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Zimbabwe, located in Southern Africa, faces a significant public health challenge due to schistosomiasis. We investigated this issue with emphasis on risk prediction of schistosomiasis for the entire population. To this end, we reviewed available data on schistosomiasis in Zimbabwe from a literature search covering the 1980-2022 period considering the potential impact of 26 environmental and socioeconomic variables obtained from public sources. We studied the population requiring praziquantel with regard to whether or not mass drug administration (MDA) had been regularly applied. Three machine-learning algorithms were tested for their ability to predict the prevalence of schistosomiasis in Zimbabwe based on the mean absolute error (MAE), the root mean squared error (RMSE) and the coefficient of determination (R2). The findings revealed different roles of the 26 factors with respect to transmission and there were particular variations between Schistosoma haematobium and S. mansoni infections. We found that the top-five correlation factors, such as the past (rather than current) time, unsettled MDA implementation, constrained economy, high rainfall during the warmest season, and high annual precipitation were closely associated with higher S. haematobium prevalence, while lower elevation, high rainfall during the warmest season, steeper slope, past (rather than current) time, and higher minimum temperature in the coldest month were rather related to higher S. mansoni prevalence. The random forest (RF) algorithm was considered as the formal best model construction method, with MAE = 0.108; RMSE = 0.143; and R2 = 0.517 for S. haematobium, and with the corresponding figures for S. mansoni being 0.053; 0.082; and 0.458. Based on this optimal model, the current total schistosomiasis prevalence in Zimbabwe under MDA implementation was 19.8%, with that of S. haematobium at 13.8% and that of S. mansoni at 7.1%, requiring annual MDA based on a population of 3,003,928. Without MDA, the current total schistosomiasis prevalence would be 23.2%, that of S. haematobium 17.1% and that of S. mansoni prevalence at 7.4%, requiring annual MDA based on a population of 3,521,466. The study reveals that MDA alone is insufficient for schistosomiasis elimination, especially that due to S. mansoni. This study predicts a moderate prevalence of schistosomiasis in Zimbabwe, with its elimination requiring comprehensive control measures beyond the currently used strategies, including health education, snail control, population surveillance and environmental management.

Vascular calcification and vascular ageing are “silent” diseases but are highly prevalent in patients with end stage renal failure and type 2 diabetes, as well as in the ageing population. Melatonin (MT) has been shown to induce cardiovascular protection effects. However, the role of MT on vascular calcification and ageing has not been well-identified. In this study, the aortic transcriptional landscape revealed clues for MT related cell-to-cell communication between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in vascular calcification and vascular ageing. Furthermore, we elucidated that it was exosomes that participate in the information transportation from ECs to VSMCs. The exosomes secreted from melatonin-treated ECs (MT-ECs-Exos) inhibited calcification and senescence of VSMCs. Mechanistically, miR-302d-5p was highly enriched in MT-ECs-Exos, while depletion of miR-302d-5p blocked the ability of MT-ECs-Exos to suppress VSMC calcification and senescence. Notably, Wnt3 was a bona fide target of miR-302d-5p and modulated VSMC calcification and senescence. Furthermore, we found that maturation of endothelial derived exosomal miR-302d-5p was promoted by WTAP in an N6-methyladenosine (m6A)-dependent manner. Interestingly, MT alleviated vascular calcification and ageing in 5/6-nephrectomy (5/6 NTP) mice, a chronic kidney disease (CKD) induced vascular calcification and vascular ageing mouse model. MT-ECs-Exos was absorbed by VSMCs in vivo and effectively prevented vascular calcification and ageing in 5/6 NTP mice. ECs-derived miR-302d-5p mediated MT induced anti-calcification and anti-ageing effects in 5/6 NTP mice. Our study suggests that MT-ECs-Exos alleviate vascular calcification and ageing through the miR-302d-5p/Wnt3 signaling pathway, dependent on m6A methylation.

Hylocereus polyrhizus, also known as pitaya or dragon fruit, is a climbing cactus grown worldwide because of its excellent performance under drought stress and appealing red-purple fruits. In practice, accelerating flower formation and inducing more flowers usually result in higher yield. However, the genes for this purpose have not been well characterized in pitaya. Previously, FLOWERING BHLHs (FBHs) have been identified as positive regulators of flower formation. In the present work, a total of eight FBHs were identified in pitaya. This is a greater number than in beet and spinach, possibly because of the recent whole-genome duplication that occurred in the pitaya genome. The phylogenetic tree indicated that the FBHs could be divided into three groups. In TYPE II, the genes of Caryophyllales encode atypical FBHs and are generated by dispersed duplication. The Ka/Ks ratios indicated that HpFBHs are under purifying selection. Promoter and expression analysis of HpFBHs revealed that they are spatiotemporally activated in flower-related tissues and responsive to multiple abiotic stresses. These results indicated that HpFBHs are involved in the flower formation of pitaya. Therefore, typical HpFBH1/3 from TYPE III and an atypical HpFBH8 from TYPE II were selected for functional verification. HpFBH3 was found to heterodimerize with HpFBH1 in the nucleus using subcellular localization, yeast two-hybrid and luciferase complementation assays. With bioinformatic analysis, all HpFBHs were predicted to transactivate downstream genes via binding to the E-boxes, which were frequently detected in the promoters of HpCOs, HpFTs and HpSOC1s. RNA-Seq datasets showed that these flowering accelerators were expressed in coordination with HpFBH3. Yeast one-hybrid and dual-luciferase reporter assays further verified that HpFBH3 transactivated HpCO7 by selectively binding to the E-boxes in the promoter. Moreover, ectopic overexpression of HpFBH3 accelerated flower formation in Arabidopsis. In summary, this study systematically characterized the typical HpFBHs, especially HpFBH3, as positive regulators of flower formation, which could be target genes for the genetic improvement of pitaya.

Abstract Lassa virus (LASV) belongs to the Arenaviridae family and causes severe hemorrhagic fever in humans. Although many vaccine candidates for Lassa fever exist, no vaccines have been approved for clinical use currently. The precursor glycoprotein complex (GPC), which is expressed as a trimer on the viral surface, is the main target for vaccine development. However, it has been a significant challenge to elicit effective neutralizing antibodies against LASV. In this study, we designed and produced a prefusion GPC trimer antigen of LASV, named GPCv2. Based on the structural information of GPC, we made modifications by replacing the amino acid at position 328 with proline and appending the trimerization domain. This resulted in a highly expressed prefusion trimeric form of GPCv2 that retained important conformational epitopes and stimulated higher levels of neutralizing antibodies. Moreover, vaccination with GPCv2 protected mice from LASV pseudovirus challenge. Additionally, immune repertoire sequencing showed that the induced immune clones in the trimeric group were more convergent and has its own unique V-J pairing bias compared with monomeric group. These findings demonstrate the potential of GPCv2 as a promising candidate antigen for an effective vaccine against LASV.

Abstract How the shape characterization of the concentration-response relationships between particulate matter (PM) and all-cause mortality influences life expectancy (LE) gains remains unclear. Based on the Pearl River Cohort, the 2021 World Health Organization air quality guidelines, and an integrated comparative risk assessment framework, we identified sigmodal relationships between PM2.5, all-cause mortality, and LE reduction. A 10-unit increase in PM2.5 was associated with an excess mortality risk of 31.2% (95% uncertainty interval: 27.6–35.0%). Reducing PM2.5 to the guideline threshold of 5 μg/m3 could prevent 0.193 (0.175–0.212) million deaths, contributing to a 4.07–year (3.60–4.52) average LE gain. In contrast, PM2.5 reductions by 5.6% and 10% resulted in smaller LE gains of 0.33 (0.28–0.38) and 0.58 (0.49–0.67) years, respectively. These findings highlight the importance of accounting for the nonlinear relationship in air pollution control and provide essential incentives for tailoring sustainable plans to enhance population longevity.

