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Abstract A role for metabolically active adipose tissue in pulmonary hypertension (PH) pathogenesis is emerging. Alterations in cellular metabolism in metabolic syndrome are triggers of PH‐related vascular dysfunction. Metabolic reprogramming in proliferative pulmonary vascular cells causes a metabolic switch from oxidative phosphorylation to glycolysis. PDE3A and PDE3B subtypes in the regulation of metabolism in pulmonary artery smooth muscle cells (PASMC) are poorly understood. We previously found that PDE3A modulates the cellular energy sensor, AMPK, in human PASMC. We demonstrate that global Pde3a knockout mice have right ventricular (RV) hypertrophy, elevated RV systolic pressures, and metabolic dysfunction with elevated serum free fatty acids (FFA). Therefore, we sought to delineate Pde3a/Pde3b regulation of metabolic pathways in PASMC. We found that PASMC Pde3a deficiency, and to a lesser extent Pde3b deficiency, downregulates AMPK, CREB and PPARγ, and upregulates pyruvate kinase dehydrogenase expression, suggesting decreased oxidative phosphorylation. Interestingly, siRNA Pde3a knockdown in adipocytes led to elevated FFA secretion. Furthermore, PASMC exposed to siPDE3A‐transfected adipocyte media led to decreased α‐SMA, AMPK and CREB phosphorylation, and greater viable cell numbers compared to controls under the same conditions. These data demonstrate that deficiencies of Pde3a and Pde3b alter pathways that affect cell growth and metabolism in PASMC.

Abstract Over the satellite era, Antarctic sea ice exhibited an overall long-term increasing trend, contrary to the Arctic reduction under global warming. However, the drastic decline of Antarctic sea ice in 2014–2018 raises questions about its interannual and decadal-scale variabilities, which are poorly understood and predicted. Here, we identify an Antarctic sea ice decadal oscillation, exhibiting a quasi-period of 8–16 years, that is anticorrelated with the Pacific Quasi-Decadal Oscillation (r = −0.90). By combining observations, Coupled Model Intercomparison Project historical simulations, and pacemaker climate model experiments, we find evidence that the synchrony between the sea ice decadal oscillation and Pacific Quasi-Decadal Oscillation is linked to atmospheric poleward-propagating Rossby wave trains excited by heating in the central tropical Pacific. These waves weaken the Amundsen Sea Low, melting sea ice due to enhanced shortwave radiation and warm advection. A Pacific Quasi-Decadal Oscillation-based regression model shows that this tropical-polar teleconnection carries multi-year predictability.

Background and objectiveType 2 Diabetes Mellitus (T2DM) with insulin resistance (IR) is prone to damage the vascular endothelial, leading to the formation of vulnerable carotid plaques and increasing ischemic stroke (IS) risk. The purpose of this study is to develop a nomogram model based on carotid ultrasound radiomics for predicting IS risk in T2DM patients.Methods198 T2DM patients were enrolled and separated into study and control groups based on IS history. After manually delineating carotid plaque region of interest (ROI) from images, radiomics features were identified and selected using the least absolute shrinkage and selection operator (LASSO) regression to calculate the radiomics score (RS). A combinatorial logistic machine learning model and nomograms were created using RS and clinical features like the triglyceride-glucose index. The three models were assessed using area under curve (AUC) and decision curve analysis (DCA).ResultsPatients were divided into the training set and the testing set by the ratio of 0.7. 4 radiomics features were selected. RS and clinical variables were all statically significant in the training set and were used to create a combination model and a prediction nomogram. The combination model (radiomics + clinical nomogram) had the largest AUC in both the training set and the testing set (0.898 and 0.857), and DCA analysis showed that it had a higher overall net benefit compared to the other models.ConclusionsThis study created a carotid ultrasound radiomics machine-learning-based IS risk nomogram for T2DM patients with carotid plaques. Its diagnostic performance and clinical prediction capabilities enable accurate, convenient, and customized medical care.

