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AIM: The aim of this study was to examine the effect of an online multidisciplinary weight loss management programme. METHODS: Between July 2016 and July 2017 this randomized controlled trial recruited patients in Nanjing, China who were living with type 2 diabetes mellitus and who were obese or overweight and randomized them to online versus conventional groups. All participants were managed by a multidisciplinary team. The experimental group was managed using the Why Wait WeChat Platform for Weight Reduction Management. RESULTS: There were 55 and 52 participants in the online and conventional groups, respectively. The decreases in fasting blood glucose (-4.26 vs. -2.99 mmol/L), 2-h postprandial blood glucose (-4.48 vs. -2.68 mmol/L) and glycated haemoglobin (-22.11 vs. -6.21 mmol/mol) were more pronounced in the online compared to conventional group (all P < 0.05). After the intervention, self-management ability parameters, including diet control, foot care and total score, were improved in the online group compared with the conventional group, as well as all indexes of quality of life (all P < 0.05). CONCLUSION: The online multidisciplinary weight loss management programme improved blood glucose in obese or overweight patients living with type 2 diabetes mellitus. Self-management ability parameters (including diet control, foot care and total score) and quality of life were improved in the online group compared with the conventional group.
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Diabetes Mellitus Tipo 2 , Programas de Redução de Peso , Humanos , Diabetes Mellitus Tipo 2/terapia , Glicemia , Sobrepeso , Qualidade de Vida , Obesidade/terapia , Redução de PesoRESUMO
Infections with Salmonella enterica serovars Typhi and Paratyphi A cause an estimated 14 million cases of enteric fever annually. Here, the controlled nature of challenge studies is exploited to identify genetic variants associated with enteric fever susceptibility. Human challenge participants were genotyped by Illumina OmniExpress-24 BeadChip array (n = 176) and/or transcriptionally profiled by RNA sequencing (n = 174). While the study was underpowered to detect any single nucleotide polymorphisms (SNPs) significant at the whole-genome level, two SNPs within CAPN14 and MIATNB were identified with P < 10-5 for association with development of symptoms or bacteremia following oral S. Typhi or S. Paratyphi A challenge. Imputation of classical human leukocyte antigen (HLA) types from genomic and transcriptomic data identified HLA-B*27:05, previously associated with nontyphoidal Salmonella-induced reactive arthritis, as the HLA type most strongly associated with enteric fever susceptibility (P = 0.011). Gene sets relating to the unfolded protein response/heat shock and endoplasmic reticulum-associated protein degradation were overrepresented in HLA-B*27:05+ participants following challenge. Furthermore, intracellular replication of S. Typhi is higher in C1R cells transfected with HLA-B*27:05 (P = 0.02). These data suggest that activation of the unfolded protein response by HLA-B*27:05 misfolding may create an intracellular environment conducive to S. Typhi replication, increasing susceptibility to enteric fever.
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Febre Paratifoide , Salmonella enterica , Febre Tifoide , Predisposição Genética para Doença , Voluntários Saudáveis , Humanos , Salmonella paratyphi A , Salmonella typhi , Febre Tifoide/genéticaRESUMO
Human leukocyte antigen (HLA) B*51:01 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly genetically associated with Behçet's disease (BD). Previous studies have defined two subgroups of HLA-B*51 peptidome containing proline (Pro) or alanine (Ala) at position 2 (P2). Little is known about the unconventional non-Pro/Ala2 HLA-B*51-bound peptides. We aimed to study the features of this novel subpeptidome, and investigate its regulation by ERAP1. CRISPR-Cas9 was used to generate an HLA-ABC-triple knockout HeLa cell line (HeLa.ABC-KO), which was subsequently transduced to express HLA-B*51:01 (HeLa.ABC-KO.B51). ERAP1 was silenced using lentiviral shRNA. Peptides bound to HLA-B*51:01 were eluted and analyzed by mass spectrometry. The characteristics of non-Pro/Ala2, Pro2, and Ala2 peptides and their alteration by ERAP1 silencing were investigated. Effects of ERAP1 silencing on cell surface expression of HLA-B*51:01 were studied using flow cytometry. More than 20% of peptides eluted from HLA-B*51:01 lacked Pro or Ala at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared with the Pro2 and Ala2 subpeptidomes and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant leucine at position Ω). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to â¼40%, increased the percentage of longer (10-mer and 11-mer) peptides eluted from HLA-B*51:01 complexes, and abrogated the predominance of leucine at P1. Interestingly knockdown of ERAP1 altered the length and N-terminal residue usage of non-Ala2&Pro2 and Ala2 but not the Pro2 peptides. Finally, ERAP1 silencing regulated the expression levels of cell surface HLA-B*51 in a cell-type-dependent manner. In conclusion, we have used a novel methodology to identify an unconventional but surprisingly abundant non-Pro/Ala2 HLA-B*51:01 subpeptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.
