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BACKGROUND AND OBJECTIVE: The apnoea-hypopnoea index (AHI) and oxygen desaturation index (ODI) encounter challenges in capturing the intricate relationship between obstructive sleep apnoea (OSA) and cardiovascular disease (CVD) risks. Although novel hypoxic indices have been proposed to tackle these limitations, there remains a gap in comprehensive validation and comparisons across a unified dataset. METHODS: Samples were derived from the Sleep Heart Health Study (SHHS), involving 4485 participants aged over 40 years after data quality screening. The study compared several key indices, including AHI, ODI, the reconstructed hypoxic burden (rHB), the percentage of sleep time with the duration of respiratory events causing desaturation (pRED_3p) and the sleep breathing impairment index (SBII), in relation to CVD mortality and morbidity risks. Adjusted Cox proportional models were employed to calculate hazard ratios (HRs) for each index, and comparisons were performed. RESULTS: SBII and pRED_3p exhibited significant correlations with both CVD mortality and morbidity, with SBII showing the highest adjusted HR (95% confidence interval) for mortality (2.04 [1.25, 3.34]) and pRED_3p for morbidity (1.43 [1.09-1.88]). In contrast, rHB was only significant in predicting CVD mortality (1.63 [1.05-2.53]), while AHI and ODI did not show significant correlations with CVD outcomes. The adjusted models based on SBII and pRED_3p exhibited optimal performance in the CVD mortality and morbidity datasets, respectively. CONCLUSION: This study identified the optimal indices for OSA-related CVD risks prediction, SBII for mortality and pRED_3p for morbidity. The open-source online platform provides the computation of the indices.
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Doenças Cardiovasculares , Hipóxia , Índice de Gravidade de Doença , Apneia Obstrutiva do Sono , Humanos , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/fisiopatologia , Apneia Obstrutiva do Sono/mortalidade , Masculino , Feminino , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/diagnóstico , Pessoa de Meia-Idade , Hipóxia/epidemiologia , Hipóxia/fisiopatologia , Idoso , Medição de Risco/métodos , Adulto , Fatores de Risco de Doenças Cardíacas , Saturação de Oxigênio/fisiologia , Modelos de Riscos ProporcionaisRESUMO
The image source method (ISM) is often used to simulate room acoustics due to its ease of use and computational efficiency. The standard ISM is limited to simulations of room impulse responses between point sources and omnidirectional receivers. In this work, the ISM is extended using spherical harmonic directivity coefficients to include acoustic diffraction effects. These effects occur in practice when transducers are mounted on audio devices of finite spatial extent, e.g., modern smart speakers with loudspeakers and microphones. The proposed method is verified using finite element simulations of various loudspeaker and microphone configurations in a shoebox-shaped room. It is shown that the accuracy of the proposed method is related to the sizes, shapes, number, and positions of the devices inside a room. A simplified version of the proposed method, which can significantly reduce computational effort, is also presented. The proposed method and its simplified version can simulate room transfer functions more accurately than currently available image source methods and can aid the development and evaluation of speech and acoustic signal processing algorithms, including speech enhancement, acoustic scene analysis, and acoustic parameter estimation.
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Our brain processes the different timescales of our environment's temporal input stochastics. Is such a temporal input processing mechanism key for consciousness? To address this research question, we calculated measures of input processing on shorter (alpha peak frequency, APF) and longer (autocorrelation window, ACW) timescales on resting-state high-density EEG (256 channels) recordings and compared them across different consciousness levels (awake/conscious, ketamine and sevoflurane anaesthesia, unresponsive wakefulness, minimally conscious state). We replicate and extend previous findings of: (i) significantly longer ACW values, consistently over all states of unconsciousness, as measured with ACW-0 (an unprecedented longer version of the well-know ACW-50); (ii) significantly slower APF values, as measured with frequency sliding, in all four unconscious states. Most importantly, we report a highly significant correlation of ACW-0 and APF in the conscious state, while their relationship is disrupted in the unconscious states. In sum, we demonstrate the relevance of the brain's capacity for input processing on shorter (APF) and longer (ACW) timescales - including their relationship - for consciousness. Albeit indirectly, e.g., through the analysis of electrophysiological activity at rest, this supports the mechanism of temporo-spatial alignment to the environment's temporal input stochastics, through relating different neural timescales, as one key predisposing factor of consciousness.
