Factor XII and prekallikrein promote microvascular inflammation and psoriasis in mice.

BACKGROUND AND PURPOSE: Psoriasis is an autoimmune inflammatory skin disease, featuring microvascular abnormalities and elevated levels of bradykinin. Contact activation of Factor XII can initiate the plasma kallikrein-kinin cascade, producing inflammation and angioedema. The role of Factor XII in psoriasis is unknown. EXPERIMENTAL APPROACH: The effects of deficiency of Factor XII or its enzymatic substrate, prekallikrein, were examined in the imiquimod-induced mouse model of psoriasis. Skin microcirculation was assessed using intravital confocal microscopy and laser Doppler flowmeter. A novel antibody blocking Factor XII activation was evaluated for psoriasis prevention. KEY RESULTS: Expression of Factor XII was markedly up-regulated in human and mouse psoriatic skin. Genetic deletion of Factor XII or prekallikrein, attenuated imiquimod-induced psoriatic lesions in mice. Psoriatic induction increased skin microvascular blood perfusion, causing vasodilation, hyperpermeability and angiogenesis. It also promoted neutrophil-vascular interaction, inflammatory cytokine release and enhanced Factor XII / prekallikrein enzymatic activity with elevated bradykinin. Factor XII or prekallikrein deficiency ameliorated these microvascular abnormalities and abolished bradykinin increase. Antagonism of bradykinin B2 receptors reproduced the microvascular protection of Factor XII / prekallikrein deficiency, attenuated psoriatic lesions, and prevented protection by Factor XII / prekallikrein deficiency against psoriasis. Furthermore, treatment of mice with Factor XII antibody alleviated experimentally induced psoriasis and suppressed microvascular inflammation. CONCLUSION AND IMPLICATIONS: Activation of Factor XII promoted psoriasis via prekallikrein-dependent formation of bradykinin, which critically mediated psoriatic microvascular inflammation. Inhibition of contact activation represents a novel therapeutic strategy for psoriasis.

Integrated toxicity of secondary, tertiary, wetland effluents on human stem cells triggered by ERα and PPARγ agonists.

Residual pollutants in discharged and reused water pose both direct and indirect human exposure. However, health effects caused by whole effluent remain largely unknown due to the lack of human relevant model for toxicity test. Effluents from four secondary wastewater treatment plants (SWTPs), a tertiary wastewater treatment plant (TWTP) and a constructed wetland (CW) were evaluated for the integrated toxicity of the organic extractions. Multiple-endpoint human mesenchymal stem cells (MSCs) assay was used as an in vitro model relevant to human health. The effluents caused cytotoxicity, oxidative stress and genotoxicity in MSCs. The osteogenic and neurogenic differentiation were inhibited and the adipogenic differentiation were stimulated by some of the effluent extractions. The SWTP, TWTP and CW treatments reduced integrated biomarker response (IBR) by 26.3 %, 17.5 % and 33.3 % respectively, where the IBR values of final CW (8.3) and TWTP (8.2) effluents were relatively lower than SWTPs (9.1). Among multiple biomarkers, the inhibition of osteogenesis was the least reduced by wastewater treatment. Besides, ozone disinfection in tertiary treatment increased cytotoxicity and differentiation effects suggesting the generation of toxic products. The mRNA expressions of estrogen receptor alpha (ERα) and peroxisome proliferator-activated receptor gamma (PPARγ) were significantly upregulated by effluents. The inhibitory effects of effluents on neural differentiation were mitigated after antagonizing ERα and PPARγ in the cells. It is suggested that ERα and PPARγ agonists in effluents were largely accountable for the impairment of stem cell differentiation. Besides, the concentrations of n-C29H60, o-cresol, fluorene and phenanthrene in the effluents were significantly correlated with the intergrated stem cell toxicity. The present study provided toxicological evidence for the relation between water contamination and human health, with an insight into the key toxicity drivers. The necessity for deep water treatment and the potential means were suggested for improving water quality.

Visit-to-visit HbA1c variability, dementia, and hippocampal atrophy among adults without diabetes.

