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In this article, we searched the research literatures related to clinical investigation of non-invasive positive pressure ventilation (NPPV) in acute respiratory failure(ARF)/chronic respiratory failure(CRF) between 1本文通过Medline检索2021-10-01至2022-09-30期间无创正压通气（NPPV）用于治疗呼吸衰竭患者的相关临床研究文献并进行综述。在NPPV和高流量鼻导管氧疗（HFNC）治疗新型冠状病毒肺炎相关急性呼吸衰竭（ARF）中有3个大型随机对照试验，结果显示，NPPV（包括单水平持续气道正压通气和双水平气道内正压）可以降低气管插管率，HFNC的效果存在争论。此外，在NPPV治疗ARF的结局预测模型、NPPV相关的心搏骤停事件和人机界面对NPPV治疗效果的影响等方面也取得了一定进展。NPPV在气管插管前预氧合和辅助撤机拔管的研究中显示，NPPV可以减少气管插管过程中严重低氧血症的发生；有助于减少拔管后再次气管插管的风险。在长期家庭应用NPPV方面，提出成功启动的5个指标，但临床实践中符合5个指标的比例低，以及心理干预对长期NPPV依从性的影响等，这些研究结果有助于临床上合理选择和优化应用NPPV。.

Background Speckle tracking echocardiography provides quantification of myocardial deformation and is useful in the assessment of myocardial function. Right ventricular (RV) strain has been suggested as a sensitive tool for diagnosing cardiomyopathies and assessing long term patient outcomes for patients with pulmonary hypertension, severe tricuspid regurgitation and COVID-19 infection. Recent advances in deep learning (DL) have made promising advances in automating the labour-intensive delineation of regions of interest (ROIs). However, compared to echocardiograms with left ventricular (LV) strain, RV strain data is scarce, making DL models difficult to train. Purpose To investigate whether annotated LV strain data could be beneficial in training a DL model for automatic RV strain when using a limited RV dataset. Methods The dataset consisted of anonymized still frames from 141 echocardiograms of the RV in the RV-focused 4 chamber view with corresponding cardiologist-defined ROI. Exams included healthy subjects and patients with heart failure, valvular disease, and conduction abnormalities. ROIs and still images were extracted at the mid-systole, and then quality assessed by an experienced cardiologist as high, medium, or low. The dataset was randomly split into 68%/17%/15% sets for training, validation, and testing. A convolutional neural network for image segmentation (U-Net) with a residual neural network (ResNet50) encoder was used, with a combination of binary cross entropy and Dice loss functions. Augmentation, predefined ImageNet weights and pre-training were also employed. For pre-training, 715 still images in the apical 4 chamber view with LV defined ROIs were used, both in their original and horizontally flipped view. Predicted ROIs were reintroduced into commercially available echocardiogram analysis software to automatically calculate longitudinal strain (LS) values. Results The model pre-trained with the flipped LV images achieved the highest performance with a mean absolute difference of 1.26 percentage points (95% confidence interval (CI): 0.62–1.89 percentage points) between manually measured and DL-assisted LS. Median absolute LS difference was 0.85 (95% CI: 0.28–1.57) percentage points. A Bland-Altman plot revealed two outliers and no obvious trends. In comparison, the mean and median absolute LS differences for the model without pre-training were 1.87 (95% CI: 0.73–3.00) and 1.09 (95% CI: 0.56–1.63) percentage points, respectively. Conclusions The current study demonstrates that DL-assisted, automated RV strain measurement is feasible even with a small dataset, and that performance can be increased by using images annotated for LV strain. While the majority of the predicted RV strain results were within the typical range of intra- and interobserver variability, a few outliers were observed. These outliers could possibly be avoided with the use of larger datasets. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research council of Norway

The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a “cytokine storm,” we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients reveals distinct immunological features of COVID-19 ARDS., Here, the authors perform transcriptional profiling on tracheal aspirates of adults requiring mechanical ventilation for SARS-CoV2-induced acute respiratory distress syndrome (ARDS) and identify a dysregulated host response predicted to predicted to be potentially modulated by dexamethasone.

The material testing machine and the split Hopkinson pressure bar (SHPB) were adopted, respectively, to conduct the static and dynamic compression tests on granite specimens heat treated by...

Neutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domains toward neutralizing epitopes. We constructed a VH-phage library and targeted the angiotensin-converting enzyme 2 (ACE2) binding interface of the SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified VH binders to two non-overlapping epitopes and further assembled these into multivalent and bi-paratopic formats. These VH constructs showed increased affinity to Spike (up to 600-fold) and neutralization potency (up to 1,400-fold) on pseudotyped SARS-CoV-2 virus when compared to standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with a half-maximal inhibitory concentration (IC50) of 4.0 nM (180 ng ml-1). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain engaging an RBD at the ACE2 binding site, confirming our original design strategy.

