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This study presents a data-driven approach to identifying anomaly-sensitive parameters through a multiscale, multifaceted analysis of simulated respiratory flows. The anomalies under consideration include a pharyngeal model with three levels of constriction (M1, M2, M3) and a flapping uvula with two types of kinematics (K1, K2). Direct numerical simulations (DNS) were implemented to solve the wake flows induced by a flapping uvula; instantaneous vortex images, as well as pressures and velocities at seven probes, were recorded for twelve cycles. Principal component analysis (PCA), wavelet-based multifractal spectrum and scalogram, and Poincaré mapping were implemented to identify anomaly-sensitive parameters. The PCA results demonstrated a reasonable periodicity of instantaneous vortex images in the leading vector space and revealed distinct patterns between models with varying uvula kinematics (K1, K2). At higher PCA ranks, the periodicity gradually decays, eventually transitioning to a random pattern. The multifractal spectra and scalograms of pressures in the pharynx (P6, P7) show high sensitivity to uvula kinematics, with the pitching mode (K2) having a wider spectrum and a left-skewed peak than the heaving mode (K1). Conversely, the Poincaré maps of velocities and pressures in the pharynx (Vel6, Vel7, P6, P7) exhibit high sensitivity to pharyngeal constriction levels (M1–M3), but not to uvula kinematics. The parameter sensitivity to anomaly also differs with the probe site; thus, synergizing measurements from multiple probes with properly extracted anomaly-sensitive parameters holds the potential to localize the source of snoring and estimate the collapsibility of the pharynx.

Abstract Background COVID-19 is a global pandemic. Understanding the immune responses in pregnant women recovering from COVID-19 may suggest new therapeutic approaches. Methods We performed a cross-sectional study between March 1, 2020, and September 1, 2020. Participants were assigned into the convalescent COVID-19 group if they had a previous COVID-19 infection during pregnancy or the healthy control group. RNA-Seq was performed on human umbilical cord mesenchymal stem cells (hUMSCs) and human amniotic mesenchymal stem cells (hAMSCs). Immunohistochemical staining, cytokine testing, lymphocyte subset analysis, RNA-Seq, and functional analyses were performed on the placental and umbilical cord blood (UCB) and compared between the two groups. Results A total of 40 pregnant women were enrolled, with 13 in the convalescent group and 27 in the control group. There were 1024, 46, and 32 differentially expressed genes (DEGs) identified in the placental tissue, hUMSCs, and hAMSCs between the convalescent and control groups, respectively. Enrichment analysis showed those DEGs were associated with immune homeostasis, antiviral activity, cell proliferation, and tissue repair. Levels of IL-6, TNF-α, total lymphocyte counts, B lymphocytes, Tregs percentages, and IFN-γ expressing CD4+ and CD8+ T cells were statistically different between two groups (p ≤ 0.05). ACE2 and TMPRSS2 expressed on the placenta were not different between the two groups (p > 0.05). Conclusion Multiple changes in immune responses occurred in the placental tissue, hUMSCs, and hAMSCs after maternal recovery from COVID-19, which might imply their protective roles against COVID-19 infection.

Abstract Background Recent studies have shown that mesenchymal stem cell (MSC) therapy has potential therapeutic effects for patients with end-stage liver diseases. However, a consensus on the efficacy and safety of MSCs has not been reached. Methods A systemic literature review was conducted by searching the Cochrane Library and PubMed databases for articles that evaluated the impact of MSC therapy on the outcomes among patients with end-stage liver disease. Various parameters, including pre- and post-treatment model of end-stage liver disease (MELD) score, serum albumin (ALB), total bilirubin (TB), coagulation function, aminotransferase, and survival rate, were evaluated. Results This meta-analysis included a final total of 13 studies and 854 patients. The results indicated improved liver parameters following MSC therapy at different time points, including in terms of MELD score, TB level, and ALB level, compared with conventional treatment. Furthermore, the MSC treatment increased the overall survival rate among patients with liver cirrhosis and acute-on-chronic liver failure (ACLF). The changes in transaminase level and coagulation function differed between the different therapies at various post-treatment time points, indicating that MSC therapy provided no significant benefits in this regard. The further subgroup analysis stratified by liver background revealed that patients with ACLF benefit more from MSC therapy at most time points with improved liver function, including in terms of MELD score, TB level, and ALB level. In addition, no serious side effects or adverse events were reported following MSC therapy. Conclusions The meta-analysis results suggest that MSC therapy is safe and results in improved liver function and survival rates among patients with end-stage liver disease. The subgroup analysis stratified by liver background indicated that patients with ACLF benefit more from MSC therapy than patients with liver cirrhosis at most time points.

