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1.
J Hazard Mater ; 435: 129009, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35500344

RESUMO

Constructing catalysts with simple structures, uniform effective sites, and excellent performance is crucial for understanding the reaction mechanism of target pollutants. Herein, the single-atom catalyst of Mn-intercalated graphitic carbon nitride (Mn/g-C3N4) was prepared. It was found that the intercalated Mn atoms acted as strong electron donors to effectively tune the electronic structure distribution of the in-situ N atoms, providing a large number of negative potential atomic-scale sites for catalytic reactions. In the detection, the in-situ N atom established an electron bridge for the transient electrostatic trapping of free Pb(II), which induced Pb-N-Mn coordination bonding. Even in g-C3N4-loaded Mn nanoparticles, the N atom was again confirmed to be the interaction site for coupling with Pb. And the MnII-N4-C/MnIV-N4-C cycle actively participated in the electrocatalysis of Pb(II) was confirmed. Moreover, Mn/g-C3N4 achieved highly stable and accurate detection for Pb(II) with a sensitivity of 2714.47 µA·µM-1·cm-2. And excellent reproducibility and specific detection of real water samples made the electrode practical. This study contributes to understanding the changes in the electronic structure of chemically inert substrates after single-atom intercalation and the interaction between contaminants and the microstructure of sensitive materials, providing a guiding strategy for designing highly active electrocatalytic interfaces for accurate electroanalysis.

2.
J Biochem Mol Toxicol ; : e23044, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35499365

RESUMO

Inhibition of histone deacetylase (HDAC) may be a useful approach in the treatment of disorders characterized by cognitive dysfunction. Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has demonstrated neuroprotective effects. Here, we attempted to investigate the protective effects of DEX on postoperative cognitive dysfunction (POCD) involving HDAC2. Male C57BL/6 mice were selected to develop a POCD model, where HDAC2, HIF-1α, and PFKFB3 expression was quantified. DEX was administered before POCD modeling. Then the cognitive function of POCD mice was evaluated with the open field and Y-maze tests. Meanwhile, lipopolysaccharide (LPS) was employed to induce BV-2 microglial cells to simulate the inflammatory response. The contents of TNF-α, IL-6, and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA) in mouse serum and BV-2 cell supernatant. Abundant expression of HDAC2, HIF-1α, and PFKFB3 was confirmed in POCD mice (p < 0.05). Cognitive dysfunction in POCD mice could be alleviated following pharmacological inhibition of HDAC2 by FK228 (p < 0.05). Mechanistically, HDAC2 upregulated HIF-1α and PFKFB3 and promoted the secretion of inflammatory factors in LPS-exposed BV-2 cells (p < 0.05). DEX attenuated neuroinflammation and the resulting cognitive dysfunction by decreasing HDAC2 expression and HIF-1α-dependent PFKFB3 upregulation in POCD mice (p < 0.05). In conclusion, DEX-regulated HDAC2 may play an inhibitory role in mice with POCD through regulation of the HIF-1α/PFKFB3 axis.

3.
Front Physiol ; 13: 855522, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35514359

RESUMO

Although vomiting is commonly recognized as a protective reaction in response to toxic stimuli, the elaborate sensory processes and necessary molecular components are not fully clear, which is due to a lack of appropriate experimental animal models. Vomiting reflex to volatile chemicals renders locust one candidate for vomiting model. Here, we identified a panel of chemical cues that evoked evident vomiting in locust nymphs and demonstrated the selected combinatorial coding strategy that palps but not antennae olfactory receptor neurons (ORNs) employed. Specifically, knocking down individual palp odorant receptors (ORs) such as OR17, OR21, and OR22 attenuated the vomiting intensity evoked by E-2-hexenal and hexanal, while suppression of OR12 and OR22 augmented vomiting to E-2-hexenal and 2-hexanone, respectively. Furthermore, dual-RNAi treatment against OR17 or OR21 together with OR22 resulted in a much lower response intensity than that of individual OR suppression. Furthermore, OR12 was revealed in palp sensilla basiconica (pb) subtype 3 to tune the neuronal decaying activity to E-2-hexenal. Finally, anterograde labeling indicated that palp ORNs primarily projected into the lobus glomerulatus (LG), and the projection neurons (PNs) in the LG further projected into the accessary calyx (ACA). Together, the establishment of an olfaction-inducible vomiting model in locusts deepens the understanding of olfactory coding logics and provides an opportunity to clarify the neural basis underlying animal vomiting.

