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In a previous paper [Ghysels et al., J. Chem. Phys. 126, 224102 (2007)] the mobile block Hessian (MBH) approach was presented. The method was designed to accurately compute vibrational modes of partially optimized molecular structures. The key concept was the introduction of several blocks of atoms, which can move as rigid bodies with respect to a local, fully optimized subsystem. The choice of the blocks was restricted in the sense that none of them could be connected, and also linear blocks were not taken into consideration. In this paper an extended version of the MBH method is presented that is generally applicable and allows blocks to be adjoined by one or two common atoms. This extension to all possible block partitions of the molecule provides a structural flexibility varying from very rigid to extremely relaxed. The general MBH method is very well suited to study selected normal modes of large macromolecules (such as proteins and polymers) because the number of degrees of freedom can be greatly reduced while still keeping the essential motions of the molecular system. The reduction in the number of degrees of freedom due to the block linkages is imposed here directly using a constraint method, in contrast to restraint methods where stiff harmonic couplings are introduced to restrain the relative motion of the blocks. The computational cost of this constraint method is less than that of an implementation using a restraint method. This is illustrated for the α-helix conformation of an alanine-20-polypeptide. [ABSTRACT FROM AUTHOR]

Vibrational force fields for the ground states of 1,3-butadiene, 1,3,5-hexatriene, and 1,3,5,7-octatetraene are calculated from extended Pariser–Parr–Pople CI theory. For the ground state of butadiene, the principal π-system force constants are compared to those determined by empirical, other semiempirical, and ab initio methods. The calculated vibrational frequency shifts for a series of deuterium substituted butadienes are found to be in good agreement with experiment. Trends in the principal π-system force constants of the polyenes for the ground states of ethylene through octatetraene are described, including the effects of introducing cis linkages in the polyene chain and of using single- vs single-plus-double-excitation CI. Correlations between the force constants and the calculated vibrational frequencies are discussed, and current assignments of the vibrational spectra of the polyenes are examined in view of the theoretical results. [ABSTRACT FROM AUTHOR]

Excitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators are therapeutic candidates that inhibit AMPAR activation and can compete with positive modulators to control AMPAR function through unresolved mechanisms. Here we show that allosteric inhibition pushes AMPARs into a distinct state that prevents both activation and positive allosteric modulation. We used cryo-electron microscopy to capture AMPARs bound to glutamate, while a negative allosteric modulator, GYKI-52466, and positive allosteric modulator, cyclothiazide, compete for control of the AMPARs. GYKI-52466 binds in the ion channel collar and inhibits AMPARs by decoupling the ligand-binding domains from the ion channel. The rearrangement of the ligand-binding domains ruptures the cyclothiazide site, preventing positive modulation. Our data provide a framework for understanding allostery of AMPARs and for rational design of therapeutics targeting AMPARs in neurological diseases., (© 2024. The Author(s).)

The dengue virus (DENV), composed of four distinct but serologically related Flaviviruses, causes the most important emerging viral disease, with nearly 400 million infections yearly. Currently, there are no approved therapies. Although DENV infection induces lifelong immunity against the same serotype, the antibodies raised contribute to severe disease in heterotypic infections. Therefore, understanding the mechanism of DENV neutralization by antibodies is crucial in the design of vaccines against all serotypes. This study reports a comparative structural and energetic analysis of the monoclonal antibody (mAb) 4E11 in complex with its target domain III of the envelope protein for all four DENV serotypes. We use extensive replica molecular dynamics simulations in conjunction with the binding free energy calculations. Further single point and double mutations were designed through computational site-directed mutagenesis and observed that the re-engineered antibody exhibits high affinity to binding and broadly neutralizing activity against serotypes. Our results showed improved binding affinity by the gain of enthalpy, which could be attributed to the stabilization of salt-bridge and hydrogen bond interactions at the antigen-antibody interface. The findings provide valuable results in understanding the structural dynamics and energetic contributions that will be helpful to the design of high-affinity antibodies against dengue infections., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Motor fatigue, during 30 seconds of maximum voluntary isometric contraction (MVIC) was simultaneously evaluated by the decline in mechanical force output, and from the compression in the power spectrum obtained from surface electromyogram (sEMG). Measurements were performed in patients diagnosed with amyotrophic lateral sclerosis (ALS) and normal control (NC) in two muscle groups, elbow flexors (EF) and ankle dorsiflexors (DF). The decline in force output, as a manifestation of mechanical fatigue, was digitally calculated online by partitioning the force versus time curve to determine the percent of MVIC reduction over a 30 sec period and was expressed as force fatigue index (FFI). The compression in the sEMG power spectrum, as a manifestation of myoelectrical fatigue, was tracked by calculating the median frequency shift (MFS) from the first 5 sec to the last 5 sec of the 30 sec MVIC using digital Fast Fourier Transformation. In ALS patients, the significantly higher reduction in mechanical force output during the 30 sec MVIC (higher FFI) was accompanied with significantly less compression in the sEMG power spectrum (less MFS) as compared to NC ( P ≤0.005) in the two muscle groups. This dissociation between the mechanical and myoelectrical manifestation of muscle fatigue in ALS indicates that a reduction in muscle fiber conduction velocity (MFCV) may be a contributing peripheral factor in the pathogenesis of muscle fatigue in ALS. Alterations in motor unit functionality, especially in type II fast motor unit muscle fibers, and structural damage in denervated muscle fibers may contribute to the lower MFCV during motor fatigue in ALS patients. [ABSTRACT FROM AUTHOR]