OBJECTIVES: Adults without diabetes are not completely healthy; they are probably heterogeneous with several potential health problems. The management of hemoglobin A1c (HbA1c) is crucial among patients with diabetes; but whether similar management strategy is needed for adults without diabetes is unclear. Thus, this study aimed to investigate the associations of visit-to-visit HbA1c variability with incident dementia and hippocampal volume among middle-aged and older adults without diabetes, providing potential insights into this question. METHODS: We conducted a prospective analysis for incident dementia in 10,792 participants (mean age 58.9 years, 47.8 % men) from the UK Biobank. A subgroup of 3793 participants (mean age 57.8 years, 48.6 % men) was included in the analysis for hippocampal volume. We defined HbA1c variability as the difference in HbA1c divided by the mean HbA1c over the 2 sequential visits ([latter - former]/mean). Dementia was identified using hospital inpatient records with ICD-9 codes. T1-structural brain magnetic resonance imaging was conducted to derive hippocampal volume (normalized for head size). The nonlinear and linear associations were examined using restricted cubic spline (RCS) models, Cox regression models, and multiple linear regression models. RESULTS: During a mean follow-up (since the second round) of 8.4 years, 90 (0.8 %) participants developed dementia. The RCS models suggested no significant nonlinear associations of HbA1c variability with incident dementia and hippocampal volume, respectively (All P > 0.05). Above an optimal cutoff of HbA1c variability at 0.08, high HbA1c variability (increment in HbA1c) was associated with an increased risk of dementia (Hazard Ratio, 1.88; 95 % Confidence Interval, 1.13 to 3.14, P = 0.015), and lower hippocampal volume (coefficient, -96.84 mm3, P = 0.037), respectively, in models with adjustment of covariates including age, sex, etc. Similar results were found for a different cut-off of 0. A series of sensitivity analyses verified the robustness of the findings. CONCLUSIONS: Among middle-aged and older adults without diabetes, increasing visit-to-visit HbA1c variability was associated with an increased dementia risk and lower hippocampal volume. The findings highlight the importance of monitoring and controlling HbA1c fluctuation in apparently healthy adults without diabetes.

Inhibitory effects of ultrasonic and rosmarinic acid on lipid oxidation and lipoxygenase in large yellow croaker during cold storage.

Lipid oxidation will lead to the deterioration of flavor, color and texture of aquatic products with high fatty acid content. The mechanism of ultrasound (US) combined with rosmarinic acid (RA) on lipid oxidation and endogenous enzyme activities of large yellow croaker during cold-storage (4 ℃) was investigated. The result showed that the US and RA have synergistic effects in delaying lipid oxidation and inhibiting endogenous lipase and lipoxygenase (LOX) activities related to oxidation. The inhibition of LOX activity by RA was dose-dependent, and US showed a negative effect on the inhibition of enzyme activity in the presence of low concentration RA. Moreover, RA changes the enzyme structure through static fluorescence quenching and interaction with enzyme molecules. Hydrogen bonding and hydrophobic interaction are the main interaction forces between RA and LOX. This study could provide basic mechanism of US treatment cooperating with polyphenols to inhibit lipid oxidation during food preservation.

Low Dose of Deoxynivalenol Aggravates Intestinal Inflammation and Barrier Dysfunction Induced by Enterotoxigenic Escherichia coli Infection through Activating Macroautophagy/NLRP3 Inflammasomes.

The toxicity of deoxynivalenol (DON) in healthy humans and animals has been extensively studied. However, whether the natural-low-dose DON is scatheless under unhealthy conditions, especially intestinal injury, is unknown. Infection of enterotoxigenic Escherichia coli (ETEC) is a classical intestinal injury model. In this study, we explored the effects of low-dose DON on intestinal injury induced by the ETEC infection and the underlying mechanism in piglets, mice, and IPEC-J2 monolayer cells. Results showed that significant growth slowdown, severe diarrhea, and intestinal damage, bacterial multiplication, and translocation were observed in the experimental group (low-dose DON, 0.75 mg/kg in feed for piglets, and 1 mg/kg body weight for mice, combined with the ETEC infection). Meanwhile, more aggressive intestinal inflammation and barrier dysfunction were observed in animals and IPEC-J2 monolayer cells. Higher expression levels of NLRP3 inflammasome and LC3B were observed in jejunum and IPEC-J2 in the experimental group. After treatment with NLRP3 or caspase1 inhibitors, excessive intestinal inflammation rather than barrier dysfunction in the experimental group was limited. CRISPR-Cas9-mediated knockout of LC3B alleviated intestinal inflammation and barrier dysfunction and also inhibited NLRP3 inflammasome. In conclusion, a low dose of DON aggravates intestinal inflammation and barrier dysfunction induced by the ETEC infection by activating macroautophagy and NLRP3 inflammasome.

Recent developments in mesoporous polydopamine-derived nanoplatforms for cancer theranostics.

