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Diverse oxygen generation strategies have been developed to overcome hypoxia in tumors for enhancing the therapeutic efficacy, but inevitably suffering from tedious synthesis process of oxygen generators in vitro before in vivo administration. Herein, we show direct injection of commercially and clinically used KMnO

The multicolored Asian lady beetle, Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae), is an important natural enemy in agricultural ecosystems. In spite of being a carnivore consuming protein-rich preys, the lady beetles often consume carbohydrate-rich food like nectar or honeydew. However, most studies on nutrition regulation of carnivores mainly focus on protein and lipid, two major macronutrients in preys. In this study, nutrition regulation of protein and carbohydrate has been investigated in the 4th instar larvae of H. axyridis using Geometric Framework. We provided the insects two pairs of foods, one a protein-biased one and the second carbohydrate-biased, to determine the intake target. We then confined them to nutritionally imbalanced foods to examine how they regulated food intake to achieve maximal performance. The larvae performed well on the 2 foods that containing the closest P : C ratios to the intake target, but, surprisingly, the lipid content was much lower than that in the choice experiment. The lady beetles seemed to maintain the optimal lipid content by consuming carbohydrate-rich food. Moreover, consuming the carbohydrate-rich food was less metabolically expensive than the protein-rich food. Therefore, switching behavior between plant and animal foods actually reflects their nutritive needs. These findings extended our understanding of predator forage behavior and its influence on food web in ecosystems, and shed light on the role of agri-environment schemes in meeting the nutritional need of predators in field.

Leucine-rich-repeat kinase 2 (LRRK2) belongs to the Roco GTPase family and is a large multidomain protein harboring both GTPase and kinase activities. LRRK2 plays indispensable roles in many processes, such as autophagy and vesicle trafficking in mitosis. In this study, we showed the critical roles of LRRK2 in mammalian oocyte meiosis. LRRK2 is mainly accumulated at the meiotic spindle periphery during oocyte maturation. Depleting LRRK2 led to the polar body extrusion defects and also induced large polar bodies in mouse oocytes. Mass spectrometry analysis and co-immunoprecipitation results showed that LRRK2 was associated with several actin-regulating factors, such as Fascin and Rho-kinase (ROCK), and depletion of LRRK2 affected the expression of ROCK, phosphorylated cofilin, and Fascin. Further analysis showed that LRRK2 depletion did not affect spindle organization but caused the failure of spindle migration, which was largely due to the decrease of cytoplasmic actin filaments. Moreover, LRRK2 showed a similar localization pattern to mitochondria, and LRRK2 was associated with several mitochondria-related proteins. Indeed, mitochondrial distribution and function were both disrupted in LRRK2-depleted oocytes. In summary, our results indicated the critical roles of LRRK2 in actin assembly for spindle migration and mitochondrial function in mouse oocyte meiosis.

SHARPIN, together with RNF31/HOIP and RBCK1/HOIL1, form the linear ubiquitin chain assembly complex (LUBAC) E3 ligase that catalyzes M1-linked polyubiquitination. Mutations in RNF31/HOIP and RBCK/HOIL1 in humans and Sharpin in mice lead to autoinflammation and immunodeficiency, but the mechanism underlying the immune dysregulation remains unclear. We now show that the phenotype of the Sharpin(cpdm/cpdm) mice is dependent on CYLD, a deubiquitinase previously shown to mediate removal of K63-linked polyubiquitin chains. Dermatitis, disrupted splenic architecture, and loss of Peyer's patches in the Sharpin(cpdm/cpdm) mice were fully reversed in Sharpin(cpdm/cpdm) Cyld(−/−) mice. We observed enhanced association of RIPK1 with the death-signaling Complex II following TNF stimulation in Sharpin(cpdm/cpdm) cells, a finding dependent on CYLD since we observed reversal in Sharpin(cpdm/cpdm) Cyld(−/−) cells. Enhanced RIPK1 recruitment to Complex II in Sharpin(cpdm/cpdm) cells correlated with impaired phosphorylation of CYLD at serine 418, a modification reported to inhibit its enzymatic activity. The dermatitis in the Sharpin(cpdm/cpdm) mice was also ameliorated by the conditional deletion of Cyld using LysM-cre or Cx3cr1-cre indicating that CYLD-dependent death of myeloid cells is inflammatory. Our studies reveal that under physiological conditions, TNF- and RIPK1-dependent cell death is suppressed by the linear ubiquitin-dependent inhibition of CYLD. The Sharpin(cpdm/cpdm) phenotype illustrates the pathological consequences when CYLD inhibition fails.

The AIE bio-probes have attracted extensive attention because of their good brightness, long-term in situ retention ability, photostability and low cytotoxicity. Recently, the transformation of ACQ to AIE has become very popular, which is very important for the further development of AIE probes. Herein, a series of novel dyes (NR-Lyso-Ⅰ, NR-Lyso-Ⅱ, NR-Lyso-III, NR-Lyso-IV) were designed and synthesized. It was found that alkylation of 4-aminonaphthalimide could achieve the transformation of the dye from ACQ to AIE effect due to the growth of carbon chain. Moreover, the AIE probe NR-Lyso-IV exhibited dual-state emission (DSE) and large Stokes shift (＞100 nm), excellent selectivity, photostability, and low cytotoxicity, which was able to simultaneous visualize the lipid droplets (LDs) and lysosomes of HeLa cells and zebrafish.

Herein, a two-step hydrothermal pretreatment combined with alkali extraction method was applied to deconstruct the poplar cell walls for enzymatic hydrolysis. Results revealed that 88.1 % of hemicelluloses and 77.6 % of lignin were removed during the integrated treatment performed at 180 °C and a maximum enzymatic hydrolysis efficiency of 96.1 % was achieved. Confocal Raman microscopy suggested that the removal of hemicelluloses from cell walls was inhomogeneous, and most hemicelluloses were released from the secondary wall. In addition, 35.2–56.8 % of hemicelluloses were isolated from the integrated treatment. Detailed structural analysis revealed that the water-soluble hemicelluloses possessed more branched structure than the alkali-soluble hemicelluloses and the hemicelluloses isolated from the poplar were mainly composed of a linear backbone of (1→4)-β- d -Xylp with 4-O-Me-α-d-GlcpA attached as side chains. This work provides an efficient pathway to transform poplar into fermentable sugars and hemicelluloses with considerable yield.