Abstract The secondary prevention strategy for cardiovascular disease (CVD) does not include anti-inflammatory treatment, which may lead to long-term inflammation in some patients. The aim of this study was to assess the association between inflammatory risk based on the Glasgow Prognostic Score (GPS) and long-term mortality risk in patients with CVD. This study included 3833 patients (≥ 20 years old) with CVD in the National Health and Nutrition Survey from 1999 to 2010 in the United States. The mortality rate was determined by correlation with the National Death Index on December 31, 2019. The GPS consists of the serum C-reactive protein and the serum albumin. The primary outcome was all-cause death, which included cardiac death and non-cardiac death. Cox proportional hazards adjusted for demographic factors and traditional cardiovascular risk factors were used to test the impact of the GPS on mortality. The sensitivity analysis was conducted on subsets within the cohort of patients with CVD, including congestive heart failure, coronary artery disease, angina, heart attack, and stroke. Among 3833 CVD patients with a median follow-up of 9.6 years, 2431 (63.4%) all-cause deaths, 822 (21.4%) cardiac deaths, and 1609 (41.9%) non-cardiac deaths were recorded. After full model adjustment, compared with those of the GPS (0) group, the hazard ratios (HRs) of all-cause death for GPS (1) and GPS (2) were 1.66 (95% confidence interval (CI), 1.48–1.86) and 2.75 (95% CI 2.01–3.75), respectively (P for trend

Abstract Background Duodenal adenocarcinoma (DA) has a high recurrence rate, making the prediction of recurrence after surgery critically important. Methods Our objective is to develop a machine learning-based model to predict the postoperative recurrence of DA. We conducted a multicenter, retrospective cohort study in China. 1830 patients with DA who underwent radical surgery between 2012 and 2023 were included. Wrapper methods were used to select optimal predictors by ten machine learning learners. Subsequently, these ten learners were utilized for model development. The model's performance was validated using three separate cohorts, and assessed by the concordance index (C-index), time-dependent calibration curve, time-dependent receiver operating characteristic curves, and decision curve analysis. Results After selecting predictors, ten feature subsets were identified. And ten feature subsets were combined with the ten machine learning learners in a permutation, resulting in the development of 100 predictive models, and the Penalized Regression + Accelerated Oblique Random Survival Forest model (PAM) exhibited the best predictive performance. The C-index for PAM was 0.882 (95% CI 0.860–0.886) in the training cohort, 0.747 (95% CI 0.683–0.798) in the validation cohort 1, 0.736 (95% CI 0.649–0.792) in the validation cohort 2, and 0.734 (95% CI 0.674–0.791) in the validation cohort 3. A publicly accessible web tool was developed for the PAM. Conclusions The PAM has the potential to identify postoperative recurrence in DA patients. This can assist clinicians in assessing the severity of the disease, facilitating patient follow-up, and aiding in the formulation of adjuvant treatment strategies.

Abstract Despite the outstanding clinical success of immunotherapy, its therapeutic efficacy in glioblastoma (GBM) is still limited. To identify critical regulators of GBM immunity, we constructed a mouse single-guide RNA (sgRNA) library corresponding to all disease-related immune genes, and performed an in vivo CRISPR knockout (KO) screen in syngeneic GBM mouse models. We demonstrated that the deletion of GDF15 in GBM cells ameliorated the immunosuppressive tumor microenvironment (TME) and enhanced the antitumor efficacy of immune checkpoint blockade (ICB) response. Moreover, we designed unique nanoparticles for efficient encapsulation of CRISPR-Cas9, noninvasive brain delivery and tumor cell targeting, demonstrating an effective and safe strategy for GDF15 gene therapy. The CRISPR-Cas9 nanoparticles, known as ANPSS (Cas9/sgRNA), are easily created by enclosing a single Cas9/sgRNA complex in a polymer shell that is sensitive to glutathione. This shell also contains a dual-action ligand that aids in crossing the blood‒brain barrier, targeting tumor cells, and selectively releasing Cas9/sgRNA. Our encapsulating nanoparticles demonstrated promising GBM targeting, resulting in high GDF15 gene editing efficiency within brain tumors while showing minimal off-target gene editing in high-risk tissues. Treatment with ANPSS (Cas9/sgGDF15) effectively halted tumor growth, reversed immune suppression, and enhanced the efficacy of ICB therapy. These results emphasize the potential role of GDF15 in modulating the immune microenvironment and enhancing the effectiveness of current immunotherapy strategies for GBM. Graphical Abstract

Abstract Avian influenza viruses (AIVs) present an ongoing threat of human infections. Continuous surveillance is important for detecting new infections and verifying prevention and control measures. Swabs of the external environment and throat swabs of employees were collected from six farmers’ markets in Beijing to detect influenza A virus. Positive samples were sequenced, and their genetic characteristics analyzed. In total, 3251 environmental samples were collected from 2019 to 2023, 11 of which were positive for influenza A virus (positivity rate of 0.34%), including nine for H9N2 and two for H7N9. In a genetic analysis, all H7N9 samples showed low pathogenicity, and no mutations at highly pathogenic sites were detected. All 1135 throat swab samples from staff were negative for influenza A virus. At present, the detection rate of AIVs in farmers’ markets is very low, and no adaptive mutations allowing cross-host transmission were found, indicating a low risk of AIV infection among the people of Beijing.

Abstract The debate over the optimal orientation of Ag2Se thin films and its influence on thermoelectric performance remains ongoing. Here, we report a wet-chemical selenization-based anisotropy optimization technique to control the in-plane orientation of the Ag2Se thin film, steering it away from (002) nearly parallel planes that hinder charge carrier mobility. This approach enables us to achieve an impressive power factor of 30.8 μW cm−1 K−2 at 343 K. The as-fabricated Ag2Se thin film demonstrates remarkable durability, retaining over 90% of its power factor after six months of air exposure, and outstanding flexibility, with performance variation staying within 5% after 2000 bending cycles at a 5 mm radius. These attributes are attributed to the controlled film thickness, crystallinity, and strong adhesion to the polyimide substrate. Additionally, the as-assembled slotted thermoelectric device delivers an output power of 0.58 μW and a competitive power density of 807 μW cm−2 at a temperature difference of 20 K, alongside a high normalized power density of 1.8 μW cm−2 K−2, highlighting its potential for practical application. This study provides valuable insights into the design of high-performance, highly flexible thermoelectric thin films for real-world applications.

Abstract Mammalian epididymal epithelial cells are crucial for sperm maturation. Historically, vacuole-like ultrastructures in epididymal epithelial cells were observed via transmission electron microscopy but were undefined. Here, we utilize volume electron microscopy (vEM) to generate 3D reconstructions of epididymal epithelial cells and identify these vacuoles as intercellular organelle reservoirs (IORs) in the lateral intercellular space (LIS), which contains protein aggregates, autophagosomes, lysosome-related organelles and mitochondrial residues. Immunolabelling of organelle markers such as P62, LC3, LAMP1 and TOMM20 confirm these findings. The IOR size or number varies across four epididymal regions and decreases with age. Rab27a mutant mice exhibit reduced IORs in the caput epididymis and a subfertility phenotype, suggesting the involvement of Rab27a in the formation of IORs. Furthermore, we observe the presence of IORs between intestinal epithelial cells besides epididymis. Amino acid transporters at IOR edges suggest dynamic protein recycling. Our findings reveal that the IOR is an important structure critical for organelle turnover and recycling outside epithelial cells with limited self-degradation capabilities.

Abstract Spatial transcriptomics technologies can capture gene expression at spatial loci. However, at certain resolutions, the obtained gene expression reflects the sum of either a heterogeneous or homogeneous set of cells, rather than individual cell. This limitation gives rise to the deconvolution algorithm to make cell-type inferences at each location. Yet, the vast majority of deconvolution methods that have been developed ignore the spatial information of the tissue and the communications between the cells or spots. To overcome these afflictions, we proposed a deconvolution method, non-negative least squares-based and optimization search-based deconvolution (NODE), that combines cell-type-specific information from single-cell RNA sequencing (scRNA-seq) and intercellular communications in tissue. NODE deconvolution algorithm, incorporating the spatial information of the tissue, allows us to quantify intercellular communications at the same instant. NODE can not only utilize optimization method to infer the deconvolution results of spatial transcriptomics data and reduce the probability of overfitting situations, but also make reasonable inferences for spatial communications. Subsequently, we applied NODE to four datasets to validate the correctness of the NODE deconvolution results and compare them with existing deconvolution algorithms. NODE also inferred spatial communications and validated them in tissue development of human heart.