Abstract Tumor microenvironment and metabolic reprogramming are critical for tumor metastasis. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are widely involved in the formation of tumor microenvironment and present oncogenic phenotypes to facilitate lymph node metastasis (LNM) in response to small extracellular vesicles (sEV) released by gastric cancer (GC) cells. However, whether metabolic reprograming mediates transformation of BM-MSCs remains elusive. Herein, we revealed that the capacity of LNM-GC-sEV educating BM-MSCs was positively correlated with the LNM capacity of GC cells themselves. Fatty acid oxidation (FAO) metabolic reprogramming was indispensable for this process. Mechanistically, CD44 was identified as a critical cargo for LNM-GC-sEV enhancing FAO via ERK/PPARγ/CPT1A signaling. ATP was shown to activate STAT3 and NF-κB signaling to induce IL-8 and STC1 secretion by BM-MSCs, thereby in turn facilitating GC cells metastasis and increasing CD44 levels in GC cells and sEV to form a persistent positive feedback loop between GC cells and BM-MSCs. The critical molecules were abnormally expressed in GC tissues, sera and stroma, and correlated with the prognosis and LNM of GC patients. Together, our findings uncover the role of metabolic reprogramming mediated BM-MSCs education by LNM-GC-sEV, which presents a novel insight into the mechanism underlying LNM and provides candidate targets for GC detection and therapy.

Abstract Brain white matter (WM) networks have been widely studied in neuropsychiatric disorders. However, few studies have evaluated alterations in WM network topological organization in patients with methamphetamine (MA) dependence. Therefore, using machine learning classification methods to analyze WM network topological attributes may give new insights into patients with MA dependence. In the study, diffusion tensor imaging-based probabilistic tractography was used to map the weighted WM networks in 46 MA-dependent patients and 46 control subjects. Using graph-theoretical analyses, the global and regional topological attributes of WM networks for both groups were calculated and compared to determine inter-group differences using a permutation-based general linear model. In addition, the study used a support vector machine (SVM) learning approach to construct a classifier for discriminating subjects with MA dependence from control subjects. Relative to the control group, the MA-dependent group exhibited abnormal topological organization, as evidenced by decreased small-worldness and modularity, and increased nodal efficiency in the right medial superior temporal gyrus, right pallidum, and right ventromedial putamen; the MA-dependent group had the higher hubness scores in 25 regions, which were mainly located in the default mode network. An SVM trained with topological attributes achieved classification accuracy, sensitivity, specificity, and kappa values of 98.09% ± 2.59%, 98.24% ± 4.00%, 97.94% ± 4.26%, and 96.18% ± 5.19% for patients with MA dependence. Our results may suggest altered global WM structural networks in MA-dependent patients. Furthermore, the abnormal WM network topological attributes may provide promising features for the construction of high-efficacy classification models.

Based on the demand for high-power output, a spatial beam combining 7-channel quantum cascade lasers (QCLs) is demonstrated in this paper. A “2 + 3 + 2” stepped structure is designed to convert the seven beam spots into a circular arrangement. An aspherical lens with a large numerical aperture (NA) of 0.85 and a focal length of 1.873 mm is used in each single QCL for collimation, and seven reflectors are utilized in the 7-channel QCLs combined in the spatial beam. After combining the spatial beam, the maximum continuous output power of the system is 3.6 W, and the beam quality M2 is 5.59 in the fast axis and 8.3 in the slow axis, respectively.

Cicadas are heavy fliers well known for their life cycles and sound production; however, their flight capabilities have not been extensively investigated. Here, we show for the first time that cicadas appropriate backward flight for additional maneuverability. We studied this flight mode using computational fluid dynamics (CFD) simulations based on three-dimensional reconstructions of high-speed videos captured in a laboratory. Backward flight was characterized by steep body angles, high angles of attack, and high wing upstroke velocities. Wing motion occurred in an inclined stroke plane that was fixed relative to the body. Likewise, the directions of the half-stroke-averaged aerodynamic forces relative to the body (local frame) were constrained in a narrow range (

BackgroundThe hepatoprotective effect of interleukin 22 (IL-22) has been reported in several models of liver injuries, including alcohol-associated liver disease (ALD). However, the intestinal role of IL-22 in alcoholic hepatitis remains to be elucidated.MethodsIntestinal IL-22 levels were measured in mice fed with alcohol for 8 weeks. IL-22 was then administered to alcohol-fed mice to test its protective effects on alleviating alcoholic hepatitis, focusing on intestinal protection. Acute IL-22 treatment was conducted in mice to further explore the link between IL-22 and the induction of antimicrobial peptide (AMP). Intestinal epithelial cell-specific knockout of signal transducer and activator of transcription 3 (STAT3) mice were generated and used for organoid study to explore its role in IL-22-mediated AMP expression and gut barrier integrity.ResultsAfter alcohol feeding for 8 weeks, the intestinal levels of IL-22 were significantly reduced in mice. IL-22 treatment to alcohol-fed mice mitigated liver injury as indicated by normalized serum transaminase levels, improved liver histology, reduced lipid accumulation, and attenuated inflammation. In the intestine, alcohol-reduced Reg3γ and α-defensins levels were reversed by IL-22 treatment. IL-22 also improved gut barrier integrity and decreased endotoxemia in alcohol-fed mice. While alcohol feeding significantly reduced Akkermansia, IL-22 administration dramatically expanded this commensal bacterium in mice. Regardless of alcohol, acute IL-22 treatment induced a fast and robust induction of intestinal AMPs and STAT3 activation. By using in vitro cultured intestinal organoids isolated from WT mice and mice deficient in intestinal epithelial-STAT3, we further demonstrated that STAT3 is required for IL-22-mediated AMP expression. In addition, IL-22 also regulates intestinal epithelium differentiation as indicated by direct regulation of sodium-hydrogen exchanger 3 via STAT3.ConclusionOur study suggests that IL-22 not only targets the liver but also benefits the intestine in many aspects. The intestinal effects of IL-22 include regulating AMP expression, microbiota, and gut barrier function that is pivotal in ameliorating alcohol induced translocation of gut-derived bacterial pathogens and liver inflammation.

