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1.
Med Image Anal ; 75: 102304, 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34818611

RESUMO

Disease heterogeneity is a significant obstacle to understanding pathological processes and delivering precision diagnostics and treatment. Clustering methods have gained popularity for stratifying patients into subpopulations (i.e., subtypes) of brain diseases using imaging data. However, unsupervised clustering approaches are often confounded by anatomical and functional variations not related to a disease or pathology of interest. Semi-supervised clustering techniques have been proposed to overcome this and, therefore, capture disease-specific patterns more effectively. An additional limitation of both unsupervised and semi-supervised conventional machine learning methods is that they typically model, learn and infer from data using a basis of feature sets pre-defined at a fixed anatomical or functional scale (e.g., atlas-based regions of interest). Herein we propose a novel method, "Multi-scAle heteroGeneity analysIs and Clustering" (MAGIC), to depict the multi-scale presentation of disease heterogeneity, which builds on a previously proposed semi-supervised clustering method, HYDRA. It derives multi-scale and clinically interpretable feature representations and exploits a double-cyclic optimization procedure to effectively drive identification of inter-scale-consistent disease subtypes. More importantly, to understand the conditions under which the clustering model can estimate true heterogeneity related to diseases, we conducted extensive and systematic semi-simulated experiments to evaluate the proposed method on a sizeable healthy control sample from the UK Biobank (N = 4403). We then applied MAGIC to imaging data from Alzheimer's disease (ADNI, N = 1728) and schizophrenia (PHENOM, N = 1166) patients to demonstrate its potential and challenges in dissecting the neuroanatomical heterogeneity of common brain diseases. Taken together, we aim to provide guidance regarding when such analyses can succeed or should be taken with caution. The code of the proposed method is publicly available at https://github.com/anbai106/MAGIC.

2.
Anticancer Res ; 41(10): 4761-4769, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593425

RESUMO

BACKGROUND/AIM: The early stage of atherosclerosis (AS) demonstrates a lipid-driven inflammatory cytokine increase. In the present study, we aimed to use ultrasound-targeted microbubble delivery (UTMD) therapy with the Endostar-loaded target microbubbles (MBs) to reduce AS-related inflammatory response. MATERIALS AND METHODS: Normal and lipopolysaccharide (LPS) induced human umbilical vein endothelial cells (HUVECs) were placed in a parallel-plate flow chamber. MBs were perfused through the parallel-plate flow chamber to mimic physiological blood flow. Five groups were set up: G1: Negative control (normal HUVECs); G2: LPS control (LPS induced HUVECs); G3: ICAM-1-loaded-MBs (MBi); G4: Endostar-loaded-MBs (MBe) and G5: Endostar-ICAM-1-loaded-MBs (MBei). mRNA expression of inflammatory factors and release of inflammatory cytokines were detected by RT-PCR and ELISA, respectively. RESULTS: After treatment with MBei, the mRNA expression of cell adhesion molecule-1 (CD31) (p=0.004), endothelin-1 (ET-1) (p=0.010), von willebrand factor (vWF) (p=0.018), extracellular regulated protein kinases (ERK) (p=0.046) and nuclear factor kappa B (NF-κB) (p=0.003) were significantly reduced compared to LPS-induced HUVECs. Release of inflammatory cytokines including tissue factor (TF) (p=0.033), tissue factor pathway inhibitor (TF-PI) (p=0.019), ET-1 (p=0.014), vWF (p=0.030) and blood-coagulation factor VIIα (FVIIα) (p=0.000) were also significantly reduced compared to LPS-induced HUVECs. CONCLUSION: UTMD therapy can inhibit the inflammatory response by reducing atherosclerotic-related inflammatory factors, suggesting a potential treatment at the early-stage of AS.


