Publications by authors named "Lei Shen"

493 Publications

TDRD3 promotes DHX9 chromatin recruitment and R-loop resolution.

Nucleic Acids Res 2021 Jul 30. Epub 2021 Jul 30.

Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope National Cancer Center, Duarte, CA 91010, USA.

R-loops, which consist of a DNA/RNA hybrid and a displaced single-stranded DNA (ssDNA), are increasingly recognized as critical regulators of chromatin biology. R-loops are particularly enriched at gene promoters, where they play important roles in regulating gene expression. However, the molecular mechanisms that control promoter-associated R-loops remain unclear. The epigenetic 'reader' Tudor domain-containing protein 3 (TDRD3), which recognizes methylarginine marks on histones and on the C-terminal domain of RNA polymerase II, was previously shown to recruit DNA topoisomerase 3B (TOP3B) to relax negatively supercoiled DNA and prevent R-loop formation. Here, we further characterize the function of TDRD3 in R-loop metabolism and introduce the DExH-box helicase 9 (DHX9) as a novel interaction partner of the TDRD3/TOP3B complex. TDRD3 directly interacts with DHX9 via its Tudor domain. This interaction is important for recruiting DHX9 to target gene promoters, where it resolves R-loops in a helicase activity-dependent manner to facilitate gene expression. Additionally, TDRD3 also stimulates the helicase activity of DHX9. This stimulation relies on the OB-fold of TDRD3, which likely binds the ssDNA in the R-loop structure. Thus, DHX9 functions together with TOP3B to suppress promoter-associated R-loops. Collectively, these findings reveal new functions of TDRD3 and provide important mechanistic insights into the regulation of R-loop metabolism.
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http://dx.doi.org/10.1093/nar/gkab642DOI Listing
July 2021

Novel Noncoding RNA CircPTK2 Regulates Lipolysis and Adipogenesis in Cachexia.

Mol Metab 2021 Jul 23:101310. Epub 2021 Jul 23.

Department of General Surgery, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, People's Republic of China. Electronic address:

Objective: Cancer associated cachexia is a devastating pathological symptom characterized by skeletal muscle wasting and fat storage depletion. Circular RNA, a newly discovered class of noncoding RNAs with important roles in regulating lipid metabolism, has not been fully understood in the pathology of cachexia. We aimed to identify circular RNAs that are upregulated in adipose tissues from cachectic patients and explore their function and mechanism in lipid metabolism.

Methods: Whole transcriptome RNA sequencing was applied to screen for differentially expressed circRNAs. Quantitative reverse transcription PCR was applied to detect the expression level of circPTK2 in adipose tissues. Diagnostic value of circPTK2 was evaluated in adipose tissues from patients with or without cachexia. Then, function experiments in vitro and in vivo were performed to evaluate the effects of circPTK2 on lipolysis and adipogenesis. Mechanistically, luciferase reporter assay, RNA immunoprecipitation and fluorescent in situ hybridization were performed to confirm the interaction between circPTK2 and miR-182-5p in adipocyte.

Results: We detected 66 differentially expressed circular RNA candidates and proved that circPTK2 was upregulated in adipose tissues from cachectic patients. Then we identified that circPTK2 was closely related to pathological process of cachexia and could be used as a diagnostic marker. Mechanistically, circPTK2 competitively bound to miR-182-5p and abrogated the suppression on its target gene JAZF1, which finally led to promotion of lipolysis and inhibition of adipogenesis. In vivo experiments demonstrated that overexpression of circPTK2 inhibited adipogenesis and enhanced lipolysis.

Conclusions: Our findings reveal the novel role of circPTK2 in promoting lipolysis and reducing adipogenesis via a ceRNA mechanism and provide a potential diagnostic biomarker and therapeutic target for cancer associated cachexia.
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http://dx.doi.org/10.1016/j.molmet.2021.101310DOI Listing
July 2021

Regional disparity in clinker emission factors and their potential reduction in China.

Environ Sci Pollut Res Int 2021 Jul 23. Epub 2021 Jul 23.

MNR Key Laboratory of Metallogeny and Mineral Assessment, Institute of Mineral Resources, Chinese Academy of Geological Sciences, Beijing, 100037, China.

Detailed analysis the disparity and reduction potential of clinker emission factors at the provincial level is important for regional reduction policies. Using the surveyed data from 185 new suspension and pre-heater (NSP) process lines and 69 shaft kiln lines, this study firstly analyzed the disparity in emission factors based on production process, production scale, and regional distribution in 2015. We found that the emission factor of the shaft kiln process (898.24 kg/t) is higher than that of the NSP process (858.59 kg/t), and that small-scale production lines have higher emission factors than large-scale lines both for the two process. China's clinker emission factors increase from the eastern to the western regions. Then, we estimated the reduction potential of structural adjustment, raw material substitution, and energy saving and fuel substitution in regional emission factors by 2030. The result shows that emission factors of the surveyed provinces will decrease by 101.41-174.60 kg/t compared to the values in 2015, which mainly contributes by energy saving and fuel substitution (65.98%), and raw material substitution (25.72%). And structural adjustment contributes only a small part reduction for most investigated provinces. The national average emission factor is estimated to be 715.33 kg/t in 2030, which indicates a reduction of 16.65%. These results can provide valuable feedback to government officials on the effectiveness of existing measures and also serve as a reference for future decisions on emission reduction polices.
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http://dx.doi.org/10.1007/s11356-021-15415-yDOI Listing
July 2021

A resident stromal cell population actively restrains innate immune response in the propagation phase of colitis pathogenesis in mice.

Sci Transl Med 2021 Jul;13(603)

Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.

Inflammatory bowel disease (IBD) affects 0.3% of the global population, yet the etiology remains poorly understood. Anti-inflammation therapy has shown great success, but only 60% of patients with IBD benefit from it, indicating that new targets are needed. Here, we report the discovery of an intrinsic counter regulatory mechanism in colitis pathogenesis that may be targeted for IBD treatment. In response to microbial invasion, resident Vimentin stromal cells, connective tissue cells genetically marked by Twist2, are activated during the propagation phase of the disease, but not during initiation and resolution phases, and become a primary source of prostaglandin E (PGE). PGE induction requires a nuclear factor κB-independent, TLR4-p38MAPK-Cox2 pathway activation. Ablation of each of the pathway genes, but not or , in Twist2 cells enhanced M1 macrophage polarization and granulocyte/T helper 1 (T1)/T17 infiltration and aggravated colitis development. PGE administration ameliorated colitis in mouse models with defective PGE production but not in animals with normal PGE induction. Analysis of clinical samples and public domain data revealed increased expression of Cox2, the rate-limiting enzyme of PGE biosynthesis, in inflamed tissues, and especially in colon VimentinTwist2 stromal cells, in about 60% of patients with active Crohn's disease or ulcerative colitis. Moreover, Cox2 protein expression was negatively correlated with disease severity, suggesting an involvement of stromal cells in IBD pathogenesis. Thus, the study uncovers an active immune pathway in colitic inflammation that may be targeted to treat patients with IBD with defects in PGE production.
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http://dx.doi.org/10.1126/scitranslmed.abb5071DOI Listing
July 2021

Application of linked color imaging in the diagnosis of early gastrointestinal neoplasms and precancerous lesions: a review.