Glottal vibration is fundamental to breathing-related disorders and respiratory sound generation. However, responses of the flow and acoustics to glottal vibrations of different frequencies are unclear. The objective of this study is to numerically evaluate the influences of glottal vibration frequencies on inspiratory airflow dynamics and flow-induced sound signals; this is different from normal phonation that is driven by controlled expiratory flows. A computational model was developed that comprised an image-based mouth–throat–lung model and a dynamic glottis expanding/contracting following a sinusoidal waveform. Large Eddy simulations were used to solve the temporal and spatial flow evolutions, and pressure signals were analyzed using different transform algorithms (wavelet, Hilbert, Fourier, etc.). Results show that glottal vibrations significantly altered the flows in the glottis and trachea, especially at high frequencies. With increasing vibration frequencies, the vortices decreased in scale and moved from the main flow to the walls. Phase shifts occurred between the glottis motion and glottal flow rates for all frequencies considered. Due to this phase shift, the pressure forces resisted the glottal motion in the first half of contraction/expansion and assisted the glottal motion in the second half of contraction/expansion. The magnitude of the glottal flow fluctuation was approximately linear with the vibration frequency (~f0), while the normal pressure force increased nonlinearly with the frequency (~f01.85). Instantaneous pressure signals were irregular at low vibration frequencies (10 and 20 Hz) but became more regular with increasing frequencies in the pressure profile, periodicity, and wavelet-transformed parameters. The acoustic characteristics specific to the glottal vibration frequency were explored in temporal and frequency domains, which may be used individually or as a combination in diagnosing vocal fold dysfunction, snoring, sleep apnea, or other breathing-related diseases.

Abstract The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread into more than 200 countries and infected approximately 203 million people globally. COVID-19 is associated with high mortality and morbidity in some patients, and this disease still does not have effective treatments with reproducibly appreciable outcomes. One of the leading complications associated with COVID-19 is acute respiratory distress syndrome (ARDS); this is an anti-viral host inflammatory response, and it is usually caused by a cytokine storm syndrome which may lead to multi-organ failure and death. Currently, COVID-19 patients are treated with approaches that mostly fall into two major categories: immunomodulators, which promote the body’s fight against viruses efficiently, and antivirals, which slow or stop viruses from multiplying. These treatments include a variety of novel therapies that are currently being tested in clinical trials, including serum, IL-6 antibody, and remdesivir; however, the outcomes of these therapies are not consistently appreciable and remain a subject of debate. Mesenchymal stem/stromal cells (MSCs), the multipotent stem cells that have previously been used to treat viral infections and various respiratory diseases such as ARDS exhibit immunomodulatory properties and can ameliorate tissue damage. Given that SARS-CoV-2 targets the immune system and causes tissue damage, it is presumable that MSCs are being explored to treat COVID-19 patients. This review summarizes the potential mechanisms of action of MSC therapy, progress of MSC, and its related products in clinical trials for COVID-19 therapy based on the outcomes of these clinical studies.

IntroductionDietary fiber (DF) regulates immune response and barrier function by interacting with epithelial cells and immune cells. However, the differences in the regulation of intestinal health of different pig breeds by DF remain obscure.MethodsA total of 60 healthy pigs (20 pigs/breed) from Taoyuan black (TB), Xiangcun black (XB), and Duroc (DR) pigs (body weight = 11.00 ± 1.00 kg) were fed two different levels (low and high) of DF for 28 days to evaluate the differences in the modulation of intestinal immunity and barrier function by DF in different pig breeds.ResultsTB and XB pigs had higher plasma Eos level, Eos%, and Lym% but lower Neu level compared with the DR pigs when fed low DF (LDF). The TB and XB pigs had higher plasma Eos, MCV, and MCH levels and Eos% while lower Neu% compared with the DR pigs when fed high DF (HDF). HDF decreased IgA, IgG, IgM, and sIgA concentrations in the ileum of TB and XB pigs compared with the DR pigs, while the plasma IgG and IgM concentrations of TB pigs were higher than those of the DR pigs. Moreover, compared with the DR pigs, HDF decreased the levels of IL-1β, IL-17, and TGF-β in the plasma, and IL-1β, IL-2, IL-6, IL-10, IL-17, IFN-γ, TGF-β, and TNF-α in the ileum of TB and XB pigs. However, HDF did not affect the mRNA expression of cytokines in the ileum of TB, XB, and DR pigs, while HDF increased the TRAF6 expression of TB pigs compared with the DR pigs. In addition, HDF increased the Claudin abundance of TB and DR pigs compared with the pigs feeding with LDF. Moreover, in the LDF and HDF groups, the XB pigs had higher protein abundances of Claudin and ZO-1 compared with the TB and DR pigs.ConclusionsDF regulated the TB and DR pigs’ plasma immune cells, the XB pigs showed enhanced barrier function, and the DR pigs had increased ileal inflammation, which indicates that Chinese indigenous pigs are more DF tolerant than the DR pigs.

