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Posttranslational modifications (PTMs) of proteins play central roles in regulating the protein structure, interactome, and functions. A notable modification site is the aromatic side chain of Tyr, which undergoes modifications such as phosphorylation and nitration. Despite the biological and physiological importance of Tyr-PTMs, our current understanding of the mechanisms by which these modifications contribute to human health and disease remains incomplete. This knowledge gap arises from the absence of natural amino acids that can mimic these PTMs and the lack of synthetic tools for the site-specific introduction of aromatic PTMs into proteins. Herein, we describe a facile method for the site-specific chemical installation of aromatic PTMs into proteins through palladium-mediated S-C(sp2) bond formation under ambient conditions. We demonstrate the incorporation of novel PTMs such as Tyr-nitration and phosphorylation analogs to synthetic and recombinantly expressed Cys-containing peptides and proteins within minutes and in good yields. To demonstrate the versatility of our approach, we employed it to prepare 10 site-specifically modified proteins, including nitrated and phosphorylated analogs of Myc and Max proteins. Furthermore, we prepared a focused library of site-specifically nitrated and phosphorylated α-synuclein (α-Syn) protein, which enabled, for the first time, deciphering the role of these competing modifications in regulating α-Syn conformation aggregation in vitro. Our strategy offers advantages over synthetic or semisynthetic approaches, as it enables rapid and selective transfer of rarely explored aromatic PTMs into recombinant proteins, thus facilitating the generation of novel libraries of homogeneous posttranslationally modified proteins for biomarker discovery, mechanistic studies, and drug discovery.
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Klebsiella pneumoniae is considered as the most common pathogen of hospital-acquired pneumonia. K. pneumoniae has emerged as the superbug which had shown multidrug resistance (MDR) as well as extensively drug resistance. Carbapenem resistant K. pneumoniae (CRKP) has become a menace for the treatment with monotherapy of the patients mainly admitted in intensive care units. Hence, in the present study we collected total 187 sputum isolates of K. pneumoniae and performed the antimicrobial susceptibility testing by using the automated Vitek-2 system and broth micro-dilution method (67 CRKP). The combination study of solithromycin with meropenem, colistin, cefotaxime, piperacillin and tazobactam, nitrofurantoin, tetracycline, levofloxacin, curcumin and nalidixic acid was performed by using checkerboard assay. We observed the high rate of resistance towards ampicillin, cefotaxime, ceftriaxone, cefuroxime and aztreonam. The colistin and tigecycline were the most sensitive drugs. The CRKP were 36%, maximum were from the patients of ICUs. The best synergistic effect of solithromycin was with meropenem and cefotaxime (100%), colistin and tetracycline (80%). So, these combinations can be a choice of treatment for the infections caused by MDR CRKP and other Gram-negative bacteria where the monotherapy could not work.
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The rapid adaptation of SARS-CoV-2 within the host species and the increased viral transmission triggered the evolution of different SARS-CoV-2 variants. Though numerous monoclonal antibodies (mAbs) have been identified as prophylactic therapy for SARS-CoV-2, the ongoing surge in the number of SARS-CoV-2 infections shows the importance of understanding the mutations in the spike and developing novel vaccine strategies to target all variants. Here, we report the map of experimentally validated 74 SARS-CoV-2 neutralizing mAb binding epitopes of all variants. The majority (87.84%) of the potent neutralizing epitopes are localized to the receptor-binding domain (RBD) and overlap with each other, whereas limited (12.16%) epitopes are found in the N-terminal domain (NTD). Notably, 69 out of 74 mAb targets have at least one mutation at the epitope sites. The potent epitopes found in the RBD show higher mutations (4-10aa) compared to lower or modest neutralizing antibodies, suggesting that these epitopes might co-evolve with the immune pressure. The current study shows the importance of determining the critical mutations at the antibody recognition epitopes, leading to the development of broadly reactive immunogens targeting multiple SARS-CoV-2 variants. Further, vaccines inducing both humoral and cell-mediated immune responses might prevent the escape of SARS-CoV-2 variants from neutralizing antibodies.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Epitopos/genética , Anticorpos Neutralizantes , COVID-19/prevenção & controle , Anticorpos Monoclonais/genética , Anticorpos AntiviraisRESUMO
