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The Assessment andAppraisal Method for Ecological Construction Targets (the Method) was promulgated in 2016, which provided a concrete instruction for China’s air pollution control and established an explicit standard for reducing air pollutant concentration. This study implements a sharp regression discontinuity (RD) design and makes an assessment on air quality control effectiveness of the Method based on the high-volume big data acquired from 173 cities in China. The results show that the Method has significantly improved air pollution control on the overall air quality index (AQI) and reducing concentrations of PM2.5, PM10, SO2, NO2, and CO across the country in the observation periods. However, no reduction effect was observed for O3. The robustness tests support the conclusion as well. Besides, the heterogeneity analysis illustrates that the policy had a significant short-term treatment effect in East, South, Central, North, Northwest, Southwest, and Northeast China. However, the Method’s effect is found to decline over time either nationwide or regionally according to the persistence analysis. Therefore, this article puts forward several suggestions regarding the formulation of long-term regulations for air pollution control, the transformation of the growth model for sustainable development, and optimization of the incentive system for improved pollution control and prevention.

Estimating food- and nutrient-income elasticities is important for making food and nutrition policies to combat malnutrition. There are many studies that have estimated the relationship between income growth and food/nutrient demand in China, but the results are highly heterogeneous. We conducted a meta-analysis in China to systematically review the elasticity of food, calories, and other nutrients to income. We considered a meta-sample using a collection of 64 primary studies covering 1537 food-income elasticities, 153 nutrient-income elasticities, and 147 calorie-income elasticity estimates. There are significant differences in the size of the income elasticities across food and nutrient groups. We found that food- and calorie-income elasticity appear to decline as per capita income increases, except for vitamin and aquatic products. We also found a publication bias for food and calories, and in particular, the study attributes may be important, as they can influence estimates. Given the limited study on nutrient-income elasticity, understanding the impact of income changes on nutrient intake is an important direction worthy of further research.

Effective phage cocktails consisting of multiple virus types are essential for successful phage therapy against pandrug-resistant pathogens, including Salmonella enterica serovar (S.) Typhimurium. Here we show that a Salmonella phage, F118P13, with non-productive infection and a lytic phage, PLL1, combined to inhibit pandrug-resistant S. Typhimurium growth and significantly limited resistance to phages in vitro. Further, intraperitoneal injection with this unique phage combination completely protected mice from Salmonella-induced death and inhibited bacterial proliferation rapidly in various organs. Furthermore, the phage combination treatment significantly attenuated the inflammatory response, restored the generation of CD4+ T cells repressed by Salmonella, and allowed macrophages and granulocytes to participate in immunophage synergy to promote bacterial clearance. Crucially, the non-productive phage F118P13 is less likely to be cleared by the immune system in vivo, thus providing an alternative to phage cocktail against bacterial infections.

The microbial fuel cell has been considered a promising alternative to traditional fossil energy. It has great potential in energy production, waste management, and biomass valorization. However, it has several technical issues, such as low power generation efficiency and operational stability. These issues limit the scale-up and commercialization of MFC systems. This review presents the latest progress in microbial community selection and genetic engineering techniques for enhancing microbial electricity production. The summary of substrate selection covers defined substrates and some inexpensive complex substrates, such as wastewater and lignocellulosic biomass materials. In addition, it also includes electrode modification, electron transfer mediator selection, and optimization of operating conditions. The applications of MFC systems introduced in this review involve wastewater treatment, production of value-added products, and biosensors. This review focuses on the crucial process of microbial fuel cells from preparation to application and provides an outlook for their future development.

Patients with persistent sciatic artery are at high risk for development of limb ischemia, aneurysm formation, and embolism. In this report, we identify a nonclassified left leg persistent sciatic artery in a patient with chronic limb ischemia. Vascular reconstruction was carried out by common iliac-deep femoral artery bypass to restore adequate arterial flow. Our approach to placement of the distal anastomosis on the deep femoral artery instead of on the popliteal artery, which is used in routine practice, may potentially increase treatment efficacy and decrease surgical complications. At 2-year follow-up, the patient remained asymptomatic and in good health. Keywords: Persistent sciatic artery (PSA), Bypass, Patency

In recent years, research on immunotherapy has made great progress. Currently, immunotherapy has made significant breakthrough, especially programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint inhibitors (e.g, Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab and Avelumab, etc.) have brought clinical benefits to patients with various pathological types of lung cancer, including squamous cell carcinoma, adenocarcinoma and small cell lung cancer. In this paper, the application value and current status of PD-1/PD-L1 checkpoint inhibitors in lung cancer were comprehensively analyzed by reviewing and interpreting representative clinical studies. Based on the results of various large-scale clinical trials results, the indications of immunotherapy in lung cancer have been continuously broadened, and the details of immunotherapy have also been constantly optimized. However, immunotherapy still faces many challenges, such as the selection of immune combination strategies, the exploration of biomarkers, the management of adverse events, the feasibility of application of driver gene mutation population and so on. In this article, we made a systematic review about the latest progress of PD-1/PD-L1 checkpoint inhibitors in lung cancer, in order to provide cutting-edge reference for the clinical workers.