Brain resting-state functional connectivity (rsFC) has been widely analyzed in substance use disorders (SUDs), including methamphetamine (MA) dependence. Most of these studies utilized Pearson correlation analysis to assess rsFC, which cannot determine whether two brain regions are connected by direct or indirect pathways. Moreover, few studies have reported the application of rsFC-based graph theory in MA dependence. We evaluated alterations in Tikhonov regularization-based rsFC and rsFC-based topological attributes in 46 MA-dependent patients, as well as the correlations between topological attributes and clinical variables. Moreover, the topological attributes selected by least absolute shrinkage and selection operator (LASSO) were used to construct a support vector machine (SVM)-based classifier for MA dependence. The MA group presented a subnetwork with increased rsFC, indicating overactivation of the reward circuit that makes patients very sensitive to drug-related visual cues, and a subnetwork with decreased rsFC suggesting aberrant synchronized spontaneous activity in subregions within the orbitofrontal cortex (OFC) system. The MA group demonstrated a significantly decreased area under the curve (AUC) for the clustering coefficient (Cp) (Pperm < 0.001), shortest path length (Lp) (Pperm = 0.007), modularity (Pperm = 0.006), and small-worldness (σ, Pperm = 0.004), as well as an increased AUC for global efficiency (E.glob) (Pperm = 0.009), network strength (Sp) (Pperm = 0.009), and small-worldness (ω, Pperm < 0.001), implying a shift toward random networks. MA-related increased nodal efficiency (E.nodal) and altered betweenness centrality were also discovered in several brain regions. The AUC for ω was significantly positively associated with psychiatric symptoms. An SVM classifier trained by 36 features selected by LASSO from all topological attributes achieved excellent performance, cross-validated prediction area under the receiver operating characteristics curve, accuracy, sensitivity, specificity, and kappa of 99.03 ± 1.79, 94.00 ± 5.78, 93.46 ± 8.82, 94.52 ± 8.11, and 87.99 ± 11.57%, respectively (Pperm < 0.001), indicating that rsFC-based topological attributes can provide promising features for constructing a high-efficacy classifier for MA dependence.

Improving cotton (Gossypium hirsutum L.) yield and water use efficiency (WUE) under future climate scenarios by optimizing irrigation regimes is crucial in hyper-arid areas. Assuming a current baseline atmospheric carbon dioxide concentration (CO2atm) of 380 ppm (baseline, BL0/380), the Root Zone Water Quality Model (RZWQM2) was used to evaluate the effects of four climate change scenarios—S1.5/380 (∆Tair°=1.5 °C,∆CO2atm=0), S2.0/380 (∆Tair°=2.0 °C,∆CO2atm=0), S1.5/490 (∆Tair°=1.5 °C,∆CO2atm=+110 ppm) and S2.0/650 (∆Tair°=2.0 °C,∆CO2atm=+270 ppm) on soil water content (θ), soil temperature (Tsoil°), aboveground biomass, cotton yield and WUE under full irrigation. Cotton yield and irrigation water use efficiency (IWUE) under 10 different irrigation management strategies were analysed for economic benefits. Under the S1.5/380 and S2.0/380 scenarios, the average simulated aboveground biomass of cotton (vs. BL0/380) declined by 11% and 16%, whereas under S1.5/490 and S2.0/650 scenarios it increased by 12% and 30%, respectively. The simulated average seed cotton yield (vs. BL0/380) increased by 9.0% and 20.3% under the S1.5/490 and S2.0/650 scenarios, but decreased by 10.5% and 15.3% under the S1.5/380 and S2.0/380 scenarios, respectively. Owing to greater cotton yield and lesser transpiration, a 9.0% and 24.2% increase (vs. BL0/380) in cotton WUE occurred under the S1.5/490 and S2.0/650 scenarios, respectively. The highest net income ($3741 ha−1) and net water yield ($1.14 m−3) of cotton under climate change occurred when irrigated at 650 mm and 500 mm per growing season, respectively. These results suggested that deficit irrigation can be adopted in irrigated cotton fields to address the agricultural water crisis expected under climate change.

