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Background: The high prevalence of chronic inflammatory diseases or autoimmune reactions is a major source of concern and affects the quality of life of patients. Chronic inflammatory or autoimmune diseases are associated with many diseases in humans, including asthma, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and cancer. Splenic tyrosine kinase (SYK) is a non–receptor tyrosine kinase that plays an important role in immune receptor signalling in immune and inflammatory responses. Methods: This is a review article in which we searched for keywords "splenic tyrosine kinase", "inflammation" and "autoimmune diseases" in published literature such as Pubmed and Web of Science to collect relevant information and then conducted a study focusing on the latest findings on the involvement of SYK in chronic inflammatory or autoimmune diseases. Results: This paper reviews the regulation of Fcγ, NF–κB, B cell and T cell–related signalling pathways by SYK, which contributes to disease progression in chronic inflammatory and autoimmune diseases such as airway fibrosis, inflammatory skin disease and inflammatory bowel disease. Conclusion: This paper shows that SYK plays an important role in chronic inflammatory and autoimmune diseases. syk targets hematological, autoimmune and other inflammatory diseases and therefore, inhibition of SYK expression or blocking its related pathways may provide new ideas for clinical prevention and treatment of inflammatory or autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background: Single‐cell transcriptomics has revolutionised our understanding of the cellular composition of the tumour microenvironment (TME) in nasopharyngeal carcinoma (NPC). Despite this progress, a key limitation of this technique has been its inability to capture epithelial/tumour cells, which has hindered further investigation of tumour heterogeneity and immune escape in NPC. Methods: In this study, we aimed to address these limitations by analysing the transcriptomics and spatial characteristics of NPC tumour cells at single‐cell resolution using scRNA/snRNA‐seq and imaging mass cytometry techniques. Results: Our findings demonstrate multiple patterns of immune escape mechanisms in NPC, including the loss of major histocompatibility complex (MHC) molecules in malignant cells, induction of epithelial–mesenchymal transition in fibroblast‐like malignant cells and the use of hyperplastic cells in tumour nests to protect tumour cells from immune infiltration. Additionally, we identified, for the first time, a CD8+ natural killer (NK) cell cluster that is specific to the NPC TME. Conclusions: These findings provide new insights into the complexity of NPC immune landscape and may lead to novel therapeutic strategies for this disease. [ABSTRACT FROM AUTHOR]

The China Fusion Engineering Test Reactor (CFETR), a superconducting magnetic confinement tokamak fusion reactor, will develop a high-performance torus cryopump to pump torus plasma exhaust gas. The inlet valve is one of the key components of the cryopump, and it is used to isolate the cryopump from the plasma for regeneration, to control the pumping speed of the cryopump, and to operate as a pressure relief valve in case of a failure, such as the cryopipe breaking inside the cryopump chamber. This paper presents a novel inlet valve. Ensuring that the design of the inlet valve meets the above requirements will be a challenge. In order to verify the reliability of the inlet valve, its critical components are analyzed and optimized by the Finite Element Method. The effect of the stroke of the inlet valve on pumping performance is then estimated by the Monte Carlo Method, and the pressure profile in the whole flow field is studied to predict the cryopump's behavior. Finally, the seismic capacity of the optimized inlet valve is analyzed, and the mechanical performance of the inlet valve is shown to meet CFETR design criteria. These design and analysis results will provide technical support and references for the development of the CFETR torus cryopump. [ABSTRACT FROM AUTHOR]

Background: The lipopeptide herbicolin A (HA) secreted by the biocontrol agent Pantoea agglomerans ZJU23 is a promising antifungal drug to combat fungal pathogens by targeting lipid rafts, both in agricultural and clinical settings. Improvement of HA production would be of great significance in promoting its commercialization. This study aims to enhance the HA production in ZJU23 by combining fermentation optimization and strain engineering. Results: Based on the results in the single-factor experiments, corn steep liquor, temperature and initial pH were identified as the significant affecting factors by the Plackett–Burman design. The fermentation medium and conditions were further optimized using the Box-Behnken response surface method, and the HA production of the wild type strain ZJU23 was improved from ~ 87 mg/mL in King's B medium to ~ 211 mg/mL in HA induction (HAI) medium. A transposon library was constructed in ZJU23 to screen for mutants with higher HA production, and two transcriptional repressors for HA biosynthesis, LrhA and PurR, were identified. Disruption of the LrhA gene led to increased mRNA expression of HA biosynthetic genes, and subsequently improved about twofold HA production. Finally, the HA production reached ~ 471 mg/mL in the ΔLrhA mutant under optimized fermentation conditions, which is about 5.4 times higher than before (~ 87 mg/mL). The bacterial suspension of the ΔLrhA mutant fermented in HAI medium significantly enhanced its biocontrol efficacy against gray mold disease and Fusarium crown rot of wheat, showing equivalent control efficacies as the chemical fungicides used in this study. Furthermore, HA was effective against fungicide resistant Botrytis cinerea. Increased HA production substantially improved the control efficacy against gray mold disease caused by a pyrimethanil resistant strain. Conclusions: This study reveals that the transcriptional repressor LrhA negatively regulates HA biosynthesis and the defined HAI medium is suitable for HA production. These findings provide an extended basis for large-scale production of HA and promote biofungicide development based on ZJU23 and HA in the future. [ABSTRACT FROM AUTHOR]

The Xianshuihe fault zone, on the southeastern margin of the Qinghai-Tibet Plateau, is one of the most tectonically active regions on Earth, with intensive and frequent seismic activity. However, knowledge of its long-term seismicity is based mainly on trench excavations which have the shortcomings of discontinuity and chronological uncertainties. By contrast, however, lake sediments can provide long and continuous records of paleoearthquakes. In this study, we used high-resolution X-Ray Fluorescence (XRF) core scanning of a 3.92 m-long piston core from Muge Co, a lake in the Xianshuihe fault zone, to establish a paleoearthquake sequence with a well-constrained chronology spanning the past 11 kyr. The most recent seismic events recorded in the lacustrine deposits are well correlated with the historical record of regional earthquakes, enabling us to interpret similar deposits deeper within the core as the product of earthquakes. Thirty-three earthquakes were identified within a radius of 30 km around Muge Co. Paleoseismicity was weaker at the beginning of the Holocene and from 9.0 to 8.0 cal kyr BP; there were seismically quiescent periods from 10.8 to 9.0 cal kyr BP, and from 8.0 to 5.5 cal yr BP; and from 5.5 cal kyr BP to the present, major earthquakes occurred frequently, with shorter recurrence intervals. Our paleoearthquake record is generally supported by paleoseismic records revealed in trench excavations within 30 km of Muge Co. After subtracting the event layers caused by earthquakes, pollen and XRF core scanning data were used to reconstruct a record of climate change during the Holocene. This record is in good agreement with changes in the Indian Summer Monsoon inferred from climate proxy records from Dongge Cave and Hongyuan peatland during the Holocene. Wavelet analyses of arboreal pollen percentages and principal component analysis results (PC1) from Muge Co, and records of δ13C from Hongyuan peatland and δ18O from Dongge Cave, indicate common periodicities of ∼80, ∼100, ∼200, ∼500, ∼1000, and ∼ 1500-yr above or below the 95% confidence level. • Thirty-three paleoearthquakes are identified in Xianshuihe fault zone in the Holocene. • The earthquake occurrence is short during the last 5500 years. • Climate reconstruction based on pollen is in line with Indian Summer Monsoon change. • Earthquakes have effect on detrital elements entering the lake in the last 5500 years. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and morbidity and mortality rates continue to rise. Atherosclerosis constitutes the principal etiology of CVDs. Endothelial injury, inflammation, and dysfunction are the initiating factors of atherosclerosis. Recently, we reported that endothelial adenosine receptor 2 A (ADORA2A), a G protein-coupled receptor (GPCR), plays critical roles in neovascularization disease and cerebrovascular disease. However, the precise role of endothelial ADORA2A in atherosclerosis is still not fully understood. Here, we showed that ADORA2A expression was markedly increased in the aortic endothelium of humans with atherosclerosis or Apoe -/- mice fed a high-cholesterol diet. In vivo studies unraveled that endothelial-specific Adora2a deficiency alleviated endothelial-to-mesenchymal transition (EndMT) and prevented the formation and instability of atherosclerotic plaque in Apoe -/- mice. Moreover, pharmacologic inhibition of ADORA2A with KW6002 recapitulated the anti-atherogenic phenotypes observed in genetically Adora2a-deficient mice. In cultured human aortic endothelial cells (HAECs), siRNA knockdown of ADORA2A or KW6002 inhibition of ADORA2A decreased EndMT, whereas adenoviral overexpression of ADORA2A induced EndMT. Mechanistically, ADORA2A upregulated ALK5 expression via a cAMP/PKA/CREB axis, leading to TGFβ-Smad2/3 signaling activation, thereby promoting EndMT. In conclusion, these findings, for the first time, demonstrate that blockade of ADORA2A attenuated atherosclerosis via inhibition of EndMT induced by the CREB1-ALK5 axis. This study discloses a new link between endothelial ADORA2A and EndMT and indicates that inhibiting endothelial ADORA2A could be an effective novel strategy for the prevention and treatment of atherosclerotic CVDs. [Display omitted] • ADORA2A is upregulated in ECs under atherosclerotic circumstances. • ADORA2A deletion or inhibition suppresses the formation of atherosclerotic lesions by inhibiting EndMT. • ADORA2A induces EndMT via activation of the cAMP-CREB1-ALK5 axis. [ABSTRACT FROM AUTHOR]

