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1.
J Xray Sci Technol ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32039881

RESUMO

BACKGROUND: Low dose computed tomography (LDCT) reduces radiation damage to patients. However, with the decrease of radiation dose, LDCT images of the lung often appear some serious problems such as poor contrast, noise and streak artifacts. OBJECTIVE: To improve the quality of lung LDCT images, this study proposed and investigated a new denoising method based on classification training structure combined dictionary for lung LDCT images. METHODS: First, top-hat transform and anisotropic diffusion with a shock filter (ADSF) algorithm are used to enhance the image contrast and image details. Second, an adaptive dictionary is trained and used for noise reduction. Third, more image details are extracted from the residual image by using the atom activity measurement. The final result is obtained by combining the dictionary denoising result with the extracted detail information. The proposed method is then validated by both simulated and clinical lung LDCT images. Four metrics including Contrast-to-Noise Ratio (CNR), Noise Suppression Index (NSI), Edge Preserving Index (EPI), and Blurring Index (BI) are computed to quantitatively evaluate image quality. RESULTS: The results showed that the CNR, NSI, EPI, and BI of our method reached 8.953, 0.9500, 0.7230 and 0.0170, respectively. Noise and streak artifacts can be removed from lung LDCT images while keeping and retaining more details. CONCLUSIONS: Comparing with the results of other methods tested using the same dataset, this study demonstrated that our new method significantly improved quality of the lung LDCT images.

2.
Nat Commun ; 11(1): 528, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047147

RESUMO

Compared to individual hot days/nights, compound hot extremes that combine daytime and nighttime heat are more impactful. However, past and future changes in compound hot extremes as well as their underlying drivers and societal impacts remain poorly understood. Here we show that during 1960-2012, significant increases in Northern Hemisphere average frequency (~1.03 days decade-1) and intensity (~0.28 °C decade-1) of summertime compound hot extremes arise primarily from summer-mean warming. The forcing of rising greenhouse gases (GHGs) is robustly detected and largely accounts for observed trends. Observationally-constrained projections suggest an approximate eightfold increase in hemispheric-average frequency and a threefold growth in intensity of summertime compound hot extremes by 2100 (relative to 2012), given uncurbed GHG emissions. Accordingly, end-of-century population exposure to compound hot extremes is projected to be four to eight times the 2010s level, dependent on demographic and climate scenarios.

3.
Nanomedicine ; : 102167, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32006685

RESUMO

The application of photodynamic therapy (PDT) is of ever-increasing importance in the treatment of malignant tumors; however, there are several major constraints that make it impossible to achieve optimal therapeutic effects. Our objective is to develop a novel photosensitizing drug for skin cancer. In the experiment, we fabricated four-arm-poly ethylene glycol modified amino-rich graphite phase carbon nitride nanosheets (AGCN-PEG), which have good stability in physiological solution and show selective accumulation in tumor cells. Under hypoxic conditions, the AGCN-PEG induced PDT can effectively inhibit growth on A431 human epidermoid carcinoma cells in vivo and in vitro. What's more, after being combined with TMPyP4, the therapeutic effect of AGCN-PEG was greatly improved.

4.
EBioMedicine ; 52: 102638, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32014820

RESUMO

BACKGROUND: To improve the early diagnosis of hepatocellular carcinoma (HCC), more effective diagnostic biomarkers are needed. A combination of biomarkers is reported to distinguish individuals with early-stage HCC from at-risk individuals. METHODS: Participants in this study were recruited from six hospitals in China. Literature review was used to choose 19 candidate proteins, a case-control study in the discovery stage was used to identify five proteins (P5) that constituted a diagnostic model. In the training and validation stages, the effectiveness of P5 for detecting early-stage HCC was tested (cross-sectional study). Finally, a nested case-control study independent of the other stages was set up to evaluate the P5 in the preclinical diagnosis of HCC. FINDINGS: Between February 2013 and June 2017, a total of 1396 participants were recruited. A panel of 5 proteins (P5: OPN, GDF15, NSE, TRAP5 and OPG) showed high diagnostic accuracy when differentiating the early-stage HCC from the at-risk group, with AUCs of 0·892, 0·907 and 0·852 for the training stage, validation cohort 1 and cohort 2 data sets, respectively. In the prediction set, the sensitivity of P5 for diagnosing preclinical HCC increased with time, starting from 12 months before to the time of definitive clinical diagnosis (range, 46·15% to 86·67%). INTERPRETATION: The P5 panel has the potential to screen populations at high risk of developing HCC and can enable the early diagnosis of HCC. FUNDING: Research supported by grants from eight funds. All sources of funding were declared at the end of the text.

