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Abstract Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role in regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable in vital life processes such as cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, a sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key processes like mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, which have garnered increasing attention from researchers to unveil their specific molecular mechanisms. In this review, we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC. Furthermore, the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail. We also discuss agonists or antagonists targeting MQC, aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.

Abstract Buck converter is a good candidate for the non‐isolated auxiliary power supply (APS) due to its simple structure and high efficiency. However, it can hardly be adopted in applications that required a very high step‐down ratio due to the difficulty to realize an ultra‐low duty cycle, especially when the switching frequency becomes higher and higher. Here, an improved Buck converter is proposed for high‐frequency and high‐step‐down‐ratio APS application. With the control method based on energy extraction, the proposed topology can achieve an ultra‐low equivalent duty cycle. Thus, a high step‐down ratio can be achieved under a high switching frequency. Moreover, the proposed structure can be applied on several types of the main power stage through the power switch sharing technique. Finally, the prototype with the switching frequency of 1 MHz and the step‐down ratio of 18:1 is verified by the experimental results.

Ultraviolet (UV) photodetectors (PDs) based on nanowire (NW) hold significant promise for applications in fire detection, optical communication, and environmental monitoring. As optoelectronic devices evolve towards lower dimensionality, multifunctionality, and integrability, multicolor PDs have become a research hotspot in optics and electronic information. This study investigates the enhancement of detection capability in a light-trapping ZnO NW array through modification with Pt nanoparticles (NPs) via magnetron sputtering and hydrothermal synthesis. The optimized PD exhibits superior performance, achieving a responsivity of 12.49 A/W, detectivity of 4.07 × 1012 Jones, and external quantum efficiency (EQE) of 4.19 × 103%, respectively. In addition, the Pt NPs/ZnO NW/ZnO PD maintains spectral selectivity in the UV region. These findings show the pivotal role of Pt NPs in enhancing photodetection performance through their strong light absorption and scattering properties. This improvement is associated with localized surface plasmon resonance induced by the Pt NPs, leading to enhanced incident light and interfacial charge separation for the specialized configurations of the nanodevice. Utilizing metal NPs for device modification represents a breakthrough that positively affects the preparation of high-performance ZnO-based UV PDs.

Recent studies confirmed that pyroptosis is involved in the progression of pulmonary hypertension (PH), which could promote pulmonary artery remodeling. Urolithin A (UA), an intestinal flora metabolite of ellagitannins (ETs) and ellagic acid (EA), has been proven to possess inhibitory effects on pyroptosis under various pathological conditions. However, its role on PH remained undetermined. To investigate the potential of UA in mitigating PH, mice were exposed to hypoxia (10% oxygen, 4 weeks) to induce PH, with or without UA treatment. Moreover, in vitro experiments were carried out to further uncover the underlying mechanisms. The in vivo treatment of UA suppressed the progression of PH via alleviating pulmonary remodeling. Pyroptosis-related genes were markedly upregulated in mice models of PH and reversed after the administration of UA. In accordance with that, UA treatment significantly inhibited hypoxia-induced pulmonary arterial smooth muscle cell (PASMC) pyroptosis via the AMPK/NF-κB/NLRP3 pathway. Our results revealed that UA treatment effectively mitigated PH progression through inhibiting PASMC pyroptosis, which represents an innovative therapeutic approach for PH.

Abstract Background Fishing communities surrounding Lake Victoria in Uganda have HIV prevalence of 28% and incidence rates of 5 per 100 person years. More than 50% of the local fishermen are infected with Schistosoma mansoni (S. mansoni). We investigated the role of S. mansoni coinfection as a possible modifier of immune responses against HIV. Using polychromatic flow cytometry and Gran-ToxiLux assays, HIV specific responses, T cell phenotypes, antibody-dependent cell-mediated cytotoxic (ADCC) potency and titres were compared between participants with HIV-S. mansoni coinfection and participants with HIV infection alone. Results S. mansoni coinfection was associated with a modified pattern of anti-HIV responses, including lower frequency of bifunctional (IFNγ + IL-2 − TNF-α+) CD4 T cells, higher overall CD4 T cell activation and lower HIV ADCC antibody titres, compared to participants with HIV alone. Conclusions These results support the hypothesis that S. mansoni infection affects T cell and antibody responses to HIV in coinfected individuals.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated death, occurring during or within 6 hours after transfusion. Reports indicate that TRALI can be categorized as having or lacking acute respiratory distress syndrome (ARDS) risk factors. There are two types of TRALI in terms of its pathogenesis: antibody-mediated and non-antibody-mediated. The key initiation steps involve the priming and activation of neutrophils, with neutrophil extracellular traps (NETs) being established as effector molecules formed by activated neutrophils in response to various stimuli. These NETs contribute to the production and release of reactive oxygen species (ROS) and participate in the destruction of pulmonary vascular endothelial cells. The significant role of NETs in TRALI is well recognized, offering a potential pathway for TRALI treatment. Moreover, platelets, macrophages, endothelial cells, and complements have been identified as promoters of NET formation. Concurrently, studies have demonstrated that the storage of platelets and concentrated red blood cells (RBC) can induce TRALI through bioactive lipids. In this article, recent clinical and pre-clinical studies on the pathophysiology and pathogenesis of TRALI are reviewed to further illuminate the mechanism through which NETs induce TRALI. This review aims to propose new therapeutic strategies for TRALI, with the hope of effectively improving its poor prognosis.

IntroductionThe generation of an HIV-1 vaccine able to induce long-lasting protective immunity remains a main challenge. Here, we aimed to modify next-generation soluble, prefusion-stabilized, close-to-native, glycan-engineered clade C gp140 envelope (Env) trimers (sC23v4 KIKO and ConCv5 KIKO) for optimal display on the cell surface following homologous or heterologous vector delivery.MethodsA combination of the following modifications scored best regarding the preservation of closed, native-like Env trimer conformation and antigenicity when using a panel of selected broadly neutralizing (bnAb) and non-neutralizing (nnAb) monoclonal antibodies for flow cytometry: i) replacing the natural cleavage site with a native flexible linker and introducing a single amino acid substitution to prevent CD4 binding (*), ii) fusing a heterologous VSV-G-derived transmembrane moiety to the gp140 C-terminus, and iii) deleting six residues proximal to the membrane.ResultsWhen delivering membrane-tethered sC23v4 KIKO* and ConCv5 KIKO* via DNA, VSV-GP, and NYVAC vectors, the two native-like Env trimers provide differential antigenicity profiles. Whereas such patterns were largely consistent among the different vectors for either Env trimer, the membrane-tethered ConCv5 KIKO* trimer adopted a more closed and native-like structure than sC23v4 KIKO*. In immunized mice, VSV-GP and NYVAC vectors expressing the membrane-tethered ConCv5 KIKO* administered in prime/boost combination were the most effective regimens for the priming of Env-specific CD4 T cells among all tested combinations. The subsequent booster administration of trimeric ConCv5 KIKO* Env protein preserved the T cell activation levels between groups. The evaluation of the HIV-1-specific humoral responses induced in the different immunization groups after protein boosts showed that the various prime/boost protocols elicited broad and potent antibody responses, preferentially of a Th1-associated IgG2a subclass, and that the obtained antibody levels remained high at the memory phase.DiscussionIn summary, we provide a feasible strategy to display multiple copies of native-like Env trimers on the cell surface, which translates into efficient priming of sustained CD4+ T cell responses after vector delivery as well as broad, potent, and sustained antibody responses following booster immunizations with the homologous, prefusion-stabilized, close-to-native ConCv5 KIKO* gp140 Env trimer.

