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The flesh color of pummelo (Citrus maxima) fruits is highly diverse and largely depends on the level of carotenoids, which are beneficial to human health. It is vital to investigate the regulatory network of carotenoid biosynthesis to improve the carotenoid content in pummelo. However, the molecular mechanism underlying carotenoid accumulation in pummelo is not fully understood. In this study, we identified a novel histone methyltransferase gene, CgSDG40, involved in carotenoid regulation by analyzing the flesh transcriptome of typical white-fleshed pummelo, red-fleshed pummelo and extreme-colored F1 hybrids from a segregated pummelo population. Expression of CgSDG40 corresponded to flesh color change and was highly coexpressed with CgPSY1. Interestingly, CgSDG40 and CgPSY1 are located physically adjacent to each other on the chromosome in opposite directions, sharing a partially overlapping promoter region. Subcellular localization analysis indicated that CgSDG40 localizes to the nucleus. Overexpression of CgSDG40 significantly increased the total carotenoid content in citrus calli relative to that in wild type. In addition, expression of CgPSY1 was significantly activated in overexpression lines relative to wild type. Taken together, our findings reveal a novel histone methyltransferase regulator, CgSDG40, involved in the regulation of carotenoid biosynthesis in citrus and provide new strategies for molecular design breeding and genetic improvement of fruit color and nutritional quality.

Abstract Background Most patients with acute myeloid leukemia (AML) eventually develop drug resistance, leading to a poor prognosis. Dysregulated long gene non coding RNAs (lincRNAs) have been implicated in chemoresistance in AML. Unfortunately, the effects of lincRNAs which participate in regulating the Adriamycin (ADR) resistance in AML cells remain unclear. Thus, the purpose of this study is to determine LINC00987 function in ADR-resistant AML. Methods In this study, ADR-resistant cells were constructed. LINC00987, miRNAs, and HMGA2 mRNA expression were measured by qRT-PCR. P-GP, BCRP, and HMGA2 protein were measured by Western blot. The proliferation was analyzed by MTS and calculated IC50. Soft agar colony formation assay and TUNEL staining were used to analyze cell colony formation and apoptosis. Xenograft tumor experiment was used to analyze the xenograft tumor growth of ADR-resistant AML. Results We found that higher expression of LINC00987 was observed in AML patients and associated with poor overall survival in AML patients. LINC00987 expression was increased in ADR-resistant AML cells, including ADR/MOLM13 and ADR/HL-60 cells. LINC00987 downregulation reduces ADR resistance in ADR/MOLM13 and ADR/HL-60 cells in vitro and in vivo, while LINC00987 overexpression enhanced ADR resistance in MOLM13 and HL-60 cells. Additionally, LINC00987 functions as a competing endogenous RNA for miR-4458 to affect ADR resistance in ADR/MOLM13 and ADR/HL-60 cells. HMGA2 is a target of miR-4458. LINC00987 knockdown and miR-4458 overexpression reduced HMGA2 expression. HMGA2 overexpression enhanced ADR resistance, which reversed the function of LINC00987 silencing in suppressing ADR resistance of ADR/MOLM13 and ADR/HL-60 cells. Conclusions Downregulation of LINC00987 weakens ADR resistance by releasing miR-4458 to deplete HMGA2 in ADR/MOLM13 and ADR/HL-60. Therefore, LINC00987 may act as the therapeutic target for treating chemoresistant AML.

IntroductionPrimary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin’s lymphoma that affects brain parenchyma, eyes, cerebrospinal fluid, and spinal cord. Diagnosing PCNSL can be challenging because imaging studies often show similar patterns as other brain tumors, and stereotactic brain lesion biopsy conformation is invasive and not always possible. This study aimed to validate a previous proteomic profiling (PMID: 32610669) of cerebrospinal fluid (CSF) and develop a CSF-based proteomic panel for accurate PCNSL diagnosis and differentiation.MethodsCSF samples were collected from patients of 30 PCNSL, 30 other brain tumors, and 31 tumor-free/benign controls. Liquid chromatography tandem-mass spectrometry targeted proteomics analysis was used to establish CSF-based proteomic panels.ResultsFinal proteomic panels were selected and optimized to diagnose PCNSL from tumor-free controls or other brain tumor lesions with an area under the curve (AUC) of 0.873 (95%CI: 0.723-0.948) and 0.937 (95%CI: 0.807- 0.985), respectively. Pathways analysis showed diagnosis panel features were significantly enriched in pathways related to extracellular matrices-receptor interaction, focal adhesion, and PI3K-Akt signaling, while prion disease, mineral absorption and HIF-1 signaling were significantly enriched with differentiation panel features.DiscussionThis study suggests an accurate clinical test panel for PCNSL diagnosis and differentiation with CSF-based proteomic signatures, which may help overcome the challenges of current diagnostic methods and improve patient outcomes.

Studies on odontogenesis are of great importance to treat dental abnormalities and tooth loss. However, the odontogenesis process was poorly studied in humans, especially at the early developmental stages. Here, we combined RNA sequencing (RNA-seq) with Laser-capture microdissection (LCM) to establish a spatiotemporal transcriptomic investigation for human deciduous tooth germs at the crucial developmental stage to offer new perspectives to understand tooth development and instruct tooth regeneration. Several hallmark events, including angiogenesis, ossification, axonogenesis, and extracellular matrix (ECM) organization, were identified during odontogenesis in human dental epithelium and mesenchyme from the cap stage to the early bell stage. ECM played an essential role in the shift of tooth-inductive capability. Species comparisons demonstrated these hallmark events both in humans and mice. This study reveals the hallmark events during odontogenesis, enriching the transcriptomic research on human tooth development at the early stage.

