Enhanced Prediction of Malignant Cerebral Edema in Large Vessel Occlusion with Successful Recanalization Through Automated Weighted Net Water Uptake.

BACKGROUND: Malignant cerebral edema (MCE) is associated with both net water uptake (NWU) and infarct volume. We hypothesized that NWU weighted by the affected Alberta Stroke Program Early Computed Tomography Score (ASPECTS) regions could serve as a quantitative imaging biomarker of aggravated edema development in acute ischemic stroke with large vessel occlusion (LVO). The aim of this study was to evaluate the performance of weighted NWU (wNWU) to predict MCE in patients with mechanical thrombectomy (MT). METHODS: We retrospectively analyzed consecutive patients who underwent MT due to LVO. NWU was computed from nonenhanced computed tomography scans upon admission using automated ASPECTS software. wNWU was derived by multiplying NWU with the number of affected ASPECTS regions in the ischemic hemisphere. Predictors of MCE were assessed through multivariate logistic regression analysis and receiver operating characteristic curves. RESULTS: NWU and wNWU were significantly higher in MCE patients than in non-MCE patients. Vessel recanalization status influenced the performance of wNWU in predicting MCE. In patients with successful recanalization, wNWU was an independent predictor of MCE (adjusted odds ratio 1.61; 95% confidence interval [CI] 1.24-2.09; P < 0.001). The model integrating wNWU, National Institutes of Health Stroke Scale, and collateral score exhibited an excellent performance in predicting MCE (area under the curve 0.80; 95% CI 0.75-0.84). Among patients with unsuccessful recanalization, wNWU did not influence the development of MCE (adjusted odds ratio 0.99; 95% CI 0.60-1.62; P = 0.953). CONCLUSIONS: This study revealed that wNWU at admission can serve as a quantitative predictor of MCE in LVO with successful recanalization after MT and may contribute to the decision for early intervention.

Simulation study on creep deformation of the impeller in lead-bismuth eutectic environment through fluid-solid coupling method.

Lead-based reactor is a new type of reactor using liquid lead or lead-bismuth alloy as a coolant. As the core working element of the main pump, the impeller is subjected to a huge load when conveying heavy metal liquids and is highly susceptible to damage. In this study, we used ANSYS and FLUENT software to investigate the stress, deformation, and creep deformation of the nuclear main pump impeller under a liquid lead-bismuth environment by the fluid-solid coupling method. The maximum equivalent force of the impeller was located at the junction of the blade and hub, which was prone to fatigue damage under the action of alternating load. The stress, deformation, and creep characteristics of the impeller blade were observed to generally increase with rotational speed. Particularly, the junction of the blade root and hub exhibited high susceptibility to stress concentration and fatigue damage. At a flow rate of 0.64 m/s and a speed of 690 r/min, the maximum equivalent force was 16.7 MPa, which was lower than the yield strength of 316L stainless steel. Additionally, the maximum deformation was less than 0.63 mm. Over a five-year period, the creep of the impeller ranged from a minimum of 0.228% to a maximum of 0.447%, indicating that the impeller can reliably operate in a liquid lead-bismuth environment for at least five years.

Multidimensional Interactive Cascading Nanochips for Detection of Multiple Liver Diseases via Precise Metabolite Profiling.

It is challenging to detect and differentiate multiple diseases with high complexity/similarity from the same organ. Metabolic analysis based on nanomatrix-assisted laser desorption/ionization mass spectrometry (NMALDI-MS) is a promising platform for disease diagnosis, while the enhanced property of its core nanomatrix materials has plenty of room for improvement. Herein, a multidimensional interactive cascade nanochip composed of iron oxide nanoparticles (FeNPs)/MXene/gold nanoparticles (AuNPs), IMG, is reported for serum metabolic profiling to achieve high-throughput detection of multiple liver diseases. MXene serves as a multi-binding site and an electron-hole source for ionization during NMALDI-MS analysis. Introduction of AuNPs with surface plasmon resonance (SPR) properties facilitates surface charge accumulation and rapid energy conversion. FeNPs are integrated into the MXene/Au nanocomposite to sharply reduce the thermal conductivity of the nanochip with negligible heat loss for strong thermally-driven desorption, and construct a multi-interaction proton transport pathway with MXene and AuNPs for strong ionization. Analysis of these enhanced serum fingerprint signals detected from the IMG nanochip through a neural network model results in differentiation of multiple liver diseases via a single pass and revelation of potential metabolic biomarkers. The promising method can rapidly and accurately screen various liver diseases, thus allowing timely treatment of liver diseases.

