Shared Genetic Architecture Among Gastrointestinal Diseases, Schizophrenia, and Brain Subcortical Volumes.

BACKGROUND AND HYPOTHESIS: The gut-brain axis plays important roles in both gastrointestinal diseases (GI diseases) and schizophrenia (SCZ). Moreover, both GI diseases and SCZ exhibit notable abnormalities in brain subcortical volumes. However, the genetic mechanisms underlying the comorbidity of these diseases and the shared alterations in brain subcortical volumes remain unclear. STUDY DESIGN: Using the genome-wide association studies data of SCZ, 14 brain subcortical volumes, and 8 GI diseases, the global polygenic overlap and local genetic correlations were identified, as well as the shared genetic variants among those phenotypes. Furthermore, we conducted multi-trait colocalization analyses to bolster our findings. Functional annotations, cell-type enrichment, and protein-protein interaction (PPI) analyses were carried out to reveal the critical etiology and pathology mechanisms. STUDY RESULTS: The global polygenic overlap and local genetic correlations informed the close relationships between SCZ and both GI diseases and brain subcortical volumes. Moreover, 84 unique lead-shared variants were identified. The associated genes were linked to vital biological processes within the immune system. Additionally, significant correlations were observed with key immune cells and the PPI analysis identified several histone-associated hub genes. These findings highlighted the pivotal roles played by the immune system for both SCZ and GI diseases, along with the shared alterations in brain subcortical volumes. CONCLUSIONS: These findings revealed the shared genetic architecture contributing to SCZ and GI diseases, as well as their shared alterations in brain subcortical volumes. These insights have substantial implications for the concurrent development of intervention and therapy targets for these diseases.

Nonactivated Aziridine Synthesis by Intermolecular Polarity-Mismatched Carboamination of Unactivated Alkenes with Unactivated Alkyl Halides.

A general intermolecular polarity-mismatched carboamination reaction of unactivated alkenes with unactivated alkyl halides has been developed. A series of nonactivated alkyl-substituted aziridines were constructed in exclusive regioselectivity. The dual polarity-mismatched mechanism might be involved.

De novo design of SARS-CoV-2 main protease inhibitors with characteristic binding modes.

The coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spreads rapidly all over the world. The main protease (Mpro) is significant to the replication and transcription of viruses, making it an attractive drug target against coronaviruses. Here, we introduce a series of novel inhibitors which are designed de novo through structure-based drug design approach that have great potential to inhibit SARS-CoV-2 Mproin vitro. High-resolution structures show that these inhibitors form covalent bonds with the catalytic cysteine through the novel dibromomethyl ketone (DBMK) as a reactive warhead. At the same time, the designed phenyl group beside the DBMK warhead inserts into the cleft between H41 and C145 through π-π stacking interaction, splitting the catalytic dyad and disrupting proton transfer. This unique binding model provides novel clues for the cysteine protease inhibitor development of SARS-CoV-2 as well as other pathogens.

Sulfated Laminarin Polysaccharides Reduce the Adhesion of Nano-COM Crystals to Renal Epithelial Cells by Inhibiting Oxidative and Endoplasmic Reticulum Stress.

Purpose: Adhesion between calcium oxalate crystals and renal tubular epithelial cells is a vital cause of renal stone formation; however, the drugs that inhibit crystal adhesion and the mechanism of inhibition have yet to be explored. Methods: The cell injury model was constructed using nano-COM crystals, and changes in oxidative stress levels, endoplasmic reticulum (ER) stress levels, downstream p38 MAPK protein expression, apoptosis, adhesion protein osteopontin expression, and cell-crystal adhesion were examined in the presence of Laminarin polysaccharide (DLP) and sulfated DLP (SDLP) under protected and unprotected conditions. Results: Both DLP and SDLP inhibited nano-COM damage to human kidney proximal tubular epithelial cell (HK-2), increased cell viability, decreased ROS levels, reduced the opening of mitochondrial membrane permeability transition pore, markedly reduced ER Ca2+ ion concentration and adhesion molecule OPN expression, down-regulated the expression of ER stress signature proteins including CHOP, Caspase 12, and p38 MAPK, and decreased the apoptosis rate of cells. SDLP has a better protective effect on cells than DLP. Conclusions: SDLP protects HK-2 cells from nano-COM crystal-induced apoptosis by reducing oxidative and ER stress levels and their downstream factors, thereby reducing crystal-cell adhesion interactions and the risks of kidney stone formation.

