray absorption near edge structure (HERFD-XANES) at the Ni K-edge together with valence-to-core x-ray emission spectroscopy (vtc-XES) and x-ray absorption (XAS) at the Ni L3-edge were employed to unveil the structure and electronic properties of the reaction intermediates. These techniques, coupled with unsupervised and supervised machine learning methodologies and density functional theory, enabled a comprehensive characterization of the local atomistic and electronic structure of the working Ni-N-C catalysts. Specifically, we were able to distinguish between the structural and electronic changes of the Ni sites associated with the CO2RR functionality from the effect of radiation-induced damage, providing direct insight into the bond formation between the Ni centers and CO2RR intermediates such as CO adsorbates. Published by the American Physical Society 2024

MATTopo: Topology-preserving Medial Axis Transform with Restricted Power Diagram

We present a novel topology-preserving 3D medial axis computation framework based on volumetric restricted power diagram (RPD), while preserving the medial features and geometric convergence simultaneously, for both 3D CAD and organic shapes. The volumetric RPD discretizes the input 3D volume into sub-regions given a set of medial spheres. With this intermediate structure, we convert the homotopy equivalency between the generated medial mesh and the input 3D shape into a localized contractibility checking for each restricted element (power cell, power face, power edge), by checking their connected components and Euler characteristics. We further propose a fractional Euler characteristic algorithm for efficient GPU-based computation of Euler characteristic for each restricted element on the fly while computing the volumetric RPD. Compared with existing voxel-based or point-cloud-based methods, our approach is the first to adaptively and directly revise the medial mesh without globally modifying the dependent structure, such as voxel size or sampling density, while preserving its topology and medial features. In comparison with the feature preservation method MATFP [Wang et al. 2022], our method provides geometrically comparable results with fewer spheres and more robustly captures the topology of the input 3D shape.

Investigating the relationship between body structure status, work activity type, and the prevalence of musculoskeletal disorders among detergent industry workers.

The physical condition of workers' body structure and assigned duties, can contribute to the prevalence of musculoskeletal disorders. This study aimed to investigate the relationship between body structure status, type of work activity, and the prevalence of musculoskeletal disorders among workers in the detergent industry. This cross-sectional study involved 148 industrial workers selected based on inclusion criteria and their medical checkup records. Data collection for the study included a demographic information questionnaire, a body map questionnaire, and an assessment of the workers' musculoskeletal system conducted by three physiotherapists simultaneously. 54.1% of the participants had a total body structure score classified as poor or fair. The neck region showed the highest prevalence of musculoskeletal disorders (51.4%), followed by the lower back region (35.1%). Significant associations were found between abnormalities in the upper and middle limbs of the body and the prevalence of pain in the right shoulder region (Fisher/F = 9.29, P≤0.05) as well as the intermediate back region (F = 10.28, P≤0.01). Office workers experienced a higher prevalence of neck pain than workers in the product line and technical roles, with a statistically significant Odds Ratio (OR) ranging between 2.7 and 6.6 times. Conversely, industrial workers who operate powered machinery showed a higher prevalence of pain in the left shoulder (OR = 3.93) and left foot (OR = 4.07). Meanwhile, workers involved in loading and unloading tasks had a higher prevalence of pain in the middle back (OR = 3.61) and right foot (OR = 4.5) compared to office workers. The prevalence of pain in the right shoulder and middle back may be due to abnormalities in the upper and intermediate body structure. Production line workers reported a higher prevalence of pain in the left shoulder, middle back, and foot compared to office workers.

Structural Properties of [N1888][TFSI] Ionic Liquid: A Small Angle Neutron Scattering and Polarizable Molecular Dynamics Study.

