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The global existence of smooth solution and the long-time asymptotic stability of the equilibrium to vacuum free boundary problem of the spherically symmetric Euler equations with damping and solid core have been obtained for arbitrary finite positive gas constant A in the state equation p = A ρ γ with p being the pressure and ρ the density, provided that γ > 4 / 3 , initial perturbation is small and the radius of the equilibrium R is suitably larger than the radius of the solid core r 0. Moreover, we obtain the pointwise convergence from the smooth solution to the equilibrium in a surprisingly exponential time-decay rate. The proof is mainly based on weighted energy method in Lagrangian coordinate. [ABSTRACT FROM AUTHOR]

Rising temperatures can increase the risk of mental disorders. As climate change intensifies, the future disease burden due to mental disorders may be underestimated. Using data on the number of daily emergency department visits for mental disorders at 30 hospitals in Beijing, China during 2016–2018, the relationship between daily mean temperature and such visits was assessed using a quasi-Poisson model integrated with a distributed lag nonlinear model. Emergency department visits for mental disorders attributed to temperature changes were projected using 26 general circulation models under four climate change scenarios. Stratification analyses were then conducted by disease subtype, sex, and age. The results indicate that the temperature-related health burden from mental disorders was projected to increase consistently throughout the 21st century, mainly driven by high temperatures. The future temperature-related health burden was higher for patients with mental disorders due to the use of psychoactive substances and schizophrenia as well as for women and those aged <65 years. These findings enhance our knowledge of how climate change could affect mental well-being and can be used to advance and refine targeted approaches to mitigating and adapting to climate change with a view on addressing mental disorders. • Future temperature-related health burden for mental disorders (MDs) will increase. • High temperatures pose a greater future health burden for MDs. • Those with substance use disorders and schizophrenia were at higher risk. • Female patients and patients aged <65 years were more susceptible to temperature. [ABSTRACT FROM AUTHOR]

Sodium selenite was added to basal diet at five levels (0.10, 0.42, 0.67, 1.06 and 1.46 mg Se/kg) and fed fish for 8 weeks. The dietary selenium requirement of juvenile blunt snout bream (Megalobrama amblycephala) was quantified. Dietaryseleniums at 0.67–1.06 mg Se/kg improved weight gain rate, specific growth rate and feed efficiency. The optimal amount was 0.96 mg/kg, for which the specific growth rate was 1.798%/day and the weight gain rate was 173.852% (p < 0.05). Se deposition in muscle was increased (p < 0.05) at ≥0.67 mg/kg, but moisture, protein, lipid and ash content were not affected. Physiological status and lipid metabolism were improved by 1.06–1.46 mg/kg dietary selenium based on total protein and albumin in plasma, and total cholesterol and triglycerides (p < 0.05). Activities of hepatic anti-oxidant enzymes catalase, total superoxide dismutase, glutathione peroxidase and reduced glutathione were enhanced at Se1.06 (p < 0.05). However, malondialdehyde content was lowered at Se1.06 (p < 0.05). Expression of anti-inflammatory cytokines, nuclear factor erythroid 2-related factor 2 (Nrf2) and kelch-like ECH-associated protein 1 (Keap-1) in liver were elevated at Se1.06 (p < 0.05), as were mRNA levels of glutathione peroxidase, copper zinc superoxide dismutase and catalase. Expression of pro-inflammatory cytokines, interleukin 8, tumour necrosis factor-α and transforming growth factor-β were inhibited at 0.67–1.46 mg/kg (p < 0.05). In general, 0.96 mg/kg was optimal, and optimal selenium enhanced antioxidant stress tolerance and anti-inflammatory ability. • Growth performance, plasma biochemical parameters were affected by dietary selenium levels. • The dietary selenium requirement was estimated to be 0.96 mg/kg of diet. • The optimal dietary selenium level could reduce plasma cholesterol, then improve the hepatic antioxidant capacity. • The optimal dietary selenium level could enhance the hepatic antioxidant and anti-inflammatory ability. [ABSTRACT FROM AUTHOR]

We study in this paper the uniform regularity and relaxation limit for the outer pressure problem of one dimensional gas dynamics with several thermal nonequilibrium modes. The uniform regularity is established for the initial data satisfying the compatible conditions on the boundary. The relaxation limit to equilibrium flow or frozen flow is also investigated by a compactness argument. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a significant risk factor for mild cognitive impairment (MCI) and the acceleration of MCI to dementia. The high glucose level induce disturbance of neurovascular (NV) coupling is suggested to be one potential mechanism, however, the neuroimaging evidence is still lacking. To assess the NV decoupling pattern in early diabetic status, 33 T2DM without MCI patients and 33 healthy control subjects were prospectively enrolled. Then, they underwent resting state functional MRI and arterial spin labeling imaging to explore the hub-based networks and to estimate the coupling of voxel-wise cerebral blood flow (CBF)-degree centrality (DC), CBF-mean amplitude of low-frequency fluctuation (mALFF) and CBF- mean regional homogeneity (mReHo). We further evaluated the relationship between NV coupling pattern and cognitive performance (false discovery rate corrected). T2DM without MCI patients displayed significant decrease in the absolute CBF-mALFF, CBF-mReHo coupling of CBFnetwork and in the CBF-DC coupling of DCnetwork. Besides, networks which involved CBF and DC hubs mainly located in the default mode network (DMN). Furthermore, less severe disease and better cognitive performance in T2DM patients were significantly correlated with higher coupling of CBF-DC, CBF-mALFF or CBF-mReHo, especially for the cognitive dimensions of general function and executive function. Thus, coupling of CBF-DC, CBF-mALFF and CBF-mReHo may serve as promising indicators to reflect NV coupling state and to explain the T2DM related early cognitive impairment. Image 1 [ABSTRACT FROM AUTHOR]

Iron is an important mineral element for fish. In this study, we investigated the influences of dietary iron deficiency on intestinal immune function as well as underlying signaling of on-growing grass carp (Ctenopharyngodon idella). Fish were fed with six graded level of dietary iron for sixty days, and a fourteen days' challenge test under infection of Aeromonas hydrophila thereafter. Results showed that compared with optimal iron level, iron deficiency increased enteritis morbidity, decreased lysozyme (LZ) and acid phosphatase (ACP) activities, complement 3 (C3), C4 and immunoglobulin M (IgM) concentrations and down-regulated mRNA levels of hepcidin, liver expressed antimicrobial peptide 2A (LEAP-2A), LEAP-2B, Mucin2, β-defensin-1, anti-inflammatory cytokines transforming growth factor β1 (TGF-β1), TGF-β2, interleukin 4/13A (IL-4/13A), IL-4/13B, IL-10, IL-11 and IL-15, inhibitor of κBα (IκBα), target of rapamycin (TOR) and ribosomal protein S6 kinase 1 (S6K1), whereas up-regulated mRNA levels of pro-inflammatory cytokines IL-1β, interferon γ2 (IFN-γ2), IL-8, IL-12p35, IL-12p40 and IL-17D, nuclear factor kappa B (NF-κB) p65, IκB kinases α (IKKα), IKKβ and eIF4E-binding protein (4E-BP) in intestine of on-growing grass carp, indicating that iron deficiency impaired intestinal immune function of fish under infection of A. hydrophila. Besides, iron excess also increased enteritis morbidity and impaired immune function of fish under infection of A. hydrophila. In addition, the effect of ferrous fumarate on intestinal immune function of on-growing grass carp is more efficient than ferrous sulfate. Finally, based on ability against enteritis, LZ activities in mid intestine and distal intestine, we recommended adding 83.37, 86.71 and 85.39 mg iron/kg into diet, respectively. • Iron deficiency decreased enteritis resistance of fish. • Iron deficiency decreased antibacterial compounds and antibacterial peptides in intestine of fish. • Iron deficiency aggravated inflammation in intestine of fish. • Iron regulated NF-κB and TOR signaling in intestine of fish. [ABSTRACT FROM AUTHOR]

