Causal structure learning is one of the major fields in causal inference. Only the Markov equivalence class (MEC) can be learned from observational data; to fully orient unoriented edges, ...experimental data need to be introduced from external intervention experiments to improve the identifiability of causal graphs. Finding suitable intervention targets is key to intervention experiments. We propose a causal structure active learning strategy based on graph structures. In the context of randomized experiments, the central nodes of the directed acyclic graph (DAG) are considered as the alternative intervention targets. In each stage of the experiment, we decompose the chain graph by removing the existing directed edges; then, each connected component is oriented separately through intervention experiments. Finally, all connected components are merged to obtain a complete causal graph. We compare our algorithm with previous work in terms of the number of intervention variables, convergence rate and model accuracy. The experimental results show that the performance of the proposed method in restoring the causal structure is comparable to that of previous works. The strategy of finding the optimal intervention target is simplified, which improves the speed of the algorithm while maintaining the accuracy.
The giant panda evolved from omnivorous bears. It lives on a bamboo-dominated diet at present, but it still retains a typical carnivorous digestive system and is genetically deficient in ...cellulose-digesting enzymes. To find out whether this endangered mammalian species, like other herbivores, has successfully developed a gut microbiota adapted to its fiber-rich diet, we conducted a 16S rRNA gene-based large-scale structural profiling of the giant panda fecal microbiota. Forty-five captive individuals were sampled in spring, summer, and late autumn within 1 year. Significant intraindividual variations in the diversity and structure of gut microbiota across seasons were observed in this population, which were even greater than the variations between individuals. Compared with published data sets involving 124 gut microbiota profiles from 54 mammalian species, these giant pandas, together with 9 captive and 7 wild individuals investigated previously, showed extremely low gut microbiota diversity and an overall structure that diverged from those of nonpanda herbivores but converged with those of carnivorous and omnivorous bears. The giant panda did not harbor putative cellulose-degrading phylotypes such as Ruminococcaceae and Bacteroides bacteria that are typically enriched in other herbivores, but instead, its microbiota was dominated by Escherichia/Shigella and Streptococcus bacteria. Members of the class Clostridia were common and abundant in the giant panda gut microbiota, but most of the members present were absent in other herbivores and were not phylogenetically related with known cellulolytic lineages. Therefore, the giant panda appears not to have evolved a gut microbiota compatible with its newly adopted diet, which may adversely influence the coevolutionary fitness of this herbivore.
The giant panda, an endangered mammalian species endemic to western China, is well known for its unique bamboo diet. Unlike other herbivores that have successfully evolved anatomically specialized digestive systems to efficiently deconstruct fibrous plant matter, the giant panda still retains a gastrointestinal tract typical of carnivores. We characterized the fecal bacterial communities from a giant panda population to determine whether this animal relies on its symbiotic gut microbiota to cope with the complex carbohydrates that dominate its diet, as is common in other herbivores. We found that the giant panda gut microbiota is low in diversity and highly variable across seasons. It also shows an overall composition typical of bears and entirely differentiated from other herbivores, with low levels of putative cellulose-digesting bacteria. The gut microbiota of this herbivore, therefore, may not have well adapted to its highly fibrous diet, suggesting a potential link with its poor digestive efficiency.
To report the final results of a phase 2 high-dose gene therapy clinical trial in choroideremia.
Design: Phase 2 clinical trial. Participants: Six men (aged 32-72 years) with genetically-confirmed ...advanced choroideremia. Patients received subfoveal injection of AAV2-REP1 (1011 genome particles in 0.1 mL) in the worse-sighted eye. Outcome Measures: Primary measure was best-corrected visual acuity (BCVA) change from baseline in the treated eye compared to the untreated eye. Secondary endpoints included change from baseline in microperimetry, fundus autofluorescence, and spectral-domain optical coherence tomography (OCT). Safety evaluations included adverse events, viral shedding in body fluids, and vector antibody responses.
Baseline mean ETDRS BCVA was 65.3 ± 8.8 (SD, range 56-77, 20/32-20/80) letters in the treated eyes and 77.0 ± 4.2 (69-81, 20/25-20/40) letters in the untreated eyes. At 2 years, 1 treated eye improved by 10 letters and another by 5 letters, while 1 untreated eye improved by 4 letters. All other eyes were within 2 letters of baseline. Baseline microperimetry sensitivities in the treated eyes were poor (1.2 ± 2.1 (0, 5.1) dB) and showed no significant change. No serious adverse event occurred. Two patients developed an atrophic retinal hole in a nonfunctioning macular area where baseline OCT showed preexisting thinning. Intraoperative microscope-integrated OCT allowed proper subretinal injection with avoidance of excessive foveal stretching and macular hole formation.
