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Fabrication of polymer films with superb mechanical properties is far from mature compared to that of fibers, hampering the further engineering applications of lightweight polymer materials. Herein, high density polyethylene (HDPE) films reinforced with re-dispersed or refined reduced graphene oxide (rGO) are prepared via a facile melt-stretching strategy. The incorporation of only 0.2 wt% rGO is demonstrated to endow the melt-stretched film (80× stretch ratio) with ultrahigh Young's modulus of 2.9 GPa and tensile strength of 162.2 MPa, which are comparable to many engineering plastics and also significantly superior to the existing HDPE/graphene composites. More importantly, these modulus and strength values are increased by 71 and 65% compared to the neat PE (80×), respectively, far more than the theoretical prediction with the mixing rule. Experimental characterizations indicate that the high-efficient mechanical enhancement is attributed to the strong synergy of melt stretching-driven crystallization and rGO re-dispersion or refinement in constructing the compact and robust shish-kebabs crystal network. Such microstructural characteristics greatly promote the load transfer along the covalently bonded molecular chains, and also from polymer to rigid fillers under loading. Furthermore, the excellent puncture resistance and thermo-mechanical properties of PE/rGO films have been demonstrated. This work provides a feasible way towards scalable manufacturing of high-performance polymer nanocomposite films from general plastics and carbonaceous nanomaterials. [Display omitted] • HDPE/rGO nanocomposite films are fabricated by a facile melt stretching process. • Superb mechanical performance of films is achieved at very low filler content. • Melt stretching-driven rGO re-dispersion or refinement is demonstrated. • rGO re-dispersion enhances the formation of robust shish-kebabs crystal network. • Good puncture resistance and thermo-mechanical properties of films are revealed. [ABSTRACT FROM AUTHOR]

In many industrial processes, polymer melt undergoes complex flow-cooling environments before being solidified into the final products. Investigating polymer crystallization under processing conditions is a necessary step to predict and customize the structures and properties of semicrystalline polymers. Herein, the crystallization behavior of high-density polyethylene (HDPE) under combined melt stretching and fast cooling fields was studied through a homemade extensional rheometer. A series of HDPE samples were prepared by cooling the stretched melt at different cooling rates (0.02–220 °C/s) immediately after flow, or after waiting for different times of isothermal crystallization at 128 °C. Microstructural characterizations confirm four different structural states related to the evolution of shish-kebabs after melt stretching, namely generation of shish precursors, shish crystal growth, kebab lamellar growth, and perfection of shish-kebabs, which diversify greatly the structures and morphologies of the final solidified samples. By prolonging the isothermal crystallization time at high temperature, the fast cooling-induced lamellae keep decreasing in thickness. This supports the occurrence of molecular segregation caused by shish-kebabs growth at high temperature, which reduces the molecular weight of the remaining un-crystallized melt. In addition, quantitative analysis of crystalline orientation manifests that the lamellar growth during isothermal process takes strictly the shish as a template and adopts a high orientation, while the fast cooling-induced lamellae are only related to the chains conformation of un-crystallized melt prior to cooling. This work would be essential to advance the in-depth understanding on the actual industrial processing of semicrystalline polymeric materials. [Display omitted] • Melt crystallization of HDPE under combined stretching and fast cooling fields was studied. • Four different structural states related to the evolution of shish-kebabs after flow were identified. • Molecular segregation caused by shish-kebabs growth at high temperature was suggested. • Isothermal and non-isothermal crystallization under flow presented different lamellar growth modes. [ABSTRACT FROM AUTHOR]

The pancreatic ATP-sensitive potassium (KATP) channel, a complex of four sulfonylurea receptor 1 (SUR1) and four potassium channel Kir6.2 subunits, regulates insulin secretion by linking metabolic changes to β-cell membrane potential. Sulfonylureas inhibit KATP channel activities by binding to SUR1 and are widely used to treat type II diabetes. We report here that sulfonylureas also function as chemical chaperones to rescue KATP channel trafficking defects caused by two SUR1 mutations, A116P and V187D, identified in patients with congenital hyperinsulinism. Sulfonylureas markedly increased cell surface expression of the A116P and V187D mutants by stabilizing the mutant SUR1 proteins and promoting their maturation. By contrast, diazoxide, a potassium channel opener that also binds SUR1, had no effect on surface expression of either mutant. Importantly, both mutant channels rescued to the cell surface have normal ATP, MgADP, and diazoxide sensitivities, demonstrating that SUR1 harboring either the A116P or the V187D mutation is capable of associating with Kir6.2 to form functional KATP channels. Thus, sulfonylureas may be used to treat congenital hyperinsulinism caused by certain KATP channel trafficking mutations. [ABSTRACT FROM AUTHOR]

