RESUMO
The animal origin of SARS-CoV-2 remains elusive, lacking a plausible evolutionary narrative that may account for its emergence. Its spike protein resembles certain segments of BANAL-236 and RaTG13, two bat coronaviruses considered possible progenitors of SARS-CoV-2. Additionally, its spike contains a furin motif, a common feature of rodent coronaviruses. To explore the possible involvement of rodents in the emergence of SARS-CoV-2 spike, we examined the crystal structures of the spike receptor-binding domains (RBDs) of BANAL-236 and RaTG13 each complexed with mouse receptor ACE2. Both RBDs have residues at positions 493 and 498 that align well with two virus-binding hotspots on mouse ACE2. Our biochemical evidence supports that both BANAL-236 and RaTG13 spikes can use mouse ACE2 as their entry receptor. These findings point to a scenario in which these bat coronaviruses may have coinfected rodents, leading to a recombination of their spike genes and a subsequent acquisition of a furin motif in rodents, culminating in the emergence of SARS-CoV-2.
Assuntos
Enzima de Conversão de Angiotensina 2 , Quirópteros , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Animais , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Quirópteros/virologia , Camundongos , SARS-CoV-2/metabolismo , SARS-CoV-2/química , Humanos , Receptores Virais/metabolismo , Receptores Virais/química , COVID-19/virologia , COVID-19/metabolismo , Cristalografia por Raios X , Ligação Proteica , Coronavirus/metabolismo , Coronavirus/genética , Modelos MolecularesRESUMO
Phagocytes promptly resolve ingested targets to replenish lysosomes and maintain their responsiveness. The resolution process requires that degradative hydrolases, solute transporters, and proteins involved in lipid traffic are delivered and made active in phagolysosomes. It also involves extensive membrane remodeling. We report that cation channels that localize to phagolysosomes were essential for resolution. Specifically, the conductance of Na+ by two-pore channels (TPCs) and the presence of a Na+ gradient between the phagolysosome lumen and the cytosol were critical for the controlled release of membrane tension that permits deformation of the limiting phagolysosome membrane. In turn, membrane deformation was a necessary step to efficiently transport the cholesterol extracted from cellular targets, permeabilizing them to hydrolases. These results place TPCs as regulators of endomembrane remodeling events that precede target degradation in cases when the target is bound by a cholesterol-containing membrane. The findings may help to explain lipid metabolism dysfunction and autophagic flux impairment reported in TPC KO mice and establish stepwise regulation to the resolution process that begins with lysis of the target.
Assuntos
Fagossomos , Canais de Dois Poros , Camundongos , Animais , Fagossomos/metabolismo , Lisossomos/metabolismo , Hidrolases/metabolismo , Colesterol/metabolismoRESUMO
A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-191,2. A key to tackling this pandemic is to understand the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor-angiotensin-converting enzyme 2 (ACE2)-in humans3,4. Here we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 (engineered to facilitate crystallization) in complex with ACE2. In comparison with the SARS-CoV RBD, an ACE2-binding ridge in SARS-CoV-2 RBD has a more compact conformation; moreover, several residue changes in the SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD-ACE2 interface. These structural features of SARS-CoV-2 RBD increase its ACE2-binding affinity. Additionally, we show that RaTG13, a bat coronavirus that is closely related to SARS-CoV-2, also uses human ACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in ACE2 recognition shed light on the potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies that target receptor recognition by SARS-CoV-2.
