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Summary: Lipoxin A4 (LA4), a bioactive product of arachidonic acid, has been shown to exert strong anti‐inflammatory activity. By contrast, the anti‐inflammatory action of LA4 in a renal ischaemia–reperfusion (RIR)‐mediated acute lung inflammation (ALI) model and the potential pathogenesis of the condition is still unclear. The aim of the current research was to investigate the effect of LA4 on RIR‐induced ALI. The rat ALI model was induced by RIR. LA4 was injected via the tail vein immediately after RIR. The results indicate that LA4 markedly inhibits inflammatory cells infiltration, attenuates myeloperoxidase activity, and reduces the concentration of inflammatory mediators and Toll‐like receptor 4 (TLR4) in RIR‐induced ALI. Furthermore, LA4 suppressed nuclear factor kappa B (NF‐κB) p65 and mitogen‐activated protein kinase (MAPK) activation. The protective effect of LA4 in RIR‐stimulated ALI was reversed by BOC‐2 (an antagonist of the LA4 receptor). These results indicate that LA4 exerts powerful anti‐inflammatory functions in RIR‐induced ALI by attenuating TLR4 expression via MAPK and NF‐κB signalling. Accordingly, LA4 might be an underlying treatment drug for RIR‐induced ALI. [ABSTRACT FROM AUTHOR]

Based on overlapping domain decomposition, a new class of parallel split least‐squares (PSLS) mixed finite element methods is presented for solving parabolic problem. The algorithm is fully parallel. In the overlapping domains, the partition of unity is applied to distribute the corrections reasonably, which makes that the new method only needs one or two iteration steps to reach given accuracy at each time step while the classical Schwarz alternating methods need many iteration steps. The dependence of the convergence rate on the spacial mesh size, time increment, iteration times, and subdomains overlapping degree is analyzed. Some numerical results are reported to confirm the theoretical analysis. [ABSTRACT FROM AUTHOR]

SnTox1 induces programmed cell death and the up-regulation of pathogenesis-related genes including chitinases. Additionally, SnTox1 has structural homology to several plant chitin-binding proteins., Therefore, we evaluated SnTox1 for chitin binding and localization. We transformed an avirulent strain of Parastagonospora nodorum as well as three nonpathogens of wheat ( Triticum aestivum), including a necrotrophic pathogen of barley, a hemibiotrophic pathogen of sugar beet and a saprotroph, to evaluate the role of SnTox1 in infection and in protection from wheat chitinases., SnTox1 bound chitin and an SnTox1-green fluorescent fusion protein localized to the mycelial cell wall. Purified SnTox1 induced necrosis in the absence of the pathogen when sprayed on the leaf surface and appeared to remain on the leaf surface while inducing both epidermal and mesophyll cell death. SnTox1 protected the different fungi from chitinase degradation. SnTox1 was sufficient to change the host range of a necrotrophic pathogen but not a hemibiotroph or saprotroph., Collectively, this work shows that SnTox1 probably interacts with a receptor on the outside of the cell to induce cell death to acquire nutrients, but SnTox1 accomplishes a second role in that it protects against one aspect of the defense response, namely the effects of wheat chitinases. [ABSTRACT FROM AUTHOR]

Direct synthesis of hierarchical zeolites currently relies on the use of surfactant-based templates to produce mesoporosity by the random stacking of 2D zeolite sheets or the agglomeration of tiny zeolite grains. The benefits of using nonsurfactant polymers as dual-function templates in the fabrication of hierarchical zeolites are demonstrated. First, the minimal intermolecular interactions of nonsurfactant polymers impose little interference on the crystallization of zeolites, favoring the formation of 3D continuous zeolite frameworks with a long-range order. Second, the mutual interpenetration of the polymer and the zeolite networks renders disordered but highly interconnected mesopores in zeolite crystals. These two factors allow for the synthesis of single-crystalline, mesoporous zeolites of varied compositions and framework types. A representative example, hierarchial aluminosilicate (meso-ZSM-5), has been carefully characterized. It has a unique branched fibrous structure, and far outperforms bulk aluminosilicate (ZSM-5) as a catalyst in two model reactions: conversion of methanol to aromatics and catalytic cracking of canola oil. Third, extra functional groups in the polymer template can be utilized to incorporate desired functionalities into hierarchical zeolites. Last and most importantly, polymer-based templates permit heterogeneous nucleation and growth of mesoporous zeolites on existing surfaces, forming a continuous zeolitic layer. In a proof-of-concept experiment, unprecedented core-shell-structured hierarchical zeolites are synthesized by coating mesoporous zeolites on the surfaces of bulk zeolites. [ABSTRACT FROM AUTHOR]

