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Wearable sensors have recently attracted extensive interest not only in the field of healthcare monitoring but also for convenient and intelligent human-machine interactions. However, challenges such as wearable comfort, multiple applicable conditions, and differentiation of mechanical stimuli are yet to be fully addressed. Herein, we developed a breathable and waterproof electronic skin (E-skin) that can perceive pressure/strain with nonoverlapping signals. The synergistic effect from magnetic attraction and nanoscaled aggregation renders the E-skin with microscaled pores for breathability and three-dimensional microcilia for superhydrophobicity. Upon applied pressure, the bending of conductive microcilia enables sufficient contacts for resistance decrease, while the stretching causes increased resistance due to the separation of conductive materials. The optimized E-skin exhibits a high gauge factor of 7.747 for small strain (0-80%) and a detection limit down to 0.04%. The three-dimensional microcilia also exhibit a sensitivity of -0.0198 kPa

Because use and dosing of mood stabilizers (MSs) to treat bipolar disorder (BD) patients in Asia are not well documented, we examined prevalence and clinical correlates of treatment of Asian BD patients with relatively high doses of MSs.We conducted a pharmacoepidemiological survey across 13 Asian countries and territory in the Research on Asian Psychotropic Prescription Patterns Consortium. Mood stabilizer doses were converted to lithium carbonate equivalents (Li-eq milligrams per day). We compared relatively high (900 Li-eq mg/day) versus lower MS doses by bivariate comparisons, followed by multivariable linear regression to identify factors associated with higher MS doses.Among 1647 participants, MS dose averaged 584 (confidence interval, 565-603 Li-eq mg/d). Preliminarily, the 13.1% of the subjects given greater than 900 mg/d versus those given lower doses were younger, male, currently hospitalized, not currently depressed, and reported lifetime suicidal ideation; they also received relatively high doses of antipsychotics, received electroconvulsive treatment within the previous 12 months, and had greater ratings of tremors and sedation. By linear regression modeling, the mean proportion given high doses of MS was associated significantly and independently with higher doses of antipsychotics, younger age, male sex, hospitalized, more years of illness, country, higher body mass index, recent electroconvulsive treatment, and being in illness remission.Relatively high doses of MSs for BD are prevalent, but vary markedly among Asian countries, and are particularly likely among young males, ill for many years, and given high doses of antipsychotics or ECT. These characteristics allow better identification of patient profiles that can guide treatment of BD patients.

Osteoarthritis (OA) is the most prevalent joint disorder occurring with articular cartilage degradation, which includes a switch from an articular to a growth-plate chondrocyte phenotype. Epigenetics serves as a new therapeutic target but histone modification changes in OA remain elusive. Here, we investigated the profiles of four histone modifications in normal and OA chondrocytes. The repressive mark H3K27me3 was significantly lost in OA, associated with up-regulated gene expression. Surprisingly, many of these genes were occupied by both H3K27me3 and H3K4me3 in normal chondrocytes, showing a poised bivalent state. These bivalent genes are deemed to be activated during the hypertrophy of growth plate chondrocytes. Furthermore, inflammation induced the expression of demethylase KDM6B and decreased H3K27me3 level in OA chondrocytes, which was rescued by the KDM6B inhibitor GSK-J4. Altogether, our results suggest an inherited bivalent epigenetic signature on developmental genes that makes articular chondrocytes prone to hypertrophy and contribute to a promising epigenetic therapy for OA.The Paper ExplainedProblemOsteoarthritis (OA) affects as much as 40% of the elderly population, representing the largest cause of age-related disability. The high susceptibility to OA suggests an intrinsic and systemic characteristic in articular chondrocytes that makes cartilage prone to degeneration.ResultsEpigenetic bivalent genes, which are occupied with both H3K27me3 and H3K4me3, are considered to poise expression of developmental genes. Surprisingly, we reported bivalency for hypertrophy related genes in normal articular chondrocytes. These bivalent genes need to be activated in growth plate chondrocytes for extracellular matrix degradation and ossification, but are left as a “bomb” for degeneration in articular chondrocytes. We further found that inflammation induced KDM6B remove H3K27me3 to activate hypertrophy related genes that promote OA.ImpactOur results suggest an inherited epigenetic signature that makes articular chondrocytes prone to hypertrophy and ossification and contribute to a promising epigenetic therapy for OA.