Background. Approximately 70% of congenital deafness is attributable to genetic causes. Incidence of congenital deafness is known to be higher in families with consanguineous marriage. In this study, we investigated the genetic causes in three consanguineous Pakistani families segregating with prelingual, severe-to-profound deafness. Results. Through targeted next-generation sequencing of 414 genes known to be associated with deafness, homozygous variants c.536del (p. Leu180Serfs ∗ 20) in TECTA, c.3719 G>A (p. Arg1240Gln) in MYO7A, and c.482+1986_1988del in HGF were identified as the pathogenic causes of enrolled families. Interestingly, in one large consanguineous family, an additional c.706G>A (p. Glu236Lys) variant in the X-linked POU3F4 gene was also identified in multiple affected family members causing deafness. Genotype-phenotype cosegregation was confirmed in all participating family members by Sanger sequencing. Conclusions. Our results showed that the genetic causes of deafness are highly heterogeneous. Even within a single family, the affected members with apparently indistinguishable clinical phenotypes may have different pathogenic variants. [ABSTRACT FROM AUTHOR]

Background. Nasopharyngeal carcinoma (NPC) is a rare but highly aggressive tumor that is predominantly encountered in Southeast Asia and China in particular. Aside from radiotherapy, no effective therapy that specifically treats NPC is available, including targeted drugs. Finding more sensitive biomarkers is important for new drug discovery and for evaluating patient prognosis. Methods. mRNA expression datasets from the Gene Expression Omnibus database (GSE53819, GSE64634, and GSE40290) were selected. After all samples in each dataset were subjected to quality control using principal component analyses, the qualified samples were used for additional analyses. The genes that were significantly expressed in each dataset were intersected to identify the most significant of these. Gene functional enrichment analyses were performed on these genes, using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses. The protein–protein interaction network of selected genes was analyzed using the Search Tool for the Retrieval of Interacting Genes database. Significantly, differentially expressed genes were further verified with two RNA-seq datasets (GSE68799 and GSE12452), as well as in clinical samples. Results. In all, 34 (8 upregulated genes and 26 downregulated) genes were identified as significantly differentially expressed. The immune response and the regulation of cell proliferation were the most enriched biological GO terms. Using reverse transcription quantitative real-time PCR (RT-qPCR), the genes MMP1, AQP9, and TNFAIP6 were detected to be upregulated, and FAM3D, CR2, and LTF were downregulated in NPC tissue samples. Conclusion. This study provides information on the genes that may be involved in the development of NPC and suggests possible druggable targets and biomarkers for diagnosing and evaluating the prognosis of NPC. [ABSTRACT FROM AUTHOR]

The human gamma herpesvirus Epstein-Barr virus (EBV; HHV4), infects most adults and is an important contributor to the development of many types of lymphoid and epithelial cancers. Essential contributions of viral genes to viral replication are known, but the potential contributions of cell genes are less well delineated. A key player is the viral protein Zta (BZLF1, ZEBRA, Z). This sequence-specific DNA-binding protein can disrupt EBV latency by driving the transcription of target genes and by interacting with the EBV lytic origin of replication. Here we used an unbiased proteomics approach to identify the Zta-interactome in cells derived from a Burkitt's lymphoma. Isolating Zta and associated proteins from Burkitt's lymphoma cells undergoing EBV replication, followed by Tandem Mass Tag (TMT) mass spectrometry resulted in the identification of thirty-nine viral and cellular proteins within the Zta interactome. An association of Zta with the cellular protein NFATc2 was validated in independent experiments. Furthermore, the ability of Zta to attenuate the activity of an NFAT-dependent promoter was shown which suggests a functional consequence for the association. The expression of Zta is itself regulated through NFAT activity, suggesting that Zta may contribute to a feed-back loop that would limit its own expression, thus aiding viral replication by preventing the known toxic effects of Zta overexpression. [ABSTRACT FROM AUTHOR]

Background and Purpose: Inactivation of the gene for adenosine A2A receptors (ADORA2A for humans and Adora2a for rodents) protects against brain injury in experimental stroke. However, the cell-specific pathogenic effects of A2A receptors in thromboembolic stroke and the underlying mechanisms remain undefined. Here, we tested the hypothesis that inhibition of endothelial A2A receptors after thromboembolic stroke improves post-stroke outcomes via down-regulation of inflammation.Experimental Approach: Thromboembolic stroke was induced by embolic middle cerebral artery occlusion in mice. Post-stroke outcomes were determined with neurological deficit scoring, infarct volume, inflammatory marker expression, brain leukocyte infiltration, blood-brain barrier (BBB) leakage, and oedema assessment. Anti-inflammatory effects of silencing the gene for A2A receptors or pharmacological antagonism of these receptors were assessed in vitro.Key Results: Thromboembolic stroke induced Adora2a expression in the brain. Mice globally deficient in Adora2a (Adora2a-/- ) were resistant to stroke injury. Mice specifically deficient in endothelial Adora2a (Adora2aΔVEC ) showed reduced leukocyte infiltration, BBB leakage, and oedema after stroke, along with attenuated downstream proinflammatory markers, both in vivo and in vitro. The A2A receptor antagonist, KW 6002, also reduced brain injury and inflammation after stroke. Inactivation of ADORA2A inhibited endothelial inflammation via suppression of the NLRP3 inflammasome, down-regulating cleaved caspase 1 and IL-1β expression.Conclusions and Implications: Specific inactivation of endothelial A2A receptors mitigated ischaemic brain injury and improved post-stroke outcomes, at least partly, through anti-inflammatory effects via blockade of NLRP3 inflammasome activity. Our findings may open new approaches to vascular protection after ischaemic stroke. [ABSTRACT FROM AUTHOR]