BACKGROUND: Antimicrobial resistance (AMR) is a critical global issue that poses significant threats to human health, animal welfare, and the environment. With the increasing emergence of resistant microorganisms, the effectiveness of current antimicrobial medicines against common infections is diminishing. This study aims to conduct a competitive meta-analysis of surveillance data on resistant microorganisms and their antimicrobial resistance patterns in two countries, Egypt and the United Kingdom (UK). METHODS: Data for this study were obtained from published reports spanning the period from 2013 to 2022. In Egypt and the UK, a total of 9,751 and 10,602 food samples were analyzed, respectively. Among these samples, 3,205 (32.87%) in Egypt and 4,447 (41.94%) in the UK were found to contain AMR bacteria. RESULTS: In Egypt, the predominant resistance was observed against ß-lactam and aminoglycosides, while in the United Kingdom, most isolates exhibited resistance to tetracycline and ß-lactam. The findings from the analysis underscore the increasing prevalence of AMR in certain microorganisms, raising concerns about the development of multidrug resistance. CONCLUSION: This meta-analysis sheds light on the escalating AMR problem associated with certain microorganisms that pose a higher risk of multidrug resistance development. The significance of implementing One Health AMR surveillance is emphasized to bridge knowledge gaps and facilitate accurate AMR risk assessments, ensuring consumer safety. Urgent actions are needed on a global scale to combat AMR and preserve the effectiveness of antimicrobial treatments for the well-being of all living beings.
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Anti-Infecciosos , Saúde Única , Animais , Humanos , Antibacterianos/uso terapêutico , beta-Lactamas , Farmacorresistência Bacteriana , Egito , Reino UnidoRESUMO
Integrating photoactive π-chromophoric guest molecules inside the MOF nanopore can result in the emergence of light-responsive features, which in turn can be utilized for developing photoactive materials with inherent properties of MOF. Herein, we report the confining of π-chromophoric tetracene (TET) molecules inside the nanospace of postmodified Zr-MOF-808 (Zr-MOF) with MBA molecules (MBA = 2-(5'-methyl-[2,2'-bipyridine]-5-yl)acetic acid) for effectively utilizing its light-harvesting properties toward photocatalytic CO2 reduction. The confinement of the TET molecules as a photosensitizer and the covalent grafting of a catalytically active [Re(MBA)(CO)3Cl] complex, postsynthetically, result in a single integrated catalytic system named Zr-MBA-TET-Re-MOF. Photoreduction of CO2 over Zr-MBA-TET-Re-MOF showed the evolution of 805 µmol g-1 CO with 99.9% selectivity after 10 h of continuous visible light irradiation in water without any additional sacrificial electron donor and having the apparent quantum efficiency of 1.3%. In addition, the catalyst demonstrated an appreciable activity even under direct sunlight irradiation in aqueous medium with a maximum production of 362.7 µmol g-1 CO, thereby mimicking artificial photosynthesis. Moreover, electron transfer from TET to the catalytic center was supported by the formation of photoinduced TET radical cation, as inferred from in situ UV-vis spectra, electron paramagnetic resonance (EPR) analysis, and transient absorption (TA) studies. Additionally, the in situ diffuse reflectance infrared Fourier transform (DRIFT) measurements support that the photoreduction of CO2 to CO proceeds via *COOH intermediate formation. The close proximity of the light-harvesting molecule and catalytic center facilitated facile electron transfer from the photosensitizer to the catalyst during the CO2 reduction.
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BACKGROUND: The use of left bundle branch pacing (LBBP) has dramatically increased since it was first described in 2016, but to date there are no published data on the safety of performing magnetic resonance imaging (MRI) in these patients. METHODS: Patients with LBBP who underwent MRI between January 2016 and October 2022 were retrospectively studied in our clinical center, which has a special program for imaging patients with cardiac devices. All patients underwent close cardiac monitoring throughout the MRI scans. Occurrence of arrhythmias or other adverse effects during MRI were assessed. LBBP lead parameters immediately pre- and post-MRI and at an outpatient follow-up were compared. RESULTS: Fifteen patients with LBBP underwent a total of 19 MRI sessions during the study period. Lead parameters did not significantly change after the MRI or on follow-up, which took place at a median of 91 days after the MRI. No patient developed arrhythmias during the MRI sessions, and no adverse effects such as lead dislodgement were reported. CONCLUSION: Although larger studies are necessary to verify our findings, MRI in patients with LBBP appears safe based on this initial case series.
