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1.
NPJ Precis Oncol ; 6(1): 2, 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35027673

RESUMO

Several clinical trials have shown the safety and effectiveness of PD-1/PD-L1 inhibitors in neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC). However, 18-83% patients can benefit from it. In this study, we aimed to assess the association of PD-L1 expression, tumor mutation burden, copy number alteration (CNA, including copy number gain and loss) burden with the pathologic response to neoadjuvant PD-1 blockade and investigate the changes in the tumor immune microenvironment (TIME) during neoadjuvant immunotherapy in NSCLC. Pre-immunotherapy treatment tumor samples from twenty-nine NSCLC patients who received neoadjuvant immunotherapy with sintilimab, an anti-PD-1 drug, were subjected to targeted DNA sequencing and PD-L1 immunochemistry staining. The pathological response was positively correlated with tumor proportion score (TPS) of PD-L1 and negatively correlated with copy number gain (CNgain) burden. Of note, the combination of CNgain burden and TPS can better stratify major pathological response (MPR) patients than did CNgain or TPS alone. Whereas, TMB showed a limited correlation with pathological regression. Additionally, PD-1 blockade led to an increase in CD8+PD-1-T cells which was clinically relevant to MPR as evaluated by multiplex immunofluorescence. A significant reduction in CD19+ cells was observed in the Non-MPR group but not in the MPR group, indicating the involvement of B cells in improving neoadjuvant immunotherapy response in NSCLC. Together, our study provides new data for the correlation of PD-L1 expression and genomic factors with drug response in neoadjuvant immunotherapy settings in NSCLC. The changes of TIME may provide novel insight into the immune responses to neoadjuvant anti-PD-1 therapy.

2.
Hepatology ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35007334

RESUMO

The study objective was to compare the effectiveness of microwave ablation (MWA) and laparoscopic liver resection (LLR) on solitary 3-5cm HCC over time. From 2008 to 2019, 1,289 patients from 12 hospitals were enrolled in this retrospective study. Diagnosis of all lesions were based on histopathology. Propensity score matching (PSM) was used to balance all baseline variables between the two groups in 2008-2019 (n =335 in each group) and 2014-2019 (n =257 in each group) cohorts, respectively. For cohort 2008-2019, during a median follow-up of 35.8 months, there were no differences in overall survival (OS) between MWA and LLR (Hazard ratio (HR): 0.88, 95% confidence interval (CI) 0.65-1.19, P =0.420), and MWA was inferior to LLR regarding disease-free survival (DFS) (HR 1.36, 95%CI (1.05-1.75), P =0.017). For cohort 2014-2019, there was comparable OS (HR 0.85, 95%CI (0.56-1.30), P =0.460) and approached statistical significance for DFS (HR 1.33, 95%CI (0.98-1.82), P =0.071) between MWA and LLR. Subgroup analyses showed comparable OS in 3.1-4.0cm HCCs (HR 0.88, 95%CI (0.53-1.47), P =0.630) and 4.1-5.0cm HCCs (HR 0.77, 95%CI (0.37-1.60), P =0.483) between two modalities. For both cohorts, MWA shared comparable major complications (both P >0.05), shorter hospitalization and lower cost to LLR (all P <0.001). Conclusion: MWA might be a first-line alternative to LLR for solitary 3-5cm HCC in selected patients with technical advances, especially for patients unsuitable for LLR.

3.
Nat Commun ; 13(1): 130, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013271

RESUMO

Mechanochemistry has been studied for some time, but research on the reactivity of charges exchanged by contact-electrification (CE) during mechanical stimulation remains scarce. Here, we demonstrate that electrons transferred during the CE between pristine dielectric powders and water can be utilized to directly catalyze reactions without the use of conventional catalysts. Specifically, frequent CE at Fluorinated Ethylene Propylene (FEP) - water interface induces electron-exchanges, thus forming reactive oxygen species for the degradation of an aqueous methyl orange solution. Contact-electro-catalysis, by conjunction of CE, mechanochemistry and catalysis, has been proposed as a general mechanism, which has been demonstrated to be effective for various dielectric materials, such as Teflon, Nylon-6,6 and rubber. This original catalytic principle not only expands the range of catalytic materials, but also enables us to envisage catalytic processes through mechano-induced contact-electrification.