In this study, we investigate the quaternary ammonium-based ionic liquid (QAIL), methyltrioctylammonium bis(trifluoromethylsulfonyl)imide, [N1888][TFSI], utilizing small angle neutron scattering (SANS) measurements and polarizable molecular dynamics (MD) simulations to characterize the short- and long-range liquid structure. Scattering structure factors show signatures of three length scales in reciprocal space indicative of alternating polarity (k ∼ 0.44 Å-1), charge (k ∼ 0.75 Å-1), and neighboring or adjacent (k ∼ 1.46 Å-1) domains. Excellent agreement between simulation and experimental scattering structure factors validates various simulation analyses that provide detailed atomistic characterization of the different length scale correlations. The first solvation shell structure is illustrated by obtaining radial, angular, dihedral, and combined distribution functions, where two dominant spatial motifs, N+···N- and N+···O-, compete for optimal packing around the polar head of the [N1888]+ cation. Intermediate and long-range structures are governed by the balance between local electroneutrality and octyl chain networking, respectively. By computing the charge-correlation structure factor, SZZ, and the spatial extent of the octyl chain network using graph theory, the bulk-phase structure of [N1888][TFSI] is characterized in terms of electrostatic screening and apolar domain formation length scales.

Reactions of Aluminum Oxide Cluster Cations with Ethane: A Mass-Spectrometric and Vibrational Spectroscopy Study.

The pathways for the reactions of aluminum oxide cluster ions with ethane have been measured. For selected ions (Al2O+, Al3O2 +, Al3O4 +, Al4O7 +) the structure of the collisionally-stabilized reaction intermediates were explored by measuring the photodissociation vibrational spectra from 2600 cm-1-3100 cm-1. Density functional theory was used to calculate features of the potential energy surfaces for the reactions and the vibrational spectra of intermediates. Generally, more than one isomer contributes to the observed spectrum. The oxygen-deficient clusters Al2O+ and Al3O2 + have large C-H activation barriers, so only the entrance channel complexes in which intact C2H6 binds to aluminum are observed. This interaction leads to a substantial (~200 cm-1) red shift of the C-H symmetric stretch in ethane, indicating significant weakening of the proximal C-H bonds. In Al3O4 +, the complex formed by interactions with three C2H6 is investigated and, in addition to entrance channel complexes, the C-H activation intermediate Al3O4H+(C2H5)(C2H6)2 is observed. For oxygen-rich Al4O7 +, the C2H6 is favored to bind at an aluminum site far from the reactive superoxide group, reducing the reactivity. As expected, oxygen-rich species and open-shell cluster ions have smaller barriers for C-H bond activation, except for Al3O4 + which is predicted and observed to be reactive.

Synthesis research on the herbicide safe agent Furilazole

Furfural and nitromethane were utilized as raw materials for the synthesis of the herbicide-safe agent Furilazole through the Henry reaction, nitro reduction and addition-cyclization-acylation. A comprehensive investigation into the involved reaction processes was conducted, leading to the identification of barium hydroxide octahydrate as the catalyst for the Henry reaction. The continuous use methodology of the excess catalyst was determined through TGA/DSC curve analysis, and a rational purification method for Henry reaction products was proposed. The nitro reduction reaction employed Pd/C catalysis, while the subsequent addition-cyclization-acylation reaction was achieved in a single step. Five impurities affecting the reaction process were identified, and their potential mechanisms of formation were postulated. Optimization of synthetic process conditions was carried out for all involved reactions. The structures of intermediates, impurities, and products were characterized using NMR, HRMS, TGA/DSC and FTIR.

High-performance and fabrication-tolerant edge coupler on thin film lithium niobate based on a three-dimensional inverse taper

Thin film lithium niobate has been widely considered as a promising photonic integration platform. However, due to the non-vertical sidewall of lithium niobate etching, it is challenging to design an efficient fiber coupler for the submicron-sized lithium niobate waveguide. Here, a high-performance edge coupler to a cleaved fiber is introduced on the thin film lithium niobate platform using a sharp three-dimensional taper. The proposed taper structure, which ensures a nearly adiabatical transition of both transverse-electric (TE) and transverse-magnetic (TM) modes, is formed by two standard patterning steps for lithium niobate. A silica ridge waveguide is used as the intermediate transition structure between the taper and a high-numerical-aperture fiber. The simulated coupling losses are as low as −0.1 dB per facet, while the experimental mean values reach −0.29 and −0.24 dB for TE and TM modes, respectively. The coupling spectra exhibit a flat wavelength response, which almost coincides for both polarizations. The 0.5-dB coupling bandwidth is beyond 180 nm. Within this bandwidth, the worst coupling losses are −0.61 and −0.56 dB for TE and TM modes, respectively, and the polarization-dependent loss is below 0.17 dB. The present edge coupler also exhibits a good fabrication tolerance, and its fabrication can also facilitate wafer-scale processing without wafer dicing and end-facet polishing.