Significance Macrophages play a crucial role in chronic inflammatory diseases, such as nonalcoholic steatohepatitis (NASH) and inflammatory bowel disease, but how the proinflammatory function of macrophages is controlled is not well understood. In this work, we identified TBK1 as a pivotal anti-inflammatory factor in macrophages that restricts inflammation in different disease models. Myeloid cell–specific TBK1 deficiency causes spontaneous development of metabolic disorders in aged mice and exacerbates high-fat diet–induced fatty liver disease with NASH-like symptoms. The Tbk1-MKO mice are also hypersensitive to experimental colitis. We obtained genetic evidence that TBK1 is crucial for controlling proinflammatory signaling pathway in macrophages. These findings establish TBK1 as a pivotal anti-inflammatory factor and a potential therapeutic target for the treatment of inflammatory diseases., Proinflammatory cytokine production by innate immune cells plays a crucial role in inflammatory diseases, but the molecular mechanisms controlling the inflammatory responses are poorly understood. Here, we show that TANK-binding kinase 1 (TBK1) serves as a vital regulator of proinflammatory macrophage function and protects against tissue inflammation. Myeloid cell–conditional Tbk1 knockout (MKO) mice spontaneously developed adipose hypertrophy and metabolic disorders at old ages, associated with increased adipose tissue M1 macrophage infiltration and proinflammatory cytokine expression. When fed with a high-fat diet, the Tbk1-MKO mice also displayed exacerbated hepatic inflammation and insulin resistance, developing symptoms of nonalcoholic steatohepatitis. Furthermore, myeloid cell–specific TBK1 ablation exacerbates inflammation in experimental colitis. Mechanistically, TBK1 functions in macrophages to suppress the NF-κB and MAP kinase signaling pathways and thus attenuate induction of proinflammatory cytokines, particularly IL-1β. Ablation of IL-1 receptor 1 (IL-1R1) eliminates the inflammatory symptoms of Tbk1-MKO mice. These results establish TBK1 as a pivotal anti-inflammatory mediator that restricts inflammation in different disease models.

Ubiquitin-mediated proteolysis is essential for protein homeostasis, and its defects lead to the development of various cardiomyopathies and heart failure. By reversing the ubiquitination and degradation of target proteins, deubiquitinases (DUBs) play a crucial role in protein homeostasis. However, the importance of DUBs in cardiac pathophysiology is largely unknown. Here we addressed the role of the DUB OTU domain aldehyde binding-1 (OTUB1) in the heart. Bioinformatics analysis reveals an upregulation of OTUB1 in hypertrophic and failing human hearts. In cultured cardiomyocytes, adrenergic agonists induced upregulation and activation of OTUB1. Silencing OTUB1 in repressed adrenergic agonists-induced fetal gene re-activation, protein synthesis and cardiomyocyte hypertrophy. In vivo , mice deficient of OTUB1 in the heart developed dilated cardiomyopathy and heart failure, leading to premature lethality. The severe cardiac phenotype is accompanied by lipid accumulation, ER dilatation, prevalent autophagic vesicles containing ribosomes, as well as dysregulated expression of metabolic and ribosome genes. Delivery of wild-type OTUB1, but not the enzymatic dead mutant, via AAV9 to OTUB1-deficient hearts attenuated cardiac dysfunction and prolonged the lifespan of mice. Mechanistically, loss of OTUB1 suppressed the degradation of Deptor, an inhibitory mTOR regulator, leading to impaired mTOR signaling in cultured cardiomyocytes and mouse hearts. Collectively, these findings suggest OTUB1 is required for physiological cardiac growth by fine-tuning mTOR signaling and identify OTUB1 as a novel regulator of cardiac homeostasis.

Purpose To evaluate the potential role of MR findings and DWI parameters in predicting small regional lymph nodes metastases (with short-axis diameter Methods A total of 127 patients, 82 in training group and 45 in testing group, with histopathologically diagnosed PDACs who underwent pancreatectomy were retrospectively analyzed. PDACs were divided into two groups of positive and negative lymph node metastases (LNM) based on the pathological results. Pancreatic cancer characteristics, short axis of largest lymph node, and DWI parameters of PDACs were evaluated. Results Univariate and multivariate analyses showed that extrapancreatic distance of tumor invasion, short-axis diameter of the largest lymph node, and mean diffusivity of tumor were independently associated with small LNM in patients with PDACs. The combining MRI diagnostic model yielded AUCs of 0.836 and 0.873, and accuracies of 81.7% and 80% in the training and testing groups. The AUC of the MRI model for predicting LNM was higher than that of subjective MRI diagnosis in the training group (rater 1, P = 0.01; rater 2, 0.008) and in a testing group (rater 1, P = 0.036; rater 2, 0.024). Comparing the subjective diagnosis, the error rate of the MRI model was decreased. The defined LNM-positive group by the MRI model showed significantly inferior overall survival compared to the negative group (P = 0.006). Conclusions The MRI model showed excellent performance for individualized and noninvasive prediction of small regional LNM in PDACs. It may be used to identify PDACs with small LNM and contribute to determining an appropriate treatment strategy for PDACs.

Microglia have been implicated in neuroinflammatory diseases, including multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). We demonstrate that microglia mediate EAE disease progression via a mechanism relying on the noncanonical nuclear factor kB (NF-κB) pathway. Microglia-specific deletion of the noncanonical NF-κB-inducing kinase (NIK) impairs EAE disease progression. Although microglial NIK is dispensable for the initial phase of T cell infiltration into the central nervous system (CNS) and EAE disease onset, it is critical for the subsequent CNS recruitment of inflammatory T cells and monocytes. Our data suggest that following their initial CNS infiltration, T cells activate the microglial noncanonical NF-κB pathway, which synergizes with the T cell-derived cytokine granulocyte-macrophage colony-stimulating factor to induce expression of chemokines involved in the second-wave of T cell recruitment and disease progression. These findings highlight a mechanism of microglial function that is dependent on NIK signaling and required for EAE disease progression.