Therap Adv Gastroenterol 2021 6;14:17562848211025925. Epub 2021 Jul 6.

Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.

Introduction: Minimally invasive endoscopic resection is often effective in the management of early gastrointestinal tumors. However, advanced and more effective methods of endoscopic examination are required to improve the rate of diagnosing early gastrointestinal tumors.

Discussion: The development of dye-based image-enhanced endoscopy (d-IEE) and equipment-based image-enhanced endoscopy (e-IEE) has helped improve the diagnostic rate of early gastrointestinal tumor using endoscopy. In some special cases, these methods are still not accurate in diagnosing lesions. On the basis of these e-IEEs, a new endoscopic technique, linked color imaging (LCI), that combines a specific short wavelength narrow band of light with white light, has been developed.

Conclusion: In this article, we summarized the characteristics of LCI and the development of research regarding digestive tract examination.

Plain Language Summary: At present, the complete diagnosis of early gastrointestinal tumors and precancerous lesions can be made by gastrointestinal endoscopy. With the improvement of therapeutic instruments and operators' experience, endoscopic therapy can often achieve significant effect in the treatment of early gastrointestinal tumors. The development and spread of equipment-based image-enhanced endoscopy (e-IEE) mode has helped improve the diagnosis rate of early gastrointestinal tumors under endoscopy. However, in some special cases, these methods are still not accurate for the diagnosis of lesions. On the basis of these E-IEEs, a new endoscopic technique, linked color imaging (LCI), has been developed, which combines a specific short wavelength narrow band of light with white light. LCI can significantly improve the diagnostic rate of all types of gastrointestinal mucosal lesions. Tumor lesions and inflammatory lesions can be distinguished by observing the mucosal microvascular structure and color difference. LCI helps detect early gastrointestinal mucosal lesions by taking advantage of the differences in light absorption of different wavelengths and contrast of enhanced colors in the later stage.
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http://dx.doi.org/10.1177/17562848211025925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264738PMC
July 2021

Mode converter with C+L band coverage based on the femtosecond laser inscribed long period fiber grating.

Opt Lett 2021 Jul;46(14):3340-3343

The mode converter (MC) is one of the key components for mode division multiplexing (MDM). Here, we experimentally demonstrate an all-fiber long period grating (LPG) based MC inscribed in the few-mode fiber (FMF) with the line-by-line femtosecond laser irradiation technique. Experimental characterization results agree well with the theoretical calculations, and a clear mode evolution from the mode to the mode is observed with the tuning of the operation wavelength. An average mode conversion efficiency of more than 90% and an average insertion loss of less than 5 dB, together with a polarization-dependent loss of less than 3 dB, are achieved over the C+L band with a good repeatability. The proposed MC based on the LPG inscribed into the FMF has the advantages of mode scalability, compact size, and wideband operation, which is desired for the wavelength division multiplexing (WDM) and MDM hybrid transmission.
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http://dx.doi.org/10.1364/OL.431760DOI Listing
July 2021

Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19.

N Engl J Med 2021 Jul 14. Epub 2021 Jul 14.

From Massachusetts General Hospital and Harvard Medical School, Boston (M. Dougan); Eli Lilly (A.N., A.C.A., J.V.N., K.L.C., M. Durante, G.O., A.E.S., T.R.H., P.J.E., R.E.H., N.L.K., J.S., D.R.P., M.C.D., P. Klekotka, L.S., D.M.S.), and Franciscan Health (I.S.) - both in Indianapolis; Valley Clinical Trials-Northridge, Northridge (M.A.), the Department of Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles (P.C.), and Long Beach Clinical Trials, Long Beach (B.H.) - all in California; the Las Vegas Medical Research Center, Las Vegas (B.M.); Baylor University Medical Center and Baylor Scott and White Research Institute, Dallas (R.L.G.), and Gadolin Research, Beaumont (R.P.) - both in Texas; NOLA Research Works, New Orleans (C.H.), and Clinical Trials of Southwest Louisiana, Lake Charles (J.M.) - both in Louisiana; Vitalink Research, Union, SC (J.B.); Eastside Research Associates, Redmond, WA (C.C.); Monroe Biomedical Research, Monroe, NC (A.I.); Cook County Health, Chicago (G.H.); Indago Research and Health Center, Hialeah, FL (J.C.); and Georgetown University, Washington, DC (P. Kumar).

Background: Patients with underlying medical conditions are at increased risk for severe coronavirus disease 2019 (Covid-19). Whereas vaccine-derived immunity develops over time, neutralizing monoclonal-antibody treatment provides immediate, passive immunity and may limit disease progression and complications.

Methods: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, a cohort of ambulatory patients with mild or moderate Covid-19 who were at high risk for progression to severe disease to receive a single intravenous infusion of either a neutralizing monoclonal-antibody combination agent (2800 mg of bamlanivimab and 2800 mg of etesevimab, administered together) or placebo within 3 days after a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The primary outcome was the overall clinical status of the patients, defined as Covid-19-related hospitalization or death from any cause by day 29.

Results: A total of 1035 patients underwent randomization and received an infusion of bamlanivimab-etesevimab or placebo. The mean (±SD) age of the patients was 53.8±16.8 years, and 52.0% were adolescent girls or women. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab-etesevimab group had a Covid-19-related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, -4.8 percentage points; 95% confidence interval [CI], -7.4 to -2.3; relative risk difference, 70%; P<0.001). No deaths occurred in the bamlanivimab-etesevimab group; in the placebo group, 10 deaths occurred, 9 of which were designated by the trial investigators as Covid-19-related. At day 7, a greater reduction from baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab than among those who received placebo (difference from placebo in the change from baseline, -1.20; 95% CI, -1.46 to -0.94; P<0.001).

