CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype Specific Vulnerability in IDH2- and TET2-Mutant Cells.

Clonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial cells to perform CRISPR/Cas9 screens in mutant HSPCs. Our data reveal that loss of the histone demethylase family members Kdm3b and Jmjd1c specifically reduces the fitness of Idh2- and Tet2-mutant HSPCs. Kdm3b loss in mutant cells leads to decreased expression of critical cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to inhibition of downstream JAK2 signaling. Our study nominates an epigenetic regulator and an epigenetically regulated receptor signaling pathway as genotype-specific therapeutic targets and provides a scalable platform to identify genetic dependencies in mutant HSPCs.

Qualitative and quantitative analysis of chemical components in Qianggan capsule by UHPLC-Q-TOF-MS/MS and LC-sMRM.

Qianggan capsule (QGC) is a complex preparation composed of 16 traditional Chinese medicines (TCM) that can clear heat and dampness, fortify the spleen and blood, typify qi and relieve depression. However, the chemical composition of QGC remains incompletely understood, despite its clinical use in treating chronic hepatitis and liver injury. The objective of this study was to explore the quality markers of QGC through qualitative and quantitative analysis of its chemical components. First, the chemical composition of QGC was qualitatively analyzed using UHPLC-Q-TOF-MS/MS. Subsequently, the LC-sMRM method was developed and optimized to accurately quantify various chemical components of 10 batches of QGC. Finally, the variations in chemical components between batches were analyzed via multivariate statistical analysis. UHPLC-Q-TOF-MS/MS analysis revealed 167 chemical constituents in QGC, comprised of 48 flavonoids, 32 terpenoids, 18 phenolic acids, 9 coumarins, 9 phenylpropanoids, and 51 nucleosides, sugars, amino acids, anthraquinones, and other compounds. The LC-sMRM method was established for the quantitative analysis of 42 chemical components in 10 batches of QGC. The ultrasonic-assisted extraction parameters were optimized using RSM. Compared with conventional MRM, sMRM demonstrated superior sensitivity and precision. PCA and OPLS-DA identified eight chemical components with content differences among batches. This study established the chemical composition of QGC, offering useful guidance for assessing its quality.

Strength and Failure Analysis of Fiber-Wound Composite Gas Cylinder via Numerical Simulation.

Based on the classical grid theory and related regulations, a structure model of a fiber-wound composite gas cylinder was designed in this paper. Based on the design results, a finite element model of a fully wound composite cylinder of an aluminum alloy inner liner with a working pressure of 35 MPa was established based on the ABAQUS software, and its stress distribution under working pressure and minimum burst pressure was analyzed. According to engineering experience, the pressure tolerance of composite cylinders can be improved by proper autofrettage pressure before working pressure, so the influence of autofrettage pressure was analyzed in this paper. The optimum autofrettage pressure was selected by setting the autofrettage gradient, and damage analysis was carried out on the cylinder with nominal working pressure of 35 MPa based on the Hashin failure criterion. The results show the initial damage sequence: matrix stretching occurs before the fiber stretching, and the damage generally starts from the spiral-wound layer. The tensile damage first appears in the transition section between the head and the barrel body, and the damage of the spiral-wound layer develops from the inner layer of the wound layer to the outer layer, while the damage of the circumferentially wound layer develops from the outer layer to the inner layer.

Metabolic activation and cytochrome P450 inhibition of piperlonguminine mediated by CYP3A4.

