Lasting differential gene expression of circulating CD8 T cells in chronic HCV infection with cirrhosis identifies a role for Hedgehog signaling in cellular hyperfunction.

Background: The impact of chronic hepatic infection on antigen non-specific immune cells in circulation remains poorly understood. We reported lasting global hyperfunction of peripheral CD8 T cells in HCV-infected individuals with cirrhosis. Whether gene expression patterns in bulk CD8 T cells are associated with the severity of liver fibrosis in HCV infection is not known. Methods: RNA sequencing of blood CD8 T cells from treatment naïve, HCV-infected individuals with minimal (Metavir F0-1 ≤ 7.0 kPa) or advanced fibrosis or cirrhosis (F4 ≥ 12.5 kPa), before and after direct-acting antiviral therapy, was performed. CD8 T cell function was assessed by flow cytometry. Results: In CD8 T cells from pre-DAA patients with advanced compared to minimal fibrosis, Gene Ontology analysis and Gene Set Enrichment Analysis identified differential gene expression related to cellular function and metabolism, including upregulated Hedgehog (Hh) signaling, IFN-α, -γ, TGF-ß response genes, apoptosis, apical surface pathways, phospholipase signaling, phosphatidyl-choline/inositol activity, and second-messenger-mediated signaling. In contrast, genes in pathways associated with nuclear processes, RNA transport, cytoskeletal dynamics, cMyc/E2F regulation, oxidative phosphorylation, and mTOR signaling, were reduced. Hh signaling pathway was the top featured gene set upregulated in cirrhotics, wherein hallmark genes GLI1 and PTCH1 ranked highly. Inhibition of Smo-dependent Hh signaling ablated the expression of IFN-γ and perforin in stimulated CD8 T cells from chronic HCV-infected patients with advanced compared to minimal fibrosis. CD8 T cell gene expression profiles post-DAA remained clustered with pre-DAA profiles and disparately between advanced and minimal fibrosis, suggesting a persistent perturbation of gene expression long after viral clearance. Conclusions: This analysis of bulk CD8 T cell gene expression in chronic HCV infection suggests considerable reprogramming of the CD8 T cell pool in the cirrhotic state. Increased Hh signaling in cirrhosis may contribute to generalized CD8 T cell hyperfunction observed in chronic HCV infection. Understanding the lasting nature of immune cell dysfunction may help mitigate remaining clinical challenges after HCV clearance and more generally, improve long term outcomes for individuals with severe liver disease.

Tetrahedral Framework Nucleic Acid-Based Delivery of Astaxanthin Suppresses Chondrocyte Pyroptosis and Modulates Oxidative Stress for the Treatment of Osteoarthritis.

Worldwide, osteoarthritis (OA) is regarded as the most widespread, distressing, and limiting chronic disease affecting degenerative joints, and there is currently no disease-modifying treatment for OA. The pathogenesis of OA is significantly linked with oxidative stress and the process of pyroptosis. Astaxanthin (Ast) is a natural keto-carotenoid pigment with potent antioxidant activity and has been shown to effectively alleviate cartilage damage in OA. However, its poor water solubility and high sensitivity to light, temperature, and pH greatly limit its bioavailability. In this study, we developed Ast-loaded tetrahedral framework nucleic acids (tFNAs) for Ast delivery (TAC). Compared with free Ast and tFNAs, TAC exhibited improved drug stability and cellular uptake. Most importantly, TAC effectively protected chondrocytes against oxidative stress-induced pyroptosis, promoted extracellular matrix anabolism by chondrocytes, and ultimately alleviated cartilage damage in a rat DMM model. Thus, we believe that TACs hold great promise for the treatment of OA. This article is protected by copyright. All rights reserved.

Interleukin-1ß moderates the relationships between middle frontal-mACC/insular connectivity and depressive symptoms in bipolar II depression.

