Upregulation of CYR61 by TGF-ß and YAP signaling exerts a counter-suppression of hepatocellular carcinoma.

Transforming growth factor-ß (TGF-ß) and Hippo signaling are two critical pathways engaged in cancer progression by regulating both oncogenes and tumor suppressors, yet how the two pathways coordinately exert their functions in the development of hepatocellular carcinoma (HCC) remains elusive. In this study, we firstly conducted an integrated analysis of public liver cancer databases and our experimental TGF-ß target genes, identifying CYR61 as a pivotal candidate gene relating to HCC development. The expression of CYR61 is downregulated in clinical HCC tissues and cell lines than that in the normal counterparts. Evidence revealed that CYR61 is a direct target gene of TGF-ß in liver cancer cells. In addition, TGF-ß-stimulated Smad2/3 and the Hippo pathway downstream effectors YAP and TEAD4 can form a protein complex on the promoter of CYR61, thereby activating the promoter activity and stimulating CYR61 gene transcription in a collaborative manner. Functionally, depletion of CYR61 enhanced TGF-ß- or YAP-mediated growth and migration of liver cancer cells. Consistently, ectopic expression of CYR61 was capable of impeding TGF-ß- or YAP-induced malignant transformation of HCC cells in vitro and attenuating HCC xenograft growth in nude mice. Finally, transcriptomic analysis indicates that CYR61 can elicit an antitumor program in liver cancer cells. Together, these results add new evidence for the crosstalk between TGF-ß and Hippo signaling and unveil an important tumor suppressor function of CYR61 in liver cancer.

Tilted Bragg grating in a glycerol-infiltrated specialty optical fiber for temperature and strain measurements.

In this Letter, we propose an in-line tilted fiber Bragg grating sensor for temperature and strain measurements. The grating is inscribed in a specialty optical fiber using tightly focused femtosecond laser pulses and the line-by-line direct writing method. Beside the central core in which the grating is produced, a hollow channel filled with glycerol aqueous solution significantly improves the sensitivity of the fiber cladding modes due to its high thermo-optic coefficient. We show that the temperature sensitivity of the core mode is 9.8 pm/°C, while the one of the cladding modes is strongly altered and can reach -24.3 pm/°C, in the investigated range of 20-40°C. For the strain measurement, sensitivities of the core mode and the cladding modes are similar (∼0.60 pm/µÎµ) between 0 and 2400 µÎµ. The significative difference of temperature sensitivity between the two modes facilitates the discrimination of the dual parameters in simultaneous measurements.

Macrophages regulate healing-associated fibroblasts in diabetic wound.

BACKGROUND: Recovery from a foot ulcer is compromised in a diabetic status, due to the impaired tissue microenvironment that consists of altered inflammation, angiogenesis and fibrosis. Phenotypic alterations in both macrophages and fibroblasts have been detected in the diabetic wound. Recently, a fibroblast subpopulation that expresses high matrix metalloproteinase 1 (MMP1), MMP3, MMP11 and Chitinase-3-Like Protein 1 (CHI3L1) was associated with a successful diabetic wound healing. However, it is not known whether these healing-associated fibroblasts are regulated by macrophages. METHODS AND RESULTS: We used bioinformatic tools to analyze selected public databases on normal and diabetic skin from patients, and identified genes significantly altered in diabetes. In a mouse model for diabetic wound healing, we detected not only a loss of the spatiotemporal changes in interleukin 1ß (IL1ß), IL6, IL10 and vascular endothelial growth factor A (VEGF-A) in wound macrophages, but also a compromised expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in healing-associated wound fibroblasts in a diabetic status. Co-culture with diabetic macrophages significantly reduced the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from non-diabetic wound. Co-culture with non-diabetic macrophages or diabetic macrophages supplied with IL6 significantly increased the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from diabetic wound. Moreover, macrophage-specific expression of IL6 significantly improved wound healing and angiogenesis in diabetic mice. CONCLUSIONS: Macrophages may induce the activation of wound-healing-associated fibroblasts, while the defective macrophages in diabetes may be corrected with IL6 treatment as a promising therapy for diabetic foot disease.

Repurposing Anticancer Drugs Targeting the MAPK/ERK Signaling Pathway for the Treatment of Respiratory Virus Infections.

