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Abstract Excessive iron accumulation in the brain cortex increases the risk of cognitive deterioration. However, interregional relationships (defined as susceptibility connectivity) of local brain iron have not been explored, which could provide new insights into the underlying mechanisms of cognitive decline. Seventy-six healthy controls (HC), 58 participants with mild cognitive impairment due to probable Alzheimer’s disease (MCI-AD) and 66 participants with white matter hyperintensity (WMH) were included. We proposed a novel approach to construct a brain susceptibility network by using Kullback‒Leibler divergence similarity estimation from quantitative susceptibility mapping and further evaluated its topological organization. Moreover, sparse logistic regression (SLR) was applied to classify MCI-AD from HC and WMH with normal cognition (WMH-NC) from WMH with MCI (WMH-MCI).The altered susceptibility connectivity in the MCI-AD patients indicated that relatively more connectivity was involved in the default mode network (DMN)-related and visual network (VN)-related connectivity, while more altered DMN-related and subcortical network (SN)-related connectivity was found in the WMH-MCI patients. For the HC vs. MCI-AD classification, the features selected by the SLR were primarily distributed throughout the DMN-related and VN-related connectivity (accuracy = 76.12%). For the WMH-NC vs. WMH-MCI classification, the features with high appearance frequency were involved in SN-related and DMN-related connectivity (accuracy = 84.85%). The shared and specific patterns of the susceptibility network identified in both MCI-AD and WMH-MCI may provide a potential diagnostic biomarker for cognitive impairment, which could enhance the understanding of the relationships between brain iron burden and cognitive decline from a network perspective.

White matter hyperintensities (WMH) are widely observed in older adults and are closely associated with cognitive impairment. However, the underlying neuroimaging mechanisms of WMH-related cognitive dysfunction remain unknown. This study recruited 61 WMH individuals with mild cognitive impairment (WMH-MCI, n = 61), 48 WMH individuals with normal cognition (WMH-NC, n = 48) and 57 healthy control (HC, n = 57) in the final analyses. We constructed morphological networks by applying the Kullback-Leibler divergence to estimate interregional similarity in the distributions of regional gray matter volume. Based on morphological networks, graph theory was applied to explore topological properties, and their relationship to WMH-related cognitive impairment was assessed. There were no differences in small-worldness, global efficiency and local efficiency. The nodal local efficiency, degree centrality and betweenness centrality were altered mainly in the limbic network (LN) and default mode network (DMN). The rich-club analysis revealed that WMH-MCI subjects showed lower average strength of the feeder and local connections than HC (feeder connections: P = 0.034; local connections: P = 0.042). Altered morphological connectivity mediated the relationship between WMH and cognition, including language (total indirect effect: −0.010; 95 % CI: −0.024, −0.002) and executive (total indirect effect: −0.010; 95 % CI: −0.028, −0.002) function. The altered topological organization of morphological networks was mainly located in the DMN and LN and was associated with WMH-related cognitive impairment. The rich-club connection was relatively preserved, while the feeder and local connections declined. The results suggest that single-subject morphological networks may capture neurological dysfunction due to WMH and could be applied to the early imaging diagnostic protocol for WMH-related cognitive impairment.