A multi-institutional comparison of retrospective deformable dose accumulation for online adaptive magnetic resonance-guided radiotherapy.

Background and Purpose: Application of different deformable dose accumulation (DDA) solutions makes institutional comparisons after online-adaptive magnetic resonance-guided radiotherapy (OA-MRgRT) challenging. The aim of this multi-institutional study was to analyze accuracy and agreement of DDA-implementations in OA-MRgRT. Material and Methods: One gold standard (GS) case deformed with a biomechanical-model and five clinical cases consisting of prostate (2x), cervix, liver, and lymph node cancer, treated with OA-MRgRT, were analyzed. Six centers conducted DDA using institutional implementations. Deformable image registration (DIR) and DDA results were compared using the contour metrics Dice Similarity Coefficient (DSC), surface-DSC, Hausdorff-distance (HD95%), and accumulated dose-volume histograms (DVHs) analyzed via intraclass correlation coefficient (ICC) and clinical dosimetric criteria (CDC). Results: For the GS, median DDA errors ranged from 0.0 to 2.8 Gy across contours and implementations. DIR of clinical cases resulted in DSC > 0.8 for up to 81.3% of contours and a variability of surface-DSC values depending on the implementation. Maximum HD95%=73.3 mm was found for duodenum in the liver case. Although DVH ICC > 0.90 was found after DDA for all but two contours, relevant absolute CDC differences were observed in clinical cases: Prostate I/II showed maximum differences in bladder V28Gy (10.2/7.6%), while for cervix, liver, and lymph node the highest differences were found for rectum D2cm3 (2.8 Gy), duodenum Dmax (7.1 Gy), and rectum D0.5cm3 (4.6 Gy). Conclusion: Overall, high agreement was found between the different DIR and DDA implementations. Case- and algorithm-dependent differences were observed, leading to potentially clinically relevant results. Larger studies are needed to define future DDA-guidelines.

Trichostatin A Promotes Cytotoxicity of Cisplatin, as Evidenced by Enhanced Apoptosis/Cell Death Markers.

Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the cytotoxicity of the genotoxic anticancer drug cisplatin, yet the underlying mechanism remains poorly understood. Herein, we revealed that TSA at a low concentration (1 µM) promoted the cisplatin-induced activation of caspase-3/6, which, in turn, increased the level of cleaved PARP1 and degraded lamin A&C, leading to more cisplatin-induced apoptosis and G2/M phase arrest of A549 cancer cells. Both ICP-MS and ToF-SIMS measurements demonstrated a significant increase in DNA-bound platinum in A549 cells in the presence of TSA, which was attributable to TSA-induced increase in the accessibility of genomic DNA to cisplatin attacking. The global quantitative proteomics results further showed that in the presence of TSA, cisplatin activated INF signaling to upregulate STAT1 and SAMHD1 to increase cisplatin sensitivity and downregulated ICAM1 and CD44 to reduce cell migration, synergistically promoting cisplatin cytotoxicity. Furthermore, in the presence of TSA, cisplatin downregulated TFAM and SLC3A2 to enhance cisplatin-induced ferroptosis, also contributing to the promotion of cisplatin cytotoxicity. Importantly, our posttranslational modification data indicated that acetylation at H4K8 played a dominant role in promoting cisplatin cytotoxicity. These findings provide novel insights into better understanding the principle of combining chemotherapy of genotoxic drugs and HDAC inhibitors for the treatment of cancers.

Dihydroartemisinin induces ferroptosis in T cell acute lymphoblastic leukemia cells by downregulating SLC7A11 and activating the ATF4­CHOP signaling pathway.