Abstract Objectives To investigate the association of albumin-corrected anion gap (ACAG) with non-alcoholic fatty liver disease (NAFLD) and clinically significant fibrosis (CSF) defined by vibration-controlled transient elastography measurements. Methods This cross-sectional study including 4531 participants was conducted using the data from the NHANES database of cycles 2017–2018. The outcomes were set as NAFLD vs. non-NAFLD and NAFLD with CSF vs. NAFLD without CSF. The generalized additive model and restricted cubic spline analyses were used to assess the nonlinear relationship. The generalized linear models, logistic regression models, sensitivity analysis, P trend test, subgroup analysis, and mediation analysis were employed to analyze the association. Finally, an ACAG-based model was constructed and evaluated. Results A higher ACAG level was an independent risk factor for NAFLD (P 0.05). The sensitivity analysis and P trend test results substantiated the significantly positive relationship between ACAG and NAFLD (P

Abstract Background This study aims to assess the efficacy and safety of Qingpeng ointment (QPO), a Tibetan medicine for alleviating symptoms in individuals with acute gouty arthritis (AGA). Methods This study was a randomized, double-blind, placebo-controlled trial that involved individuals with AGA whose joint pain, as measured on a visual analog scale (VAS) from 0 to 10, was equal to or greater than 3. The participants were randomly assigned to either the QPO or the placebo group and received their respective treatments twice daily for seven consecutive days. In case of intolerable pain, the participants were allowed to use diclofenac sodium sustained-release tablets as a rescue medicine. The primary outcomes measured were joint pain and swelling, while the secondary outcomes included joint mobility, redness, serum uric acid levels, C-reactive protein levels, and the amount of remaining rescue medicine. Any adverse events that occurred during the trial were also recorded. Results A total of 203 cases were divided into two groups, with balanced baselines: 102 in the QPO group and 101 in the placebo group. For joint pain, differences between the groups were notable in the VAS scores [1.75 (0, 3.00) versus 2.00 (1.00, 3.50); P = 0.038], changes in VAS [5.00 (3.00, 6.00) versus 4.00 (2.00, 6.00); P = 0.036], and disappearance rate [26.47% compared to 15.84%; P = 0.046] after treatment. Concerning joint swelling, significant between-group differences were observed in the VAS scores [1.00 (0, 2.30) versus 2.00 (0.70, 3.00); P = 0.032] and disappearance rate [33.33% compared to 21.78%; P = 0.046] at treatment completion. The QPO group exhibited a statistically significant mobility improvement compared to the placebo group (P = 0.004). No significant differences were found in other secondary outcomes. Five patients, four from the QPO group and one from the other, encountered mild adverse events, primarily skin irritation. All of these cases were resolved after dosage reduction or discontinuation of the medication. Conclusions Compared to the placebo, QPO exhibits positive effects on AGA by alleviating pain, reducing swelling, and enhancing joint mobility, without causing significant adverse effects. Trial Registration ISRCTN34355813. Registered on 25/01/2021.

AbstractMacrophages play a crucial role in tumor initiation and progression, while macrophage-associated gene signature in colorectal cancer (CRC) patients has not been investigated. Our study aimed to identify macrophage-related molecular subgroups and develop a macrophage-related risk model to predict CRC prognosis. The mRNA expression profile and clinical information of CRC patients were obtained from TCGA and GEO databases. CRC patients from TCGA were divided into high and low macrophage subgroups based on the median macrophage score. The ESTIMATE and CIBERSORT algorithms were used to assess immune cell infiltration between subgroups. GSVA and GSEA analyses were performed to investigate differences in enriched pathways between subgroups. Univariate and LASSO Cox regression were used to build a prognostic risk model, which was further validated in the GSE39582 dataset. A high macrophage score subgroup was associated with poor prognosis, highly activated immune-related pathways and an immune-active microenvironment. A total of 547 differentially expressed macrophage-related genes (DEMRGs) were identified, among which seven genes (including RIMKLB, UST, PCOLCE2, ZNF829, TMEM59L, CILP2, DTNA) were identified by COX regression analyses and used to build a risk score model. The risk model shows good predictive and diagnostic values for CRC patients in both TCGA and GSE39852 datasets. Furthermore, multivariate Cox regression analysis showed that the risk score was an independent risk factor for overall survival in CRC patients. Our findings provided a novel insight into macrophage heterogeneity and its immunological role in CRC. This risk score model may serve as an effective prognostic tool and contribute to personalised clinical management of CRC patients.

Glaucoma is a chronic ocular disease characterized by optic atrophy and visual field defect. The main risk factor for glaucoma onset and progression is elevated intraocular pressure, which is caused by increased aqueous humor outflow resistance. Currently, the primary method for glaucoma therapy is the use of intraocular pressure lowering drugs. However, these drugs, when administered through eye drops, have low bioavailability, require frequent administration, and often result in adverse effects. To overcome these challenges, the application of nanotechnology for drug delivery has emerged as a promising approach. Nanoparticles can physically adsorb, encapsulate, or chemically graft drugs, thereby improving their efficacy, retention time, and reducing adverse reactions. Moreover, nanotechnology has opened up new avenues for ocular administration. This article provides a comprehensive review of nano systems for intraocular pressure lowering drugs, encompassing cholinergic agonists, β-adrenergic antagonists, α-adrenergic agonists, prostaglandin analogs, carbonic anhydrase inhibitors, Rho kinase inhibitors, and complex preparations. The aim is to offer novel insights for the development of nanotechnology in the field of intraocular pressure lowering drugs.

Abstract Apoptosis releases numerous apoptotic vesicles that regulate processes such as cell proliferation, immunity, and tissue regeneration and repair. Now, it has also emerged as an attractive candidate for biotherapeutics. However, apoptotic vesicles encompass a diverse range of subtypes, and it remains unclear which specific subtypes play a pivotal role. In this study, we successfully isolated different apoptotic vesicle subtypes based on their sizes and characterized them using NTA and TEM techniques, respectively. We compared the functional variances among the distinct subtypes of apoptotic vesicles in terms of stem cell proliferation, migration, and differentiation, as well as for endothelial cell and macrophage function, effectively identifying subtypes that exhibit discernible functional differences. ApoSEV (with diameter 1000 nm) played the opposite effect on cell function and tissue regeneration. Lastly, employing protein analysis and gene sequencing techniques, we elucidated the intrinsic mechanisms underlying these differences between different subtypes of apoEVs. Collectively, this study identified that apoptotic vesicle subtypes possessed distinct bio‐functions in regulating stem cell function and behaviour and modulating tissue regeneration, which primarily attribute to the distinct profiling of protein and mRNA in different subtypes. This comprehensive analysis of specific subtypes of apoEVs would provide novel insights for potential therapeutic applications in cell biology and tissue regeneration.