Barley net form net blotch ( NFNB), caused by the necrotrophic fungus Pyrenophora teres f. teres, is a destructive foliar disease in barley-growing regions worldwide. Little is known about the genetic and molecular basis of this pathosystem. Here, we identified a small secreted proteinaceous necrotrophic effector ( NE), designated PttNE1, from intercellular wash fluids of the susceptible barley line Hector after inoculation with P. teres f. teres isolate 0-1. Using a barley recombinant inbred line (RIL) population developed from a cross between the sensitive/susceptible line Hector and the insensitive/resistant line NDB 112 ( HN population), sensitivity to PttNE1, which we have named SPN1, mapped to a common resistance/susceptibility region on barley chromosome 6H. PttNE1- SPN1 interaction accounted for 31% of the disease variation when the HN population was inoculated with the 0-1 isolate. Strong accumulation of hydrogen peroxide and increased levels of electrolyte leakage were associated with the susceptible reaction, but not the resistant reaction. In addition, the HN RIL population was evaluated for its reactions to 10 geographically diverse P. teres f. teres isolates. Quantitative trait locus ( QTL) mapping led to the identification of at least 10 genomic regions associated with disease, with chromosomes 3H and 6H harbouring major QTLs for resistance/susceptibility. SPN1 was associated with all the 6H QTLs, except one. Collectively, this information indicates that the barley- P. teres f. teres pathosystem follows, at least partially, an NE-triggered susceptibility ( NETS) model that has been described in other necrotrophic fungal disease systems, especially in the Dothideomycete class of fungi. [ABSTRACT FROM AUTHOR]