Conclusions: Among high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of Covid-19-related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501.).
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http://dx.doi.org/10.1056/NEJMoa2102685DOI Listing
July 2021

Quasi-Paired Pt Atomic Sites on Mo C Promoting Selective Four-Electron Oxygen Reduction.

Adv Sci (Weinh) 2021 Jul 14:e2101344. Epub 2021 Jul 14.

Department of Materials Science and Engineering, National University of Singapore, Singapore, 117574, Singapore.

Atomically dispersed Pt species are advocated as a promising electrocatalyst for the oxygen reduction reaction (ORR) to boost noble metal utilization efficiency. However, when assembled on various substrates, isolated Pt single atoms are often demonstrated to proceed through the two-electron ORR pathway due to the unfavorable O─O bond cleavage thermodynamics in the absence of catalytic ensemble sites. In addition, although their distinct local coordination environments at the exact single active sites are intensively explored, the interactions and synergy between closely neighboring single atom sites remain elusive. Herein, atomically dispersed Pt monomers strongly interacting on a Mo C support is demonstrated as a model catalyst in the four-electron ORR, and the beneficial interactions between two closely neighboring and yet non-contiguous Pt single atom sites (named as quasi-paired Pt single atoms) are shown. Compared to isolated Pt single atom sites, the quasi-paired Pt single atoms deliver a superior mass activity of 0.224 A mg and near-100% selectivity toward four-electron ORR due to the synergistic interaction from the two quasi-paired Pt atom sites in modulating the binding mode of reaction intermediates. Our first-principles calculations reveal a unique mechanism of such quasi-paired configuration for promoting four-electron ORR.
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http://dx.doi.org/10.1002/advs.202101344DOI Listing
July 2021

Bending-loss-resistant distributed Brillouin curvature sensor based on an erbium-doped few-mode fiber.

Opt Lett 2021 Jul;46(13):3239-3242

We developed a bending-loss-resistant distributed Brillouin curvature sensor based on an erbium-doped few-mode fiber (Er-FMF) and differential pulse-width pair Brillouin optical time-domain analysis. With Er ion amplification compensating for bending-induced optical loss, radii in the ∼0.3 to 2.02 cm range could be monitored correctly. The corresponding Brillouin frequency shift variations were in the range of 91.7 to 9 MHz, which agrees well with theoretical calculations. The sensitivity of the Er-FMF device increased inversely with the bending radius, with the optimal sensitivity of 292.7 MHz/cm obtained at a radius of 0.3 cm. To the best of our knowledge, this is the smallest radius of curvature detected and highest sensitivity reported to date, indicating potential applications in distributed sharp-bend sensing, such as intelligent robotics and structural health monitoring.
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http://dx.doi.org/10.1364/OL.426957DOI Listing
July 2021

Diagnostic value of nuclear medicine imaging and ultrasonography in subacute thyroiditis.

Am J Transl Res 2021 15;13(5):5629-5634. Epub 2021 May 15.

Department of Ultrasound, The Second People's Hospital of Dongying Dongying, Shandong Province, China.

Objective: To analyze and compare the diagnostic value of nuclear medicine and ultrasonography in subacute thyroiditis.

Methods: Sixty patients with subacute thyroiditis admitted to our hospital were included into the observation group, and 60 healthy controls who underwent physical examination in our hospital during the same period were enrolled into the control group. Examinations of nuclear medicine and ultrasonography were performed in the neck, and the results were compared between the two groups.

Results: There were significant differences in the width and thickness of thyroid bilateral lobes between the two groups (P<0.05), and for patients in the observation group, the detection rates of nuclear medicine technique and ultrasonography were 98.33% and 95.00%, respectively. Both methods showed no significant difference in the detection rate of subacute thyroiditis (P>0.05).

Conclusion: Both nuclear medicine imaging and ultrasonography can provide clinical guidance for diagnosis and treatment of subacute thyroiditis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205701PMC
May 2021

Effluent Osteopontin levels reflect the peritoneal solute transport rate.

Open Med (Wars) 2021 7;16(1):847-853. Epub 2021 Jun 7.

Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People's Republic of China.

Long-term peritoneal dialysis (PD) is accompanied by low-grade intraperitoneal inflammation and may eventually lead to peritoneal membrane injury with a high solute transport rate and ultrafiltration failure. Osteopontin (OPN) is highly expressed through the stimulation of pro-inflammatory cytokines in many cell types. This study aimed to investigate the potential of OPN as a new indicator of peritoneal deterioration. One hundred nine continuous ambulatory PD patients were analyzed. The levels of OPN and IL-6 in peritoneal effluents or serum were analyzed by ELISA kits. The mean effluent OPN concentration was 2.39 ± 1.87 ng/mL. The OPN levels in drained dialysate were correlated with D/P Cr ( < 0.0001, = 0.54) and D/D0 glucose ( < 0.0001, = 0.39). Logistic regression analysis showed that the OPN levels in peritoneal effluents were an independent predictive factor for the increased peritoneal solute transport rate (PSTR) obtained by the peritoneal equilibration test ( < 0.001). The area under the receiver operating characteristic curve of OPN was 0.84 (95% CI: 0.75-0.92) in predicting the increased PSTR with a sensitivity of 86% and a specificity of 67%. The joint utilization of effluent OPN with age, effluent IL-6, and serum albumin further increased the specificity (81%). Thus, OPN may be a useful indicator of peritoneal deterioration in patients with PD.
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http://dx.doi.org/10.1515/med-2021-0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186560PMC
June 2021

Simple and precise characterization of differential modal group delay arising in few-mode fiber.

Opt Lett 2021 Jun;46(12):2856-2859

In this Letter, we propose a simple and high-precision differential modal group delay (DMGD) characterization method for few-mode fibers (FMF) by using the frequency-modulated continuous wave. Since the detected signals are located at the low-frequency range, our DMGD characterization method waives the use of expensive equipment, such as vector network or optical spectrum analyzers. Due to the high linearity of the used Mach-Zehnder modulator, our DMGD measurement is free from the complex auxiliary interferometer, leading to an improvement of characterization precision. Meanwhile, we propose a novel spectrum recovery algorithm to overcome the shortcoming that the traditional fast Fourier transform (FFT) method is incapable to deal with spectrum features arising in a periodic signal. Therefore, the characterization precision is no longer limited by the FFT length. When a commercial 23299.8 m two-mode fiber is used in the experiment, the DMGD measurement of mode relative to mode has a high precision of ±0.007/ over the C-band. Our proposed method shows the potential for characterizing the wavelength-dependent DMGD of FMF with more than two LP modes.
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http://dx.doi.org/10.1364/OL.423950DOI Listing
June 2021

MicroRNA-296-5p inhibits cell proliferation by targeting HMGA1 in colorectal cancer.