4.
Langmuir ; 2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-34979082

RESUMO

Modern electronics continue to shrink down the sizes while becoming more and more powerful. To improve heat dissipation of electronics, fillers used in the semiconductor packaging process need to possess both high electrical and thermal conductivity. Graphene is known to improve thermal conductivity but suffers from van der Waals interactions and thus poor processibility. In this study, we wrapped silver microflakes with graphene sheets, which can enable intercoupling of phonon- and electron-based thermal transport, to improve the thermal conductivity. Using just 1.55 wt % graphene for wrapping can achieve a 2.64-times greater thermal diffusivity (equivalent to 254.196 ± 10.123 W/m·K) over pristine silver flakes. Graphene-wrapped silver flakes minimize the increase of electrical resistivity, which is one-order higher (1.4 × 10-3 Ω·cm) than the pristine flakes (5.7 × 10-4 Ω·cm). Trace contents of wrapped graphene (<1.55 wt %) were found to be enough to bridge the void between Ag flakes, and this enhances the thermal conductivity. Graphene loading at 3.76 wt % (beyond the threshold of 1.55 wt %) results in the significant graphene aggregation that decreases thermal diffusivity to as low as 16% of the pristine Ag filler. This work recognizes that suitable amounts of graphene wrapping can enhance heat dissipation, but too much graphene results in unwanted aggregation that hinders thermal conducting performance.

5.
Phytochemistry ; 196: 113077, 2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-34990976

RESUMO

A total of twelve highly oxygenated isoryanodane (also known as cinncassiol D-type) diterpenoids including nine undescribed ones, named cinnacassins A-I, were isolated from the leaves of Cinnamomum cassia. Their chemical structures were elucidated by extensive spectrometric and spectroscopic techniques including HRESIMS, 1D and 2D NMR, single-crystal X-ray diffraction analysis, calculated 13C-NMR DP4+ analysis, and chemical methods. The absolute configuration of cinnacassin A was unambiguously delineated by single-crystal X-ray diffraction analysis. Cinnacassin H represents the first example of 16-O-glucosylated isoryanodane diterpenoid, and cinnacassin I is the first isoryanod-13(18)-ene diterpenoid. The relationship of the configuration C-18 and the chemical shifts of H2-19 and C-20 in the 19-hydroxy-isoryanodane diterpenoids was discussed, and the 18S-configuration of three known 19-hydroxy-isoryanodane diterpenoids, cinncassiol D1, 19-O-ß-D-glucopyranosyl-cinncassiol D1, and cinncassiol D3 was assigned. All the isolated isoryanodane diterpenoids were evaluated for their immunomodulatory effects in vitro, and cinnacassin A and cinncassiol D1 enhanced the proliferation of Con A-induced murine T cells with enhancement rates ranging from 17.9% to 45.4%, which were more potent than the positive control, thymosin α1. In addition, cinncassiol D1 significantly promoted the proliferation of LPS-induced murine B cells with an enhancement rate up to 116.1%, two-fold more potent than thymosin α1 at a concentration of 1.5625 µM.