Sustained improvement or maintenance of BCVA is achievable in choroideremia with high-dose AAV2-REP1, indicating BCVA is a viable primary outcome in advanced choroideremia. Choroideremia gene therapy delivered with intraoperative OCT has a good safety profile.
Breast cancer (BC) is the most generally diagnosed cancer and the driving cause of cancer-related death. Transmembrane (TMEM) proteins have been reported to serve as prognostic indicators in a ...variety of cancers, and it can offer therapeutic targets for carcinoma. However, the function of TMEM in BC remains unclear. In this study, TMEM9A, a member of TMEM family, was screened as the candidate gene after analyzing the profiles of GSE42568 and GEPIA-BRCA database via bioinformatic method. The upregulated expression of TMEM9A was confirmed in BC samples compared with the paired normal tissues. Hence, we speculated that TMEM9A might promote BC progression. To test the hypothesis, we performed a series of loss/gain-of-function experiments and found that BC cells with TMEM9A deletion inhibited cell proliferation, migration, and invasion along with induced apoptosis. Conversely, TMEM9A overexpression reversed the trend. Mechanically, TMEM9A knockdown blocked the Wnt/β-catenin signaling pathway as evidenced by the increased adenomatous polyposis coli (APC) expression and decreased β-catenin, cyclin D1, and axis inhibition protein 2 (AXIN2) expression. Furthermore, over-activation of the Wnt/β-catenin pathway by transfecting BC cells with β-Catenin-S33Y (β-Catenin tyrosine for serine at codon 33) plasmids reversed the effects caused by TMEM9A knockdown. In conclusion, TMEM9A may play a tumor-promoting role in BC progression via activating the Wnt/β-catenin signaling pathway. Therefore, TMEM9A may be an effective therapeutic option for BC.
In this paper, a compound-Gaussian model (CGM) with the Nakagami-distributed textures (CGNG) is proposed to model sea clutter at medium/high grazing angles. The corresponding amplitude distributions ...are referred to as the CGNG distributions. The analysis of measured data shows that the CGNG distributions can provide better goodness-of-the-fit to sea clutter at medium/high grazing angles than the four types of commonly used biparametric distributions. As a new type of amplitude distribution, its parameter estimation is important for modelling sea clutter. The estimators from the method of moments (MoM) and the zlog(z) estimator from the method of generalized moments are first given for the CGNG distributions. However, these estimators are sensitive to sporadic outliers of large amplitude in the data. As the second contribution of the paper, outlier-robust tri-percentile estimators of the CGNG distributions are proposed. Moreover, experimental results using simulated and measured sea clutter data are reported to show the suitability of the CGNG amplitude distributions and outlier-robustness of the proposed tri-percentile estimators.
The main objective of this work is to identify the end-gas combustion mode transition under different initial thermodynamic conditions and to focus on the role of pressure waves in autoignition ...formation and detonation development in the confined space by a group of two-dimensional (2D) numerical simulations with detailed chemistry of H2/air mixture. Pressure waves with different strengths are obtained by the flame acceleration in closed chambers with and without obstacles under three different initial temperatures. The results indicate that with the increase of initial temperature, there exist three different end-gas autoignition transition modes: autoignition promoted by strong flame acceleration, autoignition suppressed by weak flame acceleration and autoignition independent of flame acceleration. It is also shown that there are three types of end-gas autoignition-induced detonation initiation: (1) detonation initiated directly by the pressure wave generated from the flame propagation; (2) detonation initiated directly by the pressure wave generated from other hot-spot autoignition; (3) autoignition to detonation transition based on the reactivity gradient theory. Meanwhile, to further identify the autoignition transition mode under continuous variation of pressure wave intensity and initial temperature, an idealized physical model, with the Mach number of the pressure wave as the link between the flame propagation duration and autoignition time of the end-gas, is proposed. It is shown that the autoignition can be suppressed by the elevated flame speed when the pressure wave is weak, while it cannot be prevented intrinsically when the temperature of the end-gas is high or the pressure wave is strong enough. Moreover, different autoignition propagation modes are identified from Bradley's diagram, including deflagration, developing detonation and thermal explosion, and the combined effects of reactivity and pressure wave strength are discussed as well.