BackgroundThe mechanism of gait and balance dysfunction (GBD) in cerebral small vessel disease (CSVD) remains unclear. Evidence supports cognition engages in GBD of CSVD. The cerebellum is important in motor and cognition, while little is known about the influence of the cerebellum on GBD in CSVD.MethodsThis study is a retrospective cohort study. All participants of this study were enrolled from the CSVD individuals in Nanjing Drum Tower Hospital from 2017 to 2021. The GBD of CSVD patients was defined as Tinetti Test score ≤ 23. Cerebral cortical thickness, cerebellar gray matter volume, the amplitude of low-frequency fluctuation, functional connectivity, and modular interaction were calculated to determine the cortical atrophy and activity patterns of CSVD patients with GBD. The effect of cognitive domains during GBD in CSVD patients was explored by correlation analyses.ResultsA total of 25 CSVD patients were recruited in CSVD patients with GBD group (Tinetti Test score ≤ 23, mean age ± standard deviation: 70.000 ± 6.976 years), and 34 CSVD patients were recruited in CSVD patients without GBD group (Tinetti Test score > 23, mean age ± standard deviation: 64.029 ± 9.453 years). CSVD patients with GBD displayed worse cognitive performance and cortical atrophy in the right cerebellum VIIIa and bilateral superior temporal gyrus than those without GBD. The right postcentral gyrus, left inferior temporal gyrus, right angular gyrus, right supramarginal gyrus and right middle frontal gyrus were functionally overactivated and showed decreased modular interaction with the right cerebellum. Tinetti Test scores were negatively related to the volume of the right cerebellum VIIIa in CSVD patients with GBD. Notably, memory, especially visuospatial memory, was greatly associated with GBD in CSVD.ConclusionThe cortical atrophy and altered functional activity in sensorimotor area and ventral attention network in the cerebellum and cerebrum may underlying the GBD in CSVD. Memory might be critically cognitively responsible for GBD in CSVD.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that progressively affects bulbar and limb function. Despite increasing recognition of the disease as a multinetwork disorder characterized by aberrant structural and functional connectivity, its integrity agreement and its predictive value for disease diagnosis remain to be fully elucidated. In this study, we recruited 37 ALS patients and 25 healthy controls (HCs). High-resolution 3D T1-weighted imaging and resting-state functional magnetic resonance imaging were, respectively, applied to construct multimodal connectomes. Following strict neuroimaging selection criteria, 18 ALS and 25 HC patients were included. Network-based statistic (NBS) and the coupling of grey matter structural–functional connectivity (SC–FC coupling) were performed. Finally, the support vector machine (SVM) method was used to distinguish the ALS patients from HCs. Results showed that, compared with HCs, ALS individuals exhibited a significantly increased functional network, predominantly encompassing the connections between the default mode network (DMN) and the frontoparietal network (FPN). The increased structural connections predominantly involved the inter-regional connections between the limbic network (LN) and the DMN, the salience/ventral attention network (SVAN) and FPN, while the decreased structural connections mainly involved connections between the LN and the subcortical network (SN). We also found increased SC–FC coupling in DMN-related brain regions and decoupling in LN-related brain regions in ALS, which could differentiate ALS from HCs with promising capacity based on SVM. Our findings highlight that DMN and LN may play a vital role in the pathophysiological mechanism of ALS. Additionally, SC–FC coupling could be regarded as a promising neuroimaging biomarker for ALS and shows important clinical potential for early recognition of ALS individuals.

Retinal imaging being a potential biomarker for Alzheimer’s disease is gradually attracting the attention of researchers. However, the association between retinal parameters and AD neuroimaging biomarkers, particularly structural changes, is still unclear. In this cross-sectional study, we recruited 25 cognitively impaired (CI) and 21 cognitively normal (CN) individuals. All subjects underwent retinal layer thickness and microvascular measurements with optical coherence tomography angiography (OCTA). Gray matter and white matter (WM) data such as T1-weighted magnetic resonance imaging and diffusion tensor imaging, respectively, were also collected. In addition, hippocampal subfield volumes and WM tract microstructural alterations were investigated as classical AD neuroimaging biomarkers. The microvascular and retinal features and their correlation with brain structural imaging markers were further analyzed. We observed a reduction in vessel density (VD) at the inferior outer (IO) sector (p = 0.049), atrophy in hippocampal subfield volumes, such as the subiculum (p = 0.012), presubiculum (p = 0.015), molecular_layer_HP (p = 0.033), GC-ML-DG (p = 0.043) and whole hippocampus (p = 0.033) in CI patients. Altered microstructural integrity of WM tracts in CI patients was also discovered in the cingulum hippocampal part (CgH). Importantly, we detected significant associations between retinal VD and gray matter volumes of the hippocampal subfield in CI patients. These findings suggested that the retinal microvascular measures acquired by OCTA may be markers for the early prediction of AD-related structural brain changes.

Glymphatic dysfunction has been linked to cognitive decline in several neurodegenerative diseases. In cerebral small vessel disease (CSVD), the mechanism of white matter hyperintensities (WMH)-related cognitive impairment (CI) is still under investigation. The diffusion tensor image (DTI) analysis along the perivascular space (ALPS) method has been considered to be a reliable parameter to evaluate glymphatic function. Therefore, we applied the ALPS-index to determine the influence of glymphatic function on CI in CSVD. In total, 137 CSVD patients (normal cognitive group, mild CI group, and dementia group) and 52 normal controls were included in this study. The ALPS-index was calculated based on the DTI. Correlation analyses and mediation analysis were conducted to examine the relationship between glymphatic function and cognition. Remarkable differences in the ALPS-index were observed between subjects with and without CI. The ALPS-index was negatively correlated with age, WMH volume, and general cognitive function in all CSVD patients. In the mild CI group, the ALPS-index was independently positively related to episodic memory, and mediated the relationship between WMH volume and episodic memory. In conclusion, the ALPS-index is a potential marker for early recognition of CI in CSVD. Glymphatic dysfunction mediates the relationship between WMH and CI in CSVD.