5.
J Diabetes Res ; 2020: 2354108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32064275

RESUMO

Aims: The underlying mechanisms involved in Vitamin A- (VA-) related changes in glucose metabolic disorders remain unclear. Recent evidence suggests that intestinal microbiota is closely linked to the metabolic syndrome. Here, we explored whether and how intestinal microbiota affects glucose homeostasis in VA-deficient diet-fed mice. Methods: Six-week-old male C57BL/6 mice were randomly placed on either a VA-sufficient (VAS) or VA-deficient (VAD) diet for 10 weeks. Subsequently, a subclass of the VAD diet-fed mice was switched to a VA-deficient rescued (VADR) diet for an additional 8 weeks. The glucose metabolic phenotypes of the mice were assessed using glucose tolerance tests and immunohistochemistry staining. Changes in intestinal microbiota were assessed using 16S gene sequencing. The intestinal morphology, intestinal permeability, and inflammatory response activation signaling pathway were assessed using histological staining, western blots, quantitative-PCR, and enzyme-linked immunosorbent assays. Results: VAD diet-fed mice displayed reduction of tissue VA levels, increased area under the curve (AUC) of glucose challenge, reduced glucose-stimulated insulin secretion, and loss of ß cell mass. Redundancy analysis showed intestinal microbiota diversity was significantly associated with AUC of glucose challenge and ß cell mass. Redundancy analysis showed intestinal microbiota diversity was significantly associated with AUC of glucose challenge and κB signaling pathway activation. Reintroduction of dietary VA to VAD diet-fed mice restored tissue VA levels, endocrine hormone profiles, and inflammatory response, which are similar to those observed following VAS-controlled changes in intestinal microbiota. Conclusions: We found intestinal microbiota effect islet function via controlling intestinal inflammatory phenotype in VAD diet-fed mice. Intestinal microbiota influences could be considered as an additional mechanism for the effect of endocrine function in a VAD diet-driven mouse model.

6.
J Affect Disord ; 264: 163-171, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32056746

RESUMO

BACKGROUND: Electroconvulsive therapy (ECT) can lead to rapid and effective responses in major depressive disorder (MDD). However, the precise neural mechanisms of ECT for MDD are still unclear. Previous work has confirmed that thalamocortical circuits play an important role in emotion and cognition. However, the relationship between mechanisms of ECT for MDD and thalamocortical connectivity has not yet been investigated. METHOD: Thalamocortical functional connectivity analysis was performed on resting-state functional magnetic resonance imaging (fMRI) data collected from 28 MDD patients both pre- and post-ECT treatment, as well as 20 healthy controls. The cortex was parceled into six regions of interest (ROIs), which were used as seeds to assess the functional connectivity between the cortex and each voxel in the thalamus. Then, functional connectivity between the identified thalamic subregions and the rest of the brain was quantified to better localize thalamocortical connectivity related to ECT. Structural connectivity among the functionally abnormal regions was also determined using probabilistic tractography from diffusion tensor imaging (DTI) data. RESULTS: There was decreased parietal cortex-left pulvinar and left pulvinar-bilateral precuneus functional connectivity in post-ECT MDD patients, compared to pre-ECT MDD patients. Furthermore, functional connectivity strength of parietal cortex-left pulvinar and left pulvinar-bilateral precuneus was negative correlation with verbal fluency test scores in post-ECT MDD patients. No significant change was found in structural connectivity analysis. LIMITATIONS: The sample size of our study was not large. CONCLUSION: Our findings implicate that the specific abnormalities in thalamocortical circuit may be associated with cognitive impairment induced by ECT.