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Fascículo Atrioventricular , Bloqueio de Ramo , Humanos , Bloqueio de Ramo/diagnóstico por imagem , Bloqueio de Ramo/terapia , Bloqueio de Ramo/etiologia , Estimulação Cardíaca Artificial/métodos , Estudos Retrospectivos , Eletrocardiografia/métodos , Resultado do TratamentoRESUMO
Nanobiotechnology, as a novel and more specialized branch of science, has provided a number of nanostructures such as nanoparticles, by utilizing the methods, techniques, and protocols of other branches of science. Due to the unique features and physiobiological characteristics, these nanostructures or nanocarriers have provided vast methods and therapeutic techniques, against microbial infections and cancers and for tissue regeneration, tissue engineering, and immunotherapies, and for gene therapies, through drug delivery systems. However, reduced carrying capacity, abrupt and non-targeted delivery, and solubility of therapeutic agents, can affect the therapeutic applications of these biotechnological products. In this article, we explored and discussed the prominent nanobiotechnological methods and products such as nanocarriers, highlighted the features and challenges associated with these products, and attempted to conclude if available nanostructures offer any scope of improvement or enhancement. We aimed to identify and emphasize the nanobiotechnological methods and products, with greater prospect and capacity for therapeutic improvements and enhancements. We found that novel nanocarriers and nanostructures, such as nanocomposites, micelles, hydrogels, microneedles, and artificial cells, can address the associated challenges and inherited drawbacks, with help of conjugations, sustained and stimuli-responsive release, ligand binding, and targeted delivery. We recommend that nanobiotechnology, despite having few challenges and drawbacks, offers immense opportunities that can be harnessed in delivering quality therapeutics with precision and prediction. We also recommend that, by exploring the branched domains more rigorously, bottlenecks and obstacles can also be addressed and resolved in return.
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Nanocompostos , Nanopartículas , Nanoestruturas , Neoplasias , Humanos , Sistemas de Liberação de Medicamentos/métodos , Nanoestruturas/química , Micelas , Nanopartículas/química , Neoplasias/tratamento farmacológico , Portadores de Fármacos/químicaRESUMO
Coronavirus disease-19 (COVID-19) is caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2) and is responsible for a higher degree of morbidity and mortality worldwide. There is a smaller number of approved therapeutics available to target the SARS-CoV-2 virus, and the virus is evolving at a fast pace. So, there is a continuous need for new therapeutics to combat COVID-19. The main protease (Mpro ) enzyme of SARS-CoV-2 is essential for replication and transcription of the viral genome, thus could be a potent target for the treatment of COVID-19. In the present study, we performed an in-silico screening analysis of 400 diverse bioactive inhibitors with proven antibacterial and antiviral properties against Mpro drug target. Ten compounds showed a higher binding affinity for Mpro than the reference compound (N3), with desired physicochemical properties. Furthermore, in-depth docking and superimposition revealed that three compounds (MMV1782211, MMV1782220, and MMV1578574) are actively interacting with the catalytic domain of Mpro . In addition, the molecular dynamics simulation study showed a solid and stable interaction of MMV178221-Mpro complex compared to the other two molecules (MMV1782220, and MMV1578574). In line with this observation, MM/PBSA free energy calculation also demonstrated the highest binding free energy of -115.8â kJ/mol for MMV178221-Mpro compound. In conclusion, the present in silico analysis revealed MMV1782211 as a possible and potent molecule to target the Mpro and must be explored inâ vitro and inâ vivo to combat the COVID-19.
