Toward morphologically relevant extracellular matrix: nanofiber-hydrogel composites for tumor cell culture.

The natural extracellular matrix (ECM) consists of a continuous integrated fibrin network and a negatively charged proteoglycan-based matrix. In this work, we report a novel three-dimensional nanofiber hydrogel composite that mimics the natural ECM structure, exhibiting both degradability and mechanical characteristics comparable to that of tumor tissue. The embedded nanofiber improves the hydrogel mechanical properties, and varying the fiber density can match the elastic modulus of different tumor tissues (1.51-10.77 kPa). The degradability of the scaffold gives sufficient space for tumor cells to secrete and remodel the ECM. The expression levels of cancer stem cell markers confirmed the development of aggressive and metastatic phenotypes of prostate cancer cells in the 3D scaffold. Similar results were obtained in terms of anticancer resistance of prostate cancer cells in 3D scaffolds showing stem cell-like properties, suggesting that the current bionic 3D scaffold tumor model has broad potential in the development of effective targeted agents.

Combined skin dilator and titanium mesh application to repair scalp and skull defects: a case report.

We report a case of skin dilator combined with titanium mesh to repair scalp and skull defects. An 18-year-old male with a scalp defect and skull necrosis due to high-voltage electrical burns was admitted to our hospital. In the first stage, the wound was debrided, antibiotics were applied to control the infection, and two skin dilators were embedded under the scalp after debridement. In the second stage, necrotic skull material was removed, the skull defect was repaired using titanium mesh, and the scalp defect was repaired by transferring expanded flaps. The patient was followed up for 6 months, recovering well and achieving a satisfactory head shape.

Janus Membranes Patch Achieves High-Quality Tendon Repair: Inhibiting Exogenous Healing and Promoting Endogenous Healing.

The imbalance between endogenous and exogenous healing is the fundamental reason for the poor tendon healing. In this study, a Janus patch was developed to promote endogenous healing and inhibit exogenous healing, leading to improved tendon repair. The upper layer of the patch is a poly(dl-lactide-co-glycolide)/polycaprolactone (PLGA/PCL) nanomembrane (PMCP-NM) modified with poly(2-methylacryloxyethyl phosphocholine) (PMPC), which created a lubricated and antifouling surface, preventing cell invasion and mechanical activation. The lower layer is a PLGA/PCL fiber membrane loaded with fibrin (Fb) (Fb-NM), serving as a temporary chemotactic scaffold to regulate the regenerative microenvironment. In vitro, the Janus patch effectively reduced 92.41% cell adhesion and 79.89% motion friction. In vivo, the patch inhibited tendon adhesion through the TGF-ß/Smad signaling pathway and promoted tendon maturation. This Janus patch is expected to provide a practical basis and theoretical guidance for high-quality soft tissue repair.

Curcumin inhibits prostate cancer by upregulating miR-483-3p and inhibiting UBE2C.

Prostate cancer (PCa) is an extremely common genitourinary malignancy among elderly men. Many evidence have shown the efficacy of curcumin (CUR) in inhibiting the progression of PCa. However, the pharmacological function of CUR in PCa is still not quite clear. In this research, CUR was found to suppress the proliferation and enhance the apoptotic rate in in vitro PCa cell models in a dose- and time-dependent manner. In a xenograft animal model, the administration of CUR contributed to a significant decrease in the growth of the xenograft tumor induced by the transplanted PC-3 cells. Ubiquitin-conjugating enzyme E2 C is implicated in the modulation of multiple types of cancers. In humans, the expression levels of UBE2C are significantly higher in PCa versus benign prostatic hyperplasia. Treatment with CUR decreased the expression of UBE2C, whereas it increased miR-483-3p expression. In contrast with the control mice, the CUR-treated mice showed a significant reduction in UBE2C and Ki-67 in PCa cells. The capability of proliferation, migration, and invasion of PCa cells was inhibited by the knockdown of UBE2C mediated by siRNA. Furthermore, dual luciferase reporter gene assay indicated the binding of miR-483-3p to UBE2C. In summary, CUR exerts its antitumor effects through regulation of the miR-483-3p/UBE2C axis by decreasing UBE2C and increasing miR-483-3p. The findings may also provide new molecular markers for PCa diagnosis and treatment.