Monkeypox is a zoonotic infectious skin disease initially endemic in Africa only. However, some countries are now beginning to report cases of apparent community transmission. In Computer Aided Diagnosis, deep learning has gained substantial improvement over traditional methods. Commonly, training a supervised deep model requires a large number of labeled samples. However, the collection and annotation of new disease images such as human monkeypox are time-consuming and expensive. Thus, we introduce a few-shot learning based approach for the recognition of human monkeypox in images. It requires merely a small number of training samples. In particular, it is a novel framework built with a normal backbone and auxiliary backbones. They are co-trained with Self-supervised Learning and Cross-domain Adaption techniques. The self-supervision penalty is used to help the auxiliary backbones effectively learn priors from source domain. The combined features across different domains are unified through a power transform layer. Extensive experiments are conducted on a task of recognizing chickenpox, measles, and human monkeypox diseases in a three-way few-shot manner. The results demonstrate that our method outperforms mainstream few-shot learning algorithms such as meta-learning based and fine-tuning based methods. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract The endoplasmic reticulum-Golgi intermediate compartment protein-53 (ERGIC-53, aka LMAN1), which cycles between the endoplasmic reticulum (ER) and Golgi, is a known cargo receptor for a number of soluble proteins. However, whether LMAN1 plays a role as a trafficking factor in the central nervous system is largely unknown. Here, we determined the role of LMAN1 on endogenous protein levels of the Cys-loop superfamily of neuroreceptors, including gamma-aminobutyric acid type A receptors (GABA A Rs), 5-hydroxytryptamine (serotonin) type 3 (5-HT 3) receptors, and nicotinic acetylcholine receptors (nAChRs). Knockdown of LMAN1 reduces the surface trafficking of endogenous β3 subunits of GABA A Rs in mouse hypothalamic GT1-7 neurons. Furthermore, Western blot analysis of brain homogenates from LMAN1 knockout mice demonstrated that loss of LMAN1 decreases the total protein levels of 5HT 3 A receptors and γ2 subunits of GABA A Rs. LMAN1 knockout regulates the ER proteostasis network by upregulating ERP44 without changing calnexin levels. Interestingly, despite the critical role of the glycan-binding function of LMAN1 in its other known cargo clients, LMAN1 interacts with GABA A Rs in a glycan-independent manner. In summary, LMAN1 is a trafficking factor for certain neuroreceptors in the central nervous system. This is the first report of LMAN1 function in membrane protein trafficking. Highlights • LMAN1 promotes the surface trafficking of endogenous GABA A Rs. • LMAN1 positively regulates total protein levels of endogenous GABA A Rs and 5-HT 3 Rs. • Knockdown of LMAN1 upregulates ERP44 in the central nervous system. • LMAN1 interacts with GABA A Rs in a glycan-independent manner. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects and potential mechanisms of dietary iron on immune function and structural integrity in gill of young grass carp ( Ctenopharyngodon idella ). A total of 630 grass carp (242.32 ± 0.58 g) were fed diets containing graded levels of iron at 12.15 (basal diet), 35.38, 63.47, 86.43, 111.09, 136.37 and 73.50 mg/kg for 60 days. Subsequently, a challenge test was conducted by infection with Flavobacterium columnare to investigate the effects of dietary iron on gill immune function and structural integrity in young grass carp. First, the results indicated that compared with the optimal iron level, iron deficiency decreased lysozyme (LZ) and acid phosphatase (ACP) activities, complement 3 (C3), C4 and immunoglobulin M (IgM) contents, and down-regulated the mRNA levels of antibacterial peptides, anti-inflammatory cytokines (except IL-4/13B), inhibitor of κBα (IκBα), target of rapamycin (TOR) and ribosomal protein S6 kinase 1 (S6K1). In contrast, iron deficiency up-regulated the mRNA levels of pro-inflammatory cytokines (except IL-6 and IFN-γ2), nuclear factor κB p65 (NF-κBp65), IκB kinases α (IKK), IKKβ, IKKγ, eIF4E-binding protein 1 (4E-BP1) and 4E-BP2 in gill of young grass carp, indicating that iron deficiency could impair immune function in fish gill. Second, iron deficiency down-regulated the mRNA levels of inhibitor of apoptosis protein (IAP) and myeloid cell leukemia 1 (Mcl-1), decreased activities and mRNA levels of antioxidant enzymes, down-regulated the mRNA levels of NF-E2-related factor 2 (Nrf2) and tight junction proteins (except claudin-12 and -15), and simultaneously increased malondialdehyde (MDA), protein carbonyl (PC) and reactive oxygen species (ROS) contents. Iron deficiency also up-regulated mRNA levels of cysteinyl aspartic acid-protease (caspase) -2, -7, -8, -9, Fas ligand (FasL), apoptotic protease activating factor-1 (Apaf-1), B-cell-lymphoma-2 associated X protein (Bax), p38 mitogen-activated protein kinase (p38MAPK), Kelch-like ECH-associating protein (Keap) 1a, Keap1b, claudin-12, -15 and MLCK, indicating that iron deficiency could disturb the structural integrity of gill in fish. Third, iron excess impaired immune function and structural integrity in gill of young grass carp. Forth, there was a better effect of ferrous fumarate than ferrous sulfate in young grass carp. Finally, the iron requirements based on ability against gill rot, ACP activity and MDA content in gill of young grass carp were estimated to be 76.52, 80.43 and 83.17 mg/kg, respectively. [ABSTRACT FROM AUTHOR]

This study was conducted to investigate the effects of dietary iron on the growth, and immune function and structural integrity in head kidney, spleen and skin as well as the underlying signaling of young grass carp ( Ctenopharyngodon idella ). Total 630 grass carp (242.32 ± 0.58 g) were fed diets containing graded levels of iron at 12.15 (basal diet), 35.38, 63.47, 86.43, 111.09, 136.37 mg/kg (diets 2–6 were added with ferrous fumarate) and 73.50 mg/kg (diet 7 was added with ferrous sulfate) diet for 60 days. Then, a challenge test was conducted by infection of Aeromonas hydrophila for 14 days. The results firstly showed that compared with optimal iron level, iron deficiency decreased lysozyme (LZ) and acid phosphatase (ACP) activities, complement 3 (C3), C4 and immunoglobulin M (IgM) contents and down-regulated the mRNA levels of antibacterial peptides, anti-inflammatory cytokines, inhibitor of κBα (IκBα), target of rapamycin (TOR) and ribosomal protein S6 kinase 1 (S6K1), whereas up-regulated the mRNA levels of pro-inflammatory cytokines, nuclear factor kappa B (NF-κB) p65, IκB kinases β (IKKβ) and eIF4E-binding protein (4E-BP) in head kidney and spleen of young grass carp ( P < 0.05), indicating that iron deficiency impaired immune function in head kidney and spleen of fish. Secondly, iron deficiency down-regulated the mRNA levels of B-cell lymphoma-2 (Bcl-2), myeloid cell leukemia 1 (Mcl-1), and inhibitor of apoptosis protein (IAP), and decreased activities and mRNA levels of antioxidant enzymes, down-regulated the mRNA levels of NF-E2-related factor 2 (Nrf2) and tight junction complexes, and up-regulated mRNA levels of cysteinyl aspartic acid-protease (caspase) -2, -3, -7, -8, -9, apoptotic protease activating factor-1 (Apaf-1), Bcl-2 associated X protein (Bax), Fas ligand (FasL), p38 mitogen-activated protein kinase (p38MAPK), Kelch-like ECH-associating protein (Keap) 1a, Keap1b, claudin-12 and myosin light chain kinase (MLCK), and increased malondialdehyde (MDA), protein carbonyl (PC) and reactive oxygen species (ROS) contents in head kidney and spleen of young grass carp ( P < 0.05), indicating that iron deficiency impaired structural integrity in head kidney and spleen of fish. Thirdly, iron deficiency increased skin hemorrhage and lesion morbidity, and impaired immune function and structural integrity in skin of fish. Fourthly, iron excess decreased growth and impaired the immune function and structural integrity in head kidney, spleen and skin of fish. Besides, in young grass carp, based on PWG and ability against skin hemorrhage and lesion, the efficacy of ferrous fumarate relative to ferrous sulfate was 140.32% and 126.48%, respectively, and the iron requirements based on PWG, ability against skin hemorrhage and lesion, ACP activities and MDA contents in head kidney and spleen were estimated to be 75.65, 87.03, 79.74, 78.93, 83.17 and 82.14 mg/kg diet (based on ferrous fumarate), respectively. [ABSTRACT FROM AUTHOR]

Promoting angiogenesis is a key therapeutic target for protection from chronic ischemic cardiac injury. Endothelial-Monocyte-Activating-Polypeptide-II (EMAP II) protein, a tumor-derived cytokine having anti-angiogenic properties in cancer, is markedly elevated following myocardial ischemia. We examined whether neutralization of EMAP II induces angiogenesis and has beneficial effects on myocardial function and structure after chronic myocardial infarction (MI). EMAP II antibody (EMAP II AB), vehicle, or non-specific IgG (IgG) was injected ip at 30 min and 3, 6, and 9 days after permanent coronary artery occlusion in mice. EMAP II AB, compared with vehicle or non-specific antibody, significantly, p < 0.05, improved the survival rate after MI, reduced scar size and attenuated the development of heart failure, i.e., left ventricular ejection fraction was significantly higher in EMAP II AB group, fibrosis was reduced by 24%, and importantly, more myocytes were alive in EMAP II AB group in the infarct area. In support of an angiogenic mechanism, capillary density (193/HPF vs . 172/HPF), doubling of the number of proliferating endothelial cells, and angiogenesis related biomarkers were upregulated in mice receiving EMAP II AB treatment as compared to IgG. Furthermore, EMAP II AB prevented EMAP II protein inhibition of in vitro tube formation in HUVECs. We conclude that blockade of EMAP II induces angiogenesis and improves cardiac function following chronic MI, resulting in reduced myocardial fibrosis and scar formation and increased capillary density and preserved viable myocytes in the infarct area. [ABSTRACT FROM AUTHOR]

We propose a new efficient and accurate numerical method based on harmonic polynomials to solve boundary value problems governed by 3D Laplace equation. The computational domain is discretized by overlapping cells. Within each cell, the velocity potential is represented by the linear superposition of a complete set of harmonic polynomials, which are the elementary solutions of Laplace equation. By its definition, the method is named as Harmonic Polynomial Cell (HPC) method. The characteristics of the accuracy and efficiency of the HPC method are demonstrated by studying analytical cases. Comparisons will be made with some other existing boundary element based methods, e.g. Quadratic Boundary Element Method (QBEM) and the Fast Multipole Accelerated QBEM (FMA-QBEM) and a fourth order Finite Difference Method (FDM). To demonstrate the applications of the method, it is applied to some studies relevant for marine hydrodynamics. Sloshing in 3D rectangular tanks, a fully-nonlinear numerical wave tank, fully-nonlinear wave focusing on a semi-circular shoal, and the nonlinear wave diffraction of a bottom-mounted cylinder in regular waves are studied. The comparisons with the experimental results and other numerical results are all in satisfactory agreement, indicating that the present HPC method is a promising method in solving potential-flow problems. The underlying procedure of the HPC method could also be useful in other fields than marine hydrodynamics involved with solving Laplace equation. [ABSTRACT FROM AUTHOR]

