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Background: The relationship between Protein Convertase Subtilisin Kexin Type 9 inhibitor (PCSK9i) and psychiatric adverse events (AEs) remains unclear due to the limitations of clinical trials. In this study, PCSK9i‐related psychiatric AEs were realistically observed and systematically summarized in the real world by data mining the FDA AE Reporting System (FAERS). Method: Total AEs between the third quarter of 2015 and the first quarter of 2023 were obtained from FAERS. Psychiatric AEs were identified using disproportionality analysis and clinical prioritization of signals using a rating scale, followed by univariate logistic regression to explore factors influencing psychiatric AEs. Results: Psychiatric AEs accounted for 6.7% of the total number of PCSK9i reports. Eighteen psychiatric AEs were defined as PCSK9i‐related psychiatric adverse events (ppAEs) (lower 95% CI of both ROR >1 and IC025 > 0). The median age of ppAE reports was 68 years, and female patients accounted for 22.67% of reports, including 41.40% of reports with a serious outcome. Eleven (61.11%) and seven (38.89%) ppAEs were classified as weak and moderate clinical priority, respectively. The median time to onset of ppAEs was 149 and 196 days after treatment with evolocumab and alirocumab, respectively. Patients weighing ≥80 kg were 1.59 times more likely to experience ppAEs. Conclusion: The results of this study facilitate the prioritization of psychiatric AE signals by healthcare professionals with the goal of mitigating the risk of PCSK9i‐related psychiatric AEs. However, as an exploratory study, our findings need to be confirmed in large‐scale prospective studies. [ABSTRACT FROM AUTHOR]

Geospatial data, especially remote sensing (RS) data, are of significant importance for public services and production activities. Expertise is critical in processing raw data, generating geospatial information, and acquiring domain knowledge and other remote sensing applications. However, existing geospatial service platforms are more oriented towards the professional users in the implementation process and final application. Building appropriate geographic applications for non-professionals remains a challenge. In this study, a geospatial data service architecture is designed that links desktop geographic information system (GIS) software and cloud-based platforms to construct an efficient user collaboration platform. Based on the scalability of the platform, four web apps with different themes are developed. Data in the fields of ecology, oceanography, and geology are uploaded to the platform by the users. In this pilot phase, the gap between non-specialized users and experts is successfully bridged, demonstrating the platform's powerful interactivity and visualization. The paper finally evaluates the capability of building spatial data infrastructures (SDI) based on GeoNode and discusses the current limitations. The support for three-dimensional data, the improvement of metadata creation and management, and the fostering of an open geo-community are the next steps. [ABSTRACT FROM AUTHOR]