The present study aimed to investigate the functional components from Bushen Yijing Formula and their inhibition of endothelial–mesenchymal transition (EndMT) and fibrosis in human umbilical vascular endothelial cells (HUVECs). HUVEC fibrosis was induced by treatment of transforming growth factor β (TGF-β) as the cellular model. Expression of EndMT biomarker gene and cofactors were determined by quantitative real-time-PCR, western blotting, and immunofluorescence. Angiogenesis capacity of vein endothelial cells was evaluated using tube formation assay. Ursolic acid and drug-contained serum ameliorated EndMT biomarker gene expression changes and angiogenesis capacity suppression induced by TGF-β treatment. Slug, Snail, and Twist gene expression and phosphorylation of mammalian target of rapamycin (mTOR) and AKT altered by TGF-β in HUVECs were suppressed by ursolic acid and drug-contained serum. Treatment with the mTOR signaling pathway inhibitor, rapamycin, inhibited the phosphorylation of mTOR and AKT, decreased Snail and Vimentin protein levels, and increased VE-cad protein levels. Overexpression of Snail gene promoted expression of EndMT-related genes and suppressed angiogenesis in HUVECs, which were attenuated by application of ursolic acid and drug-contained serum. Ursolic acid from Bushen Yijing Formula inhibits human umbilical vein endothelial cell EndMT and fibrosis, mediated by AKT/mTOR signaling and Snail gene expression. Keywords: Bushen Yijing Formula, Ursolic acid, mTOR signaling, Snail

Direct detection (DD) is one of the most attractive solutions for short and medium reach optical fiber transmission in comprehensive consideration of digital signal processing (DSP), power consumption, and cost. Various single side band (SSB) DD techniques have been widely investigated to detect and process the complex signal. In this paper, we propose a novel approach which uses only high-speed digital input/outputs (IO) to generate both quadrature phase shift keying (QPSK) signal and virtual carrier signal. A transmission of 4 × 32 Gb/s QPSK signal over 1200-km standard single mode fiber (SSMF) in block-wise manner has been successfully demonstrated. Only a single polarization in-phase-and-quadrature (IQ) modulator and one single photodiode (PD) are used for each channel. Compared with conventional DSP of coherent detection, the DSP in the proposed scheme is also simplified that only fixed frequency compensation is required without additional phase noise elimination. The overall system complexity has been greatly reduced.

Topology optimization has demonstrated its power in structural design under a variety of physical disciplines. Generally, a topology optimization problem is formulated with clearly-defined problem setup. Both design domain shape and boundary condition are clearly-defined during pre-processing. Optimization with multiple choices of design domains or boundary conditions have to be performed with multiple runs of the algorithm to make the best choice among the selective problem setups. The computational cost is proportional to the number of problem setup choices which can be inefficient if a large number of choices are involved. Therefore, to save the computational cost, a novel topology optimization method is developed to solve the design problem with selective problem setups. This method employs a novel meshing strategy and material interpolation model to unify the multiple problem setups into a single optimization problem. Therefore, the optimization algorithm only runs once to concurrently derive the optimal structural shape and the best problem setup choice in a very efficient manner. In addition, the problem formulation is simple. Only N more design variables are added to realize the interpolation among N+1 problem setup choices, other than the density variables for structural topology description. A few numerical examples will be demonstrated to show the effectiveness of the proposed method.

Gastric carcinoma (GC) heterogeneity represents a major barrier to accurate diagnosis and treatment. Here, we established a comprehensive single-cell transcriptional atlas to identify the cellular heterogeneity in malignant epithelial cells of GC using single-cell RNA sequencing (scRNA-seq). A total of 49,994 cells from nine patients with paired primary tumor and normal tissues were analyzed by multiple strategies. This study focused on the malignant epithelial cells, which were divided into three subtypes, including pit mucous cells, chief cells, and gastric and intestinal cells. The trajectory analysis results suggest that the differentiation of the three subtypes could be from the pit mucous cells to the chief cells and then to the gastric and intestinal cells. Lauren’s histopathology of GC might originate from various subtypes of malignant epithelial cells. The functional enrichment analysis results show that the three subtypes focused on different biological processes (BP) and pathways related to tumor development. In addition, we generated and validated the prognostic signatures for predicting the OS in GC patients by combining the scRNA-seq and bulk RNA sequencing (bulk RNA-seq) datasets. Overall, our study provides a resource for understanding the heterogeneity of GC that will contribute to accurate diagnosis and prognosis.

