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A magnetic solid phase extraction method based on magnetic covalent organic frameworks (TpBD@Fe

In order to avoid the energy consumption of dewatering and dust pollution in the preparation of non-sintered lightweight aggregates from dredged sediment, a new low-dust process of preparing non-sintered extruded wrap-shell aggregates (TH-WSLAs-W) by extrusion granulation is proposed and applied to produce TH-WSLAs-W baking-free bricks (TH-WSLAB-W). The basic physical properties (cylinder compressive strength, bulk density and water absorption) and microstructure of TH-WSLAs-W was explored. It shows that the curing agent will form a hydrophobic gel film around the sediment particles and form a network structure, which enhances the cylinder compressive strength (6.7 MPa) and frost resistance of TH-WSLAs-W. In addition, the interfacial transition zone among TH-WSLAB-Ws was studied by scanning electron microscope. It found that the micropore structure endow the TH-WSLAs-W with excellent water absorption and drainage property, promoting the hydration of cement, promising the integration of aggregate and cement, and its compressive strength reaches 20.5 MPa.

Cell division is fundamental to all cellular life. Most of the archaea employ one of two alternative division machineries, one centered around the prokaryotic tubulin homolog FtsZ and the other around the endosomal sorting complex required for transport (ESCRT). However, neither of these mechanisms has been thoroughly characterized in archaea. Here, we show that three of the four PRC (Photosynthetic Reaction Center) barrel domain proteins ofHaloferax volcanii(renamedCelldivisionproteins B1/2/3 (CdpB1/2/3)), play important roles in division. CdpB1 interacts directly with the FtsZ membrane anchor SepF and is essential for division, whereas deletion ofcdpB2andcdpB3causes a major and a minor division defect, respectively. Orthologs of CdpB proteins are also involved in cell division in other haloarchaea. Phylogenetic analysis shows that PRC barrel proteins are widely distributed among archaea, including the highly conserved CdvA protein of the crenarchaeal ESCRT-based division system. Thus, diverse PRC barrel proteins appear to be central to cell division in most if not all archaea. Further study of these proteins is expected to elucidate the division mechanisms in archaea and their evolution.

Shexiang Baoxin Pill (SBP) has an excellent therapeutic effect on atherosclerosis (AS), but the combinational mechanisms of SBP against AS remains unclear. This study aimed to investigate the combinational mechanisms...

Butenyl-spinosyn is a highly effective and broad-spectrum biopesticide produced by Saccharopolyspora pogona. However, the yield of this compound is difficult to increase because the regulatory mechanism of secondary metabolism is still unknown. Here, the transcriptional regulator Sp13016 was discovered to be highly associated with butenyl-spinosyn synthesis and bacterial growth. Overexpression of sp13016 improved butenyl-spinosyn production to a level that was 2.84-fold that of the original strain, while deletion of sp13016 resulted in a significant decrease in yield and growth inhibition. Comparative proteomics revealed that these phenotypic changes were attributed to the influence of Sp13016 on the central carbon metabolism pathway to regulate the supply of precursors. Our research helps to reveal the regulatory mechanism of butenyl-spinosyn biosynthesis and provides a reference for increasing the yield of natural products of Actinomycetes.

The mechanism for traditional Chinese medicine in treating of recurrent spontaneous abortion is not clear. This study aims to explore the mechanism of baotaiyin in the treatment of recurrent abortion by regulating the immune inflammatory axis of interleukin (IL)-23/helper T cell (Th)17.Spontaneous abortion model mice were randomly divided into a model group, 3 dose (low, medium, and high) groups of baotaiyin, with 10 mice in each group. After 14 days of medication, the levels of IL-17, IL-23, IL-10, and TGF-β in serum were detected with enzyme-linked immunosorbent assay. The proportion of Th17 and regulatory T cells (Treg) cells in spleen lymphocytes was tested with flow cytometry. The expressions of (retinoid-related orphan receptor γt, ROR-γt) and forkhead box P3 (FOXP3) mRNA in decidua tissues was detected with RT-PCR. Embryo absorption rate was counted.Compared with the model group, the absorption rate of embryo and Th17/Treg cell ratio in baotaiyin medium- and high-dose groups were decreased significantly (all P0.05); the levels of IL-17 and IL-23 in serum were decreased (both P0.05), while the levels of TGF-β and IL-10 in baotaiyin medium- and high-dose groups were increased (P0.05, P0.01, respectively); the expression of ROR-γt mRNA was decreased and the expression of FOXP3 mRNA was increased (all P0.01) in decidua tissues of baotaiyin medium- and high-dose groups.Baotaiyin inhibits the positive feedback cycle of IL-23/Th17 immune inflammatory axis, which regulates Th17/Treg cell balance, mediates the maternal and fetal immune tolerance, and prevents the recurrent abortion.

