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Abstract Genetic generalized epilepsies (GGE) exhibit widespread morphometric alterations in the subcortical structures. Subcortical structures are essential for understanding GGE pathophysiology, but their fine-grained morphological diversity has yet to be comprehensively investigated. Furthermore, the relationships between macroscale morphological disturbances and microscale molecular chemoarchitectures are unclear. High-resolution structural images were acquired from patients with GGE (n = 97) and sex- and age-matched healthy controls (HCs, n = 184). Individual measurements of surface shape features (thickness and surface area) of seven bilateral subcortical structures were quantified. The patients and HCs were then compared vertex-wise, and shape anomalies were co-located with brain neurotransmitter profiles. We found widespread morphological alterations in GGE and prominent disruptions in the thalamus, putamen, and hippocampus. Shape area dilations were observed in the bilateral ventral, medial, and right dorsal thalamus, as well as the bilateral lateral putamen. We found that the shape area deviation pattern was spatially correlated with the norepinephrine transporter and nicotinic acetylcholine (Ach) receptor (α 4 β 2 ) profiles, but a distinct association was seen in the muscarinic Ach receptor (M 1 ). The findings provided a comprehensive picture of subcortical morphological disruptions in GGE, and further characterized the associated molecular mechanisms. This information may increase our understanding of the pathophysiology of GGE.

Maintaining immune homeostasis is crucial for neonatal health following birth, as neonates encounter the colonization of gut flora and a plethora of external antigens. Myeloid-derived suppressor cells (MDSCs), a group of innate immune cells of myeloid origin with immunosuppressive functions, are known for their significant role in promoting tumor progression. Recent studies, however, have highlighted the critical immunoprotective functions of neonatal MDSCs. Unlike tumor-associated MDSCs, neonatal MDSCs exhibit strong antibacterial activity and play a vital role in preventing inflammatory responses in newborns. This review provides a comprehensive overview of the etiology, characteristics, immunomodulatory functions, and regulatory mechanisms of neonatal MDSCs, emphasizing their role in neonatal inflammatory diseases. This insight aims to provide new strategies for the immunotherapy of neonatal inflammatory diseases.

In order to explore the distribution characteristics of “three zones” of spontaneous combustion in goaf under different ventilation modes, based on the engineering background of “two into one” ventilation mode at 1532 (1) working face of Gubei Mine, and based on airflow control equation, concentration component equation and energy equation, by using the Fluent numerical simulation method, the multi-physical coupling numerical model of coal spontaneous combustion and the real-time dynamic advance model of working face are established, and the distribution characteristics of “three zones” of spontaneous combustion in goaf by the “110 construction method” under three ventilation modes are simulated. The results show that with the continuous advance of the working face, under the conditions of ventilation mode 1 (air intake from the machine side and gob-side entry retaining, return air along the return air lane) and ventilation mode 2 (air intake from the machine side and along the return lane, and return air in gob-side entry retaining), the oxidation spontaneous combustion belt in the goaf is evenly distributed in the side of the belt machine, the middle of the working face and the side of the lane, and the oxygen concentration distribution is not much different. About 50 days after mining, the highest temperature appeared in the deep side of the transportation lane, and the temperature at this position did not increase with the continuous advance of the working face. Under the condition of ventilation mode 3 (air intake in gob-side entry retaining and return air lane, and air return at the side of the machine lane), the oxidation spontaneous combustion belt at the side of the goaf retaining roadway becomes 2-4 times wider, the middle of the working face and the side of the belt conveyor become obviously narrow, the oxygen volume fraction at the side of the belt conveyor in the goaf is lower, the oxygen concentration at the side of the belt conveyor is higher, and the air leakage increases significantly. The high temperature location of goaf mainly appears in the side of the stop line of 1532(1) working face, and the temperature of goaf here is the highest after 50 days of working face. In summary, combined with the actual situation of the site, the width and location of the oxidation spontaneous combustion belt are analyzed, and the ventilation mode 3 is finally determined to be more conducive to preventing the occurrence of coal spontaneous combustion, which provides theoretical guidance for the prevention of coal spontaneous combustion in mines.