Abstract Autoimmune uveitis (AU) is a kind of immune‐mediated disease resulting in irreversible ocular damage and even permanent vision loss. However, the precise mechanism underlying dynamic immune changes contributing to disease initiation and progression of AU remains unclear. Here, we induced an experimental AU (EAU) model with IRBP651‐670 and found that day[D]14 was the inflammatory summit with remarking clinical and histopathological manifestations and the activation of retinal microglia exhibited a time‐dependent pattern in the EAU course. We conducted single‐cell RNA sequencing of retinal immune cells in EAU mice at four time points and found microglia constituting the largest proportion, especially on D14. A novel inflammatory subtype (Cd74high Ccl5high) of retinal microglia was identified at the disease peak that was closely associated with modulating immune responses. In vitro experiments indicated that inflammatory stimuli induced proinflammatory microglia with the upregulation of CD74 and CCL5, and CD74 overexpression in microglia elicited their proinflammatory phenotype via nuclear factor‐kappa B signaling that could be attenuated by the treatment of neutralizing CCL5 antibody to a certain extent. In‐vivo blockade of Cd74 and Ccl5 effectively alleviated retinal microglial activation and disease phenotype of EAU. Therefore, we propose targeting CD74 and CCL5 of retinal microglia as promising strategies for AU treatment.

This paper studies the event-triggered saturated adaptive iterative learning control (ETSAILC) problem for the fractional-order multi-agent systems (FOMASs) subject to the local Lipschitz nonlinearities and the input saturation. First, a event-triggered mechanism is proposed to ensure that events occur along an iteration axis, and all follower agents synchronously broadcast their states at each triggering iteration step, receive and restore the information from their neighbors. Next, the ETSAILC protocol is designed and the event-triggered condition is presented. Then, the composite energy function (CEF) with the form of fractional-order integral is constructed and is utilized for the convergence analysis of iterative learning process, thereby the boundedness of closed-loop signals is proved and a sufficient condition guaranteeing the perfect consensus is obtained. It is for the first time to extend the CEF method into the field of fractional-order systems. Finally, compared with the existing consensus protocols, simulations demonstrate that the proposed controller can effectively handle the local Lipschitz nonlinearities and the input saturation and obtain the perfect control of consensus. Meanwhile, the number of control input update and the amount of transmitted information are obviously reduced.

Abstract The tropical western Pacific (TWP) has profound influences on climate. ENSO is an important source of interannual variability of TWP SST, but extratropical precursors are far less known. Here we show a significant interhemispheric influence from subtropical Southwest Pacific (SWP) on the TWP. Observational analysis suggests that SWP SST in boreal spring has strong coherence with TWP 6 months later. The spring SWP warming signal exhibits a unique interhemispheric propagation embedded in the southerly cross-equatorial flow over the western Pacific. The wind-evaporation-SST feedback initiates and maintains the progression of warm SST anomalies toward the TWP in autumn. The climate model successfully reproduces such an interhemispheric SST propagation. The seasonal evolution of SST variability improves the predictability of the warm pool SST by about 6 months. An SWP SST-based prediction model shows considerable hindcast skill (r = 0.80, p

Membrane fouling is a key factor limiting the application of a membrane bioreactor (MBR), and membrane-surface modification holds the potential to control membrane fouling and solves this problem. In the research, novel nanocomposite membranes were designed and fabricated using antimicrobial copper nanoparticles (CuNPs) coupled with powdered active carbon (PAC) to mitigate membrane fouling. The successful coating was confirmed by SEM, XRD, and FTIR analysis. Compared with a pristine membrane, the functionalization of CuNPs and PAC improved the hydrophilicity of the modified membrane but led to a lower permeate flux. The result of antimicrobial adhesion experiments showed that the modified M-CuOC displayed high antibacterial activity with the bacteria count decreased by 72%. In MBR operation, the modified M-CuOC leads to the removal efficiency of chemical oxygen demand (COD) increasing to 93%, with better filtration performance under a lower TMP rise. The fouling-resistance analysis demonstrated that, although the intrinsic membrane resistance of modified M-CuOC slightly increased, the reversible and irreversible fouling resistances obviously decreased by 45% and 90%. Moreover, the membrane flux recovery efficiency of the modified M-CuOC also increased by 35%. Overall, these results indicated that, in addition to an improvement in antifouling performance, the functionalization of CuNPs and PAC also enhanced the membrane flux recovery efficiency, revealing a good antifouling potential in a practical application.

