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101.
Repeated outbreaks due to H3N1 low pathogenicity avian influenza viruses (LPAIV) in Belgium were associated with unusually high mortality in chicken in 2019. Those events caused considerable economic losses and prompted restriction measures normally implemented for eradicating high pathogenicity avian influenza viruses (HPAIV). Initial pathology investigations and infection studies suggested this virus to be able to replicate systemically, being very atypical for H3 LPAIV. Here, we investigate the pathogenesis of this H3N1 virus and propose a mechanism explaining its unusual systemic replication capability. By intravenous and intracerebral inoculation in chicken, we demonstrate systemic spread of this virus, extending to the central nervous system. Endoproteolytic viral hemagglutinin (HA) protein activation by either tissue-restricted serine peptidases or ubiquitous subtilisin-like proteases is the functional hallmark distinguishing (H5 or H7) LPAIV from HPAIV. However, luciferase reporter assays show that HA cleavage in case of the H3N1 strain in contrast to the HPAIV is not processed by intracellular proteases. Yet the H3N1 virus replicates efficiently in cell culture without trypsin, unlike LPAIVs. Moreover, this trypsin-independent virus replication is inhibited by 6-aminohexanoic acid, a plasmin inhibitor. Correspondingly, in silico analysis indicates that plasminogen is recruitable by the viral neuraminidase for proteolytic activation due to the loss of a strongly conserved N-glycosylation site at position 130. This mutation was shown responsible for plasminogen recruitment and neurovirulence of the mouse brain-passaged laboratory strain A/WSN/33 (H1N1). In conclusion, our findings provide good evidence in natural chicken strains for N1 neuraminidase-operated recruitment of plasminogen, enabling systemic replication leading to an unusual high pathogenicity phenotype. Such a gain of function in naturally occurring AIVs representing an established human influenza HA-subtype raises concerns over potential zoonotic threats.  相似文献   
102.
Entomopathogenic fungi such as Metarhizium rileyi and Beauveria bassiana are widely used insect biological control agents. Little, however, is known concerning genetic or enzymatic factors that differentiate the mechanisms employed by these two fungal pathogens to infect target hosts. Infection by either of these organisms is known to increase levels of the growth and molting hormone, ecdysone, which also regulates the expression of a number of innate immune pathways. M. rileyi, but not B. bassiana, has apparently evolved an ecdysteroid-22-oxidase (MrE22O) that inactivate ecdysone. We show that deletion of MrE22O impaired virulence compared with the wild-type strain, with an increase in ecdysone titer seen in hosts that was coupled to an increase in the expression of antimicrobial genes. An M. rileyi strain engineered to overexpress MrE22O (MrE22OOE), as well as trans-expression in B. bassiana (Bb::MrE220OE) resulted, in strains displaying enhanced virulence and dampening of host immune responses compared with their respective wild-type parental strains. These results indicate that ecdysone plays an important role in mediating responses to fungal infection and that some insect pathogenic fungi have evolved mechanisms for targeting this hormone as a means for facilitating infection.  相似文献   
103.
Absorption of light in excess of the capacity for photosynthetic electron transport is damaging to photosynthetic organisms. Several mechanisms exist to avoid photodamage, which are collectively referred to as nonphotochemical quenching. This term comprises at least two major processes. State transitions (qT) represent changes in the relative antenna sizes of photosystems II and I. High energy quenching (qE) is the increased thermal dissipation of light energy triggered by lumen acidification. To investigate the respective roles of qE and qT in photoprotection, a mutant (npq4 stt7-9) was generated in Chlamydomonas reinhardtii by crossing the state transition–deficient mutant (stt7-9) with a strain having a largely reduced qE capacity (npq4). The comparative phenotypic analysis of the wild type, single mutants, and double mutants reveals that both state transitions and qE are induced by high light. Moreover, the double mutant exhibits an increased photosensitivity with respect to the single mutants and the wild type. Therefore, we suggest that besides qE, state transitions also play a photoprotective role during high light acclimation of the cells, most likely by decreasing hydrogen peroxide production. These results are discussed in terms of the relative photoprotective benefit related to thermal dissipation of excess light and/or to the physical displacement of antennas from photosystem II.  相似文献   
104.
The present study was designed to examine the association of positive youth development with the likelihood of tobacco, alcohol, marijuana, hard drug, and sex initiation between 5th and 10th grades. A national, largely middle-class sample of 5,305 adolescents, participating in a longitudinal study funded by the National 4-H Council (although not all participants were enrolled in 4-H or other after-school programs), completed measures of positive youth development (PYD) constructs and of tobacco, alcohol, marijuana, and hard drug use once per year between 5th and 10th grades. At the 9th and 10th grade assessments, adolescents were asked whether they had initiated sexual intercourse and, if so, at what age they had first engaged in intercourse. Although the present sample was somewhat lower risk compared to national averages, survival analysis models indicated that PYD was significantly and negatively associated with the initiation hazards for tobacco use, marijuana use, and sex initiation for girls only, and with hard drug use for both genders. PYD was also positively associated with the odds of condom use across genders. Results are discussed with regard to PYD as a preventive process.  相似文献   
105.
The discovery that genetic mutations in several cellular pathways can increase lifespan has lent support to the notion that pharmacological inhibition of aging pathways can be used to extend lifespan and to slow the onset of age‐related diseases. However, so far, only few compounds with such activities have been described. Here, we have conducted a chemical genetic screen for compounds that cause the extension of chronological lifespan of Schizosaccharomyces pombe. We have characterized eight natural products with such activities, which has allowed us to uncover so far unknown anti‐aging pathways in S. pombe. The ionophores monensin and nigericin extended lifespan by affecting vacuolar acidification, and this effect depended on the presence of the vacuolar ATPase (V‐ATPase) subunits Vma1 and Vma3. Furthermore, prostaglandin J2 displayed anti‐aging properties due to the inhibition of mitochondrial fission, and its effect on longevity required the mitochondrial fission protein Dnm1 as well as the G‐protein‐coupled glucose receptor Git3. Also, two compounds that inhibit guanosine monophosphate (GMP) synthesis, mycophenolic acid (MPA) and acivicin, caused lifespan extension, indicating that an imbalance in guanine nucleotide levels impinges upon longevity. We furthermore have identified diindolylmethane (DIM), tschimganine, and the compound mixture mangosteen as inhibiting aging. Taken together, these results reveal unanticipated anti‐aging activities for several phytochemicals and open up opportunities for the development of novel anti‐aging therapies.  相似文献   
106.