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COVID-19 , Humanos , Antivirais/farmacologia , Reposicionamento de Medicamentos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , SARS-CoV-2RESUMO
Recently, the major environmental pollution produced by the release of wastewater in liquid type is one of the most extensive forms of foremost pollution in water ecosystems. In this article, the Bi2O3/g-C3N4 nanocomposite with a direct Z-scheme was effectively obtained by a facile hydrothermal system. The crystal structures, surface morphology, chemical composition, and the optical belongings of the as-obtained composite catalysts were examined by Power XRD, FT-IR spectra, High-resolution XPS spectra, FE-SEM images with EDX spectra, High-resolution TEM images, UV-Vis DRS, and PL spectra respectively. Furthermore, the photocatalytic performance was assessed by the degradation of aqueous Rhodamine B (Rh B) dye under visible-light exposure. The Bi2O3/g-C3N4 composite photocatalysts (PCs) showed the maximum photo-degradation efficiency through a rate constant value of 0.0149 min-1, which is 4.9 and 5.3 folds superior to Bi2O3, and GCN, respectively. The better GBO2 nanocomposite PCs showed a superior photocatalytic degradation performance (>82%) of aqueous Rh B dye after five successive recycles. Moreover, based on these outcomes of the radical scavenging test, a direct and effective Z-scheme photocatalytic charger transfer mechanism was also projected. Finally, the reusability of the as-obtained Bi2O3/g-C3N4 nanocomposite has better stability and reusability, which was a favourable applicant for wastewater handling.
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Ecossistema , Nanopartículas , Espectroscopia de Infravermelho com Transformada de Fourier , Águas Residuárias , Fontes de Energia Elétrica , ÁguaRESUMO
The chemical synthesis of site-specifically modified transcription factors (TFs) is a powerful method to investigate how post-translational modifications (PTMs) influence TF-DNA interactions and impact gene expression. Among these TFs, Max plays a pivotal role in controlling the expression of 15 % of the genome. The activity of Max is regulated by PTMs; Ser-phosphorylation at the N-terminus is considered one of the key regulatory mechanisms. In this study, we developed a practical synthetic strategy to prepare homogeneous full-length Max for the first time, to explore the impact of Max phosphorylation. We prepared a focused library of eight Max variants, with distinct modification patterns, including mono-phosphorylated, and doubly phosphorylated analogues at Ser2/Ser11 as well as fluorescently labeled variants through native chemical ligation. Through comprehensive DNA binding analyses, we discovered that the phosphorylation position plays a crucial role in the DNA-binding activity of Max. Furthermore, in vitro high-throughput analysis using DNA microarrays revealed that the N-terminus phosphorylation pattern does not interfere with the DNA sequence specificity of Max. Our work provides insights into the regulatory role of Max's phosphorylation on the DNA interactions and sequence specificity, shedding light on how PTMs influence TF function.
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Regulação da Expressão Gênica , Fatores de Transcrição , Fatores de Transcrição/metabolismo , Fosforilação , Sequência de Aminoácidos , Processamento de Proteína Pós-Traducional , DNA/metabolismoRESUMO
Virtually all SARS-CoV-2 vaccines currently in clinical testing are stored in a refrigerated or frozen state prior to use. This is a major impediment to deployment in resource-poor settings. Furthermore, several of them use viral vectors or mRNA. In contrast to protein subunit vaccines, there is limited manufacturing expertise for these nucleic-acid-based modalities, especially in the developing world. Neutralizing antibodies, the clearest known correlate of protection against SARS-CoV-2, are primarily directed against the receptor-binding domain (RBD) of the viral spike protein, suggesting that a suitable RBD construct might serve as a more accessible vaccine ingredient. We describe a monomeric, glycan-engineered RBD protein fragment that is expressed at a purified yield of 214 mg/l in unoptimized, mammalian cell culture and, in contrast to a stabilized spike ectodomain, is tolerant of exposure to temperatures as high as 100 °C when lyophilized, up to 70 °C in solution and stable for over 4 weeks at 37 °C. In prime:boost guinea pig immunizations, when formulated with the MF59-like adjuvant AddaVax, the RBD derivative elicited neutralizing antibodies with an endpoint geometric mean titer of â¼415 against replicative virus, comparing favorably with several vaccine formulations currently in the clinic. These features of high yield, extreme thermotolerance, and satisfactory immunogenicity suggest that such RBD subunit vaccine formulations hold great promise to combat COVID-19.
