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Abstract Objective The insula is an important part of the posttraumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) neuropathological activity pattern. It is composed of functionally different subdivisions and each of which plays different role in PTH neuropathology. Methods Ninety-four mTBI patients were included in this study. Based on perfusion imaging data obtained from arterial spin labelling (ASL) perfusion magnetic resonance imaging (MRI), this study evaluated the insular subregion perfusion-based functional connectivity (FC) and its correlation with clinical characteristic parameters in patients with PTH after mTBI and non-headache mTBI patients. Results The insular subregions of mTBI + PTH (mTBI patients with PTH) and mTBI-PTH (mTBI patients without PTH) group had positive perfusion-based functional connections with other insular nuclei and adjacent discrete cortical regions. Compared with mTBI-PTH group, significantly increased resting-state perfusion-based FC between the anterior insula (AI) and middle cingulate cortex (MCC)/Rolandic operculum (ROL), between posterior insula (PI) and supplementary motor area (SMA), and decreased perfusion-based FC between PI and thalamus were found in mTBI + PTH group. Changes in the perfusion-based FC of the left posterior insula/dorsal anterior insula with the thalamus/MCC were significant correlated with headache characteristics. Conclusions Our findings provide new ASL-based evidence for changes in the perfusion-based FC of the insular subregion in PTH patients attributed to mTBI and the association with headache features, revealing the possibility of potential neuroplasticity after PTH. These findings may contribute to early diagnosis of the disease and follow-up of disease progression.

Abstract Background Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor outcomes, especially in older AML patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer drug because it selectively induces the extrinsic apoptosis of tumor cells without affecting normal cells. However, clinical trials have shown that the responses of patients to TRAIL are significantly heterogeneous. It is necessary to explore predictable biomarkers for the preselection of AML patients with better responsiveness to TRAIL. Here, we investigated the critical role of tumor protein p53 inducible nuclear protein 2 (TP53INP2) in the AML cell response to TRAIL treatment. Methods First, the relationship between TP53INP2 and the sensitivity of AML cells to TRAIL was determined by bioinformatics analysis of Cancer Cell Line Encyclopedia datasets, Cell Counting Kit-8 assays, flow cytometry (FCM) and cell line-derived xenograft (CDX) mouse models. Second, the mechanisms by which TP53INP2 participates in the response to TRAIL were analyzed by Western blot, ubiquitination, coimmunoprecipitation and immunofluorescence assays. Finally, the effect of TRAIL alone or in combination with the BCL-2 inhibitor venetoclax (VEN) on cell survival was explored using colony formation and FCM assays, and the effect on leukemogenesis was further investigated in a patient-derived xenograft (PDX) mouse model. Results AML cells with high TP53INP2 expression were more sensitive to TRAIL in vitro and in vivo. Gain- and loss-of-function studies demonstrated that TP53INP2 significantly enhanced TRAIL-induced apoptosis, especially in AML cells with nucleophosmin 1 (NPM1) mutations. Mechanistically, cytoplasmic TP53INP2 maintained by mutant NPM1 functions as a scaffold bridging the ubiquitin ligase TRAF6 to caspase-8 (CASP 8), thereby promoting the ubiquitination and activation of the CASP 8 pathway. More importantly, simultaneously stimulating extrinsic and intrinsic apoptosis signaling pathways with TRAIL and VEN showed strong synergistic antileukemic activity in AML cells with high levels of TP53INP2. Conclusion Our findings revealed that TP53INP2 is a predictor of responsiveness to TRAIL treatment and supported a potentially individualized therapeutic strategy for TP53INP2-positive AML patients.

If it is desired to experimentally verify the regularity in the effects of air-voids on the properties of concrete, methods of altering voids must be relied on. Consequently, this research explored a method that reduced the curing air pressure after mixing concrete so as to modify air-void characteristics. In addition, in order to avoid introducing variables besides air-voids, a limit was placed on the duration of low-pressure maintenance, which was restoring the air pressure to atmospheric pressure after the formation of the concrete's air pressure transient resistant strength. The results showed that if the reduction in air pressure was insufficient, the differential pressure between the inside and outside of the original bubbles was not enough to cause them to break through energy barriers resulting in expansion. Only bubble regeneration due to the decrease in gas solubility was observed. When the differential pressure exceeded the energy barriers, bubble expansion could be achieved. In addition, it was possible to achieve the air pressure transient resistant strength in short time, which was achieved in only 7 h for the concrete used in this paper. Water loss calculation, X-ray diffraction, thermogravimetry-derivate thermogravimetry, scanning electron microscope, and mercury intrusion porosimetry were used to evaluate the hydration of the concrete confirming that the low-air pressure curing of 7 h had almost no effect on hydration. The method proposed can provide an effective means of specimen preparation for scientific research involving the effects of air-voids on the properties of concrete.

Abstract Background Gamma-glutamyltransferase 5 (GGT5), one of the two members in the GGT family (GGT1 and GGT5), plays a crucial role in oxidative regulation, inflammation promotion, and drug metabolism. Particularly in the tumorigenesis of various cancers, its significance has been recognized. Nevertheless, GGT5’s role in gastric cancer (GC) remains ambiguous. This study delves into the function and prognostic significance of GGT5 in GC through a series of in vitro experiments. Methods Employing online bioinformatics analysis tools such as The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Kaplan–Meier plotter, and cBioPortal, we explored GGT5 characteristics and functions in GC. This encompassed aberrant expression, prognostic value, genomic alterations and mutations, immune cell infiltration, and associated signaling pathways. Immunohistochemistry was conducted to assess GGT5 expression in GC and adjacent normal tissues. Subsequently, univariate and multivariate logistic regression analyses were applied to investigate the associations between GGT5 and clinical characteristics. CCK8, wound healing, and migration assays were utilized to evaluate the impact of GGT5 on cell viability and migration. Additionally, Gene Set Enrichment Analysis (GSEA) and Western blot analysis were performed to scrutinize the activity of the epithelial–mesenchymal transformation (EMT) signaling pathway under GGT5 regulation. Results GGT5 exhibits upregulation in gastric cancer, with its overexpression significantly linked to histological differentiation in GC patients (P

Abstract Background Manual therapy (MT) is frequently used in combination with management of osteoarthritis of the knee, but there is no consensus on the exact efficacy of this treatment strategy. The purpose of this systematic review and meta-analysis was to evaluate the pain relief and safety of MT for treatment of knee osteoarthritis (KOA). Methods Randomized controlled trials evaluating MT in patients with KOA in major English and Chinese journals were searched in the following databases: Wanfang, China Science and Technology Journal Database (VIP database), China National Knowledge Infrastructure (CNKI), PubMed, Embase, Web of Science, and the Cochrane Library databases through June 2023. The methodological quality and quality of evidence of the included studies were assessed using Cochrane’s risk-of-bias 2 (ROB 2) tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. Data analysis was performed using Stata version 15.0 software. After use of Galbraith plots to exclude studies that could lead to heterogeneity, random effects models were used to analyze the remaining data and test the consistency of the findings. We used meta-regression to assess the effect of treatment period, patient age, and sex ratio on outcomes. Funnel plots and Egger’s test were used to evaluate publication bias. Sensitivity analyses were used to determine the reliability of the results. Results A total of 25 studies, with 2376 participants, were included in this review. The overall methodological quality of the included studies was limited. Our findings suggest that MT has a positive impact on pain relief outcomes in KOA patients. The meta-analysis showed that MT was superior to usual care (SMD = 2.04, 95% CI 0.94, 3.14, I 2 = 96.3%; low evidence quality) and exercise (SMD = 1.56, 95% CI 0.41, 2.71, I 2 = 96.3%; low evidence quality) for reducing pain. In terms of improvement in visual analogue scale (VAS) scores, MT treatment beyond 4 weeks (SMD = 1.56, 95% CI 0.41, 2.71, I 2 = 96.3%) may be superior to treatments less than or equal to 4 weeks (SMD = 1.24, 95% CI 0.56, 1.95, I 2 = 94.7%). No serious adverse events associated with MT were reported. Conclusions MT may be effective at reducing pain in patients with KOA and may be more effective after a 4-week treatment period. Compared with usual care and exercise therapy, MT may be superior at reducing KOA pain in the short term (9 weeks), but its long-term efficacy requires careful consideration of evidence-based outcomes. MT appears to be safe for KOA patients, though clinicians should inform patients of the potential risk of MT-related adverse events.