Pyrenophora teres, causal agent of net blotch of barley, exists in two forms, designated P. teres f. teres and P. teres f. maculata, which induce net form net blotch (NFNB) and spot form net blotch (SFNB), respectively. Significantly more work has been performed on the net form than on the spot form although recent activity in spot form research has increased because of epidemics of SFNB in barley-producing regions. Genetic studies have demonstrated that NFNB resistance in barley is present in both dominant and recessive forms, and that resistance/susceptibility to both forms can be conferred by major genes, although minor quantitative trait loci have also been identified. Early work on the virulence of the pathogen showed toxin effector production to be important in disease induction by both forms of pathogen. Since then, several laboratories have investigated effectors of virulence and avirulence, and both forms are complex in their interaction with the host. Here, we assemble recent information from the literature that describes both forms of this important pathogen and includes reports describing the host-pathogen interaction with barley. We also include preliminary findings from a genome sequence survey. Pyrenophora teres Drechs. Kingdom Fungi; Phylum Ascomycota; Subphylum Pezizomycotina; Class Dothideomycete; Order Pleosporales; Family Pleosporaceae; Genus Pyrenophora, form teres and form maculata. To date, no clear morphological or life cycle differences between the two forms of P. teres have been identified, and therefore they are described collectively. Towards the end of the growing season, the fungus produces dark, globosely shaped pseudothecia, about 1-2 mm in diameter, on barley. Ascospores measuring 18-28 µm × 43-61 µm are light brown and ellipsoidal and often have three to four transverse septa and one or two longitudinal septa in the median cells. Conidiophores usually arise singly or in groups of two or three and are lightly swollen at the base. Conidia measuring 30-174 µm × 15-23 µm are smoothly cylindrical and straight, round at both ends, subhyaline to yellowish brown, often with four to six pseudosepta. Morphologically, P. teres f. teres and P. teres f. maculata are indistinguishable. Comprehensive work on the host range of P. teres f. teres has been performed; however, little information on the host range of P. teres f. maculata is available. Hordeum vulgare and H. vulgare ssp. spontaneum are considered to be the primary hosts for P. teres. However, natural infection by P. teres has been observed in other wild Hordeum species and related species from the genera Bromus, Avena and Triticum, including H. marinum, H. murinum, H. brachyantherum, H. distichon, H. hystrix, B. diandrus, A. fatua, A. sativa and T. aestivum (, Rev. Plant Pathol. 52:269-290). In artificial inoculation experiments under field conditions, P. teres f. teres has been shown to infect a wide range of gramineous species in the genera Agropyron, Brachypodium, Elymus, Cynodon, Deschampsia, Hordelymus and Stipa (Brown et al., 1993, Plant Dis. 77:942-947). Additionally, 43 gramineous species were used in a growth chamber study and at least one of the P. teres f. teres isolates used was able to infect 28 of the 43 species tested. However, of these 28 species, 14 exhibited weak type 1 or 2 reactions on the NFNB 1-10 scale (). These reaction types are small pin-point lesions and could possibly be interpreted as nonhost reactions. In addition, the P. teres f. teres host range was investigated under field conditions by artificially inoculating 95 gramineous species with naturally infected barley straw. Pyrenophora teres f. teres was re-isolated from 65 of the species when infected leaves of adult plants were incubated on nutrient agar plates; however, other than Hordeum species, only two of the 65 host species exhibited moderately susceptible or susceptible field reaction types, with most species showing small dark necrotic lesions indicative of a highly resistant response to P. teres f. teres. Although these wild species have the potential to be alternative hosts, the high level of resistance identified for most of the species makes their role as a source of primary inoculum questionable. Two types of symptom are caused by P. teres. These are net-type lesions caused by P. teres f. teres and spot-type lesions caused by P. teres f. maculata. The net-like symptom, for which the disease was originally named, has characteristic narrow, dark-brown, longitudinal and transverse striations on infected leaves. The spot form symptom consists of dark-brown, circular to elliptical lesions surrounded by a chlorotic or necrotic halo of varying width. [ABSTRACT FROM AUTHOR]

Xanthomonas translucens is a group of gram‐negative bacteria that can cause important diseases in cereal crops and forage grasses. Different pathovars have been defined according to their host ranges, and molecular and biochemical characteristics. Pathovars have been placed into two major groups: translucens and graminis. The translucens group contains the pathovars causing bacterial leaf streak (BLS) on cereal crops such as wheat, barley, triticale, rye, and oat. In recent years, BLS has re‐emerged as a major problem for many wheat‐ and barley‐producing areas worldwide. The biology of the pathogens and the host–pathogen interactions in cereal BLS diseases were poorly understood. However, recent genome sequence data have provided an insight into the bacterial phylogeny and identification and pathogenicity/virulence. Furthermore, identification of sources of resistance to BLS and mapping of the resistance genes have been initiated. Taxonomy: Kingdom Bacteria; Phylum Proteobacteria; Class Gammaproteobacteria; Order Xanthomonadales; Family Xanthomonadaceae; Genus Xanthomonas; Species X. translucens; translucens group pathovars: undulosa, translucens, cerealis, hordei, and secalis; graminis group pathovars: arrhenatheri, graminis, poae, phlei; newly established pathovar: pistaciae. Host range: X. translucens mainly infects plant species in the Poaceae with the translucens group on cereal crop species and the graminis group on forage grass species. However, some strains have been isolated from, and are able to infect, ornamental asparagus and pistachio trees. Most pathovars have a narrow host range, while a few can infect a broad range of hosts. Genome: The complete genome sequence is available for two X. translucens pv. undulosa strains and one pv. translucens strain. A draft genome sequence is also available for at least one strain from each pathovar. The X. translucens pv. undulosa strain Xt4699 was the first to have its complete genome sequenced, which consists of 4,561,137 bp with total GC content approximately at 68% and 3,528 predicted genes. Virulence mechanisms: Like most xanthomonads, X. translucens utilizes a type III secretion system (T3SS) to deliver a suite of T3SS effectors (T3Es) inside plant cells. Transcription activator‐like effectors, a special group of T3Es, have been identified in most of the X. translucens genomes, some of which have been implicated in virulence. Genetic factors determining host range virulence have also been identified. [ABSTRACT FROM AUTHOR]