A Nucleic Acid-Based LYTAC Plus Platform to Simultaneously Mediate Disease-Driven Protein Downregulation.

Protein degradation techniques, such as proteolysis-targeting chimeras (PROTACs) and lysosome-targeting chimeras (LYTACs), have emerged as promising therapeutic strategies for the treatment of diseases. However, the efficacy of current protein degradation methods still needs to be improved to address the complex mechanisms underlying diseases. Herein, a LYTAC Plus hydrogel engineered is proposed by nucleic acid self-assembly, which integrates a gene silencing motif into a LYTAC construct to enhance its therapeutic potential. As a proof-of-concept study, vascular endothelial growth factor receptor (VEGFR)-binding peptides and mannose-6 phosphate (M6P) moieties into a self-assembled nucleic acid hydrogel are introduced, enabling its LYTAC capability. Small interference RNAs (siRNAs) is then employed that target the angiopoietin-2 (ANG-2) gene as cross-linkers for hydrogel formation, giving the final LYTAC Plus hydrogel gene silencing ability. With dual functionalities, the LYTAC Plus hydrogel demonstrated effectiveness in simultaneously reducing the levels of VEGFR-2 and ANG-2 both in vitro and in vivo, as well as in improving therapeutic outcomes in treating neovascular age-related macular degeneration in a mouse model. As a general material platform, the LYTAC Plus hydrogel may possess great potential for the treatment of various diseases and warrant further investigation.

Spider-Silk-like Fiber Mat-Covered Polypropylene Warp-Knitted Hernia Mesh for Inhibition of Fibrosis under Dynamic Environment.

Hernia surgery is a widely performed procedure, and the use of a polypropylene mesh is considered the standard approach. However, the mesh often leads to complications, including the development of scar tissue that wraps around the mesh and causes it to shrink. Consequently, there is a need to investigate the relationship between the mesh and scar formation as well as to develop a hernia mesh that can prevent fibrosis. In this study, three different commercial polypropylene hernia meshes were examined to explore the connection between the fabric structure and mechanical properties. In vitro dynamic culture was used to investigate the mechanism by which the mechanical properties of the mesh in a dynamic environment affect cell differentiation. Additionally, electrospinning was employed to create polycaprolactone spider-silk-like fiber mats to achieve mechanical energy dissipation in dynamic conditions. These fiber mats were then combined with the preferred hernia mesh. The results demonstrated that the composite mesh could reduce the activation of fibroblast mechanical signaling pathways and inhibit its differentiation into myofibroblasts in dynamic environments.

Enantioselective synthesis of [4]helicenes by organocatalyzed intermolecular C-H amination.

Catalytic asymmetric synthesis of helically chiral molecules has remained an outstanding challenge and witnessed fairly limited progress in the past decades. Current methods to construct such compounds almost entirely rely on catalytic enantiocontrolled fused-ring system extension. Herein, we report a direct terminal peri-functionalization strategy, which allows for efficient assembling of 1,12-disubstituted [4]carbohelicenes via an organocatalyzed enantioselective amination reaction of 2-hydroxybenzo[c]phenanthrene derivates with diazodicarboxamides. The key feature of this approach is that the stereochemical information of the catalyst could be transferred into not only the helix sense but also the remote C-N axial chirality of the products, thus enabling the synthesis of [4]- and [5]helicenes with both structural diversity and stereochemical complexity in good efficiency and excellent enantiocontrol. Besides, the large-scale preparations and representative transformations of the helical products further demonstrate the practicality of this protocol. Moreover, DFT calculations reveal that both the hydrogen bonds and the C-H---π interactions between the substrates and catalyst contribute to the ideal stereochemical control.

Improving combination cancer immunotherapy by manipulating dual immunomodulatory signals with enzyme-triggered, cell-penetrating peptide-mediated biomodulators.