The functional alterations of the brain in bipolar II depression (BDII-D) and their clinical and inflammatory associations are understudied. We aim to investigate the functional brain alterations in BDII-D and their relationships with inflammation, childhood adversity, and psychiatric symptoms, and to examine the moderating effects among these factors. Using z-normalized amplitude of low-frequency fluctuation (zALFF), we assessed the whole-brain resting-state functional activity between 147 BDII-D individuals and 150 healthy controls (HCs). Differential ALFF regions were selected as seeds for functional connectivity analysis to observe brain connectivity alterations resulting from abnormal regional activity. Four inflammatory cytokines including interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) and five clinical scales including Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), Positive and Negative Syndrome Scale (PANSS), Columbia-Suicide Severity Rating Scale (C-SSRS), and Childhood Trauma Questionnaire (CTQ) were tested and assessed in BDII-D. Partial correlations with multiple comparison corrections identified relationships between brain function and inflammation, childhood adversity, and psychiatric symptoms. Moderation analysis was conducted based on correlation results and previous findings. Compared to HCs, BDII-D individuals displayed significantly lower zALFF in the superior and middle frontal gyri (SFG and MFG) and insula, but higher zALFF in the occipital-temporal area. Only the MFG and insula-related connectivity exhibited significant differences between groups. Within BDII-D, lower right insula zALFF value correlated with higher IL-6, CRP, and emotional adversity scores, while lower right MFG zALFF was related to higher CRP and physical abuse scores. Higher right MFG-mid-anterior cingulate cortex (mACC) connectivity was associated with higher IL-1ß. Moreover, IL-1ß moderated associations between higher right MFG-mACC/insula connectivity and greater depressive symptoms. This study reveals that abnormal functional alterations in the right MFG and right insula were associated with elevated inflammation, childhood adversity, and depressive symptoms in BDII-D. IL-1ß may moderate the relationship between MFG-related connectivity and depressive symptoms.

NIR-II fluorescence imaging without intended excitation light.

Nowadays, second near-infrared window (NIR-II) dyes are almost excited by laser diodes, but none of the white light (400-700 nm) excited NIR-II imaging has been studied because of the lack of suitable optical probes. Herein, a novel blue-shifted NIR-II dye, TPA-TQT, has been selected for use in multi-wavelength white light emitting diode (LED) excited NIR-II imaging. This white LED barely caused photo-quenching of the dyes, especially indocyanine green (ICG), whereas the ICG's brightness decreased by 90% under continuous 808 nm laser irradiation. Compared to single-wavelength LED, multi-wavelength LED showed a lower background and similar signal-to-background ratios. This system provided high image resolution to identify blood vessels (103 µm), lymphatic capillaries (129.8 µm), and to monitor hindlimb ischemia-reperfusion and lymphatic inflammation. Furthermore, white LED excited NIR-II fluorescence imaging-guided surgery (FIGS) was successfully performed in 4T1 tumor-bearing mice. Impressively, the lighting LED-based NIR-II FIGS was found to clearly delineate small lesions of metastatic tumors of about ∼350 µm diameter and further was able to guide surgical removal. Overall, multi-wavelength LED-based NIR-II imaging is a promising imaging strategy for tumor delineation and other biomedical applications.

Identification of the Cirratiomycin Biosynthesis Gene Cluster in Streptomyces Cirratus: Elucidation of the Biosynthetic Pathways for 2,3-Diaminobutyric Acid and Hydroxymethylserine.

Cirratiomycin, a heptapeptide with antibacterial activity, was isolated and characterized in 1981; however, its biosynthetic pathway has not been elucidated. It contains several interesting nonproteinogenic amino acids, such as (2S,3S)-2,3-diaminobutyric acid ((2S,3S)-DABA) and α-(hydroxymethyl)serine, as building blocks. Here, we report the identification of a cirratiomycin biosynthetic gene cluster in Streptomyces cirratus. Bioinformatic analysis revealed that several Streptomyces viridifaciens and Kitasatospora aureofaciens strains also have this cluster. One S. viridifaciens strain was confirmed to produce cirratiomycin. The biosynthetic gene cluster was shown to be responsible for cirratiomycin biosynthesis in S. cirratus in a gene inactivation experiment using CRISPR-cBEST. Interestingly, this cluster encodes a nonribosomal peptide synthetase (NRPS) composed of 12 proteins, including those with an unusual domain organization: a stand-alone adenylation domain, two stand-alone condensation domains, two type II thioesterases, and two NRPS modules that have no adenylation domain. Using heterologous expression and in vitro analysis of recombinant enzymes, we revealed the biosynthetic pathway of (2S,3S)-DABA: (2S,3S)-DABA is synthesized from l-threonine by four enzymes, CirR, CirS, CirQ, and CirB. In addition, CirH, a glycine/serine hydroxymethyltransferase homolog, was shown to synthesize α-(hydroxymethyl)serine from d-serine in vitro. These findings broaden our knowledge of nonproteinogenic amino acid biosynthesis.