4.
Mol Biomed ; 3(1): 13, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35543798

RESUMO

Liquid-liquid phase separation (LLPS) has received significant attention in recent biological studies. It refers to a phenomenon that biomolecule exceeds the solubility, condensates and separates itself from solution in liquid like droplets formation. Our understanding of it has also changed from memebraneless organelles to compartmentalization, muti-functional crucibles, and reaction regulators. Although this phenomenon has been employed for a variety of biological processes, recent studies mainly focus on its physiological significance, and the comprehensive research of the underlying physical mechanism is limited. The characteristics of side chains of amino acids and the interaction tendency of proteins function importantly in regulating LLPS thus should be pay more attention on. In addition, the importance of post-translational modifications (PTMs) has been underestimated, despite their abundance and crucial functions in maintaining the electrostatic balance. In this review, we first introduce the driving forces and protein secondary structures involved in LLPS and their different physical functions in cell life processes. Subsequently, we summarize the existing reports on PTM regulation related to LLPS and analyze the underlying basic principles, hoping to find some common relations between LLPS and PTM. Finally, we speculate several unreported PTMs that may have a significant impact on phase separation basing on the findings.

5.
Am J Cancer Res ; 12(4): 1707-1726, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35530279

RESUMO

Hepatocellular carcinoma (HCC) has high morbidity and mortality rates. It is therefore imperative to study the underlying mechanism of HCC to identify potential prognostic biomarkers and therapeutic targets. Recently, GINS2 has been identified to be a cancer-promoting gene in different cancer types. Nevertheless, the exact mechanism of GINS2 in HCC remains to be elucidated. To systematically explore the significance of GINS2, we first assessed the relative expression of GINS2 in pan-cancers based on data obtained from the HCCDB, TIMER, and TCGA databases. Then, we explored the clinical significance of GINS2 in HCC through Kaplan-Meier method as well as univariate and multivariate cox regression analysis. Additionally, functional enrichment analysis of GINS2 was done through GO, KEGG, PPI network, and immune cell infiltration analyses. Functional experiments were also conducted to investigate the biological significance of GINS2 in HCC cell lines. Our research revealed that GINS2 is involved in HCC progression and highlighted its potential value as a crucial diagnostic and therapeutic target for HCC.