The treatment and repair of large bone defects remains a major therapeutic challenge in the clinical setting. Nanofiber scaffolds fabricated via the electrospinning technique have been developed as a universal method for bone regeneration due to their suitable properties. However, traditional two-dimensional (2D) nanofiber mats are usually too dense, which may prevent cell infiltration and growth, thereby restricting their application. Herein, a three-dimensional (3D) polycaprolactone nanofiber scaffold was developed, modified by biomineralization and silk fibroin coating. The scaffold possessed a parallel array of nanofiber surfaces, mimicking the parallel structure of fibrils in natural bone tissue. Furthermore, the fabricated radially or laterally interconnected macrochannels were investigated to elucidate the effect of the scaffold structure on bone regeneration. In vitro studies revealed that the scaffolds could guide cell arrangement and that the radially aligned scaffold demonstrated a stronger ability to promote cell proliferation. In vivo results showed that the radially aligned scaffold could guide tissue arrangement and remodeling and support a significantly faster regeneration rate of bone tissue. Therefore, 3D-mineralized polycaprolactone nanofiber scaffolds with radially interconnected macrochannels and aligned nanofibers are expected to be used in tissue engineering, including in the repair of bone defects, cartilage or other composite tissues. [ABSTRACT FROM AUTHOR]

Trivalent iron (Fe3+)-dependent anaerobic oxidation of methane (Fe-AOM), which is mediated by metal-reducing bacteria, is widely recognized as a major sink for the greenhouse gas methane (CH 4), and is a key driver of the carbon (C) biogeochemical cycle. However, the effect of Fe3+ addition on AOM in the present investigation is still ambiguous, and the mechanism is vague. In this study, we investigated the mechanism of changes in AOM response to Fe3+ input at different wetlands by using laboratory incubation methods combined with molecular biology techniques. Results indicated that Fe3+ input did not always lead to promoted AOM rates, which may be mediated by complex environmental factors, while lower soil total nitrogen (TN) had a positive effect on the response of AOM subjected to Fe3+ input. Notably, the promoted response of AOM was regulated by higher soil microbial diversity, of which the Shannon index was a key indicator leading to variation in the AOM response. Additionally, several biomarkers, including Planctomycetota and Burkholderiaceae , were key microorganisms responsible for alterations in AOM response. Our results suggest that the capacity of Fe3+ cycling-mediated AOM may gradually decrease in light of increasing anthropogenic N and Fe inputs to global estuarine wetlands, while its reaction processes will become more complex and more strongly coupled with multiple environmental factors. This finding contributes to the enhanced understanding and prediction of the wetland CH 4 -related C with Fe cycles, as well as provides theoretical support for the underlying mechanisms. [Display omitted] • The mechanism of the change in the response to Fe3+ input by AOM was investigated. • Fe3+ input did not necessarily contribute to the AOM rate. • Lower soil TN content positively influenced the response of AOM. • Higher Shannon index has a positive effect on the response of AOM. • Planctomycetota , Burkholderiaceae , etc. caused variation in the response of AOM. [ABSTRACT FROM AUTHOR]