Amphiphilic hyaluronic acid-poly(l-histidine) (HA-PHis) copolymer was designed for use as a tumor targeted and pH-sensitive nanocarrier for intracellular delivery of doxorubicin. After CD44 ...receptor-mediated cellular uptake, doxorubicin was released rapidly in an intracellular low pH environment. Display omitted
Hyaluronic acid (HA) was conjugated with hydrophobic poly(l-histidine) (PHis) to prepare a pH-responsive and tumor-targeted copolymer, hyaluronic acid–g-poly(l-histidine) (HA-PHis), for use as a carrier for anti-cancer drugs. The effect of the degree of substitution (DS) on the pH-responsive behaviour of HA-PHis copolymer micelles was confirmed by studies of particles of different sizes. In vitro drug release studies demonstrated that doxorubicin (DOX) was released from HA-PHis micelles in a pH-dependent manner. In vitro cytotoxicity assays showed that all the blank micelles were nontoxic. However, MTT assay against Michigan Cancer Foundation-7 (MCF-7) cells (overexpressed CD44 receptors) showed that DOX-loaded micelles with a low PHis DS were highly cytotoxic. Cellular uptake experiments revealed that these pH-responsive HA-PHis micelles taken up in great amounts by receptor-mediated endocytosis and DOX were efficiently delivered into cytosol. Moreover, micelles with the lowest DS exhibited the highest degree of cellular uptake, which indicated that the micelles were internalized into cells via CD44 receptor-mediated endocytosis and the carboxylic groups of HA are the active binding sites for CD44 receptors. Endocytosis inhibition experiments and confocal images demonstrated that HA-PHis micelles were internalized into cells mainly via clathrin-mediated endocytosis and delivered to lysosomes, triggering release of DOX into the cytoplasm. These results confirm that the biocompatible pH-responsive HA-PHis micelles are a promising nanosystem for the intracellular targeted delivery of DOX.
The functional aspects of mast cell-microglia interactions are important in neuroinflammation. Our previous studies have demonstrated that mast cell degranulation can directly induce microglia ...activation. However, the role of mast cells in Lipopolysaccharide (LPS)-induced microglia activation, neuroinflammation and cognitive impairment has not been clarified.
This study investigated the interaction between brain microglia and mast cells
through site-directed injection of cromolyn into rat right hypothalamus using stereotaxic techniques. Cognitive function was subsequently assessed using trace fear conditioning and Y maze tests. Mast cells in rat brain were stained with toluidine blue and counted using Cell D software. Microglia activation was assessed by Iba1 immunohistochemistry both in rat brain and in mast cell-deficient Kit
mice. Receptor expression in rat microglia was determined using flow cytometry analysis. Cytokine levels in rat brain tissue and cell supernatant were measured using high-throughput ELISA. Western blotting was used to analyze Cell signaling proteins.
In this study, intraperitoneal injection of 1 mg/kg LPS induced mast cell activation in hypothalamus and cognitive dysfunction in rats, and that this process can be repressed by the mast cell stabilizer cromolyn (200 μg). Meanwhile, in mice, LPS IP injection induced significant microglia activation 24 h later in the hypothalamus of wild-type (WT) mice, but had little effect in Kit
mice. The stabilization of mast cells in rats inhibited LPS-induced microglia activation, inflammatory factors release, and the activation of MAPK, AKT, and NF-κB signaling pathways. We also found that LPS selectively provokes upregulation of H
R, H
R, PAR2, and TLR4, but downregulation of H
R and H
R, in ipsilateral hypothalamus microglia; these effects were partially inhibited by cromolyn. In addition, LPS was also found to induce activation of P815 cells
, consistent with findings from
experiments. These activated P815 cells also induced cytokine release from microglia, which was mediated by the MAPK signaling pathway.
Taken together, our results demonstrate that stabilization of mast cells can inhibit LPS-induced neuroinflammation and memory impairment, suggesting a novel treatment strategy for neuroinflammation-related diseases.
Introduction
Acute respiratory distress syndrome (ARDS) is a common complication of sepsis, which significantly increases the mortality rate. This work explored the diagnostic value of serum NOD-like ...receptor family pyrin domain containing 3 (NLRP3) concentration in patients with sepsis for ARDS, and the predictive value of serum NLRP3 concentration at the time of diagnosis for death 28 days after treatment.
Methods
A total of 150 sepsis patients were included in this study, including age-matched two groups of patients, 75 patients with ARDS and 75 patients without ARDS. In addition, 60 age-matched healthy patients with physical examination were recruited in this study. Serum NLRP3 concentration was determined by enzyme-linked immunosorbent assay (ELISA). The diagnostic values of serum NLRP3 concentration for ARDS in sepsis patients were evaluated by receiver operating characteristics (ROC) analysis. Correlation of serum NLRP3 with APACHE II score and SOFA were performed by Spearman correlation analysis.
Results
Pulmonary infection, APACHE II score and serum NLRP3 concentration were risk factors for patients with sepsis complicated with ARDS. ROC curve results showed that the specificity of serum NLRP3 concentration was 74.67%, the sensitivity was 76.00%, and the area under the curve (AUC) was 0.82 (p<0.001). APACHE II score and SOFA were significantly positively correlated with serum NLRP3 concentration. Baseline serum NLRP3 levels had significant predictive value for 28-day mortality in sepsis patients complicated with ARDS.
Conclusion
Serum NLRP3 concentration has clinical value in the diagnosis of sepsis complicated with ARDS.
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