Oral squamous cell carcinoma (OSCC) is a major malignant cancer of the head and neck. Long non-coding RNAs (lncRNAs) have emerged as critical regulators during the development and progression of cancers. This study aimed to identify a lncRNA-related signature with prognostic value for evaluating survival outcomes and to explore the underlying molecular mechanisms of OSCC. Associations between overall survival (OS), disease-free survival (DFS) and candidate lncRNAs were evaluated by Kaplan–Meier survival analysis and univariate and multivariate Cox proportional hazards regression analyses. The robustness of the prognostic significance was shown via the Gene Expression Omnibus (GEO) database. A total of 2,493 lncRNAs were differentially expressed between OSCC and control samples (fold change >2, p

Background There is high variability in the clinical outcomes of patients with acute ischemic stroke (AIS) after mechanical thrombectomy (MT). Methods 217 consecutive patients with anterior circulation large vessel occlusion who underwent MT between August 2018 and January 2022 were analysed. The primary outcome was functional independence defined as a modified Rankin Scale score of 0-2 at 3 months. In the derivation cohort (August 2018 to December 2020), 7 ensemble ML models were trained on 70% of patients and tested on the remaining 30%. The model's performance was further validated on the temporal validation cohort (January 2021 to January 2022). The SHapley Additive explanations (SHAP) framework was applied to interpret the prediction model. Results Derivation analyses generated a 9-item score (PFCML-MT) comprising age, National Institutes of Health Stroke Scale score, collateral status, and postoperative laboratory indices (albumin-to-globulin ratio, estimated glomerular filtration rate, blood neutrophil count, C-reactive protein, albumin and serum glucose levels). The area under the curve was 0.87 for the test set and 0.84 for the temporal validation cohort. SHAP analysis further determined the thresholds for the top continuous features. This model has been translated into an online calculator that is freely available to the public (https://zhelvyao-123-60-sial5s.streamlitapp.com). Conclusions Using ML and readily available features, we developed an ML model that can potentially be used in clinical practice to generate real-time, accurate predictions of the outcome of patients with AIS treated with MT. [ABSTRACT FROM AUTHOR]

Density functional theory calculations based on plane-wave expansion and a pseudopotential treatment have been carried out for atomic hydrogen adsorbed on Rh(111) at 0.25 and 1 monolayer (ML) coverages. The preferred binding site for hydrogen was found to be the fcc hollow site. The global three-dimension potential energy surfaces were obtained by spline interpolation. The calculated hydrogen diffusion barrier of 121 meV at 0.25 ML agrees well with the experimental result of 140 meV at 0.3 ML. The vibrational wave functions and the corresponding energies for atomic hydrogen on the calculated potentials were calculated by using the discrete variable representation and Lanczos method. The calculated results showed that the low-lying vibrational states exhibit strong localized characters, whereas the higher states show significant delocalized characters. The calculated vibrational frequencies agree well with the recent available experimental values. Particularly, the calculated blueshift of 10.6 (7.2) meV for the vibrational excitation parallel to the metal surface when the H(D) coverage is changed from 0.25 ML to 1 ML is in excellent agreement with the observed value of 11 (7) meV. [ABSTRACT FROM AUTHOR]

The first step of the hydrolytic deimination of l-arginine catalyzed by arginine deiminase is examined using ab initio quantum mechanical/molecular mechanical molecular dynamics simulations. Two possible protonation states of the nucleophilic Cys406 residue were investigated, and the corresponding activation free energies were obtained via umbrella sampling. Our calculations indicated a reaction free-energy barrier of 21.3 kcal/mol for the neutral cysteine, which is in reasonably good agreement with the experimental kcatvalue of 6.3 s−1, i.e., a barrier of 16.7 kcal/mol. On the other hand, the deprotonated Cys nucleophile yields a free-energy barrier of 6.7 kcal/mol, much lower than the experimental result. The reaction free-energy barriers along with other data suggest that the Cys nucleophile is dominated by its protonated state in the Michaelis complex, and the reaction barrier corresponds largely to its deprotonation. [ABSTRACT FROM AUTHOR]