The present study aimed to investigate the anti-leukemic effects of dihydroartemisinin (DHA) on T-cell acute lymphoblastic leukemia (T-ALL) cell lines, Jurkat and Molt-4, and the underlying mechanisms. Cell Counting Kit-8 was performed to measure cell viability. Cell apoptosis and cell cycle distribution were assessed by flow cytometry. The expression levels of ATF4 and CHOP mRNA were assessed by reverse transcription-quantitative PCR, while the protein abundance of SLC7A11, GPX4, ATF4 and CHOP was determined by western blotting. Moreover, malondialdehyde, glutathione (GSH) and reactive oxygen species (ROS) assays were used to detect the levels of ferroptosis. The results showed that DHA suppressed T-ALL cell viability in vitro, and induced cell cycle arrest at S or G2/M phase. DHA also induced ROS burst, activated endoplasmic reticulum (ER) stress, disrupted the system Xc--GSH-GSH peroxidase 4 antioxidant system, and increased lipid peroxide accumulation, resulting in cell death. By contrast, the pharmacological inhibition of ferroptosis alleviated DHA-induced cell death, confirming that DHA induces T-ALL cell death via ferroptosis. Mechanistically, the effect of DHA on ferroptosis was partly mediated by downregulating SLC7A11 and upregulating the ATF4-CHOP signaling pathway, which is associated with ER stress. These results indicated that DHA may induce ferroptosis in T-ALL cell lines and could represent a promising therapeutic agent for treating T-ALL.

First report of leaf blight on pumpkin caused by Nigrospora sphaerica in China.

Pumpkin (Cucurbita moschata), which belongs to the gourd family (Cucurbitaceae), is widely planted throughout the world. In June 2023, many pumpkin plants (cv. Miben) displayed leaf blight and chlorosis in fields located in Suizhou (31.99°N, 113.02°E), Hubei Province, China. The disease incidence ranged from 30 to 40% in nine fields, 6.3 ha in total. The symptoms were irregularly shaped lesions that expanded along the mid-vein until the leaf turned brown and wilted. Fungal isolations were performed as described previously (Liu et al. 2023). Twenty pumpkin leaf samples with typical symptoms were collected and cut into 1 cm×1 cm pieces. The diseased tissue was surface-sterilized in 75% ethanol for 30 sec, plated on potato dextrose agar (PDA) medium and incubated at 25℃ for 3 days. Then, the emerging single fungal hyphal tip was transferred onto PDA plates to obtain purified isolates. A total of eighteen isolates on PDA plates were initially white and then developed to dark gray. The 5-day-old cultures growing on mung bean medium produced conidia that were black, single-celled, smooth, spherical or oblate, and ranged in size from 14.5 to 20.8 µm×13.3 to 20.5 µm (n=50). Therefore, the isolates were morphologically identified as Nigrospora sphaerica. Moreover, the genomic DNA of the isolates (HB-P1,HB-P2, and HB-P3) was extracted for amplification and sequencing of the regions of internal transcribed spacer (ITS) (White et al. 1990), nuclear large subunit rRNA (nLSU) (O'Donnell 1992; Rehner and Samuels 1994), and ß-tubulin (TUB2) (Glass and Donaldson 1995), with primers ITS1/ITS4, LROR/LR3, and Bt2a/Bt2b, respectively. Sequences were submitted to GenBank under accession numbers PP348112, PP348113, PP348114 (ITS), PP411414, PP411415, PP411416 (nLSU), and PP357438, PP357439, PP357440 (TUB2). BLASTn showed that the sequences ITS, nLSU, and TUB2 of HB-P1, HB-P2, and HB-P3 had >99% nucleotide identities ((ITS: 100%, 508/508 bp, MF996488.1; 99.8%, 506/507, ON326588.1; 100%, 500/500 ,MK748317.1), (nLSU: 99.83%, 573/574, KT462720.1; 99.83% , 574/575 bp, KT462720.1; 99.65%, 575/577, KT462720.1), and (TUB2: 100%, 388/388, MN719407.1; 99.74%, 387/388, MN719407.1; 100%, 387/387, MN719407.1)) with Nigrospora sphaerica, respectively. A multilocus (ITS, nLSU and TUB2) phylogenetic analysis indicated that the isolates were Nigrospora sphaerica. Pathogenicity of three isolates were tested on pumpkin plants (cv. Miben). Fifteen pumpkin plants were inoculated by spraying the leaves (1×106 spores/ml), respectively, and 10 pumpkin plants were treated with sterile water as a negative control. All plants were incubated in an artificial climate box (LongYue, ShangHai) at 25℃ for 12 days. The experiment was repeated three times. Twelve days later, the inoculated pumpkin plants developed symptoms of leaf blight, while the control plants remained healthy. Then, pathogens were re-isolated from the each leaf of inoculated pumpkin plants and not from the control plants. Nigrospora sphaerica has been previously reported to cause leaf spot on watermelon in Malaysia (Ismail and Abd Razak 2021). To our knowledge, this is the first report of N. sphaerica causing leaf blight on pumpkin in China. This new disease can cause leaf blight, which may affect pumpkin productivity.