The metallization of polyetherimide (PEI) is widely considered to enhance its surface properties and enhance its application in engineering fields; however, adhesion is a key factor in determining the reliability of PEI metallization. A Ni/Cu/Ni multilayer coating was successfully manufactured on a batch of PEI resin reinforced with glass fibers by a two-step metallization process, including sandblasting and activation/acceleration. The microstructure and morphology of the top-surface and cross-section of the coatings were observed by scanning electron microscopy. The chemical state and composition of the deposits were characterized by both X-ray photoelectron and energy-dispersive spectroscopy. The adhesion state was qualitatively evaluated by cross-cut tests with 3M tape. The surface roughness of the substrate significantly increased after the sandblasting process, which could improve the adhesion between the multilayer coating and the PEI substrate. After the standard activation process, the acceleration made an effect on the deposition of the initial Ni layer for electroless plating. The influence of acceleration on the appearance quality of metallization on the PEI substrate was studied and, at the same time, the mechanism of acceleration was investigated and addressed.

Previous studies have reported that T cell immunoglobulin domain and mucin domain-3 (TIM-3) 574T>G and 1516G>T are associated with the risk of asthma. However, the results are inconsistent due to the small sample size and varied age in studies. We performed this meta-analysis to systematically evaluated the effect of TIM-3 574T>G and 1516G>T genetic polymorphisms on asthma. Eligible articles that reported an association between TIM-3 574T>G and 1516G>T genetic polymorphisms and asthma were searched in PubMed, Medline, EMBASE, Google Scholar, and China National Knowledge Infrastructure up to April 2020. Random or fixed-effects models were used to calculate the summary of odds ratios (ORs) and 95% confidence intervals (CIs) to detect any potential associations between TIM-3 genetic polymorphisms and asthma. Subgroup and sensitivity analyses were performed to assess the potential sources of heterogeneity and the robustness of the pooled estimation. Publication bias was analyzed using the Egger test. A total of 11 case-control studies including 2077 asthma patients and 2122 control subjects were finally analyzed (published data form 2004-2018). The pooled results indicated that TIM-3 574T>G genetic polymorphisms were significantly associated with an increased risk of asthma under the dominant model (GG vs. GT +TT: ORs=2.26, 95% CI 1.09-4.69) and allele model (G vs T: ORs=2.60, 95% CI 1.20-5.64). However, no significant associations between TIM-3 1516G>T genetic polymorphisms with asthma in any model was found. No evidence of publication bias was observed. Our study indicates that TIM-3 574T>G genetic polymorphisms were associated with increased risk of asthma and the TIM-3 1516G>T genetic polymorphisms may not be correlated with asthma.

Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.

An attack of congestive heart failure (CHF) can cause symptoms such as difficulty breathing, dizziness, or fatigue, which can be life-threatening in severe cases. An electrocardiogram (ECG) is a simple and economical method for diagnosing CHF. Due to the inherent complexity of ECGs and the subtle differences in the ECG waveform, misdiagnosis happens often. At present, the research on automatic CHF detection methods based on machine learning has become a research hotspot. However, the existing research focuses on an intra-patient experimental scheme and lacks the performance evaluation of working under noise, which cannot meet the application requirements. To solve the above issues, we propose a novel method to identify CHF using the ECG-Convolution-Vision Transformer Network (ECVT-Net). The algorithm combines the characteristics of a Convolutional Neural Network (CNN) and a Vision Transformer, which can automatically extract high-dimensional abstract features of ECGs with simple pre-processing. In this study, the model reached an accuracy of 98.88% for the inter-patient scheme. Furthermore, we added different degrees of noise to the original ECGs to verify the model’s noise robustness. The model’s performance in the above experiments proved that it could effectively identify CHF ECGs and can work under certain noise.