Molecular Dynamic Simulation and Experiment Validation on the Diffusion Behavior of Diffusion Welded Fe-Ti by Hot Isostatic Pressing Process.

A reliable bonding interface between steel and Ti alloy is required for producing a steel/Ti bimetal composite. In this study, molecular dynamic simulations and diffusion welding experiments using the hot isostatic pressing process were conducted to study the atomic diffusion at the Fe-Ti interface. The simulation results indicate that the diffusion layer thickness is thinner in single crystals compared to polycrystals at the same temperature. This difference may be explained by polycrystals having grain boundaries, which increase atomic disorder and facilitate diffusion. The radial distribution function (RDF) curves for Fe-Fe and Ti-Ti exhibit a similar pattern over time, with a main peak indicating the highest atom density within a specific radius range and relatively strong binding between the central atoms and their nearest neighbors. The observed changes in the diffusion coefficient with temperature in the simulations align well with the experimental results. This study enhances the understanding of Fe-Ti interface diffusion mechanism and provides valuable insights for broader applications of steel/Ti bimetal composites.

Core-Shell Structure Design of Hollow Mesoporous Silica Nanospheres Based on Thermo-Sensitive PNIPAM and pH-Responsive Catechol-Fe3+ Complex.

A kind of core-shell hybrid nanoparticle comprised of a hollow mesoporous silica nanoparticles (HMS) core and a copolymer shell bearing N-(3,4-dihydroxyphenethyl) methacrylamide (DMA) and N-isopropylacrylamide (NIPAM) as responsive moieties was prepared. Moreover, the factors that could impact the surface morphology and hierarchical porous structure were discussed. In the presence of Fe3+, catechol-Fe3+ complexes were formed to achieve pH-responsive polymer shell, combining with thermal-sensitiveness of poly(N-isopropylacrylamide). Doxorubicin (DOX) was applied as a model drug and the behaviors of its loading/release behaviors were investigated to prove the idea. The results exhibited a significant drug loading capacity of 8.6% and embed efficiency of 94.6% under 1 mg ml-1 DOX/PBS solution. In fact, the loading capacity of drug can be easily improved to as high as 28.0% by increasing the DOX concentration. The vitro cytotoxicity assay also indicated that the as-prepared nanoparticles have no significant cytotoxicity on RAW 264.7 cells. The in vitro experiment showed that the cumulative release of DOX was obviously dependent on the temperature and pH values. This pH/temperature-sensitive hollow mesoporous silica nanosphere is expected to have potential applications in controlled drug release.

Synthesis, nematocidal activity and SAR study of novel difluoromethylpyrazole carboxamide derivatives containing flexible alkyl chain moieties.

A series of novel difluoromethylpyrazole carboxamides derivatives were synthesized by introduction of flexible alkyl chain. Nematicidal bioassay results showed that some of them exhibited good control efficacy against M. incognita, which indicated that these difluoromethylpyrazole carboxamides derivatives might be potential novel lead compounds for discovery new nematicides. The nematicidal activity was affected by the substituted position in the molecule, especially the substitution group on the alkyl chain. It was found that the compound 6-9 and 6-23 possess about 50% inhibition effect against M. incognita even at 5.0 and 1.0 mg L-1. Meanwhile, greenhouse field trial showed the nematicidal activity of compound 6-9 is a litter weaker than that of Abamectin. The mammalian toxicology results indicated that compound 6-9 was a low-toxicity and low-sensitive compound. In conclusion compound 6-9 is a potential candidate for further development. In addition, the molecular docking simulations revealed that compounds 6 with a flexible NHCOO show its binding affinities for the acetylcholine receptor (AChR), which may provide useful information for further design novel nematicides.

Synthesis, nematocidal activity and docking study of novel chiral 1-(3-chloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives.