Abstract Background Accurate and efficient cell grouping is essential for analyzing single-cell transcriptome sequencing (scRNA-seq) data. However, the existing clustering techniques often struggle to provide timely and accurate cell type groupings when dealing with datasets with large-scale or imbalanced cell types. Therefore, there is a need for improved methods that can handle the increasing size of scRNA-seq datasets while maintaining high accuracy and efficiency. Methods We propose CDSKNNXMBD (Community Detection based on a Stable K-Nearest Neighbor Graph Structure), a novel single-cell clustering framework integrating partition clustering algorithm and community detection algorithm, which achieves accurate and fast cell type grouping by finding a stable graph structure. Results We evaluated the effectiveness of our approach by analyzing 15 tissues from the human fetal atlas. Compared to existing methods, CDSKNN effectively counteracts the high imbalance in single-cell data, enabling effective clustering. Furthermore, we conducted comparisons across multiple single-cell datasets from different studies and sequencing techniques. CDSKNN is of high applicability and robustness, and capable of balancing the complexities of across diverse types of data. Most importantly, CDSKNN exhibits higher operational efficiency on datasets at the million-cell scale, requiring an average of only 6.33 min for clustering 1.46 million single cells, saving 33.3% to 99% of running time compared to those of existing methods. Conclusions The CDSKNN is a flexible, resilient, and promising clustering tool that is particularly suitable for clustering imbalanced data and demonstrates high efficiency on large-scale scRNA-seq datasets.

Background The authors aimed to elucidate the relationship between latest ischemic event and the incidence of subsequent ischemic stroke in patients with symptomatic artery occlusion. Methods and Results We analyzed the association between qualifying event—the latest ischemic event (transient ischemic attack [TIA] or stroke)—and the incidence of ipsilateral ischemic stroke in patients with symptomatic artery occlusion treated with medical therapy alone in CMOSS (Carotid or Middle Cerebral Artery Occlusion Surgery Study). The incidence of CMOSS primary outcomes, including any stroke or death within 30 days after randomization or ipsilateral ischemic stroke between 30 days and 2 years, between the bypass surgical and medical groups, stratified by qualifying events, was also compared. Of the 165 patients treated with medical therapy alone, 75 had a TIA and 90 had a stroke as their qualifying event. The incidence of ipsilateral ischemic stroke did not significantly differ between patients with a TIA and those with a stroke as their qualifying event (13.3% versus 6.7%, P=0.17). In multivariate analysis, the qualifying event was not associated with the incidence of ipsilateral ischemic stroke. There were no significant differences in the CMOSS primary outcomes between the surgical and medical groups, regardless of the qualifying event being TIA (10.1% versus 12.2%, P=0.86) or stroke (6.7% versus 8.9%, P=0.55). Conclusions Among patients with symptomatic artery occlusion and hemodynamic insufficiency, the risk of subsequent ipsilateral ischemic stroke does not appear to be lower in patients presenting with a TIA compared with those with a stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01758614.

The crystalline agents can be used to improve the concrete frost resistance by its densification effect on the microstructure of concrete, while the effect of which depends on the type and penetration process of the crystalline agents. This study, therefore, aimed to investigate the effect of two types of crystalline materials, in terms of organic and inorganic one, and two kinds of penetration methods including surface coating and soaking, in concrete. In addition to freeze-thaw test and electric flux test, the thermal gravity analysis, mercury intrusion porosimetry and scanning electron microscope were carried out. The results showed that after vacuum drying and soaking treatment, the material’s penetration depth has reached 7 mm. Deeper penetration depth shifted the freeze-thaw failure mode sudden to gradual, significantly enhancing frost resistance as a result. Among them, organic crystalline agent increased frost resistance by 2.5 times and decreased electrical flux by approximately 90 %, while inorganic crystalline agent only enhanced frost resistance by 1.5 times and reduced electrical flux by only about 37 %. From a reaction mechanism perspective, the hydrophobic layer within the pores formed by organic crystalline material has the most contribution, in which the needle-like substances generated by inorganic one filled the pores with limited effect to barrier water.

Abstract Ruthenium (Ru) is a promising electrocatalyst for the hydrogen evolution reaction (HER), despite suffering from low activity in non‐acidic conditions due to the high kinetic energy barrier of H2O dissociation. Herein, the synthesis of carbon nanosheet‐supported RuP/Ru heterostructures (RuP/Ru@CNS) from a natural polysaccharide is reported and demonstrates its behavior as an effective HER electrocatalyst in non‐acidic conditions. The RuP/Ru@CNS exhibits low overpotential (106 mV at 200 mA·cm−2) in alkaline electrolyte, exceeding most reported Ru‐based electrocatalysts. The electron shuttling between Ru atoms at the RuP/Ru interface results in a lowered energy barrier for H2O dissociation by electron‐deficient Ru atoms in the pure Ru phase, as well as optimized H* adsorption of electron‐gaining Ru atoms in the neighboring RuP. A low H* spillover energy barrier between Ru atoms at the RuP/Ru interface further boosts HER kinetics. This study demonstrates a sustainable method for the fabrication of efficient Ru‐based electrocatalysts and provides a more detailed understanding of interface effects in HER catalysis.

Background: Doxorubicin (DOX) is a chemotherapeutic drug, while its clinical use is greatly limited by the life-threatening cardiotoxicity. N6-methyladenosine (m6A) RNA modification participates in varieties of cellular processes. Nonetheless, it remains elusive whether m6A modification and its methyltransferase METTL3 are involved in the progression of DOX-induced cardiotoxicity (DIC). Methods: Mice were administrated with DOX (accumulative dosage of 20 mg/kg) repeatedly to establish a chronic DIC model. Cardiomyocyte-specific conditional METTL3 knockout mice were employed to evaluate the effects of altered m6A RNA modification on DIC. The effects of METTL3 on cardiomyocyte ferroptosis were also examined in response to DOX stimulation. Results: DOX led to increased levels in m6A modification and METTL3 expression in cardiomyocytes in a c-Jun-dependent manner. METTL3-knockout mice exhibited improved cardiac function, remodeling and injury following DOX insult. Besides, inhibition of METTL3 alleviated DOX-induced iron accumulation and ferroptosis in cardiomyocytes, whereas METTL3 overexpression exerted the opposite effects. Mechanistically, METTL3 promoted m6A modification of TFRC mRNA, a critical gene governing iron uptake, and enhanced its stability through recognition of the m6A reader protein, IGF2BP2. Moreover, pharmacological administration of a highly selective METTL3 inhibitor STM2457 effectively ameliorated DIC in mice. Conclusion: METTL3 plays a cardinal role in the etiology of DIC by regulating cardiac iron metabolism and ferroptosis through TFRC m6A modification. Inhibition of METTL3 might be a potential therapeutic avenue for DIC.