Electrochemical enzymatic biosensors represent a promising, low-cost technology for point-of-care (POC) diagnostics that allows fast response and simple sample processing procedures. In this review, we summarize up-to-date literature on NAD+/NADH (β-nicotinamide adenine dinucleotide)-dependent electrochemical dehydrogenase biosensors and highlight their applications in human physiological fluids. A brief comparison of various enzyme immobilization procedures is first presented, discussing preparation processes and principal analytical performance characteristics. In the following section, we briefly discuss classes of biosensors based on redox mediators-mediated electron transfer systems (METs). Finally, the conclusion section summarizes the ongoing challenges in the fabrication of NAD+-dependent electrochemical dehydrogenase biosensors and gives an outlook on future research studies.

Background: Triglyceride glycemic (TyG) index is a novel tool for assessing insulin resistance (IR). Recently, TyG index as a potential biomarker f or gestational diabetes mellitus (GDM) has been studied, but its performance is yet inc onclusive. Thus, we performed this systemic review and meta-analysis to evaluate th e performance of TyG index in predicting GDM. Methods: Studies published before March 1, 2021, with comparison of TyG index between GDM patients and healthy controls were retrieved from multiple databases (PubMed, Web of Science, The Cochrane Library, and Embase). The mean diff erence (MD) of TyG index in GDM patients and healthy controls was pooled using ran dom-effect models. Results: Differentiation of TyG index between patients with GDM and cont rols showed significant results. Overall, there is a four-fold increase in T yG index in GDM patients compared with controls (MD: 0.22, 95% CI: 0.07–0.36, P = 0.003; I2 = 71%, P = 0.009). In subgroup analyses according to gestational time, TyG index in t he second trimester predicted GDM with low heterogeneity (MD: 0.26, 95% CI: 0.15–0. 37, P < 0.001; I2 = 0%, P = 0.54), while no such correlation was found in the first trimest er. Conclusion: TyG index, especially in the second trimester, could be a prom ising biomarker for predicting GDM.

N6-metyladenosine (m6A) RNA methylation has been proven to be involved in diverse biological processes, but its potential roles in the development of lipopolysaccharide (LPS) induced retinal pigment epithelium (RPE) inflammation have not been revealed. In this study, we explored the effects and underlying mechanisms of methyltransferase-like 3 (METTL3) in LPS stimulated RPE cells. Proliferation of METTL3-silenced RPE cells was examined by Cell counting kit-8 (CCK8) and 5-Ethynyl-2´-Deoxyuridine (Edu). Expression of tight junction proteins ZO-1 and Occludin, and secretion of inflammatory factors interleukins (IL)-1, 6 and 8 were detected by Western blotting or Enzyme-linked immunosorbent assay (ELISA). RNA sequencing and methylated RNA immunoprecipitation (MeRIP) sequencing were used to analyze the target gene nuclear receptor subfamily 2 group F member 1 (NR2F1) of METTL3. Our results showed that both human RPE (hRPE) cells and ARPE19 cells exhibited inhibited proliferation, tight junction protein expression, and increased inflammatory factor secretion after METTL3 silencing. Mechanistically, we found that NR2F1, as a METTL3-methylated target gene, inhibits Occludin level and promotes IL-6 secretion of RPE cells in an m6A-dependent manner. Interestingly, NR2F1 deficiency reversed the decreased Occludin expression and increased IL-6 secretion in METTL3-defective RPE cells. In conclusion, our study revealed that METTL3 attenuates RPE cell inflammation by methylating NR2F1, suggesting the critical role of METTL3 in RPE cells.