Immunosuppressive tumor microenvironments challenge the effectiveness of protein-based biopharmaceuticals in cancer immunotherapy. Reestablishing tumor cell immunogenicity by enhancing calreticulin (CRT) exposure is expected to improve tumor immunotherapy. Given that CRT translocation is inherently modulated by phosphorylated eIF2α, the selective inhibition of protein phosphatase 1 (PP1) emerges as an effective strategy to augment tumor immunogenicity. To harness the PP1-disrupting potential of GADD34-derived motifs and address their limited intracellular delivery, we integrated these sequences into an enzyme-triggered, cell-penetrating peptide-mediated chimeric protein scaffold. This design not only facilitates efficient cytoplasmic delivery of these immunostimulatory motifs to induce "eat-me" signaling, but also provides a versatile platform for combination immunotherapy. Fabrication of biomodulators with cytotoxic BLF1 provides additional "eat-me" signaling through phosphatidylserine exposure or that with an immunomodulatory designed ankyrin repeat protein disables "don't-find-me" signaling by antagonizing PD-L1. Notably, these bifunctional biomodulators exhibit remarkable ability to induce macrophage phagocytosis, dendritic cell maturation, and CD8+ T activation, ultimately substantially inhibiting tumor growth. This study presents a modular genetic coding strategy for PP1-centered therapies that enables seamless integration of immunostimulatory sequences into protein-based anti-tumor cocktail therapies, thereby offering novel alternatives for improving antitumor efficacy.

In Situ Vaccination with An Injectable Nucleic Acid Hydrogel for Synergistic Cancer Immunotherapy.

Recently, therapeutic cancer vaccines have emerged as promising candidates for cancer immunotherapy. Nevertheless, their efficacies are frequently impeded by challenges including inadequate antigen encapsulation, insufficient immune activation, and immunosuppressive tumor microenvironment. Herein, we report a three-in-one hydrogel assembled by nucleic acids (NAs) that can serve as a vaccine to in situ trigger strong immune response against cancer. Through site-specifically grafting the chemodrug, 7-ethyl-10-hydroxycamptothecin (also known as SN38), onto three component phosphorothioate (PS) DNA strands, a Y-shaped motif (Y-motif) with sticky ends is self-assembled, at one terminus of which an unmethylated cytosine-phosphate-guanine (CpG) segment is introduced as an immune agonist. Thereafter, programmed cell death ligand-1 (PD-L1) siRNA that performs as immune checkpoint inhibitor is designed as a crosslinker to assemble with the CpG- and SN38-containing Y-motif, resulting in the formation of final NA hydrogel vaccine. With three functional agents inside, the hydrogel can remarkably induce the immunogenic cell death to enhance the antigen presentation, promoting the dendritic cell maturation and effector T lymphocyte infiltration, as well as relieving the immunosuppressive tumor environment. When inoculated twice at tumor sites, the vaccine demonstrates a substantial antitumor effect in melanoma mouse model, proving its potential as a general platform for synergistic cancer immunotherapy.

Micro-nano hierarchical scaffold providing temporal-matched biological constraints for tendon reconstruction.

Due to the limitations of tendon biology, high-quality tendon repair remains a clinical and scientific challenge. Here, a micro-nano hierarchical scaffold is developed to promote orderly tendon regeneration by providing temporal-matched biological constraints. In short, fibrin (Fb), which provides biological constraints, is loaded into poly (DL-lactide-co-glycolide) nanoyarns with suitable degradation cycles (Fb-loaded nanofiber yarns (Fb-NY)). Then further combined with braiding technology, temporary chemotactic Fb scaffolds with tendon extracellular matrix-like structures are obtained to initiate the regeneration process. At the early stage of healing (2 w), the regeneration microenvironment is regulated (inducing M2 macrophages and restoring the early blood supply necessary for healing) by Fb, and the alignment of cells and collagen is induced by nanoyarn. At the late healing stage (8 w), with the degradation of Fb-NY, non-functional vascular regression occurs, and the newborn tissues gradually undergo load-bearing remodeling, restoring the anvascularous and ordered structure of the tendon. In summary, the proposed repair strategy provides temporal-matched biological constraints, offering a potential pathway to reconstruct the ordered structure and function of tendons.