Respiratory virus infections remain a significant challenge to human health and the social economy. The symptoms range from mild rhinitis and nasal congestion to severe lower respiratory tract dysfunction and even mortality. The efficacy of therapeutic drugs targeting respiratory viruses varies, depending upon infection time and the drug resistance engendered by a high frequency of viral genome mutations, necessitating the development of new strategies. The MAPK/ERK pathway that was well delineated in the 1980s represents a classical signaling cascade, essential for cell proliferation, survival, and differentiation. Since this pathway is constitutively activated in many cancers by oncogenes, several drugs inhibiting Raf/MEK/ERK have been developed and currently used in anticancer treatment. Two decades ago, it was reported that viruses such as HIV and influenza viruses could exploit the host cellular MAPK/ERK pathway for their replication. Thus, it would be feasible to repurpose this category of the pathway inhibitors for the treatment of respiratory viral infections. The advantage is that the host genes are not easy to mutate such that the drug resistance rarely occurs during short-period treatment of viruses. Therefore, in this review we will summarize the research progress on the role of the MAPK/ERK pathway in respiratory virus amplification and discuss the potential of the pathway inhibitors (MEK inhibitors) in the treatment of respiratory viral infections.

Phosphorylation of enteroviral 2Apro at Ser/Thr125 benefits its proteolytic activity and viral pathogenesis.

Enteroviral 2A proteinase (2Apro ), a well-established and important viral functional protein, plays a key role in shutting down cellular cap-dependent translation, mainly via its proteolytic activity, and creating optimal conditions for Enterovirus survival. Accumulated data show that viruses take advantage of various signaling cascades for their life cycle; studies performed by us and others have demonstrated that the extracellular signal-regulated kinase (ERK) pathway is essential for enterovirus A71 (EV-A71) and other viruses replication. We recently showed that ERK1/2 is required for the proteolytic activity of viral 2Apro ; however, the mechanism underlying the regulation of 2Apro remains unknown. Here, we demonstrated that the 125th residue Ser125 of EV-A71 2Apro or Thr125 of coxsackievirus B3 2Apro , which is highly conserved in the Enterovirus, was phosphorylated by ERK1/2. Importantly, 2Apro with phosphor-Ser/Thr125 had much stronger proteolytic activity toward eukaryotic initiation factor 4GI and rendered the virus more efficient for multiplication and pathogenesis in hSCARB2 knock-in mice than that in nonphospho-Ser/Thr125A (S/T125A) mutants. Notably, phosphorylation-mimic mutations caused deleterious changes in 2Apro catalytic function (S/T125D/E) and in viral propagation (S125D). Crystal structure simulation analysis showed that Ser125 phosphorylation in EV-A71 2Apro enabled catalytic Cys to adopt an optimal conformation in the catalytic triad His-Asp-Cys, which enhances 2Apro proteolysis. Therefore, we are the first to report Ser/Thr125 phosphorylation of 2Apro increases enteroviral adaptation to the host to ensure enteroviral multiplication, causing pathogenicity. Additionally, weakened viruses containing a S/T125A mutation could be a general strategy to develop attenuated Enterovirus vaccines.

Transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation.

AMP-activated protein kinase (AMPK) functions as an energy sensor and is pivotal in maintaining cellular metabolic homeostasis. Numerous studies have shown that down-regulation of AMPK kinase activity or protein stability not only lead to abnormality of metabolism but also contribute to tumor development. However, whether transcription regulation of AMPK plays a critical role in cancer metastasis remains unknown. In this study, we demonstrate that AMPKα1 expression is down-regulated in advanced human breast cancer and is associated with poor clinical outcomes. Transcription of AMPKα1 is inhibited on activation of PI3K and HER2 through ΔNp63α. Ablation of AMPKα1 expression or inhibition of AMPK kinase activity leads to disruption of E-cadherin-mediated cell-cell adhesion in vitro and increased tumor metastasis in vivo. Furthermore, restoration of AMPKα1 expression significantly rescues PI3K/HER2-induced disruption of cell-cell adhesion, cell invasion, and cancer metastasis. Together, these results demonstrate that the transcription control is another layer of AMPK regulation and suggest a critical role for AMPK in regulating cell-cell adhesion and cancer metastasis.

Metformin Suppresses Stemness of Non-Small-Cell Lung Cancer Induced by Paclitaxel through FOXO3a.

