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Abstract Background Constipation is one of the most common gastrointestinal disorders afflicting the population, with recent observational studies implicating dysfunction of the gut microbiota in constipation. Despite observational studies indicating a relationship, a clear causality remains unclear. This study aims to use two-sample Mendelian randomization (MR) to establish a clearer causal relationship between the two. Methods A two-sample Mendelian randomization (MR) study was performed using the gut microbiota summary Genome-Wide Association Studies (GWAS) statistics from MiBioGen consortium (n = 13,266) and constipation GWAS summary statistics from the IEU OpenGWAS database. The causality between gut microbiota and constipation is primarily analyzed using the inverse-variance weighted (IVW) method and reinforced by an additional four methods, including MR-Egger, Weighted Median, Simple Mode, and Weighted Mode. Finally, funnel plot, heterogeneity test, horizontal pleiotropy test, and leave-one-out test were used to evaluate the reliability of MR results. Results IVW estimates suggested that the bacterial species Anaerotruncus, Butyricimonas, and Hungatella were causally associated with constipation. The odds ratio (OR) values of Anaerotruncus, Butyricimonas, and Hungatella were 1.08 (95% CI = 1.02–1.13; P = 0.007), 1.07 (95% CI = 1.01–1.13; P = 0.015), 1.03 (95% CI = 1.00-1.06; P = 0.037) respectively. Meanwhile, Ruminiclostridium 9 and Intestinibacter have been shown to be associated with a reduced risk of constipation. The OR of Ruminiclostridium 9 = 0.75(95% CI = 0.73–0.78, P

Background: Glioblastoma (GBM) poses a significant medical challenge due to its aggressive nature and poor prognosis. Mitochondrial unfolded protein response (UPRmt) and the heat shock factor 1 (HSF1) pathway play crucial roles in GBM pathogenesis. Post-translational modifications, such as SUMOylation, regulate the mechanism of action of HSF1 and may influence the progression of GBM. Understanding the interplay between SUMOylation-modified HSF1 and GBM pathophysiology is essential for developing targeted therapies. Methods: We conducted a comprehensive investigation using cellular, molecular, and in vivo techniques. Cell culture experiments involved establishing stable cell lines, protein extraction, Western blotting, co-immunoprecipitation, and immunofluorescence analysis. Mass spectrometry was utilized for protein interaction studies. Computational modeling techniques were employed for protein structure analysis. Plasmid construction and lentiviral transfection facilitated the manipulation of HSF1 SUMOylation. In vivo studies employed xenograft models for tumor growth assessment. Results: Our research findings indicate that HSF1 primarily undergoes SUMOylation at the lysine residue K298, enhancing its nuclear translocation, stability, and downstream heat shock protein expression, while having no effect on its trimer conformation. SUMOylated HSF1 promoted the UPRmt pathway, leading to increased GBM cell proliferation, migration, invasion, and reduced apoptosis. In vivo studies have confirmed that SUMOylation of HSF1 enhances its oncogenic effect in promoting tumor growth in GBM xenograft models. Conclusion: This study elucidates the significance of SUMOylation modification of HSF1 in driving GBM progression. Targeting SUMOylated HSF1 may offer a novel therapeutic approach for GBM treatment. Further investigation into the specific molecular mechanisms influenced by SUMOylated HSF1 is warranted for the development of effective targeted therapies to improve outcomes for GBM patients.