Summary: Ustilaginoidins, toxic to plants, animals and human, are one of major types of mycotoxins produced by Ustilaginoidea virens. In this study, a gene cluster containing the polyketide synthase gene UvPKS1 was analysed via gene replacement and biochemical studies to determine ustilaginoidin biosynthetic pathway in U. virens. UvPKS1 was first proven to be responsible for the first step of ustilaginoidin biosynthesis, since neither ustilaginoidin derivatives nor intermediates were produced when UvPKS1 was deleted. Replacement of ugsO greatly reduced ustilaginoidin production but increased the ratios of dehydrogenated/hydrogenated ustilagioidin derivatives. The enhanced growth rate of the ΔugsO mutant indicates that accumulation of certain ustilaginoidin derivatives may adversely affect mycelial growth in U. virens. Deletion of ugsT encoding a putative MFS transporter disrupted the ability to generate ustilaginoidins. The ustilaginoidin derivatives produced in the ΔugsJ mutant all lack C3‐methyl, indicating that UgsJ is responsible for C3‐methylation. Only monomeric intermediates, such as 3‐methyl‐dihydro‐nor‐rubrofusarin, but no ustilaginoidin derivatives were generated in the ΔugsL mutant, indicating that UgsL is responsible for the dimerization of nor‐rubrofusarin derivatives to produce ustilaginoidins. However, ugsR2 deletion had no dramatic effect on ustilaginoidin biosynthesis. Together, biochemical analyses with bioinformatics and chemoinformatics uncover a multiple‐step enzyme‐catalysed pathway for ustilaginoidin biosynthesis in U. virens. [ABSTRACT FROM AUTHOR]

A new synthetic strategy is developed for fabricating hierarchically structured zeolite materials, which features the use of cationic non‐surfactant polymers as dual‐functional templates. Y. Han and co‐workers show, on page 1881, that the mutual interpenetration of the polymer and the zeolite networks renders disordered but highly interconnected mesopores in zeolite crystals. This strategy also enables the synthesis of unprecedented core‐shell‐structured hierarchical zeolites. [ABSTRACT FROM AUTHOR]

Pt supported on KOH-activated mesoporous carbon (K-AMC) was used to catalyze glycerol oxidation under base-free conditions at room temperature. To study the relationship between the carbon surface chemistry and the catalytic performance of the K-AMC-based Pt catalysts, different levels of surface oxygen functional groups (SOFGs) on the AMC supports were induced by thermal treatment at different temperatures under inert or H2 gas. A strong effect of the surface chemistry was observed on AMC-supported Pt catalysts for glycerol oxidation. The presence of carboxylic acid groups impedes the adsorption of glycerol, which leads to the reduction of catalytic activity, whereas the presence of high-desorption-temperature SOFGs, such as phenol, ether, and carbonyl/quinone groups, provide hydrophilicity to the carbon surface that improves the adsorption of glycerol molecules on Pt metal surface, which is beneficial for the catalytic activity. [ABSTRACT FROM AUTHOR]

Efficient low‐temperature hydrodeoxygenation (HDO) of lignin derivatives to produce biofuels and high value‐added chemicals is still of challenge. Here, we have constructed a high active and stable 0.2 wt.% Pd/MS‐HZSM‐5(30) catalyst, and 94.7 % yield of 2‐methoxy‐4‐methylphenol (MMP) can be achieved in HDO of vanillin (VAN, a typical platform molecule of lignin derivatives) under milder reaction conditions (60 °C, 5 h, molar ratio of VAN/Pd=1200, water phase), outperforming the most works reported recently. Detailed experimental and mechanistic studies demonstrated that the superior catalytic performance was due to the rapid hydrogenolysis of generated intermediate (vanillyl alcohol, VAL) to MMP proceeded in an interfacial microenvironmental created by Pd NPs and acidic sites in Pd/MS‐HZSM‐5(30). These new insights will provide potential guidance for the efficient low‐temperature production of biofuels and valuable chemicals from lignin derivatives or raw lignin. [ABSTRACT FROM AUTHOR]