Shish-kebab structure fiber with nano and micro diameter regulate macrophage polarization for anti-inflammatory and bone differentiation.

Biopolymer grafts often have limited biocompatibility, triggering excessive inflammatory responses similar to foreign bodies. Macrophage phenotype shifts are pivotal in the inflammatory response and graft success. The effects of the morphology and physical attributes of the material itself on macrophage polarization should be the focus. In this study, we prepared electrospun fibers with diverse diameters and formed a shish-kebab (SK) structure on the material surface by solution-induced crystallization, forming electrospun fiber scaffolds with diverse pore sizes and roughness. In vitro cell culture experiments demonstrated that SK structure fibers could regulate macrophage differentiation toward M2 phenotype, and the results of in vitro simulation of in vivo tissue reconstruction by the microenvironment demonstrated that the paracrine role of M2 phenotype macrophages could promote bone marrow mesenchymal stem cells (BMSCs) to differentiate into osteoblasts. In rats implanted with a subcutaneous SK-structured fiber scaffold, the large-pore size and low-stiffness SK fiber scaffolds demonstrated superior immune performance, less macrophage aggregation, and easier differentiation to the anti-inflammatory M2 phenotype. Large pore sizes and low-stiffness SK fiber scaffolds guide the morphological design of biological scaffolds implanted in vivo, which is expected to be an effective strategy for reducing inflammation when applied to graft materials in clinical settings.

Improving nanochemoimmunotherapy efficacy by boosting "eat-me" signaling and downregulating "don't-eat-me" signaling with Ganoderma lucidum polysaccharide-based drug delivery.

To address the challenges posed by low immunogenicity and immune checkpoints during cancer treatment, we propose an alternative strategy that combines immunogenic cell death (ICD) effects with CD47/SIRPα blockade to reactivate phagocytosis of tumor cells by macrophages with polysaccharide-based drug delivery. In this study, the EGFR inhibitor gefitinib was identified as a novel CD47 modulator, which promoted the translocation of CD47 molecules from the cell membrane to endosomes through the EGFR-Rab5 pathway, leading to reduced cell surface CD47 levels and limiting interaction with SIRPα. Based on this finding, we developed prophagocytic mixed nanodrugs to enhance macrophage phagocytosis by encapsulating ICD inducer doxorubicin and CD47 inhibitor gefitinib with immunostimulatory polysaccharides from Ganoderma lucidum. This approach downregulated cell surface CD47 expression to attenuate "don't-eat-me" signaling, while increasing doxorubicin accumulation in tumors by inhibiting drug-resistance proteins, leading to more exposure of calreticulin and amplifying the "eat-me" signaling. In vivo experiments demonstrated that this approach significantly suppressed intraperitoneal tumor dissemination, reversed doxorubicin-induced weight loss, and effectively induced macrophage polarization, dendritic cell maturation, and CD8+ T cell activation. These findings highlighted the significant potential of our macrophage-centered therapeutic strategy using polysaccharide-based nanocarriers and provided new perspectives for chemoimmunotherapy.