Single-Frame Supervision for Spatio-Temporal Video Grounding.

Spatio-Temporal Video Grounding (STVG) aims at localizing the spatio-temporal tube of a specific object in an untrimmed video given a free-form natural language query. As the annotation of tubes is labor intensive, researchers are motivated to explore weakly supervised approaches in recent works, which usually results in significant performance degradation. To achieve a less expensive STVG method with acceptable accuracy, this work investigates the "single-frame supervision" paradigm that requires a single frame labeled with a bounding box within the temporal boundary of the fully supervised counterpart as the supervisory signal. Based on the characteristics of the STVG problem, we propose a Two-Stage Multiple Instance Learning (T-SMILE) method, which creates pseudo labels by expanding the annotated frame to its contextual frames, thereby establishing a fully-supervised problem to facilitate further model training. The innovations of the proposed method are three-folded, including 1) utilizing multiple instance learning to dynamically select instances in positive bags for the recognition of starting and ending timestamps, 2) learning highly discriminative query features by incorporating spatial prior constraints in cross-attention, and 3) designing a curriculum learning-based strategy that iterative assigns dynamic weights to spatial and temporal branches, thereby gradually adapting to the learning branch with larger difficulty. To facilitate future research on this task, we also contribute a large-scale benchmark containing 12,469 videos on complex scenes with single-frame annotation. The extensive experiments on two benchmarks demonstrate that T-SMILE significantly outperforms all weakly-supervised methods. Remarkably, it also performs better than some fully-supervised methods associated with much more annotation labor costs. The dataset and codes are available at https://github.com/qumengxue/T-SMILE.

Semi-Supervised Coupled Thin-Plate Spline Model for Rotation Correction and Beyond.

Thin-plate spline (TPS) is a principal warp that allows for representing elastic, nonlinear transformation with control point motions. With the increase of control points, the warp becomes increasingly flexible but usually encounters a bottleneck caused by undesired issues, e.g., content distortion. In this paper, we explore generic applications of TPS in single-image-based warping tasks, such as rotation correction, rectangling, and portrait correction. To break this bottleneck, we propose the coupled thin-plate spline model (CoupledTPS), which iteratively couples multiple TPS with limited control points into a more flexible and powerful transformation. Concretely, we first design an iterative search to predict new control points according to the current latent condition. Then, we present the warping flow as a bridge for the coupling of different TPS transformations, effectively eliminating interpolation errors caused by multiple warps. Besides, in light of the laborious annotation cost, we develop a semi-supervised learning scheme to improve warping quality by exploiting unlabeled data. It is formulated through dual transformation between the searched control points of unlabeled data and its graphic augmentation, yielding an implicit correction consistency constraint. Finally, we collect massive unlabeled data to exhibit the benefit of our semi-supervised scheme in rotation correction. Extensive experiments demonstrate the superiority and universality of CoupledTPS over the existing state-of-the-art (SoTA) solutions for rotation correction and beyond. The code and data will be available at https://github.com/nie-lang/CoupledTPS.

Bio-accumulation and health risk assessments of per- and polyfluoroalkyl substances in wheat grains.