Cancer stem cells (CSCs) play a pivotal role in drug resistance and metastasis. Among the key players, Forkhead box O3a (FOXO3a) acts as a tumor suppressor. This study aimed to unravel the role of FOXO3a in mediating the inhibitory effect of metformin on cancer stemness derived from paclitaxel (PTX)-resistant non-small-cell lung cancer (NSCLC) cells. We showed that CSC-like features were acquired by the chronic induction of resistance to PTX, concurrently with inactivation of FOXO3a. In line with this, knockdown of FOXO3a in PTX-sensitive cells led to changes toward stemness, while overexpression of FOXO3a in PTX-resistant cells mitigated stemness in vitro and remarkably curbed the tumorigenesis of NSCLC/PTX cells in vivo. Furthermore, metformin suppressed the self-renewal ability of PTX-resistant cells, reduced the expression of stemness-related markers (c-MYC, Oct4, Nanog and Notch), and upregulated FOXO3a, events concomitant with the activation of AMP-activated protein kinase (AMPK). All these changes were recapitulated by silencing FOXO3a in PTX-sensitive cells. Intriguingly, the introduction of the AMPK dominant negative mutant offset the inhibitory effect of metformin on the stemness of PTX-resistant cells. In addition, FOXO3a levels were elevated by the treatment of PTX-resistant cells with MK2206 (an Akt inhibitor) and U0126 (a MEK inhibitor). Collectively, our findings indicate that metformin exerts its effect on FOXO3a through the activation of AMPK and the inhibition of protein kinase B (Akt) and MAPK/extracellular signal-regulated kinase (MEK), culminating in the suppression of stemness in paclitaxel-resistant NSCLC cells.

Cellulose-degrading bacteria improve conversion efficiency in the co-digestion of dairy and chicken manure by black soldier fly larvae.

Black soldier fly larvae (BSFL) have potential utility in converting livestock manure into larval biomass as a protein source for livestock feed. However, BSFL have limited ability to convert dairy manure (DM) rich in lignocellulose. Our previous research demonstrated that feeding BSFL with mixtures of 40% dairy manure and 60% chicken manure (DM40) provides a novel strategy for significantly improving their efficiency in converting DM. However, the mechanisms underlying the efficient conversion of DM40 by BSFL are unclear. In this study, we conducted a holistic study on the taxonomic stucture and potential functions of microbiota in the larval gut and manure during the DM and DM40 conversion by BSFL, as well as the effects of BSFL on cellulosic biodegradation and biomass production. Results showed that BSFL can consume cellulose and other nutrients more effectively and harvest more biomass in a shorter conversion cycle in the DM40 system. The larval gut in the DM40 system yielded a higher microbiota complexity. Bacillus and Amphibacillus in the BSFL gut were strongly correlated with the larval cellulose degradation capacity. Furthermore, in vitro screening results for culturable cellulolytic microbes from the larval guts showed that the DM40 system isolated more cellulolytic microbes. A key bacterial strain (DM40L-LB110; Bacillus subtilis) with high cellulase activity from the larval gut of DM40 was validated for potential industrial applications. Therefore, mixing an appropriate proportion of chicken manure into DM increased the abundance of intestinal bacteria (Bacillus and Amphibacillus) producing cellulase and improved the digestion ability (particularly cellulose degradation) of BSFL to cellulose-rich manure through changes in microbial communities composition in intestine. This study reveals the microecological mechanisms underlying the high-efficiency conversion of cellulose-rich manure by BSFL and provide potential applications for the large-scale cellulose-rich wastes conversion by intestinal microbes combined with BSFL.

Cluster-enabled patterning of copper nanostructures from aqueous solution using a femtosecond laser.

A one-step method for patterning low-resistivity nanoscale copper wire is proposed herein to solve the challenging issues of using common metals rather than noble metal nanostructures fabricated by direct laser writing in solution. A complexing and a reducing agent were introduced for the single-photon absorption of copper solution in the visible range and to enable two-photon absorption with a femtosecond laser. Copper clusters were generated prior to direct laser writing to decrease induced laser energy during two-photon absorption and accelerate copper nanowire patterning to avoid the boiling of copper solution. A surfactant was used to restrain the overgrowth of copper clusters to obtain written nanowires with high uniformity. By controlling the laser writing parameters, the obtained copper wire had a minimum width of 230 nm and a resistivity of 1.22 × 10-5Ω·m. Our method paves the way for the fabrication of common metal nanodevices by direct laser writing.