Summary: Background: The present study aims to better understand the efficacy and safety of mesenchymal stromal cells (MSCs) in treating severe/critical patients with COVID-19. Methods: PubMed, the Cochrane Library, and the Chinese electronic database CNKI were searched from inception up to Dec 19, 2021. Original comparative studies for MSC treatment + standard treatment for severe/critical patients with COVID-19, with placebo or standard treatment as the control group, were included. The primary outcomes were in-hospital mortality and adverse events (AEs). A meta-analysis was performed to compare the mortality rates between the two groups. Then, a subgroup analysis was performed according to the category of the disease (severe or critical) and MSC dose. Afterwards, a descriptive analysis was performed for AEs and secondary outcomes. The funnel plot and Egger's test were used for the publication bias assessment. Findings: Compared to placebo or standard care, MSCs provide significant benefit in the treatment of patients with severe/critical COVID-19, in terms of in-hospital mortality rate (odds ratio: 0.52, 95% CI 0.32-0.84), with very low heterogeneity (P=0.998 [Q test], I2=0.0%) and less AEs. No significant difference was found in mortality rate due to the different disease categories or MSC doses. Furthermore, no publication bias was found. Interpretation: The present study demonstrates that MSCs are highly likely to reduce mortality and are safe to use for patients with severe or critical COVID-19, regardless of whether 1-3 doses are applied. However, due to the small sample size of the included studies, further high-quality, large-scale trials are needed to confirm this statement in the future. Funding: The National Key Research and Development Program of China (No. 2020YFC0860900), the Science and Technology Project of Wuhan (No. 2020020602012112), the Tianjin Science and Technology Research Program (18PTSYJC00070 and 16PTWYHZ00030), Haihe Laboratory of Cell Ecosystem Innovation Fund (HH22KYZX0046), and the Tianjin Free Trade Zone Innovation Development Project (ZMCY-03-2021002-01) funded the study. We are also grateful for the support from the 3551 Talent Plan of China Optics Valley.

Background and Aims: Transforming growth factor β1 (TGF-β1) secreted from activated Kupffer cells (KC) promotes the progression of nonalcoholic steatohepatitis (NASH) to liver fibrosis. N6-methyladenosine (m6A) RNA modification participates in various cell stress responses, yet it remains unknown whether it plays a role in TGF-β1 upregulation in activated KCs. Methods: Western blot, dot blot, and liquid chromatography with tandem mass spectrometry were used to determine the expression of m6A methyltransferase, METTL3, and METTL14, as well as global m6A modification. RNA-sequencing and m6A-seq were employed to screen differentially expressed genes and responsive m6A peaks. Nuclear factor κB (NF-κB)–mediated METTL3/METTL14 transactivation were validated with chromatin immunoprecipitation polymerase chain reaction and dual-luciferase reporter system, and the role of m6A in TGF-β1 upregulation was further verified in METTL3/METTL14-deficient KCs and myeloid lineage cell-specific METTL14 knockout mice. Results: Serum lipopolysaccharide (LPS) concentration is increased in high-fat diet–induced NASH rats. TGF-β1 upregulation is closely associated with METTL3/METTL14 upregulation and global m6A hypermethylation, in both NASH rat liver and LPS-activated KCs. LPS-responsive m6A peaks are identified on the 5′ untranslated region (UTR) of TGF-β1 messenger RNA (mRNA). NF-κB directly transactivates METTL3 and METTL14 genes. LPS-stimulated TGF-β1 expression is abolished in METTL3/METTL14-deficient KCs and myeloid lineage cell-specific METTL14 knockout mice. Mutation of m6A sites on the 5′UTR of TGF-β1 mRNA blocks LPS-induced increase of luciferase reporter activity. Conclusions: NF-κB acts as transcription factor to transactivate METTL3/METTL14 genes upon LPS challenge, leading to global RNA m6A hypermethylation. Increased m6A on the 5′UTR of TGF-β1 mRNA results in m6A-dependent translation of TGF-β1 mRNA in a cap-independent manner. We identify a novel role of m6A modification in TGF-β1 upregulation, which helps to shed light on the molecular mechanism of NASH progression.

Background & Aims: Aryl hydrocarbon receptor (AhR) is a liver-enriched xenobiotic receptor that plays important role in detoxification response in liver. This study aimed to investigate how AhR signaling may impact the pathogenesis of alcohol-related liver disease (ALD). Methods: Chronic alcohol feeding animal studies were conducted with mouse models of hepatocyte-specific AhR knockout (AhRΔhep) and NAD(P)H quinone dehydrogenase 1 (NQO1) overexpression, and dietary supplementation of the AhR ligand indole-3-carbinol. Cell studies were conducted to define the causal role of AhR and NQO1 in regulation of redox balance and apoptosis. Results: Chronic alcohol consumption induced AhR activation and nuclear enrichment of NQO1 in hepatocytes of both alcoholic hepatitis patients and ALD mice. AhR deficiency exacerbated alcohol-induced liver injury, along with reduction of NQO1. Consistently, in vitro studies demonstrated that NQO1 expression was dependent on AhR. However, alcohol-induced NQO1 nuclear translocation was triggered by decreased cellular oxidized nicotinamide adenine dinucleotide (NAD+)-to-NADH ratio, rather than by AhR activation. Furthermore, both in vitro and in vivo overexpression NQO1 prevented alcohol-induced hepatic NAD+ depletion, thereby enhancing activities of NAD+-dependent enzymes and reversing alcohol-induced liver injury. In addition, therapeutic targeting of AhR in the liver with dietary indole-3-carbinol supplementation efficiently reversed alcoholic liver injury by AhR-NQO1 signaling activation. Conclusions: This study demonstrated that AhR activation is a protective response to counteract alcohol-induced hepatic NAD+ depletion through induction of NQO1, and targeting the hepatic AhR-NQO1 pathway may serve as a novel therapeutic approach for ALD.

