Design, Synthesis, and Biological Evaluation of the Quorum-Sensing Inhibitors of Pseudomonas aeruginosa PAO1.

Due to the resistance of Gram-negative bacteria Pseudomonas aeruginosa PAO1 to most clinically relevant antimicrobials, the use of traditional antibiotic treatments in hospitals is challenging. The formation of biofilms, which is regulated by the quorum-sensing (QS) system of Pseudomonas aeruginosa (PA), is an important cause of drug resistance. There are three main QS systems in P. aeruginosa: the las system, the rhl system, and the pqs system. The inhibitors of the las system are the most studied. Previously, the compound AOZ-1 was found to have a certain inhibitory effect on the las system when screened. In this study, twenty-four compounds were designed and synthesized by modifying the Linker and Rings of AOZ-1. Using C. violaceum CV026 as a reporter strain, this study first assessed the inhibitory effects of new compounds against QS, and their SAR was investigated. Then, based on the SAR analysis of compound AOZ-1 derivatives, the parent core of AOZ-1 was replaced to explore the structural diversity. Then, nine new compounds were designed and synthesized with a new nucleus core component of 3-amino-tetrahydro-l,3-oxazin-2-one. The compound Y-31 (IC50 = 91.55 ± 3.35 µM) was found to inhibit the QS of C. violaceum CV026. Its inhibitory effect on C. violaceum CV026 was better than that of compound AOZ-1 (IC50 > 200 µM). Furthermore, biofilm formation is one of the important causes of Pseudomonas aeruginosa PAO1 resistance. In this study, it was found that compound Y-31, with a new nucleus core component of 3-amino-tetrahydro-l,3-oxazin-2-one, had the highest biofilm inhibition rate (40.44%). The compound Y-31 has a certain inhibitory effect on the production of PAO1 virulence factors (pyocyanin, rhamnolipid, and elastase) and swarming. When the concentration of compound Y-31 was 162.5 µM, the inhibition rates of pyocyanin, rhamnolipid, and elastase were 22.48%, 6.13%, and 22.67%, respectively. In vivo, the lifetime of wildtype Caenorhabditis elegans N2 infected with P. aeruginosa PAO1 was markedly extended by the new parent nucleus Y-31. This study also performed cytotoxicity experiments and in vivo pharmacokinetics experiments on the compound Y-31. In conclusion, this study identified a compound, Y-31, with a new nucleus core component of 3-amino-tetrahydro-l,3-oxazin-2-one, which is a potential agent for treating P. aeruginosa PAO1 that is resistant to antibiotics and offers a way to discover novel antibacterial medications.

[Analysis of differential metabolites of spikes of Prunella vulgaris at different stages based on UPLC-MS/MS].

Prunella vulgaris, aptly named for its withering at the summer solstice, displays significant variation in quality arising from differing harvest time. However, research on the chemical composition changes of its spikes at various stages is limited, and the specific metabolites remain unclear. In order to elucidate the metabolites and metabolic pathways of the spikes of P. vulgaris, the current study deployed ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) and targeted metabolomics to characterize the compound variability in the spikes of P. vulgaris across different periods. Multivariate statistical techniques such as principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA) were used to identify the differences in metabolites, and relevant metabolic pathways were analyzed. A total of 602 metabolites were identified by metabolomics, of which organic acids and their derivatives were the most abundant, followed by flavonoids. Multiple differential metabolites, including p-hydroxybenzoic acids and gallic acids were identified based on variable importance in projection(VIP)>1 and P<0.05. The results of enrichment analysis suggested that isoflavonoids biosynthesis, aminobenzoate degradation, benzoate degradation, anthocyanins biosynthesis, metabolic pathways, microbial metabolism in different environments, secondary plant metabolite biosynthesis, tryptophan metabolism, and phenylpropanoid synthesis were the main metabolic pathways. These results intend to elucidate the dynamic changes of differential metabolites of P. vulgaris and provide a theoretical basis for further study of the harvesting mechanism of spikes of P. vulgaris.

Missense mutation of c.635 T > C in CAPN3 impairs muscle injury repair in a Limb-Girdel Muscular Dystropy Model.