Extracellular polymeric substances (EPS) constitutes crucial elements within bacterial biofilms, facilitating accelerated antimicrobial resistance and conferring defense against the host's immune cells. Developing precise and effective antibiofilm approaches and strategies, tailored to the specific characteristics of EPS composition, can offer valuable insights for the creation of novel antimicrobial drugs. This, in turn, holds the potential to mitigate the alarming issue of bacterial drug resistance. Current analysis of EPS compositions relies heavily on colorimetric approaches with a significant bias, which is likely due to the selection of a standard compound and the cross-interference of various EPS compounds. Considering the pivotal role of EPS in biofilm functionality, it is imperative for EPS research to delve deeper into the analysis of intricate compositions, moving beyond the current focus on polymeric materials. This necessitates a shift from heavy reliance on colorimetric analytic methods to more comprehensive and nuanced analytical approaches. In this study, we have provided a comprehensive summary of existing analytical methods utilized in the characterization of EPS compositions. Additionally, novel strategies aimed at targeting EPS to enhance biofilm penetration were explored, with a specific focus on highlighting the limitations associated with colorimetric methods. Furthermore, we have outlined the challenges faced in identifying additional components of EPS and propose a prospective research plan to address these challenges. This review has the potential to guide future researchers in the search for novel compounds capable of suppressing EPS, thereby inhibiting biofilm formation. This insight opens up a new avenue for exploration within this research domain.

Abstract Germline-somatic mutation interactions are universal and associated with tumorigenesis, but their role in breast cancer, especially in non-Caucasians, remains poorly characterized. We performed large-scale prospective targeted sequencing of matched tumor-blood samples from 4079 Chinese females, coupled with detailed clinical annotation, to map interactions between germline and somatic alterations. We discovered 368 pathogenic germline variants and identified 5 breast cancer DNA repair-associated genes (BCDGs; BRCA1/BRCA2/CHEK2/PALB2/TP53). BCDG mutation carriers, especially those with two-hit inactivation, demonstrated younger onset, higher tumor mutation burden, and greater clinical benefits from platinum drugs, PARP inhibitors, and immune checkpoint inhibitors. Furthermore, we leveraged a multiomics cohort to reveal that clinical benefits derived from two-hit events are associated with increased genome instability and an immune-activated tumor microenvironment. We also established an ethnicity-specific tool to predict BCDG mutation and two-hit status for genetic evaluation and therapeutic decisions. Overall, this study leveraged the large sequencing cohort of Chinese breast cancers, optimizing genomics-guided selection of DNA damaging-targeted therapy and immunotherapy within a broader population.

Stem cell senescence and exhaustion, a hallmark of aging, lead to declines in tissue repair and regeneration in aged individuals. Emerging evidence has revealed that epigenetic regulation plays critical roles in the self-renew, lineage-commitment, survival, and function of stem cells. Moreover, epigenetic alterations are considered important drivers of stem cell dysfunction during aging. In this review, we focused on current knowledge of the histone modifications in the aging of mesenchymal stem cells (MSCs). The aberrant epigenetic modifications on histones, including methylation and acetylation, have been found in aging MSCs. By disturbing the expression of specific genes, these epigenetic modifications affect the self-renew, survival, and differentiation of MSCs. A set of epigenetic enzymes that write or erase these modifications are critical in regulating the aging of MSCs. Furthermore, we discussed the rejuvenation strategies based on epigenetics to prevent stem cell aging and/or rejuvenate senescent MSCs.

Abstract Microbes well-adapted to the Arctic Ocean are promising for producing novel compounds, due to their fancy strategies for adaptation and being under-investigated. Two new phenazine alkaloids (1 and 2) and one new phenoxazine (3) were isolated from Nocardiopsis dassonvillei 502F, a strain originally isolated from Arctic deep-sea sediments. AntiSMASH analysis of the genome of Nocardiopsis dassonvillei 502F revealed the presence of 16 putative biosynthetic gene clusters (BGCs), including a phenazine BGC. Most of the isolated compounds were evaluated for their antibacterial, antiallergic, and cytotoxic activities. Among them, compounds 4 and 5 exhibited potent in vitro cytotoxic activities against osteosarcoma cell line 143B with IC50 values 0.16 and 20.0 μM, respectively. Besides, the results of antiallergic activities of compounds 6–8 exhibited inhibitory activities with IC50 values of 10.88 ± 3.05, 38.88 ± 3.29, and 2.44 ± 0.17 μg/mL, respectively (IC50 91.6 μM for the positive control loratadine). Graphical Abstract

The epithelial–mesenchymal transition (EMT) phenotype, identified as a significant clinical indicator in regard to cancer, manifests as a biological process wherein cells transition from having epithelial to mesenchymal characteristics. Physiologically, EMT plays a crucial role in tissue remodeling, promoting healing, repair, and responses to various types of tissue damage. This study investigated the impact of BNE-RRC on oral cancer cells (KB) and revealed its significant effects on cancer cell growth, migration, invasion, and the EMT. BNE-RRC induces the epithelial-like morphology in KB cells, effectively reversing the EMT to a mesenchymal–epithelial transition (MET). Extraordinarily, sustained culturing of cancer cells with BNE-RRC for 14 days maintains an epithelial status even after treatment withdrawal, suggesting that BNE-RRC is a potential therapeutic agent for cancer. These findings highlight the promise of BNE-RRC as a comprehensive therapeutic agent for cancer treatment that acts by inhibiting cancer cell growth, migration, and invasion while also orchestrating a reversal of the EMT process. In this study, we propose that BNE-RRC could be an effective agent for cancer treatment.