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Eletroencefalografia , Inconsciência , Humanos , Encéfalo/fisiologia , Estado de Consciência/fisiologia , Estado Vegetativo PersistenteRESUMO
Numerous variants of unknown significance (VUSs) exist in hereditary breast and ovarian cancers. Although multiple methods have been developed to assess the significance of BRCA1/2 variants, functional discrepancies among these approaches remain. Therefore, a comprehensive functional evaluation system for these variants should be established. We performed conventional homologous recombination (HR) assays for 50 BRCA1 and 108 BRCA2 VUSs and complementarily predicted VUSs using a statistical logistic regression prediction model that integrated six in silico functional prediction tools. BRCA1/2 VUSs were classified according to the results of the integrative in vitro and in silico analyses. Using HR assays, we identified 10 BRCA1 and 4 BRCA2 VUSs as low-functional pathogenic variants. For in silico prediction, the statistical prediction model showed high accuracy for both BRCA1 and BRCA2 compared with each in silico prediction tool individually and predicted nine BRCA1 and seven BRCA2 variants to be pathogenic. Integrative functional evaluation in this study and the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines strongly suggested that seven BRCA1 variants (p.Glu272Gly, p.Lys1095Glu, p.Val1653Leu, p.Thr1681Pro, p.Phe1761Val, p.Thr1773Ile, and p.Gly1803Ser) and four BRCA2 variants (p.Trp31Gly, p.Ser2616Phe, p.Tyr2660Cys, and p.Leu2792Arg) were pathogenic. This study demonstrates that integrative evaluation using conventional HR assays and optimized in silico prediction comprehensively classified the significance of BRCA VUSs for future clinical applications.
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Neoplasias da Mama , Neoplasias Ovarianas , Humanos , Feminino , Proteína BRCA1/genética , Predisposição Genética para Doença , Proteína BRCA2/genética , Recombinação Homóloga , Neoplasias da Mama/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologiaRESUMO
In this paper, a security enhanced physical layer encryption scheme is proposed for coherent optical polarization division multiplexing (PDM) systems. The concept of a digital optical polarization scrambler (DOPS) is introduced to apply high speed rotation of state of polarization (RSOP) to the transmitted signal, which enables encryption based on polarization perturbations and offers superior flexibility in polarization management. By utilizing different combinations of digital polarization device matrices and adjusting their key parameters, four encryption modes are designed. The proposed encryption scheme is successfully implemented in a PDM-QPSK system at the data rate of 32 Gbps. Experimental results demonstrate that authorized users can successfully decrypt the received signal, while the eavesdroppers cannot derive useful information with a bit error rate (BER) at approximately 0.5. To enhance system security, a 5-D chaotic system is introduced with superior properties of high sensitivity to initial values and improved uniform distribution, which guarantees the large entropy and further the system's security. This scheme can effectively prevent against brute attacks with the expanded key space of 1060.
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Time delays are a signature of many physical systems, including the brain, and considerably shape their dynamics; moreover, they play a key role in consciousness, as postulated by the temporo-spatial theory of consciousness (TTC). However, they are often not known a priori and need to be estimated from time series. In this study, we propose the use of permutation entropy (PE) to estimate time delays from neural time series as a more robust alternative to the widely used autocorrelation window (ACW). In the first part, we demonstrate the validity of this approach on synthetic neural data, and we show its resistance to regimes of nonstationarity in time series. Mirroring yet another example of comparable behavior between different nonlinear systems, permutation entropy-time delay estimation (PE-TD) is also able to measure intrinsic neural timescales (INTs) (temporal windows of neural activity at rest) from hd-EEG human data; additionally, this replication extends to the abnormal prolongation of INT values in disorders of consciousness (DoCs). Surprisingly, the correlation between ACW-0 and PE-TD decreases in a state-dependent manner when consciousness is lost, hinting at potential different regimes of nonstationarity and nonlinearity in conscious/unconscious states, consistent with many current theoretical frameworks on consciousness. In summary, we demonstrate the validity of PE-TD as a tool to extract relevant time scales from neural data; furthermore, given the divergence between ACW and PE-TD specific to DoC subjects, we hint at its potential use for the characterization of conscious states.