Piperlonguminine (PLG) is a major alkaloid found in Piper longum fruits. It has been shown to possess a variety of biological activities, including anti-tumor, anti-hyperlipidemic, anti-renal fibrosis and anti-inflammatory properties. Previous studies have reported that PLG inhibits various CYP450 enzymes. The main objective of this study was to identify reactive metabolites of PLG in vitro and assess its ability to inhibit CYP450. In rat and human liver microsomal incubation systems exposed to PLG, two oxidized metabolites (M1 and M2) were detected. Additionally, in microsomes where N-acetylcysteine was used as a trapping agent, N-acetylcysteine conjugates (M3, M4, M5 and M6) of four isomeric O-quinone-derived reactive metabolites were found. The formation of metabolites was dependent on NADPH. Inhibition and recombinant CYP450 enzyme incubation experiments showed that CYP3A4 was the primary enzyme responsible for the metabolic activation of PLG. This study characterized the O-dealkylated metabolite (M1) through chemical synthesis. The IC50 shift assay showed time-dependent inhibition of CYP3A4, 2C9, 2E1, 2C8 and 2D6 by PLG. This research contributes to the understanding of PLG-induced enzyme inhibition and bioactivation.

A triple read-out visible biosensing platform based on multifunctional nanozyme and bipolar electrode for multi-mode detection and imaging of CEA.

In this paper, a proposal of closed bipolar electrode (BPE) and nanozyme based multi-mode biosensing platform is first presented. As a novel integrated chip, multi-mode-BPE (MMBPE) combines enzyme-linked immunoassay (ELISA), electrochemiluminescence (ECL), ECL imaging and light emitting diode (LED) imaging, enabling highly sensitive triple read-out visible detection of cancer embryonic antigen (CEA). The ECL probe Ab2@Au@Co3O4/CoFe2O4 hollow nanocubes (HNCs) with excellent peroxidase (POD) activity is introduced into the BPE cathode through immune adsorption. The Au@Co3O4/CoFe2O4 HNCs can increase the rate of hydrogen peroxide oxidation of TMB, thus promoting the reaction, and can be used for ELISA detection of CEA at different concentrations. The modification of the BPE sensing interface and reporting interface involved the introduction of the luminescent reagent Ru(bpy)32+ to the BPE anode. The decomposition rate of H2O2 increased under the catalytic action of Au@Co3O4/CoFe2O4 HNCs nanozyme, leading to an accelerated electron transfer rate in the MMBPE system and an enhanced ECL signal from Ru(bpy)32+. The LED imaging technology further provides a convenient and visible approach for CEA imaging in which no additional chemicals are needed. The integration of nanoenzymes as the catalytic core in MMBPE system provides impetus, while the combination of nanozymes with BPE expands the application of nanoenzymes in the field of biological analysis. The integration of intelligent chips with multiple modes of detection shows portable, miniaturized, and integrated excellent properties which meets the requirements of modern detection devices and thus offers a flexible approach for determination of nucleic acids, proteins, and cells.

Organic photoelectrochemical transistor based on cascaded DNA network structure modulated ZnIn2S4/MXene Schottky junction for sensitive ATP detection.

Organic photoelectrochemical transistor (OPECT) biosensor is now appearing in perspective of public, which characterized by amplified the grating electrode potential by ion transport. In this study, the DNA network formed by the hybridization chain reaction (HCR) detects the target adenosine triphosphate (ATP) by adjusting the surface potential of the new heterojunction of ZnIn2S4/MXene. The formation of DNA network amplifies the detection signal of ATP. Significantly, OPECT biosensor could further amplify the signal, which calculated the gain achieved 103, which is consistent with the gain signal of the previously reported OPECT biosensor. Furthermore, the OPECT biosensor achieved a highly sensitivity detection of the target ATP, which the linear detection range is 0.03 pM-30 nM, and the detection limit is 0.03 pM, and illustrated a high selectivity to ATP. The proposed OPECT biosensor achieved signal amplification by adjusting the surface potential of ZnIn2S4/MXene through cascade DNA network, which provides a new direction for the detection of biomolecules.

Comparative efficacy and safety of COVID-19 vaccines in phase III trials: a network meta-analysis.