6.
J Environ Sci (China) ; 111: 229-239, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34949352

RESUMO

Eutrophication and harmful cyanobacterial blooms threaten water resources all over the world. There is a great controversy about controlling only phosphorus or controlling both nitrogen and phosphorus in the management of lake eutrophication. The primary argument against the dual nutrients control of eutrophication is that nitrogen fixation can compensate the nitrogen deficits. Thus, it is of great necessary to study the factors that can significantly affect the nitrogen fixation. Due to the difference of climate and human influence, the water quality of different lakes (such as water temperature, N:P ratio and water residence time) is also quite different. Numerous studies have reported that the low N:P ratio can intensify the nitrogen fixation capacities. However, the effects of temperature and water residence time on the nitrogen fixation remain unclear. Thus, 30 shallows freshwater lakes in the eastern plain of China were selected to measure dissolved N2 and Ar concentrations through N2: Ar method using a membrane inlet mass spectrometer to quantify the nitrogen fixation capacities and investigate whether the temperature and water residence time have a great impact on nitrogen fixation. The results have shown that the short lake water residence time can severely inhibit the nitrogen fixation capacities through inhibiting the growth of nitrogen-fixing cyanobacteria, changing the N:P ratio and resuspending the solids from sediments. Similarly, lakes with low water temperature also have a low nitrogen fixation capacity, suggesting that controlling nitrogen in such lakes is feasible if the growth of cyanobacteria is limited by nitrogen.


Assuntos
Cianobactérias , Eutrofização , China , Humanos , Lagos , Nitrogênio/análise , Fósforo/análise , Temperatura
7.
Exp Neurol ; 347: 113899, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34678230

RESUMO

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) destroys white matter, and this destruction is aggravated by secondary neuroinflammatory reactions. Although white matter injury (WMI) is strongly correlated with poor neurological function, understanding of white matter integrity maintenance is limited, and no available therapies can effectively protect white matter. One candidate approach that may fulfill this goal is cannabinoid receptor 2 (CB2) agonist treatment. Here, we confirmed that a selective CB2 agonist, JWH133, protected white matter after TBI. METHODS: The motor evoked potentials (MEPs), open field test, and Morris water maze test were used to assess neurobehavioral outcomes. Brain tissue loss, WM damage, Endoplasmic reticulum stress (ER stress), microglia responses were evaluated after TBI. The functional integrity of WM was measured by diffusion tensor imaging (DTI) and transmission electron microscopy (TEM). Primary microglia and oligodendrocyte cocultures were used for additional mechanistic studies. RESULTS: JWH133 increased myelin basic protein (MBP) and neurofilament heavy chain (NF200) levels and anatomic preservation of myelinated axons revealed by DTI and TEM. JWH133 also increased the numbers of oligodendrocyte precursor cells and mature oligodendrocytes. Furthermore, JWH133 drove microglial polarization toward the protective M2 phenotype and modulated the redistribution of microglia in the striatum. Further investigation of the underlying mechanism revealed that JWH133 downregulated phosphorylation of the protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) signaling pathway and its downstream signals eukaryotic translation initiation factor 2 α (eIF2α), activating transcription factor 4 (ATF4) and Growth arrest and DNA damage-inducible protein (GADD34); this downregulation was followed by p-Protein kinase B(p-Akt) upregulation. In primary cocultures of microglia and oligodendrocytes, JWH133 decreased phosphorylated PERK expression in microglia stimulated with tunicamycin and facilitated oligodendrocyte survival. These data reveal that JWH133 ultimately alleviates WMI and improves neurological behavior following TBI. However, these effects were prevented by SR144528, a selective CB2 antagonist. CONCLUSIONS: This work illustrates the PERK-mediated interaction between microglia and oligodendrocytes. In addition, the results are consistent with recent findings that microglial polarization switching accelerates WMI, highlighting a previously unexplored role for CB2 agonists. Thus, CB2 agonists are potential therapeutic agents for TBI and other neurological conditions involving white matter destruction.


Assuntos
Canabinoides/farmacologia , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/metabolismo , Transdução de Sinais/fisiologia , Substância Branca/metabolismo , eIF-2 Quinase/biossíntese , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Canabinoides/uso terapêutico , Células Cultivadas , Modelos Animais de Doenças , Potencial Evocado Motor/efeitos dos fármacos , Potencial Evocado Motor/fisiologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Ratos , Ratos Sprague-Dawley , Substância Branca/diagnóstico por imagem , Substância Branca/efeitos dos fármacos , Substância Branca/lesões , eIF-2 Quinase/antagonistas & inibidores
8.
J Hazard Mater ; 424(Pt B): 127546, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34879532