The thymus-derived lymphocytes of jawed vertebrates have four T-cell receptor (TCR) chains that play a significant role in immunity. As chickens have commercial value, their immune systems require a great deal of attention. Local chicken breeds are an essential part of poultry genetic resources in China. Here, we used high-throughput sequencing to analyze the TCRα and TCRβ repertoires and their relative expression levels in the native chicken breeds Baier Buff, Longyou Partridge, Xiaoshan, and Xianju. We found that TCR Vα and TCR Vβ were expressed and included 17, 19, 17, and six segments of the Vα2, Vα3, Vβ1, and Vβ2 subgroups, respectively. V-J pairing was biased; Jα11 was utilized by nearly all Vα segments and was the most commonly used. Breed-specific V segments and V-J pairings were detected as well. The results of the principal coordinate analysis (PCoA) as well as the V-J pairing and CDR3 diversity analyses suggested that the four local chicken breeds did not significantly differ in terms of TCR diversity. Hence, they expressed not significant differentiation, and they are rich genetic resources for the development and utilization of immune-related poultry breeding. • Both Vα subgroups and Vβ subgroups are expressed in chicken. • Various TCR diversity with V segments, V-J pairing, and CDR3 diversity. • No significant differentiation of TCR diversity parameters among local chicken breeds. [ABSTRACT FROM AUTHOR]

[Display omitted] • Propose a preparation method for 3D-printed bioceramics with immunomodulation, angiogenesis, and osteogenesis. • Finding that 3D-printed bioceramics have excellent mineralization properties. • Finding that 3D-printed bioceramic scaffolds can solve implant migration and ectopic osteogenesis of DBM. • 3D-printed bioceramics have excellent biosafety, immunomodulation, angiogenesis, and osteogenesis. Personalized repair of bone defects remains a tremendous clinical challenge. Developing 3D-printed bioceramics with excellent osteogenic potential is an effective therapeutic strategy to overcome this challenge. In this study, we prepared composite bioceramics (designated as CSC-DBM) with immunomodulatory, vascularization, and osteogenesis based on calcium silicate (CS) bioceramics, calcium sulfate (CSH), and decalcified bone matrix (DBM). CSC-DBM bioceramics has an unmatched biomineralization potential due to the synergistic promotion of CS and CSH. Meanwhile, CSC-DBM bioceramics could effectively modulate the immune response, induce M2 macrophage polarization, promote vascular regeneration, and further enhance new bone formation. In summary, this composite bioceramics made of CS bioceramics, CSH, and DBM can provide a new solution for bone defect repair in the clinic. [ABSTRACT FROM AUTHOR]

The AP-1 member Fra-1 is overexpressed in TNBC and plays crucial roles in tumor progression and treatment resistance. In a previous large-scale screen, we identified PARP1 to be among 118 proteins that interact with endogenous chromatin-bound Fra-1 in TNBC cells. PARP1 inhibitor (olaparib) is currently in clinical use for treatment of BRCA-mutated TNBC breast cancer. Here, we demonstrate that the Fra-1-PARP1 interaction impacts the efficacy of olaparib treatment. We show that PARP1 interacts with and downregulates Fra-1, thereby reducing AP-1 transcriptional activity. Olaparib treatment, or silencing of PARP1, consequently, increases Fra-1 levels and enhances its transcriptional activity. Increased Fra-1 can have adverse effect, including treatment resistance. We also found that a large fraction of PARP1-regulated genes was dependent on Fra-1. We show that by inhibiting Fra-1/AP-1, non-BRCA-mutated TNBC cells can become sensitized to olaparib treatment. We identify that high PARP1 expression is indicative of a poor clinical outcome in breast cancer patients overall (P = 0.01), but not for HER-2 positive patients. In conclusion, by exploring the functionality of the Fra-1 and PARP1 interaction, we propose that targeting Fra-1 could serve as a combinatory therapeutic approach to improve olaparib treatment outcome for TNBC patients. [ABSTRACT FROM AUTHOR]