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Hydrogen sulfide (H2S) plays a vital role in regulating many important physiological functions. However, H2S-containing industrial wastewater is inevitably pumped into the environment which seriously contaminates water supplies and foodstuffs. So it is crucial to develop a single fluorescent probe for H2S detection with high sensitivity and selectivity. Herein, a colorimetric and turn-on near infrared (NIR) fluorescent probe NRDNP based on benzophenoxazine was designed and synthesized by thiolysis of 2,4-dinitrophenyl (DNP) ether as the specific reaction site strategy to achieve highly specific H2S detection in living systems. The studies demonstrated that the probe NRDNP exhibited excellent sensing performance toward H2S with an about 80-fold NIR fluorescence enhancement, a rapid response within 10 min, excellent sensitivity with a detection limit of 19 nM and good selectivity. Furthermore, the NRDNP is an optical sensor which visually changes in terms of the fluorescence colour/intensity upon sensing gaseous H2S molecules. NRDNP has low cytotoxicity and has been successfully applied in the fluorescence imaging of H2S in living cells, suggesting that it would be an effective tool for H2S detection in living systems.
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Corantes Fluorescentes , Sulfeto de Hidrogênio , Éteres , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Sulfeto de Hidrogênio/análise , Imagem Óptica , Águas ResiduáriasRESUMO
BACKGROUND: Horizontal gene transfer (HGT) has been documented in many herbivorous insects, conferring the ability to digest plant material and promoting their remarkable ecological diversification. Previous reports suggest HGT of antibacterial enzymes may have contributed to the insect immune response and limit bacterial growth. Carnivorous insects also display many evolutionary successful lineages, but in contrast to the plant feeders, the potential role of HGTs has been less well-studied. RESULTS: Using genomic and transcriptomic data from 38 species of ladybird beetles, we identified a set of bacterial cell wall hydrolase (cwh) genes acquired by this group of beetles. Infection with Bacillus subtilis led to upregulated expression of these ladybird cwh genes, and their recombinantly produced proteins limited bacterial proliferation. Moreover, RNAi-mediated cwh knockdown led to downregulation of other antibacterial genes, indicating a role in antibacterial immune defense. cwh genes are rare in eukaryotes, but have been maintained in all tested Coccinellinae species, suggesting that this putative immune-related HGT event played a role in the evolution of this speciose subfamily of predominant predatory ladybirds. CONCLUSION: Our work demonstrates that, in a manner analogous to HGT-facilitated plant feeding, enhanced immunity through HGT might have played a key role in the prey adaptation and niche expansion that promoted the diversification of carnivorous beetle lineages. We believe that this represents the first example of immune-related HGT in carnivorous insects with an association with a subsequent successful species radiation.
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Antibiose/genética , Evolução Biológica , Besouros/genética , Transferência Genética Horizontal , Genes Bacterianos , Genes de Insetos , Adaptação Biológica , Animais , Parede Celular/química , Parede Celular/enzimologia , Besouros/enzimologia , Interações Hospedeiro-Patógeno , Hidrolases/genéticaRESUMO
In this paper, we propose a novel multi-user access in wireless optical communication based on the quantum detection of the coherent state. In this case, the coherent states are used as the signal carrier and a technique of quantum detection is applied to distinguish between signals from different users. To accomplish this task, two main quantum measurement methods are introduced; one is minimum error discrimination (MED), and the other is unambiguous state discrimination (USD). The theoretical derivation implies that the two methods can both distinguish between the signals from different users efficiently when the average photon number is large enough. Typically, the numerical result shows that in the two-user case, the channel capacity will approach the theoretical maximum limit when the average photon number is greater than 2.5 for MED and 5 for USD in the absence of noise. The MED gains more channel capacity than the USD at the same average photon number. However, the USD wins the error-correction scene with its free-error capability. Furthermore, the detection error probability and channel capacity for the USD with the thermal noise are examined. The result shows that increasing the signal average photon number can continue the USD's advantage of error-free detection even if in the presence of thermal noise. In addition, compared with non-orthogonal multiple access (NOMA), the bit error rate (BER) against signal-to-noise rate (SNR) performance of USD has been improved.
