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Abstract Osteoarthritis is a degenerative joint disease with joint pain as the main symptom, caused by fibrosis and loss of articular cartilage. Due to the complexity and heterogeneity of osteoarthritis, there is a lack of effective individualized disease-modifying osteoarthritis drugs in clinical practice. Chondrocyte senescence is reported to participate in occurrence and progression of osteoarthritis. Here we show that small molecule 10-hydroxy-2-decenoic acid suppresses cartilage degeneration and relieves pain in the chondrocytes, cartilage explants from osteoarthritis patients, surgery-induced medial meniscus destabilization or naturally aged male mice. We further confirm that 10-hydroxy-2-decenoic acid exerts a protective effect by targeting the glycosylation site in the Asp_Arg_Hydrox domain of aspartyl β-hydroxylase. Mechanistically, 10-hydroxy-2-decenoic acid alleviate cellular senescence through the ERK/p53/p21 and GSK3β/p16 pathways in the chondrocytes. Our study uncovers that 10-hydroxy-2-decenoic acid modulate cartilage metabolism by targeting aspartyl β-hydroxylase to inhibit chondrocyte senescence in osteoarthritis. 10-hydroxy-2-decenoic acid may be a promising therapeutic drug against osteoarthritis.

This study demonstrates the feasibility and effectiveness of utilizing native soils as a resource for inocula to produce n-caproate through the chain elongation (CE) platform, offering new insights into anaerobic soil processes. The results reveal that all five of the tested soil types exhibit CE activity when supplied with high concentrations of ethanol and acetate, highlighting the suitability of soil as an ideal source for n-caproate production. Compared with anaerobic sludge and pit mud, the native soil CE system exhibited higher selectivity (60.53%), specificity (82.32%), carbon distribution (60.00%), electron transfer efficiency (165.00%), and conductivity (0.59 ms∙cm−1). Kinetic analysis further confirmed the superiority of soil in terms of a shorter lag time and higher yield. A microbial community analysis indicated a positive correlation between the relative abundances of Pseudomonas, Azotobacter, and Clostridium and n-caproate production. Moreover, metagenomics analysis revealed a higher abundance of functional genes in key microbial species, providing direct insights into the pathways involved in n-caproate formation, including in situ CO2 utilization, ethanol oxidation, fatty acid biosynthesis (FAB), and reverse beta-oxidation (RBO). The numerous functions in FAB and RBO are primarily associated with Pseudomonas, Clostridium, Rhodococcus, Stenotrophomonas, and Geobacter, suggesting that these genera may play roles that are involved or associated with the CE process. Overall, this innovative inoculation strategy offers an efficient microbial source for n-caproate production, underscoring the importance of considering CE activity in anaerobic soil microbial ecology and holding potential for significant economic and environmental benefits through soil consortia exploration.

Abstract Semantic segmentation plays a crucial role in interpreting remote sensing images, especially in high-resolution scenarios where finer object details, complex spatial information and texture structures exist. To address the challenge of better extracting semantic information and ad-dressing class imbalance in multiclass segmentation, we propose utilizing diffusion models for remote sensing image semantic segmentation, along with a lightweight classification module based on a spatial-channel attention mechanism. Our approach incorporates unsupervised pretrained components with a classification module to accelerate model convergence. The diffusion model component, built on the UNet architecture, effectively captures multiscale features with rich contextual and edge information from images. The lightweight classification module, which leverages spatial-channel attention, focuses more efficiently on spatial-channel regions with significant feature information. We evaluated our approach using three publicly available datasets: Postdam, GID, and Five Billion Pixels. In the test of three datasets, our method achieved the best results. On the GID dataset, the overall accuracy was 96.99%, the mean IoU was 92.17%, and the mean F1 score was 95.83%. In the training phase, our model achieved good performance after only 30 training cycles. Compared with other models, our method reduces the number of parameters, improves the training speed, and has obvious performance advantages.

Background: The mechanism by which chondrocyte senescence aggravate OA progression has not yet been well elucidated. The aim of this study was to investigate the chondrocyte senescence related gene biosignatures in OA, and to analyze on the underlying mechanisms of senescence in OA. Materials and methods: We intersected osteoarthritis dataset GSE82107 from GEO database and senescence dataset from CellAge database of human senescence-associated genes based on genetic manipulations experiments plus gene expression profilin, and screened out 4 overlapping genes. The hub genes were verified in vitro and in human OA cartilage tissues by qRT-PCR. We further confirmed the function of mitogen-activated protein kinase 12 (MAPK12) and Fos proto-oncogene (FOS) in OA in vitro and in vivo by qRT-PCR, western blotting, Edu staining, immunofluorescence, SA-β-gal staining, HE, IHC, von frey test, and hot plate. Results: 1458 downregulated and 218 upregulated DEGs were determined from GSE82107, and 279 human senescence-associated genes were downloaded from CellAge database. After intersection assay, we screened out 4 overlapping genes, of which FOS, CYR61 and TNFSF15 were upregulated, MAPK12 was downregulated. The expression of MAPK12 was obviously downregulated, whereas the expression profiles of FOS, CYR61 and TNFSF15 were remarkedly upregulated in H2O2- or IL-1β-stimulated C28/I2 cells, human OA cartilage tissues, and knee cartilage of aging mice. Furthermore, both MAPK12 over-expression and FOS knock-down can promote cell proliferation and cartilage anabolism, inhibit cell senescence and cartilage catabolism, relieve joint pain in H2O2- or IL-1β-stimulated C28/I2 cells and mouse primary chondrocytes, destabilization of the medial meniscus (DMM) mice. Conclusion: This study explored that MAPK12 and FOS are involved in the occurrence and development of OA through modulating chondrocyte senescence. They might be biomarkers of OA chondrocyte senescence, and provides some evidence as subsequent possible therapeutic targets for OA. The translational potential of this article: The translation potential of this article is that we revealed MAPK12 and FOS can effectively alleviate OA by regulating chondrocyte senescence, and thus provided potential therapeutic targets for prevention or treatment of OA in the future.

The evolutionary dynamics of cancer, characterized by its profound heterogeneity, demand sophisticated tools for a holistic understanding. This review delves into tumor phylogenetics, an essential approach bridging evolutionary biology with oncology, offering unparalleled insights into cancer's evolutionary trajectory. We provide an overview of the workflow, encompassing study design, data acquisition, and phylogeny reconstruction. Notably, the integration of diverse data sets emerges as a transformative step, enhancing the depth and breadth of evolutionary insights. With this integrated perspective, tumor phylogenetics stands poised to redefine our understanding of cancer evolution and influence therapeutic strategies.

n-Caproate, which is produced via chain elongation (CE) using waste biomass, can supply various fossil-derived products, thus advancing the realization of carbon neutrality. Ammonia released from the degradation of nitrogen-rich waste biomass can act as a nutrient or an inhibitor in anaerobic bioprocesses, including CE, with the distinction being primarily dependent on its concentration. Currently, the optimal concentration of ammonia and the threshold of toxicity for open-culture n-caproate production using ethanol as an electron donor, along with the underlying mechanisms, remain unclear. This study revealed that the optimal concentration of ammonia for n-caproate production was 2.0 g∙L−1, whereas concentrations exceeding this threshold markedly suppressed the CE performance. Exploration of the mechanism revealed the involvement of two forms of ammonia (i.e., ammonium ions and free ammonia) in this inhibitory behavior. High ammonia levels (5.0 g∙L−1) induced excessive ethanol oxidation and suppressed the reverse β-oxidation (RBO) process, directly leading to the enhanced activities of enzymes (phosphotransacetylase and acetate kinase) responsible for acetate formation and diminished activities of butyryl-coenzyme A (CoA):acetyl-CoA transferase, caproyl-CoA:butyryl-CoA transferase, and caproyl-CoA:acetyl-CoA transferase that are involved in the syntheses of n-butyrate and n-caproate. Furthermore, the composition of the microbial community shifted from Paraclostridium dominance (at 0.1 g∙L−1 ammonia) to a co-dominance of Fermentimonas, Clostridium sensu stricto 12, and Clostridium sensu stricto 15 at 2.0 g∙L−1 ammonia. However, these CE-functional bacteria were mostly absent in the presence of excessive ammonia (5.0 g∙L−1 ammonia). Metagenomic analysis revealed the upregulation of functions such as RBO, fatty acid synthesis, K+ efflux, adenosine triphosphatase (ATPase) metabolism, and metal cation export in the presence of 2.0 g∙L−1 ammonia, collectively contributing to enhanced n-caproate production. Conversely, the aforementioned functions (excluding metal cation export) and K+ influx were suppressed by excessive ammonia, undermining both ammonia detoxification and n-caproate biosynthesis. The comprehensive elucidation of ammonia-driven mechanisms influencing n-caproate production, as provided in this study, is expected to inspire researchers to devise effective strategies to alleviate ammonia-induced inhibition.