Limb-girdle muscular dystrophy recessive 1 (LGMDR1), previously known as LGMD2A, is a specific LGMD caused by a gene mutation encoding the calcium-dependent neutral cysteine protease calpain-3 (CAPN3). In our study, the compound heterozygosity with two missense variants c.635 T > C (p.Leu212Pro) and c.2120A > G (p.Asp707Gly) was identified in patients with LGMDR1. However, the pathogenicity of c.635 T > C has not been investigated. To evaluate the effects of this novel likely pathogenic variant to the motor system, the mouse model with c.635 T > C variant was prepared by CRISPR/Cas9 gene editing technique. The pathological results revealed that a limited number of inflammatory cells infiltrated the endomyocytes of certain c.635 T > C homozygous mice at 10 months of age. Compared with wild-type mice, motor function was not significantly impaired in Capn3 c. 635 T > C homozygous mice. Western blot and immunofluorescence assays further indicated that the expression levels of the Capn3 protein in muscle tissues of homozygous mice were similar to those of wild-type mice. However, the arrangement and ultrastructural alterations of the mitochondria in the muscular tissues of homozygous mice were confirmed by electron microscopy. Subsequently, muscle regeneration of LGMDR1 was simulated using cardiotoxin (CTX) to induce muscle necrosis and regeneration to trigger the injury modification process. The repair of the homozygous mice was significantly worse than that of the control mice at day 15 and day 21 following treatment, the c.635 T > C variant of Capn3 exhibited a significant effect on muscle regeneration of homozygous mice and induced mitochondrial damage. RNA-sequencing results demonstrated that the expression levels of the mitochondrial-related functional genes were significantly downregulated in the mutant mice. Taken together, the results of the present study strongly suggested that the LGMDR1 mouse model with a novel c.635 T > C variant in the Capn3 gene was significantly dysfunctional in muscle injury repair via impairment of the mitochondrial function.

Early autoimmunity and outcome in virus encephalitis: a retrospective study based on tissue-based assay.

To explore the autoimmune response and outcome in the central nervous system (CNS) at the onset of viral infection and correlation between autoantibodies and viruses. METHODS: A retrospective observational study was conducted in 121 patients (2016-2021) with a CNS viral infection confirmed via cerebrospinal fluid (CSF) next-generation sequencing (cohort A). Their clinical information was analysed and CSF samples were screened for autoantibodies against monkey cerebellum by tissue-based assay. In situ hybridisation was used to detect Epstein-Barr virus (EBV) in brain tissue of 8 patients with glial fibrillar acidic protein (GFAP)-IgG and nasopharyngeal carcinoma tissue of 2 patients with GFAP-IgG as control (cohort B). RESULTS: Among cohort A (male:female=79:42; median age: 42 (14-78) years old), 61 (50.4%) participants had detectable autoantibodies in CSF. Compared with other viruses, EBV increased the odds of having GFAP-IgG (OR 18.22, 95% CI 6.54 to 50.77, p<0.001). In cohort B, EBV was found in the brain tissue from two of eight (25.0%) patients with GFAP-IgG. Autoantibody-positive patients had a higher CSF protein level (median: 1126.00 (281.00-5352.00) vs 700.00 (76.70-2899.00), p<0.001), lower CSF chloride level (mean: 119.80±6.24 vs 122.84±5.26, p=0.005), lower ratios of CSF-glucose/serum-glucose (median: 0.50[0.13-0.94] vs 0.60[0.26-1.23], p=0.003), more meningitis (26/61 (42.6%) vs 12/60 (20.0%), p=0.007) and higher follow-up modified Rankin Scale scores (1 (0-6) vs 0 (0-3), p=0.037) compared with antibody-negative patients. A Kaplan-Meier analysis revealed that autoantibody-positive patients experienced significantly worse outcomes (p=0.031). CONCLUSIONS: Autoimmune responses are found at the onset of viral encephalitis. EBV in the CNS increases the risk for autoimmunity to GFAP.

Comprehensive analysis of the roles of fatty acid transport related proteins in clear cell renal cell carcinoma.