Hypertensive retinopathy (HR) is a retinal disease that may lead to vision loss and blindness. Sex-determining region Y (SRY)-box (SOX) family transcription factors have been reported to be involved in HR development. In this study, the role and upstream mechanism of SRY-box transcription factor 17 (SOX17) in HR pathogenesis were investigated.SOX17 and miR-194-5p levels in Angiotensin II (Ang II)-stimulated human retinal microvascular endothelial cells (HRMECs) and retinas of mice were detected by RT-qPCR. SOX17 protein level as well as levels of tight junction proteins and vascular endothelial growth factor (VEGF) signaling-associated proteins were quantified by western blotting. Tube formation assays were performed to evaluate angiogenesis in HRMECs. The structure of mouse retinal tissues was observed by HE staining. The interaction between miR-194-5p and SOX17 was confirmed by a luciferase reporter assay.SOX17 was upregulated in HRMECs treated with Ang II. SOX17 knockdown inhibited angiogenesis in Ang II-stimulated HRMECs and increased tight junction protein levels. Mechanically, SOX17 was targeted by miR-194-5p. Moreover, miR-194-5p upregulation restrained angiogenesis and increased tight junction protein levels in Ang II-treated HRMECs, and the effect was reversed by SOX17 overexpression. MiR-194-5p elevation inactivated VEGF signaling via targeting SOX17. miR-194-5p alleviated pathological symptoms of HR in Ang II-treated mice, and its expression was negatively correlated with SOX17 expression in the retinas of model mice.MiR-194-5p upregulation suppressed Ang II-stimulated HRMEC dysfunction and mitigates the symptoms of HR in mice by regulating the SOX17/VEGF signaling.

Early word learning may get off the ground by mapping words to referents that accompany them. For example, a child might learn the meaning of the word “apple” from hearing “apple” in the presence of apples. However, when a word occurs without a handy referent, the other words that accompany it might provide a rich source of information about its meaning, because words similar in meaning occur in similar contexts of other words. For example, “apple” and “mango” both co-occur with words such as “juicy” and “sweet”. Therefore, a child who has mapped “apple” to apples but has never seen a mango may nonetheless learn that a mango is something similar to an apple from their shared co-occurrence with “juicy” or “sweet”. Thus, it is possible to learn new words by linking them to known words that occur in similar contexts. Such learning might be critical for extending word learning well beyond mapping individual words to referents. However, we know little about the learning mechanisms that support learning new words from context. The current work highlights, implements and contrasts two candidate mechanisms for learning words from context. The goal is to provide a foundation for evaluating whether these mechanisms play important roles in word learning during child development

Pathological cartilage calcification plays an important role in osteoarthritis progression but in which the origin of calcified extracellular vesicles (EVs) and their effects remain unknown. Here, we demonstrate that pathological cartilage calcification occurs in the early stage of the osteoarthritis in which the calcified EVs are closely involved. Autophagosomes carrying the minerals are released in EVs, and calcification is induced by those autophagy-regulated calcified EVs. Autophagy-derived microtubule-associated proteins 1A/1B light chain 3B (LC3)–positive EVs are the major population of calcified EVs that initiate pathological calcification. Release of LC3-positive calcified EVs is caused by blockage of the autophagy flux resulted from histone deacetylase 6 (HDAC6)–mediated microtubule destabilization. Inhibition of HDAC6 activity blocks the release of the LC3-positive calcified EVs by chondrocytes and effectively reverses the pathological calcification and degradation of cartilage. The present work discovers that calcified EVs derived from autophagosomes initiate pathological cartilage calcification in osteoarthritis, with potential therapeutic targeting implication.