The present report aimed to evaluate the results of screen mutations of the fibrillin (FBN) 1 gene and analyze the symptoms in one Chinese patient clinically diagnosed with Marfan syndrome (MFS). Clinical data were collected and FBN1 gene sequencing was performed. Genomic DNA was extracted from the blood sample of the patient. All 65 exons were screened using a polymerase chain reaction assay. The diagnosis of MFS was confirmed via identification of symptoms presenting in the skeletal system (arachnodactyly, walker wrist and thumb signs) and the ocular system (ectopia lentis), in addition to a positive family history. The patient's cardiovascular manifestations (dilatation of the four cardiac chambers, severe mitral valve regurgitation and a large saccular aneurysm of the non-coronary sinus of Valsalva) were atypical to those that most frequently occur in cases of MFS. Following gene sequencing, two novel heterozygous mutations of the FBN-1 gene were identified: c.3442C>G in exon 27, proline replaced with alanine (p. Pro1148Ala) and c.6388G>A in exon 52, glutamic acid replaced with lysine (p. Glu2130Lys). The clinical symptoms and family history were important in the diagnosis of MFS, however the atypical signs that presented in the cardiovascular system may be associated with the disease, and may be noted for further cases in the future. Gene sequencing further verified the correct diagnosis of MFS. [ABSTRACT FROM AUTHOR]

A novel tri-functional probe HEX-OND was developed for detecting Pb(II), cysteine (Cys), and K(I) by fluorescence quenching, recovery, and amplification strategies respectively, based on Pb(II)-induced chair-type G-quadruplex (CGQ) and K(I)-induced parallel G-quadruplex (PGQ). The thermodynamic mechanism was illustrated as that HEX-OND transformed into CGQ by associating equimolar Pb(II) (K1 = 1.10 ± 0.25 × 106 L/mol), forcing (G)2 spontaneously approaching and static-quenching HEX (5′-hexachlorofluorescein phosphoramidite) in the photo-induced electron transfer (PET) way by the van der Waals force and hydrogen bond (K2 = 5.14 ± 1.65 × 107 L/mol); the additional Cys recovered fluorescence in the molecular ratio of 2:1 via Pb(II)-precipitation induced CGQ destruction (K3 = 3.03 ± 0.77 × 109 L/mol); the equimolar K(I) induced HEX-OND transforming into PGQ (K4 = 3.53 ± 0.30 × 104 L/mol) and specifically associating with the equimolar N-methyl mesoporphyrin IX (NMM) by hydrophobic force (K5 = 3.48 ± 1.08 × 105 L/mol), leading to the fluorescence enhancement. Moreover, the practicability results showed that the detection limits reached a nanomolar level for Pb(II) and Cys and micromolar for K(I), with mere disturbances for 6, 10, and 5 kinds of other substances, respectively; no significant deviations of the real sample detection results were found between the well-understood methods with ours in detecting Pb(II) and Cys, and K(I) could be recognized and quantified even in the presence of Na(I) with 5000 and 600 fold respectively. The results demonstrated the triple-function, sensitivity, selectivity, and tremendous application feasibility of the current probe in sensing Pb(II), Cys, and K(I). [ABSTRACT FROM AUTHOR]

Cordycepin is an extract from the Cordyceps genus of ascomycete fungi. In the present study, the anticancer potential of cordycepin against nasopharyngeal carcinoma (NPC), and the potential underlying mechanisms, were investigated. Using Cell Counting Kit 8, wound-healing and Transwell assays, cordycepin was found to reduce the viability and inhibit the migration of C666-1 cells in a dose-dependent manner. In addition, in colony formation assays, co-treatment with cordycepin and cisplatin inhibited the proliferation of C666-1 cells. Furthermore, RNA sequencing analysis identified 72 significantly differentially expressed genes and different signaling pathways that may be regulated by cordycepin. After treatment with cordycepin, the expression levels of ERK1/2, phosphorylated ERK1/2 and β-catenin were significantly downregulated. Therefore, cordycepin may be a novel candidate for NPC treatment or a co-treatment candidate with cisplatin in chemotherapy. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate negative influences of single specific spoilage organism (SSO) on little yellow croaker under modified atmosphere packaging (MAP) by biochemical properties characterization and spoilage-related volatile indicators identification. The assays of chemical spoilage indexes (CSIs) demonstrated that SSO would accelerate deterioration. The Shewanella glacialipiscicola (S.lgacialipiscicola)-inoculated fish samples with higher rejection degree (76.47 ± 2.15%), pH value (7.18 ± 0.03), TVB-N contents (63.21 ± 5.13 mg/100 g), K-value (93.76 ± 4.10%) and lower chewiness value (84.40 ± 14.39 g), indicated the stronger spoilage ability of S. galacialipiscicola than Carnobacterium maltaromaticum (C.maltaromaticum). Volatile compound (VOC) metabolites produced by microbial activity were characterized by GC-MS, a total of 21 and 25 VOC compounds were identified in fish sample inoculated with S. galacialipiscicola or C. maltaromaticum , respectively. The spoilage-related volatile indicators were screened through multivariate statistic analysis. The indicators of S. glacialipiscicola were indole and trimethylamine, while indole, trimethylamine and dodecanol were screened for C. maltaromaticum. Furthermore, significant correlation was observed by mathematical models between CSIs and VOC indicators. This study revealed the spoilage behaviors and related VOC production of certain SSO, providing a basis for spoilage mechanism investigation and targeted inhibition of SSO. • Influences of single SSO on little yellow croaker under MAP were investigated. • Different SSOs exhibited various spoilage behaviors due to their microbial activities. • Spoilage-related volatile indicators were screened by multivariate statistic analysis. • Identification of spoilage-related volatile was helpful for spoilage evaluation. [ABSTRACT FROM AUTHOR]

Aims Abdominal aortic aneurysm (AAA) is a common, serious vascular disease with no effective pharmacological treatment. The nucleoside adenosine plays an important role in modulating vascular homeostasis, which prompted us to determine whether adenosine kinase (ADK), an adenosine metabolizing enzyme, modulates AAA formation via control of the intracellular adenosine level, and to investigate the underlying mechanisms. Methods and results We used a combination of genetic and pharmacological approaches in murine models of AAA induced by calcium chloride (CaCl2) application or angiotensin II (Ang II) infusion to study the role of ADK in the development of AAA. In vitro functional assays were performed by knocking down ADK with adenovirus-short hairpin RNA in human vascular smooth muscle cells (VSMCs), and the molecular mechanisms underlying ADK function were investigated using RNA-sequencing, isotope tracing, and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The heterozygous deficiency of ADK protected mice from CaCl2- and Ang II-induced AAA formation. Moreover, specific knockout of ADK in VSMCs prevented Ang II-induced AAA formation, as evidenced by reduced aortic extracellular elastin fragmentation, neovascularization, and aortic inflammation. Mechanistically, ADK knockdown in VSMCs markedly suppressed the expression of inflammatory genes associated with AAA formation, and these effects were independent of adenosine receptors. The metabolic flux and ChIP-qPCR results showed that ADK knockdown in VSMCs decreased S-adenosylmethionine (SAM)-dependent transmethylation, thereby reducing H3K4me3 binding to the promoter regions of the genes that are associated with inflammation, angiogenesis, and extracellular elastin fragmentation. Furthermore, the ADK inhibitor ABT702 protected mice from CaCl2-induced aortic inflammation, extracellular elastin fragmentation, and AAA formation. Conclusion Our findings reveal a novel role for ADK inhibition in attenuating AAA via epigenetic modulation of key inflammatory genes linked to AAA pathogenesis. [ABSTRACT FROM AUTHOR]

Objective: It remains elusive which factors may influence the morbidity and mortality of lung metastasis (LM) in Laryngeal Squamous Cell Carcinoma (LSCC) patients. The aim of the present study was to investigate factors influencing LM and the survival outcomes of LSCC patients with LM.Methods: We identified 10,935 patients with LSCC from 2010 to 2014 using the Surveillance, Epidemiology and End Results database. Multivariate logistic regression analysis was used to determine the factors associated with the presence of LM. Multivariate cox regression analysis was used to identify covariates associated with increased all-cause mortality in patients with LM.Results: Among 10,935 patients with LSCC, 232 (2.12%) patients had LM. The median survival time of patients with LM was 8 months, and 8.37% of patients survived after 3 years. Patients with age ≥ 60 years old, unmarried status, supraglottis, overlapping lesion of larynx, subglottis, pathological grade III, T4 stage, N1 stage, N2 stage, N3 stage and bone, brain or liver metastases were more likely to have LM. Survival analysis showed that chemotherapy and radiotherapy suggested better survival of LSCC patients with LM while pathological grade IV was associated with an increased all-cause mortality.Conclusion: The incidence of LSCC patients with LM varied by age, married status, and tumor subtypes. LSCC patients with LM had poor survival, and only 8.37% of patients survived after 3 years. However, chemotherapy and radiotherapy were found as independent favorable prognostic factors for survival. [ABSTRACT FROM AUTHOR]

