An end-to-end method for predicting compound-protein interactions based on simplified homogeneous graph convolutional network and pre-trained language model.

Identification of interactions between chemical compounds and proteins is crucial for various applications, including drug discovery, target identification, network pharmacology, and elucidation of protein functions. Deep neural network-based approaches are becoming increasingly popular in efficiently identifying compound-protein interactions with high-throughput capabilities, narrowing down the scope of candidates for traditional labor-intensive, time-consuming and expensive experimental techniques. In this study, we proposed an end-to-end approach termed SPVec-SGCN-CPI, which utilized simplified graph convolutional network (SGCN) model with low-dimensional and continuous features generated from our previously developed model SPVec and graph topology information to predict compound-protein interactions. The SGCN technique, dividing the local neighborhood aggregation and nonlinearity layer-wise propagation steps, effectively aggregates K-order neighbor information while avoiding neighbor explosion and expediting training. The performance of the SPVec-SGCN-CPI method was assessed across three datasets and compared against four machine learning- and deep learning-based methods, as well as six state-of-the-art methods. Experimental results revealed that SPVec-SGCN-CPI outperformed all these competing methods, particularly excelling in unbalanced data scenarios. By propagating node features and topological information to the feature space, SPVec-SGCN-CPI effectively incorporates interactions between compounds and proteins, enabling the fusion of heterogeneity. Furthermore, our method scored all unlabeled data in ChEMBL, confirming the top five ranked compound-protein interactions through molecular docking and existing evidence. These findings suggest that our model can reliably uncover compound-protein interactions within unlabeled compound-protein pairs, carrying substantial implications for drug re-profiling and discovery. In summary, SPVec-SGCN demonstrates its efficacy in accurately predicting compound-protein interactions, showcasing potential to enhance target identification and streamline drug discovery processes.Scientific contributionsThe methodology presented in this work not only enables the comparatively accurate prediction of compound-protein interactions but also, for the first time, take sample imbalance which is very common in real world and computation efficiency into consideration simultaneously, accelerating the target identification and drug discovery process.

Antibacterial activity and mechanisms of D-3263 against Staphylococcus aureus.

Multi-drug-resistant Staphylococcus aureus infections necessitate novel antibiotic development. D-3263, a transient receptor potential melastatin member 8 (TRPM8) agonist, has potential antineoplastic properties. Here, we reported the antibacterial and antibiofilm activities of D-3263. Minimum inhibitory concentrations (MICs) against S. aureus, Enterococcus faecalis and E. faecium were ≤ 50 µM. D-3263 exhibited bactericidal effects against clinical methicillin-resistant S. aureus (MRSA) and E. faecalis strains at 4× MIC. Subinhibitory D-3263 concentrations effectively inhibited S. aureus and E. faecalis biofilms, with higher concentrations also clearing mature biofilms. Proteomic analysis revealed differential expression of 29 proteins under 1/2 × MIC D-3263, influencing amino acid biosynthesis and carbohydrate metabolism. Additionally, D-3263 enhanced membrane permeability of S. aureus and E. faecalis. Bacterial membrane phospholipids phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CL) dose-dependently increased D-3263 MICs. Overall, our data suggested that D-3263 exhibited potent antibacterial and antibiofilm activities against S. aureus by targeting the cell membrane.

Identification of endothelial and mesenchymal FOXF1 enhancers involved in alveolar capillary dysplasia.

Mutations in the FOXF1 gene, a key transcriptional regulator of pulmonary vascular development, cause Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins, a lethal lung disease affecting newborns and infants. Identification of new FOXF1 upstream regulatory elements is critical to explain why frequent non-coding FOXF1 deletions are linked to the disease. Herein, we use multiome single-nuclei RNA and ATAC sequencing of mouse and human patient lungs to identify four conserved endothelial and mesenchymal FOXF1 enhancers. We demonstrate that endothelial FOXF1 enhancers are autoactivated, whereas mesenchymal FOXF1 enhancers are regulated by EBF1 and GLI1. The cell-specificity of FOXF1 enhancers is validated by disrupting these enhancers in mouse embryonic stem cells using CRISPR/Cpf1 genome editing followed by lineage-tracing of mutant embryonic stem cells in mouse embryos using blastocyst complementation. This study resolves an important clinical question why frequent non-coding FOXF1 deletions that interfere with endothelial and mesenchymal enhancers can lead to the disease.