RESUMO

Thorium is a radioactive heavy metal and an emerging environmental pollutant. Ecological and human health risks from thorium exposure are growing with the excavation of rare earth metals and implementation of thorium-based nuclear reactors. Thorium poisoning is associated with carcinogenesis, liver impairments, and congenital anomalies. To date, the biomolecular targets that underlie thorium-induced toxicity remain unknown. Here, we used in vitro enzymatic activity assays to comprehensively evaluate the effects of thorium on the mitochondrial respiration process. Thorium was found to inhibit respiratory chain complex IV (cytochrome c oxidase) at sub-micromolar concentrations (IC50 ~ 0.4 µM, 90 µg/L). This is lower than the thorium level limit (246 µg/L) in drinking water specified by the World Health Organization. The inhibitory effects were further verified in mitochondria from human bone and liver cells (thorium mainly deposits in these organs). The inhibition of cytochrome c oxidase can readily rationalize well-documented cellular toxicities of thorium, such as alteration of mitochondrial membrane potential and production of reactive oxygen species. Therefore, cytochrome c oxidase is potentially a key molecular target underlying thorium-induced toxicological effect.

9.
Brain Behav Immun ; 99: 119-129, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34563620

RESUMO

AIM: Gut microbiota play an important role in the pathogenesis of gut hypomotility and are critical for the production of the intestinal immune system and the maintenance of the intestinal homeostasis. Patients with psychotic disorders are at a high risk of antipsychotic-induced constipation. However, the mechanisms might be more than neurotransmission properties of antipsychotics. METHODS: We recruited a total of 45 patients with constipation according to Rome IV criteria and objective test for colonic motility and the other 45 gender- and age-matching patients without constipation and investigated their differences in composition of gut microbiota. The demographic and serum metabolic indices were collected. The subjective constipation assessment scale (CAS) and the Bristol stool classification (BSS) were also used to evaluate the degree of constipation in both groups. The fecal samples were analysed using the 16S rRNA gene sequencing. RESULTS: The constipation group had a significantly increased alpha diversity in Observed species, Chao 1, and ACE as compared to the non-constipation group. At the phylum levels, the relative abundances of Bacteroidetes and Fusobacteria decreased significantly, while those of Firmicutes, Verrucomicrobia, and Synergistetes increased significantly in the constipation group. At the genus level, the relative abundances of Christensenella and Desulfovibrio were higher in the constipation group. The α-diversity indices of gut microbiota were correlated positively with the levels of serum total bile acid and correlated negatively with BSS scores. The BSS scores were positively correlated with the relative abundance of Bacteroidetes but negatively correlated with the relative abundance of Firmicutes. PICRUSt analysis revealed the potential metabolic pathways of lipopolysaccharide, vitamin B6, riboflavin, pyruvate, and propionate functions. CONCLUSIONS: The alternation of the gut microbiota in schizophrenia patients with antipsychotic-induced constipation indicates antipsychotic agents might affect gastrointestinal motility via varying microbiome-related metabolites, and the specific bacteria, such as Synergistetes which might act as an anti-inflammatory factor in the healthy human gut, related to colonic transit motility seem inconsistent to the findings from previous literature in gastroenterology. However, the causal effects are still unknown. Our study provides a new possibility to understand the mechanisms of antipsychotic-induced constipation.

10.
J Hazard Mater ; 423(Pt A): 127032, 2022 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-34474365

RESUMO

An integrated gasification-flameless combustion-melting process was approached by a twin-cyclonic flow in a hazardous waste thermal treatment plant. A series of advanced scrubber, cyclonic demister, activated carbon adsorption, and baghouse processes were equipped for the end-of-pipe treatment. The untreated filterable particulate matter, CO, and NOx levels were only 283, 47.1, and 15.9 mg/Nm3, indicating the flameless combustion inhibited their formation by narrowing the post-combustion zone. The filterable particle mass-size distribution was equally contributed by nucleation, accumulation, and coarse formations, while their number concentration was predominated by nucleation (99.6%). That could enhance the adsorption of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) on ultrafine particles. Both total mass and toxic equivalent concentrations of PCDD/Fs were reduced 99.9% by the new air pollution control system when a slight reformation occurred during scrubbing. However, the escaped PCDD/Fs were mainly distributed on the ultrafine particles, which should be further inhibited by either increasing their sizes or equipping backup filtrations. Finally, the new process concentrates the PCDD/Fs into the scrubbing sludge, which could be recirculated back into the thermal process. This study not only reveals the emission risk of the ultrafine particle-bound PCDD/Fs, but also provides an effective process to remove them for industrial application.