Biomass from agriculture, forestry, and urban wastes is a potential renewable organic resource for energy generation. Many investigations have demonstrated that anaerobic fungi and methanogens could be co-cultured to degrade lignocellulose for methane generation. Thus, this study aimed to evaluate the effect of natural anaerobic fungi-methanogens co-culture on the methane production and lignocellulosic degradation of wastes from rice, corn and sugarcane. Hu sheep rumen digesta was used to develop a natural anaerobic fungi-methanogen co-culture. The substrates were rice straw (RS), rich husk (RH), corn stover (CS), corn cobs (CC), and sugarcane baggage (SB). Production of total gas and methane, metabolization rate of reducing sugar, glucose, and xylose, digestibility of hemicellulose and cellulose, activity of carboxymethylcellulase and xylanase, and concentrations of total acid and acetate were highest (P < 0.05) in CC, moderate (P < 0.05) in RS and CS, and lowest (P < 0.05) in SB and RH. The pH, lactate and ethanol were lowest (P < 0.05) in CC, moderate (P < 0.05) in RS and CS, and lowest (P < 0.05) SB and RH. Formate was lowest (P < 0.05) in CC, RS and CS, moderate (P < 0.05) in SB, and lowest (P < 0.05) in RH. Therefore, this study indicated that the potential of methane production and lignocellulosic degradation by natural anaerobic fungi-methanogens co-culture were highest in CC, moderate in RS and CS, and lowest in SB and RH. [ABSTRACT FROM AUTHOR]

Background: Providing high-quality roughage is crucial for improvement of ruminant production because it is an essential component of their feed. Our previous study showed that feeding bio-fermented rice straw (BF) improved the feed intake and weight gain of sheep. However, it remains unclear why feeding BF to sheep increased their feed intake and weight gain. Therefore, the purposes of this research were to investigate how the rumen microbiota and serum metabolome are dynamically changing after feeding BF, as well as how their changes influence the feed intake, digestibility, nutrient transport, meat quality and growth performances of sheep. Twelve growing Hu sheep were allocated into 3 groups: alfalfa hay fed group (AH: positive control), rice straw fed group (RS: negative control) and BF fed group (BF: treatment). Samples of rumen content, blood, rumen epithelium, muscle, feed offered and refusals were collected for the subsequent analysis. Results: Feeding BF changed the microbial community and rumen fermentation, particularly increasing (P < 0.05) relative abundance of Prevotella and propionate production, and decreasing (P < 0.05) enteric methane yield. The histomorphology (height, width, area and thickness) of rumen papillae and gene expression for carbohydrate transport (MCT1), tight junction (claudin-1, claudin-4), and cell proliferation (CDK4, Cyclin A2, Cyclin E1) were improved (P < 0.05) in sheep fed BF. Additionally, serum metabolome was also dynamically changed, which led to up-regulating (P < 0.05) the primary bile acid biosynthesis and biosynthesis of unsaturated fatty acid in sheep fed BF. As a result, the higher (P < 0.05) feed intake, digestibility, growth rate, feed efficiency, meat quality and mono-unsaturated fatty acid concentration in muscle, and the lower (P < 0.05) feed cost per kg of live weight were achieved by feeding BF. Conclusions: Feeding BF improved the growth performances and meat quality of sheep and reduced their feed cost. Therefore, bio-fermentation of rice straw could be an innovative way for improving ruminant production with minimizing production costs. [ABSTRACT FROM AUTHOR]

Complex biochemical reactions take place in the nucleus all the time. Transcription machines must follow the rules. The chromatin state, especially the three‐dimensional structure of the genome, plays an important role in gene regulation and expression. The super enhancers are important for defining cell identity in mammalian developmental processes and human diseases. It has been shown that the major components of transcriptional activation complexes are recruited by super enhancer to form phase‐separated condensates. We summarize the current knowledge about super enhancer in the 3D genome. Furthermore, a new related transcriptional regulation model from super enhancer is outlined to explain its role in the mammalian cell progress. [ABSTRACT FROM AUTHOR]

A novel indicator film incorporating roselle anthocyanin extracts (RAE) was prepared to monitor shrimp freshness. Hydroxypropyl methylcellulose (HPMC) modified polyvinyl alcohol (PVA) was applied as film-forming substrates to obtain better functions. Structural characterization results suggested compositions were well dispersed and confirmed the structural modification. The addition of HPMC would improve film functions through generation of new interactions. The films with a ratio (HPMC-to-PVA) of 3:1 exhibited stronger tensile strength (91.88 ± 0.13 MPa), hydrophobic (moisture content of 10.44 ± 0.65%, water contact angle of 56.40 ± 3.11°), barrier properties and larger color variations in response to pH changes, demonstrating positive influences of physical functions on indication properties. Thus, a relationship among structural, physical and indication functions was proposed. Furthermore, the films were applied for shrimp freshness real-time monitoring. The film color changed from rose-red to light green at 4 d, corresponding to the onset of spoilage, and then turned into yellow at 8 d, when the shrimp was severely spoilage. The strong correlation between total color difference and chemical spoilage indexes (P <.05) was observed. Therefore, the incorporation of HPMC could improve film functional characteristics by structural modification of new interaction formation, and the PVA/HPMC/RAE films could be applied as intelligent packaging for real-time shrimp freshness monitoring. • Novel indicator films incorporating roselle anthocyanins and HPMC modified PVA were developed. • Components of film matrix were combined by hydrogen bonds. • Film functional characteristics were significantly enhanced by the introduction of HPMC through structural modification. • The influences of film-forming substrate ratios on functional properties were studied. • The PVA/HPMC/RAE films exhibited promising capability to monitor shrimp freshness. [ABSTRACT FROM AUTHOR]

Abstract The goal of the study is to develop a novel pH-indicating intelligent packaging by using purple potato extractions (PPE), chitosan and surface-deacetylated chitin nanofibers (CN). Since the major pH-sensitive pigment of PPE was anthocyanin (24.3 mg/g), whether anthocyanins could be loaded on a solid phase to prevent its color fading was further tested. The results of Fourier transform infrared spectrophotometry (FT-IR) and differential scanning calorimetry (DSC) indicated that PPE was efficiently attached into the chitosan film. Meanwhile, adding CN (0.450%, w/v) into chitosan film could significantly enhance the tensile strength (TS), the water-resistant ability and the roughness of chitosan film. Whereas higher content of CN (0.600%, w/v) did not further improve mechanical properties and CN would distribute unevenly due to aggregation in the films. In addition to pH-indicating ability, CS-CN-PPE exhibited the extraordinary antioxidant activities and this provides another advantage of packaging readily oxidizable substances. Taken together, the current study provided a novel and biocompatible packaging with strengthened mechanical property and intelligent pH indicator. Highlights • Developed a novel pH-indicating intelligent film by purple potato extractions, chitosan and surface-deacetylated chitin nanofibers. • Anthocyanins in purple potato extractions could be loaded on the films to prevent its color fading. • Proper adding of surface-deacetylated chitin nanofibers enhanced the mechanical properties of the films. • The films exhibited extraordinary antioxidant activities. [ABSTRACT FROM AUTHOR]