Diet intake accounts for >90% of selenium (Se) exposure in humans, with rice being the main source of Se intake for >60% of the Chinese population. In this study, 48 rice grain samples labeled Se-enriched were obtained from 22 major rice producing areas in China through online sources. Their total Se contents, Se speciation, and Se bioaccessibility were evaluated to provide a holistic view of Se-enriched rice in the market. The total Se contents were 0.006–0.951 ​μg ​g−1 (average 0.249 ​μg ​g−1), which showed great regional variations, with 73% of the samples satisfying the Se-enriched standard based on GB/T22499-2008 (0.04–0.30 ​mg ​kg−1). Over 80% of Se in the rice samples was organic Se species including selenomethionine, selenocysteine and methylselenocysteine, with selenomethionine being the main Se species, accounting for 61–98%. Based on a modified physiologically-based extraction test (MPBET), the Se bioaccessibility in 33 selected samples was 8.05–49.6% (28.6%) in the gastric phase and 18.1–117% (82.5%) in the intestinal phase. Further, Se bioaccessibility was positively correlated with organic Se (r ​= ​0.89–0.93), but not with inorganic Se (selenite and selenate), suggesting that Se bioaccessibility depended on organic Se in these rice grains. The data call for re-evaluation of Se-enriched rice in the market. Further, the potential risk of long-term consumption of Se-enriched rice in the market towards human health should be studied.

Abstract Conventional resistive gate driving circuits suffer from significant recovery gate driving losses, especially at MHz ranges. The increasing gate driving losses brought by high switching frequency place a limitation to the high power density converter design. This paper proposes a novel floating resonant gate driver which maintains high efficiency at several megahertz operating frequency. The gate loss reduction is achieved by adopting a resonant process with driving power recycling. Part of the gate driving power can be recycled to a gate driving capacitor in the gate driving loop during charging and discharging. The proposed gate driver merges the merits of fast switching speed and low gate driving losses. A prototype of LLC power converter with the proposed floating resonant gate driver operating at 3.5 MHz is implemented. According to the experimental verification, the proposed gate driver realized a driving loss reduction by 70% and theoretical analysis is in good agreement with experimental results.

Thrombin is an important ischemia/reperfusion injury (IRI) mediator in patients with ST-elevation myocardial infarction (STEMI). This study examines the use of bivalirudin, a direct thrombin inhibitor, in reducing IRI in STEMI patients. STEMI patients (n = 21) were treated with bivalirudin and compared to 21 patients treated with unfractionated heparin (UFH) from the EARLY Assessment of Myocardial Tissue Characteristics by CMR in STEMI (EARLY-MYO-CMR) registry (NCT03768453). Infarct size (IS) and left ventricular ejection fraction (LVEF) were comparable between the two groups at follow up. During the first cardiac magnetic resonance (CMR) scan within the first week after percutaneous coronary intervention (PCI), all patients in both the bivalirudin and UFH groups exhibited myocardial edema. However, the myocardium edema volume was significantly less in the bivalirudin group (p < 0.05). At the one-month follow-up, a smaller proportion of patients in the bivalirudin group than in the UFH group exhibited myocardial edema (4.7% vs. 33.3%, p < 0.05). At the three-month follow-up, myocardial edema had completely resolved in the bivalirudin group, while it persisted in two patients in the UFH group. The incidence and volume of microvascular obstruction (MVO) were significantly lower in the bivalirudin group during the acute phase. Additionally, the incidence of intramyocardial hemorrhage (IMH) was significantly lower in the bivalirudin group during both the acute and follow up (p < 0.05). These findings were corroborated by T2 and T1 mapping results. The study concluded that the use of bivalirudin for anticoagulation is associated with attenuated IRI in STEMI patients who receive primary PCI.

Variant Polycomb complexes can have tissue-specific roles during development. Here they show that PCGF6 controls lineage-specification in human PSCs by promoting neuroectoderm differentiation and repressing mesendoderm differentiation via distinct downstream targets.

Here, a high-performance dual-gate ionsensitive field-effect transistor (ISFET) was designed for pH detection based on the high carrier mobility and chemical stability of In2O3. To optimize the structural parameters of the ISFET, the ISFET model with a dual-gate structure was constructed using the Silvaco TCAD. The effects of the channel layer and gate dielectric layer parameters on the performance of the ISFET model were investigated in the dual-gate structure. Following the optimal parameters of the simulation, the dual-gate ISFET chip was fabricated by microfabrication techniques. The pH sensitivity of the fabricated chip was 321.54 mV/pH and exhibited good stability with low drift and hysteresis voltage. In addition, we also tested the pH change caused by the hydrogen peroxide oxidation reaction under catalysis by horseradish peroxidase. The sensitivity was up to 103.28 µA/mM, verifying this high-performance ISFET can be used to detect pH changes of trace substances in the biosensing field.

Abstract The chromatin remodeler CHD8, which belongs to the ATP-dependent chromatin remodelers CHD family, is one of the most high-risk mutated genes in autism spectrum disorders. However, the role of CHD8 in neural differentiation and the mechanism of CHD8 in autism remains unclear, despite there are a few studies based on the CHD8 haploinsufficient models. Here, we generate the CHD8 knockout human ESCs by CRISPR/Cas9 technology and characterize the effect of loss-of-function of CHD8 on pluripotency maintenance and lineage determination by utilizing efficient directed differentiation protocols. The results show loss-of-function of CHD8 does not affect human ESC maintenance although having slight effect on proliferation and cell cycle. Interestingly, CHD8 depletion results in defective neuroectoderm differentiation, along with severe cell death in neural progenitor stage. Transcriptome analysis also indicates CHD8 does not alter the expression of pluripotent genes in ESC stage, but in neural progenitor cells depletion of CHD8 induces the abnormal expression of the apoptosis genes and suppresses neuroectoderm-related genes. These results provide the evidence that CHD8 plays an essential role in the pluripotency exit and neuroectoderm differentiation as well as the regulation of apoptosis during neurogenesis.