Abnormal proliferation of vascular smooth muscle cells (VSMCs) is a common feature of many vascular remodeling diseases. Because long non-coding RNAs (lncRNAs) play a critical role in cardiovascular diseases, we analyzed the key lncRNAs that regulate VSMC proliferation. Microarray analysis identified 2,643 differentially expressed lncRNAs (DELs) and 3,720 differentially expressed coding genes (DEGs) between fetal bovine serum (FBS) starvation-induced quiescent human aortic smooth muscle cells (HASMCs) and platelet-derived growth factor-BB (PDGF-BB)-stimulated proliferative HASMCs. Gene Ontology and pathway analyses of the identified DEGs and DELs demonstrated that many lncRNAs were enriched in pathways related to cell proliferation. One of the upregulated lncRNAs in proliferative HASMC was HIF1A anti-sense RNA 2 (HIF1A-AS2). HIF1A-AS2 suppression decreased HASMC proliferation via the miR-30e-5p/CCND2 mRNA axis. We have thus identified key DELs and DEGs involved in the regulation of PDGF-BB induced HASMC proliferation. Moreover, HIF1A-AS2 promotes HASMC proliferation, suggesting its potential involvement in VSMC proliferative vascular diseases.

The ubiquitin-editing enzyme A20 has a pivotal role in restricting autoimmune and inflammatory responses. New studies suggest that A20 prevents inflammatory diseases using a non-catalytic mechanism involving ubiquitin binding.

Direct transformation of bioethanol fermentation residues to valuable products is a challenge for current bioethanol fermentation processes. Traditionally, the addition of carbohydrate will reduce the performance of lignin-based resin, which greatly limits the transformation of fermentation residues (lignin-rich component) into resin. In this study, we overcame this challenge by the simple and novel strategy of producing high-quality co-condensed fermentation residue-based resins (FRs) over inexpensive sodium hydroxide and sodium carbonate as catalysts. Herein, thorough characterization of the physical properties, chemical structures, and curing behavior was performed to acquire additional data for the prepared resins obtained from two different types of fermentation residues. The current study is the first to meticulously investigate the synergistic effect of lignin and carbohydrates on resins. The mechanism results indicate that numerous co-condensed linkages were formed to produce resins with a firm structure. More importantly, when carbohydrate-rich solid residues were used instead of wheat flour, successful adjustment of viscosity, prevention of excessive osmosis, and increased bonding strength of the FRs occurred. Under the synergistic effect, the produced green FRs were utilized to manufacture plywood with a satisfactory bonding strength (1.07 MPa). The emission of formaldehyde, a harmful volatile organic compound, was also reduced by 94%. This work developed a promising sustainable technology with no waste production for direct transformation of bioethanol fermentation residues from bioethanol manufacturing. The technique reported here vastly broadens the application of fermentation waste and advances the bioethanol industry.

Elucidating the structural characteristics and changes of lignin during biorefining is considerably important for lignin valorization. To examine the structural transformations of lignin under deep...

TANK-binding kinase 1 (TBK1) responds to microbial stimuli and mediates the induction of type I interferon (IFN). Here, we show that TBK1 is also a central mediator of growth factor signalling; this function of TBK1 relies on a specific adaptor—TBK-binding protein 1 (TBKBP1). TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation by growth factors but not by innate immune stimuli. Although the TBK1–TBKBP1 signalling axis is not required for the induction of type I IFN, it mediates mTORC1 activation and oncogenesis. Conditional deletion of either TBK1 or TBKBP1 in lung epithelial cells inhibits tumourigenesis in a mouse model of lung cancer. In addition to promoting tumour growth, the TBK1–TBKBP1 axis facilitates tumour-mediated immunosuppression through a mechanism that involves induction of the checkpoint molecule PD-L1 and stimulation of glycolysis. These findings suggest a PKCθ–TBKBP1–TBK1 growth factor signalling axis that mediates both tumour growth and immunosuppression. Zhu et al. show that, in response to growth factors, TBKBP1 recruits TBK1 to promote its activation by PKCθ, thereby facilitating mTORC1 activation, tumour-mediated immunosuppression and tumourigenesis.

Objective To compare the clinical effect differences of biān (砭) stone hot compress combined with acupuncture at cervical Jiājĭ (夹脊EX-B2) acupoint and simple acupuncture at cervical EX-B2 for axial pain after cervical laminectomy with implant fixation (LIF) operation. Methods A total of 80 patients with axial pain after cervical LIF operation were randomly assigned into the biān (砭) stone hot compress combined with acupuncture at cervical EX-B2 group (Group A) and the acupuncture at cervical EX-B2 group (Group B), and 40 patients in each group. The group A was treated by biān (砭) stone hot compress and acupuncture at cervical EX-B2, while the group B was treated by acupuncture at cervical EX-B2. Both of groups were treated once a day, one course of treatment consisted of 7 days, 6-day treatment plus 1-day rest, and there were 3 courses of treatment in total. The pain score (Visual analogue scale,VAS), neck dysfunction indices (NDI), and serum creatine phosphokinase (CPK) levels of patients were compared before and after the treatment, and their clinical effects were evaluated. Results The VAS score, NDI, and CPK in patients of the two groups after treatment were all lower than those before treatment (all P Conclusions The biān (砭) stone hot compress combined with acupuncture at cervical EX-B2 acupoint was better than acupuncture at cervical EX-B2 alone in treatment of axial pain after cervical LIF operation. In the group A, therapeutic effects were improved by relieving pain, improving neck function, and repairing muscle injury.