Polydopamine (PDA), which is derived from marine mussels, has excellent potential in early diagnosis of diseases and targeted drug delivery owing to its good biocompatibility, biodegradability, and photothermal conversion. However, when used as a solid nanoparticle, the application of traditional PDA is restricted because of the low drug-loading and encapsulation efficiencies of hydrophobic drugs. Nevertheless, the emergence of mesoporous materials broaden our horizon. Mesoporous polydopamine (MPDA) has the characteristics of a porous structure, simple preparation process, low cost, high specific surface area, high light-to-heat conversion efficiency, and excellent biocompatibility, and therefore has gained considerable interest. This review provides an overview of the preparation methods and the latest applications of MPDA-based nanodrug delivery systems (chemotherapy combined with radiotherapy, photothermal therapy combined with chemotherapy, photothermal therapy combined with immunotherapy, photothermal therapy combined with photodynamic/chemodynamic therapy, and cancer theranostics). This review is expected to shed light on the multi-strategy antitumor therapy applications of MPDA-based nanodrug delivery systems.

Aminode: Identification of Evolutionary Constraints in the Human Proteome.

Evolutionarily constrained regions (ECRs) are a hallmark for sites of critical importance for a protein's structure or function. ECRs can be inferred by comparing the amino acid sequences from multiple protein homologs in the context of the evolutionary relationships that link the analyzed proteins. The compilation and analysis of the datasets required to infer ECRs, however, are time consuming and require skills in coding and bioinformatics, which can limit the use of ECR analysis in the biomedical community. Here, we developed Aminode, a user-friendly webtool for the routine and rapid inference of ECRs. Aminode is pre-loaded with the results of the analysis of the whole human proteome compared with proteomes from 62 additional vertebrate species. Profiles of the relative rates of amino acid substitution and ECR maps of human proteins are available for immediate search and download on the Aminode website. Aminode can also be used for custom analyses of protein families of interest. Interestingly, mapping of known missense variants shows great enrichment of pathogenic variants and depletion of non-pathogenic variants in Aminode-generated ECRs, suggesting that ECR analysis may help evaluate the potential pathogenicity of variants of unknown significance. Aminode is freely available at http://www.aminode.org .

Effect of sulfate ions on growth and pollutants removal of self-flocculating microalga Chlorococcum sp. GD in synthetic municipal wastewater.

Sulfate is a primary sulfur source and can be available in wastewaters. Nevertheless, effect of sulfate ions on growth and pollutants removal of microalgae seems to be less investigated. At the present study, self-flocculating microalga Chlorococcum sp. GD was grown in synthetic municipal wastewater with different sulfate concentrations. Results indicated that Chlorococcum sp. GD grew better in synthetic municipal wastewater with 18, 45, 77, 136 and 271mg/L SO42- than in wastewater without SO42-. Chlorococcum sp. GD had also excellent removal efficiencies of nitrogen and phosphorus and effectively flocculated in sulfate wastewater. Sulfate deprivation weakened the growth, pollutants removal and self-flocculation of Chlorococcum sp. GD in wastewater. Antioxidative enzymes activity significantly increased and photosynthetic activity significantly decreased when Chlorococcum sp. GD was cultivated in sulfate-free wastewater. Sulfate deprivation probably reduced cell activity of growth, pollutants removal and flocculation via inducing the over-accumulation of reactive oxygen species (ROS).

A comparative study on flocculating ability and growth potential of two microalgae in simulated secondary effluent.

The flocculating ability was an important property to microalgal harvesting, especially in secondary effluent. In this study, the flocculating ability of two microalgae, Chlorococcum sp. GD and Parachlorella kessleri TY, was evaluated after 10d of cultivation in secondary effluent. After 180min of settling, the flocculating ability of Chlorococcum sp. GD and P. kessleri TY was 84.43% and 16.23%, respectively. It was suggested that Chlorococcum sp. GD was an excellent self-flocculating microalgae. The mechanism on self-flocculating of Chlorococcum sp. GD was probably related to hydrophobic extracellular polymeric substances (EPS). Besides, compared to P. kessleri TY, the nitrogen and phosphorus removal efficiency of Chlorococcum sp. GD was high, which was up to 66.51% and 74.19%, respectively. Chlorococcum sp. GD also had high lipid content and biomass concentration. Therefore, Chlorococcum sp. GD could be regarded as a promising candidate for microalgal cultivation and harvesting in secondary effluent.

Development of adaptive pneumatic tourniquet systems based on minimal inflation pressure for upper limb surgeries.

