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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.

The gravity and gradient anomalies contain valuable information about the underground geological structures at various depths. Deep and shallow buried source bodies are able to be identified through multi-scale field separation processes, and visual comprehensions of geological structures can be obtained via 3D density inversion techniques. In this study, we propose an improved 3D imaging strategy based on gravitational field separation using the preferential continuation filter. This strategy incorporates the relationship between spectral features and buried depths of source bodies, allowing for a one-step transformation from planar gravity and full-tensor gradient field observations to a 3D density structure in the wave-number domain. Synthetic tests validate the effectiveness and robustness of the gravity and gradient imaging approaches, highlighting their advantages in high vertical resolution and low computational requirements. Nonetheless, it should be noted that the imaging effects of horizontal gradients Γxx and Γyy are unsatisfactory due to their weak noise resistance. Thus, they are not suitable for real data applications. The other imaging approaches are further applied to recover the subsurface 3D density structure beneath the Weishan cone in Wudalianchi Volcanic Field, Northeastern China. Our results provide insights into the possible location and shape of the low-density magma chamber. Also, the potential presence of partial melts is inferred and supported from a gravity perspective. The primary advantage of these approaches is their ability to generate a reasonable geological model in scenarios with limited prior information and physical property constraints. As a result, they have significant practical value in the field of applied geophysics, including mineral exploration and volcanology studies.

Abstract 18F‐Fluorodeoxyglucose positron emission tomography (18F‐FDG PET) is widely employed to reveal metabolic abnormalities linked to Parkinson's disease (PD) at a systemic level. However, the individual metabolic connectome details with PD based on 18F‐FDG PET remain largely unknown. To alleviate this issue, we derived a novel brain network estimation method for individual metabolic connectome, that is, Jensen‐Shannon Divergence Similarity Estimation (JSSE). Further, intergroup difference between the individual's metabolic brain network and its global/local graph metrics was analyzed to investigate the metabolic connectome's alterations. To further improve the PD diagnosis performance, multiple kernel support vector machine (MKSVM) is conducted for identifying PD from normal control (NC), which combines both topological metrics and connection. Resultantly, PD individuals showed higher nodal topological properties (including assortativity, modularity score, and characteristic path length) than NC individuals, whereas global efficiency and synchronization were lower. Moreover, 45 most significant connections were affected. Further, consensus connections in occipital, parietal, and frontal regions were decrease in PD while increase in subcortical, temporal, and prefrontal regions. The abnormal metabolic network measurements depicted an ideal classification in identifying PD of NC with an accuracy up to 91.84%. The JSSE method identified the individual‐level metabolic connectome of 18F‐FDG PET, providing more dimensional and systematic mechanism insights for PD.

Pests and diseases significantly impact the quality and yield of maize. As a result, it is crucial to conduct disease diagnosis and identification for timely intervention and treatment of maize pests and diseases, ultimately enhancing the quality and economic efficiency of maize production. In this study, we present an enhanced maize pest identification model based on ResNet50. The objective was to achieve efficient and accurate identification of maize pests and diseases. By utilizing convolution and pooling operations for extracting shallow-edge features and compressing data, we introduced additional effective channels (environment–cognition–action) into the residual network module. This step addressed the issue of network degradation, establishes connections between channels, and facilitated the extraction of crucial deep features. Finally, experimental validation was performed to achieve 96.02% recognition accuracy using the ResNet50 model. This study successfully achieved the recognition of various maize pests and diseases, including maize leaf blight, Helminthosporium maydis, gray leaf spot, rust disease, stem borer, and corn armyworm. These results offer valuable insights for the intelligent control and management of maize pests and diseases.

The intrinsic flexibility of membranes proteins still poses a challenge in determining their active structure. Here the authors describe the development of a method that combines chemical footprinting and mass spectrometry to assist in determining the structure of native membrane proteins and their dynamics.

Understanding the higher-order structure of membrane proteins (MPs), which are vital for numerous biological processes, is crucial for comprehending their function. Although several biophysical approaches have been used to study the structure of MPs, limitations exist owing to the proteins’ dynamic nature and heterogeneity. Mass spectrometry (MS) is emerging as a powerful tool for investigating membrane protein structure and dynamics. Studying MPs using MS, however, must meet several challenges including the lack of stability and solubility of MPs, the complexity of the protein–membrane system, and the difficulty of digestion and detection. To meet these challenges, recent advances in MS have engendered opportunities in resolving the dynamics and structures of MP. This article reviews achievements over the past few years that enable the study of MPs by MS. We first introduce recent advances in hydrogen deuterium exchange and native mass spectrometry for MPs and then focus on those footprinting methods that report on protein structure.