Exp Ther Med 2021 Aug 24;22(2):793. Epub 2021 May 24.

The Medical Department of the Xiamen University, Xiamen, Fujian 361000, P.R. China.

An increasing body of evidence indicates the involvement of microRNAs (miRNAs/miRs) in the initiation and progression of colorectal cancer (CRC). miR-296-5p was recently identified as a tumor suppressor in a variety of human cancer types; however, its function in CRC remains largely unknown. The present study demonstrated that the expression of miR-296-5p was significantly downregulated in CRC tissues and cell lines. The overexpression of miR-296-5p markedly inhibited proliferation, and induced cell cycle arrest and apoptosis in CRC cells. Bioinformatics analysis suggested that high mobility group AT-hook 1 (HMGA1) may be a target of miR-296-5p in CRC cells. Further experiments showed that miR-296-5p bound the 3'-untranslated region of HMGA1 and decreased its expression in CRC cells. HMGA1 was overexpressed in CRC tissues and was inversely correlated with the expression of miR-296-5p. The restoration of HMGA1 significantly reversed the inhibitory effect of miR-296-5p on the proliferation of CRC cells. Overall, the findings of the present study indicate that miR-296-5p suppressed the progression of CRC, at least partially via targeting HMGA1. Thus, miR-296-5p is a potential target for novel therapies in CRC.
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http://dx.doi.org/10.3892/etm.2021.10225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170657PMC
August 2021

Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial.

JAMA 2021 07;326(1):46-55

Eli Lilly and Co, Indianapolis, Indiana.

Importance: Preventive interventions are needed to protect residents and staff of skilled nursing and assisted living facilities from COVID-19 during outbreaks in their facilities. Bamlanivimab, a neutralizing monoclonal antibody against SARS-CoV-2, may confer rapid protection from SARS-CoV-2 infection and COVID-19.

Objective: To determine the effect of bamlanivimab on the incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities.

Design, Setting, And Participants: Randomized, double-blind, single-dose, phase 3 trial that enrolled residents and staff of 74 skilled nursing and assisted living facilities in the United States with at least 1 confirmed SARS-CoV-2 index case. A total of 1175 participants enrolled in the study from August 2 to November 20, 2020. Database lock was triggered on January 13, 2021, when all participants reached study day 57.

Interventions: Participants were randomized to receive a single intravenous infusion of bamlanivimab, 4200 mg (n = 588), or placebo (n = 587).

Main Outcomes And Measures: The primary outcome was incidence of COVID-19, defined as the detection of SARS-CoV-2 by reverse transcriptase-polymerase chain reaction and mild or worse disease severity within 21 days of detection, within 8 weeks of randomization. Key secondary outcomes included incidence of moderate or worse COVID-19 severity and incidence of SARS-CoV-2 infection.

Results: The prevention population comprised a total of 966 participants (666 staff and 300 residents) who were negative at baseline for SARS-CoV-2 infection and serology (mean age, 53.0 [range, 18-104] years; 722 [74.7%] women). Bamlanivimab significantly reduced the incidence of COVID-19 in the prevention population compared with placebo (8.5% vs 15.2%; odds ratio, 0.43 [95% CI, 0.28-0.68]; P < .001; absolute risk difference, -6.6 [95% CI, -10.7 to -2.6] percentage points). Five deaths attributed to COVID-19 were reported by day 57; all occurred in the placebo group. Among 1175 participants who received study product (safety population), the rate of participants with adverse events was 20.1% in the bamlanivimab group and 18.9% in the placebo group. The most common adverse events were urinary tract infection (reported by 12 participants [2%] who received bamlanivimab and 14 [2.4%] who received placebo) and hypertension (reported by 7 participants [1.2%] who received bamlanivimab and 10 [1.7%] who received placebo).

Conclusions And Relevance: Among residents and staff in skilled nursing and assisted living facilities, treatment during August-November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection. Further research is needed to assess preventive efficacy with current patterns of viral strains with combination monoclonal antibody therapy.

Trial Registration: ClinicalTrials.gov Identifier: NCT04497987.
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http://dx.doi.org/10.1001/jama.2021.8828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176388PMC
July 2021

Effect of Acetylene Links on Electronic and Optical Properties of Semiconducting Graphynes.

ACS Omega 2021 Apr 19;6(16):10997-11004. Epub 2021 Apr 19.

Department of Mechanic Engineering & Engineering Science, National University of Singapore, Singapore 117575, Singapore.

The family of graphynes, novel two-dimensional semiconductors with various and fascinating chemical and physical properties, has attracted great interest from both scientific and industrial communities. Currently, the focus is on graphdiyne or graphyne-2. In this work, we systematically study the effect of acetylene, i.e., carbon-carbon triple bond, links on the electronic and optical properties of a series of graphynes (graphyne-, where = 1-5, the number of acetylene bonds) using ab initio calculations. We find an even-odd pattern, i.e., = 1, 3, 5 and = 2, 4 having different features, which has not been discovered in studying graphyne or graphdiyne alone. It is found that as the number of acetylene bonds increases, the electron effective mass increases continuously in the low-energy range because of the flatter conduction band induced by the longer acetylene links. Meanwhile, longer acetylene links result in a larger red shift of the imaginary part of the dielectric function, loss function, and extinction coefficient. In this work, we propose an effective method to tune and manipulate both the electronic and optical properties of graphynes for the applications in optoelectronic devices and photochemical catalysis.
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http://dx.doi.org/10.1021/acsomega.1c00840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153916PMC
April 2021

Probing of the internal damage morphology in multilayered high-temperature superconducting wires.

Nat Commun 2021 May 25;12(1):3110. Epub 2021 May 25.

Key Laboratory of Mechanics on Disaster and Environment in Western China attached to the Ministry of Education of China, Lanzhou University, Lanzhou, Gansu, PR China.

The second generation HTS wires have been used in many superconducting components of electrical engineering after they were fabricated. New challenge what we face to is how the damages occur in such wires with multi-layer structure under both mechanical and extreme environment, which also dominates their quality. In this work, a macroscale technique combined a real-time magneto-optical imaging with a cryogenic uniaxial-tensile loading system was established to investigate the damage behavior accompanied with magnetic flux evolution. Under a low speed of tensile strain, it was found that the local magnetic flux moves gradually to form intermittent multi-stack spindle penetrations, which corresponds to the cracks initiated from substrate and extend along both tape thickness and width directions, where the amorphous phases at the tip of cracks were also observed. The obtained results reveal the mechanism of damage formation and provide a potential orientation for improving mechanical quality of these wires.
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http://dx.doi.org/10.1038/s41467-021-23487-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149865PMC
May 2021

Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response.