Assuntos
Anti-Inflamatórios/farmacologia , Fibrinolíticos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Microbolhas , Anti-Inflamatórios/química , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , Aterosclerose/terapia , Adesão Celular , Endostatinas/química , Endostatinas/farmacologia , Fibrinolíticos/química , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Lipopolissacarídeos/toxicidade , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologia , Ultrassom
3.
Plants (Basel) ; 10(9)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34579400

RESUMO

Soil bacteria play a key role in the plant-soil system and can regulate the growth of Phoebe bournei seedlings under fertilization. However, there are few reports on how soil bacteria respond to fertilization and regulate seedling growth. This study adopted the "3414" field fertilization experiment, combined with soil microbial sequencing, nutrient contents, and biomass measurement, to explore the changes of soil chemical properties and bacterial structure under different NPK fertilization conditions and to establish the coupling relationship between soil bacteria, soil nutrients, and plant growth. The results showed that NPK fertilization decreased soil pH; increased soil N, P, and K content; reduced bacterial diversity and abundance; promoted the growth of dominant bacterial species; and enhanced Phoebe bournei seedlings' soil N, P, and K elements. NPK fertilization promoted Proteobacteria growth, especially of three genera (Methylobacterium, Sphingobium, and Acinetobacter) and Actinobacteria, while it decreased Acidobacteria and Chloroflexi. By reducing the ratio of N to K and increasing P, NPK fertilization can slow soil acidification, promote bacterial reproduction, maintain P. bournei seedlings' soil ecological stability, and balance the seedlings' growth and sustainable soil utilization. AD3, Pseudomonas, and Rhodanobacter can be used as the marker species for N, P, and K fertilization, respectively, while Methylobacterium, Brevundimonas, Acinetobacter, and Sphingobium can be used as indicator species for soil pH and soil N, P, and K content changes, respectively. These results provided a theoretical basis and technical guidance for the effective fertilization and cultivation of robust P. bournei seedlings.

4.
Sheng Wu Gong Cheng Xue Bao ; 37(8): 2976-2983, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472314

RESUMO

Life sciences are the disciplines most closely related with human beings. As experimental disciplines, life sciences develop rapidly and highly intersect in many scientific fields. Under the "double first-class" initiative, the comprehensive development-oriented talent training system has put forward an urgent need for life sciences literacy and comprehensive ability training of college students. Taking the reform of liberal education curriculum system as an opportunity, we developed a series of eight life sciences practical liberal courses for students with non-biology majors. The courses cover all sub-disciplines or directions of life sciences, and aim to foster interdisciplinary talents with life sciences knowledge and literacy, as well as practical and innovative abilities. These courses could serve as references for experimental teaching centers in colleges and universities to set up practical liberal and experimental courses.


Assuntos
Disciplinas das Ciências Biológicas , Estudantes , Currículo , Humanos , Universidades
5.
Artigo em Inglês | MEDLINE | ID: mdl-34532938

RESUMO

There are few reports about purely organic phosphorescence scintillators, and the relationship between molecular structures and radioluminescence in organic scintillators is still unclear. Here, we presented isomerism strategy to study the effect of molecular structures on radioluminescence. The isomers can achieve phosphorescence efficiency of up to 22.8 % by ultraviolet irradiation. Under X-ray irradiation, both m-BA and p-BA show excellent radioluminescence, while o-BA has almost no radioluminescence. Through experimental and theoretical investigation, we found that radioluminescence was not only affected by non-radiation in emissive process, but also highly depended on the material conductivity caused by the different molecular packing. This study not only allows us to clearly understand the relationship between the molecular structures and radioluminescence, but also provides a guidance to rationally design new organic scintillators.

6.
ACS Appl Mater Interfaces ; 13(33): 39394-39403, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34392674

RESUMO

A kind of silicone rubber (SR)/paraffin (Pa)@silicon dioxide (SiO2)@polydopamine (PDA) phase-change composite was prepared in this work. The double-shelled Pa@SiO2@PDA phase-change microcapsules were constructed by oxidative self-polymerization of dopamine (DA) in Tris-HCl buffer solution. The effect of the DA content on the properties of Pa@SiO2@PDA microcapsules and SR/Pa@SiO2@PDA composites was researched. Due to the protective effect of SiO2, PDA layer, and SR matrix, the SR/Pa@SiO2@PDA composites have good leak-proofing performance, and the leakage rate of SR/Pa@SiO2@PDA-2 is as low as 0.45%. Phase-change enthalpies of the Pa@SiO2@PDA microcapsules and SR/Pa@SiO2@PDA composites are reduced slightly with increasing DA content. Meanwhile, the composites displayed improved mechanical strength. The tensile strength of SR/Pa@SiO2@PDA-2 can be up to 0.560 MPa, which is 1.85 times higher than the tensile strength of pure SR/Pa@SiO2 because the interface compatibility between Pa@SiO2 microcapsules and SR is improved through hydrogen bonding between the abundant groups on the PDA surface and the matrix. Moreover, the rough surface of the PDA-modified microcapsules also enhances the interface interaction through physical "interlocking". The new kind of SR/Pa@SiO2@PDA composite can be used for thermal management.