Abstract Dysregulated circular RNAs (circRNAs) contribute to tumourigenesis and cancer progression. However, the expression patterns and biological functions of circRNAs in colorectal cancer (CRC) remain elusive. Here, RNA sequencing and bioinformatics analyses are applied to screen for aberrantly expressed circRNAs. The expression of circFBXW4 in CRC tissues and cell lines is determined by quantitative real‐time PCR. A series of in vitro and in vivo biological function assays are implemented to assess the functions of circFBXW4. The regulatory mechanisms linking circFBXW4, miR‐338‐5p, and SLC5A7 are explored by western blotting, dual luciferase reporter assays, and RNA pull‐down assays. CircFBXW4 is dramatically downregulated in CRC tissues and cell lines. circFBXW4 downregulation is clearly correlated with malignant features and patient overall survival in CRC. Functionally, ectopic expression of circFBXW4 strikingly impairs the proliferation, migration, and invasion capacities of CRC cells in vitro and in vivo, whereas circFBXW4 knockdown has the opposite effects. Mechanistically, circFBXW4 competitively binds to miR‐338‐5p and prevents it from interacting with and repressing its target SLC5A7, thus suppressing the progression of CRC. This study reveals the specific critical role of circFBXW4 in inhibiting CRC progression via the miR‐338‐5p/SLC5A7 axis and provides an additional target for eradicating CRC.

ABSTRACT Through a long-term micro-area positioning experiment (2006-2017), the precise fertilization locations of spring maize (Zea mays L.) in Jilin, China, were investigated using an embedded cement bucket pot. The effects of different fertilization placements and additional application of organic manure on maize yield, biomass, grain nutrient uptake, and soil fertility were examined. Six treatments were designed: base fertilizer + topdressing shallow application (BF1TD1); base fertilizer deep + topdressing shallow application (BF2TD1); base fertilizer + topdressing deep application (BF1TD2); base fertilizer deep + topdressing deep application (BF2TD2); base fertilizer + topdressing + organic manure shallow application (BF1TD1 + OS); and base fertilizer + topdressing shallow application + organic manure deep application (BF1TD1 + OD). After 12 years of continuous experimentation, the findings revealed that BF2TD2, BF1TD1 + OS, and BF1TD1 + OD exhibited 10.59 %, 25.17 %, and 29.34 % higher average yields than BF1TD1, respectively. Deep topdressing was more beneficial in increasing maize yield and nutrient accumulation, and additionally, increasing the use of organic fertilizer enhanced plant biomass and nutrient uptake. Over the 12 years considered, the soil organic matter in the 0-20 cm and 20-40 cm layers increased by 45.96 % and 80.61 %, respectively, and the soil pH increased from 0.38 to 0.48. In general, the deep application of organic manure was more beneficial for soil retention as it can increase soil fertility in the 0-40 cm layer. Considering the high yield and nutrient absorption and utilization of maize, technical advancement for soil fertilizer in whole-field tillage layers was crucial.

Abstract Background Couples with balanced chromosome rearrangement (BCR) are at high risk of recurrent miscarriages or birth defects due to chromosomally abnormal embryos. This study aimed to provide real-world evidence of the euploidy rate of blastocysts from couples with BCR using preimplantation genetic testing (PGT) and to guide pretesting genetic counselling. Methods A continuous four-year PGT data from couples with BCR were retrospectively analyzed. Biopsied trophectoderm cells were amplified using whole genome amplification, and next-generation sequencing was performed to detect the chromosomal numerical and segmental aberrations. Clinical data and molecular genetic testing results were analyzed and compared among the subgroups. Results A total of 1571 PGT cycles with 5942 blastocysts were performed chromosomal numerical and segmental aberrations detection during the four years. Of them, 1034 PGT cycles with 4129 blastocysts for BCR couples were included; 68.96% (713/1034) PGT cycles had transferable euploid embryos. The total euploidy rate of blastocysts in couples carrying the BCR was 35.29% (1457/4129). Couples with complex BCR had euploid blastocyst rates similar to those of couples with non-complex BCR (46.15% vs. 35.18%, P > 0.05). Chromosome inversion had the highest chance of obtaining a euploid blastocyst (57.27%), followed by Robertsonian translocation (RobT) (46.06%), and the lowest in reciprocal translocation (RecT) (30.11%) (P 0.05). RecT had the highest proportion of blastocysts with translocated chromosome-associated abnormalities (74.23%, 1527/2057), followed by RobT (54.60%, 273/500) and inversion (30.85%, 29/94) (P

Introduction: Myocardial injury is a serious complication in sepsis with high mortality. Zero-valent iron nanoparticles (nanoFe) displayed novel roles in cecal ligation and puncture (CLP)-induced septic mouse model. Nonetheless, its high reactivity makes it difficult for long-term storage. Objectives: To overcome the obstacle and improve therapeutic efficiency, a surface passivation of nanoFe was designed using sodium sulfide. Methods: We prepared iron sulfide nanoclusters and constructed CLP mouse models. Then the effect of sulfide-modified nanoscale zero-valent iron (S-nanoFe) on the survival rate, blood routine parameters, blood biochemical parameters, cardiac function, and pathological indicators of myocardium was observed. RNA-seq was used to further explore the comprehensive protective mechanisms of S-nanoFe. Finally, the stability of S-nanoFe-1d and S-nanoFe-30 d, together with the therapeutic efficacy of sepsis between S-nanoFe and nanoFe was compared. Results: The results revealed that S-nanoFe significantly inhibited the growth of bacteria and exerted a protective role against septic myocardial injury. S-nanoFe treatment activated AMPK signaling and ameliorated several CLP-induced pathological processes including myocardial inflammation, oxidative stress, mitochondrial dysfunction. RNA-seq analysis further clarified the comprehensive myocardial protective mechanisms of S-nanoFe against septic injury. Importantly, S-nanoFe had a good stability and a comparable protective efficacy to nanoFe. Conclusions: The surface vulcanization strategy for nanoFe has a significant protective role against sepsis and septic myocardial injury. This study provides an alternative strategy for overcoming sepsis and septic myocardial injury and opens up possibilities for the development of nanoparticle in infectious diseases.

Introduction: Liver fibrosis is a life-threatening pathological anomaly which usually evolves into advanced liver cirrhosis and hepatocellular carcinoma although limited therapeutic option is readily available. FUN14 domain containing 1 (FUNDC1) is a mitophagy receptor with little information in liver fibrosis. Objective: This study was designed to examine the role for FUNDC1 in carbon tetrachloride (CCl4)-induced liver injury. Methods: GEO database analysis and subsequent validation of biological processes including western blot, immunofluorescence, and co-immunoprecipitation were applied to clarify the regulatory role of FUNDC1 on mitophagy and ferroptosis. Results: Our data revealed elevated FUNDC1 levels in liver tissues of patients with liver fibrotic injury and CCl4-challenged mice. FUNDC1 deletion protected against CCl4-induced hepatic anomalies in mice. Moreover, FUNDC1 deletion ameliorated CCl4-induced ferroptosis in vivo and in vitro. Mechanically, FUNDC1 interacted with glutathione peroxidase (GPx4), a selenoenzyme to neutralize lipid hydroperoxides and ferroptosis, via its 96–133 amino acid domain to facilitate GPx4 recruitment into mitochondria from cytoplasm. GPx4 entered mitochondria through mitochondrial protein import system-the translocase of outer membrane/translocase of inner membrane (TOM/TIM) complex, prior to degradation of GPx4 mainly through mitophagy along with ROS-induced damaged mitochondria, resulting in hepatocyte ferroptosis. Conclusion: Taken together, our data favored that FUNDC1 promoted hepatocyte injury through GPx4 binding to facilitate its mitochondrial translocation through TOM/TIM complex, where GPx4 was degraded by mitophagy to trigger ferroptosis. Targeting FUNDC1 may be a promising therapeutic approach for liver fibrosis.