Precision detection of hepatocellular carcinoma-associated telomerase RNA with SA@Comb-HCR nanosystem.

Accurate intracellular visualization of human telomerase RNA (hTR) is imperative for early diagnosis and treatment monitoring of hepatocellular carcinoma (HCC). While isothermal amplification-based DNA cascade strategies are promising, challenges persist in achieving great intake efficiency of detection probes within tumor cells and enhancing intracellular reaction efficiency. This study introduces a SA@Comb-HCR nanosystem, a highly effective approach for in situ hTR detection in HCC cells. Sodium alginate-coated liposomes ensures efficient nanoprobe delivery, which are then combined with proximity effect-inspired signal amplification. The coating of sodium alginate facilitates receptor-mediated endocytosis, prevents serum protein adhesion, and mitigates cationic liposome cytotoxicity. The designed Comb-like consolidated hairpin probe enhances the concentration of the local reactant, resulting in cascade amplification upon hTR activation. This technique achieves precision detection of intracellularly overexpressed hTR in HCC cells with a remarkable detection limit of 0.7 pM. This approach holds great promise for advancing targeted and sensitive early clinical diagnosis of HCC.

Eml1 promotes axonal growth by enhancing αTAT1-mediated microtubule acetylation.

Microtubule stabilization is critical for axonal growth and regeneration, and many microtubule-associated proteins are involved in this process. In this study, we found that the knockdown of echinoderm microtubule-associated protein-like 1 (EML1) hindered axonal growth in cultured cortical and dorsal root ganglion neurons. We further revealed that EML1 facilitated the acetylation of microtubules and that the impairment of axonal growth due to EML1 inhibition could be restored by treatment with deacetylase inhibitors, suggesting that EML1 affected tubulin acetylation. Moreover, we verified an interaction between EML1 and the alpha-tubulin acetyltransferase 1, which is responsible for the acetylation of alpha-tubulin. We thus proposed that EML1 might regulate microtubule acetylation and stabilization via alpha-tubulin acetyltransferase 1 and then promote axon growth. Finally, we verified that the knockdown of EML1 in vivo also inhibited sciatic nerve regeneration. Our findings revealed a novel effect of EML1 on microtubule acetylation during axonal regeneration.

GIP attenuates neuronal oxidative stress by regulating glucose uptake in spinal cord injury of rat.

AIM: Glucose-dependent insulinotropic polypeptide (GIP) is a ligand of glucose-dependent insulinotropic polypeptide receptor (GIPR) that plays an important role in the digestive system. In recent years, GIP has been regarded as a hormone-like peptide to regulate the local metabolic environment. In this study, we investigated the antioxidant role of GIP on the neuron and explored the possible mechanism. METHODS: Cell counting Kit-8 (CCK-8) was used to measure cell survival. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect apoptosis in vitro and in vivo. Reactive oxygen species (ROS) levels were probed with 2', 7'-Dichloro dihydrofluorescein diacetate (DCFH-DA), and glucose intake was detected with 2-NBDG. Immunofluorescence staining and western blot were used to evaluate the protein level in cells and tissues. Hematoxylin-eosin (HE) staining, immunofluorescence staining and tract-tracing were used to observe the morphology of the injured spinal cord. Basso-Beattie-Bresnahan (BBB) assay was used to evaluate functional recovery after spinal cord injury. RESULTS: GIP reduced the ROS level and protected cells from apoptosis in cultured neurons and injured spinal cord. GIP facilitated wound healing and functional recovery of the injured spinal cord. GIP significantly improved the glucose uptake of cultured neurons. Meanwhile, inhibition of glucose uptake significantly attenuated the antioxidant effect of GIP. GIP increased glucose transporter 3 (GLUT3) expression via up-regulating the level of hypoxia-inducible factor 1α (HIF-1α) in an Akt-dependent manner. CONCLUSION: GIP increases GLUT3 expression and promotes glucose intake in neurons, which exerts an antioxidant effect and protects neuronal cells from oxidative stress both in vitro and in vivo.