6.
J Thorac Imaging ; 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35576551

RESUMO

PURPOSE: This study sought to determine whether machine learning (ML) can be used to better identify the risk factors and establish the prediction models for the prevalence and severity of coronary artery calcification (CAC) in nondialysis chronic kidney disease (CKD) patients and compare the performance of distinctive ML models with conventional logistic regression (LR) model. MATERIALS AND METHODS: In all, 3701 Chinese nondialysis CKD patients undergoing noncontrast cardiac computed tomography (CT) scanning were enrolled from November 2013 to December 2017. CAC score derived from the cardiac CT was calculated with the calcium scoring software and was used to assess and stratify the prevalence and severity of CAC. Four ML models (LR, random forest, support vector machine, and k-nearest neighbor) and the corresponding feature ranks were conducted. The model that incorporated the independent predictors was shown as the receiver-operating characteristic (ROC) curve. Area under the curve (AUC) was used to present the prediction value. ML model performance was compared with the traditional LR model using pairwise comparisons of AUCs. RESULTS: Of the 3701 patients, 943 (25.5%) patients had CAC. Of the 943 patients with CAC, 764 patients (20.6%) and 179 patients (4.8%) had an Agatston CAC score of 1 to 300 and ≥300, respectively. The primary cohort and the independent validation cohort comprised 2957 patients and 744 patients, respectively. For the prevalence of CAC, the AUCs of ML models were from 0.78 to 0.82 in the training data set and the internal validation cohort. For the severity of CAC, the AUCs of the 4 ML models were from 0.67 to 0.70 in the training data set and from 0.53 to 0.70 in the internal validation cohort. For the prevalence of CAC, the AUC was 0.80 (95% confidence interval [CI]: 0.77-0.83) for ML (LR) versus 0.80 (95% CI: 0.77-0.83) for the traditional LR model (P=0.2533). For the severity of CAC, the AUC was 0.70 (95% CI: 0.63-0.77) for ML (LR) versus 0.70 (95% CI: 0.63-0.77) for traditional LR model (P=0.982). CONCLUSIONS: This study constructed prediction models for the presence and severity of CAC based on Agatston scores derived from noncontrast cardiac CT scanning in nondialysis CKD patients using ML, and showed ML LR had the best performance.

7.
Biosens Bioelectron ; 211: 114349, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35576722

RESUMO

DNA nanomachines, a delicate type of molecular machines, have been a research hotspot in biotechnology and materials. Here a two-dimensional (2D) DNA walking nanomachine with high working efficiency and low cost was easily assembled by using graphene oxide (GO) as the working platform for precisely fluorescent bioassay through the binding of target hepatitis B virus DNA (HBV-DNA) and the driving force of Exonuclease III (Exo III). The presence of HBV-DNA made continuous Exo III digestion of the FAM-modified DNA (FAM-DNA) in double-strand DNA (dsDNA) part in a burnt-bridge mechanism to output a "one-to-more" amplified signal. Accordingly, a 2D DNA walking nanomachine with simple operation and high cost-performance ratio was constructed. The walking speed of nanomachine was found to be regulated by loading DNA density on single sheet of GO. Furthermore, this nanomachine had low background since the dual energy transfer including fluorescence resonance energy transfer (FRET) from FAM to BHQ1 and the long-range resonance energy transfer (LrRET) from FAM to GO, making the biosensing applications highly promising.

8.
J Agric Food Chem ; 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35562189

RESUMO

Sesquiterpenyl epoxy-cyclohexenoids (SECs) that depend on a polyketide synthase-terpenoid synthase (PKS-TPS) pathway are widely distributed in plant pathogenic fungi. However, the biosynthesis and function of the acetylated SECs still remained cryptic. Here, we identified that AOL_s00215g 273 (273) was responsible for the acetylation of SECs in Arthrobotrys oligospora via the construction of Δ273, in which the acetylated SECs were absent and major antibacterial nonacetylated SECs accumulated. Mutant Δ273 displayed increased trap formation, and nematicidal and antibacterial activities but decreased fungal growth and soil colonization. Glutamine, a key precursor for NH3 as a trap inducer, was highly accumulated, and biologically active phenylpropanoids and antibiotics were highly enriched in Δ273. The decreased endocytosis and increased autophagosomes, with the most upregulated genes involved in maintaining DNA and transcriptional stability and pathways related to coronavirus disease and exosome, suggested that lack of 273 might result in increased virus infection and the acetylation of SECs played a key role in fungal diverse antagonistic ability.