Vascular leakage and inflammation are pathological hallmarks of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Endothelial cells (ECs) serve as a semipermeable barrier and play a key role in disease progression. It is well known that fibroblast growth factor receptor 1 (FGFR1) is required for maintaining vascular integrity. However, how endothelial FGFR1 functions in ALI/ARDS remains obscure. Here, we revealed that conditional deletion of endothelial FGFR1 aggravated LPS-induced lung injury, including inflammation and vascular leakage. Inhibition of its downstream Rho-associated coiled-coil–forming protein kinase 2 (ROCK2) by AAV Vec-tie-shROCK2 or its selective inhibitor TDI01 effectively attenuated inflammation and vascular leakage in a mouse model. In vitro, TNFα-stimulated human umbilical vein endothelial cells (HUVECs) showed decreased FGFR1 expression and increased ROCK2 activity. Furthermore, knockdown of FGFR1 activated ROCK2 and thus promoted higher adhesive properties to inflammatory cells and higher permeability in HUVECs. TDI01 effectively suppressed ROCK2 activity and rescued the endothelial dysfunction. These data demonstrated that the loss of endothelial FGFR1 signaling mediated an increase in ROCK2 activity, which led to an inflammatory response and vascular leakage in vivo and in vitro. Moreover, inhibition of ROCK2 activity by TDI01 provided great value and shed light on clinical translation.

Potassium (K) metal batteries have attracted great attention owing to their low price, widespread distribution, and comparable energy density. However, the arbitrary dendrite growth and side reactions of K metal are attributed to high environmental sensitivity, which is the Achilles' heel of its commercial development. Interface engineering between the current collector and K metal can tailor the surface properties for K-ion flux accommodation, dendrite growth inhibition, parasitic reaction suppression, etc. We have designed bifunctional layers via prepassivation, which can be recognized as an O/F-rich Sn-K alloy and a preformed solid-electrolyte interphase (SEI) layer. This Sn-K alloy with high substrate-related binding energy and Fermi level demonstrates strong potassiophilicity to homogeneously guide K metal deposition. Simultaneously, the preformed SEI layer can effectually eliminate side reactions initially, which is beneficial for the spatially and temporally KF-rich SEI layer on K metal. K metal deposition and protection can be implemented by the bifunctional layers, delivering great performance with a low nucleation overpotential of 0.066 V, a high average Coulombic efficiency of 99.1%, and durable stability of more than 900 h (1 mA cm

Janes et al. developed an anti-ADAM10 mAb (8C7) that binds to an active form of ADAM10 present in tumors, particularly in stem-like cells. Administration of 8C7 inhibits Notch activity and tumor growth in mouse models, including regrowth after chemotherapy., The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance.

Despite the robust healing capacity of the liver, regenerative failure underlies numerous hepatic diseases, including the JAG1 haploinsufficient disorder, Alagille syndrome (ALGS). Cholestasis due to intrahepatic duct (IHD) paucity resolves in certain ALGS cases but fails in most with no clear mechanisms or therapeutic interventions. We find that modulating jag1b and jag2b allele dosage is sufficient to stratify these distinct outcomes, which can be either exacerbated or rescued with genetic manipulation of Notch signaling, demonstrating that perturbations of Jag/Notch signaling may be causal for the spectrum of ALGS liver severities. Although regenerating IHD cells proliferate, they remain clustered in mutants that fail to recover due to a blunted elevation of Notch signaling in the distal-most IHD cells. Increased Notch signaling is required for regenerating IHD cells to branch and segregate into the peripheral region of the growing liver, where biliary paucity is commonly observed in ALGS. Mosaic loss- and-gain-of-function analysis reveals Sox9b to be a key Notch transcriptional effector required cell autonomously to regulate these cellular dynamics during IHD regeneration. Treatment with a small-molecule putative Notch agonist stimulates Sox9 expression in ALGS patient fibroblasts and enhances hepatic sox9b expression, rescues IHD paucity and cholestasis, and increases survival in zebrafish mutants, thereby providing a proof-of-concept therapeutic avenue for this disorder.