Although various strategies have been utilized to accelerate bone regeneration in bone tissue engineering (BTE), the treatment and repair of large bone defects remains a clinical challenge worldwide. Inspired by the natural extracellular matrix of bone tissue, organic-inorganic composite scaffolds with three-dimensional (3D) porous structures, sufficient mechanical properties, excellent cytocompatibility, osteoconductivity, and osteogenic potential have received considerable attention within the field of bone engineering. In this work, a novel epichlorohydrin (ECH)-crosslinked hydroxyethyl cellulose (HEC)/soy protein isolate (SPI) porous bi-component scaffold (EHSS) with hydroxyapatite (HAp) functionalization (EHSS/HAp) was constructed for bone defect repair via the combination of lyophilization and in situ biomimetic mineralization. Systematic characterization experiments were performed to assess the morphology, HAp-forming properties, mechanical properties and degradation rate of the scaffold. The results indicated that the prepared scaffolds exhibited an interconnected porous structure, a biomimetic HAp coating on their surfaces, improved mechanical properties in compression and a controllable degradation rate. In particular, semiquantitative analysis showed that the calcium/phosphorus (Ca/P) ratio of EHSS/HAp with 70% SPI content (1.65) was similar to that of natural bone tissue (1.67) according to energy dispersive X-ray spectroscopy analysis. In vitro cell culture experiments indicated that the EHSS/HAp with 70% SPI content showed improved cytocompatibility and was suitable for MC3T3-E1 cell attachment, proliferation and growth. Consistently, in vitro osteogenic differentiation studies showed that EHSS/HAp with 70% SPI content can significantly accelerate the expression of osteogenesis-related genes (Col-1, Runx2, OPN, and OCN) during osteogenic differentiation of MC3T3-E1 cells. Furthermore, when applied to the repair of critical-sized cranial defects in a rat model, EHSS/HAp with 70% SPI was capable of significantly promoting tissue regeneration and integration with native bone tissue. Microscopic computed tomography (micro-CT) results demonstrated that the bone defect site was nearly occupied with newly formed bone at 12 weeks after implantation of EHSS/HAp with 70% SPI content into the defect. Hematoxylin and eosin (H&E) staining and Masson's trichrome staining of histological sections further confirmed that EHSS/HAp with 70% SPI markedly promoted new bone formation and maturation. Collectively, our results demonstrate the potential of EHSS/HAp scaffolds with 70% SPI for successful bone defect repair and regeneration. [ABSTRACT FROM AUTHOR]

[Display omitted] • Propose a high porosity bioglass preparation method. • Finding bioglass enhances mild magnetothermal therapy. • The mechanism relies on calcium ions during glass degradation. • The composite scaffold has superior biosafety and osteogenic effect. Bone defects and tumor cell residues after bone tumor resection have always been a challenge. We tried to investigate a kind of bioglass with both bone repair and tumor killing capability to achieve two birds with one stone. We used a Sol-Gel method to prepare the high porous magnetic bioglass (MBG) and then compounded the MBG with calcium sulfate (CS) bone cement to form the composite scaffold (CS-MBG). We found that the CS-MBG could reach about 43 °C under the condition of magnetic field in vitro. Under this condition, CS-MBG would release Ca2+ resulting in the cell death of calcium overload. Meanwhile, the suitable pH and osteogenic activity of CS-MBG can promote the postoperative bone repair and inhibit the growth of bone tumors. Our work has innovatively designed a magnetic bioglass and verified its mechanism of synergistic hyperthermia against tumor, providing a new idea for the treatment of tumor bone defects with magnetic bioglass. [ABSTRACT FROM AUTHOR]

Bone regeneration requires the interaction of osteogenesis, osteolysis, and angiogenesis as well as an appropriate immune microenvironment. Recombinant human parathyroid hormone (PTH1-34) is approved for clinical anti-osteoporosis treatment because of its good osteogenic activity, osteoclastosis, and angiogenesis. However, the phenomenon of net bone resorption limits its use in local bone repair. Our group provides an effective strategy for multifunctional calcium phosphate (CaP) ceramics with modulating M1 macrophage pro-inflammatory effects, and bone regeneration. CaP ceramic scaffold is functionalized with parathyroid hormone related peptide-1 (PTHrP-1) for bone defect repair. First, peptide-functionalized true bone ceramic (TBC) scaffold exhibit limited M1 macrophage pro-inflammatory effects to improve the osteogenic microenvironment. Second, PTHrP-1 retains the osteogenic activity and angiogenic properties of PTH1-34 while downregulating osteoclast activity to induce favorable bone formation. Third, the peptide modified by tri-continuous aspartic acids (D3) and serine phosphorylation (PSer) has high affinity to the natural CaP matrix, achieving a slow release of PTHrP-1 in the TBC scaffold. Fourth, the carboxyl group of aspartate combined with calcium effectively promotes hydroxyapatite (HAP) nucleation and completes self-assembled mineralization. which is beneficial for bone regeneration. The results show that PTHrP-1-TBC is more suitable for bone regeneration than TBC scaffold and unmodified peptide alone. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a group of malignant heterogeneous cancer arising from the biliary tree. CCA has become a global health problem with rising incidence and mortality that threatens the health of human beings. The immune microenvironment of CCA is characterized by abundant cancer-associated fibroblast and suppressive immune components. The increasing body of knowledge and recent developments in transcriptomic studies have given insight into the immune landscape of CCA, paving the way for better application of immunotherapy. Immunotherapy mainly applies in a limited subset of CCA with deficient mismatch and high microsatellite instability. With limited response rates and treatment efficacy, researchers are looking into novel strategies on combination strategies and alternatives, such as immune vaccines and adoptive cell therapy. Biomarker identification is also critical for patient selection. We present an up-to-date summary of the current research on immunotherapy for CCA patients, covering pre-clinical and clinical exploration beyond immune checkpoint inhibitors, immune vaccines, and adoptive cell therapy. In addition, we review the promising biomarkers for CCA immunotherapy and discuss recent development. [ABSTRACT FROM AUTHOR]