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Aminopeptidases/metabolismo , Síndrome de Behçet/metabolismo , Antígenos HLA-B/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Peptídeos/metabolismo , Proteoma/metabolismo , Aminoácidos/metabolismo , Membrana Celular/metabolismo , Inativação Gênica , Células HeLa , Humanos , Ligação ProteicaRESUMO
The surgical masks have been essential consumables for public in the COVID-19 pandemic. However, long-time wearing masks will make wearers feel uncomfortable and massive discarded non-biodegradable masks lead to a heavy burden on our environment. In this paper, we adopt degradable chitosan@silver (CS@Ag) core-shell fibers and plant fibers to prepare an eco-friendly mask with excellent thermal comfort, self-sterilization, and antiviral effects. The thermal network of CS@Ag core-shell fibers highly improves the in-plane thermal conductivity of masks, which is 4.45 times higher than that of commercial masks. Because of the electrical conductivity of Ag, the fabricated mask can be electrically heated to warm the wearer in a cold environment and disinfect COVID-19 facilely at room temperature. Meanwhile, the in-situ reduced silver nanoparticles (AgNPs) endow the mask with superior antibacterial properties. Therefore, this mask shows a great potential to address the urgent need for a thermally comfortable, antibacterial, antiviral, and eco-friendly mask. Supplementary Information: The online version contains supplementary material available at 10.1007/s10570-022-04582-x.
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Polyolefins are important commodity plastics, yet their lack of functional groups limits their applications. The functionalization of C-H bonds holds promise for incorporating functionalities into polymers of ethylene and linear α-olefins. However, the selective functionalization of polyolefins derived from branched alkenes, even monobranched, 1,1-substituted alkenes, has not been achieved. These polymers are less reactive, due to steric effects, and they are prone to chain scission that degrades the polymer. We report the chemoselective and regioselective oxidation of a commercially important polymer of a branched olefin, polyisobutene. A polyfluorinated ruthenium-porphyrin catalyst incorporates ketone units into polyisobutene at methylene positions without chain cleavage. The oxidized polymer is thermally stable, yet it undergoes programmed reactions and possesses enhanced wetting properties.
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The amination of aryl halides has become one of the most commonly practiced C-N bond-forming reactions in pharmaceutical and laboratory syntheses. The widespread use of strong or poorly soluble inorganic bases for amine activation nevertheless complicates the compatibility of this important reaction class with sensitive substrates as well as applications in flow and automated synthesis, to name a few. We report a palladium-catalyzed C-N coupling using Et3N as a weak, soluble base, which allows a broad substrate scope that includes bromo- and chloro(hetero)arenes, primary anilines, secondary amines, and amide type nucleophiles together with tolerance for a range of base-sensitive functional groups. Mechanistic data have established a unique pathway for these reactions in which water serves multiple beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H2O generates, after proton loss, a coordinatively unsaturated Pd-OH species that can bind amine substrate triggering intramolecular N-H heterolysis. This water-assisted pathway operates efficiently with even weak terminal bases, such as Et3N. The use of a simple, commercially available ligand, PAd3, is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom cross-coupling reactions with sensitive substrates and functionality.