Explores strategies to develop mosaic chemotherapeutic approaches for amyotrophic lateral sclerosis/motor neurone disease (ALS/MND). Inclusion of beta-2 adrenergic agonists for ALS/MND treatment; Pathogenesis-based and symptom-directed therapies in ALS/MND; Effect of beta-2 adrenergic agonists in the central nervous system and muscular system; Side-effects of beta-2 adrenergic agonists.

Background: The aldehyde dehydrogenase 2 (ALDH2) rs671 (A) allele has been implicated in neurodegeneration, potentially through oxidative and inflammatory pathways. The study aims to investigate the effects of the ALDH2 rs671 (A) allele and high sensitivity C-reactive protein (hs-CRP) on the clinical phenotypes of amyotrophic lateral sclerosis (ALS) in male and female patients. Methods: Clinical data and ALDH2 rs671 genotype of 143 ALS patients, including 85 males and 58 females, were collected from January 2018 to December 2022. All patients underwent assessment using the Chinese version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Complete blood count and metabolic profiles were measured. Clinical and laboratory parameters were compared between carriers and non-carriers of the rs671 (A) allele in males and females, respectively. The significant parameters and rs671 (A) Allele were included in multivariate linear regression models to identify potential contributors to motor and cognitive impairment. Mediation analysis was employed to evaluate any mediation effects. Results: Male patients carrying rs671 (A) allele exhibited higher levels of hs-CRP than non-carriers (1.70 mg/L vs. 0.50 mg/L, p = 0.006). The rs671 (A) allele was identified as an independent risk factor for faster disease progression only in male patients (b = 0.274, 95% CI = 0.048-0.499, p = 0.018). The effect of the rs671 (A) allele on the executive function in male patients was fully mediated by hs-CRP (Indirect effect = -1.790, 95% CI = -4.555--0.225). No effects of the rs671 (A) allele or hs-CRP were observed in female ALS patients. The effects of the ALDH2 rs671 (A) allele and the mediating role of hs-CRP in male patients remained significant in the sensitivity analyses. Conclusion: The ALDH2 rs671 (A) allele contributed to faster disease progression and hs-CRP mediated cognitive impairment in male ALS patients. [ABSTRACT FROM AUTHOR]

Objective: The aim of our study was to compare the clinical value of pathological spontaneous activity (PSA) in different thoracic paraspinal muscles (TPMs) in amyotrophic lateral sclerosis (ALS). Methods: A total of 116 ALS patients were retrospectively analyzed over 31 ± 8 months concerning the occurrence of PSA in T9–T11 TPM. The occurrence of PSA was correlated with pulmonary function and clinical disability. Results: The positive sharp wave (PSW) potentials were more frequently observed than fibrillation (fib) in T9–T11 segments. The PSA positive frequency of bulbar‐onset ALS (B‐ALS) is less than upper limb‐onset ALS (U‐ALS) and lower limb‐onset ALS (L‐ALS) at the levels of T10 and T11 TPM (p = 0.050, p = 0.001). The fibs/PSWs in TPM indicated high sensitivity and negative predictive value for forced vital capacity (FVC) < 80%. Linear correlation analysis indicated that PSA of TPM was associated with pulmonary ventilation function (PVF). Associations also exist between clinical parameters and PVF as well as the disease severity. Conclusions: The occurrence of T9‐TPM fibs/PSWs was correlated with clinical disability and is extremely helpful in implying an involvement of PVF. The T9‐TPM typically provided a good practical indicator for comprehensive disease evaluation, which was irrelevant to the site of onset. [ABSTRACT FROM AUTHOR]