Recent developments on the electron optics simulator (EOS) are reported in this paper. The EOS is a finite element two-dimensional (2D) and three-dimensional (3D) electrostatic particle steady-state trajectory code that has been widely used for beam optics modeling of vacuum electronic devices. To extend the application scope and improve the computation efficiency, four significant advances have been made and are presented in this paper. First, the code is reprogrammed to consider physical models that contain dielectrics and to support charge excitation. Second, more primary particle emission models are added in EOS to meet the needs for simulating electron and ion optics devices for diverse applications. For the precise simulation of the secondary electron emission, the Vaughan model is improved, and the Furman model is newly added in EOS. Finally, the algebraic multigrid algorithm has been embedded in EOS, which can significantly improve the computation efficiency for problems with large-scale matrices. For these developments, the necessary principles and corresponding performance are shown in detail in this paper.

BackgroundCentral catheter bloodstream infections (CRBSI) is a major cause of healthcare-associated infections. However, few factors are generally accepted and some studies have conflicting finding about some factors, possibly caused by limitation associated with an individual study. This study was to identify risk factors for CRBSI in intensive care units.MethodsWe searched the PubMed, Cochrane Library, Web of science and EMBASE databases and the 4 top Chinese-language databases, including WanFang data, China National Knowledge Infrastructure (CNKI), and Chinese Science and Technology Journal Database (VIP), China Biology Medicine disc (CBM) as of July 2023. Case control and cohort studies were included. Two authors independently screened the literature and evaluated the quality of the studies using the Newcastle-Ottawa scale (NOS). The pooled effect size was estimated using the odds ratio (OR), and the corresponding 95% confidence interval (CI) was calculated. The Cochrane Q (χ2) and I2 tests were used to assess heterogeneity among studies, and each risk factor was tested for its robustness using fixed- or random-effects models.FindingsA total of 32 studies enrolled, among which eleven factors were identified, they were divided into two categories: modifiable and unmodifiable factors. Modifiable factors: duration of catheterization (≥ 5d) (OR: 2.07, 95%CI: 1.41-3.03), duration of catheterization (≥ 7d) (OR: 3.62, 95%CI: 2.65-4.97), duration of catheterization (≥ 14d)(OR: 4.85, 95%CI: 3.35-7.01), total parenteral nutrition (OR: 2.27,95%CI: 1.56-3.29), use of multiple-lumen catheters(OR: 3.41, 95%CI: 2.27-5.11), times of tube indwelling (OR: 3.50, 95%CI: 2.93-4.17), length of ICU stay (OR: 4.05, 95%CI: 2.41-6.80), the position of indwelling(OR: 2.41, 95%CI: 2.03-2.85); Unmodifiable factors: APACHEII scores (OR: 1.84, 95%CI: 1.54-2.20), Age≥ 60 years old (OR: 2.19, 95%CI: 1.76-2.73), the extensive use of antibiotic (OR: 3.54, 95%CI: 1.65-7.61), Diabetes mellitus (OR: 3.06, 95%CI: 2.56-3.66), Immunosuppression (OR: 2.87, 95%CI: 2.08-3.95).ConclusionsEffective interventions targeting the above modifiable factors may reduce the risk of developing CRBSI in ICU and improve the clinical outcome of patients. Further prospective studies are needed to confirm these findings.

(1) Background: A rise in intraocular pressure (IOP) and decreased retinal ganglion cells are frequent indicators of effective modeling of chronic ocular hypertension in mice. In this study, the sensitivity of the mouse model to pharmaceutical therapy to reduce intraocular tension was assessed, the model’s safety was confirmed using a cytotoxicity test, and the success rate of the mouse model of ocular hypertension was assessed by assessing alterations in IOP and neurons in the ganglion cell layer. (2) Methods: A mouse model of chronic ocular hypertension was produced in this study by employing photocrosslinkable sericin hydrogel injection and LED lamp irradiation. The eyes of 25 C57BL/6 male mice were subjected to 405 nm UV light from the front for 2 min after being injected with 5 μL of sericin hydrogel in the anterior chamber of the left eye. IOP in the mice was measured daily, and IOP rises greater than 5 mmHg were considered intraocular hypertension. When the IOP was lowered, the intervention was repeated once, but the interval between treatments was at least 2 weeks. The right eyes were not treated with anything as a normal control group. Mice eyeballs were stained with HE, Ni-type, and immunofluorescence to assess the model’s efficacy. Two common drugs (tafluprost eye drops and timolol eye drops) were provided for one week after four weeks of stable IOP, and IOP changes were assessed to determine the drug sensitivity of the mouse model of chronic ocular hypertension. Furthermore, CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS) was utilized to investigate the safety of the ocular hypertension model by evaluating the deleterious effects of photocrosslinkable sericin hydrogel on cells. (3) Results: Before injection, the basal IOP was (9.42 ± 1.28) mmHg (1 kPa = 7.5 mmHg) in the experimental group and (9.08 ± 1.21) in the control group. After injection, cataract occurred in one eye, corneal edema in one eye, endophthalmitis in one eye, iris incarceration in one eye, and eyeball atrophy in one eye. Five mice with complications were excluded from the experiment, and twenty mice were left. Four weeks after injection, the IOP of the experimental group was maintained at (19.7 ± 4.52) mmHg, and that of the control group was maintained at (9.92 ± 1.55) mmHg, and the difference between the two groups was statistically significant (p < 0.05). Before the intervention, the IOP in the experimental group was (21.7 ± 3.31) mmHg in the high IOP control group, (20.33 ± 2.00) mmHg in the tafluprost eye drops group, and (20.67 ± 3.12) mmHg in the timolol maleate eye drops group. The IOP after the intervention was (23.2 ± 1.03) mmHg, (12.7 ± 2.11) mmHg, and (10.4 ± 1.43) mmHg, respectively. Before and after the intervention, there were no significant differences in the high-IOP control group (p > 0.05), there were statistically significant differences in the timolol eye drops group (p < 0.05), and there were statistically significant differences in the tafluprost eye drops group (p < 0.05). One week after drug withdrawal, there was no significant difference in IOP among the three groups (p > 0.05). In the high-IOP group, the protein (sericin hydrogel) showed a short strips or fragmented structure in the anterior chamber, accompanied by a large number of macrophages and a small number of plasma cells. The shape of the chamber angle was normal in the blank control group. The number of retinal ganglion cells decreased significantly 8 weeks after injection of sericin hydrogel into the anterior chamber, and the difference was statistically significant compared with the blank control group (p < 0.05). After the cells were treated with photocrosslinkable sericin hydrogel, there was no significant difference in the data of the CellTiter 96® assay kit of MTS compared with the blank control group (p > 0.05). (4) Conclusions: A mouse model of chronic intraocular hypertension can be established successfully by injecting sericin in the anterior chamber and irradiating with ultraviolet light. The model can simulate the structural and functional changes of glaucoma and can effectively reduce IOP after the action of most antihypertensive drugs, and it is highly sensitive to drugs. Sericin has no obvious toxic effect on cells and has high safety.