7.
J Ophthalmol ; 2021: 6684045, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457359

RESUMO

Purpose: To identify the molecular etiology of a Chinese family with nonsyndromic macular dystrophy. Methods: Ophthalmic examinations were performed, and genomic DNA was extracted from available family members. Whole exome sequencing of two members (the proband and her unaffected mother) and Sanger sequencing in available family members were performed to screen potential pathogenic variants. Results: Novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the major facilitator superfamily domain containing 8 gene (MFSD8) were suspected to be involved in this family's macular dystrophy phenotype. The novel c.1066C>T variant in the MFSD8 gene probably resulted in substitution of serine for proline at the 356th residue and was predicted to be "uncertain significance" through in silico analyses. The novel c.1102+2T>C variant in the MFSD8 gene was likely to affect the splicing form and predicted to be "pathogenic." Conclusion: The novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the MFSD8 gene are likely responsible for the isolated macular dystrophy phenotype in this family. This study enlarged the MFSD8 gene mutant spectrum and might provide more accurate genetic counseling for this family.

8.
J Biomed Nanotechnol ; 17(5): 873-888, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34082873

RESUMO

Tissue engineering is a promising approach for the treatment of chronic lower back pain (LBP) caused by intervertebral disc degeneration (IDD) resulting from degeneration and inflammation of annulus fibrosus (AF) tissue. However, scaffold with an anti-inflammatory effect on AF cells has not been reported. In this study, we fabricated a polylactide-glycolide (PLGA)/poly-ε-caprolactone (PCL)Zdextran (DEX) composite membrane loaded with plastrum testudinis extract (PTE), a Traditional Chinese Medicine herbal extract, via electrospinning. The membranes were characterized by mechanical measurements and scanning electron microscopy (SEM). Using an in vitro inflammation model induced by interleukin (IL)-1ß, the cytocompatibility and anti-inflammatory effects of the composites were investigated by CCK-8 assay and flow cytometry. Potential regulatory mechanisms were examined by RT-qPCR and Western blotting. The results showed that the P10P8D2 (PLGA 10 g, PCL 8 g, DEX 2 g) composite nanofiber membrane exhibited the most uniform diameter distribution, best mechanical properties, a moderate degradation rate, and the best cytocompatibility characteristics. The optimal concentration of PTE was 120 µg/mL. Importantly, P10P8D2 combined with PTE exhibited anti-inflammatory and cell proliferation promotion effects. Moreover, the NF-κBB/NLRP3/IL-ß signaling pathway was inactivated. Our findings suggested that the nanofiber membrane composed of P10P8D2 and PTE has anti-inflammatory and pro-proliferation effects on AF cells. It may provide an effective strategy for AF tissue regeneration.


Assuntos
Anel Fibroso , Nanofibras , Anti-Inflamatórios/farmacologia , Caproatos , Dextranos , Lactonas , Extratos Vegetais , Poliésteres , Engenharia Tecidual , Extratos de Tecidos , Tecidos Suporte
9.
Adv Mater ; 33(25): e2101852, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33988874

RESUMO

Solution-processed metal-halide perovskites hold great promise in developing next-generation low-cost, high-performance photodetectors. However, the weak absorption of perovskites beyond the near-infrared spectral region posts a stringent limitation on their use for broadband photodetectors. Here, the rational design and synthesis of an upconversion nanoparticles (UCNPs)-perovskite nanotransducer are presented, namely UCNPs@mSiO2 @MAPbX3 (X = Cl, Br, or I), for broadband photon detection spanning from X-rays, UV, to NIR. It is demonstrated that, by in situ crystallization and deliberately tuning the material composition in the lanthanide core and perovskites, the nanotransducers allow for a high stability and show a wide linear response to X-rays of various dose rates, as well as UV/NIR photons of various power densities. The findings provide an opportunity to explore the next-generation broadband photodetectors in the field of high-quality imaging and optoelectronic devices.