Rapid and Sensitive Detection of Verticillium dahliae from Soil Using LAMP-CRISPR/Cas12a Technology.

Cotton Verticillium wilt is mainly caused by the fungus Verticillium dahliae, which threatens the production of cotton. Its pathogen can survive in the soil for several years in the form of microsclerotia, making it a destructive soil-borne disease. The accurate, sensitive, and rapid detection of V. dahliae from complex soil samples is of great significance for the early warning and management of cotton Verticillium wilt. In this study, we combined the loop-mediated isothermal amplification (LAMP) with CRISPR/Cas12a technology to develop an accurate, sensitive, and rapid detection method for V. dahliae. Initially, LAMP primers and CRISPR RNA (crRNA) were designed based on a specific DNA sequence of V. dahliae, which was validated using several closely related Verticillium spp. The lower detection limit of the LAMP-CRISPR/Cas12a combined with the fluorescent visualization detection system is approximately ~10 fg/µL genomic DNA per reaction. When combined with crude DNA-extraction methods, it is possible to detect as few as two microsclerotia per gram of soil, with the total detection process taking less than 90 min. Furthermore, to improve the method's user and field friendliness, the field detection results were visualized using lateral flow strips (LFS). The LAMP-CRISPR/Cas12a-LFS system has a lower detection limit of ~1 fg/µL genomic DNA of the V. dahliae, and when combined with the field crude DNA-extraction method, it can detect as few as six microsclerotia per gram of soil, with the total detection process taking less than 2 h. In summary, this study expands the application of LAMP-CRISPR/Cas12a nucleic acid detection in V. dahliae and will contribute to the development of field-deployable diagnostic productions.

Honokiol regulates ovarian cancer cell malignant behavior through YAP/TAZ pathway modulation.

BACKGROUND: Ovarian cancer (OVCA) stands as one of the most fatal gynecological malignancies. Honokiol (HNK) has been substantiated by numerous studies for its anti-tumor activity against malignancies including OVCA. Consequently, this work was designed to elucidate the impact of HNK-mediated modulation of the YAP/TAZ pathway on the biological functions of OVCA cells. METHODS: OVCA cells were subjected to treatment with varying concentrations (0, 25, 50, 75, and 100 µM) of HNK, concomitant with the administration of YAP agonist (XMU). Assessment of cellular viability was executed employing the CCK-8 assay, while quantification of cellular proliferation transpired via colony formation assays. Apoptosis was ascertained using flow cytometry, and expression of apoptosis-related proteins (caspase-3, Bcl-2, Bax), EMT-related proteins (E-cadherin, N-cadherin), migration-associated proteins (MMP-2, MMP-9), and YAP/TAZ pathway-related proteins was evaluated by western blot. Transwell experiments were conducted to assess cellular migratory and invasive propensities. Xenograft tumor models were built to observe tumor growth (volume and weight), apoptosis was assessed by TUNEL staining, and Ki67 expression was evaluated through IHC. RESULTS: HNK exerted inhibitory effects on the viability and proliferative capacity of OVCA cells, elicited apoptotic responses, curtailed the migratory and invasive tendencies of cells, and downregulated the YAP/TAZ pathway. Stimulation with YAP agonist (XMU-MP-1) partially attenuated the impacts of HNK on OVCA cell biology. Experiments in vivo confirmed that HNK inhibited OVCA tumor growth. CONCLUSION: The outcomes of this investigation conclusively established that HNK orchestrated the modulation of the YAP/TAZ pathway, thereby exerting control over the malignant phenotypic manifestations of OVCA cells. The ascertained function of HNK in restraining cellular proliferation and tumor progression provided novel evidence of its anti-proliferative activity within OVCA cells.

The role of hydraulic conductivity in the Pine Island Glacier's subglacial water distribution.