Nanobodies that neutralize Monoclonal antibodies that bind to the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) show therapeutic promise but must be produced in mammalian cells and need to be delivered intravenously. By contrast, single-domain antibodies called nanobodies can be produced in bacteria or yeast, and their stability may enable aerosol delivery. Two papers now report nanobodies that bind tightly to spike and efficiently neutralize SARS-CoV-2 in cells. Schoof et al. screened a yeast surface display of synthetic nanobodies and Xiang et al. screened anti-spike nanobodies produced by a llama. Both groups identified highly potent nanobodies that lock the spike protein in an inactive conformation. Multivalent constructs of selected nanobodies achieved even more potent neutralization. Science, this issue p. 1473, p. 1479, Potent neutralizers of SARS-CoV-2 are identified by screening either synthetic or llama-produced nanobodies., The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo–electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.

Without an effective prophylactic solution, infections from SARS-CoV-2 continue to rise worldwide with devastating health and economic costs. SARS-CoV-2 gains entry into host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). Disruption of this interaction confers potent neutralization of viral entry, providing an avenue for vaccine design and for therapeutic antibodies. Here, we develop single-domain antibodies (nanobodies) that potently disrupt the interaction between the SARS-CoV-2 Spike and ACE2. By screening a yeast surface-displayed library of synthetic nanobody sequences, we identified a panel of nanobodies that bind to multiple epitopes on Spike and block ACE2 interaction via two distinct mechanisms. Cryogenic electron microscopy (cryo-EM) revealed that one exceptionally stable nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for SARS-CoV-2 Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains stability and function after aerosolization, lyophilization, and heat treatment. These properties may enable aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia, promising to yield a widely deployable, patient-friendly prophylactic and/or early infection therapeutic agent to stem the worst pandemic in a century.

Neutralizing agents against SARS-CoV-2 are urgently needed for treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domain binders with high affinity toward neutralizing epitopes without the need for high-resolution structural information. We constructed a VH-phage library and targeted a known neutralizing site, the angiotensin-converting enzyme 2 (ACE2) binding interface of the trimeric SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified 85 unique VH binders to two non-overlapping epitopes within the ACE2 binding site on Spike-RBD. This enabled us to systematically link these VH domains into multivalent and bi-paratopic formats. These multivalent and bi-paratopic VH constructs showed a marked increase in affinity to Spike (up to 600-fold) and neutralization potency (up to 1400-fold) on pseudotyped SARS-CoV-2 virus when compared to the standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with half-minimal inhibitory concentration (IC50) of 4.0 nM (180 ng/mL). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain bound an RBD at the ACE2 binding site, explaining its increased neutralization potency and confirming our original design strategy. Our results demonstrate that targeted selection and engineering campaigns using a VH-phage library can enable rapid assembly of highly avid and potent molecules towards therapeutically important protein interfaces.

A serious public health crisis is currently unfolding due to the SARS-CoV-2 pandemic. SARS-CoV-2 viral entry depends on an interaction between the receptor binding domain of the trimeric viral Spike protein (Spike-RBD) and the dimeric human angiotensin converting enzyme 2 (ACE2) receptor. While it is clear that strategies to block the Spike/ACE2 interaction are promising as anti-SARS-CoV-2 therapeutics, our current understanding is insufficient for the rational design of maximally effective therapeutic molecules. Here, we investigated the mechanism of Spike/ACE2 interaction by characterizing the binding affinity and kinetics of different multimeric forms of recombinant ACE2 and Spike-RBD domain. We also engineered ACE2 into a split Nanoluciferase-based reporter system to probe the conformational landscape of Spike-RBDs in the context of the Spike trimer. Interestingly, a dimeric form of ACE2, but not monomeric ACE2, binds with high affinity to Spike and blocks viral entry in pseudotyped virus and live SARS-CoV-2 virus neutralization assays. We show that dimeric ACE2 interacts with an RBD on Spike with limited intra-Spike avidity, which nonetheless contributes to the affinity of this interaction. Additionally, we demonstrate that a proportion of Spike can simultaneously interact with multiple ACE2 dimers, indicating that more than one RBD domain in a Spike trimer can adopt an ACE2-accessible “up” conformation. Our findings have significant implications on the design strategies of therapeutic molecules that block the Spike/ACE2 interaction. The constructs we describe are freely available to the research community as molecular tools to further our understanding of SARS-CoV-2 biology.