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Aminas/química , Água/química , Aminação , Carbono/química , Catálise , Ligantes , Nitrogênio/química , Paládio/químicaRESUMO
Group 10 metal catalysts have shown much promise for the copolymerization of nonpolar with polar alkenes to directly generate functional materials, but access to high copolymer molecular weights nevertheless remains a key challenge toward practical applications in this field. In the context of identifying new strategies for molecular weight control, we report a series of highly polarized P(V)-P(III) chelating ligands that manifest unique space filling and electrostatic effects within the coordination sphere of single component Pd polymerization catalysts and exert important influences on (co)polymer molecular weights. Single component, cationic phosphonic diamide-phosphine (PDAP) Pd catalysts are competent to generate linear, functional polyethylenes with Mw up to ca. 2 × 105 g mol-1, significantly higher than prototypical catalysts in this field, and with polar content up to ca. 9 mol %. Functional groups are positioned by these catalysts almost exclusively along the main chain, not at chain ends or ends of branches, which mimics the microstructures of commercial linear low-density polyethylenes. Spectroscopic, X-ray crystallographic, and computational data indicate PDAP coordination to Pd manifests cationic yet electron-rich active species, which may correlate to their complementary catalytic properties versus privileged catalysts such as electrophilic α-diimine (Brookhart-type) or neutral phosphine-sulfonato (Drent-type) complexes. Though steric blocking within the catalyst coordination sphere has long been a reliable strategy for catalyst molecular weight control, data from this study suggest electronic control should be considered as a complementary concept less prone to suppression of comonomer enchainment that can occur with highly sterically congested catalysts.
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Fast, base-promoted protodeboronation of polyfluoroaryl and heteroaryl boronic acids complicates their use in Suzuki-Miyaura coupling (SMC) because a base is generally required for catalysis. We report a "cationic" SMC method using a PAd3-Pd catalyst that proceeds at rt in the absence of a base or metal mediator. A wide range of sensitive boronic acids, particularly polyfluoroaryl substrates that are poorly compatible with classic SMC conditions, undergo clean coupling. Stoichiometric experiments implicate the intermediacy of organopalladium cations, which supports a long-postulated cationic pathway for transmetalation in SMC.
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OBJECTIVE: Association of position 97 (P97) residue polymorphisms in human leucocyte antigen (HLA)-B, including HLA-B*27, with ankylosing spondylitis (AS) has recently been reported. We studied the effect of P97 variations on cell surface expression of the AS-associated HLA-B*27 and HLA-B*51, and the AS-protective HLA-B*7. METHODS: Flow cytometry was used to measure surface expression of HLA-B*27 in C1R/HeLa cells expressing HLA-B*27 (N97) and six mutants at P97 (N97T, N97S, N97V, N97R, N97W and N97D). Transporter associated with antigen processing-deficient T2, tapasin-deficient 220, ß2m-deficient HCT15 and endoplasmic reticulum aminopeptidase 1 or ß2m-clustered regularly interspaced short palindromic repeats/Cas9-knockout HeLa cells were used to provide evidence for specific protein interactions. Surface expression of HLA-B*7/HLA-B*51 P97 mutants was also studied. RESULTS: Mutation of HLA-B*27 P97 to the AS risk residue threonine increased cell surface free heavy chain (FHC) expression. Protective residues (serine or valine) and non-AS-associated residues (arginine or tryptophan) did not alter FHC expression. The N97D mutation reduced expression of conventional and FHC forms of HLA-B*27. Differences in FHC expression levels between HLA-B*27, HLA-B*27-N97T and HLA-B*27-N97D were dependent on the presence of functional ß2m. HLA-B*7, which has an AS-protective serine at P97, expressed lower levels of FHC than HLA-B*27 or HLA-B*51. Introduction of asparagine at P97 of both HLA-B*7 and HLA-B*51 increased FHC expression. CONCLUSIONS: The nature of P97 residue affects surface expression of HLA-B*27, B*7 and B*51, with AS-associated residues giving rise to higher FHC expression levels. The association of P97 amino acid polymorphisms with AS could be, at least in part, explained by its effect on HLA-B*27 FHC cell surface expression.