Polyfluorene-based conjugated nanocomposites with in-situ gold nanoparticles: Synthesis via rational chemical passivation and characterization of supramolecular fibrillar structures

We present a rational and innovative chemical approach for synthesizing and characterizing conjugated polymer nanocomposites as direct passivation of gold nanoparticles (AuNPs), highlighting intrinsic morphologies and distinct photophysical properties in the solid state. The pioneering synthesis of polyfluorene with thiol, LaPPS79.10, revolutionized its application as a direct passivator of AuNPs, resulting in stable nanocomposites with the capacity for storage in the dry state and subsequent redispersion in organic solvent. The presence of AuNPs with average diameters of 3.5 ± 1.3 nm induced the formation of an interconnected fibrillar supramolecular network (ribbon-like) and several microdomains in the nanocomposite (LaPPS79.10+AuNPs), correlated by XRD, TEM and SEM measurements. Characterization of the polyfluorene precursor derivative, LaPPS10, revealed bundle-like morphologies with aggregation-induced emission (AIE). Introducing thiol groups into the intermediate structure induced polymer chain organization (LaPPS79.10), leading to unique straw-like and lenticular bundle morphologies, disrupting the non-planar π-π packing and quenching the emission, a case of aggregation-caused quenching (ACQ). In LaPPS79.10+AuNPs, the proximity of the π system to the Au localized surface plasmon resonance (LSPR) resulted in high absorption, negligible self-absorption, and efficient emission quenching, as well as improved thermal resistance compared to the original polymer. The unprecedented discovery of the properties resulting from the electronic interaction between the π system of the AuNPs passivating polymer and the effects of plasmonic resonance represents a significant advance in nanoscience, opening new perspectives for exciting applications in organic photovoltaic devices and metamaterials.

Electron tomography visualization of HIV-1 virions trapped by fusion inhibitors to host cells in infected tissues.

HIV-1 delivers its genetic material to infect a cell after fusion of the viral and host cell membranes, which takes place after the viral envelope (Env) binds host receptor and co-receptor proteins. Binding of host receptor CD4 to Env results in conformational changes that allow interaction with a host co-receptor (CCR5 or CXCR4). Further conformational rearrangements result in an elongated pre-hairpin intermediate structure in which Env is anchored to the viral membrane by its transmembrane region and to the host cell membrane by its fusion peptide. Although budding virions can be readily imaged by electron tomography (ET) of HIV-1-infected tissues and cultured cells, virions that are fusing (attached to host cells via pre-hairpin intermediates) are not normally visualized, perhaps because the process of membrane fusion is too fast to capture by ET. To image virions during fusion, we used fusion inhibitors to prevent downstream conformational changes in Env that lead to membrane fusion, thereby trapping HIV-1 virions linked to target cells by pre-hairpin intermediates. ET of HIV-1 pseudovirions bound to CD4+/CCR5+ TZM-bl cells revealed presumptive pre-hairpin intermediates as 2-4 narrow spokes linking a virion to the cell surface. To extend these results to a more physiological setting, we used ET to image tissues and organs derived from humanized bone marrow/liver/thymus mice infected with HIV-1 and then treated with CPT31, a high-affinity D-peptide fusion inhibitor linked to cholesterol. Trapped HIV-1 virions were found in all tissues studied (small intestine, mesenteric lymph nodes, spleen, and bone marrow), and spokes representing pre-hairpin intermediates linking trapped virions to cell surfaces were similar in structure and number to those seen in the previous pseudovirus and cultured cell ET study.IMPORTANCETrapped and untrapped HIV-1 virions, both mature and immature, were distinguished by localizing spokes via 3D tomographic reconstructions of HIV-1 infected and fusion-inhibitor-treated tissues of humanized mice. The findings of trapped HIV-1 virions in all tissues examined demonstrate a wide distribution of the CPT31 inhibitor, a desirable property for a potential therapeutic. In addition, the presence of virions trapped by spokes, particularly in vascular endothelial cells, demonstrates that the fusion inhibitors can be used as markers for potential HIV-1-target cells within tissues, facilitating the mapping of HIV-1 target cells within the complex cellular milieu of infected tissues.