Mycobacterium tuberculosis is a major public health concern and requires prompt treatment. Goals of treatment include curing the individual patient and protecting the community from ongoing tuberculosis transmission. To achieve durable cure, regimens must include multiple agents given concurrently and in a manner to ensure completion of therapy. This article focuses on preferred regimens of drug-susceptible tuberculosis under current guidelines by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America and World Health Organization. In addition, topics including patient centered care, poor treatment outcomes, and adverse effects are also discussed.

A historic haze event, characterized by lengthy, large-scale and severe pollution, occurred in the Yangtze River Delta (YRD) of China from 1 to 10 December 2013. This haze event significantly influenced air quality throughout the region, especially in urban areas. Aerosol physical, chemical and optical properties were measured in Shanghai. Sometimes the 1 h average particle concentration (e.g., PM2.5) exceeded 600 µg m−3. Inorganic water-soluble ions in particles, trace gases and aerosol optical coefficients had a similar tendency to increase evidently from clear to hazy episodes. A combination of various factors contributed to the formation and evolution of the haze event, among which meteorological conditions, local anthropogenic emissions and pollutants are the major factors. High pressure system, calm surface wind and subsidence airflow were responsible for the decrease of planetary boundary layer (PBL) and the accumulation of pollutants. Atmospheric visibility correlated strongly with relative humidity (RH), particle number in size of 600–1400 nm other than particulate water-soluble species and particle mass (PM2.5). The particle hygroscopicity plays an important role in atmospheric visibility reduction. The results are somewhat helpful to forecast and eliminate regional atmospheric pollution in China.

Excessive zinc (Zn) uptake is toxic to both plants and animals. 24-Epibrassinolide (EBL), a plant steroid hormone, plays a pivotal role in regulating plant resistance to various stresses. In this s...

The carbon (C) cycling in semiarid and arid areas remains largely unexplored, despite the wide distribution of drylands globally. Rehabilitation practices have been carried out in many desertified areas, but information on the C sequestration capacity of recovering vegetation is still largely lacking. Using the eddy-covariance technique, we measured the net ecosystem CO2 exchange (NEE) over a recovering shrub ecosystem in northwest China throughout 2012 in order to (1) quantify NEE and its components and to (2) examine the dependence of C fluxes on biophysical factors at multiple timescales. The annual budget showed a gross ecosystem productivity (GEP) of 456 g C m−2 yr−1 (with a 90% prediction interval of 449–463 g C m−2 yr−1) and an ecosystem respiration (Re) of 379 g C m−2 yr−1 (with a 90% prediction interval of 370–389 g C m−2 yr−1), resulting in a net C sink of 77 g C m−2 yr−1 (with a 90% prediction interval of 68–87 g C m−2 yr−1). The maximum daily NEE, GEP and Re were −4.7, 6.8 and 3.3 g C m−2 day−1, respectively. Both the maximum C assimilation rate (i.e., at the optimum light intensity) and the quantum yield varied over the growing season, being higher in summer and lower in spring and autumn. At the half-hourly scale, water deficit exerted a major control over daytime NEE, and interacted with other stresses (e.g., heat and photoinhibition) in constraining C fixation by the vegetation. Low soil moisture also reduced the temperature sensitivity of Re (Q10). At the synoptic scale, rain events triggered immediate pulses of C release from the ecosystem, followed by peaks of CO2 uptake 1–2 days later. Over the entire growing season, leaf area index accounted for 45 and 65% of the seasonal variation in NEE and GEP, respectively. There was a linear dependence of daily Re on GEP, with a slope of 0.34. These results highlight the role of abiotic stresses and their alleviation in regulating C cycling in the face of an increasing frequency and intensity of extreme climatic events.

The effects of foliar application of 24-epibrassinolide (EBR) on chlorophyll content, oxidative damage, and antioxidant capacity in eggplant (Solanum melongena L.) seedlings during a short-term chilling stress and subsequent recovery were investigated. The eggplant seedlings pretreated with 0.1 μM EBR were exposed to 5 °C for 12 h in the dark and then recovered under a normal temperature for another 12 h. The results show that EBR alleviated a chilling-induced oxidative stress reflected by a decrease in malondialdehyde and H2O2 content, O2 ·− production rate, and an increase in chlorophyll content and activities of superoxide dismutase, guaicol peroxidase, and catalase. The EBR pretreatment also promoted activities of ascorbate peroxidase, glutathione reductase, dehydroascorbate reductase, as well as the accumulation of ascorbic acid (AsA) and glutathione (GSH) involved in the AsA-GSH cycle. Moreover, after the12 h recovery, EBR plus chilling treated leaves showed no significant changes in content of MDA and chlorophyll a, lower reactive oxygen species (ROS) content, and greater activities of AsA-GSH cycle enzymes than in seedlings only chilled. The results suggest that EBR alleviated an oxidative damage caused by the dark chilling stress and accelerated a recovery rate mainly through increasing the ROS scavenging system including the AsA-GSH cycle.