Paint coated corrosion detection and evaluation is a big challenge for steel performance and structure health. Eddy current pulsed thermography (ECPT) technique is investigated because it can reflect the corrosion physical properties through paint coating by the infrared signal. This paper proposes skewness method, which presents the feature of temperature curve’s shape automatically, and compares it with principal component analysis (PCA), phase analysis, and kurtosis feature extraction methods for paint coated corrosion characterization and evaluation. The averaged skewness shows the best sensitivity for 0–6 months corrosion. The normalized second principal component (PC) presents good sensitivity and the best measurement scale for corroded time. Furthermore, the temperature curve analysis proves that the electrical conductivity dominates the induced heating and heat distribution. The corrosion height is utilized to explain why ECPT technique is valid within 10 months corroded time. ECPT technique is proved as a smart sensor system for paint coated corrosion detection and characterization.

Background: Coronary inflammation causes significantly increased risk of cardiovascular disease (CVD) in diabetic patients. This study investigated the relationship between coronary local inflammation, detected by pericoronary fat attenuation index (FAI), and different blood glucose control levels in low-risk acute coronary syndrome (ACS) patients with or without diabetes. Methods: A total of 309 patients with low-risk ACS were classified into three groups: non-diabetes, well-regulated diabetes, and poorly regulated diabetes. Pericoronary FAI around the proximal or left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA), were evaluated by coronary computed tomography angiography (CCTA), and systemic inflammatory variables and other biochemical indicators were detected by flow cytometry. Results: Pericoronary FAI values around the proximal LAD, LCX, and RCA in poorly regulated diabetes were significantly higher than those in well-regulated diabetes and non-diabetes, whereas those in well-regulated diabetes were not statistically different from those in non-diabetes. Further, plasma glycated hemoglobin (HbA1c) level was positively correlated with the pericoronary FAI values in LAD, LCX, and RCA. However, no significantly increased systemic inflammatory mediators were found in diabetic patients with poor glycemic control. Conclusions: Diabetic patients with poor glycemic control may have higher coronary local inflammation as detected by pericoronary FAI surrounding the three major coronary arteries. Clinical Trial Registration: NCT05590858.

To control HIV infection there is a need for vaccines to induce broad, potent and long-term B and T cell immune responses. With the objective to accelerate and maintain the induction of substantial levels of HIV-1 Env-specific antibodies and, at the same time, to enhance balanced CD4 and CD8 T cell responses, we evaluated the effect of concurrent administration of MF59-adjuvanted Env protein together with DNA or NYVAC vectors at priming to establish if early administration of Env leads to early induction of antibody responses. The primary goal was to assess the immunogenicity endpoint at week 26. Secondary endpoints were (i) to determine the quality of responses with regard to RV144 correlates of protection and (ii) to explore a potential impact of two late boosts. In this study, five different prime/boost vaccination regimens were tested in rhesus macaques. Animals received priming immunizations with either NYVAC or DNA alone or in combination with Env protein, followed by NYVAC + protein or DNA + protein boosts. All regimens induced broad, polyfunctional and well-balanced CD4 and CD8 T cell responses, with DNA-primed regimens eliciting higher response rates and magnitudes than NYVAC-primed regimens. Very high plasma binding IgG titers including V1/V2 specific antibodies, modest antibody-dependent cellular cytotoxicity (ADCC) and moderate neutralization activity were observed. Of note, early administration of the MF59-adjuvanted Env protein in parallel with DNA priming leads to more rapid elicitation of humoral responses, without negatively affecting the cellular responses, while responses were rapidly boosted after repeated immunizations, indicating the induction of a robust memory response. In conclusion, our findings support the use of the Env protein component during priming in the context of an heterologous immunization regimen with a DNA and/or NYVAC vector as an optimized immunization protocol against HIV infection.

BackgroundThis study aimed to investigate the hypothesis that specific pattern of myocardial work (MW) distribution in patients with acute anterior ST-segment elevation myocardial infarction (STEMI) could provide prognostic value for predicting left ventricular (LV) remodeling.MethodsA total of 98 first anterior wall STEMI patients treated with primary percutaneous coronary intervention [85 men (86.7%), mean age: 58 ± 12 years] were enrolled. Transthoracic echocardiography was performed 24–72 h after angioplasty and during 3-month follow-up. MW was estimated from the left ventricular pressure–strain loop derived from speckle tracking echocardiography and simultaneous noninvasive brachial artery cuff pressure. The primary endpoint was early LV remodeling, defined as an increase in LV end-diastolic volume ≥20% compared with baseline at 3 months after STEMI. Major adverse cardiac events and combined clinical outcomes were recorded.ResultsLV remodeling was present in 32 patients (33%), who exhibited lower global and culprit-regional work index (WI), constructive work (CW), work efficiency (WE), and specifically, greater differences of WE (delta-WE) and CW (delta-CW) between the culprit and non-culprit region than those without LV remodeling both at the acute phase and follow-up (all P < 0.0125). During follow-up, all global and regional WI, CW, and WE were improved (P < 0.0125 compared with baseline), with less improvement in patients with LV remodeling. In multivariate analysis, baseline delta-WE (odds ratio: 2.304; 95% CI: 1.093–4.856, P = 0.028) and peak troponin I level (odds ratio: 1.035; 95%CI: 1.008–1.063, P = 0.010) were independently associated with early LV remodeling. Patients with greater delta-WE at baseline were associated with a higher incidence of heart failure and combined clinical outcomes during follow-up.ConclusionAfter reperfused acute anterior STEMI, patients with LV remodeling presented with more inhomogeneous MW distribution. The absolute difference of WE between culprit and non-culprit territory at the acute phase is an independent predictor for early LV remodeling.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier: NCT05107102.