Global climate warming leads to ever-increasing glacier mass loss. Pine Island Glacier in Antarctica is one of the largest contributors to global sea level rise (SLR). One of the biggest uncertainties in the assessment of glacier contribution to SLR at present are subglacial hydrology processes which are less well known than other ice dynamical processes. We use the Glacier Drainage System (GlaDS) model which couples both distributed and channelized components to simulate the basal hydrology of Pine Island Glacier with basal sliding and meltwater production taken from a full-Stokes Elmer/Ice model fitting observed surface velocities. We find ≈100 km long Rothlisberger channels up to 26 m in diameter extending up glacier from the grounding line along the main trunk of Pine Island Glacier delivering 51 m3 s-1 of fresh water to the grounding line. Channelization occurs at high water pressure because of high basal melt rates (maximum of 1 m a-1) caused by high rates of shear heating in regions with fast ice flow (>1000 m a-1). We simulate a shallow "swamp" of 0.8 m water depth where flow transitions from a distributed system into the channels. We performed a set of 38 sensitivity experiments varying sheet and channel conductivity over 4 orders of magnitude. We find a threshold behavior in distributed sheet conductivity above which basal water pressures are unaffected by changing channel conductivities. Our findings suggest a strong need to better understand controls on basal water conductivity through the distributed system. This issue is critical to improve model-based predictive capability for the Pine Island Glacier and, more generally, the Antarctic Ice Sheet.

CovEpiAb: a comprehensive database and analysis resource for immune epitopes and antibodies of human coronaviruses.

Coronaviruses have threatened humans repeatedly, especially COVID-19 caused by SARS-CoV-2, which has posed a substantial threat to global public health. SARS-CoV-2 continuously evolves through random mutation, resulting in a significant decrease in the efficacy of existing vaccines and neutralizing antibody drugs. It is critical to assess immune escape caused by viral mutations and develop broad-spectrum vaccines and neutralizing antibodies targeting conserved epitopes. Thus, we constructed CovEpiAb, a comprehensive database and analysis resource of human coronavirus (HCoVs) immune epitopes and antibodies. CovEpiAb contains information on over 60 000 experimentally validated epitopes and over 12 000 antibodies for HCoVs and SARS-CoV-2 variants. The database is unique in (1) classifying and annotating cross-reactive epitopes from different viruses and variants; (2) providing molecular and experimental interaction profiles of antibodies, including structure-based binding sites and around 70 000 data on binding affinity and neutralizing activity; (3) providing virological characteristics of current and past circulating SARS-CoV-2 variants and in vitro activity of various therapeutics; and (4) offering site-level annotations of key functional features, including antibody binding, immunological epitopes, SARS-CoV-2 mutations and conservation across HCoVs. In addition, we developed an integrated pipeline for epitope prediction named COVEP, which is available from the webpage of CovEpiAb. CovEpiAb is freely accessible at https://pgx.zju.edu.cn/covepiab/.

Resveratrol attenuates cyclosporin A-induced upregulation of the thromboxane A2 receptor and hypertension via the AMPK/SIRT1 and MAPK/NF-κB pathways in the rat mesenteric artery.

Cyclosporin A, an immunosuppressive agent, is extensively utilized for the prevention of transplant rejection and treat autoimmune disease in the clinic, despite its association with a high risk of hypertension development among patients. Resveratrol is a kind of non-flavonoid phenolic compound that widely exists in many plants. The aim of the present study was to investigate the mechanism by which resveratrol ameliorates cyclosporin A-induced hypertension. The arterial rings of the mesentery were incubated with cyclosporin A and resveratrol in vitro. Rats were administered cyclosporin A and/or resveratrol for 3 weeks in vivo. Blood pressure was measured via the tail arteries. Vasoconstriction curves were recorded using a sensitive myograph. The protein expression was evaluated through Western blotting. This study demonstrated that resveratrol mitigated the cyclosporin A-induced increase in blood pressure in rats. Furthermore, resveratrol markedly inhibited the cyclosporin A-induced upregulation of thromboxane A2 receptor-mediated vasoconstriction in the rat mesenteric artery both in vitro and in vivo. Moreover, resveratrol activated AMPK/SIRT1 and inhibited the MAPK/NF-κB signaling pathway. In conclusion, resveratrol restored the cyclosporin A-induced upregulation of the thromboxane A2 receptor and hypertension via the AMPK/SIRT1 and MAPK/NF-κB pathways in rats.

