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Quantum interference (QI) has been identified as a promising strategy for designing molecular-scale electronic devices. Heteroatom doping can effectively tailor the local structures and electronic states of intrinsic molecules, and endow them with modified electron transport properties. Herein, the impacts of multiple heteroatom substitution on destructive quantum interference (DQI) have been investigated based on tripodal meta-linked phenyl derivatives. Orbital views based on the Hückel method qualitatively predict the meta-anchored molecules with DQI features, while the introduction of nitrogen atoms can alleviate the suppression of DQI at the Fermi level (EF). This is generally consistent with the movement or even removal of the antiresonance dips in transmission spectra. The substituent on position 2 can raise the antiresonance energy, while the substituent on position 4 or 6 can lower the antiresonance energy. When more than one nitrogen atom is incorporated, the impact of the substitution on positions 4 and 6 can be superimposed and the substitution on positions 2 and 4 can be partly cancelled. The experimental single-molecule conductance for tripodal molecules follows the trend of 0N-3SMe < 1N-3SMe < 3N-3SMe < 2N-3SMe, in agreement with the theoretical prediction. Additionally, the regulation is the intrinsic property depending on the position and number of the nitrogen atoms in the backbone and is irrelevant to the number and type of the anchoring groups. Our findings provide qualitative guidance for tuning the electron transport based on DQI in heterocycle molecular devices.
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To determine distribution of severe acute respiratory syndrome coronavirus 2 in hospital wards in Wuhan, China, we tested air and surface samples. Contamination was greater in intensive care units than general wards. Virus was widely distributed on floors, computer mice, trash cans, and sickbed handrails and was detected in air ≈4 m from patients.
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Microbiologia do Ar , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/transmissão , Pneumonia Viral/transmissão , Aerossóis , COVID-19 , Hospitais , Humanos , Unidades de Terapia Intensiva , Pandemias , SARS-CoV-2RESUMO
It is very important to analyse the most advantageous connection style for quinoidal thiophene derivatives, which are used in n-type organic semiconductor transport materials. In the present work, the charge transport properties of three series of quinoidal thiophene derivatives, oligothiophene (series A), thienothiophene (series B) and benzothiophene (series C), are systematically investigated by employing full quantum charge transfer theory combined with kinetic Monte-Carlo simulation. The single crystal structures of the molecules we had constructed were predicted using the USPEX program combined with density functional theory (DFT) and considering the dispersion corrected. Our theoretical results expounded how the different connection styles, including oligo-, thieno-, and benzo-thiophene in the quinoidal thiophenes derivatives, effectively tune their electronic structures, and revealed how their intermolecular interactions affect the molecular packing patterns and hence their charge transport properties by symmetry-adapted perturbation theory (SAPT). In the meantime we also elucidated the role of end-cyano groups in noncovalent interactions. Furthermore, it is clarified that quinoidal thiophene derivatives show excellent carrier transport properties due to their optimal molecular stacking motifs and larger electronic couplings besides their low energy gap. In addition, our theoretical results demonstrate that quinoidal oligothiophene derivatives (n = 3-5) with more thiophene rings will have ambipolar transport properties, so quinoidal thienothiophene and benzothiophene derivatives should be promising alternatives as n-type OSCs. When we focused only on the electronic transport properties in the three series of molecules, quinoidal benzothiophene derivatives were slightly better than quinoidal oligothiophene or thienothiophene derivatives.
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To obtain anthracene-based derivatives with electron transport behavior, two series of anthracene-based derivatives modified by trifluoromethyl groups (-CF3) and cyano groups (-CN) at the 9,10-positions of the anthracene core were studied. Their electronic structures and crystal packings were also analyzed and compared. The charge-carrier mobilities were evaluated by quantum nuclear tunneling theory based on the incoherent charge-hopping model. Our results suggest that introducing -CN groups at 9,10-positions of the anthracene core is more favorable than introducing -CF3 to maintain great planar rigidity of the anthracene skeleton, decreasing more lowest unoccupied molecular orbital energy levels (0.45-0.55 eV), reducing reorganization energies, and especially forming a tight packing motif. Eventually, the excellent electron transport materials could be obtained. The molecule 1-B in Series 1 containing -CF3 groups is an ambipolar organic semiconductor (OSC) material with a 2D transport network, and its value of µh-max/µe-max is 1.75/0.47 cm2 V-1 s-1 along different directions; 2-A and 2-C in Series 2 with -CN groups are excellent n-type OSC candidates with the maximum intrinsic mobilities of 3.74 and 2.69 cm2 V-1 s-1 along the π-π stacking direction, respectively. Besides, the Hirshfeld surface and quantum theory of atoms in molecules analyses were applied to reveal the relationship between noncovalent interactions and crystal stacking.