7.
Chin J Traumatol ; 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-32057562

RESUMO

PURPOSE: To explore the significance of traditional vascular reconstruction and covered stent for limb salvage after subclavian artery injury. METHODS: Patients with subclavian artery injury admitted to Beijing Jishuitan Hospital from January 2010 to December 2018 were retrospectively analyzed. All the injuries have been confirmed by intraoperative exploration, computed tomography angiography or digital subtraction angiography. Complete or partial amputation injuries were excluded. Mild artery defect or partial intimal damage was treated by interventional implantation, while other patients received open surgeries, including direct suture of small defect less than 2 cm and transplantation with autologous vein or artificial blood when the defect was more than 2 cm. Patients were divided into open surgery group and stent implantation group based on the treatment they received. Patients were followed up at 2 weeks (first stage) and 6 months (second stage) after operation to investigate limb salvage. Student's t-test was used to compare the general data between two groups and Chi-square test to analyze the rate of limb salvage. RESULTS: Altogether 50 cases of subclavian artery injury were treated, including 36 cases of open surgery and 14 cases of stent implantation. Combination of nerve injury was observed in 27 cases (75.0%) in open surgery group and 12 cases (85.7%) in stent implantation group. Amputation developed in 3 cases with open surgery and 1 case with stent implantation. Consequently the rate of successful limb salvage was respectively 91.7 (33/36) and 92.9% (13/14), revealing no significant difference (p > 0.05). CONCLUSION: Rapid reconstruction of blood circulation is crucial following subclavian artery injury, no matter what kinds of treatment strategies have been adopted. Interventional stent implantation can achieve a good effect for limb salvage.

8.
Int J Biochem Cell Biol ; : 105716, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32058048

RESUMO

G-protein-signaling modulator 2 (GPSM2) belongs to a protein family that regulates activation of G proteins and plays an important role in mitotic spindle orientation. However, the role of GPSM2 in lung adenocarcinoma (LUAD) is still unclear. In this study, it was found that GPSM2 correlates with clinicopathological features and patient's prognosis in LUAD. Knocking down GPSM2 promoted LUAD cell proliferation in vitro and in vivo. Mechanistically, it was demonstrated that GPSM2 knockdown accelerates cell proliferation via the EGFR pathway. These results confirmed that GPSM2 played an important role in LUAD. Moreover, GPSM2, as an independent prognostic factor, may serve as a potential drug target and prognostic biomarker in LUAD.

9.
Int J Mol Sci ; 21(4)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059402

RESUMO

Salicylic acid (SA) is considered to play an important role in plant responses to environmental stresses. However, the detailed protective mechanisms in photosynthesis are still unclear. We therefore explored the protective roles of SA in photosystem II (PSII) in Arabidopsis thaliana under high light. The results demonstrated that 3 h of high light exposure resulted in a decline in photochemical efficiency and the dissipation of excess excitation energy. However, SA application significantly improved the photosynthetic capacity and the dissipation of excitation energy under high light. Western blot analysis revealed that SA application alleviated the decrease in the levels of D1 and D2 protein and increased the amount of Lhcb5 and PsbS protein under high light. Results from photoinhibition highlighted that SA application could accelerate the repair of D1 protein. Furthermore, the phosphorylated levels of D1 and D2 proteins were significantly increased under high light in the presence of SA. In addition, we found that SA application significantly alleviated the disassembly of PSII-LHCII super complexes and LHCII under high light for 3 h. Overall, our findings demonstrated that SA may efficiently alleviate photoinhibition and improve photoprotection by dissipating excess excitation energy, enhancing the phosphorylation of PSII reaction center proteins, and preventing the disassembly of PSII super complexes.