9.
Atherosclerosis ; 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35577614

RESUMO

BACKGROUND AND AIMS: People living with HIV (HIV+) are surviving longer due to effective antiretroviral therapy. Cardiovascular disease is a leading cause of non-AIDS related clinical events. We determined HIV-related factors associated with coronary artery stenosis progression. METHODS: We performed serial coronary CT angiography among HIV+ and HIV-uninfected (HIV-) men in the Multicenter AIDS Cohort Study. The median inter-scan interval was 4.5 years. Stenosis was graded as 0, 1-29, 30-49, 50-69 or ≥70%. Progression was defined as an increase ≥2 categories. Suppressed HIV infection was consistent viral loads <50 copies/mL allowing 1 "blip" <500 copies/mL, otherwise considered viremic. Multivariable Poisson regression analysis assessed adjusted associations between HIV serostatus and viremia with coronary stenosis progression. RESULTS: The sample included 310 HIV+ (31% viremic) and 234 HIV- men. The median age was 53 years, 30% Black and 23% current smokers. Viremic men were 2.3 times more likely to develop coronary stenosis progression than HIV- men (adjusted RR 2.30; 95% CI, 1.32-4.00, p = 0.003), with no difference in progression between HIV+ suppressed and HIV- men (RR 1.10; 95% CI, 0.70-1.74, p = 0.67). There was a progressive increase in adjusted relative risk with greater viremia (p = 0.03). Men with >1 viral load >500 copies/ml demonstrated greatest stenosis progression (RR 3.01; 95% CI, 1.53-4.92, p = 0.001 compared with HIV- men). Suppressed HIV+ men with suboptimal antiretroviral adherence had greater stenosis progression (RR 1.91; 95% CI 1.12-3.24, p = 0.02) than HIV + suppressed men with optimal adherence. CONCLUSIONS: Coronary artery stenosis progression was associated with suboptimal HIV RNA suppression and antiretroviral therapy adherence. Effective ongoing HIV virologic suppression and antiretroviral therapy adherence may mitigate risk for coronary disease events among people living with HIV.

10.
Transpl Immunol ; 72: 101593, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35367619

RESUMO

OBJECTIVE: To investigate the clinical features, early diagnosis, and treatment methods of Pneumocystis jirovecii pneumonia (PJP) after renal transplantation (RT). METHODS: We retrospectively analyzed the clinical data of 80 patients with confirmed PJP who underwent RT between 2018 and 2021 in our hospital. RESULTS: In the present study, the incidence of PJP was 6.2% (80/1300). A 50% of cases (40 out of 80 patients) had developed a PJP infection during the first 6 months after RT and 81.3% (65 out of 80 patients) within 12 months. The median onset time of PJP was 6.5 months after RT. The most common symptom was fever (73.8%), followed by progressive dyspnea (51.3%) and dry cough (31.3%). In the initial phase of PJP, the most frequent CT finding was the presence of diffuse ground-grass shadows. In all, 27.5%, 37.5%, and 35% patients were diagnosed by induced sputum metagenomic next-generation sequencing (mNGS), peripheral blood mNGS, and characteristic clinical diagnostic features, respectively. The median 1,3-ß-D-glucan level was 500 pg/mL, while the median C-reactive protein level was 63.4 mg/L. In most patients (83.8%), the procalcitonin levels were negative. The mean serum creatinine level was 171.9 ± 87.4 µmol/L. Of the 80 patients, 37 (46.2%) had coexisting cytomegalovirus (CMV) infection. All patients were treated with trimethoprim-sulfamethoxazole and third generation cephalosporin to prevent bacterial infection. The methylprednisolone dose (40-120 mg/d) varied according to illness. CONCLUSION: PJP usually occurs within 1 year after RT, typically within 6 months. Fever, dry cough, and progressive dyspnea are the most common clinical symptoms. PJP should be highly suspected if the patient has clinical symptoms and diffuse, patchy, ground-glass opacities on CT in both lungs after RT within 1 year. Peripheral blood or induced sputum mNGS is helpful for early diagnosis of PJP. Trimethoprim-sulfamethoxazole is still the first choice for the treatment of PJP. Combined use of caspofungin can reduce the dose and adverse reactions of trimethoprim-sulfamethoxazole in theory.