To investigate the periodontal health status of type 2 diabetes patients in the Endocrinology Department of Shanghai Sixth People's Hospital, to explore relevant influencing factors of chronic periodontitis, so as to provide epidemiological basis for targeted prevention and treatment of periodontal diseases in patients with type 2 diabetes.Periodontal examination and questionnaire survey of patients with type 2 diabetes who visited the Endocrinology Department of Shanghai Sixth People's Hospital from November 2018 to December 2018 were conducted. Criteria in "Basic Methods for Oral Health Survey" recommended by WHO was referred to check and score the relevant periodontal indicators, including probing depth, bleeding on probing, attachment loss, calculus index, plaque index, etc. Sociodemographic information, diabetes history, periodontal health-related behaviors, and other information were collected through questionnaires. SPSS 22.0 software package was used for statistical analysis.Of the 916 patients with type 2 diabetes who participated in the survey, 670 patients with periodontitis were detected. The overall prevalence of periodontitis was 73.14%, and the number of missing teeth per capita was 4.85. The age of diabetic patients, the duration of diabetes, and the presence or absence of complications were risk factors for periodontitis. As the patients grew, the duration of the disease increased, and diabetes-related complications appeared, the prevalence of periodontitis in patients with diabetes increased significantly (P＜0.05).Periodontal health of patients with type 2 diabetes in the surveyed region is not optimistic. Early prevention and treatment of periodontitis is extremely important. It is necessary to pay attention to the periodontal health status of elderly patients with long-term disease and diabetes, and to carry out targeted oral prevention and health care work for this population.

Foam concrete is fire resistant and durable and has broad applicability as a building insulation material. However, cement has high energy consumption and causes pollution, necessitating an environment-friendly cementitious material to replace the cement used to prepare foam concrete. In this study, foam concrete was prepared through chemical foaming. The influence of the foaming agent material, foam stabiliser, and fly ash on the basic properties of the foam concrete, including the dry bulk density, compressive strength, and thermal conductivity, was studied, and the pore structure was characterised. The results show that with an increase in the hydrogen peroxide (H2O2) content, the dry bulk density, compressive strength, and thermal conductivity of foam concrete decreases, whereas the pore diameter increases (0.495 to 0.746 mm). When the calcium stearate content is within 1.8%, the pore size tends to increase (0.547 to 0.631 mm). With increase in the fly ash content, the strength of foam concrete gradually decreases, and the dry bulk density first decreases and then increases. When the blending ratio of fly ash is 10-40%, the thermal conductivity gradually decreases; an extreme thermal conductivity of 0.0824 W/(m·K) appears at the blending ratio of 40%, and the dry bulk density is 336 kg/m3. ispartof: MATERIALS vol:15 issue:18 ispartof: location:Switzerland status: published

[Image: see text] Kidney fibrosis is accompanied by vascular dysfunction. Discovering new ways to ameliorate dysfunctional angiogenesis may bypass kidney fibrosis. YAP (Yes-associated protein) plays a multifaceted role during angiogenesis. Here, we found that selectively targeting YAP signaling in the endothelium ameliorates unilateral ureteral obstruction (UUO)-induced kidney fibrosis. Genetic deletion of Yap1, encoding YAP protein, in VE-cadherin(+) endothelial cells inhibited endothelial-to-mesenchymal transition (EndMT) and dysfunctional angiogenesis and improved obstructive nephropathy and kidney fibrosis. Treatment with the systemic YAP inhibitor verteporfin worsened kidney fibrosis symptoms because of its lack of cell specificity. In an attempt to identify endothelial-specific YAP modulators, we found that G-protein-coupled receptor coagulation factor II receptor-like 1 (F2RL1) was highly expressed in vessels after UUO-induced kidney fibrosis. The F2RL1 peptide antagonist FSLLRY-NH2 selectively blocked YAP activity in endothelial cells and ameliorated kidney fibrosis. Thus, selective antagonization of endothelial YAP activity might bypass kidney fibrosis and provide new avenues for the design of antifibrotic therapies.

The vasculature occupies a large area of the body, and none of the physiological activities can be carried out without blood vessels. Blood vessels are not just passive conduits and barriers for delivering blood and nutrients. Meanwhile, endothelial cells covering the vascular lumen establish vascular niches by deploying some growth factors, known as angiocrine factors, and actively participate in the regulation of a variety of physiological processes, such as organ regeneration and fibrosis and the occurrence and development of cancer. After organ injury, vascular endothelial cells regulate the repair process by secreting various angiocrine factors, triggering the proliferation and differentiation process of stem cells. Therefore, analyzing the vascular niche and exploring the factors that maintain vascular homeostasis can provide strong theoretical support for clinical treatment targeting blood vessels. Here we mainly discuss the regulatory mechanisms of the vascular niche in organ regeneration and fibrosis.