Protein arginine deiminase 4 (PAD4) catalyzes the citrullination of the peptidylarginine via two successive stages: deimination and hydrolysis. Herein, by employing state-of-the-art Born−Oppenheimer ab initio QM/MM molecular dynamics simulations with the umbrella sampling method, we characterized the catalytic mechanism of the hydrolysis reaction: first, the nucleophilic attack of a water molecule to the Cζof the thiouronium intermediate yields a stable tetrahedral intermediate, and then the S−Cζbond breaks to generate the final product, citrulline. Throughout the hydrolysis reaction, His471 and Asp473 play pivotal catalytic roles by first enhancing the nucleophilic ability of the active water through forming shorter and low-barrier hydrogen bonds and then by serving as proton-accepting groups to deprotonate the water molecule, which is consistent with experimental findings. At the transition state, the spontaneous proton transfer among the reactive water, His471 and Asp473 have been observed. The determined overall free energy barrier for this hydrolysis stage is 16.5 kcal·mol−1, which is lower than the barrier of 20.9 kcal·mol−1for the deimination stage determined previously with the same computational approach [J. Phys. Chem. B2009, 113, 12750−12758]. Thus, the rate-determining step of the PAD4-catalyzed citrullination is the first step of the deimination. Our current work further demonstrates the strength and applicability of the ab initio QM/MM MD approach in simulating enzyme reactions. [ABSTRACT FROM AUTHOR]

The newly discovered SpvC effector protein from Salmonella typhimuriuminterferes with the host immune response by dephosphorylating mitogen-activated protein kinases (MAPKs) with a β-elimination mechanism. To understand this unique phosphothreonine lyase catalysis, the dynamics of the enzyme−substrate complex of the SpvC effector is investigated with a 3.2 ns molecular dynamics simulation, which reveals that the phosphorylated peptide substrate is tightly held in the active site by a hydrogen bond network and the lysine general base is positioned for the abstraction of the alpha hydrogen. The catalysis is further modeled with density functional theory (DFT) in a truncated active-site model at the B3LYP/6-31+G(d,p) level of theory. The DFT calculations indicate the reaction proceeds via a single transition state, featuring a concerted proton abstraction from the α-carbon by Lys136 and β-elimination of the phosphate leaving group. Key kinetic isotopic effects are predicted based on the truncated active-site model. [ABSTRACT FROM AUTHOR]

The protein arginine deiminase 4 (PAD4) catalyzes the citrullination of the peptidylarginine and plays a critical role in rheumatoid arthritis (RA) and gene regulation. Understanding its catalytic mechanism is not only of fundamental importance but also of significant medical interest for the rational design of new inhibitors. By employing on-the-fly Born−Oppenheimer ab initio QM/MM molecular dynamics simulations, we have demonstrated that it is unlikely for the active site cysteine and histidine to exist as a thiolate−imidazolium ion pair in the PAD4 Michaelis reactant complex. Instead, a substrate-assisted proton transfer mechanism for the deimination reaction step has been characterized: both Cys645 and His471 in the PAD4 active site are neutral prior to the reaction; the deprotonation of Cys645 by the substrate arginine occurs in concert with the nucleophilic addition of the Cys thiolate to Cζof the substrate, and leads to a covalent tetrahedral intermediate; then, the Cζ−Nη1bond cleaves and the resulted ammonia is displaced by a solvent water molecule. The initial deprotonation and nucleophilic attack step is found to be rate-determining. The computed free energy barrier with B3LYP(6-31G*) QM/MM MD simulations and umbrella sampling is 20.9 kcal·mol−1, consistent with the experimental kinetic data. During the deimination, His471 plays an important role in stabilizing the transition state through the formation of the hydrogen bond with the guanidinium group. Our current studies further demonstrated the viability and strength of the ab initio QM/MM molecular dynamics approach in simulating enzyme reactions. [ABSTRACT FROM AUTHOR]

The newly discovered bacterial phosphothreonine lyases perform a post-translational modification of host cell signaling proteins through a novel catalytic mechanism that irreversibly removes the phosphate group from a phosphorylated threonine via β-elimination. This "eliminylation" reaction is shown by ab initio QM/MM studies to proceed via an E1cB-like pathway, in which the carbanion intermediate is stabilized by an enzyme oxyanion hole provided by Lys104 and Tyr158 of SpvC. [ABSTRACT FROM AUTHOR]