11.
Nat Commun ; 13(1): 1909, 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35393423

RESUMO

The use of inorganic solid-state electrolytes is considered a viable strategy for developing high-energy Li-based metal batteries. However, suppression of parasitic interfacial reactions and growth of unfavorable Li metal depositions upon cycling are challenging aspects and not yet fully addressed. Here, to better understand these phenomena, we investigate various sulfide inorganic solid electrolytes (SEs), i.e., Li7-xPS6-xClx (x = 0.6, 1.0, 1.3, 1.45, and 1.6), via ex situ and in situ physicochemical and electrochemical measurements. We found that the Cl distribution and the cooling process applied during the SE synthesis strongly influence the evolution of the Li|SE interface in terms of microstructure, interphase composition, and morphology. Indeed, for a SE with a moderate chlorine content (i.e., x = 1.3) and obtained via a slow cooling process after sintering, the Cl atoms are located on the surface of the SE grains as interconnected LiCl nanoparticles that form an extended LiCl-based framework. This peculiar microstructure facilitates the migration of the Cl ions to the Li|SE interface during electrochemical cycling, thus, favouring the formation of a LiCl-rich interphase layer capable of improving the battery cycling performances.

12.
Front Psychiatry ; 13: 837774, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35444569

RESUMO

Objective: This study aimed to explore transcranial electrical stimulation (tES) to relieve peripartum anxiety and depressive symptoms in women undergoing cesarean section with combined spinal-epidural anesthesia. Methods: This double-blind, randomized, sham-controlled trial was conducted in the Affiliated Hospital of Xuzhou Medical University from March 2021 and May 2021. One hundred and forty-eight full-term parturients giving birth by elective cesarean section were selected, and 126 were included in the intent-to-treat analysis. Parturients were provided standardized anesthesia and randomized to the active-tES (a-tES) group and sham-tES group. Parturients and outcome assessors were blinded to treatment allocation. The primary outcome was the changes in peripartum mental health disorders, including anxiety, assessed by the Pregnancy-Related Anxiety Questionnaire-Revised 2 (PRAQ-R2). Secondary outcomes included peripartum depressive symptoms, assessed by the Edinburgh Postnatal Depression Scale (EPDS), maternal satisfaction, fatigue level, sleep quality index, and pain score during and after operation. Data were collected before entering the operating room (T0), between post-anesthesia and pre-surgery (T1), before leaving the operating room (T2), and at 24 h post-surgery (T3). Results: One hundred and twenty-six eligible parturients were enrolled in the two groups: a-tES group (N = 62) and sham-tES group (N = 64). Treatment with tES resulted in significantly lower scores of anxiety compared with sham-tES (T2: P < 0.001; T3: P = 0.001). Moreover, the a-tES groups showed a significant reduction in depression scores (T2: P = 0.003; T3: P = 0.032). Conclusion: In this randomized pilot study, tES treatment is efficacious in alleviating peripartum anxiety and depressive symptoms in women undergoing cesarean section and has been demonstrated to be a novel strategy for improving peripartum mental health disorders. Clinical Trial Registration: [www.chictr.org.cn], identifier [ChiCTR2000040963].

13.
J Phys Chem Lett ; 13(15): 3310-3316, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35389645

RESUMO

We report a new physical phenomenon of active and enhanced control of the spin Hall conductivity (SHC) in a family of metal-ferroelectric multilayers. Rather than the direction of the built-in electric field, such ferroelectric regulation of SHC originates from the drastic change of the interfacial electronic state along with its intrinsic Berry phase near the Fermi level due to the distinct hybridization between the metal film and substrate when the ferroelectric polarization reverses. Using Pt/PbZrTiO3 multilayers as a representative model, we demonstrate the controllability of a large magnitude and even the sign of SHC in the Pt film at the two interfaces with an antitype conducting carrier in a ferroelectric substrate. The interfacial Rashba effect plays a role in contributing to the change of SHC through spin-projected band analysis. The present work makes a fundamental theoretical discovery and opens up a new direction to manipulate spin-charge conversion of thin-film layered structures by ferroelectricity, which is crucial for designing future electric and spintronic devices.