BACKGROUND: Over a dozen vaccines are in or have completed phase III trials at an unprecedented speed since the World Health Organization (WHO) declared COVID-19 a pandemic. In this review, we aimed to compare and rank these vaccines indirectly in terms of efficacy and safety using a network meta-analysis. METHODS: We searched Embase, MEDLINE, and the Cochrane Library for phase III randomized controlled trials (RCTs) from their inception to September 30, 2023. Two investigators independently selected articles, extracted data, and assessed the risk of bias. Outcomes included efficacy in preventing symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the incidence of serious adverse events (SAEs) according to vaccine type and individual vaccines in adults and elderly individuals. The risk ratio and mean differences were calculated with 95% confidence intervals using a Bayesian network meta-analysis. RESULTS: A total of 25 RCTs involving 22 vaccines were included in the study. None of vaccines had a higher incidence of SAEs than the placebo. Inactivated virus vaccines might be the safest, with a surface under the cumulative ranking curve (SUCRA) value of 0.16. BIV1-CovIran showed the highest safety index (SUCRA value: 0.13), followed by BBV152, Soberana, Gam-COVID-Vac, and ZF2001. There were no significant differences among the various types of vaccines regarding the efficacy in preventing symptomatic SARS-CoV-2 infection, although there was a trend toward higher efficacy of the mRNA vaccines (SUCRA value: 0.09). BNT162b2 showed the highest efficacy (SUCRA value: 0.02) among the individual vaccines, followed by mRNA-1273, Abdala, Gam-COVID-Vac, and NVX-CoV2373. BNT162b2 had the highest efficacy (SUCRA value: 0.08) in the elderly population, whereas CVnCoV, CoVLP + AS03, and CoronaVac were not significantly different from the placebo. CONCLUSIONS: None of the different types of vaccines were significantly superior in terms of efficacy, while mRNA vaccines were significantly inferior in safety to other types. BNT162b2 had the highest efficacy in preventing symptomatic SARS-CoV-2 infection in adults and the elderly, whereas BIV1-CovIran had the lowest incidence of SAEs in adults.

High-risk and silent clonal hematopoietic genotypes in patients with nonhematologic cancer.

ABSTRACT: Clonal hematopoiesis (CH) identified by somatic gene variants with variant allele fraction (VAF) ≥ 2% is associated with an increased risk of hematologic malignancy. However, CH defined by a broader set of genotypes and lower VAFs is ubiquitous in older individuals. To improve our understanding of the relationship between CH genotype and risk of hematologic malignancy, we analyzed data from 42 714 patients who underwent blood sequencing as a normal comparator for nonhematologic tumor testing using a large cancer-related gene panel. We cataloged hematologic malignancies in this cohort using natural language processing and manual curation of medical records. We found that some CH genotypes including JAK2, RUNX1, and XPO1 variants were associated with high hematologic malignancy risk. Chronic disease was predicted better than acute disease suggesting the influence of length bias. To better understand the implications of hematopoietic clonality independent of mutational function, we evaluated a set of silent synonymous and noncoding mutations. We found that silent CH, particularly when multiple variants were present or VAF was high, was associated with increased risk of hematologic malignancy. We tracked expansion of CH mutations in 26 hematologic malignancies sequenced with the same platform. JAK2 and TP53 VAF consistently expanded at disease onset, whereas DNMT3A and silent CH VAFs mostly decreased. These data inform the clinical and biological interpretation of CH in the context of nonhematologic cancer.

RCCD1 promotes breast carcinogenesis through regulating hypoxia-associated mitochondrial homeostasis.