Assuntos
Betacoronavirus/química , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Receptores Virais/química , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Zoonoses/virologia , Enzima de Conversão de Angiotensina 2 , Animais , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/metabolismo , Sítios de Ligação , COVID-19 , China/epidemiologia , Quirópteros/virologia , Coronavirus/química , Coronavirus/isolamento & purificação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Cristalização , Cristalografia por Raios X , Reservatórios de Doenças/virologia , Eutérios/virologia , Humanos , Modelos Moleculares , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Ligação Proteica , Domínios Proteicos , Estabilidade Proteica , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/química , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Zoonoses/epidemiologia , Zoonoses/transmissãoRESUMO
The sudden emergence and rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant has raised questions about its animal reservoir. Here, we investigated receptor recognition of the omicron's receptor-binding domain (RBD), focusing on four of its mutations (Q493R, Q498R, N501Y, and Y505H) surrounding two mutational hotspots. These mutations have variable effects on the RBD's affinity for human angiotensin-converting enzyme 2 (ACE2), but they all enhance the RBD's affinity for mouse ACE2. We further determined the crystal structure of omicron RBD complexed with mouse ACE2. The structure showed that all four mutations are viral adaptations to mouse ACE2: three of them (Q493R, Q498R, and Y505H) are uniquely adapted to mouse ACE2, whereas the other one (N501Y) is adapted to both human ACE2 and mouse ACE2. These data reveal that the omicron RBD was well adapted to mouse ACE2 before omicron started to infect humans, providing insight into the potential evolutionary origin of the omicron variant.
Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Animais , Humanos , Camundongos , Enzima de Conversão de Angiotensina 2/genética , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Peptidil Dipeptidase A/metabolismo , COVID-19/genética , Ligação Proteica , MutaçãoRESUMO
BACKGROUND: Growing evidence indicates antimicrobial resistance disproportionately affects individuals living in socially vulnerable areas. This study evaluated the association between the CDC/ATSDR Social Vulnerability Index (SVI) and Streptococcus pneumoniae (SP) antimicrobial resistance (AMR) in the United States. METHODS: Adult patients ≥18 years with 30-day nonduplicate SP isolates from ambulatory/hospital settings from January 2011 to December 2022 with zip codes of residence were evaluated across 177 facilities in the BD Insights Research Database. Isolates were identified as SP AMR if they were non-susceptible to ≥1 antibiotic class (macrolide, tetracycline, extended-spectrum cephalosporins, or penicillin). Associations between SP AMR and SVI score (overall and themes) were evaluated using generalized estimating equations with repeated measurements within county to account for within-cluster correlations. RESULTS: Of 8008 unique SP isolates from 574 US counties across 39 states, the overall proportion of AMR was 49.9%. A significant association between socioeconomic status (SES) theme and SP AMR was detected with higher SES theme SVI score (indicating greater social vulnerability) associated with greater risk of AMR. On average, a decile increase of SES, indicating greater vulnerability, was associated with a 1.28% increased risk of AMR (95% confidence interval [CI], .61%, 1.95%; P = .0002). A decile increase of household characteristic score was associated with a 0.81% increased risk in SP AMR (95% CI, .13%, 1.49%; P = .0197). There was no association between racial/ethnic minority status, housing type and transportation theme, or overall SVI score and SP AMR. CONCLUSIONS: SES and household characteristics were the SVI themes most associated with SP AMR.
Assuntos
Antibacterianos , Infecções Pneumocócicas , Vulnerabilidade Social , Streptococcus pneumoniae , Humanos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/isolamento & purificação , Estados Unidos/epidemiologia , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/epidemiologia , Idoso , Farmacorresistência Bacteriana , Adulto Jovem , Adolescente , Testes de Sensibilidade MicrobianaRESUMO
IMPORTANCE: The COVID-19 pandemic exposed limitations of conventional antibodies as therapeutics, including high cost, limited potency, ineffectiveness against new viral variants, and primary reliance on injection-only delivery. Nanobodies are single-domain antibodies with therapeutic potentials. We discovered three anti-SARS-CoV-2 nanobodies, named Nanosota-2, -3, and -4, from an immunized alpaca. Nanosota-2 is super potent against prototypic SARS-CoV-2, Nanosota-3 is highly potent against the omicron variant, and Nanosota-4 is effective against both SARS-CoV-1 and SARS-CoV-2. In addition to their super potency and combined broad antiviral spectrum, these nanobodies are cost-effective, can be easily adapted to new viral variants through phage display, and can potentially be administered as inhalers. The Nanosota series are powerful therapeutic candidates to combat circulating SARS-CoV-2 and prepare for possible future coronavirus pandemics.
Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos de Domínio Único , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais/uso terapêutico , COVID-19/terapia , Pandemias , Anticorpos de Domínio Único/farmacologia , Glicoproteína da Espícula de CoronavírusRESUMO
BACKGROUND: Infections caused by multi-drug resistant Gram-negative pathogens are associated with worse clinical outcomes in critically ill patients. We evaluated hospital outcomes based on adequacy of overall and newer antibacterial therapy for Enterobacterales (ENT) and Pseudomonas aeruginosa (PsA) in US patients. METHODS: Hospitalized adults ≥ 18 years old with facility-reported antibiotic susceptibility from 2018-2022 across 161 facilities in the BD Insights Research Database were identified as ENT- or PsA-positive. Generalized linear mixed models were used to evaluate the impact of inadequate empiric therapy (IET) and time to initiate newer antibacterials (ceftazidime-avibactam; ceftolozane-tazobactam; cefiderocol; meropenem-vaborbactam; eravacycline; and imipenem-cilcastatin-relebactam) on hospital mortality and post-culture length of stay (LOS). RESULTS: Among 229,320 ENT and 36,027 PsA susceptibility results, 1.7% and 16.8% were carbapenem non-susceptible (carb-NS), respectively. Median time to first susceptibility result was longer for carb-NS vs. carb susceptible in ENT (64 h vs. 48 h) and PsA (67 h vs. 60 h). For ENT, IET was associated with significantly higher mortality (odds ratio [OR],1.29 [95% CI, 1.16-1.43, P < 0.0001]) and longer hospital LOS (14.8 vs. 13.3, P < 0.0001). Delayed start to newer antibacterial therapy was associated with significantly greater hospital mortality for ENT (P = 0.0182) and PsA (P = 0.0249) and significantly longer post-culture LOS for ENT (P < 0.0001) and PsA (P < 0.0001). CONCLUSIONS: Overall, IET and delayed use of newer antibacterials are associated with significantly worse hospital outcomes. More rapid identification of high-risk patients can facilitate adequate therapy and timely use of newer antibacterials developed for resistant Gram-negative pathogens.
Assuntos
Antibacterianos , Infecções por Pseudomonas , Pseudomonas aeruginosa , Humanos , Antibacterianos/uso terapêutico , Feminino , Masculino , Pseudomonas aeruginosa/efeitos dos fármacos , Pessoa de Meia-Idade , Idoso , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/mortalidade , Adulto , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/mortalidade , Testes de Sensibilidade Microbiana , Hospitalização , Tempo de Internação , Mortalidade Hospitalar , Enterobacteriaceae/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Resultado do Tratamento , Idoso de 80 Anos ou mais , Estados UnidosRESUMO
BACKGROUND: Evidence regarding the relationship between fasting blood glucose (FBG) and suicide attempts (SA) in patients with major depressive disorder (MDD) was limited. Therefore, the objective of this research was to investigate whether FBG was independently related to SA in Chinese patients with first-episode drug-naïve (FEDN) MDD after adjusting for other covariates. METHODS: The present study was a cross-sectional study. A total of 1718 participants (average age: 34.9 ± 12.4 years, 65.8% females) with FEDN MDD were involved in a hospital in China from September 2016 to December 2018. Multiple logistic regression analysis and smooth curve fitting were used to estimate the association between FBG and the risk of SA. The threshold effect was examined by the two-piecewise linear regression model. Interaction and stratified analyses were conducted according to sex, education, marital status, comorbid anxiety, and psychotic symptoms. RESULTS: The prevalence of SA in patients with FEDN MDD was 20.1%. The result of fully adjusted binary logistic regression showed FBG was positively associated with the risk of SA (odds ratio (OR) = 1.62, 95% CI: 1.13-2.32). Smoothing plots also revealed a nonlinear relationship between FBG and SA, with the inflection point of FBG being 5.34 mmol/l. The effect sizes and the confidence intervals on the left and right sides of the inflection point were 0.53 (0.32-0.88, P = 0.014) and 1.48 (1.04-2.10, P = 0.030), respectively. CONCLUSIONS: A U-shaped relationship between FBG and SA in FEDN MDD patients was found, with the lowest risk of SA at a FBG of 5.34 mmol/l, indicating that both the lower and higher FBG levels may lead to an increased risk of SA.