Background & Aims: Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and triglyceride (TG)-enriched lipid droplets and cell death. The present study aimed to investigate how FFA or TG induces hepatocyte injury, thereby contributing to the development of ALD. Methods: Hepatocyte-specific DGAT1 knockout (DGAT1Δhep) mice and lysosome-associated membrane protein 2 (LAMP2) overexpression mice were generated and subjected to chronic alcohol feeding. Cell studies were conducted to define the causal role and underlying mechanism of FFA-induced hepatocellular injury. Results: Hepatocyte-specific DGAT1 deletion exacerbated alcohol-induced liver injury by increasing lipid accumulation and endoplasmic reticulum (ER) stress, reducing LAMP2 protein levels, and impairing autophagy function. Cell studies revealed that FFAs, rather than TG, induced ER stress via ATF4 activation, which, in turn, down-regulated LAMP2, thereby impairing autophagy flux. LAMP2 overexpression in the liver restored autophagy function and ameliorated alcohol-induced liver injury in mice. Reducing hepatic FFAs by peroxisome proliferator-activated receptor α activation attenuated ER stress, restored LAMP2 protein levels, and improved autophagy flux. In addition, suppression of LAMP2 and autophagy function was also detected in the liver of patients with severe alcoholic hepatitis. Conclusions: This study demonstrates that accumulation of hepatic FFAs, rather than TG, plays a crucial role in the pathogenesis of ALD by suppressing LAMP2-autophagy flux pathway through ER stress signaling, which represents an important mechanism of FFA-induced hepatocellular injury in ALD.

Background: There has been a recent appreciation that some metabolic enzymes can profoundly influence the nature of the immune response produced in macrophages. However, the role of mitochondrial phosphoenolpyruvate carboxykinase (PCK2) in immune response remains unknown. This study aims to investigate the role of PCK2 in lipopolysaccharides (LPS)-induced activation in Kupffer cells.Methods: Inflammatory cytokines were determined by real-time quantitative reverse transcription-polymerase chain action (qRT-PCR) and flow cytometric analysis using a cytometric bead array. Western blotting and immunofluorescence staining were used to determine PCK2 expression and subcellular distribution under confocal laser microscopy. qRT-PCR, flow cytometry, and high-performance liquid chromatography (HPLC) were used to determine mitochondrial function. Pharmacological inhibition, knockdown, and overexpression of PCK2 were used to confirm its function. Co-immunoprecipitation (Co-IP) was performed to determine MAPK/NF-κB phosphorylation.Results: Inflammatory response was significantly increased in LPS-treated mice and Kupffer cells. During the inflammatory process, the protein level of PCK2 was significantly upregulated in Kupffer cells. Interestingly, the localization of PCK2 was mainly in cytosol rather than mitochondria after LPS stimulation. Gain-of-function and loss-of-function analyses found that PCK2 overexpression significantly upregulated the levels of inflammation markers, whereas PCK2 knockdown or inhibition significantly mitigated LPS-induced inflammatory response in Kupffer cells. Furthermore, PCK2 promoted protein phosphorylation of NF-κB and AKT/MAPK, the major signaling pathways, controlling inflammatory cascade activation.Conclusion: We identified a novel function of PCK2 in mediating LPS-induced inflammation and provided mechanistic insights into the regulation of inflammatory response in Kupffer cells. Therefore, PCK2 may serve as a novel therapeutic target for the regulation of Kupffer cells-mediated inflammatory responses.

As one of few animals with the capability to execute agile yawing maneuvers, it is quite desirable to take inspiration from hummingbird flight aerodynamics. To understand the wing and body kinematics and associated aerodynamics of a hummingbird performing a free yawing maneuver, a crucial step in mimicking the biological motion in robotic systems, we paired accurate digital reconstruction techniques with high-fidelity computational fluid dynamics (CFD) simulations. Results of the body and wing kinematics reveal that to achieve the pure yaw maneuver, the hummingbird utilizes very little body pitching, rolling, vertical, or horizontal motion. Wing angle of incidence, stroke, and twist angles are found to be higher for the inner wing (IW) than the outer wing (OW). Unsteady aerodynamic calculations reveal that drag-based asymmetric force generation during the downstroke (DS) and upstroke (US) serves to control the speed of the turn, a characteristic that allows for great maneuvering precision. A dual-loop vortex formation during each half-stroke is found to contribute to asymmetric drag production. Wake analysis revealed that asymmetric wing kinematics led to leading-edge vortex strength differences of around 59% between the IW and OW. Finally, analysis of the role of wing flexibility revealed that flexibility is essential for generating the large torque necessary for completing the turn as well as producing sufficient lift for weight support.