Introduction

Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). An early manifestation of CVD is endothelial dysfunction which can lead to functional and morphological vascular abnormalities. Classical CVD risk factors and inflammation are both implicated in causing endothelial dysfunction in RA. The objective of the present study was to examine the effect of baseline inflammation, cumulative inflammation, and classical CVD risk factors on the vasculature following a six-year follow-up period.

Methods

A total of 201 RA patients (155 females, median age (25th to 75th percentile): 61 years (53 to 67)) were examined at baseline (2006) for presence of classical CVD risk factors and determination of inflammation using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). At follow-up (2012) patients underwent assessments of microvascular and macrovascular endothelium-dependent and endothelium-independent function, along with assessment of carotid atherosclerosis. The CRP and ESR were recorded from the baseline study visit to the follow-up visit for each patient to calculate cumulative inflammatory burden.

Results

Classical CVD risk factors, but not RA disease-related inflammation, predicted microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-independent function and carotid atherosclerosis. These findings were similar in a sub-group of patients free from CVD, and not receiving non-steroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors or biologics. Cumulative inflammation was not associated with microvascular and macrovascular endothelial function, but a weak association was apparent between area under the curve for CRP and carotid atherosclerosis.

Conclusions

Classical CVD risk factors may be better long-term predictors of vascular function and morphology than systemic disease-related inflammation in patients with RA. Further studies are needed to confirm if assessments of vascular function and morphology are predictive of long-term CV outcomes in RA.  相似文献   
107.

Introduction

Adipokines such as adiponectin, leptin, and visfatin/nicotinamide phosphoribosyltransferase (NAMPT) have recently emerged as pro-inflammatory mediators involved in the pathophysiology of rheumatoid arthritis (RA). We aimed to determine whether serum adipokine levels independently predicted early radiographic disease progression in early RA.

Methods

In total, 791 patients were included from the prospective Etude et Suivi des POlyarthrites Indifférenciées Récentes (ESPOIR) cohort who met the American College of Rheumatology-European League Against Rheumatism criteria for RA (n = 632) or had undifferentiated arthritis (UA) (n = 159). Enzyme-linked immunosorbent assay (ELISA) was used to assess baseline serum levels of adiponectin, leptin, and visfatin/NAMPT. In the RA group, we tested the association of serum adipokine levels and (a) baseline radiographic damage and (b) radiographic disease progression, defined as a change >0 or ≥5 in total Sharp-van der Heijde Score (∆SHS) between inclusion and 1 year (∆SHS ≥1 or rapid radiographic progression: ∆SHS ≥5), adjusting for confounders (age, sex, body-mass index, insulin resistance, C-reactive protein level, Disease Activity Score in 28 joints, Health Assessment Questionnaire score, autoantibody status, steroid use, and radiographic evidence of RA damage at inclusion).