Assuntos
Glicemia , Transtorno Depressivo Maior , Tentativa de Suicídio , Humanos , Feminino , Masculino , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/epidemiologia , Adulto , Estudos Transversais , Tentativa de Suicídio/estatística & dados numéricos , Tentativa de Suicídio/psicologia , China/epidemiologia , Glicemia/análise , Pessoa de Meia-Idade , Jejum/sangue , Adulto Jovem , Fatores de Risco , Prevalência , População do Leste AsiáticoRESUMO
AIM: The impaired function of tubular mitochondria is critical in diabetic kidney disease (DKD) progression. RUNX3 is down-regulated in DKD models. We intend to explore the effects of RUNX3 on mitochondrial dysfunction and renal tubule injury in DKD and related mechanisms. METHODS: The development of diabetes models involved injecting mice with streptozotocin while treating HK-2 cells with high glucose (HG). By using immunohistochemical techniques, the renal localizations of RUNX3 were identified. Levels of adenosine triphosphate (ATP), mitochondrial membrane potential, and biochemical index were detected by appropriate kits. Reactive oxygen species (ROS) generation was assessed with dihydroethidium and MitoSOX Red staining. Apoptosis was assessed by flow cytometry and TUNEL. RUNX3 ubiquitination was measured. RESULTS: RUNX3 was mainly present in renal tubules. Overexpressing RUNX3 increased Mfn2, Mfn1, ATP levels, and mitochondrial membrane potential, reduced Drp1 and ROS levels and cell apoptosis, as well as Cyt-C release into the cytoplasm. RUNX3 overexpression displayed a reduction in urinary albumin to creatinine ratio, Hemoglobin A1c, serum creatinine, and blood urea nitrogen. Overexpressing TLR4 attenuated the inhibitory effect of RUNX3 overexpression on mitochondrial dysfunction and cell apoptosis. HG promoted RUNX3 ubiquitination and SMURF2 expression. RUNX3 knockdown cancelled the inhibitory effect of SMURF2 on mitochondrial dysfunction and cell apoptosis. CONCLUSION: SMURF2 interference inhibits RUNX3 ubiquitination and TLR4/NF-κB signalling pathway, thereby alleviating renal tubule injury.
Assuntos
Subunidade alfa 3 de Fator de Ligação ao Core , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Apoptose , Linhagem Celular , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Potencial da Membrana Mitocondrial , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genéticaRESUMO
Early studies have shown that the gut microbiota is a critical target during cadmium exposure. The prebiotic activity of epigallocatechin-3-gallate (EGCG) plays an essential role in treating intestinal inflammation and damage. However, the exact intestinal barrier protection mechanism of EGCG against cadmium exposure remains unclear. In this experiment, four-week-old mice were exposed to cadmium (5â¯mgâ¯kg-1) for four weeks. Through 16â¯S rDNA analysis, we found that cadmium disrupted the gut microbiota and inhibited the indole metabolism pathway of tryptophan (TRP), which serves as the principal microbial production route for endogenous ligands to activate the aryl hydrocarbon receptor (AhR). Additionally, cadmium downregulated the intestinal AhR signaling pathway and harmed the intestinal barrier function. Treatment with EGCG (20â¯mgâ¯kg-1) and the AhR agonist 6-Formylindolo[3,2-b] carbazole (FICZ) (1⯵g/d) significantly activated the AhR pathway and alleviated intestinal barrier injury. Notably, EGCG partially restored the gut microbiota and upregulated the TRP-indole metabolism pathway to increase the level of indole-related AhR agonists. Our findings demonstrate that cadmium dysregulates common gut microbiota to disrupt TRP metabolism, impairing the AhR signaling pathway and intestinal barrier. EGCG reduces cadmium-induced intestinal functional impairment by intervening in the intestinal microbiota to metabolize AhR agonists. This study offers insights into the toxic mechanisms of environmental cadmium and a potential mechanism to protect the intestinal barrier with EGCG.