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2,5-Difluoro-7,7,8,8-tetracyanoquinodimethane (F2-TCNQ) was recently reported to display excellent electron transport properties in single crystal field-effect transistors (FETs). Its carrier mobility can reach 25 cm2 V-1 s-1 in devices. However, its counterparts TCNQ and F4-TCNQ (tetrafluoro-7,7,8,8-tetracyanoquinodimethane) do not exhibit the same highly efficient behavior. To better understand this significant difference in charge carrier mobility, a multiscale approach combining semiclassical Marcus hopping theory, a quantum nuclear enabled hopping model and molecular dynamics simulations was performed to assess the electron mobilities of the Fn-TCNQ (n = 0, 2, 4) systems in this work. The results indicated that the outstanding electron transport behavior of F2-TCNQ arises from its effective 3D charge carrier percolation network due to its special packing motif and the nuclear tunneling effect. Moreover, the poor transport properties of TCNQ and F4-TCNQ stem from their invalid packing and strong thermal disorder. It was found that Marcus theory underestimated the mobilities for all the systems, while the quantum model with the nuclear tunneling effect provided reasonable results compared to experiments. Moreover, the band-like transport behavior of F2-TCNQ was well described by the quantum nuclear enabled hopping model. In addition, quantum theory of atoms in molecules (QTAIM) analysis and symmetry-adapted perturbation theory (SAPT) were used to characterize the intermolecular interactions in TCNQ, F2-TCNQ and F4-TCNQ crystals. A primary understanding of various noncovalent interaction responses for crystal formation is crucial to understand the structure-property relationships in organic molecular materials.
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Lyssaviruses, including Rabies virus, Duvenhage virus, European bat lyssavirus 1, European bat lyssavirus 2, Australian bat lyssavirus, and Irkut virus (IRKV), have caused human fatalities, but infection of IRKV in dogs has not been previously reported. In China, a dead dog that previously bit a human was determined to be infected with IRKV. Pathogenicity tests revealed that IRKVs can cause rabies-like disease in dogs and cats after laboratory infection. The close relationship between humans and pets, such as dogs and cats, may generate a new spillover-spreading route for IRKV infection. Therefore, additional attention should be paid to trans-species infection of IRKV between bats and dogs or dogs and humans through investigation of the prevalence and circulation patterns of IRKV in China.
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Doenças do Cão/transmissão , Lyssavirus/isolamento & purificação , Infecções por Rhabdoviridae/transmissão , Animais , China , Transmissão de Doença Infecciosa , Vetores de Doenças , Doenças do Cão/virologia , Cães , Genes Virais , Humanos , Lyssavirus/genética , Lyssavirus/patogenicidade , Masculino , Filogenia , Infecções por Rhabdoviridae/veterinária , Infecções por Rhabdoviridae/virologiaRESUMO
Chinese ferret badger (FB)-transmitted rabies is a serious threat to public health in southeast China. Although mostly associated with dogs, the rabies virus (RABV) presents genetic diversity and has a significantly wide host range in China. Instead of the dog- and wildlife-associated China II lineage in the past decades, the China I lineage has become the main epidemic group hosted and transmitted by dogs. In this study, four new lineages, including 43 RABVs from FBs, have been classified within the dog-dominated China I lineage since 2014. FB RABVs have been previously categorized in the China II lineage. Moreover, FB-hosted viruses seem to have become the main independent FB-associated clade in the phylogenetic tree. This claim suggests that the increasing genetic diversity of RABVs in FBs is a result of the selective pressure from coexisting dog rabies. FB transmission has become complicated and serious with the coexistence of dog rabies. Therefore, apart from targeting FB rabies, priority should be provided by the appropriate state agencies to perform mass immunization of dog against rabies.
