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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.

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.

[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.

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.

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。.

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.

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.

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.

Chromosome copy-number variations are a hallmark of cancer. Among them, the prevalent chromosome 17p deletions are associated with poor prognosis and can promote tumorigenesis more than TP53 loss. Here, we use multiple functional genetic strategies and identify a new 17p tumor suppressor gene (TSG), plant homeodomain finger protein 23 (PHF23). Its deficiency impairs B-cell differentiation and promotes immature B-lymphoblastic malignancy. Mechanistically, we demonstrate that PHF23, an H3K4me3 reader, directly binds the SIN3–HDAC complex through its N-terminus and represses its deacetylation activity on H3K27ac. Thus, the PHF23–SIN3–HDAC (PSH) complex coordinates these two major active histone markers for the activation of downstream TSGs and differentiation-related genes. Furthermore, dysregulation of the PSH complex is essential for the development and maintenance of PHF23-deficient and 17p-deleted tumors. Hence, our study reveals a novel epigenetic regulatory mechanism that contributes to the pathology of 17p-deleted cancers and suggests a susceptibility in this disease. Significance: We identify PHF23, encoding an H3K4me3 reader, as a new TSG on chromosome 17p, which is frequently deleted in human cancers. Mechanistically, PHF23 forms a previously unreported histone-modifying complex, the PSH complex, which regulates gene activation through a synergistic link between H3K4me3 and H3K27ac. This article is highlighted in the In This Issue feature, p. 1

The lung's unique extracellular matrix (ECM), while providing structural support for cells, is critical in the regulation of developmental organogenesis, homeostasis and injury-repair responses. The ECM, via biochemical or biomechanical cues, regulates diverse cell functions, fate and phenotype. The composition and function of lung ECM become markedly deranged in pathological tissue remodeling. ECM-based therapeutics and bioengineering approaches represent promising novel strategies for regeneration/repair of the lung and treatment of chronic lung diseases. In this review, we assess the current state of lung ECM biology, including fundamental advances in ECM composition, dynamics, topography, and biomechanics; the role of the ECM in normal and aberrant lung development, adult lung diseases and autoimmunity; and ECM in the regulation of the stem cell niche. We identify opportunities to advance the field of lung ECM biology and provide a set recommendations for research priorities to advance knowledge that would inform novel approaches to the pathogenesis, diagnosis, and treatment of chronic lung diseases.

Respiratory failure is the leading cause of early death after acute CSCI. Tracheotomy is an effective approach to reduce mortality and improve the clinical outcomes. However, the optimal timing for tracheotomy remains controversial. Hence, the study aimed to compare the clinical outcomes of tracheotomy in patients with acute cervical spinal cord injury (CSCI) at different timing. A retrospectively review was performed of acute CSCI patients who underwent tracheotomy in the intensive care unit of Haian Hospital between January 2014 and June 2019. 124 CSCI patients were included and stratified into three groups based on the timing of tracheotomy: early group (≤4 days from initial intubation), medium group (4–10 days from initial intubation), and late group (≥10 days from initial intubation). The clinical outcomes and functional outcomes were analyzed. No significant intergroup differences in baseline characteristics were observed. The late group needed significantly longer duration of mechanical ventilation, longer ICU stay, and suffered higher ICU mortality, higher pneumonia after tracheotomy than the early and medium groups. More patients in the early and medium groups successfully weaned from mechanical ventilation. The early and medium groups achieved better improvement of JOA and NDI scores than the late group at one year after surgery and at the final follow-up. Early to medium term tracheotomy may lead to better clinical and functional outcomes in patients with acute CSCI who require prolonged mechanical ventilation.

The sensitivity and linearity are critical parameters that can preserve the high pressure-resolution across a wide range and simplify the signal processing process of flexible tactile sensors. Although extensive micro-structured dielectrics have been explored to improve the sensitivity of capacitive sensors, the attenuation of sensitivity with increasing pressure is yet to be fully resolved. Herein, a novel dielectric layer based on the gradient micro-dome architecture (GDA) is presented to simultaneously realize the high sensitivity and ultrabroad linearity range of capacitive sensors. The gradient micro-dome pixels with rationally collocated amount and height can effectively regulate the contact area and hence enable the linear variation in effective dielectric constant of the GDA dielectric layer under varying pressures. With systematical optimization, the sensor exhibits the high sensitivity of 0.065 kPa-1 in an ultrabroad linearity range up to 1700 kPa, which is first reported. Based on the excellent sensitivity and linearity, the high pressure-resolution can be preserved across the full scale of pressure spectrum. Therefore, potential applications such as all-round physiological signal detection in diverse scenarios, control instruction transmission with combinatorial force inputs, and convenient Morse code communication with non-overlapping capacitance signals are successfully demonstrated through a single sensor device.