Abstract Background Increasing evidence showed that carbamylated lipoprotein accelerated atherosclerosis. However, whether such modification of high-density lipoprotein (HDL) particles alters in type 2 diabetes mellitus (T2DM) patients and facilitates vascular complications remains unclear. We aimed to investigate the alteration of the carbamylation in HDL among T2DM patients and clarify its potential role in atherogenesis. Methods A total of 148 consecutive T2DM patients undergoning angiography and 40 age- and gender-matched control subjects were included. HDL was isolated from plasma samples, and the concentration of HDL carbamyl-lysine (HDL-CBL) was measured. Furthermore, the HDL from subjects and in-vitro carbamylated HDL (C-HDL) was incubated with endothelial cells and monocyte to endothelial cell adhesion. Adhesion molecule expression and signaling pathway were detected. Results Compared with the control group, the HDL-CBL level was remarkably increased in T2DM patients (6.13 ± 1.94 vs 12.00 ± 4.06 (ng/mg), P

Shenerjiangzhi formulation (SEJZ) is a new traditional Chinese medicine formulation (patent number: CN110680850A). SEJZ contains Eleutherococcus senticosus (Rupr. and Maxim.), Maxim (Araliaceae; E. senticosus radix and rhizome), Lonicera japonica Thunb (Caprifoliaceae; Lonicera japonica branch, stem), Crataegus pinnatifida Bunge (Rosaceae; Crataegus pinnatifida fruit), and Auricularia auricula. SEJZ has been designed to treat hyperlipidemia. Despite the therapeutic benefits of SEJZ, its underlying mechanism of action is not known. We explored the efficacy of SEJZ against hyperlipidemia by integrating network pharmacology and 16S rRNA gene sequencing and elucidated its mechanism of action. First, SEJZ targets were found through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and from the literature. Hyperlipidemia-related therapeutic targets were obtained from GeneCards, Online Mendelian Inheritance in Man, and DrugBank databases. Then, Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape were applied for the analyses and construction of a protein–protein interaction (PPI) network. The Kyoto Encyclopedia of Genes and Genomes database was employed to identify signaling pathways that were enriched. Second, the therapeutic effects of SEJZ against hyperlipidemia induced by consumption of a high-fat diet in rats were evaluated by measuring body weight changes and biochemical tests. SEJZ treatment was found to alleviate obesity and hyperlipidemia in rats. Finally, 16S rRNA gene sequencing showed that SEJZ could significantly increase the abundance of short-chain fatty acid-producing bacteria, restore the intestinal barrier, and maintain intestinal-flora homeostasis. Using PICRUSt2, six metabolic pathways were found to be consistent with the results of network pharmacology: “African trypanosomiasis”, “amoebiasis”, “arginine and proline metabolism”, “calcium signaling pathway”, “NOD-like receptor signaling pathway”, and “tryptophan metabolism”. These pathways might represent how SEJZ works against hyperlipidemia. Moreover, the “African trypanosomiasis pathway” had the highest association with core genes. These results aid understanding of how SEJZ works against dyslipidemia and provide a reference for further studies.

Diesel-polluted soil is unstable and easy to migrate with environmental changes and causes secondary pollution. In this paper, 0# diesel is used as the pollutant, and lime fly ash is selected as the solidifying material. This paper selects four curing ages of 7D, 14D, 21D, and 28D and four pollution concentrations of 0%, 5%, 10%, and 15%. 20%, 25%, 30%, and 35% four moisture content variables were used to conduct an unconfined compression test, direct shear test, and scanning electron microscope test on diesel-contaminated red clay. The results show that the curing age significantly affects the curing effect, and the curing age of 21D is the optimal age. The mechanical properties of the cured soil were the best at the optimum age and when the pollution concentration was 5%. The mechanical properties of the solidified soil with a moisture content of 30% are the best at the optimal age and the same pollution concentration. Additionally, the scanning electron microscope data indicate that when the pollution concentration increases, the cement created by the interaction of lime, fly ash, and pozzolan increasingly forms. The “oil film” generated by diesel oil seeping into the soil is bound and unable to fill the soil’s pores, hence reducing the soil’s strength.

Background The pericoronary fat attenuation index (FAI) is assessed using standard coronary computed tomography angiography, and it has emerged as a novel imaging biomarker of coronary inflammation. The present study assessed whether increased pericoronary FAI values on coronary computed tomography angiography were associated with vulnerable plaque components and their intracellular cytokine levels in patients with non‐ST elevation acute coronary syndrome. Methods and Results A total of 195 lesions in 130 patients with non‐ST elevation acute coronary syndrome were prospectively included. Lesion‐specific pericoronary FAI, plaque components and other plaque features were evaluated by coronary computed tomography angiography. Local T cell subsets and their intracellular cytokine levels were detected by flow cytometry. Lesions with pericoronary FAI values >−70.1 Hounsfield units exhibited spotty calcification (43.1% versus 25.0%, P=0.015) and low‐attenuation plaques (17.6% versus 4.2%, P=0.016) more frequently than lesions with lower pericoronary FAI values. Further quantitative plaque compositional analysis showed that increased necrotic core volume (Pearson’s r=0.324, P

In marine engineering, the installation of structures inevitably involves the process of water exit. This paper studies the vertical force, the shape of the free surface, and the evolution of the water entrained in a cavity in the process of lifting a structure, so as to provide guidance for practical engineering operations. Using a 1:8 experimental model, this paper derives the governing equations based on the Reynolds-averaged Navier–Stokes approach and uses the volume of fluid method to capture the shape change of the free surface. The vertical forces obtained at different lifting speeds are found to be in good agreement with the results of previous model tests. The results show that the numerical simulation method and mesh generation described in this paper can simulate the changes in the physical quantities associated with the structure in the process of water exit. The vertical force on the structure increases nonlinearly as the lifting speed rises, and the maximum lifting speed is conservatively estimated to be 0.034 m/s using the Det Norske Veritas recommended method. The maximum vertical force occurs as the whole structure leaves the water. The water entrained in the structure is mainly located at the sides and bottom. The lifting velocity plays an important role in the water exit process. The water exit force first increases and then decreases to a stable value as the lifting velocity increases, while the maximum water exit force increases nonlinearly.

With the advancement of technology and science, the power system is getting more intelligent and flexible, and the way people use electric energy in their daily lives is changing. Monitoring the condition of electrical energy loads, particularly in the early detection of aberrant loads and behaviors, is critical for power grid maintenance and power theft detection. In this paper, we combine the widely used deep learning model Transformer with the clustering approach K-means to estimate power consumption over time and detect anomalies. The Transformer model is used to forecast the following hour’s power usage, and the K-means clustering method is utilized to optimize the prediction results, finally, the anomalies is detected by comparing the predicted value and the test value. On real hourly electric energy consumption data, we test the proposed model, and the results show that our method outperforms the most commonly used LSTM time series model.

Epigenetic modifications play a crucial role in neurogenesis, learning, and memory, but the study of their role in early neuroectoderm commitment from pluripotent inner cell mass is relatively lacking. Here we utilized the system of directed neuroectoderm differentiation from human embryonic stem cells and identified that KDM6B, an enzyme responsible to erase H3K27me3, was the most upregulated enzyme of histone methylation during neuroectoderm differentiation by transcriptome analysis. We then constructed KDM6B-null embryonic stem cells and found strikingly that the pluripotent stem cells with KDM6B knockout exhibited much higher neuroectoderm induction efficiency. Furthermore, we constructed a series of embryonic stem cell lines knocking out the other H3K27 demethylase KDM6A, and depleting both KDM6A and KDM6B, respectively. These cell lines together confirmed that KDM6 impeded early neuroectoderm commitment. By RNA-seq, we found that the expression levels of a panel of WNT genes were significantly affected upon depletion of KDM6. Importantly, the result that WNT agonist and antagonist could abolish the differential neuroectoderm induction due to manipulating KDM6 further demonstrated that WNT was the major downstream of KDM6 during early neural induction. Moreover, we found that the chemical GSK-J1, an inhibitor of KDM6, could enhance neuroectoderm induction from both embryonic stem cells and induced pluripotent stem cells. Taken together, our findings not only illustrated the important role of the histone methylation modifier KDM6 in early neurogenesis, providing insights into the precise epigenetic regulation in cell fate determination, but also showed that the inhibitor of KDM6 could facilitate neuroectoderm differentiation from human pluripotent stem cells.