Monomer unfolding of a bacterial ESCRT-III superfamily member is coupled to oligomer disassembly.

The inner membrane associated protein of 30 kDa (IM30), a member of the endosomal sorting complex required for transport (ESCRT-III) superfamily, is crucially involved in the biogenesis and maintenance of thylakoid membranes in cyanobacteria and chloroplasts. In solution, IM30 assembles into various large oligomeric barrel- or tube-like structures, whereas upon membrane binding it forms large, flat carpet structures. Dynamic localization of the protein in solution, to membranes and changes of the oligomeric states are crucial for its in vivo function. ESCRT-III proteins are known to form oligomeric structures that are dynamically assembled from monomeric/smaller oligomeric proteins, and thus these smaller building blocks must be assembled sequentially in a highly orchestrated manner, a still poorly understood process. The impact of IM30 oligomerization on function remains difficult to study due to its high intrinsic tendency to homo-oligomerize. Here, we used molecular dynamics simulations to investigate the stability of individual helices in IM30 and identified unstable regions that may provide structural flexibility. Urea-mediated disassembly of the IM30 barrel structures was spectroscopically monitored, as well as changes in the protein's tertiary and secondary structure. The experimental data were finally compared to a three-state model that describes oligomer disassembly and monomer unfolding. In this study, we identified a highly stable conserved structural core of ESCRT-III proteins and discuss the advantages of having flexible intermediate structures and their putative relevance for ESCRT-III proteins.

Synthesis of Novel Pseudo-Enantiomeric Phase-Transfer Catalysts from Cinchona Alkaloids and Application to the Hydrolytic Dynamic Kinetic Resolution of Racemic 3-Phenyl-2-oxetanone.

Naturally occurring Cinchona alkaloids such as quinidine (QD)/cinchonine (CN) and their diastereomers, quinine (QN)/cinchonidine (CD), have been recognized as pseudo-enantiomeric pairs. Utilizing these pseudo-enantiomeric alkaloids as chiral resources provides complementary enantioselectivity in many asymmetric reactions. During the screening of Cinchona alkaloid phase-transfer catalysts (PTCs) in the hydrolytic dynamic kinetic resolution of racemic 3-phenyl-2-oxetanone (1) to tropic acid (2), we found that the introduction of a 4-trifluoromethylphenyl group at the vinyl terminus of BnQN significantly reduced the enantioselectivity to 41% enantiomeric excess (ee). The optimized structure of tetrahedral intermediates (TI, PTC + 1 + OH-) of hydrolysis obtained by density functional theory (DFT) calculations shows that the orientation of the quinoline and benzene rings of QD class PTC are nearly parallel to each other and to construct a greatly extended π-electron cloud surface, allowing good π-π interaction with the benzene ring of 1.

Electrocatalysts for Urea Synthesis from CO2 and Nitrogenous Species: From CO2 and N2/NOx Reduction to urea synthesis.

The traditional industrial synthesis of urea relies on the energy-intensive and polluting process, namely the Haber-Bosch method for ammonia production, followed by the Bosch-Meiser process for urea synthesis. In contrast, electrocatalytic C-N coupling from carbon dioxide (CO2) and nitrogenous species presents a promising alternative for direct urea synthesis under ambient conditions, bypassing the need for ammonia production. This review provides an overview of recent progress in the electrocatalytic coupling of CO2 and nitrogen sources for urea synthesis. It focuses on the role of intermediate species and active site structures in promoting urea synthesis, drawing from insights into reactants' adsorption behavior and interactions with catalysts tailored for CO2 reduction, nitrogen reduction, and nitrate reduction. Advanced electrocatalyst design strategies for urea synthesis from CO2 and nitrogenous species under ambient conditions are explored, providing insights for efficient catalyst design. Key challenges and prospective directions are presented in the conclusion. Mechanistic studies elucidating the C-N coupling reaction and future development directions are discussed. The review aims to inspire further research and development in electrocatalysts for electrochemical urea synthesis.