Summary: Parastagonospora nodorum is an economically important necrotrophic fungal pathogen of wheat. Parastagonospora nodorum secretes necrotrophic effectors that target wheat susceptibility genes to induce programmed cell death (PCD). In this study, we cloned and functionally validated SnTox5 and characterized its role in pathogenesis.We used whole genome sequencing, genome‐wide association study (GWAS) mapping, CRISPR‐Cas9‐based gene disruption, gain‐of‐function transformation, quantitative trait locus (QTL) analysis, haplotype and isoform analysis, protein modeling, quantitative PCR, and laser confocal microscopy to validate SnTox5 and functionally characterize SnTox5.SnTox5 is a mature 16.26 kDa protein with high structural similarity to SnTox3. Wild‐type and mutant P. nodorum strains and wheat genotypes of SnTox5 and Snn5, respectively, were used to show that SnTox5 not only targets Snn5 to induce PCD but also facilitates the colonization of the mesophyll layer even in the absence of Snn5.Here we show that SnTox5 facilitates the efficient colonization of the mesophyll tissue and elicits PCD specific to host lines carrying Snn5. The homology to SnTox3 and the ability of SnTox5 to facilitate the colonizing of the mesophyll also suggest a role in the suppression of host defense before PCD induction. See also the Commentary on this article by Kanyuka et al., 233: 11–14. [ABSTRACT FROM AUTHOR]

Summary: Parastagonospora nodorum is a fungal pathogen of wheat. As a necrotrophic specialist, it deploys effector proteins that target dominant host susceptibility genes to elicit programmed cell death (PCD). Here we identify and functionally validate the effector targeting the host susceptibility genes Snn2, Snn6 and Snn7.We utilized whole‐genome sequencing, association mapping, gene‐disrupted mutants, gain‐of‐function transformants, virulence assays, bioinformatics and quantitative PCR to characterize these interactions.A single proteinaceous effector, SnTox267, targeted Snn2, Snn6 and Snn7 to trigger PCD. Snn2 and Snn6 functioned cooperatively to trigger PCD in a light‐dependent pathway, whereas Snn7‐mediated PCD functioned in a light‐independent pathway. Isolates harboring 20 SnTox267 protein isoforms quantitatively varied in virulence. The diversity and distribution of isoforms varied between populations, indicating adaptation to local selection pressures. SnTox267 deletion resulted in the upregulation of effector genes SnToxA, SnTox1 and SnTox3.We validated a novel effector operating in an inverse‐gene‐for‐gene manner to target three genetically distinct host susceptibility genes and elicit PCD. The discovery of the complementary gene action of Snn2 and Snn6 indicates their potential function in a guard or decoy model. Additionally, differences in light dependency in the elicited pathways and upregulation of unlinked effectors sheds new light onto a complex fungal necrotroph–host interaction. See also the Commentary on this article by Kanyuka et al., 233: 11–14. [ABSTRACT FROM AUTHOR]