ReHoGCNES-MDA: prediction of miRNA-disease associations using homogenous graph convolutional networks based on regular graph with random edge sampler.

Numerous investigations increasingly indicate the significance of microRNA (miRNA) in human diseases. Hence, unearthing associations between miRNA and diseases can contribute to precise diagnosis and efficacious remediation of medical conditions. The detection of miRNA-disease linkages via computational techniques utilizing biological information has emerged as a cost-effective and highly efficient approach. Here, we introduced a computational framework named ReHoGCNES, designed for prospective miRNA-disease association prediction (ReHoGCNES-MDA). This method constructs homogenous graph convolutional network with regular graph structure (ReHoGCN) encompassing disease similarity network, miRNA similarity network and known MDA network and then was tested on four experimental tasks. A random edge sampler strategy was utilized to expedite processes and diminish training complexity. Experimental results demonstrate that the proposed ReHoGCNES-MDA method outperforms both homogenous graph convolutional network and heterogeneous graph convolutional network with non-regular graph structure in all four tasks, which implicitly reveals steadily degree distribution of a graph does play an important role in enhancement of model performance. Besides, ReHoGCNES-MDA is superior to several machine learning algorithms and state-of-the-art methods on the MDA prediction. Furthermore, three case studies were conducted to further demonstrate the predictive ability of ReHoGCNES. Consequently, 93.3% (breast neoplasms), 90% (prostate neoplasms) and 93.3% (prostate neoplasms) of the top 30 forecasted miRNAs were validated by public databases. Hence, ReHoGCNES-MDA might serve as a dependable and beneficial model for predicting possible MDAs.

Honokiol induces ferroptosis in ovarian cancer cells through the regulation of YAP by OTUB2.

BACKGROUND: Ovarian cancer (OVCA) is prevalent in female reproductive organs. Despite recent advances, clinical outcomes remain poor, warranting fresh treatment avenues. Honokiol has an inhibitory effect on proliferation, invasion, and survival of cancer cells in vitro and in vivo. Therefore, this study intended to explore specific molecular mechanism by which honokiol affected OVCA progression. METHODS: Bioinformatics analyzed the drug honokiol that bound to OTU deubiquitinase, ubiquitin aldehyde binding 2 (OTUB2). Cellular thermal shift assay (CETSA) verified the binding relationship between honokiol and OTUB2. Cell counting kit 8 (CCK-8) tested the IC50 value and cell viability of OVCA cells after honokiol treatment. Corresponding assay kits determined malonic dialdehyde (MDA) and Fe2+ levels in OVCA cells. Flow cytometry measured reactive oxygen species levels. Western blot detected OTUB2, SLC7A11, and transcriptional co-activators Yes-associated protein (YAP) expression, and quantitative polymerase chain reaction (qPCR) detected OTUB2 expression. Immunohistochemistry (IHC) detected the expression level of Ki67 protein in tumor tissues. RESULTS: Honokiol was capable of inducing ferroptosis in OVCA cells. CETSA confirmed that honokiol could bind to OTUB2. Further cell functional and molecular experiments revealed that honokiol induced ferroptosis in OVCA cells via repression of YAP signaling pathway through binding to OTUB2. In addition, in vivo experiments have confirmed that honokiol could inhibit the growth of OVCA. CONCLUSION: Honokiol induced ferroptosis in OVCA cells via repression of YAP signaling pathway through binding to OTUB2, implicating that OTUB2 may be an effective target for OVCA treatment, and our study results may provide new directions for development of more effective OVCA treatment strategies.

Artificial intelligence technology improves the accuracy of preoperative planning in primary total hip arthroplasty.