Biochemical analysis of packing and assembling heptad repeat motifs in the coronavirus spike protein trimer.

During a coronavirus infection, the spike protein undergoes sequential structural transitions triggered by its receptor and the host protease at the interface between the virus and cell membranes, thereby mediating membrane fusion. After receptor binding, the heptad repeat motif (HR1/HR2) within the viral spike protein bridges the viral and cellular membranes; however, the intermediate conformation adopted by the spike protein when drawing the viral and cellular membranes into close proximity remains unclear due to its transient and unstable nature. Here, we experimentally induced conformational changes in the spike protein of a murine coronavirus by incubating the virus with its receptor, followed by exposure to trypsin. We then treated the virus/receptor complex with proteinase K to probe the tightly packed core structure of the spike protein. The conformations of the spike protein were predicted from the sizes of the protease digestion products detected by western blot analysis. Upon receptor binding, two bands (each showing different reactivity with a fusion-inhibiting HR2-peptide) were detected; we propose that these bands correspond to the packed and unpacked HR1/HR2 motifs. After trypsin-mediated triggering, measurement of temperature and time dependency revealed that packing of the remaining unpacked HR1/HR2 motifs and assembly of three HR1 motifs in a trimer occur almost simultaneously. Thus, the trimeric spike protein adopts an asymmetric-unassembled conformation after receptor binding, followed by direct assembly into the post-fusion form triggered by the host protease. This biochemical study provides mechanistic insight into the previously unknown intermediate structure of the viral fusion protein.IMPORTANCEDuring infection by an enveloped virus, receptor binding triggers fusion between the cellular membrane and the virus envelope, enabling delivery of the viral genome to the cytoplasm. The viral spike protein mediates membrane fusion; however the molecular mechanism underlying this process is unclear. This is because using structural biology methods to track the transient conformational changes induced in the unstable spike trimer is challenging. Here, we harnessed the ability of protease enzymes to recognize subtle differences on protein surfaces, allowing us to detect structural differences in the spike protein before and after conformational changes. Differences in the size of the degradation products were analyzed by western blot analysis. The proposed model explaining the conformational changes presented herein is a plausible candidate that provides valuable insight into unanswered questions in the field of virology.

Abiotic Acyl Transfer Cascades Driven by Aminoacyl Phosphate Esters and Self-Assembly.

Biochemical acyl transfer cascades, such as those initiated by the adenylation of carboxylic acids, are central to various biological processes, including protein synthesis and fatty acid metabolism. Designing cascade reactions in aqueous media remains challenging due to the need to control multiple, sequential reactions in a single pot and manage the stability of reactive intermediates. Herein, we developed abiotic cascades using aminoacyl phosphate esters, the synthetic counterparts of biological aminoacyl adenylates, to drive sequential chemical reactions and self-assembly in a single pot. We demonstrated that the structural elements of amino acid side chains (aromatic versus aliphatic) significantly influence the reactivity and half-lives of aminoacyl phosphate esters, ranging from hours to days. This behavior, in turn, affects the number of couplings we can achieve in the network and the self-assembly propensity of activated intermediate structures. The cascades are constructed using bifunctional peptide substrates featuring side chain nucleophiles. Specifically, aromatic amino acids facilitate the formation of transient thioesters, which preorganized into spherical aggregates and further couple into chimeric assemblies composed of esters and thioesters. In contrast, aliphatic amino acids, which lack the ability to form such structures, predominantly undergo hydrolysis, bypassing further transformations after thioester formation. Additionally, in mixtures containing multiple aminoacyl phosphate esters and peptide substrates, we achieved selective product formation by following a distinct pathway that favors subsequent reactions through reactivity changes and self-assembly. By coupling chemical reactions with molecules of varying reactivity time scales, we can drive multiple reaction clocks with distinct lifetimes and self-assembly dynamics, facilitating precise temporal and structural regulation.