Pathological cartilage calcification plays an important role in osteoarthritis progression but in which the origin of calcified extracellular vesicles (EVs) and their effects remain unknown. Here, we demonstrate that pathological cartilage calcification occurs in the early stage of the osteoarthritis in which the calcified EVs are closely involved. Autophagosomes carrying the minerals are released in EVs, and calcification is induced by those autophagy-regulated calcified EVs. Autophagy-derived microtubule-associated proteins 1A/1B light chain 3B (LC3)-positive EVs are the major population of calcified EVs that initiate pathological calcification. Release of LC3-positive calcified EVs is caused by blockage of the autophagy flux resulted from histone deacetylase 6 (HDAC6)-mediated microtubule destabilization. Inhibition of HDAC6 activity blocks the release of the LC3-positive calcified EVs by chondrocytes and effectively reverses the pathological calcification and degradation of cartilage. The present work discovers that calcified EVs derived from autophagosomes initiate pathological cartilage calcification in osteoarthritis, with potential therapeutic targeting implication.

The lack of experienced ophthalmologists limits the early diagnosis of retinal diseases. Artificial intelligence can be an efficient real-time way for screening retinal diseases.To develop and prospectively validate a deep learning (DL) algorithm that, based on ocular fundus images, recognizes numerous retinal diseases simultaneously in clinical practice.This multicenter, diagnostic study at 65 public medical screening centers and hospitals in 19 Chinese provinces included individuals attending annual routine medical examinations and participants of population-based and community-based studies.Based on 120 002 ocular fundus photographs, the Retinal Artificial Intelligence Diagnosis System (RAIDS) was developed to identify 10 retinal diseases. RAIDS was validated in a prospective collected data set, and the performance between RAIDS and ophthalmologists was compared in the data sets of the population-based Beijing Eye Study and the community-based Kailuan Eye Study.The performance of each classifier included sensitivity, specificity, accuracy, F1 score, and Cohen κ score.In the prospective validation data set of 208 758 images collected from 110 784 individuals (median [range] age, 42 [8-87] years; 115 443 [55.3%] female), RAIDS achieved a sensitivity of 89.8% (95% CI, 89.5%-90.1%) to detect any of 10 retinal diseases. RAIDS differentiated 10 retinal diseases with accuracies ranging from 95.3% to 99.9%, without marked differences between medical screening centers and geographical regions in China. Compared with retinal specialists, RAIDS achieved a higher sensitivity for detection of any retinal abnormality (RAIDS, 91.7% [95% CI, 90.6%-92.8%]; certified ophthalmologists, 83.7% [95% CI, 82.1%-85.1%]; junior retinal specialists, 86.4% [95% CI, 84.9%-87.7%]; and senior retinal specialists, 88.5% [95% CI, 87.1%-89.8%]). RAIDS reached a superior or similar diagnostic sensitivity compared with senior retinal specialists in the detection of 7 of 10 retinal diseases (ie, referral diabetic retinopathy, referral possible glaucoma, macular hole, epiretinal macular membrane, hypertensive retinopathy, myelinated fibers, and retinitis pigmentosa). It achieved a performance comparable with the performance by certified ophthalmologists in 2 diseases (ie, age-related macular degeneration and retinal vein occlusion). Compared with ophthalmologists, RAIDS needed 96% to 97% less time for the image assessment.In this diagnostic study, the DL system was associated with accurately distinguishing 10 retinal diseases in real time. This technology may help overcome the lack of experienced ophthalmologists in underdeveloped areas.

Spinosyns, the secondary metabolites produced by Saccharopolyspora spinosa, are the active ingredients in a family of novel biological insecticides. Although the complete genome sequence of S. spinosa has been published, the transcriptome of S. spinosa remains poorly characterized. In this study, high-throughput RNA sequencing (RNA-seq) technology was applied to dissect the transcriptome of S. spinosa. Through transcriptomic analysis of different periods of S. spinosa growth, we found large numbers of differentially expressed genes and classified them according to their different functions. Based on the RNA-seq data, the CRISPR-Cas9 method was used to knock out the PEP phosphonomutase gene (orf 06952-4171). The yield of spinosyns A and D in S. spinosa-ΔPEP was 178.91 mg/L and 42.72 mg/L, which was 2.14-fold and 1.76-fold higher than that in the wild type (83.51 and 24.34 mg/L), respectively. The analysis of the mutant strains also verified the validity of the transcriptome data. The deletion of the PEP phosphonomutase gene leads to an increase in pyruvate content and affects the biosynthesis of spinosad. The replenishment of phosphoenol pyruvate in S. spinosa provides the substrate for the production of spinosad. We envision that these transcriptomic analysis results will contribute to the further study of secondary metabolites in actinomycetes.