Regulator of chromosome condensation domain-containing protein 1 (RCCD1), previously reported as a partner of histone H3K36 demethylase KDM8 involved in chromosome segregation, has been identified as a potential driver for breast cancer in a recent transcriptome-wide association study. We report here that, unexpectedly, RCCD1 is also localized in mitochondria. We show that RCCD1 resides in the mitochondrial matrix, where it interacts with the mitochondrial contact site/cristae organizing system (MICOS) and mitochondrial DNA (mtDNA) to regulate mtDNA transcription, oxidative phosphorylation, and the production of reactive oxygen species. Interestingly, RCCD1 is upregulated under hypoxic conditions, leading to decreased generation of reactive oxygen species and alleviated apoptosis favoring cancer cell survival. We show that RCCD1 promotes breast cancer cell proliferation in vitro and accelerates breast tumor growth in vivo. Indeed, RCCD1 is overexpressed in breast carcinomas, and its level of expression is associated with aggressive breast cancer phenotypes and poor patient survival. Our study reveals an additional dimension of RCCD1 functionality in regulating mitochondrial homeostasis, whose dysregulation inflicts pathologic states such as breast cancer.

Risk factors for symptomatic malignant pleural effusion recurrence in patients with actionable mutations in advanced lung adenocarcinoma.

Background: Malignant pleural effusion (MPE) comes generally with high mortality and poor prognosis. Recurrence of symptomatic MPE is always accompanied by poor survival quality. In lung adenocarcinoma, researchers speculate whether patients with actionable mutation or without are applicable to different management models for MPE. Under the background of the high mutation probability and the encouraging therapeutic response in Asians, researches on the risk factors of MPE are in need. Methods: This retrospective review included 343 metastatic lung adenocarcinoma patients with MPE. Recurrence was defined as recurrent symptomatic MPE requiring the second thoracentesis to relieve symptoms within 300 days after the first thoracentesis. Univariable and multivariable Cox regression analysis were utilized to investigate independent risk factors for MPE recurrence. Results: Of the 343 patients involved, 139 experienced MPE recurrence within 300 days; 34.3% in 201 patients with actionable mutations and 51.2% in 129 patients without actionable mutations are in the recurrence. The median recurrence-free survival (RFS) of the group without mutations was 161 days. The median RFS of the other group with mutations was 300 days. Patients with actionable mutations showed a significantly lower hazard of MPE recurrence on univariate analysis. The multivariate analysis indicated that receiving targeted therapy after the first thoracentesis within 30 days, lower neutrophil-to-lymphocyte ratio (NLR) level, lower serum lactate dehydrogenase (s-LDH) level, and lower serum carcinoembryonic antigen (s-CEA) level were independent protective factors. In subgroup analysis, risk factors differed. Receiving targeted therapy after the first thoracentesis within 30 days remained an independent factor in the mutated patients. Conclusions: The findings herein indicated the characteristics of specific patients at high risk for MPE recurrence in lung adenocarcinoma. Patients with actionable mutations benefit more in MPE recurrence and could benefit from targeted therapy and active intrapleural management.

Zebrafish in Lung Cancer Research.

Zebrafish is increasingly used as a model organism for cancer research because of its genetic and physiological similarities to humans. Modeling lung cancer (LC) in zebrafish has received significant attention. This review focuses on the insights gained from using zebrafish in LC research. These insights range from investigating the genetic and molecular mechanisms that contribute to the development and progression of LC to identifying potential drug targets, testing the efficacy and toxicity of new therapies, and applying zebrafish for personalized medicine studies. This review provides a comprehensive overview of the current state of LC research performed using zebrafish, highlights the advantages and limitations of this model organism, and discusses future directions in the field.

NFIB facilitates replication licensing by acting as a genome organizer.

The chromatin-based rule governing the selection and activation of replication origins in metazoans remains to be investigated. Here we report that NFIB, a member of Nuclear Factor I (NFI) family that was initially purified in host cells to promote adenoviral DNA replication but has since mainly been investigated in transcription regulation, is physically associated with the pre-replication complex (pre-RC) in mammalian cells. Genomic analyses reveal that NFIB facilitates the assembly of the pre-RC by increasing chromatin accessibility. Nucleosome binding and single-molecule magnetic tweezers shows that NFIB binds to and opens up nucleosomes. Transmission electron microscopy indicates that NFIB promotes nucleosome eviction on parental chromatin. NFIB deficiency leads to alterations of chromosome contacts/compartments in both G1 and S phase and affects the firing of a subset of origins at early-replication domains. Significantly, cancer-associated NFIB overexpression provokes gene duplication and genomic alterations recapitulating the genetic aberrance in clinical breast cancer and empowering cancer cells to dynamically evolve growth advantage and drug resistance. Together, these results point a role for NFIB in facilitating replication licensing by acting as a genome organizer, shedding new lights on the biological function of NFIB and on the replication origin selection in eukaryotes.