Highlights This work provides a brand-new approach to the “conversion-protection” strategy to overcome the drawbacks of composite cathode interfaces. The Mo3Ni3N not only makes it difficult for hydroxide groups (-OH) to survive on the surface but also allows the in situ surface reconstruction to generate the ultra-stable MoS2-Mo3Ni3N heterostructures after the initial cycling stage. The Mo-Ni@NPCs/LCO/LPSC-based ASSLBs achieve high-capacity retention (90.62%) and excellent cycle life (1000 cycles).

Abstract Background Differentiated thyroid cancer (DTC) accounts for the majority of thyroid cancers. The preoperative diagnosis of extrathyroidal extension (ETE) in DTC patients is highly important. However, two-dimensional ultrasound (2D-US) has several limitations in diagnosing ETE. This study aimed to evaluate the efficiency of OmniView of three-dimensional ultrasound (3D-OmniView) in assessing the ETE of DTC patients compared with that of 2D-US. Methods Patients who underwent thyroid surgery for nodules adjacent to the thyroid capsule between February 2016 and January 2018 were prospectively enrolled in this study. Both 2D-US and 3D-OmniView were used to evaluate ETE of thyroid nodules. The definition for ETE in ultrasound images was capsule disruption, or capsule disruption and surrounding tissue invasion. Intraoperative and pathological findings of ETE were considered positive. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and area under the ROC curve (AUC) were calculated. Results A total of 176 DTC nodules from 137 patients were included in this study. ETE was identified in 67.0% of the nodules. The sensitivity, accuracy, NPV and AUC of 3D-OmniView for predicting ETE were significantly greater than those of 2D-US. The sensitivity and specificity of 2D-US and 3D-OmniView were 51.7% and 79.7%, respectively (P 1 cm than in evaluating ETE in nodules ≤ 1 cm. Conclusion 3D-OmniView was more precise in predicting ETE of DTC nodules than 2D-US. 3D-OmniView is recommended for further evaluation of all thyroid nodules adjacent to the thyroid capsule. ETE was easier to detect by ultrasound for nodules > 1 cm than for nodules ≤ 1 cm.

Abstract Glioblastoma (GBM) is a primary brain tumor known for its high levels of aggressiveness and resistance to current treatments such as radiotherapy and chemotherapy. As a result, there is a pressing need for innovative therapeutic approaches to combat GBM. Thus, we have developed an engineered multifunctional extracellular vesicle (EV) delivery system that offers an "all-in-one" strategy for GBM therapy. Our approach involved the use of genetic engineering to the long-lasting production of PD-1 and the brain-specific peptide angiopep-2 on the surface of EVs. These modified EVs were then utilized to rejuvenate exhausted CD8+ T cells blocking PD-L1, resulting in significant therapeutic benefits for GBM treatment. Furthermore, the EVs contained Cas9 protein and sgRNA for precise and minimally invasive gene therapy, which addressing the key barriers associated with in vivo CRISPR‒Cas9 gene editing treatment. The multigene editing of EVs resulted in efficient intratumor multisite gene editing (PLK1: 58.6%, VEGF: 52.7%), leading to the successful apoptosis of tumor cells in vivo and demonstrating an antiangiogenic effect. This research introduces a promising universal platform for combining immune checkpoint blockade therapy with gene editing treatment. Graphical Abstract

Abstract Aims Nutrition and inflammation status play a vital role in the prognosis of patients with heart failure (HF). This study aimed to investigate the association between the advanced lung cancer inflammation index (ALI), a novel composite indicator of inflammation and nutrition, and short‐term mortality among critically ill patients with HF. Methods This retrospective study included 548 critically ill patients with HF from the MIMIC‐IV database. ALI was computed using body mass index, serum albumin and neutrophil–lymphocyte ratio. The primary endpoint was all‐cause in‐hospital mortality, and the secondary endpoint was 90 day mortality. Kaplan–Meier survival curve analysis with long‐rank test and Cox proportional hazards regression models were employed to assess the relationship between baseline ALI and short‐term mortality risk. The incremental predictive ability of ALI was evaluated by C‐statistic, continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results The average age of 548 patients was 72.2 (61.9, 82.1) years, with 60% being male. Sixty‐three patients (11.5%) died in the hospital, and 114 patients (20.8%) died within 90 days of intensive care unit admission. The Kaplan–Meier analysis revealed that the cumulative incidences of both in‐hospital and 90 day mortality were significantly higher in patients with lower ALI (log‐rank test, in‐hospital mortality: P

Ultra-WideBand (UWB) radar exhibits strong antijamming capabilities and high penetrability, making it widely used for through-wall human-target detection. Although single-transmitter, single-receiver radar offers the advantages of a compact size and lightweight design, it cannot achieve Two-Dimensional (2D) target localization. Multiple-Input Multiple-Output (MIMO) array radar can localize targets but faces a trade-off between size and resolution and involves longer computation durations. This paper proposes an automatic multitarget detection method based on distributed through-wall radar. First, the echo signal is preprocessed in the time domain and then transformed into the time-frequency domain. Target candidate distance cells are identified using a constant false alarm rate detection method, and candidate signals are enhanced using a filtering matrix. The enhanced signals are then correlated based on vital information, such as breathing, to achieve target matching. Finally, a positioning module is employed to determine the radar’s location, enabling rapid and automatic detection of the target’s location. To mitigate the effect of occasional errors on the final positioning results, a scene segmentation method is used to achieve 2D localization of human targets in through-wall scenarios. Experimental results demonstrate that the proposed method can successfully detect and localize multiple targets in through-wall scenarios, with a computation duration of 0.95 s based on the measured data. In particular, the method is over four times faster than other methods.

High-resolution line scan cameras with wide-angle lenses are highly accurate and efficient for tunnel detection. However, due to the curvature of the tunnel, there are variations in object distance that exceed the depth of field of the lens, resulting in uneven defocus blur in the captured images. This can significantly affect the accuracy of defect recognition. While existing deblurring algorithms can improve image quality, they often prioritize results over inference time, which is not ideal for high-speed tunnel image acquisition. To address this issue, we developed a lightweight tunnel structure defect deblurring network (TSDDNet) for curved-tunnel line scanning with wide-angle lenses. Our method employs an innovative progressive structure that balances network depth and feature breadth to simultaneously achieve good performance and short inference time. The proposed depthwise ResBlocks significantly improves the parameter efficiency of the network. Additionally, the proposed feature refinement block captures the structurally similar features to enhance the image details, increasing the peak signal-to-noise ratio (PSNR). A raw dataset containing tunnel blur images was created using a high-resolution line scan camera and used to train and test our model. TSDDNet achieved a PSNR of 26.82 dB and a structural similarity index measure of 0.888, while using one-third of the parameters of comparable alternatives. Moreover, our method exhibited a higher computational speed than that of conventional methods, with inference times of 8.82 ms for a single 512 × 512 pixel image patch and 227.22 ms for completely processing a 2048 × 2560 pixel image. The test results indicated that the structural scalability of the network allows it to accommodate large inputs, making it effective for high-resolution images.