10.
J Transl Med ; 18(1): 68, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046736

RESUMO

AIM: Inflammation within the perivascular adipose tissue (PVAT) in obesity plays an important role in cardiovascular disorders. C-reactive protein (CRP) level in obesity patients is significantly increased and associated with the occurrence and progression of cardiovascular disease. We tested the hypothesis CRP derived from PVAT in obesity contributes to vascular remodeling after injury. METHODS: A high-fat diet (HFD) significantly increased CRP expression in PVAT. We transplanted thoracic aortic PVAT from wild-type (WT) or transgenic CRP-expressing (CRPTG) mice to the injured femoral artery in WT mice. RESULTS: At 4 weeks after femoral artery injury, the neointimal/media ratio was increased significantly in WT mice that received PVAT from CRPTG mice compared with that in WT mice that received WT PVAT. Transplanted CRPTG PVAT also significantly accelerated adventitial macrophage infiltration and vasa vasorum proliferation. It was revealed greater macrophage infiltration in CRPTG adipose tissue than in WT adipose tissue and CRP significantly increased the adhesion rate of monocytes through receptor Fcγ RI. Proteome profiling showed CRP over-expression promoted the expression of chemokine (C-X-C motif) ligand 7 (CXCL7) in adipose tissue, transwell assay showed CRP increased monocyte migration indirectly via the induction of CXCL7 expression in adipocytes. CONCLUSION: CRP derived from PVAT was significantly increased in HFD mice and promoted neointimal hyperplasia after vascular injury.

11.
Sci Total Environ ; 717: 137190, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32062279

RESUMO

Sulfate and nitrate from secondary reactions remain as the most abundant inorganic species in atmospheric particle matter (PM). Their formation is initiated by oxidation (either in gas phase or particle phase), followed by neutralization reaction primarily by NH3, or by other alkaline species such as alkaline metal ions if available. The different roles of NH3 and metal ions in neutralizing H2SO4 or HNO3, however, are seldom investigated. Here we conducted semi-continuous measurements of SO42-, NO3-, NH4+, and their gaseous precursors, as well as alkaline metal ions (Na+, K+, Ca2+, and Mg2+) in wintertime Beijing. Analysis of aerosol acidity (estimated from a thermodynamic model) indicated that preferable sulfate formation was related to low pH conditions, while high pH conditions promote nitrate formation. Data in different mass fraction ranges of alkaline metal ions showed that in some ranges the role of NH3 was replaced by alkaline metal ions in the neutralization reaction of H2SO4 and HNO3 to form particulate SO42- and NO3-. The relationships between mass fractions of SO42- and NO3- in those ranges of different alkaline metal ion content also suggested that alkaline metal ions participate in the competing neutralization reaction of sulfate and nitrate. The implication of the current study is that in some regions the chemistry to incorporate sulfur and nitrogen into particle phase might be largely affected by desert/fugitive dust and sea salt, besides NH3. This implication is particularly relevant in coastal China and those areas with strong influence of dust storm in the North China Plain (NCP), both of which host a number of megacities with deteriorating air quality.

12.
Mol Carcinog ; 2020 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-32064687

RESUMO

Colorectal cancer (CRC) is a kind of malignant cancer with high morbidity and mortality. The purpose of this study was to explore potential regulated key genes involved in CRC through bioinformatics analysis and experimental verification. The gene expression profile data were downloaded from the Gene Expression Omnibus, and the differential expression genes were detected in cancerous and paracancerous samples of CRC patients, respectively. Then functional enrichment analysis, such as the Kyoto Encyclopedia of Genes and Genomes pathway analysis as well as the protein-protein interaction network were constructed, and the highly related genes were clustered by Molecular COmplex DEtection algorithm to find out the core interaction in different genes' crosstalk. The genes affecting CRC prognosis were screened by the Human Protein Atlas database. In addition, the expression level of core genes was detected by GEPIA database, and the core genes' changes in large-scale cancer genome data set were directly analyzed by cBioPortal database. The expression of the predicted hub genes DSN1, AHCY, and ERCC6L was verified by reverse-transcription quantitative polymerase chain reaction in CRC cells. The gene function of DSN1 was analyzed by wound healing and colony formation assays. The results showed that silencing of DSN1 could significantly reduce the migration and proliferation of CRC cells. Further, BUB1B, the potential interacting protein of DSN1, was also predicted via bioinformatics analysis. Above all, this study shows that bioinformatics analysis combined with experimental method verification provide more potential vital genes for the prevention and therapy of CRC.