Temperature is one of the important factors affecting the mechanical properties of geotechnical soils, and its role in engineering construction in China cannot be underestimated. In order to study the effects of temperature and zinc contamination concentration on the mechanical properties of Guilin local red clay, a temperature-controlled triaxial shear test was conducted on Guilin red clay under three variables of temperature, zinc contamination concentration and surrounding pressure. The test findings revealed that there are significant differences in the effects of temperature, zinc contamination concentration and surrounding pressure on the mechanical properties of Guilin red clay. The stress–strain curves of the red clay at various temperatures, contamination concentrations and envelope pressures are of the strain-hardening type, and the deformation modulus showed a tendency to increase rapidly with increasing strain, then decrease rapidly, and finally, decrease slowly. With the increase of temperature, the cohesion of Zn-contaminated red clay increases, while the angle of internal friction increases and then decreases, both of which increase the shear strength of red clay. As the concentration of Zn contamination grows, the shear strength of the red clay increases, while the internal friction angle increases and then decreases, and the shear strength of the soil increases and then decreases. The shear strength of the Zn-contaminated red clay improved as the surrounding pressure increased.

The heavy metal contamination of red clay in Guilin is a serious problem. Lead ions pollute red clay and have a series of effects, which affect the macroscopic properties of red clay. However, fundamentally, the effects occur because the internal microstructure of red clay is eroded by Pb2+, which results in the change in the macroscopic properties of red clay. Therefore, we adopted a mercury injection experiment and used electronic microscope Pb2+ to explore the microscopic mechanism through which red clay is internally influenced. From the mercury injection experiment, we found that an increase in the concentration of Pb2+ increased soil pore diameter and volume, and that a higher heavy metal content of Pb2+ had a greater effect on red clay cementation. Using scanning electron microscopy, we found that when the micro-image magnification was 500 and 20,000 times, the inside of the red clay pore increased with the increase in the concentration of Pb2+, showing that the heavy metal within the microstructure damaged the red clay. The above two experiments showed that heavy metal ions increase the intergranular fractures of red clay, and the thickness of the double layer reduces, which results in the weakening of the interaction force between particles.

With the continuous improvement of the construction of the ecological economic system in the new era, the problem of heavy metal pollution has become an important issue in urban construction. In this paper, Zn2+ contaminated red clay is used as the research object, and calcium superphosphate and calcium oxide are used as curing agents to conduct the simultaneous test of unconfined compressive strength-resistivity. The mechanical properties and resistivity of the contaminated soil under different test conditions were analyzed to investigate their effects on the cured red clay. The results showed that different contamination concentrations showed different weakening effects on the unconfined compressive strength of red clay soils, and the unconfined compressive strength of cured soils increased significantly. The age of maintenance affects the unconfined compressive strength of cured soil, and the growth of unconfined compressive strength is most obvious in the age of 0–7 day. After that, it tends to be stable with the growth of age. The deformation modulus of contaminated soil before and after curing was reduced to different degrees. Before and after curing, the resistivity of contaminated soil decreased with the increase of ion concentration, and the resistivity of cured soil increased with the increase of curing agent incorporation rate under the same contamination concentration. The research results can enrich the soil treatment problem of heavy metal contaminated sites and provide theoretical support for the application of this type of curing agent in the field engineering of Zn2+ contaminated red clay soil.

Background: Recent studies have suggested that soluble suppression of tumorigenicity-2 (sST2), an inflammation-related protein receptor, is associated with atherosclerotic diseases. This study aimed to investigate the potential predictive value of sST2 on plaque vulnerability by assessing whether elevated serum levels of sST2 are associated with vulnerable plaque features in patients with non-ST-elevation acute coronary syndrome (ACS).Methods: A total of 120 patients with non-ST-elevation ACS (167 lesions) were prospectively enrolled and evaluated by standard coronary computed tomography angiography (CCTA) and coronary angiography in this study. Serum sST2 levels were measured by ELISA (Presage® ST2 Assay Kit, Critical Diagnostics), and semiautomated software (QAngioCT, Medis) was used to quantify coronary plaques.Results: The included patients were divided into 4 groups by serum sST2 level quartiles. Volumetric analysis of the whole lesion revealed that patients with higher sST2 levels had a larger absolute necrotic core (NC) volume (Quartile 4 vs. Quartile 1, 86.16 ± 59.71 vs. 45.10 ± 45.80 mm3, P = 0.001; Quartile 4 vs. Quartile 2, 86.16 ± 59.71 vs. 50.22 ± 42.56 mm3, P = 0.002) and a higher NC percentage (Quartile 4 vs. Quartile 1, 35.16 ± 9.82 vs. 23.21 ± 16.18%, P < 0.001; Quartile 4 vs. Quartile 2, 35.16 ± 9.82% vs. 22.50 ± 14.03%, P < 0.001; Quartile 4 vs. Quartile 3, 35.16 ± 9.82% vs. 25.04 ± 14.48%, P < 0.001). Correlation analysis revealed that serum sST2 levels were positively correlated with the NC (r = 0.323, P < 0.001) but negatively correlated with dense calcium (r = −0.208, P = 0.007). Furthermore, among those with plaque calcification, patients with spotty calcification exhibited higher serum sST2 levels than those with large calcification (26.06 ± 16.54 vs. 17.55 ± 7.65 ng/mL, P = 0.002). No significant differences in plaque components at the level of the minimal lumen area (MLA) were found among the groups.Conclusions: Serum sST2 levels were correlated with different coronary plaque components in patients with non-ST-elevation ACS. A higher serum level of sST2 was correlated with plaque vulnerability.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT04797819.