Abstract Background SP gene family, consisting of SP100, SP110, SP140, and SP140L, has been implicated in the initiation and advancement of numerous malignancies. Nevertheless, their clinical significance in glioma remains incompletely understood. Method Expression levels and prognostic significance of SP family members were evaluated in the TCGA and CGGA datasets. Multifactorial analysis was used to identify SP gene family members that can independently impact the prognosis of glioma patients. A SP140‐based predictive risk model/nomogram was developed in TCGA dataset and validated in CGGA dataset. The model's performance was evaluated through receiver operating characteristic (ROC) curves, calibration plots, and decision curve analyses. Phenotypic associations of SP140 and TRIM22 were examined through CancerSEA and TIMER. The effect of SP140 inhibitor in glioma progress and TRIM22/PI3K/AKT signaling pathway was confirmed in U251/U87 glioma cells. Results The SP family members exhibited elevated expression in gliomas and were negatively correlated with prognosis. SP140 emerged as an independent prognostic factor, and a SP140‐based nomogram/predictive risk model demonstrated high accuracy. SP140 inhibitor, GSK761, lead to the suppression of TRIM22 expression and the PI3K/AKT signaling pathway. GSK761 also restrain glioma proliferation, migration, and invasion. Furthermore, SP140 and TRIM22 coexpressed in glioma cells with high level of vascular proliferation, TRIM22 is closely associated with the immune cell infiltration. Conclusion SP140‐based nomogram proved to be a practical tool for predicting the survival of glioma patients. SP140 inhibitor could suppress glioma progress via TRIM22/PI3K/AKT signaling pathway.

To analyze the dynamic response of a rigid M-shaped jumper subjected to combined internal and external flows, a one-way coupled fluid–structure interaction process is applied. First, CFD simulations are conducted separately for the internal and external fluid domains. The pressure histories on the inner and outer walls are exported and loaded into the finite element model using inverse distance interpolation. Then, FEA is performed to determine the dynamic response, followed by a fatigue assessment based on the obtained stress data. The displacement, acceleration, and stress distribution along the M-shaped jumper are obtained. External flow velocity dominates the displacements, while internal flow velocity dominates the vibrations and stresses. The structural response to the combined effect of internal and external flows, plus the response to gravity alone, equals the sum of the structural responses to internal flow alone and external flow alone. Fatigue damage is calculated for the bend exhibiting the most intense vibration and higher stress levels, and the locations with significant damage correspond to areas with high maximum von Mises stress. This paper aims to evaluate multiple flow fields acting simultaneously on subsea pipelines and to identify the main factors that provide valuable information for their design, monitoring, and maintenance.

BackgroundRecombinant Schistosoma mansoni Tetraspanin-2 formulated on Alhydrogel (Sm-TSP-2/Alhydrogel) is being developed to prevent intestinal and hepatic disease caused by S. mansoni. The tegumentary Sm-TSP-2 antigen was selected based on its unique recognition by cytophilic antibodies in putatively immune individuals living in areas of ongoing S. mansoni transmission in Brazil, and preclinical studies in which vaccination with Sm-TSP-2 protected mice following infection challenge.MethodsA randomized, observer-blind, controlled, Phase 1b clinical trial was conducted in 60 healthy adults living in a region of Brazil with ongoing S. mansoni transmission. In each cohort of 20 participants, 16 were randomized to receive one of two formulations of Sm-TSP-2 vaccine (adjuvanted with Alhydrogel only, or with Alhydrogel plus the Toll-like receptor-4 agonist, AP 10-701), and 4 to receive Euvax B hepatitis B vaccine. Successively higher doses of antigen (10 μg, 30 μg, and 100 μg) were administered in a dose-escalation fashion, with progression to the next dose cohort being dependent upon evaluation of 7-day safety data after all participants in the preceding cohort had received their first dose of vaccine. Each participant received 3 intramuscular injections of study product at intervals of 2 months and was followed for 12 months after the third vaccination. IgG and IgG subclass antibody responses to Sm-TSP-2 were measured by qualified indirect ELISAs at pre- and post-vaccination time points through the final study visit.ResultsSm-TSP-2/Alhydrogel administered with or without AP 10-701 was well-tolerated in this population. The most common solicited adverse events were mild injection site tenderness and pain, and mild headache. No vaccine-related serious adverse events or adverse events of special interest were observed. Groups administered Sm-TSP-2/Alhydrogel with AP 10-701 had higher post-vaccination levels of antigen-specific IgG antibody. A significant dose-response relationship was seen in those administered Sm-TSP-2/Alhydrogel with AP 10-701. Peak anti-Sm-TSP-2 IgG levels were observed approximately 2 weeks following the third dose, regardless of Sm-TSP-2 formulation. IgG levels fell to low levels by Day 478 in all groups except the 100 μg with AP 10-701 group, in which 57% of subjects (4 of 7) still had IgG levels that were ≥4-fold higher than baseline. IgG subclass levels mirrored those of total IgG, with IgG1 being the predominant subclass response.ConclusionsVaccination of adults with Sm-TSP-2/Alhydrogel in an area of ongoing S. mansoni transmission was safe, minimally reactogenic, and elicited significant IgG and IgG subclass responses against the vaccine antigen. These promising results have led to initiation of a Phase 2 clinical trial of this vaccine in an endemic region of Uganda.Trial registrationNCT03110757.