SummaryBrassinosteroids (BRs) have been implicated in the responses of plants to various environmental stresses.To explore the mechanism(s) of BRs in the tolerance of plants to low temperatures, 24-epibrassinolide (EBR)-induced changes in chlorophyll concentrations, gas exchange parameters, chlorophyll fluorescence, and anti-oxidant defence systems in eggplant (Solanum melongena L.) were studied under chilling stress conditions. Seedlings were exposed to 10°C/5°C (day/night) chilling temperatures for 8 d, with or without a single spray of 0.1 ?M EBR applied 24 h beforehand.The EBR treatment partially overcame the inhibition of growth caused by 8 d of chilling stress.The application of EBR to chilled seedlings had a significant effect on photosynthesis, as reflected by increases in the concentrations of chlorophyll a, chlorophyll b, and total chlorophyll, the net photosynthetic rate (Pn), stomatal conductance (gs), the quantum efficiency of PSII (Fv/Fm), the efficiency of the excitation capture of open PSI...

Explanations for the occurrence of hysteresis (asynchronicity) between diel soil respiration (Rs) and soil temperature (Ts) have evoked both biological and physical mechanisms. The specifics of these explanations, however, tend to vary with the particular ecosystem or biome being investigated. So far, the relative degree of control of biological and physical processes on hysteresis is not clear for drylands. This study examined the seasonal variation in diel hysteresis and its biological control in a desert-shrub ecosystem in northwest (NW) China. The study was based on continuous measurements of Rs, air temperature (Ta), temperature at the soil surface and below (Tsurf and Ts), volumetric soil water content (SWC), and photosynthesis in a dominant desert shrub (i.e., Artemisia ordosica) over an entire year in 2013. Trends in diel Rs were observed to vary with SWC over the growing season (April to October). Diel variations in Rs were more closely associated with variations in Tsurf than with photosynthesis as SWC increased, leading to Rs being in phase with Tsurf, particularly when SWC > 0.08 m3 m−3 (ratio of SWC to soil porosity = 0.26). However, as SWC decreased below 0.08 m3 m−3, diel variations in Rs were more closely related to variations in photosynthesis, leading to pronounced hysteresis between Rs and Tsurf. Incorporating photosynthesis into a Q10-function eliminated 84.2 % of the observed hysteresis, increasing the overall descriptive capability of the function. Our findings highlight a high degree of control by photosynthesis and SWC in regulating seasonal variation in diel hysteresis between Rs and temperature., published version, peerReviewed

This study was carried out to understand the mechanism of protection of plants under cold stress by exogenous 24-epibrassinolide (EBR). The eggplant (Solanum melongena L.) seedlings were pretreated with five concentrations of EBR (0, 0.05, 0.1, 0.2 and 0.4 °M) and then exposed to day/night temperatures of 10/5 °C for 8 d. The results show that EBR, especially 0.1 °M EBR, dramatically alleviated growth suppression and a decrease in chlorophyll content and photosynthetic rate caused by the cold stress. In addition, EBR also decreased malondialdehyde content and O2·− production rate induced by the cold stress, and increased the activities of superoxide dismutase, guaiacol peroxidase, catalase, and ascorbate peroxidase, and proline content. The results of the present study suggest that exogenous EBR could improve cold tolerance of eggplant by regulating photosynthesis and antioxidative systems.

Cordyceps (= Cordyceps sensu lato) fungi are rather well known as entomopathogens and also for their medicinal importance in curing many diseases. Many cordyceps species with widespread distribution throughout China have been recorded earlier. However, their taxonomy, hosts, life cycles and the plants on which the host insects reside in are poorly understood, and have sometimes led to confusion in the proper identification of the species. In this study, Xuefeng Cordyceps collected from Xuefeng Mountain, Hunan, China are identified and an assessment of their life cycles, proper hosts and plants they are associated with is made through morphological and DNA sequence- based analyses. Morphological characterization reveals that Ophiocordyceps xuefengensis from this region as commonly accepted by mycologists and local people. Species collected also include Beauveria bassiana (sexual and asexual), Metacordyceps taii (syn. of Metarhizium guizhouense ), Ophiocordyceps macroacicularis and Ophiocordyceps ramosissimum . Our result challenges previous taxonomic arrangement with regard to host identity. The hosts, previously mistaken for larvae of Endoclita nodus , are corrected herein as larvae of Endoclita davidi (Lepidoptera: Hepialidae). Ribosomal DNA sequence analyses based on the ITS regions also confirm that Clerodendrum cyrtophyllum (Lamiaceae) is the plant on which the host insects reside. Morphological illustrations, where appropriate, are given for the cordyceps species, hosts and plants. The infection mechanism and life cycle of the cordyceps are also outlined.