Humic-like substances (HULIS), as important components of brown carbon (BrC), play an important role in climate change. In this study, one-year PM 2.5 samples from 2017 to 2018 were collected at Nanjing, China and the water soluble HULIS and other chemical species were analyzed to investigate the seasonal variations, optical properties and possible sources. The HULIS concentrations exhibited highest in winter and lowest in summer. The annual averaged HULIS concentration was 2.61 ± 1.79 μg m−3, accounting for 45 ± 13% of water-soluble organic carbon (WSOC). The HULIS light absorption coefficient at 365 nm (Abs 365, HULIS) averagely accounted for 71 ± 19% of that of WSOC, suggesting that HULIS are the main light-absorbing components in WSOC. The annual averaged Ångström absorption exponent and mass absorption efficiency of HULIS at 365 nm were 5.22 ± 0.77 and 1.71 ± 0.70 m2 g−1. Good correlations between HULIS with levoglucosan and K+ suggested biomass burning (BB) influence on HULIS. High concentrations of HULIS and secondary species (e.g., NO 3 −, SO 4 2−, NH 4 +, C 2 O 4 2−) were found in present of high relative humidity, indicating strong aqueous phase secondary HULIS formation. Secondary HULIS produced from anthropogenic and biogenic precursors were quantified based on the positive matrix factorization (PMF) model and the results showed that both fossil (55%) and biogenic (45%) emission sources made great contributions to HULIS. Fossil fuel combustion significantly contributed to HULIS formation throughout the whole year, which were enriched with more secondary HULIS (30%) than primary HULIS (25%). Strongest BB contribution (39%) was found in winter and biogenic SOA contribution (32%) was found in summer. A multiple linear regression (MLR) method was further applied to obtain specific source contributions to Abs 365, HULIS and the results showed that strong light-absorbing chromophores were produced from anthropogenic precursors. Our results highlight the anthropogenic SOA and fossil fuels combustion contributions to HULIS in addition to the biggest contributor, BB, in urban area in China. • Optical properties and sources of HULIS in PM 2.5 at Nanjing, China were explored. • High HULIS and secondary species levels were observed under high relative humidity. • Secondary HULIS from anthropogenic and biogenic precursors were quantified. • Both fossil (55%) and biogenic (45%) sources made great contributions to HULIS. • HULIS produced from anthropogenic precursors showed stronger UV absorption. [ABSTRACT FROM AUTHOR]

The prostate cancer is one of the leading causes of men's cancer mortality. The development of alternative chemotherapeutic strategies is urgent. Berberine has displayed significant anti-prostate cancer activities. The underlying mechanisms are not fully understood. In the current study, we found that berberine induced apoptosis and programmed necrosis in cultured prostate cancer cells (LNCaP and PC-82 lines), and necrosis weighted more than apoptosis in contributing berberine's cytotoxicity. We demonstrated that mitochondrial protein cyclophilin-D (Cyp-D) is required for berberine-induced programmed necrosis. Inhibition of Cyp-D by its inhibitors cyclosporin A (CSA) or sanglifehrin A (SFA), and by Cyp-D shRNA depletion alleviated berberine-induced prostate cancer cell necrosis (but not apoptosis). Our data found that in prostate cancer cells, berberine induced reactive oxygen species (ROS) production, which dictated P53 translocation to mitochondria, where it physically interacted with Cyp-D to open mitochondrial permeability transition pore (mPTP). The anti-oxidant N-acetylcysteine (NAC), the P53 inhibitor pifithrin-α (PFTα) as well as P53 siRNA knockdown suppressed berberine-induced P53 mitochondrial translocation and Cyp-D association, thus inhibiting mitochondrial membrane potential (MMP) decrease and prostate cancer cell necrosis. In summary, the results of the present study provide mechanistic evidence that both apoptosis and programmed necrosis attribute to berberine's cytotoxicity in prostate cancer cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • Yeast two-hybrid technology were utilized to analyze the interactions between 038R and other core proteins of CQIV. • Three CQIV core proteins, including 032R, 125R and 160L, were identified to interact with 038R. • 038R and 125R were colocalized in the cytoplasm of Sf9 cells. • Both of 038R and 125R were essential for CQIV replication in Cherax quadricarinatus cells. Iridovirids are a group icosahedral viruses containing linear double-stranded DNA, and mainly infect invertebrates and poikilothermic vertebrates. Cherax quadricarinatus iridovirus (CQIV) is a new species of the family Iridoviridae and can cause high mortality in shrimps. In CQIV genome, there are 25 conserved genes and the putative products are involved in several viral processes. In this study, three core protein including CQIV-032R, CQIV-125R and CQIV-160L were identified to interact with CQIV-038R by yeast two-hybrid (Y2H), and the interaction between CQIV-038R and CQIV-125R was further confirmed by co-immunoprecipitation (Co-IP) assays. In the expression system, EGFP-038R and mCherry-125R were colocalized in the cytoplasm when co-expressed in Sf9 cells. Moreover, silencing the expression of 038R, 125R or both of these two proteins respectively in C. quadricarinatus cells by small interfering RNAs showed significantly inhibit CQIV replication. Collectively, we identified the interaction between 038R and 125R, and demonstrated they are essential for CQIV replication. [ABSTRACT FROM AUTHOR]

Abstract: Embryonic stem cells (ESCs) have unlimited capacity for self-renewal and can differentiate into various cell types when induced. They also have an unusual cell cycle control mechanism driven by constitutively active cyclin dependent kinases (Cdks). In mouse ESCs (mESCs). It is proposed that the rapid cell proliferation could be a necessary part of mechanisms that maintain mESC self-renewal and pluripotency, but this hypothesis is not in line with the finding in human ESCs (hESCs) that the length of the cell cycle is similar to differentiated cells. Therefore, whether rapid cell proliferation is essential for the maintenance of mESC state remains unclear. We provide insight into this uncertainty through chemical intervention of mESC cell cycle. We report here that inhibition of Cdks with olomoucine II can dramatically slow down cell proliferation of mESCs with concurrent down-regulation of cyclin A, B and E, and the activation of the Rb pathway. However, mESCs display can recover upon the removal of olomoucine II and are able to resume normal cell proliferation without losing self-renewal and pluripotency, as demonstrated by the expression of ESC markers, colony formation, embryoid body formation, and induced differentiation. We provide a mechanistic explanation for these observations by demonstrating that Oct4 and Nanog, two major transcription factors that play critical roles in the maintenance of ESC properties, are up-regulated via de novo protein synthesis when the cells are exposed to olomoucine II. Together, our data suggest that short-term inhibition of cell proliferation does not compromise the basic properties of mESCs. [Copyright &y& Elsevier]

Abstract: Human studies indicate augmented myocardial lipid metabolism in females, and that sex and obesity interact to predict myocardial fatty acid oxidation and storage. Altered lipid dynamics precede cardiomyopathies, and many studies now address high fat diets. Conversely, caloric restriction (CR), is the most studied model for longevity and stress resistance, including protection against myocardial ischemia. However, no information exists on the effects of long-term caloric restriction (CR) on triacylglyceride (TAG) content and dynamics in the heart. This study explored the effects of CR, sex and age on TAG dynamics in mouse hearts. Male and female SVJ129 mice were fed either normal (ND) or CR diet for 3 or 10months. In 5-month-old mice, CR similarly decreased cardiac TAG in males (ND: 25.5±4.5nmol/mg protein; CR: 12.6±2.7, P<0.05) and females (ND: 30.1±4.4; CR: 13.7±1.2) (no significant differences in TAG content were seen between sexes). CR reduced the contribution of exogenous palmitate to oxidative metabolism in males and females, by 15% and 11% respectively, versus ND, without affecting cardiac workload. CR also induced a larger reduction in TAG turnover in male (68%) than female hearts (38%). Interestingly, in 5month old male mice, CR reproduced the lower TAG turnover rates of middle-aged males (ND 13-month-old male=423±76nmol/mgprotein/min). Thus, long term CR reduces TAG pool dynamics. Despite reduced content, hearts of female mice subjected to CR retained a more dynamic TAG pool than males, while males respond with greater metabolic remodeling of cardiac lipid dynamics. [Copyright &y& Elsevier]

Abstract: Oxidized low-density lipoprotein (ox-LDL) is involved in the pathogenesis of atherosclerosis and atherosclerotic plaque rupture by promoting lipid accumulation, proinflammatory responses, and cell death. LDL is mainly oxidized in the subendothelial layer of the vascular wall and then can be taken up by vascular endothelial cells. However, little is known about the intracellular processing of the damaged LDL. Previous studies found that autophagy is involved in degrading oxidized proteins under oxidative stress conditions in Arabidopsis thaliana, while ox-LDL can activate autophagy in EA.hy926 endothelial cells, suggesting a possible role of autophagy in the degradation of ox-LDL by endothelial cells. The present study showed that ox-LDL aggregated in human umbilical vein endothelial cells (HUVECs) and brought about an increase in the formation of autophagosomes and autolysosomes. Ox-LDL-induced increase in the autophagic level was blocked by treatment with the autophagy inhibitor 3-methyladenine and increased by the autophagy inducer rapamycin, while the aggregation of Dil-labled ox-LDL was increased by 3-methyladenine and decreased by rapamycin. In addition, Dil-labeled ox-LDL colocalized with the autophagy marker MDC, microtubule-associated protein light chain 3 (MAP1-LC3), and lysosome-associated membrane protein 2a (lamp2a). HUVECs treated with Dil-labeled-ox-LDL showed a much greater degree of overlap of MAP1-LC3 and Lamp2a than control. The results suggest that ox-LDL activates the autophagic lysosome pathway in HUVECs through the LC3/beclin1 pathway, leading to the degradation of ox-LDL. [Copyright &y& Elsevier]