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CDK1 plays key roles in cell cycle progression through the G2/M phase transition and activation of homologous recombination (HR) DNA repair pathway. Accordingly, various CDK1 inhibitors have been developed for cancer therapy that induce prolonged G2 arrest and/or sensitize cells to DNA damaging agents in tumor cells, resulting in cell death. However, CDK1 inhibition can induce resistance to DNA damage in certain conditions. The mechanism of different DNA damage sensitivity is not completely understood. We performed immunofluorescence and flow cytometry analysis to investigate DNA damage responses in human tumor cells during low and high dose treatments with RO-3306, a selective CDK1 inhibitor. This comparative investigation demonstrated that RO-3306-induced G2 arrest prevented cells with DNA double-strand breaks from transitioning into the M-phase and that the cells maintained their DNA repair capacity in G2-phase, even under RO-3306 dose-dependent DNA repair inhibition. These findings reveal that CDK1 inhibitor-induced DNA repair inhibition and cell cycle control, which regulate each other during the G2/M phase transition determine the cellular sensitivity to DNA damage, providing insight useful for developing clinical strategies targeting CDK1 inhibition in tumor cells.
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Proteína Quinase CDC2/antagonistas & inibidores , Divisão Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Humanos , Quinolinas/farmacologia , Reparo de DNA por Recombinação/efeitos dos fármacos , Tiazóis/farmacologiaRESUMO
This study proposes an encryption scheme combining cellular automata (CA) and DNA encoding to improve security of a coherent optical orthogonal frequency division multiplexing (CO-OFDM) system, wherein key sequences are generated with good randomness and unpredictability by a 4-dimensional hyper-chaotic system. A base scrambling pseudo random binary sequence (PRBS) generated by the CA is introduced, which results in better scrambling effect and randomness in the conventional complex DNA encoding. The randomness, complexity and security of the system is enhanced due to 6 variable keys (key space of â¼10138). An experiment conducted in a 40 GHz 16QAM CO-OFDM system over an 80 km standard single mode fiber (SSMF) shows that the authorized user can successfully decrypt the received signal, while the eavesdroppers cannot derive useful information with bit error rate (BER) at approximately 0.5. An allowable optical signal to noise ratio (OSNR) penalty of 0.5 dB will be introduced to achieve same BER before and after encryption due to the error propagation of cellular automata.
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Algoritmos , Redes de Comunicação de Computadores , DNA/análise , Telecomunicações , Desenho de Equipamento , Humanos , Dispositivos Ópticos , Processamento de Sinais Assistido por ComputadorRESUMO
Utilizing cost-effective raw materials to prepare high-performance silicon-based anode materials for lithium-ion batteries (LIBs) is both challenging and attractive. Herein, a porous SiFe@C (pSiFe@C) composite derived from low-cost ferrosilicon is prepared via a scalable three-step procedure, including ball milling, partial etching, and carbon layer coating. The pSiFe@C material integrates the advantages of the mesoporous structure, the partially retained FeSi2 conductive phase, and a uniform carbon layer (12-16â nm), which can substantially alleviate the huge volume expansion effect in the repeated lithium-ion insertion/extraction processes, effectively stabilizing the solid-electrolyte interphase (SEI) film and markedly enhancing the overall electronic conductivity of the material. Benefiting from the rational structure, the obtained pSiFe@C hybrid material delivers a reversible capacity of 1162.1â mAh g-1 after 200â cycles at 500â mA g-1 , with a higher initial coulombic efficiency of 82.30 %. In addition, it shows large discharge capacities of 803.1 and 600.0â mAh g-1 after 500â cycles at 2 and 4â A g-1 , respectively, manifesting an excellent electrochemical lithium storage. This work provides a good prospect for the commercial production of silicon-based anode materials for LIBs with a high lithium-storage capacity.