Photoluminescent flexible nanopaper-based Fe3+ sensors were fabricated by carbon quantum dot (CQD) grafted oxidized cellulose nanofibrils (OCNF). Transparent and tunable luminescent CQD–OCNF nanopapers were facilely synthesized from citric acid, ethanediamine and an OCNF suspension using a one-pot hydrothermal method without catalysts. The morphology and chemical structures of the CQD–OCNF nanopapers were investigated by TEM, SEM, XRD, FT-IR spectroscopy, XPS and CP/MAS 13C NMR spectroscopy. The carboxyl groups of OCNF were covalently bonded to the amino groups of the newly-formed CQDs. The resultant CQD–OCNF nanopapers presented high transparency in bright field imaging and strong blue emission under ultraviolet excitation. The CQD–OCNF nanopaper was used as a highly sensitive and selective fluorescent sensor for Fe3+ ions. This study provides a facile and effective method for fabricating luminescent CQD–OCNF nanopapers with high selectivity for the detection of Fe3+.

Background/purpose: Cone-beam computed tomography-derived augmented fluoroscopy (CBCT-AF) for use in guiding endobronchial dye marking of small pulmonary nodules prior to thoracoscopic surgery is still under development. We sought to evaluate the effect of the cumulative experience on procedural parameters of CBCT-AF-guided endobronchial dye marking for preoperative localization of small pulmonary nodules. Methods: Clinical variables and treatment outcomes of the 30 initial patients with small pulmonary nodules who were managed with CBCT-AF-guided endobronchial dye marking followed by thoracoscopic resection in our institution were analyzed. Two sequential groups of patients (group I and group II, n = 15 each) were compared with regard to localization time and radiation doses. The Mann–Whitney U test and chi-square test or Fisher exact test were used in the statistical analyses. Results: In the entire cohort, the median size of solitary pulmonary nodules on preoperative computed tomography (CT) images was 9.3 mm (interquartile range, 7.4–13.6 mm), and their median distance from the pleural surface was 15.2 mm (interquartile range, 10.3–27.1 mm). The median tumor depth-to-size ratio was 1.6 (interquartile range, 1.1–2.3). A significant reduction in single DynaCT radiation (3690.4 versus [vs.] 1132.3 μGym2; P

CD8+ T cells and natural killer (NK) cells are central cellular components of immune responses against pathogens and cancer, which rely on interleukin (IL)-15 for homeostasis. Here we show that IL-15 also mediates homeostatic priming of CD8+ T cells for antigen-stimulated activation, which is controlled by a deubiquitinase, Otub1. IL-15 mediates membrane recruitment of Otub1, which inhibits ubiquitin-dependent activation of AKT, a kinase that is pivotal for T cell activation and metabolism. Otub1 deficiency in mice causes aberrant responses of CD8+ T cells to IL-15, rendering naive CD8+ T cells hypersensitive to antigen stimulation characterized by enhanced metabolic reprograming and effector functions. Otub1 also controls the maturation and activation of NK cells. Deletion of Otub1 profoundly enhances anticancer immunity by unleashing the activity of CD8+ T cells and NK cells. These findings suggest that Otub1 controls the activation of CD8+ T cells and NK cells by functioning as a checkpoint of IL-15-mediated priming.

Enzymatic hydrolysis of biomass is highly dependent on the changes in chemical compositions and structural characteristics after pretreatment. γ-Valerolactone (GVL)/dilute acid pretreatment is an effective approach to remove hemicelluloses and lignin and disrupt the cell wall structure, leading to the improvement of enzymatic hydrolysis. This study examined the influence of chemical compositions and structural features on the enzymatic hydrolysis of Eucalyptus urophylla from GVL/dilute acid pretreatment. Results revealed that glucose yield showed a positive correlation with removal rate of hemicelluloses and lignin. Particularly, there was no direct correlation of cellulose crystallinity on enzymatic hydrolysis. The highest glucose yield of 89.1% was achieved when the pretreatment was performed with GVL/H2O solution (4:1, v/v) containing 100 mM H2SO4 at 120 °C for 60 min. Meanwhile, under the mentioned conditions, 16.5% of lignin with a high purity (only contained 0.09% sugars) and molecular weight (3450 g/mol) was fractionated, which can be served as feedstock for future utilization. In short, an extensive understanding of the pretreated biomass and the obtained lignin during the GVL/dilute acid pretreatment will be beneficial for value-added applications of biomass.

Mammalian oocyte maturation involves a unique asymmetric cell division, in which meiotic spindle formation and actin filament-mediated spindle migration to the oocyte cortex are key processes. Here, we report that the vesicle trafficking regulator, RAB35 GTPase, is involved in regulating cytoskeleton dynamics in mouse oocytes. RAB35 GTPase mainly accumulated at the meiotic spindle periphery and cortex during oocyte meiosis. Depletion of RAB35 by morpholino microinjection led to aberrant polar body extrusion and asymmetric division defects in almost half the treated oocytes. We also found that RAB35 affected SIRT2 and αTAT for tubulin acetylation, which further modulated microtubule stability and meiotic spindle formation. Additionally, we found that RAB35 associated with RHOA in oocytes and modulated the ROCK–cofilin pathway for actin assembly, which further facilitated spindle migration for oocyte asymmetric division. Importantly, microinjection of Myc-Rab35 cRNA into RAB35-depleted oocytes could significantly rescue these defects. In summary, our results suggest that RAB35 GTPase has multiple roles in spindle stability and actin-mediated spindle migration in mouse oocyte meiosis.

NF-κB, a family of transcription factors regulating diverse biological processes including immune responses, is activated by canonical and noncanonical pathways based on degradation of IκBα and processing of the IκB-like protein p100, respectively. Although p100 responds to noncanonical NF-κB stimuli for processing, it does not undergo degradation, but rather becomes accumulated, along with canonical NF-κB activation. We show here that the stability of p100 is tightly controlled by a deubiquitinase, Otub1. Otub1 deficiency not only promotes signal-induced p100 processing and noncanonical NF-κB activation but also causes steady-state p100 degradation, leading to aberrant NF-κB activation in the canonical pathway. B-cell-conditional deletion of Otub1 results in B-cell hyperplasia, antibody hyper-production, and lupus-like autoimmunity. Otub1-deficient B cells display aberrantly activated phenotypes and overproduce the cytokine IL-6, contributing to autoimmunity induction. Thus, maintenance of p100 stability by Otub1 serves as an unusual mechanism of NF-κB regulation that prevents autoimmunity.