A high-throughput RNA-mediated gene silencing system was developed for Cochliobolus sativus (anamorph: Bipolaris sorokiniana), the causal agent of spot blotch, common root rot and black point in barley and wheat. The green fluorescent protein gene ( GFP) and the proteinaceous host-selective toxin gene ( ToxA) were first introduced into C. sativus via the polyethylene glycol (PEG)-mediated transformation method. Transformants with a high level of expression of GFP or ToxA were generated. A silencing vector (pSGate1) based on the Gateway cloning system was developed and used to construct RNA interference (RNAi) vectors. Silencing of GFP and ToxA in the transformants was demonstrated by transformation with the RNAi construct expressing hairpin RNA (hpRNA) of the target gene. The polyketide synthase gene ( CsPKS1), involved in melanin biosynthesis pathways in C. sativus, was also targeted by transformation with the RNAi vector (pSGate1- CsPKS1) encoding hpRNA of the CsPKS1 gene. The transformants with pSGate1- CsPKS1 exhibited an albino phenotype or reduced melanization, suggesting effective silencing of the endogenous CsPKS1 in C. sativus. Sectors exhibiting the wild-type phenotype of the fungus appeared in some of the CsPKS1-silenced transformants after subcultures as a result of inactivation or deletions of the RNAi transgene. The gene silencing system established provides a useful tool for functional genomics studies in C. sativus and other filamentous fungi. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of mannose-binding lectin (MBL) gene polymorphism on the immune system and the significance of vaginal MBL concentration in the pathogenesis of vulvovaginal candidiasis (VVC) and recurrent VVC (rVVC).Patients and Methods: Mannose-binding lectin concentrations in CVL samples from 111 women were collected between August 2004 and November 2004, 51 with VVC, 6 with rVVC patients, and 54 healthy women. CVL MBL concentrations were determined by enzyme-linked immunosorbent assay, and MBL gene polymorphism was analyzed by polymerase chain reaction and the restriction fragment length polymorphism method.Results: Cervicovaginal lavage MBL concentration (17.80 ng/mL) and gene mutation frequency (33.33%) were both significantly higher in women with VVC (P<0.01) than in controls (odds ratio [OR], 2.93; 95% confidence interval [CI], 1.14-7.57; P<0.05). On the other hand, MBL concentration was lower in women with rVVC (0.30 ng/mL) than in controls (1.28 ng/mL) (P<0.05), although MBL gene mutation frequency (83.33%) was significantly higher in women with rVVC than in controls (OR, 26.87; 95% CI, 2.76-261.65; P<0.01).Conclusions: The presence of VVC can increase vaginal MBL level, which may be an immune response against Candida albicans infection; in women with rVVC, the low level of MBL in the vagina caused by mutation in the MBL gene may play a role in the recurrence of the infection. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is one of the most common movement disorders with loss of dopaminergic neurons and the presence of Lewy bodies in certain brain areas. However, it is not clear how Lewy body (inclusion with protein aggregation) formation occurs. Mutations in leucine‐rich repeat kinase 2 (LRRK2) can cause a genetic form of PD and contribute to sporadic PD with the typical Lewy body pathology. Here, we used our recently identified LRRK2 GTP‐binding inhibitors as pharmacological probes to study the LRRK2‐linked ubiquitination and protein aggregation. Pharmacological inhibition of GTP‐binding by GTP‐binding inhibitors (68 and Fx2149) increased LRRK2‐linked ubiquitination predominantly via K27 linkage. Compound 68‐ or Fx2149 increased G2019S‐LRRK2‐linked ubiquitinated aggregates, which occurred through the atypical linkage types K27 and K63. Coexpression of K27R and K63R, which prevented ubiquitination via K27 and K63 linkages, reversed the effects of 68 and Fx2149. Moreover, 68 and Fx2149 also promoted G2019S‐LRRK2‐linked aggresome (Lewy body‐like inclusion) formation via K27 and K63 linkages. These findings demonstrate that LRRK2 GTP‐binding activity is critical in LRRK2‐linked ubiquitination and aggregation formation. These studies provide novel insight into the LRRK2‐linked Lewy body‐like inclusion formation underlying PD pathogenesis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the antifungal susceptibility at pH 7.0 and pH 4.0 of 5 antifungal agents against Candida albicans isolated from patients with vulvovaginal candidiasis.Methods: Antifungal susceptibility testing at pH 7.0 and pH 4.0 was performed using the broth microdilution method (CLSI, document M27-A2).Results: The minimal inhibitory concentrations (MICs) of miconazole, clotrimazole, fluconazole, and nystatin against C. albicans at pH 4.0 were significantly higher than those at pH 7.0 (0.25 vs 0.03 μg/mL, 0.50 vs 0.03 μg/mL, 0.50 vs 0.25 μg/mL, and 32 vs 2 μg/mL, respectively; P<0.001), whereas the MIC of itraconazole at pH 4.0 was lower than that at pH 7.0 (0.030 vs 0.125 μg/mL; P<0.001). The susceptibility rate of C. albicans to itraconazole at pH 4.0 was significantly higher than at pH 7.0 (95.0% vs 51.7%; P<0.001). The susceptibility rate to itraconazole at pH 7.0 was significantly lower than the susceptibility rate to fluconazole (51.7% vs 100.0%; P<0.001), whereas the susceptibility rates to the 2 drugs were similar at pH 4.0 (95.0% and 96.7%, respectively).Conclusion: Media at different pH values should be used for sensitivity tests according to the environment of C. albicans. [ABSTRACT FROM AUTHOR]