Liver fibrosis is one main histological characteristic of nonalcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes with no approved therapies. The role of the gut microbiota in NASH pathogenesis has not been thoroughly illustrated, especially how the gut microbiota derives metabolites to influence the distal liver in NASH. Here, we performed 16S rDNA amplicon sequencing analysis of feces from a mouse NASH model induced by a Western diet and CCl4 injury and found genera under Streptococcaceae, Alcaligenaceae, Oscillibacter, and Pseudochrobactrum, which are related metabolites of TMAO. Injection of the gut microbial metabolite TMAO reduced the progression of liver fibrosis in the mouse NASH model. Further analysis revealed that the anti-fibrotic TMAO normalized gut microbiota diversity and preserved liver sinusoidal endothelial cell integrity by inhibiting endothelial beta 1-subunit of Na (+), K (+)-ATPase (ATP1B1) expression. Collectively, our findings suggest TMAO-mediated crosstalk between microbiota metabolites and hepatic vasculature, and perturbation of this crosstalk disrupts sinusoidal vasculature to promote liver fibrosis in NASH.

Exploration of wearable strain sensors in diverse application scenarios is one global requirement for shaping the future of our intelligent community. However, state-of-the-art wearable devices still face challenges such as interference under humid conditions and chemical/mechanical fragility. Here, a facile and fluorine-free approach is introduced to realize a sensitive, robust and superhydrophobic strain sensor via the in situ formation of microcilia on the PDMS surface, followed by a two-step swelling process. The swelling process facilitates the penetration of carbon black nanoparticles into the PDMS matrix to render the conductive network suitable for strain sensing, while the decoration of silica nanoparticles along with the microcilia forms a hierarchical architecture for water repellency. The sensing performance was optimized, including the sensitivity (gauge factor of 354), working range (up to 250%), and long-term stability (>10 000 cycles). The superhydrophobic surface exhibits excellent resistance to mechanical abrasion, chemical corrosion, and high-speed water impact, etc. Demonstrations, such as body motion perception, wireless and underwater communications, Morse code generation, underwater jet impact, reveal the potential of the sensor as a robust platform for broad applications not only in air but also for underwater or under harsh condition uses.

Rapid droplet detachment from the surface in a "pancake rebound" has recently attracted abundant interest owing to the contact time control for applications in anti-icing and self-cleaning. Even though the pancake rebound on rigid substrates has been realized, the establishment of artificial structures on a flexible counterpart with droplet impact behavior studies has rarely been reported. Here, we introduced a facile approach to fabricating a flexible superhydrophobic film decorated with tunable hierarchical micro/nanostructures for water repellency. With the appropriately optimized architecture, the pancake rebound with reduced contact time can be realized when reaching a specific Weber number on the microcones. We also observed that the pancake rebound on microcilia could be realized by regulating the energy-transfer process on the flexible film during the droplet impact. A tightly stretched and suspended film can serve as the "spring" to store the elastic energy transferred from the kinetic energy of the penetrated droplet while converting back to kinetic energy during the emptying process with a reduced contact time of 5.2 ms. With the preserved water repellency on diverse curvatures, the study raises a new avenue to realize superhydrophobic surfaces and rapid droplet detachment with the potential for a broader spectrum toward practical scenarios in our daily life.

Histone variants and the associated post-translational modifications that govern the stemness of haematopoietic stem cells (HSCs) and differentiation thereof into progenitors (HSPCs) have not been well defined. H3.3 is a replication-independent H3 histone variant in mammalian systems that is enriched at both H3K4me3- and H3K27me3-marked bivalent genes as well as H3K9me3-marked endogenous retroviral repeats. Here we show that H3.3, but not its chaperone Hira, prevents premature HSC exhaustion and differentiation into granulocyte-macrophage progenitors. H3.3-null HSPCs display reduced expression of stemness and lineage-specific genes with a predominant gain of H3K27me3 marks at their promoter regions. Concomitantly, loss of H3.3 leads to a reduction of H3K9me3 marks at endogenous retroviral repeats, opening up binding sites for the interferon regulatory factor family of transcription factors, allowing the survival of rare, persisting H3.3-null HSCs. We propose a model whereby H3.3 maintains adult HSC stemness by safeguarding the delicate interplay between H3K27me3 and H3K9me3 marks, enforcing chromatin adaptability.