Clinical application of doxorubicin (DOX) is heavily hindered by DOX cardiotoxicity. Several theories were postulated for DOX cardiotoxicity including DNA damage and DNA damage response (DDR), although the mechanism(s) involved remains to be elucidated. This study evaluated the potential role of TBC domain family member 15 (TBC1D15) in DOX cardiotoxicity. Tamoxifen-induced cardiac-specific Tbc1d15 knockout (Tbc1d15CKO) or Tbc1d15 knockin (Tbc1d15CKI) male mice were challenged with a single dose of DOX prior to cardiac assessment 1 week or 4 weeks following DOX challenge. Adenoviruses encoding TBC1D15 or containing shRNA targeting Tbc1d15 were used for Tbc1d15 overexpression or knockdown in isolated primary mouse cardiomyocytes. Our results revealed that DOX evoked upregulation of TBC1D15 with compromised myocardial function and overt mortality, the effects of which were ameliorated and accentuated by Tbc1d15 deletion and Tbc1d15 overexpression, respectively. DOX overtly evoked apoptotic cell death, the effect of which was alleviated and exacerbated by Tbc1d15 knockout and overexpression, respectively. Meanwhile, DOX provoked mitochondrial membrane potential collapse, oxidative stress and DNA damage, the effects of which were mitigated and exacerbated by Tbc1d15 knockdown and overexpression, respectively. Further scrutiny revealed that TBC1D15 fostered cytosolic accumulation of the cardinal DDR element DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Liquid chromatography–tandem mass spectrometry and co-immunoprecipitation denoted an interaction between TBC1D15 and DNA-PKcs at the segment 594–624 of TBC1D15. Moreover, overexpression of TBC1D15 mutant (∆594–624, deletion of segment 594–624) failed to elicit accentuation of DOX-induced cytosolic retention of DNA-PKcs, DNA damage and cardiomyocyte apoptosis by TBC1D15 wild type. However, Tbc1d15 deletion ameliorated DOX-induced cardiomyocyte contractile anomalies, apoptosis, mitochondrial anomalies, DNA damage and cytosolic DNA-PKcs accumulation, which were canceled off by DNA-PKcs inhibition or ATM activation. Taken together, our findings denoted a pivotal role for TBC1D15 in DOX-induced DNA damage, mitochondrial injury, and apoptosis possibly through binding with DNA-PKcs and thus gate-keeping its cytosolic retention, a route to accentuation of cardiac contractile dysfunction in DOX-induced cardiotoxicity.

Abstract Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet β-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.

Aims: Heart failure with preserved ejection fraction (HFpEF) is a devastating health issue although limited knowledge is available for its pathogenesis and therapeutics. Given the perceived involvement of mitochondrial dysfunction in HFpEF, this study was designed to examine the role of mitochondrial dynamics in the etiology of HFpEF. Method and results: Adult mice were placed on a high fat diet plus l-NAME in drinking water (‘two-hit’ challenge to mimic obesity and hypertension) for 15 consecutive weeks. Mass spectrometry revealed pronounced changes in mitochondrial fission protein Drp1 and E3 ligase FBXL4 in ‘two-hit’ mouse hearts. Transfection of FBXL4 rescued against HFpEF-compromised diastolic function, cardiac geometry, and mitochondrial integrity without affecting systolic performance, in conjunction with altered mitochondrial dynamics and integrity (hyperactivation of Drp1 and unchecked fission). Mass spectrometry and co-IP analyses unveiled an interaction between FBXL4 and Drp1 to foster ubiquitination and degradation of Drp1. Truncated mutants of FBXL4 (Delta-Fbox) disengaged interaction between FBXL4 and Drp1. Metabolomic and proteomics findings identified deranged fatty acid and glucose metabolism in HFpEF patients and mice. A cellular model was established with concurrent exposure of high glucose and palmitic acid as a ‘double-damage’ insult to mimic diastolic anomalies in HFpEF. Transfection of FBXL4 mitigated ‘double-damage’-induced cardiomyocyte diastolic dysfunction and mitochondrial injury, the effects were abolished and mimicked by Drp1 knock-in and knock-out, respectively. HFpEF downregulated sarco(endo)plasmic reticulum (SR) Ca2+ uptake protein SERCA2a while upregulating phospholamban, RYR1, IP3R1, IP3R3 and Na+-Ca2+ exchanger with unaltered SR Ca2+ load. FBXL4 ablated ‘two-hit’ or ‘double-damage’-induced changes in SERCA2a, phospholamban and mitochondrial injury. Conclusion: FBXL4 rescued against HFpEF-induced cardiac remodeling, diastolic dysfunction, and mitochondrial injury through reverting hyperactivation of Drp1-mediated mitochondrial fission, underscoring the therapeutic promises of FBXL4 in HFpEF.

Abstract Background Structural rearrangements in highly repetitive heterochromatin regions can result in miscarriage or foetal malformations; however, detecting and preventing the transmission of these rearrangements has been challenging. Recently, the completion of sequencing of the complete human genome (T2T‐CHM13) has made it possible to accurately characterise structural rearrangements in these regions. We developed a method based on T2T‐CHM13 and nanopore sequencing to detect and block structural rearrangements in highly repetitive heterochromatin sequences. Methods T2T‐CHM13‐based “Mapping Allele with Resolved Carrier Status” was performed for couples who carry structural rearrangements in heterochromatin regions. Using nanopore sequencing and the T2T‐CHM13 reference genome, the precise breakpoints of inversions and translocations close to the centromere were detected and haplotypes were constructed using flanking single‐nucleotide polymorphisms (SNPs). Haplotype linkage analysis was then performed by comparing consistent parental SNPs with embryonic SNPs to determine whether the embryos carried hereditary inversions or balanced translocations. Based on copy number variation and haplotype linkage analysis, we transplanted normal embryos, which were further verified by an amniotic fluid test. Results To validate this approach, we used nanopore sequencing of families with inversions and reciprocal translocations close to the centromere. Using the T2T‐CHM13 reference genome, we accurately detected inversions and translocations in centromeres, constructed haplotypes and prevented the transmission of structural rearrangements in the offspring. Conclusions This study represents the first successful application of T2T‐CHM13 in human reproduction and provides a feasible protocol for detecting and preventing the transmission of structural rearrangements of heterochromatin in embryos.

ObjectiveThere is currently no non-invasive examination that can fully determine the diagnosis of osteomyelitis. SPECT/CT tomographic fusion imaging can provide both local metabolic activity and anatomical information to determine the condition and location. This study evaluates the diagnostic efficacy of 99mTc-MDP SPECT/CT in bone infections, compared to MRI.MethodsIn this multicenter retrospective study, 363 patients with suspected bone and joint infections or osteomyelitis were included. Participants underwent 99mTc-MDP SPECT/CT and/or MRI examinations, supplemented by pathogenic bacterial cultures and histopathological analysis.ResultsOnly SPECT/CT was tested in 169 patients, and only MRI was used in 116. 78 people have implemented both inspections and have detailed information. The diagnostic sensitivity and specificity of SPECT/CT for infection were 96% and 92% respectively, with an accuracy of 96%. For MRI, these figures were 88%, 84%, and 87% respectively.ConclusionThis represents the largest global study to date evaluating osteomyelitis and bone infection diagnosis using 99mTc-MDP SPECT/CT tomographic fusion imaging. The findings indicate that 99mTc-MDP SPECT/CT fusion imaging offers superior diagnostic accuracy compared to MRI. This is particularly evident in cases involving metallic implants and chronic infections. 99mTc-MDP SPECT/CT fusion imaging emerges as a highly suitable non-invasive diagnostic modality, facilitating enhanced clinical follow-up and treatment.