Assuntos
Cádmio , Catequina , Microbioma Gastrointestinal , Receptores de Hidrocarboneto Arílico , Transdução de Sinais , Triptofano , Animais , Catequina/análogos & derivados , Catequina/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Triptofano/metabolismo , Triptofano/análogos & derivados , Cádmio/toxicidade , Transdução de Sinais/efeitos dos fármacos , Masculino , Intestinos/efeitos dos fármacos , Intestinos/patologia , Camundongos Endogâmicos C57BL , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Indóis/farmacologia , Carbazóis/farmacologiaRESUMO
Uranium extraction from seawater (UES), a potential approach to securing the long-term uranium supply and sustainability of nuclear energy, has experienced significant progress in the past decade. Promising adsorbents with record-high capacities have been developed by diverse innovative synthetic strategies, and scale-up marine field tests have been put forward by several countries. However, significant challenges remain in terms of the adsorbents' properties in complex marine environments, deployment methods, and the economic viability of current UES systems. This review presents an up-to-date overview of the latest advancements in the UES field, highlighting new insights into the mechanistic basis of UES and the methodologies towards the function-oriented development of uranium adsorbents with high adsorption capacity, selectivity, biofouling resistance, and durability. A distinctive emphasis is placed on emerging electrochemical and photochemical strategies that have been employed to develop efficient UES systems. The most recent achievements in marine tests by the major countries are summarized. Challenges and perspectives related to the fundamental, technical, and engineering aspects of UES are discussed. This review is envisaged to inspire innovative ideas and bring technical solutions towards the development of technically and economically viable UES systems.
Assuntos
Urânio , Urânio/química , Água do Mar/química , AdsorçãoRESUMO
Advanced oxidation technologies based on hydroxyl radical (â¢OH) and sulfate radical (SO4-â¢) are two common types of advanced oxidation technologies, but there are not many reports on the application of advanced oxidation methods in actual wastewater pretreatment. This article compares the pre-treatment performance of Fe2+/H2O2 and Fe2+/Persulfate systems in actual pharmaceutical wastewater, and combines EEM, GC-MS, and toxicity testing results to explore the differences in TOC, COD, and NH3-N removal rates, optimal catalyst dosage, applicable pH range, toxicity of effluent after reaction, and pollutant structure between the two systems. The results indicate that the Fe2+/H2O2 system has a higher pollutant removal rate (TOC: 71.9%, COD: 66.9%, NH3-N: 34.1%), but also requires a higher catalyst (Fe2+) concentration (6.0 g/L), and its effluent exhibits characteristic peaks of aromatic proteins. The Fe2+/Persulfate system has a wider pH range (pH ≈ 3-7) and is more advantageous in treating wastewater containing more cyclic organic compounds, but the effluent contains some sulfur-containing compounds. In addition, toxicity tests have shown that the toxicity reduction effect of the Fe2+/Persulfate system is stronger than that of the Fe2+/H2O2 system.