Different biological groups show biased responses to similar or different environmental stressors on different scales. The selection of bioindicators based on pressure characteristics is the basis for accurately assessing ecological quality. In this study, we investigated the responses of common bioindicators, namely, macroinvertebrates and fish, to multiple stressors in temperate mountain and plain streams of northeast China. We used 56 indices, including the single biological evaluation index and biological evaluation index system, to analyze and compare characteristic response to different scales under varying environmental stressors. The principal component analysis (PCA) showed that PCA axis 1 in the catchment scale explained 83.6% and 96.1% of the variance in mountain and plain rivers, respectively, which characterized the comprehensive pressure gradient integrated by land-use development and water pollution. PCA axis 1 explained 40.7% and 53.9% of variance in mountain and plain rivers on the reach scale and 63.1% and 61.8% of variance on the site scale. The correlation analysis showed responses of different indices to abiotic variables which did not overlap. Macroinvertebrate and fish indices successfully explained the change in water chemistry on a small scale, whereas fish indices additionally explained the change in land use on a large scale. Macroinvertebrate and fish indices were recommended because of their rich responses to environmental stressors, particularly in plain rivers. For mountain stream biomonitoring programs, especially in the Taizi River of northeastern China, we suggest that macroinvertebrates and fish should be used separately or jointly according to the actual capacity and cost, Moreover, compared with the possible differences in the evaluation results of different single biological evaluation indexes, the biological evaluation index system shows more stable monitoring results, and the single sensitivity index is more significant in biological evaluation, and more sensitive to some special environmental factors.

Chronic hepatic diseases such as nonalcoholic steatohepatitis (NASH) suppress liver regeneration and lead to fibrosis and cirrhosis. Decoding the cellular and molecular network underlying this fibrotic maladaptation might aid in combatting NASH, a growing health challenge with no approved therapies. Here, we used multiomics analysis of human cirrhotic liver, a Western diet– and carbon tetrachloride (CCl

Upon sensing pathogen-associated patterns and secreting interferons (IFNs) into the environment, host cells perceive extracellular type I IFNs by the IFNα/β receptors IFNAR1 and IFNAR2 to stimulate downstream innate immune signaling cascades. Through the use of chemical probes, we demonstrated that IFNAR2 facilitates hepatitis C virus (HCV) entry. Silencing of IFNAR2 significantly attenuated HCV proliferation. IFNAR2 binds infectious HCV virions through a direct interaction of its D2 domain with the C-terminal end of apolipoprotein E (apoE) on the viral envelope and facilitates virus entry into host cells. The antibody against the IFNAR2 D2 domain attenuates IFNAR2-apoE interaction and impairs HCV infection. The recombinant IFNAR2 protein and the chemical probe potently inhibit major HCV genotypes in various human liver cells in vitro. Moreover, the impact of a chemical probe on HCV genotype 2a is also documented in immune-compromised humanized transgenic mice. Our results not only expand the understanding of the biology of HCV entry and the virus-host relationship but also reveal a new target for the development of anti-HCV entry inhibitors.

Background: Tumor cells benefit from tumor-associated macrophages (TAMs) promoting tumor growth and modulating functions of other cells in tumor microenvironment (TME). However, how tumor cells regulate the property of TAMs during tumor invasion remains to be defined. Methods: Mouse tumor models and cancer patients' samples were analyzed to determine LAMP2a expression in TAMs. In vitro mouse primary macrophages were used to assess LAMP2a-modulated macrophage activation, and to verify LAMP2a's target proteins. The effect of LAMP2a-knockdown on tumor progression and TME maintaining was determined by using mouse tumor models. Findings: Lysosome associated membrane protein type 2A (LAMP2a) is upregulated in TAMs by tumor cells and important for tumor progression. LAMP2a expression in TAMs, but not in tumor cells, is associated with poor prognosis in breast cancer. LAMP2a inactivation induced by either shRNA or CRISPR/Cas9 prevents TAMs activation and tumor growth. LAMP2a degrades PRDX1 (peroxiredoxin 1) and CRTC1 (CREB-regulated transcription coactivator 1) to promote macrophage pro-tumorigenic activation. Interpretation: Our study suggests that tumor cells utilize LAMP2a-PRDX1/CRTC1 axis to modulate TAMs activation and promote tumor growth, reveals the role of LAMP2a in macrophage study and TAM-targeting tumor immunotherapy. Fund: National Natural Science Foundation of China (No. 81602492); National Key Research and Development Program of China (No. 2016YFA0201402). Keywords: LAMP2a, Tumor-associated macrophage, Chaperone-mediated autophagy, Macrophage activation, Tumor microenvironment