AMP-activated protein kinase ß1 or ß2 deletion enhances colon cancer cell growth and tumorigenesis.

Abnormal metabolism is a major hallmark of cancer and has been validated as a therapeutic target. Adenine monophosphate-activated protein kinase (AMPK), an αßγ heterotrimer, performs essential functions in cancer progression due to its central role in maintaining the homeostasis of cellular energy. While the contributions of AMPKα and AMPKγ subunits to cancer development have been established, specific roles of AMPKß1 and AMPKß2 isoforms in cancer development are poorly understood. Here, we show the functions of AMPKß1 and AMPKß2 in colon cancer. Specifically, deletion of AMPKß1 or AMPKß2 leads to increased cell proliferation, colony formation, migration, and tumorigenesis in HCT116 and HT29 colon cancer cells. Interestingly, the AMPKß1 and AMPKß2 isoforms have slightly different effects on regulating cancer metabolism, as colon cancer cells with AMPKß1 knockout showed decreased rates of glycolysis-related oxygen consumption, while AMPKß2 deletion led to enhanced rates of oxygen consumption due to oxidative phosphorylation. These results demonstrate that functional AMPKß1 and AMPKß2 inhibit growth and tumorigenesis in colon cancer cells, suggesting their potential as effective targets for colon cancer therapy.

Discovery of Raf Family Is a Milestone in Deciphering the Ras-Mediated Intracellular Signaling Pathway.

The Ras-Raf-MEK-ERK signaling pathway, the first well-established MAPK pathway, plays essential roles in cell proliferation, survival, differentiation and development. It is activated in over 40% of human cancers owing to mutations of Ras, membrane receptor tyrosine kinases and other oncogenes. The Raf family consists of three isoforms, A-Raf, B-Raf and C-Raf. Since the first discovery of a truncated mutant of C-Raf as a transforming oncogene carried by a murine retrovirus, forty years of extensive studies have provided a wealth of information on the mechanisms underlying the activation, regulation and biological functions of the Raf family. However, the mechanisms by which activation of A-Raf and C-Raf is accomplished are still not completely understood. In contrast, B-Raf can be easily activated by binding of Ras-GTP, followed by cis-autophosphorylation of the activation loop, which accounts for the fact that this isoform is frequently mutated in many cancers, especially melanoma. The identification of oncogenic B-Raf mutations has led to accelerated drug development that targets Raf signaling in cancer. However, the effort has not proved as effective as anticipated, inasmuch as the mechanism of Raf activation involves multiple steps, factors and phosphorylation of different sites, as well as complex interactions between Raf isoforms. In this review, we will focus on the physiological complexity of the regulation of Raf kinases and their connection to the ERK phosphorylation cascade and then discuss the role of Raf in tumorigenesis and the clinical application of Raf inhibitors in the treatment of cancer.

Chronic Intermittent Hypoxia Exposure Alternative to Exercise Alleviates High-Fat-Diet-Induced Obesity and Fatty Liver.

Obesity often concurs with nonalcoholic fatty liver disease (NAFLD), both of which are detrimental to human health. Thus far, exercise appears to be an effective treatment approach. However, its effects cannot last long and, moreover, it is difficult to achieve for many obese people. Thus, it is necessary to look into alternative remedies. The present study explored a noninvasive, easy, tolerable physical alternative. In our experiment, C57BL/6 mice were fed with a high-fat diet (HFD) to induce overweight/obesity and were exposed to 10% oxygen for one hour every day. We found that hypoxia exerted protective effects. First, it offset HFD-induced bodyweight gain and insulin resistance. Secondly, hypoxia reversed the HFD-induced enlargement of white and brown adipocytes and fatty liver, and protected liver function. Thirdly, HFD downregulated the expression of genes required for lipolysis and thermogenesis, such as UCP1, ADR3(beta3-adrenergic receptor), CPT1A, ATGL, PPARα, and PGC1α, M2 macrophage markers arginase and CD206 in the liver, and UCP1 and PPARγ in brown fat, while these molecules were upregulated by hypoxia. Furthermore, hypoxia induced the activation of AMPK, an energy sensing enzyme. Fourthly, our results showed that hypoxia increased serum levels of epinephrine. Indeed, the effects of hypoxia on bodyweight, fatty liver, and associated changes in gene expression ever tested were reproduced by injection of epinephrine and prevented by propranolol at varying degrees. Altogether, our data suggest that hypoxia triggers stress responses where epinephrine plays important roles. Therefore, our study sheds light on the hope to use hypoxia to treat the daunting disorders, obesity and NAFLD.

