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Sustained and intense inflammation is the pathological basis for intervertebral disc degeneration (IVDD). Effective antagonism or reduction of local inflammatory factors may help regulate the IVDD microenvironment and reshape the extracellular matrix of the disc. This study reports an immunomodulatory hydrogel microsphere system combining cell membrane-coated mimic technology and surface chemical modification methods by grafting neutrophil membrane-coated polylactic-glycolic acid copolymer nanoparticles loaded with transforming growth factor-beta 1 (TGF-β1) (T-NNPs) onto the surface of methacrylic acid gelatin anhydride microspheres (GM) via amide bonds. The nanoparticle-microsphere complex (GM@T-NNPs) sustained the long-term release of T-NNPs with excellent cell-like functions, effectively bound to pro-inflammatory cytokines, and improved the release kinetics of TGF-β1, maintaining a 36 day-acting release. GM@T-NNPs significantly inhibited lipopolysaccharide-induced inflammation in nucleus pulposus cells in vitro, downregulated the expression of inflammatory factors and matrix metalloproteinase, and upregulated the expression of collagen-II and aggrecan. GM@T-NNPs effectively restored intervertebral disc height and significantly improved the structure and biomechanical function of the nucleus pulposus in a rat IVDD model. The integration of biomimetic technology and nano-drug delivery systems expands the application of biomimetic cell membrane-coated materials and provides a new treatment strategy for IVDD.

IntroductionMembers of the plant-specific B3 transcription factor superfamily play crucial roles in various plant growth and developmental processes. Despite numerous valuable studies on B3 genes in other species, little is known about the B3 superfamily in pearl millet.Methods and resultsHere, through comparative genomic analysis, we identified 70 B3 proteins in pearl millet and categorized them into four subfamilies based on phylogenetic affiliations: ARF, RAV, LAV, and REM. We also mapped the chromosomal locations of these proteins and analyzed their gene structures, conserved motifs, and gene duplication events, providing new insights into their potential functional interactions. Using transcriptomic sequencing and real-time quantitative PCR, we determined that most PgB3 genes exhibit upregulated expression under drought and high-temperature stresses, indicating their involvement in stress response regulation. To delve deeper into the abiotic stress roles of the B3 family, we focused on a specific gene within the RAV subfamily, PgRAV-04, cloning it and overexpressing it in tobacco. PgRAV-04 overexpression led to increased drought sensitivity in the transgenic plants due to decreased proline levels and peroxidase activity.DiscussionThis study not only adds to the existing body of knowledge on the B3 family’s characteristics but also advances our functional understanding of the PgB3 genes in pearl millet, reinforcing the significance of these factors in stress adaptation mechanisms.

Introduction: Spinal cord injury (SCI) is associated with microenvironment imbalance, thereby resulting in poor regeneration and recovery of the spinal cord. Gene therapy can be used to balance the inflammatory response, however target genes cannot exist in localized injured areas.Methods: A genetically engineered electrospun scaffold (GEES) to achieve long-term immunoregulation and nerve repair was constructed. By combining the microfluidic and electrospinning techniques, interleukin-10 plasmid (pIL10) was loaded into lipid nanoparticles (LNPs) (pIL10-LNP), which was encapsulated to the nerve growth factor (NGF). Immunofluorescence staining, qRT-PCR, ELISA, flow cytometry, and other tests were employed to comprehensively assess the role of GEES in modulating macrophage polarization and facilitating neural repair.Results: The results showed that the scaffold released >70% of the pIL10-LNP within 10 d and continued slow release within 30 d. In vitro cell experiments have demonstrated that GEES effectively stimulates macrophages to secrete anti-inflammatory cytokines and facilitates the differentiation of neural stem cells into neuronal cells. In rat T9 SCI model, the GEES significantly inhibited the inflammatory response in the acute and chronic phases of SCI by transfecting local tissues with slow-release pIL10-LNP to promote the release of the anti-inflammatory factor IL10, thereby creating a favorable microenvironment. With the addition of NGF, the repair and regeneration of nerve tissues was effectively promoted, and the post-SCI motor function of rats improved.Discussion: GEES can regulate post-SCI immune responses through continuous and effective gene delivery, providing a new strategy for the construction of electrospun scaffolds for nerve repair in gene therapy.