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Reservatórios de Doenças/veterinária , Doenças do Cão/epidemiologia , Furões/virologia , Vírus da Raiva/genética , Raiva/epidemiologia , Animais , Encéfalo/virologia , China/epidemiologia , Reservatórios de Doenças/virologia , Doenças do Cão/transmissão , Doenças do Cão/virologia , Cães , Ligação Genética , Variação Genética , Filogenia , Filogeografia , Raiva/transmissão , Raiva/veterinária , Raiva/virologiaRESUMO
Rabies is a lethal neurological disease caused by the neurotropic rabies virus (RABV). To investigate the innate immune response in the brain during rabies infection, key gene transcripts indicative of innate immunity in a mouse model system were measured using real-time RT-PCR. Mice were infected via the intracerebral or intramuscular route with either attenuated rabies virus (SRV9) or pathogenic rabies virus (BD06). Infection with SRV9 resulted in the early detection of viral replication and the rapid induction of innate immune response gene expression in the brain. BD06 infection elicited innate immune response gene expression during only the late stage of infection. We measured Na-fluorescein uptake to assess blood-brain barrier (BBB) permeability, which was enhanced during the early stage of SRV9 infection and significantly enhanced during the late stage of BD06 infection. Furthermore, early SRV9 replication increased the maturation and differentiation of dendritic cells (DCs) and B cells in the inguinal lymph nodes and initiated the generation of virus-neutralizing antibodies (VNAs), which cooperate with the innate immune response to eliminate virus from the CNS. However, BD06 infection did not stimulate VNA production; thus, the virus was able to evade the host immune response and cause encephalitis. The rabies virus phosphoprotein has been reported to counteract IFN activation. In an in vitro study of the relationship between IFN antagonism and RABV pathogenicity, we demonstrated that SRV9 more strongly antagonized IFN activity than did BD06. Therefore, there is no positive relationship between the IFN antagonist activity of the virus and its pathogenicity.
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Encéfalo/patologia , Imunidade Inata , Vacina Antirrábica/administração & dosagem , Vacina Antirrábica/imunologia , Vírus da Raiva/imunologia , Raiva/patologia , Animais , Barreira Hematoencefálica , Diferenciação Celular , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Evasão da Resposta Imune , Injeções Intramusculares , Interferons/antagonistas & inibidores , Linfonodos/imunologia , Camundongos Endogâmicos BALB C , Permeabilidade , Reação em Cadeia da Polimerase em Tempo RealRESUMO
A theoretical study was carried out to investigate the electronic structures and the charge transport properties of a series of naphthodithiophene diimide (NDTI) thiophene α-substituted derivatives NDTI-X using density functional theory and classical Marcus charge transfer theory. This study deeply revealed the structure-property relationships by analyzing the intermolecular interactions in crystal structures of C8-NDTI and C8-NDTI-Cl thoroughly by using the Hirshfeld surface, QTAIM theories and symmetry-adapted perturbation theory (SAPT). Our results suggested that a 2-D brick-like π-stacking structure makes C8-NDTI-Cl a more excellent n-type semiconducting material with µmax-e of 2.554 cm2 V-1 s-1 than C8-NDTI with a herringbone-like slipped π-stacking motif. In addition, the calculated results showed that by modifying the thiophene α-positions of NDTI with electron-withdrawing substituents, -F, -Cl and -CN, low-lying LUMO energy levels and a high adiabatic electron affinity EA(a) can be obtained; while introducing electron-donating groups, benzene (-B), thiophene (-T), benzo[b]thiophene (-BT) and naphtha[2,3-b]thiophene (-NT), expanded the molecular π-conjugated backbone, and narrow band gaps, high EA(a) and small reorganization energies can be obtained. Theoretical simulations predict that NDTI-CN is an excellent air-stable n-type organic semiconducting material with an average electron mobility µe of up to 1.743 cm2 V-1 s-1. Owing to their high EA(a), moderate adiabatic ionization potential IP(a) as well as small hole and electron reorganization energies, NDTI-BT and NDTI-NT are two well-balanced air-stable ambipolar semiconducting materials. The theoretical average hole/electron mobilities are as high as 2.708/3.739 cm2 V-1 s-1 for C8-NDTI-NT and 1.597/2.350 cm2 V-1 s-1 for C8-NDTI-BT, respectively.
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Rabies remains a continuous threat to public health in Beijing. In this study, a total of 224 brain tissues were collected from suspected infected stray dogs within Beijing between January 2015 and December 2016. Among them, total of 67 samples were diagnosed positive for rabies. In the phylogenetic analysis, rabies in Beijing is currently a relatively independent public health issue originating from local rabid dogs apart from the imported cases from elsewhere in the country. Because vaccination of unregistered dogs against rabies is still neglected in Beijing and other regions of China, national and local authorities should play central roles in all related aspects, such as development of policies, engagement of stakeholders for public and professional education, entire vaccination process, and animal management.