13.
Sci Rep ; 10(1): 2751, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066780

RESUMO

The close proximity of esophagus to the left atrial posterior wall predisposes esophagus to thermal injury during catheter ablation for atrial fibrillation (AF). In this retrospective study, we aimed to investigate risk factors of esophageal injury (EI) caused by catheter ablation for AF. Patients who underwent first-time AF ablation from July 2013 to June 2018 were included. The esophagus was visualized by oral soluble contrast during ablation for all patients and a subset of patients were selected to undergo endoscopic ultrasonography (EUS) to estimate EI post ablation. Degree of EI was categorized as Kansas City classification: type 1: erythema; type 2: ulcers (2a: superficial ulcers; 2b: deep ulcers); type 3: perforation (3a: perforation without communication with the atria; 3b: atrioesophageal fistula [AEF]). Of 3,852 patients, 236 patients (61.5 ± 9.7 years; male, 69%) received EUS (EUS group) and 3616 (63.2 ± 10.9 years; male, 61.1%) without EUS (No-EUS group). In EUS group, EI occurred in 63 patients (type 1 EI in 35 and type 2 EI in 28), and no type 3 EI was observed during follow up. In a multivariable logistic regression analysis, an overlap between the ablation lesion and esophagus was an independent predictor of EI (odds ratio, 21.2; 95% CI: 6.23-72.0; P < 0.001). In No-EUS group, esophagopericardial fistula (EPF; n = 3,0.08%) or AEF (n = 2,0.06%) was diagnosed 4-37 days after ablation. In 3 EPF patients, 2 completely recovered with conservative management and 1 died. Two AEF patients died. Ablation at the vicinity of the esophagus predicts risk of EI. EUS post ablation may prevent the progression of EI and should be considered in management of EI. It remains challenging to identify patients with high risk of EI.

14.
Environ Sci Technol ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32068395

RESUMO

NH3 is the most important gaseous alkaline pollutant, which when accumulated at high concentrations can have a serious impact on animal and human health. More importantly, NH3 emissions will react with acidic pollutant gases to form PM2.5 in the atmosphere, which also poses a huge threat to human activities. The use of adsorbents for NH3 removal from emission sources or air is an urgent issue. However, there are difficulties in the compatibility between high adsorption capacity and recyclability for most conventional adsorbents. In this work, a structural transformation strategy using MOFs is proposed for large-scale and recyclable NH3 adsorption. A series of M(BDC) (M = Cu, Zn, Cd) materials can transform to one-dimensional M(BDC)(NH3)2 after NH3 adsorption, resulting in repeatable adsorption capacities of 17.2, 14.1, and 7.4 mmol/g, respectively. These MOFs can be completely regenerated at 250 °C for 80 min with no adsorption capacity loss. Besides, breakthrough and cycle tests indicate that Cu(BDC) and Zn(BDC) show good performance in the removal of low-concentrations of NH3 from the air. Overall, combining the advantages of high adsorption capacity and recyclability due to the reversible structural transformation, Cu(BDC) and Zn(BDC) can be employed as ideal adsorbent candidates for NH3 removal.