Clinically used iodinated computer tomography (CT) contrast agents suffer from low sensitivity, and the emerging lanthanide-chelates and CT imaging nanoagents raise great safety concerns. The fusion of high sensitivity and good biocompatibility is highly desired for the development of CT contrast agents. Herein, we propose a facile and green one-pot synthesis strategy for the fabrication of a small molecular CT contrast agent, Bi-diethylene triamine pentaacetate acid (DTPA) complex, for high-performance CT and spectral CT imaging. The Bi-DTPA exhibits yield of near 100%, outstanding water solubility, favorable biocompatibility, large-scale production capability, and superior X-ray attenuation ability, and is successfully applied in high-quality in vivo kidney imaging and gastrointestinal tract CT imaging and appealing spectral CT imaging. The proposed contrast agent can be rapidly excreted from body, avoiding the potential side effects caused by the long-term retention in vivo. Furthermore, our design shows great potential in developing diverse multifunctional contrast agents via chemical modification. The proposed Bi-DTPA with unique superiorities shows a bright prospect in clinic CT imaging, especially spectral CT imaging, and lays down a new way for the design of high-performance CT contrast agents with great clinical transformation potential.

γ-Valerolactone (GVL)/water/acid has been developed as a mild solvent system to pretreat biomass. In this study, Eucalyptus was pretreated with 80/20 GVL/water with the addition of H2SO4 (20–100 mM) at 120 °C for 30–60 min, and the resulting cellulose-enriched residual fractions were further enzymatically hydrolyzed. Results showed that the pretreatment of Eucalyptus with GVL/water/acid system led to a significant decrease in the contents of lignin and hemicelluloses, and the enzymatic hydrolysis efficiency of the pretreated sample was significantly improved. Meanwhile, the removal of lignin and hemicelluloses from the cell walls during the pretreatment process was monitored by the confocal Raman spectra. Under the optimum conditions (50 mM H2SO4 and 60 min), the delignification rate was up to 90.7% and the cellulose content in the residue was reached to 86.1%. The high cellulose content led to a high cellulose conversion rate and the glucose yield was 6.1-fold higher than that of the raw material without pretreatment. In short, this process provided an efficient approach to remove hemicelluloses and lignin from Eucalyptus to enhance enzymatic hydrolysis for bioethanol production.

Cytoskeleton which includes microtubule and actin filaments plays important roles during mammalian oocyte maturation. In the present study, we showed that protein kinase C mu (PKC mu) was one potential key molecule which affected cytoskeleton dynamics in mouse oocytes. Our results showed that PKC mu expressed and localized at the poles of the spindle during oocyte maturation, and PKC mu expression reduced in the oocytes from 6-month-old mice or 24 hr in vitro culture. We knocked down the expression of PKC mu in oocytes using morpholino injection to explore the relationship between PKC mu and subcellular structure defects. The loss of PKC mu reduced oocyte maturation competence, showing with decreased polar body extrusion rate and increased rate of symmetric division. Further analysis indicated that PKC mu decrease caused the spindle organization defects, and this could be confirmed by the decreased tubulin acetylation level. Moreover, we found that PKC mu affected the phosphorylation level of cofilin for actin assembly, which further affected cytoplasmic actin distribution and spindle positioning. In summary, our data indicated that PKC mu is one key factor for oocyte maturation through its roles on the spindle organization and actin filament distribution.

NF-κB-mediated inflammatory phenotypic switching of vascular smooth muscle cells (VSMCs) plays a central role in atherosclerosis and neointimal formation. However, little is known about the roles of circRNAs in the regulation of NF-κB signaling. Here, we identify the involvement of circ-Sirt1 that was one of transcripts of SIRT1 host gene in VSMC inflammatory response and neointimal hyperplasia. First, in the cytoplasm, circ-Sirt1 directly interacts with and sequesters NF-κB p65 from nuclear translocation induced by TNF-α in a sequence-dependent manner. The inhibitory complex of circ-Sirt1-NF-κB p65 is not dependent on IκBα. Second, circ-Sirt1 binds to miR-132/212 that interferes with SIRT1 mRNA, and facilitates the expression of host gene SIRT1. Increased SIRT1 results in deacetylation and inactivation of the nuclear NF-κB p65. These findings illustrate that circ-Sirt1 is a novel non-coding RNA regulator of VSMC phenotype.

The identification of new diagnostic and therapeutic biomarkers might be helpful to understand molecular mechanism of cancer pathogenesis and develop anti-cancer targets. This study reported the alteration of Sodium channel 1 subunit alpha (SCNN1A) expression, its prognostic significance and biological roles in pancreatic cancer. Bioinformatics database was searched to explore the expression of SCNN1A in pancreatic cancer specimens and analysis results were further validated by qRT-PCR and Western blot assay. The correlation between SCNN1A expression and clinicopathological characteristics and its impact on survival outcome of pancreatic cancer patients were investigated using GEPIA database and Kaplan-Meier plotter. Loss- and gain-of-functional experiments in vitro were done to investigate the biological function of SCNN1A in pancreatic cancer. Bioinformatics analysis and validation experiment showed that SCNN1A was frequently overexpressed in pancreatic cancer specimens and cell lines (P 0.001), and there were significant relevance between high SCNN1A expression and TP53 mutation (P 0.05) as well as unfavorable prognosis of pancreatic cancer patients (HR for overall survival: 1.9, P = 0.003 and HR for disease-free survival: 1.7, P = 0.014). The silencing of SCNN1A suppressed cell proliferation, migration and invasion and induced cell apoptosis (P 0.05), while its overexpression promoted aggressive phenotypes of pancreatic cancer cells in vitro (P 0.05). SCNN1A possessed oncogenic function and its dysregulation could be implicated in the development and metastasis of pancreatic cancer.