SummaryNitric oxide (NO) is an active molecule involved in many physiological functions in plants. To characterise the roles of NO in the tolerance of eggplant (Solanum melongena L.) to salt stress, the protective effects of exogenous sodium nitroprusside (SNP), a donor of NO, applied at different concentrations (0, 0.05, 0.1, or 0.2 mM), on plant biomass, photosynthesis, and anti-oxidant capacity were evaluated. The application of SNP alleviated the suppression of growth in eggplant under salt stress, as reflected by a higher accumulation of biomass. In parallel with growth, the application of SNP to salt-stressed plants resulted in enhanced photosynthetic parameters such as the net photosynthetic rate (Pn), stomatal conductance (gs), transpiration rate (Tr), and intercellular CO2 concentration (Ci), as well as an increased quantum efficiency of PSII (Fv/Fm), efficiency of excitation capture of open PSII centres (Fv’/Fm’), quantum yield of PSII ( psii) and photochemical quenching coefficient (qP). Furthe...

The effects of exogenous 24-epibrassinolide (EBR) on the growth, oxidative damage, antioxidant system and ion contents in eggplant (Solanum melongena L.) seedlings under salt stress were investigated. Eggplant seedlings were exposed to 90 mM NaCl with 0, 0.025, 0.05, 0.10 and 0.20 mg dm−3 EBR for 10 d. EBR, especially at concentration 0.05 mg dm−3, alleviated growth suppression caused by NaCl stress, decreased electrolyte leakage, superoxide production and content of malondialdehyde and H2O2 in NaCl-treated plants. EBR also increased activities of superoxide dismutase, guaiacol peroxidase, catalase and ascorbate peroxidase and the contents of ascorbic acid and reduced glutathione. Furthermore, we also found that Na+, Cl− contents were decreased, K+, Ca2+ contents and K+/Na+, Ca2+/Na+ ratios were increased in the presence of EBR under salt stress.

HIV protease inhibitors (PIs) are the cornerstone of Highly Active Antiretroviral Therapy (HAART). Their antiretroviral potent is attributable to their pharmacokinetic properties. Yet, as the pharmacologic target of HIV PIs is localized within HIV-infected cells, cellular pharmacokinetic properties must also be determined to predict not only efficacy, but also toxicity. In this review, we review recent studies about cellular pharmacokinetics of current marketed HIV PIs, as well as the physicochemical properties of HIV PIs and their drug transporters and enzymes. Additionally, a summary of potential strategies for optimizing cellular pharmacokinetics of HIV PIs and initial ideas to study cellular pharmacokinetics is also discussed. Cellular pharmacokinetics of HIV PIs is an important budding field of research that will significantly influence efficacy and toxicity profiles of these essential drugs, and we hope our review will aid in fundamental knowledge for future research.

The role of endoplasmic reticulum (ER) stress is a rapidly emerging field of interest in the pathogenesis of metabolic diseases. Recent studies have shown that chronic activation of ER stress is closely linked to dysregulation of lipid metabolism in several metabolically important cells including hepatocytes, macrophages, β-cells, and adipocytes. Adipocytes are one of the major cell types involved in the pathogenesis of the metabolic syndrome. Recent advances in dissecting the cellular and molecular mechanisms involved in the regulation of adipogenesis and lipid metabolism indicate that activation of ER stress plays a central role in regulating adipocyte function. In this paper, we discuss the current understanding of the potential role of ER stress in lipid metabolism in adipocytes. In addition, we touch upon the interaction of ER stress and autophagy as well as inflammation. Inhibition of ER stress has the potential of decreasing the pathology in adipose tissue that is seen with energy overbalance.

BACKGROUND AND PURPOSE Intracellular pharmacokinetics of anticancer drugs in multi-drug resistance (MDR) cancer cells is hugely important in the evaluation and improvement of drug efficacy. By using adriamycin as a probe drug in MDR cancer cells, we developed a cellular pharmacokinetic-pharmacodynamic (PK-PD) model to reveal the correlation between cellular pharmacokinetic properties and drug resistance. In addition, the ability of 20(S)-ginsenoside Rh2 (20(S)-Rh2) to reverse MDR was further investigated. EXPERIMENTAL APPROACH The cellular pharmacokinetics of adriamycin were analysed visually and quantitatively in human breast cancer cells MCF-7 and in adriamycin-resistant MCF-7 (MCF-7/Adr) cells. Mitochondria membrane potential was assayed to evaluate the apoptotic effect of adriamycin. Subsequently, a PK-PD model was developed via MATLAB. KEY RESULTS Visual and quantitative data of the dynamic subcellular distribution of adriamycin revealed that it accumulated in cells, especially nuclei, to a lesser and slower extent in MCF-7/Adr than in MCF-7 cells. 20(S)-Rh2 increased the rate and amount of adriamycin entering cellular/subcellular compartments in MCF-7/Adr cells through inhibition of P-glycoprotein (P-gp) activity, in turn augmenting adriamycin-induced apoptosis. The integrated PK-PD model mathematically revealed the pharmacokinetic mechanisms of adriamycin resistance in MCF-7/Adr cells and its reversal by 20(S)-Rh2. CONCLUSIONS AND IMPLICATIONS P-gp, which is overexpressed and functionally active at cellular/subcellular membranes, influences the cellular pharmacokinetic and pharmacological properties of adriamycin in MCF-7/Adr cells. Inhibition of P-gp activity represents a key mechanism by which 20(S)-Rh2 attenuates adriamycin resistance. Even more importantly, our findings provide a new strategy to explore the in-depth mechanisms of MDR and evaluate the efficacy of MDR modulators.