Cell Discov 2021 May 25;7(1):36. Epub 2021 May 25.

State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

The current pathological and molecular classification of pancreatic ductal adenocarcinoma (PDAC) provides limited guidance for treatment options, especially for immunotherapy. Cancer-associated fibroblasts (CAFs) are major players of desmoplastic stroma in PDAC, modulating tumor progression and therapeutic response. Using single-cell RNA sequencing, we explored the intertumoral heterogeneity among PDAC patients with different degrees of desmoplasia. We found substantial intertumoral heterogeneity in CAFs, ductal cancer cells, and immune cells between the extremely dense and loose types of PDACs (dense-type, high desmoplasia; loose-type, low desmoplasia). Notably, no difference in CAF abundance was detected, but a novel subtype of CAFs with a highly activated metabolic state (meCAFs) was found in loose-type PDAC compared to dense-type PDAC. MeCAFs had highly active glycolysis, whereas the corresponding cancer cells used oxidative phosphorylation as a major metabolic mode rather than glycolysis. We found that the proportion and activity of immune cells were much higher in loose-type PDAC than in dense-type PDAC. Then, the clinical significance of the CAF subtypes was further validated in our PDAC cohort and a public database. PDAC patients with abundant meCAFs had a higher risk of metastasis and a poor prognosis but showed a dramatically better response to immunotherapy (64.71% objective response rate, one complete response). We characterized the intertumoral heterogeneity of cellular components, immune activity, and metabolic status between dense- and loose-type PDACs and identified meCAFs as a novel CAF subtype critical for PDAC progression and the susceptibility to immunotherapy.
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http://dx.doi.org/10.1038/s41421-021-00271-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149399PMC
May 2021

Derivation and validation of a nomogram model for pulmonary thromboembolism in patients undergoing lung cancer surgery.

Transl Lung Cancer Res 2021 Apr;10(4):1829-1840

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Background: A specific risk-stratification tool is needed to facilitate safe and cost-effective approaches to the prophylaxis of acute pulmonary thromboembolism (PTE) in lung cancer surgery patients. This study aimed to develop and validate a simple nomogram model for the prediction of PTE after lung cancer surgery using readily obtainable clinical characteristics.

Methods: A total of 14,427 consecutive adult patients who underwent lung cancer surgery between January 2015 and July 2018 in our institution were retrospectively reviewed. Included in the cohort were 136 patients who developed PTE and 544 non-PTE patients. The patients were randomly divided into the derivation group (70%, 95 PTE patients and 380 non-PTE patients) and the validation group (30%, 41 PTE patients and 164 non-PTE patients). A nomogram model was developed based on the results of multivariate logistic analysis in the derivation group. The cut-off values were defined using Youden's index. The prognostic accuracy was measured by area under the curve (AUC) values.

Results: In the derivation group, multivariate logistic analysis was carried out to evaluate the risk score. The risk assessment model contained five variables: age [95% confidence interval (CI): 1.008-1.083, P=0.016], body mass index (95% CI: 1.077-1.319, P=0.001), operation time (95% CI: 1.002-1.014, P=0.008), the serum level of cancer antigen 15-3 (CA15-3) before surgery (95% CI: 1.019-1.111, P=0.005), and the abnormal results of compression venous ultrasonography before surgery (95% CI: 2.819-18.838, P<0.001). All of them were independent risk factors of PTE. To simplify the risk assessment model, a nomogram model was established, which showed a good predictive performance in the derivation group (AUC 0.792, 95% CI: 0.734-0.853) and in the validation group (AUC 0.813, 95% CI: 0.737-0.890).

Conclusions: A high-performance nomogram was established on the risk factors for PTE in patients undergoing lung cancer surgery. The nomogram could be used to provide an individual risk assessment and guide prophylaxis decisions for patients. Further external validation of the model is needed in lung cancer surgery patients in other clinical centers.
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http://dx.doi.org/10.21037/tlcr-21-109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107740PMC
April 2021

Risk Factors and Anticoagulation Therapy in Patients With Isolated Distal Deep Vein Thrombosis in the Early Post-operative Period After Thoracic Surgery.

Front Surg 2021 28;8:671165. Epub 2021 Apr 28.

Department of Ultrasound, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Isolated distal deep vein thrombosis (IDDVT) accounts for ~50% of all patients diagnosed with deep venous thrombosis (DVT), but the diagnosis and optimal management of IDDVT remains unclear and controversial. The aim of this study was to explore potential risk factors and predictors of IDDVT, and to evaluate different strategies of anticoagulation therapy. A total of 310 consecutive patients after thoracic surgery, who underwent whole-leg ultrasonography as well as routine measurements of D-dimer levels before and after surgery were evaluated. The general clinical data, anticoagulant therapy, pre- and postoperative D-dimer levels were collected. Differences between IDDVT, DVT and non-DVT groups were calculated. Logistic regression analysis was used to analyze risk factors of postoperative IDDVT. Age and postoperative D-dimer levels were significantly higher in IDDVT group than in non DVT group ( = 0.0053 and < 0.001, respectively). Logistic regression analysis showed that postoperative D-dimer level was a significant independent predictor of IDDVT even when adjusted for age and operation method ( = 0.0003). There were no significant side effects associated with both full-dose and half-dose anticoagulation regimens. Half-dose therapy was associated with a significant decrease in the requirement for anticoagulation medications after discharge ( = 0.0002). Age and D-dimer levels after surgery are strong predictors of IDDVT following thoracic surgery. Half-dose therapeutic anticoagulation has the same efficiency in preventing IDDVT progression, is not associated with any additional risks of adverse effects compared to a full-dose regimen, and may be adopted for treating IDDVT patients after thoracic surgery.
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http://dx.doi.org/10.3389/fsurg.2021.671165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113622PMC
April 2021

Noninvasive detection of human dehydroepiandrosterone, progesterone and testosterone using LC-MS/MS revealed effects of birth control pills/devices and body weight on ovulatory prediction.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Jun 21;1174:122716. Epub 2021 Apr 21.