Assuntos
Poluentes Ambientais , Peróxido de Hidrogênio , Águas Residuárias , Cromatografia Gasosa-Espectrometria de Massas , Compostos de Enxofre , Preparações FarmacêuticasRESUMO
Bottom-up fabrication protocols for uniform 3D hierarchical structures in solution are rare. We report two different approaches to fabricate uniform 3D spherulites and their precursors using mixtures of poly(ferrocenyldimethylsilane) (PFS) block copolymer (BCP) and PFS homopolymer (HP). Both protocols are designed to promote defects in 2D assemblies that serve as intermediate structures. In a multistep seeded growth protocol, we add the BCP/HP mixture to (1D) rod-like PFS micelles in a selective solvent as first-generation seeds. This leads to 2D platelet structures. If this step is conducted at a high supersaturation, secondary crystals form on the basal surface of these platelets. Co-crystallization and rapid crystallization of BCP/HP promote the formation of defects that act as nucleation sites for secondary crystals, resulting in multilayer platelets. This is the key step. The multilayer platelets serve as second-generation seeds upon subsequent addition of BCP/HP blends and, with increasing supersaturation, lead to the sequential formation of uniform (3D) hedrites, sheaves, and spherulites. Similar structures can also be obtained by a simple one-pot direct self-assembly (heating-cooling-aging) protocol of PFS BCP/HP blends. In this case, for a carefully chosen but narrow temperature range, PFS HPs nucleate formation of uniform structures, and the annealing temperature regulates the supersaturation level. In both protocols, the competitive crystallization kinetics of HP/BCP affects the morphology. Both protocols exhibit broad generality. We believe the morphological transformation from 2D to 3D structures, regulated by defect formation, co-crystallization, and supersaturation levels, could apply to various semicrystalline polymers. Moreover, the 3D structures are sufficiently robust to serve as recoverable carriers for nanoparticle catalysts, exhibiting valuable catalytic activity and opening new possibilities for applications requiring exquisite 3D structures.
RESUMO
Due to the accelerated appearance of antimicrobial-resistant (AMR) pathogens in clinical infections, new first-in-class antibiotics, operating via novel modes of action, are desperately needed. Brevicidine, a bacterial nonribosomally produced cyclic lipopeptide, has shown potent and selective antimicrobial activity against Gram-negative pathogens. However, before our investigations, little was known about how brevicidine exerts its potent bactericidal effect against Gram-negative pathogens. In this study, we find that brevicidine has potent antimicrobial activity against AMR Enterobacteriaceae pathogens, with MIC values ranging between 0.5 µM (0.8 mg/L) and 2 µM (3.0 mg/L). In addition, brevicidine showed potent antibiofilm activity against the Enterobacteriaceae pathogens, with the same 100% inhibition and 100% eradication concentration of 4 µM (6.1 mg/L). Further mechanistic studies showed that brevicidine exerts its potent bactericidal activity by interacting with lipopolysaccharide in the outer membrane, targeting phosphatidylglycerol and cardiolipin in the inner membrane, and dissipating the proton motive force of bacteria. This results in metabolic perturbation, including the inhibition of ATP synthesis; the inhibition of the dehydrogenation of NADH; the accumulation of reactive oxygen species in bacteria; and the inhibition of protein synthesis. Finally, brevicidine showed a good therapeutic effect in a mouse peritonitis-sepsis model. Our findings pave the way for further research on the clinical applications of brevicidine to combat prevalent infections caused by AMR Gram-negative pathogens worldwide.
Assuntos
Antibacterianos , Enterobacteriaceae , Animais , Camundongos , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Bactérias , Lipopeptídeos/farmacologia , Testes de Sensibilidade Microbiana , Bactérias Gram-NegativasRESUMO
Rumination is closely linked to the onset and maintenance of major depressive disorder (MDD). Prior neuroimaging studies have identified the association between self-reported rumination trait and the functional coupling among a network of brain regions using resting-state functional magnetic resonance imaging (MRI). However, little is known about the underlying neural circuitry mechanism during active rumination in MDD. Degree centrality (DC) is a simple metric to denote network integration, which is critical for higher-order psychological processes such as rumination. During an MRI scan, individuals with MDD (N = 45) and healthy controls (HC, N = 46) completed a rumination state task. We examined the interaction effect between the group (MDD vs. HC) and condition (rumination vs. distraction) on vertex-wise DC. We further characterized the identified brain region's functional involvement with Neurosynth and BrainMap. Network-wise seed-based functional connectivity (FC) analysis was also conducted for the identified region of interest. Finally, exploratory correlation analysis was conducted between the identified region of interest's network FCs and self-reported in-scanner affect levels. We found that a left superior frontal gyrus (SFG) region, generally overlapped with the frontal eye field, showed a significant interaction effect. Further analysis revealed its involvement with executive functions. FCs between this region, the frontoparietal, and the dorsal attention network (DAN) also showed significant interaction effects. Furthermore, its FC to DAN during distraction showed a marginally significant negative association with in-scanner affect level at the baseline. Our results implicated an essential role of the left SFG in the rumination's underlying neural circuitry mechanism in MDD and provided novel evidence for the conceptualization of rumination in terms of impaired executive control.