Abstract Although mitochondria are crucial for recovery after spinal cord injury (SCI), therapeutic strategies to modulate mitochondrial metabolic energy to coordinate the immune response and nerve regeneration are lacking. Here, a ligand‐screened cerium‐based metal‐organic framework (MOF) with better ROS scavenging and drug‐loading abilities is encapsulated with polydopamine after loading creatine to obtain microcapsules (Cr/Ce@PDA nanoparticles), which reverse the energy deficits in both macrophages and neuronal cells by combining ROS scavenging and energy supplementation. It reprogrames inflammatory macrophages to the proregenerative phenotype via the succinate/HIF‐1α/IL‐1β signaling axis. It also promotes the regeneration and differentiation of neural cells by activating the mTOR pathway and paracrine function of macrophages. In vivo experiments further confirm the effect of the microcapsules in regulating early ROS‐inflammation positive‐feedback chain reactions and continuously promoting nerve regeneration. This study provides a new strategy for correcting mitochondrial energy deficiency in the immune response and nerve regeneration following SCI.

Intervertebral disc degeneration (IVDD) is commonly caused by imbalanced oxygen metabolism-triggered inflammation. Overcoming the shortcomings of antioxidants in IVDD treatment, including instability and the lack of targeting, remains challenging. Microfluidic and surface modification technologies were combined to graft chitosan nanoparticles encapsulated with strong reductive black phosphorus quantum dots (BPQDs) onto GelMA microspheres via amide bonds to construct oxygen metabolism-balanced engineered hydrogel microspheres (GM@CS-BP), which attenuate extracellular acidosis in nucleus pulposus (NP), block the inflammatory cascade, reduce matrix metalloproteinase expression (MMP), and remodel the extracellular matrix (ECM) in intervertebral discs (IVDs). The GM@CS-BP microspheres reduce H2O2 intensity by 229%. Chemical grafting and electrostatic attraction increase the encapsulation rate of BPQDs by 167% and maintain stable release for 21 days, demonstrating the antioxidant properties and sustained modulation of the BPQDs. After the GM@CS-BP treatment, western blotting revealed decreased acid-sensitive ion channel-3 and inflammatory factors. Histological staining in an 8-week IVDD model confirmed the regeneration of NP. GM@CS-BP microspheres therefore maintain a balance between ECM synthesis and degradation by regulating the positive feedback between imbalanced oxygen metabolism in IVDs and inflammation. This study provides an in-depth interpretation of the mechanisms underlying the antioxidation of BPQDs and a new approach for IVDD treatment.

This study numerically simulated and investigated the flow field characteristics of a typical dual-pulse solid rocket motor with a soft pulse separation device through thermal insulation ablation under high-temperature dual-pulse erosion. The ablation rate of ethylene -propylene-diene monomer (EPDM) insulator was measured after the experiment. Experimental results were analyzed through scanning electron microscopy and microcomputed tomography. The ablation mechanism of the EPDM insulator under the operation conditions of a dual-pulse solid rocket motor was evaluated by analyzing the results. The results reveal that the internal flow field of the motor with a soft pulse separation device is uniform. The original charred layer existing on the EPDM insulator surface in the first pulse combustor is the decisive factor affecting the final ablation rate of the dual-pulse motor during the second pulse operation, and the ablation characteristic region is easily formed with the exfoliation of the charred layer. The ablation rate difference of the insulator increases with gas velocity.