Abstract Objective HIV-1 rapidly establishes a persistent infection that can be contained under life-long antiretroviral therapy (ART) but not cured. One major viral reservoir is the peripheral lymph node (LN) follicles. Studying the impact of novel HIV-1 treatment and vaccination approaches on cells residing in germinal centers is essential for rapid progress towards HIV-1 prevention and cure. Results We enrolled 9 asymptomatic adult volunteers with a newly diagnosed HIV-1 infection and CD4 T cell counts ≥ 350/ml. The patients underwent venous blood collection and inguinal lymph node excision surgery in parallel. Mononuclear cells were extracted from blood and tissues simultaneously. Participants were followed up regularly for 2 weeks until complete healing of the surgical wounds. All participants completed the lymph node excision surgery without clinical complications. Among the 9 volunteers, one elite controller was identified. The number of mononuclear cells recovered from lymph nodes ranged from 68 to 206 million and correlated positively with lymph node size. This is the first study to show that lymph node biopsy is a safe procedure and can be undertaken with local experts in rural settings. It provides a foundation for detailed immune response investigations during future clinical trials.

Space launch projects are extremely risky, and any equipment failure or human error may lead to disastrous consequences. Probabilistic risk assessment (PRA) is beneficial to qualitative analysis of risk, but it has not been paid enough attention in risk analysis for space launch systems (SLSs). Compared with most qualitative risk analysis in this field, this paper proposes a risk analysis framework based on Bayesian network (BN) with fuzzy method, which is suitable for probabilistic risk analysis of SLS. This method establishes a risk analysis model of SLS based on statistics and expert experience and reduces the uncertainty of the model by using fuzzy theory. By predicting the system risk probabilities, diagnosing the key risk causes, determining the risk conduction path, and performing a sensitivity analysis, the proposed risk analysis framework is aimed at alleviating this drawback to deal more effectively with the uncertainties in the field of space launches. A case study of space launches demonstrates and verifies the proposed method, and it also provides guidance for similar engineering projects.

Automatic control of intelligent vehicles depends heavily on accurate lane-level location information. The traditional digital map cannot meet the automatic driving requirements, and it is very difficult for lane-level road maps (LRMs) to achieve a good balance between the representation accuracy and data storage volume. To tackle this problem, we obtain the recursive definition of a lane line by analyzing road lanes using the fractal geometry theory. Subsequently, we construct a recursive feedback system and model it. On this basis, an autonomous storage optimization LRM generation strategy based on cascaded NURBS is devised. According to the input data density, this framework generates an LRM with the minimum data storage volume within the error constraint. It is mainly composed of two modules: (1) a random fractal and (2) an adaptive iteration memory optimizer, based on cascaded NURBS error feedback. First, the whole lane is divided into several meta lane line modules. Second, data sampling/interpolation is carried out iteratively according to the NURBS fitting error and symmetry of road geometry. In this way, the storage space used to store lane lines and other information is automatically optimized. Last, a simulation experiment is carried out by using a dataset obtained from a park. The simulation results show that the proposed method can achieve high accuracy and high storage efficiency. Under the constraint of a 0.1 m curve fitting error, the average memory demand of the lane line elements is less than 2.4 bytes/m.

DNA vectors have been widely used as a priming of poxvirus vaccine in prime/boost regimens. Whether the number of DNA impacts qualitatively or quantitatively the immune response is not fully explored. With the aim to reinforce T-cell responses by optimizing the prime-boost regimen, the multicentric EV03/ANRS VAC20 phase I/II trial, randomized 147 HIV-negative volunteers to either 3xDNA plus 1xNYVAC (weeks 0, 4, 8 plus 24; n = 74) or to 2xDNA plus 2xNYVAC (weeks 0, 4 plus 20, 24; n = 73) groups. T-cell responses (IFN-γ ELISPOT) to at least one peptide pool were higher in the 3xDNA than the 2xDNA groups (91% and 80% of vaccinees) (P = 0.049). In the 3xDNA arm, 26 (37%) recipients developed a broader T-cell response (Env plus at least to one of the Gag, Pol, Nef pools) than in the 2xDNA (15; 22%) arms (primary endpoint; P = 0.047) with a higher magnitude against Env (at week 26) (P

Accurate estimations can provide a solid basis for decision-making and policy-making that have experienced some kind of complication and uncertainty. Accordingly, a multivariable grey convolution model (GMC (1, n)) having correct solutions is put forward to deal with such complicated and uncertain issues, instead of the incorrect multivariable grey model (GM (1, n)). However, the conventional approach to computing background values of the GMC (1, n) model is inaccurate, and this model’s forecasting accuracy cannot be expected. Thereby, the drawback analysis of the GMC (1, n) model is conducted with mathematical reasoning, which can explain why this model is inaccurate in some applications. In order to eliminate the drawbacks, a new optimized GMC (1, n), shorted for OGMC (1, n), is proposed, whose background values are calculated based on Simpson’ rule that is able to efficiently approximate the integration of a function. Furthermore, its extended version that uses the Gaussian rule to discretize the convolution integral, abbreviated as OGMCG (1, n), is proposed to further enhance the model’s forecasting ability. In general, these two optimized models have such advantages as simplified structure, consistent forecasting performance, and satisfactory efficiency. Three empirical studies are carried out for verifying the above advantages of the optimized model, compared with the conventional GMC (1, n), GMCG (1, n), GM (1, n), and DGM (1, n) models. Results show that the new background values can effectively be calculated based on Simpson’s rule, and the optimized models significantly outperform other competing models in most cases.

Decision time, also known as choice reaction time, has been frequently discussed in the field of psychology. The Hick–Hyman Law (HHL) has been a fundamental model that has revealed the quantitative relationship between the mean choice reaction time of human and the information entropy of stimuli. However, the HHL is only focused on rule-based behavior in which rules for selecting response according to stimulus are certain and neglects to model the knowledge-based behavior in which choices are uncertain and influenced by human belief. In this article, we explored the decision time related to one basic knowledge-based behavior—uncertain binary choice, where selections of response are determined by human belief degrees but not by stimuli uncertainties. Two experiments were conducted: one for verifying the HHL and the other for uncertain binary choice. The former (experiment) demonstrated the effectiveness of the HHL, and the latter one indicated that there is an exponential relationship existing between decision time and entropy of belief degree in uncertain binary choice. Moreover, data obtained from both experiments showed that the disturbance term of decision time should not be seen as probabilistic as existing studies have assumed, which highlighted the necessity and advantage of uncertain regression analysis.