Realizing the diagnosis of lung cancer at an inchoate stage is significant to get valuable time to conduct curative surgery. In this work, we relied on a density functional theory (DFT)-proposed Ru-SnS2 monolayer as a novel, promising biosensor for lung cancer diagnosis through exhaled gas analysis. The results indicated that the Ru-SnS2 monolayer has admirable adsorption performance for three typical volatile organic compounds (VOCs) of lung cancer patients, which therefore results in a remarkable change in the electronic behavior of the Ru-doped surface. As a consequence, the conductivity of the Ru-SnS2 monolayer increases after gas adsorption based on frontier molecular orbital theory. This provides the possibility to explore the Ru-SnS2 monolayer as a biosensor for lung cancer diagnosis at an early stage. In addition, the desorption behavior of three VOCs from the Ru-SnS2 surface is studied as well. Our calculations aim at proposing novel sensing nanomaterials for experimentalists to facilitate the progress in lung cancer prognosis.

Butenyl-spinosyn is a highly effective and broad-spectrum biopesticide produced by

The association between clinicopathologic characteristics and the relapse of fibrous gingival hyperplasia is unknown.The records of 211 consecutive patients with a clinicopathologic diagnosis of fibrous gingival hyperplasia were retrieved. Patients who experienced relapse after surgical excision of the lesion were considered case patients (n = 30). All control patients were informed that there was no recurrence (n = 181). Logistic regression was used to evaluate the associations among different characteristics and the recurrence. Stratified analyses on sex was applied to identify the different associations.Binary logistic regression showed that patients with ulcer (odds ratio [OR], 3.23; 95% CI, 1.18 to 8.83) or mechanical stimulation (OR, 2.42; 95% CI, 1.03 to 5.68) had a higher risk of experiencing recurrence. Stratified analysis of sex identified significant association in females (ulcer: OR, 4.04; 95% CI, 1.14 to 14.34; mechanical stimulation: OR, 3.30; 95% CI, 1.15 to 9.42). No significant difference was observed in males (ulcer: OR, 2.44; 95% CI, 0.40 to 15.06; mechanical stimulation: OR, 1.62; 95% CI, 0.28 to 9.40). Male patients with larger epulides had fewer recurrence (OR, 0.13; 95% CI, 0.02 to 0.74). There was no significant difference in pathologic calcification between case and control patients (P.05).Patients with ulcer and mechanical stimulation may have a high risk of experiencing recurrent epulis.More attention should be paid to patients with ulcer and mechanical stimulation. Apart from complete surgical removal, it is important to remove local stimulation to prevent recurrence of these lesions.

Anti-CD20 therapy delays type 1 diabetes mellitus (T1DM) progression in both nonobese diabetic (NOD) mice and new-onset patients. The mechanism is not completely defined. This study aimed to investigate the effects of anti-CD20 therapy on T helper 17 (Th17) cells and regulatory T cells (Tregs) in NOD mice. The role of B cell depletion in T1DM development was also examined.NOD mice were randomly divided into two groups. The mice in the experimental group were treated with an anti-CD20 antibody, while the control mice were treated with an isotype-matched control antibody. After treatment, islet morphology and inflammation, Th17 and Treg cell frequencies in the pancreas and spleen, serum cytokine and anti-glutamic acid decarboxylase (GAD) antibody levels, interleukin (IL)-17A levels in the pancreas and spleen, insulin expression in islet cells and islet β cell function were measured.Decreased blood glucose and increased insulin secretion were found in the exprimental group compared with the CON group. A lower islet inflammation score was also found in the experimental group. Decreased Th17 cell and IL-17A levels and augmented Treg cell levels were found in the spleen and pancreas after anti-CD20 treatment. The serum levels of B cell activating factor (BAFF), IL-17A, IL-17F, IL-23 and anti-GAD autoantibodies were decreased in the experimental group, while higher serum levels of IL-10 and transforming growth factor (TGF)-β were found.Anti-CD20 therapy might have some beneficial effects that improve β cell function by relieving islet inflammation through regulation of Th17/Treg cells and the proinflammatory/anti-inflammatory balance.