10.
Nat Commun ; 12(1): 2845, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990588

RESUMO

Quantifying the overall magnitude of every single locus' genetic effect on the widely measured human phenome is of great challenge. We introduce a unified modelling technique that can consistently provide a total genetic contribution assessment (TGCA) of a gene or genetic variant without thresholding genetic association signals. Genome-wide TGCA in five UK Biobank phenotype domains highlights loci such as the HLA locus for medical conditions, the bone mineral density locus WNT16 for physical measures, and the skin tanning locus MC1R and smoking behaviour locus CHRNA3 for lifestyle. Tissue-specificity investigation reveals several tissues associated with total genetic contributions, including the brain tissues for mental health. Such associations are driven by tissue-specific gene expressions, which share genetic basis with the total genetic contributions. TGCA can provide a genome-wide atlas for the overall genetic contributions in each particular domain of human complex traits.


Assuntos
Genoma Humano , Modelos Genéticos , Bancos de Espécimes Biológicos/estatística & dados numéricos , Simulação por Computador , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Anotação de Sequência Molecular/estatística & dados numéricos , Herança Multifatorial/genética , Especificidade de Órgãos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
11.
Front Cardiovasc Med ; 8: 652746, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33969016

RESUMO

Myocardial infarction (MI) is one of the leading causes of death worldwide, and knowing the early warning signs of MI is lifesaving. To expand our knowledge of MI, we analyzed plasma metabolites in MI and non-MI chest pain cases to identify markers for alerting about MI occurrence based on metabolomics. A total of 230 volunteers were recruited, consisting of 146 chest pain patients admitted with suspected MI (85 MIs and 61 non-MI chest pain cases) and 84 control individuals. Non-MI cardiac chest pain cases include unstable angina (UA), myocarditis, valvular heart diseases, etc. The blood samples of all suspected MI cases were collected not longer than 6 h since the onset of chest pain. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry were applied to identify and quantify the plasma metabolites. Multivariate statistical analysis was utilized to analyze the data, and principal component analysis showed MI could be clearly distinguished from non-MI chest pain cases (including UA and other cases) in the scores plot of metabolomic data, better than that based on the data constructed with medical history and clinical biochemical parameters. Pathway analysis highlighted an upregulated methionine metabolism and downregulated arginine biosynthesis in MI cases. Receiver operating characteristic curve (ROC) and adjusted odds ratio (OR) were calculated to evaluate potential markers for the diagnosis and prediction ability of MI (MI vs. non-MI cases). Finally, gene expression profiles from the Gene Expression Omnibus (GEO) database were briefly discussed to study differential metabolites' connection with plasma transcriptomics. Deoxyuridine (dU), homoserine, and methionine scored highly in ROC analysis (AUC > 0.91), sensitivity (>80%), and specificity (>94%), and they were correlated to LDH and AST (p < 0.05). OR values suggested, after adjusting for gender, age, lipid levels, smoking, type II diabetes, and hypertension history, that high levels of dU of positive logOR = 3.01, methionine of logOR = 3.48, and homoserine of logOR = 1.61 and low levels of isopentenyl diphosphate (IDP) of negative logOR = -5.15, uracil of logOR = -2.38, and arginine of logOR = -0.82 were independent risk factors of MI. Our study highlighted that metabolites belonging to pyrimidine, methionine, and arginine metabolism are deeply influenced in MI plasma samples. dU, homoserine, and methionine are potential markers to recognize MI cases from other cardiac chest pain cases after the onset of chest pains. Individuals with high plasma abundance of dU, homoserine, or methionine have increased risk of MI, too.

12.
Front Chem ; 9: 682006, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981679

RESUMO

Detection of haloalkanes is of great industrial and scientific importance because some haloalkanes are found serious biological and atmospheric issues. The development of a flexible, wearable sensing device for haloalkane assays is highly desired. Here, we develop a paper-based microfluidic sensor to achieve low-cost, high-throughput, and convenient detection of haloalkanes using perovskite nanocrystals as a nanoprobe through anion exchanging. We demonstrate that the CsPbX3 (X = Cl, Br, or I) nanocrystals are selectively and sensitively in response to haloalkanes (CH2Cl2, CH2Br2), and their concentrations can be determined as a function of photoluminescence spectral shifts of perovskite nanocrystals. In particular, an addition of nucleophilic trialkyl phosphines (TOP) or a UV-photon-induced electron transfer from CsPbX3 nanocrystals is responsible for achieving fast sensing of haloalkanes. We further fabricate a paper-based multichannel microfluidic sensor to implement fast colorimetric assays of CH2Cl2 and CH2Br2. We also demonstrate a direct experimental observation on chemical kinetics of anion exchanging in lead-halide perovskite nanocrystals using a slow solvent diffusion strategy. Our studies may offer an opportunity to develop flexible, wearable microfluidic sensors for haloalkane sensing, and advance the in-depth fundamental understanding of the physical origin of anion-exchanged nanocrystals.