Oocyte maturation is essential for fertilization and early embryo development, and proper organelle functions guarantee this process to maintain high-quality oocytes. The type B trichothecene nivalenol (NIV) is a mycotoxin produced by Fusarium oxysporum and is commonly found in contaminated food. NIV intake affect growth, the immune system, and the female reproductive system. Here, we investigated NIV toxicity on mouse oocyte quality. Transcriptome analysis results showed that NIV exposure altered the expression of multiple genes involved in spindle formation and organelle function in mouse oocytes, indicating its toxicity on mouse oocyte maturation. Further analysis indicated that NIV exposure disrupted spindle structure and chromosome alignment, possibly through tubulin acetylation. NIV exposure induced aberrant mitochondria distribution and reduced mitochondria number, mitochondria membrane potential (MMP), and ATP levels. In addition, NIV caused the abnormal distribution of the Golgi apparatus and altered the expression of the vesicle trafficking protein Rab11. ER distribution was also disturbed under NIV exposure, indicating the effects of NIV on protein modification and transport in oocytes. Thus, our results demonstrated that NIV exposure affected spindle structure and organelles function in mouse oocytes.

Increasing application for lignin due to its unique aromatic structures has encouraged the development of pretreatment techniques for lignin separation and recovery. In this work, the integration of microwave-assisted hydrothermal pretreatment (MW-HTP) and alkaline post-treatment was proposed for separating lignin from poplar wood and revealing its structural characteristics. Results showed that the yields of the lignins fractionated via the integrated treatment based on MW-HTP were increased up to 52.6%, and their associated sugars contents were clearly decreased to 0.19–0.09%, as compared to the fractionated lignins without the microwave pretreatment (29.8% and 0.29%). Interestingly, the integrated treatment based on MW-HTP promoted the cracking of β-O-4 ethers in the lignin macromolecules of poplar wood, resulting in the raise of their phenol OH groups up to 2.36 mmol/g. Overall, the fulfillment of this work will be conducive to improve the fractionation and efficient utilization of lignin in biorefinery industry.

Hydrothermal processes are an attractive clean technology and cost-effective engineering platform for biorefineries based in the conversion of biomass to biofuels and high-value bioproducts under the basis of sustainability and circular bioeconomy. The deep and detailed knowledge of the structural changes by the severity of biomasses hydrothermal fractionation is scientifically and technological needed in order to improve processes effectiveness, reactors designs, and industrial application of the multi-scale target compounds obtained by steam explosion and liquid hot water systems. The concept of the severity factor [log10 (Ro)] established>30 years ago, continues to be a useful index that can provide a simple descriptor of the relationship between the operational conditions for biomass fractionation in second generation of biorefineries. This review develops a deep explanation of the hydrothermal severity factor based in lignocellulosic biomass fractionation with emphasis in research advances, pretreatment operations and the applications of severity factor kinetic model.

Objectives RAB14 is a member of small GTPase RAB family which localizes at the endoplasmic reticulum (ER), Golgi apparatus and endosomal compartments. RAB14 acts as molecular switches that shift between a GDP‐bound inactive state and a GTP‐bound active state and regulates circulation of vesicles between the Golgi and endosomal compartments. In present study, we investigated the roles of RAB14 during oocyte meiotic maturation. Materials and methods Microinjection with siRNA and exogenous mRNA for knock down and rescue, and immunofluorescence staining, Western blot and real‐time RT‐PCR were utilized for the study. Results Our results showed that RAB14 localized in the cytoplasm and accumulated at the cortex during mouse oocyte maturation, and it was also enriched at the spindle periphery. Depletion of RAB14 did not affect polar body extrusion but caused large polar bodies, indicating the failure of asymmetric division. We found that absence of RAB14 did not affect spindle organization but caused the spindle migration defects, and this might be due to the regulation on cytoplasmic actin assembly via the ROCK‐cofilin signalling pathway. We also found that RAB14 depletion led to aberrant Golgi apparatus distribution. Exogenous Myc‐Rab14 mRNA supplement could significantly rescue these defects caused by Rab14 siRNA injection. Conclusions Taken together, our results suggest that RAB14 affects ROCK‐cofilin pathway for actin‐based spindle migration and Golgi apparatus distribution during mouse oocyte meiotic maturation., RAB14 localized in the cytoplasm and accumulated at the cortex during mouse oocyte maturation, and it was also enriched at the spindle periphery. Depletion of RAB14 caused large polar bodies, indicating the failure of asymmetric division. Absence of RAB14 did not affect spindle organization but caused the spindle migration defects, and this might be due to the regulation on cytoplasmic actin assembly via the ROCK‐cofilin signalling pathway. We also found that RAB14 depletion led to aberrant Golgi apparatus distribution. Exogenous Myc‐Rab14 mRNA supplement could significantly rescue these defects caused by Rab14 siRNA injection. Our results suggest that RAB14 affects ROCK‐cofilin pathway for actin‐based spindle migration and Golgi apparatus distribution during mouse oocyte meiotic maturation.

Mammalian oocyte quality is critical for fertilization and early embryo development. The type B trichothecene nivalenol (NIV) is a mycotoxin produced by Fusarium oxysporum, and it is commonly found with deoxynivalenol in contaminated food or feed. NIV has been shown to affect the immune system and female reproductive system, cause emesis and growth retardation. Here, we investigated the toxicity of NIV on mouse oocyte quality, as well as the protective effects of melatonin on the NIV-exposed oocytes. We found NIV exposure caused meiotic arrest and further induced the failure of polar body extrusion in mouse oocytes. Transcriptome analysis data showed that NIV exposure altered the expression of multiple pathway-related genes in oocytes, indicating its wide toxicity on oocyte maturation. Based on the RNA-seq data, we showed that NIV exposure induced oxidative stress and caused DNA damage in oocytes. Besides, autophagy, and early apoptosis were also found in NIV-exposed oocytes. Treatment with melatonin significantly ameliorated these defects through its effects on ROS level. Thus, our results demonstrated that exposure to NIV affected oocyte quality and melatonin treatment could reduce the defects caused by NIV in mouse oocytes.