Background: Ubiquitination controls almost all cellular processes. The dysregulation of ubiquitination signals is closely associated with the initiation and progression of multiple diseases. However, there is little comprehensive research on the interaction and potential function of ubiquitination regulators (UBRs) in spermatogenesis and cancer. Methods: We systematically characterized the mRNA and protein expression of UBRs across tissues and further evaluated their roles in testicular development and spermatogenesis. Subsequently, we explored the genetic alterations, expression perturbations, cancer hallmark-related pathways, and clinical relevance of UBRs in pan-cancer. Results: This work reveals heterogeneity in the expression patterns of UBRs across tissues, and the expression pattern in testis is the most distinct. UBRs are dynamically expressed during testis development, which are critical for normal spermatogenesis. Furthermore, UBRs have widespread genetic alterations and expression perturbations in pan-cancer. The expression of 79 UBRs was identified to be closely correlated with the activity of 32 cancer hallmark-related pathways, and ten hub genes were screened for further clinical relevance analysis by a network-based method. More than 90% of UBRs can affect the survival of cancer patients, and hub genes have an excellent prognostic classification for specific cancer types. Conclusions: Our study provides a comprehensive analysis of UBRs in spermatogenesis and pan-cancer, which can build a foundation for understanding male infertility and developing cancer drugs in the aspect of ubiquitination. [ABSTRACT FROM AUTHOR]

Background and Purpose: Pathological angiogenesis is a major cause of irreversible blindness in individuals with neovascular age-related macular degeneration (nAMD). Macrophages and microglia (MΦ) contribute to aberrant ocular angiogenesis. However, the role of glucose metabolism of MΦ in nAMD is still undefined. Here, we have investigated the involvement of glycolysis, driven by the kinase/phosphatase PFKFB3, in the development of choroidal neovascularization (CNV).Experimental Approach: CNV was induced in mice with laser photocoagulation. Choroid/retinal pigment epithelium (RPE) complexes and MΦ were isolated for analysis by qRT-PCR, western blot, flow cytometry, immunostaining, metabolic measurements and angiogenesis assays.Key Results: MΦ accumulated within the CNV of murine nAMD models and expressed high levels of glycolysis-related enzymes and M1/M2 polarization markers. This phenotype of hyper-glycolytic and activated MΦ was replicated in bone marrow-derived macrophages stimulated by necrotic RPE in vitro. Myeloid cell-specific knockout of PFKFB3, a key glycolytic activator, attenuated pathological neovascularization in laser-induced CNV, which was associated with decreased expression of MΦ polarization markers and pro-angiogenic factors, along with decreased sprouting of vessels in choroid/RPE complexes. Mechanistically, necrotic RPE increased PFKFB3-driven glycolysis in macrophages, leading to activation of HIF-1α/HIF-2α and NF-κB, and subsequent induction of M1/M2 markers and pro-angiogenic cytokines, finally promoting macrophage reprogramming towards an angiogenic phenotype to facilitate development of CNV. The PFKFB3 inhibitor AZ67 also inhibited activation of HIF-1α/HIF-2α and NF-κB signalling and almost completely prevented laser-induced CNV in mice.Conclusions and Implications: Modulation of PFKFB3-mediated macrophage glycolysis and activation is a promising strategy for the treatment of nAMD. [ABSTRACT FROM AUTHOR]

Background: Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of arterial diseases, especially in arterial restenosis after angioplasty or stent placement. VSMCs reprogram their metabolism to meet the increased requirements of lipids, proteins, and nucleotides for their proliferation. De novo purine synthesis is one of critical pathways for nucleotide synthesis. However, its role in proliferation of VSMCs in these arterial diseases has not been defined.Methods: De novo purine synthesis in proliferative VSMCs was evaluated by liquid chromatography-tandem mass spectrometry. The expression of ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase), the critical bifunctional enzyme in the last 2 steps of the de novo purine synthesis pathway, was assessed in VSMCs of proliferative arterial neointima. Global and VSMC-specific knockout of Atic mice were generated and used for examining the role of ATIC-associated purine metabolism in the formation of arterial neointima and atherosclerotic lesions.Results: In this study, we found that de novo purine synthesis was increased in proliferative VSMCs. Upregulated purine synthesis genes, including ATIC, were observed in the neointima of the injured vessels and atherosclerotic lesions both in mice and humans. Global or specific knockout of Atic in VSMCs inhibited cell proliferation, attenuating the arterial neointima in models of mouse atherosclerosis and arterial restenosis.Conclusions: These results reveal that de novo purine synthesis plays an important role in VSMC proliferation in arterial disease. These findings suggest that targeting ATIC is a promising therapeutic approach to combat arterial diseases. [ABSTRACT FROM AUTHOR]

Malignancy is one of the common diseases with high mortality worldwide and the most important obstacle to improving the overall life expectancy of the population in the 21st century. Currently, single or combined treatments, including surgery, chemotherapy, and radiotherapy, are still the mainstream regimens for tumor treatment, but they all present significant side effects on normal tissues and organs, such as organ hypofunction, energy metabolism disorders, and various concurrent diseases. Based on this, theranostic measures for the highly selective killing of tumor cells have always been a hot area in cancer-related fields, among which photodynamic therapy (PDT) is expected to be an ideal candidate for practical clinical application due to its precise targeting and excellent safety performance, so-called PDT refers to a therapeutic method mainly composed of photosensitizers (PSs), laser light, and reactive oxygen species (ROS). Photoimmunotherapy (PIT), a combination of PDT and immunotherapy, can induce systemic antitumor immune responses and inhibit continuing growth and distant metastasis of residual tumor cells, demonstrating a promising application prospect. This article reviews the types of immune responses that occur in the host after PDT treatment, including innate and adaptive immunity. To further help PIT-related drugs improve their pharmacokinetic properties and bioavailability, we highlight the potential improvement of photodynamic immunotherapy from three aspects: immunostimulatory agents, tumor-associated antigens (TAAs) as well as different immune cells. Finally, we focus on recent advances in various strategies and shed light on their corresponding mechanisms of immune activation and possible clinical applications such as cancer vaccines. Having discovered the inherent potential of PDT and the mechanisms that PDT triggers host immune responses, a variety of immunotherapeutic strategies have been investigated in parallel with approaches to improve PDT efficiency. However, it remains to be further elucidated under what conditions the immune effect induced by PDT can achieve tumor immunosuppression and to what extent PDT-induced antitumor immunity will lead to complete tumor rejection. Currently, PIT presents several outstanding intractable challenges, such as the aggregation ability of PSs locally in tumors, deep tissue penetration ability of laser light, immune escape, and biological toxicity, and it is hoped that these issues raised will help to point out the direction of preclinical research on PIT and accelerate its transition to clinical practice. [ABSTRACT FROM AUTHOR]

Mangiferin(MGF) exhibits crucial biological roles, including antioxidant and anti-inflammatory functions. However, how to clearly elucidate the functioning mechanism of MGF for inhibiting cisplatin-induced hearing loss requires in-depth investigation. In this work, we aimed at gaining insight into how MGF functions as the protective agent against cisplatin-triggered ototoxicity using various assays. The variation for reactive oxygen species (ROS) concentrations was determined with MitoSOX-Red and 2′,7′-Dichlorodihydrofluorescein diacetate staining (DCFH-DA). The protective function and corresponding mechanism of MGF in hair cell survival in the House Ear Institute-Organ of Corti (HEI-OC1) cell line were assessed using RNA sequencing (RNA-Seq). Our findings demonstrated that MGF significantly alleviated cisplatin-induced injury to hair cells in vitro, encompassing cell lines and cochlear explants, as well as in vivo models, including C57BL/6 J mice and zebrafish larvae. Mechanistic studies revealed that MGF reversed the increased accumulation of ROS and inhibited cell apoptosis through mitochondrial-mediated intrinsic pathway. Moreover, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting data indicated MGF protected against cisplatin-mediated ototoxicity via the mitogen-activated protein kinase pathway (MAPK). These findings demonstrated MGF has significant potential promise in combating cisplatin-induced ototoxicity, offering a foundation for expanded investigation into therapeutic approaches for auditory protection. • Mangiferin proved potential for ameliorating hearing loss with in vitro and in vivo evidence. • Mangiferin alleviated hair cells against cisplatin-mediated ototoxicity by scavenging ROS and mitochondrial protection. • Otoprotection mechanism is interference with the MAPK signaling pathway and the intrinsic apoptosis pathway in mitochondria. [ABSTRACT FROM AUTHOR]