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Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Antivirais/biossíntese , Vacinas contra COVID-19/biossíntese , COVID-19/prevenção & controle , Receptores Virais/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/genética , Animais , Anticorpos Neutralizantes/biossíntese , Sítios de Ligação , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Cobaias , Células HEK293 , Temperatura Alta , Humanos , Imunogenicidade da Vacina , Modelos Moleculares , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios Proteicos , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Receptores Virais/química , Receptores Virais/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , SARS-CoV-2/química , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Vacinação , Potência de VacinaRESUMO
High-altitude pulmonary edema (HAPE) is a noncardiogenic form of pulmonary edema, which is induced upon exposure to hypobaric hypoxia at high altitude (HA). Hypobaric hypoxia generates reactive oxygen species that may damage telomeres and disturb normal physiological processes. Telomere complex comprises of multiple proteins, of which, tankyrase (TNKS) is actively involved in DNA damage repairs. We hence investigated the association of TNKS and telomeres with HAPE to delineate their potential role at HA. The study was performed in three groups, High-altitude pulmonary edema patients (HAPE-p, n = 200), HAPE-resistant sojourners (HAPE-r, n = 200) and highland permanent healthy residents (HLs, n = 200). Variants of TNKS were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Plasma TNKS level was estimated using enzyme-linked immunosorbent assay, expression of TNKS and relative telomere length were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and telomerase activity was assessed by the telomere repeat amplification protocol assay. TNKS poly-ADP ribosylates the telomere-repeat factor (TRF), which is a negative regulator of telomere length. Consequently, TRF expression was also measured by RT-qPCR. The TNKS heterozygotes rs7015700GA were prevalent in HLs compared to the HAPE-p and HAPE-r. The plasma TNKS was significantly decreased in HAPE-p than HAPE-r (P = 0.006). TNKS was upregulated 9.27 folds in HAPE-p (P = 1.01E-06) and downregulated in HLs by 3.3 folds (P = 0.02). The telomere length was shorter in HAPE-p compared to HAPE-r (P = 0.03) and HLs (P = 4.25E-4). The telomerase activity was significantly higher in HAPE-p compared to both HAPE-r (P = 0.01) and HLs (P = 0.001). HAPE-p had the lowest TNKS levels (0.186 ± 0.031 ng/µl) and the highest telomerase activity (0.0268 amoles/µl). The findings of the study indicate the association of TNKS and telomeres with HA adaptation/maladaptation.
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Doença da Altitude/genética , Predisposição Genética para Doença , Hipertensão Pulmonar/genética , Tanquirases/genética , Telomerase/genética , Homeostase do Telômero/genética , Adulto , Idoso , Alelos , Altitude , Doença da Altitude/fisiopatologia , Dano ao DNA/genética , Reparo do DNA/genética , Feminino , Estudos de Associação Genética , Genótipo , Voluntários Saudáveis , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipóxia/genética , Hipóxia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição/genética , Telômero/genéticaRESUMO
Middle East respiratory syndrome coronavirus (MERS-CoV) targets the epithelial cells of the respiratory tract both in humans and in its natural host, the dromedary camel. Virion attachment to host cells is mediated by 20-nm-long homotrimers of spike envelope protein S. The N-terminal subunit of each S protomer, called S1, folds into four distinct domains designated S1A through S1D Binding of MERS-CoV to the cell surface entry receptor dipeptidyl peptidase 4 (DPP4) occurs via S1B We now demonstrate that in addition to DPP4, MERS-CoV binds to sialic acid (Sia). Initially demonstrated by hemagglutination assay with human erythrocytes and intact virus, MERS-CoV Sia-binding activity was assigned to S subdomain S1A When multivalently displayed on nanoparticles, S1 or S1A bound to human erythrocytes and to human mucin in a strictly Sia-dependent fashion. Glycan array analysis revealed a preference for α2,3-linked Sias over α2,6-linked Sias, which correlates with the differential distribution of α2,3-linked Sias and the predominant sites of MERS-CoV replication in the upper and lower respiratory tracts of camels and humans, respectively. Binding is hampered by Sia modifications such as 5-N-glycolylation and (7,)9-O-acetylation. Depletion of cell surface Sia by neuraminidase treatment inhibited MERS-CoV entry of Calu-3 human airway cells, thus providing direct evidence that virus-Sia interactions may aid in virion attachment. The combined observations lead us to propose that high-specificity, low-affinity attachment of MERS-CoV to sialoglycans during the preattachment or early attachment phase may form another determinant governing the host range and tissue tropism of this zoonotic pathogen.