Abstract The hallmark of pulmonary hypertension (PH) is vascular remodeling. We have previously shown that human pulmonary microvascular endothelial cells (hPMVEC) respond to hypoxia with epidermal growth factor (EGF) mediated activation of the receptor tyrosine kinase, EGF receptor (EGFR), resulting in arginase‐2 (Arg2)‐dependent proliferation. We hypothesized that the release of EGF by hPMVEC could result in the proliferation of human pulmonary arterial smooth muscle cells (hPASMC) via activation of EGFR on the hPASMC leading to Arg2 up‐regulation. To test this hypothesis, we used conditioned media (CM) from hPMVEC grown either in normoxia (NCM) or hypoxia (HCM). Human PASMC were incubated in normoxia with either HCM or NCM, and HCM caused significant induction of Arg2 and viable cell numbers. When HCM was generated with either an EGF‐neutralizing antibody or an EGFR blocking antibody the resulting HCM did not induce Arg2 or increase viable cell numbers in hPASMC. Adding an EGFR blocking antibody to HCM, prevented the HCM‐induced increase in Arg2 and viable cell numbers. HCM induced robust phosphorylation of hPASMC EGFR. When hPASMC were transfected with siRNA against EGFR the HCM‐induced increase in viable cell numbers was prevented. When hPASMC were treated with the arginase antagonist nor‐NOHA, the HCM‐induced increase in viable cell numbers was prevented. These data suggest that hypoxic hPMVEC releases EGF, which activates hPASMC EGFR leading to Arg2 protein expression and an increase in viable cell numbers. We speculate that EGF neutralizing antibodies or EGFR blocking antibodies represent potential therapeutics to prevent and/or attenuate vascular remodeling in PH associated with hypoxia.

Sea surface temperature (SST) over the western North Pacific (WNP) exhibits strong decadal to multidecadal variability and in this region, warm waters fuel the tropical cyclones (TCs). Observational records show pronounced decadal variations in WNP TC metrics during 1950–2018. Statistical analysis of the various TC metrics suggests that the annual average intensity of WNP TCs is closely linked to the AMO (r = 0.86 at decadal timescales, p < 0.05). Observations and coupled atmosphere-ocean simulations show that the decadal WNP SST variations regarded as the primary driver of TC intensity, are remotely controlled by the AMO. Corresponding to the WNP SST warming, the local SLP gets lower and the tropospheric air becomes warmer and moister, enhancing atmospheric instability and the generation of convective available potential energy. These favorable changes in the background environment provide more “fuel” to the development of deep convection and intensify the WNP TCs. The footprints of AMO in WNP SST and atmospheric states through trans-basin interaction eventually exert a significant impact on the TC intensity over the WNP region.

Multidecadal variations in Hadley circulation (HC) strength have been observed during the historical period, which have significant implications for global and regional climate. However, the relationship between HC intensities in the two hemispheres remains unclear. In this study, we identify an interhemispheric seesaw in the annual HC strength at multidecadal timescales. This seesaw pattern physically corresponds to the meridional movement of the ascending branch of annual HC, leading to strengthened HC in one hemisphere and weakened HC in the other. The HC strength seesaw strongly correlates with the tropical land surface precipitation at multidecadal timescales, particularly for the monsoonal land regions. Further analyses link the HC strength seesaw to the Atlantic multidecadal variability (AMV). A suite of Atlantic Pacemaker experiments successfully reproduces the multidecadal HC strength seesaw and its relation to the AMV. The Northern Hemisphere SST warming associated with the positive AMV phase induces a northward shift of the upward branch of HC, and the Southern Hemispheric HC is strengthened in contrast to the weakened Northern Hemispheric HC. Comparisons of the North Atlantic SST forced HC changes between the coupled air–sea model and stand-alone atmospheric model suggest an important and non-negligible role of the SST footprint of AMV over the Indo-Pacific basins. The AMV and its Indo-Pacific SST footprint make a comparable contribution to the SST changes in the Northern Hemisphere, which control the movement of the HC ascending branch and thereby the interhemispheric seesaw in HC strength.