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Antígenos de Superfície/genética , Antígeno HLA-B27/genética , Espondilite Anquilosante/genética , Microglobulina beta-2/metabolismo , Transportadores de Cassetes de Ligação de ATP/deficiência , Transportadores de Cassetes de Ligação de ATP/genética , Aminopeptidases/deficiência , Aminopeptidases/genética , Antígenos de Superfície/metabolismo , Asparagina/genética , Citometria de Fluxo , Antígeno HLA-B27/química , Antígeno HLA-B27/metabolismo , Antígeno HLA-B51/genética , Antígeno HLA-B51/metabolismo , Antígeno HLA-B7/genética , Antígeno HLA-B7/metabolismo , Células HeLa , Humanos , Proteínas de Membrana Transportadoras/deficiência , Proteínas de Membrana Transportadoras/genética , Antígenos de Histocompatibilidade Menor/genética , Mutação , Serina/genética , Espondilite Anquilosante/imunologia , Treonina/genética , Transfecção , Valina/genética , Microglobulina beta-2/genéticaRESUMO
BACKGROUND: Glutaric aciduria type II (GA II) is an autosomal recessive disorder affecting fatty acid and amino acid metabolism. The late-onset form of GA II disorder is almost exclusively associated with mutations in the electron transfer flavoprotein dehydrogenase (ETFDH) gene. Till now, the clinical features of late-onset GA II vary widely and pose a great challenge for diagnosis. The aim of the current study is to characterize the clinical phenotypes and genetic basis of a late-onset GAII patient. METHODS: In this study, we described the clinical and biochemical manifestations of a 23-year-old female Chinese patient with late-onset GA II, and performed genomic DNA-based PCR amplifications and sequence analysis of ETFDH gene of the whole pedigree. We also used in-silicon tools to analyze the mutation and evaluated the pathogenicity of the mutation according to the criteria proposed by American College of Medical Genetics and Genomics (ACMG). RESULTS: The muscle biopsy of this patient revealed lipid storage myopathy. Blood biochemical test and urine organic acid analyses were consistent with GA II. Direct sequence analysis of the ETFDH gene (NM_004453) revealed compound heterozygous mutations: c.250G > A (p.A84T) on exon 3 and c.920C > G (p.S307C) on exon 8. Both mutations were classified as "pathogenic" according to ACMG criteria. CONCLUSIONS: In conclusion, our study described the phenotype and genotype of a late-onset GA II patient, reiterating the importance of ETFDH gene screening in these patients.
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Flavoproteínas Transferidoras de Elétrons/genética , Estudos de Associação Genética , Heterozigoto , Proteínas Ferro-Enxofre/genética , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Mutação , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Idade de Início , Povo Asiático , Sequência de Bases , Flavoproteínas Transferidoras de Elétrons/química , Éxons , Feminino , Expressão Gênica , Genes Recessivos , Genótipo , Humanos , Proteínas Ferro-Enxofre/química , Modelos Moleculares , Deficiência Múltipla de Acil Coenzima A Desidrogenase/diagnóstico , Deficiência Múltipla de Acil Coenzima A Desidrogenase/etnologia , Deficiência Múltipla de Acil Coenzima A Desidrogenase/fisiopatologia , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/química , Linhagem , Fenótipo , Adulto JovemRESUMO
We report here the remarkable properties of PAd3, a crystalline air-stable solid accessible through a scalable SN1 reaction. Spectroscopic data reveal that PAd3, benefiting from the polarizability inherent to large hydrocarbyl groups, exhibits unexpected electron releasing character that exceeds other alkylphosphines and falls within a range dominated by N-heterocyclic carbenes. Dramatic effects in catalysis are also enabled by PAd3 during Suzuki-Miyaura cross-coupling of chloro(hetero)arenes (40 examples) at low Pd loading, including the late-stage functionalization of commercial drugs. Exceptional space-time yields are demonstrated for the syntheses of industrial precursors to valsartan and boscalid from chloroarenes with â¼2 × 10(4) turnovers in 10 min.