Per- and polyfluoroalkyl substances (PFASs) have been widely detected in various food, which has attracted worldwide concern. However, the factors influencing the transfer and bio-accumulation of PFASs from soils to wheat in normal farmland, is still ambiguous. We investigated the PFASs accumulation in agricultural soils and grains from 10 cites, China, and evaluated the health risks of PFASs via wheat consumption. Our results show that ∑PFASs in soils range from 0.34 µg/kg to 1.59 µg/kg with PFOA and PFOS dominating, whilst ∑PFASs in wheats range from 2.74 to 6.01 µg/kg with PFOA, PFBA and PFHxS dominating. The lower pH conditions and high total organic carbon (TOC) could result in the higher accumulation of PFASs in soils and subsequently in wheat grains, whilst the bioaccumulation factors of PFASs increase with increasing pH conditions but not with TOC. The estimated daily intake (EDI) values of PFBA, PFOA, and PFHxS are relatively high, but data supports that ingesting wheat grains does not result in any potential risk to the human beings. Our studies provided more information about PFASs accumulation in wheat grains, and help us understand the current potential risks of PFASs in food.

Multi-modal segmentation with missing image data for automatic delineation of gross tumor volumes in head and neck cancers.

BACKGROUND: Head and neck (HN) gross tumor volume (GTV) auto-segmentation is challenging due to the morphological complexity and low image contrast of targets. Multi-modality images, including computed tomography (CT) and positron emission tomography (PET), are used in the routine clinic to assist radiation oncologists for accurate GTV delineation. However, the availability of PET imaging may not always be guaranteed. PURPOSE: To develop a deep learning segmentation framework for automated GTV delineation of HN cancers using a combination of PET/CT images, while addressing the challenge of missing PET data. METHODS: Two datasets were included for this study: Dataset I: 524 (training) and 359 (testing) oropharyngeal cancer patients from different institutions with their PET/CT pairs provided by the HECKTOR Challenge; Dataset II: 90 HN patients(testing) from a local institution with their planning CT, PET/CT pairs. To handle potentially missing PET images, a model training strategy named the "Blank Channel" method was implemented. To simulate the absence of a PET image, a blank array with the same dimensions as the CT image was generated to meet the dual-channel input requirement of the deep learning model. During the model training process, the model was randomly presented with either a real PET/CT pair or a blank/CT pair. This allowed the model to learn the relationship between the CT image and the corresponding GTV delineation based on available modalities. As a result, our model had the ability to handle flexible inputs during prediction, making it suitable for cases where PET images are missing. To evaluate the performance of our proposed model, we trained it using training patients from Dataset I and tested it with Dataset II. We compared our model (Model 1) with two other models which were trained for specific modality segmentations: Model 2 trained with only CT images, and Model 3 trained with real PET/CT pairs. The performance of the models was evaluated using quantitative metrics, including Dice similarity coefficient (DSC), mean surface distance (MSD), and 95% Hausdorff Distance (HD95). In addition, we evaluated our Model 1 and Model 3 using the 359 test cases in Dataset I. RESULTS: Our proposed model(Model 1) achieved promising results for GTV auto-segmentation using PET/CT images, with the flexibility of missing PET images. Specifically, when assessed with only CT images in Dataset II, Model 1 achieved DSC of 0.56 ± 0.16, MSD of 3.4 ± 2.1 mm, and HD95 of 13.9 ± 7.6 mm. When the PET images were included, the performance of our model was improved to DSC of 0.62 ± 0.14, MSD of 2.8 ± 1.7 mm, and HD95 of 10.5 ± 6.5 mm. These results are comparable to those achieved by Model 2 and Model 3, illustrating Model 1's effectiveness in utilizing flexible input modalities. Further analysis using the test dataset from Dataset I showed that Model 1 achieved an average DSC of 0.77, surpassing the overall average DSC of 0.72 among all participants in the HECKTOR Challenge. CONCLUSIONS: We successfully refined a multi-modal segmentation tool for accurate GTV delineation for HN cancer. Our method addressed the issue of missing PET images by allowing flexible data input, thereby providing a practical solution for clinical settings where access to PET imaging may be limited.

Learnable Feature Augmentation Framework for Temporal Action Localization.