OBJECTIVE: This study aimed to explore the clinical significance of fatty acid transport-related protein (FATRP) in patients with clear cell renal cell carcinoma(ccRCC). METHODS: RNA-seq data and corresponding clinical data of ccRCC were obtained from TCGA data portal. Seventeen key FATRP genes were comprehensively investigated using bioinformatics approaches to systematically investigate their expression patterns in ccRCC. In addition, the correlation between the expression levels of these genes and clinicopathological features in ccRCC was further explored. RESULTS: Among the 17 key FATRP genes, only FABP5, FABP6, and FABP7 could be regarded as ideal biomarkers for ccRCC, as they were highly expressed in ccRCC tumor tissues, and positively correlates with tumor progression and poor prognosis. FABP6 had the highest copy number variations (CNV) events (63.07 %), and ccRCC patients with FABP6 amplification had a better prognosis than the unaltered group. DNA methylation levels of FABP6 and FABP7 were downregulated in ccRCC tumor tissues compared to those in normal tissues. FABP5 showed the opposite results. Moreover, a novel four FATRP gene (FABP1, FABP5, FABP7, FATP2) and three clinical parameter (age, stage, and grade) prediction model was constructed and that comprised a significant independent prognostic signature. CONCLUSIONS: Only a few FATRP genes are upregulated in ccRCC tumor tissue, and positively correlate with tumor progression and poor prognosis. The accuracy of a single gene of these FATRP genes as predictors of progression and prognosis of ccRCC is limited. The performance of the novel prediction model proposed by this study was much better than that of any single gene.

Elevated serum FGF21 is an independent predictor for adverse events in hemodialysis patients from two large centers: a prospective cohort study.

Introduction: We explored the relationship and the predictive value of serum fibroblast growth factor 21 (FGF21) with all-cause mortality, major adverse cardiovascular events (MACEs) and pneumonia in hemodialysis (HD) patients.Methods: A total of 388 Chinese HD patients from two HD centers were finally enrolled in this prospective cohort study (registration number: ChiCTR 1900028249) between January 2018 and December 2018. Serum FGF21 was detected. Patients were followed up with a median period of 47 months to record the MACEs and pneumonia until death or 31 December 2022.Results: The incidence of all-cause mortality, MACEs and pneumonia in HD patients were 20.6%, 29.6%, and 34.8%, respectively. The optimal cutoffs for FGF21 to predict all-cause mortality, MACEs and pneumonia were 437.57 pg/mL, 216.99 pg/mL and 112.79 pg/mL. Multivariate Cox regression analyses showed that FGF21, as a categorical variable, was an independent predictor for all-cause mortality, MACEs and pneumonia (HR, 3.357, 95% CI, 2.128-5.295, p < 0.001; HR, 1.575, 95% CI, 1.046-2.371, p = 0.029; HR, 1.784; 95% CI, 1.124-2.830; p = 0.014, respectively). The survival nomogram, MACEs-free survival nomogram and pneumonia-free survival nomogram based on FGF21 constructed for individualized assessment of HD patients had a high C-index with 0.841, 0.706 and 0.734.Conclusion: Higher serum FGF21 is an independent predictor of all-cause mortality, MACEs and pneumonia in HD patients.

Discovery of Novel STING Inhibitors Based on the Structure of the Mouse STING Agonist DMXAA.

The stimulator-of-interferon-gene (STING) protein is involved in innate immunity. The drug DMXAA (5,6-dimethylxanthenone-4-acetic acid) proved to be a potent murine-STING (mSTING) agonist but had little effect on human-STING (hSTING). In this paper, we draw upon the comparison of different crystal structures and protein-ligand interaction relationships analysis to venture the hypothesis that the drug design of DMXAA variants has the potential to convert STING agonists to inhibitors. Based on our previous discovery of two DMXAA analogs, 3 and 4 (both could bind to STING), we structurally optimized them and synthesized new derivatives, respectively. In binding assays, we found compounds 11 and 27 to represent STING binders that were superior to the original structures and discussed the structure-activity relationships. All target compounds were inactive in cellular assays for the screening of STING agonistic activity. Gratifyingly, we identified 11 and 27 as STING inhibitors with micromolar activity in both hSTING and mSTING pathways. In addition, 11 and 27 inhibited the induction of interferon and inflammatory cytokines activated by 2'3'-cGAMP without apparent cytotoxicity. These findings break the rigid thinking that DMXAA provides the structural basis specifically for STING agonists and open up more possibilities for developing novel STING agonists or inhibitors.