15.
Postgrad Med J ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015189

RESUMO

Obesity is a growing chronic health problem worldwide. Studies about acupuncture for obesity treatment are many. But there are some doubts about the effectiveness of acupuncture versus sham acupuncture in treating obesity due to its lack of medical evidence. Therefore, the aim of this study is to assess the efficacy of acupuncture for obesity treatment and provide clinic evidence. Four English databases (PubMed, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials) and four Chinese databases (China National Knowledge Infrastructure, Chinese BioMedical Database, Chinese Scientific Journal Database and Wan-Fang Data) were searched from their receptions to August 2019. Randomized controlled trials (RCTs) using the comparison between acupuncture and sham acupuncture to treat simple obesity were included. The primary outcome of body mass index (BMI) would be used to measure the effect of acupuncture on obesity. According to the trial data extraction form based on the Cochrane Handbook, two reviewers separately extracted the data. Risk of bias of the RCTs was assessed by the Cochrane Risk of Bias Tool. The study included 8 RCTs with 403 patients. When compared with sham acupuncture, acupuncture showed obviously effect in BMI reduction (MD=1.0kg/m2, 95% CI=0.6 to 1.4, P<0.001). There was also significant reduction in body weight (MD=1.85kg, 95%CI=0.82 to 2.88, p<0.001), WC (MD=0.97cm, 95%CI=0.24 to 1.71, p=0.01) and body fat mass percentage (MD=1.01, 95%CI=0.25 to 1.77, p<0.05). However, WHR (MD=0.01, 95%CI=0 to 0.03, p>0.05) was not statistically and significantly different between the acupuncture and control groups. Adverse effects were reported in 3 studies. The review suggests that acupuncture is an effective therapy for simple obesity rather than a placebo effect. This potential benefit needs to be further evaluated by longer-term and more rigorous RCTs.

16.
J Cell Physiol ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017846

RESUMO

Chemokines and their receptors show a strong relationship with poor clinical outcomes in various cancers. However, their underlying mechanisms remain to be fully elucidated. In our research, we found C-C chemokine receptor 7 (CCR7) and its ligand chemokine ligand 21 (CCL21) were abnormally abundant in oral squamous cell carcinoma (OSCC) tissues, and CCR7 expression was correlated with poor prognosis of OSCC. After exogenous CCL21 stimulation, epithelial-mesenchymal transition (EMT) was promoted in OSCC cells, and cancer stem cell-related markers CD133, CD44, BMI1, ALDH1A1, and OCT4 increased. The migration, invasion, tumorsphere formation, and colony formation abilities of OSCC cells were enhanced, indicating that the stemness of OSCC cells was also improved. The knockdown and overexpression of CCR7 efficiently affected the CCL21-induced EMT and stemness of OSCC cells. When treated with CCL21, the phospho-JAK2 and phospho-STAT3 markedly increased. The inhibitor of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) significantly suppressed CCL21-induced EMT and stemness of OSCC cells. In conclusion, CCL21/CCR7 axis regulated EMT progress and promoted the stemness of OSCC by activating the JAK2/STAT3 signaling pathway. CCL21/CCR7 might be an effective target for OSCC prevention and treatment.

17.
Artigo em Inglês | MEDLINE | ID: mdl-32022596

RESUMO

BACKGROUND: Based on the cardiac hormone atrial natriuretic peptide (ANP) and its seminal role in blood pressure (BP) homeostasis, we investigated the chronic BP lowering actions of a novel ANP analogue currently entering clinical trials for hypertension. Previous reports demonstrate that this analogue MANP activates the guanylyl cyclase A receptor (GC-A) and results in more potent biological actions compared to ANP, and thus may represent a new therapeutic drug for hypertension. OBJECTIVES: A major goal was to establish that chronic subcutaneous (SC) delivery of MANP is feasible and hypotensive together with cGMP effects. We investigated the BP lowering and cGMP-activating actions of acute and chronic SC delivery in normal and hypertensive rats. Further, we explored vascular mechanisms of MANP in human aortic smooth muscle cells (HASMC) and ex vivo in isolated arteries. METHODS AND RESULTS: In normal rats with a single SC injection, MANP promoted robust dose-dependent BP lowering actions and natriuresis, together with cGMP activation. Most importantly in hypertensive rats, once a day SC injection of MANP for 7 days induced cGMP elevation and long-term BP reduction compared to Vehicle. Mechanistically, in HASMC, MANP activated cGMP and attenuated angiotensin II mediated increases in intracellular Ca2+ levels while directly vasorelaxing arterial rings. CONCLUSION: Our study demonstrates for the first time the effectiveness of SC administration of MANP for 7 days and provides innovative, vascular mechanisms of BP regulation supporting its continued development as a novel therapeutic for hypertension.