Residue contact maps provide a condensed two-dimensional representation of three-dimensional protein structures, serving as a foundational framework in structural modeling but also as an effective tool in their own right in identifying inter-helical binding sites and drawing insights about protein function. Treating contact maps primarily as an intermediate step for 3D structure prediction, contact prediction methods have limited themselves exclusively to sequential features. Now that AlphaFold2 predicts 3D structures with good accuracy in general, we examine (1) how well predicted 3D structures can be directly used for deciding residue contacts, and (2) whether features from 3D structures can be leveraged to further improve residue contact prediction. With a well-known benchmark dataset, we tested predicting inter-helical residue contact based on AlphaFold2’s predicted structures, which gave an 83% average precision, already outperforming a sequential features-based state-of-the-art model. We then developed a procedure to extract features from atomic structure in the neighborhood of a residue pair, hypothesizing that these features will be useful in determining if the residue pair is in contact, provided the structure is decently accurate, such as predicted by AlphaFold2. Training on features generated from experimentally determined structures, we leveraged knowledge from known structures to significantly improve residue contact prediction, when testing using the same set of features but derived using AlphaFold2 structures. Our results demonstrate a remarkable improvement over AlphaFold2, achieving over 91.9% average precision for a held-out subset and over 89.5% average precision in cross-validation experiments.

Abstract Soil salinization is a growing issue that limits agriculture globally. Understanding the mechanism underlying salt tolerance in halophytic grasses can provide new insights into engineering plant salinity tolerance in glycophytic plants. Seashore paspalum (Paspalum vaginatum Sw.) is a halophytic turfgrass and genomic model system for salt tolerance research in cereals and other grasses. However, the salt tolerance mechanism of this grass largely unknown. To explore the correlation between Na+ accumulation and salt tolerance in different tissues, we utilized two P. vaginatum accessions that exhibit contrasting tolerance to salinity. To accomplish this, we employed various analytical techniques including ICP-MS-based ion analysis, lipidomic profiling analysis, enzyme assays, and integrated transcriptomic and metabolomic analysis. Under high salinity, salt-tolerant P. vaginatum plants exhibited better growth and Na+ uptake compared to salt-sensitive plants. Salt-tolerant plants accumulated heightened Na+ accumulation in their roots, leading to increased production of root-sourced H2O2, which in turn activated the antioxidant systems. In salt-tolerant plants, metabolome profiling revealed tissue-specific metabolic changes, with increased amino acids, phenolic acids, and polyols in roots, and increased amino acids, flavonoids, and alkaloids in leaves. High salinity induced lipidome adaptation in roots, enhancing lipid metabolism in salt-tolerant plants. Moreover, through integrated analysis, the importance of amino acid metabolism in conferring salt tolerance was highlighted. This study significantly enhances our current understanding of salt-tolerant mechanisms in halophyte grass, thereby offering valuable insights for breeding and genetically engineering salt tolerance in glycophytic plants.

Abstract Photocatalytic carboxylation of alkenes with CO2 is a promising and sustainable strategy to synthesize high value-added carboxylic acids. However, it is challenging and rarely investigated for unactivated alkenes due to their low reactivities. Herein, we report a visible-light photoredox-catalyzed arylcarboxylation of unactivated alkenes with CO2, delivering a variety of tetrahydronaphthalen-1-ylacetic acids, indan-1-ylacetic acids, indolin-3-ylacetic acids, chroman-4-ylacetic acids and thiochroman-4-ylacetic acids in moderate-to-good yields. This reaction features high chemo- and regio-selectivities, mild reaction conditions (1 atm, room temperature), broad substrate scope, good functional group compatibility, easy scalability and facile derivatization of products. Mechanistic studies indicate that in situ generation of carbon dioxide radical anion and following radical addition to unactivated alkenes might be involved in the process.

AbstractThe southeastern margin of the Bayanhar block (BHB) is located at the junction of the Bayanhar block and the southern China block (SCB). Strong earthquakes occurred frequently in this region because of the intensive tectonic movement. The stress changes caused by strong earthquakes and the observed background seismicity can be used to forecast strong earthquake probability in this region. Therefore, we construct a 3D (three Dimension) viscoelastic finite element model that includes the complex fault system, inhomogeneous medium, tectonic stress, and gravity to simulate the evolutionary stress field when using the observed Global Positioning System (GPS) vectors as the boundary conditions. In addition, we calculate the strong earthquake probability based on the calculated stress and a Poisson probability distribution. The stress evolution result shows the Xianshuihe fault (XSHF), the Huya fault (HYF) and the southern segment except for the Yaan County of Longmenshan fault (LMSF) are located in the stress enhancement area indicating high seismic potential. However, the Minjiang fault (MJF) is located in the stress shadow area. After the Lushan and Jiuzhaigou earthquakes, there is still a high possibility of strong earthquakes in the MJF, HYF, and LMSF zone, according to the strong earthquake probability result.