Background: Primary angle closure glaucoma (PACG) is the leading cause of irreversible blindness in Asia, and no reliable, effective diagnostic, and predictive biomarkers are used in clinical routines. A growing body of evidence shows metabolic alterations in patients with glaucoma. We aimed to develop and validate potential metabolite biomarkers to diagnose and predict the visual field progression of PACG. Methods: Here, we used a five-phase (discovery phase, validation phase 1, validation phase 2, supplementary phase, and cohort phase) multicenter (EENT hospital, Shanghai Xuhui Central Hospital), cross-sectional, prospective cohort study designed to perform widely targeted metabolomics and chemiluminescence immunoassay to determine candidate biomarkers. Five machine learning (random forest, support vector machine, lasso, K-nearest neighbor, and GaussianNaive Bayes [NB]) approaches were used to identify an optimal algorithm. The discrimination ability was evaluated using the area under the receiver operating characteristic curve (AUC). Calibration was assessed by Hosmer-Lemeshow tests and calibration plots. Results: Studied serum samples were collected from 616 participants, and 1464 metabolites were identified. Machine learning algorithm determines that androstenedione exhibited excellent discrimination and acceptable calibration in discriminating PACG across the discovery phase (discovery set 1, AUCs=1.0 [95% CI, 1.00–1.00]; discovery set 2, AUCs = 0.85 [95% CI, 0.80–0.90]) and validation phases (internal validation, AUCs = 0.86 [95% CI, 0.81–0.91]; external validation, AUCs = 0.87 [95% CI, 0.80–0.95]). Androstenedione also exhibited a higher AUC (0.92–0.98) to discriminate the severity of PACG. In the supplemental phase, serum androstenedione levels were consistent with those in aqueous humor (r=0.82, p=0.038) and significantly (p=0.021) decreased after treatment. Further, cohort phase demonstrates that higher baseline androstenedione levels (hazard ratio = 2.71 [95% CI: 1.199–6.104], p=0.017) were associated with faster visual field progression. Conclusions: Our study identifies serum androstenedione as a potential biomarker for diagnosing PACG and indicating visual field progression. Funding: This work was supported by Youth Medical Talents – Clinical Laboratory Practitioner Program (2022-65), the National Natural Science Foundation of China (82302582), Shanghai Municipal Health Commission Project (20224Y0317), and Higher Education Industry-Academic-Research Innovation Fund of China (2023JQ006).

Abstract Backgrounds The novel concept of microwave dynamic therapy (MDT) solves the problem of incomplete tumor eradication caused by non-selective heating and uneven temperature distribution of microwave thermal therapy (MWTT) in clinic, but the poor delivery of microwave sensitizer and the obstacle of tumor hypoxic microenvironment limit the effectiveness of MDT. Results Herein, we engineer a liquid metal-based nanozyme LM@ZIF@HA (LZH) with eutectic Gallium Indium (EGaIn) as the core, which is coated with CoNi-bimetallic zeolite imidazole framework (ZIF) and hyaluronic acid (HA). The flexibility of the liquid metal and the targeting of HA enable the nanozyme to be effectively endocytosed by tumor cells, solving the problem of poor delivery of microwave sensitizers. Due to the catalase-like activity, the nanozyme catalyze excess H2O2 in the tumor microenvironment to generate O2, alleviating the restriction of the tumor hypoxic microenvironment and promoting the production of ROS under microwave irradiation. In vitro cell experiments, the nanozyme has remarkable targeting effect, oxygen production capacity, and microwave dynamic effect, which effectively solves the defects of MDT. In the constructed patient-derived xenograft (PDX) model, the nanozyme achieves excellent MDT effect, despite the heterogeneity and complexity of the tumor model that is similar to the histological and pathological features of the patient. The tumor volume in the LZH + MW group is only about 1/20 of that in the control group, and the tumor inhibition rate is as high as 95%. Conclusion The synthesized nanozyme effectively solves the defects of MDT, improves the targeted delivery of microwave sensitizers while regulating the hypoxic microenvironment of tumors, and achieves excellent MDT effect in the constructed PDX model, providing a new strategy for clinical cancer treatment.

Abstract Background There is no consensus on the optimal reconstruction technique after proximal gastrectomy. The purpose of this study was to retrospectively compare the surgical outcomes among esophagogastrostomy (EG) anastomosis, gastric tube (GT) reconstruction and double-tract (DT) reconstruction in patients who underwent laparoscopic proximal gastrectomy (LPG) to clarify the superior reconstruction method. Methods This study enrolled 164 patients who underwent LPG at the Northern Jiangsu People's Hospital in Jiangsu between January 2017 to January 2022 (EG: 51 patients; GT: 77 patients; DT: 36 patients). We compared the clinical and pathological characteristics, surgical features, postoperative complications, nutritional status, and quality of life (QOL) among the above three groups. Results Mean operative time was longer with the DT group than the remaining two groups (p = 0.001). With regard to postoperative complications, considerable differences in the postoperative reflux symptoms (p = 0.042) and reflux esophagitis (p = 0.040) among the three groups were found. For the nutritional status, total protein, hemoglobin and albumin reduction rates in the GT group were significantly higher than the other two groups at 12 months postoperatively. In the PGSAS-45, three assessment items were better in the DT group significantly compared with the esophageal reflux subscale (p = 0.047, Cohen’s d = 0.44), dissatisfaction at the meal (p = 0.009, Cohen’s d = 0.58), and dissatisfaction for daily life subscale (p = 0.012, Cohen’s d = 0.56). Conclusions DT after LPG is a valuable reconstruction technique with satisfactory surgical outcomes, especially regarding reduced reflux symptoms, improving the postoperative nutritional status and QOL.

Abstract Abnormal alternative splicing (AS) caused by alterations in spliceosomal factors is implicated in cancers. Standard models posit that splice site selection is mainly determined by early spliceosomal U1 and U2 snRNPs. Whether and how other mid/late-acting spliceosome components such as USP39 modulate tumorigenic splice site choice remains largely elusive. We observed that hepatocyte-specific overexpression of USP39 promoted hepatocarcinogenesis and potently regulated splice site selection in transgenic mice. In human liver cancer cells, USP39 promoted tumor proliferation in a spliceosome-dependent manner. USP39 depletion deregulated hundreds of AS events, including the oncogenic splice-switching of KANK2. Mechanistically, we developed a novel RBP-motif enrichment analysis and found that USP39 modulated exon inclusion/exclusion by interacting with SRSF6/HNRNPC in both humans and mice. Our data represented a paradigm for the control of splice site selection by mid/late-acting spliceosome proteins and their interacting RBPs. USP39 and possibly other mid/late-acting spliceosome proteins may represent potential prognostic biomarkers and targets for cancer therapy.

Objective: Joint stiffness results from the coupling of the nervous system and joint mechanics, and thus stiffness is a comprehensive representation of joint stability. It has been reported that moxibustion can alleviate general weakness and fatigue symptoms and subsequently may influence joint stiffness. This study investigated whether moxibustion could enhance knee joint stiffness in recreational athletes pre- and post-fatigue. Methods: Eighteen participants were randomized into intervention (5 males: 20.6 ± 1.5 yr; 4 females: 20.8 ± 1.5 yr) and control groups (5 males: 19.4 ± 0.9 yr; 4 females: 20.5 ± 0.6 yr). The intervention group received indirect moxibustion applied to acupoints ST36 (bilateral) and CV4 for 30 min every other day for 4 consecutive weeks. The control group maintained regular exercise without moxibustion. Peak torque (PT) of right knee extensor, relaxed and contracted muscle stiffness (MS) of vastus lateralis, and knee extensor musculoarticular stiffness (MAS) was assessed with an isokinetic dynamometer (IsoMed 2000), myometer, and free oscillation technique, respectively. Measurements were taken at three time points: pre-intervention, post-intervention/pre-fatigue, and post-fatigue. Results: MAS (P = 0.006) and PT (P = 0.007) in the intervention group increased more from pre-to post-intervention compared with the control group. Post-fatigue MAS (P = 0.016) and PT (P = 0.031) increased more in the intervention group than in the control group. Conclusion: Moxibustion enhanced PT and knee MAS, suggesting that this intervention could be used in injury prevention and benefit fatigue resistance in young recreational athletes.

