Impaired Functional Criticality of Human Brain during Alzheimer's Disease Progression

The progression of Alzheimer's Disease (AD) has been proposed to comprise three stages, subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD. Was brain dynamics across the three stages smooth? Was there a critical transition? How could we characterize and study functional criticality of human brain? Based on dynamical characteristics of critical transition from nonlinear dynamics, we proposed a vertex-wise Index of Functional Criticality (vIFC) of fMRI time series in this study. Using 42 SCD, 67 amnestic MCI (aMCI), 34 AD patients as well as their age-, sex-, years of education-matched 54 NC, our new method vIFC successfully detected significant patient-normal differences for SCD and aMCI, as well as significant negative correlates of vIFC in the right middle temporal gyrus with total scores of Montreal Cognitive Assessment (MoCA) in SCD. In comparison, standard deviation of fMRI time series only detected significant differences between AD patients and normal controls. As an index of functional criticality of human brain derived from nonlinear dynamics, vIFC could serve as a sensitive neuroimaging marker for future studies; considering much more vIFC impairments in aMCI compared to SCD and AD, our study indicated aMCI as a critical stage across AD progression

Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β.

Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90β. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90β inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90β and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90β play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation

The role of EGFR mutation as a prognostic factor in survival after diagnosis of brain metastasis in non-small cell lung cancer: A systematic review and meta-analysis

Abstract Background The brain is a common site for metastasis in non-small-cell lung cancer (NSCLC). This study was designed to evaluate the relationship between the mutational of the epidermal growth factor receptor (EGFR) and overall survival (OS) in NSCLC patients with brain metastases. Methods Searches were performed in PubMed, EmBase, and the Cochrane Library to identify studies evaluating the association of EGFR mutation with OS in NSCLC patients through September 2017. Results 4373 NSCLC patients with brain metastases in 18 studies were involved. Mutated EGFR associated with significantly improved OS compared with wild type. Subgroup analyses suggested that this relationship persisted in studies conducted in Eastern, with retrospective design, with sample size ≥500, mean age of patients ≥65.0 years, percentage male < 50.0%, percentage of patients receiving tyrosine kinase inhibitor ≥30.0%. Finally, although significant publication bias was observed using the Egger test, the results were not changed after adjustment using the trim and fill method. Conclusions This meta-analysis suggests that EGFR mutation is an important predictive factor linked to improved OS for NSCLC patients with brain metastases. It can serve as a useful index in the prognostic assessment of NSCLC patients with brain metastases

Generalizable Whole Slide Image Classification with Fine-Grained Visual-Semantic Interaction

Whole Slide Image (WSI) classification is often formulated as a Multiple Instance Learning (MIL) problem. Recently, Vision-Language Models (VLMs) have demonstrated remarkable performance in WSI classification. However, existing methods leverage coarse-grained pathogenetic descriptions for visual representation supervision, which are insufficient to capture the complex visual appearance of pathogenetic images, hindering the generalizability of models on diverse downstream tasks. Additionally, processing high-resolution WSIs can be computationally expensive. In this paper, we propose a novel "Fine-grained Visual-Semantic Interaction" (FiVE) framework for WSI classification. It is designed to enhance the model's generalizability by leveraging the interaction between localized visual patterns and fine-grained pathological semantics. Specifically, with meticulously designed queries, we start by utilizing a large language model to extract fine-grained pathological descriptions from various non-standardized raw reports. The output descriptions are then reconstructed into fine-grained labels used for training. By introducing a Task-specific Fine-grained Semantics (TFS) module, we enable prompts to capture crucial visual information in WSIs, which enhances representation learning and augments generalization capabilities significantly. Furthermore, given that pathological visual patterns are redundantly distributed across tissue slices, we sample a subset of visual instances during training. Our method demonstrates robust generalizability and strong transferability, dominantly outperforming the counterparts on the TCGA Lung Cancer dataset with at least 9.19% higher accuracy in few-shot experiments. The code is available at: https://github.com/ls1rius/WSI_FiVE.Comment: Accepted by CVPR 202