Background: Tumor cells benefit from tumor-associated macrophages (TAMs) promoting tumor growth and modulating functions of other cells in tumor microenvironment (TME). However, how tumor cells regulate the property of TAMs during tumor invasion remains to be defined. Methods: Mouse tumor models and cancer patients' samples were analyzed to determine LAMP2a expression in TAMs. In vitro mouse primary macrophages were used to assess LAMP2a-modulated macrophage activation, and to verify LAMP2a's target proteins. The effect of LAMP2a-knockdown on tumor progression and TME maintaining was determined by using mouse tumor models. Findings: Lysosome associated membrane protein type 2A (LAMP2a) is upregulated in TAMs by tumor cells and important for tumor progression. LAMP2a expression in TAMs, but not in tumor cells, is associated with poor prognosis in breast cancer. LAMP2a inactivation induced by either shRNA or CRISPR/Cas9 prevents TAMs activation and tumor growth. LAMP2a degrades PRDX1 (peroxiredoxin 1) and CRTC1 (CREB-regulated transcription coactivator 1) to promote macrophage pro-tumorigenic activation. Interpretation: Our study suggests that tumor cells utilize LAMP2a-PRDX1/CRTC1 axis to modulate TAMs activation and promote tumor growth, reveals the role of LAMP2a in macrophage study and TAM-targeting tumor immunotherapy. Funding Statement: National Key Research and Development Program of China (No. 2016YFA0201402); National Natural Science Foundation of China (No. 81602492). Declaration of Interests: All authors declare that they have no competing interests. Ethics Approval Statement: All animal experiments were approved by the institutional Animal Care and Use Committee. All patient samples concerned studies were approved by West China Hospital IRB committee. All human subjects (except for tissue microarray) were obtained from patients who were receiving treatment in West China Hospital, with all patients fully informed consent.

Here we focus on the molecular characterization of clinically significant histological subtypes of early-stage lung adenocarcinoma (esLUAD), which is the most common histological subtype of lung cancer. Within lung adenocarcinoma, histology is heterogeneous and associated with tumor invasion and diverse clinical outcomes. We present a gene signature distinguishing invasive and non-invasive tumors among esLUAD. Using the gene signatures, we estimate an Invasiveness Score that is strongly associated with survival of esLUAD patients in multiple independent cohorts and with the invasiveness phenotype in lung cancer cell lines. Regulatory network analysis identifies aurora kinase as one of master regulators of the gene signature and the perturbation of aurora kinases in vitro and in a murine model of invasive lung adenocarcinoma reduces tumor invasion. Our study reveals aurora kinases as a therapeutic target for treatment of early-stage invasive lung adenocarcinoma.

Aquatic ecosystem mesocosm refers to an artificially constructed near-natural simulation facility in aquatic ecosystem. With aquatic ecosystem mesocosms, experiments on the responses of biological communities can be conducted by controlling physical, chemical and other habitat conditions. Mesocosm experiments can bridge the gap between laboratory experiments and field experiments. Laboratory experiment can only simulate a small number of simple factors, whereas field experimental systems are complex and difficult to conduct controlled experiments. By resear-ching into global long-term mesocosms, we classified them into four types,水生态系统中宇宙指人工构建的河流、湖泊、湿地、海洋等水生态系统近自然模拟装置,可以控制一定的物理、化学要素和生境条件,开展生物群落响应研究。中宇宙实验可以弥补传统实验室小型装置模拟要素过于简单,而野外现实系统复杂不可控制和难以开展对比实验的局限。本文列举了当前国际上多个科研机构长期运行的水生态系统中宇宙,将其归纳为流水型中宇宙、围隔装置、陆基模拟池、移动式水槽4类,各类中宇宙一般包括物理-生物模拟系统、自动调控系统、监测分析系统、中央控制系统。近年来,我国水生态系统的研究逐渐从单一环境要素向生态系统整体转变,对中宇宙模拟实验的需求愈加迫切。建议我国水生态系统中宇宙建设应提高结构复杂性,并与野外现场监测相结合,共同支撑更大尺度系统的整体模拟。.