In gas-insulated switchgear (GIS), partial discharge (PD) can be monitored by detecting sulfur hexafluoride-nitrogen (SF6-N2) decomposition components. In this paper, silver oxide (Ag2O) modification was introduced to improve the gas-sensing properties of graphene-like indium nitride (InN). The adsorption process of NO2, SO2F2, SOF2 and SOF4 on Ag2O-InN was simulated based on the first principles calculation and density functional theory (DFT). The gas sensing mechanism was revealed by density of states theory and molecular orbital theory. It is found that Ag2O doping greatly improves the adsorption properties of InN to NO2 and SOF2 molecules. The adsorption capacity of Ag2O-InN to the four gas molecules is: NO2 > SOF2 > SOF4 > SO2F2. All adsorptions can proceed spontaneously, and the gas molecules are electron donors and Ag2O-InN is an electron acceptor. Through the analysis of recovery time, it is found that NO2 is difficult to desorb from the substrate due to the significant adsorption energy of −2.201 eV, while SOF4, SOF2 and SO2F2 have a moderate adsorption energy of −0.185 eV, −0.754 eV and 0.173 eV and extremely short desorption time. The conductivity of the whole system changed after these four gases were adsorbed on the Ag2O-InN monolayer. In summary, Ag2O-InN can be used as NO2 adsorbent and gas sensors to detect SOF4, SOF2 and SO2F2. This paper provides a method for on-line monitoring of partial discharge in GIS.

Through computational fluid dynamics (CFD) simulations of a model manta ray body, the hydrodynamic role of manta-like bioinspired flapping is investigated. The manta ray model motion is reconstructed from synchronized high-resolution videos of manta ray swimming. Rotation angles of the model skeletal joints are altered to scale the pitching and bending, resulting in eight models with different pectoral fin pitching and bending ratios. Simulations are performed using an in-house developed immersed boundary method-based numerical solver. Pectoral fin pitching ratio (PR) is found to have significant implications in the thrust and efficiency of the manta model. This occurs due to more optimal vortex formation and shedding caused by the lower pitching ratio. Leading edge vortexes (LEVs) formed on the bottom of the fin, a characteristic of the higher PR cases, produced parasitic low pressure that hinders thrust force. Lowering the PR reduces the influence of this vortex while another LEV that forms on the top surface of the fin strengthens it. A moderately high bending ratio (BR) can slightly reduce power consumption. Finally, by combining a moderately high BR = 0.83 with PR = 0.67, further performance improvements can be made. This enhanced understanding of manta-inspired propulsive mechanics fills a gap in our understanding of the manta-like mobuliform locomotion. This motivates a new generation of manta-inspired robots that can mimic the high speed and efficiency of their biological counterpart.

In addition to their aerodynamic properties, insect wings also move odor plumes closer to sensory organs. Li et al. show that Drosophila wings may trade optimal aerodynamic performance for improved olfactory function during flight.

Abstract Background Vitellogenin (VTG) is a precursor of egg yolk proteins synthesized within the liver of oviparous vertebrates. Betaine is an important methyl donor that is reported to improve egg production of laying hens with an unclear mechanism. In the present study, we fed betaine-supplemented diet (0.5%) to laying hens for 4 wk and investigated its effect on VTGII expression in the liver. Results Betaine did not affect chicken weight, but significantly (P

Although it has been proposed that the Fas and Fas ligand (FasL) may protect ejaculated spermatozoa against apoptosis induced by lipoperoxidative damage and against lymphocytes present in the female genital tract, studies reported conflicting results on the presence of Fas receptors in ejaculated human spermatozoa. Furthermore, the expression of Fas/FasL on mature spermatozoa has not been observed in several important mammals. Using seven species, we observed the possibility for species difference in Fas/FasL expression on mature spermatozoa by both immunofluorescence microscopy and western blot analysis. Whereas intensive signals of Fas immunolabelling were detected in sperm head and middle piece and weak signals observed in the tail in 86-100% of the mouse, rat, bull, ram, and buck spermatozoa, only weak signals were detected on the whole body of 27% boar spermatozoa and in the head of 21% human spermatozoa. The pattern of FasL localization was identical to that of Fas in spermatozoa from human, mouse, rat, ram, and buck, but boar and bull spermatozoa showed weak and intensive FasL signals, respectively, only in the head. Western blotting further confirmed the Fas and FasL expression in mouse, rat, bull, ram, and buck, but not in human and boar spermatozoa. Taken together, the results revealed a marked species difference in Fas/FasL expression and an extensive co-expression of Fas and FasL among mature mammalian spermatozoa, suggesting that whereas spermatozoa from most species may be protected by Fas/FasL, those from human and boar may not use the Fas system for protection.

To change flight direction, flying animals modulate aerodynamic force either relative to their bodies to generate torque about the center of mass, or relative to the flight path to produce centripetal force that curves the trajectory. In employing the latter, the direction of aerodynamic force remains fixed in the body frame and rotations of the body redirect the force. While both aforementioned techniques are essential for flight, it is critical to investigate how an animal balances the two to achieve aerial locomotion. Here, we measured wing and body kinematics of cicada (Tibicen linnei) in free flight, including flight periods of both little and substantial body reorientations. It is found that cicadas employ a common force vectoring technique to execute all these flights. We show that the direction of the half-stroke averaged aerodynamic force relative to the body is independent of the body orientation, varying in a range of merely 20 deg. Despite directional limitation of the aerodynamic force, pitch and roll torque are generated by altering wing angle of attack and its mean position relative to the center of mass. This results in body rotations which redirect the wing force in the global frame and consequently change the flight trajectory.