Abstract: Recordings of neuronal activity in freely moving rats are common in experiments where electrical signals are transmitted using cables. Such techniques are not common in monkeys because their prehensile abilities are thought to preclude such techniques. However, analysis of brain mechanisms underlying spatial navigation and cognition require the subject to walk. We have developed techniques for recordings in freely moving monkeys in two different situations: a 5×5m testing laboratory and in a 50m2 open field environment. Neuronal signals are sent to amplifiers and data acquisition systems using cables or telemetry. These techniques provide high quality recordings of single neurons during behaviors such as foraging, walking, and the performance of memory tasks and thus provide a unique opportunity to study primate behavior in a semi-natural situation. [Copyright &y& Elsevier]

Although there are numerous strategies to counteract the death of dopaminergic neurons in Parkinson's disease (PD), there are currently no treatments that delay or prevent the disease course, indicating that early protective treatments are needed. Targeting axonal degeneration, a key initiating event in PD, is required to develop novel therapies; however, its underlying molecular mechanisms are not fully understood. Here, we studied axonal degeneration induced by 6-hydroxydopamine (6-OHDA) in vitro and in vivo. We found that metabotropic glutamate receptor 5 (mGluR5) expression increased during 6-OHDA-induced axonal degeneration in primary neurons and that blockade of mGluR5 by its antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[(2-methyl-1, 3-thiazol-4-yl) ethynyl]-pyridine (MTEP) almost completely attenuated the degenerative process in vitro. Furthermore, a rapid increase in intra-axonal calcium levels following 6-OHDA treatment was visualized using a calcium-sensitive fluorescence probe and a calcium chelator prevented the axonal degenerative process induced by 6-OHDA in vitro , whereas application of the mGluR5 antagonist MPEP partially attenuated the increase in intra-axonal calcium. The screening of calcium targets revealed that calpain activation and an increase in phosphorylated extracellular signal-regulated kinase (p-ERK) were calcium dependent during 6-OHDA-induced axonal degeneration in vitro. Consistent with these in vitro findings, blockade of mGluR5 with MPEP attenuated the degeneration of dopaminergic axons induced by 6-OHDA injection into the striatum prior to soma death in the early stage of PD in an in vivo animal model. In addition, MPEP inhibited the increase in mGluR5 expression levels, calpain activation and the elevation of p-ERK in the striatum triggered by 6-OHDA injection in vivo. Taken together, these data identify an mGluR5-calcium-dependent cascade that causes axonal degeneration, and suggest that mGluR5 antagonists could provide effective therapy to prevent the disease process of PD. • mGluR5 controls 6-OHDA-induced axonal degeneration by altering intra-axonal calcium flux. • Calpain activation and phosphorylation of ERK are further downstream targets during 6-OHDA-induced axonal degeneration. • Both blockade of mGluR5 and calcium inhibitor markedly attenuate the process of axonal degeneration. [ABSTRACT FROM AUTHOR]

Continental islands are often dynamic in regard to the origin and evolution of their biota. Although colonizations from mainland Southeast Asia to Hainan Island have been reported, the role of Hainan Island as a source for continental biota has not been considered. Goniurosaurus is a genus comprised of nocturnal ground geckos. We reexamined the evolutionary history of Goniurosaurus using both molecular phylogenetics and morphological comparisons. All phylogenetic trees recovered G. zhoui as sister to G. hainanensis  +  G. lichtenfelderi , which together are the sister lineage of G. bawanglingensis . The recovery of this “Hainan clade” contradicts previous classifications that placed G. bawanglingensis within the G. luii group. Moreover, ancestral trait reconstruction revealed that body band number might have decreased two or three times independently within Goniurosaurus from four to three. The divergence between the continental G. luii group and the Hainan clade was estimated at ∼34.7 Mya (CI = 22.3–48.6), possibly correlating with the vicariance event between Hainan Island and the mainland. G. lichtenfelderi diverged from G. hainanensis very recently, which might be associated with a historical dispersal event from Hainan Island to Vietnam during glacial periods. Our study improves the understanding of Goniurosaurus systematics and reveals the important role of Hainan Island in bidirectional colonizations. [ABSTRACT FROM AUTHOR]

Abstract: Background: Neuroinflammation mediated by microglia has been implicated in delirium. Suppression of microglial activation may therefore contribute to alleviate delirium. It has been reported that dexmedetomidine (DEX) has a potent anti-inflammatory property. In the present study, we investigated the effects of DEX on the production of proinflammatory mediators in lipopolysaccharide-stimulated microglia. Materials and methods: The concentrations of DEX were chosen to correspond to 1, 10, and 100 times of clinically relevant concentration (i.e., 1, 10, and 100ng/mL). The levels of proinflammatory mediators, such as inducible nitric oxide synthase or nitric oxide, prostaglandin E2, interleukin 1β, and tumor necrosis factor α, were measured. Results: DEX at 1ng/mL did not affect the production of proinflammatory mediators. DEX at 10 and 100ng/mL significantly inhibited the release of nitric oxide, prostaglandin E2, interleukin 1β, and tumor necrosis factor α and the expression of inducible nitric oxide synthase messenger RNA. Conclusions: These results suggest that DEX is a potent suppressor of lipopolysaccharide-induced inflammation in activated microglia and may be a potential therapeutic agent for the treatment of intensive care unit delirium. [Copyright &y& Elsevier]

Abstract: Background: Neuroinflammatory response triggered by surgery has been increasingly reported to be associated with postoperative cognitive dysfunction. Proinflammatory cytokines, such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), play a pivotal role in mediating surgery-induced neuroinflammation. The role of cyclooxygenase-2 (COX-2), a critical regulator in inflammatory response, in surgery-induced neuroinflammation is still unknown. The aim of the study was to investigate the changes of COX-2 expression and prostaglandin E2 (PGE2) production in the hippocampus in aged rats following partial hepatectomy. The effects of selective COX-2 inhibitor (parecoxib) on hippocampal proinflammatory cytokine expression were also evaluated. Methods: Aged rats were randomly divided into three groups: control (n = 10), surgery (n = 30), and parecoxib (n = 30). Control animals received sterile saline to control for the effects of injection stress. Rats in the surgery group received partial hepatectomy under isoflurane anesthesia and sterile saline injection. Rats in the parecoxib group received surgery and anesthesia similar to surgery group rats, and parecoxib treatment. On postanesthetic days 1, 3, and 7, animals were euthanized to assess levels of hippocampal COX-2 expression, PGE2 production, and cytokines IL-1β and TNF-α expression. The effects of parecoxib on proinflammatory cytokine expression were also assessed. Results: Partial hepatectomy significantly increased COX-2 expression, PGE2 production, and proinflammatory cytokine expression in the hippocampus in aged rats on postoperative days 1 and 3. Parecoxib inhibited hippocampal IL-1β and TNF-α expression through downregulation of the COX-2/PGE2 pathway. Conclusion: COX-2 may play a critical role in surgery-induced neuroinflammation. The COX-2 inhibitor may be a promising candidate for treatment of neuroinflammation caused by surgical trauma. [Copyright &y& Elsevier]

Trichloroethylene (TCE) was once a widely applied industrial solvent, but is now an infamous contaminant in groundwater. Although anaerobic reductive dechlorination is considered a greener remediation approach, the accumulation of toxic intermediates, such as vinyl chloride (VC), and a longer remediation period are highly concerning. Biostimulation and bioaugmentation have been developed to solve these problems. The former method may not be effective, and the latter may introduce foreign genes. Here, we propose a new approach by applying environmental stresses to reshape the indigenous microbiome. In this study, by using the Taguchi method, the effects of heating, pH, salinity, and desiccation were systematically examined. The optimum conditions were defined as 50 °C, pH 9, 3.50% salinity (w/v), and 21% volumetric water content (θ W). The top performing group, G7, can complete the conversion of 11.81 mg/L TCE into ethene in 3.0 days with a 1.23% abundance of Dehalococcoides mccartyi 195 (Dhc 195). Redundancy analysis confirmed that temperature and salinity were the predominant factors in reorganizing the microbiomes. The microbiome structure and its effectiveness can last for at least 90 d. The repetitive selection conditions and sustainable degradation capability strongly supported that microbiome reengineering is feasible for the rapid bioremediation of TCE-contaminated environmental matrices. [Display omitted] • A reshaped microbiome finished the complete conversion of TCE (11.81 mg/L) to ethene within 3.0 days. • A new microbial association was found between Dehalococcoides mccartyi 195, Desulfuromonas michiganensis , and Cloacibacillus porcorum. • Temperature and salinity were the most predominant factors in reshaping the microbiomes and improving the biodegradation rate. • Repetitive selecting conditions on different cultures implied feasibility in field application. [ABSTRACT FROM AUTHOR]