Results

Adiponectin level was independently associated with baseline total SHS (adjusted β = 0.12; P = 0.006). It was also associated with ∆SHS ≥1 (adjusted odds ratio (aOR) = 1.84 (1.25 to 2.72)) involving erosive as well as narrowing disease progression (aOR = 1.73 (1.17 to 2.55) and 1.93 (1.04 to 3.57), respectively). Serum adiponectin level predicted ∆SHS ≥5 (aOR = 2.0 (1.14 to 3.52)). Serum leptin level was independently associated only with ∆SHS >0 (aOR = 1.59 (1.05 to 2.42)). Conversely, serum visfatin/NAMPT level and radiographic disease progression were unrelated. Considering the receiver-operated characteristic curves, the best adiponectin cut-offs were 4.14 μg/ml for ∆SHS ≥1 and 6.04 μg/ml for ∆SHS ≥5, with a good specificity (58% and 75% for ∆SHS ≥1 and ∆SHS ≥5, respectively) and high negative predictive values (75% and 92% for ∆SHS ≥1 or ∆SHS ≥5, respectively).

Conclusion

Serum adiponectin level is a simple useful biomarker associated with early radiographic disease progression in early RA, independent of RA-confounding factors and metabolic status.  相似文献   
108.
Abstract

CPE-C is a potent antitumor and antiviral agent. It is active against a variety of preclinical murine and human xenograft tumor models in vivo as well as DNA and RNA viruses in vitro.  相似文献   
109.
The comparison of genetic divergence or genetic distances, estimated by pairwise FST and related statistics, with geographical distances by Mantel test is one of the most popular approaches to evaluate spatial processes driving population structure. There have been, however, recent criticisms and discussions on the statistical performance of the Mantel test. Simultaneously, alternative frameworks for data analyses are being proposed. Here, we review the Mantel test and its variations, including Mantel correlograms and partial correlations and regressions. For illustrative purposes, we studied spatial genetic divergence among 25 populations of Dipteryx alata (“Baru”), a tree species endemic to the Cerrado, the Brazilian savannas, based on 8 microsatellite loci. We also applied alternative methods to analyze spatial patterns in this dataset, especially a multivariate generalization of Spatial Eigenfunction Analysis based on redundancy analysis. The different approaches resulted in similar estimates of the magnitude of spatial structure in the genetic data. Furthermore, the results were expected based on previous knowledge of the ecological and evolutionary processes underlying genetic variation in this species. Our review shows that a careful application and interpretation of Mantel tests, especially Mantel correlograms, can overcome some potential statistical problems and provide a simple and useful tool for multivariate analysis of spatial patterns of genetic divergence.  相似文献   
110.
Circulating nucleic acids (CNAs) are under investigation as a liquid biopsy in cancer. However there is wide variation in blood processing and methods for isolation of circulating free DNA (cfDNA) and microRNAs (miRNAs). Here we compare the extraction efficiency and reproducibility of 4 commercially available kits for cfDNA and 3 for miRNA using spike-in of reference templates. We also compare the effects of increasing time between venepuncture and centrifugation and differential centrifugation force on recovery of CNAs. cfDNA was quantified by TaqMan qPCR and targeted deep sequencing. miRNA profiles were assessed with TaqMan low-density arrays and assays. The QIAamp® DNA Blood Mini and Circulating nucleic acid kits gave the highest recovery of cfDNA and efficient recovery (>90%) of a 564bp spike-in. Moreover, targeted sequencing revealed overlapping cfDNA profiles and variant depth, including detection of HER2 gene amplification, using the Ion AmpliSeq™Cancer Hotspot Panel v2. Highest yields of miRNA and the synthetic Arabidopsis thaliana miR-159a spike-in were obtained using the miRNeasy Serum/Plasma kit, with saturation above 200 µl of plasma. miRNA profiles showed significant variation with increasing time before centrifugation (p<0.001) and increasing centrifugation force, with depletion of platelet associated miRNAs, whereas cfDNA was unaffected. However, sample replicates showed excellent reproducibility on TaqMan low density arrays (ρ = 0.96, p<0.0001). We also successfully generated miRNA profiles for plasma samples stored > 12 years, highlighting the potential for analysis of stored sample biobanks. In the era of the liquid biopsy, standardisation of methods is required to minimise variation, particularly for miRNA.  相似文献   
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