It is important to understand the impact of wing-morphing on aerodynamic performance in the study of flapping-wing flight of birds and insects. We use a flapping plate hinged with a trailing-edge flap as a simplified model for flexible/morphing wings in hovering. The trailing-edge flapping motion is optimized by an adjoint-based approach. The optimized configuration suggests that the trailing-edge flap can substantially enhance the overall lift. Further analysis indicates that the lift enhancement by the trailing-edge flapping is from the change of circulation in two ways: the local circulation change by the rotational motion of the flap, and the modification of vortex shedding process by the relative location between the trailing-edge flap and leading-edge main plate.

This paper describes a computational study of the hydrodynamics of a ray-inspired underwater vehicle conducted concurrently with experimental measurements. High-resolution stereo-videos of the vehicle’s fin motions during steady swimming are obtained and used as a foundation for developing a high fidelity geometrical model of the oscillatory fin. A Cartesian grid based immersed boundary solver is used to examine the flow fields produced due to these complex artificial pectoral fin kinematics. Simulations are carried out at a smaller Reynolds number in order to examine the hydrodynamic performance and understand the resultant wake topology. Results show that the vehicle’s fins experience large spanwise inflexion of the distal part as well as moderate chordwise pitching during the oscillatory motion. Most thrust force is generated by the distal part of the fin, and it is highly correlated with the spanwise inflexion. Two sets of inter-connected vortex rings are observed in the wake right behind each fin. Those vortex rings induce strong backward flow jets which are mainly responsible for the fin thrust generation.

We numerically solved the acoustic and flow field around cicada wing models with parametrically varied flexibility using the hydrodynamic/acoustic splitting method. We observed a gradual change of sound directivity with flexibility. We found that flexible wings generally produce lower sound due to reduced aerodynamic forces, which were further found to scale with the dynamic pressure force defined as the integration of dynamic pressure over the wing area. Unlike conventional scaling where the incoming flow velocity is used as the reference to calculate the force coefficients, here only the normal component of the relative velocity of the wing to the flow was used to calculate the dynamic pressure, putting kinematic factors into the dynamic pressure force and leaving the more fundamental physics to the force coefficients. A high correlation was found between the aerodynamic forces and the dynamic pressure. The scaling is also supported by previously reported data of revolving wing experiments.

It is widely accepted that lipopolysaccharide and volatile fatty acids (VFA) accumulate in the digestive tract of ruminants fed diets containing high portions of grain. Compared to the ruminal epithelium, the hindgut epithelium is composed of a monolayer structure that is more "leaky" for lipopolysaccharide and susceptible to organic acid-induced damage. The aim of this study was to investigate changes in epithelial structure, apoptosis and inflammatory response in the hindgut of goats fed a high-concentrate diet for 6 weeks.Eight local Chinese goats with rumen cannulas were randomly assigned to two groups: one group was fed a high-concentrate diet (65% concentrate of dry matter, HC) and the other group was fed a low-concentrate diet (35% concentrate of dry matter, LC) for 6 wks. Ruminal fluid, plasma, and hindgut mucosa tissues were collected. Histological techniques, real-time PCR and western blotting were used to evaluate the tissues structure, cell apoptosis and local inflammation in the hindguts.Feeding HC diet for 6 wks resulted in a significant decrease of ruminal pH (p

PURPOSE: The mechanism underlying the decline in milk quality during periods of feeding high-concentrate diets to dairy ruminants is not well documented. The aim of this study was to investigate the metabolic changes in the liver that contribute to the input of substrate precursors to the mammary gland after feeding a high-concentrate diet to lactating goats for a long period. EXPERIMENTAL DESIGN: Eight mid-lactating goats with rumen cannulas were randomly assigned to two groups. For 9 weeks, the treatment group was fed a high-concentrate diet (60% concentrate of dry matter, HC) and the control group was fed a low-concentrate diet (40% concentrate of dry matter, LC). Ruminal fluid, plasma, and liver tissues were sampled, microarray techniques and real-time polymerase chain reaction were used to evaluate metabolic parameters and gene expression in liver. RESULTS: Feeding a 60%-concentrate diet for 9 weeks resulted in a significant decrease in rumen pH. Changes in fat and protein content also occurred, which negatively affected milk quality. Plasma levels of leptin (p = 0.058), non-esterified fatty acid (p = 0.071), and glucose (p = 0.014) increased markedly in HC group. Plasma cortisol concentration was significantly elevated in the treatment group (p

The manta is the largest marine organism to swim by dorsoventral oscillation (flapping) of the pectoral fins. The manta has been considered to swim with a high efficiency stroke, but this assertion has not been previously examined. The oscillatory swimming strokes of the manta were examined by detailing the kinematics of the pectoral fin movements swimming over a range of speeds and by analyzing simulations based on computational fluid dynamic potential flow and viscous models. These analyses showed that the fin movements are asymmetrical up- and downstrokes with both spanwise and chordwise waves interposed into the flapping motions. These motions produce complex three-dimensional flow patterns. The net thrust for propulsion was produced from the distal half of the fins. The vortex flow pattern and high propulsive efficiency of 89% were associated with Strouhal numbers within the optimal range (0.2–0.4) for rays swimming at routine and high speeds. Analysis of the swimming pattern of the manta provided a baseline for creation of a bio-inspired underwater vehicle, MantaBot.