Abstract Background Traumatic brain injury (TBI) has been a worldwide problem for neurosurgeons. Patients with severe TBI may undergo craniotomy. These patients often require sedation after craniotomy. Dexmedetomidine (DEX) has been used in patients receiving anesthesia and in intensive care units. Not much is known about the postoperative effect of DEX in patients with severe TBIs undergoing craniotomy. The purpose of this study was to explore the effects of postoperative DEX administration on severe TBI patients who underwent craniotomy. Methods Patients who underwent craniectomy for severe TBI at our hospital between January 2019 and February 2022 were included in this study. The patients were admitted to the intensive care unit (ICU) after surgery to receive sedative medication. The patients were then divided into DEX and control groups. We analyzed the sedation, hemodynamics, and other conditions of the patients (hypoxemia, duration of ventilation during endotracheal intubation, whether tracheotomy was performed, and the duration in the ICU) during their ICU stay. Other conditions, such as delirium after the patients were transferred to the general ward, were also analyzed. Results A total of 122 patients were included in this study. Among them, 53 patients received DEX, and the remaining 69 did not. The incidence of delirium in the general ward in the DEX group was significantly lower than that in the control group (P 0.05). Conclusion The use of DEX in the ICU can effectively reduce the incidence of delirium in patients who return to the general ward after craniotomy. DEX had no adverse effect on the prognosis of patients other than causing bradycardia.

Abstract Early endosomes (EEs) are crucial in cargo sorting within vesicular trafficking. While cargoes destined for degradation are retained in EEs and eventually transported to lysosomes, recycled cargoes for the plasma membrane (PM) or the Golgi undergo segregation into specialized membrane structures known as EE buds during cargo sorting. Despite this significance, the molecular basis of the membrane expansion during EE bud formation has been poorly understood. In this study, we identify a protein complex comprising SHIP164, an ATPase RhoBTB3, and a retromer subunit Vps26B, which promotes the formation of EE buds at Golgi–EE contacts. Our findings reveal that Vps26B acts as a novel Rab14 effector, and Rab14 activity regulates the association of SHIP164 with EEs. Depletion of SHIP164 leads to enlarged Rab14+ EEs without buds, a phenotype rescued by wild-type SHIP164 but not the lipid transfer-defective mutants. Suppression of RhoBTB3 or Vps26B mirrors the effects of SHIP164 depletion. Together, we propose a lipid transport-dependent pathway mediated by the RhoBTB3–SHIP164–Vps26B complex at Golgi–EE contacts, which is essential for EE budding.

The sediment biogeochemistry of phosphorus (P) and biogenic silica (BSi) in the southern South China Sea shelf (SSCS) is inadequate understood. Here, we examine the spatial distributions of P species and BSi in surface sediments across the Sunda Shelf and explore their relationships with satellite data of sea surface chlorophyll-a (Chla), suspended particulate matter (SPM), particulate organic carbon, particulate inorganic carbon, primary production (PP), and phytoplankton functional types. The total sediment P (TSP), in the range from 283.94 to 579.94 μg/g dry sediment, was dominated by inorganic P with higher levels in stations outside the Lupar and Saribas estuaries. The TSP was composed of seven different P species including Ca-IP and Ca-OP (58%), Detr-P (15%), Exch-P (11%), Fe-IP (10%), Ref-P (4%) and Ads-IP (2%) based on a sequential extraction method. The concentrations of various sediment P species were found significantly correlated with satellite climatological SPM, diatom biomass, and monthly climatological pico-PP revealing the importance of biological production for the sediment P storage, whereas the sediment BSi concentration showed no correlations with any of the above satellite products. An elevated R2 value in the regression of BSi with the in-situ depth-integrated Chla points to the need of developing satellite algorithms with vertical profiles from space. Finally, we argue that future studies of the SSCS sediment biogeochemistry may be benefited from data of hyperspectral and geostationary satellites.

Fermented meat products is the meat products with special flavor, color, texture and longer shelf life formed by a series of changes under natural or artificially controlled conditions by the action of microorganisms or enzymes. Fermented meat products is popular with consumers, but they are rich in protein and have a great potential for high levels of biogenic amines. Among them, histamine and tyramine are the most toxic. Consumption of tyramine-rich foods might cause headache, hypertension and other adverse reactions. Therefore, it is extremely necessary to control the tyramine content in fermented meat products. In this paper, the formation pathways, control methods and effects of tyramine in fermented meat products are reviewed. Among them, the main formation pathway is the decarboxylation of tyrosine by the action of decarboxylase, in addition to the existence of chemical pathways related to lipid oxidation products, while the more effective control methods are the addition of auxiliaries and the inoculation of fermentation agents. This paper aims to provid a theoretical support for reducing the tyramine content in fermented meat products and improving the safety of fermented meat products.

Abstract An increasing number of studies have indicated the crucial involvement of long non-coding RNAs (lncRNAs) in the onset and progression of malignancies. However, a complete understanding of the molecular mechanism underlying the effect of abnormally expressed lncRNAs on breast cancer (BC) remains elusive. This study aimed to elucidate the influence of the lncRNA small nucleolar RNA host gene 1 (SNHG1) on BC progression and its underlying mechanism. Our findings revealed a conspicuous up-regulation of SNHG1 in both BC tissues and cells. The downregulation of SNHG1 was observed to inhibit BC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) processes, while simultaneously promoting apoptosis. Furthermore, dual-luciferase reporter gene and RNA pull-down assays established that SNHG1 targeted miR-641 expression, while miR-641 targeted RRS1. Rescue studies demonstrated that in vitro SNHG1 silencing could be reversed by the miR-641 inhibitor, as well as by RRS1 upregulation. Moreover, in vivo downregulation of SNHG1 was found to inhibit BC growth. Through the inhibition of the miR-641 level, SNHG1 elevated the level of the downstream target RRS1, thereby fostering BC growth, migration, and invasion while inhibiting apoptosis. These findings suggest that SNHG1 may represent a potential therapeutic target for BC treatment.

Abstract Alternative polyadenylation plays an important role in cancer initiation and progression; however, current transcriptome-wide association studies mostly ignore alternative polyadenylation when identifying putative cancer susceptibility genes. Here, we perform a pan-cancer 3′ untranslated region alternative polyadenylation transcriptome-wide association analysis by integrating 55 well-powered (n > 50,000) genome-wide association studies datasets across 22 major cancer types with alternative polyadenylation quantification from 23,955 RNA sequencing samples across 7,574 individuals. We find that genetic variants associated with alternative polyadenylation are co-localized with 28.57% of cancer loci and contribute a significant portion of cancer heritability. We further identify 642 significant cancer susceptibility genes predicted to modulate cancer risk via alternative polyadenylation, 62.46% of which have been overlooked by traditional expression- and splicing- studies. As proof of principle validation, we show that alternative alleles facilitate 3′ untranslated region lengthening of CRLS1 gene leading to increased protein abundance and promoted proliferation of breast cancer cells. Together, our study highlights the significant role of alternative polyadenylation in discovering new cancer susceptibility genes and provides a strong foundational framework for enhancing our understanding of the etiology underlying human cancers.

C12H20N2PdCl2, monoclinic, P21/c (no. 14), a = 16.2780(2) Å, b = 6.97160(10) Å, c = 13.07070(10) Å, β = 102.780(1)°, V = 1446.56(3) Å3, Z = 4, Rgt (F) = 0.0261, wRref (F 2) = 0.0707, T = 291 K.