Wadsworth Center, New York State Department of Health, Albany, NY, United States; Department of Pathology, Upstate Medical University, Syracuse, NY, United States. Electronic address:

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been increasingly used to measure steroids in human saliva. We studied the performance of a conventional LC-MS/MS for measuring dehydroepiandrosterone (DHEA), testosterone and progesterone in human saliva. These three steroids were co-extracted by liquid-liquid extraction and derivatized. Derivatives were resolved on a C18 column and quantified using an LC-MS/MS (AB Sciex API 2000) instrument. The assay's limits of quantification were 0.03 ng/mL for all three steroids. Inter-assay coefficients of variation were 16.6-18.8% (DHEA), 12.0-15.8% (testosterone), and 12.7-19.3% (progesterone). Assay linearity analysis showed R of 0.9926, 0.9750 and 0.9949 for DHEA, testosterone and progesterone, respectively. No carry-over between samplings was observed. An ion-enhancement effect of 11.6% for DHEA determination and ion-suppression effects of 13.9% and 20.7% for analysis of progesterone and testosterone, respectively, were determined. No interferences by 9 steroid analogs were detected. Spiked recoveries were 85.5% (DHEA), 86.5% (testosterone), and 92.6% (progesterone). Comparison with laboratory developed test (LDT)-LC-MS/MS methods by other New York State Department of Health certified laboratories revealed R = 0.9425 (DHEA, LC-MS/MS = 1.0267 LDT + 21.989), R = 0.9849 (testosterone, LC-MS/MS = 0.9447 LDT + 9.8037), and R = 0.9736 (progesterone, LC-MS/MS = 1.1196 LDT + 0.0985). Reference intervals for the 3 steroids in saliva for young males and females were estimated. Results of intra-individual salivary progesterone analysis indicated that caution should be exercised when using progesterone concentrations in predicting ovulation for females who are under treatment with birth control pills/devices or has body a weight of > 90 kg.
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http://dx.doi.org/10.1016/j.jchromb.2021.122716DOI Listing
June 2021

Pepper NAC-type transcription factor NAC2c Balances the Trade-off Between Growth and Defense Responses.

Plant Physiol 2021 Apr 26. Epub 2021 Apr 26.

Key Laboratory of Applied Genetics of universities in Fujian Province, Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, China.

Plant responses to pathogen attacks and to high temperature stress (HTS) are distinct in nature but generally share several signaling components. How plants produce specific responses through these common signaling intermediates remains elusive. With the help of reverse-genetics approaches, we describe here the mechanism underlying trade-offs in pepper (Capsicum annuum) between growth, immunity and thermotolerance. The NAC-type transcription factor CaNAC2c was induced by HTS and Ralstonia solanacearum infection (RSI). CaNAC2c inhibited pepper growth, promoted immunity against RSI by activating jasmonate-mediated immunity and H2O2 accumulation, and promoted HTS responses by activating Heat shock factor A5 (CaHSFA5) transcription and blocking H2O2 accumulation. We show that CaNAC2c physically interacts with CaHSP70 and CaNAC029 in a context-specific manner. Upon HTS, CaNAC2c-CaHSP70 interaction in the nucleus protected CaNAC2c from degradation and resulted in the activation of thermotolerance by increasing CaNAC2c binding and transcriptional activation of its target promoters. CaNAC2c did not induce immunity-related genes under HTS, likely due to the degradation of CaNAC029 by the 26S proteasome. Upon RSI, CaNAC2c interacted with CaNAC029 in the nucleus and activated jasmonate-mediated immunity but was prevented from activating thermotolerance-related genes. In non-stressed plants, CaNAC2c was tethered outside the nucleus by interaction with CaHSP70, and thus was unable to activate either immunity or thermotolerance. Our results indicate that pepper growth, immunity and thermotolerance are coordinately and tightly regulated by CaNAC2c via its inducible expression and differential interaction with CaHSP70 and CaNAC029.
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http://dx.doi.org/10.1093/plphys/kiab190DOI Listing
April 2021

Paracrine interleukin-8 affects mesenchymal stem cells through the Akt pathway and enhances human umbilical vein endothelial cell proliferation and migration.

Biosci Rep 2021 May;41(5)

Department of Anatomy, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, P.R. China.

Interleukin-8 (IL-8) promotes cell homing and angiogenesis, but its effects on activating human bone marrow mesenchymal stem cells (BMSCs) and promoting angiogenesis are unclear. We used bioinformatics to predict these processes. In vitro, BMSCs were stimulated in a high-glucose (HG) environment with 50 or 100 μg/ml IL-8 was used as the IL-8 group. A total of 5 μmol/l Triciribine was added to the two IL-8 groups as the Akt inhibitor group. Cultured human umbilical vein endothelial cells (HUVECs) were cultured in BMSCs conditioned medium (CM). The changes in proliferation, apoptosis, migration ability and levels of VEGF and IL-6 in HUVECs were observed in each group. Seventy processes and 26 pathways were involved in vascular development, through which IL-8 affected BMSCs. Compared with the HG control group, HUVEC proliferation absorbance value (A value), Gap closure rate, and Transwell cell migration rate in the IL-8 50 and IL-8 100 CM groups were significantly increased (P<0.01, n=30). However, HUVEC apoptosis was significantly decreased (P<0.01, n=30). Akt and phospho-Akt (P-Akt) protein contents in lysates of BMSCs treated with IL-8, as well as VEGF and IL-6 protein contents in the supernatant of BMSCs treated with IL-8, were all highly expressed (P<0.01, n=15). These analyses confirmed that IL-8 promoted the expression of 41 core proteins in BMSCs through the PI3K Akt pathway, which could promote the proliferation and migration of vascular endothelial cells. Therefore, in an HG environment, IL-8 activated the Akt signaling pathway, promoted paracrine mechanisms of BMSCs, and improved the proliferation and migration of HUVECs.
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http://dx.doi.org/10.1042/BSR20210198DOI Listing
May 2021

Pristimerin reduces dextran sulfate sodium-induced colitis in mice by inhibiting microRNA-155.

Int Immunopharmacol 2021 May 23;94:107491. Epub 2021 Mar 23.