A series of novel chiral fluorinated pyrazole carboxamides derivatives were designed and synthesized. All these title compounds were confirmed by NMR and MS. The primarily nematocidal activity results indicated that some of them exhibited good control efficacy against the tomato root-knot nematode disease caused by Meloidogyne incognita. The docking results indicated that compound 5n interact with amino acid residue Tyr 121, Trp 279 of AchE via hydrogen bond.

The hepatitis B virus e antigen suppresses the respiratory burst and mobility of human monocytes and neutrophils.

The Hepatitis B virus (HBV) e antigen (HBeAg) is a secretory, non-structural protein, and associated with persistent infection of HBV. Previous studies indicate that HBeAg is able to regulate T cell-mediated responses, however, the interaction between HBeAg and the innate immune system is poorly understood. In this study, we demonstrated that recombinant HBeAg (rHBe) bound to human peripheral blood monocytes, neutrophils, and B lymphocytes but not to T lymphocytes. We focused on investigating the effects of HBeAg on monocytes and neutrophils and found that rHBe decreased the respiratory burst in both types of cells. Furthermore, we observed that cell migration in monocytes and neutrophils was suppressed by rHBe in a transwell assay. The attenuation of rHBe was not caused by a general cytotoxic effect because rHBe treatment stimulated low levels of cytokine and chemokine production by monocytes and it promoted neutrophil survival. Since the recruitment of monocytes and neutrophils to the infected site is crucial for the initiation of inflammation, HBeAg may modulate innate immune responses by diminishing the respiratory burst and migration of monocytes and neutrophils, which might interfere with the subsequent innate and adaptive immune responses against HBV, leading to the establishment of chronic infection.

Hepatitis D virus isolates with low replication and epithelial-mesenchymal transition-inducing activity are associated with disease remission.

Clearance of hepatitis D virus (HDV) viremia leads to disease remission. Large hepatitis delta antigen (L-HDAg) has been reported to activate transforming growth factor ß, which may induce epithelial-mesenchymal transition (EMT) and fibrogenesis. This study analyzed serum HDV RNA "quasispecies" in HDV-infected patients at two stages of infection: before and after alanine aminotransferase (ALT) elevations. Included in the study were four patients who went into remission after ALT elevation and three patients who did not go into remission and progressed to cirrhosis or hepatocellular carcinoma. Full-length HDV cDNA clones were obtained from the most abundant HDV RNA species at the pre- and post-ALT elevation stages. Using an in vitro model consisting of Huh-7 cells transfected with cloned HDV cDNAs, the pre- or post-ALT elevation dominant HDV RNA species were characterized for (i) their replication capacity by measuring HDV RNA and HDAg levels in transfected cells and (ii) their capacity to induce EMT by measuring the levels of the mesenchymal-cell-specific protein vimentin, the EMT regulators twist and snail, and the epithelial-cell-specific protein E-cadherin. Results show that in patients in remission, the post-ALT elevation dominant HDV RNA species had a lower replication capacity in vitro and lower EMT activity than their pre-ALT elevation counterparts. This was not true of patients who did not go into remission. The expression of L-HDAg, but not small HDAg, increased the expression of the EMT-related proteins. It is concluded that in chronically infected patients, HDV quasispecies with a low replication capacity and low EMT activity are associated with disease remission.

Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma.