PEBP4 Directs the Malignant Behavior of Hepatocellular Carcinoma Cells via Regulating mTORC1 and mTORC2.

Phosphatidylethanolamine binding protein 4 (PEBP4) is an understudied multifunctional small protein. Previous studies have shown that the expression of PEBP4 is increased in many cancer specimens, which correlates to cancer progression. The present study explored the mechanism by which PEBP4 regulates the growth and progression of hepatocellular carcinoma cells. Thus, we showed that knockdown of PEBP4 in MHCC97H cells, where its expression was relatively high, diminished activities of serine/threonine protein kinase B (PKB, also known as Akt), mammalian target of rapamycin complex 1(mTORC1), and mTORC2, events that were not restored by insulin-like growth factor 1 (IGF-1). Conversely, overexpression of PEBP4 in MHCC97L cells with the low endogenous level yielded opposite effects. Furthermore, physical association of PEBP4 with Akt, mTORC1, and mTORC2 was observed. Interestingly, introduction of AktS473D mutant, bypassing phosphorylation by mTORC2, rescued mTORC1 activity, but without effects on mTORC2 signaling. In contrast, the effect of PEBP4 overexpression on the activity of mTORC1 but not that of mTORC2 was suppressed by MK2206, a specific inhibitor of Akt. In conjunction, PEBP4 knockdown-engendered reduction of cell proliferation, migration and invasion was partially rescued by Akt S473D while increases in these parameters induced by overexpression of PEBP4 were completely abolished by MK2206, although the expression of epithelial mesenchymal transition (EMT) markers appeared to be fully regulated by the active mutant of Akt. Finally, knockdown of PEBP4 diminished the growth of tumor and metastasis, whereas they were enhanced by overexpression of PEBP4. Altogether, our study suggests that increased expression of PEBP4 exacerbates malignant behaviors of hepatocellular cancer cells through cooperative participation of mTORC1 and mTORC2.

Rapid cultivation of anammox sludge based on Ca-alginate cell beads.

Current gel entrapment technology has certain advantages for the enrichment of anammox sludge. In this study, the optimal preparation conditions and cultivation equipment of Ca-alginate cell beads for the culturing anammox sludge were proposed. The preparation parameters of the Ca-alginate cell beads were as follows: 3% sodium alginate, 4% CaCl2, VSA:Vcell = 1:1, a drop height of 9 cm, stirring speed of 300 rpm, and cross-linking time of 24 h. The prepared cell beads were regular spheres with a uniform size and hard texture. Throughout the 9 days of cultivation, the number of anammox bacteria in the Ca-alginate cell beads was 4.3 times that of the initial sludge, and the color of the cell beads changed from yellowish-brown to reddish-brown. Scanning electron microscopy (SEM) analysis showed that the SA gel beads had a good microporous structure. The fluorescence in situ hybridization (FISH) results illustrated that the bacteria were mostly dispersed inside the Ca-alginate cell beads. Additionally, the qPCR results implied that only a relatively small amount of anammox biomass (2.74×106 copies/gel-bead) was required to quickly start the anammox process. The anammox bacteria in the Ca-alginate cell beads grew with a fast growth rate in a short period and exhibited high activity due to diffusion limitations. In addition, the anammox bacteria cultivated in the Ca-alginate cell beads could adapt to the increase in substrate concentration in a short period. The optimal incubation time of this gel entrapment method for anammox sludge was no more than 17 days under the experimental conditions of this work. Therefore, this simple and practicable gel entrapment method may serve as a suitable pre-culture means for the rapid enrichment of anammox bacteria.

AMPK inhibits Smad3-mediated autoinduction of TGF-ß1 in gastric cancer cells.