Study on the Properties of rhodamine B fluorescent probe Y2ST

Rhodamine B, hydrazine hydrate, and HCl generated the intermediate LBXJ. Next, LBXJ, chromone 3-formaldehyde, and 100 % ethanol prepared the probe Y2ST. NMR, IR, and MS. described the intermediate and probe structures. Following the determination of the structure, tests were conducted on the response time, pH value, linearity, detection limit, accuracy, coordination ratio, and recovery of samples. Additionally, the fluorescence selectivity of ions was compared. The rate of Zn2+ detection in zinc gluconate was 96.1 % at 5 × 10−6 mol/L--5 × 10−5 mol/L, while the detection limit of Y2ST was 0.7 × 10−6 mol/L. It can be applied to Zn2+ content determination.

NeuroimaGene: an R package for assessing the neurological correlates of genetically regulated gene expression

BackgroundWe present the NeuroimaGene resource as an R package designed to assist researchers in identifying genes and neurologic features relevant to psychiatric and neurological health. While recent studies have identified hundreds of genes as potential components of pathophysiology in neurologic and psychiatric disease, interpreting the physiological consequences of this variation is challenging. The integration of neuroimaging data with molecular findings is a step toward addressing this challenge. In addition to sharing associations with both molecular variation and clinical phenotypes, neuroimaging features are intrinsically informative of cognitive processes. NeuroimaGene provides a tool to understand how disease-associated genes relate to the intermediate structure of the brain.ResultsWe created NeuroimaGene, a user-friendly, open access R package now available for public use. Its primary function is to identify neuroimaging derived brain features that are impacted by genetically regulated expression of user-provided genes or gene sets. This resource can be used to (1) characterize individual genes or gene sets as relevant to the structure and function of the brain, (2) identify the region(s) of the brain or body in which expression of target gene(s) is neurologically relevant, (3) impute the brain features most impacted by user-defined gene sets such as those produced by cohort level gene association studies, and (4) generate publication level, modifiable visual plots of significant findings. We demonstrate the utility of the resource by identifying neurologic correlates of stroke-associated genes derived from pre-existing analyses.ConclusionsIntegrating neurologic data as an intermediate phenotype in the pathway from genes to brain-based diagnostic phenotypes increases the interpretability of molecular studies and enriches our understanding of disease pathophysiology. The NeuroimaGene R package is designed to assist in this process and is publicly available for use.

Structural basis for receptor-binding domain mobility of the spike in SARS-CoV-2 BA.2.86 and JN.1

Since 2019, SARS-CoV-2 has undergone mutations, resulting in pandemic and epidemic waves. The SARS-CoV-2 spike protein, crucial for cellular entry, binds to the ACE2 receptor exclusively when its receptor-binding domain (RBD) adopts the up-conformation. However, whether ACE2 also interacts with the RBD in the down-conformation to facilitate the conformational shift to RBD-up remains unclear. Herein, we present the structures of the BA.2.86 and the JN.1 spike proteins bound to ACE2. Notably, we successfully observed the ACE2-bound down-RBD, indicating an intermediate structure before the RBD-up conformation. The wider and mobile angle of RBDs in the up-state provides space for ACE2 to interact with the down-RBD, facilitating the transition to the RBD-up state. The K356T, but not N354-linked glycan, contributes to both of infectivity and neutralizing-antibody evasion in BA.2.86. These structural insights the spike-protein dynamics would help understand the mechanisms underlying SARS-CoV-2 infection and its neutralization.

DFT Study on Bucherer–Bergs multicomponent synthesis of hydantoins

ABSTRACT The Bucherer–Bergs multicomponent synthesis of hydantoins has been meticulously examined using density functional theory (DFT) at the B3LYP/6-311G level to scrutinise the reaction mechanism in diethyl ether as a solvent. This study explores all plausible pathways, optimises the structures of intermediates, and identifies corresponding transition states. Furthermore, a comprehensive computational analysis of molecular structures and their energy-structural correlations has been conducted.