Fotagliptin monotherapy with alogliptin as an active comparator in patients with uncontrolled type 2 diabetes mellitus: a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2 diabetes mellitus (T2DM).To report the findings from a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, which was designed to assess the efficacy and safety of a novel DPP-4 inhibitor fotagliptin in treatment-naive patients with T2DM. METHODS: Patients with T2DM were randomized to receive fotagliptin (n = 230), alogliptin (n = 113) or placebo (n = 115) at a 2:1:1 ratio for 24 weeks of double-blind treatment period, followed by an open-label treatment period, making up a total of 52 weeks. The primary efficacy endpoint was to determine the superiority of fotagliptin over placebo in the change of HbA1c from baseline to Week 24. All serious or significant adverse events were recorded. RESULTS: After 24 weeks, mean decreases in HbA1c from baseline were -0.70% for fotagliptin, -0.72% for alogliptin and -0.26% for placebo. Estimated mean treatment differences in HbA1c were -0.44% (95% confidence interval [CI]: -0.62% to -0.27%) for fotagliptin versus placebo, and -0.46% (95% CI: -0.67% to -0.26%) for alogliptin versus placebo, and 0.02% (95%CI: -0.16% to 0.19%; upper limit of 95%CI < margin of 0.4%) for fotagliptin versus alogliptin. So fotagliptin was non-inferior to alogliptin. Compared with subjects with placebo (15.5%), significantly more patients with fotagliptin (37.0%) and alogliptin (35.5%) achieved HbA1c < 7.0% after 24 weeks of treatment. During the whole 52 weeks of treatment, the overall incidence of hypoglycemia was low for both of the fotagliptin and alogliptin groups (1.0% each). No drug-related serious adverse events were observed in any treatment group. CONCLUSIONS: In summary, the study demonstrated improvement in glycemic control and a favorable safety profile for fotagliptin in treatment-naive patients with T2DM. TRIAL REGISTRATION: ClinicalTrail.gov NCT05782192.

A multifunctional surgical suture with electroactivity assisted by oligochitosan/gelatin-tannic acid for promoting skin wound healing and controlling scar proliferation.

Surgical wound closure is accomplished most frequently with sutures, optimally proceeding rapidly and without complication. However, surgical sutures can trigger foreign body reactions and incite abnormal collagen deposition. Sustained inflammation can result in abnormal wound healing with hypertrophic scar formation. Therefore, evolution of suture material to inhibit inflammation and scar formation is of great clinical significance. In the present study, commercial 3-0 PPDO [poly(p-dioxanone)] suture was used as the base material and modified by adding two layers: a drug-loaded layer and an electroactive layer. The former layer was curcumin (Cur) encapsulated by PLGA [poly (lactic-co-glycolic acid)] and the latter layer was composed of oligochitosan-gelatin/tannic acid/polypyrrole (OCS-GE/TA/PPy). The multifunctional sutures, named S@LC@CGTP, had desirable sustained-drug release properties in vitro where Cur could be released for 8 days due to the action of PLGA. The three-dimensional network structure of OCS-GE/TA ensured S@LC@CGTP against surface cracking and maintained electrical. Furthermore, using an in vivo experiment, S@LC@CGTP could attenuate inflammation and promote scar-free wound healing according to suppression of infiltrating inflammatory cells, down-regulation of TGF-ß1 and collagen type I expression, and improved collagen arrangement. Cumulatively, we indicated that S@LC@CGTP suture material has great potential to facilitate optimal, nearly scarless healing of surgical incisions.

Cobweb-Inspired Micro/Nanostructured Scaffolds for Soft Tissue Regeneration with Inhibition Effect of Fibrosis under Dynamic Environment.

In soft tissue repair, fibrosis can lead to repair failure and long-term chronic pain in patients. Excessive mechanical stimulation of fibroblasts is one of the causes of fibrosis during abdominal wall regeneration. Inspired by the cobweb, a polycaprolactone beaded fiber is prepared by electrospinning. The cobweb-inspired structure attenuates the mechanical stimulation of cells under a dynamic environment. Nano-protrusions are introduced into the scaffold for further inhibition of fibrosis by self-induced crystallization. A machine is built for in vitro dynamic culture and rat abdominal subcutaneous embedding experiments are performed to verify the inhibiting effect of fibrosis in a dynamic environment in vivo. Results show that the expression of integrin ß1 and α-smooth muscle actin is inhibited by the cobweb-inspired structure under dynamic culture. The results of hematoxylin and eosin and Masson's trichrome indicate that the cobweb-inspired structure has a good inhibitory effect on fibrosis in a dynamic environment in vivo. In general, the cobweb-inspired scaffold with nano-protrusions has a good ability to inhibit fibrosis under both static and dynamic environments. It is believed that the scaffold has promising applications in the field of inhibiting fibrosis caused by mechanical stimulation.

Design and characterization of a novel tumor-homing cell-penetrating peptide for drug delivery in TGFBR3 high-expressing tumors.