Metallointercalated-DNA Nanotubes as Functional Light Antenna for Organic Photoelectrochemical Transistor Biosensor with Minimum Background.

Organic photoelectrochemical transistor (OPECT) biosensor with a removed background is desired but remains challenging. So far, scientists still lack a solution to this issue. The light-matter interplay is expected to achieve an advanced OPECT with unknown possibilities. Here, we address this challenge by tailoring a unique heterogeneous light antenna as the functional gating module and its cascade interaction with a proper channel, which is exemplified by bioinduced [Ru(bpy)2dppz]2+-intercalated DNA nanotubes (NTs)/NiO heterojunction and its modulation against a diethylenetriamine-treated poly(ethylene dioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) channel. Light stimulation of the antenna can generate the obvious cathodic photocurrent and, hence, modulate the channel, accomplishing OPECT with a minimal background and the hitherto highest current gain of 19 000. Linking with nucleic acid hybridization using microRNA-155 as the representative target, the device achieves sensitive biosensing down to 5.0 fM.

A formally certified end-to-end implementation of Shor's factorization algorithm.

Quantum computing technology may soon deliver revolutionary improvements in algorithmic performance, but it is useful only if computed answers are correct. While hardware-level decoherence errors have garnered significant attention, a less recognized obstacle to correctness is that of human programming errors-"bugs." Techniques familiar to most programmers from the classical domain for avoiding, discovering, and diagnosing bugs do not easily transfer, at scale, to the quantum domain because of its unique characteristics. To address this problem, we have been working to adapt formal methods to quantum programming. With such methods, a programmer writes a mathematical specification alongside the program and semiautomatically proves the program correct with respect to it. The proof's validity is automatically confirmed-certified-by a "proof assistant." Formal methods have successfully yielded high-assurance classical software artifacts, and the underlying technology has produced certified proofs of major mathematical theorems. As a demonstration of the feasibility of applying formal methods to quantum programming, we present a formally certified end-to-end implementation of Shor's prime factorization algorithm, developed as part of a framework for applying the certified approach to general applications. By leveraging our framework, one can significantly reduce the effects of human errors and obtain a high-assurance implementation of large-scale quantum applications in a principled way.

Timing and water temperature of drip irrigation regulate cotton growth and yield under film mulching in arid areas of Xinjiang.

BACKGROUND: Cotton (Gossypium hirsutum L.) is the fiber crop most widely cultivated globally and one of the most important commercial crops in China, irrigation is closely related to the growth of cotton. A water temperature for irrigation that is too low or too high inhibits cotton growth. Poor irrigation timing results in water and nutrient deficiencies that reduce cotton yield. Therefore, it is necessary to determine the appropriate irrigation timing and water temperature. METHOD: We conducted an experiment in an arid region of north-western China to assess the effects of irrigation timing and water temperature on soil temperature and the photosynthetic characteristics, biomass, total nitrogen (N), and seed cotton yield. Two irrigation times (daytime and nighttime) and four water temperatures (15, 20, 25, and 30 °C) were combined into eight treatments. RESULTS: Our results showed that water warming and nighttime irrigation improved the photosynthesis, biomass, N concentration (the proportion of total N weight in the plant biomass, in g kg-1 ), N content (the mass of total N, in g plant-1 ), and cotton yield. The optimal water temperature range for photosynthesis was 25.7-28.7 °C. Water warming also boosted the biomass allocation to the stem and increased the N allocation to the stem and leaf. Nighttime irrigation enhanced these phenomena. Water warming also increased the number of bolls per plant but reduced the single boll weight, increasing the seed cotton yield by 5.88-11.46%. At the same water temperature, irrigation during the night increased the number of bolls per plant and the single boll weight, improving the seed cotton yield by 2.95-4.31%. Among them, NI25 (nighttime irrigation with 25 °C water temperature) increased the yield by 14.13-14.90% compared with CK (daytime irrigation with 15 °C water temperature), which offers the best combination for increasing the yield. CONCLUSION: Our study clarifies the optimal irrigation timing and water temperature for cotton production under drip irrigation with film mulching, providing valuable information for improving the cotton yield in arid areas with temperate continental climate. © 2023 Society of Chemical Industry.