Temporal action localization (TAL) has drawn much attention in recent years, however, the performance of previous methods is still far from satisfactory due to the lack of annotated untrimmed video data. To deal with this issue, we propose to improve the utilization of current data through feature augmentation. Given an input video, we first extract video features with pre-trained video encoders, and then randomly mask various semantic contents of video features to consider different views of video features. To avoid damaging important action-related semantic information, we further develop a learnable feature augmentation framework to generate better views of videos. In particular, a Mask-based Feature Augmentation Module (MFAM) is proposed. The MFAM has three advantages: 1) it captures the temporal and semantic relationships of original video features, 2) it generates masked features with indispensable action-related information, and 3) it randomly recycles some masked information to ensure diversity. Finally, we input the masked features and the original features into shared action detectors respectively, and perform action classification and localization jointly for model learning. The proposed framework can improve the robustness and generalization of action detectors by learning more and better views of videos. In the testing stage, the MFAM can be removed, which does not bring extra computational costs. Extensive experiments are conducted on four TAL benchmark datasets. Our proposed framework significantly improves different TAL models and achieves the state-of-the-art performances.

A review of the ecotoxicological status of microplastic pollution in African freshwater systems.

Microplastics (MPs) have found extensive application globally due to their low cost, flexibility and light weight. Microplastic pollution is a growing environmental concern that poses significant threats to aquatic ecosystems worldwide, including African freshwater systems. Nevertheless, although Africa houses some of the deepest and largest freshwater rivers and lakes in the world such as Lake Tanganyika and Victoria, River Congo and the Nile, there is limited information available regarding the presence of MPs in these inland waters. Selected published data on MPs in African freshwater systems, including sediments, biota, rivers, and lakes, were incorporated in this review. The study discovered that the sampling technique employed has a major impact on the morphological characteristics and abundance of MPs in African freshwater systems. Fibers and fragments were the most common shapes; black, white, and transparent were the most prevalent colors; and polyethene terephthalate, polystyrene, and polypropylene were the frequently dominant polymers. As the distance between the sampling sites increased geographically, the polymer similarities declined. MPs have been found to translocate into body cells and tissues where they are capable of causing genetic mutations, cytotoxicity, oxidative stress and neurotoxicity. In Africa, MPs are poorly managed and monitored, and there has been insufficient research done on the possibility that they could be present in drinking water. Considering the fact that humans in the continent are exposed to freshwater and aquatic organisms, the risk assessment routes are currently unvalidated, therefore it was recommended that African nations should strengthen their capacity for plastic management and environmental monitoring. This review provides up to date information on the occurrence, prevalence, ecotoxicity and management of MPs across African freshwater systems.

Lymphocyte counts predict optimal timing of chemotherapy reinitiation after antivirus treatment for herpes zoster in children with leukemia.

Herpes zoster (HZ) is rare in healthy children, but more prevalent in those with leukemia. Optimal timing of chemotherapy reinitiation after HZ treatment is challenging because chemotherapy suppresses immunity and increases risk of HZ relapse. We aimed to optimize the timing of chemotherapy reinitiation after HZ therapy in children with leukemia. The study included 31 children with acute leukemia and HZ infection. General information, clinical symptoms, laboratory test results, duration of HZ treatment, and prognosis were compared with those of children with leukemia alone. Correlation analysis was performed for 20 children who restarted chemotherapy after HZ treatment. Of 31 children with leukemia and HZ, 67.74% had lesions at multiple sites. The median time from chemotherapy initiation to HZ onset was 14.1 (1.5-29.5) months. Among 27 children included in the follow-up, there was one case of HZ relapse. After excluding children who did not continue chemotherapy after HZ treatment, the median interval between completion of HZ therapy and chemotherapy reinitiation in the remaining 20 children was 8.00 (- 3 to 27) days. Lymphocyte counts (LY#) on restarting chemotherapy correlated inversely with HZ lesion healing time (p < 0.05). LY# at the time of HZ onset were lower than those pre- and post-onset, and lower than those in the control group (p < 0.05). In conclusion, children with leukemia have a good HZ prognosis, but an increased risk of HZ recurrence. LY# at the time of chemotherapy reinitiation may be a useful indicator for selecting the optimal interval between antiviral therapy completion and chemotherapy reinitiation.

Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation.