Real-time intraoperative guidance during minimally invasive neurosurgical procedures (e.g., endonasal transsphenoidal surgery) is often limited to endoscopy and CT-guided image navigation, which can be suboptimal at locating underlying blood vessels and nerves. Accidental damage to these critical structures can have severe surgical complications, including patient blindness and death. Photoacoustic image guidance was previously proposed as a method to prevent accidental injury. While the proposed technique remains promising, the original light delivery and sound reception components of this technology require alterations to make the technique suitable for patient use. This paper presents simulation and experimental studies performed with both an intact human skull (which was cleaned from tissue attachments) and a complete human cadaver head (with contents and surrounding tissue intact) in order to investigate optimal locations for ultrasound probe placement during photoacoustic imaging and to test the feasibility of a modified light delivery design. Volumetric x-ray CT images of the human skull were used to create k-Wave simulations of acoustic wave propagation within this cranial environment. Photoacoustic imaging of the internal carotid artery (ICA) was performed with this same skull. Optical fibers emitting 750 nm light were inserted into the nasal cavity for ICA illumination. The ultrasound probe was placed on three optimal regions identified by simulations: (1) nasal cavity, (2) ocular region, and (3) 1 mm-thick temporal bone (which received 9.2%, 4.7%, and 3.8% of the initial photoacoustic pressure, respectively, in simulations). For these three probe locations, the contrast of the ICA in comparative experimental photoacoustic images was 27 dB, 19 dB, and 12 dB, respectively, with delay-and-sum (DAS) beamforming and laser pulse energies of 3 mJ, 5 mJ, and 4.2 mJ, respectively. Short-lag spatial coherence (SLSC) beamforming improved the contrast of these DAS images by up to 15 dB, enabled visualization of multiple cross-sectional ICA views in a single image, and enabled the use of lower laser energies. Combined simulation and experimental results with the emptied skull and >1 mm-thick temporal bone indicated that the ocular and nasal regions were more optimal probe locations than the temporal ultrasound probe location. Results from both the same skull filled with ovine brains and eyes and the human cadaver head validate the ocular region as an optimal acoustic window for our current system setup, producing high-contrast (i.e., up to 35 dB) DAS and SLSC photoacoustic images within the laser safety limits of a novel, compact light delivery system design that is independent of surgical tools (i.e., a fiber bundle with 6.8 mm outer diameter, 2 mm-diameter optical aperture, and an air gap spacing between the sphenoid bone and fiber tips). These results are promising toward identifying, quantifying, and overcoming major system design barriers to proceed with future patient testing.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a poor prognosis and limited therapeutic options. Alpha-fetoprotein (AFP), an established clinical biomarker of HCC, has been employed as an attractive target for T cell-based immunotherapy against this disease given its high expression in the tumor and restricted expression in normal tissues. We have identified a number of T cell receptors (TCRs) recognizing the HLA-A*02:01 restricted AFP158−166 peptide FMNKFIYEI, providing a TCR candidate pool for identifying TCRs with optimal clinical benefit. To select the ideal AFP TCR for clinical use, we evaluated the efficacy and safety profile of 7 TCRs by testing their potency toward AFP-expressing HCC cells and their specificity based upon reactivity to normal and transformed cells covering a wide variety of primary cell types and HLA serotypes. Furthermore, we assessed their cross-reactivity to potential protein candidates in the human genome by an extensive alanine scan (X-scan). We first selected three TCR candidates based on the in vitro anti-tumor activity. Next we eliminated two potential cross-reactive TCRs based on their reactivity against normal and transformed cells covering a variety of primary cell types and HLA serotypes, respectively. We then excluded the potential cross-reactivity of the selected TCR with a protein candidate identified by X-scan. At present we have selected an AFP TCR with the optimal affinity, function, and safety profile, bearing properties that are expected to allow AFP TCR redirected T cells to specifically differentiate between AFP levels on tumor and normal tissues. An early phase clinical trial using T cells transduced with this TCR to treat HCC patients (NCT03971747) has been initiated.

Elucidating the regulation mechanism of integrin αIIbβ3 is key to understand platelet biology and thrombotic diseases. Previous in vitro studies have implicated a role of migfilin in the support of platelet αIIbβ3 activation, however, contribution of migfilin to thrombosis and hemostasis in vivo and a detailed mechanism of migfilin in platelets are not known. In this study, with migfilin deletion (migfilin-/-) mice, we report that migfilin is a pivotal positive regulator of hemostasis and thrombosis. Migfilin-/- mice showed a nearly doubled tail-bleeding time and a prolonged occlusion time in Fecl3-induced mesenteric arteriolar thrombosis. Migfilin deficiency impedes platelet thrombi formation on collagen surface and impairs platelet aggregation and dense-granule secretion. Supported by characteristic functional readings and phosphorylation status of distinctive signaling molecules in the bidirectional signaling processes of αIIbβ3, the functional defects of migfilin-/- platelets appear to be mechanistically associated with a compromised outside-in signaling, rather than inside-out signaling. A synthesized cell-permeable migfilin peptide harboring filamin A binding sequence rescued the defective function and phosphorylation of signaling molecules of migfilin-/- platelets. Finally, migfilin does not influence the binding of filamin A and β3 subunit of αIIbβ3 in resting platelets, but hampers the re-association of filamin A and β3 during the conduct of outside-in signaling, suggesting that migfilin functions through regulating the interaction dynamics of αIIbβ3 and filamin A in platelets. Our study enhances the current understanding of platelet integrin αIIbβ3-mediated outside-in signaling and proves that migfilin is an important regulator for platelet activation, hemostasis and thrombosis.