Background Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is known to play an immunomodulatory role in a variety of tumors, but its role in ulcerative colitis (UC) remains to be elucidated. The present study aimed to investigate the effects of exogenous CEACAM1 on UC using a mouse model. Materials and methods UC in female Balb/c mice was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Hundred microliters of 1% TNBS was supplied through abdominal smearing for sensitization. Then after 7 d, 100 μL 0.5% TNBS was administered by a transrectal injection. After injection, the mice were placed in an upside-down position for 1 min. The CEACAM1 treatment was performed by receiving a transrectal injection of 109 pfu of CEACAM1. The mice were weighed, and the colonic mucosa damage was scored. The effects of exogenous CEACAM1 expression on mouse colon inflammation, apoptosis, and CD4 T lymphocyte infiltration in UC were examined. Results CEACAM1 expression was significantly reduced in the colon tissue of mice with UC, and the expression of exogenous CEACAM1 improved the symptoms of UC, as evidenced by hematoxylin-eosin staining and histopathologic scores. Moreover, exogenous CEACAM1 reduced the levels of inflammatory cytokines, suppressed CD4 T cell infiltration, and effectively inhibited apoptosis in the colon of TNBS-induced UC mice. Conclusions The expression of exogenous CEACAM1 effectively rescues the symptoms of TNBS-induced UC in mice by inhibiting inflammation, T cell infiltration, and apoptosis in the colon. [ABSTRACT FROM AUTHOR]

Highlights: [•] Novel magnetic Fe3O4@SiO2@PVPA microspheres were fabricated and characterized. [•] The Fe3O4@SiO2@PVPA microspheres were used as IMAC matrix to immobilize Ce(IV) ions. [•] The affinity microspheres showed promising application in phosphopeptides enrichment. [ABSTRACT FROM AUTHOR]

Abstract: Background: Heme oxygenase-1 (HO-1) has been shown to have antioxidant and anti-apoptotic properties. The present study transduced HO-1 protein into intestinal tissues using PEP-1, a cell-penetrating peptide, and investigated its potentiality in prevention against intestinal ischemia/reperfusion (I/R) injury. Materials and methods: PEP-1-HO-1 fusion protein was administered intravenously to explore the time and dose characteristics through measuring serum HO-1 levels. Twenty-four male Sprague-Dawley rats were randomly divided into three groups: sham, intestinal I/R (II/R), II/R + PEP-1-HO-1 fusion protein (HO). The model was established by occluding the superior mesenteric artery for 45 min followed by 120 min reperfusion. In HO group, PEP-1-HO-1 was administered intravenously 30 min before ischemia, whereas animals in sham and II/R groups received the equal volume of physiological saline. After the experiment, the intestines were harvested for determination of histologic injury, wet/dry ratio, enzyme activity, apoptosis, and His-probe protein (one part of PEP-1-HO-1). Results: Levels of serum HO-1 were dose- and time-dependent manner after intravenous injection of PEP-1-HO-1. I/R caused deterioration of histologic characteristics and increases in histologic injury scoring, wet/dry ratio, myeloperoxidase activity, malondialdehyde, and intestinal apoptosis. These changes were also accompanied by a decrease in superoxide dismutase activity (P < 0.05). PEP-1-HO-1 treatment significantly reversed these changes (P < 0.05). Furthermore, His-probe protein expression was only detected in PEP-1-HO-1–treated animals. Conclusion: Treatment of PEP-1-HO-1 attenuates intestinal I/R injury, which might be attributable to its antioxidant and anti-apoptotic roles of HO-1. [Copyright &y& Elsevier]

Fruit vinegar is typically produced through a two-stage submerged fermentation involving Saccharomyces cerevisiae (alcohol fermentation) and Acetobacter pasteurianus (acetic acid fermentation). In order to enhance its flavor and nutritional properties, Lactiplantibacillus plantarum and Komagataeibacter europaeus were introduced into the respective stages. The fermentation process was monitored to assess their individual and combined effects, while non-targeted metabolomic analysis aided amino acids and organic acids analysis was applied to characterize the metabolic profiles and identify the differential metabolites. Lactic acid accumulated by L. plantarum , enhanced energy metabolism and ethanol respiratory chain, thereby promoting the K. europaeus growth. In the presence of K. europaeus, A. pasteurianus biomass increased 36–57% , leading to elevated acetic acid synthesis. The co-fermentation systems, especially those containing K. europaeus , exhibited enhanced conversion of shikimic acid to aromatic amino acids and their derivatives such as ferulic acid, isoferulic acid, serotonin, l -kynuanine, phenylacetaldehyde and benzaldehyde. The co-fermentation with K. europaeus and L. plantarum resulted in an enhancement of ethyl phenylacetate, ethyl lactate and ethyl hexanoate production, thereby intensifying the fruity aroma profile. The findings presented here contributed to a deeper comprehension of bioconversion mechanism involving multiple species in cider vinegar fermentation processes. [Display omitted] • L. plantarum enhanced energy metabolism and ethanol oxidation in acetate fermentation. • Lactic acid accumulation by L. plantarum benefited K. europaeus growth. • With K. europaeus, A. pasteurianus biomass and acetic acid increased. • Co-fermentation systems improved the conversion of aromatic amino acids. • Co-fermentation enhanced the fruity aroma compounds. [ABSTRACT FROM AUTHOR]

Urban flood risk assessment plays a crucial role in disaster prevention and mitigation. A scientifically accurate assessment and risk stratification method are of paramount importance for effective flood risk management. This study aims to propose a comprehensive urban flood risk assessment approach by coupling GeoDetector-Dematel and Clustering Method to enhance the accuracy of urban flood risk evaluation. Based on simulation results from hydraulic models and existing literature, the research established a set of urban flood risk assessment indicators comprising 10 metrics across two dimensions: hazard factors and vulnerability factors, among which vulnerability factors include exposure factors, sensitivity factors, and adaptability factors. Subsequently, the research introduced the GeoDetector-Dematel method to determine indicator weights, significantly enhancing the scientific rigor and precision of weight calculation. Finally, the research employed the K-means clustering method to risk zonation, providing a more scientifically rational depiction of the spatial distribution of urban flood risks. This novel comprehensive urban flood risk assessment method was applied in the Fangzhuang area of Beijing. The results demonstrated that this integrated approach effectively enhances the accuracy of urban flood risk assessment. In conclusion, this research offers a new methodology for urban flood risk assessment and contributes to decision-making in disaster prevention and control measures. [Display omitted] • A novel integrated urban flood risk assessment approach is proposed. • A set of urban flood risk assessment index system is established. • A novel method using GeoDetector-Dematel determines index weights. • K-means method is introduced to obtain more scientific flood risk. [ABSTRACT FROM AUTHOR]

Lysine crotonylation (Kcr) is a newly identified protein translational modification and is involved in major biological processes including glycolysis, but its role in colorectal cancer (CRC) is unknown. Here, we found that the Kcr of α enolase (ENO1) was significantly elevated in human CRC tissues compared with the paratumoral tissues. CREB-binding protein (CBP) functioned as a crotonyltranferase of ENO1, and SIRT2 was involved in the decrotonylation of ENO1. Using quantitative mass spectrometry for crotonylomics analysis, we further found that K420 was the main Kcr site of ENO1 and ENO1 K420 Kcr promoted the growth, migration, and invasion of CRC cells in vitro by enhancing the activity of ENO1 and regulating the expression of tumor-associated genes. Our study reveals an important mechanism by which ENO1 regulates CRC through crotonylation. • The Kcr of α enolase (ENO1) is significantly upregulated in colorectal cancer. • CBP and SIRT2 are key regulators of ENO1 Kcr in HCT116 cells. • ENO1 K420 Kcr enhances the growth, migration and invasion of CRC cells in vitro. • ENO1 K420 Kcr desensitizes cancer cells to glucose depletion by enhancing the activity of ENO1 enzyme. • ENO1 K420 Kcr regulates a variety of tumor-associated signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract: This research examined whether the non-conscious activation of an implicit appraisal concept could affect responses associated with the corresponding emotion as predicted by appraisal theories. Explicit and implicit emotional responses were examined. We focused on implicit unfairness and its effect on anger. The results show that subliminal activation of implicit unfairness affected implicit anger responses (anger facial expression and latency responses to anger words) but not explicit anger feelings (i.e., reported anger). The non-conscious effect of implicit unfairness was specific to anger, as no effect on sadness, fear, and guilt was found. [Copyright &y& Elsevier]

Abstract: Adsorption of ammonia (NH3) onto activated carbons prepared from palm shells impregnated with sulfuric acid (H2SO4) was investigated. The effects of activation temperature and acid concentration on pore surface area development were studied. The relatively large micropore surface areas of the palm-shell activated carbons prepared by H2SO4 activation suggest their potential applications in gas adsorption. Adsorption experiments at a fixed temperature showed that the amounts of NH3 adsorbed onto the chemically activated carbons, unlike those prepared by CO2 thermal activation, were not solely dependent on the specific pore surface areas of the adsorbents. Further adsorption tests for a wide range of temperatures suggested combined physisorption and chemisorption of NH3. Desorption tests at the same temperature as adsorption and at an elevated temperature were carried out to confirm the occurrence of chemisorption due to the interaction between NH3 and some oxygen functional groups via hydrogen bonding. The surface functional groups on the adsorbent surface were detected by Fourier transform infrared spectroscopy. The amounts of NH3 adsorbed by chemisorption were correlated with the contents of elemental oxygen present in the adsorbents. Mechanisms for chemical activation and adsorption processes are proposed based on the observed phenomena. [Copyright &y& Elsevier]