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Infecções por Coronavirus/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Polissacarídeos/metabolismo , Receptores Virais/metabolismo , Ácidos Siálicos/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Animais , Camelus , Infecções por Coronavirus/virologia , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Humanos , Mucinas , Glicoproteína da Espícula de Coronavírus/genética , Ligação ViralRESUMO
Hemoptysis due to saphenous venous graft (SVG) aneurysm is an extremely rare condition and published literature has described the role of conservative management, surgical resection, and covered stent. Here, we report a successful placement of a covered stent for SVG aneurysm in a 56-year-old male who presented with hemoptysis. He was a known diabetic and had undergone a coronary artery bypass grafting 5 years ago. Computed tomography (CT) chest and fiberoptic bronchoscopy performed in another local hospital had revealed blood in the left lingula with spillover into the left lung parenchyma. Hence, he had received empirical anti-tuberculosis medication for 2 months without any improvement. He was referred to our hospital for further management of hemoptysis. Multidetector CT (MDCT) angiography of the chest covering coronaries performed at our hospital revealed SVG aneurysm that was managed with covered stent placement.
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Aneurisma/etiologia , Ponte de Artéria Coronária/efeitos adversos , Hemoptise/etiologia , Veia Safena/transplante , Aneurisma/diagnóstico por imagem , Aneurisma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada MultidetectoresRESUMO
Despite the exponential growth of social media use, whether and how social media use may affect entrepreneurial entry remains a key research gap. In this study we examine whether individuals' social media use influences their entrepreneurial entry. Drawing on social network theory, we argue that social media use allows individuals to obtain valuable social capital, as indicated by their offline social network, which increases their entrepreneurial entry. We further posit the relationship between social media use and entrepreneurial entry depends on individuals' trust propensity based on the nature of social media as weak ties. Our model was supported by a nationally representative survey of 18,873 adults in China over two years. As the first paper on the role of social media on entrepreneurial entry, we hope our research highlights and puts forward research intersecting social media and entrepreneurship.
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Middle East respiratory syndrome coronavirus (MERS-CoV) infections in humans can cause asymptomatic to fatal lower respiratory lung disease. Despite posing a probable risk for virus transmission, asymptomatic to mild infections can go unnoticed; a lack of seroconversion among some PCR-confirmed cases has been reported. We found that a MERS-CoV spike S1 protein-based ELISA, routinely used in surveillance studies, showed low sensitivity in detecting infections among PCR-confirmed patients with mild clinical symptoms and cross-reactivity of human coronavirus OC43-positive serum samples. Using in-house S1 ELISA and protein microarray, we demonstrate that most PCR-confirmed MERS-CoV case-patients with mild infections seroconverted; nonetheless, some of these samples did not have detectable levels of virus-neutralizing antibodies. The use of a sensitive and specific serologic S1-based assay can be instrumental in the accurate estimation of MERS-CoV prevalence.
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Anticorpos Antivirais/imunologia , Infecções por Coronavirus/imunologia , Imunidade Humoral/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Infecções por Coronavirus/virologia , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Fatores de TempoRESUMO
Indole-2-carboxamide derivatives are inhibitors of MmpL3, the cell wall-associated mycolic acid transporter of Mycobacterium tuberculosis In the present study, we characterized indoleamide effects on bacterial cell morphology and reevaluated pharmacokinetics and in vivo efficacy using an optimized oral formulation. Morphologically, indoleamide-treated M. tuberculosis cells demonstrated significantly higher numbers of dimples near the poles or septum, which may serve as the mechanism of cell death for this bactericidal scaffold. Using the optimized formulation, an expanded-spectrum indoleamide, compound 2, showed significantly improved pharmacokinetic (PK) parameters and in vivo efficacy in mouse infection models. In a comparative study, compound 2 showed superior efficacy over compound 3 (NITD-304) in a high-dose aerosol mouse infection model. Since indoleamides are equally active on drug-resistant M. tuberculosis, these findings demonstrate the therapeutic potential of this novel scaffold for the treatment of both drug-susceptible and drug-resistant tuberculosis.