The generation of a vaccine against HIV-1 able to induce durable protective immunity continues a major challenge. The modest efficacy (31.2%) of the phase III RV144 clinical trial provided the first demonstration that a prophylactic HIV/AIDS vaccine is achievable but emphasized the need for further refinements of vaccine candidates, formulations, and immunization regimens. Here, we analyzed in mice the immunogenicity profile elicited by different homologous and heterologous prime/boost combinations using the modified rhabdovirus VSV-GP combined with DNA or poxviral NYVAC vectors, all expressing trimeric membrane-bound Env (gp145) of HIV-1 96ZM651 clade C, with or without purified gp140 protein component. In cultured cells infected with recombinant VSV-GP or NYVAC viruses, gp145 epitopes at the plasma membrane were recognized by human HIV-1 broadly neutralizing antibodies (bNAbs). In immunized mice, the heterologous combination of VSV-GP and NYVAC recombinant vectors improved the induction of HIV-1 Env-specific humoral and cellular immune responses compared to homologous prime/boost protocols. Specifically, the combination of VSV-GP in the prime and NYVAC in the boost induced higher HIV-1 Env-specific T cell (CD4/CD8 T cells and T follicular helper -Tfh- cells) immune responses compared to the use of DNA or NYVAC vectors in the prime and VSV-GP in the boost. Such enhanced T cell responses correlated with an enhancement of the Env-specific germinal center (GC) B cell population and with a heavily biased Env-specific response toward the Th1-associated IgG2a and IgG3 subclasses, while the other groups showed a Th2-associated IgG1 bias. In summary, our T and B cell population data demonstrated that VSV-GP-based vectors could be taken into consideration as an optimized immunogenic HIV-1 vaccine candidate component against HIV-1 when used for priming in heterologous combinations with the poxvirus vector NYVAC as a boost.

Stabilization of the HIV-1 Envelope glycoprotein trimer (Env) in its native pre-fusion closed conformation is regarded as one of several requirements for the induction of neutralizing antibody (nAb) responses, which, in turn, will most likely be a prerequisite for the development of an efficacious preventive vaccine. Here, we systematically analyzed how the stepwise stabilization of a clade C consensus (ConC) Env immunogen impacts biochemical and biophysical protein traits such as antigenicity, thermal stability, structural integrity, and particle size distribution. The increasing degree of conformational rigidification positively correlates with favorable protein characteristics, leading to optimized homogeneity of the protein preparations, increased thermal stability, and an overall favorable binding profile of structure-dependent broadly neutralizing antibodies (bnAbs) and non-neutralizing antibodies (non-nAbs). We confirmed that increasing the structural integrity and stability of the Env trimers positively correlates with the quality of induced antibody responses by the immunogens. These and other data contribute to the selection of ConCv5 KIKO as novel Env immunogens for use within the European Union’s H2020 Research Consortium EHVA (European HIV Alliance) for further preclinical analysis and phase 1 clinical development.

The delivery of HIV-1 envelope (Env) trimer-based immunogens on the surface of nanoparticles holds promise to promote immunogenicity with the aim of inducing a potent, durable and broad neutralizing antibody (bnAb) response. Towards that goal, we examined the covalent conjugation of Env to 100 nm and 200 nm silica nanoparticles (SiNPs) to optimize conjugation density and attachment stability. Env was redesigned to enable site-specific cysteine-mediated covalent conjugation while maintaining its structural integrity and antigenicity. Env was anchored to different sized SiNPs with a calculated spacing of 15 nm between adjacent trimers. Both particle sizes exhibited high in vitro stability over a seven-day period. After attachment, 100 nm particles showed better colloidal stability compared to 200 nm particles. Importantly, the antigenic profile of Env was not impaired by surface attachment, indicating that the quaternary structure was maintained. In vitro Env uptake by dendritic cells was significantly enhanced when Env was delivered on the surface of nanoparticles compared to soluble Env. Furthermore, multivalent Env displayed efficiently activated B cells even at Env concentrations in the low nanomolar range. In mice, antibody responses to nanoparticle-coupled Env were stronger compared to the free protein and had equivalent effects at lower doses and without adjuvant.

Abstract Background In recent years, ionic liquids and enzymes have been widely used in the separation and extraction processes of natural products. Chlorogenic acid (CGA) has important biological and pharmacological activities. It is significant to develop a green and efficient method to extract GCA from Flos Lonicera japonica (FLJ) by integrating the advantages of the ionic liquids and enzymes. Results The optimal type of enzyme and ionic liquid was screened. Pectinase in [C6mim] Br aqueous phase was demonstrated to be an ideal combination. The parameters including extraction time, extraction temperature, pH, enzyme amount, and IL concentration were optimized systematically. Scanning electronic microscopy of FLJ samples demonstrated that pectinase and ionic liquid disposal both obviously facilitated the extraction process by destroying the structure of cell wall. Circular dichroism spectroscopy showed that ionic liquid enhanced the activity of the pectinase by altering its secondary structure. Conclusions Compared with previous reported methods, ionic liquid-based enzyme-assisted extraction of GCA from FLJ was proved to be efficient and practical, offering a higher yield in a shorter time. A novel process was proposed for the extraction of active component from natural resources.

Background: It has been hypothesised that Schistosoma co-infection exacerbates HIV progression, and hence anthelminthic intervention in co-infected individuals will delay it. We evaluated effects of high-intensity versus low-intensity praziquantel treatment of schistosomiasis on HIV disease progression among co-infected patients from fishing populations around Lake Victoria, Uganda. Methods: Between August 2012 and September 2015, we conducted an open-label randomised, controlled trial. Adults, antiretroviral therapy-naïve, CD4 counts ≥350 cells/μl, HIV and S. mansoni co-infected, were randomised 1:1 to praziquantel (40mg/kg) given quarterly (starting at enrolment) or annually (starting 12 weeks after enrolment; such that low-intensity participants were still untreated when sampled at 12 weeks). A non-randomised HIV-positive S. mansoni-negative comparison group was recruited. The primary outcome was mean change in plasma viral load at 12 and 60 weeks. Results: In total 363 participants (high-intensity 113, low-intensity 113, comparison group 137) were recruited; 96 (85.0%), 97 (85.8%) and 107 (78.1%) completed 60 weeks of follow up, respectively. Adjusting for baseline age and viral load, the geometric mean ratio (aGMR [95%CI]) viral load for high-intensity vs low-intensity groups at 12 weeks was 0.90 [0.65, 1.25] p=0.55 and at 60 weeks 1.88 [0.78, 4.53] p=0.16. Results in the comparison group were similar to trial arms. High-intensity, compared to low-intensity, treatment resulted in substantially lower S. mansoni prevalence at all follow up visits (p