CeP2O7, a close structural relative of ZrP2O7, and many other MIVX2O7 (X – P, V, As) phases, forms on heating Ce(HPO4)2·xH2O between ∼300 and 600 °C and decomposes by oxygen loss at higher temperatures. In-situ X-ray diffraction measurements showed, for some precursor batches, the formation of CeP2O7 in two distinct stages. At room temperature, CeP2O7 is pseudocubic, but probably triclinic, displaying positive thermal expansion below ∼115 °C. Above this temperature, there is a transition to cubic symmetry (Pa3) with the linear coefficient of thermal expansion going to zero at ∼450 °C and becoming negative at higher temperatures. CeP2O7 probably undergoes two phase transitions on compression below ∼10.5 GPa. The phase existing between 0.65 and ∼5 GPa is soft with an average bulk modulus of ∼18 GPa.

In the present study, quantitative trait loci (QTLs) controlling seed storability based on relative germination rate (%) were dissected using a saturated linkage map and a recombinant inbred lines (RILs) derived from a cross of japonica cultivar Asominori (Oryza sativa L.) and indica cultivar IR24 (Oryza sativa L.). A total of three QTLs (qRGR-1, qRGR-3 and qRGR-9) were detected on chromosomes 1, 3 and 9 with LOD score ranging from 3.45 to 6.95 and the phenotypic variance explained from 16.72% to 28.63%. The IR24 alleles were all associated with seed storability at all the three QTLs. The existence of these QTLs was confirmed using IR24 chromosome segment substitution lines (CSSLs) in Asominori genetic background (AIS). By QTL comparative analysis, the QTL, qRGR-9 on chromosomes 9 appeared to be consistent with another rice population, this region may provide an important region for isolating this responsible gene. These results also provide the possibilities of enhancing Seed storability in rice breeding program by marker-assisted selection (MAS) and pyramiding QTLs.

The pressure dependence of the lattice parameters of the ternary layered carbide, Ti2SC, was measured by using synchrotron radiation X-ray diffraction and a diamond anvil cell setup. The experiment ...

Soil respiration (Rs) and its biophysical controls were measured over a fixed sand dune in a desert-shrub ecosystem in northwest China in 2012 to explore the mechanisms controlling the spatial heterogeneity in Rs and to understand the plant effects on the spatial variation in Rs in different phenophases. The measurements were carried out on four slope orientations (i.e., windward, leeward, north- and south-face) and three height positions on each slope (i.e., lower, upper, and top) across the phenophases of the dominant shrub species (Artemisia ordosica). Coefficient of variation (i.e., standard deviation/mean) of Rs across the 11 microsites over our measurement period was 23.5 %. Soil respiration was highest on the leeward slope, but lowest on the windward slope. Over the measurement period, plant-related factors, rather than micro-hydrometeorological factors, affected the topographic variation in Rs. During the flowering-bearing phase, root biomass affected Rs most, explaining 72 % of the total variation. During the leaf coloration-defoliation phase, soil nitrogen content affected Rs the most, explaining 56 % of the total variation. Our findings highlight that spatial pattern in Rs was dependent on plant distribution over a desert sand dune, and plant-related factors largely regulated topographic variation in Rs, and such regulations varied with plant phenology.

Driven piles are used widely both offshore and onshore. However, accurate axial capacity and load-displacement prediction is difficult at sand-dominated sites, and offshore practice is moving towards cone penetration test (CPT) based design methods developed from instrumented pile research and database studies. However, onshore use of these methods remains limited; there is a paucity of high quality case histories to assess their potential benefits clearly, and application in layered profiles may be uncertain. This paper presents new tests on prestressed concrete (PHC) pipe piles driven in sands for a major new Yangtze River bridge project in China, assessing the performance of the ‘new CPT’ and conventional capacity approaches, considering the influence of weak sublayers on base resistance and noting the marked changes in shaft capacity that apply over time.