Abstract Universal newborn hearing screening (UNHS) and audiological diagnosis are crucial for children with congenital hearing loss (HL). The objective of this study was to analyze hearing screening techniques, audiological outcomes and risk factors among children referred from a UNHS program in Beijing. A retrospective analysis was performed in children who were referred to our hospital after failing UNHS during a 9-year period. A series of audiological diagnostic tests were administered to each case, to confirm and determine the type and degree of HL. Risk factors for HL were collected. Of 1839 cases, 53.0% were referred after only transient evoked otoacoustic emission (TEOAE) testing, 46.1% were screened by a combination of TEOAE and automatic auditory brainstem response (AABR) testing, and 1.0% were referred after only AABR testing. HL was confirmed in 55.7% of cases. Ears with screening results that led to referral experienced a more severe degree of HL than those with results that passed. Risk factors for HL were identified in 113 (6.1%) cases. The main risk factors included craniofacial anomalies (2.7%), length of stay in the neonatal intensive care unit longer than 5 days (2.4%) and birth weight less than 1500 g (0.8%). The statistical data showed that age (P

Abstract Background Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that affects individuals across their lifespan. Early diagnosis and intervention are crucial for improving outcomes. However, current diagnostic methods are often time-consuming, and costly, making them inaccessible to many families. In the current study, we aim to test caregiver-child interaction as a potential tool for screening children with ASD in clinic. Methods We enrolled 85 preschool children (Mean age: 4.90 ± 0.65 years, 70.6% male), including ASD children with or without developmental delay (DD), and typical development (TD) children, along with their caregivers. ASD core symptoms were evaluated by Childhood Autism Rating Scale (CARS) and Autism Diagnostic Observation Schedule-Calibrated Severity Scores (ADOS-CSS). Behavioral indicators were derived from video encoding of caregiver-child interaction, including social involvement of children (SIC), interaction time (IT), response of children to social cues (RSC), time for caregiver initiated social interactions (GIS) and time for children initiated social interactions (CIS)). Power spectral density (PSD) values were calculated by EEG signals simultaneously recorded. Partial Pearson correlation analysis was used in both ASD groups to investigate the correlation among behavioral indicators scores and ASD symptom severity and PSD values. Receiver operating characteristic (ROC) analysis was used to describe the discrimination accuracy of behavioral indicators. Results Compared to TD group, both ASD groups demonstrated significant lower scores of SIC, IT, RSC, CIS (all p values

Abstract Osteoarthritis (OA) is a full-joint, multifactorial, degenerative and inflammatory disease that seriously affects the quality of life of patients due to its disabling and pain-causing properties. ER stress has been reported to be closely related to the progression of OA. The inositol-requiring enzyme 1α/X-box-binding protein-1 spliced (IRE1α/XBP1s) pathway, which is highly expressed in the chondrocytes of OA patients, promotes the degradation and refolding of abnormal proteins during ER stress and maintains the stability of the ER environment of chondrocytes, but its function and the underlying mechanisms of how it contributes to the progression of OA remain unclear. This study investigates the role of IRE1α/ERN1 in OA. Specific deficiency of ERN1 in chondrocytes spontaneously resulted in OA-like cartilage destruction and accelerated OA progression in a surgically induced arthritis model. Local delivery of AdERN1 relieved degradation of the cartilage matrix and prevented OA development in an ACLT-mediated model. Mechanistically, progranulin (PGRN), an intracellular chaperone, binds to IRE1α, promoting its phosphorylation and splicing of XBP1u to generate XBP1s. XBP1s protects articular cartilage through TNF-α/ERK1/2 signaling and further maintains collagen homeostasis by regulating type II collagen expression. The chondroprotective effect of IRE1α/ERN1 is dependent on PGRN and XBP1s splicing. ERN1 deficiency accelerated cartilage degeneration in OA by reducing PGRN expression and XBP1s splicing, subsequently decreasing collagen II expression and triggering collagen structural abnormalities and an imbalance in collagen homeostasis. This study provides new insights into OA pathogenesis and the UPR and suggests that IRE1α/ERN1 may serve as a potential target for the treatment of joint degenerative diseases, including OA.

Heterosis is widely used in crop production, but phenotypic dominance and its underlying causes in soybeans, a significant grain and oil crop, remain a crucial yet unexplored issue. Here, the phenotypes and transcriptome profiles of three inbred lines and their resulting F1 seedlings were analyzed. The results suggest that F1 seedlings with superior heterosis in leaf size and biomass exhibited a more extensive recompilation in their transcriptional network and activated a greater number of genes compared to the parental lines. Furthermore, the transcriptional reprogramming observed in the four hybrid combinations was primarily non-additive, with dominant effects being more prevalent. Enrichment analysis of sets of differentially expressed genes, coupled with a weighted gene co-expression network analysis, has shown that the emergence of heterosis in seedlings can be attributed to genes related to circadian rhythms, photosynthesis, and starch synthesis. In addition, we combined DNA methylation data from previous immature seeds and observed similar recompilation patterns between DNA methylation and gene expression. We also found significant correlations between methylation levels of gene region and gene expression levels, as well as the discovery of 12 hub genes that shared or conflicted with their remodeling patterns. This suggests that DNA methylation in contemporary hybrid seeds have an impact on both the F1 seedling phenotype and gene expression to some extent. In conclusion, our study provides valuable insights into the molecular mechanisms of heterosis in soybean seedlings and its practical implications for selecting superior soybean varieties.

The Chinese Maze Murders , a Chinese culture-based detective novel transcreated by Dutch sinologist Robert Hans van Gulik, represents Chinese cultures multimodally and reconciles Chinese-English cultural gaps effectively. Figuring out what cross-cultural functions and contributions of illustration-text multimodal combinations in The Chinese Maze Murders make would be inspiring for effectively promoting and applying multimodal ways in Chinese-English cultural translation. Yet, there is a scarcity of translation studies investigating it directly. This multimodal corpus-based study first identifies the different culture-representing features of the illustration-text multimodal combinations in the Chinese and English versions of The Chinese Maze Murders quantitatively, and then proposes the fundamental functions and contributions of illustration-text combinations that could facilitate cross-cultural translation qualitatively. The corpus textual statistics show that the Chinese version comprises 23.04% material cultural elements and 76.96% non-material cultural elements. While the English version comprises 36.58% material cultural elements and 63.42% non-material cultural elements. The different type-allocation of textually represented cultural elements in two language versions is regarded as an operating result of the mechanism of illustration-text multimodal combinations. Based on further retroductive corpus statistics-derived example analysis, it is argued that illustration-text multimodal combinations could facilitate cross-cultural translation in (a) transforming abstract cultural elements into concrete cultural elements, (b) integrating cultural elements as “meaning wholes,” and (c) visualizing cultural implications. This study sheds new light on the cultural functions of illustration-text multimodal combinations in translation, which provides practical implications for mitigating the cultural incommensurability of Chinese-English translation.

Microfracture density in fault damage zones can reflect spatial variability that decays in intensity as a function of distance from the fault, which is crucial in understanding the mechanical, seismological, and fluid-flow properties of the fault system. However, few studies explored the characteristics of fracture density between the two sides of active dip-slip faults due to rare field observations. Here, we measured and modeled microfractures across an active thrust fault associated with the 2008 Mw 7.9 Wenchuan earthquake in the Longmen Shan, eastern Tibetan Plateau. The results showed that the microfracture density at the Qingping site developed more intensely in the hanging wall than in the footwall for an exposed thrust fault, indicating an asymmetrical pattern. The hidden thrust fault at the Jushui site showed that microfractures developed more intensely in vertical planes in the hanging wall than in the footwall, whereas microfractures developed similarly in horizontal planes within the two sides, indicating a quasiasymmetrical pattern. Comparing the data at the two sites with computational modeling, we suggest that fault geometry might exert a first-order control of the asymmetrical microfracture density pattern, which is helpful for revealing different deformational behaviors of rock masses in the fault damage zones and better understanding the hanging-wall effect for evaluating seismic hazards on active thrust faults.