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Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Administração Oral , Animais , Antituberculosos/química , Antituberculosos/farmacocinética , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Indóis/química , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/citologia , Tuberculose/microbiologiaRESUMO
BACKGROUND: Patients with postural tachycardia syndrome (POTS) experience chronic symptoms of orthostatic intolerance. There are minimal data detailing the demographics, clinical features and clinical course of this condition. This online, community-based survey highlights patients' experience with POTS. It consists of the largest sample of POTS patients reported to date. OBJECTIVES: To describe the demographics, past medical history, medications, treatments and diagnostic journey for patients living with POTS. METHODS: Postural tachycardia syndrome patients completed an online, community-based, cross-sectional survey. Participants were excluded if they had not received a diagnosis of POTS from a physician. The questions focused on the patient experience and journey, rather than physiological responses. RESULTS: The final analysis included 4835 participants. POTS predominantly affects white (93%) females (94%) of childbearing age, with approximately half developing symptoms in adolescence (mode 14 years). POTS is a chronic multisystem disorder involving a broad array of symptoms, with many patients diagnosed with comorbidities in addition to POTS. POTS patients often experience lengthy delays [median (interquartile range) 24 (6-72) months] and misdiagnosis, but the diagnostic delay is improving. POTS patients can present with a myriad of symptoms most commonly including lightheadedness (99%), tachycardia (97%), presyncope (94%), headache (94%) and difficulty concentrating (94%). CONCLUSIONS: These data provide important insights into the background, clinical features and diagnostic journey of patients suffering from POTS. These data should serve as an essential step for moving forward with future studies aimed at early and accurate diagnoses of these patients leading to appropriate treatments for their symptoms.
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Síndrome da Taquicardia Postural Ortostática/psicologia , Síndrome da Taquicardia Postural Ortostática/terapia , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome da Taquicardia Postural Ortostática/diagnóstico , Síndrome da Taquicardia Postural Ortostática/fisiopatologia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: RBx 14255 is a fluoroketolide in pre-clinical evaluation with potent activity against MDR Gram-positive pathogens. OBJECTIVES: To investigate the efficacy of RBx 14255 against bacterial meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis or Haemophilus influenzae in an experimental murine meningitis model. METHODS: In vitro activity of RBx 14255 was evaluated against clinical isolates of S. pneumoniae, N. meningitidis and H. influenzae. The in vivo efficacy of RBx 14255 was evaluated against bacterial meningitis, induced with S. pneumoniae 3579 erm(B), S. pneumoniae MA 80 erm(B), N. meningitidis 1852 and H. influenzae B1414 in a murine meningitis model. RESULTS: RBx 14255 showed strong in vitro bactericidal potential against S. pneumoniae, N. meningitidis and H. influenzae with MIC ranges of 0.004-0.1, 0.03-0.5 and 1-4 mg/L, respectively. In a murine meningitis model, a 50 mg/kg dose of RBx 14255, q12h, resulted in significant reduction of bacterial counts in the brain compared with the pretreatment control. The concentration of RBx 14255 in brain tissue correlated well with the efficacy in this mouse model. CONCLUSIONS: RBx 14255 showed superior bactericidal activity in time-kill assays in vitro and in vivo in an experimental murine meningitis model. RBx 14255 could be a promising candidate for future drug development against bacterial meningitis.
Assuntos
Antibacterianos/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Cetolídeos/farmacologia , Neisseria meningitidis/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Animais , Antibacterianos/química , Modelos Animais de Doenças , Infecções por Haemophilus/tratamento farmacológico , Infecções por Haemophilus/microbiologia , Cetolídeos/química , Meningite Meningocócica/tratamento farmacológico , Meningite Meningocócica/microbiologia , Meningite Meningocócica/patologia , Camundongos , Testes de Sensibilidade Microbiana , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/patologiaRESUMO
Here, we are reporting a single-step transformation of N-protected α,ß-unsaturated γ-amino amides into 5,5-disubstituted γ-lactams through a base-mediated new molecular rearrangement. In contrast to the known N- to C(O) cyclization of saturated γ-amino acids into corresponding γ-lactams, the new rearrangement involves the cyclization between N-terminal Cγ- to C-terminal amide N. The cyclization process was initiated by the migration of double bond from α,ß â ß,γ position. The enamine-imine tautomerization of the new ß,γ-double bond and subsequent 5-exo-trig cyclization of terminal amide leads to the formation of N-protected 5,5-disubstituted γ-lactam. The structures of various γ-lactams obtained from the rearrangement were studied in single crystals. Overall, the results reported here demonstrate the facile and single-step transformation of N-protected α,ß-unsaturated γ-amino amides into γ-lactams and provided an excellent opportunity to construct small-molecule peptidomimetics.