Back to the Starting Point: on the Simulation of Initial Magnetic Fields and Spin Periods of Non-accretion Pulsars

Neutron stars (NSs) play essential roles in modern astrophysics. Magnetic fields and spin periods of newborn (zero age) NSs have large impact on the further evolution of NSs, which are however poorly explored in observation due to the difficulty of finding newborn NSs. In this work, we aim to infer the magnetic fields and spin periods (Bi and Pi) of zero-age NSs from the observed properties of NS population. We select non-accretion NSs (NANSs) whose evolution is solely determined by magnetic dipole radiation. We find that both Bi and Pi can be described by log-normal distribution and the fitting sensitively depends on our parameters.Comment: 8 pages, 5 figures, accepted for publication in Ap

Efficacy and safety of external-beam radiation therapy for hepatocellular carcinoma: An overview of current evidence according to the different target population

n/

In Vitro Activity of Plant Extracts and Alkaloids against Clinical Isolates of Extended-Spectrum b-Lactamase (ESBL)-Producing Strains

The antibacterial activity of 80% ethanol extracts of 10 medicinal plants collected in Yunnan (Southwest China), was tested against clinical isolates of extended-spectrum b-lactamase (ESBL)-producing strains. Their MIC values ranged between 1.56–12.50 mg/mL. The most active plant extract was Chelidonium majus L. (MIC = 1.56 mg/mL). Two potent isoquinoline alkaloids, 8-hydroxydihydrosanguinarine and 8-hydroxydihydrochelerythrine, were identified as the major active principles through bioassay-guided fractionation and identification of the active ethyl acetate fraction from C. majus, with minimum MIC/MBC values of 15.63/62.50 mg/mL

Gray and White Matter Abnormality in Patients With T2DM-Related Cognitive Dysfunction: A Systemic Review and Meta-Analysis

Aims/hypothesis Brain structure abnormality in patients with type 2 diabetes mellitus (T2DM)-related cognitive dysfunction (T2DM-CD) has been reported for decades in magnetic resonance imaging (MRI) studies. However, the reliable results were still unclear. This study aimed to make a systemic review and meta-analysis to find the significant and consistent gray matter (GM) and white matter (WM) alterations in patients with T2DM-CD by comparing with the healthy controls (HCs). Methods Published studies were systemically searched from PubMed, MEDLINE, Cochrane Library and Web of Science databases updated to November 14, 2021. Studies reporting abnormal GM or WM between patients with T2DM-CD and HCs were selected, and their significant peak coordinates (x, y, z) and effect sizes (z-score or t-value) were extracted to perform a voxel-based meta-analysis by anisotropic effect size-signed differential mapping (AES-SDM) 5.15 software. Results Total 15 studies and 16 datasets (1550 participants) from 7531 results were involved in this study. Compared to HCs, patients with T2DM-CD showed significant and consistent decreased GM in right superior frontal gyrus, medial orbital (PFCventmed. R, BA 11), left superior temporal gyrus (STG. L, BA 48), and right calcarine fissure / surrounding cortex (CAL. R, BA 17), as well as decreased fractional anisotropy (FA) in right inferior network, inferior fronto-occipital fasciculus (IFOF. R), right inferior network, longitudinal fasciculus (ILF. R), and undefined area (32, −60, −42) of cerebellum. Meta-regression showed the positive relationship between decreased GM in PFCventmed.R and MoCA score, the positive relationship between decreased GM in STG.L and BMI, as well as the positive relationship between the decreased FA in IFOF.R and age or BMI. Conclusions/interpretation T2DM impairs the cognitive function by affecting the specific brain structures. GM atrophy in PFCventmed. R (BA 11), STG. L (BA 48), and CAL. R (BA 17), as well as WM injury in IFOF. R, ILF. R, and undefined area (32, −60, −42) of cerebellum. And those brain regions may be valuable targets for future researches. Age, BMI, and MoCA score have a potential influence on the altered GM or WM in T2DM-CD