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Compostos Organofosforados/química , Fosfinas/química , Catálise , Elétrons , Compostos Heterocíclicos/química , Metano/análogos & derivados , Metano/químicaRESUMO
OBJECTIVE: Human leucocyte antigen (HLA)-B27 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly associated with ankylosing spondylitis (AS). ERAP1 is a key aminopeptidase in HLA class I presentation and can potentially alter surface expression of HLA-B27 free heavy chains (FHCs). We studied the effects of ERAP1 silencing/inhibition/variations on HLA-B27 FHC expression and Th17 responses in AS. METHODS: Flow cytometry was used to measure surface expression of HLA class I in peripheral blood mononuclear cells (PBMCs) from patients with AS carrying different ERAP1 genotypes (rs2287987, rs30187 and rs27044) and in ERAP1-silenced/inhibited/mutated HLA-B27-expressing antigen presenting cells (APCs). ERAP1-silenced/inhibited APCs were cocultured with KIR3DL2CD3ε-reporter cells or AS CD4+ T cells. Th17 responses of AS CD4+ T cells were measured by interleukin (IL)-17A ELISA and Th17 intracellular cytokine staining. FHC cell surface expression and Th17 responses were also measured in AS PBMCs following ERAP1 inhibition. RESULTS: The AS-protective ERAP1 variants, K528R and Q730E, were associated with reduced surface FHC expression by monocytes from patients with AS and HLA-B27-expressing APCs. ERAP1 silencing or inhibition in APCs downregulated HLA-B27 FHC surface expression, reduced IL-2 production by KIR3DL2CD3ε-reporter cells and suppressed the Th17 expansion and IL-17A secretion by AS CD4+ T cells. ERAP1 inhibition of AS PBMCs reduced HLA class I FHC surface expression by monocytes and B cells, and suppressed Th17 expansion. CONCLUSIONS: ERAP1 activity determines surface expression of HLA-B27 FHCs and potentially promotes Th17 responses in AS through binding of HLA-B27 FHCs to KIR3DL2. Our data suggest that ERAP1 inhibition has potential for AS treatment.