13.
Drug Des Devel Ther ; 15: 87-97, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33469262

RESUMO

Background and Purpose: Cardiotoxicity is an important side effect of the treatment of a malignant tumor with Doxorubicin. Currently, decreasing the dosage of Doxorubicin to alleviate the side effects on cardiac function is the common method to deal with the cardiotoxicity induced by Doxorubicin. The present study aims to investigate the therapeutic effects of Roflumilast on Doxorubicin-induced inflammation and cellular senescence, as well as the potential mechanism in H9c2 myocardial cells. Methods: The injured cardiac cell model was established by incubation with 5 µmol/L Doxorubicin. MTT was used to evaluate the cell viability of treated H9c2 cardiac cells. The expression of 4-HNE was determined using an immunofluorescence assay. The gene expression levels of IL-17, IL-6, TNF-α, IL-4, PAI-1, p21, and SIRT1 were evaluated using qRT-PCR and the protein levels of Gpx4, PAI-1, p21, and SIRT1 were determined using Western blot analysis. Secretions of IL-17, IL-6, TNF-α, IL-4, CK-MB, and cTnI were measured using ELISA. Cellular senescence was assessed using SA-ß-Gal staining. Si-RNA technology was used to knockdown the expression of SIRT1 in H9c2 cardiac cells. Results: Cell viability of H9c2 cardiac cells was significantly inhibited by Doxorubicin but rescued by Roflumilast. The upregulated 4-HNE and downregulated Gpx4 were reversed by Roflumilast. The secretions of IL-6 and IL-17 were promoted by Doxorubicin and suppressed by Roflumilast. The increased SA-ß-Gal staining induced by Doxorubicin was inhibited by Roflumilast. P21 and PAI-1 were significantly upregulated and SIRT1 was greatly downregulated by Doxorubicin, all of which were reversed by Roflumilast. The anti-senescent effect of Roflumilast was abolished by knocking down SIRT1. Conclusion: Roflumilast might attenuate Doxorubicin-induced inflammation and cellular senescence in cardiomyocytes by upregulating SIRT1.


Assuntos
Aminopiridinas/farmacologia , Benzamidas/farmacologia , Inflamação/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Animais , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Ciclopropanos/farmacologia , Doxorrubicina/antagonistas & inibidores , Inflamação/induzido quimicamente , Miócitos Cardíacos/metabolismo , Ratos , Sirtuína 1/metabolismo
14.
BMC Infect Dis ; 21(1): 127, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514323

RESUMO

BACKGROUND: To investigate the CT imaging and clinical features of three atypical presentations of coronavirus disease 2019 (COVID-19), namely (1) asymptomatic, (2) CT imaging-negative, and (3) re-detectable positive (RP), during all disease stages. METHODS: A consecutive cohort of 79 COVID-19 patients was retrospectively recruited from five independent institutions. For each presentation type, all patients were classified into atypical vs. typical groups (i.e., asymptomatic vs.symptomatic, CT imaging-negative vs. CT imaging-positive, and RP and non-RP,respectively). The chi-square test, Student's t test, and Kruskal-Wallis H test were performed to compare CT imaging and clinical features of atypical vs. typical patients for all three presentation categories. RESULTS: In our COVID-19 cohort, we found 12.7% asymptomatic patients, 13.9% CT imaging-negative patients, and 8.9% RP patients. The asymptomatic patients had fewer hospitalization days (P=0.043), lower total scores for bilateral lung involvement (P< 0.001), and fewer ground-glass opacities (GGOs) in the peripheral area (P< 0.001) than symptomatic patients. The CT imaging-negative patients were younger (P=0.002), had a higher lymphocyte count (P=0.038), had a higher lymphocyte rate (P=0.008), and had more asymptomatic infections (P=0.002) than the CT imaging-positive patients. The RP patients with moderate COVID-19 had lower total scores of for bilateral lung involvement (P=0.030) and a smaller portion of the left lung affected (P=0.024) than non-RP patients. Compared to their first hospitalization, RP patients had a shorter hospitalization period (P< 0.001) and fewer days from the onset of illness to last RNA negative conversion (P< 0.001) at readmission. CONCLUSIONS: Significant CT imaging and clinical feature differences were found between atypical and typical COVID-19 patients for all three atypical presentation categories investigated in this study, which may help provide complementary information for the effective management of COVID-19.