Printed circuit heat exchangers (PCHEs) are widely used as recuperators in the supercritical carbon dioxide (S-CO2) Brayton cycle design. The variation of heat sources will have a great impact on the heat transfer effect of the recuperator. It is of interest to study the fast calculation of flow and heat transfer performance of PCHEs under different operating conditions to obtain the optimal comprehensive performance and provide guidance for the operation control strategy analysis. Herein, a fast calculation method is established through a one-dimensional model of a PCHE based on Modelica. The effects of working medium mass flow rate and inlet temperature on the flow and heat transfer process are analyzed from the three aspects of heat transfer rate, flow pressure drop, and comprehensive performance, and the mass flow rate matching optimization is realized. The results show that increased mass flow rate increases heat transfer rate and flow pressure drop. The efficiency evaluation coefficient (EEC) has a maximum value at which the mass flow rate values of the cold and hot channels are best matched, and the comprehensive performance is optimal. When the mass flow rate of the heat channel is 4.8 g/s, the maximum EEC is 1.42, corresponding to the mass flow rate of the cold channel, 4.2 g/s. Compared with the design condition, the heat transfer rate increases by 62.1%, and the total pump power increases by 14.2%. When the cold channel inlet temperature increases, EEC decreases rapidly, whereas EEC increases when the hot channel inlet temperature increases. The conclusions can provide theoretical support for the design and operation of PCHEs.

Ocular alkali burns recruit neutrophils and triggers neutrophil extracellular trap (NET)-neovascularization cascade effects that limit ocular surface reconstruction and functional repair. However, effective inhibition of the release of neutrophil extracellular traps after a corneal chemical injury, coordination of intrinsic immunity with corneal repair, and exploration of more effective and non-invasive drug-delivery modes are still urgently needed. Using an in vitro coculture system, we found that an alkaline environment stimulates neutrophils to release NETs, which can be regulated by deoxyribonuclease I (DNase I). Inspired by this, we loaded DNase I, which effectively regulates NETs, onto chitosan nanoparticles and combined them with silk fibroin to construct a composite hydrogel that can sustainably regulate NETs. The hydrogel reduced neutrophil extracellular trap production by 50% and neovascularization by approximately 70% through sustained DNase I release after a corneal alkali burn. The complex hydrogel promotes ocular surface reconstruction by modulating the intrinsic immune-cascade neovascularization effect, providing a new research basis for the construction of nanobiomaterials that modulate pathological neovascularization.

Abstract Background In complex injuries, external fixation device represents a challenge to maintain negative-pressure wound therapy (NPWT). In this trial, we compared a combination of bone wax and colostomy paste versus bone wax alone to seal NPWT around external fixation devices. Methods Debridement surgeries of limbs with open fracture and large soft tissue defect need NPWT to be applied around the external fixation devices were randomized into two groups. The seal between external fixation devices and the drape was established using either bone wax first and then reinforced with colostomy paste or bone wax alone. The primary outcome was seal failure within 3 days of debridement. Secondary outcomes included the number of seal failure per debridement surgery and the time spent in repairing the seal within 3 days. Results A total of 56 debridement surgeries were enrolled: 28 to the bone wax/colostomy paste group versus 28 to the bone wax control group. One patient in the control group died 1 day after the first debridement surgery. One patient in the bone wax/colostomy paste group was transferred to other hospitals within 3 days. The final analysis included 27 debridement surgeries in the bone wax/colostomy paste group and 27 debridement surgeries in the control group. The rate of seal failure (defined by loss of negative pressure at anytime within 3 days) was 81.5% (22/27) in the control group versus 11.1% (3/27) in the bone wax/colostomy paste group (p

The regeneration of critical-size bone defects on long bones has remained a significant challenge because of the complex anatomical structure and vascular network. In such circumstances, current biomaterial forms with homogeneous structure and function can hardly satisfy the need for both osteogenesis and angiogenesis. In the current study, a heterogeneous biomimetic structured scaffold was constructed with the help of a 3D printed mold to simultaneously mimic the outer/inner periosteum and intermediate bone matrix of a natural long bone. Because of the reinforcement via modified mesoporous bioactive glass nanoparticles (MBGNs), enhanced structural stability and adequate osteogenic capacity could be achieved for the intermediate layer of this scaffold. Conversely, GelMA incorporated with VEGF-loaded liposome exhibiting controlled release of the angiogenic factor was applied to the inner and outer layers of the scaffold. The resulting heterogeneous structured scaffold was shown to successfully guide bone regeneration and restoration of the natural bone anatomic structure, rendering it a promising candidate for future orthopedic clinical studies.

HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC (21c) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells (DC50 = 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21b reveled favorable plasma exposures referring to both the parent 21b and the conversed acid 21c. Further in vivo studies of 21b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases.

Neolamarckia cadamba (Roxb.) Bosser is a fast-growing deciduous tree species and belongs to the Neolamarckia genus of the Rubiaceae family. This species has great economic and medical values in addition to being an important timber species for multiple industrial purposes. However, few studies have examined the genetic diversity and population structure in the natural distribution of this species in China. Here, we applied both the haploid nrDNA ITS (619 bp for aligned sequences) and mtDNA (2 polymorphic loci) markers to investigate 10 natural populations (239 individuals in total) that covered most of the distribution of the species in China. The results showed that the nucleotide diversity was π = 0.1185 ± 0.0242 for the nrDNA ITS markers and π = 0.00038 ± 0.00052 for the mtDNA markers. The haplotype diversity for the mtDNA markers was h = 0.1952 ± 0.2532. The population genetic differentiation was small (Fstn = 0.0294) for the nrDNA ITS markers but large (Fstm = 0.6765) for the mtDNA markers. There were no significant effects of isolation by distance (IBD), by elevation, and by two climatic factors (annual average precipitation and tem perature). A geographic structure among populations (Nst

Abstract Cytoplasmic male sterility (CMS) is a widely used genetic tool in modern hybrid rice breeding. Most genes conferring rice gametophytic CMS are homologous to orf79 and co‐transcribe with atp6. However, the origin, differentiation and flow of these mitochondrial genes in wild and cultivated rice species remain unclear. In this study, we performed de novo assembly of the mitochondrial genomes of 221 common wild rice (Oryza rufipogon Griff.) and 369 Asian cultivated rice (Oryza sativa L.) accessions, and identified 16 haplotypes of atp6‐orf79‐like structures and 11 orf79 alleles. These homologous structures were classified into 4 distinct groups (AO‐I, AO‐II, AO‐III and AO‐IV), all of which were observed in O. rufipogon but only AO‐I was detected in O. sativa, causing a decrease in the frequency of atp6‐orf79‐like structures from 19.9% to 8.1%. Phylogenetic and biogeographic analyses revealed that the different groups of these gametophytic CMS‐related genes in O. rufipogon evolved in a multicentric pattern. The geographical origin of the atp6‐orf79‐like structures was further traced back, and a candidate region in north‐east of Gangetic Plain on the Indian Peninsula (South Asia) was identified as the origin centre of AO‐I. The orf79 alleles were detected in all three cytoplasmic types (Or‐CT0, Or‐CT1 and Or‐CT2) of O. rufipogon, but only two alleles (orf79a and orf79b) were observed in Or‐CT0 type of O. sativa, while no orf79 allele was found in other types of O. sativa. Our results also revealed that the orf79 alleles in cultivated rice originated from the wild rice population in South and South‐East Asia. In addition, strong positive selection pressure was detected on the sequence variations of orf79 alleles, and a special evolutionary strategy was noted in these gametophytic CMS‐related genes, suggesting that their divergence could be beneficial to their survival in evolution.

Inflammatory responses determine the pathological course of spinal cord injury. Here, the authors report on pH responsive fibers for triggered release of IL-4 plasmid liposomes and sustained release of nerve growth factor to regulate the immune response and promote nerve regeneration to enhance functional recovery.