Wnt signaling is one of the major signaling pathways that regulate cell differentiation, tissue patterning and stem cell homeostasis and its dysfunction causes many human diseases, such as cancer. It is of tremendous interests to understand how Wnt signaling is regulated in a precise manner both temporally and spatially. Naked cuticle (Nkd) acts as a negative-feedback inhibitor for Wingless (Wg, a fly Wnt) signaling in Drosophila embryonic development. However, the role of Nkd remains controversial in later fly development, particularly on the canonical Wg pathway. In the present study, we show that nkd is essential for wing pattern formation, such that both gain and loss of nkd result in the disruption of Wg target expression in larvae stage and abnormal adult wing morphologies. Furthermore, we demonstrate that a thirty amino acid fragment in Nkd, identified previously in Wharton lab, is critical for the canonical Wg signaling, but is dispensable for Wg/planar cell polarity pathway. Putting aside the pleiotropic nature of nkd function, i.e. its role in the Decapentaplegic signaling, we conclude that Nkd universally inhibits the canonical Wg pathway across a life span of Drosophila development. • nkd is essential for wing pattern formation in larvae stage. • Both gain and loss of nkd result in abnormal adult wing morphologies. • A 30 amino acid fragment in Nkd is dispensable for Wg/planar cell polarity pathway. [ABSTRACT FROM AUTHOR]

• A relatively inactive dynamic brain status occurred more often in SSNHL participants. Early-stage SSNHL participants showed decreased brain status transition number. • Disturbed neurovascular coupling restricted to the primary auditory cortex occurred in the intermediate- and late-stage SSNHL patients. • A significant shrinkage of the left medial superior frontal gyrus developed at the late stage. • Our study offered neuroimaging evidence for evolvement from functional to structural brain alterations of SSNHL patients with disease duration less than 1 month. A cortical plasticity after long-duration single side deafness (SSD) is advocated with neuroimaging evidence while little is known about the short-duration SSDs. In this case-cohort study, we recruited unilateral sudden sensorineural hearing loss (SSNHL) patients and age-, gender-matched health controls (HC), followed by comprehensive neuroimaging analyses. The primary outcome measures were temporal alterations of varied dynamic functional network connectivity (dFNC) states, neurovascular coupling (NVC) and brain region volume at different stages of SSNHL. The secondary outcome measures were pure-tone audiograms of SSNHL patients before and after treatment. A total of 38 SSNHL patients (21 [55%] male; mean [standard deviation] age, 45.05 [15.83] years) and 44 HC (28 [64%] male; mean [standard deviation] age, 43.55 [12.80] years) were enrolled. SSNHL patients were categorized into subgroups based on the time from disease onset to the initial magnetic resonance imaging scan: early- (n = 16; 1-6 days), intermediate- (n = 9; 7-13 days), and late- stage (n = 13; 14-30 days) groups. We first identified slow state transitions between varied dFNC states at early-stage SSNHL, then revealed the decreased NVC restricted to the auditory cortex at the intermediate- and late-stage SSNHL. Finally, a significantly decreased volume of the left medial superior frontal gyrus (SFGmed) was observed only in the late-stage SSNHL cohort. Furthermore, the volume of the left SFGmed is robustly correlated with both disease duration and patient prognosis. Our study offered neuroimaging evidence for the evolvement from functional to structural brain alterations of SSNHL patients with disease duration less than 1 month, which may explain, from a neuroimaging perspective, why early-stage SSNHL patients have better therapeutic responses and hearing recovery. [Display omitted] [ABSTRACT FROM AUTHOR]

Two Co(II)-based coordination polymers: [Co 2 (L) 2 (bib) 2 ] n (1) and {[Co 2 (L) 2 (bimb) 2 ]·2H 2 O·DMA)} n (DMA = N,N-dimethylacetamide) (2) using 4,4′-bis(thiomethylene) dibenzoic acid (H 2 L) as the first ligand, 1,4-bis(imidazol)-butane (bib) and 1,4-bis(imidazol-1-ylmethyl)benzene) (bimb) as the second ligands, were synthesized under the condition of solvothermal and characterized by X-ray single-crystal diffraction, elemental analysis, IR spectra and thermogravimetric analysis (TGA). X-ray single-crystal diffraction analysis exhibits that 1 and 2 belong to the triclinic crystal system, space group P -1. The central Co(II) ions exhibit a regular spatial tetrahedral structure which are coordinated by two O atoms from two L2− ligands and two N atoms from two N-donor ligands. Furthermore, the photocatalytic degradation properties and mechanism of 1 and 2 for methylene blue (MB) were investigated. The results show that the band gap (E g) of 1 and 2 is 3.78 eV and 3.82 eV, and the equipotential point (pH pzc) of 1 is 4.25. Both 1 and 2 show excellent photocatalytic degradation for MB. •OH is the main active substance causing MB degradation. The photocatalytic degradation for MB of 1 and 2 is in line with the first order kinetics equation. The pH pzc of complex 1 is 4.25. When pH < 4.25, 1 has a positive charge on the surface, and will generate electrostatic repulsion with MBH2+, inhibiting the adsorption of 1 to MB, so the degradation rate of MB is greatly reduced. When pH > 4.25, complex 1 has a negative charge on the surface and generates electrostatic attraction with MBH2+, which promotes the adsorption of 1 to MB, so the degradation rate of MB is greatly increased. Image 1 [ABSTRACT FROM AUTHOR]

This study aimed to investigate the role of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway in protection by peritoneal resuscitation (PR) using pyruvate-peritoneal dialysis solution (PY-PDS) against intestinal injury from hemorrhagic shock (HS) in rats. Sixty-four rats were assigned to eight groups: group SHAM; group intravenous resuscitation (VR); groups NS, LA, and PY in which the rats were subjected to HS and PR with normal saline (NS), lactate-peritoneal dialysis solution (LA-PDS), and PY-PDS, respectively, combined with VR; and groups DMSO, RPM, and AG490 in which the rats were subjected to HS and VR with pretreatment of dimethyl sulfoxide (DMSO), rapamycin (RPM), and tyrphostin B42 (AG490). At 2 h after HS and resuscitation, the levels of diamine oxidase, 15-F 2t -isoprostane, thromboxane B 2 , and endothelin-1, in the blood and the intestinal mucosal apoptotic index and caspase-3 were lower in groups PY, RPM, and AG490 than in groups VR, NS, LA, and DMSO. Group PY showed lower levels of malondialdehyde and myeloperoxidase and a higher level of superoxide dismutase than groups VR, NS, and LA. Phosphorylated JAK2 and phosphorylated STAT3 levels were lower in groups PY, RPM, AG490, and LA than in groups VR, NS, and DMSO. The protection mechanism of PR with PY-PDS combined with VR was related to the inhibition of the JAK/STAT signaling pathway during HS and resuscitation. The process might include suppression of oxidative stress, reduction of neutrophil infiltration, regulation of microcirculation, and inhibition of apoptosis. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic-ischemic encephalopathy (HIE) often leads to neonatal death or severe, irreversible neurological deficits. Pathologically, the occurrence of massive cell death and subsequent inflammation suggested that pyroptosis, an inflammation associated programed cell death, might play a role in HIE. Here, by measuring changes of key molecules in pyroptosis pathway in HIE patients, we discovered that their elevation levels tightly correlate with the severity of HIE. Next, we demonstrated that application of MCC950, a small molecule to inhibit NLRP3 inflammasome and thus pyroptosis, substantially alleviated pyroptosis and the injury severity in rats with neonatal hypoxic-ischemic brain damage (HIBD). Mechanistically, we showed that NLRP-3/caspase-1/GSDMD axis is required for microglia pyroptosis and activation. Our data demonstrated that microglia mediated pyroptosis played a crucial role in neonatal HIE, which shed lights into the development of intervention avenues targeting pyroptosis to treat HIE and traumatic brain injuries. • Elevation of key molecules in pyroptosis pathway in neonatal HIE patients. • MCC950 substantially alleviated pyroptosis and the injury severity of neonatal HIE. • NLRP-3/caspase-1/GSDMD axis is required for microglia pyroptosis and activation. [ABSTRACT FROM AUTHOR]

Graphical abstract Reported herein is the design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists constructed on a N 1-(isoquinolin-5-yl)- N 2-phenylpyrrolidine-1,2-dicarboxamide platform that evolved from a 5-aminoisoquinoline urea lead. Highlights • Design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists. • 3b was orally bioavailable and exhibited potent antagonism of both human and rat TRPV1. • 3b exhibited good efficacy in different pain models and did not elevate core body temperature. Abstract Reported herein is the design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists constructed on a N 1-(isoquinolin-5-yl)- N 2-phenylpyrrolidine-1,2-dicarboxamide platform that evolved from a 5-aminoisoquinoline urea lead. Advancing the SAR of this series led to the eventual identification of 3b , comprising a p -Br substituted phenyl. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 3b displayed potent antagonism activated by capsaicin (IC 50 = 0.084 μM) and protons (IC 50 = 0.313 μM). In the preliminary analgesic and body temperature tests, 3b exhibited good efficacy in capsaicin-induced and heat-induced pain models and without hyperthermia side-effect. On the basis of its superior profiles, 3b could be considered as the lead candidate for the further development of antinociceptive drugs. [ABSTRACT FROM AUTHOR]