The laying performance of geese is mainly determined by follicular development and atresia, while follicular status is regulated by photoperiod. To understand the effect of photoperiod on the development of goose follicles, artificial light was used to change the photoperiod. In this study, ten healthy 220-day-old Zhedong white geese (Anser Cygnoides) with similar body weights and similar reproductive start times were reared for 60 days under long photoperiod (15 L:9 D) and short photoperiod (9 L:15 D) artificial light with the intensity controlled at 30 lux, and follicles were collected. Follicle development was analyzed by observing the morphology of follicle tissue, the localization of autophagosomes and autolysosomes, and the expression levels of apoptosis-related protein factors. Small white follicles (SWFs) were selected for RNA sequencing and bioinformatics analysis of the transcriptome. Under a long photoperiod, microtubule-associated protein 1 light chain 3 (LC3) and Caspase-3 were expressed in the granulosa cell layer and oocytes, respectively. LC3 and Caspase-3 protein expression was increased in SWF and large white follicles (LWFs), and there were more autophagosomes and autolysosomes in granulosa cells. RNA-seq found 93 differentially expressed genes (DEGs) in the short-photoperiod group, including 55 upregulated DEGs and 38 downregulated DEGs, distributed in 37 gene ontology categories. Kyoto Encyclopedia of Genes and Genomes-enriched signaling pathways revealed 5 pathways enriched in upregulated DEGs, including protein digestion and absorption, ECM-receptor interaction and regulation of lipolysis in adipocytes, and 4 pathways enriched in downregulated DEGs, such as fatty acid biosynthesis. Ten differentially expressed genes related to extracellular matrix and fatty acid metabolism (THBS2, COL12A1, MRC2, TUBA, COL1A1, COL11A1, HSPG2, FABP, MGLL , and OLAH) may be involved in the photoperiod regulation of follicle development in Zhedong white geese. The differentially expressed genes screened in this study will provide new ideas to further understand the molecular mechanism underlying photoperiod-mediated regulation of follicle development in Zhedong white geese. [ABSTRACT FROM AUTHOR]

Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the serine synthesis pathway. However, the regulatory role of PHGDH in muscle development is unclear. We report that the expression of PHGDH increased significantly during proliferation of chicken skeletal muscle satellite cells. Knockdown of PHGDH by an siRNA suppressed myoblast proliferation, whereas overexpression of PHGDH enhanced muscle cell proliferation. Furthermore, PHGDH promoted the expression of Forkhead box protein M1 (FoxM1). Knockdown of FoxM1 by an siRNA attenuated the proliferation of chicken muscle cells, whereas its overexpression significantly promoted proliferation. Additionally, siRNA-PHGDH inhibited pcDNA3.1-FoxM1-induced FoxM1 expression in chicken muscle cells. Moreover, PHGDH inhibition overcame the stimulation by pcDNA3.1-FoxM1 of cell cycle-related gene expression. We propose that PHGDH accelerates chicken muscle cell proliferation by increasing FoxM1 expression. [ABSTRACT FROM AUTHOR]