Aim: In this study, we investigate the mechanistic link between rheumatoid arthritis (RA) and periodontitis to identify a novel target (cathepsin K; Ctsk) for the treatment of comorbid periodontitis and RA. Methods: An experimental model of periodontitis with arthritis was established in DBA/1 mice. We then tested the effect of BML‐244, a specific inhibitor of Ctsk, by quantifying several inflammatory markers of TLR9 signalling both in vivo and in vitro. Results: Our results showed that periodontitis–rheumatoid arthritis comorbidity causes severer periodontal bone and joint cartilage destruction than either disease alone. Inhibition of Ctsk reduced infiltration by dendritic cells and T cells and inflammatory cytokine production; these improvements alleviated the hard‐tissue erosion in periodontitis and RA as measured by bone erosion in periodontal lesions and cartilage destruction in knee joints. Inhibition of Ctsk also decreased the expression of TLR4 and TLR9 in vivo, whereas in vitro experiments indicated that Ctsk is involved specifically in the production of cytokines in response to TLR9 engagement. Conclusion: Our data reveal that periodontitis and RA may have additive pathological effects through dysregulation of the TLR9 pathway and that Ctsk is a critical mediator of this pathway and contributes to the pathogenesis of RA and periodontitis. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long‐term efficacy and safety of daclatasvir‐based regimens administered during clinical studies. Methods: Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow‐up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non‐responders or responders who relapsed, and characterization of liver disease progression. Results: Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir‐based regimens (follow‐up cut‐off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype‐1a (42%) or ‐1b (45%) infection, and 18% had cirrhosis. Median follow‐up from parent study follow‐up Week 12 was 111 (range, 11‐246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow‐up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon‐free or interferon‐containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non‐responders, emergent non‐structural protein‐5A (NS5A) and ‐3 (NS3) substitutions were replaced by wild‐type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively. Conclusions: SVR12 was durable in 99% of recipients of daclatasvir‐based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non‐responders. [ABSTRACT FROM AUTHOR]

The pathogen Stagonospora nodorum produces multiple effectors, also known as host-selective toxins (HSTs), that interact with corresponding host sensitivity genes in an inverse gene-for-gene manner to cause the disease Stagonospora nodorum blotch (SNB) in wheat. In this study, a sensitivity gene was identified in Aegilops tauschii, the diploid D-genome donor of common wheat. The gene was mapped to the short arm of chromosome 5D and mediated recognition of the effector SnTox3, which was previously shown to be recognized by the wheat gene Snn3 on chromosome arm 5BS. Comparative mapping suggested that Snn3 and the gene on 5DS are probably homoeologous and derived from a common ancestor. Therefore, we propose to designate these genes as Snn3-B1 and Snn3-D1, respectively. Compatible Snn3-D1-SnTox3 interactions resulted in more severe necrosis in both effector infiltration and spore inoculation experiments than compatible Snn3-B1-SnTox3 interactions, indicating that Snn3-B1 and Snn3-D1 may have different affinities in SnTox3 recognition or signal transduction. Wheat bin-mapped expressed sequence tags and good levels of collinearity among the wheat Snn3 regions, rice ( Oryza sativa), and Brachypodium distachyon were exploited for saturation and fine mapping of the Snn3-D1 locus. Markers delineating the Snn3-D1 locus to a 1.4 cM interval will be useful for initiating positional cloning. Further characterization of how these homoeologous genes mediate recognition of the same pathogen effector should enhance understanding of host manipulation by necrotrophic pathogens in causing disease. [ABSTRACT FROM AUTHOR]