Experimental observations revealed that the amyloid-β 42 oligomer (AβO) can directly bind to the LilrB2 D1D2(LDD) receptor with nanomolar-affinity, leading to changes in synaptic plasticity and cognitive deficits. However, the dependence of neurotoxicity on the morphology, size, and aggregation stage (SP1, SP2) of AβO, as well as the specific molecular mechanism of AβO–LDD interaction, remain uncertain. To address these uncertainties, we investigated the interaction between the LDD neuroreceptor and AβO with different Aβ42 species (nontoxic species, toxic species, and protofibril) and sizes. Our results showed that the LDD selectively binds AβO species rather than the Aβ42 monomer, accommodating various Aβ42 dimers and trimers as well as SP2 AβO, in a specific pose in the pocket of the LDD receptor (region I). Additionally, protofibrils with exposed β1/β2 regions can also bind to region I of the LDD receptor, as observed experimentally (Cao, et al., Nat. Chem., 2018, 10, 1213; and Aim et al., Nat. Commun., 2021, 12, 3451). More extensively, we identified two additional regions of the LDD receptor, regions II and III, suitable for binding to larger AβO species at the SP1 with different molecular weights and conformations, accounting for the stronger binding strength obtained experimentally. We suggest that the two regions are more competitive than region I in causing toxicity by AβO binding. The detailed and systematic characterization for the complexes generated between the LDD receptor and various AβO species, including the protofibril, offers deep insight into the dependence of neurotoxicity on the AβO size and conformation at the molecular level, and provides novel and specific targets for drug design of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Fibrous aggregates of beta-amyloid (Aβ) is a hallmark of Alzheimer's disease (AD). Several major strategies of drugs or inhibitors, including neutral molecules, positive or negative ions, and dual-inhibitor, are used to inhibit the misfolding or aggregation of Aβ42, among which a kind of dual-inhibitor composed of a pair of positive and negative ions is emerging as the most powerful candidate. This knowledge lacks the origin of the strong inhibitory effect and synergy mechanisms blocking the development and application of such inhibitors. To this end, we employed 1 : 1 ionic pairs (IP) of oppositely charged benzothiazole molecules (+)BAM1-EG6 (Pos) and (−)BAM1-EG6 (Neg) as well as equimolar neutral BAM1-EG6 (Neu) counterpart at two pH conditions (5.5 and 7.0) to bind Aβ42 targets, Aβ42 monomer (AβM), soluble pentamer (AβP), and pentameric protofibril (AβF) models, respectively, corresponding to the products of three toxic Aβ42 development pathways, lag, exponential and fibrillation phases. Simulated results illustrated the details of the inhibitory mechanisms of IP and Neu for the AβY (Y = M, P, or F) in the three different phases, characterizing the roles of Pos and Neg of IP as well as their charged, hydrophobic groups and linker playing in the synergistic interaction, and elucidated a previously unknown molecular mechanism governing the IP-Aβ42 interaction. Most importantly, we first revealed the origin of the stronger binding of IP inhibitors to Aβ42 than that of the equimolar neutral counterparts, observing a perplexing phenomenon that the physiological condition (pH = 7.0) than the acidic one (pH = 5.5) is more favorable to the enhancement of IP binding, and finally disclosed that solvation is responsible to the enhancement because at pH 7.0, AβP and AβF act as anionic membranes, where solvation plays a critical role in the chemoelectromechanics. The result not only provides a new dimension in dual-inhibitor/drug design and development but also a new perspective for uncovering charged protein disaggregation under IP-like inhibitors. [ABSTRACT FROM AUTHOR]

We used the ray tracing technique based on the IASP91 Earth model to calculate the travel times in order to identify the phases. This technique can calculate the travel times for the seismic phases in the conventional travel time tables. The waveform data received from the stations in the Guangxi area are selected for analysis and discussion. The outcomes of the numerical modeling and its use demonstrate that there is good agreement in terms of the absolute differences between the calculated and theoretical travel times from the ISAP91 tables. The relative residuals are determined directly from the actual arrival times picking during the correlation analysis, and the validity of the travel time method for picking seismic phases by correlation analysis can be demonstrated. [ABSTRACT FROM AUTHOR]

Ferroptosis is a new form of iron-dependent cell death and plays an important role during the occurrence and development of various tumors. Increasingly, evidence shows a convincing interaction between ferroptosis and tumor immunity, which affects cancer patients' prognoses. These two processes cooperatively regulate different developmental stages of tumors and could be considered important tumor therapeutic targets. However, reliable prognostic markers screened based on the combination of ferroptosis and tumor immune status have not been well characterized. Here, we chose the ssGSEA and ESTIMATE algorithms to evaluate the ferroptosis and immune status of a TCGA breast invasive ductal carcinoma (IDC) cohort, which revealed their correlation characteristics as well as patients' prognoses. The WGCNA algorithm was used to identify genes related to both ferroptosis and immunity. Univariate COX, LASSO regression, and multivariate Cox regression models were used to screen prognostic-related genes and construct prognostic risk models. Based on the ferroptosis and immune scores, the cohort was divided into three groups: a high-ferroptosis/low-immune group, a low-ferroptosis/high-immune group, and a mixed group. These three groups exhibited distinctive survival characteristics, as well as unique clinical phenotypes, immune characteristics, and activated signaling pathways. Among them, low-ferroptosis and high-immune statuses were favorable factors for the survival rates of patients. A total of 34 differentially expressed genes related to ferroptosis-immunity were identified among the three groups. After univariate, Lasso regression, and multivariate stepwise screening, two key prognostic genes (GNAI2, PSME1) were identified. Meanwhile, a risk prognosis model was constructed, which can predict the overall survival rate in the validation set. Lastly, we verified the importance of model genes in three independent GEO cohorts. In short, we constructed a prognostic model that assists in patient risk stratification based on ferroptosis-immune-related genes in IDC. This model helps assess patients' prognoses and guide individualized treatment, which also further eelucidatesthe molecular mechanisms of IDC. [ABSTRACT FROM AUTHOR]