Abstract Phosphodiesterase 3 (PDE3), of which there are two isoforms, PDE3A and PDE3B, hydrolyzes cAMP and cGMP—cyclic nucleotides important in the regulation of pulmonary vascular tone. PDE3 has been implicated in pulmonary hypertension unresponsive to nitric oxide (NO); however, contributions of the two isoforms are not known. Furthermore, adenosine monophosphate‐activated protein kinase (AMPK), a critical regulator of cellular energy homeostasis, has been shown to be modulated by PDE3 in varying cell types. While AMPK has recently been implicated in pulmonary hypertension pathogenesis, its role and regulation in the pulmonary vasculature remain to be elucidated. Therefore, we utilized human pulmonary artery smooth muscle cells (hPASMC) to test the hypothesis that NO increases PDE3 expression in an isoform‐specific manner, thereby activating AMPK and inhibiting hPASMC proliferation. We found that in hPASMC, NO treatment increased PDE3A protein expression and PDE3 activity with a concomitant decrease in cAMP concentrations and increase in AMPK phosphorylation. Knockdown of PDE3A using siRNA transfection blunted the NO‐induced AMPK activation, indicating that PDE3A plays an important role in AMPK regulation in hPASMC. Treatment with a soluble guanylate cyclase (sGC) stimulator increased PDE3A expression and AMPK activation similar to that seen with NO treatment, whereas treatment with a sGC inhibitor blunted the NO‐induced increase in PDE3A and AMPK activation. These results suggest that NO increases PDE3A expression, decreases cAMP, and activates AMPK via the sGC‐cGMP pathway. We speculate that NO‐induced increases in PDE3A and AMPK may have implications in the pathogenesis and the response to therapies in pulmonary hypertensive disorders.

Periodic variability in the hydro-climatic system has important implications not only for climate prediction but also for planning and managing water resources. Here we identify periodic decadal variability of dry/wet conditions in Central Asia (CA) since the mid-20th century, which are tied to the Pacific quasi-decadal oscillation (PQDO) with a period of 8–16 years ( r = 0.87). The periodically varying forcing in the Pacific modulates zonal winds and moisture transport and profoundly affects the precipitation on the decadal time scale. The PQDO-related equatorial central Pacific warming significantly heats the overlying troposphere, increasing the meridional temperature/geopotential gradients in the subtropics. As a result, the strengthened westerly jet in CA transports more water vapor from the North Atlantic and increases local precipitation. The plateau to the east further amplifies the increased precipitation in eastern CA through orographic influence on the convection and large-scale circulation. The atmospheric model forced by the PQDO signal reproduces an overall consistent mechanism with the observation, indicating a robust synchronization of the Central Asian hydro-climatic system to the PQDO. The newly discovered oscillatory feature in this study may advance the predictability of Central Asian precipitation on the decadal time scale, which promotes the mitigation and prevention of natural disasters like droughts and wildfires.

The data presented in this article are related to the research article entitled “MKP-1 negatively regulates LPS-mediated IL-1β production through p38 activation and HIF-1α expression” (Talwar et al., 2017) [1]. This data describes that LPS-mediated p38 and JNK phosphorylation is enhanced in MKP-1 deficient macrophages. HIF-1α expression and its nuclear accumulation are significantly increased in the nuclear extracts of MKP-1 deficient BMDMs. MKP-1 deficient BMDMs exhibited higher expression of the coactivator p300 of HIF-1α both at baseline and after LPS challenge. Inhibition of p38 MAP kinase decreased LPS mediated HIF-1α protein levels and its nuclear translocation in MKP-1 deficient BMDMs. Inhibition of p38 MAP kinase inhibited LPS induced pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α.