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Doenças do Cão/virologia , Raiva/veterinária , Animais , Pequim/epidemiologia , Mordeduras e Picadas/epidemiologia , Cães , Humanos , Filogenia , Saúde Pública , Raiva/prevenção & controle , Raiva/transmissão , Raiva/virologia , Vacina Antirrábica/imunologia , Vírus da Raiva/genética , ZoonosesRESUMO
Pseudorabies (PR, Aujeszky's disease) is an acute, highly contagious viral disease resulting in major economic losses to the swine industry. PR is endemic in wild and domestic animals, although its natural host is the pig. Here, we report an outbreak of PR in foxes on a fur-producing farm in Yuncheng county, Shandong, China, that were fed pig offal. The diagnosis of PR was based on nervous signs and standard PCR methods and by isolation of PRV from fox brain tissue in Vero cells. The diagnosis was confirmed by an indirect immunofluorescence assay and electron microscopy. Phylogenetic analysis of a partial (804 nt) viral glycoprotein gC gene sequence indicated that it was likely to be a field strain closely related to a cluster of PRV previously identified in China.
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Surtos de Doenças , Raposas/virologia , Pseudorraiva/epidemiologia , Ração Animal , Animais , Composição de Bases , China/epidemiologia , Chlorocebus aethiops , Análise por Conglomerados , Herpesvirus Suídeo 1/genética , Herpesvirus Suídeo 1/isolamento & purificação , Herpesvirus Suídeo 1/ultraestrutura , Microscopia Eletrônica de Transmissão , Filogenia , Reação em Cadeia da Polimerase , Pseudorraiva/patologia , Pseudorraiva/virologia , Análise de Sequência de DNA , Suínos , Células Vero , Proteínas do Envelope Viral/genética , Cultura de VírusRESUMO
Mammalian orthoreoviruses (MRVs) are widespread and infect virtually all mammals. We report here the first case of a natural mutant and reassortant serotype 3 reovirus from mink in China, known as MRV3 SD-14. Whole-genome sequence analysis showed that the MRV3 SD-14 may have resulted from a reassortment involving MRVs that infected swine, humans and mink. Interestingly, the S1 segment, which encodes the viral attachment protein σ1, which influences viral virulence and cell tropism in the host, had a stop codon mutation at amino acid 246. Surveillance of the virulence and evolution of MRVs in humans and other animals deserves more attention.
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Genoma Viral , Orthoreovirus Mamífero 3/classificação , Orthoreovirus Mamífero 3/genética , Vison/virologia , RNA Viral/genética , Vírus Reordenados/classificação , Vírus Reordenados/genética , Animais , China , Códon sem Sentido , Humanos , Dados de Sequência Molecular , Análise de Sequência de DNA , Suínos , Proteínas do Envelope Viral/genéticaRESUMO
A series of pentacene derivatives, halogen-substituted and thiophene- and pyridine-substituted, have been studied with a focus on the electronic properties and charge transport properties using density functional theory and classical Marcus charge-transfer theory. The transport properties of holes and electrons have been studied to get insight into the effect of halogenation and heteroatom substitution on transport and injection of charge carriers. The calculation results revealed that fluorination and chlorination can effectively lower the lowest unoccupied molecular orbital (LUMO) level, modulate the hole and electron reorganization energy, improve the stacking mode of the crystal structure, and enhance the ambipolar characteristic. Chlorination gives a better ambipolar characteristic. On the basis of halogen substitution, the substitution of terminal benzene ring of triisopropyl-silylethynyl-pentacene (TIPS-PEN) by a thiophene or pyridine will greatly lower the LUMO level and improve the stacking mode, leading to more suitable ambipolar materials. Hence, both intra- and extra-ring substitution are favorable to enhance the ambipolar transport property of TIPS-PEN.