Abstract Background Arginase-1 (ARG1) promotes collagen synthesis and cell proliferation. ARG1 is highly expressed in various tumour cells. The mechanisms of ARG1 in epithelial-to-mesenchymal transition (EMT)-associated cataracts were studied herein. Methods C57BL/6 mice, a human lens epithelial cell line (HLEC-SRA01/04), and human lens capsule samples were used in this study. The right lens anterior capsule of the mouse eye was punctured through the central cornea with a 26-gauge hypodermic needle. Human lens epithelial cells (HLECs) were transfected with ARG1-targeted (siARG1) or negative control siRNA (siNC). For gene overexpression, HLECs were transfected with a plasmid bearing the ARG1 coding sequence or an empty vector. Medium containing 0.2% serum with or without transforming growth factor beta-2 (TGF-β2) was added for 6 or 24 h to detect mRNA or protein, respectively. The expression of related genes was measured by quantitative real-time polymerase chain reaction (RT–qPCR), western blotting, and immunohistochemical staining. Transwell assays and wound healing assays were used to determine cell migration. Cell proliferation, superoxide levels, nitric oxide (NO) levels, and arginase activity were estimated using Cell Counting Kit-8 assays, a superoxide assay kit, an NO assay kit, and an arginase activity kit. Results ARG1, alpha-smooth muscle actin (α-SMA), fibronectin, and Ki67 expression increased after lens capsular injury, while zonula occludens-1 (ZO-1) expression decreased. Fibronectin and collagen type I alpha1 chain (collagen 1A1) expression increased, and cell migration increased significantly in ARG1-overexpressing HLECs compared with those transfected with an empty vector after TGF-β2 treatment. These effects were reversed by ARG1 knockdown. The arginase-related pathway plays an important role in EMT. mRNAs of enzymes of the arginase-related pathway were highly expressed after ARG1 overexpression. ARG1 knockdown suppressed these expression changes. Numidargistat (CB-1158) dihydrochloride (CB-1158), an ARG1 inhibitor, suppressed TGF-β2-induced anterior subcapsular cataract (ASC) by reducing the proliferation of lens epithelial cells (LECs) and decreasing fibronectin, α-SMA, collagen 1A1, and vimentin expression. Compared with that in nonanterior subcapsular cataract (non-ASC) patients, the expression of ARG1, collagen 1A1, vimentin, fibronectin, and Ki67 was markedly increased in ASC patients. Conclusions ARG1 can regulate EMT in EMT-associated cataracts. Based on the pathogenesis of ASC, these findings are expected to provide new therapeutic strategies for patients. Graphical abstract

Abstract Spinel Li4Ti5O12 (LTO) is a promising candidate for lithium-ion battery anodes because of its exceptional stability and safety. However, its extensive application is limited by a high comprehensive cost, poor electronic conductivity, and other inherent defects. This work presents a novel synthesis procedure to synthesize carbon-coated Fe-doped LTO composites through carbon reduction, in the presence of Fe-containing industrial H2TiO3 as the titanium source, and glucose as the carbon source. The presence of the Fe-dopant is confirmed through XRD, with Rietveld refinement and EDS experiments. Results show that Fe2+ replaces a portion of Ti4+ after doping, leading to an increase in the LTO cell parameters and the corresponding cell volume. FLTO/C, presents a capacity of 153.79 mAh g−1 at 10 C, and the capacity decay per cycle is only 0.0074% after 1000 cycles at 5 C. Moreover, EIS experiments indicate that the incorporation of Fe and carbon lowers the charge transfer resistance and improves the diffusion and migration of Li+. Notably, since this preparation process requires no additional Fe source as a raw material, it is simple, cost-effective, and suitable for large-scale production and further application.

Abstract Background Albuminuria has been suggested as an atherosclerotic risk factor among the general population. However, whether this association will be amplified in patients with coronary artery disease (CAD) is unknown. It is also unknown whether diabetes mellitus confounds the association. We aim to analyse the prognosis of elevated urine albumin creatinine ratio (uACR) in the CAD population with or without type 2 diabetes mellitus (T2DM). Methods This multi-center registry cohort study included 5,960 patients with CAD. Patients were divided into T2DM and non-T2DM group, and baseline uACR levels were assessed on three grades (low: uACR

Abstract Background Glutaric acidemia type 1 (GA1) is a rare autosomal recessive inherited metabolic disorder caused by variants in the gene encoding the enzyme glutaryl-CoA dehydrogenase (GCDH). The estimated prevalence of GA1 and the mutational spectrum of the GCDH gene vary widely according to race and region. The aim of this study was to assess the acylcarnitine profiles and genetic characteristics of patients with GA1 in Fujian Province, southeastern China. Results From January 2014 to December 2022, a total of 1,151,069 newborns (631,016 males and 520,053 females) were screened using MS/MS in six newborn screening (NBS) centers in Fujian Province and recruited for this study. Through NBS, 18 newborns (13 females and 5 males) were diagnosed with GA1. Thus, the estimated incidence of GA1 was 1 in 63,948 newborns in Fujian province. In addition, 17 patients with GA1 were recruited after clinical diagnosis. All but one patient with GA1 had a remarkable increase in glutarylcarnitine (C5DC) concentrations. The results of urinary organic acid analyses in 33 patients showed that the concentration of glutaric acid (GA) increased in all patients. The levels of C5DC and GA in patients identified via NBS were higher than those in patients identified via clinical diagnosis (P C, p.(?) (63.38%), c.1261G > A, p.Ala421Thr (5.63%), and c.406G > T, p.Gly136Cys (4.22%). The most abundant genotype observed was c.[1244-2 A > C]; [1244-2 A > C] (18/35, 52.43%) and its phenotype corresponded to high excretors (HE, GA > 100 mmol/mol Cr). Conclusions In conclusion, we investigated the biochemical and molecular features of 35 unrelated patients with GA1. C5DC concentrations in dried blood spots and urinary GA are effective indicators for a GA1 diagnosis. Our study also identified a GCDH variant spectrum in patients with GA1 from Fujian Province, southeastern China. Correlation analysis between genotypes and phenotypes provides preliminary and valuable information for genetic counseling and management.

Progranulin (PGRN) is a multifunctional growth factor involved in many physiological processes and disease states. The apparent protective role of PGRN and the importance of chondrocyte autophagic function in the progression of osteoarthritis (OA) led us to investigate the role of PGRN in the regulation of chondrocyte autophagy. PGRN knockout chondrocytes exhibited a deficient autophagic response with limited induction following rapamycin, serum starvation, and IL-1β-induced autophagy. PGRN-mediated anabolism and suppression of IL-1β-induced catabolism were largely abrogated in the presence of the BafA1 autophagy inhibitor. Mechanistically, during the process of OA, PGRN and the ATG5–ATG12 conjugate form a protein complex; PGRN regulates autophagy in chondrocytes and OA through, at least partially, the interactions between PGRN and the ATG5–ATG12 conjugate. Furthermore, the ATG5–ATG12 conjugate is critical for cell proliferation and apoptosis. Knockdown or knockout of ATG5 reduces the expression of ATG5–ATG12 conjugate and inhibits the chondroprotective effect of PGRN on anabolism and catabolism. Overexpression of PGRN partially reversed this effect. In brief, the PGRN-mediated regulation of chondrocyte autophagy plays a key role in the chondroprotective role of PGRN in OA. Such studies provide new insights into the pathogenesis of OA and PGRN-associated autophagy in chondrocyte homeostasis.

Many vision-based bolt looseness detection methods that directly observe the bolts have been developed. However, these methods have many limitations in terms of the conditions and processes of their implementation. To address these problems, this paper proposed a fully automated vision-based bolt looseness detection method for a rigid multi-bolt connection. The proposed method combines digital shearing speckle pattern interferometry (DSSPI) and recurrent neural network (RNN) and involves capturing speckle fringe patterns under various looseness cases using the DSSPI system and classifying these patterns with an RNN model to detect the loose bolts. The proposed method can detect all the bolts within the measured surface at one time, which is efficient. On the other hand, it eliminates the need for prior information such as the initial angle and position of each bolt. It can even detect unseen bolts in multi-bolt connections, making it applicable for connections in complex structures in which occlusion often occurs. Additionally, the method eliminates the complex process of distortion rectification. These features make the method achieve a single-judgment time (four bolts at one detection) of only 4.70 millisecond with a detection accuracy over 99%, which has potential for the real-time detection of loose bolts in multi-bolt connections.