Abstract Background Triple‐negative breast cancer (TNBC) presents the most challenging subtype of all breast cancers because of its aggressive clinical phenotypes and absence of viable therapy targets. In order to identify effective molecular targets for treating patients with TNBC, we conducted an integration analysis of our recently published TNBC dataset of quantitative proteomics and RNA‐Sequencing, and found the abnormal upregulation of chromosome 9 open reading frame 142 (C9orf142) in TNBC. However, the functional roles of C9orf142 in TNBC are unclear. Methods In vitro and in vivo functional experiments were performed to assess potential roles of C9orf142 in TNBC. Immunoblotting, real‐time quantitative polymerase chain reaction (RT‐qPCR), and immunofluorescent staining were used to investigate the expression levels of C9orf142 and its downstream molecules. The molecular mechanisms underlying C9orf142‐regulated mouse double minute 2 (MDM2)‐binding protein (MTBP) were determined by chromatin immunoprecipitation (ChIP) and dual‐luciferase reporter assays. Results In TNBC tissues and metastatic lymph nodes, we observed that C9orf142 exhibited abnormal up‐regulation, and its elevated expression was indicative of unfavorable prognosis for TNBC patients. Both in vitro and in vivo functional experiments demonstrated that C9orf142 accelerated TNBC growth and metastasis. Further mechanism exploration revealed that C9orf142 transcriptionally activated MTBP, thereby regulating its downstream MDM2/p53/p21 signaling axis and the transition of cell cycle from G1 to S phase. Functional rescue experiment demonstrated that knockdown of MTBP attenuated C9orf142‐mediated tumour growth and metastasis. Furthermore, depletion of C9orf142 remarkably increased the responsiveness of TNBC cells to CDK4/6 inhibitor abemaciclib. Conclusions Together, these findings unveil a previously unrecognized effect of C9orf142 in TNBC progression and responsiveness to CDK4/6 inhibitor, and emphasize C9orf142 as a promising intervention target for TNBC treatment.

Abstract Background To examine the levels of exosome-derived connexin 43 (Cx43) in plasma and estimate its forecast value in patients with melanoma. Methods We measured the plasma exosome-derived Cx43 levels in the plasma of 112 melanoma patients and 50 healthy controls. Results The plasma exosome-derived Cx43 levels in patients with melanoma were substantially downregulated as opposed to the levels in healthy controls (P

The international investment arbitration system between investors and host countries originated from the international commercial arbitration system. International investment disputes are usually disputes caused by the host country’s policies to protect public interests and the dissatisfaction of private investors caused by regulations. There are few methods for intelligently recommending judgment documents based on factual texts in international investment arbitration cases. Because of this, this paper proposes a recommendation algorithm for international investment arbitration adjudication documents based on multimodal feature fusion. This paper teaches the structural information of paragraph tags and the relationship between paragraph contexts and incomplete judgment documents. The algorithm achieves a good structuring effect of international investment arbitration documents.

We introduce a unique soft lithographic operation that exploits stamp roof collapse-induced gaps to selectively remove an alkanethiol self-assembled monolayer (SAM) on Au to generate surface patterns that are orders of magnitude smaller than structures on the original elastomer stamp. The smallest achieved feature dimension is 5 nm using a micrometer-scale structured stamp in a chemical lift-off lithography (CLL) process. Molecular patterns retained in the gaps between stamp features and their circumscribed or inscribed circles follow mathematical predictions, and their sizes can be tuned by altering the stamp structure dimensions, including height, pitch, and shape. These generated surface molecular patterns can function as biorecognition arrays or be transferred to the underneath Au layer for metallic structure creation. By combining CLL process with this gap phenomenon, soft material properties that are previously thought as demerits can be used to achieve sub-10 nm features in a straightforward sketch.

Abstract Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, which is characterized by high heterogeneity and metabolic dysregulation. Inositol monophosphatase 1(IMPA1) is critical for the metabolism of inositol, which has profound effects on gene expression and other biological processes. Here, we report for the first time that IMPA1 was upregulated in TNBC cell lines and tissues, and enhanced cell colony formation and proliferation in vitro and tumorigenicity in vivo. Additionally, IMPA1 promoted cell motility in vitro and metastatic lung colonization in vivo. Mechanistic investigations by transcriptome sequencing revealed that 4782 genes were differentially expressed between cells with IMPA1 knockdown and control cells. Among the differentially expressed genes after IMPA1 knockdown, five significantly altered genes were verified via qRT‐PCR assays. Morerover, we found that the expression profile of those five targets as a gene set was significantly associated with IMPA1 status in TNBC cells. As this gene set was associated with mTOR pathway and epithelial‐mesenchymal transition (EMT) process, we further confirmed that IMPA1 induced mTOR activity and EMT process, which at least in part contributed to IMPA1‐induced TNBC progression. Collectively, our findings reveal a previously unrecognized role of IMPA1 in TNBC progression and identify IMPA1 as a potential target for TNBC therapy.