Abstract The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common hereditary disease that causes late-onset renal cyst development and end-stage renal disease. Preimplantation genetic testing for monogenic disease (PGT-M) has emerged as an effective strategy to prevent pathogenic mutation transmission rely on SNP linkage analysis between pedigree members. Yet, it remains challenging to establish reliable PGT-M methods for ADPKD cases or other monogenic diseases with de novo mutations or without a family history. Here we reported the application of long-read sequencing for direct haplotyping in a female patient with de novo PKD1 c.11,526 G > C mutation and successfully established the high-risk haplotype. Together with targeted short-read sequencing of SNPs for the couple and embryos, the carrier status for embryos was identified. A healthy baby was born without the PKD1 pathogenic mutation. Our PGT-M strategy based on long-read sequencing for direct haplotyping combined with targeted SNP haplotype can be widely applied to other monogenic disease carriers with de novo mutation.

The swelling behaviors and water retention of superabsorbent sand-fixing materials prepared from acrylic acid/acrylamide copolymer (AA/AM) and acid-modified attapulgite under ultrasonic treatments and different pH conditions were investigated. The results demonstrated that a suitable amount of attapulgite can effectively improve the absorption capacity and saltwater performance. The superabsorbent achieved the highest absorptions of 1257.54 g/g and 209.45 g/g in distilled water and a 0.9 wt% NaCl solution, and a higher water absorbency occurred over a wide pH range of 5~9 when the ultrasonic power was 200 W and the attapulgite content was 10%. The addition of attapulgite could significantly increase the water absorption and retention.

Cold chain packaging faces high levels of uncertainty due to its complex nature and dynamic environments during transportation, and the importance of safety and risk management. This study aims to propose a risk assessment model for cold chain packaging based on a fuzzy Bayesian Network. A case study on vaccine cold chain shipping containers is conducted for the illustration of the risk management model, and risk factors like container risk, packaging risk, monitoring risk and handling risk, occupational and product safety risk have been identified and assessed. This paper will add new knowledge to the field of cold chain packaging, which still lacks research attention, and will be useful for industry managers to gain a better understand of the dynamics and risks of cold chain packaging.

Background: It has been reported that the human family with sequence similarity 198, member B (Fam198b) play an important role in the occurrence and development of various cancers. Nevertheless, its function in gastric cancer is not completely clear. Hereby, we investigated the function and prognostic value of Fam198b in gastric cancer and further validated the results in gastric cancer through a series of in vitro experiments. Methods: We used R software and online bioinformatics analysis tools-GEPIA2, TIMER2, Kaplan-Meier plotter, cBioPortal, TISIDB COSMIC, and STRING to study the characteristics and functions of Fam198b in GC, such as aberrant expression, prognostic value, genomic alterations, immune microenvironment, anticancer drug sensitivity, and related signaling pathways. In addition, in vitro experiments such as immunohistochemistry (IHC), cell function experiments, and signaling pathway experiments were performed to validate the key conclusions. Result: Fam198b is obviously highly expressed in gastric cancer, and its expression is intensively correlated with tumor prognosis. The etiology of abnormal Fam198b expression was superficially investigated and validated by associating genomic alterations and the immune microenvironment. Furthermore, Fam198b is intensively correlated with the sensitivity of multiple antitumor drugs. It was demonstrated by functional enrichment analysis that Fam198b was linked to myogenesis, angiogenesis, epithelial mesenchymal transition and cytokine binding. It was observed in vitro experiments that knockdown Fam198b could significantly inhibit tumor cell proliferation and migration. These results were reversed when Fam198b was overexpressed. It was validated by signaling pathway experiments that Fam198b promoted gastric cancer progression by up-regulating the PI3K/AKT/BCL-2 signaling pathway. Conclusion: As a novel biomarker to predict GC prognosis and tumor progression, Fam198b is a promising therapeutic target to reverse tumor progression.

Objective: This study aims to analyze a severe adverse reaction of pulmonary fibrosis induced by dronedarone hydrochloride tablets, and to provide a reference for clinical rational medication through drug precautions. Methods: A case of pulmonary fibrosis induced by dronedarone hydrochloride tablets, along with related literature was retrospectively analyzed. Results: Patients over 65 years old with a history of exposure to amiodarone may increase the incidence of pulmonary toxicity induced by dronedarone, and dronedarone should not be selected as a substitute treatment drug for patients with amiodarone-induced pulmonary toxicity. Conclusions: It is recommended that clinicians monitor the diffusion capacity of carbon monoxide and lung ventilation function of patients before and after using dronedarone for treatment. For patients with a history of amiodarone exposure, intermittent monitoring of chest X-rays and lung function is necessary. If lung function decreases, dronedarone should be immediately discontinued.

Identifying the interactions of land use functions (LUFs) is of great significance for alleviating the contradiction between human and land, and promoting sustainable use of land resources. However, few studies concerned the interactions of LUFs in urban agglomerations of ecologically fragile areas in China at a fine scale. In this study, we constructed a quantitative and visualized evaluation system of LUFs that conforms to three primary functions, ten sub-functions, and nineteen indicators of Lanzhou-Xining urban agglomeration (LXUA) in the upper reaches of the Yellow River basin based on the production-living- ecological functions. Then, the comprehensive evaluation method, hot spot analysis, and geographic weighted regression (GWR) model were used to identify the interactions among LUFs and influencing factors of LXUA from 2000 to 2020 at the county and grid scales. The results show that the LXUA is dominated by ecological function (EF), and EF and living function (LF) showing a “U” shaped change feature, while production function (PF) show an inverted “U” shaped change feature. Meanwhile, the cold spots and hot spots of PF and EF present the spatial characteristic of “overall dispersion and local aggregation”, while the LF has no cold spots, and the hot spots present the spatial characteristic of “point-axis”. Moreover, the PF and LF are in a synergistic relationship at two scales, with complementarity in space, while the EF and PF and the PF and LF are both in a trade-offs relationship, with overlap in space. Finally, socioeconomic development factors have remarkable impact on LUFs at the county scale, while LUFs at the grid scale is the comprehensive result of natural conditions, socioeconomic factors, accessibility and political factors. The results can provide references for the LXUA to differentiated design the land use policy, and provide empirical case for other ecologically fragile areas to alleviate the trade-offs of LUFs.

Introduction: Internal fistula across the posterior wall of stomach and the transverse colon caused by foreign bodies in the alimentary tract presents an extremely rare medical entity. Presentation of case: We report an aschizophrenia female patient with onset of internal fistula across the posterior wall of stomach and the transverse colon triggered by swallowed magnetic metal beads. The patient was admitted to the emergency room of Northern Jiangsu People’s Hospital because of acute right lower abdominal pain. Emergency routine abdominal CT scan revealed acute appendicitis and a set of foreign body in digestive tract. Discussion: The foreign body in the stomach was removed by open surgery after tentative Endoscopic foreign body removal and laparoscopic appendectomy and exploration. In the process of exploring the gastric wall, it was found that one of magnet beads was embedded in the posterior wall of stomach and adhered to part of the transverse colon. After separation, it was found that an internal fistula was formed across the posterior wall of stomach and the transverse colon. As the patient ate only a small amount of food within 2 days, and the intestines were in good condition, we performed partial transverse colectomy, end-to-side anastomosis and gastric wall repair. Conclusion: This case shows that for long-term foreign bodies in the digestive tract, we should be beware of the onset of gastrointestinal perforation. Moreover, perforation caused by the force acting on a blunt foreign body often results in atypical imaging findings, and the diagnosis of perforation cannot be clearly determined by imaging findings such as the presence of free gas downstream of the diaphragm. This poses new challenges for clear diagnosis and treatment.