Abstract While overweight/obesity has become a major public health issue worldwide, any association between body mass index (BMI) and therapeutic response in neoadjuvant targeted therapy treated HER2 positive breast cancer patients remain unclear. The information from a total of four-hundred and ninety-one neoadjuvant targeted therapy treated HER2 positive breast cancer patients from four institutions were retrospectively collected. Univariate and multivariate logistic analysis was developed to determine the association between BMI and therapeutic response. A meta-analysis of published literature was then conducted to confirm the effect of overweight/obesity on pCR for patients treated with neoadjuvant targeted therapy. Restricted cubic spline (RCS) adjusted for confounding factors demonstrated a decrease pCR with increasing BMI (OR = 0.937, P = 0.045). Patients were then categorized into under/normal weight (n = 299) and overweight/obesity (n = 192). Overweight/obese patients were independently associated with a poor therapeutic response. In the subgroup analysis, a significant negative impact of overweight/obesity on pCR can be observed both in single-targeted (OR = 0.556; P = 0.02) and dual-targeted (OR = 0.392; P = 0.021) populations. Six eligible studies involving 984 neoadjuvant targeted therapy treated HER2 positive breast cancer patients were included in the meta-analysis. The meta-analysis also demonstrated that overweight/obesity was significantly associated with a poor response to neoadjuvant anti-HER2 therapy (OR = 0.68; P = 0.007). Our result show that overweight and obese HER2 positive breast cancer patients are less likely to achieve pCR after neoadjuvant targeted therapy.

A model was constructed to estimate Primary production (PP) and examine the effect of the dominant phytoplankton group on PP, using a dataset collected in 2019 in the South China Sea (SCS) based on phytoplankton absorption coefficient at 443nm [aph(443)] and photosynthetically active radiation (PAR). There was a significant log-log linear correlation between PP and the product of aph(443) and PAR (aph(443)×PAR), with an adjusted R2 of 0.64. The model was validated using K-fold cross-validation and an in situ dataset collected in 2018 in the SCS basin. The results showed that the model had good generalisability and was suitable across marine environments, including basin, coastal, and offshore areas. The model was more sensitive to changes in PAR than changes in aph(443). Phytoplankton in the diatom-dominant and haptophyte-dominant clusters were in the light-limited stage, and their PP values increased with increasing aph(443)×PAR. However, Prochlorococcus-dominant samples exhibited photoinhibition, and the PP values decreased with increasing aph(443)×PAR, likely due to their bio-optical characteristics. The model’s predictive power was related to the photo-physiological state of dominant phytoplankton, which performs well in light-limited conditions but not in cases of massive photoinhibition. This study provides insight into the development of phytoplankton-specific aph-based PP models.

Abstract The acute myeloid leukemia (AML) patients obtain limited benefits from current immune checkpoint blockades (ICBs), although immunotherapy have achieved encouraging success in numerous cancers. Here, we found that V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint, is highly expressed in primary AML cells and associated with poor prognosis of AML patients. Targeting VISTA by anti-VISTA mAb boosts T cell-mediated cytotoxicity to AML cells. Interestingly, high expression of VISTA is positively associated with hyperactive STAT3 in AML. Further evidence showed that STAT3 functions as a transcriptional regulator to modulate VISTA expression by directly binding to DNA response element of VISTA gene. We further develop a potent and selective STAT3 inhibitor W1046, which significantly suppresses AML proliferation and survival. W1046 remarkably enhances the efficacy of VISTA mAb by activating T cells via inhibition of STAT3 signaling and down-regulation of VISTA. Moreover, combination of W1046 and VISTA mAb achieves a significant anti-AML effect in vitro and in vivo. Overall, our findings confirm that VISTA is a potential target for AML therapy which transcriptionally regulated by STAT3 and provide a promising therapeutic strategy for immunotherapy of AML.

Abstract Glioma is the most common malignant tumor of the central nervous system in adults. The tumor microenvironment (TME) is related to poor prognosis in glioma patients. Glioma cells could sort miRNA into exosomes to modify TME. And hypoxia played an important role in this sorting process, but the mechanism is not clear yet. Our study was to find miRNAs sorted into glioma exosomes and reveal the sorting process. Sequencing analysis of glioma patients cerebrospinal fluid (CSF) and tissue showed that miR-204-3p tends to be sorted into exosomes. miR-204-3p suppressed glioma proliferation through the CACNA1C/MAPK pathway. hnRNP A2/B1 can accelerate exosome sorting of miR-204-3p by binding a specific sequence. Hypoxia plays an important role in exosome sorting of miR-204-3p. Hypoxia can upregulate miR-204-3p by upregulating the translation factor SOX9. Hypoxia promotes the transfer of hnRNP A2/B1 to the cytoplasm by upregulating SUMOylation of hnRNP A2/B1 to eliminate miR-204-3p. Exosomal miR-204-3p promoted tube formation of vascular endothelial cells through the ATXN1/STAT3 pathway. The SUMOylation inhibitor TAK-981 can inhibit the exosome-sorting process of miR-204-3p to inhibit tumor growth and angiogenesis. This study revealed that glioma cells can eliminate the suppressor miR-204-3p to accelerate angiogenesis under hypoxia by upregulating SUMOylation. The SUMOylation inhibitor TAK-981 could be a potential drug for glioma. This study revealed that glioma cells can eliminate the suppressor miR-204-3p to accelerate angiogenesis under hypoxia by upregulating SUMOylation. The SUMOylation inhibitor TAK-981 could be a potential drug for glioma.

Regulator of ribosome synthesis 1 (RRS1), a crucial regulatory factor in ribosome biogenesis, exerts a remarkable impact on the progression of breast cancer (BC). However, the exact mechanisms and pathways have not yet been fully elucidated. To investigate the impact of RRS1 on BC growth and metastasis, along with its underlying mechanisms. We discovered that RRS1 is overexpressed in BC tissues and cell lines. This study aims to regulate the level of RRS1 through lentiviral transfection technology to explore its potential function in BC cells. Knockdown of RRS1 resulted in the inhibition of cell proliferation, invasion, and migration, whereas overexpression had the opposite effects. We firstly identified the interaction between RRS1 and Glucose-Regulated Protein 78 (GRP78) using Co-immunoprecipitation (Co-IP) combined with mass spectrometry analysis, providing evidences of co-localization and positive regulation between RRS1 and GRP78. We observed that RRS1 inhibited the degradation of GRP78 through the ubiquitin–proteasome pathway, resulting in the stabilization of GRP78. In addition, our findings suggested that RRS1 promoted BC progression by activating the GRP78-mediated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. In conclusion, this newly discovered RRS1/GRP78 signaling axis provides a molecular and theoretical basis for further exploring the mechanisms of breast cancer invasion and metastasis.

Distributed optical fiber acoustic sensing (DAS) is promising for long-distance intrusion-anomaly detection tasks. However, realistic settings suffer from high-intensity interference noise, compromising the detection performance of DAS systems. To address this issue, we propose STNet, an intrusion detection network based on the Stockwell transform (S-transform), for DAS systems, considering the advantages of the S-transform in terms of noise resistance and ability to detect disturbances. Specifically, the signal detected by a DAS system is divided into space–time data matrices using a sliding window. Subsequently, the S-transform extracts the time-frequency features channel by channel. The extracted features are combined into a multi-channel time-frequency feature matrix and presented to STNet. Finally, a non-maximum suppression algorithm (NMS), suitable for locating intrusions, is used for the post-processing of the detection results. To evaluate the effectiveness of the proposed method, experiments were conducted using a realistic high-speed railway environment with high-intensity noise. The experimental results validated the satisfactory performance of the proposed method. Thus, the proposed method offers an effective solution for achieving high intrusion detection rates and low false alarm rates in complex environments.