The endogenous mitochondrial quality control (MQC) system serves to protect mitochondria against cellular stressors. Although mitochondrial dysfunction contributes to cardiac damage during many pathological conditions, the regulatory signals influencing MQC disruption during septic cardiomyopathy (SC) remain unclear. This study aimed to investigate the involvement of pyruvate kinase M2 (PKM2) and prohibitin 2 (PHB2) interaction followed by MQC impairment in the pathogenesis of SC. We utilized LPS-induced SC models in PKM2 transgenic (PKM2TG) mice, PHB2S91D-knockin mice, and PKM2-overexpressing HL-1 cardiomyocytes. After LPS-induced SC, cardiac PKM2 expression was significantly downregulated in wild-type mice, whereas PKM2 overexpression in vivo sustained heart function, suppressed myocardial inflammation, and attenuated cardiomyocyte death. PKM2 overexpression relieved sepsis-related mitochondrial damage via MQC normalization, evidenced by balanced mitochondrial fission/fusion, activated mitophagy, restored mitochondrial biogenesis, and inhibited mitochondrial unfolded protein response. Docking simulations, co-IP, and domain deletion mutant protein transfection experiments showed that PKM2 phosphorylates PHB2 at Ser91, preventing LPS-mediated PHB2 degradation. Additionally, the A domain of PKM2 and the PHB domain of PHB2 are required for PKM2-PHB2 binding and PHB2 phosphorylation. After LPS exposure, expression of a phosphorylation-defective PHB2S91A mutant negated the protective effects of PKM2 overexpression. Moreover, knockin mice expressing a phosphorylation-mimetic PHB2S91D mutant showed improved heart function, reduced inflammation, and preserved mitochondrial function following sepsis induction. Abundant PKM2 expression is a prerequisite to sustain PKM2-PHB2 interaction which is a key element for preservation of PHB2 phosphorylation and MQC, presenting novel interventive targets for the treatment of septic cardiomyopathy.

Germline AIP variants in sporadic young acromegaly and pituitary gigantism: clinical and genetic insights from a Han Chinese cohort.

PURPOSE: Variants in the Aryl hydrocarbon receptor-interacting protein (AIP) gene have been identified in sporadic acromegaly and pituitary gigantism, especially in young patients, with a predisposition to aggressive clinical phenotype and poor treatment efficacy. The clinical characteristics of patients with sporadic acromegaly and pituitary gigantism as well as AIP variants in Han Chinese have been rarely reported. We aimed to identify AIP gene variants and analyze the clinical characteristics of patients with sporadic acromegaly and pituitary gigantism in Han Chinese. METHODS: The study included 181 sporadic acromegaly (N = 163) and pituitary gigantism (N = 18) patients with an onset age of no more than 45 years old, who were diagnosed, treated, and followed up in Huashan Hospital. All 6 exons and their flanking regions of the AIP gene were analyzed with Sanger sequencing or NGS. The clinical characteristics were compared between groups with and without AIP variants. RESULTS: Germline AIP variants were found in 15/181 (8.29%) cases. In patients with an onset age ≤30 years old, AIP variants were identified in 12/133 (9.02%). Overall, 13 variants were detected. The pathogenic (P) variants p.R304X and p.R81X were identified in four cases, with two instances of each variant. Six exon variants (p.C254R, p.K103fs, p.Q228fs, p.Y38X, p.Q213*, and p.1115 fs) have not been reported before, which were likely pathogenic (LP). Patients with P/LP variants had younger onset ages, a higher prevalence of pituitary gigantism, larger tumor volumes, and a higher percentage of Ki-67-positive cells in tumors. In addition, the group with P/LP variants showed a less significant reduction of GH levels in an acute octreotide suppression test (OST) [17.7% (0, 65.0%) vs. 80.5% (63.9%, 90.2%), P = 0.001], and a trend of less GH decrease after the 3-month treatment with long-acting somatostatin analogs (SSAs). CONCLUSION: Germline AIP variants existed in sporadic Chinese Han acromegaly and pituitary gigantism patients and were more likely to be detected in young patients. AIP variants were associated with more aggressive tumor phenotypes and less response to SSA treatment.

Reprogrammable and reconfigurable mechanical computing metastructures with stable and high-density memory.