Abstract Collective cooperation is essential for many social and biological systems, yet understanding how it evolves remains a challenge. Previous investigations report that the ubiquitous heterogeneous individual connections hinder cooperation by assuming individuals update strategies at identical rates. Here we develop a general framework by allowing individuals to update strategies at personalised rates, and provide the precise mathematical condition under which universal cooperation is favoured. Combining analytical and numerical calculations on synthetic and empirical networks, we find that when individuals’ update rates vary inversely with their number of connections, heterogeneous connections actually outperform homogeneous ones in promoting cooperation. This surprising property undercuts the conventional wisdom that heterogeneous structure is generally antagonistic to cooperation and, further helps develop an efficient algorithm OptUpRat to optimise collective cooperation by designing individuals’ update rates in any population structure. Our findings provide a unifying framework to understand the interplay between structural heterogeneity, behavioural rhythms, and cooperation.

Epilepsy is a chronic neurological disease. Here we describe the generation of induced pluripotent stem cells (iPSCs) from a patient diagnosed as epilepsy caused by ATP1A2 gene mutation. Induced pluripotent stem cells (iPSCs) were developed using non-integrating episomal vectors containing OCT4, SOX2, KLF4, BCL-XL and C-MYC. The established iPSC line (SDCHi007-A) displayed pluripotent cell morphology, high expression levels of pluripotency markers, differentiation potential in vitro, normal karyotype, and remaining the original ATP1A2 gene mutation.

ObjectivesChronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated neuropathy defined by clinical progression for more than 2 months. 16-20% of CIDP patients may present with rapidly progressive weakness that resembles GBS, known as acute-onset CIDP (A-CIDP). However, it is challenging to distinguish from GBS-TRF because of their similar clinical symptom and features. In this case review, we report a patient with A-CIDP with the detection of anti-GM3 and anti-sulfatides antibodies, which rarely have been in A-CIDP and may account for her progressive and recurrent symptoms.MethodsWe analyzed existing medical literature and described a clinical case of A-CIDP with antibodies positive.ResultsWe reported a 56-year-old female presented with bilateral lower extremity weakness and distal numbness. She experienced similar symptoms four times and responded well to the IVIg therapy. Lumbar puncture demonstrated albumin-cytologic dissociation and EDX examination revealed multiple peripheral nerve damage. After ruling out other demyelination diseases, a diagnosis of A-CIDP was made.DiscussionThe antiganglioside and anti-sulfatide antibodies are involved in CIDP pathogenesis and can help to distinguish A-CIDP and other variants. To prevent secondary damage, it is important to monitor relapse and remission symptoms along the treatment line. A rare case of A-CIDP is discussed concerning the detection of anti-GM3 and anti-sulfatides antibodies, thus making a retrospective comparison of antibodies in some literature to understand A-CIDP better.

The Notch signaling pathway is evolutionarily conserved across metazoan species and plays key roles in many physiological processes. The Notch receptor is activated by two families of canonical ligands (Delta-like and Serrate/Jagged) where both ligands and receptors are single-pass transmembrane proteins usually with large extracellular domains, relative to their intracellular portions. Upon interaction of the core binding regions, presented on opposing cell surfaces, formation of the receptor/ligand complex initiates force-mediated proteolysis, ultimately releasing the transcriptionally-active Notch intracellular domain. This review focuses on structural features of the extracellular receptor/ligand complex, the role of post-translational modifications in tuning this complex, the contribution of the cell membrane to ligand function, and insights from acquired and genetic diseases.