Abstract Background Glabridin (Glab) is a bioactive component of licorice that can ameliorate diabetes, but its role in diabetic nephropathy (DN) has seldom been reported. Herein, we explored the effect and underlying mechanism of Glab on DN. Methods The bioactive component-target network of licorice against DN was by a network pharmacology approach. The protective effect of Glab on the kidney was investigated by a high-fat diet with streptozotocin induced-diabetic rat model. High glucose-induced NRK-52E cells were used for in vitro studies. The effects of Glab on ferroptosis and VEGF/Akt/ERK pathways in DN were investigated in vivo and in vitro using qRT-PCR, WB, and IHC experiments. Results Bioinformatics analysis constructed a network comprising of 10 bioactive components of licorice and 40 targets for DN. 13 matching targets of Glab were mainly involved in the VEGF signaling pathway. Glab treatment ameliorated general states and reduced FBG, HOMA-β, and HOMA-insulin index of diabetic rats. The renal pathological changes and the impaired renal function (the increased levels of Scr, BUN, UREA, KIM-1, NGAL, and TIMP-1) were also improved by Glab. Moreover, Glab repressed ferroptosis by increasing SOD and GSH activity, and GPX4, SLC7A11, and SLC3A2 expression, and decreasing MDA and iron concentrations, and TFR1 expression, in vivo and in vitro. Mechanically, Glab significantly suppressed VEGF, p-AKT, p-ERK1/2 expression in both diabetic rats and HG-induced NRK-52E cells. Conclusions This study revealed protective effects of Glab on the kidney of diabetic rats, which might exert by suppressing ferroptosis and the VEGF/Akt/ERK pathway.

Basalt fiber (BF) is deemed a new environmentally friendly and high-performance fiber material due to its high strength, electrical insulation, corrosion resistance and high temperature resistance. Yet, the surface inertness restricts its practical application. In this work, the BF was irradiated and activated by electron beam, followed by in situ growth of SiO2 using a hydrothermal method, then composites with polypropylene (PP) were prepared by microinjection molding. According to the results of scanning electron microscopy (SEM) and Fourier transform infrared (FTIR), more active sites can be formed after irradiation, thus more SiO2 nanoparticles were generated on the surface of BF. Consequently, the rough surface of modified BF could provide stronger shear force during melt processing and resulted in a higher orientation of the molecular chains, increasing the lamellar thickness and generating more highly ordered β crystals in the composites. I400BF-gSiO2 exhibited the highest content of β crystals with the crystallinity of 53.62% and orientation of β (300) crystal plane of 0.91, which were 8.66% and 0.04 higher than those of the composite with pristine BF. Furthermore, due to the perfection of crystals, increased interfaces and interfacial interlocking between PP molecules and modified BF, I400BF-gSiO2 showed good overall performance, with storage modulus of 8000 MPa at −100 °C, glass transition temperature of 23.03 °C and tensile strength of 62.2 MPa, which was 1900 MPa, 1.23 °C and 29.6 MPa higher than neat PP. Hence, the surface roughing strategy proposed in this work is expected to provide some insight and promote the application of BF reinforced thermoplastic composites.