Using machine learning on new feature sets extracted from three-dimensional models of broken animal bones to classify fragments according to break agent.

Distinguishing agents of bone modification at paleoanthropological sites is an important means of understanding early hominin evolution. Fracture pattern analysis is used to help determine site formation processes, including whether hominins were hunting or scavenging for animal food resources. Determination of how these behaviors manifested in ancient human sites has major implications for our biological and behavioral evolution, including social and cognitive abilities, dietary impacts of having access to in-bone nutrients like marrow, and cultural variation in butchering and food processing practices. Nevertheless, previous analyses remain inconclusive, often suffering from lack of replicability, misuse of mathematical methods, and/or failure to overcome equifinality. In this paper, we present a new approach aimed at distinguishing bone fragments resulting from hominin and carnivore breakage. Our analysis is founded on a large collection of scanned three-dimensional models of fragmentary bone broken by known agents, to which we apply state of the art machine learning algorithms. Our classification of fragments achieves an average mean accuracy of 77% across tests, thus demonstrating notable, but not overwhelming, success for distinguishing the agent of breakage. We note that, while previous research applying such algorithms has claimed higher success rates, fundamental errors in the application of machine learning protocols suggest that the reported accuracies are unjustified and unreliable. The systematic, fully documented, and proper application of machine learning algorithms leads to an inherent reproducibility of our study, and therefore our methods hold great potential for deciphering when and where hominins first began exploiting marrow and meat, and clarifying their importance and influence on human evolution.

Self-Reinforced PTLG Copolymer with Shish Kebab Structures and a Bionic Surface as Bioimplant Materials for Tissue Engineering Applications.

Green and biodegradable materials with great mechanical properties and biocompatibility will offer new opportunities for next-generation high-performance biological materials. Herein, the novel oriented shish kebab crystals of a novel poly(trimethylene carbonate-lactide-glycolide) (PTLG) vascular stent are first reported to be successfully fabricated through a feasible solid-state drawing process to simultaneously enhance the mechanical performance and biocompatibility. The crystal structure of this self-reinforced vascular stent was transformed from spherulites to a shish kebab crystal, which indicates the mechanical interlocking effect and prevents the lamellae from slipping with a significant improvement of mechanical strength to 333 MPa. Meanwhile, it is different from typical biomedical polymers with smooth surface structures, and the as-obtained PTLG vascular stent exhibits a bionic surface morphology with a parallel micro groove and ridge structure. These ridges and grooves were attributed to the reorganization of cytoskeleton fiber bundles following the direction of blood flow shear stress. The structure and parameters of these morphologies were highly similar to the inner surface of blood vessels of the human, which facilitates cell adhesion growth to improve its proliferation, differentiation, and activity on the surface of PTLG.

Naringenin reduces oxidative stress and necroptosis, apoptosis, and pyroptosis in random-pattern skin flaps by enhancing autophagy.

BACKGROUND: Random skin flap grafting is one of the most commonly used techniques in plastic and orthopedic surgery. However, necrosis resulting from ischemia and ischemia-reperfusion injury in the distal part of the flap can severely limit the clinical application of the flap. Studies have revealed that naringenin reduces pyroptosis, apoptosis, and necroptosis, inhibits oxidative stress, and promotes autophagy. In this study, the effects of Naringenin on flap viability and its underlying mechanism were evaluated. METHODS: Mice with random skin flaps were randomly allocated to control, Naringenin, and Naringenin + 3-methyladenine groups. On postoperative day 7, flap tissues were collected to estimate angiogenesis, necroptosis, apoptosis, pyroptosis, oxidative stress, and autophagy via hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. RESULTS: The results revealed that naringenin promoted the viability of the random flaps as well as angiogenesis, while inhibiting oxidative stress and decreasing pyroptosis, apoptosis, and necroptosis. These effects were reversed by the autophagy inhibitor 3-methyladenine. CONCLUSIONS: The findings indicated that naringenin treatment could promote flap survival by inhibiting pyroptosis, apoptosis, necroptosis, and alleviating oxidative stress, caused by the activation of autophagy.