Assuntos
Transtorno Depressivo Maior , Humanos , Encéfalo/diagnóstico por imagem , Córtex Pré-Frontal , Função Executiva , Lobo Frontal , Imageamento por Ressonância Magnética , Mapeamento EncefálicoRESUMO
Surface open polar sites within the voids of porous molecular crystals define the localized physicochemical environment for critical functions such as gas separation and molecular recognition. This study presents a new charge-assisted hydrogen bonding (H-bonding) motif, by exploiting inorganic ammonium (NH4 + ) cations as H-bond donors, to regulate the assembly of C2 -symmetric carboxylic tectons for building robust H-bonded frameworks with permanent ultra-micropores and open oxygen sites. Diverse building blocks are bridged by tetrahedral NH4 + to expand distinctive H-bonded networks with varied pore architectures. Particularly, the open polar oxygen sites can be switched by altering NH4 + sources to tune the deprotonation of carboxyl-containing tectons. The activated porous PTBA·NH4 ·DMF preserves the pore architecture and open polar oxygen sites, exhibiting remarkably selective sorption of CO2 (107.8 cm3 g-1 ,195 K) over N2 (11.2 cm3 g-1 , 77 K) and H2 (1.4 cm3 g-1 , 77 K).
RESUMO
Macrophages as the main cause of cancer immunosuppression, how to effectively induce macrophage M1 polarization remain the major challenge in lung cancer therapy. Herein, inspired by endogenous reactions, a strategy is proposed to coactivate macrophage M1 polarization by reactive oxygen species (ROS) and nitric oxide (NO) with self-autocatalytic cascade reaction. To enhance the generation of NO and ROS, NO Precursor-Arginine as capping agents for inducing synthesis two kinds of chiral ruthenium nanozyme (D/L-Arginine@Ru). Under the properties of Ru nanozymes through synchronously mimicking the activity of oxidase and nitric oxide synthase (NOS), chiral Ru nanozyme can rapidly generate 1 O2 and O2 at first stage, and then catalyze Arginine to produce sufficient NO, thus enhance macrophage M1 polarization to reverse tumor immunosuppression. Moreover, combination the antitumor activity of 1 O2 , NO, the chiral Ru nanozymes realize the "cocktail therapy" by inducing tumor cell apoptosis as well as ferroptosis. In addition, the chirality influences the bioactivity of Ru nanozymes that L-Arginine@Ru shows the better therapeutic effect with stronger catalytic activity and natural homology. It is hoped the high performance of chiral Ru nanozyme with "cocktail therapy" is an effective therapeutic reagent and can provide a feasible treatment strategy for tumor catalytic therapy.