BackgroundThe outbreak of the highly infectious coronavirus disease 2019 (COVID-19) renders a huge physical and psychological risk to the public, especially to the medics. Additionally, self-leadership has proven to improve self-efficacy and mediate tension, such as nervousness and depression. Therefore, a cross-sectional survey was conducted to explore the association of self-leadership with acute stress responses (ASRs) and acute stress disorders (ASDs) in medics during the COVID-19 epidemic.MethodsSelf-reported online questionnaires were administered, and 627 participants were finally included. The data were analyzed using the univariate analysis and the logistical regression model to identify whether self-leadership and sociodemographic and epidemic characteristics were associated with mental health, including ASRs and ASDs.ResultsInitially, 790 medics responded. Of these, 627 remained after excluding for invalid questionnaires and those with a substantial amount of missing data. Therefore, the participation validity rate was 79.37%. Frontline medical staff (β = 0.338; p < 0.001), possibility of infection among people around the medic being mild (β = 0.141; p < 0.001), subjective estimation of epidemic duration being 3–6 months (β = 0.074; p < 0.05), self-sets (β = −0.022; p < 0.001), self-punishment (β = 0.229; p < 0.001), belief hypothesis and evaluation (β = −0.147; p < 0.05), and successful foresight (β = 0.105; p < 0.05) were statistically significant with ASRs. Marital status [adjusted odds ratio (AOR) =1.813; 95% CI (1.141, 2.881); p = 0.012], being a frontline worker [AOR = 25.760; 95% CI (14.220, 46.667); p < 0.001], visiting Hubei in the previous 14 days [AOR = 3.656; 95% CI (1.500, 8.911); p = 0.004], self-punishment [AOR = 1.352; 95% CI (1.180, 1.548); p < 0.001], and self-dialogue [AOR = 1.256; 95% CI (11.063, 1.483); p = 0.007] were the risk factors for ASD. Conversely, having frontline medical staff in one's family [AOR = 0.523; 95% CI (0.297, 0.923); p = 0.025], self-sets [AOR = 0.814; 95% CI (0.715, 0.826); p = 0.002], and belief hypothesis and evaluation [AOR = 0.796; 95% CI (0.672, 0.943); p = 0.038] were the protective factors.ConclusionThe special working environment of the COVID-19 epidemic resulted in ASR and ASD. Notably, findings revealed a positive association between ASR symptoms and frontline medical staff, the subjective estimation of epidemic duration, self-punishment, and successful foresight. Nevertheless, marital status, having visited Hubei in the previous 14 days, and self-dialogue were the risk factors accounting for ASD symptoms. Surprisingly, having frontline medical staff in one's family, self-sets, and belief hypothesis and evaluation had potential benefits for ASD symptoms.

Ecological preferences and life history strategies have enormous impacts on the evolution and phenotypic diversity of salamanders, but the yet established reliable ecological indicators from bony skeletons hinder investigations into the paleobiology of early salamanders. Here, we statistically demonstrate by using time-calibrated cladograms and geometric morphometric analysis on 71 specimens in 36 species, that both the shape of the palate and many non-shape covariates particularly associated with vomerine teeth are ecologically informative in early stem- and basal crown-group salamanders. Disparity patterns within the morphospace of the palate in ecological preferences, life history strategies, and taxonomic affiliations were analyzed in detail, and evolutionary rates and ancestral states of the palate were reconstructed. Our results show that the palate is heavily impacted by convergence constrained by feeding mechanisms and also exhibits clear stepwise evolutionary patterns with alternative phenotypic configurations to cope with similar functional demand. Salamanders are diversified ecologically before the Middle Jurassic and achieved all their present ecological preferences in the Early Cretaceous. Our results reveal that the last common ancestor of all salamanders share with other modern amphibians a unified biphasic ecological preference, and metamorphosis is significant in the expansion of ecomorphospace of the palate in early salamanders.