In this work, we designed and synthesized two series of MOR/TRPV1 dual active ligands using a pharmacophore fusion strategy and evaluated their biological activities. Compound 5a , which has the key pharmacodynamic groups of fentanyl and 1 , exhibited not only satisfactory dual pharmacological activity for MOR (EC 50 = 53.7 nM) and TRPV1 (IC 50 = 32.9 nM) in vitro , but also had promising analgesic activity in vivo. In addition, compound 5a did not lead to the development of hyperthermia side effects and analgesic tolerance. [Display omitted] • Two series of novel MOR/TRPV1 dual-active ligands were designed and synthesized using the classical MOR agonists pethidine and fentanyl and our previously reported TRPV1 antagonist 1 as lead compounds. • Compound 5a not only exhibited the most promising dual pharmacological activity for MOR (EC 50 = 53.7 nM) and TRPV1 (IC 50 = 32.9 nM) in vitro , but also exerted potent analgesic effects in vivo by simultaneously agonizing MOR and antagonizing TRPV1. • More importantly, compound 5a avoided the development of hyperthermic side effects associated with TRPV1 as well as MOR-related analgesic tolerance. Currently, the development of effective analgesic drugs with few side effects remains a great challenge. Studies have suggested that multi-target drug treatments show high efficacy and reduced side effects compared to single-target drug therapies. In this work, we designed and synthesized two series of novel MOR/TRPV1 dual active ligands in which the phenylpiperidine group or the N -phenyl- N -(piperidin-4-yl) propionamide group as the MOR pharmacophore was fused to the benzylpiperazinyl urea-based TRPV1 pharmacophore. In particular, compound 5a exhibited promising dual pharmacological activity for MOR (EC 50 = 53.7 nM) and TRPV1 (IC 50 = 32.9 nM) in vitro. In formalin tests, compound 5a showed potent, dose-dependent in vivo analgesic activity in both the 1st and 2nd phases. Gratifyingly, compound 5a did not cause the side effects of hyperthermia and analgesic tolerance. Consistent with its in vitro activity, compound 5a also simultaneously agonized MOR and antagonized TRPV1 in vivo. Further studies on compound 5a showed acceptable pharmacokinetic properties and brain permeability. Furthermore, molecular docking studies showed that compound 5a tightly bound to the active pockets of hMOR and hTRPV1, respectively. Overall, this work shows the promise in discovering new analgesic treatments through the strategy of simultaneously targeting MOR and TRPV1 with a single molecule. [ABSTRACT FROM AUTHOR]

Foam cell formation, which is caused by imbalanced cholesterol influx and efflux by macrophages, plays a vital role in the occurrence and development of atherosclerosis. Humanin (HN), a mitochondria-derived peptide, can prevent the production of reactive oxygen species and death of human aortic endothelial cells exposed to oxidized low-density lipoprotein (ox-LDL) and has a protective effect on patients with in early atherosclerosis. However, the effects of HN on the regulation of cholesterol metabolism in RAW 264.7 macrophages are still unknown. This study was designed to investigate the role of [Gly14]-humanin (HNG) in lipid uptake and cholesterol efflux in RAW 264.7 macrophages. Flow cytometry and live cell imaging results showed that HNG reduced Dil-ox-LDL accumulation in the RAW 264.7 macrophages. A similar result was obtained for lipid accumulation by measuring cellular cholesterol content. Western blot analysis showed that ox-LDL treatment upregulated not only the protein expression of CD36 and LOX-1, which mediate ox-LDL endocytosis, but also ATP-binding cassette (ABC) transporter A1 and ABCG1, which mediate ox-LDL exflux. HNG pretreatment inhibited the upregulation of CD36 and LOX-1 levels, prompting the upregulation of ABCA1 and ABCG1 levels induced by ox-LDL. Therefore we concluded that HNG could inhibit ox-LDL-induced macrophage-derived foam cell formation, which occurs because of a decrease in lipid uptake and an increase in cholesterol efflux from macrophage cells. [ABSTRACT FROM AUTHOR]

The Coronavirus Disease 2019 (COVID-19) lockdown policy reduced anthropogenic emissions and impacted the atmospheric chemical characteristics in Chinese urban cities. However, rare studies were conducted at the high mountain site. In this work, in-situ measurements of light absorption by carbonaceous aerosols and carbon dioxide (CO 2) concentrations were conducted at Waliguan (WLG) over the northeastern Tibetan Plateau of China from January 3 to March 30, 2020. The data was employed to explore the influence of the COVID-19 lockdown on atmospheric chemistry in the background-free troposphere. During the sampling period, the light absorption near-infrared (>470 nm) was mainly contributed by BC (>72%), however, BC and brown carbon (BrC) contributed equally to light absorption in the short wavelength (∼350 nm). The average BC concentrations in the pre-, during and post-lockdown were 0.28 ± 0.25, 0.18 ± 0.16, and 0.28 ± 0.20 μg m−3, respectively, which decreased by approximately 35% during the lockdown period. Meanwhile, CO 2 also showed slight decreases during the lockdown period. The declined BC was profoundly attributed to the reduced emissions (∼86%), especially for the combustion of fossil fuels. Moreover, the declined light absorption of BC, primary and secondary BrC decreased the solar energy absorbance by 35, 15, and 14%, respectively. The concentration weighted trajectories (CWT) analysis suggested that the decreased BC and CO 2 at WLG were exclusively associated with the emission reduction in the eastern region of WLG. Our results highlighted that the reduced anthropogenic emissions attributed to the lockdown in the urban cities did impact the atmospheric chemistry in the free troposphere of the Tibetan Plateau. • BC decreased up to 35% with 15% due to meteorological conditions and 85% due to emissions, and with 20% due to biomass burning and 80% due to fossil.. • Solar energy absorbed by BC, primary, and secondary brown carbon decreased 35, 15, and 14%, respectively.. • The main potential source area was the eastern urban near the site and the intensity of both BC and CO2 decreased.. • The eastern BC and CO2 accounted for 97% and 108% of the decline for the total BC and CO2. [ABSTRACT FROM AUTHOR]

The structural, elastic, electronic and optical properties of K 2 CuBiX 6 (X ​= ​Br, Cl) are studied by the first principle calculation in this paper. Their structural and thermodynamic stabilities are guaranteed by the formation energy, binding energy and Born-Huang criterion. The results of elastic constants show that the two materials are ductile and can be applied in foldable optoelectronic devices. Besides, The calculated bandgap values are 1.03 ​eV and 1.44 ​eV for K 2 CuBiBr 6 and K 2 CuBiCl 6 , respectively, which is just in the ideal energy gap range of semiconductors. K 2 CuBiX 6 has very small effective mass advantageous to carrier transport. In addition, the optical properties analysis shows that K 2 CuBiX 6 has excellent light absorption properties in ultraviolet–visible wavelength. Due to their suitable bandgaps and good light absorption, K 2 CuBiX 6 has a promising application in solar cells and other optoelectronic devices. In this study, the perovskites K 2 CuBiX 6 (X ​= ​Br, Cl) are proposed as functional materials in solar cells. [Display omitted] • The K 2 CuBiX 6 (X ​= ​Br, Cl) are very suitable for photosensitive materials of solar cells. • The K 2 CuBiX 6 can be a potential candidate for excellent light absorbing material. • The K 2 CuBiX 6 is the structural and thermodynamic stabilities. [ABSTRACT FROM AUTHOR]

Background Penehyclidine hydrochloride (PHC) is a new anticholinergic drug, which has been shown to have a good curative effect for sepsis. Beta arrestins have been demonstrated to play important roles in sepsis. This study is to investigate the effects of PHC on pulmonary microvascular permeability and on expressions of beta arrestins in lung injury induced by the cecal ligation and puncture (CLP) procedure. Materials and methods Thirty healthy female mice were randomly divided into three groups (n = 10 each): sham operation group (control group), CLP group (CLP group), and PHC 0.45 mg/kg group (PHC group). In the PHC group, mice were given an intraperitoneal injection of PHC 0.45 mg/kg 1 h before surgery. Mice in the other two groups received an intraperitoneal injection of the same volume of normal saline. At 12 h after surgery, serum and bronchoalveolar lavage fluid were collected to examine lung permeability index. The lung tissue samples were collected to examine expressions of myosin light chain kinase (MLCK), vascular endothelial-cadherin (VE-cadherin), vascular cell adhesion molecule 1 (VCAM-1), myeloperoxidase (MPO), NF-κB, and beta arrestins. Results Compared with the control group, pulmonary microvascular permeability, MPO activity, NF-κB, VCAM-1, and MLCK expressions were significantly increased, whereas VE-cadherin and beta-arrestin protein expressions were obviously decreased in CLP group. Furthermore, compared with the CLP group, PHC group markedly decreased pulmonary microvascular permeability, MPO activity, NF-κB, VCAM-1, and MLCK expressions, and increased expressions of VE-cadherin and beta arrestins. Conclusions This study suggests that in the CLP-induced lung injury model, PHC could reduce pulmonary microvascular permeability by upregulating expressions of beta arrestins. [ABSTRACT FROM AUTHOR]

Abstract: Background: Postoperative cognitive dysfunction, a common complication after surgery in elderly patients, is an increasing and largely underestimated problem without a defined etiology. Neuroinflammation plays an important role in the pathogenesis of postoperative cognitive dysfunction. The present study sought to investigate the role of neuroinflammation mediated by high-mobility group box 1 (HMGB1), S100B, and the receptor for advanced glycation end product (RAGE) in cognitive dysfunction after partial hepatectomy in aged mice. Materials and methods: Old C57BL/6 mice were randomly divided into three groups: normal control (n = 18), anesthetic (n = 66), and surgery (n = 66). The mice in the surgery or anesthetic group received isoflurane anesthesia for either partial hepatectomy or no surgery, respectively. Cognitive function was subsequently assessed using a Y-maze. HMGB1, S100B, RAGE, interleukin-1β, and nuclear factor-kappaB p65 levels were measured at 12 h and 1, 3, and 7 d after surgery. Immunofluorescence double labeling was performed to study the colocalization between RAGE and its ligands, HMGB1 and S100B. Results: The mice’s learning and memory abilities were significantly impaired at 1 and 3 d and 2 and 4 d after surgery, respectively. The expression of HMGB1, S100B, RAGE, and nuclear factor-kappaB p65 had increased significantly at 12 h and 1 and 3 d after surgery. The interleukin-1β level was significantly increased at 1 and 3 d after surgery. The interaction of HMGB1 or S100B with RAGE was confirmed at 1 d after surgery. Conclusions: These data suggest that HMGB1, S100B, and RAGE signaling modulate the hippocampal inflammatory response and might play key roles in surgery-induced cognitive decline. [Copyright &y& Elsevier]