The Atlantic warm pool (AWP) has profound impacts on extreme weather events and climate variability. Factors influencing the AWP and its predictability are still not fully understood. Other than local ocean–atmosphere feedbacks and El Niño Southern Oscillation, we find an extratropical precursor from the Northeast Pacific (known as the Blob), which leads the AWP by 1 year with a robust correlation ( r = 0.68). A suite of Northeast Pacific pacemaker experiments successfully reproduces the leading influence of the Blob on the AWP. The preceding summer Blob-related sea surface temperature (SST) warming signal can be transmitted towards the lower latitudes through the seasonal footprint mechanism, leading to the central Pacific warming in the winter and following spring. Such a strong tropical Pacific SST heating excites an anomalous atmospheric wave train that resembles the Pacific/North American (PNA) teleconnection pattern. At the downstream portion of the PNA, the low sea surface pressure anomalies can be found over the AWP region during the following spring. The anomalous low initiates the AWP SST warming, and the AWP warmer SST can persist into summer and is further amplified due to ocean–atmosphere feedbacks. Our results show that the North Pacific Blob may act as a useful predictor of the AWP 1 year in advance through trans-basin interactions. A Blob-based prediction model shows considerable hindcast skill for the observed AWP SST anomaly.

Upon antigen stimulation, T lymphocytes undergo dramatic changes in metabolism to fulfill the bioenergetic, biosynthetic and redox demands of proliferation and differentiation. Glutathione (GSH) plays an essential role in controlling redox balance and cell fate. While GSH can be recycled from Glutathione disulfide (GSSG), the inhibition of this recycling pathway does not impact GSH content and murine T cell fate. By contrast, the inhibition of the de novo synthesis of GSH, by deleting either the catalytic (Gclc) or the modifier (Gclm) subunit of glutamate–cysteine ligase (Gcl), dampens intracellular GSH, increases ROS, and impact T cell differentiation. Moreover, the inhibition of GSH de novo synthesis dampened the pathological progression of experimental autoimmune encephalomyelitis (EAE). We further reveal that glutamine provides essential precursors for GSH biosynthesis. Our findings suggest that glutamine catabolism fuels de novo synthesis of GSH and directs the lineage choice in T cells.

Mitogen-activated protein kinase phosphatase (Mkp)-1 exerts its anti-inflammatory activities during Gram-negative sepsis by deactivating p38 and c-Jun N-terminal kinase (JNK). We have previously shown that Mkp-1+/+ mice, but not Mkp-1−/− mice, exhibit hypertriglyceridemia during severe sepsis. However, the regulation of hepatic lipid stores and the underlying mechanism of lipid dysregulation during sepsis remains an enigma. To understand the molecular mechanism underlying the sepsis-associated metabolic changes and the role of Mkp-1 in the process, we infected Mkp-1+/+ and Mkp-1−/− mice with Escherichia coli i.v., and assessed the effects of Mkp-1 deficiency on tissue lipid contents. We also examined the global gene expression profile in the livers via RNA-seq. We found that in the absence of E. coli infection, Mkp-1 deficiency decreased liver triglyceride levels. Upon E. coli infection, Mkp-1+/+ mice, but not Mkp-1−/− mice, developed hepatocyte ballooning and increased lipid deposition in the livers. E. coli infection caused profound changes in the gene expression profile of a large number of proteins that regulate lipid metabolism in wildtype mice, while these changes were substantially disrupted in Mkp-1−/− mice. Interestingly, in Mkp-1+/+ mice E. coli infection resulted in downregulation of genes that facilitate fatty acid synthesis but upregulation of Cd36 and Dgat2, whose protein products mediate fatty acid uptake and triglyceride synthesis, respectively. Taken together, our studies indicate that sepsis leads to a substantial change in triglyceride metabolic gene expression programs and Mkp-1 plays an important role in this process.