Introduction: As a primary stability-indicating parameter, potency should be strategically evaluated during each phase of vaccine development. Herein, we present potency testing during the early clinical development of the Schistosoma mansoni (Sm) Tetraspanin-2 vaccine formulated on Alhydrogel (Sm-TSP-2/Al). As Sm-TSP-2/Al does not induce sterilizing immunity against its target pathogen (Sm) in animal models, potency is measured by “serological substitution”, a method that can add significant variation to the potency metric, especially when used in a compliance (or ‘single data point’) approach. Methods: Potency data were analyzed using the compliance approach to determine if two clinical lots of Sm-TSP-2/Al retained potency over 84 and 36 months post-release, respectively. These same data were also analyzed by: i) least-squares regression with a joinpoint regression analysis; ii) control charting of stability slopes; and iii) bootstrap modeling. Nested-regression and bootstrapping were used to compare the potency of the first (#11-69F-003) and second (#1975) clinical lots of Sm-TSP-2/Al. Results: Despite significant variability in the immune assay, both clinical lots of Sm-TSP-2/Al remained potent for 84 and 36 months, respectively, in all four statistical approaches. The first lot of Sm-TSP-2/Al showed a gain in potency starting at 36 months post-release as captured by joinpoint regression. The two clinical lots of Sm-TSP-2/Al had comparable long-term potency. Conclusion: While a compliance approach can monitor the long-term stability of Sm-TSP-2/Al, it risks putting this critical stability-indicating parameter out of specification with each time point tested due to statistical multiplicity. Alternative statistical methods, such as joinpoint regression or bootstrapping, do not have this limitation and offer even more precise estimations of potency, with the added benefit of also providing predictive analytics. Nested regression and bootstrapping were shown to be a viable alternatives for lot-to-lot comparisons of the stability of Sm-TSP-2/Al. Instructions for implementing both these potency testing approaches are provided.

A novel 5-Acetoxy-1-(6-chloropyridin-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester derivatives Htcdodtta (1), and it’s five complexes, [Cu2(L1)2]·(CH3CN) (2), [Cu2(L2)1.63(L3)0.37]·(CH3OH)0.5 (3), [Cu2(L3)(L4)]·(C2H5OH)0.5·(CH3OH)0.5 (4), [Cu2(L4)(L5)]·(H2O) (5) and [Cu2(L1)1.18(L2)0.82] (6) have been synthesized. The Htcdodtta, HL1-HL5 were formed in-situ reaction. HL1-HL5 are homologues which possess two chiral carbons. Compounds 1–6 were characterized using single-crystal X-ray diffraction, IR, and elemental analysis. Compounds 2–6 are dinuclear copper complexes. The in vitro cytotoxicities of compounds 1–4 against a variety of cell lines were evaluated by MTT assays. Hela cancer cell apoptosis assay of 1 and 2 were examined by flow cytometry. The cell apoptosis in NP69, A549, Capan-2, Hela, HepG2, and HUVECs cell lines induced by compound 2 was further affirmed by cellular morphology observations.

Traumatic brain injury (TBI), also known as head injury or brain injury, refers to the head injury caused by mechanical impact. It is necessary to develop effective new therapies for TBI injury. Gastrodin (GAS) is the main bioactive ingredient from the rhizome of Gastrodia elata and has significant therapeutic effect on nervous system diseases. However, the protective effects of GAS on brain tissue and related regulatory mechanism in traumatic brain injury remain elusive. Herein, we explored the role of GAS in traumatic brain injury and its related mechanism. We found Gastrodin reduced brain tissue injury and improved functional recovery of injury nerve in TBI rats, and alleviated inflammation. Gastrodin decreased the level of pyroptosis in brain tissue of TBI rats. Further, we found GAS suppressed NLRP3 inflammasome signaling pathway, and therefore suppressed pyroptosis and exerted neuroprotective effect. GAS could serve as a promising drug for TBI treatment.

[This corrects the article DOI: 10.1371/journal.pntd.0005574.].

To solve the problem of low interlayer strength of 3D plastic powder printing, in this work, magnetized carbon nanotubes (CNTs) are added to the epoxy powder of 3D printing, and a 0.3 T magnetic field is introduced on the printed powder box to explore the interfacial enhancement effect of CNTs on the interlayer strength of 3D printing of plastic powder. The results show that the magnetized CNTs are vertically arranged in the interlayer, which greatly improves the interlayer bonding strength of 3D plastic printing. When the content of magnetized CNTs is below 4 wt. %, the interlayer bonding strength of epoxy resin 3D printing increases as the content of CNTs increases; when the content of CNTs was 4 wt. %, the interlayer bonding strength increased to a maximum of 4.5 MPa, 50% higher than the unadded specimen; when the content of CNTs increased to 4–6 wt. %, the interlayer bonding strength of the specimens is between 4.5 MPa and 4.3 MPa, basically unchanged; when the content of CNTs increased to more than 7 wt. %, the interfacial strength decreased.