Objective: This study aimed to compare the upgrade rate and cancer detection rate between the 18F-DCFPyL PET/MRI-guided ultrasound fusion targeted biopsy (TB) and systematic biopsy in selected patients with suspected prostate cancer (the molecular imaging prostate-specific membrane antigen score of ≥2 and multiparametric MRI Prostate Imaging Reporting and Data System score of ≥4). Methods: Eighty-seven selected biopsy-naive patients were randomized into two groups: TB (n=41) and systematic biopsy (control; n=46). Patients diagnosed with clinically significant prostate cancer proceeded to radical prostatectomy. The primary outcome was the pathological upgrade rate. Secondary outcomes, including the cancer detection rate, incidence of repeat biopsy, positive surgical margin, complications, and prostate-specific antigen level at 6 weeks postoperatively, were compared between the groups using the Pearson or Fisher's exact test, as appropriate. Results: In the study, prostate cancer was ultimately detected in all patients. The TB group successfully identified all tumors, whereas five patients in the control group initially missed diagnosis. The pathological upgrade rates for the TB and control groups were 31.7 % and 56.5%, respectively. Overall, the detection rate for clinically significant prostate cancer (the International Society of Urological Pathology grade of ≥2) was significantly higher in the TB group (92.7%) compared with the control group (76.1%, p=0.035). However, no significant difference was found in the detection rate of all prostate cancer. Complications (Clavien–Dindo grade of ≤2) occurred in both the TB group (n=11) and control group (n=13). No statistically significant difference was observed between the groups in terms of the positive surgical margin, complications, or 6-week postoperative prostate-specific antigen level. Conclusion: The 18F-DCFPyL PET/MRI-guided ultrasound fusion TB alone was an efficient modality in diagnosing selected patients with prostate cancer.

Abstract The Spatial Data Lab (SDL) project is a collaborative initiative by the Center for Geographic Analysis at Harvard University, KNIME, Future Data Lab, China Data Institute, and George Mason University. Co-sponsored by the NSF IUCRC Spatiotemporal Innovation Center, SDL aims to advance applied research in spatiotemporal studies across various domains such as business, environment, health, mobility, and more. The project focuses on developing an open-source infrastructure for data linkage, analysis, and collaboration. Key objectives include building spatiotemporal data services, a reproducible, replicable, and expandable (RRE) platform, and workflow-driven data analysis tools to support research case studies. Additionally, SDL promotes spatiotemporal data science training, cross-party collaboration, and the creation of geospatial tools that foster inclusivity, transparency, and ethical practices. Guided by an academic advisory committee of world-renowned scholars, the project is laying the foundation for a more open, effective, and robust scientific enterprise.

Abstract Echinacoside (ECH), one of the most representative phenylethanoid glycosides (PhGs), has considerable neuroprotective effects and is an effective ingredient in numerous commercial drugs. Here, we elucidate the complete ECH biosynthetic pathway in the medicinal plant Cistanche tubulosa. In total, 14 related genes are cloned and functionally characterized. Two upstream pathways for tyrosol biosynthesis from L-tyrosine are identified: one includes separate decarboxylation, deamination and reduction steps; the other uses microbial-like transamination, decarboxylation and reduction steps. In addition, a distinct downstream assembly process from tyrosol to ECH is revealed that includes sequential glucosylation, acylation, hydroxylation, and rhamnosylation to form acteoside, and ends with a final glucosylation converting acteoside to ECH. Furthermore, the de novo synthesis of 23 PhG derivatives is achieved via the heterologous expression of different combinations of the functional genes in tobacco. Our findings provide insights into the biosynthesis of ECH and a platform for alternative production of complex PhGs.

Abstract Ferroelectric capacitive memories (FCMs) utilize ferroelectric polarization to modulate device capacitance for data storage, providing a new technological pathway to achieve two-terminal non-destructive-read ferroelectric memory. In contrast to the conventional resistive memories, the unique capacitive operation mechanism of FCMs transfers the memory reading and in-memory computing to charge domain, offering ultra-high energy efficiency, better compatibility to large-scale array, and negligible read disturbance. In recent years, extensive research has been conducted on FCMs. Various device designs were proposed and experimentally demonstrated with progressively enhanced performance, showing remarkable potential of the novel technology. This article summarizes several typical FCM devices by introducing their mechanisms, comparing their performance, and discussing their limitations. We further investigate the capacitive crossbar array operation and review the recent progress in the FCM integration and array-level demonstrations. In addition, we present the computing-in-memory applications of the FCMs to realize ultra-low-power machine learning acceleration for future computing systems.

Abstract Receptor activator of nuclear factor kappa-B ligand (RANKL) initiates a complex signaling cascade that is crucial for inducing osteoclast differentiation and activation. RANKL-induced signaling has been analyzed in detail, and the involvement of TNF receptor-associated factor 6 (TRAF6), calmodulin-dependent protein kinase (CaMK), NF-κB, mitogen-activated protein kinase (MAPK), activator protein-1 (AP-1), and molecules that contain an immunoreceptor tyrosine-based activation motif (ITAM) has been reported. However, the precise molecular steps that regulate RANKL signaling remain largely unknown. Here, we revealed the indispensable role of a class III histone deacetylase (SIRT5) in the processes of RANKL-induced osteoclast differentiation and activation. SIRT5 expression in osteoclasts was increased during osteoclastogenesis upon stimulation with RANKL. The RANKL-induced signaling activation was suppressed in SIRT5-deficient osteoclasts but enhanced by SIRT5 overexpression. Mice with global or conditional monocytic lineage knockout of SIRT5 had increased bone mass and reduced osteoclast numbers. In the cytoplasm, SIRT5 interacted with the scaffold protein JNK-interacting protein 4 (JIP4) to finely regulate MAPK signaling, which was critical for osteoclast differentiation and activation. Pharmacological inhibition of the catalytic activity of SIRT5 effectively reversed bone loss in ovariectomized mice. Taken together, the results of this study reveal that the SIRT5-JIP4 axis is a novel positive regulator that finely regulates RANKL-induced osteoclast differentiation and suggest that targeting this axis is a therapeutic strategy for preventing osteoporotic bone loss. Graphical Abstract

Abstract The aberrant upregulation of Yes-associated protein 1 (YAP1) in a variety of solid cancers contributes to tumor progression and poor clinical outcomes, rendering it an appealing therapeutic target. However, effective therapies to directly target YAP1 remain challenging. In this study, we perform a high-throughput screening and identify Casein kinase II (CK2) as an uncharacterized upstream regulator of YAP1 turnover in cancer cells of ovarian cancer and several other cancer types. Pharmacological inhibition of Casein kinase II by Silmitasertib or genetic depletion of the catalytic subunit of Casein kinase II (CK2α) markedly destabilizes YAP1 and consequently suppresses its oncogenic functions in vitro and in vivo. Moreover, we reveal that DUB3 as a bona fide deubiquitinase of YAP1, which functionally links CK2 and YAP1 stability in a variety of human cancers. Mechanistically, CK2α directly phosphorylates DUB3 at Thr495, thereby facilitating DUB3-mediated deubiquitination process of YAP1. On the contrary, the loss of Thr495 phosphorylation by the phosphorylation-defective mutant DUB3 T495A, the cancer-related mutant DUB3 D496H and CK2 inhibition failed to deubiquitinate and stabilize YAP1 effectively. Notably, upregulated expressions of CK2α and DUB3 in ovarian cancer positively correlate with YAP1 overexpression. Collectively, our findings demonstrate the functional significance of the CK2α-DUB3 axis in YAP1 stabilization and YAP1-driven tumor progression, highlighting that strategies to target this axis might be of benefit in the clinical management of ovarian cancer and several other lethal cancers with aberrantly upregulated YAP1.

The room temperature plasticity of magnesium alloy is poor because of its unique crystal structure. After extrusion or rolling process, the grain orientation of as-cast Mg alloy tends to be the same, and it shows obvious intense basal texture, which makes it show obvious tensile and compressive asymmetry and anisotropy. Texture control plays a crucial role in enhancing their mechanical properties, formability, and corrosion resistance. The grain c-axis of the extruded Mg alloy is deflected at a certain angle through predeformation treatment, shear deformation and other composite severe plastic deformation (SPD) processes. This results in refined grain size and adjusted texture orientation. The process also facilitates recrystallization, and the orientation of newly formed grains during continuous dynamic recrystallization (CDRX) is similar to that of the parent crystals but may deviate slightly. The discontinuous dynamic recrystallization (DDRX) process produces new grains with a randomly distributed orientation. Consequently, the initial dense basal texture has been decreased, the basal slip systems are significantly activated, and plasticity is greatly improved. The continued action of non-basal slip concurrently enhances plasticity.The present paper provides a comprehensive overview of the texture regulation technology and mechanism of Mg alloy subjected to shear strain and torsional deformation, including extrusion, rolling, and bending. The beneficial effects of texture control on the mechanical characteristics, formability, and corrosion resistance of Mg alloys were elucidated by integrating twinning, recrystallization, and non-basal slip processes. The future development trends and challenges of Mg alloy plastic technology are finally proposed.