Objectives: Half of the patients who have tailored resection of the suspected epileptogenic zone for drug-resistant epilepsy have recurrent postoperative seizures. Although neuroimaging has become an indispensable part of delineating the epileptogenic zone, no validated method uses neuroimaging of presurgical target area to predict an individual’s post-surgery seizure outcome. We aimed to develop and validate a machine learning-powered approach incorporating multimodal neuroimaging of a presurgical target area to predict an individual’s post-surgery seizure outcome in patients with drug-resistant focal epilepsy.Materials and Methods: One hundred and forty-one patients with drug-resistant focal epilepsy were classified either as having seizure-free (Engel class I) or seizure-recurrence (Engel class II through IV) at least 1 year after surgery. The presurgical magnetic resonance imaging, positron emission tomography, computed tomography, and postsurgical magnetic resonance imaging were co-registered for surgical target volume of interest (VOI) segmentation; all VOIs were decomposed into nine fixed views, then were inputted into the deep residual network (DRN) that was pretrained on Tiny-ImageNet dataset to extract and transfer deep features. A multi-kernel support vector machine (MKSVM) was used to integrate multiple views of feature sets and to predict seizure outcomes of the targeted VOIs. Leave-one-out validation was applied to develop a model for verifying the prediction. In the end, performance using this approach was assessed by calculating accuracy, sensitivity, and specificity. Receiver operating characteristic curves were generated, and the optimal area under the receiver operating characteristic curve (AUC) was calculated as a metric for classifying outcomes.Results: Application of DRN–MKSVM model based on presurgical target area neuroimaging demonstrated good performance in predicting seizure outcomes. The AUC ranged from 0.799 to 0.952. Importantly, the classification performance DRN–MKSVM model using data from multiple neuroimaging showed an accuracy of 91.5%, a sensitivity of 96.2%, a specificity of 85.5%, and AUCs of 0.95, which were significantly better than any other single-modal neuroimaging (all p ˂ 0.05).Conclusion: DRN–MKSVM, using multimodal compared with unimodal neuroimaging from the surgical target area, accurately predicted postsurgical outcomes. The preoperative individualized prediction of seizure outcomes in patients who have been judged eligible for epilepsy surgery could be conveniently facilitated. This may aid epileptologists in presurgical evaluation by providing a tool to explore various surgical options, offering complementary information to existing clinical techniques.

Mild cognitive impairment (MCI) is generally considered to be a key indicator for predicting the early progression of Alzheimer’s disease (AD). Currently, the brain connection (BC) estimated by fMRI data has been validated to be an effective diagnostic biomarker for MCI. Existing studies mainly focused on the single connection pattern for the neuro-disease diagnosis. Thus, such approaches are commonly insufficient to reveal the underlying changes between groups of MCI patients and normal controls (NCs), thereby limiting their performance. In this context, the information associated with multiple patterns (e.g., functional connectivity or effective connectivity) from single-mode data are considered for the MCI diagnosis. In this paper, we provide a novel multiple connection pattern combination (MCPC) approach to combine different patterns based on the kernel combination trick to identify MCI from NCs. In particular, sixty-three MCI cases and sixty-four NC cases from the ADNI dataset are conducted for the validation of the proposed MCPC method. The proposed method achieves 87.40% classification accuracy and significantly outperforms methods that use a single pattern.

Subjective cognitive decline (SCD) is considered the earliest stage of the clinical manifestations of the continuous progression of Alzheimer’s Disease (AD). Previous studies have suggested that multimodal brain networks play an important role in the early diagnosis and mechanisms underlying SCD. However, most of the previous studies focused on a single modality, and lacked correlation analysis between different modal biomarkers and brain regions. In order to further explore the specific characteristic of the multimodal brain networks in the stage of SCD, 22 individuals with SCD and 20 matched healthy controls (HCs) were recruited in the present study. We constructed the individual morphological, structural and functional brain networks based on 3D-T1 structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI), respectively. A t-test was used to select the connections with significant difference, and a multi-kernel support vector machine (MK-SVM) was applied to combine the selected multimodal connections to distinguish SCD from HCs. Moreover, we further identified the consensus connections of brain networks as the most discriminative features to explore the pathological mechanisms and potential biomarkers associated with SCD. Our results shown that the combination of three modal connections using MK-SVM achieved the best classification performance, with an accuracy of 92.68%, sensitivity of 95.00%, and specificity of 90.48%. Furthermore, the consensus connections and hub nodes based on the morphological, structural, and functional networks identified in our study exhibited abnormal cortical-subcortical connections in individuals with SCD. In addition, the functional networks presented more discriminative connections and hubs in the cortical-subcortical regions, and were found to perform better in distinguishing SCD from HCs. Therefore, our findings highlight the role of the cortical-subcortical circuit in individuals with SCD from the perspective of a multimodal brain network, providing potential biomarkers for the diagnosis and prediction of the preclinical stage of AD.