Abstract Within the color singlet model, we calculate the exclusive production of double charmonia, double bottomonia, and double $$B_c$$ B c mesons at future super Z factory. The two heavy quarkonia or $$B_c$$ B c ’s are either two S-wave Fock states ( $$^1S_0, ~^3S_1$$ 1 S 0 , 3 S 1 ), or one S-wave and one P-wave states ( $$^1P_1,~^3P_J~(J=0,1,2)$$ 1 P 1 , 3 P J ( J = 0 , 1 , 2 ) ). The top three $$Z^0$$ Z 0 propagated channels in cross sections for double charmonia are $$\sigma {(J/\psi +h_c)}_{Z^0}=(454.0^{+39.1}_{-59.2})\times 10^{-5} fb, \sigma {(\eta _c+\chi _{c2})}_{Z^0}=(284.2^{+22.2}_{-35.3})\times 10^{-5} fb$$ σ ( J / ψ + h c ) Z 0 = ( 454 . 0 - 59.2 + 39.1 ) × 10 - 5 f b , σ ( η c + χ c 2 ) Z 0 = ( 284 . 2 - 35.3 + 22.2 ) × 10 - 5 f b , and $$\sigma {(\eta _c+\chi _{c0})}_{Z^0}=(137.0^{+9.9}_{-16.4})\times 10^{-5} fb$$ σ ( η c + χ c 0 ) Z 0 = ( 137 . 0 - 16.4 + 9.9 ) × 10 - 5 f b . For double bottomonia, they are $$\sigma {(\eta _b+\Upsilon )}_{Z^0}=(428.6^{+67.9}_{-60.9})\times 10^{-4} fb, \sigma {(\Upsilon +\chi _{b2})}_{Z^0}=(230.6^{+23.6}_{-22.2})\times 10^{-4} fb$$ σ ( η b + Υ ) Z 0 = ( 428 . 6 - 60.9 + 67.9 ) × 10 - 4 f b , σ ( Υ + χ b 2 ) Z 0 = ( 230 . 6 - 22.2 + 23.6 ) × 10 - 4 f b , and $$\sigma {(\Upsilon +\Upsilon )}_{Z^0}=(119.9^{+18.4}_{-16.6})\times 10^{-4} fb$$ σ ( Υ + Υ ) Z 0 = ( 119 . 9 - 16.6 + 18.4 ) × 10 - 4 f b . For double $$B_c$$ B c mesons, they are $$\sigma {(B_c^{*+}+B_c^{*-})}_{Z^0}=(1150^{+87}_{-84})\times 10^{-3} fb$$ σ ( B c ∗ + + B c ∗ - ) Z 0 = ( 1150 - 84 + 87 ) × 10 - 3 f b , $$\sigma {(B_c^{*+}+\chi _{bc2}^-)}_{Z^0}=(1133^{-16}_{+22})\times 10^{-3} fb$$ σ ( B c ∗ + + χ b c 2 - ) Z 0 = ( 1133 + 22 - 16 ) × 10 - 3 f b , and $$\sigma {(\eta _{bc}^++B_c^{*-})}_{Z^0}=(634.6^{+47.8}_{-45.8})\times 10^{-3} fb$$ σ ( η bc + + B c ∗ - ) Z 0 = ( 634 . 6 - 45.8 + 47.8 ) × 10 - 3 f b . Here the uncertainties come from the varying masses of constituent heavy quarks, which bring up to 20% corrections. The cross sections of double $$B_c$$ B c mesons are roughly one order of magnitude larger than those of the double bottomonia, and two orders of magnitude larger than those of the double charmonia. To make it helpful for experimental study, we present the total cross sections $$\sigma $$ σ as functions of CM energy $$\sqrt{s}$$ s , $$\sigma $$ σ as functions of the renormalization scale $$\mu $$ μ , the angle distributions $$d\sigma /dcos\theta $$ d σ / d c o s θ , and the $$p_T$$ p T distributions $$d\sigma /dp_{t}$$ d σ / d p t . We also find that the initial state radiation can bring about 30–40% suppresions when 1% $$m_Z$$ m Z energy is losing, and cross sections can increase by about 2–3 times or decrease by an order of magnitude when adopting different potential models which becomes the major source of uncertainty. The numerical results show that it might be not optimistic for the experimental observation, but it is still far from excluded at the FCC-ee and also the CEPC running in the Z factory mode.

Objective The ASTRUM-005 trial showed that serplulimab plus chemotherapy (SEP) significantly extended survival time compared with chemotherapy in the treatment of small cell lung cancer. But the survival benefits of SEP came at high costs, and its economy is not clear. Therefore, this study aimed to evaluate the cost-effectiveness of SEP from the perspective of the Chinese healthcare system.Design A partition survival model was built to simulate the outcomes. The clinical data came from the ASTRUM-005 trial, and only direct medical costs were included in the model. The utility values referred to the published literature. Scenario analyses 1 and 2 explored outcomes in the presence of a patient assistance plan (PAP) and different simulation periods, respectively. Scenario analysis 3 compared the cost-effectiveness of atezolizumab plus chemotherapy (AEP) with SEP by network meta-analysis. Sensitivity analyses were conducted to assess the robustness of the results.Outcome measures Total costs, incremental costs, life years, quality-adjusted life years (QALYs), incremental QALYs and incremental cost-effectiveness ratio (ICER).Results Compared with chemotherapy, SEP achieved an additional 0.34 QALYs at incremental costs of US$41 682.63, with an ICER of US$122 378.86/QALY. When PAP was available, ICER was US$58 316.46/QALY. In the simulation time of 5 years and 20 years, the ICER was US$132 637.97/QALY and US$118 054.59/QALY, respectively. When compared with AEP, SEP not only reduced the costs by US$47 244.87 but also gained 0.07 QALYs more. Sensitivity analyses showed that the price of serplulimab and the utility value of the progression-free survival stage were the main influencing parameters, and the results were stable.Conclusions Compared with chemotherapy, SEP was not cost-effective from the perspective of the Chinese healthcare system. However, SEP was absolutely dominant in comparison with AEP.

Abstract Orthodontic tooth movement relies on bone remodeling and periodontal tissue regeneration in response to the complicated mechanical cues on the compressive and tensive side. In general, mechanical stimulus regulates the expression of mechano-sensitive coding and non-coding genes, which in turn affects how cells are involved in bone remodeling. Growing numbers of non-coding RNAs, particularly mechano-sensitive non-coding RNA, have been verified to be essential for the regulation of osteogenesis and osteoclastogenesis and have revealed how they interact with signaling molecules to do so. This review summarizes recent findings of non-coding RNAs, including microRNAs and long non-coding RNAs, as crucial regulators of gene expression responding to mechanical stimulation, and outlines their roles in bone deposition and resorption. We focused on multiple mechano-sensitive miRNAs such as miR-21, - 29, -34, -103, -494-3p, -1246, -138-5p, -503-5p, and -3198 that play a critical role in osteogenesis function and bone resorption. The emerging roles of force-dependent regulation of lncRNAs in bone remodeling are also discussed extensively. We summarized mechano-sensitive lncRNA XIST, H19, and MALAT1 along with other lncRNAs involved in osteogenesis and osteoclastogenesis. Ultimately, we look forward to the prospects of the novel application of non-coding RNAs as potential therapeutics for tooth movement and periodontal tissue regeneration.