Abstract Background Due to the lack of effective treatment options, the prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) remains poor. Although chimeric antigen receptor (CAR)-T-cell therapy has shown promising effects in acute lymphoblastic leukemia (ALL) and lymphoma, its application in R/R AML is limited by “off-target” effects, which lead to severe bone marrow suppression and limit its clinical application. CAR-natural killer (NK) cells not only exhibit antitumor effects but also demonstrate increased safety and universality. We have developed a new CAR construct that targets CD33 and modified NK cells, specifically eliminating AML cells while reducing severe side effects on stem cells. Methods The CD33-targeting domain was selected by CAR-T cells, and this optimized CAR construct was subsequently transduced into umbilical cord-derived NK cells via a retroviral vector. Preclinical efficacy and safety studies were conducted both in vitro and in vivo. Ten eligible patients with R/R AML aged 18–65 years who received one or more infusions of anti-CD33 CAR-NK cells following the preconditioning regimen were enrolled. We assessed the response rates and treatment-related side effects post-infusion, while also documenting the long-term efficacy of the therapy. Results The CD33 sequence was selected on the basis of its antitumor efficacy and safety in CAR-T-cell studies conducted both in vitro and in vivo. CD33 CAR-NK cells demonstrated efficacy comparable to that of CD33 CAR-T cells but showed limited toxicity to hematopoietic stem cells (HSCs). Ten patients, with a median of five prior lines of treatment, completed the efficacy evaluation (range, 3–8). No grade 3–4 adverse events were observed, except bone marrow suppression, which was relieved within one month. No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GVHD) were reported following CAR-NK cell infusion. Only one patient experienced grade 2 cytokine release syndrome (CRS) and presented with persistent fever. By day 28, six of ten patients had achieved minimal residual disease (MRD)-negative complete remission. Conclusions Our preclinical and clinical data demonstrated the primary efficacy and safety of CD33 CAR-NK cells for patients with R/R AML. Expanded samples and longer follow-up periods are needed to provide further efficacy data. Trial registration NCT05008575 ( https://clinicaltrials.gov/study/NCT05008575 ).

Abstract High temperature stress seriously affects the quality and yield of vegetable crops, especially cucumber (Cucumis sativus L.). However, the metabolic dynamics and gene regulatory network of cucumber in response to high temperature stress remain poorly studied. In this study, we identified a heat-tolerant cucumber Gy14 and a heat-sensitive cucumber 32X. RNA-seq analysis of Gy14 and 32X under high temperature stress showed that some differentially expressed genes (DEGs) were related to the biosynthesis of secondary metabolites. Metabolomic analysis revealed that there were more phenylpropanoids and their downstream derivatives in Gy14 compared to that in 32X under Re_2d condition (2 normal days recovery after heat). Integrated analysis of transcriptome and metabolome revealed that these upregulated genes played a pivotal role in flavonoid biosynthesis. Moreover, high temperature stress significantly induced the expression of the gibberellin (GA) biosynthesis genes and exogenous application of GA3 alleviated the damage of high temperature to cucumber seedlings. Together, these findings provided new insights into the transcriptome response and metabolomic reprogramming of cucumber against high temperature stress.

Abstract Van der Waals interaction in multilayer structures was predicted to be of many-body character, almost in parallel with the establishment of Lifshitz theory. However, the diminishing interaction between layers separated by a finite-thickness intermediate layer prevents experimental verification of the many-body nature. Here we verify the substrate contribution at the adhesion between the atomic force microscopy tip and the supported graphene, by taking advantage of the atomic-scale proximity of two objects separated by graphene. While the pairwise dispersion theory overestimates the substrate contribution at critical adhesive pressures, the many-body dispersion theory remedies this deficiency, highlighting the non-additivity nature of substrate contribution. The many-body effect is further understood through the energy spectrum of charge density fluctuations. These findings open the door to modulating the van der Waals interaction on two-dimensional material surfaces, which would be relevant to various technologies, including microelectromechanical systems and surface molecular assembly.

Abstract The shortwave infrared (SWIR) region is an ideal spectral window for next-generation bioimaging to harness improved penetration and reduced phototoxicity. SWIR spectral activity may also be accessed via supramolecular dye aggregation. Unfortunately, development of dye aggregation remains challenging. We propose a crystal-aided aggregate synthesis (CAASH) approach to introduce a layer of rationality for the development of J-aggregate and the successful development of a water-soluble SWIR JV-aggregate with a bisbenzannulated silicon rhodamine scaffold (ESi5). The resulting SWIR-aggregates exhibit excellent stabilities toward organic solvents, pH, sonication, photobleaching, thiols, and endogenous oxidative species. Notably, the aggregates have a high structure-dependent melting temperature of ca. 330-335 K. In fact, the heating/annealing process can be exploited to reduce aggregation disorder. The aggregates are biocompatible and have broad potential in in vivo fluorescence and photoacoustic imaging and more.

Abstract Doxorubicin, a representative drug of the anthracycline class, is widely used in cancer treatment. However, Doxorubicin-induced cardiotoxicity (DIC) presents a significant challenge in its clinical application. Mitochondrial dysfunction plays a central role in DIC, primarily through disrupting mitochondrial dynamics. This study aimed to investigate the impact of Rnd3 (a Rho family GTPase 3) on DIC, with a focus on mitochondrial dynamics. Cardiomyocyte-specific Rnd3 transgenic mice (Rnd3-Tg) and Rnd3LSP/LSP mice (N-Tg) were established for in vivo experiments, and adenoviruses harboring Rnd3 (Ad-Rnd3) or negative control (Ad-Control) were injected in the myocardium for in vitro experiments. The DIC model was established using wild-type, N-Tg, and Rnd3-Tg mice, with subsequent intraperitoneal injection of Dox for 4 weeks. The molecular mechanism was explored through RNA sequencing, immunofluorescence staining, co-immunoprecipitation assay, and protein-protein docking. Dox administration induced significant mitochondrial injury and cardiac dysfunction, which was ameliorated by Rnd3 overexpression. Further, the augmentation of Rnd3 expression mitigated mitochondrial fragmentation which is mediated by dynamin-related protein 1 (Drp1), thereby ameliorating the PANoptosis (pyroptosis, apoptosis, and necroptosis) response induced by Dox. Mechanically, the interaction between Rnd3 and Rho-associated kinase 1 (Rock1) may impede Rock1-induced Drp1 phosphorylation at Ser616, thus inhibiting mitochondrial fission and dysfunction. Interestingly, Rock1 knockdown nullified the effects of Rnd3 on cardiomyocytes PANoptosis, as well as Dox-induced cardiac remodeling and dysfunction elicited by Rnd3. Rnd3 enhances cardiac resilience against DIC by stabilizing mitochondrial dynamics and reducing PANoptosis. Our findings suggest that the Rnd3/Rock1/Drp1 signaling pathway represents a novel target for mitigating DIC, and modulating Rnd3 expression could be a strategic approach to safeguarding cardiac function in patients undergoing Dox treatment. The graphical abstract illustrated the cardioprotective role of Rnd3 in DIC. Rnd3 directly binds to Rock1 in cytoplasm and ameliorates mitochondrial fission by inhibiting Drp1 phosphorylation at ser616, thereby alleviating PANoptosis (apoptosis, pyroptosis, and necroptosis) in DIC.