Assuntos
COVID-19/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Radiografia Torácica , Tomografia Computadorizada por Raios X , Adulto , Infecções Assintomáticas , COVID-19/epidemiologia , China/epidemiologia , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Estudos Retrospectivos , SARS-CoV-2
15.
Nature ; 591(7848): 92-98, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33307546

RESUMO

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.


Assuntos
COVID-19/genética , COVID-19/fisiopatologia , Estado Terminal , 2',5'-Oligoadenilato Sintetase/genética , COVID-19/patologia , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 21/genética , Cuidados Críticos , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Reposicionamento de Medicamentos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Pulmão/patologia , Pulmão/fisiopatologia , Pulmão/virologia , Masculino , Família Multigênica/genética , Receptor de Interferon alfa e beta/genética , Receptores CCR2/genética , TYK2 Quinase/genética , Reino Unido
16.
Biomaterials ; 269: 120534, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33243425

RESUMO

The dual functional implants of antibacteria and osteointegration are highly demanded in orthopedic and dentistry, especially for patients who suffer from diabetes or osteoporosis simultaneously. However, there is lack of the facile and robust method to produce clinically applicable implants with this dual function although coatings possessing single function have been extensively developed. Herein, hyperbranched poly-L-lysine (HBPL) polymers were covalently immobilized onto the alkali-heat treated titanium (Ti) substrates and implants by using 3-glycidyloxypropyltrimethoxysilane (GPTMS) as the coupling agent, which displayed excellent antibacterial activity against S. aureus and E. coli with an efficiency as high as 89.4% and 92.2% in vitro, respectively. The HBPL coating also significantly promoted the adhesion, spreading, proliferation and osteogenic differentiation of MC3T3-E1 cells in vitro. Furthermore, the results of a S. aureus infection rat model in vivo ulteriorly verified that the HBPL-modified screws had good antibacterial and anti-inflammatory abilities at an early stage of implantation and better osteointegration compared with the control Ti screws.


Assuntos
Osseointegração , Titânio , Animais , Antibacterianos/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Escherichia coli , Humanos , Osteogênese , Polilisina/farmacologia , Ratos , Staphylococcus aureus , Propriedades de Superfície , Titânio/farmacologia
17.
Comput Biol Med ; 129: 104127, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33333364

RESUMO

Thanks to advancements in diagnosis and treatment, prostate cancer patients have high long-term survival rates. Currently, an important goal is to preserve quality of life during and after treatment. The relationship between the radiation a patient receives and the subsequent side effects he experiences is complex and difficult to model or predict. Here, we use machine learning algorithms and statistical models to explore the connection between radiation treatment and post-treatment gastro-urinary function. Since only a limited number of patient datasets are currently available, we used image flipping and curvature-based interpolation methods to generate more data to leverage transfer learning. Using interpolated and augmented data, we trained a convolutional autoencoder network to obtain near-optimal starting points for the weights. A convolutional neural network then analyzed the relationship between patient-reported quality-of-life and radiation doses to the bladder and rectum. We also used analysis of variance and logistic regression to explore organ sensitivity to radiation and to develop dosage thresholds for each organ region. Our findings show no statistically significant association between the bladder and quality-of-life scores. However, we found a statistically significant association between the radiation applied to posterior and anterior rectal regions and changes in quality of life. Finally, we estimated radiation therapy dose thresholds for each organ. Our analysis connects machine learning methods with organ sensitivity, thus providing a framework for informing cancer patient care using patient reported quality-of-life metrics.