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Toll-like receptor 22 (TLR22) exists exclusively in aquatic animals and recognizes double stranded RNA (dsRNA). In the present study, a tlr22 gene and its 5'-flanking sequence were cloned from turbot, Scophthalmus maximus, its immune responsive expression was subsequently studied in vivo. The turbot (sm)tlr22 gene spans over 5.6 kb with a structure of 4 exon-3 intron and encodes 962 amino acids. The deduced protein shows the highest sequence identity (76.7%) to Japanese flounder Tlr22 and possesses a signal peptide sequence, a leucine-rich repeat (LRR) domain composed of 27 LRR motifs, a transmembrane region and a Toll/interleukin-1 receptor (TIR) domain. Phylogenetic analysis grouped it with other teleost Tlr22s. The interferon-stimulated response element (ISRE) and signal transducer and activator of transcription (STAT) binding site important for the basal transcriptional activity of TLR3 were predicted in the 5'-flanking sequence of smtlr22 gene. Quantitative real-time PCR (qPCR) analysis demonstrated the constitutive expression of smtlr22 mRNA in all examined tissues with higher levels in the head kidney, kidney and spleen. Further, smtlr22 expression was significantly up-regulated following challenge with polyinosinic: polycytidylic acid (poly I:C), lipopolysaccharide (LPS) or turbot reddish body iridovirus (TRBIV) in the gills, head kidney, spleen and muscle, with maximum increases ranging from 2.56 to 6.24 fold upon different immunostimulants and organs. These findings suggest a possible role of Smtlr22 in the immune responses to the infections of a broad range of pathogens that include DNA and RNA viruses and Gram-negative bacteria.
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Linguados/genética , Linguados/imunologia , Regulação da Expressão Gênica/fisiologia , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Animais , Sequência de Bases , Clonagem Molecular , Componentes do Gene , Perfilação da Expressão Gênica , Brânquias/virologia , Iridovirus , Lipopolissacarídeos , Dados de Sequência Molecular , Filogenia , Poli I-C , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Homologia de SequênciaRESUMO
We describe the isolation and complete genome sequence of a new calicivirus, FBCV-JX12, isolated from a ferret badger (Melogale moschata). Comparison of FBCV-JX12 with other vesiviruses revealed that it shared the highest amino acid sequence identities of 71.6, 60.5, and 59.3% in the nonstructural protein, VP1, and VP2, respectively, with MCV-DL2007 (mink calicivirus). Phylogenetic analysis of the whole genomic sequence showed that it clustered most closely with MCV-DL2007 of the genus Vesivirus, but with low nucleotide similarity in the three open reading frames (62.1-68.5%).
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Infecções por Caliciviridae/veterinária , Caliciviridae/classificação , Caliciviridae/isolamento & purificação , Furões/virologia , Animais , Sequência de Bases , Caliciviridae/genética , Infecções por Caliciviridae/virologia , China , Genoma Viral , Dados de Sequência Molecular , Fases de Leitura Aberta , Filogenia , Proteínas não Estruturais Virais/genéticaRESUMO
Human rabies is a serious public health problem that can't be ignored. Rabies immune globulin (RIG) is an indispensable component of rabies post-exposure prophylaxis (PEP). However, current PEP relies on RIG purified from pooled human or equine plasma, which are either in chronic shortage or associated with safety concerns. Monoclonal antibodies have become widely accepted as safer and more cost-effective alternatives to RIG products in recent years. Here, we assessed the neutralization breadth of human monoclonal antibody ormutivimab and its protective efficacy in PEP models. Ormutivimab was able to neutralize a broad panel of Chinese prevalent street RABVs with neutralizing potency form 198-1487.6 IU/mL. Furthermore, ormutivimab offered comparable protection to that with HRIG both at standard doses (20 IU/kg) and higher doses (100 IU/kg and 200 IU/kg). The interference of ormutivimab on vaccine potency was also analyzed and found slightly reduced neutralizing antibody titers similar to HRIG. The broad-spectrum neutralization activities, highly protective potency, and rapid onset of action make ormutivimab an effective candidate for human rabies PEP.
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Vacina Antirrábica , Vírus da Raiva , Raiva , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais , Cavalos , Humanos , Modelos Animais , Profilaxia Pós-Exposição , Raiva/prevenção & controleRESUMO
Structural design of organic π-conjugated small molecules allows the energy band structure and electronic properties of the molecules to be tuned as needed, which provides a feasible strategy for enhancing the performance of optoelectronic devices. The introduction of bridging structures is a common structural modification method to adjust the rigidity and coplanarity of the molecular backbone, thus affecting the molecular packing. However, patterning of organic single-crystalline microstructures based on conjugated ladder molecules with different bridging structures still remains challenging for large-area integration of optoelectronic devices. In this paper, a controlled dewetting process is applied to obtain organic single-crystalline arrays with precise positioning and a regular morphology based on two isomers with silicon-oxygen bridging and their two carbon-oxygen-bridged analogues. Molecules with different bridging structures show disparate packing models due to the difference of dihedral angles and ring tensions. A microwire-array ultraviolet photodetector based on the oxygen-silicon-bridging ladder molecule exhibits a high light on/off ratio of 24 and a responsivity of 0.63 mA W-1 owing to the effective π-π stacking governed by the molecular planarity. This work not only provides a universal method for the integration of organic optoelectronic devices but also explains the effect of bridging structure engineering on molecular assembly and optoelectronic performance.