Renmin Hospital of Wuhan University, Hubei Key Laboratory of Digestive System Disease, Wuhan 430060, Hubei Province, China. Electronic address:

Pristimerin (Pris), which is a natural triterpenoid compound extracted from the Celastraceae plant, has an effect on intestinal inflammation, but its mechanism needs further study. Human genome-wide analysis found that the expression of microRNA-155 in the blood and colon tissue of patients with IBD was increased. Therefore, we studied the effect of Pris on a model of DSS-induced colitis in mice and investigated whether Pris inhibited the expression of microRNA-155. We obtained a mouse model of acute experimental colitis by allowing the mice to drink a 3% by mass DSS solution freely for 7 days. Pris solutions at different concentrations were injected via the abdomen to simulate the therapeutic effect of Pris on colitis. The body weight and faeces were measured and recorded daily. The mice were sacrificed by the cervical dislocation method after the experiment, and the colon length and histological changes, as well as the changes in Nrf2 in the colon tissue, were measured. The activities of the antioxidant enzymes GSH, GSH-Px and SOD were examined. The expression levels of microRNA-155, IL-1β, IL-6, IL-17, and TNF-α in the colon were detected by RT-PCR technology, and the expression of NF-κB p65 in the colon was detected by western blotting. Our study shows that Pris can reduce the DAI score, obviously alleviate weight loss, and decrease the colon pathological tissue damage caused by DSS. Pris can inhibit the increase in microRNA-155 expression induced by DSS-induced colitis. Our study has shown that Pris may reduce DSS-induced colitis in mice by inhibiting the expression of microRNA-155, and further inhibition of the inflammatory response and oxidative stress occurred.
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http://dx.doi.org/10.1016/j.intimp.2021.107491DOI Listing
May 2021

Effectiveness and Safety of Hwangchil-Unripe Bokbunja Extract Mixture on Blood Pressure: A Randomized Double-Blind Placebo-Controlled Clinical Trial.

J Med Food 2021 Mar;24(3):258-266

Department of Sasang Constitutional Medicine, College of Korean Medicine, Woosuk University, Jeonju, Korea.

From 25% to 50% of adults are affected by prehypertension. Prehypertension increases the risk of hypertension and affects the heart and systemic vascular system. Food mixed tree essence of called Hwangchil in Korean and immature fruit of , called Bokbunja (HDR-2), have been studied for safety and effectiveness against prehypertension studies. This study was a randomized double-blind placebo-controlled multicenter clinical trial lasting 19 months from October 2017 to May 2019. The 88 subjects who enrolled in the study were divided into two groups. The treatment group was provided HDR-2 and the other group took a placebo. Both HDR-2 and placebo were in the form of capsules, and the dose was 900 mg per day. Subjects took HDR-2 or placebo capsules once a day for 8 weeks before dinner. The primary observational indicators were systolic blood pressure (SBP) and diastolic blood pressure (DBP), and the secondary observational indicators were mean arterial pressure (MAP), mean pulse pressure, pulse rate, angiotensin-converting enzyme activity, renin activity, aldosterone, and highly sensitive-C reactive protein. The number of measurements was three times: the first visit in the screening week, the second visit in 4 weeks, and the third visit was after 8 weeks. Significant study results showed that the SBP and MAP of the HDR-2 group after 8 weeks were lower than those of the placebo group. Adverse events were not significantly different between the two groups. In conclusion, these results suggest that HDR-2 may be a useful intervention for the management of prehypertension. The protocol was registered in the Korean Clinical Trial Registration system (http://cris.nih.go.kr; registration number: KCT0004300).
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http://dx.doi.org/10.1089/jmf.2020.4820DOI Listing
March 2021

The clinical features, management, and survival of elderly patients with colorectal cancer.

J Gastrointest Oncol 2021 Feb;12(1):89-99

Department of Gastroenterology, the First Medical Center of PLA General Hospital, Beijing, China.

Background: As the population ages, the number of elderly patients with colorectal cancer is increasing year by year. However, older people have rarely been the focus of studies on colorectal cancer. Therefore, in the present study, we aimed to carry out a retrospective analysis of this patient subgroup.

Methods: A retrospective study of clinical data of patients aged over 80 years who died from colorectal cancer in our hospital between 1993 and 2020 was performed. Logistic regression, the Kaplan-Meier method, and a multivariate Cox proportional hazards model were used to analyze the overall survival and treatment outcomes of the patients.

Results: A total of 87 patients were included in the study. The overall median survival was 45 months. In most patients, the primary lesion was located in the right colon. One-quarter of the patients refused to accept any treatment. Patients with stage IV tumors, who accounted for the largest proportion of the study population, displayed a higher rate of abandoning treatment than did patients of other stages. Almost all patients with stages II and III accepted surgery. Patients who underwent surgery to treat their colorectal cancer had longer survival than those who did not.

Conclusions: Old age should not be a reason for giving up treatment for colorectal cancer. The treatment of colorectal cancer patients aged 80 years and above requires individualized evaluation and more aggressive treatment to achieve greater benefits.
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http://dx.doi.org/10.21037/jgo-21-63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944162PMC
February 2021

The long noncoding RNA MALAT1 modulates adipose loss in cancer-associated cachexia by suppressing adipogenesis through PPAR-γ.

Nutr Metab (Lond) 2021 Mar 10;18(1):27. Epub 2021 Mar 10.

Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

Background: Cancer-associated cachexia is a multifactorial syndrome defined by progressive weight loss with ongoing loss of adipose tissue and skeletal muscle. Adipose loss occurs in the early stage of cachexia and is associated with reduced quality of life and survival time. Although numerous lncRNAs are regarded as novel regulators in adipose metabolism, the role of lncRNAs that selectively modulate the development of adipose loss in cachexia remains limited.

Methods: In this study, we analyzed microarray data of lncRNAs in adipose loss and further explored the function and mechanism of MALAT1 in adipose loss. First, we explored the expression and function of MALAT1 in adipose cell by quantitative PCR and RNA knockdown. Subsequently, the mechanism of MALAT1 involvement in adipose loss was analyzed via RNA-seq, bioinformatics analysis and reporter gene assay. Finally, we explored the clinical significance of MALAT1 through correlation analysis.

Results: Cellular experiments revealed that knocking down MALAT1 significantly inhibited the process of adipogenesis. RNA-seq data showed that numerous adipogenic genes were downregulated upon MALAT1 knockdown. A protein-protein interaction network analysis identified PPAR-γ as the central node transcription factor, the inhibition of which explains the downregulation of numerous adipogenic genes. A reporter gene assay suggested that MALAT1 can regulate the gene expression of PPAR-γ at the transcriptional level. Moreover, MALAT1 was weakly expressed in the subcutaneous white adipose tissue of cancer-associated cachexia patients and was related to low fat mass index and poor prognosis in cancer patients.

Conclusions: This study indicated that MALAT1 is associated with adipose loss in cancer-associated cachexia by regulating adipogenesis through PPAR-γ, which may potentially be a novel target for the diagnosis and treatment of cancer-associated cachexia in the clinic.
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http://dx.doi.org/10.1186/s12986-021-00557-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944636PMC
March 2021

Design and research of life-saving cotton-blended miners' clothing.