While the physical interactions between the Golgi apparatus (Golgi) and lipid droplets (LDs) have been suggested through system-level imaging, the Golgi-LD membrane contact sites (MCSs) remain largely uncharacterized. Here, we show evidence to support the existence of Golgi-LD MCSs in HEK293 cells. We further suggest that vacuolar protein sorting-associated protein 13B (VPS13B) localizes to and promotes the formation of Golgi-LD contacts upon oleic acid (OA) stimulation using 3D high-resolution microscopy. Depletion of VPS13B moderately affects the formation of Golgi-LD contacts upon OA treatment in addition to the fragmentation of the Golgi. Although cellular functions of VPS13B-mediated contacts are still elusive, these findings may provide a new insight into related diseases caused by loss-of-function mutations of VPS13B.

The vertical distribution of suspended particulate matter (SPM) in the Pearl River Estuary (PRE) during winter has not been widely reported. The aim of this paper is to describe the high-resolution vertical distribution of SPM along the transect based on the in-situ observations (including SPM, attenuation coefficient, and particle backscattering coefficient) from three transects of the winter cruise in the northern South China Sea in 2020. The empirical relationship between SPM and bio-optical parameters with correlation coefficients greater than 0.7 is also established and combined with model data to further discuss the mechanism of river discharge and seawater intrusion effects on the vertical distribution of SPM. In the horizontal distribution, the mass concentration of SPM was high in the nearshore region and was low in the offshore region. In the vertical direction, the mass concentration of SPM in the offshore region was more homogeneous, while the mass concentration of SPM in the nearshore region varied greatly, showing a pattern of high bottom and middle layer or high bottom and surface layer. The difference in the vertical distribution of SPM in the nearshore area is the combined effect of river discharge and seawater intrusion on the resuspension of sediment and the inhibition of the spread of high SPM.

The estimated prevalence of tetrahydrobiopterin deficiency (BH4D) and the mutational spectrum of the causal 6-pyruvoyl-tetrahydropterin synthase (PTS) gene vary widely according to race and region. This study assessed the prevalence and genetic characteristics of BH4D in Fujian Province, southeastern China. A total of 3,204,067 newborns were screened between 2012 and 2022 based on the phenylalanine level and the phenylalanine/tyrosine ratio in dried blood spots. Differential diagnosis was determined by the urine purine spectrum, dihydropteridine reductase activity in red blood cells, and genetic testing. The PTS mutation spectrum and genotypes were determined by next-generation sequencing. A total of 189 newborns were diagnosed with hyperphenylalaninemia (HPA) over the study period, including 159 with phenylalanine hydroxylase deficiency and 30 with BH4D. Therefore, the prevalence of BH4D in Fujian was 9.36 per 1,000,000 live births (30/3,204,067) and the proportion of BH4D among patients with HPA was 15.87% (30/189). A total of 58 PTS alleles were identified in the 29 patients with PTS deficiency (PTPSD), and those alleles were composed of 10 different variants, including eight missense variants and two splice-site variants. The most prevalent variants were c.155A>G, p.Asn52Ser (44.83%); c.259C>T, p.Pro87Ser (39.66%); and c.84-291A>G, p.Tyr27Argfs*8 (3.45%). The predominant genotype was c [155A>G]; [259C>T] (11/29, 37.93%). The prevalence of BH4D and the spectrum of associated PTS mutations were successfully determined for the first time in Fujian Province, southeastern China. Since the mutation spectrum of PTS is region-specific, such data will facilitate molecular diagnosis and genetic counseling in PTPSD cases.

Many viruses often use a protein degradation system (e.g., the ubiquitin-proteasome pathway or lysosome pathway) to modulate viral propagation and viral pathogenesis. We reported that hepatitis C virus (HCV) infection promotes the lysosomal degradation of hepatocyte nuclear factor-1α (HNF-1α) via chaperone-mediated autophagy (CMA) through an NS5A-mediated association of HNF-1α with cellular chaperone heat shock cognate 70 kDa (HSC70) protein. HSC70 binds to the pentapeptide KFERQ motif (also known as a CMA-targeting motif) on HNF-1α protein and promotes the lysosomal degradation of HNF-1α. The KFERQ motif plays a crucial role in the two lysosomal degradation pathways, CMA and endosomal microautophagy (eMI). Herein, we searched for a novel substrate of HCV-induced lysosomal degradation by examining the NS5A-interacting proteins that carry the KFERQ motif. We identified diacylglycerol O-acyltransferase 1 (DGAT1), which is a key factor for HCV particle formation, as a candidate substrate for HCV-induced lysosomal degradation pathway. The region spanning from amino acids 149–153 of DGAT1 protein matches the rule for the KFERQ motif. DGAT1 protein was co-immunoprecipitated with HSC70, whereas DGAT1 Q149A mutant was not co-immunoprecipitated with HSC70, suggesting that the KFERQ motif is responsible for the interaction between DGAT1 and HSC70. Knockdown of LAMP-2A protein in HCV J6/JFH1-infected cells did not recover DGAT1 protein, whereas knockdown of VPS4B recovered the level of DGAT1 protein, suggesting that DGAT1 is degraded via eMI. These findings lead us to propose that HCV NS5A protein facilitates the recruitment of HSC70 to DGAT1, thereby promoting the lysosomal degradation of DGAT1 via eMI. Abbreviations 3-MA: 3-methyladenine; aa: amino acids; AH: amphipathic helix; BSA: bovine serum albumin; CMA: chaperone-mediated autophagy; DAAs: direct-acting antiviral; DGAT1: diacylglycerol O-acyltransferase 1; DMSO: dimethyl sulfoxide; EL: extracellular lumen; eMI: endosomal microautophagy; ESCRT: endosomal sorting complex required for transport; HA: hemagglutinin; HCV: hepatitis C virus; HNF-1α: hepatocyte nuclear factor-1α; HRP: horseradish peroxidase; HSC70: heat shock cognate 70 kDa protein; IB: immunoblotting; IL: intracellular lumen; IP: immunoprecipitation; LAMP-2A: lysosome-associated membrane protein type 2A; LCS: low-complexity sequences; mAb: monoclonal antibody; MOI: multiplicity of infection; MVB: multivesicular bodies; NS: nonstructural protein; pAb: polyclonal antibody; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PLA: proximity ligation assay; PS: phosphatidylserine; RT: room temperature; TM: transmembrane; TSG: tumor susceptibility gene; VPS4A: vacuolar protein sorting-associated protein 4A; VPS4B: vacuolar protein sorting-associated protein 4B

Abstract Background Intratumoral heterogeneity is the primary challenge in the treatment of glioblastoma (GBM). The presence of glioma stem cells (GSCs) and their conversion between different molecular phenotypes contribute to the complexity of heterogeneity, culminating in preferential resistance to radiotherapy. ARP2/3 (actin-related protein-2/3) complexes (ARPs) are associated with cancer migration, invasion and differentiation, while the implications of ARPs in the phenotype and resistance to radiotherapy of GSCs remain unclear. Methods We screened the expression of ARPs in TCGA-GBM and CGGA-GBM databases. Tumor sphere formation assays and limiting dilution assays were applied to assess the implications of ARPC1B in tumorigenesis. Apoptosis, comet, γ-H2AX immunofluorescence (IF), and cell cycle distribution assays were used to evaluate the effect of ARPC1B on radiotherapy resistance. Immunoprecipitation (IP) and mass spectrometry analysis were used to detect ARPC1B-interacting proteins. Immune blot assays were performed to evaluate protein ubiquitination, and deletion mutant constructs were designed to determine the binding sites of protein interactions. The Spearman correlation algorithm was performed to screen for drugs that indicated cell sensitivity by the expression of ARPC1B. An intracranial xenograft GSC mouse model was used to investigate the role of ARPC1B in vivo. Results We concluded that ARPC1B was significantly upregulated in MES-GBM/GSCs and was correlated with a poor prognosis. Both in vitro and in vivo assays indicated that knockdown of ARPC1B in MES-GSCs reduced tumorigenicity and resistance to IR treatment, whereas overexpression of ARPC1B in PN-GSCs exhibited the opposite effects. Mechanistically, ARPC1B interacted with IFI16 and HuR to maintain protein stability. In detail, the Pyrin of IFI16 and RRM2 of HuR were implicated in binding to ARPC1B, which counteracted TRIM21-mediated degradation of ubiquitination to IFI16 and HuR. Additionally, the function of ARPC1B was dependent on IFI16-induced activation of NF-κB pathway and HuR-induced activation of STAT3 pathway. Finally, we screened AZD6738, an ataxia telangiectasia mutated and rad3-related (ATR) inhibitor, based on the expression of ARPC1B. In addition to ARPC1B expression reflecting cellular sensitivity to AZD6738, the combination of AZD6738 and radiotherapy exhibited potent antitumor effects both in vitro and in vivo. Conclusion ARPC1B promoted MES phenotype maintenance and radiotherapy resistance by inhibiting TRIM21-mediated degradation of IFI16 and HuR, thereby activating the NF-κB and STAT3 signaling pathways, respectively. AZD6738, identified based on ARPC1B expression, exhibited excellent anti-GSC activity in combination with radiotherapy.