Background and Purpose: Excess nutrient‐induced endothelial cell inflammation is a hallmark of high fat diet (HFD)‐induced metabolic syndrome. Pharmacological activation of the protein kinase AMP‐activated α1 (PRKAA1) also known as AMPKα1, shows its beneficial effects in many studies of cardiometabolic disorders. However, AMPKα1, as a major cellular sensor of energy and nutrients in endothelial cells, has not been studied for its physiological role in excess nutrient‐induced endothelial cell (EC) inflammation. Experimental Approach Wild‐type and EC‐specific Prkaa1 knockout mice were fed with an HFD. Body weight, fat mass composition, glucose, and lipid levels were monitored regularly. Insulin sensitivity was analysed systemically and in major metabolic organs/tissues. Inflammation status in metabolic organs/tissues were examined with quantitative RT‐PCR and flow cytometry. Additionally, metabolic status, inflammation severity, and signalling in cultured ECs were assayed with multiple approaches at the molecular level. Key Results: EC Prkaa1 deficiency unexpectedly alleviated HFD‐induced metabolic syndromes including decreased body weight and fat mass, enhanced glucose clearance and insulin sensitivity, and relieved adipose inflammation and hepatic steatosis. Mechanistically, PRKAA1 knockdown in cultured ECs reduced endothelial glycolysis and fatty acid oxidation, decreased levels of acetyl‐CoA and suppressed transcription of inflammatory molecules mediated by ATP citrate lyase and histone acetyltransferase p300. Conclusions and Implications: This unexpected pro‐inflammatory effect of endothelial AMPKα1/PRKAA1 in a metabolic context provides additional insight in AMPKα1/PRKAA1 activities. An in‐depth study and thoughtful consideration should be applied when AMPKα1/PRKAA1 is used as a therapeutic target in the treatment of metabolic syndrome. [ABSTRACT FROM AUTHOR]

Detecting nitroreductase (NTR) activity in hypoxic cells and tissues in situ represents an important step toward accurate delineation of hypoxic disease loci. However, it remains challenging to develop fluorescent probes with the necessary attributes of selectivity, sensitivity, precise targeting and aqueous solubility. Herein, two kinds of fluorescent probes (NNP and cRGD-NNP) built on a 2-nitroimidazole sensing platform were synthesized for the detection of NTR activity in cell and in vivo models of hypoxia. In the presence of NADH, NNP displayed high selectivity for NTR, a strong fluorescence enhancement (108 fold), and a low detection limit (3.6 ng mL−1). Benefiting from the hydrophilic structure and tumor-targeting properties of the cRGD cyclopeptide group, the probe cRGD-NNP efficiently detected NTR activity in MCF cancer cells under hypoxia. In addition, the liposome-encapsulated probe was successfully applied to visualize NTR during liver inflammation in mice. [ABSTRACT FROM AUTHOR]

Fertility refers to the ability of animals to maintain reproductive function and give birth to offspring, which is an important indicator to measure the productivity of animals. Fertility is affected by many factors, among which environmental factors may also play key roles. During the past years, substantial research studies have been conducted to detect the factors related to fecundity, including genetic factors and environmental factors. However, the identified genes associated with fertility from countless previous studies are randomly dispersed in the literature, whereas some other novel fertility-related genes are needed to detect from omics-based datasets. Here, we constructed a fertility index factor database FifBase based on manually curated published literature and RNA-Seq datasets. During the construction of the literature group, we obtained 3301 articles related to fecundity for 13 species from PubMed, involving 2823 genes, which are related to 75 fecundity indicators or 47 environmental factors. Eventually, 1558 genes associated with fertility were filtered in 10 species, of which 1088 and 470 were from RNA-Seq datasets and text mining data, respectively, involving 2910 fertility-gene pairs and 58 fertility-environmental factors. All these data were cataloged into FifBase (http://www.nwsuaflmz.com/FifBase/), where the fertility-related factor information, including gene annotation and environmental factors, can be browsed, retrieved and downloaded with the user-friendly interface. [ABSTRACT FROM AUTHOR]

In this study, halochromic smart films were produced, characterized, and applied to monitor the freshness of hairtail and shrimp in real-time. Red cabbage anthocyanins (RCAs) solution illustrated significant color variations (red-pink-blue-green) in different pH environments. RCAs were successfully immobilized into chitosan (CS)/oxidized-chitin nanocrystals (OCN) composites through hydrogen bonding, and cohesive film structures were formed. When the proper concentration of RCAs was incorporated into the composites, improved water vapor permeability (WVP), oxygen permeability (OP), mechanical, UV-blocking, and antioxidant properties were observed. Moreover, the smart films exhibited distinguishable changes of color to ammonia vapor and acidic/alkaline environment within short time intervals, which were easy to discern by naked eyes. Finally, the smart films were applied to monitor the freshness of hairtail (Trichiurus lepturus) and shrimp (Penaeus vannamei). The film color changed significantly during storage time, and three stages of product freshness (fresh, medium fresh, and spoiled) were successfully differentiated. Strong correlations among three freshness indicators and two colorimetric parameters were also identified and analyzed. Overall, the smart system assembled from non-toxic and biodegradable components could contribute to monitoring the freshness of seafood, like hairtail and shrimp, in real-time. • Biopolymer-based smart films immobilized with red cabbage anthocyanins were produced by a casting method. • The smart films possessed strong UV-blocking, water vapor, and oxygen barrier properties. • The smart films responded sensitively to volatile ammonia vapor and acidic/alkaline solutions. • The smart films exhibited significant changes of color during the spoilage process of hairtail and shrimp. • Strong correlations were among colorimetric parameters and TVC, pH values, and TVB-N contents. [ABSTRACT FROM AUTHOR]

Background and Purpose: Macrophage infiltration into the lungs is a characteristic of pulmonary hypertension (PH). Glycolysis is the main metabolic pathway for macrophage activation. However, the effect of macrophage glycolysis on the development of PH remains unknown. We investigated the effect of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKBF3), a critical enzyme of macrophage glycolysis, on PH development.Experimental Approach: Lung tissues from PH patients were examined by immunostaining with macrophage markers. PH was induced in Wistar rats with SU5416/hypoxia and in mice with hypoxia. Lungs and macrophages were isolated for analysis by RT-PCR, western blot, flow cytometry, and immunostaining.Key Results: Expression of glycolytic molecules was increased in circulating peripheral blood mononuclear cells (PBMCs) and lung macrophages of PH patients. These results were also found in lung macrophages of SU5416/hypoxia (Su/Hx)-induced PH rats and hypoxia-induced PH mice. PH was ameliorated in myeloid-specific Pfkfb3-deficient mice (Pfkfb3ΔMϕ ) or mice treated with the PFKFB3 inhibitor 3PO, compared with their controls. Alveolar macrophages of PH Pfkfb3ΔMϕ mice produced lower levels of growth factors and pro-inflammatory cytokines than those of control mice. Circulating myeloid cells and lung myeloid cells were much fewer in PH Pfkfb3ΔMϕ mice than controls. Mechanistically, overexpression of Hif1a or Hif2a in bone marrow-derived macrophages (BMDMs) cultured with bone marrow of Pfkfb3ΔMϕ mice restored the decreased expression of pro-inflammatory cytokines and growth factors.Conclusions and Implications: Myeloid Pfkfb3 deficiency protects mice from PH, thereby suggesting that myeloid PFKFB3 is one of the important targets in the therapeutic effect of PFKFB3 inhibition in PH treatment. [ABSTRACT FROM AUTHOR]