Mechanical computing encodes information in deformed states of mechanical systems, such as multistable structures. However, achieving stable mechanical memory in most multistable systems remains challenging and often limited to binary information. Here, we report leveraging coupling kinematic bifurcation in rigid cube-based mechanisms with elasticity to create transformable, multistable mechanical computing metastructures with stable, high-density mechanical memory. Simply stretching the planar metastructure forms a multistable corrugated platform. It allows for independent mechanical or magnetic actuation of individual bistable element, serving as pop-up voxels for display or binary units for various tasks such as information writing, erasing, reading, encryption, and mechanologic computing. Releasing the pre-stretched strain stabilizes the prescribed information, resistant to external mechanical or magnetic perturbations, whereas re-stretching enables editable mechanical memory, akin to selective zones or disk formatting for information erasure and rewriting. Moreover, the platform can be reprogrammed and transformed into a multilayer configuration to achieve high-density memory.

Fully 3D-Printed Miniature Soft Hydraulic Actuators with Shape Memory Effect for Morphing and Manipulation.

Miniature shape-morphing soft actuators driven by external stimuli and fluidic pressure hold great promise in morphing matter and small-scale soft robotics. However, it remains challenging to achieve both rich shape morphing and shape locking in a fast and controlled way due to the limitations of actuation reversibility and fabrication. Here, fully 3D-printed, sub-millimeter thin-plate-like miniature soft hydraulic actuators with shape memory effect (SME) for programable fast shape morphing and shape locking, are reported. It combines commercial high-resolution multi-material 3D printing of stiff shape memory polymers (SMPs) and soft elastomers and direct printing of microfluidic channels and 2D/3D channel networks embedded in elastomers in a single print run. Leveraging spatial patterning of hybrid compositions and expansion heterogeneity of microfluidic channel networks for versatile hydraulically actuated shape morphing, including circular, wavy, helical, saddle, and warping shapes with various curvatures, are demonstrated. The morphed shapes can be temporarily locked and recover to their original planar forms repeatedly by activating SME of the SMPs. Utilizing the fast shape morphing and locking in the miniature actuators, their potential applications in non-invasive manipulation of small-scale objects and fragile living organisms, multimodal entanglement grasping, and energy-saving manipulators, are demonstrated.

Cardioprotective potentials of myricetin on doxorubicin-induced cardiotoxicity based on biochemical and transcriptomic analysis.

Doxorubicin (DOX) is a commonly used anthracycline in cancer chemotherapy. The clinical application of DOX is constrained by its cardiotoxicity. Myricetin (MYR) is a natural flavonoid widely present in many plants with antioxidant and anti-inflammatory properties. However, MYR's beneficial effects and mechanisms in alleviating DOX-induced cardiotoxicity (DIC) remain unknown. C57BL/6 mice were injected with 15 mg/kg of DOX to establish the DIC, and MYR solutions were administrated by gavage to investigate its cardioprotective potentials. Histopathological analysis, physiological indicators assessment, transcriptomics analysis, and RT-qPCR were used to elucidate the potential mechanism of MYR in DIC treatment. MYR reduced cardiac injury produced by DOX, decreased levels of cTnI, AST, LDH, and BNP, and improved myocardial injury and fibrosis. MYR effectively prevented DOX-induced oxidative stress, such as lowered MDA levels and elevated SOD, CAT, and GSH activities. MYR effectively suppressed NLRP3 and ASC gene expression levels to inhibit pyroptosis while regulating Caspase1 and Bax levels to reduce cardiac cell apoptosis. According to the transcriptomic analysis, glucose and fatty acid metabolism were associated with differential gene expression. KEGG pathway analysis revealed differential gene enrichment in PPAR and AMPK pathways, among others. Following validation, MYR was found to alleviate DIC by regulating glycolipid metabolism and AMPK pathway-related genes. Our findings demonstrated that MYR could mitigate DIC by regulating the processes of oxidative stress, apoptosis, and pyroptosis. MYR is critical in improving DOX-induced myocardial energy metabolism abnormalities mediated by the AMPK signaling pathway. In conclusion, MYR holds promise as a therapeutic strategy for DIC.