Tapping into Permutation Symmetry for Improved Detection of k-Symmetric Extensions.

Symmetric extensions are essential in quantum mechanics, providing a lens through which to investigate the correlations of entangled quantum systems and to address challenges like the quantum marginal problem. Though semi-definite programming (SDP) is a recognized method for handling symmetric extensions, it struggles with computational constraints, especially due to the large real parameters in generalized qudit systems. In this study, we introduce an approach that adeptly leverages permutation symmetry. By fine-tuning the SDP problem for detecting k-symmetric extensions, our method markedly diminishes the searching space dimensionality and trims the number of parameters essential for positive-definiteness tests. This leads to an algorithmic enhancement, reducing the complexity from O(d2k) to O(kd2) in the qudit k-symmetric extension scenario. Additionally, our approach streamlines the process of verifying the positive definiteness of the results. These advancements pave the way for deeper insights into quantum correlations, highlighting potential avenues for refined research and innovations in quantum information theory.

Phenoxyaromatic Acid Analogues as Novel Radiotherapy Sensitizers: Design, Synthesis and Biological Evaluation.

Radiotherapy is a vital approach for brain tumor treatment. The standard treatment for glioblastoma (GB) is maximal surgical resection combined with radiotherapy and chemotherapy. However, the non-sensitivity of tumor cells in the hypoxic area of solid tumors to radiotherapy may cause radioresistance. Therefore, radiotherapy sensitizers that increase the oxygen concentration within the tumor are promising for increasing the effectiveness of radiation. Inspired by hemoglobin allosteric oxygen release regulators, a series of novel phenoxyacetic acid analogues were designed and synthesized. A numerical method was applied to determine the activity and safety of newly synthesized compounds. In vitro studies on the evaluation of red blood cells revealed that compounds 19c (∆P50 = 45.50 mmHg) and 19t (∆P50 = 44.38 mmHg) improve the oxygen-releasing property effectively compared to positive control efaproxiral (∆P50 = 36.40 mmHg). Preliminary safety evaluation revealed that 19c exhibited no cytotoxicity towards HEK293 and U87MG cells, while 19t was cytotoxic toward both cells with no selectivity. An in vivo activity assay confirmed that 19c exhibited a radiosensitization effect on orthotopically transplanted GB in mouse brains. Moreover, a pharmacokinetic study in rats showed that 19c was orally available.

EZH2 is a potential prognostic predictor of glioma.

The enhancer of zeste homologue 2 (EZH2) is a histone H3 lysine 27 methyltransferase that promotes tumorigenesis in a variety of human malignancies by altering the expression of tumour suppressor genes. To evaluate the prognostic value of EZH2 in glioma, we analysed gene expression data and corresponding clinicopathological information from the Chinese Glioma Genome Atlas, the Cancer Genome Atlas and GTEx. Increased expression of EZH2 was significantly associated with clinicopathologic characteristics and overall survival as evaluated by univariate and multivariate Cox regression. Gene Set Enrichment Analysis revealed an association of EZH2 expression with the cell cycle, DNA replication, mismatch repair, p53 signalling and pyrimidine metabolism. We constructed a nomogram for prognosis prediction with EZH2, clinicopathologic variables and significantly correlated genes. EZH2 was demonstrated to be significantly associated with several immune checkpoints and tumour-infiltrating lymphocytes. Furthermore, the ESTIMATE and Timer Database scores indicated correlation of EZH2 expression with a more immunosuppressive microenvironment for glioblastoma than for low grade glioma. Overall, our study demonstrates that expression of EZH2 is a potential prognostic molecular marker of poor survival in glioma and identifies signalling pathways and immune checkpoints regulated by EHZ2, suggesting a direction for future application of immune therapy in glioma.

Single-Molecule Conductance through an Isoelectronic B-N Substituted Phenanthrene Junction.