Self-guided disentangled representation learning for single image dehazing.

Image dehazing has received extensive research attention as images collected in hazy weather are limited by low visibility and information dropout. Recently, disentangled representation learning has made excellent progress in various vision tasks. However, existing networks for low-level vision tasks lack efficient feature interaction and delivery mechanisms in the disentanglement process or an evaluation mechanism for the degree of decoupling in the reconstruction process, rendering direct application to image dehazing challenging. We propose a self-guided disentangled representation learning (SGDRL) algorithm with a self-guided disentangled network to realize multi-level progressive feature decoupling through sharing and interaction. The self-guided disentangled (SGD) network extracts image features using the multi-layer backbone network, and attribute features are weighted using the self-guided attention mechanism for the backbone features. In addition, we introduce a disentanglement-guided (DG) module to evaluate the degree of feature decomposition and guide the feature fusion process in the reconstruction stage. Accordingly, we develop SGDRL-based unsupervised and semi-supervised single image dehazing networks. Extensive experiments demonstrate the superiority of the proposed method for real-world image dehazing. The source code is available at https://github.com/dehazing/SGDRL.

Ezrin inhibition alleviates oxidative stress and pyroptosis via regulating TRPML1-calcineurin axis mediated enhancement of autophagy in spinal cord injury.

Spinal cord injury (SCI) presents profound ramifications for patients, leading to diminished motor and sensory capabilities distal to the lesion site. Once SCI occurs, it not only causes great physical and psychological problems for patients but also imposes a heavy economic burden. Ezrin is involved in various cellular processes, including signal transduction, cell death, inflammation, chemotherapy resistance and the stress response. However, whether Ezrin regulates functional repair after SCI and its underlying mechanism has not been elucidated. Here, our results showed that there is a marked augmentation of Ezrin levels within neurons and Ezrin inhibition markedly diminished glial scarring and bolstered functional recuperation after SCI. RNA sequencing indicated the potential involvement of pyroptosis, oxidative stress and autophagy in the enhancement of functional recovery upon reduced Ezrin expression. Moreover, the inhibition of Ezrin expression curtailed pyroptosis and oxidative stress by amplifying autophagy. Our studies further demonstrated that Ezrin inhibition promoted autophagy by increasing TFEB activity via the Akt-TRPML1-calcineurin pathway. Finally, we concluded that inhibiting Ezrin expression alleviates pyroptosis and oxidative stress by enhancing TFEB-driven autophagy, thereby promoting functional recovery after SCI, which may be a promising therapeutic target for SCI treatment.

Lithium Slag and Solid Waste-Based Binders for Cemented Lithium Mica Fine Tailings Backfill.

To mitigate the adverse effects of fine-grained lithium mica tailings and other solid wastes generated from the extraction of lithium ore mining, as well as the limitations of traditional cement-based binders for lithium mica fine tailings, this study explores the feasibility of using a binder composed of ordinary Portland cement, lithium slag, fly ash, and desulfurization gypsum to stabilize lithium fine tailings into cemented lithium tailings backfill. Compared with traditional cementitious binders, an extensive array of experiments and analyses were conducted on binders formed by various material proportion combinations, employing uniaxial compressive strength tests, microstructural morphology, grayscale analyses, and flowability tests. The results show the following: (1) In this study, an LSB binder exhibiting superior mechanical properties compared to traditional cementitious binders was identified, with an optimal OPC:LS:FA:DG ratio of 2:1:1:1. (2) In the context of cemented lithium mica fine tailings, the LSB-CLTB material exhibits higher unconfined compressive strength and lower self-weight compared to OPC-CLTB materials. At a binder content of 10 wt%, the UCS values achieved by the LSB-CLTB material at curing periods of 7 days, 14 days, and 28 days are 0.97 MPa, 1.52 MPa, and 2.1 MPa, respectively, representing increases of 40.6%, 34.5%, and 44.8% over the compressive strength of OPC-based materials under the same conditions. (3) The LSB binder not only exhibits enhanced pozzolanic reactivity but also facilitates the infilling of detrimental pores through its inherent particle size and the formation of AFt and C-(A)-S-H gels via hydration reactions, thereby effectively improving the compressive strength performance of fine-grained tailings backfill.