High dimensional quantum key distribution is regarded as one of the most promising ways to boost the performance of quantum communication. In this paper, we propose a new scheme of high dimensional quantum key distribution in advantage of improving the efficiency by hybridly encoding the temporal and polarization degrees of freedom. The experimental setup consisting of merely off-the-shelf components is also discussed. Only two time slots are used to achieve 4-dimensional encoding, which can enhance the system frequency or reduce the requirement for the time resolution of the detector. The interference efficiency is increased to 100% during the phase basis decoding, which improves the secure key rate and the working distance. The performance of the proposed scheme is analyzed with finite-size effect. Numerical results show that the secure key rate is much higher than the previous protocol or the 2-dimensional version. [ABSTRACT FROM AUTHOR]

Recently, more and more vacancy-ordered double perovskites have been proposed as functional materials in optoelectronic devices. In this paper, a simulation work on the structural, electronic and optical properties of vacancy-ordered double perovskites Tl 2 TiX 6 (X ​= ​Cl, Br, I) has been carried out by using first-principles calculations to reveal their potential application in optoelectronic devices. The Goldschmidt's tolerance factors of these compounds are very close to the ideal value of 1 for cubic perovskites, which confirm their structural stability. Moreover, the formation energies of these compounds were also calculated to evaluate their thermodynamic stability. The theoretically predicted lattice constants of Tl 2 TiCl 6 , Tl 2 TiBr 6 and Tl 2 TiI 6 are 10.060 ​Å, 10.553 ​Å and 11.320 ​Å, respectively, which can provide references for future experimental research. The calculated electronic properties indicate that Tl 2 TiCl 6 , Tl 2 TiBr 6 and Tl 2 TiI 6 have direct bandgaps of 3.39 ​eV, 2.57 ​eV and 1.58 ​eV, respectively, showing ideal bandgap nature for optoelectronic applications. Compared with many vacancy-ordered double perovskites, the three Tl 2 TiX 6 compounds all show the advantage of small effective mass of holes. In addition, the investigation of optical properties, such as reflectivity, absorption coefficient and energy loss function in the photon energy range of 0–25 ​eV further confirms the potential utilization of these Tl 2 TiX 6 compounds in optoelectronic devices. In this study, vacancy-ordered double perovskites Tl 2 TiX 6 (X ​= ​Cl, Br, I) are proposed as functional materials in solar cells and other optoelectronic devices. [Display omitted] • The structural and optoelectronic properties of perovskite materials Tl 2 TiX 6 (X = Cl, Br, I) were studied theoretically. • The results show that they are functional materials with direct bandgap nature. • Compared with many vacancy-ordered double perovskites, the effective mass of holes of the studied compounds is very small. • The three Tl 2 TiX 6 compounds are suitable for optoelectronic applications. [ABSTRACT FROM AUTHOR]

Abstract: One of the main mechanisms for multidrug resistance (MDR) involves multidrug resistance gene 1 (MDR1) which encodes P-glycoprotein (Pgp). Pgp acts as a drug efflux pump and exports chemotherapeutic agents from cancer cells. Specific inhibition of Pgp expression by gene therapy is considered a well-respective strategy having less innate toxicities. At present, the investigation of DRz in reversal MDR is scarce. In the study, phosphorothioate DRz that targets to the translation initiation codon AUG was synthesized and transfected into breast cancer cells and leukemia cells with MDR phenotype. ASODN (antisense oligonucleotide) and ribozyme targets to the same region were also synthesized for comparison analysis. Alterations in MDR1 mRNA and Pgp were determined by RT-PCR, Northern blot, flow cytometry and Rh123 retention tests. Chemosensitivity of the treated cells was determined by MTT assay. The results showed that DRz could significantly suppress expression of MDR1 mRNA and inhibit synthesis of Pgp. The efflux activity of Pgp was inhibited accordingly. Chemosensitivity assay showed that a 21-fold reduction in drug resistance for Adriamycin and a 45-fold reduction in drug resistance for Vinblastine were found in the treated cells 36h after transfection. These data suggest that DRz targeted to the translation initiation codon AUG can reverse MDR phenotype in cancer cells and restore their chemosensitivity. Moreover, the reversal efficiency of DRz is better than that of ribozyme and ASODN targets to the same region of MDR1 mRNA. [Copyright &y& Elsevier]

Abstract: Recently we described an ischemic preconditioning induced by repetitive coronary stenosis, which is induced by 6 episodes of non-lethal ischemia over 3days, and which also resembles the hibernating myocardium phenotype. When compared with traditional second window of ischemic preconditioning using cDNA microarrays, many genes which differed in the repetitive coronary stenosis appeared targeted to metabolism. Accordingly, the goal of this study was to provide a more in depth analysis of changes in metabolism in the different models of delayed preconditioning, i.e., second window and repetitive coronary stenosis. This was accomplished using a metabolomic approach based on liquid chromatography–mass spectrometry (LC–MS) and gas chromatography–mass spectrometry (GC–MS) techniques. Myocardial samples from the ischemic section of porcine hearts subjected to both models of late preconditioning were compared against sham controls. Interestingly, although both models involve delayed preconditioning, their metabolic signatures were radically different; of the total number of metabolites that changed in both models (135 metabolites) only 7 changed in both models, and significantly more, p <0.01, were altered in the repetitive coronary stenosis (40%) than in the second window (8.1%). The most significant changes observed were in energy metabolism, e.g., phosphocreatine was increased 4 fold and creatine kinase activity increased by 27.2%, a pattern opposite from heart failure, suggesting that the repetitive coronary stenosis and potentially hibernating myocardium have enhanced stress resistance capabilities. The improved energy metabolism could also be a key mechanism contributing to the cardioprotection observed in the repetitive coronary stenosis and in hibernating myocardium. This article is part of a Special Issue entitled “Focus on Cardiac Metabolism”. [Copyright &y& Elsevier]

In order to find new TRPV1 antagonists without obvious side effects, three series of piperazine urea derivatives were designed, synthesized and evaluated using classical TRPV1 ligands BCTC and GRT12360 as leading compounds. [Display omitted] • Three series of new piperazine urea TRPV1 antagonists were designed, synthesized and evaluated based on classical TRPV1 antagonists BCTC and GRT12360. • The most effective compound 5ac showed mode selective antagonism and avoided the side effects of hyperthermia. • Compound 5ac is more effective than positive control BCTC in CAP and heat-induced pain models. Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with high permeability to Ca2+, which can be activated by low pH, noxious heat and vanilloid compounds such as capsaicin. TRPV1 has been proved to be very important in the process of pain production and is considered to be a highly effective analgesic target. In this work, three series of new piperazine urea TRPV1 antagonists were designed, synthesized and evaluated based on classical TRPV1 antagonists BCTC and GRT12360. Among them, N -(4,6-dimethylpyridin-2-yl)-4-(2-(pyrrolidin-1-yl)benzyl)piperazine-1-carboxamide (5ac) was finally identified, which had excellent TRPV1 antagonistic activity (IC 50 (CAP) = 9.80 nM), good bioavailability and did not cause side effects of hyperthermia. In the study of molecular docking, the compound 5ac fitted well with the amino acid residues on rTRPV1 through hydrophobic interaction. Collectively, compound 5ac is an efficient TRPV1 antagonist and can be used as a candidate for the development of analgesic drugs. [ABSTRACT FROM AUTHOR]

Abstract: We examined pressure overload left ventricular (LV) hypertrophy (H) induced by aortic banding in transgenic mice with cardiac-specific expression of a dominant negative (DN) p38α (TG) and wild type controls (WT). In response to chronic pressure overload, induced by aortic constriction, LV/BW increased more, p <0.05, in female TG (6.4±0.2, n =7) than in WT female (5.1±0.2, n =10), or male TG or WT (5.0±0.2, n =10 vs. 5.5±0.2, n =8). Lung/BW, an index of LV decompensation, was significantly higher, p <0.05, in banded female TG (14 ±1.2 mg/g) than in WT females (9.0±0.8), or male TG or WT (8.2±0.7 vs. 9.3±1.3). This was associated with higher premature mortality, p <0.05, in banded female TG mice (42%) compared with banded WT females (10%), TG males (13%), or WT males (17%). In male, but not female, TG mice, the number of TUNEL-positive cells was smaller, p <0.05, compared with WT. Phospho-Akt kinase activity increased (p <0.05) in female TG after banding, but not in males. After ovariectomy, chronic pressure overload no longer induced greater mortality, greater LVH, or p-Akt levels in female TG mice, and like male TG mice, apoptosis was protected. DN-p38α enhanced estrogen-induced activation of Akt in cultured cardiac myocytes. Thus, inhibition of p38α MAPK paradoxically augments LVH resulting in cardiac decompensation and increased mortality in response to pressure overload more in female mice than male mice, which could be due to increased Akt activation and/or through cross-talk between p38α MAPK and Akt. [Copyright &y& Elsevier]