A thicker layer of multi-walled carbon nanotubes (MWCNTs)/waterborne polyurethane (WPU) anticorrosive and conductive coating was respectively prepared on the Q235 steel substrate by brushing (Br) and electrostatic spraying (ES) in this work. The effect of coating process on the dispersion of the MWCNTs and the electrical conductivity, corrosion resistance, and bond strength of the coating was investigated. It was shown that the coating prepared by ES (ES coating) had a smooth surface, few defects and evenly dispersed MWCNTs. The coating prepared by Br (Br coating) had a rough surface, some defects and obviously agglomerated MWCNTs. The electrical conductivity, corrosion resistance, and bond strength of the ES coating were higher than those of the Br coating with the same MWCNT content. As the MWCNT content increased, the electrical conductivity of the ES coating increased, however, its corrosion resistance and bond strength first increased and then decreased. The resistivity of ES 0.3 wt% MWCNTs/WPU coating (12808.4 Ω·m) met the standard requirement of the conductive coating. Its corrosion rate was 3.50×10-5 mm/a immersed in 3.5 wt% NaCl solution. Its bond strength to the Q235 steel substrate was higher than that of ES pure WPU coating. As the MWCNT content increased, the electrical conductivity of the Br coating increased, however, its corrosion resistance and bond strength decreased. When the MWCNT content was 0.6 wt%, the Br coating would conduct electricity. Its corrosion rate was 5.24×10-2 mm/a.

Lithium cobalt oxide (LiCoO2), which has been successfully applied in commercial lithium-ion batteries for portable devices, possesses a theoretical specific capacity of 274 mAh g−1. However, its actual capacity is only half of the theoretical specific capacity, because the charging voltage is restricted below 4.2 V. If a higher charging voltage is applied, an irreversible phase transition of LiCoO2 during delithiation would occur, resulting in severe capacity fading. Therefore, it is essential to investigate the electrochemically driven phase transition of LiCoO2 cathode material to approach its theoretical capacity. In this work, it was observed that LiCoO2 partially degraded to Co3O4 after 150 charging-discharging cycles. From the perspective of crystallography, the conventional cell of LiCoO2 was rebuilt to an orthonormal coordinate, and the transition path from layered LiCoO2 to cubic Co3O4 proposed. The theoretical analysis indicated that the electrochemically driven phase transition from LiCoO2 to Co3O4 underwent several stages. Based on this, an experimental verification was made by doping LiCoO2 with Al, In, Mg, and Zr, respectively. The doped samples theoretically predicted behavior. The findings in this study provide insights into the electrochemically driven phase transition in LiCoO2, and the phase transition can be eliminated to improve the capacity of LiCoO2 to its theoretical value.

The bow-flared section may be simplified in the prediction of slamming loads and whipping responses of ships. However, the difference of hydrodynamic characteristics between the water entry of the simplified sections and that of the original section has not been well documented. In this study, the water entry of several different bow-flared sections was numerically investigated using the computational fluid dynamics method based on Reynolds-averaged Navier–Stokes equations. The motion of the grid around the section was realized using the overset mesh method. Reasonable grid size and time step were determined through convergence studies. The application of the numerical method in the water entry of bow-flared sections was validated by comparing the present predictions with previous numerical and experimental results. Through a comparative study on the water entry of one original section and three simplified sections, the influences of simplification of the bow-flared section on hydrodynamic characteristics, free surface evolution, pressure field, and impact force were investigated and are discussed here.

Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) plays a role in the digestion of host hemoglobin by adult N. americanus hookworms. Vaccination of laboratory animals with recombinant Na-GST-1 is associated with significant protection from challenge infection. Recombinant Na-GST-1 was expressed in Pichia pastoris and adsorbed to aluminum hydroxide adjuvant (Alhydrogel) according to current Good Manufacturing Practice. Two Phase 1 trials were conducted in 142 healthy adult volunteers in the United States and Brazil, first in hookworm-naïve individuals and then in residents of a N. americanus endemic area in Brazil. Volunteers received one of three doses of recombinant Na-GST-1 (10, 30, or 100 μg) adjuvanted with Alhydrogel, adjuvanted with Alhydrogel and co-administered with an aqueous formulation of Glucopyranosyl Lipid A (GLA-AF), or the hepatitis B vaccine. Vaccinations were administered via intramuscular injection on days 0, 56, and 112. Na-GST-1/Alhydrogel was well tolerated in both hookworm-naïve and hookworm-exposed adults, with the most common adverse events being mild to moderate injection site pain and tenderness, and mild headache and nausea; no vaccine-related severe or serious adverse events were observed. Antigen-specific IgG antibodies were induced in a dose-dependent fashion, with increasing levels observed after each vaccination in both trials. The addition of GLA-AF to Na-GST-1/Alhydrogel did not result in significant increases in specific IgG responses. In both the US and Brazil studies, the predominant IgG subclass induced against Na-GST-1 was IgG1, with lesser amounts of IgG3. Vaccination of both hookworm-naïve and hookworm-exposed adults with recombinant Na-GST-1 was safe, well tolerated, and resulted in significant antigen-specific IgG responses. Based on these results, this vaccine will be advanced into clinical trials in children and eventual efficacy studies.ClinicalTrials.gov (NCT01261130 for the Brazil trial and NCT01385189 for the US trial).

A new generation of vaccines for the neglected tropical diseases (NTDs) have now advanced into clinical development, with the Na-GST-1/Alhydrogel Hookworm Vaccine already being tested in Phase 1 studies in healthy adults. The current manuscript focuses on the often overlooked critical aspects of NTD vaccine product development, more specifically, vaccine stability testing programs. A key measure of vaccine stability testing is "relative potency" or the immunogenicity of the vaccine during storage. As with most NTD vaccines, the Na-GST-1/Alhydrogel Hookworm Vaccine was not developed by attenuation or inactivation of the pathogen (Necator americanus), so conventional methods for measuring relative potency are not relevant for this investigational product. Herein, we describe a novel relative potency testing program and report for the first time on the clinical lot of this NTD vaccine during its first 60 months of storage at 2-8°C. We also describe the development of a complementary functional assay that measures the ability of IgG from animals or humans immunized with Na-GST-1/Alhydrogel to neutralize this important hookworm enzyme. While 90% inhibition of the catalytic activity of Na-GST-1 was achieved in animals immunized with Na-GST-1/Alhydrogel, lower levels of inhibition were observed in immunized humans. Moreover, anti-Na-GST-1 antibodies from volunteers in non-hookworm endemic areas were better able to inhibit catalytic activity than anti-Na-GST-1 antibodies from volunteers resident in hookworm endemic areas. The results described herein provide the critical tools for the product development of NTD vaccines.

The demand for nucleic acid and protein derivatives from formalin-fixed paraffin-embedded (FFPE) tissue has greatly increased due to advances in extraction and purification methods, making these derivatives available for numerous genomic and proteomic platforms. Previously, DNA, RNA, microRNA (miRNA), or protein derived from FFPE tissue blocks were considered "unfit" for such platforms, as the process of tissue immobilization by FFPE resulted in cross-linked, fragmented, and chemically modified macromolecules. We conducted a systematic examination of nucleic acids and proteins co-extracted from 118 FFPE blocks sampled from the AIDS and Cancer Specimen Resource (ACSR) at The George Washington University after stratification by storage duration and the three most common tumor tissue types at the ACSR (adenocarcinoma, squamous cell carcinoma, and papillary carcinoma). DNA, RNA, miRNA, and protein could be co-extracted from 98% of the FFPE blocks sampled, with DNA and miRNA "fit" for diverse genomic purposes including sequencing. While RNA was the most labile of the FFPE derivatives, especially when assessed by RNA integrity number (RIN), it was still "fit" for genomic methods that use smaller sequence lengths, e.g., quantitative PCR. While more than half of the protein derivatives were fit for proteomic purposes, our analyses indicated a significant interaction effect on the absorbance values for proteins derived from FFPE, implying that storage duration may affect protein derivatives differently by tumor tissue type. The mean absorbance value for proteins derived from more recently stored FFPE was greater than protein derived from older FFPE, with the exception of adenocarcinoma tissue. Finally, the fitness of one type of derivative was weakly associated with the fitness of derivatives co-extracted from the same FFPE block. The current study used several novel quality assurance approaches and metrics to show that archival FFPE tissue blocks are a valuable resource for contemporary genomic and proteomic platforms.