Abstract The accumulation of misfolded and aggregated proteins is a hallmark of neurodegenerative proteinopathies. Although multiple genetic loci have been associated with specific neurodegenerative diseases (NDs), molecular mechanisms that may have a broader relevance for most or all proteinopathies remain poorly resolved. In this study, we developed a multi‐layered network expansion (MLnet) model to predict protein modifiers that are common to a group of diseases and, therefore, may have broader pathophysiological relevance for that group. When applied to the four NDs Alzheimer's disease (AD), Huntington's disease, and spinocerebellar ataxia types 1 and 3, we predicted multiple members of the insulin pathway, including PDK1, Akt1, InR, and sgg (GSK‐3β), as common modifiers. We validated these modifiers with the help of four Drosophila ND models. Further evaluation of Akt1 in human cell‐based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability in all models. Moreover, treatment of AD model mice with SC79 enhanced their long‐term memory and ameliorated dysregulated anxiety levels, which are commonly affected in AD patients. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins involved in the pathophysiology of entire disease groups and identify potential therapeutic targets that have relevance across disease boundaries. MLnet can be used for any group of diseases and is available as a web tool at http://ssbio.cau.ac.kr/software/mlnet.

Indoor PM2.5 pollution is one of the leading causes of death and disease worldwide. As monitoring indoor PM2.5 concentrations on a large scale is challenging, it is urgent to assess population-level exposure and related health risks to develop an easy-to-use and generalized model to predict indoor PM2.5 concentrations and spatiotemporal variations at the global level. Existing machine learning models of indoor PM2.5 are prone to deliver single-point predictions, and their input strategies are not widely applicable. Here, we developed a Bayesian neural network (BNN) model for predicting the distribution of daily average urban residential PM2.5 concentration based on multiple data sources available from nationwide comprehensive sensor-monitoring records in China. The BNN model showed good performance with a 10-fold cross-validation R2 of 0.70, mean-absolute-error of 9.45 μg/m3, root-mean-square error of 13.3 μg/m3, and 95 % prediction interval coverage of 85 %. To demonstrate the application process, this model was applied to predict indoor PM2.5 concentrations on a large spatiotemporal scale. Our modeled population-weighted annual indoor PM2.5 concentration for China in 2019 was 22.8 μg/m3, far exceeding the WHO standard. The validity of the model at the population level can be further bolstered, making it valuable for assessing and managing indoor air pollution-related health risks.

AbstractMechanical high-intensity focused ultrasound (M-HIFU), which includes histotripsy, is a non-ionizing, non-thermal ablation technology that can be delivered by noninvasive methods. Because acoustic cavitation is the primary mechanism of tissue disruption, histotripsy is distinct from the conventional HIFU techniques resulting in hyperthermia and thermal injury. Phase I human trials have shown the initial safety and efficacy of histotripsy in treating patients with malignant liver tumors. In addition to tissue ablation, a promising benefit of M-HIFU has been stimulating a local and systemic antitumor immune response in preclinical models and potentially in the Phase I trial. Preclinical studies combining systemic immune therapies appear promising, but clinical studies of combinations have been complicated by systemic toxicities. Consequently, combining M-HIFU with systemic immunotherapy has been demonstrated in preclinical models and may be testing in future clinical studies. An additional alternative is to combine intratumoral M-HIFU and immunotherapy using microcatheter-placed devices to deliver both M-HIFU and immunotherapy intratumorally. The promise of M-HIFU as a component of anti-cancer therapy is promising, but as forms of HIFU are tested in preclinical and clinical studies, investigators should report not only the parameters of the energy delivered but also details of the preclinical models to enable analysis of the immune responses. Ultimately, as clinical trials continue, clinical responses and immune analysis of patients undergoing M-HIFU including forms of histotripsy will provide opportunities to optimize clinical responses and to optimize application and scheduling of M-HIFU in the context of the multi-modality care of the cancer patient.

Collector probes have been used to examine tungsten divertor leakage in a variety of scenarios with low-Z impurity seeding during operation with the new tungsten-coated SAS-VW divertor in DIII-D. Measurements of tungsten deposition on collector probes inserted into the far Scrape-off-Layer (SOL) are used to deduce how efficiently tungsten leaks out of the closed, V-shaped divertor after it is eroded from the target surfaces. Qualitative differences in the tungsten deposition patterns across the collector probes provide clear experimental evidence that the SOL conditions depend on the low-Z impurity seeding conditions. These measurements show that in scenarios where neon gas is injected into the plasma, the tungsten divertor leakage and SOL transport depend on the poloidal location from which the neon is injected. In particular, neon injection from the Inner Midplane and Outer Midplane appear to each result in higher divertor leakage by a factor of 2 to 3 compared to cases with neon injection from either the SOL Crown or from the SAS-VW divertor itself.

AbstractThe relationship between serum insulin-like growth factor-1 (IGF-1) levels and anemia in patients undergoing maintenance hemodialysis (MHD) remains unclear. This cross-sectional study included patients who underwent MHD treatment for >3 months at our dialysis center in March 2021. Demographic and clinical data were recorded. Blood samples were collected before the hemodialysis sessions, and general serum biochemical parameters, routine blood markers, and serum IGF-1 levels were measured. Patients were divided into a group without anemia (hemoglobin ≥110 g/L) and a group with anemia (hemoglobin

AbstractTo predict the number of casualties in dwellings when a strong earthquake occurs, this paper investigated the seismic performances of masonry buildings located in a rural town where earthquake occurs frequently with high earthquakes. The incremental dynamic analysis method was employed to estimate the available escape time and the collapse probability of building under those selected ground motions with a series of peak accelerations. Meanwhile, the required safety escape time of the building was obtained through evacuation simulation analysis. According to the safe evacuation criteria, the probability of casualties in terms of earthquake intensity measure was predicted. The results show that available escape time decreases with the increase of peak ground acceleration level. While the required safety escape time increases with the number of building layers subjoining; residents on the upper floors have a lower probability of escape. The present work implied that the residents on the higher floors must seek temporary security zones in their rooms to reduce casualties.

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel instigator for mitochondrial dysfunction, and plays an important role in the pathogenesis of cardiovascular diseases. However, the role and mechanism of DNA-PKcs in angiotensin II (Ang II)-induced vascular remodeling remains obscure. Methods: Rat aortic smooth muscle cells (SMC) and VSMC-specific DNA-PKcs knockout (DNA-PKcsΔVSMC) mice were employed to examine the role of DNA-PKcs in vascular remodeling and the underlying mechanisms. Blood pressure of mice was monitored using the tail-cuff and telemetry methods. The role of DNA-PKcs in vascular function was evaluated using vascular relaxation assessment. Results: In the tunica media of remodeled mouse thoracic aortas, and renal arteries from hypertensive patients, elevated DNA-PKcs expression was observed along with its cytoplasmic translocation from nucleus, suggesting a role for DNA-PKcs in vascular remodeling. We then infused wild-type (DNA-PKcsfl/fl) and DNA-PKcsΔVSMC mice with Ang II for 14 days to establish vascular remodeling, and demonstrated that DNA-PKcsΔVSMC mice displayed attenuated vascular remodeling through inhibition of dedifferentiation of VSMCs. Moreover, deletion of DNA-PKcs in VSMCs alleviated Ang II-induced vasodilation dysfunction and hypertension. Mechanistic investigations denoted that Ang II-evoked rises in cytoplasmic DNA-PKcs interacted with dynamin-related protein 1 (Drp1) at its TQ motif to phosphorylate Drp1S616, subsequently promoting mitochondrial fragmentation and dysfunction, as well as reactive oxygen species (ROS) production. Treatment of irbesartan, an Ang II type 1 receptor (AT1R) blocker, downregulated DNA-PKcs expression in VSMCs and aortic tissues following Ang II administration. Conclusion: Our data revealed that cytoplasmic DNA-PKcs in VSMCs accelerated Ang II-induced vascular remodeling by interacting with Drp1 at its TQ motif and phosphorylating Drp1S616 to provoke mitochondrial fragmentation. Maneuvers targeting DNA-PKcs might be a valuable therapeutic option for the treatment of vascular remodeling and hypertension.