Angiocrine factors, such as Notch ligands, supplied by the specialized endothelial cells (ECs) within the bone marrow and splenic vascular niche play an essential role in modulating the physiology of adult hematopoietic stem and progenitor cells (HSPCs). However, the relative contribution of various Notch ligands, specifically jagged-2, to the homeostasis of HSPCs is unknown. Here, we show that under steady state, jagged-2 is differentially expressed in tissue-specific vascular beds, but its expression is induced in hematopoietic vascular niches after myelosuppressive injury. We used mice with EC-specific deletion of the gene encoding jagged-2 (Jag2) to demonstrate that while EC-derived jagged-2 was dispensable for maintaining the capacity of HSPCs to repopulate under steady-state conditions, by activating Notch2 it did contribute to the recovery of HSPCs in response to myelosuppressive conditions. Engraftment and/or expansion of HSPCs was dependent on the expression of endothelial-derived jagged-2 following myeloablation. Additionally, jagged-2 expressed in bone marrow ECs regulated HSPC cell cycle and quiescence during regeneration. Endothelial-deployed jagged-2 triggered Notch2/Hey1, while tempering Notch2/Hes1 signaling in HSPCs. Collectively, these data demonstrate that EC-derived jagged-2 activates Notch2 signaling in HSPCs to promote hematopoietic recovery and has potential as a therapeutic target to accelerate balanced hematopoietic reconstitution after myelosuppression.

Purpose To demonstrate the feasibility of imaging-guided catheter-directed delivery of endothelial cell therapy in a porcine model of cirrhosis for liver regeneration. Materials and Methods After approval from the institutional animal care and use committee, autologous liver endothelial cells were grown from core hepatic specimens from swine. Cirrhosis was induced in swine by means of transcatheter infusion of ethanol and iodized oil into the hepatic artery. Three weeks after induction of cirrhosis, the swine were randomly assigned to receive autologous cell therapy (endothelial cells, n = 4) or control treatment (phosphate-buffered saline, n = 4) by means of imaging-guided transhepatic intraportal catheterization. Fluorescence-activated cell sorting analysis was performed on biopsy samples 1 hour after therapy. Three weeks after intraportal delivery of endothelial cells, the swine were euthanized and the explanted liver underwent quantitative pathologic examination. Statistical analysis was performed with an unpaired t test by using unequal variance. Results Liver endothelial cells were successfully isolated, cultured, and expanded from eight 20-mm, 18-gauge hepatic core samples to 50 × 106 autologous cells per pig. Intraportal delivery of endothelial cell therapy or saline was technically successful in all eight swine, with no complications. Endothelial cells were present in the liver for a minimum of 1 hour after intraportal infusion. Swine treated with endothelial cell therapy showed mean levels of surrogate markers of hepatobiliary injury that were consistent with decreases in hepatic fibrosis and biliary ductal damage relative to the control animals, although statistical significance was not met in this pilot study: The mean percentage of positive pixels at Masson trichrome staining was 7.28% vs 5.57%, respectively (P = .20), the mean proliferation index with cytokeratin wide-spectrum was 2.55 vs 1.13 (P = .06), and the mean proliferation index with Ki67 was 7.08 vs 4.96 (P = .14). Conclusion The results confirm the feasibility of imaging-guided catheter-directed endothelial cell therapy with an intraportal technique for the treatment of cirrhosis in a porcine model. A trend toward decreased liver fibrosis with endothelial cell therapy was observed. Larger animal studies and human studies are necessary to confirm significance. © RSNA, 2017.

Water resources emergency management can mitigate regional damage from water emergencies. Taking Tongzhou District, Nantong City as the study area, this paper proposes technical and engineering measures to improve the water emergency management system. This paper chooses groundwater as the alternative emergency water source, and proposes an emergency wells layout scheme according to the disparities between current groundwater supply capacities and the emergency water demands in each planning unit in 2020. Jiuweigang River and Tonglv River are proposed as water-dilution channels to improve the surface water environment and provide suitable water to Tongzhou District by means of sluice gates. Lastly, this paper describes the water resources emergency management mechanism, including the organization system, the response mechanism, and the supporting measures.

