Induction of defensive enzymes (isozymes) during defense against two different fungal pathogens in pear calli

Activities of defensive enzymes peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), polyphenol oxidase (PPO) and esterase (EST) and their isozymes in pear calli were studied to reveal their role in the defensive response to different fungal infections and to find some clues to enhance their antimicrobial properties. The results confirm the fact that the activities and isozymes of these five enzymes showed differences in response to different fungal infections. After the inoculation of two different fungi for the same calli, its defensive enzymes’ activities changed relatively when compared with those of the control and in Botryosphaeria berengriana f.sp. piricola (BBP)-infected calli, the enzymes’ activities changed more significantly than those of Monilinia fructigena Honcy (MFH). Meanwhile, more new isozymes were induced by BBP infection. These are in agreement with the fact that the BBP-infected calli decay was slower than that of the MFH. These results suggest that enhancing defensive enzymes’ activities and inducing new isozymes may be related to mitigating pathogen-induced oxidative damage which result in the decrease of calli decay, and this implies that antioxidant defense response may be involved in the mechanisms of plant against fungal pathogen.Keywords: Pear callus, fungi infection, defense enzyme, isozyme, biochemical defense mechanis

HLA-DRB1 May Be Antagonistically Regulated by the Coordinately Evolved Promoter and 3′-UTR under Stabilizing Selection

HLA-DRB1 is the most polymorphic MHC (major histocompatibility complex) class II gene in human, and plays a crucial role in the development and function of the immune system. Extensive polymorphisms exist in the promoter and 3′-UTR of HLA-DRB1, especially a LTR (Long terminal repeat) element in the promoter, which may be involved in the expression regulation. However, it remains unknown how the polymorphisms in the whole promoter region and 3′-UTR to regulate the gene expression. In this study, we investigated the extensive polymorphisms in the HLA-DRB1 promoter and 3′-UTR, and how these polymorphisms affect the gene expression in both independent and jointly manners. It was observed that most of the haplotypes in the DRB1 promoter and 3′-UTR were clustered into 4 conserved lineages (H1, H2, H3 and H4), and showed high linkage disequilibrium. Compared with H1 and H2 lineage, a LTR element in the promoter of H3 and H4 lineage significantly suppressed the promoter activity, whereas the activity of the linked 3′-UTR increased, leading to no apparent difference in the final expression product between H1/H2 and H3/H4 lineage. Nevertheless, compared with the plasmid with a promoter and 3′-UTR from the same lineage, the recombinant plasmid with a promoter from H2 and a 3′-UTR from H3 showed about double fold increased luciferase activity, Conversely, the recombinant plasmid with a promoter from H3 and a 3′-UTR from H2 resulted in about 2-fold decreased luciferase activity. These results indicate that the promoter and 3′-UTR of HLA-DRB1 may antagonistically regulate the gene expression, which may be subjected to stabilizing selection. These findings may provide a novel insight into the mechanisms of the diseases associated with HLA-DRB1 genes

IRE1α Determines Ferroptosis Sensitivity Through Regulation of Glutathione Synthesis

Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α\u27s endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is evolutionarily conserved. Genetic deficiency and pharmacological inhibition of IRE1α have similar effects in inhibiting ferroptosis and reducing renal ischemia-reperfusion injury in mice. Our findings reveal a previously unidentified role of IRE1α to regulate ferroptosis and suggests inhibition of IRE1α as a promising therapeutic strategy to mitigate ferroptosis-associated pathological conditions

Compatibility-tuned distribution of nanoparticles in co-continuous rubber structures toward microwave absorption enhancement

Development of novel and versatile approaches to engineer composites with light density, broad effective bandwidth and high microwave absorption (MA) capacity is of great importance. Here, co-continuous natural rubber/epoxidized natural rubber (NR/ENR) blends with a selective distribution of conductive carbon black nanoparticles (CCBs), have been fabricated by tow-roll mixing. ENR with abundant epoxide groups shows inferior wettability to CCB than NR, which is responsible for the preferential location of CCB in the NR/ENR blend. Increasing the epoxidation level of ENR promotes the preferential location of CCB and creates stronger dielectric loss, thus enhancing the MA properties of CCB/NR/ENR composites. When the epoxidation level increases to 40 mol%, the MA capacity of the composite has been significantly enhanced by 40%. Meanwhile, the qualified frequency bandwidth (RL < −10 dB) of composites with ENR is 85% broader than that of CCB/NR composites. Such a novel approach of compatibility-tuned nanoparticles distribution in co-continuous rubber blends will significantly promote the multi-functional use of rubber and carbonaceous resources

Early Non-Response as a Predictor of Later Non-Response to Antipsychotics in Schizophrenia: A Randomized Trial