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Aminopeptidases/antagonistas & inibidores , Cadeias Pesadas de Imunoglobulinas/metabolismo , Espondilite Anquilosante/imunologia , Células Th17/imunologia , Adulto , Aminopeptidases/genética , Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Técnicas de Cocultura , Feminino , Inativação Gênica , Genótipo , Antígeno HLA-B27/metabolismo , Humanos , Interleucina-2/biossíntese , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor , Monócitos/imunologia , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: To explore the functional basis for the association between ankylosing spondylitis (AS) and single-nucleotide polymorphisms (SNPs) in the IL23R-IL12RB2 intergenic region. METHODS: We performed conditional analysis on genetic association data and used epigenetic data on chromatin remodelling and transcription factor (TF) binding to identify the primary AS-associated IL23R-IL12RB2 intergenic SNP. Functional effects were tested in luciferase reporter assays in HEK293T cells and allele-specific TF binding was investigated by electrophoretic mobility gel shift assays. IL23R and IL12RB2 mRNA levels in CD4+ T cells were compared between cases homozygous for the AS-risk 'A' allele and the protective 'G' allele. The proportions of interleukin (IL)-17A+ and interferon (IFN)-γ+ CD4+ T-cells were measured by fluorescence-activated cell sorting and compared between these AS-risk and protective genotypes. RESULTS: Conditional analysis identified rs11209032 as the probable causal SNP within a 1.14â kb putative enhancer between IL23R and IL12RB2. Reduced luciferase activity was seen for the risk allele (p<0.001) and reduced H3K4me1 methylation observed in CD4+ T-cells from 'A/A' homozygotes (p=0.02). The binding of nuclear extract to the risk allele was decreased â¼3.5-fold compared with the protective allele (p<0.001). The proportion of IFN-γ+ CD4+ T-cells was increased in 'A/A' homozygotes (p=0.004), but neither IL23R nor IL12RB2 mRNA was affected. CONCLUSIONS: The rs11209032 SNP downstream of IL23R forms part of an enhancer, allelic variation of which may influence Th1-cell numbers. Homozygosity for the risk 'A' allele is associated with more IFN-γ-secreting (Th1) cells. Further work is necessary to explain the mechanisms for these important observations.
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Diferenciação Celular/genética , Receptores de Interleucina-12/genética , Receptores de Interleucina/genética , Espondilite Anquilosante/genética , Células Th1/fisiologia , Adulto , Alelos , DNA Intergênico , Feminino , Citometria de Fluxo , Estudos de Associação Genética , Variação Genética , Genótipo , Células HEK293 , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Endoplasmatic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme involved in trimming of peptides to an optimal length for presentation by major histocompatibility complex (MHC) class I molecules. Polymorphisms in ERAP1 have been associated with chronic inflammatory diseases, including ankylosing spondylitis (AS) and psoriasis, and subsequent in vitro enzyme studies suggest distinct catalytic properties of ERAP1 variants. To understand structure-activity relationships of this enzyme we determined crystal structures in open and closed states of human ERAP1, which provide the first snapshots along a catalytic path. ERAP1 is a zinc-metallopeptidase with typical H-E-X-X-H-(X)(18)-E zinc binding and G-A-M-E-N motifs characteristic for members of the gluzincin protease family. The structures reveal extensive domain movements, including an active site closure as well as three different open conformations, thus providing insights into the catalytic cycle. A K(528)R mutant strongly associated with AS in GWAS studies shows significantly altered peptide processing characteristics, which are possibly related to impaired interdomain interactions.
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Aminopeptidases/química , Sequência de Aminoácidos , Substituição de Aminoácidos , Aminopeptidases/genética , Aminopeptidases/metabolismo , Apresentação de Antígeno , Domínio Catalítico/genética , Cristalografia por Raios X , Antígeno HLA-B27/metabolismo , Humanos , Antígenos de Histocompatibilidade Menor , Modelos Moleculares , Mutagênese Sítio-Dirigida , Polimorfismo de Nucleotídeo Único , Conformação Proteica , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Espondilite Anquilosante/enzimologia , Espondilite Anquilosante/genéticaRESUMO
To mitigate food spoilage caused by microbial contamination and extend the shelf life of food, antibacterial and eco-friendly biological packaging materials as an alternative to petroleum-based plastics is encouraged. Herein, an innovative and green composite film with triple antibacterial activity has been fabricated by introducing prussian blue nanoparticles (PBNPs) into chitosan (CS)-based films blended with gelatin (Gel) for the preservation of food, named CS/Gel/PB film. Due to the incorporation of PBNPs, CS/Gel/PB film exhibits enhanced mechanical, barrier and water resistance, and thermal abilities. The inherent bacterial trapping and killing capabilities of CS (contact killing), photothermal/photodynamic killing based on the excellent photothermal property of PBNPs under NIR irradiation synergistically facilitate the sterilization against Escherichia coli and Staphylococcus aureus (antibacterial ratio = 99.99 %). The film exhibits outstanding preservation capability in product storage, significantly extending the shelf life of strawberry and pork to 15 and 7 days, respectively. Meanwhile, the cytotoxicity assessment of CS/Gel/PB against HepG2 cells ascertains a cell viability exceeding 96 %, indicating a negligible toxicity level. Additionally, this film also exhibits superior biodegradability (preliminary degradation on the 10th day and completion on the 40th day) compared with PE film. Overall, these properties demonstrate great potential of CS/Gel/PB film as a novel packaging material.