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Sepsis is a medical emergency demanding early diagnosis and tailored antimicrobial therapy. Every hour of delay in initiating effective therapy measurably increases patient mortality. Blood culture is currently the reference standard for detecting bloodstream infection, a multistep process which may take one to several days. Here, we report a novel paradigm for earlier detection and the simultaneous identification of pathogens in spiked blood cultures by means of a metabolomic "fingerprint" of the volatile mixture outgassed by the organisms. The colorimetric sensor array provided significantly faster detection of positive blood cultures than a conventional blood culture system (12.1 h versus 14.9 h, P < 0.001) while allowing for the identification of 18 bacterial species with 91.9% overall accuracy within 2 h of growth detection. The colorimetric sensor array also allowed for discrimination between unrelated strains of methicillin-resistant Staphylococcus aureus, indicating that the metabolomic fingerprint has the potential to track nosocomial transmissions. Altogether, the colorimetric sensor array is a promising tool that offers a new paradigm for diagnosing bloodstream infections.
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Bactérias/isolamento & purificação , Técnicas Bacteriológicas/métodos , Técnicas Biossensoriais/métodos , Análise Química do Sangue/métodos , Sangue/microbiologia , Colorimetria/métodos , Sepse/diagnóstico , Bactérias/classificação , Humanos , Metabolômica/métodos , Sepse/microbiologia , TempoRESUMO
BACKGROUND: The COVID-19 pandemic, ongoing for over 2 years with evolving viral strains, including the highly infectious Omicron variant, underscores the pivotal role of Traditional Chinese Medicine (TCM) in pandemic intervention. Qingfei Paidu Granules (QFPG) are incorporated into the national TCM diagnosis and treatment protocol. This study aims to assess the clinical effectiveness of QFPG combined with nonpharmacological interventions in asymptomatic novel coronavirus infection. MATERIALS AND METHODS: Using a full-group randomized controlled trial, asymptomatic individuals from 3 wards of Fangcang Hospital were randomly assigned to 3 groups, each comprising 150 cases: F1, the nonpharmacological treatment group, receiving only Five Elements Music Therapy and Gongfa Therapy; F2, the comprehensive treatment group, receiving QFPG treatment combined with Five Elements Music Therapy and Gongfa Therapy; and F3, the pharmacological treatment group, receiving only QFPG treatment. The treatment duration for each group was 6 days. Clinical efficacy and safety among different treatment groups were observed, including the conversion time of COVID-19 nucleic acid detection, duration of hospitalization, conversion rate from mild to moderate cases, and occurrence of adverse events. RESULTS: All 450 participants were included and completed the study. The conversion rates on the first day of treatment were 10.7%, 30%, and 11.3% for the F1, F2, and F3 groups, respectively. Compared to F1, both F2 and F3 showed shortened first conversion time and time to double negative results, with first conversion times of 1.92 days for F2 and 2.29 days for F3. Additionally, the time in F2 was shorter compared to F3. Hospitalization duration was shortened in both F2 and F3 compared to F1, with no statistically significant difference between F2 and F3. The conversion rate from mild to moderate cases was lower in both F2 and F3 compared to F1, but the difference between F2 and F3 was not significant. CONCLUSION: Combining QFPG with traditional Chinese nonpharmacological interventions effectively shortened the conversion time of COVID-19 nucleic acid detection and reduced the conversion rate from asymptomatic infection to mild/moderate cases. This treatment approach is worth promoting in the management of asymptomatic patients during pandemics. TRIAL REGISTRATION: ClinicalTrials.gov, ChiCTR2200059007.