The distinct genomic and epidemiological features of Chinese lung cancer patients suggest the presence of alternative causal mechanisms. Here, the authors present the genomic landscape of 149 Chinese NSCLC patients and reveal distinct mutational signatures associated with inflammatory microenvironments.

The accurate design flood of hydraulic engineering is an important precondition to ensure the safety of residents, and the high precision estimation of flood frequency is a vital perquisite. The Xiangjiang River basin, which is the largest river in Hunan Province of China, is highly inclined to floods. This paper aims to investigate the annual maximum flood peak (AMFP) risk of Xiangjiang River basin under the climate context employing the Bayesian nonstationary time-varying moment models. Two climate covariates, i.e., the average June-July-August Artic Oscillation and sea level pressure in the Northwest Pacific Ocean, are selected and found to exhibit significant positive correlation with AMFP through a rigorous statistical analysis. The proposed models are tested with three cases, namely, stationary, linear-temporal and climate-based conditions. The results both indicate that the climate-informed model demonstrates the best performance as well as sufficiently explain the variability of extreme flood risk. The nonstationary return periods estimated by the expected number of exceedances method are larger than traditional ones built on the stationary assumption. In addition, the design flood could vary with the climate drivers which has great implication when applied in the context of climate change. This study suggests that nonstationary Bayesian modelling with climatic covariates could provide useful information for flood risk management.

Binding of programmed cell death ligand 1 (PD-L1) to its receptor programmed cell death protein 1 (PD-1) can lead to the inactivation of cytotoxic T lymphocytes, which is one of the mechanisms for immune escape of tumors. Immunotherapy based on this mechanism has been applied in clinic with some remaining issues such as drug resistance. Exosomal PD-L1 derived from tumor cells is considered to play a key role in mediating drug resistance. Here, the effects of various tumor-derived exosomes and tumor-derived exosomal PD-L1 on tumor progression are summarized and discussed. Researchers have found that high expression of exosomal PD-L1 can inhibit T cell activation in in vitro experiments, but the function of exosomal PD-L1 in vivo remains controversial. In addition, the circulating exosomal PD-L1 has high potential to act as an indicator to evaluate the clinical effect. Moreover, therapeutic strategy targeting exosomal PD-L1 is discussed, such as inhibiting the biogenesis or secretion of exosomes. Besides, some specific methods based on the strategy of inhibiting exosomes are concluded. Further study of exosomal PD-L1 may provide an effective and safe approach for tumor treatment, and targeting exosomal PD-L1 by inhibiting exosomes may be a potential method for tumor treatment.

To address the global phenomenon of the salinisation of large land areas, a quantitative inversion model of the salinity of saline soils and soil visible–near-infrared (NIR) spectral data was developed by considering saline soils in Zhenlai County, Jilin Province, China as the research object. The original spectral data were first subjected to Savitzky–Golay (SG) smoothing, multiplicative scattering correction (MSC) pre-processing, and a combined transformation technique. The pre-processed spectral data were then analysed to construct the difference index (DI), ratio index (RI), and normalised difference index (NDI), and the Spearman rank correlation coefficient (r) between these three spectral indices and the salt content in the samples was calculated, while a combined spectral index (r > 0.8) was eventually selected as a sensitive spectral index. Finally, a quantitative inversion model for the salinity of saline soils was developed, and the model’s accuracy was evaluated based on partial least squares regression (PLSR), the random forest (RF) algorithm, and the radial basis function (RBF) neural network algorithm. The results indicated that the inversion of soil salt content using the selected combination of spectral indices based on the RBF neural network algorithm was the most effective, with the prediction model yielding an R2 value of 0.950, a root mean square error (RMSE) of 1.014, and a relative percentage deviation (RPD) of 4.479, which suggested a good prediction effect.

Dietary inadequacy is a major challenge among young children in Ghana. Nutritional policies are required for optimum child nutrition and development. This study explored food consumption and dietary diversity by socioeconomic status and geographical location among children aged 6–23 months in Ghana. We used the latest national representative, cross-sectional data from the Ghana Demographic and Health Survey (GDHS-2014). A total of 887 children aged 6–23 months were used in the final analysis. The survey collected data on children’s food consumption through their mothers in the 24 h recall method. Multiple logistic regression models were used to assess the relationship between socioeconomic status and geographical location with food consumption and adequate dietary diversity after adjusting for control variables. The study revealed an association between specific food item consumption, food groups, and dietary diversity by socioeconomic and geographic characteristics. However, dairy consumption increased faster than other nutritional foods when socioeconomic status increased. Furthermore, the study revealed that children’s chances of consuming particular food items and food groups differed across Ghana’s 10 regions. The average probabilities of consuming adequate dietary diversity between the Greater Accra region and Ashanti region were 43% vs. 8% (p < 0.001). Consumption of grains, root, and tubers were relatively higher but low for Vitamin A-rich fruits and vegetables and legumes and nuts for children aged 6–23 months in Ghana. Overall, the mean dietary diversity score was low (3.39; 95% CI: 3.30–3.49) out of eight food groups, and the prevalence of adequate dietary diversity was 22% only. There is a need for policy interventions to ensure appropriate dietary practices to promote healthy growth of children.