Abstract Hedyotis diffusa Willd (HDW) possesses heat-clearing, detoxification, anti-cancer, and anti-inflammatory properties. However, its effects on rheumatoid arthritis (RA) remain under-researched. In this study, we identified potential targets of HDW and collected differentially expressed genes of RA from the GEO dataset GSE77298, leading to the construction of a drug-component-target-disease regulatory network. The intersecting genes underwent GO and KEGG analysis. A PPI protein interaction network was established in the STRING database. Through LASSO, RF, and SVM-RFE algorithms, we identified the core gene MMP9. Subsequent analyses, including ROC, GSEA enrichment, and immune cell infiltration, correlated core genes with RA. mRNA–miRNA–lncRNA regulatory networks were predicted using databases like TargetScan, miRTarBase, miRWalk, starBase, lncBase, and the GEO dataset GSE122616. Experimental verification in RA-FLS cells confirmed HDW’s regulatory impact on core genes and their ceRNA expression. We obtained 11 main active ingredients of HDW and 180 corresponding targets, 2150 RA-related genes, and 36 drug-disease intersection targets. The PPI network diagram and three machine learning methods screened to obtain MMP9, and further analysis showed that MMP9 had high diagnostic significance and was significantly correlated with the main infiltrated immune cells, and the molecular docking verification also showed that MMP9 and the main active components of HDW were well combined. Next, we predicted 6 miRNAs and 314 lncRNAs acting on MMP9, and two ceRNA regulatory axes were obtained according to the screening. Cellular assays indicated HDW inhibits RA-FLS cell proliferation and MMP9 protein expression dose-dependently, suggesting HDW might influence RA’s progression by regulating the MMP9/miR-204-5p/MIAT axis. This innovative analytical thinking provides guidance and reference for the future research on the ceRNA mechanism of traditional Chinese medicine in the treatment of RA.

Abstract Deciphering the complex relationship between neuroanatomical connections and functional activity in primate brains remains a daunting task, especially regarding the influence of monosynaptic connectivity on cortical activity. Here, we investigate the anatomical-functional relationship and decompose the neuronal-tracing connectome of marmoset brains into a series of eigenmodes using graph signal processing. These cellular connectome eigenmodes effectively constrain the cortical activity derived from resting-state functional MRI, and uncover a patterned cellular-functional decoupling. This pattern reveals a spatial gradient from coupled dorsal-posterior to decoupled ventral-anterior cortices, and recapitulates micro-structural profiles and macro-scale hierarchical cortical organization. Notably, these marmoset-derived eigenmodes may facilitate the inference of spontaneous cortical activity and functional connectivity of homologous areas in humans, highlighting the potential generalizing of the connectomic constraints across species. Collectively, our findings illuminate how neuronal-tracing connectome eigenmodes constrain cortical activity and improve our understanding of the brain’s anatomical-functional relationship.

Abstract Background and aims Severe acute pancreatitis (SAP) is potentially lethal. Considering the role of inflammation in the progression of acute pancreatitis (AP), this study aims to develop a model based on inflammatory indexes for identifying the presence of SAP. Methods Overall, 253 patients with AP who were consecutively admitted between July 2018 and November 2020 were screened, of whom 60 had SAP. Systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), neutrophil-to-platelet ratio (NPR), systemic inflammation response index (SIRI), platelet-to-albumin ratio (PAR), C-reactive protein-to-albumin ratio (CAR), C-reactive protein-to-lymphocyte ratio (CLR), and triglyceride glucose (TyG) index were calculated. Multivariate logistic regression analyses were performed to identify independent risk factors of SAP. Then, inflammation-based models were established. Receiver operating characteristics (ROC) curve analyses were performed. Area under ROC curve (AUROC) was calculated. Results Diabetes mellitus, fatty liver, high white blood cell count (WBC), C-reactive protein (CRP), red blood cell distribution width (RDW), procalcitonin (PCT), SII, NLR, NPR, CAR, CLR, and TyG index, and a low LMR were significantly associated with SAP. Considering the collinearity among these variables, 10 multivariate logistic regression analyses were separately performed. Finally, four independent inflammation-based models were established. Of them, the best one, which was calculated as follows: 1.204*fatty liver (yes = 1; no = 0) + 0.419*PCT + 0.005*CLR - 2.629, had an AUROC of 0.795 with a specificity of 73.4% and a sensitivity of 71.7%. Conclusion The inflammation-based model consisting of fatty liver, PCT, and CLR has a good diagnostic performance for SAP.