Assuntos
Poluentes Atmosféricos , Benzofuranos , Dibenzodioxinas Policloradas , Poluentes Atmosféricos/análise , Dibenzofuranos , Dibenzofuranos Policlorados/análise , Monitoramento Ambiental , Resíduos Perigosos/análise , Incineração , Tamanho da Partícula , Dibenzodioxinas Policloradas/análise
11.
Neural Regen Res ; 17(3): 577-586, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34380897

RESUMO

MicroRNA-491-5p (miR-491-5p) plays an important role in regulating cell proliferation and migration; however, the effect of miR-491-5p on neovascularization after traumatic brain injury remains poorly understood. In this study, a controlled cortical injury model in C57BL/6 mice and an oxygen-glucose deprivation model in microvascular endothelial cells derived from mouse brain were established to simulate traumatic brain injury in vivo and in vitro, respectively. In the in vivo model, quantitative real-time-polymerase chain reaction results showed that the expression of miR-491-5p increased or decreased following the intracerebroventricular injection of an miR-491-5p agomir or antagomir, respectively, and the expression of miR-491-5p decreased slightly after traumatic brain injury. To detect the neuroprotective effects of miR-491-p, neurological severity scores, Morris water maze test, laser speckle techniques, and immunofluorescence staining were assessed, and the results revealed that miR-491-5p downregulation alleviated neurological dysfunction, promoted the recovery of regional cerebral blood flow, increased the number of lectin-stained microvessels, and increased the survival of neurons after traumatic brain injury. During the in vitro experiments, the potential mechanism of miR-491-5p on neovascularization was explored through quantitative real-time-polymerase chain reaction, which showed that miR-491-5p expression increased or decreased in brain microvascular endothelial cells after transfection with an miR-491-5p mimic or inhibitor, respectively. Dual-luciferase reporter and western blot assays verified that metallothionein-2 was a target gene for miR-491-5p. Cell counting kit 8 (CCK-8) assay, flow cytometry, and 2?,7?-dichlorofluorescein diacetate (DCFH-DA) assay results confirmed that the downregulation of miR-491-5p increased brain microvascular endothelial cell viability, reduced cell apoptosis, and alleviated oxidative stress under oxygen-glucose deprivation conditions. Cell scratch assay, Transwell assay, tube formation assay, and western blot assay results demonstrated that miR-491-5p downregulation promoted the migration, proliferation, and tube formation of brain microvascular endothelial cells through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor pathway. These findings confirmed that miR-491-5p downregulation promotes neovascularization, restores cerebral blood flow, and improves the recovery of neurological function after traumatic brain injury. The mechanism may be mediated through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway and the alleviation of oxidative stress. All procedures were approved by Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China (approval No. 2020-304) on June 22, 2020.

12.
Food Chem ; 367: 130660, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34390907

RESUMO

In this work, a quantitative image analysis method based on cyanine dye-upconversion nanoparticles composite luminescent nanoprobe for the detection of nitrite was developed. The nanoprobe was constructed by combining the NaYF4:Yb,Tm@NaYF4 upconversion nanoparticles (UCNPs) and the new cyanine dye IR-790. The upconversion nanoparticles transferred energy to IR-790, resulting in the luminescence quenching, while the luminescence of UCNPs was recovered after adding NO2-. The increase in photons was related to the concentration of NO2-. Under the optimal experimental conditions, the detection range was 0.20-140 µM and the limit of detection was 0.030 µM. The measurement for NO2- can be completed in 29 min. The method has the characteristics of fast response (~0.1 s), low sample consumption (10 µL) and powerful data support (550 frame time series images). Furthermore, the quantitative image analysis method was successfully applied for the analysis of nitrite in environmental water and food samples.