A three-dimensional convective heat transfer model of a microchannel pin-fin hybrid heat sink was established. Considering the non-uniform heat generation of 3D stacked chips, the splitting distance of pin-fins was optimized by minimizing the maximum heat sink temperature under different heat fluxes in the hotspot, the Reynolds numbers at the entrance of the microchannel, and the proportions of the pin-fin volume. The average pressure drop and the performance evaluation criteria were considered to be the performance indexes to analyze the influence of each parameter on the flow performance and comprehensive performance, respectively. The results showed that the maximum temperature of the hybrid heat sink attained a minimum value with an increase in the splitting distance. The average pressure drop in the center passage of the microchannel first increased and then decreased. Furthermore, the optimal value could not be simultaneously obtained with the maximum temperature. Therefore, it should be comprehensively considered in the optimization design. The heat flux in the hotspot was positively correlated with the maximum heat sink temperature. However, it had no effect on the flow pressure drop. When the Reynolds number and the pin-fin diameter increased, the maximum heat sink temperature decreased and the average pressure drop of the microchannel increased. The comprehensive performance of the hybrid heat sink was not good at small Reynolds numbers, but it significantly improved as the Reynolds number gradually increased. Choosing a bigger pin-fin diameter and the corresponding optimal value of the splitting distance in a given Reynolds number would further improve the comprehensive performance of a hybrid heat sink.

Bacteriophage T4 lysozyme (T4L) is a glycosidase that is widely applied as a natural antimicrobial agent in the food industry. Due to its wide applications and small size, T4L has been regarded as a model system for understanding protein dynamics and for large-scale protein engineering. Through structural insights from the single conformation of T4L, a series of mutations (L99A,G113A,R119P) have been introduced, which have successfully raised the fractional population of its only hydrolysis-competent excited state to 96%. However, the actual impact of these substitutions on its dynamics remains unclear, largely due to the lack of highly efficient sampling algorithms. Here, using our recently developed travelling-salesman-based automated path searching (TAPS), we located the minimum-free-energy path (MFEP) for the transition of three T4L mutants from their ground states to their excited states. All three mutants share a three-step transition: the flipping of F114, the rearrangement of α0/α1 helices, and final refinement. Remarkably, the MFEP revealed that the effects of the mutations are drastically beyond the expectations of their original design: (a) the G113A substitution not only enhances helicity but also fills the hydrophobic Cavity I and reduces the free energy barrier for flipping F114; (b) R119P barely changes the stability of the ground state but stabilizes the excited state through rarely reported polar contacts S117OG:N132ND2, E11OE1:R145NH1, and E11OE2:Q105NE2; (c) the residue W138 flips into Cavity I and further stabilizes the excited state for the triple mutant L99A,G113A,R119P. These novel insights that were unexpected in the original mutant design indicated the necessity of incorporating path searching into the workflow of rational protein engineering.

A numerical simulation model of embedded liquid microchannels for cooling 3D multi-core chips is established. For the thermal management problem when the operating power of a chip changes dynamically, an intelligent method combining BP neural network and genetic algorithm is used for distribution optimization of coolant flow under the condition with a fixed total mass flow rate. Firstly, a sample point dataset containing temperature field information is obtained by numerical calculation of convective heat transfer, and the constructed BP neural network is trained using these data. The “working condition–flow distribution–temperature” mapping relationship is predicted by the BP neural network. The genetic algorithm is further used to optimize the optimal flow distribution strategy to adapt to the dynamic change of power. Compared with the commonly used uniform flow distribution method, the intelligently optimized nonuniform flow distribution method can further reduce the temperature of the chip and improve the temperature uniformity of the chip.

Big infectious diseases do harm to the whole society, and it is highly crucial to control them on time. The major purpose of this article is to theoretically demonstrate that the Chinese government’s intervention in large-scale infectious diseases is successful and efficient. Two potential strategies were considered: strategy 1 was infectious disease without government intervention, and strategy 2 was infectious disease with government intervention. By evolution model, this article illustrates the efficiency of big infectious disease reimbursement policy in China. Without government reimbursement, this article finds that high expenditures accelerate the disease infection. The number of infected persons decreases under big infectious disease reimbursement policy in China. The higher the treatment costs, the more important the government intervention. Big infectious disease reimbursement policy in China can serve as an efficient example to cope with big infectious diseases.