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Cross-disease genome-wide association studies (GWASs) unveil pleiotropic loci, mostly situated within the non-coding genome, each of which exerts pleiotropic effects across multiple diseases. However, the challenge "W-H-W" (namely, whether, how, and in which specific diseases pleiotropy can inform clinical therapeutics) calls for effective and integrative approaches and tools. We here introduce a pleiotropy-driven approach specifically designed for therapeutic target prioritization and evaluation from cross-disease GWAS summary data, with its validity demonstrated through applications to two systems of disorders (neuropsychiatric and inflammatory). We illustrate its improved performance in recovering clinical proof-of-concept therapeutic targets. Importantly, it identifies specific diseases where pleiotropy informs clinical therapeutics. Furthermore, we illustrate its versatility in accomplishing advanced tasks, including pathway crosstalk identification and downstream crosstalk-based analyses. To conclude, our integrated solution helps bridge the gap between pleiotropy studies and therapeutics discovery.
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Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo ÚnicoRESUMO
While genome-wide studies have identified genomic loci in hosts associated with life-threatening Covid-19 (critical Covid-19), the challenge of resolving these loci hinders further identification of clinically actionable targets and drugs. Building upon our previous success, we here present a priority index solution designed to address this challenge, generating the target and drug resource that consists of two indexes: the target index and the drug index. The primary purpose of the target index is to identify clinically actionable targets by prioritising genes associated with Covid-19. We illustrate the validity of the target index by demonstrating its ability to identify pre-existing Covid-19 phase-III drug targets, with the majority of these targets being found at the leading prioritisation (leading targets). These leading targets have their evolutionary origins in Amniota ('four-leg vertebrates') and are predominantly involved in cytokine-cytokine receptor interactions and JAK-STAT signaling. The drug index highlights opportunities for repurposing clinically approved JAK-STAT inhibitors, either individually or in combination. This proposed strategic focus on the JAK-STAT pathway is supported by the active pursuit of therapeutic agents targeting this pathway in ongoing phase-II/III clinical trials for Covid-19.
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COVID-19 , Animais , Janus Quinases/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição STAT/genética , Citocinas/metabolismoRESUMO
Asthma is a chronic disease that is caused by a combination of genetic risks and environmental triggers and can affect both adults and children. Genome-wide association studies have revealed partly distinct genetic architectures for its two age-of-onset subtypes (namely, adult-onset and childhood-onset). We reason that identifying shared and distinct drug targets between these subtypes may inform the development of subtype-specific therapeutic strategies. In attempting this, we here introduce Priority Index for Asthma or PIA, a genetics-led and network-driven drug target prioritisation tool for asthma. We demonstrate the validity of the tool in improving drug target prioritisation for asthma compared to the status quo methods, as well as in capturing the underlying etiology and existing therapeutics for the disease. We also illustrate how PIA can be used to prioritise drug targets for adult- and childhood-onset asthma, as well as to identify shared and distinct pathway crosstalk genes. Shared crosstalk genes are mostly involved in JAK-STAT signaling, with clinical evidence supporting that targeting this pathway may be a promising drug repurposing opportunity for both subtypes. Crosstalk genes specific to childhood-onset asthma are enriched for PI3K-AKT-mTOR signaling, and we identify genes that are already targeted by licensed medications as repurposed drug candidates for this subtype. We make all our results accessible and reproducible at http://www.genetictargets.com/PIA. Collectively, our study has significant implications for asthma computational medicine research and can guide the future development of subtype-specific therapeutic strategies for the disease.