Assuntos
Luminescência , Nanopartículas , Corantes , Nitritos
13.
Neural Regen Res ; 17(1): 163-169, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34100452

RESUMO

Studies have shown that downregulation of nuclear-enriched autosomal transcript 1 (Neat1) may adversely affect the recovery of nerve function and the increased loss of hippocampal neurons in mice. Whether Neat1 has protective or inhibitory effects on neuronal cell apoptosis after secondary brain injury remains unclear. Therefore, the effects of Neat1 on neuronal apoptosis were observed. C57BL/6 primary neurons were obtained from the cortices of newborn mice and cultured in vitro, and an oxygen and glucose deprivation cell model was established to simulate the secondary brain injury that occurs after traumatic brain injury in vitro. The level of Neat1 expression in neuronal cells was regulated by constructing a recombinant adenovirus to infect neurons, and the effects of Neat1 expression on neuronal apoptosis after oxygen and glucose deprivation were observed. The experiment was divided into four groups: the control group, without any treatment, received normal culture; the oxygen and glucose deprivation group were subjected to the oxygen and glucose deprivation model protocol; the Neat1 overexpression and Neat1 downregulation groups were treated with Neat1 expression intervention techniques and were subjected to the in oxygen and glucose deprivation protocol. The protein expression levels of neurons p53-induced death domain protein 1 (PIDD1, a pro-apoptotic protein), caspase-2 (an apoptotic priming protein), cytochrome C (a pro-apoptotic protein), and cleaved caspase-3 (an apoptotic executive protein) were measured in each group using the western blot assay. To observe changes in the intracellular distribution of cytochrome C, the expression levels of cytochrome C in the cytoplasm and mitochondria of neurons from each group were detected by western blot assay. Differences in the cell viability and apoptosis rate between groups were detected by cell-counting kit 8 assay and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, respectively. The results showed that the apoptosis rate, PIDD1, caspase-2, and cleaved caspase-3 expression levels significantly decreased, and cell viability significantly improved in the Neat1 overexpression group compared with the oxygen and glucose deprivation group; however, Neat1 downregulation reversed these changes. Compared with the Neat1 downregulation group, the cytosolic cytochrome C level in the Neat1 overexpression group significantly decreased, and the mitochondrial cytochrome C level significantly increased. These data indicate that Neat1 upregulation can reduce the release of cytochrome C from the mitochondria to the cytoplasm by inhibiting the PIDD1-caspase-2 pathway, reducing the activation of caspase-3, and preventing neuronal apoptosis after oxygen and glucose deprivation, which might reduce secondary brain injury after traumatic brain injury. All experiments were approved by the Animal Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China, on December 19, 2020 (approval No. 2020-895).

14.
Methods Mol Biol ; 2410: 209-228, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34914049

RESUMO

The COVID-19 pandemic brought to the fore the urgent need for vaccine design and delivery platforms that can be rapidly deployed for manufacture and distribution. Though the mRNA and adenoviral vector platforms have been enormously successful to control SARS-CoV-2 viral infections, it is unclear if this could be replicated against more complex pathogens or the emerging variants. Recently, we described a "universal" platform that can incorporate multiple vaccine targets into the same nanoparticle scaffold by CRISPR engineering of bacteriophage T4. A T4-COVID vaccine designed with this technology elicited broad immunogenicity and complete protection against virus challenge in a mouse model. Here, we describe the detailed methodology to generate recombinant bacteriophage T4 backbones using CRISPR that can also be broadly applicable to other bacteriophages that abundantly pervade the Earth.