Abstract Epilepsies are a group of neurological disorders characterized by abnormal spontaneous brain activity, involving multiscale changes in brain functional organizations. However, it is not clear to what extent the epilepsy-related perturbations of spontaneous brain activity affect macroscale intrinsic dynamics and microcircuit organizations, that supports their pathological relevance. We collect a sample of patients with temporal lobe epilepsy (TLE) and genetic generalized epilepsy with tonic-clonic seizure (GTCS), as well as healthy controls. We extract massive temporal features of fMRI BOLD time-series to characterize macroscale intrinsic dynamics, and simulate microcircuit neuronal dynamics used a large-scale biological model. Here we show whether macroscale intrinsic dynamics and microcircuit dysfunction are differed in epilepsies, and how these changes are linked. Differences in macroscale gradient of time-series features are prominent in the primary network and default mode network in TLE and GTCS. Biophysical simulations indicate reduced recurrent connection within somatomotor microcircuits in both subtypes, and even more reduced in GTCS. We further demonstrate strong spatial correlations between differences in the gradient of macroscale intrinsic dynamics and microcircuit dysfunction in epilepsies. These results emphasize the impact of abnormal neuronal activity on primary network and high-order networks, suggesting a systematic abnormality of brain hierarchical organization.

Abstract For the current stellar spectral simulation can not realize the stellar color temperature information with large dynamic range simulation, this paper proposes a broad spectrum high-resolution subdivision and spatial beam zoning modulation combined with a large dynamic range of stellar radiation information simulation method, designed a kind of imaging and non-imaging stellar radiation information simulation optical system, using an optical system to achieve multi-color temperature spectrum and large dynamic range stellar simulation. The experimental results show that the designed system can simultaneously achieve the spectral simulation accuracy (single point evaluation) better than ± 7% in the range of spectral 450–1000 nm and color temperature 3000–11,000 K; on the premise of ensuring the spectral simulation accuracy, the magnitude simulation range reaches 0 to + 12 Mv, and the magnitude simulation accuracy is better than ± 0.05 Mv; Accurate simulation of stellar spectral information and energy large dynamic range tuning is realized, and the system is extended. The system function has been extended to realize the switching of broadband and narrowband modes, The half-peak width of the narrowband output beam is better than 4.1 nm, which extends the application of the spectral simulation technology and provides the theoretical and technical basis for the ground calibration of the development of the high-precision stellar radiation information ground simulation system.

Abstract Background The bimolecular fluorescence complementation (BiFC) assay is commonly used for investigating protein–protein interactions. While several BiFC detection systems have been developed, there is a limited amount of research focused on using laser scanning confocal microscope (LSCM) techniques to observe protoplasts. Protoplasts are more susceptible to damage and instability compared to their original cell state due to the preparation treatments they undergo, which makes it challenging for researchers to manipulate them during observation under LSCMs. Therefore, it is crucial to utilize microscope techniques properly and efficiently in BiFC assays. Results When the target fluorescence is weak, the autofluorescence of chloroplast particles in protoplasts can interfere with the detection of BiFC signals localized in the nuclear region. Spectrum analysis revealed that chloroplast autofluorescence can be excited by lasers of various types, with the highest fluorescence signal observed at around 660 nm. Furthermore, our investigation into the impact of different pipette tips on the integrity of protoplast samples indicated that the utilization of cut tips with larger openings can mitigate cell breakage. We presented a workflow of LSCM techniques for investigating protoplast BiFC and discussed the microscopic manipulation involved in sample preparation and image capturing. Conclusion When the BiFC signals are weak, they may be affected by chloroplast autofluorescence. However, when used properly, the autofluorescence of chloroplasts can serve as an excellent internal marker for effectively distinguishing other signals. In combination with other findings, this study can provide valuable reference for researchers conducting BiFC assays and related studies.

The human brain is organized as segregation and integration units and follows complex developmental trajectories throughout life. The cortical manifold provides a new means of studying the brain's organization in a multidimensional connectivity gradient space. However, how the brain's morphometric organization changes across the human lifespan remains unclear. Here, leveraging structural magnetic resonance imaging scans from 1,790 healthy individuals aged 8 to 89 years, we investigated age-related global, within- and between-network dispersions to reveal the segregation and integration of brain networks from 3D manifolds based on morphometric similarity network (MSN), combining multiple features conceptualized as a "fingerprint" of an individual's brain. Developmental trajectories of global dispersion unfolded along patterns of molecular brain organization, such as acetylcholine receptor. Communities were increasingly dispersed with age, reflecting more disassortative morphometric similarity profiles within a community. Increasing within-network dispersion of primary motor and association cortices mediated the influence of age on the cognitive flexibility of executive functions. We also found that the secondary sensory cortices were decreasingly dispersed with the rest of the cortices during aging, possibly indicating a shift of secondary sensory cortices across the human lifespan from an extreme to a more central position in 3D manifolds. Together, our results reveal the age-related segregation and integration of MSN from the perspective of a multidimensional gradient space, providing new insights into lifespan changes in multiple morphometric features of the brain, as well as the influence of such changes on cognitive performance.