Bone metastasis is a common, yet serious, complication of breast cancer. Breast cancer cells that extravasate from blood vessels to the bone devastate bone quality by interacting with bone cells and disrupting the bone remodeling balance. Although exercise is often suggested as a cancer intervention strategy and mechanical loading during exercise is known to regulate bone remodeling, its role in preventing bone metastasis remains unknown. We developed a novel in vitro microfluidic tissue model to investigate the role of osteocytes in the mechanical regulation of breast cancer bone metastasis. Metastatic MDA-MB-231 breast cancer cells were cultured inside a 3D microfluidic lumen lined with human umbilical vein endothelial cells (HUVECs), which is adjacent to a channel seeded with osteocyte-like MLO-Y4 cells. Physiologically relevant oscillatory fluid flow (OFF) (1 Pa, 1 Hz) was applied to mechanically stimulate the osteocytes. Hydrogel-filled side channels in-between the two channels allowed real-time, bi-directional cellular signaling and cancer cell extravasation over 3 days. The applied OFF was capable of inducing intracellular calcium responses in osteocytes (82.3% cells responding with a 3.71 fold increase average magnitude). Both extravasation distance and percentage of extravasated side-channels were significantly reduced with mechanically stimulated osteocytes (32.4% and 53.5% of control, respectively) compared to static osteocytes (102.1% and 107.3% of control, respectively). This is the first microfluidic device that has successfully integrated stimulatory bone fluid flow, and demonstrated that mechanically stimulated osteocytes reduced breast cancer extravasation. Future work with this platform will determine the specific mechanisms involved in osteocyte mechanoregulation of breast cancer bone metastasis, as well as other types of cancer metastasis and diseases.

Intravesical instillation is an efficient drug delivery route for the local treatment of various urological conditions. Nevertheless, intravesical instillation is associated with several challenges, including pain, urological infection, and frequent clinic visits for catheterization; these difficulties support the need for a simple and easy intravesical drug delivery platform. Here, we propose a novel biodegradable intravesical device capable of long-term, local drug delivery without a retrieval procedure. The intravesical device is composed of drug encapsulating biodegradable polycaprolactone (PCL) microcapsules and connected by a bioabsorbable Polydioxanone (PDS) suture with NdFeB magnets in the end. The device is easily inserted into the bladder and forms a 'ring' shape optimized for maximal mechanical stability as informed by finite element analysis. In this study, inserted devices were retained in a swine model for 4 weeks. Using this device, we evaluated the system's capacity for delivery of lidocaine and resiquimod and demonstrated prolonged drug release. Moreover, a cost-effectiveness analysis supports device implementation compared to the standard of care. Our data support that this device can be a versatile drug delivery platform for urologic medications.

Poor oral health status may increase the risk of cardiovascular disease. However, whether a specific association exists between tooth loss and hypertension is inconclusive. Accordingly, a quantitative systematic review was conducted to investigate the relationship between tooth loss and hypertension.Systematic search, data analysis and quality assessment were conducted on relevant literature published in PubMed, Embase, Web of Science and Cochrane Libraries until October 2021. Odds ratio (OR) with 95% confidence interval (CI) was used as effect size to evaluate the association between tooth loss and hypertension. Meta-regression and subgroup analyses were performed to identify whether difference was associated with study-level factors.Of the 56 studies selected, 28 studies in 16 different countries involving 1,224,821 individuals were eligible for the systematic review. After adjustment for confounding factors, individuals with tooth loss had a higher risk for hypertension (OR 1.20; 95%CI 1.10-1.30, IThe results suggest a bidirectional association between tooth loss and hypertension. Future longitudinal prospective studies are required to establish causality between tooth loss and hypertension.Subjects with severe tooth loss should be carefully monitored for the manifestation of hypertension. The oral health status of hypertensive patients should also be meticulous maintained to prevent unwarranted tooth loss.