Regenerative capacity is frequently impaired in aged organs. Stress to aged organs often causes scar formation (fibrosis) at the expense of regeneration. It remains to be defined how hematopoietic and vascular cells contribute to aging-induced regeneration to fibrotic transition. Here, we find that aging aberrantly reprograms the crosstalk between hematopoietic and vascular cells to impede the regenerative capacity and enhance fibrosis. In aged lung, liver, and kidney, induction of Neuropilin-1/hypoxia-inducible-factor 2α (HIF2α) suppresses anti-thrombotic and anti-inflammatory endothelial protein C receptor (EPCR) pathway, leading to formation of pro-fibrotic platelet-macrophage rosette. Activated platelets via supplying interleukin 1α synergize with endothelial-produced angiocrine chemokine to recruit fibrogenic TIMP1high macrophages. In mouse models, genetic targeting of endothelial Neuropilin-1-HIF2α, platelet interleukin 1α, or macrophage TIMP1 normalized the pro-fibrotic hematopoietic-vascular niche and restored the regenerative capacity of old organs. Targeting of aberrant endothelial node molecules might help propel "regeneration without scarring" in the repair of multiple organs.

Herein, we report the discovery of a series of new P300/CBP-associated factor (PCAF) bromodomain (BRD) inhibitors, which were obtained through a hit discovery process and subsequent structure-based optimization and structure-activity relationship analyses toward a retrieved hit compound (12). Among these inhibitors, ( R, R)-36n is the most potent one with an IC50 of 7 nM in homogeneous time-resolved fluorescence assay and a KD of 78 nM in isothermal titration calorimetry assay. This compound also exhibited activity against GCN5 and FALZ, but weak or no activity against other 29 BRD proteins and 422 kinases, indicating considerable selectivity. X-ray cocrystal structure analysis revealed the molecular interaction mode and the precise stereochemistry required for bioactivity. Cellular activity, preliminary RNA-seq analysis, and pharmacokinetic properties were also examined for this compound. Collectively, this study provides a versatile tool molecule to explore molecular mechanisms of PCAF BRD regulation and also offers a new lead compound for drug discovery targeting PCAF.

Transplantation of bone marrow stromal cells (BMSCs) is a promising therapy for ischemic stroke, but the poor oxygen environment in brain lesions limits the efficacy of cell-based therapies. Here, we tested whether hypoxic preconditioning (HP) could augment the efficacy of BMSC transplantation in a rat ischemic stroke model and investigated the underlying mechanism of the effect of HP. In vitro, BMSCs were divided into five passage (P0, P1, P2, P3, and P4) groups, and HP was applied to the groups by incubating the cells with 1% oxygen for 0, 4, 8, 12, and 24 h, respectively. We demonstrated that the expression of hypoxia-inducible factor-1α (HIF-1α) was increased in the HP-treated BMSCs, while their viability was unchanged. We also found that HP decreased the apoptosis of BMSCs during subsequent simulated ischemia-reperfusion (I/R) injury, especially in the 8-h HP group. In vivo, a rat transient focal cerebral ischemia model was established. These rats were administered normal cultured BMSCs (N-BMSCs), HP-treated BMSCs (H-BMSCs), or DMEM cell culture medium (control) at 24 h after the ischemic insult. Compared with the DMEM control group, the two BMSC-transplanted groups exhibited significantly improved functional recovery and reduced infarct volume, especially the H-BMSC group. Moreover, HP decreased neuronal apoptosis and enhanced the expression of BDNF and VEGF in the ischemic brain. Survival and differentiation of transplanted BMSCs were also increased by HP, and the quantity of engrafted BMSCs was significantly correlated with neurological function improvement. These results suggest that HP may enhance the therapeutic efficacy of BMSCs in an ischemic stroke model. The underlying mechanism likely involves the inhibition of caspase-3 activation and an increasing expression of HIF-1α, which promotes angiogenesis and neurogenesis and thereby reduces neuronal death and improves neurological function.