Time Series Segmentation and Residual Trend analysis (TSS-RESTREND) can detect an abrupt change that was undetected by Residual Trend analysis (RESTREND), but it is usually combined with the Global Inventory for Mapping and Modeling Studies (GIMMS) Normalized Difference Vegetation Index (NDVI), which cannot detect detailed vegetation changes in small areas. Hence, we used Time Series Segmentation and Residual Trend analysis (TSS-RESTREND) and Moderate Resolution Imaging Spectroradiometer (MODIS) NDVI (MOD-TR) to analyze the vegetation dynamic of the Pearl River Delta region (PRD) in this study. To choose the most suitable MODIS NDVI from MOD13Q1 (250 m), MOD13A1 (500 m), and MOD13A2 (1 km), whole and local comparison of results of the break year and MOD-TR were used. Meanwhile, a comparison of vegetation change at the city-scale was also implemented. Moreover, to reduce insignificant trend pixels in TSS-RESTREND, a combination method of TSS-RESTREND and RESTREND (CTSS-RESTREND) was proposed. We found that: (1) MOD13Q1 and MOD13A1 two NDVI were suitable for combination with TSS-RESTREND to detect vegetation change in PRD, but MOD13Q1 was a better choice when considering the accuracy of local detailed vegetation change; (2) CTSS-RESTREND could detect more pixels with a significant change (i.e., significant increase and significant decrease) than those of TSS-RESTREND and RESTREND. Also, its effectiveness could be verified by Landsat data; (3) at the city-scale, the CTSS-RESTREND detected that only vegetation decreases in Shenzhen, Foshan, Dongguan, and Zhongshan were higher than vegetation increases, but, significant vegetation changes (i.e., decreases and increases) were mainly concentrated in Huizhou, Jiangmen, Zhaoqing, and Guangzhou.

Background: It has been hypothesised that Schistosoma co-infection exacerbates HIV progression, and hence anthelminthic intervention in co-infected individuals will delay it. We evaluated effects of high-intensity versus low-intensity praziquantel treatment of schistosomiasis on HIV disease progression among co-infected patients from fishing populations around Lake Victoria, Uganda. Methods: Between August 2012 and September 2015, we conducted an open-label randomised, controlled trial. Adults, antiretroviral therapy-naïve, CD4 counts ≥350 cells/μl, HIV and S. mansoni co-infected, were randomised 1:1 to praziquantel (40mg/kg) given quarterly (starting at enrolment) or annually (starting 12 weeks after enrolment; such that low-intensity participants were still untreated when sampled at 12 weeks). A non-randomised HIV-positive S. mansoni-negative comparison group was recruited. The primary outcome was mean change in plasma viral load at 12 and 60 weeks. Results: In total 363 participants (high-intensity 113, low-intensity 113, comparison group 137) were recruited; 96 (85.0%), 97 (85.8%) and 107 (78.1%) completed 60 weeks of follow up, respectively. Adjusting for baseline age and viral load, the geometric mean ratio (aGMR [95%CI]) viral load for high-intensity vs low-intensity groups at 12 weeks was 0.90 [0.65, 1.25] p=0.55 and at 60 weeks 1.88 [0.78, 4.53] p=0.16. Results in the comparison group were similar to trial arms. High-intensity, compared to low-intensity, treatment resulted in substantially lower S. mansoni prevalence at all follow up visits (p

Mycobacterium tuberculosis (Mtb) and helminth infections elicit antagonistic immune effector functions and are co-endemic in several regions of the world. We therefore hypothesized that helminth infection may influence Mtb-specific T-cell immune responses. We evaluated the cytokine profile of Mtb-specific T cells in 72 individuals with pulmonary TB disease recruited from two Sub-Saharan regions with high and moderate helminth burden i.e. 55 from Tanzania (TZ) and 17 from South Africa (SA), respectively. We showed that Mtb-specific CD4 T-cell functional profile of TB patients from Tanzania are primarily composed of polyfunctional Th1 and Th2 cells, associated with increased expression of Gata-3 and reduced expression of T-bet in memory CD4 T cells. In contrast, the cytokine profile of Mtb-specific CD4 T cells of TB patients from SA was dominated by single IFN-γ and dual IFN-γ/TNF-α and associated with TB-induced systemic inflammation and elevated serum levels of type I IFNs. Of note, the proportion of patients with Mtb-specific CD8 T cells was significantly reduced in Mtb/helminth co-infected patients from TZ. It is likely that the underlying helminth infection and possibly genetic and other unknown environmental factors may have caused the induction of mixed Th1/Th2 Mtb-specific CD4 T cell responses in patients from TZ. Taken together, these results indicate that the generation of Mtb-specific CD4 and CD8 T cell responses may be substantially influenced by environmental factors in vivo. These observations may have major impact in the identification of immune biomarkers of disease status and correlates of protection.

Extracellular matrix metalloproteinase inducer (EMMPRIN) is an important pro-inflammatory protein involved in the cellular functions of monocytes/macrophages. We have hypothesized that high-level heterogeneousness of protein glycosylation of EMMPRIN may have functional relevance to its biological effects and affect the inflammatory activity of monocytes/macrophages.The glycosylation patterns of EMMPRIN expressed by monocytes/macrophages (THP-1 cells) in response to different extracellular stimuli were observed, and the structures of different glycosylation forms were identified. After the purification of highly- and less-glycosylated proteins respectively, the impacts of different glycosylation forms on the pro-inflammatory effects of EMMPRIN were examined in various aspects, such as cell adhesion to endothelial cells, cell migrations, cytokine expression, and activation of inflammatory signalling pathway.1) It was mainly the highly-glycosylated form of EMMPRIN (HG-EMMPRIN) that increased after being exposed to inflammatory signals (PMA and H2O2). 2) Glycosylation of EMMPRIN in monocytes/macrophages led to N-linked-glycans being added to the protein, with the HG form containing complex-type glycans and the less-glycosylated form (LG) the simple type. 3) Only the HG-EMMPRIN but not the LG-EMMPRIN exhibited pro-inflammatory effects and stimulated inflammatory activities of the monocytes/macrophages (i.e., activation of ERK1/2 and NF-κB pathway, enhanced monocyte-endothelium adhesion, cell migration and matrix metalloproteinase -9 expression).Post-transcriptional glycosylation represents an important mechanism that determines the biological effects of EMMPRIN in monocytes/macrophages. Glycosylation of EMMPRIN may serve as a potential target for regulating the inflammatory activities of monocytes/macrophages.

BACKGROUND AND OBJECTIVES: The predictive value of plaque characteristics assessed by virtual histology-intravascular ultrasound (VH-IVUS) including fibrous tissue (FT), fibrofatty (FF), necrotic core (NC) and dense calcium (DC) in identifying distal embolization after percutaneous coronary intervention (PCI) is still controversial. We performed a systematic review and meta-analysis to summarize the association of pre-PCI plaque composition and post-PCI distal embolization in acute coronary syndrome patients. METHODS: Studies were identified in PubMed, OVID, EMBASE, the Cochrane Library, the Current Controlled Trials Register, reviews, and reference lists of relevant articles. A meta-analysis using both fixed and random effects models with assessment of study heterogeneity and publication bias was performed. RESULTS: Of the 388 articles screened, 10 studies with a total of 872 subjects (199 with distal embolization and 673 with normal flow) met the eligibility of our study. Compared with normal flow groups, significant higher absolute volume of NC [weighted mean differences (WMD): 5.79 mm3, 95% CI: 3.02 to 8.55 mm3; p