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COVID-19 , Medicamentos de Ervas Chinesas , SARS-CoV-2 , Humanos , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , Feminino , COVID-19/terapia , Pessoa de Meia-Idade , Adulto , Medicina Tradicional Chinesa/métodos , Tratamento Farmacológico da COVID-19 , Resultado do Tratamento , Terapia Combinada , Infecções Assintomáticas/terapiaRESUMO
Pseudorabies virus (PRV) is a highly contagious viral disease, which leads to severe financial losses in the breeding industry worldwide. Presently, PRV is mainly controlled using live attenuated and inactivated vaccines. However, these vaccines have an innate tendency to lose their structural conformation upon exposure to environmental and chemical stressors and cannot provide full protection against the emerging prevalent PRV variants. In this work, first, we synthesized aminated ZIF-7/8 nanoparticles (NPs), and then chemical bond-coated alginate dialdehyde (ADA, a type of dioxide alginate saccharide) on their surface via Schiff base reaction to obtain ZIF-7/8-ADA NPs. The as-fabricated ZIF-7/8-ADA NPs exhibited high stability, monodispersity and a high loading ratio of antigen. Furthermore, the ZIF-7/8-ADA NPs showed good biocompatibility in vitro and in vivo. Using ZIF-7/8-ADA NPs as an adjuvant and inactivated PRV as a model antigen, we constructed a PR vaccine through a simple mixture. The immunity studies indicated that ZIF-7/8-ADA induced an enhancement in the Th1/Th2 immune response, which was superior to that of the commercial ISA201, alum adjuvant and ZIF-7/8. Due to the pH-sensitive release of the antigen in lysosomes, the as-prepared PR vaccine subsequently accelerated the antigen presentation and improved the immune responses in vitro and in vivo. The results of PRV challenge using mice as the model demonstrated that ZIF-7/8-ADA achieved the same preventive effect as the commercial ISA201 and was much better than the alum adjuvant, and thus can serve as a promising delivery system and adjuvant to enhance humoral and cellular responses against PRV infection.
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Adjuvantes Imunológicos , Alginatos , Estruturas Metalorgânicas , Nanopartículas , Animais , Alginatos/química , Alginatos/farmacologia , Camundongos , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Pseudorraiva/prevenção & controle , Pseudorraiva/imunologia , Herpesvirus Suídeo 1/imunologia , Vacinas contra Pseudorraiva/imunologia , Vacinas contra Pseudorraiva/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Portadores de Fármacos/química , Vacinação/métodos , Camundongos Endogâmicos BALB C , FemininoRESUMO
The unique features of the sulfenamides' S(II)-N bond lead to interesting stereochemical properties and significant industrial functions. Here we present a chemoselective Chan-Lam coupling of sulfenamides to prepare N-arylated sulfenamides. A tridentate pybox ligand governs the chemoselectivity favoring C-N bond formation, and overrides the competitive C-S bond formation by preventing the S,N-bis-chelation of sulfenamides to copper center. The Cu(II)-derived resting state of catalyst is captured by UV-Vis spectra and EPR technique, and the key intermediate is confirmed by the EPR isotope response using 15N-labeled sulfenamide. A computational mechanistic study reveals that N-arylation is both kinetically and thermodynamically favorable, with deprotonation of the sulfenamide nitrogen atom occurring prior to reductive elimination. The origin of ligand-controlled chemoselectivity is explored, with the interaction between the pybox ligand and the sulfenamide substrate controlling the energy of the S-arylation and the corresponding product distribution, in agreement with the EPR studies and kinetic results.
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Presently, the traditional methods employed for detecting livestock and poultry meat predominantly involve sensory evaluation conducted by humans, chemical index detection, and microbial detection. While these methods demonstrate commendable accuracy in detection, their application becomes more challenging when applied to large-scale production by enterprises. Compared with traditional detection methods, machine vision and hyperspectral technology can realize real-time online detection of large throughput because of their advantages of high efficiency, accuracy, and non-contact measurement, so they have been widely concerned by researchers. Based on this, in order to further enhance the accuracy of online quality detection for livestock and poultry meat, this article presents a comprehensive overview of methods based on machine vision, hyperspectral, and multi-sensor information fusion technologies. This review encompasses an examination of the current research status and the latest advancements in these methodologies while also deliberating on potential future development trends. The ultimate objective is to provide pertinent information and serve as a valuable research resource for the non-destructive online quality detection of livestock and poultry meat.