Background: RANKL and SCLEROSTIN antibodies have provided a strong effective choice for treating osteoporosis in the past years, which suggested novel molecular target identification and therapeutic strategies development are important for the treatment of osteoporosis. The therapeutic effect of verapamil, a drug previously used for cardiovascular diseases, on diabetes was due to the inhibition of TXNIP expression, which has also been reported as a target in mice osteoporosis. Whether verapamil-inhibited TXNIP expression is related to osteoporosis and how it works on the molecular level is worthy to be explored. Methods: The polymorphism genotyping analysis was performed on patients with different degrees of osteoporosis. The responsiveness of bone marrow-derived macrophage cells (bone marrow-derived mesenchymal stem cells) to verapamil was evaluated by CCK-8, TRAP staining assay (ALP and AR staining assay), Bone Resorption Assay, and RNA-Sequencing. The expression and cytoplasmic efflux of ChREBP were determined by western blotting and immunofluorescence. Bilateral ovariectomy models were created, rescued by verapamil injection and the effectiveness was evaluated by Micro-CT and Histological analysis. Results: Here we discovered that rs7211 single nucleotide polymorphism (SNP) of TXNIP is closely associated with increased femur neck bone mineral density (BMD) and decreased osteoporosis rate, suggesting the importance of TXNIP in the development of osteoporosis. Verapamil suppresses Txnip expression, reduces bone turnover rate and thus rescues ovariectomy-induced mice bone loss. Mechanistically, verapamil promoted ChREBP cytoplasmic efflux, regulated Pparγ expression both mediating Txnip-MAPK, NF-κ B axis in osteoclasts, and suppressed the ChREBP-Txnip-Bmp2 axis in osteoblasts. Conclusions: The results of our study show the correlation of rs7211 TXNIP-T allele with Chinese increased femur neck BMD and decreased osteoporosis rate. In addition, verapamil can rescue mice from osteoporosis by regulateing ChREBP, Pparγ-Txnip-MAPK, NF-κ B axis in osteoclasts and ChREBP-Txnip-Bmp2 axis in osteoblasts. The translational potential of this article: The inhibition of Txnip by verapamil in osteoclasts and osteoblasts leads to low bone turnover and reduced bilateral ovariectomy-induced mice bone loss, which points out its great clinical translation potential on postmenopausal osteoporosis treatment.

Abstract Adaptive radiotherapy (ART) provides greater benefits than intensity-modulated radiotherapy (IMRT) regarding dosimetric outcomes in patients with cervical cancer. To investigate the clinical benefits of ART, we have collected data from 115 cervical cancer patients who underwent radical radiotherapy at our institution. Fifty-nine patients received a single course of IMRT. Fifty-six patients underwent offline ART, defined as the reduction of the gross tumor volume (GTV) by at least 30% after 30 Gy of radiotherapy, followed by a modified treatment plan for the second-stage. After treatment, 53 patients of ART group achieved a partial response (PR) or completement response (CR), resulting in an objective response rate (ORR) of 94.6% for the ART group, compared to 93.2% for the IMRT group. Patients in both groups exhibited no significant differences in acute toxicities. However, the incidence of chronic constipation was significantly higher in the IMRT group compared to the ART group (p = 0.021). With a median follow-up time of 27 months, the ART group experienced a higher mortality (10/56) than the IMRT group (6/59). However, the difference between the two groups was not statistically significant. In summary, ART may be advantageous in reducing the incidence of chronic constipation among patients with locally advanced cervical cancer, and both clinical prognosis and near-term survival are satisfactory.

Abstract The risk of suicide in patients with major depressive disorder (MDD) poses a major concern, with studies suggesting that genetics may be a contributing factor. Although there are many transcriptomic studies on postmortem brain tissue related to suicidal behavior, the blood transcriptional mechanisms of suicidal ideation (SI) remain unknown. This study utilized a weighted gene coexpression network analysis (WGCNA) approach to investigate the associations between gene coexpression modules and SI in individuals with MDD using peripheral blood RNA-seq data from 75 MDD patients with SI (MDD_SI), 82 MDD patients without SI (MDD_nSI), and 149 healthy controls (HC). An ANCOVA was conducted to assess differences in gene coexpression modules among groups, with age and sex included as covariates. The gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) databases were used to annotate module functions. Results indicated that the magenta module (associated with RNA splicing processes) differentiated MDD_SI from MDD_nSI (p = 0.021), while the green module (related to immune and inflammatory responses) distinguished MDD_SI from HC (p = 0.004). Additionally, three modules showed differences between MDD_nSI and HC: magenta (p = 0.009), brown (related to innate immunity and mitochondrial metabolism; p = 0.001), and turquoise (associated with energy metabolism and neurodegeneration; p = 0.005). Our findings highlight that gene expression regulation, immune response, and inflammation may be linked to SI in patients with MDD, while pathways associated with innate immunity, energy metabolism, mitochondrial function, and neurodegeneration appear to be more broadly related to MDD.

Abstract Aging increases the risk for Alzheimer’s disease (AD), driving pathological changes like amyloid-β (Aβ) buildup, inflammation, and oxidative stress, especially in the prefrontal cortex (PFC). We present the first subcellular-resolution spatial transcriptome atlas of the human prefrontal cortex (PFC), generated with Stereo-seq from six male AD cases at varying neuropathological stages and six age-matched male controls. Our analyses revealed distinct transcriptional alterations across PFC layers, highlighted disruptions in laminar structure, and exposed AD-related shifts in layer-to-layer and cell-cell interactions. Notably, we identified genes highly upregulated in stressed neurons and nearby glial cells, where AD diminished stress-response interactions that promote Aβ clearance. Further, cell-type-specific co-expression analysis highlighted three neuronal modules linked to neuroprotection, protein dephosphorylation, and Aβ regulation, with all modules downregulated as AD progresses. We identified ZNF460 as a transcription factor regulating these modules, offering a potential therapeutic target. In summary, this spatial transcriptome atlas provides valuable insight into AD’s molecular mechanisms.

Abstract Background Major depressive disorder (MDD) is a recurrent and persistent mental illness. However, there is a lack of research that distinguishes the severity of comorbid anxiety disorders in MDD, and insufficient evidence exists regarding the prevalence of MDD patients with comorbid moderate-to-severe anxiety in the Chinese population. Methods The study included 1718 MDD patients (894 with moderate-to-severe anxiety symptoms and 824 without moderate-to-severe anxiety symptoms). Clinical symptoms and development were assessed using the Hamilton Depression Rating Scale-17 (HAMD-17), Hamilton Anxiety Rating Scale-14 (HAMA-14), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression (CGI). The blood pressure and thyroid hormone levels were measured. Results We found that the incidence of MDD patients with moderate-to-severe anxiety symptoms was 52.04%. The prevalence of recent suicide attempts in MDD comorbid moderate-to-severe anxiety patients was 31.8%, which was 4.24 times higher than that in patients without moderate-to-severe anxiety. Additionally, suicide attempters had elevated levels of thyroid stimulating hormone (TSH), anti-thyroglobulin (TgAb), thyroid peroxidases antibody (TPOAb), systolic blood pressure (SBP), and diastolic blood pressure (DBP) compared to non-suicide attempters. We further identified CGI score, TSH, TPOAb, and DBP as influential factors for recent suicide attempts in MDD individuals who had moderate-to-severe anxiety symptoms. These indexes could distinguish between suicide attempts and non-suicide attempts in MDD patients with moderate-to-severe anxiety symptoms. Conclusions Our findings mainly indicated a high prevalence of recent suicide attempts in MDD patients with moderate-to-severe anxiety. Several clinical correlates, thyroid hormones, and blood pressure might contribute to recent suicide attempts in MDD patients with moderate-to-severe anxiety symptoms.

Abstract Swine acute diarrhoea syndrome coronavirus (SADS-CoV), a novel HKU2-related coronavirus of bat origin, is a newly emerged swine enteropathogenic coronavirus that causes severe diarrhoea in piglets. SADS-CoV has a broad cell tropism with the capability to infect a wide variety of cells from human and diverse animals, which implicates its ability to hold high risks of cross-species transmission. The intracellular antiviral immunity, comprised of the intrinsic and innate immunity, represents the first line of host defence against viral infection prior to the onset of adaptive immunity. To date, there are no vaccines and drugs approved to prevent or treat SADS-CoV infection. Understanding of the mutual relationship between SADS-CoV infection and host immunity is crucial for the development of novel vaccines and drugs against SADS-CoV. Here, we review recent advancements in our understanding of the interplay between SADS-CoV infection and the host intrinsic and innate immunity. The extensive and in-depth investigation on their interactive relationship will contribute to the identification of new targets for developing intervention strategies to control SADS-CoV infection.