Aims Adenosine receptors and extracellular adenosine have been demonstrated to modulate vascular smooth muscle cell (VSMC) proliferation and neointima formation. Adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels but is function in VSMC remains unclear. Here, we investigated the role of ADK in vascular injury-induced smooth muscle proliferation and delineated the mechanisms underlying its action. Methods and results We found that ADK expression was higher in the neointima of injured vessels and in platelet-derived growth factor-treated VSMCs. Genetic and pharmacological inhibition of ADK was enough to attenuate arterial injury-induced neointima formation due to inhibition of VSMC proliferation. Mechanistically, using infinium methylation assays and bisulfite sequencing, we showed that ADK metabolized the intracellular adenosine and potentiated the transmethylation pathway, then induced the aberrant DNA hypermethylation. Pharmacological inhibition of aberrant DNA hypermethylation increased KLF4 expression and suppressed VSMC proliferation as well as the neointima formation. Importantly, in human femoral arteries, we observed increased ADK expression and DNA hypermethylation as well as decreased KLF4 expression in neointimal VSMCs of stenotic vessels suggesting that our findings in mice are relevant for human disease and may hold translational significance. Conclusion Our study unravels a novel mechanism by which ADK promotes VSMC proliferation via inducing aberrant DNA hypermethylation, thereby down-regulating KLF4 expression and promoting neointima formation. These findings advance the possibility of targeting ADK as an epigenetic modulator to combat vascular injury. [ABSTRACT FROM AUTHOR]

Background: BRAFV600E mutation is the most common mutation in thyroid cancer. It strongly activates MAPK/ERK pathway and indicates an invasive subtype of thyroid cancer. PLX4032 is a selective oral inhibitor of the BRAFV600 kinase although with limited effect in treating this panel of thyroid cancer, due to the feedback activation of MAPK/ERK as well as PI3K/AKT pathways. It was investigated that Vitamin C plays a positive role in inhibiting these pathways in thyroid cancer. However, whether Vitamin C could enhance the antitumor effect of PLX4032 remains largely unclear. Methods: The antitumor efficacy of combination therapy with PLX4032 and Vitamin C on BRAFMT thyroid cancer cell was assessed by the MTT assay, EdU assay and colony formation, Chou-Talalay way was employed to analyze the synergistic effect. Flow cytometry were employed to assess cells' apoptosis and cell cycle arrest in response to combination therapy. Xenograft models were used to test its in vivo antitumor activity. Western blot and IHC were applied to investigate the mechanism underlying synergistic effect. Results: PLX4032 or Vitamin C monotherapy was mildly effective in treating BRAFMT thyroid cancer cell and xenografts model. The combination therapy significantly inhibited cancer cell proliferation and tumor growth in nude mice, and induced cell apoptosis and cell cycle arrest compared to either monotherapy. PLX4032 monotherapy induced feedback activation of MAPK/ERK as well as PI3K/AKT pathway; while combination therapy significantly relieved this feedback. Conclusion: Vitamin C promotes the antitumor effect of PLX4032 in BRAFMT thyroid cancer cell and xenografts model via relieving the feedback activation of MAPK/ERK as well as PI3K/AKT pathway. PLX4032/Vitamin C combination may be a potential therapeutic approach to treat BRAFMT thyroid cancer. [ABSTRACT FROM AUTHOR]

A 10 kA high-temperature superconductor current lead (HTS-CL) using a double-tube stainless steel (SS) shunt has been designed, fabricated, and tested at Institute of plasma physics, Chinese Academy of Sciences (ASIPP). The current lead consists of 80 parallel the second generation HTS coated conductor with critical current of 220 A at 77 K in self-field, a double-tube SS shunt, and Cu connectors. The 80 YBCO tapes are divided into 20 so-called panels, which are soldered into the 20 grooves on the surface of the double-tube SS shunt and Cu connectors, each panel contains four parallel YBCO tapes. A double-tube shunt consisting of two coaxial tubes is designed. A series of tests were performed to verify the feasibility of the HTS-CL. The measured joint resistance is about 0.3–0.4 μΩ/cm2. The transport current of 10.515 kA was carried between 5 and 65 K for 1010 s with no quenching. The LOFA time of 569 s and the burnout time over 15 s meeting the design requirements. [ABSTRACT FROM AUTHOR]

[Display omitted] • Aptamer with high affinity and specificity for human plasminogen Kringle 5 were obtained by SELEX. • The common motif of these aptamers is a critical region for their recognition of Kringle 5. • The binding mechanism for the aptamers specific binding to Kringle 5 was revealed. • Aptamer KG-4 showed a dose-dependent inhibition effect of Kringle 5 function in vitro. Plasminogen Kringle 5 is one of the most potent cytokines identified to inhibit the proliferation and migration of vascular endothelial cells. Herein, six aptamer candidates that specifically bind to Kringle 5 were generated by the systematic evolution of ligands by exponential enrichment (SELEX). After 10 rounds of screening against Kringle 5, a highly enriched ssDNA pool was sequenced and the representative aptamers were subjected to binding assays to evaluate their affinity and specificity. The preferred aptamer KG-4, which demonstrated a low dissociation constant (K d) of ∼ 432 nM and excellent selectivity for Kringle 5. A conserved "motif" of eight bases located at the stem-loop intersection, common to the aptamer, was further confirmed as the recognition element for binding with Kringle 5. The bulge formed by the motif and depression on the lysine binding site of Kringle 5 were both located at the binding interface, and the "induced fit" between their structures played a central role in the recognition process. Kringle 5 interacts KG-4 primarily through enthalpy-driven van der Waals forces and hydrogen bond. The key nucleotides A34 and C35 at motif on KG-4 and the positively charged amino acids in the loop 1 and loop 4 regions on Kringle 5 play a major role in the interaction. Furthermore, KG-4 dose-dependently reduced the proliferation inhibition of vascular endothelial cells by Kringle 5 and had a blocking effect on the function of Kringle 5 in inhibiting migration and promoting apoptosis of vascular endothelial cells in vitro. This study put a new light on protein-aptamer binding mechanism and may provide insight into the treatment of ischemic diseases by target depletion of Kringle 5. [ABSTRACT FROM AUTHOR]

To ensile rice straw (ENRS), a combination of lactic acid bacteria (LAB), consisting of Lactobacillus plantarum , L. buchneri and Pediococcus acidilactici at a ratio of 2:1:1 was added to rice straw (RS), and stored for 42 days at room temperature. We examined: 1) the nutritive quality of ENRS; 2) in vitro rumen fermentation parameters and microbiota composition with ENRS as substrate; and, 3) serum metabolites and average daily gain (ADG) of growing Hu lambs consuming ENRS. Ensiling of rice straw increased in vitro neutral detergent fiber (NDF) and acid detergent fiber (ADF) degradabilities (both P < 0.05), and total gas production (P < 0.05) but decreased (P < 0.05) methane (CH4) production. In addition, ensiling increased bacterial diversity and reduced the relative abundance of the methanogen Methanobrevibacter. Twelve male Hu lambs (initial live body weight = 25.2 ± 0.47 kg), aged 70 (± 6) days, were assigned randomly to one of two groups (n = 6) and offered a total mixed ration (TMR) that included 400 g/kg DM of either RS or ENRS for 4 weeks. Ensiling ruptured the physical structure of the RS, decreased (P < 0.05) dry matter and hemicellulose contents, and increased (P < 0.05) the concentrations of lactate, acetate and organic acids. Feeding ENRS up-regulated purine metabolism and improved ADG and gain to feed ratio of Hu lambs when compared to RS. In summary, ensiling was effective in improving both the nutritive quality of the feed and ADG of the lambs. [ABSTRACT FROM AUTHOR]