BACKGROUND: Pneumatic tourniquets are medical devices that occlude blood flow to distal part of extremities and are commonly used in upper limb surgeries to provide a dry, clean and bloodless field. To decrease pressure-related injuries and potential risk of complications subjected to the high inflation pressure of pneumatic tourniquet, minimal inflation pressures are recommended. METHODS: A new occlusion pressure mathematical model for the upper limb was established based on the correlation analysis between several possible influencing parameters and the minimal pneumatic tourniquet pressure at which the peripheral pulse disappeared was recorded using a digital plethysmograph. A prototype of an adaptive pneumatic tourniquet which automatically varies the pressure in the tourniquet cuff according to the above prediction model was developed for the upper limb which used the lowest possible inflation pressure to achieve occlusion. The prototype comprises a blood pressure monitoring module, an inflatable tourniquet cuff, and a pressure relief mechanism to maintain an optimal cuff inflation pressure. Simulation experiments were conducted to verify the function and stability of the designed adaptive pneumatic tourniquet and clinical experiments using volunteers were undertaken to evaluate the performance of the prototype design in achieving adequate haemostasis in the upper limb. RESULTS: Results demonstrated that the mean arterial occlusion pressure was 152.3 ± 16.7 mmHg, obviously below the 250 to 300 mmHg previously recommended (J Bone Joint Surg Br 68:625-628, 1986 and Arthroscopy 11:307-311, 1995). CONCLUSIONS: In conclusion, this adaptive method and apparatus which can provide minimal inflation pressure may be a clinically practical alternative for upper limb surgery performed with pneumatic tourniquets.

[Development of an adaptive pneumatic tourniquet].

A new adaptive pneumatic tourniquet was developed for limb operation and first-aid. The crucial hardware circuits of the adaptive pneumatic tourniquet were designed based on the microprocessor C8051F340 and blood pressure module CSN602, software was programmed and an experiment was carried out for verifying the system. Results showed that the prototype could measure accurately systolic blood pressure, heart rate and other relative parameters and the designed device could adjust tourniquet cuff's pressure through inflation and deflation according to systolic blood pressure and limb circumference. This designed system integrated the advantages of the adaptive pneumatic tourniquet, and could be used for controlling life-threatening extremity hemorrhage operation and maintaining a bloodless opeation field.

[Development of an automatic pneumatic tourniquet system that determines pressures in synchrony with systolic blood pressure].

The correlation coefficients between arterial occlusion pressure and systolic blood pressure, diastolic blood pressure, limb circumference, body mass etc were obtained through healthy volunteer experiments, in which tourniquet were applied on upper/lower extremities. The prediction equations were derived from the data of experiments by multiple regression analysis. Based on the microprocessor C8051F340, a new pneumatic tourniquet system that can determine tourniquet pressure in synchrony with systolic blood pressure was developed and verified the function and stability of designed system. Results showed that the pneumatic tourniquet which automatically adjusts occlusion pressure in accordance with systolic blood pressure could stop the flow of blood to get a bloodless field.

Evaluation of emergency tourniquets for prehospital use in China.

OBJECTIVE: Massive hemorrhage is life-threatening during armed conflicts. Tourniquets are important medical devices used to reduce severe bleeding in trauma. The aim of this study was to empirically evaluate the current tourniquets used in China and provide information to emergency nurses in selecting the appropriate tourniquet. METHODS: Five tourniquets were self-applied by 20 healthy participants. The blood flow distal to the tourniquet site was assessed using vascular Doppler ultrasound. Application time, pain, numbness, and other parameters were evaluated. RESULTS: The bladder tourniquet and windlass tourniquet effectively occluded arterial blood flow with success rates higher than 75% in both the upper and lower extremities. The Cargo-strap was the fastest to apply, taking (7.22+/-2.30) s for the upper extremity and (6.48+/-2.40) s for the lower extremity. The rubber tube was the most painful, and the improvised tourniquet was the least efficient. The success rates were higher in the lower extremity than in the upper extremity (P less than 0.05, X(2) equal to 5.714). CONCLUSIONS: The bladder tourniquet and the windlass tourniquet are efficient tourniquets, although the windlass is superior with respect to portability and pain. The Cargo-strap and rubber tourniquets have several disadvantages that reduce their suitability for field use. The improvised tourniquet is not recommended because of low efficiency and severe pain during implementation.

Morphological evolution and ordered quantum structure formation in heteroepitaxial core--shell nanowires.

We have performed three-dimensional dynamic simulations to study strain-driven morphological evolution and the formation of quantum structures on heteroepitaxial core--shell nanowire surfaces. Our simulations show that depending on geometric and material parameters, such as the radius of the wire, the thickness of the shell, and the mismatch strain, various surface morphologies including smooth core--shell nanowire surfaces, nanoring arrays, nanowire arrays, and ordered quantum dot arrays can be obtained by controlling initial surface configurations through prepatterning. It is also shown that these quantum structures may be trapped in a metastable state and may undergo a series of metastable state transitions during subsequent dynamic evolution. Our results identify possible pathways for fabrication of ordered quantum structures on the epitaxial core--shell nanowire surfaces and provide guidelines for achieving smooth core--shell structures.