Hedychium coronarium J. Koenig is a multipurpose plant with significant economic value, but it has been overexploited and listed as a vulnerable, near threatened or endangered species. In vitro culture methods have been used for propagating disease-free propagules for its conservation and production. However, explant contamination has been a bottleneck in in vitro propagation due to the use of rhizomes as the explant source. Plants in the family Zingiberaceae have pseudostems that support inflorescences, while rhizomes are considered true stems. The present study, for the first time, reported that the pseudostem bears nodes and vegetative buds and could actually be true stems. The evaluation of different sources of explants showed that mature node explants derived from the stem were the most suitable ones for in vitro culture because of the lowest contamination and the highest bud break rates. Culture of mature node explants on MS medium supplemented with 13.32, 17.76, and 22.20 μM 6-benzylaminopurine (BA), each in combination with 9.08 μM thidiazurin (TDZ) and 0.05 μM α-naphthaleneacetic acid (NAA) induced the conversion of buds to micro-rhizomes in six weeks. More than 96% of the micro-rhizomes cultured on MS medium supplemented with 17.76 μM BA, 6.81 μM TDZ, and 2.46 μM indole-3-butyric acid (IBA) were converted to globular-shaped clumps with protocorm-like bodies (PLBs). Further culture of a piece of the clumps induced more than 15 adventitious shoots. Adventitious roots were produced at the base of adventitious shoots, and plantlets were readily transplanted to a substrate for acclimatization in a shaded greenhouse. The survival rate of the plants in the greenhouse was up to 90%. Plants grew vigorously, and there were no off-types from the regenerated 11,100 plants. Our study also, for the first time, shows that H. coronarium can be regenerated via PLBs, which may represent a new way of the in vitro propagation of H. coronarium. The established protocol could be used for the increased propagation of H. coronarium for conservation or commercial production.

Based on a solid orthotropic material with penalization (SOMP) and a double smoothing and projection (DSP) approach, this work proposes a methodology to find an optimal structure design which takes the hybrid deposition path (HDP) pattern and the anisotropic material properties into consideration. The optimized structure consists of a boundary layer and a substrate. The substrate domain is assumed to be filled with unidirectional zig-zag deposition paths and customized infill patterns, while the boundary is made by the contour offset deposition paths. This HDP is the most commonly employed path pattern for the fused deposition modeling (FDM) process. A critical derivative of the sensitivity analysis is presented in this paper, which ensures the optimality of the final design solutions. The effectiveness of the proposed method is validated through several 2D numerical examples.

To address the problem of malnutrition in poor rural areas of China, this study aims to examine the effects of social-psychological factors in food consumption of rural residents in poor counties of Southwest China. In addition, it investigates the role of perceived need and habit within the theory of planned behavior (TPB) in predicting food consumption. A survey with random sampling was conducted on rural residents (n = 424), and the theoretical frameworks of both the standard and extended TPB were applied for comparison purposes. Structural equation modeling was applied to test the relationships among constructs. Consumption of five food items was studied, respectively: meat, eggs, dairy, fish, and fruits. Results showed that incorporation of perceived need and habit substantially increased the explanatory power of the TPB, but these factors only had significant direct effects on intention rather than behavior. Perceived need and habit are stronger predictors of intention than any other TPB construct for consumption of all food items except for meat. We found indirect effects of the constructs in the extended TPB model on consumption to be different across food items. Practical implications to improve consumption of different food items were proposed accordingly.

BackgroundAlthough atrial fibrillation (AF) is the most common abnormal heart rhythm and its prevalence continues to rise, there is a marked paucity of effective and safe antiarrhythmic drugs for AF. This study was done to test whether combined use of dofetilide and mexiletine exhibits not only a synergistic effect on AF suppression but also a safer profile in drug‐induced ventricular proarrhythmias. Methods and ResultsThe effects of dofetilide plus mexiletine on atrial effective refractory period (ERP), AF inducibility, QT, and QT‐related ventricular arrhythmias were studied using the isolated arterially perfused rabbit atrial and ventricular wedge preparations. Dofetilide or mexiletine alone mildly to moderately prolonged atrial ERP, but their combined use produced a markedly rate‐dependent increase in atrial ERP. Dofetilide (3 nmol/L) plus mexiletine (10 μmol/L) increased the ERP by 28.2% from 72.2±5.7 to 92.8±5.9 ms (n=9, P