Polycrystalline Fe3C (cementite) was compressed in a neon pressure medium to 30.5 GPa at 300 K using diamond-anvil cell techniques. Angular dispersive X-ray diffraction of Fe3C was measured using monochromatic synchrotron radiation and imaging plates. No phase transition was observed up to the highest pressure studied. The pressure–volume data were fitted to a third-order Birch–Murnaghan equation of state. With V 0 constrained to a measured value of 155.28 A3, the best fit yielded a 300-K isothermal bulk modulus K 0 = 174 ± 6 GPa, and its pressure derivative at constant temperature K 0 ′ =(K 0 /P) T = 4.8±0.8.

Measurements of Cloud condensation nuclei (CCN), condensation nuclei (CN) and aerosol chemical composition were performed simultaneously at an urban site of Shanghai from 6 to 9 November 2010. The variations of CCN number concentration (NCCN) and aerosol activity (activated aerosol fraction, NCCN/NCN) were examined during a fog-haze co-occurring event. Anthropogenic pollutants emitted from vehicles and unfavorable meteorological conditions such as low planetary boundary layer (PBL) height exerted a great influence on CN and black carbon (BC) loadings. NCCN at 0.2% supersaturation (SS) mostly fell in the range of 994 to 6268 cm−3, and the corresponding NCCN/NCN varied between 0.09 and 0.57. NCCN and NCCN/NCN usually were higher in hazy days due to increased aerosol concentration in the accumulation mode (100–500 nm), and lower in foggy-hazy and clear days. BC mass concentration posed a strong positive effect on NCCN in foggy-hazy and hazy days, whereas it poorly correlated with NCCN in clear days. NCCN/NCN was weakly related with BC both in foggy-hazy/hazy and clear days. By using a simplified particle hygroscopicity (κ), the calculated critical dry size (CDS) of activated aerosol did not exceed 130 nm at 0.2% SS in spite of diverse aerosol chemical compositions. The predicted NCCN at 0.2% SS was very successful compared with the observed NCCN in clear days (R2=0.96) and foggy-hazy/hazy days (R2=0.91). In addition, their corresponding ratios of predicted to observed NCCN were on average 0.95 and 0.92, respectively. More organic matter is possibly responsible for this closure difference between foggy-hazy/hazy and clear days. These results reveal that the particulate pollutant burden exerts a significant impact on NCCN, especially NCCN/NCN promotes effectively during the polluted periods.

The carbon (C) cycling in semiarid and arid areas remains largely unexplored, despite the wide distribution of drylands globally. Rehabilitation practices have been carried out in many desertified areas, but information on the C sequestration potential of recovering vegetation is still largely lacking. Using the eddy-covariance technique, we measured the net ecosystem CO2 exchange (NEE) over a recovering shrub ecosystem in northwest China throughout 2012 in order to (1) quantify NEE and its components, (2) examine the dependence of C fluxes on biophysical factors at multiple timescales. The annual budget showed a gross ecosystem productivity (GEP) of 456 ± 8 g C m−2 yr−1 and an ecosystem respiration (Re) of 379 ± 3 g C m−2 yr−1, resulting in a net C sink of 77 ± 7 g C m−2 yr−1. The maximum daily NEE, GEP and Re were −4.7, 6.8 and 3.3 g C m−2 day−1, respectively. Both the maximum C assimilation rate (i.e., at optimum light intensity) and the quantum yield varied strongly over the growing season, being higher in summer and lower in spring and autumn. At the half-hourly scale, water stress exerted a major control over daytime NEE, and interacted with heat stress and photoinhibition in constraining C fixation by the vegetation. Low soil moisture also reduced the temperature sensitivity of Re (Q10). At the synoptic scale, rain events triggered immediate pulses of C release from the ecosystem, followed by peaks of CO2 uptake 1–2 days later. Over the entire growing season, leaf area index accounted for 45 and 65% of the seasonal variation in NEE and GEP, respectively. There was a linear dependence of daily Re on GEP, with a slope of 0.34. These results highlight the role of abiotic stresses and their alleviation in regulating C cycling in the face of an increasing frequency and intensity of extreme climatic events.

Taxonomy of a tetrigid genus Formosatettixoides Zheng is reviewed. Two new species, Formosatettixoides nigellus n. sp. and Formosatettixoides dabieshanensis n. sp. are described. Redescription of the characters of the genus is given, the distribution and an updated key to the now 10 species of the genus are presented.

Characters of the tetrigid genus Alulatettix Liang are redescribed. Three new species, Alulatettix nigromarginalis n. sp., Alulatettix flavotibialis n. sp., and Alulatettix tianzhushanensis n. sp., are described. An updated key to the species of this genus is provided.