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Asma , Estudo de Associação Genômica Ampla , Humanos , Criança , Adulto , Fosfatidilinositol 3-Quinases/genética , Asma/tratamento farmacológico , Asma/genética , Fatores de Risco , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The rapid increase of phenicol-oxazolidinone (PhO) resistance in Streptococcus suis due to transferable resistance gene optrA is a matter of concern. However, genetic mechanisms for the dissemination of the optrA gene remain to be discovered. Here, we selected 33 optrA-positive S. suis isolates for whole-genome sequencing and analysis. The IS1216E element was present in 85% of the optrA-carrying contigs despite genetic variation observed in the flanking region. IS1216E-optrA-carrying segments could be inserted into larger mobile genetic elements (MGEs), including integrative and conjugative elements, plasmids, prophages, and antibiotic resistance-associated genomic islands. IS1216E-mediated circularization occurred to form the IS1216E-optrA-carrying translocatable units, suggesting a crucial role of IS1216E in optrA spreading. Three optrA-carrying MGEs (ICESsuAKJ47_SSU1797, plasmid pSH0918, and prophage ΦSsuFJSM5_rum) were successfully transferred via conjugation at different transfer frequencies. Interestingly, two types of transconjugants were observed due to the multilocus integration of ICESsuAKJ47 into an alternative SSU1943 attachment site along with the primary SSU1797 attachment site (type 1) or into the single SSU1797 attachment site (type 2). In addition, conjugative transfer of an optrA-carrying plasmid and prophage in streptococci was validated for the first time. Considering the abundance of MGEs in S. suis and the mobility of IS1216E-optrA-carrying translocatable units, attention should be paid to the potential risks to public health from the emergence and spread of PhO-resistant S. suis. IMPORTANCE Antimicrobial resistance to phenicols and oxazolidinones by the dissemination of the optrA gene leads to treatment failure in both veterinary and human medicine. However, information about the profile of these MGEs (mobilome) that carry optrA and their transferability in streptococci was limited, especially for the zoonotic pathogen S. suis. This study showed that the optrA-carrying mobilome in S. suis includes integrative and conjugative elements (ICEs), plasmids, prophages, and antibiotic resistance-associated genomic islands. IS1216E-mediated formation of optrA-carrying translocatable units played important roles in optrA spreading between types of MGEs, and conjugative transfer of various optrA-carrying MGEs (ICEs, plasmids, and prophages) further facilitated the transfer of optrA across strains, highlighting a nonignorable risk to public health of optrA dissemination to other streptococci and even to bacteria of other genera.
Assuntos
Oxazolidinonas , Streptococcus suis , Humanos , Streptococcus suis/genética , Saúde Pública , Genes Bacterianos , Farmacorresistência Bacteriana/genética , Sequências Repetitivas DispersasRESUMO
Influenza PAN inhibitors are of particular importance in current efforts to develop a new generation of antiviral drugs due to the growing emergence of highly pathogenic influenza viruses and the resistance to existing antiviral inhibitors. Herein, we design and synthesize a set of 1,3-cis-N-substituted-1,2,3,4-tetrahydroisoquinoline derivatives to enhance their potency by further exploiting the pockets 3 and 4 in the PAN endonuclease based on the hit d,l-laudanosoline. Particularly, the lead compound 35 exhibited potent and broad anti-influenza virus effects with EC50 values ranging from 0.43 to 1.12 µM in vitro and good inhibitory activity in a mouse model. Mechanistic studies demonstrated that 35 could bind tightly to the PAN endonuclease of RNA-dependent RNA polymerase, thus blocking the viral replication to exert antiviral activity. Overall, our study might establish the importance of 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based derivatives for the development of novel PAN inhibitors of influenza viruses.