14.
Entropy (Basel) ; 24(4)2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-35455145

RESUMO

To guarantee information security in communication, quantum identity authentication plays a key role in politics, economy, finance, daily life and other fields. In this paper, a new quantum multiparty simultaneous identity authentication protocol with Greenberger-Home-Zeilinger (GHZ) state is presented. In this protocol, the authenticator and the certified parties are the participants with quantum ability, whereas the third party is a classical participant. Here, the third-party is honest and the other two parties may be dishonest. With the help of a classical third-party, a quantum authenticator and the multiple certified parties can implement two-way identity authentication at the same time. It reduces the quantum burden of participants and lowers down the trustworthiness, which makes the protocol be feasible in practice. Through further security analysis, the protocol can effectively prevent an illegal dishonest participant from obtaining a legitimate identity. It shows that the protocol is against impersonation attack, intercept-measure-resend attack and entangle-measure attack, etc. In all, the paper provides positive efforts for the subsequent security identity authentication in quantum network.

15.
Chemphyschem ; 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35478429

RESUMO

Feature representations, or descriptors, are machines' chemical language that largely shapes the prediction capability, generalizability and interpretability of machine learning models. To develop a generally applicable descriptor is highly warranted for chemists to deal with conventional prediction tasks in the context of sparsely distributed and small datasets. Inspired by the chemist's vision on molecules, we presented herein an ensemble descriptor, SPOC, curated on the principles of physical organic chemistry that integrates Structure and Physicochemical property (SPOC) of a molecule. SPOC could be readily constructed by combining molecular fingerprints, representing the structure of a given molecule, and molecular physicochemical properties extracted from RDKit or Mordred molecular descriptors. The applicability of SPOC was fully surveyed in a range of well-structured chemical databases with machine learning tasks varying from regression to classifications.

16.
Signal Transduct Target Ther ; 7(1): 141, 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35484110

RESUMO

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, there have been a few variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), one of which is the Omicron variant (B.1.1.529). The Omicron variant is the most mutated SARS-CoV-2 variant, and its high transmissibility and immune evasion ability have raised global concerns. Owing to its enhanced transmissibility, Omicron has rapidly replaced Delta as the dominant variant in several regions. However, recent studies have shown that the Omicron variant exhibits reduced pathogenicity due to altered cell tropism. In addition, Omicron exhibits significant resistance to the neutralizing activity of vaccines, convalescent serum, and most antibody therapies. In the present review, recent advances in the molecular and clinical characteristics of the infectivity, pathogenicity, and immune evasion of Omicron variant was summarized, and potential therapeutic applications in response to Omicron infection were discussed. Furthermore, we highlighted potential response to future waves and strategies to end the pandemic.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/genética , COVID-19/terapia , Humanos , Imunização Passiva , SARS-CoV-2/genética
17.
Signal Transduct Target Ther ; 7(1): 143, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35487886

RESUMO

The global coronavirus disease 2019 (COVID-19) pandemic is currently ongoing. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A high proportion of COVID-19 patients exhibit gastrointestinal manifestations such as diarrhea, nausea, or vomiting. Moreover, the respiratory and gastrointestinal tracts are the primary habitats of human microbiota and targets for SARS-CoV-2 infection as they express angiotensin-converting enzyme-2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) at high levels. There is accumulating evidence that the microbiota are significantly altered in patients with COVID-19 and post-acute COVID-19 syndrome (PACS). Microbiota are powerful immunomodulatory factors in various human diseases, such as diabetes, obesity, cancers, ulcerative colitis, Crohn's disease, and certain viral infections. In the present review, we explore the associations between host microbiota and COVID-19 in terms of their clinical relevance. Microbiota-derived metabolites or components are the main mediators of microbiota-host interactions that influence host immunity. Hence, we discuss the potential mechanisms by which microbiota-derived metabolites or components modulate the host immune responses to SARS-CoV-2 infection. Finally, we review and discuss a variety of possible microbiota-based prophylaxes and therapies for COVID-19 and PACS, including fecal microbiota transplantation (FMT), probiotics, prebiotics, microbiota-derived metabolites, and engineered symbiotic bacteria. This treatment strategy could modulate host microbiota and mitigate virus-induced inflammation.