Root exudates are known signaling agents that influence legume root nodulation, but the molecular mechanisms for nonflavonoid molecules remain largely unexplored. The number of soybean root nodules during the initial growth phase shows substantial discrepancies at distinct developmental junctures. Using a combination of metabolomics analyses on root exudates and nodulation experiments, we identify a pivotal role for certain root exudates during the rapid growth phase in promoting nodulation. Phenoxyacetic acid (POA) was found to activate the expression of GmGA2ox10 and thereby facilitate rhizobial infection and the formation of infection threads. Furthermore, POA exerts regulatory control on the miR172c-NNC1 module to foster nodule primordia development and consequently increase nodule numbers. These findings collectively highlight the important role of POA in enhancing nodulation during the accelerated growth phase of soybeans. [ABSTRACT FROM AUTHOR]

Purpose: The goal of this study was to determine the relationship between the perceptual measure of speech naturalness and objective measures of pitch, loudness, and rate control as a potential tool for assessment of ataxic dysarthria. Method: Twenty-seven participants with ataxia and 29 age- and sex-matched control participants completed the pitch glide and loudness step tasks drawn from the Frenchay Dysarthria Assessment-Second Edition (FDA-2) in addition to speech diadochokinetic (DDK) tasks. First, group differences were compared for pitch variability in the pitch glide task, loudness variability in the loudness step task, and syllable duration and speech rate in the DDK task. Then, these acoustic measures were compared with previously collected ratings of speech naturalness by speech-language pathology graduate students. Results: Robust group differences were measured for pitch variability and both DDK syllable duration and speech rate, indicating that the ataxia group had greater pitch variability, longer DDK syllable duration, and slower DDK speech rate than the control group. No group differences were measured for loudness variability. There were robust relationships between speech naturalness and pitch variability, DDK syllable duration, and DDK speech rate, but not for loudness variability. Conclusions: Objective acoustic measures of pitch variability in the FDA-2 pitch glide task and syllable duration and speech rate in the DDK task can be used to validate perceptual measures of speech naturalness. Overall, speechlanguage pathologists can incorporate both perceptual measures of speech naturalness and acoustic measures of pitch variability and DDK performance for a comprehensive evaluation of ataxic dysarthria. [ABSTRACT FROM AUTHOR]

The Janus kinase 3 (JAK3) family, particularly JAK3, is pivotal in initiating autoimmune diseases such as rheumatoid arthritis. Recent advancements have focused on developing antirheumatic drugs targeting JAK3, leading to the discovery of novel pyrazolopyrimidine-based compounds as potential inhibitors. This research employed covalent docking, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis, molecular dynamics modeling, and MM/GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy techniques to screen 41 in silico-designed pyrazolopyrimidine derivatives. Initially, 3D structures of the JAK3 enzyme were generated using SWISS-MODEL, followed by virtual screening and covalent docking via AutoDock4 (AD4). The selection process involved the AMES test, binding affinity assessment, and ADMET analysis, narrowing down the candidates to 27 compounds that passed the toxicity test. Further covalent docking identified compounds 21 and 41 as the most promising due to their high affinity and favourable ADMET profiles. Subsequent development led to the creation of nine potent molecules, with derivatives 43 and 46 showing exceptional affinity upon evaluation through molecular dynamics simulation and MM/GBSA calculations over 300 nanoseconds, comparable to tofacitinib, an approved RA drug. However, compounds L21 and L46 demonstrated stable performance, suggesting their effectiveness in treating rheumatoid arthritis and other autoimmune conditions associated with JAK3 inhibition. [ABSTRACT FROM AUTHOR]

Photosystem I (PSI) light-harvesting antenna complexes LHCI contain spectral forms that absorb and emit photons of lower energy than that of its primary electron donor, P700. The most red-shifted fluorescence is associated with the Lhca4 complex. It has been suggested that this red emission is related to the inter-chlorophyll charge transfer (CT) states. In this work we present a systematic quantum-chemical study of the CT states in Lhca4, accounting for the influence of the protein environment by estimating the electrostatic interactions. We show that significant energy shifts result from these interactions and propose that the emission of the Lhca4 complex is related not only to the previously proposed a603+-a608-state, but also to the a602+-a603-state. We also investigate how different protonation patterns of protein amino acids affect the energetics of the CT states. [ABSTRACT FROM AUTHOR]