• The China Fusion Engineering Test Reactor (CFETR) will develop a high-performance cryopump for pumping the torus vessel. • Considering the special geometries of cryosorption-panel, a research campaign has been carried out by Institute of plasma physics, Chinese Academy of Sciences (ASIPP) to analyze the structure and assess the hydraulic performance of the cryosorption-panel. • This research activity was performed by Finite Element Method (FEM) and Computational fluid dynamics method (CFD). In this article, the cryosorption-panel structure was designed and analyzed, and five representative fluid fields with different geometries were chosen, modeled and numerical simulated.. • The inlet-outlet pressure drops and flow distribution data under mass flow rates between 0.03kg/s and 0.2kg/s was collected and quantitatively analyzed. • By analyzing the simulation results, the influence of fluid field thickness and pin fin arrangement on hydraulic performance was summarized. For the cases with fluid field thickness of 4mm, 6mm, 8mm, the functional relationship of hydraulic resistance coefficient ξ versus Reynolds number (Re) was calculated respectively: ξ = 75.26Re−0.07475; ξ = 120.7Re−0.1464; ξ = 385.3Re−0.2876; The China Fusion Engineering Test Reactor (CFETR) will develop a high-performance cryopump for pumping the torus vaccum vessel. Cryosorption-panel is the key component of torus cryopump, which is applied to adsorb gaseous molecules in cryogenic conditions. Considering the special geometries of cryosorption-panel, a research campaign has been carried out by Institute of plasma physics, Chinese Academy of Sciences (ASIPP) to analyze the structure and assess the hydraulic performance of the cryosorption-panel. This research activity was performed by Finite Element Method (FEM) and Computational Fluid Dynamics Method (CFD). In this article, the cryosorption-panel structure was designed and analyzed, and five representative fluid fields with different geometries were chosen, modeled and numerical simulated. The inlet-outlet pressure drops and flow distribution data under mass flow rates between 0.03kg/s and 0.2kg/s was collected and quantitatively analyzed. By analyzing the simulation results, the influence of fluid field thickness and pin fin arrangement on hydraulic performance was summarized. For the cases with fluid field thickness of 4mm, 6mm, 8mm, the functional relationship of hydraulic resistance coefficient ξ versus Reynolds number (Re) was calculated respectively: ξ = 75.26Re−0.07475; ξ = 120.7Re−0.1464; ξ = 385.3Re−0.2876; [ABSTRACT FROM AUTHOR]

• Development of experimental control system for regenerative heating process of high-speed cryo-adsorption pump. • Design of fuzzy PID and improved generalized predictive control algorithm. • Design of experimental system for regeneration process of cryo-adsorption pump. The vacuum system of the Negative-ion-based Neutral Beam Injector (NNBI) verification prototype of the China Fusion Engineering Test Reactor (CFETR) employs a built-in ultra-high-speed cryo-adsorption pump utilizing forced-flow cooling as the main pump, which functions through four major processes: cooling, stable operation, regeneration, and temperature rise. The research analyzes the key technical problems of engineering that must be solved,such as natural regeneration takes a longer time with temperature uncontrollable, lead to low experiment efficiency. An efficient and safe controllable technical method for the regeneration heating process was proposed,and regeneration heating experimental control system, including an equipment layer, control layer, data acquisition and monitoring layer, was designed to control the regeneration heating process of the cryo-adsorption pump. The signals collected by temperature sensors are processed and transmitted through signal isolators to the host computer for display and storage.The target temperature is manually set on the host computer. An improved generalized predictive control (GPC) algorithm and a fuzzy proportional integral derivative (PID) control algorithm are used in the control layer to control the heating process.The designed activation regeneration heating control experimental system was embedded in the comprehensive experimental test bench of cryo-adsorption pump for experimental verification, and the test experiment was carried out.The results show that the system can control the regenerative heating process in an efficient, safe and stable way. This lays the foundation for further development of control functions in the regeneration process of the cryo-adsorption pump equipped in the NNBI verification prototype, and provides a design basis for the vacuum system of fusion engineering experimental reactors. [ABSTRACT FROM AUTHOR]

Testicular development during juvenile is crucial for subsequent male reproductive function. However, it remains poorly understood about the contribution of the testis microenvironment to human germ cell maturation. Therefore, we systematically analyzed scRNA-seq transcriptome and found the dramatic changes in cell-type composition in human testis during puberty. Then we constructed cell-cell communication networks between germ cells and somatic cells in the juvenile testis, which may be achieved via immune-related pathways. Our results showed that maturation-promoting factors are the switches of the Sertoli cells that drive sperm maturation. Furthermore, we found that Bisphenol A(BPA) enhanced the maturation and growth of germ cells through the Sertoli cell's secretory protein. Finally, our results indicate Bisphenol A would lead to the dysregulation of secreted protein expression in Sertoli cells during spermatogenesis, which in turn has direct cytotoxicity to Sertoli cells. Bisphenol A is one of the underlying causes of non-obstructive azoospermia (NOA). In summary, our results reveal the reproductive toxicity and molecular mechanism of Bisphenol A in Sertoli cells and male reproduction. Provide a reference for the toxicity of Bisphenol A to human reproduction. [Display omitted] • Single cell transcriptome reveals the microenvironment changes of human testis. • Cell communication network was constructed between germ cells and somatic cells. • The BPA promotes the sperm maturation through maturation promoting factor. • BPA may lead to the dysregulation of secretory protein expression by Sertoli cells. • BPA triggers non-obstructive azoospermia (NOA) via their shared molecular signals. [ABSTRACT FROM AUTHOR]

Obesity is characterized by excessive accumulation of fat in the body, which is triggered by a body energy intake larger than body energy consumption. Due to complications such as cardiovascular diseases, type 2 diabetes (T2DM), obstructive pneumonia and arthritis, as well as high mortality, morbidity and economic cost, obesity has become a major health problem. The global prevalence of obesity, and its comorbidities is escalating at alarming rates, demanding the development of additional classes of therapeutics to reduce the burden of disease further. As a central energy sensor, the AMP-activated protein kinase (AMPK) has recently been elucidated to play a paramount role in fat synthesis and catabolism, especially in regulating the energy expenditure of brown/beige adipose tissue and the browning of white adipose tissue (WAT). This review discussed the role of AMPK in fat metabolism in adipose tissue, emphasizing its role in the energy expenditure of brown/beige adipose tissue and browning of WAT. A deeper understanding of the role of AMPK in regulating fat metabolism and energy expenditure can provide new insights into obesity research and treatment. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is one of the leading causes of death in sepsis. Endothelial inflammation and dysfunction play a prominent role in development of ALI. Glycolysis is the predominant bioenergetic pathway for endothelial cells (ECs). However, the role of EC glycolysis in ALI of sepsis remains unclear. Here we show that both the expression and activity of PFKFB3, a key glycolytic activator, were markedly increased in lipopolysaccharide (LPS)-treated human pulmonary arterial ECs (HPAECs) in vitro and in lung ECs of mice challenged with LPS in vivo. PFKFB3 knockdown significantly reduced LPS-enhanced glycolysis in HPAECs. Compared with LPS-challenged wild-type mice, endothelial-specific Pfkfb3 knockout (Pfkfb3 ΔVEC) mice exhibited reduced endothelium permeability, lower pulmonary edema, and higher survival rate. This was accompanied by decreased expression of intracellular adhesion molecule-1 (Icam-1) and vascular cell adhesion molecule 1 (Vcam-1), as well as decreased neutrophil and macrophage infiltration to the lung. Consistently, PFKFB3 silencing or PFKFB3 inhibition in HPAECs and human pulmonary microvascular ECs (HPMVECs) significantly downregulated LPS-induced expression of ICAM-1 and VCAM-1, and monocyte adhesion to human pulmonary ECs. In contrast, adenovirus-mediated PFKFB3 overexpression upregulated ICAM-1 and VCAM-1 expression in HPAECs. Mechanistically, PFKFB3 silencing suppressed LPS-induced nuclear translocation of nuclear factor κB (NF-κB)-p65, and NF-κB inhibitors abrogated PFKFB3-induced expression of ICAM-1 and VCAM-1. Finally, administration of the PFKFB3 inhibitor 3PO also reduced the inflammatory response of vascular endothelium and protected mice from LPS-induced ALI. Overall, these findings suggest that targeting PFKFB3-mediated EC glycolysis is an efficient therapeutic strategy for ALI in sepsis. [ABSTRACT FROM AUTHOR]