18.
Mol Ecol Resour ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034885

RESUMO

Populus euphratica is well adapted to extreme desert environments and is an important model species for elucidating the mechanisms of abiotic stress resistance in trees. The current assembly of P. euphratica genome is highly fragmented with many gaps and errors, thereby impeding downstream applications. Here, we report an improved chromosome-level reference genome of P. euphratica (v2.0) using single-molecule sequencing and chromosome conformation capture (Hi-C) technologies. Relative to the previous reference genome, our assembly represents a nearly 60-fold improvement in contiguity, with a scaffold N50 size of 28.59 Mb. Using this genome, we have found that extensive expansion of Gypsy elements in P. euphratica led to its rapid increase in genome size compared to any other Salicaceae species studied to date, and potentially contributed to adaptive divergence driven by insertions near genes involved in stress tolerance. We also detected a wide range of unique structural rearrangements in P. euphratica, including 2,549 translocations, 454 inversions, 121 tandem and 14 segmental duplications. Several key genes likely to be involved in tolerance to abiotic stress were identified within these regions. This high-quality genome represents a valuable resource for poplar breeding and genetic improvement in the future, as well as comparative genomic analysis with other Salicaceae species.

19.
J Am Chem Soc ; 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32003986

RESUMO

In the past decades, significant advances have been made on radical Smiles rearrangement. However, the eventually formed radical intermediates in these reactions are limited to the amidyl radical, except for the few examples initiated by a N-centered radical. Here, a novel and practical radical Smiles rearrangement triggered by photoredox-catalyzed regioselective ketyl-ynamide coupling is reported, which represents the first radical Smiles rearrangement of ynamides. This method enables facile access to a variety of valuable 2-benzhydrylindoles with broad substrate scope in generally good yields under mild reaction conditions. In addition, this chemistry can also be extended to the divergent synthesis of versatile 3-benzhydrylisoquinolines through a similar ketyl-ynamide coupling and radical Smiles rearrangement, followed by dehydrogenative oxidation. Moreover, such an ynamide Smiles rearrangement initiated by intermolecular photoredox catalysis via addition of external radical sources is also achieved. By control experiments, the reaction was shown to proceed via key ketyl radical and α-imino carbon radical intermediates.

20.
J Clin Pharmacol ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32026499

RESUMO

To characterize the pharmacokinetics (PK) and exposure-response (E-R) relationship of ustekinumab, an anti-interleukin-12/interleukin-23 (IL-12/IL-23) human monoclonal antibody, in the treatment of moderately to severely active ulcerative colitis (UC), population PK and E-R modeling analyses were conducted based on the data from the pivotal phase 3 induction and maintenance studies in UC patients. The observed serum concentration-time data of ustekinumab were adequately described by a 2-compartment linear PK model with first-order absorption and first-order elimination. Body weight, baseline serum albumin, sex, and antibodies to ustekinumab were the covariates to influence ustekinumab PK, but the magnitudes of the effects of these covariates were not considered clinically relevant, and dose adjustment was not warranted. Positive E-R relationships were demonstrated between ustekinumab exposure metrics and clinical endpoints (including clinical response, clinical remission, and endoscopic healing based on Mayo score) at induction week 8 and maintenance week 44, consistent with the effectiveness of ustekinumab in the induction and maintenance treatment of patients with UC. E-R modeling results suggest that ustekinumab ∼6 mg/kg intravenous induction and 90-mg subcutaneous every-8-week maintenance dose would produce greater efficacy than the 130 mg intravenous induction and the 90-mg subcutaneous every-12-week maintenance regimen, respectively. Our work provides a comprehensive evaluation of ustekinumab PK and E-R in a modeling framework to support ustekinumab dose recommendations in patients with UC.

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