Thioredoxin reductase (TXNRD) is a selenoprotein that plays a crucial role in cellular antioxidant defense. Previously, a distinctive guiding bar motif was identified in TXNRD1, which influences the transfer of electrons. In this study, utilizing single amino acid substitution and Excitation-Emission Matrix (EEM) fluorescence spectrum analysis, we discovered that the guiding bar communicates with the FAD and modulates the electron flow of the enzyme. Differential Scanning Fluorimetry (DSF) analysis demonstrated that the aromatic amino acid in guiding bar is a stabilizer for TXNRD1. Kinetic analysis revealed that the guiding bar is vital for the disulfide reductase activity but hinders the selenocysteine-independent reduction activity of TXNRD1. Meanwhile, the guiding bar shields the selenocysteine residue of TXNRD1 from the attack of electrophilic reagents. We also found that the inhibition of TXNRD1 by caveolin-1 scaffolding domain (CSD) peptides and compound LCS3 did not bind to the guiding bar motif. In summary, the obtained results highlight new aspects of the guiding bar that restrict the flexibility of the C-terminal redox motif and govern the transition from antioxidant to pro-oxidant.

Osteoarthritis (OA) is a chronic disease characterized by cartilage damage. At present, targeted drugs are undeveloped due to unknown pathogenesis. In recent years, many studies have shown that abnormal energy metabolism such as mitochondrial dysfunction, glucose metabolism disorder and lipid metabolism abnormity in chondrocytes aggravates the deterioration of OA. The current research indicate that chondrocytes are improved from the energy metabolism pathway, it is possible to achieve the goals of OA treatment such as pain relief, inflammation reduction, delay in progression and function improvement. In this review, we focus on the association between energy metabolism of chondrocytes and the cause and development of cartilage damage in OA, aiming to clarify the potential therapeutic strategies for OA.

Abstract Background The early diagnosis and intervention of mild cognitive impairment (MCI) patients is expected to delay the progression of AD. Delayed treatment will lead to MCI patients missing the best intervention expectation. At present, the medical help-seeking behavior of this group is not optimistic. This study aimed to explore influencing factors of help-seeking behavior among patients with MCI in China based on the help-seeking behavior model. Methods Twenty-two patients with MCI were recruited to participate in semi-structured interviews via purposeful sampling with a qualitative, descriptive design. Data were analyzed by qualitative content analysis. Results The study revealed the main influencing factors of help-seeking behavior among MCI patients in China included perceived disease threat, symptom attribution, disease knowledge, use of cognitive compensation strategies, sense of foreseeable burden, social support, economic condition, and accessibility of medical service. Conclusions The help-seeking behavior of patients with MCI is affected by multiple factors. There are some key factors in different stages of the help-seeking process. Healthcare providers can utilize these factors to design targeted interventions for promoting early help-seeking of patients with MCI.

Abstract The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is frequently reported to be hyperactivated in hepatocellular carcinoma (HCC) and contributes to HCC recurrence. However, the underlying regulatory mechanisms of mTORC1 signaling in HCC are not fully understood. In the present study, we found that the expression of kinesin family member 18B (KIF18B) was positively correlated with mTORC1 signaling in HCC, and the upregulation of KIF18B and p-mTOR was associated with a poor prognosis and HCC recurrence. Utilizing in vitro and in vivo assays, we showed that KIF18B promoted HCC cell proliferation and migration through activating mTORC1 signaling. Mechanistically, we identified Actin gamma 1 (γ-Actin) as a binding partner of KIF18B. KIF18B and γ-Actin synergistically modulated lysosome positioning, promoted mTORC1 translocation to lysosome membrane, and prohibited p70 S6K from entering lysosomes for degradation, which finally led to the enhancement of mTORC1 signaling transduction. Moreover, we found that KIF18B was a direct target of Forkhead box M1, which explains the potential mechanism of KIF18B overexpression in HCC. Our study highlights the potential of KIF18B as a therapeutic target for the treatment of HCC.