Background Sarcopenia, a syndrome of progressive and generalised loss of skeletal muscle, which can increase the risk of postoperative complications of colorectal cancer, but its association with postoperative surgical site infections in colorectal cancer is still inconclusive. Objective To evaluate the association of abdominal CT-assessed sarcopenia with postoperative surgical site infections in patients undergoing colorectal cancer surgery. Methods Three hundred and twenty-eight colorectal cancer patients underwent radical surgery in Gastrointestinal Surgery, the First Affiliated Hospital of University of South China between July 2019 and December 2021 were selected. Clinical data were retrospectively collected through the electronic medical record system. Sarcopenia was diagnosed by the L3 skeletal muscle index (L3 SMI) assessed using abdominal CT. Surgical site infection was assessed using the Diagnostic Criteria of Nosocomial Infection (Trial) . Multivariate Logistic regression was applied to explore the influencing factors of postoperative surgical site infection. Results The incidence of surgical site infection in sarcopenia group was higher than that in non-sarcopenia group〔27.3% (12/44) vs 12.3% (35/284) 〕 (P

Simulations of the spontaneous rupture of potential earthquakes in the vicinity of reservoir dams can provide accurate parameters for seismic resilience assessment, which is essential for improving the seismic performance of reservoir dams. In simulations of potential spontaneous ruptures, fault geometry, regional stress fields, constitutive parameters of the fault friction law, and many other factors control the slip rate, morphology, and dislocation of the rupture, thereby affecting the simulated ground motion parameters. The focus of this study was to elucidate the effects of the background stress field on the nucleation and propagation of spontaneous ruptures based on the factors influencing potential M > 7 earthquake events on the Leibo Middle Fault (LBMF) and the Mabian-Yanjing Fault (MB-YJF) in the Xiluodu dam (XLD) region. Our simulation results show that the magnitude of the regional background stress field plays a decisive role in whether a destructive earthquake exceeding the critical magnitude will occur. We found that the direction and magnitude of the regional stress significantly affect the range of rupture propagation on the fault plane, and fault geometry affects the spatial distribution of the rupture range. Under the same regional stress field magnitude and orientation, a more destructive, high-magnitude earthquake is more likely to occur on the LBMF than on the MB-YJF.

The nutrient composition, yield, water-holding capacity, texture and microstructure of Procambraus clarkii meat from April to June 2020 and three sizes (S: 10~20 g, M: 20~30 g, L: 30~40 g) of crayfish were analyzed and compared. The results showed that the moisture content of crayfish meat tended to decrease with the month of harvesting from April to June, the ash content of crayfish meat was highest in the three sizes of crayfish in May, the 6-S protein content was highest in the S group in June, and the 4-L crude fat content was lowest in the L group in April. The crayfish meat yield decreased with size and month. The pH of crayfish meat was mainly neutral (7.09~7.22). The water-holding capacity of L decreased with increasing sampling month, and the crayfish of S and M showed a trend of decreasing and then increasing. The surface hardness of crayfish flesh gradually decreased and internal hardness increased significantly (P

BMP7 as a regenerative signaling molecule mediates stem cell migration and odontoblastic differentiation (a) and as a pro-angiogenic factor promotes revascularization of endothelial cells (b). Collagen gel supports cell adhesion, spreading, and viability (c).

IntroductionGastric cancer is a highly heterogeneous malignant tumor of the digestive system. Anti-HER2 treatment can inhibit downstream signaling pathways and improve clinical treatment and outcomes in patients with HER2 protein overexpression. Currently, two standard methods for evaluating HER2 expression status are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). However, these low-throughput assays often produce discordant or equivocal results.MethodsIn this study, we presented a new HER2 protein detection method based on mass spectrometry selected reaction monitoring (MS-SRM) and validated the method. We conducted a retrospective study on 118 formalin-fixed paraffin-embedded (FFPE) tissues from patients with advanced gastric adenocarcinoma in northern China, and we compared the MS-SRM results with those from IHC and correlated them with FISH. ResultsWe established and validated the upper and lower detection limits (300-700 amol/μg) for abnormal HER2 protein expression in advanced gastric cancer. We also found that, among samples with mixed Lauren subtypes, those with a high level of HER2 expression had typical intestinal type features in pathology. DiscussionThis study demonstrated that the MS-SRM method can overcome the limitations and deficiencies of IHC, directly quantify the expression of HER2 protein in tumor cells and be used as a supplement to IHC. It has the potential to be used as a companion diagnosis for new drugs used to treat advanced gastric cancer. Large-scale clinical validation is required.

Objective The aim is to integrate quantitative and qualitative evidence to understand the effectiveness and experience of advance care planning (ACP) for frail elderly.Design A mixed-methods systematic review and meta-analysis was conducted. Quality evaluation was conducted using critical appraisal tools from the Joanna Briggs Institute. Data were synthesised and pooled for meta-analysis or meta-aggregation as needed.Data sources An electronic search of MEDLINE, CINAHL, Embase, PubMed, PsycINFO, and Cochrane Library databases from January 2003 to April 2022.Eligibility criteria for selecting studies We included experimental and mixed-methods studies. The quantitative component attempts to incorporate a broader study design. The qualitative component aids in comprehending the participant’s experience with ACP and its efficacy.Data extraction and synthesis Two independent reviewers undertook screening, data extraction and quality assessment. The quantitative and qualitative data were synthesised and integrated using a convergent segregated approach.Results There were 12 158 articles found, and 17 matched the inclusion criteria. The quality of the quantitative component of most included studies (6/10) was rated as low, and the qualitative component of half included studies (4/8) was rated as moderate. The meta-analysis showed that the intervention of ACP for frail elderly effectively increases readiness, knowledge and process of ACP behaviours. The meta-aggregation showed that the participants hold a positive attitude towards ACP and think it facilitates expressing their preferences for the medical decision.Conclusion ACP is an effective and feasible strategy to facilitate frail elderly to express their healthcare wishes timely and improve their outcomes. This study could provide proof for a better understanding of the subject and help direct future clinical practice. More well-designed randomised controlled trials evaluating the most effective ACP interventions and tools are needed for the frail elderly population.PROSPERO registration number CRD42022329615.