We have previously shown that adenine monophosphate-activated protein kinase (AMPK) regulates transforming growth factor ß (TGF-ß)-triggered Smad3 phosphorylation. Here we report that AMPK inhibits TGF-ß1 production. First, metformin reduced mRNA levels of TGF-ß1 in gastric cancer cells, in parallel to the decrease of its protein abundance. The effects were more prominent in the cells containing LKB1, an upstream kinase of AMPK. Second, knockdown of Smad3 by siRNA abrogated the expression of TGF-ß1. Third, metformin suppressed firefly luciferase activity whose transcription was driven by TGF-ß1 promoter. In accordance, deletion of the putative binding site of Smad3 in the TGF-ß1 promoter region severely impaired the promoter activity and response to metformin. Fourth, in support of our in vitro study, clinical treatment of type 2 diabetes with metformin significantly reduced the plasma level of TGF-ß1. Finally, immunohistochemical studies revealed that TGF-ß1 was highly expressed in human gastric cancer tissues as compared with adjacent normal tissues. In contrast, p-AMPK exhibited opposite changes. Furthermore, the survival rate of gastric cancer patients was positively correlated with p-AMPK and negative with TGF-ß1. Therefore, our present studies depict a mechanism underlying AMPK suppression of TGF-ß1 autoinduction, which is mediated through inhibition of Smad3 phosphorylation and activation. Collectively, our study sheds a light on the potential usage of AMPK activators in the treatment of TGF-ß1-mediated gastric cancer progression.

Femtosecond laser induced in-situ crystallization of Tb-based luminescent metal organic framework.

Luminescent metal-organic frameworks (LMOFs) are a class of interesting and well-investigated MOF materials, which have shown remarkable prospects in the past and have been widely applied in different fields. However, due to their organic hybrid aspect, micro-/nano-patterning LMOFs in devices via a conventional semiconductor process is very challenging. In this work, we have introduced an elegant technique via nonlinear photon-chemical effect to induce the synthesis and growth of LMOFs. A facile technique for local synthesis and micro-pattering Tb-based luminescent metal organic frameworks (Tb(BTC)·G) from a solution of precursors is achieved. A single step approach micro-patterning for device integration with simultaneous chemical synthesis was proposed. Micro-devices with excellent fluorescence performance based on Tb(BTC)·G have been demonstrated. This work first suggested a high resolution bottom-up micro-patterning technique for MOF device fabrication using femtosecond laser direct writing, showing great potential on MOF based micro/nano-devices integration, especially promising for patterning high resolution luminescent MOF devices.

Prevalence of comorbidity in Chinese patients with COVID-19: systematic review and meta-analysis of risk factors.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an infectious disease characterized by cough, fever, and fatigue and 20% of cases will develop into severe conditions resulting from acute lung injury with the manifestation of the acute respiratory distress syndrome (ARDS) that accounts for more than 50% of mortality. Currently, it has been reported that some comorbidities are linked with an increased rate of severity and mortality among COVID-19 patients. To assess the role of comorbidity in COVID-19 progression, we performed a systematic review with a meta-analysis on the relationship of COVID-19 severity with 8 different underlying diseases. METHODS: PubMed, Web of Science, and CNKI were searched for articles investigating the prevalence of comorbidities in severe and non-severe COVID-19 patients. A total of 41 studies comprising 12,526 patients were included. RESULTS: Prevalence of some commodities was lower than that in general population such as hypertension (19% vs 23.2%), diabetes (9% vs 10.9%), chronic kidney disease (CKD) (2% vs 9.5%), chronic liver diseases (CLD) (3% vs 24.8%) and chronic obstructive pulmonary disease (COPD) (3% vs 8.6%), while some others including cancer (1% vs 0.6%), cardiovascular disease (6% vs 1.8%) and cerebrovascular disease (2% vs 0.9%) exhibited greater percentage in COVID-19. Cerebrovascular disease (OR = 3.70, 95%CI 2.51-5.45) was found to be the strongest risk factor in disease exacerbation, followed by CKD (OR = 3.60, 95%CI 2.18-5.94), COPD (OR = 3.14, 95% CI 2.35-4.19), cardiovascular disease (OR = 2.76, 95% CI 2.18-3.49), malignancy (OR = 2.63, 95% CI 1.75-3.95), diabetes (OR = 2.49, 95% CI 2.10-2.96) and hypertension (OR = 2.13, 95% CI 1.81-2.51). We found no correlation between CLD and increased disease severity (OR = 1.32, 95% CI 0.96-1.82). CONCLUSION: The impact of all eight underlying diseases on COVID-19 deterioration seemed to be higher in patients outside Hubei. Based on different comorbidities, COVID-19 patients tend to be at risk of developing poor outcomes to a varying degree. Thus, tailored infection prevention and monitoring and treatment strategies targeting these high-risk subgroups might improve prognosis during the COVID-19 pandemic.