Abstract This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) was hosted virtually from Philadelphia July 17–21, 2021. The conference, now held annually, highlighted cutting‐edge advances in basic, population and clinical sciences of relevance to the Society. Despite being held virtually, the 2021 congress was of the same scope and quality as an annual meeting held in person. An added feature of the program is that talks streamed at the designated times will then be available on‐line for asynchronous viewing. The program included 77 State of the Art (SOA) talks, thematically grouped in 28 sessions, given by internationally recognized leaders in the field. The SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. The topics, across the main scientific themes of the congress, include Arterial Thromboembolism, Coagulation and Natural Anticoagulants, COVID‐19 and Coagulation, Diagnostics and Omics, Fibrinogen, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostasis in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Angiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the congress.

Crystal structures of membrane proteins are highly desired for their use in the mechanistic understanding of their functions and the designing of new drugs. However, obtaining the membrane protein structures is difficult. One way to overcome this challenge is with protein fusion methods, which have been successfully used to determine the structures of many membrane proteins, including receptors, enzymes and adhesion molecules. Existing fusion strategies can be categorized into the N or C terminal fusion, the insertion fusion and the termini restraining. The fusions facilitate protein expression, purification, crystallization and phase determination. Successful applications often require further optimization of protein fusion linkers and interactions, whose design can be facilitated by a shared helix strategy and by AlphaFold prediction in the future.

ObjectiveIncreasing pieces of evidence suggest that abnormal brain connectivity plays an important role in the pathophysiology of schizophrenia. As an essential strategy in psychiatric neuroscience, the research of brain connectivity-based neuroimaging biomarkers has gained increasing attention. Most of previous studies focused on a single modality of the brain connectomics. Multimodal evidence will not only depict the full profile of the brain abnormalities of patients but also contribute to our understanding of the neurobiological mechanisms of this disease.MethodsIn the current study, 99 schizophrenia patients, 69 sex- and education-matched healthy controls, and 42 unaffected first-degree relatives of patients were recruited and scanned. The brain was parcellated into 246 regions and multimodal network analyses were used to construct brain connectivity networks for each participant.ResultsUsing the brain connectomics from three modalities as the features, the multi-kernel support vector machine method yielded high discrimination accuracies for schizophrenia patients (94.86%) and for the first-degree relatives (95.33%) from healthy controls. Using an independent sample (49 patients and 122 healthy controls), we tested the model and achieved a classification accuracy of 64.57%. The convergent pattern within the basal ganglia and thalamus–cortex circuit exhibited high discriminative power during classification. Furthermore, substantial overlaps of the brain connectivity abnormality between patients and the unaffected first-degree relatives were observed compared to healthy controls.ConclusionThe current findings demonstrate that decreased functional communications between the basal ganglia, thalamus, and the prefrontal cortex could serve as biomarkers and endophenotypes for schizophrenia.

Coagulation factor IX (FIX) is a vitamin K dependent protein and its deficiency causes hemophilia B, an X-linked recessive bleeding disorder. More than 1000 mutations in the F9 gene have been identified in hemophilia B patients. Here, we systematically summarize the structural and functional characteristics of FIX and the pathogenic mechanisms of the mutations that have been identified to date. The mechanisms of FIX deficiency are diverse in these mutations. Deletions, insertions, duplications, and indels generally lead to severe hemophilia B. Those in the exon regions generate either frame shift or inframe mutations, and those in the introns usually cause aberrant splicing. Regarding point mutations, the bleeding phenotypes vary from severe to mild in hemophilia B patients. Generally speaking, point mutations in the F9 promoter region result in hemophilia B Leyden, and those in the introns cause aberrant splicing. Point mutations in the coding sequence can be missense, nonsense, or silent mutations. Nonsense mutations generate truncated FIX that usually loses function, causing severe hemophilia B. Silent mutations may lead to aberrant splicing or affect FIX translation. The mechanisms of missense mutation, however, have not been fully understood. They lead to FIX deficiency, often by affecting FIX’s translation, protein folding, protein stability, posttranslational modifications, activation to FIXa, or the ability to form functional Xase complex. Understanding the molecular mechanisms of FIX deficiency will provide significant insight for patient diagnosis and treatment.