A model of rectangular microchannel heat sink (MCHS) with porous medium (PM) is developed. Aspect ratio of heat sink (HS) cell and length-width ratio of HS are optimized by numerical simulation method for entropy generation minimization (EGM) according to constructal theory. The effects of inlet Reynolds number (Re) of coolant, heat flux on bottom, porosity and volume proportion of PM on dimensionless entropy generation rate (DEGR) are analyzed. From the results, there are optimal aspect ratios to minimize DEGR. Given the initial condition, DEGR is 33.10% lower than its initial value after the aspect ratio is optimized. With the increase of Re, the optimal aspect ratio declines, and the minimum DEGR drops as well. DEGR gets larger and the optimal aspect ratio remains constant with the increasing of heat flux on bottom. For the different volume proportion of PM, the optimal aspect ratios are diverse, but the minimum DEGR almost stays unchanged. The twice minimized DEGR, which results from aspect ratio and length-width ratio optimized simultaneously, is 10.70% lower than the once minimized DEGR. For a rectangular bottom, a lower DEGR can be reached by choosing the proper direction of fluid flow.

Alkaline soils have a great influence on apple production in Northern China. Therefore, comprehensive evaluations of tolerance to such stress are important when selecting the most suitable apple rootstocks. We used hydroponics culturing to test 17 genotypes of apple rootstocks after treatment with 1:1 Na2CO3 and NaHCO3. When compared with the normally grown controls, stressed plants produced fewer new leaves, and had shorter roots and shoots and lower fresh and dry weights after 15 d of exposure to alkaline conditions. Their root/shoot ratios were also reduced, indicating that the roots had been severely damaged. For all stressed rootstocks, electrolyte leakage (EL) and the concentration of malondialdehyde (MDA) increased while levels of chlorophyll decreased. Changes in root activity (up or down), as well as the activities of peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT) were rootstock-dependent, possibly reflecting their differences in alkali tolerance. Using alkali injury index (AI), adversity resistance coefficients (ARC), cluster analysis, and evaluation of their physiological responses, we classified these 17 genotypes into three groups: (1) high tolerance: Hubeihaitang, Wushanbianyehaitang, Laoshanhaitang Ls2, Xiaojinbianyehaitang, and Fupingqiuzi; (2) moderate tolerance: Pingyitiancha, Laoshanhaitang Ls3, Hubeihaitang A1, Deqinhaitang, Balenghaitang, Maoshandingzi, Shandingzi, and Xinjiangyepingguo; or (3) low tolerance: Pingdinghaitang, Hongsanyehaitang, Xiaojinhaitang, and Sanyehaitang. These results will significantly contribute to the selection of the most suitable materials for rootstocks with desired levels of tolerance to alkali stress.

Neolamarckia cadamba (Roxb.) Bosser is a fast-growing deciduous tree species and belongs to the Neolamarckia genus of the Rubiaceae family. This species has great economic and medical values in addition to being an important timber species for multiple industrial purposes. However, few studies have examined the genetic diversity and population structure in the natural distribution of this species in China. Here, we applied both the haploid nrDNA ITS (619 bp for aligned sequences) and mtDNA (2 polymorphic loci) markers to investigate 10 natural populations (239 individuals in total) that covered most of the distribution of the species in China. The results showed that the nucleotide diversity was π = 0.1185 ± 0.0242 for the nrDNA ITS markers and π = 0.00038 ± 0.00052 for the mtDNA markers. The haplotype diversity for the mtDNA markers was h = 0.1952 ± 0.2532. The population genetic differentiation was small ( F s t n = 0.0294) for the nrDNA ITS markers but large ( F s t m = 0.6765) for the mtDNA markers. There were no significant effects of isolation by distance (IBD), by elevation, and by two climatic factors (annual average precipitation and tem perature). A geographic structure among populations ( N s t < G s t ) was absent. Phylogenetic analysis showed a highly genetic mixture among individuals of the ten populations. Pollen flow was substantially greater than seed flow ( m p / m s   ≫ 1.0) and played a dominant role in shaping population genetic structure. The nrDNA ITS sequences were neutral and all local populations did not undergo demographic expansion. The overall results provide fundamental information for the genetic conservation and breeding of this miraculous tree. [ABSTRACT FROM AUTHOR]