Targeted therapy has attracted more and more attention in cancer treatment in recent years. However, due to the diversity of tumor types and the mutation of target sites on the tumor surface, some existing targets are no longer suitable for tumor therapy. In addition, the long-term administration of a single targeted drug can also lead to drug resistance and attenuate drug potency, so it is important to develop new targets for tumor therapy. The expression of Type III transforming growth factor ß receptor (TGFBR3) is upregulated in colon, breast, and prostate cancer cells, and plays an important role in the occurrence and development of these cancers, so TGFBR3 may be developed as a novel target for tumor therapy, but so far there is no report on this research. In this study, the structure of bone morphogenetic protein 4 (BMP4), one of the ligands of TGFBR3 was analyzed through the docking analysis with TGFBR3 and sequence charge characteristic analysis, and a functional tumor-targeting penetrating peptide T3BP was identified. The results of fluorescent labeling experiments showed that T3BP could target and efficiently enter tumor cells with high expression of TGFBR3, especially A549 cells. When the expression of TGFBR3 on the surface of tumor cells (HeLa) was knocked down by RNA interference, the high delivery efficiency of T3BP was correspondingly reduced by 40%, indicating that the delivery was TGFBR3-dependent. Trichosanthin (TCS, a plant-derived ribosome inactivating protein) fused with T3BP can enhance the inhibitory activity of the fusion protein on A549 cells by more than 200 times that of TCS alone. These results indicated that T3BP, as a novel targeting peptide that can efficiently bind TGFBR3 and be used for targeted therapy of tumors with high expression of TGFBR3. This study enriches the supply of tumor-targeting peptides and provides a new potential application option for the treatment of tumors with high expression of TGFBR3.

Fabrication and in vitro investigation of hyperbranched poly-lysine-grafted warp knitted polypropylene sling for potential treatment of stress urinary incontinence.

Polypropylene (PP) sling implantation is the most commonly performed procedure for women with stress urinary incontinence (SUI). However, concerns have arisen regarding complications caused by slings, including the common issue of erosion, which can be attributed to various factors such as the body's response and bacterial contamination. To address these concerns, we have developed a rectangular mesh self-locking edge sling with a large pore size and lightweight design. Promising results have been obtained from preliminary in vivo mechanical reliability tests, including uniaxial tensile tests. In comparative in vitro fixed load tensile tests and simulated Tension-free Vaginal Tape (TVT) and Transobturator Vaginal Tape inside-out (TVT-O) technique tests using commercial slings, our sling demonstrated less transverse wrinkling. Both slings achieved an effective porosity of over 45% under the TVT technique. However, the commercial sling experienced a significant reduction in effective porosity during the TVT-O technique, whereas our sling maintained a stable effective porosity with minimal wrinkling. Furthermore, we successfully developed cationic hydration rejection-driven antibacterial-anti-fouling coatings on the surface of our sling by grafting hyperbranched poly-lysine (HBPL) mediated by polynorepinephrine. The HBPL coating imparts a positive charge and hydrophilicity to the sling, resulting in elevated bactericidal activity and reducing protein adhesion. An optimal grafting concentration of 20 mg mL-1 was selected, confirming the stability and biocompatibility of the sling coating. This coating is expected to reduce the likelihood of postoperative erosion. Overall, our research represents significant advancements in improving the safety and performance of PP slings for stress urinary incontinence, potentially leading to a reduction in complications following surgery.

PWL1, a G-type lectin receptor-like kinase, positively regulates leaf senescence and heat tolerance but negatively regulates resistance to Xanthomonas oryzae in rice.