Assuntos
Neoplasias Pulmonares , Rutênio , Humanos , Espécies Reativas de Oxigênio , Óxido Nítrico , Neoplasias Pulmonares/tratamento farmacológico , Arginina , MacrófagosRESUMO
The highly contagious and fast-spreading omicron variant of SARS-CoV-2 infects the respiratory tracts efficiently. The receptor-binding domain (RBD) of the omicron spike protein recognizes human angiotensin-converting enzyme 2 (ACE2) as its receptor and plays a critical role in the tissue tropism of SARS-CoV-2. Here, we showed that the omicron RBD (strain BA.1) binds to ACE2 more strongly than does the prototypic RBD from the original Wuhan strain. We also measured how individual omicron mutations affect ACE2 binding. We further determined the crystal structure of the omicron RBD (engineered to facilitate crystallization) complexed with ACE2 at 2.6 Å. The structure shows that omicron mutations caused significant structural rearrangements of two mutational hot spots at the RBD/ACE2 interface, elucidating how each omicron mutation affects ACE2 binding. The enhanced ACE2 binding by the omicron RBD may facilitate the omicron variant's infection of the respiratory tracts where ACE2 expression level is low. Our study provides insights into the receptor recognition and tissue tropism of the omicron variant. IMPORTANCE Despite the scarcity of the SARS-CoV-2 receptor-human angiotensin-converting enzyme 2 (ACE2)-in the respiratory tract, the omicron variant efficiently infects the respiratory tract, causing rapid and widespread infections of COVID-19. The omicron variant contains extensive mutations in the receptor-binding domain (RBD) of its spike protein that recognizes human ACE2. Here, using a combination of biochemical and X-ray crystallographic approaches, we showed that the omicron RBD binds to ACE2 with enhanced affinity and also elucidated the role of each of the omicron mutations in ACE2 binding. The enhanced ACE2 binding by the omicron RBD may contribute to the omicron variant's new viral tropism in the respiratory tract despite the low level of ACE2 expression in the tissue. These findings help us to understand tissue tropism of the omicron variant and shed light on the molecular evolution of SARS-CoV-2.
Assuntos
Enzima de Conversão de Angiotensina 2 , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , COVID-19/virologia , Humanos , Mutação , Ligação Proteica , Estrutura Terciária de Proteína , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
BACKGROUND: Growing evidence indicates high comorbid anxiety and depression in patients with asthma. However, the mechanisms underlying this comorbid condition remain unclear. The aim of this study was to investigate the role of inflammation in comorbid anxiety and depression in three asthma patient cohorts of the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) project. METHODS: U-BIOPRED was conducted by a European Union consortium of 16 academic institutions in 11 European countries. A subset dataset from subjects with valid anxiety and depression measures and a large blood biomarker dataset were analysed, including 198 non-smoking patients with severe asthma (SAn), 65 smoking patients with severe asthma (SAs), 61 non-smoking patients with mild-to-moderate asthma (MMA), and 20 healthy non-smokers (HC). The Hospital Anxiety and Depression Scale was used to measure anxiety and depression and a series of inflammatory markers were analysed by the SomaScan v3 platform (SomaLogic, Boulder, Colo). ANOVA and the Kruskal-Wallis test were used for multiple-group comparisons as appropriate. RESULTS: There were significant group effects on anxiety and depression among the four cohort groups (p < 0.05). Anxiety and depression of SAn and SAs groups were significantly higher than that of MMA and HC groups (p < 0.05. There were significant differences in serum IL6, MCP1, CCL18, CCL17, IL8, and Eotaxin among the four groups (p < 0.05). Depression was significantly associated with IL6, MCP1, CCL18 level, and CCL17; whereas anxiety was associated with CCL17 only (p < 0.05). CONCLUSIONS: The current study suggests that severe asthma patients are associated with higher levels of anxiety and depression, and inflammatory responses may underlie this comorbid condition.
Assuntos
Asma , Interleucina-6 , Humanos , Asma/complicações , Ansiedade , Comorbidade , Inflamação/complicações , BiomarcadoresRESUMO
Constructing well-organized organic frameworks with tailor-made functionalities potentially boost multi-domain applications. Hydrogen bonding (H-bonding) is a category of general and weak intermolecular interactions when compared with covalent bonding or metal-ligand coordination. Porous frameworks mainly assembled by H-bonding (named hydrogen-bonded organic frameworks, HOFs) are intrinsically capable of decomposing and regenerating, a distinctive advantage to improve their processability while expanding the applicability. This paper summarizes the basic building concepts of HOFs, including feasible hydrogen bonded motifs, effective molecular structures, and their emerging applications.