The application of metabolomics technology to epidemiological studies is emerging as a new approach to elucidate disease etiology and for biomarker discovery. However, analysis of metabolomics data is complex and there is an urgent need for the standardization of analysis workflow and reporting of study findings. To inform the development of such guidelines, we conducted a survey of 47 cohort representatives from the Consortium of Metabolomics Studies (COMETS) to gain insights into the current strategies and procedures used for analyzing metabolomics data in epidemiological studies worldwide. The results indicated a variety of applied analytical strategies, from biospecimen and data pre-processing and quality control to statistical analysis and reporting of study findings. These strategies included methods commonly used within the metabolomics community and applied in epidemiological research, as well as novel approaches to pre-processing pipelines and data analysis. To help with these discrepancies, we propose use of open-source initiatives such as the online web-based tool COMETS Analytics, which includes helpful tools to guide analytical workflow and the standardized reporting of findings from metabolomics analyses within epidemiological studies. Ultimately, this will improve the quality of statistical analyses, research findings, and study reproducibility.

Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC.

Clinical development of cancer drugs has a low success rate. Prognostic and predictive biomarkers using minimally invasive approaches hold promise for increasing the probability of success by enabling disease characterization, patient selection and early detection of drug treatment effect. Enumeration and molecular characterization of circulating tumor cells (CTC) may address some of these needs, and thus were evaluated for utility in a Phase I solid tumor clinical study.Blood samples for CTC analysis were obtained from 24 cancer patients in a multi-center all-comer Phase I study of MEDI-575, a novel anti-PDGFRα antibody. Samples were taken at screening and analyzed for enumeration of CTC using the CellSearch(®) platform and for molecular characterization using a novel quantitative RT-PCR assay.Fifty-nine percent of the patients showed at least 1 CTC per 7.5 ml of blood at baseline. Progression-free survival (PFS) and overall survival (OS) of patients with 0 CTCs at baseline were longer than PFS and Os for patients with 1-3 and >3 CTCs (8.8 versus 1.4 and 1.3 months PFS, P = 0.02; 9.0 vs 7.4 and 3.5 months OS, P = 0.20, respectively). Patients with 0 CTC showed a greater percentage of stable disease than the other 2 groups with 1-3 and >3 CTCs (57% vs 29% and 0%). The multimarker qRT-PCR method detected CTC in 40% of the patients, and 80% of these patients were positive for pre-selected drug target genes.CTC enumeration of patients in an all-comer study is feasible and may allow for patient stratification for PFS and Os to evaluate the clinical response of investigational agents. Gene expression profiling of isolated CTC may provide a means for molecular characterization of selected tumor targets.

MEDI-565 (also known as MT111) is a bispecific T-cell engager (BiTE®) antibody in development for the treatment of patients with cancers expressing carcinoembryonic antigen (CEA). MEDI-565 binds CEA on cancer cells and CD3 on T cells to induce T-cell mediated killing of cancer cells. To understand the molecular basis of human CEA recognition by MEDI-565 and how polymorphisms and spliced forms of CEA may affect MEDI-565 activity, we mapped the epitope of MEDI-565 on CEA using mutagenesis and homology modeling approaches. We found that MEDI-565 recognized a conformational epitope in the A2 domain comprised of amino acids 326-349 and 388-410, with critical residues F(326), T(328), N(333), V(388), G(389), P(390), E(392), I(408), and N(410). Two non-synonymous single-nucleotide polymorphisms (SNPs) (rs10407503, rs7249230) were identified in the epitope region, but they are found at low homozygosity rates. Searching the National Center for Biotechnology Information GenBank® database, we further identified a single, previously uncharacterized mRNA splice variant of CEA that lacks a portion of the N-terminal domain, the A1 and B1 domains, and a large portion of the A2 domain. Real-time quantitative polymerase chain reaction analysis of multiple cancers showed widespread expression of full-length CEA in these tumors, with less frequent but concordant expression of the CEA splice variant. Because the epitope was largely absent from the CEA splice variant, MEDI-565 did not bind or mediate T-cell killing of cells solely expressing this form of CEA. In addition, the splice variant did not interfere with MEDI-565 binding or activity when co-expressed with full-length CEA. Thus MEDI-565 may broadly target CEA-positive tumors without regard for expression of the short splice variant of CEA. Together our data suggest that MEDI-565 activity will neither be impacted by SNPs nor by a splice variant of CEA.

Microbial cloning makes Sanger sequencing of complex DNA samples possible but is labor intensive. We present a simple, rapid and robust method that enables laboratories without special equipment to perform single-molecule amplicon sequencing, although in a low-throughput manner, from sub-picogram quantities of DNA. The method can also be used for quick quality control of next-generation sequencing libraries, as was demonstrated for a metagenomic sample.