Abstract Objective This study aimed to investigate the efficacy of inflammatory markers (NLR, PLR) combined with tumor markers (CA50, CA199, CEA) in the diagnosis of colorectal cancer metastasis by a single-center retrospective study. Methods A total of 1163 CRC patients who received treatments in our hospital from January 2017 to December 2021 were enrolled retrospectively. Patients were grouped according to the absence of metastasis. The separate efficacy of tumor markers, NLR and PLR, was evaluated in the diagnosis of metastasis of colorectal cancer using ROC curve analysis, and their optimal cut-off values for distant metastases from colorectal cancer were determined. The area under the ROC curve (AUC) of the tumor markers combined with NLR and PLR was calculated by binary logistic regression analysis to evaluate the diagnostic efficacy of metastasis of colorectal cancer. In addition, patients were divided into two groups of high and low levels according to the optimal cut-off values, and the effects of NLR, PLR, and tumor markers on distant metastasis of colorectal cancer were evaluated using multiple logistic regression analysis. Result The abnormal rate of CA50, CA199, CEA, NLR, and PLR in two subgroupsIt was statistically significant (P < 0.05). After AUC testifying, the diagnostic efficacy of NLR and PLR was equivalent to that of tumor marker (P > 0.05). In assessment of liver metastasis, peritoneal metastasis, and multiple metastasis, AUC of NLR and PLR with CRC-specific tumor markers showed higher predictive efficacy than AUC without combined NLR nor PLR. The CA50, CA199, CEA, PLR, and NLR were proved independently associated with metastasis using multiple logistic regression analysis (P < 0.05). Conclusion NLR and PLR are noted tumor markers of colorectal cancer, which are characterized by noninvasive, high diagnostic efficacy, easy availability, and low cost. They can be combined with traditional tumor markers to evaluate and diagnose colorectal cancer metastasis by clinicians.

This study investigates the growth dynamics and heavy metal immobilization in Sudan grass cultivated on substrates composed of electrolytic manganese residue (EMR), phosphogypsum, and chili straw biochar. Pot experiments revealed that a substrate with phosphogypsum constituting 75% of the mix hinders Sudan grass seed germination. Compared with sole EMR utilization, the composite substrates notably enhanced plant growth, evidenced by increases in plant height and fresh weight. The integration of these substrates led to a significant elevation in total chlorophyll content (up to 54.39%) and a reduction in malondialdehyde (MDA) levels (up to 21.66%), indicating improved photosynthetic activity and lower oxidative stress. The addition of biochar reduced the content of Zn, Cd, and Mn in the roots of Sudan grass by up to 25.92%, 20.00%, and 43.17%, respectively; and reduced the content of Pb, Mn, and Cr in the shoot by up to 33.72%, 17.53%, and 26.32%, respectively. Fuzzy membership function analysis identified the optimal substrate composition as 75% EMR and 25% phosphogypsum, with 5% chili straw biochar, based on overall performance metrics. This study adopts the concept of “to treat waste with waste”. The approach is to fully consider the fertility characteristics of EMR, phosphogypsum, and biochar, underscoring the potential for utilizing waste-derived materials in cultivating Sudan grass and offering a sustainable approach to plant growth and heavy metal management.

A novel 2PRS-2PSS (P represents the prismatic pair, R represents the revolute hinge, S represents the spherical hinge) compliant parallel micromanipulator with two translational DOFs and two rotational DOFs is presented, and its compliance model and kinetostatic model are sequentially developed and analyzed. Initially, an analytical model used to describe the compliance of this micromanipulator was developed using the compliance matrix method (CMM). Through a comparison with finite element analysis, the accuracy of this analytical model is confirmed, and the influence of various dimensional and structural parameters on the compliance behavior is investigated. Subsequently, the micromanipulator is treated as an equivalent spring system, allowing for the derivation of its governing equation based on the established compliance model. From this equation, a kinetostatic model relating input forces to output displacements is derived. Validation of this model is performed by comparing analytical results with finite element simulations under specific motion trajectories, revealing a maximum relative error of 6.18%. This close agreement verifies the accuracy of the kinetostatic model. Finally, the impact of the parameters of the flexure hinge on the mapping matrix is examined to offer insights into minimizing undesired displacements, providing valuable guidance for optimizing the micromanipulator’s performance.

In order to expand the range of motion performance of the 3-PSS-compliant parallel micro-motion platform, a variable inclination angle of the mechanism’s guide rails was introduced to construct a category of generalized 3-PSS compliant parallel micro-motion platforms with distinct configurations (exhibiting different motion performances) but identical motion patterns (three translational degrees of freedom). The compliance and kinetostatics of such micro-motion platform are modeled and analyzed. Firstly, the compliance model is established based on the coordinate transformation method. Then, simplifying the micro-motion platform into a spring system, the kinetostatic model in terms of input force–output displacement is established based on the compliance model using the compliance matrix method. For practical application considerations, the kinetostatic model in terms of input displacement–output displacement is further derived based on the input force–output displacement model. Then, the correctness of the established compliance model and kinetostatic model is successively verified through finite element simulation. Finally, using two specified motion trajectories (spatial spiral trajectory and planar circular trajectory) as examples, an analysis is conducted on the influence of guide rail inclination angle variations on the kinetostatic performance of the micro-motion platform. This analysis serves as guidance for the rational design of such micro-motion platforms.

This study focuses on addressing the pollution caused by Ni in water. To enhance the removal efficiency of Ni2+, attapulgite (ATP) from Linze County, Gansu Province, China, was used as a carrier to prepare attapulgite loaded with nanoscale zero-valent iron (nZVI@ATP) via a liquid-phase reduction. This approach aims to mitigate the aggregation and oxidation tendencies of nZVI, thereby improving its performance in Ni2+ removal. The results revealed that nZVI@ATP exhibited a mesoporous structure with a specific surface area and an average pore size of 51.79 m2/g and 9.22 nm. Notably, nZVI@ATP showed a remarkably reduced agglomeration phenomenon. In addition, nZVI@ATP demonstrated a considerably more excellent adsorption performance for Ni2+ than raw ATP and pure nZVI, as its highest adsorption capacity was 143.20 mg/g when the iron–ATP ratio was 2:1 (initial concentration: 200 mg/L, initial pH: 5, temperature: 298 K, and dosing amount: 1 g/L). The adsorption of Ni2+ by nZVI@ATP followed the quasi-secondary kinetic model, and the removal rate of Ni2+ was inversely proportional to the initial concentration and directly proportional to the dosage. The adsorption capacity tended to increase and then decrease as the pH increased. The removal mechanism of Ni2+ by nZVI@ATP involved adsorption, reduction, and precipitation, with the significant mechanism being the induced Ni(OH)2 precipitation on the nZVI@ATP surface.