Research on the evaluation method of agricultural intelligent robot design solutions.

BACKGROUND: At present, agricultural robots are produced in large quantities and used in agricultural planting, and the traditional agricultural model is gradually shifting to rely on the Internet of Things and sensors to accurately detect crop growth information. The scientific and rational design of agricultural robots plays a huge role in planting and production efficiency, however, the factors affecting their design are complex and ambiguous, so it is necessary to use a rational evaluation system to make a preferential decision among multiple design options. PURPOSES: In order to reduce the subjectivity and blindness of program selection in the process of agricultural robot design, make the decision more objective and reasonable, and thus enhance the practicality and scientificity of the program, a new comprehensive evaluation method based on user requirements is proposed. METHODS: First, after researching and interviewing users and farming operations, obtaining raw information on requirements, using the Kano model to classify the requirements and establishing an evaluation index system. Secondly, the combination of hierarchical analysis(AHP) and entropy weighting method is used to assign weights to the evaluation index system, calculate the weight value and importance ranking of each index, and carry out various program designs based on the ranking. Finally, the VIKOR method was applied to evaluate and rank the design solutions. RESULTS: The new evaluation method can better complete the preferential decision of the agricultural robot design scheme and get a more perfect design scheme, which reduces the influence of human subjective thinking in the decision-making process. CONCLUSIONS: The method not only corrects the traditional evaluation method, but also effectively improves the accuracy and comprehensiveness of the design evaluation process. It also provides a reference for designers to preferably select design solutions and promotes the development of small mobile machines in the context of smart agriculture.

Zebrafish patient-derived xenografts accurately and quickly reproduce treatment outcomes in non-small cell lung cancer patients.

Zebrafish patient-derived xenograft (zPDX) models have shown great potential in predicting the short-term treatment response in various types of tumor cases. However, few studies have used zPDX models for drug screening in non-small cell lung cancer (NSCLC). We aimed to compare the treatment responses of patients with NSCLC with those of the corresponding zPDX models. Tumor cells were obtained from pleural fluid or biopsy procedures from patients with NSCLC and injected into the perivitelline space of zebrafish larvae. Then, the same antineoplastic drugs administered to the corresponding patient were tested in the successfully constructed zPDX model, for 3 days. Responses to treatment were compared. A total of 21 patients with advanced NSCLC were enrolled in our study, and 13 corresponding zPDX models were successfully established. Based on the clinical medication of enrolled patients, we provided a corresponding drug treatment to these zebrafish embryos, including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), pemetrexed/platinum (AP), or docetaxel/platinum (DP) administration. The chemosensitivity consistency rate between the clinical responses and those obtained from zPDXs was 76.9% (10/13). There was a high correlation between patient responses and the corresponding zPDX drug responses. Thus, zPDX can accurately and quickly reproduce patient responses to treatment with EGFR TKIs, AP, and DP and has a considerable potential to serve as a biological platform for predicting treatment effect on patients with NSCLC.

Trade-driven relocation of ground-level SO2 concentrations across Chinese provinces based on satellite observations.