System software for interactive human–computer data processing based on the IASP91 Earth model was designed. An interactive data processing system for visualizing earthquake data was designed and implemented via the Intel Fortran platform. The system reads and processes broadband seismic data acquired by field stations, mainly including the reading and import of raw data, pre-processing, identification of seismic phases and inter-correlation traveltimes picking. In the data processing step, shortcomings have been improved and functions have been gradually refined and enhanced, making it easier and faster to process data. It has already processed more than 1000 large seismic events received by the station from 2013 to 2018. The practical application shows that the human–computer interaction system is easy to operate, accurate, fast and flexible, and is an effective tool for processing seismic data. [ABSTRACT FROM AUTHOR]

The paper reports in silico three modified small molecules, two negatively charged E1C and E2C and one neutral TQ, which show more potent inhibitory effect than their parental molecules CQ3, TS0, and ER on the Cu2+ induced Aβ42 aggregation. In the acidic condition, TQ is the most powerful inhibitor, as it not only decreases the helix content of Cu2+‐Aβ42 complex but also increases the oxidizability; E1C/E2C however decreases the helix content of Cu2+‐Aβ42 complex but also with increased oxidizability, indicating that the inhibitory effect of the two charged molecules depends on the multiple factors, at least including the composite mechanism of helix decrease and oxidizability increase. In the basic condition, any of three modified molecules can increase the helix content of the Cu2+‐Aβ42 complex. Anyway, small molecules containing neutral and larger hydrophobic aromatic groups are always more effective in inhibiting Cu2+‐induced Aβ42 aggregation in both basic and acidic conditions. [ABSTRACT FROM AUTHOR]

The hypocenter parameters of an earthquake may give us an insight into the Earth's structure and tectonic processes. Among the hypocenter parameters, the focal depth is normally more difficult to estimate than the earthquake location (latitude and longitude). We propose to use the pPKIKP-PKIKP arrival time intervals for estimating the focal depth. We analyze the sensitivity of the pPKIKP-PKIKP arrival time interval to the earthquake depth. We measure the pPKIKP-PKIKP arrival time interval on seismograms (the vertical component), and invert the time interval data set using the simulated annealing inversion algorithm. We illustrate the inversion approach on two teleseismic earthquakes which have shallow and deep focal depths, and demonstrate that the approach is indeed appropriate to the shallow and deep event. We can obtain a reliable estimate on focal depth, even though the seismic station is sparse or in a remote part of the epicenter. [ABSTRACT FROM AUTHOR]

Pyroptosis is recently identified as an inflammatory form of programmed cell death. However, the roles of pyroptosis-related genes (PS genes) in major depressive disorder (MDD) remain unclear. This study developed a novel diagnostic model for MDD based on PS genes and explored the pathological mechanisms associated with pyroptosis. First, we obtained 23 PS genes that were differentially expressed between healthy controls and MDD cases from GSE98793 dataset. There were obvious variation in immune cell infiltration profiles and immune-related pathway enrichment between healthy controls and MDD cases. Then, a novel diagnostic model consisting of eight PS genes (GPER1 , GZMA, HMGB1 , IL1RN , NLRC4 , NLRP3 , UTS2 , and CAPN1) for MDD was constructed by random forest (RF) and least absolute shrinkage and selection operator (LASSO) analyses. ROC analysis revealed that our model has good diagnostic performance, AUC = 0.795 (95% CI 0.721–0.868). Subsequently, the consensus clustering method based on 23 differentially expressed PS genes was constructed to divide all MDD cases into two distinct pyroptosis subtypes (cluster A and B) with different immune and biological characteristics. Principal component analysis (PCA) algorithm was performed to calculate the pyroptosis scores ("PS-scores") for each sample to quantify the pyroptosis regulation subtypes. The MDD patients in cluster B had higher "PS-scores" than those in cluster A. Furthermore, we also found that MDD patients in cluster B showed lower expression levels of 11 interferon (IFN)-α isoforms. In conclusion, pyroptosis may play an important role in MDD and can provide new insights into the diagnosis and underlying mechanisms of MDD. [ABSTRACT FROM AUTHOR]