Transformations of land use from natural to anthropic type have been recognized as a significant trigger which degenerate the aquatic ecological quality seriously. However, there was still lack of enough evidence which the extent of changes in land use should be set as a biodiversity conservation target to protect aquatic ecosystem. To understand the corresponding variations of aquatic organisms to environmental gradients and set the conservation threshold values for land use, data of physicochemical parameters and macroinvertebrate communities were sampled in the Hun-Tai River Basin during 2009 and 2010. The main objectives of the present study were (i) to explore limiting factors that affect the distribution of macroinvertebrate communities with land use gradients, (ii) to estimate thresholds for the conservation of macroinvertebrate communities derived from generalized additive models (GAMs) and Threshold Indicator Taxa ANalysis (TITAN), respectively. The results indicated that macroinvertebrate communities’ structure and integrity were strongly negative with nutrient, organic contaminants content, %CropArea and %ImperviousArea. Under a precaution perspective and given current levels of land use, this research might provide some useful strategies for appropriate land exploitation management and improving water quality and biodiversity conservation in river ecological restoration.

Background & Aims Fibrosis in the liver is the main histological determinant of non-alcoholic steatohepatitis (NASH), a disease that parallels the worldwide surge in metabolic syndromes. Currently, there is no effective treatment for liver fibrosis. While Hippo/YAP (Yes-associated protein) signaling is essential for liver regeneration, its aberrant activation frequently leads to fibrosis and tumorigenesis. Unravelling “context-specific” contributions of YAP in liver repair might help selectively bypass fibrosis and preserve the pro-regenerative YAP function in hepatic diseases. Methods We used murine liver fibrosis and minipig NASH models, liver biopsies from cirrhotic patients, single-cell RNA sequencing (scRNA-Seq) and a G-protein-coupled receptor (GPCR) ligand screening system. Results YAP levels in macrophages are increased in the livers of humans and mice with liver fibrosis. The fibrogenic role of macrophage YAP was evidenced via boosting type I interferon and attenuating liver fibrosis in mice specifically lacking Yap1 in myeloid cells. scRNA-Seq further showed that defecting YAP pathway in macrophages diminished a fibrogenic vascular endothelial cell subset exhibiting pro-fibrotic molecular signatures such as CTGF and VCAM1 expression. To specifically target fibrogenic YAP in macrophages, we utilized a GPCR ligand screening system and identified a dopamine receptor D2 (DRD2) antagonist that selectively blocked YAP in macrophages but not hepatocytes. Genetic and pharmacological targeting of macrophage DRD2 attenuated liver fibrosis. In a large animal (minipig) NASH model recapitulating human pathology, DRD2 antagonist blocked fibrosis and restored hepatic architecture. Conclusions DRD2 antagonization selectively targets YAP-dependent fibrogenic crosstalk between macrophages and CTGF+VCAM1+ endothelial cells, promoting liver regeneration over fibrosis in both rodent and large animal models. Lay summary Fibrosis in the liver is one of the main histological determinants of non-alcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes. Our study demonstrates that myeloid-specific YAP deficiency attenuates liver fibrosis. Dopamine receptor D2 (DRD2) antagonization selectively blocks YAP in macrophages and thwarts liver fibrosis in both rodent and large animal models, showing the potential for the GPCR targeting-based NASH therapies.

River algal blooms have become a challenging environmental problem worldwide due to strong interference of human activities and megaprojects (e.g., big dams and large-scale water transfer projects). Previous studies on algal blooms were mainly focused on relatively static water bodies (i.e., lakes and reservoirs), but less on the large rivers. As the largest tributary of the Yangtze River of China and the main freshwater source of the South-to-North Water Diversion Project (SNWDP), the Han River has experienced frequent algal blooms in recent decades. Here we investigated the algal blooms during a decade (2003–2014) in the Han River by two gradient boosting machine (GBM) models with k-fold cross validation, which used explanatory variables from current 10-day (GBMc model) or previous 10-day period (GBMp model). Our results advocate the use of GBMp due to its higher accuracy (median Kappa = 0.9) and practical predictability (using antecedent observations) compared to GBMc. We also revealed that the algal blooms in the Han River were significantly modulated by antecedent water levels in the Han River and the Yangtze River and water level variation in the Han River, whereas the nutrient concentrations in the Han River were usually above thresholds and not limiting algal blooms. This machine-learning-based study potentially provides scientific guidance for preemptive warning and risk management of river algal blooms through comprehensive regulation of water levels during the dry season by making use of water conservancy measures in large rivers.