The removal of Cu(II)-EDTA chelates using green rust adsorption combined with ferrite formation process.

Classical adsorbents such as activated carbon are inefficient to remove Cu(II)-EDTA in solution. Moreover, the heavy metals in the generated sludge can easily be dissolved back into solution. In this research, a novel strategy developed by coupling green rust adsorption and ferrite formation technology was proposed for Cu(II)-EDTA chelate removal. At the adsorption stage, green rust sulfate (GRME(SO42-)) showed a high adsorption efficiency of chelated copper, with a capacity of 126.41 mg g-1, compared to other classical adsorbents. During the ferrite formation stage, GRME(SO42-)-based precipitate with high moisture content and slow settling rate could be transformed into ferrite-based precipitate with low moisture content and rapid settling rate. The volume and moisture content of ferrite were 2.20 and 1.45 times lower than those of GRME(SO42-) and the sedimentation velocity of ferrite was also 1.23 times higher than that of GRME(SO42-), which strongly demonstrated the necessity of the ferrite formation process. Toxicity characteristic leaching procedure (TCLP) test results showed that the metallic copper of GRME(SO42-) sludge could be more easily dissolved back into solution than that of ferrite precipitate under weak-acid conditions, indicating the stability of ferrite. In addition, after the ferrite process, the generated sludge exhibited soft magnetism and could be quickly separated within few seconds using an external magnetic field. All these results showed that the combined green rust adsorption with ferrite formation method was an efficient, recyclable and eco-friendly method for the treatment of wastewater containing Cu(II)-EDTA.

Metformin attenuates trauma-induced heterotopic ossification via inhibition of Bone Morphogenetic Protein signalling.

AMP-activated protein kinase (AMPK) is an intracellular sensor of energy homoeostasis that is activated under energy stress and suppressed in energy surplus. AMPK activation leads to inhibition of anabolic processes that consume ATP. Osteogenic differentiation is a process that highly demands ATP during which AMPK is inhibited. The bone morphogenetic proteins (BMPs) signalling pathway plays an essential role in osteogenic differentiation. The present study examines the inhibitory effect of metformin on BMP signalling, osteogenic differentiation and trauma-induced heterotopic ossification. Our results showed that metformin inhibited Smad1/5 phosphorylation induced by BMP6 in osteoblast MC3T3-E1 cells, concurrent with up-regulation of Smad6, and this effect was attenuated by knockdown of Smad6. Furthermore, we found that metformin suppressed ALP activity and mineralization of the cells, an event that was attenuated by the dominant negative mutant of AMPK and mimicked by its constitutively active mutant. Finally, administration of metformin prevented the trauma-induced heterotopic ossification in mice. In conjuncture, AMPK activity and Smad6 and Smurf1 expression were enhanced by metformin treatment in the muscle of injured area, concurrently with the reduction of ALK2. Collectively, our study suggests that metformin prevents heterotopic ossification via activation of AMPK and subsequent up-regulation of Smad6. Therefore, metformin could be a potential therapeutic drug for heterotopic ossification induced by traumatic injury.

Direct laser writing of nanoscale undoped conductive polymer.

The fabrication of poly 3,4-ethylene dioxythiophene (PEDOT) devices generally requires a separated strategy for EDOT polymerization and PEDOT coating, thus increasing th difficulty of their integration. With the goal of insolubility of PEDOT in a common solution, material modifications including grafting vinyl moiety groups on the side chain of the PEDOT can increase its solubility, but also markedly reduce the conductivity. Here, we report direct laser writing of pure EDOT monomer into PEDOT with a feature size of 140 nm. The PEDOT nanowire possesses the high conductivity of 1.28 × 105 S m-1 and can be patterned on solid and flexible substrates with various structures, thus paving the way towards organic highly conductive device fabrication and integration.