Yanli Wang,1,* Tian Chen,2,* Zhe Shi,3,* Lijinchuan Dong,1 Mengting Li,1 Bo Peng,1 Qi Li,1 Ruile Pan,4 Shuiming Xiao,1 Qing Yang,1 Ning Jiang,4 Xinmin Liu,4,5 Qin Hu,2 Ying Chen1 1Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China; 2College of Chemistry and Life Science, Beijing University of Technology, Beijing, 100124, People’s Republic of China; 3Division of Stem Cell Regulation and Application, Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 4Institute of Medicinal Plant Development, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, 100094, People’s Republic of China; 5Institute of Drug Discovery Technology, Ningbo University, Ningbo, 315000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ying Chen, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Dongzhimen Nei Nanxiao Road, Dongcheng District, Beijing, 100700, People’s Republic of China, Email ychen@icmm.ac.cn Qin Hu, College of Chemistry and Life Science, Beijing University of Technology, No. 100, Pingleyuan Road, Beijing, 100124, People’s Republic of China, Email hq07616@bjut.edu.cnBackground: During medium- to long-duration spaceflights, real-time microgravity can increase the health risks of astronauts. In particular, the disruption of intestinal homeostasis is closely related to other health problems, and it is necessary to monitor related treatment strategies. Ginseng is a well-known Chinese herbal medicine often used to maintain health. Ginseng total saponins (GTSs), which are the bioactive components of ginseng, have been reported to regulate immune homeostasis, anti-inflammation, and anti-oxidation. This study focused on the regulation of GTSs in intestinal homeostasis imbalance caused by microgravity.Methods: A hindlimb suspension (HLS) rat model was established to evaluate the intestinal protective effects of GTSs. Differentially expressed genes (DEGs) were screened using RNA-Seq. RT-PCR was performed to further focus and verify these results. The gut microbiome composition was examined based on 16S rRNA gene amplicon sequencing, and the short-chain fatty acids produced were further analyzed.Results: We found that GTSs intervention effectively improved the intestinal injury caused by simulated weightlessness, including reducing the pathological damage, increasing the expression of tight junction proteins and reducing the levels of inflammatory factors. Moreover, GTSs treatment significantly restored the levels of intestinal immunity-related genes and remodeled the gut microbiota. In particular, GTSs significantly increased the abundance of short-chain fatty acid metabolism-related bacteria, thereby increasing the level of propionic acid, butyric acid, isobutyric acid.Conclusion: Our results revealed that GTSs improved intestinal microecological disorders and impaired immune function caused by the weightlessness simulation. The underlying mechanism may be related to the “intestinal immune -microbiota-metabolic” pathway. These findings provide a theoretical basis for the precise design and development of GTSs for space-health products. Keywords: ginseng total saponins, gastrointestinal microbiome, immunity, short-chain fatty acids, weightlessness simulation

Abstract# It is worth mentioning that the Chinese version of this guideline has been published in the Chinese Journal of Multiple Organ Diseases in the Elderly (Chinese version) in the July 28, 2024 Guidelines and Consensus Column, Vol. 23, No. 7, pages 481-490.: With the rapid advancement of digitalization and intelligence in the medical field, a plethora of cutting-edge technologies are gradually being applied to revolutionize healthcare. In the medical data security privacy protection and artificial intelligence encryption computing, blockchain stands out due to its inherent characteristics of traceability, tamper-proofing, and high credibility. Although blockchain technology has been applied in various industries, its application in the medical field needs more driving force, and its development needs to be standardized. This clinical practice guideline is developed following the World Health Organization's recommended process, adopting Grading of Recommendations Assessment, Development and Evaluation in assessing evidence quality. Considering the integration of blockchain and medical scenarios, we focus on the value and implementability of practical medical applications and provide the guidance on the construction and application of medical blockchain. This practice guideline includesd 10 potential medical application scenarios and usage frameworks. It is worth highlighting that electronic medical record sharing, drug and device anti-counterfeiting, medical digital intellectual property protection, and public health management are considered to be the most easily implemented and effective medical scenarios. The recommendations in this guideline were formulated based on the consideration of stakeholder values and preferences, resource utilization, feasibility, and acceptability, may have a profound impact on the construction of medical blockchain-related scenarios in China and internationally.Registration: Practice Guidance Registration for Transparency (PREPARE) website (http://www.guidelines-registry.cn) Registration No. PREPARE-2023CN637.

Background: Corneal stiffness abnormalities play an important role in the onset and progression of keratoconus. However, the limited availability of specialty devices for measuring corneal stiffness restricts their application in clinical practice. This study aimed to develop a machine learning (ML) model that can predict corneal stiffness based on ocular structures and investigate its efficacy in diagnosing keratoconus. Methods: This retrospective study enrolled healthy individuals and keratoconus patients at the Zhongshan Ophthalmic Center from June 2018 to June 2021. Eleven features, including ocular structural parameters, intraocular pressure (IOP), and age were used to train ML regression models for predicting the stiffness parameter at first applanation (SP-A1) and the Corvis biomechanical index for Chinese populations (cCBI) measured by a Corvis ST device. Mean absolute errors (MAEs) and the area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of the models. The diagnostic efficacy of the predicted SP-A1 and cCBI for keratoconus was evaluated by the AUC, net reclassification index (NRI), and integrated discrimination improvement (IDI). Results: A total of 1,523 eyes were involved, of which 601 were diagnosed with keratoconus. The MAEs of the SP-A1 prediction were similar in cross-validation (8.95 mmHg/mm) and testing (10.65 mmHg/mm). The R2 value for the SP-A1 prediction exceeded 0.7, indicating that the performance was clinically acceptable. The AUC for the cCBI prediction was 0.935 (95% CI 0.906-0.963). The top three predictors for SP-A1 and cCBI were IOP, keratometry, and central corneal thickness. The addition of the predicted SP-A1 and cCBI significantly improved model performance in diagnosing keratoconus, with NRI of 0.607 (95% CI 0.367-0.812) and 0.188 (95% CI −0.022-0.398), and IDI of 0.028 (95% CI 0.006-0.048) and 0.045 (95% CI 0.018-0.072), respectively. Conclusion: Our models predicted SP-A1 and cCBI relatively accurately in keratoconus and normal corneas. Moreover, the predicted SP-A1 and cCBI values significantly contributed to the diagnosis of keratoconus. These models could provide a potential alternative for evaluating corneal stiffness and thus facilitate keratoconus screening.

Abstract Introduction Titanium elastic nail (TEN) fixation is a commonly used intramedullary technique, favored for its minimal incision, elastic fixation, and shorter healing time. However, the stability of TEN fixation is not always assured. We developed a new surgical approach for TEN fixation that has shown excellent clinical outcomes. This study aimed to perform a finite element analysis comparing the traditional antegrade internal TEN (ATEN) biomechanical characteristics with retrograde lateral TEN (RTEN) fixations for mid-shaft clavicle fractures. Materials and methods The CT images were obtained from the right clavicle of a 40-year-old male volunteer. Models of intact and mid-shaft clavicle fractures fixed using ATEN and RTEN were constructed. Distal clavicle displacement, von Mises stress, and von Mises strain were measured under compressive axial loading and cantilever bending loading. Results The stiffness of both TEN fixation models was lower than that of the intact clavicle under both loading conditions. However, when comparing the two fixation methods, RTEN demonstrated higher stiffness than ATEN under both cantilever bending loading (43.05% vs. 38.57%) and axial compression loading (25.73% vs. 22.44%). The peak von Mises stresses of 2 TEN models were both concentrated on the implants, with RTEN showing lower peak stress than ATEN in both conditions (1090.4 MPa vs. 1371.3 MPa under cantilever bending loading and 1112.9 MPa vs. 1433.8 MPa under axial compression loading). Conclusion Compared to ATEN, RTEN exhibits superior biomechanical properties, with higher stiffness and lower peak von Mises stress. This suggests that RTEN may allow for a shorter immobilization period and earlier rehabilitation, while also presenting a lower risk of fixation failure, such as bending or disruption. Simulation is promising but clinical studies need to be pursued before concluding that retrograde nailing is superior in consideration of the anatomy. Clinical trial number Not applicable.