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Rabies immune globulin (RIG) is an indispensable component of rabies post-exposure prophylaxis (PEP) because it provides passive immunity to prevent this otherwise inescapably fatal disease in Category III exposed patients. Even with decades of development, RIG products are still criticized for their high cost, lot-to-lot variation, and potential safety issues. They remain largely unattainable in most developing regions of the world, where demand is highest. In recent years, monoclonal antibodies (MAbs) have become widely accepted as safer and more cost-effective alternatives to RIG products. As an example, SYN023 is a 1:1 cocktail of two humanized anti-rabies MAbs previously shown to display extensive neutralizing capabilities. Here, we further assessed the efficacy of SYN023 in animal models of rabies, and found that SYN023 afforded protection equal to a standard dose of human RIG (HRIG) at 0.03 mg/kg in Syrian hamsters and 0.1 mg/kg in beagles. Potential interference with vaccine-induced immunity was analyzed for the MAbs at these concentrations. While individual MAbs did not interfere with vaccine response, SYN023 at dosages of 0.1 mg/kg and above resulted in reduced neutralizing antibody titers similar to HRIG. Thus, the in vivo characterization of SYN023 supports its utility in human rabies PEP as an efficacious alternative to RIG products.
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Toxoplasma gondii is an obligate intracellular apicomplexan parasite which is able to infect almost all warm-blooded animals. There is no information about the prevalence and genetic characterization of T. gondii in badgers (Melogale moschata) in China. Here, a total of 367 badgers were captured from different cities in Jiangxi province, Southern China. Genomic DNA was extracted from brain tissues of each badgers, and 57 (15.45%) of them were positive for T. gondii by semi-nested PCR of the B1 gene. The positive DNA samples were typed at 11 genetic markers, including 10 nuclear loci (SAG1, 5'-SAG2 and 3'-SAG2, alternative SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1) and an apicoplast locus (Apico), with multilocus polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technology. Among them, 4 were completely typed at all loci, and 2 was genotyped for 9 loci, showing that they belong to ToxoDB#9. This is the first report of prevalence and genetic characterization of T. gondii isolates from badgers in China, which contributes to broader understanding of population structure of T. gondii in China. It is important for the prevention and control of T. gondii infection in wild animals.
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Reação em Cadeia da Polimerase Multiplex/métodos , Mustelidae/parasitologia , Polimorfismo de Fragmento de Restrição , Toxoplasma/isolamento & purificação , Animais , China/epidemiologia , DNA de Protozoário/análise , Prevalência , Proteínas de Protozoários/genética , Toxoplasma/genéticaRESUMO
Rabies is a neglected zoonotic disease that is preventable in humans by appropriate post-exposure prophylaxis (PEP). However, current PEP relies on polyclonal immune globulin products purified from pooled human (HRIG) or equine (ERIG) plasma that are either in chronic shortage or in association with safety concerns. Here, we present the development of an antibody cocktail, SYN023, made of two novel monoclonal antibodies (MAb) CTB011 and CTB012 that could serve as safer and more cost-effective alternatives to the current RIG products. Both CTB011 and CTB012 are humanized MAbs that bind to non-overlapping epitopes on the rabies virus (RABV) glycoprotein (G) with sub-nanomolar affinities. Sequence analysis revealed that many of the critical residues in binding are highly conserved across different species of lyssaviruses. When combined at a 1:1 ratio, CTB011/CTB012 exhibited neutralization capabilities equivalent or superior to HRIG against 10 North American street RABV isolates in vitro and 15 prevalent Chinese RABV strains in animal models. Finally, SYN023, at a dosage of 0.03 mg/kg, was able to offer the same degree of protection as standard HRIG administration (20 IU/kg) in Syrian hamsters challenged with a highly virulent bat (Tadarida brasiliensis) RABV variant. Taken together, the high-potency and broad-spectrum neutralization demonstrated by SYN023 make it an effective candidate for human rabies PEP consideration.