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Multidrug-resistant (MDR) bacterial infections, especially those caused by Gram-negative pathogens, have emerged to be one of the world's greatest health threats. However, not only have recent decades shown a steady decline in the number of approved antimicrobial agents but a disappointing discovery also void. The development of novel antibiotics to treat MDR Gram-negative bacteria has been stagnated over the last half century. Though few compounds have shown activities in vitro, in animal models or even in clinical studies, the global antibiotic pipeline is not encouraging. There are a plethora of unexpected challenges that may arise and cannot always be solved to cause promising drugs to fail. This review intends to summarize recent research and development activities to meet the inevitable challenge in restricting the proliferation of MDR Gram-negative bacteria, with focus on compounds that have entered into clinical development stage. In addition to new analogues of existing antibiotic molecules, attention is also directed to alternative strategies to develop antibacterial agents with novel mechanisms of action.
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Antibacterianos , Descoberta de Drogas , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Aminoglicosídeos/farmacologia , Aminoglicosídeos/uso terapêutico , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Compostos Ferrosos/farmacologia , Compostos Ferrosos/uso terapêutico , Humanos , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Peptidomiméticos/farmacologia , Peptidomiméticos/uso terapêutico , Tetraciclinas/farmacologia , Tetraciclinas/uso terapêutico , Inibidores de beta-Lactamases , beta-Lactamas/farmacologia , beta-Lactamas/uso terapêuticoRESUMO
Lymphocyte function-associated antigen-1 (LFA-1) and its endothelial ligand intercellular adhesion molecule-1 (ICAM-1) are important for the migration of lymphocytes from blood vessels into lymph nodes. However, it is largely unknown whether these molecules mediate the homeostatic migration of lymphocytes from peripheral tissues into lymph nodes through lymphatic vessels. In this study, we find that, in naive mice, ICAM-1 is expressed on the sinus endothelia of lymph nodes, but not on the lymphatic vessels of peripheral tissues. In in vivo lymphocyte migration assays, memory CD4+ T cells migrated to lymph nodes from peripheral tissues much more efficiently than from blood vessels, as compared to naive CD4+ T cells. Moreover, ICAM-1 deficiency in host mice significantly inhibited the migration of adoptively transferred wild-type donor lymphocytes from peripheral tissues, but not from blood vessels, into lymph nodes. The migration of LFA-1-deficient donor lymphocytes from peripheral tissues into the lymph nodes of wild-type host mice was also significantly reduced as compared to wild-type donor lymphocytes. Furthermore, the number of memory T cells in lymph nodes was significantly reduced in the absence of ICAM-1 or LFA-1. Thus, our study extends the functions of the LFA-1/ICAM-1 adhesion pathway, indicating its novel role in controlling the homeostatic migration of lymphocytes from peripheral tissues into lymph nodes and maintaining memory T cellularity in lymph nodes.
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Vasos Linfáticos , Antígeno-1 Associado à Função Linfocitária , Animais , Camundongos , Molécula 1 de Adesão Intercelular , Linfócitos , LinfonodosRESUMO
Adjuvants are essential for the induction of robust immune responses against vaccine antigens. Small-molecule TLR7 agonists hold high potential for this purpose. In this communication, imiquimod (IMQ) bearing a cholesterol lipid moiety derivative, IMQ-Chol, was designed and synthesized as a vaccine adjuvant, which could release parent IMQ molecules in aqueous conditions via amide bond hydrolysis. We performed a series of immunological evaluations by cooperating with the inactivated foot-and-mouth disease virus (FMDV). All of the results confirmed that IMQ-Chol could stimulate the body for a prolonged time to produce strong humoral and cellular immunity with a balanced Th1/Th2 immune response through a TLR7-related MAPK pathway. In addition, the results of the proof-of-concept vaccine indicated IMQ-Chol had a good effect on preventing and treating FMD in pigs.