UNLABELLED: The epithelial-mesenchymal transition (EMT) is critical for induction of invasiveness and metastasis of human cancers. In this study we investigated the expression profiles of the EMT markers, the relationship between EMT markers and patient/tumor/viral factors, and the interplay between major EMT regulators in human hepatocellular carcinoma (HCC). Reduced E-cadherin and nonmembranous beta-catenin expression, the hallmarks of EMT, were shown in 60.2% and 51.5% of primary HCC samples, respectively. Overexpression of Snail, Twist, or Slug, the major regulators of EMT, was identified in 56.9%, 43.1%, and 51.4% of primary HCCs, respectively. Statistical analysis determined that Snail and Twist, but not Slug, are major EMT inducers in HCC: overexpression of Snail and/or Twist correlated with down-regulation of E-cadherin, nonmembranous expression of beta-catenin, and a worse prognosis. In contrast, there were no such significant differences in samples that overexpressed Slug. Coexpression of Snail and Twist correlated with the worst prognosis of HCC. Hepatitis C-associated HCC was significantly correlated with Twist overexpression. HCC cell lines with increased Snail and Twist expression (e.g., Mahlavu) exhibited a greater capacity for invasiveness/metastasis than cells with low endogenous Twist/Snail expression (e.g., Huh-7). Overexpression of Snail or/and Twist in Huh-7 induced EMT and invasiveness/metastasis, whereas knockdown of Twist or Snail in Mahlavu reversed EMT and inhibited invasiveness/metastasis. Twist and Snail were independently regulated, but exerted an additive inhibitory effect to suppress E-cadherin transcription. CONCLUSION: Our study provides a comprehensive profile of EMT markers in HCC, and the independent and collaborative effects of Snail and Twist on HCC metastasis were confirmed through different assays.

Generation of cytotoxicity against hepatitis delta virus genotypes and quasispecies by epitope modification.

BACKGROUND/AIMS: Quasispecies are likely responsible for virus escape from host immune surveillance. The aim of this study was to enhance the immune response against varied sequences within the HDV quasispecies in an attempt to control chronic delta hepatitis. METHODS: The HLA-A2 restricted peptides spanning aa 43-51 of HDAg and three variant peptides bearing single amino acid substitutions were synthesized. Their immunogenicity and capacity to induce effective CTL responses were studied in HHD-2 mice. RESULTS: Native HDV epitope produced limited cytotoxic immune response. Two modified HDV peptides (HDV 43-51 1Y; tyrosine substitution in positive 1, and 43-51 3A; alanine substitution in position 3) could enhance not only the binding affinity with HLA-A2.1 molecules but also the immunogenicity. Ex vivo interferon-gamma ELISPOT and CTL assays revealed that the two modified epitopes-induced CTLs had a higher functional avidity and produced stronger cytotoxicity to lyse constitutively HDAg-expressing Hep-G2 cells. Interestingly, the spectrums of the T cell receptor (TCR) cross-reactivity are broadened and response to multiple HDV variants by the enhanced epitopes immunization. CONCLUSIONS: The modified HDV peptides can enhance the immunogenicity and the induced CTLs can cross-react with multiple HDV variants. Combination with the two enhanced epitopes might be a potential immunotherapeutic agent to control HDV quasispecies in HLA-A2 chronic hepatitis D patients.

Hepatitis B surface antigen levels and sequences of natural hepatitis B virus variants influence the assembly and secretion of hepatitis d virus.

Various domains of hepatitis B surface antigen (HBsAg) are essential for the assembly and secretion of hepatitis D virus (HDV). This study investigated the influences of the levels and sequences of HBsAg of naturally occurring HBV variants on the assembly and secretion of HDV. Six hepatitis B virus (HBV)-producing plasmids (three genotype B and three genotype C) and six HBsAg expression plasmids that expressed various HBsAg levels were constructed from the sera of HDV-infected patients. These plasmids were cotransfected with six expression plasmids of HDV of genotype 1, 2, or 4 into the Huh-7 hepatoma cell line. Serum HBsAg and HBV DNA levels were correlated with HDV RNA levels and outcomes of chronic hepatitis D (CHD) patients. The secretion of genotype 1, 2, or 4 HDV generally correlated with HBsAg levels but not with HBV genotypes or HBV DNA levels. Swapping and residue mutagenesis experiments of HBsAg-coding sequences revealed that the residue Pro-62 in the cytosolic domain-I affects the assembly and secretion of genotype 2 and 4 HDV and not those of genotype 1. The pre-S2 N-terminal deletion HBV mutant adversely affects secretion of the three HDV genotypes. In patients, serum HDV RNA levels correlated with HBsAg levels but not with HBV DNA levels. Viremia of HDV or HBV correlated with poor outcomes. In conclusion, the assembly and secretion of HDV were influenced by the amounts and sequences of HBsAg. For an effective treatment of CHD, reduction of HBsAg production in addition to the suppression of HBV and HDV replication might be crucial.