Plant leaf senescence, caused by multiple internal and environmental factors, has an important impact on agricultural production. The lectin receptor-like kinase (LecRLK) family members participate in plant development and responses to biotic and abiotic stresses, but their roles in regulating leaf senescence remain elusive. Here, we identify and characterize a rice premature withered leaf 1 (pwl1) mutant, which exhibits premature leaf senescence throughout the plant life cycle. The pwl1 mutant displayed withered and whitish leaf tips, decreased chlorophyll content, and accelerated chloroplast degradation. Map-based cloning revealed an amino acid substitution (Gly412Arg) in LOC_Os03g62180 (PWL1) was responsible for the phenotypes of pwl1. The expression of PWL1 was detected in all tissues, but predominantly in tillering and mature leaves. PWL1 encodes a G-type LecRLK with active kinase and autophosphorylation activities. PWL1 is localized to the plasma membrane and can self-associate, mainly mediated by the plasminogen-apple-nematode (PAN) domain. Substitution of the PAN domain significantly diminished the self-interaction of PWL1. Moreover, the pwl1 mutant showed enhanced reactive oxygen species (ROS) accumulation, cell death, and severe DNA fragmentation. RNA sequencing analysis revealed that PWL1 was involved in the regulation of multiple biological processes, like carbon metabolism, ribosome, and peroxisome pathways. Meanwhile, interfering of biological processes induced by the PWL1 mutation also enhanced heat sensitivity and resistance to bacterial blight and bacterial leaf streak with excessive accumulation of ROS and impaired chloroplast development in rice. Natural variation analysis indicated more variations in indica varieties, and the vast majority of japonica varieties harbour the PWL1Hap1 allele. Together, our results suggest that PWL1, a member of LecRLKs, exerts multiple roles in regulating plant growth and development, heat-tolerance, and resistance to bacterial pathogens.

Energy partitioning in laser-induced millimeter-sized spherical cavitation up to the fourth oscillation.

To investigate the energy partitioning up to the fourth oscillation of a millimeter-scale spherical cavitation bubble induced by laser, we used nanosecond laser pulses to generate highly spherical cavitation bubbles and shadowgraphs to measure the radius-time curve. Using the extended Gilmore model and considering the continuous condensation of the vapor in the bubble, the time evolution of the bubble radius, bubble wall velocity, and pressure in the bubble is calculated till the 4th oscillation. Using Kirkwood-Bethe hypothesis, the evolution of velocity and pressure of shock wave at the optical breakdown, the first and second collapses are calculated. The shock wave energy at the breakdown and bubble collapse is directly calculated by numerical method. We found the simulated radius-time curve fits well with experimental data for the first four oscillations. The energy partition at the breakdown is the same as that in previous studies, the ratio of shock wave energy to bubble energy is about 2:1. In the first collapse and the second collapse, the ratio of shock wave energy to bubble energy is 14.54:1 and 2.81:1 respectively. In the third and fourth collapses, the ratio is less, namely than 1.5:1 and 0.42:1 respectively. The formation mechanism of the shock wave at the collapse is analyzed. The breakdown shock wave is mainly driven by the expansion of the supercritical liquid resulting from the thermalization of the energy of the free electrons in the plasma, and the collapse shock wave is mainly driven by the compressed liquid around the bubble.

Cytotoxic effects of recombinant proteins enhanced by momordin Ic are dependent on cholesterol and ganglioside GM1.

Plant-derived triterpenoid saponins have been shown to play a powerful role in enhancing the cytotoxic activity of protein therapeutics. However, the mechanism of how saponins are acting is not clearly understood. In this study, momordin Ic (MIC), a triterpenoid saponin derived from Kochia scoparia (L.) Schrad., specifically enhance the antiproliferative effect of recombinant MAP30 (a type I ribosome inactivating protein, RIP) in breast cancer cells. Subsequently, the possible mechanism of how MIC enhanced the cytotoxicity of MAP30 was analyzed in detail. We observed the level of intracellular labeled MAP30 using fluorescence microscopy and flow cytometry. And a reporter protein, GAL9, was used to monitor the role of MIC in promoting endosomal escape. We found endosomal escape does not play a role for the enhancer effect of MIC while the effect of MIC on MAP30 is cholesterol dependent and that ganglioside GM1, a lipid raft marker, can competitively inhibit cytotoxicity of MAP30 enhanced by MIC. Finally, we provided some insights into the correlation between the sugar side chain of MIC and its role in enhancing of RIP cytotoxicity and altering of drug cell tropism.