Single-molecule conductance of a B-N substituted phenanthrene derivative and its isoelectronic C═C counterpart was investigated by the scanning tunneling microscopy break junction (STM-BJ) technique. The incorporation of the B-N motif results in a better single-molecule conductivity than the C═C analogue. Furthermore, the Lewis acid-base reaction between F- and the B atom of the B-N motif leads to a decrease of the conductance of the BN derivative, which can be understood due to the shifting of the energy positions of the LUMO, as revealed by quantum transport calculations, even though the HOMO-LUMO gap decreases in the B-F Lewis acid-base. These findings provide insights for modulating electron transport properties by isoelectronic structure design. The B-N isoelectronic substituted structure could be a feasible way to design single-molecule devices such as switches and chemical sensors.

Design, synthesis and biological evaluation of acridone analogues as novel STING receptor agonists.

STING (Stimulator of Interferon Genes) has become a focal point in immunology research and a target in drug discovery. The discovery of a potent human-STING agonist is expected to revolutionize current anti-virus or cancer immunotherapy. Inspired by the structure and function of murine STING-specific agonists (DMXAA and CMA), we rationally designed and synthesized four series of novel compounds for the enhancement of human sensitivity. In the cell-based assay, we identified six compounds from all the synthetic small molecules: 2g, 9g, and 12b are STING agonists that are efficacious across species, and all have the skeleton of acridone; 1b, 1c, and 12c just function in the murine STING pathway. Notably, 12b exhibits the best activity among the six agonists, and its inductions of both human and murine STING-dependent signalling are similar to that of 2'3'-cGAMP, which is a well-known STING inducer. While a protein assay indicated that 2 g, 9 g, and 12b could activate the pathway by directly binding human STING, 12b also displayed the strongest binding affinity. Additionally, our studies show that 12b can induce faster, more powerful, and more durable responses of assorted cytokines in a native system than 2'3'-cGAMP. Consequently, our team is the first to successfully modify murine STING agonists to obtain human sensitivity, and these results suggest that 12b is a potent direct-human-STING agonist. Additionally, the acridone analogues demonstrate tremendous potential in the treatment of tumours or viral infections.

The Smad2/3/4 complex binds miR-139 promoter to modulate TGFß-induced proliferation and activation of human Tenon's capsule fibroblasts through the Wnt pathway.

The activation and proliferation of human Tenon's fibroblasts (HTFs) play a vital role in the fibrosis in the pathology of the scar formation after the glaucoma filtration surgery. Transforming growth factor ß1 (TGFß1)/Smads signaling has been reported to promote fibrosis. In our previous study, we revealed that TGFß1-induced orbital fibroblast activation and proliferation through Wnt/ß-catenin signaling. As microRNA (miR)-139 could target several factors in Wnt signaling to modulate fibrosis, here, the effect and mechanism of miR-139 in HTF activation and proliferation were investigated. miR-139 overexpression significantly reversed the TGFß1-induced increase in collagen I and α-smooth muscle actin contents and proliferation in HTFs. CTNNB1 and CTNND1 were direct downstream of miR-139 and can significantly restore the suppressive effect of miR-139 on the activation and proliferation in HTFs under TGFß1 stimulation. Smad2/3/4 complex inhibits the transcription activity of miR-139, most possibly by Smad4 binding to the miR-139 promoter. Taken together, we demonstrated a new mechanism of HTF activation and proliferation from the perspective of miRNA regulation, which may provide new strategies for improving the fibrosis after the glaucoma filtration surgery.

Structural Basis for the Inhibition of the Autophosphorylation Activity of HK853 by Luteolin.

The two-component system (TCS) is a significant signal transduction system for bacteria to adapt to complicated and variable environments, and thus has recently been regarded as a novel target for developing antibacterial agents. The natural product luteolin (Lut) can inhibit the autophosphorylation activity of the typical histidine kinase (HK) HK853 from Thermotoga maritime, but the inhibition mechanism is not known. Herein, we report on the binding mechanism of a typical flavone with HK853 by using solution NMR spectroscopy, isothermal titration calorimetry (ITC), and molecular docking. We show that luteolin inhibits the activity of HK853 by occupying the binding pocket of adenosine diphosphate (ADP) through hydrogen bonds and π-π stacking interaction structurally. Our results reveal a detailed mechanism for the inhibition of flavones and observe the conformational and dynamics changes of HK. These results should provide a feasible approach for antibacterial agent design from the view of the histidine kinases.

Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors.

Polymyxins are considered to be the last-line antibiotics that are used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria; however, the plasmid-mediated transferable colistin resistance gene (mcr-1) has rendered polymyxins ineffective. Therefore, the protein encoded by mcr-1, MCR-1, could be a target for structure-based design of inhibitors to tackle polymyxins resistance. Here, we identified racemic compound 3 as a potential MCR-1 inhibitor by virtual screening, and 26 compound 3 derivatives were synthesized and evaluated in vitro. In the cell-based assay, compound 6g, 6h, 6i, 6n, 6p, 6q, and 6r displayed more potent activity than compound 3. Notably, 25 µΜ of compound 6p or 6q combined with 2 µg·mL-1 colistin could completely inhibit the growth of BL21(DE3) expressing mcr-1, which exhibited the most potent activity. In the enzymatic assay, we elucidate that 6p and 6q could target the MCR-1 to inhibit the activity of the protein. Additionally, a molecular docking study showed that 6p and 6q could interact with Glu246 and Thr285 via hydrogen bonds and occupy well the cavity of the MCR-1 protein. These results may provide a potential avenue to overcome colistin resistance, and provide some valuable information for further investigation on MCR-1 inhibitors.

Overexpression of DNA (Cytosine-5)-Methyltransferase 1 (DNMT1) And DNA (Cytosine-5)-Methyltransferase 3A (DNMT3A) Is Associated with Aggressive Behavior and Hypermethylation of Tumor Suppressor Genes in Human Pituitary Adenomas.

BACKGROUND Alteration of DNA methylation of tumor suppressor genes (TSGs) is one of the most consistent epigenetic changes in human cancers. DNMTs play several important roles in DNA methylation and development of cancers. Regarding DNMTs protein expressions, little is known about the clinical significance and correlation with promoter methylation status of TSGs in human pituitary adenomas. MATERIAL AND METHODS We analyzed the protein expression of 3 DNMTs using immunohistochemistry and assessed DNA hypermethylation of RASSF1A, CDH13, CDH1, and CDKN2A (p16) in 63 pituitary adenomas. We examined associations between DNMTs expression and clinicopathological features or promoter methylation status of TSGs. RESULTS Overexpression of DNMTs was detected in pituitary adenomas. Frequencies of DNMT1 overexpression were significantly higher in macroadenomas, invasive tumors, and grade III and IV tumors. DNMT3A was frequently detected in invasive tumors and grade IV tumors. In addition, DNMT1 and DNMT3A were frequently detected in high-methylation tumors. Furthermore, in multivariate logistic regression, the significant association between DNMT1 or DNMT3A and high-methylation status persisted after adjusting for clinicopathological features. CONCLUSIONS Our findings suggested that tumor overexpression of DNMT1 and DNMT3A is associated with tumor aggressive behavior and high-methylation status in pituitary adenomas. Our data support a possible role of DNMT1 and DNMT3A in TSG promoter methylation leading to pituitary adenoma invasion and suggest that inhibition of DNMTs has the potential to become a new therapeutic approach for invasive pituitary adenoma.

Protective effect of mild-induced hypothermia against moderate traumatic brain injury in rats involved in necroptotic and apoptotic pathways.