OBJECTIVE: Successful total hip arthroplasty relies on accurate preoperative planning. However, the conventional preoperative planning, a two-dimensional method using X-ray template, has shown poor reliability of predicting component size. To our knowledge, artificial intelligence technology assisted three-dimensional preoperative planning is promising to improve the accuracy of preoperative planning but there is a dearth of clinical evidence. Therefore, in this study we compared the prediction accuracy of these two maneuvers. METHODS: We conducted a prospective study consisting of 117 consecutive patients who underwent a primary cementless total hip arthroplasty to compare the prediction accuracy of these two methods. The two-dimensional and artificial intelligence assisted three-dimensional planning results of the same patient were compared with the definitive implant size respectively. RESULTS: The prediction accuracy of artificial intelligence assisted three-dimensional planning for cup and the stem sizes were 66.67% (78/117) and 65.81% (77/117), two-dimensional planning was 30.77% (36/117) and 37.61% (44/117) (p < 0.05). There were poor prediction results of two-dimensional planning in patients with hip dysplasia (p = 0.004, OR = 7.143) and excessive femoral anteversion (p = 0.012, OR = 1.052), meanwhile the failure risk of stem side two-dimensional planning increased as patients got older (p = 0.003, OR = 1.118). The accuracy of artificial intelligence assisted three-dimensional planning cannot be affected by above factors. CONCLUSIONS: We confirmed that artificial intelligence assisted three-dimensional preoperative planning showed higher accuracy and stability than two-dimensional preoperative planning in primary cementless total hip arthroplasty. We believe artificial intelligence assisted three-dimensional preoperative planning technology provides surgeons a new reliable choice and offers advantages whether in simple or complicated cases.

[New research direction of organ dysfunction caused by hemorrhagic shock: mechanisms of mitochondrial quality control].

Hemorrhagic shock (HS) is one of the leading causes of death among young adults worldwide. Multiple organ dysfunction in HS is caused by an imbalance between tissue oxygen supply and demand, which is closely related to the poor prognosis of patient. Mitochondrial dysfunction is one of the key mechanisms contributing to multiple organ dysfunction in HS, while mitochondrial quality control regulates mitochondrial function through a series of processes, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, mitochondrial-derived vesicles, and mitochondrial protein homeostasis. Modulating mitochondrial quality control can improve organ dysfunction. This review aims to summarize the effects of mitochondrial dysfunction on organ function in HS and discuss the potential mechanisms of mitochondrial quality control, providing insights into the injury mechanisms underlying HS and guiding clinical management.

Associations between the built environment and physical activity in children, adults and older people: A narrative review of reviews.

BACKGROUND: Physical activity is essential for promoting public health, and it is affected by the built environment at population level. Extensive evidence exists on the associations between the built environment and physical activity, but results are inconclusive for different age groups. Therefore, we conducted a narrative review summarizing existing reviews on the associations between the built environment and physical activity for children, adults and older people and synthesized their findings. METHODS: We followed the PRISMA 2020 review procedure and searched for systematic reviews published between January 2010 and April 2022 in seven databases (Scopus, Web of Science, Medline, PsycINFO, EMBASE, SocIndex and Cochrane Library) using keywords related to the built environment, urban interventions, physical activity and health. RESULTS: The selection process yielded 29 reviews with moderate to high quality. From these reviews, we identified 21 built environment characteristics, several of which were positively related to physical activity. For example, children and older people's physical activity was positively associated with pedestrian-friendly features and general safety. Furthermore, adults and older people's physical activity was positively related to the availability and accessibility of shops/commercial services and parks/open spaces. Lastly, the walkability index was positively associated with physical activity in every age group. CONCLUSION: Our findings provide valuable information on creating health-promoting urban environments for practitioners. Further research is needed to understand which characteristics make urban environments age friendly for physical activity. Special attention should be paid to less explored promising characteristics such as street lighting and the quality of green spaces.

Correction: Zhang et al. Experimental and Numerical Studies on Hot Compressive Deformation Behavior of a Cu-Ni-Sn-Mn-Zn Alloy. Materials 2023, 16, 1445.

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Improved global 250 m 8-day NDVI and EVI products from 2000-2021 using the LSTM model.