Cost-effectiveness of analysis serplulimab plus chemotherapy as first-line therapy for PD-L1-positive advanced esophageal squamous cell carcinoma.

Objective: Our study aimed to evaluate the cost-effectiveness of the addition of serplulimab to chemotherapy (cisplatin and fluorouracil) for programmed death-ligand 1 (PD-L1) positive advanced esophageal squamous cell carcinoma (ESCC) as the first-line treatment in China. Methods: A three-state Markov model was established to assess the incremental cost-effectiveness ratio (ICER) for serplulimab plus chemotherapy versus chemotherapy alone. Survival data were extrapolated from the ASTRUM-007 trial, cost data were derived from local sources, and utilities were derived from published literature. Health outcomes were measured as quality-adjusted life-years (QALYs). Sensitivity and probability sensitivity analyses were used to investigate the robustness of the model. Results: In the base-case analysis, compared with chemotherapy alone, serplulimab gained an additional 0.16 QALYs with an incremental cost of $29,547.88, leading to an ICER of $184,674.25/QALY. Additionally, the subgroup analyses presented that the ICERs of serplulimab plus chemotherapy were $157,892.50/QALY and $127,996.45/QALY in advanced ESCC patients with 1≤ CPS< 10 and CPS≥ 10, respectively. These ICERs significantly exceeded the Chinese willingness-to-pay (WTP) threshold. The deterministic sensitivity analysis illustrated that the cost of progression-free survival in serplulimab plus chemotherapy group was the parameter with the strongest influence on the ICERs. Conclusion: In the Chinese health care system, with 3 times China's per capita gross domestic product as the WTP threshold, compared with chemotherapy alone, serplulimab combined chemotherapy is not economical for PD-L1-positive advanced ESCC in the first-line setting.

FILNet: Fast Image-Based Indoor Localization Using an Anchor Control Network.

This paper designs a fast image-based indoor localization method based on an anchor control network (FILNet) to improve localization accuracy and shorten the duration of feature matching. Particularly, two stages are developed for the proposed algorithm. The offline stage is to construct an anchor feature fingerprint database based on the concept of an anchor control network. This introduces detailed surveys to infer anchor features according to the information of control anchors using the visual-inertial odometry (VIO) based on Google ARcore. In addition, an affine invariance enhancement algorithm based on feature multi-angle screening and supplementation is developed to solve the image perspective transformation problem and complete the feature fingerprint database construction. In the online stage, a fast spatial indexing approach is adopted to improve the feature matching speed by searching for active anchors and matching only anchor features around the active anchors. Further, to improve the correct matching rate, a homography matrix filter model is used to verify the correctness of feature matching, and the correct matching points are selected. Extensive experiments in real-world scenarios are performed to evaluate the proposed FILNet. The experimental results show that in terms of affine invariance, compared with the initial local features, FILNet significantly improves the recall of feature matching from 26% to 57% when the angular deviation is less than 60 degrees. In the image feature matching stage, compared with the initial K-D tree algorithm, FILNet significantly improves the efficiency of feature matching, and the average time of the test image dataset is reduced from 30.3 ms to 12.7 ms. In terms of localization accuracy, compared with the benchmark method based on image localization, FILNet significantly improves the localization accuracy, and the percentage of images with a localization error of less than 0.1m increases from 31.61% to 55.89%.

Research on automatic matching of online mathematics courses and design of teaching activities based on multiobjective optimization algorithm.

The teaching of the optimization algorithm is a new kind of swarm intelligence optimization technique, which is superior in optimizing many simple functions. Still, it is not evident in processing some complex problems (group and teaching classification). Achieving automatic matching and knowledge transfer in online courses is imperative in mathematics education. This study proposes a design scheme MTCBO-LR (multiobjective capability optimizer-logistic regression), based on multitask optimization, which enables precise knowledge transfer and data interaction among many educators. It incorporates the standard TLBO algorithm to optimize, provides a variety of learning tactics for students at different stages of mathematics instruction, and is capable of adaptively adjusting these strategies in response to actual teaching needs. Experimental results on various datasets reveal that the proposed method enhances searchability and group diversity in various optimization extremes and outperforms similar methods in resolving to multitask teaching problems.