Assuntos
Bacteriófago T4 , Vacinas contra COVID-19 , COVID-19 , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Animais , Bacteriófago T4/genética , COVID-19/prevenção & controle , Humanos , Camundongos , Pandemias , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus
15.
Environ Pollut ; 294: 118661, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34896219

RESUMO

Zinc oxide nanoparticles (ZnO NPs) and its sulfidized form (ZnS NPs) are increasingly entering into freshwater systems through multiple pathways. However, their impacts on the composition and function of sedimentary microbial communities are still largely unknown. Here, two kinds of lake-derived microcosms were constructed and incubated with ZnO NPs, or ZnS NPs to investigate the short-term (7 days) and long-term (50 days) impacts on sedimentary microbial communities and nitrogen cycling. After 7 days, both ZnO NPs and ZnS NPs dosed microbial communities experienced distinct alterations as compared to the undosed controls. By day 50, the structural shifts of microbial communities caused by ZnO NPs were significantly enlarged, while the microbial shifts induced by ZnS NPs were largely resolved. Additionally, ZnO NPs and ZnS NPs could significantly alter nitrogen species and nitrogen cycling genes in sediments, revealing their non-negligible impacts on nitrogen cycling processes. Furthermore, our data clearly indicated that the impacts of ZnO NPs and ZnS NPs on nitrogen cycling differed distinctly in different lake-derived microcosms, and the impacts were significantly correlated with microbial community structure. Overall, this research suggests that the entrance of pristine or sulfidized ZnO NPs into freshwater systems may significantly impact the sedimentary microbial community structure and nitrogen cycling.


Assuntos
Lagos/microbiologia , Nanopartículas Metálicas/toxicidade , Microbiota , Ciclo do Nitrogênio , Óxido de Zinco , Óxido de Zinco/toxicidade
16.
Nanoscale ; 14(2): 263-276, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34918733

RESUMO

Mucosal vaccination can elicit both systemic and mucosal immunity, and therefore has the potential to not only treat mucosal immune diseases, prevent the pathogen infection at the mucosal entry sites, but also treat distant or systemic immune disorders. However, only a few mucosal vaccines have been approved for human use in the clinic. Effective mucosal immunization requires the delivery of immunogenic agents to appropriate mucosal surfaces, which remains significantly challenging due to the essential biological barriers presenting at mucosal tissues. In the past decade, remarkable progress has been made in the development of pulmonary mucosal nanovaccines. The nanovaccines leverage advanced nanoparticle-based pulmonary delivery technologies on the characteristics of large surface area and rich antigen presentation cell environment of the lungs for triggering robust immune protection against various mucosal diseases. Herein, we review current methods and formulations of pulmonary delivery, discuss the design strategies of mucosal nanovaccines for potent and long-lasting immune responses, and highlight recent advances in the application of lipid-based pulmonary nanovaccines against mucosal diseases. These advances promise to accelerate the development of novel mucosal nanovaccines for the prophylaxis and therapy of infectious diseases, and cancer, as well as autoimmune disorders at mucosal tissues.


Assuntos
Vacinas , Humanos , Imunidade nas Mucosas , Pulmão , Membrana Mucosa , Vacinação
17.
Int J Nanomedicine ; 16: 7831-7846, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34876812

RESUMO

Purpose: Small extracellular vesicles (sEV) play an irreplaceable role in cell-cell communication. However, sEV in solution aggregate with each other during preservation, leading to impairment of the structures, contents, and functions of sEV. Therefore, there is a need to develop an optimal preservation method that combines high recovery rate, low cost, convenience, and easy-transportation in one. In this study, a new preservation strategy different from the cryopreservation or lyophilization was developed by reducing sEV particles aggregation. Methods: The sEV were encapsulated in thermoresponsive gelatin methacryloyl (GelMA) hydrogels at 4°C to reduce particles aggregation during the reversible cross-linking process. The sEV movement was visualized in different mediums and particles' number, size, structure and protein of 28 days preserved sEV were compared to fresh sEV. Human umbilical vein endothelial cells (HUVEC) and rat adipose-derived stromal stem cells (rASC) were isolated and cultured with fresh and preserved sEV to test the cellular response. A mice subcutaneous model was adopted to detect controlled release and angiogenesis ability of preserved sEV. Results: Through particles tracks visualization, GelMA hydrogels significantly decreased the sEV movement. After 28 days preservation in GelMA at 4°C, the particles number, size, structure and protein of sEV were similar to fresh sEV. In vitro, preserved sEV had the same ability to promote cell proliferation, migration and angiogenesis as fresh sEV. In vivo, preserved sEV-GelMA could artificially regulate the absorptivity of GelMA hydrogels and controlled released sEV for therapeutic application, and preserved sEV encapsulated in GelMA significantly promoted angiogenesis in mice. Conclusion: Our results demonstrated that sEV encapsulated in GelMA could be a novel strategy for long-term preservation of sEV for therapeutic application.