Abstract Background Resistance to temozolomide (TMZ) is a major obstacle to preventing glioblastoma (GBM) recurrence after surgery. Although long noncoding RNAs (lncRNAs) play a variety of roles in GBM, the lncRNAs that regulate TMZ resistance have not yet been clearly elucidated. This study aims to identify lncRNAs that may affect TMZ treatment sensitivity and to explore novel therapeutic strategies to overcome TMZ resistance in GBM. Methods LncRNAs associated with TMZ resistance were identified using the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets. Quantitative real-time PCR (qRT–PCR) was used to determine the expression of PDIA3P1 in TMZ-resistant and TMZ-sensitive GBM cell lines. Both gain-of-function and loss-of-function studies were used to assess the effects of PDIA3P1 on TMZ resistance using in vitro and in vivo assays. Glioma stem cells (GSCs) were used to determine the effect of PDIA3P1 on the GBM subtype. The hypothesis that PDIA3P1 promotes proneural-to-mesenchymal transition (PMT) was established using bioinformatics analysis and functional experiments. RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to examine the interaction between PDIA3P1 and C/EBPβ. The posttranslational modification mechanism of C/EBPβ was verified using ubiquitination and coimmunoprecipitation (co-IP) experiments. CompuSyn was leveraged to calculate the combination index (CI), and the antitumor effect of TMZ combined with nefllamapimod (NEF) was validated both in vitro and in vivo. Results We identified a lncRNA, PDIA3P1, which was upregulated in TMZ-resistant GBM cell lines. Overexpression of PDIA3P1 promoted the acquisition of TMZ resistance, whereas knockdown of PDIA3P1 restored TMZ sensitivity. PDIA3P1 was upregulated in MES-GBM, promoted PMT progression in GSCs, and caused GBMs to be more resistant to TMZ treatment. Mechanistically, PDIA3P1 disrupted the C/EBPβ-MDM2 complex and stabilized the C/EBPβ protein by preventing MDM2-mediated ubiquitination. Expression of PDIA3P1 was upregulated in a time- and concentration-dependent manner in response to TMZ treatment, and TMZ-induced upregulation of PDIA3P1 was mediated by the p38α-MAPK signaling pathway. NEF is a small molecule drug that specifically targets p38α with excellent blood–brain barrier (BBB) permeability. NEF blocked TMZ-responsive PDIA3P1 upregulation and produced synergistic effects when combined with TMZ at specific concentrations. The combination of TMZ and NEF exhibited excellent synergistic antitumor effects both in vitro and in vivo. Conclusion PDIA3P1 promotes PMT by stabilizing C/EBPβ, reducing the sensitivity of GBM cells to TMZ treatment. NEF inhibits TMZ-responsive PDIA3P1 upregulation, and NEF combined with TMZ provides better antitumor effects.

Hepatitis C virus (HCV) is a positive-sense, single-stranded RNA virus that causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The release of infectious HCV particles from infected hepatocytes is a crucial step in viral dissemination and disease progression. While the exact mechanisms of HCV particle release remain poorly understood, emerging evidence suggests that HCV utilizes intracellular membrane trafficking and secretory pathways. These pathways include the Golgi secretory pathway and the endosomal trafficking pathways, such as the recycling endosome pathway and the endosomal sorting complex required for transport (ESCRT)-dependent multivesicular bodies (MVBs) pathway. This review provides an overview of recent advances in understanding the release of infectious HCV particles, with a particular focus on the involvement of the host cell factors that participate in HCV particle release. By summarizing the current knowledge in this area, this review aims to contribute to a better understanding of endosomal pathways involved in the extracellular release of HCV particles and the development of novel antiviral strategies.

In order to explore the structural changes and products of histamine degradation by multicopper oxidase (MCO) in Lactiplantibacillus plantarum LPZN19, a 1500 bp MCO gene in L. plantarum LPZN19 was cloned, and the recombinant MCO was expressed in E. coli BL21 (DE3). After purification by Ni2+-NTA affinity chromatography, the obtained MCO has a molecular weight of 58 kDa, and it also has the highest enzyme activity at 50 °C and pH 3.5, with a relative enzyme activity of 100%, and it maintains 57.71% of the relative enzyme activity at 5% salt concentration. The secondary structure of MCO was determined by circular dichroism, in which the proportions of the α-helix, β-sheet, β-turn and random coil were 2.9%, 39.7%, 21.2% and 36.1%, respectively. The 6xj0.1.A with a credibility of 68.21% was selected as the template to predict the tertiary structure of MCO in L. plantarum LPZN19, and the results indicated that the main components of the tertiary structure of MCO were formed by the further coiling and folding of a random coil and β-sheet. Histamine could change the spatial structure of MCO by increasing the content of the α-helix and β-sheet. Finally, the LC-MS/MS identification results suggest that the histamine was degraded into imidazole acetaldehyde, hydrogen peroxide and ammonia.

Sweet potatoes (Ipomoea batatas (L.) Lam.) are a widely cultivated member of the Convolvulaceae family. Despite intensive agricultural interest, the metabolic determinants of sweet potato quality remain poorly understood owing to a lack of reliable or systematic sweet potato metabolite analyses. This study aimed to reveal the mechanism of flavonoid biosynthesis using widely targeted metabolomics and qRT-PCR analysis of white (S19) and yellow (BS) sweet potatoes. We found that the PAL, C4H, 4CL, CHS, CHI, IFS, F3H, F3’H, DFR, ANS, and ANR genes were differentially expressed in BS. Upregulation of PAL, C4H, 4CL, and CHS led to the accumulation of large amounts of chalcone, which is highly expressed in yellow flesh, resulting in the yellow color of BS. In S19, the high expression of FLS and the low expression of DFR inhibited pigment accumulation, while the low expression of CHS also inhibited flavonoid synthesis, ultimately leading to the white color. In conclusion, this study identified the main differentially expressed genes and their metabolites in the flavonoid biosynthesis pathway, and preliminarily elucidated the mechanism underlying the different flesh colors in sweet potato, thus providing new insights into the composition and abundance of metabolites in sweet potatoes with different-colored flesh.

To address the complexity of small or unique reconstruction distances in digital holography, we propose an inverse cross-correlation-based algorithm for the digital holographic imaging of multiplanar objects with a large depth of field. In this method, a planar output mapping is closely around the objects, and it is established by calculating the image inverse cross-correlation matrix of the reconstructed image at similar reconstruction distances, whereby the object edges serve as the result guide. Combining the search for edge planes with the depth estimation operator, the depth of field of digital holography is improved, thus allowing for a digital holography that is capable of meeting the requirements of the holographic imaging of multiplanar objects. Compared with the traditional depth estimation operator method, the proposed method solves the reconstruction ambiguity problem in multiple planes with a simple optical path, and no additional optical or mechanical devices need to be added, thus greatly improving the reconstruction quality. The numerical calculation results and the experimental results with multiplanar samples validate the effectiveness of the proposed method.