Research progress on bioleaching recovery technology of spent lithium-ion batteries.

Bioleaching of lithium-ion batteries is a microbially catalyzed process. Under the action of redox, acid leaching and complexation in the presence of microorganisms, the valuable metals in the cathode material enter the liquid phase as ions and are subsequently recovered from the succeeding process. This technique has the advantages of being inexpensive, environmentally friendly and having simple needs. However, it is still in development and has not yet commercialized. In this paper, the technology is fully discussed based on numerous excellent studies. The contents include commonly utilized microorganisms, bioleaching mechanism, microbial stress response and metabolic activation, enhancement strategies, leaching characteristics and interfacial phenomena, process evaluation, and a critical discussion of recent research breakthroughs. They give readers with comprehensive and in-depth understanding on the bioleaching of lithium-ion batteries and help to improve the technology's industrialization. Researchers can make new explorations from the potential research directions and methods presented in this work to make biotechnology better serve resource recovery and social development.

Competitive Li+ Coordination in Ionogel Electrolytes for Enhanced Li-Ion Transport Kinetics.

Developing ionogel electrolytes based on ionic liquid instead of volatile liquid in gel polymer electrolytes is regarded to be effective to diminish safety concerns in terms of overheating and fire. Herein, a zwitterion-based copolymer matrix based on the copolymerization of trimethylolpropane ethoxylate triacrylate (ETPTA) and 2-methacryloyloxyethylphosphorylcholine (MPC, one typical zwitterion) is developed. It is shown that introducing zwitterions into ionogel electrolytes can effectively optimize local lithium-ion (Li+ ) coordination environment to improve Li+ transport kinetics. The interactions between Li+ and bis(trifluoromethanesulfonyl)imide (TFSI- )/MPC lead to the formation of Li+ coordination shell jointly occupied by MPC and TFSI- . Benefiting from the competitive Li+ attraction of TFSI- and MPC, the energy barrier of Li+ desolvation is sharply decreased and thus the room-temperature ionic conductivity can reach a value of 4.4 × 10-4 S cm-1 . Besides, the coulombic interaction between TFSI- and MPC can greatly decrease the reduction stability of TFSI- , boosting in situ derivation of LiF-enriched solid electrolyte interface  layer on lithium metal surface. As expected, the assembled Li||LiFePO4 cells deliver a high reversible discharge capacity of 139 mAh g-1 at 0.5 C and good cycling stability. Besides, the pouch cells exhibit a steady open-circuit voltage and can operate normally under abuse testing (fold, cut), showing its outstanding safety performance.

Hypsochromic Shift Donor-Acceptor NIR-II Dye for High-Efficiency Tumor Imaging.

Nowadays, second near-infrared window (NIR-II) dyes' development focuses on pursuing a longer absorption/emission wavelength and higher quantum yield, which usually means an extended π conjugation system, resulting in an enormous molecular weight and poor druggability. Most researchers thought that the reduced π conjugation system would bring on a blueshift spectrum that causes dim imaging qualities. Little efforts have been made to study smaller NIR-II dyes with a reduced π conjugation system. Herein, we synthesized a reduced π conjugation system donor-acceptor (D-A) probe TQ-1006 (Em = 1006 nm). Compared with its counterpart donor-acceptor-donor (D-A-D) structure TQT-1048 (Em = 1048 nm), TQ-1006 exhibited comparable excellent blood vessels, lymphatic drainage imaging performance, and a higher tumor-to-normal tissue (T/N) ratio. An RGD conjugated probe TQ-RGD showed an extra high contrast tumor imaging (T/N ≥ 10), further proving D-A dyes' excellent NIR-II biomedical imaging applications. Overall, the D-A framework provides a promising approach to designing next-generation NIR-II fluorophores.

Fabrication and evaluation of 3D printed poly(l-lactide) copolymer scaffolds for bone tissue engineering.