BACKGROUND: It remains a challenge to predict the long-term response to antipsychotics in patients with schizophrenia who do not respond at an early stage. This study aimed to investigate the optimal predictive cut-off value for early non-response that would better predict later non-response to antipsychotics in patients with schizophrenia. METHODS: This multicenter, 8-week, open-label, randomized trial was conducted at 19 psychiatric centers throughout China. All enrolled participants were assigned to olanzapine, risperidone, amisulpride, or aripiprazole monotherapy for 8 weeks. The positive and negative syndrome scale (PANSS) was evaluated at baseline, week 2, week 4, and week 8. The main outcome was the prediction of nonresponse. Nonresponse is defined as a \u3c 20% reduction in the total scores of PANSS from baseline to endpoint. Severity ratings of mild, moderate, and severe illness corresponded to baseline PANSS total scores of 58, 75, and 95, respectively. RESULTS: At week 2, a reduction of \u3c 5% in the PANSS total score showed the highest total accuracy in the severe and mild schizophrenia patients (total accuracy, 75.0% and 80.8%, respectively), and patients who were treated with the risperidone and amisulpride groups (total accuracy, 82.4%, and 78.2%, respectively). A 10% decrease exhibited the best overall accuracy in the moderate schizophrenia patients (total accuracy, 84.0%), olanzapine (total accuracy, 79.2%), and aripiprazole group (total accuracy, 77.4%). At week 4, the best predictive cut-off value was \u3c 20%, regardless of the antipsychotic or severity of illness (total accuracy ranging from 89.8 to 92.1%). CONCLUSIONS: Symptom reduction at week 2 has acceptable discrimination in predicting later non-response to antipsychotics in schizophrenia, and a more accurate predictive cut-off value should be determined according to the medication regimen and baseline illness severity. The response to treatment during the next 2 weeks after week 2 could be further assessed to determine whether there is a need to change antipsychotic medication during the first four weeks. TRIAL REGISTRATION: This study was registered on Clinicaltrials.gov (NCT03451734)

RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro

Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity

Leukocytes carrying Clonal Hematopoiesis of Indeterminate Potential (CHIP) Mutations invade Human Atherosclerotic Plaques.

BACKGROUND: Leukocyte progenitors derived from clonal hematopoiesis of undetermined potential (CHIP) are associated with increased cardiovascular events. However, the prevalence and functional relevance of CHIP in coronary artery disease (CAD) are unclear, and cells affected by CHIP have not been detected in human atherosclerotic plaques. METHODS: CHIP mutations in blood and tissues were identified by targeted deep-DNA-sequencing (DNAseq: coverage >3,000) and whole-genome-sequencing (WGS: coverage >35). CHIP-mutated leukocytes were visualized in human atherosclerotic plaques by mutaFISH ™. Functional relevance of CHIP mutations was studied by RNAseq. RESULTS: DNAseq of whole blood from 540 deceased CAD patients of the Munich cardIovaScular StudIes biObaNk (MISSION) identified 253 (46.9%) CHIP mutation carriers (mean age 78.3 years). DNAseq on myocardium, atherosclerotic coronary and carotid arteries detected identical CHIP mutations in 18 out of 25 mutation carriers in tissue DNA. MutaFISH ™ visualized individual macrophages carrying DNMT3A CHIP mutations in human atherosclerotic plaques. Studying monocyte-derived macrophages from Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET; n=941) by WGS revealed CHIP mutations in 14.2% (mean age 67.1 years). RNAseq of these macrophages revealed that expression patterns in CHIP mutation carriers differed substantially from those of non-carriers. Moreover, patterns were different depending on the underlying mutations, e.g. those carrying TET2 mutations predominantly displayed upregulated inflammatory signaling whereas ASXL1 mutations showed stronger effects on metabolic pathways. CONCLUSIONS: Deep-DNA-sequencing reveals a high prevalence of CHIP mutations in whole blood of CAD patients. CHIP-affected leukocytes invade plaques in human coronary arteries. RNAseq data obtained from macrophages of CHIP-affected patients suggest that pro-atherosclerotic signaling differs depending on the underlying mutations. Further studies are necessary to understand whether specific pathways affected by CHIP mutations may be targeted for personalized treatment

Evaluation of the activity of antibiotics and adjuvant strategies against dual species biofilms in the context of cystic fibrosis

Cystic fibrosis (CF) is an inherited multiorgan disease characterised by thick mucus in the airways. The morbidity and mortality of this disease are mainly related to pulmonary bacterial infections. S. aureus and P. aeruginosa are the most predominant pathogens and both species are often isolated from the same patients. This work aims to develop dual-species biofilms of S. aureus and P. aeruginosa that mimic in vivo growth conditions, and examine whether selected enzymes or phages can improve antibiotic activity against these dual-species biofilms. We first showed a cross-adaptation between co-isolates from both species coming from the same patients allowing them to form a stable dual species biofilm. We demonstrated that DNase I and alginase are useful adjuvants to antibiotics to improve efficacy against dual-species biofilm of clinical isolates. Phages also demonstrated their interest as adjuvants to antibiotics but were tested so far only against biofilms from reference strains.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 4/1

Highly Strong and Damage-Resistant Natural Rubber Membrane via Self-Assembly and Construction of Double Network

Natural rubber latex (NRL) is commonly employed to manufacture medical protective appliances. However, the characteristics of weakness and fragility of NRL membranes limit their further application. To achieve excellent strength and damage-resistance of the rubber membrane, this work reported a facile core&ndash;shell structure construction strategy via self-assembly with modified sodium lignosulfonate (MSLS) and NRL to create a tough membrane. The double network can be formed after introducing polyamide epichlorohydrin resin (PAE) into the NRL membrane. Specifically, the first robust MSLS-PAE network can break in advance to dissipate applied energy, thereby achieving high fracture energy and tensile strength of ~111.51 kJ m&minus;2 and ~37 MPa, respectively, which overtakes numerous soft materials. This work facilitates more studies on latex/lignin-based products with high performance and good stability for the functional application of biopolymer