Summary ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) are secreted metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM). In this study, we show that ADAMTS18, produced by the epithelial cells of distal airways and mesenchymal cells in lung apex at early embryonic stages, serves as a morphogen in lung development. ADAMTS18 deficiency leads to reduced number and length of bronchi, tipped lung apexes, and dilated alveoli. These developmental defects worsen lipopolysaccharide-induced acute lung injury and bleomycin-induced lung fibrosis in adult Adamts18-deficient mice. ADAMTS18 deficiency also causes increased levels of fibrillin1 and fibrillin2, bronchial microfibril accumulation, decreased focal adhesion kinase signaling, and disruption of F-actin organization. Our findings indicate that ECM homeostasis mediated by ADAMTS18 is pivotal in airway branching morphogenesis., Graphical Abstract, Highlights • ADAMTS18 serves as a morphogen in early lung development • ADAMTS18 deficiency increases lung susceptibility to injuries • ADAMTS18 affects airway branching by regulating bronchial microfibril abundance, Developmental Genetics; Molecular Biology

Here, we show that the liver-derived apolipoprotein M (ApoM) protects the lung and kidney from pro-fibrotic insults and that this circulating factor is attenuated in aged mice. Aged mouse hepatocytes exhibit transcriptional suppression of ApoM. This leads to reduced sphingosine-1-phosphate (S1P) signaling via the S1P receptor 1 (S1PR1) in the vascular endothelial cells of lung and kidney. Suboptimal S1PR1 angiocrine signaling causes reduced resistance to injury-induced vascular leak and leads to organ fibrosis. Plasma transfusion from Apom transgenic mice but not Apom knockout mice blocked fibrosis in the lung. Similarly, infusion of recombinant therapeutics, ApoM-Fc fusion protein enhanced kidney and lung regeneration and attenuated fibrosis in aged mouse after injury. Furthermore, we identified that aging alters Sirtuin-1-hepatic nuclear factor 4α circuit in hepatocytes to downregulate ApoM. These data reveal an integrative organ adaptation that involves circulating S1P chaperone ApoM+ high density lipoprotein (HDL), which signals via endothelial niche S1PR1 to spur regeneration over fibrosis.

Salt pollution and anthropogenic-accelerated weathering is globally shifting the ionic composition and increasing salinisation of fresh water. We analyzed a 40-year data set (1970s–2010s) to characterize the drastic change of dissolved ionic composition, conductivity and pH levels. We also identified causative factors in these highly polluted mountain streams in northeastern China. Dissolved salt ions (Ca2+, Mg2+ and SO42−) increased by 3.02–5.21 fold and conductivity (a proxy for salinisation) increased by 3.09 fold. The average pH values increased from 7.08 to 8.49. The dominant ions, Ca2+, Mg2+, SO42− and HCO3− + CO32−, accounted for ∼90% of ionic composition based on mass concentration. Between the 1970s and 2010s, the dominant anion shifted from HCO3− + CO32− to a mixture of SO42− and HCO3− + CO32−. Increasing mining and land development appear to be the primary driving factors for the change of Ca2+, Mg2+, SO42− and HCO3− + CO32− concentrations; whereas, agricultural land was the main driving factor for the variation in K+, Na+ and Cl− concentrations. The source of ions has shifted from a more natural weathering of carbonate rocks to one of mineral dissolution that is affected by anthropogenic activities. Our study shows that freshwater mountain streams are at risk of long lasting anthropogenic salinisation and should be considered in future management and conservation plans.

Conductivity elevation produces osmotic stress to aquatic biota and then alters biological communities. The responses of stream fish to conductivity remain unclear and strategies for protection are poorly developed. We collected data of fish and conductivity from sixty-two sites of the Taizi River to evaluate the changes to the fish community and species along the gradient of conductivity. Our results found that conductivity elevation was related to the regional development of urban and farmland and the local degradation of habitat quality. The community metrics of abundance and F-IBI, but not species richness and diversity, showed a significant linear correlation with conductivity. Conductivity of the top three F-IBI grades (excellent, good and normal) was significantly lower than those of the other two F-IBI grades (poor and bad). The boundary conductivity between normal grade and poor grade was approximately equal to 500 μS cm−1. We found different probability patterns for different species along the conductivity gradient; one capture probability pattern showed decline trend along the conductivity gradient. Except for two dominating and widespread species and one tolerant species, the remaining fish species of the first pattern should be designated as protection objects. In order to protect fish community integrity and sensitive species, sustainable land use management on the catchment scale and habitat quality improvement on the local scale should be given more attention by catchment managers.