Pretreatment is a key step in the conversion of lignocellulosic biomass to bioethanol. The development of efficient pretreatment technologies is of great significance for biomass valorization. Herein, an integrated pretreatment was proposed for enhancing the enzymatic hydrolysis of poplar and improving the isolation of hemicelluloses by coordinating microwave radiation (MW) in hydrothermal and alkali (HT-AL) pretreatment. Results showed that the cooperation of MW with HT-AL (MW-HT-AL) effectively enhanced the enzymatic digestibility of poplar and a maximum glucose yield of 89.4 % was achieved under optimum condition, which was significantly higher than that of the HT-AL treated and untreated residues (71.6 % and 28.4 %). Additionally, substantial amounts of hemicelluloses (72.4 %) were also separated during the integrated pretreatment as compared with the HT-AL pretreatment alone (54.4 %). Structural analysis revealed that the poplar hemicelluloses were typical O-acetyl-4-O-methylglucuronoxylan and the water-soluble hemicellulosic fractions were substituted with more branches than the alkali-soluble hemicellulosic fractions.

Surgical adhesives have partly replaced traditional sutures to seal and reattach tissues due to their superiorities in preventing liquids leakage and avoiding secondary damage in the surrounding wound area. Most of the existing adhesives are committed to promoting wound healing and functional recovery. A therapeutic adhesive that assists in clearing the residual tumors in the surgical area is undoubtedly meaningful to obtain a better clinical outcome. Herein, enlightened by commercial BioGlue (albumin/glutaraldehyde sealant), a biocompatible therapeutic albumin/genipin bioglue is designed for postoperative wound adhesion and tumor ablation. The albumin/genipin bioglue is formed by simple mixing of bovine serum albumin (BSA) and genipin (GP) under a 35 °C water bath for 24 h without further purification. The obtained dark-blue fluorescent adhesive exhibits a significant temperature increase accompanied by heating-induced curing once irradiated with an 808-nm laser. This unique characteristic allows BSA-GP a therapeutic adhesive for postoperative wound adhesion and photothermal elimination of residual tumors under laser irradiation. Moreover, its easy injectability and impressive photothermal efficacy also make it feasible for in situ tumor photothermal ablation. The ultrasimple synthetic strategy by mimicking BioGlue endows BSA-GP adhesive with large-scale production capacity and clinical transformation potential, which is a successful paradigm for reforming existing clinical products.

CD8 T cells are central mediators of immune responses against infections and cancer. Here we identified Dapl1 as a crucial regulator of CD8 T cell responses to cancer and infections. Dapl1 deficiency promotes the expansion of tumor-infiltrating effector memory-like CD8 T cells and prevents their functional exhaustion, coupled with increased antitumor immunity and improved efficacy of adoptive T cell therapy. Dapl1 controls activation of NFATc2, a transcription factor required for the effector function of CD8 T cells. Although NFATc2 mediates induction of the immune checkpoint receptor Tim3, competent NFATc2 activation prevents functional exhaustion of CD8 T cells. Interestingly, exhausted CD8 T cells display attenuated NFATc2 activation due to Tim3-mediated feedback inhibition; Dapl1 deletion rescues NFATc2 activation and, thereby, prevents dysfunction of exhausted CD8 T cells in chronic infection and cancer. These findings establish Dapl1 as a crucial regulator of CD8 T cell immunity and a potential target for cancer immunotherapy.

Background Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling diseases. Recently, it has been discovered that tRNA-derived small RNAs (tsRNAs), a new type of non-coding RNAs, are related to the proliferation and migration of VSMCs. tsRNAs regulate target gene expression through miRNA-like function. This study aims to explore the potential of tsRNAs in human aortic smooth muscle cell (HASMC) proliferation. Methods High-throughput sequencing was performed to analyze the tsRNA expression profile of proliferative and quiescent HASMCs. Quantitative real-time PCR (qRT-PCR) was performed to validate sequence results and subcellular distribution of AS-tDR-001370, AS-tDR-000067, AS-tDR-009512, and AS-tDR-000076. Based on microRNA-like functions of tsRNAs, we predicted target promoters, mRNAs, and circular RNAs (circRNAs), constructed tsRNA-promoter, tsRNA-mRNA, and circRNA-tsRNA interaction networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to reveal the function of target genes. Western blot and EdU incorporation assays were utilized to detect the effect of tsRNAs on HASMC proliferation. Results Compared with quiescent HASMCs, 887 up-regulated and 951 down-regulated tsRNAs in proliferative HASMCs were identified (fold change > 2 or < -2, p‑value

Hemorrhage transformation (HT) is a frequent but maybe fatal complication following acute ischemic stroke due to severe damage of the blood-brain barrier (BBB). Quantitative BBB permeability imaging is a promising method to predict HT in stroke patients for a favorable prognosis. However, clinical gadolinium chelate-based magnetic resonance (MR) imaging of the stroke suffers from a relatively low sensitivity and potential side effects of nephrogenic systemic fibrosis and intracranial gadolinium deposition. Herein, BSA-MnO2 nanoparticles (BM NPs) fabricated by a facile disinfection-mimic method were employed for the permeability imaging of BBB in the stroke for the first time. The BM NPs showed a high T1 relaxivity (r1 = 5.9 mM-1 s-1), remarkable MR imaging ability, and good biocompatibility, allowing the noninvasive timely visualization of BBB permeability in the model rats of middle cerebral artery occlusion (MCAO). Furthermore, increased peak intensity, extended imaging duration, and expanded imaging region indicated by BM NPs in MR imaging showed a good prediction for the onset of HT in MCAO rats. Therefore, BM NPs hold an attractive potential to be an alternative biocompatible MR contrast agent for the noninvasive BBB permeability imaging in vivo, benefiting the fundamental research of diverse neurological disorders and the clinical treatment for stroke patients.