The application of poly(L-lactic acid) (PLLA) in tissue engineering is limited due to its brittleness and uncontrollable degradation rate. In this study, the flexible p-dioxanone (PDO) and highly reactive glycolide (GA) units were introduced into PLLA segments by chemical modification to prepare poly(l-lactide-ran-p-dioxanone-ran-glycolide) (PLPG) copolymers. The copolymers were then processed into the PLPG scaffold by a 3D printing technology. The physicochemical properties of the PLPG copolymers were studied by NMR, DSC, XRD, GPC, and SEM. Furthermore, the mechanical properties, degradation properties, and biocompatibility of the PLPG scaffolds were also studied. The results showed that introducing PDO and GA units disrupted the regularity of PLLA, decreasing the crystallinity of the PLPG copolymers. However, introducing PDO and GA units could effectively improve the mechanical and degradation properties of the PLLA scaffolds. In vitro cell culture experiments indicated that the PLPG scaffolds supported proliferation, growth, and differentiation of MC3T3-E1 cells. The PLPG scaffolds reported herein, with controllable degradation rates and mechanical performance, may find applications in bone tissue engineering.

The design of strut/TPMS-based pore geometries in bioceramic scaffolds guiding osteogenesis and angiogenesis in bone regeneration.

The pore morphology design of bioceramic scaffolds plays a substantial role in the induction of bone regeneration. Specifically, the effects of different scaffold pore geometry designs on angiogenesis and new bone regeneration remain unclear. Therefore, we fabricated Mg/Sr co-doped wollastonite bioceramic (MS-CSi) scaffolds with three different pore geometries (gyroid, cylindrical, and cubic) and compared their effects on osteogenesis and angiogenesis in vitro and in vivo. The MS-CSi scaffolds were fabricated by digital light processing (DLP) printing technology. The pore structure, mechanical properties, and degradation rate of the scaffolds were investigated. Cell proliferation on the scaffolds was evaluated using CCK-8 assays while angiogenesis was assessed using Transwell migration assays, tube formation assays, and immunofluorescence staining. The underlying mechanism was explored by western blotting. Osteogenic ability of scaffolds was evaluated by alkaline phosphatase (ALP) staining, western blotting, and qRT-PCR. Subsequently, a rabbit femoral defect model was prepared to compare differences in the scaffolds in osteogenesis and angiogenesis in vivo. Cell culture experiments showed that the gyroid pore scaffold downregulated YAP/TAZ phosphorylation and enhanced YAP/TAZ nuclear translocation, thereby promoting proliferation, migration, tube formation, and high expression of CD31 in human umbilical vein endothelial cells (HUVECs) while strut-based (cubic and cylindrical pore) scaffolds promoted osteogenic differentiation in bone marrow mesenchymal stem cells and upregulation of osteogenesis-related genes. The gyroid pore scaffolds were observed to facilitate early angiogenesis in the femoral-defect model rabbits while the strut-based scaffolds promoted the formation of new bone tissue. Our study indicated that the pore geometries and pore curvature characteristics of bioceramic scaffolds can be precisely tuned for enhancing both osteogenesis and angiogenesis. These results may provide new ideas for the design of bioceramic scaffolds for bone regeneration.

Pinocembrin alleviates pyroptosis and apoptosis through ROS elimination in random skin flaps via activation of SIRT3.

Random skin flap grafting is the most common skin grafting technique in reconstructive surgery. Despite progress in techniques, the incidence of distal flap necrosis still exceeds 3%, which limits its use in clinical practice. Current methods for treating distal flap necrosis are still lacking. Pinocembrin (Pino) can inhibit reactive oxygen species (ROS) and cell death in a variety of diseases, such as cardiovascular diseases, but the role of Pino in random flaps has not been explored. Therefore, we explore how Pino can enhance flap survival and its specific upstream mechanisms via macroscopic examination, Doppler, immunohistochemistry, and western blot. The results suggested that Pino can enhance the viability of random flaps by inhibiting ROS, pyroptosis and apoptosis. The above effects were reversed by co-administration of Pino with adeno-associated virus-silencing information regulator 2 homolog 3 (SIRT3) shRNA, proving the beneficial effect of Pino on the flaps relied on SIRT3. In addition, we also found that Pino up-regulates SIRT3 expression by activating the AMP-activated protein kinase (AMPK) pathway. This study proved that Pino can improve random flap viability by eliminating ROS, and ROS-induced cell death through the activation of SIRT3, which are triggered by the AMPK/PGC-1α signaling pathway.