The influence of trade on ground-level SO2 concentrations in China was evaluated based on multiregional input-output (MRIO) analysis, using the ozone monitoring instrument (OMI) SO2 columns and SO2 profiles from an atmospheric chemical and transport model, MOZART-4. The provincial sum of ground-level SO2 concentrations has a good consistency with the provincial SO2 emissions (R = 0.65, p < 0.01). The provincial SO2 concentrations presented strong spatial variations, with a range of 5.1-50.6 µg/m3 and an average of 19.7 µg/m3 across China. The international trade increased the SO2 concentrations in all of the provinces and increased the national population-weighted SO2 (PWM-SO2) concentration by 2.9 µg/m3. Interprovincial trade within China decreased the ambient SO2 concentrations in Beijing, Tianjin, and Chongqing and the provinces in southeast and central China, but increased SO2 in the remaining provinces of China. In general, interprovincial trade decreased the national PWM-SO2 concentration by 5.3 µg/m3.

Intracellular galectin-3 is a lipopolysaccharide sensor that promotes glycolysis through mTORC1 activation.

How the carbohydrate binding protein galectin-3 might act as a diabetogenic and tumorogenic factor remains to be investigated. Here we report that intracellular galectin-3 interacts with Rag GTPases and Ragulator on lysosomes. We show that galectin-3 senses lipopolysaccharide (LPS) to facilitate the interaction of Rag GTPases and Ragulator, leading to the activation of mTORC1. We find that the lipopolysaccharide/galectin-3-Rag GTPases/Ragulator-mTORC1 axis regulates a cohort of genes including GLUT1, and HK2, and PKM2 that are critically involved in glucose uptake and glycolysis. Indeed, galectin-3 deficiency severely compromises LPS-promoted glycolysis. Importantly, the expression of HK2 is significantly reduced in diabetes patients. In multiple types of cancer including hepatocellular carcinoma (HCC), galectin-3 is highly expressed, and its level of expression is positively correlated with that of HK2 and PKM2 and negatively correlated with the prognosis of HCC patients. Our study unravels that galectin-3 is a sensor of LPS, an important modulator of the mTORC1 signaling, and a critical regulator of glucose metabolism.

Fabrication of biphasic cartilage-bone integrated scaffolds based on tissue-specific photo-crosslinkable acellular matrix hydrogels.

The fabrication of biphasic cartilage-bone integrated scaffolds is an attractive alternative for osteochondral repair but has proven to be extremely challenging. Existing three-dimensional (3D) scaffolds are insufficient to accurately biomimic the biphasic cartilage-bone integrated microenvironment. Currently, photo-crosslinkable hydrogels based on tissue-specific decellularized extracellular matrix (dECM) have been considered as an important technique to fabricate biomimetic scaffolds, but so far there has been no breakthrough in the photo-crosslinkable hydrogel scaffolds with biphasic cartilage-bone biomimetic microenvironment. Here, we report a novel strategy for the preparation of biomimetic cartilage-bone integrated scaffolds based on photo-crosslinkable cartilage/bone-derived dECM hydrogels, which are able to reconstruct biphasic cartilage-bone biomimetic microenvironment. The biphasic cartilage-bone integrated scaffolds provided a 3D microenvironment for osteochondral regeneration. The cartilage biomimetic scaffolds, consisting of cartilage-derived dECM hydrogels, efficiently regulated chondrogenesis of bone marrow mesenchymal stem cells (BMSCs). The bone biomimetic scaffolds, composed of cartilage/bone-derived dECM hydrogels, first regulated chondrogenesis of BMSCs, followed by endochondral ossification over time. Taken together, the biphasic cartilage-bone integrated tissue could be successfully reconstructed by subcutaneous culture based on cartilage-bone bilayered structural design. Furthermore, the biphasic cartilage-bone biomimetic scaffolds (cell-free) achieved satisfactory cartilage-bone integrated regeneration in the osteochondral defects of rabbits' knee joints.