Waterborne polyurethane (WPU) coatings hold advantages of good toughness, low cost and environmental protection. However, the low water contact angle (WCA), poor wear and corrosion resistance make them unsuitable for application in the superhydrophobic coatings such as antipollution flashover coatings for transmission lines, self-cleaning coatings for outdoor equipment and waterproof textiles. A series of superhydrophobic WPU composites (SHWPUCs) with micro-rough surface structure was prepared by electrostatic spraying nano-SiO2 particles on WPU composites with low surface energy. It showed that as the hydrophobic system content rose the WCAs of the composites first increased and then remained stationary; however, the adhesion and corrosion resistance first increased and then decreased. An appropriate addition of the hydrophobic system content would lead to a dense coating structure, but an excessive addition could increase the interfaces in the coating and then reduce the coating performance. When the mass ratio of the WPU dispersion, polytetrafluoroethylene (PTFE) particles and modified polydimethylsiloxane was 8:0.3:0.4, 10 g/m2 nano-SiO2 particles were sprayed on the uncured coating surface to construct the SHWPUC with a WCA of 156°. Compared with pure WPU coating, its adhesion and corrosion resistance increased by 12.5% and one order of magnitude, respectively; its wear rate decreased by 88.8%.

Because flammable organic solvents are emitted during the construction process, oil-based conductive coatings generally result in potential safety problems. A high content of conductive mediums can also weaken the adhesive and protective abilities of existing conductive coatings. Therefore, an anticorrosive and conductive coating was prepared on Q235 steel substrate by spraying the multi-walled carbon nanotubes (MWCNTs)/waterborne polyurethane (WPU) dispersion with a low MWCNT content in this work. The effect of the MWCNT content on the electrical conductivity, corrosion resistance, and adhesive strength of the WPU conductive coating was investigated. It was concluded that a spatial network structure of MWCNTs-WPU was formed to make the coating structure more compact. The electrical conductivity, corrosion resistance, and adhesive strength of the WPU conductive coating first increased and then decreased as the MWCNT content increased. When the MWCNT content was only 0.2 wt % (which was far lower than that of the existing conductive coatings at 1 wt %), the coating began to conduct electricity; its resistivity was 12,675.0 Ω·m. The best combination property was the 0.3 wt % MWCNTs/WPU conductive coating. Its adhesive strength was 19.99% higher than that of pure WPU coating. Its corrosion rate was about one order of magnitude lower than that of pure WPU coating after being immersed in 3.5 wt % NaCl solution for 17 days.

The cytokine profile during acute chikungunya infection that predicts future chronic arthritis has not yet been investigated. We conducted a nested case-control study comparing serum cytokine concentrations during acute chikungunya infection in cases (n = 121) that reported the presence of chronic joint pain versus age- and gender-matched controls (n = 121) who reported recovery at 20 months post infection. We observed that a robust cytokine response during acute infection was correlated with a decreased incidence of chronic joint pain and that low TNFα, IL-13, IL-2, and IL-4 during acute infection was predictive of chronic joint pain. These data suggest that a robust cytokine response is necessary for viral clearance and cytokines that are related to immune tolerance during acute infection may be protective for chronic arthritis pathogenesis.