Assuntos
COVID-19 , Microbiota , COVID-19/complicações , COVID-19/terapia , Linhagem Celular , Humanos , Peptidil Dipeptidase A/metabolismo , SARS-CoV-2
18.
Chemosphere ; 300: 134522, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35395265

RESUMO

Volatile organic compounds (VOCs) contamination may occur in subsurface soil due to various reasons and pose great threat to people. Petroleum hydrocarbon compound (PHC) is a typical kind of VOC, which can readily biodegrade in an aerobic environment. The biodegradation of vapor-phase PHC in the vadose zone consumes oxygen in the soil, which leads to the change in aerobic and anaerobic zones but has not been studied by the existing analytical models. In this study, a one-dimensional analytical model is developed to simulate the transient diffusion and oxygen-limited biodegradation of PHC vapor in homogeneous soil. Laplace transformation and Laplace inversion of the Talbot method are adopted to derive the solution. At any given time, the thickness of aerobic zone is determined by the dichotomy method. The analytical model is verified against numerical simulation and experimental results first and parametric study is then conducted. The transient migration of PHC vapor can be divided into three stages including the pure aerobic zone stage (Stage I), aerobic-anaerobic zones co-existence stage (Stage II), and steady-state stage (Stage III). The proposed analytical model should be adopted to accommodate scenarios where the transient effect is significant (Stage II), including high source concentration, deep contaminant source, high biodegradation capacity, and high water saturation. The applicability of this model to determine the breakthrough time for better vapor intrusion assessment is also evaluated. Lower first-order biodegradation rate, higher source concentration, and shallower source depth all lead to smaller breakthrough time.

19.
Bioorg Med Chem Lett ; 66: 128730, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35421578

RESUMO

ALK gene rearrangements are oncogenic drivers in approximately 5% of NSCLC. Crizotinib, a first generation ALK inhibitor, is widely prescribed for ALK-positive NSCLC in clinic. Resistance to crizotinib and other ALK inhibitors has been problematic. Addressing resistance, here we describe discovery and development of a novel, proprietary spirocyclic diamine-substituted aryl phosphine oxide series of inhibitors, which led to the identification of WX-0593 (16a) as a potent ALK inhibitor. WX-0593 inhibited the activity of both wild type and resistant mutants of ALK in vitro, showed strong antitumor activity in a crizotinib-resistant mouse PDX model. WX-0593 is currently under development in phase II/III clinical trials.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Crizotinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases
20.
J Mol Graph Model ; 114: 108189, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35453046

RESUMO

Bacterial resistance caused by widespread use and abuse of antibiotics is threatening human health, and the development of new antibacterial agents with novel antibacterial targets has become urgent. Filamenting temperature-sensitive mutant Z (FtsZ), as a key protein in bacterial division, has received extensive attention. PC190723 exhibits an outstanding antibacterial activity by producing potent inhibitory ability on FtsZ protein, but its influence on the conformation of FtsZ protein at the molecular level is still unclear. In this study, we explored the effect of PC190723 on the conformation and function of FtsZ protein through molecular dynamics (MD) simulation and post-analysis. The results showed that PC190723 increased the high-affinity conformational stability of FtsZ protein, which disrupts the normal assembly of the Z-ring. In particular, the interactions of residues S8-sheet (VAL260-GLY266) increased in the FtsZPC190723 system, which may be the reason for promotes the formation of protofilament. In brief, the mechanism of PC190723 inhibiting FtsZ protein was explained at the molecular level by MD simulation, which provides new ideas for the identification of new FtsZ inhibitors as antibacterial agents.

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