AIM: To investigate the protective effect of hypothermia (HT) on brain injury in moderate traumatic brain injury (TBI) rat models and the potential mechanisms, especially the involvement of RIPK1 in apoptosis and necroptosis. METHODS: Adult Sprague-Dawley rats were randomized to four groups: sham+normothermia (sham+NT), sham+hypothermia (sham+HT), moderate TBI+normothermia (TBI+NT) and moderate TBI+hypothermia (TBI+HT). The sham+HT and TBI+HT groups were submitted to 32°C for 6 hours. The regional cerebral blood flow (rCBF) was assessed 24 hours after TBI; 24 and 48 hours after TBI, the modified neurological severity score (mNSS) was assessed. Immediately after behavioural tests, rats were sacrificed to harvest the brain tissues. RESULTS: mNSS scores were lower in the TBI+HT group compared with the TBI+NT group (p < 0.01) and cerebral blood flow was better (p < 0.01). H&E staining of the cortex and ipsilateral hippocampus showed pyknotic and irregularly shaped neurons in TBI+NT rats, which were less frequent in TBI+HT rats. The TBI+NT and TBI+HT groups showed higher TNF-α, TRAIL, FasL, FADD, caspase-3, caspase-8, PARP-1, RIPK-1 and RIPK-3 levels than the sham+NT group (all p < 0.05), but the levels of these proteins were all lower in the TBI+HT group compared with the TBI+NT group (all p < 0.01). CONCLUSION: HT treatment significantly reduced RIPK-1 upregulation, which may inhibit necroptosis and apoptosis pathways after moderate TBI.

Giant single-molecule anisotropic magnetoresistance at room temperature.

We report an electrochemically assisted jump-to-contact scanning tunneling microscopy (STM) break junction approach to create reproducible and well-defined single-molecule spintronic junctions. The STM break junction is equipped with an external magnetic field either parallel or perpendicular to the electron transport direction. The conductance of Fe-terephthalic acid (TPA)-Fe single-molecule junctions is measured and a giant single-molecule tunneling anisotropic magnetoresistance (T-AMR) up to 53% is observed at room temperature. Theoretical calculations based on first-principles quantum simulations show that the observed AMR of Fe-TPA-Fe junctions originates from electronic coupling at the TPA-Fe interfaces modified by the magnetic orientation of the Fe electrodes with respect to the direction of current flow. The present study highlights new opportunities for obtaining detailed understanding of mechanisms of charge and spin transport in molecular junctions and the role of interfaces in determining the MR of single-molecule junctions.

A descriptive analysis of injury triage, surge of medical demand, and resource use in an university hospital after 8.12 Tianjin Port Explosion, China.

OBJECTIVE: The 8.12 Tianjin Port Explosion in 2015 caused heavy casualties. Pingjin Hospital, an affiliated college hospital in Tianjin, China participated in the rescue activities. This study aims to analyze the emergency medical response to this event and share experience with trauma physicians to optimize the use of medical resource and reduce mortality of critical patients. METHODS: As a trauma centre at the accident city, our hospital treated 298 patients. We retrospectively analyzed the data of emergency medical response, including injury triage, injury type, ICU patient flow, and medical resource use. RESULTS: There were totally 165 deaths, 8 missing, and 797 non-fatal injuries in this explosion. Our hospital treated 298 casualties in two surges of medical demand. The first one appeared at 1 h after explosion when 147 wounded were received and the second one at 4 h when 31 seriously injured patients were received, among whom 29 were transferred from Tianjin Emergency Center which was responsible for the scene injury triage. After reexamination and triage, only 11 cases were defined as critical ill patients. The over-triage rate reached as high as 62.07%. Seventeen patients underwent surgery and 17 patients were admitted to the intensive care unit. CONCLUSIONS: The present pre-hospital system is incomplete and may induce two surges of medical demand. The first one has a much larger number of casualties than predicted but the injury level is mild; while the second one has less wounded but almost all of them are critical patients. The over-triage rate is high. The hospital emergency response can be improved by an effective re-triage and implementation of a hospital-wide damage control.

MiR-15a-16 represses Cripto and inhibits NSCLC cell progression.

MicroRNAs (miRNAs) are small noncoding RNAs that have important roles in cancer. The altered expressions of miRNAs and their target genes are frequently detected in various tumors. In this study, downregulation of miR-15a-16 in nonsmall cell lung cancer (NSCLC) was found to be inversely correlated with Cripto. Results from the Luciferase reporter assay and Western blot analysis also confirmed that Cripto is a direct target of miR-15a-16. In addition, transfection of miR-15a-16 expression plasmid inhibited the invasion ability and promoted the apoptosis of NCI-H23 and NCI-H358 cells. Moreover, miR-15a-16 overexpression suppressed tumor growth in vivo. These findings clearly suggest that the downregulation of miR-15a-16 with Cripto amplification may be involved in the development of NSCLC.