Subjective cognitive decline (SCD) is considered the earliest preclinical stage of Alzheimer’s disease (AD) that precedes mild cognitive impairment (MCI). Effective and accurate diagnosis of SCD is crucial for early detection of and timely intervention in AD. In this study, brain functional connectome (i.e., functional connections and graph theory metrics) based on the resting-state functional magnetic resonance imaging (rs-fMRI) provided multiple information about brain networks and has been used to distinguish individuals with SCD from normal controls (NCs). The consensus connections and the discriminative nodal graph metrics selected by group least absolute shrinkage and selection operator (LASSO) mainly distributed in the prefrontal and frontal cortices and the subcortical regions corresponded to default mode network (DMN) and frontoparietal task control network. Nodal efficiency and nodal shortest path showed the most significant discriminative ability among the selected nodal graph metrics. Furthermore, the comparison results of topological attributes suggested that the brain network integration function was weakened and network segregation function was enhanced in SCD patients. Moreover, the combination of brain connectome information based on multiple kernel-support vector machine (MK-SVM) achieved the best classification performance with 83.33% accuracy, 90.00% sensitivity, and an area under the curve (AUC) of 0.927. The findings of this study provided a new perspective to combine machine learning methods with exploration of brain pathophysiological mechanisms in SCD and offered potential neuroimaging biomarkers for diagnosis of early-stage AD.

Functional brain network (FBN) provides an effective biomarker for understanding brain activation patterns and a diagnostic criterion for neurodegenerative diseases detections. Unfortunately, it remains challenges to estimate the biologically meaningful or discriminative FBNs accurately, because of the poor quality of functional magnetic resonance imaging data or our limited understanding of human brain. In this study, a novel FBN estimation model based on group similarity prior was proposed. In particular, we extended the FBN estimation model to tensor form and incorporated the tensor trace-norm regularizer to formulate the group similarity constraint. To verify the proposed method, we conducted experiments on identifying mild cognitive impairments (MCIs) from normal controls (NCs) based on the estimated FBNs. Experimental results illustrated that our method is effective in modeling FBNs. Consequently, we achieved 91.97% classification accuracy, outperforming the state-of-the-art methods. The post hoc analysis further demonstrated that more biologically meaningful functional brain connections were obtained using our proposed method.

Mild cognitive impairment (MCI) is often considered a critical time window for predicting early conversion to Alzheimer’s disease (AD). Brain functional connectome data (i.e., functional connections, global and nodal graph metrics) based on resting-state functional magnetic resonance imaging (rs-fMRI) provides numerous information about brain networks and has been used to discriminate normal controls (NCs) from subjects with MCI. In this paper, Student’s t-tests and group-least absolute shrinkage and selection operator (group-LASSO) were used to extract functional connections with significant differences and the most discriminative network nodes, respectively. Based on group-LASSO, the middle temporal, inferior temporal, lingual, posterior cingulate, and middle frontal gyri were the most predominant brain regions for nodal observation in MCI patients. Nodal graph metrics (within-module degree, participation coefficient, and degree centrality) showed the maximum discriminative ability. To effectively combine the multipattern information, we employed the multiple kernel learning support vector machine (MKL-SVM). Combined with functional connectome information, the MKL-SVM achieved a good classification performance (area under the receiving operating characteristic curve = 0.9728). Additionally, the altered brain connectome pattern revealed that functional connectivity was generally decreased in the whole-brain network, whereas graph theory topological attributes of some special nodes in the brain network were increased in MCI patients. Our findings demonstrate that optimal feature selection and combination of all connectome features (i.e., functional connections, global and nodal graph metrics) can achieve good performance in discriminating NCs from MCI subjects. Thus, the combination of functional connections and global and nodal graph metrics of brain networks can predict the occurrence of MCI and contribute to the early clinical diagnosis of AD.