18.
Artigo em Inglês | MEDLINE | ID: mdl-34851543

RESUMO

Sepsis, characterized with high risk of life-threatening organ dysfunction represents a major cause of health loss and World Health Organization (WHO) has labelled sepsis as the most urgent unmet medical need in 2017. The emerging biological understanding of the role of RIPK1 in sepsis has opened up an exciting opportunity to explore potent and selective RIPK1 inhibitors as an effective therapeutic strategy for SIRS and sepsis therapy. Herein, we synthesized a class of highly potent dual-mode RIPK1 inhibitors occupying both the allosteric and the ATP binding pockets, exemplified by compound 21 ( ZB-R-55 ) which is about 10-fold more potent than GSK2982772 , and exhibits excellent kinase selectivity, good oral pharmacokinetics and good therapeutic effects in the LPS-induced sepsis model, suggesting that compound ZB-R-55 is a highly promising preclinical candidate.

19.
J Chem Inf Model ; 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34873908

RESUMO

Traditionally, it is believed that the substrate and products of a monoacylglycerol lipase (MGL) share the same path to enter and exit the catalytic site. Glycerol (a product of MGL), however, was recently hypothesized to be released through a different path. In order to improve the catalytic efficacy and thermo-stability of MGL, it is important to articulate the pathways of a MGL products releasing. In this study, with structure biological approaches, biochemical experiments, and in silico methods, we prove that glycerol is released from a different path in the catalytic site indeed. The fatty acid (another product of MGL) does share the same binding path with the substrate. This discovery paves a new road to design MGL inhibitors or optimize MGL catalytic efficacy.

20.
Front Psychiatry ; 12: 769743, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858237

RESUMO

Objectives: This study aimed to investigate the effect of childhood trauma, especially its specific dimensions, and clinical risk factors for suicidal ideation in patients with schizophrenia. Methods: A total of 83 inpatients with schizophrenia were enrolled and divided into two groups: with suicidal ideation (n = 33) and without suicidal ideation (n = 50). All participants were administered the Childhood Trauma Questionnaire-Short Form, the Insomnia Severity Index, the Beck Scale for Suicide Ideation, the Modified Overt Aggression Scales, the auditory hallucination rating scale, the Hamilton Rating Scale of Depression and the Positive and Negative Syndrome Scale. Results: In our sample, 39.8% of the subjects had suicidal ideation, and 60.6% of them had suffered from childhood trauma. Patients with suicidal ideation had a higher Insomnia Severity Index score, Physical neglect score, the Childhood Trauma Questionnaire-Short Form total score (all P < 0.05) compared to those without. The logistic regression analysis revealed that physical neglect in Childhood Trauma Questionnaire was significantly associated with suicidal ideation (OR = 5.46, P < 0.05, 95% CI = 0.007-0.483). Further stepwise multiple linear regression identified that insomnia (ß = 0.272, P = 0.011) and physical neglect (ß = 0.257, P = 0.017) were strong risk factors for the severity of suicidal ideation in patients with schizophrenia. Mediation analysis showed that insomnia played a complete mediating role between physical neglect and suicidal ideation. Conclusion: Our results indicate that childhood maltreatment of physical neglect is a strong independent risk factor for suicidal ideation in schizophrenia. The risk is probably aggravated by the poor quality of sleep. Early screening and psychosocial treatment are recommended for psychotic individuals with a trauma history.

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