Assuntos
Neoplasias da Próstata , Qualidade de Vida , Humanos , Aprendizado de Máquina , Masculino , Neoplasias da Próstata/radioterapia , Dosagem Radioterapêutica
18.
Sci Rep ; 10(1): 21368, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33288851

RESUMO

The Fusarium wilt disease caused by Fusarium oxysporum f. sp. batatas (Fob) is one of the devastating diseases of sweetpotato. However, the molecular mechanisms of sweetpotato response to Fob is poorly understood. In the present study, comparative quantitative proteomic analysis was conducted to investigate the defense mechanisms involved. Two sweetpotato cultivars with differential Fob infection responses were inoculated with Fob spore suspensions and quantitatively analyzed by Tandem Mass Tags (TMT). 2267 proteins were identified and 1897 of them were quantified. There were 817 proteins with quantitative ratios of 1.2-fold change between Fob-inoculated and mock-treated samples. Further, nine differentially expressed proteins were validated by Parallel Reaction Monitoring (PRM). According to Gene Ontology (GO) annotation information, the proteins functioned in molecular metabolism, cellular component formation, and biological processes. Interestingly, the results showed that sweetpotato resistant response to Fob infection included many proteins associated with signaling transduction, plant resistance, chitinase and subtilisin-like protease. The functions and possible roles of those proteins were discussed. The results provides first insight into molecular mechanisms involved in sweetpotato defense responses to Fob.


Assuntos
Fusarium/patogenicidade , Ipomoea batatas/metabolismo , Ipomoea batatas/microbiologia , Proteômica/métodos , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Ontologia Genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
19.
J Hazard Mater ; 398: 122842, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-32768811

RESUMO

In this paper, the widely used energetic material RDX had been modified with 2D high nitrogen polymer (TAGP). Various hybrid RDX crystals (qy-RDX) with higher detonation velocity and better thermostability had been obtained as a result of strong intermolecular interactions between TAGP and RDX molecules. The performance of the qy-RDX had been characterized to clarify the inherent mechanisms. It shows that the⊿Hf of qy-RDX could be largely changed in the range of 23.4 kJ kg-1 to 1343.6 kJ kg-1, whereas the density varies only from 1.81 g cm-3 to 1.86 g cm-3. The resulted detonation velocities are in the range of 8725.5 m·s-1 to 9251.8 m·s-1, depending on the content and state of the TAGP dopant. The sensitivity of the resulted qy-RDX is much better than pristine RDX due to improved crystal quality as well as higher concentration of hydrogen bonds. The impact energy is improved from 8.5 J (RDX) to 22 J (qy-RDX-1), whereas the friction sensitivity improves form 130 N to over 360 N for the same case. The Ea for thermal decomposition of qy-RDX-1has reduced from 147.8 kJ mol-1 (RDX) to (124.5 kJ mol-1), since TAGP dopant could be considered as active catalytic sites after melting of RDX.

20.
Mol Med Rep ; 22(1): 310-316, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32377729

RESUMO

Ginkgolide B (GB) is a diterpene lactone found in the leaves of the traditional Chinese medicinal plant Ginkgo that has been shown to have various pharmacological effects. However, the anti­apoptotic properties of GB in cardiovascular disease remain poorly understood. The present study aimed to investigate the effect of GB on hydrogen peroxide­induced cell injury in cardiac H9c2 cells, and to further clarify its protective mechanism of action. An in vitro hydrogen peroxide­treated H9c2 cell model was used in order to mimic myocardial ischemia­reperfusion (I/R) injury. Cell viability was assessed by the Cell Counting Kit­8 assay. The induction of apoptosis was determined by flow cytometry and staining was performed using Hoechst 33342. In addition, the effect of GB on the expression levels of apoptosis­associated proteins was evaluated by western blot analysis. The present study demonstrated that GB protected against hydrogen peroxide­induced cytotoxicity and cell apoptosis in H9c2 cardiac cells. GB upregulated the expression level of the anti­apoptotic protein Bcl­2 and downregulated the expression levels of the pro­apoptotic proteins cleaved caspase­3 and Bax in hydrogen peroxide­treated H9c2 cells. The molecular mechanism underlying the anti­apoptotic effects of GB was subsequently detected. GB pretreatment activated the PI3K/Akt/mTOR signaling pathway and caused an increase in the phosphorylation levels of Akt and mTOR in hydrogen peroxide­treated H9c2 cells. These results revealed that GB inhibited hydrogen peroxide­induced apoptosis in H9c2 cells via activation of the PI3K/Akt/mTOR signaling pathway. These findings indicate the potential therapeutic benefits of GB in the treatment of myocardial I/R injury.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Ginkgolídeos/farmacologia , Peróxido de Hidrogênio/metabolismo , Lactonas/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Serina-Treonina Quinases TOR/metabolismo
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