In vivo calcium imaging using head-mounted miniature microscopes enables tracking activity from neural populations over weeks in freely behaving animals. Previous studies focus on inferring behavior from a population of neurons, yet it is challenging to extract neuronal signals given out-of-focus fluorescence in endoscopic data. Existing analysis pipelines include regions of interest (ROIs) identification, which might lose relevant information from false negatives or introduce unintended bias from false positives. Moreover, these methods often require prior knowledge for parameter tuning and are time-consuming for implementation. Here, we develop an end-to-end decoder to predict the behavioral variables directly from the raw microendoscopic images. Our framework requires little user input and outperforms existing decoders that need ROI extraction. We show that neuropil/background residuals carry additional behaviorally relevant information. Video analysis further reveals an optimal decoding window and dynamics between residuals and cells. Critically, saliency maps reveal the emergence of video-decomposition across our decoder, and identify distinct clusters representing different behavioral aspects. Together, we present a framework that is efficient for decoding behavior from microendoscopic imaging, and may help discover functional clustering for a variety of imaging studies.

During mouse oocyte meiotic maturation, actin filaments play multiple roles in meiosis such as spindle migration and cytokinesis. FASCIN is shown to be an actin-binding and bundling protein, making actin filaments tightly packed and parallel-aligned, and FASCIN is involved in several cellular processes like adhesion and migration. FASCIN is also a potential prognostic biomarker and therapeutic target for the treatment of metastatic disease. However, little is known about the functions of FASCIN in oocyte meiosis. In the present study, we knocked down the expression of FASCIN, and our results showed that FASCIN was essential for oocyte maturation. FASCIN was all expressed in the different stages of oocyte meiosis, and it mainly localized at the cortex of oocytes from the GV stage to the MII stage and showed a similar localization pattern with actin and DAAM1. Depletion of FASCIN affected the extrusion of the first polar body, and we also observed that some oocytes extruded from the large polar bodies. This might have resulted from the defects of actin assembly, which further affected the meiotic spindle positioning. In addition, we showed that inhibition of PKC activity decreased FASCIN expression, indicating that FASCIN might be regulated by PKC. Taken together, our results provided evidence for the important role of FASCIN on actin filaments for spindle migration and polar body extrusion in mouse oocyte meiosis.

This study aimed to analyze the most influential publications on vertebral augmentation for treating osteoporotic vertebral compression fracture. The Web of Science database was searched using the key words "percutaneous vertebroplasty," "percutaneous kyphoplasty," "balloon kyphoplasty," "vertebroplasty," "kyphoplasty," and "vertebral augmentation." The top 100 publications were arranged by citations per year and descriptively and visually analyzed. The top 100 publications were cited 25,482 times, with an average of 14.4 citations per paper per year. The corresponding authors of the publications represented 17 nations, with most authors being American (46 authors). Thirty-two journals were involved, with SPINE issuing the most publications (24 papers of the 100). Clinical research (73 of the 100 papers) outnumbered basic studies (14 papers) and systematic reviews (13 papers), and the most publications were published between 2000 and 2004. Co-citation analysis of the key words indicated that the top 5 focus areas were "complication," "balloon kyphoplasty," "vertebral compression fracture," "biomechanics," and "calcium phosphate cement." The top 3 keywords with the strongest citation bursts were "compression fracture," "cement," and "balloon kyphoplasty." The keywords with persistent strong citation bursts are "balloon kyphoplasty" and "augmentation." There are still contrary opinions about vertebral augmentation; new research should be conducted with more deliberate design and longer follow-up.

Nonylphenol (NP) belongs to the metabolites of commercial detergents, which acts as an environmental endocrine disruptor. NP is reported to have multiple toxicity including reproductive toxicity. In present study, we reported the protective effects of melatonin on the NP-exposed oocyte quality. We set up a mouse in vivo model of NP exposure (500 μg/L), by daily drinking and continued feeding for 4 weeks; and we gave a daily dose of melatonin (30 mg/kg) to the NP-exposed mice. Melatonin supplementation restores the development ability of oocytes exposed to NP, and this was due to the reduction of ROS level and DNA damage by melatonin. Melatonin could rescue aberrant mitochondria distribution, mitochondria membrane potential, which also was reflected by ATP content and mtDNA copy number. Moreover, melatonin could restore the RPS3 expression to ensure the ribosome function for protein synthesis, and reduced GRP78 protein level to protect against ER stress and ER distribution defects. We also found that vesicle protein Rab11 from Golgi apparatus was protected by melatonin at the spindle periphery of oocytes of NP-exposed mice, which further moderated LAMP2 for lysosome function. Our results indicate that melatonin protects oocytes from NP exposure through its effects on the reduction of oxidative stress and DNA damage, which might be through its amelioration on the organelles in mice.

Lignin is an underutilized renewable resource in nature because of its complex structure and special distribution in plant cell walls. The proposal of an efficient treatment and the reveal of the structural characteristics of the isolated lignin are considerably important for the sustainable valorization of lignin. In this work, a two-step of hydrothermal pretreatment combined with alkali extraction was assembled into an integrated treatment and performed to extract lignin from poplar. The yield, purity, and structural changes of the lignin isolated from different treatment conditions were comparatively investigated. Results showed that 71.8 % of lignin with ultra-high purity was isolated during the integrated treatment at 180 °C. Confocal Raman microscopy demonstrated that the delignification occurred preferentially in the secondary wall (SW) and compound middle lamella (CML), and then in the whole morphological regions of the cell wall during the integrated treatment. NMR results revealed that the cleavage of β-O-4 linkages was dominant among the various reactions, which resulted in the increase of phenolic hydroxyl groups, the decrease of molecular weight, and the heterogeneity of the isolated lignin. However, the condensation of lignin became more serious with the increase of hydrothermal pretreatment temperature. These findings provide new insights for the separation and sustainable utilization of lignin for industries.