Abstract Clear evidence shows that tumors could secrete microRNAs (miRNAs) via exosomes to modulate the tumor microenvironment (TME). However, the mechanisms sorting specific miRNAs into exosomes are still unclear. In order to study the biological function and characterization of exosomal miRNAs, we performed whole-transcriptome sequencing in 59 patients’ whole-course cerebrospinal fluid (CSF) small extracellular vesicles (sEV) and matched glioma tissue samples. The results demonstrate that miRNAs could be divided into exosome-enriched miRNAs (ExomiRNAs) and intracellular-retained miRNAs (CLmiRNAs), and exosome-enriched miRNAs generally play a dual role. Among them, miR-1298-5p was enriched in CSF exosomes and suppressed glioma progression in vitro and vivo experiments. Interestingly, exosomal miR-1298-5p could promote the immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) to facilitate glioma. Therefore, we found miR-1298-5p had different effects on glioma cells and MDSCs. Mechanically, downstream signaling pathway analyses showed that miR-1298-5p plays distinct roles in glioma cells and MDSCs via targeting SETD7 and MSH2, respectively. Moreover, reverse verification was performed on the intracellular-retained miRNA miR-9-5p. Thus, we confirmed that tumor-suppressive miRNAs in glioma cells could be eliminated through exosomes and target tumor-associated immune cells to induce tumor-promoting phenotypes. Glioma could get double benefit from it. These findings uncover the mechanisms that glioma selectively sorts miRNAs into exosomes and modulates tumor immunity.

PurposeThe effect of vitamin D level pertinent to colorectal cancer incidence, progression, or mortality risk is complicated, and study findings are mixed. Therefore, we evaluated whether serum vitamin D [25-hydroxyvitamin D, 25(OH)D] is associated with the incidence of sporadic colorectal cancer (CRC).MethodsThis study is a retrospective analysis of the relationship between serum 25(OH)D level and the risk of CRC. Age, sex, body mass index, history of polyp, disease conditions (i.e., diabetes), medications, and other eight vitamins were used as confounding factors. A total of 389 participants were enrolled in this study, including comprising 83 CRC patients without a family history and 306 healthy controls, between January 2020 and March 2021 at the Department of Colorectal Surgery and Endoscope Center at the Xinhua Hospital, Shanghai Jiao Tong University School of Medicine. Adjusted smoothing spline plots, subgroup analysis, and multivariate logistic regression analysis were conducted to estimate the relative risk between serum 25(OH)D and sporadic CRC risk.ResultsAfter fully adjusting the confounding factors, it was found that circulating 25(OH)D played a protective role in patients with CRC (OR = 0.76 [0.63, 0.92], p = 0.004) and that an adequate vitamin D level was significantly associated with a reduced CRC risk compared to vitamin D deficiency or sufficiency (OR = 0.31 [0.11, 0.9], p = 0.03). According to this study, statins did not affect the potential protective effects of vitamin D (OR = 1.02 [0.97, 1.08], p = 0.44) and may account for the inverse association between serum 25(OH)D and colorectal cancer.ConclusionAn adequate level of serum 25(OH)D was associated with a reduced CRC risk, especially for the elderly. The finding on the absence of protective effect of vitamin D in the statin use subgroup, suggests it may be one of the substantial contributing confounders, and warrants further investigation.

IntroductionIn recent years there has been an increasing interest in the field of educational computer games (ECGs). Although ECGs have been researched, more analyses still need to be performed on these variables to check their effects on language learning.MethodsTo this end, 74-third grade female state high school students from two schools in Zanjan were selected through a two-stage cluster random sampling method. The number of students in each class was 37. One of the classes (control group) was trained traditionally and the other was for one semester through the researchers-made ECGs. After completing the training, the research tools were performed as a post-test on the experimental and control groups. The data collection stage took place for about 6 months.ResultsBased on the results from the research questions, the use of training computers has been effective in increasing AR, ASR, and AA.DiscussionIt has significant implications for teachers and learners in the EFL context and opens interesting opportunities for administrators and curriculum developers to explore when planning EFL courses.

As one of the most common post-transcriptional modifications of mRNAs and noncoding RNAs, N6-methyladenosine (m6A) modification regulates almost every aspect of RNA metabolism. Evidence indicates that dysregulation of m6A modification and associated proteins contributes to glioblastoma (GBM) progression. However, the function of fat mass and obesity-associated protein (FTO), an m6A demethylase, has not been systematically and comprehensively explored in GBM. Here, we found that decreased FTO expression in clinical specimens correlated with higher glioma grades and poorer clinical outcomes. Functionally, FTO inhibited growth and invasion in GBM cells in vitro and in vivo. Mechanistically, FTO regulated the m6A modification of primary microRNA-10a (pri-miR-10a), which could be recognized by reader HNRNPA2B1, recruiting the microRNA microprocessor complex protein DGCR8 and mediating pri-miR-10a processing. Furthermore, the transcriptional activity of FTO was inhibited by the transcription factor SPI1, which could be specifically disrupted by the SPI1 inhibitor DB2313. Treatment with this inhibitor restored endogenous FTO expression and decreased GBM tumor burden, suggesting that FTO may serve as a novel prognostic indicator and therapeutic molecular target of GBM.

Abstract Background Gliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), a newly found type of endogenous noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in the pathophysiological processes and TME remodelling of various tumours. Methods CircRNA sequencing analysis was performed to explore circRNA expression profiles in normal and glioma tissues. The biological function of a novel circRNA, namely, circNEIL3, in glioma development was confirmed both in vitro and in vivo. Mechanistically, RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), luciferase reporter, and co-immunoprecipitation assays were conducted. Results We identified circNEIL3, which could be cyclized by EWS RNA-binding protein 1(EWSR1), to be upregulated in glioma tissues and to correlate positively with glioma malignant progression. Functionally, we confirmed that circNEIL3 promotes tumorigenesis and carcinogenic progression of glioma in vitro and in vivo. Mechanistically, circNEIL3 stabilizes IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3) protein, a known oncogenic protein, by preventing HECTD4-mediated ubiquitination. Moreover, circNEIL3 overexpression glioma cells drives macrophage infiltration into the tumour microenvironment (TME). Finally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and transmitted to infiltrated tumour associated macrophages (TAMs), enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3 and in turn promoting glioma progression. Conclusions This work reveals that circNEIL3 plays a nonnegligible multifaceted role in promoting gliomagenesis, malignant progression and macrophage tumour-promoting phenotypes polarization, highlighting that circNEIL3 is a potential prognostic biomarker and therapeutic target in glioma.

Abstract This multicenter phase-II trial aimed to investigate the efficacy, safety, and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC. Patients who failed from first-line EGFR-TKIs and did not harbor T790M mutation were enrolled. Toripalimab plus carboplatin and pemetrexed were administrated every three weeks for up to six cycles, followed by the maintenance of toripalimab and pemetrexed. The primary endpoint was objective-response rate (ORR). Integrated biomarker analysis of PD-L1 expression, tumor mutational burden (TMB), CD8 + tumor-infiltrating lymphocyte (TIL) density, whole-exome, and transcriptome sequencing on tumor biopsies were also conducted. Forty patients were enrolled with an overall ORR of 50.0% and disease-control rate (DCR) of 87.5%. The median progression free survival (PFS) and overall survival were 7.0 and 23.5 months, respectively. The most common treatment-related adverse effects were leukopenia, neutropenia, anemia, ALT/AST elevation, and nausea. Biomarker analysis showed that none of PD-L1 expression, TMB level, and CD8 + TIL density could serve as a predictive biomarker. Integrated analysis of whole-exome and transcriptome sequencing data revealed that patients with DSPP mutation had a decreased M2 macrophage infiltration and associated with longer PFS than those of wild type. Toripalimab plus chemotherapy showed a promising anti-tumor activity with acceptable safety profiles as the second-line setting in patients with EGFR-mutant NSCLC. DSPP mutation might serve as a potential biomarker for this combination. A phase-III trial to compare toripalimab versus placebo in combination with chemotherapy in this setting is ongoing (NCT03924050).