Background: Cerebral small vessel disease (SVD) is a common cause of cognitive dysfunction. However, little is known whether the altered reconfiguration pattern of brain modular architecture regulates cognitive dysfunction in SVD.Methods: We recruited 25 cases of SVD without cognitive impairment (SVD-NCI) and 24 cases of SVD with mild cognitive impairment (SVD-MCI). According to the Framingham Stroke Risk Profile, healthy controls (HC) were divided into 17 subjects (HC-low risk) and 19 subjects (HC-high risk). All individuals underwent resting-state functional magnetic resonance imaging and cognitive assessments. Graph-theoretical analysis was used to explore alterations in the modular organization of functional brain networks. Multiple regression and mediation analyses were performed to investigate the relationship between MRI markers, network metrics and cognitive performance.Results: We identified four modules corresponding to the default mode network (DMN), executive control network (ECN), sensorimotor network and visual network. With increasing vascular risk factors, the inter- and intranetwork compensation of the ECN and a relatively reserved DMN itself were observed in individuals at high risk for SVD. With declining cognitive ability, SVD-MCI showed a disrupted ECN intranetwork and increased DMN connection. Furthermore, the intermodule connectivity of the right inferior frontal gyrus of the ECN mediated the relationship between periventricular white matter hyperintensities and visuospatial processing in SVD-MCI.Conclusions: The reconfiguration pattern of the modular architecture within/between the DMN and ECN advances our understanding of the neural underpinning in response to vascular risk and SVD burden. These observations may provide novel insight into the underlying neural mechanism of SVD-related cognitive impairment and may serve as a potential non-invasive biomarker to predict and monitor disease progression.

Functional connectivity (FC) network has been becoming an increasingly useful tool for understanding the cerebral working mechanism and mining sensitive biomarkers for neural/mental disease diagnosis. Currently, Pearson's Correlation (PC) is the simplest and most commonly used scheme in FC estimation. Despite its empirical effectiveness, PC only encodes the low-order (i.e., second-order) statistics by calculating the pairwise correlations between network nodes (brain regions), which fails to capture the high-order information involved in FC (e.g., the correlations among different edges in a network). To address this issue, we propose a novel FC estimation method based on Matrix Variate Normal Distribution (MVND), which can capture both low- and high-order correlations simultaneously with a clear mathematical interpretability. Specifically, we first generate a set of BOLD subseries by the sliding window scheme, and for each subseries we construct a temporal FC network by PC. Then, we employ the constructed FC networks as samples to estimate the final low- and high-order FC networks by maximizing the likelihood of MVND. To illustrate the effectiveness of the proposed method, we conduct experiments to identify subjects with Mild Cognitive Impairment (MCI) from Normal Controls (NCs). Experimental results show that the fusion of low- and high-order FCs can generally help to improve the final classification performance, even though the high-order FC may contain less discriminative information than its low-order counterpart. Importantly, the proposed method for simultaneous estimation of low- and high-order FCs can achieve better classification performance than the two baseline methods, i.e., the original PC method and a recent high-order FC estimation method.

Functional brain network (FBN) has been becoming an increasingly important way to model the statistical dependence among neural time courses of brain, and provides effective imaging biomarkers for diagnosis of some neurological or psychological disorders. Currently, Pearson's Correlation (PC) is the simplest and most widely-used method in constructing FBNs. Despite its advantages in statistical meaning and calculated performance, the PC tends to result in a FBN with dense connections. Therefore, in practice, the PC-based FBN needs to be sparsified by removing weak (potential noisy) connections. However, such a scheme depends on a hard-threshold without enough flexibility. Different from this traditional strategy, in this paper, we propose a new approach for estimating FBNs by remodeling PC as an optimization problem, which provides a way to incorporate biological/physical priors into the FBNs. In particular, we introduce an L1-norm regularizer into the optimization model for obtaining a sparse solution. Compared with the hard-threshold scheme, the proposed framework gives an elegant mathematical formulation for sparsifying PC-based networks. More importantly, it provides a platform to encode other biological/physical priors into the PC-based FBNs. To further illustrate the flexibility of the proposed method, we extend the model to a weighted counterpart for learning both sparse and scale-free networks, and then conduct experiments to identify autism spectrum disorders (ASD) from normal controls (NC) based on the constructed FBNs. Consequently, we achieved an 81.52% classification accuracy which outperforms the baseline and state-of-the-art methods.