BackgroundHIV protease inhibitor (PI)-induced inflammatory response in macrophages is a major risk factor for cardiovascular diseases. We have previously reported that berberine (BBR), a traditional herbal medicine, prevents HIV PI-induced inflammatory response through inhibiting endoplasmic reticulum (ER) stress in macrophages. We also found that HIV PIs significantly increased the intracellular concentrations of BBR in macrophages. However, the underlying mechanisms of HIV PI-induced BBR accumulation are unknown. This study examined the role of P-glycoprotein (P-gp) in HIV PI-mediated accumulation of BBR in macrophages.Methodology and principal findingsCultured mouse RAW264.7 macrophages, human THP-1-derived macrophages, Wild type MDCK (MDCK/WT) and human P-gp transfected (MDCK/P-gp) cells were used in this study. The intracellular concentration of BBR was determined by HPLC. The activity of P-gp was assessed by measuring digoxin and rhodamine 123 (Rh123) efflux. The interaction between P-gp and BBR or HIV PIs was predicated by Glide docking using Schrodinger program. The results indicate that P-gp contributed to the efflux of BBR in macrophages. HIV PIs significantly increased BBR concentrations in macrophages; however, BBR did not alter cellular HIV PI concentrations. Although HIV PIs did not affect P-gp expression, P-gp transport activities were significantly inhibited in HIV PI-treated macrophages. Furthermore, the molecular docking study suggests that both HIV PIs and BBR fit the binding pocket of P-gp, and HIV PIs may compete with BBR to bind P-gp.Conclusion and significanceHIV PIs increase the concentration of BBR by modulating the transport activity of P-gp in macrophages. Understanding the cellular mechanisms of potential drug-drug interactions is critical prior to applying successful combinational therapy in the clinic.

The overwhelming impact the Human Immunodeficiency Virus (HIV) has on the world is undeniable – by the end of 2009 there were 33.3 million people living with HIV in the world, with 1.8 million deaths in that year alone (WHO 2010). In addition, the high rate of deaths can be directly attributed to the lack of available medications – only 36% of the infected population received adequate antiretroviral therapy (WHO 2009). Besides the known political and monetary issues at hand, the multiple number of HIV virus subtypes and subsubtypes that have been described are overwhelming pharmaceutical availability. In fact, most research completed on HIV therapies has occurred, and continues to occur, in Europe and America, targeting the HIV-1 strain, although much of the world population is also afflicted by HIV-2. To combat viral strain mutations, Highly Active Antiretroviral Therapy (HAART) has increased in complexity and effectively decreased deaths from opportunistic infections in those that are candidates for this treatment. However, these advances are tainted with metabolic long-term side effects, some of which are directly attributed to HIV Protease Inhibitors (PIs). HAART has been linked to cardiovascular complications in HIV-1 patients, and recent studies have shown that HIV PIs play critical roles in insulin resistance, dysregulation of lipid metabolism, and inflammation, which are all cornerstones of cardiovascular complications. In addition, HIV PI-induced atherosclerotic cardiovascular disease is becoming the leading cause of mortality in HIV-1 infected persons in developed countries. During the last decade, an extensive effort has been put forth to study HAART-induced side effects. Both in vitro and in vivo animal studies from our laboratory and others’ have linked HIV PIs with the activation of endoplasmic reticulum (ER) stress and oxidative stress as well as an increase in inflammatory cytokine production from several cell types including macrophages, hepatocytes, intestinal epithelial cells and adipocytes. However, the underlying cellular and molecular mechanisms remain to be fully identified and therapeutic strategies are currently unavailable. Understanding the root causes of HAART-associated metabolic syndrome and its potential implications for HIV-infected patients will be critical to the design of effective interventions to combat the metabolic and cardiovascular diseases

Brillouin light scattering was used to obtain elastic and piezoelectric constants for a single domain orthorhombic KNbO3 single crystal at room temperature and pressure. More than 320 measurements of longitudinal and transverse acoustic wave velocities were obtained in 160 different crystallographic directions. An inversion of these data using the literature values for the dielectric permittivity of KNbO3 resulted in the full set of elastic and piezoelectric constants for the material. It is suggested that the difference between piezoelectric constants obtained by high‐ and low‐frequency methods could be explained by the high‐frequency relaxation‐type dispersion for the dielectric constant e33 in the GHz region by analogy with BaTiO3. The directional dependence of electromechanical coupling for longitudinal and transverse acoustic waves in KNbO3 was analyzed. The obtained elastic constants were (in GPa): CE11=224(4), CE22=273(5), CE33=245(5), CE44=75(1), CE55=28.5(5), CE66=95(2), CE12=102(5), CE13=182(10)...