Intestinal dysbiosis is prominent in systemic sclerosis (SSc), but it remains unknown if and how it contributes to synchronous microvascular injury and fibrosis that characterize this disease. Trimethylamine (TMA) is generated in the gut and converted by flavin-containing monooxygenase (FMO3) to trimethylamine N-oxide (TMAO), which has been implicated in chronic cardiovascular diseases. We now show that TMAO reprograms skin fibroblasts, vascular endothelial cells and adipocytic progenitor cells to myofibroblasts in a process mediated via R-like endoplasmic reticulum kinase (PERK), a TMAO-binding protein. Remarkably, FMO3, principally expressed in the liver, was found also to be present in both isolated skin fibroblasts and in skin explants, and its expression was elevated in pericytes and fibroblasts in SSc skin biopsies and explanted dermal fibroblasts. A TMAO meta-organismal pathway in SSc thus potentially links the gut microbiome to vasculopathy and fibrosis via stromal cell reprogramming, implicating this pathway in pathogenesis, and as a target for therapy.

Spinosyns, the secondary metabolites produced by

Using the Latour system, a hybrid NRPS‐T1PKS cluster (˜20 kb) which was responsible for phthoxazolin biosynthesis was efficiently deleted in S. pogona. A TetR family transcriptional regulatory gene that could regulate the butenyl‐spinosyn biosynthesis has been identified from the phthoxazolin biosynthetic gene cluster., Summary Butenyl‐spinosyn, a promising biopesticide produced by Saccharopolyspora pogona, exhibits stronger insecticidal activity and a broader pesticidal spectrum. However, its titre in the wild‐type S. pogona strain is too low to meet the industrial production requirements. Deletion of non‐target natural product biosynthetic gene clusters resident in the genome of S. pogona could reduce the consumption of synthetic precursors, thereby promoting the biosynthesis of butenyl‐spinosyn. However, it has always been a challenge for scientists to genetically engineer S. pogona. In this study, the Latour gene knockout system (linear DNA fragment recombineering system) was established in S. pogona. Using the Latour system, a hybrid NRPS‐T1PKS cluster (˜20 kb) which was responsible for phthoxazolin biosynthesis was efficiently deleted in S. pogona. The resultant mutant S. pogona‐Δura4‐Δc14 exhibited an extended logarithmic phase, increased biomass and a lower glucose consumption rate. Importantly, the production of butenyl‐spinosyn in S. pogona‐Δura4‐Δc14 was increased by 4.72‐fold compared with that in the wild‐type strain. qRT‐PCR analysis revealed that phthoxazolin biosynthetic gene cluster deletion could promote the expression of the butenyl‐spinosyn biosynthetic gene cluster. Furthermore, a TetR family transcriptional regulatory gene that could regulate the butenyl‐spinosyn biosynthesis has been identified from the phthoxazolin biosynthetic gene cluster. Because dozens of natural product biosynthetic gene clusters exist in the genome of S. pogona, the strategy reported here will be used to further promote the production of butenyl‐spinosyn by deleting other secondary metabolite synthetic gene clusters.

The multi-bounce laser microphone utilizes optical methods to detect the displacement of a gold-covered thin film diaphragm caused by ultrasound signal pressure waves. This sensitive all-optical sensing technique provides new opportunities for advanced ultrasound imaging as it is expected to achieve a higher detection signal-to-noise ratio (SNR) in a broader spectrum, as compared to conventional ultrasonic transducers. The technique does not involve signal time-averaging and the real-time enhancement in detection SNR stems from the amplification of signal strength due to multiple bouncing off the diaphragm. The system was previously developed for detecting acoustic signatures generated by explosives and were limited to lower than 10 kHz in frequency. To demonstrate its feasibility for biomedical imaging applications, preliminary experiments were conducted to show high fidelity detection of ultrasound waves with frequencies ranging from 100 kHz to in excess of 1 MHz. Experimental results are also presented in this work demonstrating the improved detection sensitivity of the multi-bounce laser microphone in detecting ultrasound signals when compared with a commercial Fabry-Perot type optical hydrophone. Furthermore, we also applied the multi-bounce laser microphone to detect photoacoustic signatures emitted by India ink when a LED bar is used as the excitation source without signal averaging.