PURPOSE: Insulin-like growth factor (IGF) signaling through human insulin receptor isoform A (IR-A) contributes to tumorigenesis and intrinsic resistance to anti-IGF1R therapy. In the present study, we (a) developed quantitative TaqMan real time-PCR-based assays (qRT-PCR) to measure human insulin receptor isoforms with high specificity, (b) evaluated isoform expression levels in molecularly-defined breast cancer subtypes, and (c) identified the IR-A:IR-B mRNA ratio as a potential biomarker guiding patient stratification for anti-IGF therapies. EXPERIMENTAL DESIGN: mRNA expression levels of IR-A and IR-B were measured in 42 primary breast cancers and 19 matched adjacent normal tissues with TaqMan qRT-PCR assays. The results were further confirmed in 165 breast cancers. The tumor samples were profiled using whole genome microarrays and subsequently subtyped using the PAM50 breast cancer gene signature. The relationship between the IR-A:IR-B ratio and cancer subtype, as well as markers of proliferation were characterized. RESULTS: The mRNA expression levels of IR-A in the breast tumors were similar to those observed in the adjacent normal tissues, while the mRNA levels of IR-B were significantly decreased in tumors. The IR-A:IR-B ratio was significantly higher in luminal B breast cancer than in luminal A. Strong concordance between the IR-A:IR-B ratio and the composite Oncotype DX proliferation score was observed for stratifying the latter two breast cancer subtypes. CONCLUSIONS: The reduction in IR-B expression is the key to the altered IR-A:IR-B ratio observed in breast cancer. The IR-A:IR-B ratio may have biomarker utility in guiding a patient stratification strategy for an anti-IGF therapeutic.

There is much interest in characterizing the variation in a human individual, because this may elucidate what contributes significantly to a person's phenotype, thereby enabling personalized genomics. We focus here on the variants in a person's 'exome,' which is the set of exons in a genome, because the exome is believed to harbor much of the functional variation. We provide an analysis of the approximately 12,500 variants that affect the protein coding portion of an individual's genome. We identified approximately 10,400 nonsynonymous single nucleotide polymorphisms (nsSNPs) in this individual, of which approximately 15-20% are rare in the human population. We predict approximately 1,500 nsSNPs affect protein function and these tend be heterozygous, rare, or novel. Of the approximately 700 coding indels, approximately half tend to have lengths that are a multiple of three, which causes insertions/deletions of amino acids in the corresponding protein, rather than introducing frameshifts. Coding indels also occur frequently at the termini of genes, so even if an indel causes a frameshift, an alternative start or stop site in the gene can still be used to make a functional protein. In summary, we reduced the set of approximately 12,500 nonsilent coding variants by approximately 8-fold to a set of variants that are most likely to have major effects on their proteins' functions. This is our first glimpse of an individual's exome and a snapshot of the current state of personalized genomics. The majority of coding variants in this individual are common and appear to be functionally neutral. Our results also indicate that some variants can be used to improve the current NCBI human reference genome. As more genomes are sequenced, many rare variants and non-SNP variants will be discovered. We present an approach to analyze the coding variation in humans by proposing multiple bioinformatic methods to hone in on possible functional variation.

Presented here is a genome sequence of an individual human. It was produced from approximately 32 million random DNA fragments, sequenced by Sanger dideoxy technology and assembled into 4,528 scaffolds, comprising 2,810 million bases (Mb) of contiguous sequence with approximately 7.5-fold coverage for any given region. We developed a modified version of the Celera assembler to facilitate the identification and comparison of alternate alleles within this individual diploid genome. Comparison of this genome and the National Center for Biotechnology Information human reference assembly revealed more than 4.1 million DNA variants, encompassing 12.3 Mb. These variants (of which 1,288,319 were novel) included 3,213,401 single nucleotide polymorphisms (SNPs), 53,823 block substitutions (2-206 bp), 292,102 heterozygous insertion/deletion events (indels)(1-571 bp), 559,473 homozygous indels (1-82,711 bp), 90 inversions, as well as numerous segmental duplications and copy number variation regions. Non-SNP DNA variation accounts for 22% of all events identified in the donor, however they involve 74% of all variant bases. This suggests an important role for non-SNP genetic alterations in defining the diploid genome structure. Moreover, 44% of genes were heterozygous for one or more variants. Using a novel haplotype assembly strategy, we were able to span 1.5 Gb of genome sequence in segments >200 kb, providing further precision to the diploid nature of the genome. These data depict a definitive molecular portrait of a diploid human genome that provides a starting point for future genome comparisons and enables an era of individualized genomic information.