Int J Occup Saf Ergon 2021 Mar 19:1-9. Epub 2021 Mar 19.

College of Textile Science and Engineering, Jiangnan University, China.

Miners face a series of potential safety hazards in underground work, among which the life-saving function of miners' clothing is particularly important. This article investigates the causes of current mine accidents and the impact of the mine environment, analyses the design and research status of miners' uniforms from the perspective of the market and academia, and emphasizes and puts forward the idea of optimizing the design of miners' uniforms through the characteristics of miners' underground operation and the requirements for their protective performance. Based on the 2F (fashion, function) design model, the basic principles of miners' clothing design are summarized. The design of miners' clothing is studied from three design factors: positioning element, structural design and protective fabric. The purpose is to improve miners' clothing for comfort, positioning, life-saving, hygienic, antimicrobial, etc., shorten search and rescue times, and improve rescue times in mining accidents, to increase the survival rate.
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http://dx.doi.org/10.1080/10803548.2021.1896193DOI Listing
March 2021

Administration route governs the therapeutic efficacy, biodistribution and macrophage targeting of anti-inflammatory nanoparticles in the lung.

J Nanobiotechnology 2021 Feb 25;19(1):56. Epub 2021 Feb 25.

School of Biomedical Engineering, Tianjin Medical University, Tianjin, 300070, China.

Background: Uncontrolled inflammation is a central problem for many respiratory diseases. The development of potent, targeted anti-inflammatory therapies to reduce lung inflammation and re-establish the homeostasis in the respiratory tract is still a challenge. Previously, we developed a unique anti-inflammatory nanodrug, P12 (made of hexapeptides and gold nanoparticles), which can attenuate Toll-like receptor-mediated inflammatory responses in macrophages. However, the effect of the administration route on its therapeutic efficacy and tissue distribution remained to be defined.

Results: In this study, we systematically compared the effects of three different administration routes [the intratracheal (i.t.), intravenous (i.v.) and intraperitoneal (i.p.)] on the therapeutic activity, biodistribution and pulmonary cell targeting features of P12. Using the LPS-induced ALI mouse model, we found that the local administration route via i.t. instillation was superior in reducing lung inflammation than the other two routes even treated with a lower concentration of P12. Further studies on nanoparticle biodistribution showed that the i.t. administration led to more accumulation of P12 in the lungs but less in the liver and other organs; however, the i.v. and i.p. administration resulted in more nanoparticle accumulation in the liver and lymph nodes, respectively, but less in the lungs. Such a lung favorable distribution was also determined by the unique surface chemistry of P12. Furthermore, the inflammatory condition in the lung could decrease the accumulation of nanoparticles in the lung and liver, while increasing their distribution in the spleen and heart. Interestingly, the i.t. administration route helped the nanoparticles specifically target the lung macrophages, whereas the other two administration routes did not.

Conclusion: The i.t. administration is better for treating ALI using nanodevices as it enhances the bioavailability and efficacy of the nanodrugs in the target cells of the lung and reduces the potential systematic side effects.
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http://dx.doi.org/10.1186/s12951-021-00803-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905431PMC
February 2021

CCR5 signaling promotes lipopolysaccharide-induced macrophage recruitment and alveolar developmental arrest.

Cell Death Dis 2021 02 15;12(2):184. Epub 2021 Feb 15.

Department of Neonatology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kong Jiang Road, 200092, Shanghai, China.

The pathogenesis of bronchopulmonary dysplasia (BPD), involves inflammatory, mechanisms that are not fully characterized. Here we report that overexpression of C-C chemokine receptor 5 (CCR5) and its ligands is associated with BPD development. Lipopolysaccharide-induced BPD rats have increased CCR5 and interleukin-1β (IL-1β) levels, and decreased alveolarization, while CCR5 or IL-1β receptor antagonist treatments decreased inflammation and increased alveolarization. CCR5 enhances macrophage migration, macrophage infiltration in the lungs, IL-1β levels, lysyl oxidase activity, and alveolar development arrest. CCR5 expression on monocytes, and its ligands in blood samples from BPD infants, are elevated. Furthermore, batyl alcohol supplementation reduced CCR5 expression and IL-1β production in lipopolysaccharide-exposed rat lungs. Moreover, receptor-interacting kinase 3 (RIP3) upstream regulator of CCR5-cultured RIP3 macrophages exhibited partly blocked lipopolysaccharide-induced CCR5 expression. We conclude that increased CCR5 expression is a key mechanism in BPD development and represents a novel therapeutic target for treatment.
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http://dx.doi.org/10.1038/s41419-021-03464-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883330PMC
February 2021

CaWRKY28 Cys249 is required for interaction with CaWRKY40 in the regulation of pepper immunity to Ralstonia solanacearum.

Mol Plant Microbe Interact 2021 Feb 8. Epub 2021 Feb 8.

National Education Ministry Key Laboratory of Plant Genetic Improvement and Comprehensive Utilization, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China.

WRKY transcription factors have been implicated in plant response to pathogens, but how WRKY-mediated networks are organized and operate to produce appropriate transcriptional outputs remains largely unclear. Here, we identify a member of the WRKY family from pepper (Capsicum annuum), CaWRKY28, that physically interacts with CaWRKY40, a positive regulator of pepper immunity and thermotolerance. We confirmed CaWRKY28/CaWRKY40 interaction by co-immunoprecipitation, bimolecular fluorescence complementation and microscale thermophoresis. Our findings supported that CaWRKY28 is a nuclear protein that acts as positive regulator in pepper responses to the pathogenic bacterium Ralstonia solanacearum infection. It performs its function not by directly modulating the W-box containing immunity related genes but by promoting CaWRKY40 via physical interaction to bind and activate its immunity related target genes including CaPR1, CaNPR1, CaDEF1 and CaABR1, but not its thermotolerance related target gene CaHSP24. All these data indicate that CaWRKY28 interacts with and potentiates CaWRKY40 in regulating immunity against R. solanacearum infection but not thermotolerance. Importantly, we discovered that CaWRKY28 Cys249, shared by CaWRKY28 and its orthologs probably only in the Solanaceae, is crucial for the CaWRKY28-CaWRKY40 interaction. These results highlight how CaWRKY28 associates with CaWRKY40 during the establishment of WRKY networks, and how CaWRKY40 achieves its functional specificity during pepper responses to R. solanacearum infection.
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http://dx.doi.org/10.1094/MPMI-12-20-0361-RDOI Listing
February 2021
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