Background Scleroderma (SSc) is a rare autoimmune disease characterized by vascular impairment and progressive fibrosis of the skin and other organs. Oncostatin M, a member of the IL-6 family, is elevated in SSc serum and was recognized as a significant player in various stages of fibrosis. The goal of this study was to assess the contribution of the OSM/OSMRβ pathway to endothelial cell (EC) injury and activation in SSc. Methods IHC and IF were used to assess the distribution of OSM and OSMRβ in SSc (n = 14) and healthy control (n = 7) skin biopsies. Cell culture experiments were performed in human dermal microvascular endothelial cells (HDMECs) and included mRNA and protein analysis, and cell migration and proliferation assays. Ex vivo skin organoid culture was used to evaluate the effect of OSM on perivascular fibrosis. Results OSMRβ protein was elevated in dermal ECs and in fibroblasts of SSc patients. Treatments of HDMECs with OSM or IL-6+sIL-6R have demonstrated that both cytokines similarly stimulated proinflammatory genes and genes related to endothelial to mesenchymal transition (EndMT). OSM was more effective than IL-6+sIL-6R in inducing cell migration, while both treatments similarly induced cell proliferation. The effects of OSM were mediated via OSMRβ and STAT3, while the LIFR did not contribute to these responses. Both OSM and IL-6+sIL-6R induced profibrotic gene expression in HDMECs, as well as expansion of the perivascular PDGFRβ+ cells in the ex vivo human skin culture system. Additional studies in HDMECs showed that siRNA-mediated downregulation of FLI1 and its close homolog ERG resulted in increased expression of OSMRβ in HDMECs. Conclusions This work provides new insights into the role of the OSM/OSMRβ axis in activation/injury of dermal ECs and supports the involvement of this pathway in SSc vascular disease.

Background: Scleroderma (SSc) is a rare autoimmune disease characterized by vascular impairment and progressive fibrosis of the skin and other organs. Oncostatin M, a member of the IL-6 family, is elevated in SSc serum and was recognized as a significant player in various stages of fibrosis. The goal of this study was to assess the contribution of the OSM/OSMRβ pathway to endothelial cell (EC) injury and activation in SSc. Methods: IHC and IF were used to assess the distribution of OSM and OSMRβ in SSc (n=14) and healthy control (n=7) skin biopsies. Cell culture experiments were performed in human dermal microvascular endothelial cells (HDMECs) and included mRNA and protein analysis, and cell migration and proliferation assays. Ex vivo skin organoid culture was used to evaluate the effect of OSM on perivascular fibrosis.Results: OSMRβ protein was elevated in dermal ECs and in fibroblasts of SSc patients. Treatments of HDMECs with OSM or IL-6 +sIL-6R have demonstrated that both cytokines similarly stimulated proinflammatory genes and genes related to endothelial-to mesenchymal transition ((EndMT). OSM was more effective than IL-6+sIL-6R in inducing cell migration, while both treatments similarly induced cell proliferation. The effects of OSM were mediated via OSMRβ and STAT3, while the LIFR did not contribute to these responses. Both, OSM and IL-6+sIL-6R induced profibrotic gene expression in HDMECs, as well as expansion of the perivascular PDGFRβ+ cells in the ex vivo human skin culture system. Additional studies in HDMECs showed that siRNA-mediated downregulation of FLI1 and its close homolog ERG resulted in increased expression of OSMRβ in HDMECs.Conclusions: This work provides new insights into the role of the OSM/OSMRβ axis in activation/injury of dermal ECs and supports the involvement of this pathway in SSc vascular disease.

Aims To describe characteristics of COVID-19 patients with type 2 diabetes and to analyze risk factors for severity. Methods Demographics, comorbidities, symptoms, laboratory findings, treatments and outcomes of COVID-19 patients with diabetes were collected and analyzed. Results Seventy-four COVID-19 patients with diabetes were included. Twenty-seven patients (36.5%) were severe and 10 patients (13.5%) died. Higher levels of blood glucose, serum amyloid A (SAA), C reactive protein and interleukin 6 were associated with severe patients compared to non-severe ones (P, Highlights • Diabetes is a frequent comorbidity in people with COVID-19, especially in severe cases. • Clinical features of COVID-19 patients with diabetes or risk factors for severity are limited. • Hyperglycemia and dyslipidemia might be associated with severity of COVID-19 patients with type 2 diabetes. • Lower CD4+ T lymphocyte counts and higher SAA levels were independent risk factors for COVID-19 severity. • Aggressive treatments are suggested, especially when these patients had lower CD4+ T lymphocytes and higher SAA levels.