Abstract Objectives To investigate the epidemiological profile and cost burden of pediatric inpatients with tuberculous meningitis (TBM) in China. Methods We conducted a descriptive multicenter study involving pediatric TBM inpatients from 9 provincial hospitals and 20 municipal hospitals across 24 provinces in China from January 2016 to December 2021. Sociodemographic and geographic variables, admission and discharge information were extracted from face sheets of discharge medical records to describe the epidemiological characteristics. Length of hospital stay (LOS) and hospitalization expenses were used to assess disease burden. Results TBM accounted for 0.01% (971/7,647,598) of total hospitalization cases and 15.82% (971/6,138) of TB cases. The proportion of TBM children aged 1–3 (39.13%, 380/971) years were the highest. TBM children aged

Abstract Background The objective of this study was to evaluate the therapeutic effectiveness and safety of transarterial chemoembolization (TACE) combined with programmed cell death-1 (PD-1) inhibitors and lenvatinib in the treatment of unresectable intrahepatic cholangiocarcinoma (uICC). Methods This multicenter retrospective study screened patients with uICC who underwent TACE in combination with PD-1 inhibitors and lenvatinib between January 2019 and June 2023. Tislelizumab or camrelizumab (200 mg) was intravenously administered every three weeks. The daily dose of lenvatinib was 8 mg for patients weighing

Abstract Background Mesenchymal stem cell (MSC) -derived exosomes, especially adipose-derived mesenchymal stem cell exosomes (ADSC-Exos), have emerged as a promising alternative for skin damage repair with anti-inflammatory, angiogenic and cell proliferation effects while overcoming some of the limitations of MSC. However, the mechanism by which ADSC-Exos regulates inflammatory cells during wound healing remains unclear. This study investigated how ADSC-Exos regulate macrophages to promote wound healing. Methods ADSC-Exos were isolated using ultracentrifugation, with subsequent quantification of exosomes particle number. To investigate their role in wound healing, the effects of ADSC-Exos on inflammation, angiogenesis, collagen deposition and macrophage polarization were evaluated through immunohistochemical staining, immunofluorescence and western blotting. Changes in gene expression associated with ADSC-Exos-induced macrophage polarization were analyzed using qPCR. RNA sequencing was performed to identify differentially expressed genes affected by ADSC-Exos. The critical role of IL-33 in the wound healing process was further confirmed using Il33 −/− mice. Additionally, co-culture experiments were conducted to explore the effects of IL-33 on keratinocyte proliferation, collagen deposition and epithelialization. Results ADSC-Exos inhibited the expression of TNF-α and IL-6, induced M2 macrophage polarization, promoted collagen deposition and angiogenesis, and accelerated wound healing. RNA sequencing identified IL-33 as a key mediator in this process. In Il33 −/− mice, impaired wound healing and decreased M2 macrophage polarization were observed. The co-culture experiments showed that IL-33 enhanced keratinocyte function through activation of the Wnt/β-catenin signaling pathway. These findings highlight the therapeutic potential of ADSC-Exos in wound healing by modulating IL-33. Conclusions ADSC-Exos promote wound healing by regulating macrophage polarization and enhancing IL-33 release which drives keratinocyte proliferation, collagen deposition and epithelialization via the Wnt/β-catenin signaling pathway. These findings provide a mechanistic basis for the therapeutic potential of ADSC-Exos in tissue repair and regeneration.

Abstract Background High anisometropia is often accompanied by amblyopia. One percent atropine penalization is an important treatment for anisometropic amblyopia and is as effective as occlusion therapy. On the other hand, 1% atropine had the strongest effect on controlling refractive error and axial length (AL) changes in myopic patients. Case presentation A female child was diagnosed with anisometropia at the age of two. Cycloplegic retinoscopy examination revealed refraction of + 2.5 diopters the right eye and -8.5/-1.5 × 120 diopters the left eye, and full correction spectacles and patching therapy were prescribed for the child. Anisometropic amblyopia was then diagnosed because the best corrected vision acuity in highly myopic eyes is 20/100. Owing to poor compliance, visual acuity recovery in the amblyopic eye was unsatisfactory, and 1% atropine was applied two times per week for the fellow (right) eye. Since then, the fellow eye has experienced rapid myopization, with the refractive error increasing to -7.5/-1.25 × 15 diopterswithin five years. In addition, the visual acuity of the amblyopic (left) eye has improved gradually to 20/20, although the refraction status has remained stable. Conclusions In this report, a high anisometropic amblyopia patient underwent rapid myopization in the fellow eye with constant use of 1% atropine, in contrast to the stable refraction status of the amblyopic eye.

Abstract Phenylalanine (Phe), an aromatic amino acid, is a key precursor of flavonoids, which are crucial for plant growth and development. Arogenate dehydratase (ADT) catalyzes the final step in Phe biosynthesis. This study identified eleven ADT genes in G. hirsutum, twelve in G. barbadense, six in G. arboreum, and six in G. raimondii. Among them, GhADT5 exhibited the highest upregulation under alkali stress. Silencing GhADT5 using virus-induced gene silencing (VIGS) reduced cotton tolerance to alkali stress. GhADT5 silencing also led to decreased plant phenylalanine content, total flavonoid content, and activities of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD). These reductions caused intracellular accumulation of Malondialdehyde (MDA) and reactive oxygen species (ROS). This oxidative damage ultimately reduced tolerance to alkali stress. In addition, silenced plants displayed reduced stomatal aperture, cellular deformation, and irregular intercellular breaks in the leaf epidermis. In summary, these findings suggest that GhADT5 may enhance resistance to alkali stress by regulating enzymatic and non-enzymatic antioxidant systems. This study highlights the role of GhADT5 under alkali stress and provides novel insights for breeding cotton varieties with improved stress tolerance.

Abstract Obesity is a prevalent health issue among adolescents, characterized by chronic low-grade inflammation, which increases the risk of developing various chronic diseases in the future. The systemic immune-inflammation index (SII) serves as an indicator of inflammation and immune response. This study conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016, including 5,676 participants. A multivariate logistic regression model, Generalized Additive Models (GAM), and subgroup analysis were used to examine the relationship between obesity and SII. The multivariate logistic regression results revealed a significant positive correlation between log SII and adolescent obesity (1.254 [1.024–1.537]). Furthermore, the risk of obesity increased with higher quartiles of SII. Subgroup analysis and interaction tests showed that this positive association persisted across various factors, including female gender, race (Non-Hispanic White and Mexican American), non-hyperlipidemia, normal white blood cell count, and PIR

Abstract To evaluate the immunogencity and safety for three immunization schedules of inactivated poliovirus vaccine (IPV) and bivalent oral poliovirus vaccine (bOPV) for providing a basis for further optimization of the polio sequential immunization schedule. To obtain immunogenicity data and to active surveillance the occurrence of adverse events following immunization (AEFI), healthy infants ≥ 2 months of age were randomly chosen in Hebei Province, and were divided into three groups to be vaccinated with IPV-bOPV-bOPV(Group a), IPV-IPV-bOPV(Group b) and IPV-IPV-IPV(Group c) at 2, 3 and 4 months of age respectively. AEFI cases related to poliomyelitis vaccines in Hebei province by passive surveillance from January 1, 2018 to December 31, 2022 were obtained from national adverse event following immunization surveillance system (NAEFISS). After basic immunization with polio vaccine, the positive conversion rate of neutralizing antibodies of types I, II and III were all > 97.00% and the positive rates were all > 98.00%, the geometric mean titer (GMT) was significantly higher than that before basic immunization, the GMT level of neutralizing poliovirus antibody after basic immunization was the highest in type I, followed by type III, and the lowest in type II. A total of 16 AEFI cases (2.52%) were reported by active surveillance, and 2903 AEFI cases (1.40%) were reported by passive surveillance. AEFI reported by both monitoring modalities were dominated by fever of common vaccine reactions. No rare serious adverse reactions like VAPP etc. were monitored and the overall regression was positive. All three immunization schedules for polio vaccine have demonstrated good immunogenicity and safety when administered to healthy populations.