Satellite vegetation index (VI) products, such as normalized difference vegetation index (NDVI) and enhanced vegetation index (EVI), have been widely used. However, they are severely contaminated by clouds and other factors and provide false signals of the surface vegetation conditions. In this study, the new global seamless 250 m, eight-day NDVI and EVI products from 2000-2021 were developed from Moderate Resolution Imaging Spectroradiometer (MODIS) surface reflectance data using a long short-term memory (LSTM) neural network method. High-quality globally representative time series VI samples were constructed to train the model using a combination of the Savitzky-Golay filter (SG), Global LAnd Surface Satellite (GLASS) leaf area index (LAI) fitting and upper envelope methods. To evaluate the proposed method and the 250 m VI products, the MODIS VI product (MOD13Q1) was used for the inter-comparisons using four widely used VI reconstruction methods. Assuming that the MODIS VI data of high quality represents the true values, the root mean square error (RMSE) for NDVI and EVI generated by the LSTM model are 0.0734 and 0.0509, respectively.

Spatiotemporal variation of drought in the Western Sichuan Plateau based on standardized precipitation evapotranspiration index.

Drought is a destructive natural disaster in the Western Sichuan Plateau. Understanding its spatiotemporal variations has important practical significance for drought prevention, ensuring agricultural production safety, and maintaining ecosystem health in the region. Based on the daily meteorological data from 48 meteorological stations in the Western Sichuan Plateau from 1980 to 2020, we used the Penman-Monteith model to calculate potential evapotranspiration and standardized precipitation evapotranspiration index (SPEI). The temporal and spatial variations of drought in the Western Sichuan Plateau were analyzed using linear trend analysis and drought characteristics analysis methods. The results showed that the annual and spring SPEI of the Western Sichuan Plateau showed a weak wetting trend from 1980 to 2020, while summer, autumn, and winter showed a drought trend. The southwest mountains and northeast grasslands in the study region were prone to drought. The range of interannual drought impact in the study area was weakly increasing, with a decreasing trend in spring and an increasing trend in summer, autumn, and winter. The overall drought frequency in the whole region was relatively high. The areas drought of low-frequency were mainly located in parts of west and northeast of the Western Sichuan Plateau, while the rest were high frequency areas.

Propensity score-matched analysis comparing hippocampus-avoidance whole-brain radiotherapy plus simultaneous integrated boost with hippocampus­avoidance whole-brain radiotherapy alone for multiple brain metastases-a retrospective study in multiple institutions.

BACKGROUND: The optimal treatment for multiple brain metastases has been recently controversially discussed.This study was aimed to explore the feasibility of Hippocampus-Avoidance Whole-Brain Radiotherapy plus a simultaneous integrated boost (HA-WBRT + SIB) in patients with multiple brain metastases and assess tumor control in comparison with Hippocampus-Avoidance Whole-Brain Radiotherapy (HA-WBRT) alone for brain metastases. METHODS: In this study, 63 patients with multiple brain metastases (≥ 4 metastases) had undergone HA-WBRT + SIB between January 2016 and December 2020 in the observation group:HA-WBRT (30 Gy in 12 fractions, the maximum dose of the hippocampus ≤ 14 Gy) plus a simultaneous integrated boost (48 Gy in 12 fractions) for brain metastases.Overall Survival (OS), Median survival,intracranial control (IC = control within the entire brain), intracranial progression-free survival (iPFS) and adverse events were compared with the control group (a HA-WBRT retrospective cohort) by propensity score matching analysis. RESULTS: After 1:1 propensity score matching,there were 56 patients in each group (the observation group, the control group). OS, median survival and iPFS were significantly longer in the observation group (18.4 vs. 10.9 months, P<0.001), (13.0 vs. 8.0 months, P<0.001), (13.9 vs.7.8 months, P<0.001). In comparison of 1-year-IC rates, the observation group also demonstrated higher than the control group (51.8% vs. 21.4%, P = 0.002), respectively. Seven hippocampal metastases were found in the control group (4/56,7.1%) and the observation group (3/56,5.4%) after HA-WBRT. The death rate of intracranial progression were 23.2% in the observation group and 37.5% in the control group.All adverse events were not significant difference between the two groups (P>0.05). CONCLUSIONS: HA-WBRT + SIB resulted in better OS,median survival, IC, iPFS, an acceptable risk of radiation response, and a potential way of declining neurocognitive adverse events, which may be a better treatment for patients with multiple brain metastases.