Fungal secretory heme peroxidase (Class II POD) plays a significant role in biomass conversion due to its lignin-degrading activity. In this study, genome-wide identification and bioinformatics were performed to analyze P leurotus ostreatus peroxidases (PoPODs). A total of six manganese peroxidases (MnPs) and three versatile peroxidases (VPs) were obtained. Bioinformatics analysis and qRT-PCR showed that P. ostreatus mnp6 (Pomnp6) and P. ostreatus vp3 (Povp3) could be involved in lignin degradation. Both Pomnp6 and Povp3 transgenetic fungi showed significantly increased lignin degradation of cotton stalks. 1H-NMR revealed that Pomnp6 and Povp3 may preferentially degrade S-lignin in cotton stalks and mainly break β-O-4' bond linkages and hydroxyl. These results support the possible utility of Pomnp6 and Povp3 in natural straw resources and development of sustainable energy.

Dipeptidyl peptidase (DPP)-4 is a multifunctional glycoprotein involved in various biological and pathologic processes. DPP-4 has been widely recognized as a therapeutic target for type 2 diabetes mellitus but is also implicated in the development of human malignancies. Here, we show that inhibition of DPP-4 accelerates breast cancer metastasis via induction of CXCL12/CXCR4, which activates mTOR to promote epithelial-mesenchymal transition (EMT). In cultured cells, DPP-4 knockdown induced EMT and cell migration. Treatment with the DPP-4 inhibitor KR62436 (KR) promoted primary tumor growth and lung metastasis in a 4T1 tumor allograft mouse model; DPP-4 knockdown in 4T1 cells displayed similar phenotypes in vivo and in vitro. KR treatment enhanced the levels of CXCL12/CXCR4 and phosphorylated mTOR, which were associated with the induction of EMT in metastatic cancer cells. KR-induced EMT in cancer cells was inhibited by treatment with the CXCR4 inhibitor AMD3100 or the mTOR inhibitor rapamycin, and AMD3100 suppressed KR-induced metastasis in vivo. Our findings suggest that DPP-4 plays a significant role in cancer biology and that inhibition of DPP-4 promotes cancer metastasis via induction of the CXCL12/CXCR4/mTOR/EMT axis. SIGNIFICANCE: These findings reveal that inhibition of DPP-4 increases the metastatic potential of breast cancer. This is especially important given the potential use of DPP-4 inhibition as a therapeutic strategy for type 2 diabetes.

Food security relies on the resilience of staple food crops to climatic variability and extremes, but the climate resilience of European wheat is unknown. A diversity of responses to disturbance is considered a key determinant of resilience. The capacity of a sole crop genotype to perform well under climatic variability is limited; therefore, a set of cultivars with diverse responses to weather conditions critical to crop yield is required. Here, we show a decline in the response diversity of wheat in farmers' fields in most European countries after 2002-2009 based on 101,000 cultivar yield observations. Similar responses to weather were identified in cultivar trials among central European countries and southern European countries. A response diversity hotspot appeared in the trials in Slovakia, while response diversity "deserts" were identified in Czechia and Germany and for durum wheat in southern Europe. Positive responses to abundant precipitation were lacking. This assessment suggests that current breeding programs and cultivar selection practices do not sufficiently prepare for climatic uncertainty and variability. Consequently, the demand for climate resilience of staple food crops such as wheat must be better articulated. Assessments and communication of response diversity enable collective learning across supply chains. Increased awareness could foster governance of resilience through research and breeding programs, incentives, and regulation.

SENCR is a human-specific, vascular cell-enriched long-noncoding RNA (lncRNA) that regulates vascular smooth muscle cell and endothelial cell (EC) phenotypes. The underlying mechanisms of action of SENCR in these and other cell types is unknown. Here, levels of SENCR RNA are shown to be elevated in several differentiated human EC lineages subjected to laminar shear stress. Increases in SENCR RNA are also observed in the laminar shear stress region of the adult aorta of humanized SENCR-expressing mice, but not in disturbed shear stress regions. SENCR loss-of-function studies disclose perturbations in EC membrane integrity resulting in increased EC permeability. Biotinylated RNA pull-down and mass spectrometry establish an abundant SENCR-binding protein, cytoskeletal-associated protein 4 (CKAP4); this ribonucleoprotein complex was further confirmed in an RNA immunoprecipitation experiment using an antibody to CKAP4. Structure-function studies demonstrate a noncanonical RNA-binding domain in CKAP4 that binds SENCR Upon SENCR knockdown, increasing levels of CKAP4 protein are detected in the EC surface fraction. Furthermore, an interaction between CKAP4 and CDH5 is enhanced in SENCR-depleted EC. This heightened association appears to destabilize the CDH5/CTNND1 complex and augment CDH5 internalization, resulting in impaired adherens junctions. These findings support SENCR as a flow-responsive lncRNA that promotes EC adherens junction integrity through physical association with CKAP4, thereby stabilizing cell membrane-bound CDH5.

ROADMAP is a public-private advisory partnership to evaluate the usability of multiple data sources, including real-world evidence, in the decision-making process for new treatments in Alzheimer's disease, and to advance key concepts in disease and pharmacoeconomic modeling. ROADMAP identified key disease and patient outcomes for stakeholders to make informed funding and treatment decisions, provided advice on data integration methods and standards, and developed conceptual cost-effectiveness and disease models designed in part to assess whether early treatment provides long-term benefit.

Cardio-ankle vascular index (CAVI) reflects arterial stiffness and has been established as a useful surrogate marker of atherosclerosis. Contrary to the abundant data indicating slower progression of atherosclerosis with statins, studies on fibrates remain scarce. The aim of this study was thus to clarify the effect of bezafibrate on CAVI as well as on oxidative stress.

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from well-designed clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population.

Data concerning the relation between increased levels of circulating sclerostin (a physiological inhibitor of bone formation) and bone turnover in patients with chronic renal failure (CRF) are limited. Therefore, the aim of this study was to evaluate associations between plasma sclerostin levels and calcium-phosphate disturbances, markers of bone turnover as well as inflammation in haemodialysis (HD) patients.

Cancer-related fatigue (CRF) is one of the most burdensome symptoms in breast cancer survivors (BCSs), accompanied by reduced health-related quality of life (HRQOL).

Colorectal cancer has an overexpression of galectin-3 that is related to cancer progression. A decreased risk of colon cancer can be related to consumption of dietary fibers, but the entire mechanism by which this protection occurs remains unclear. Pectin is a type of dietary fiber that possesses β-galactosides and can bind and inhibit galectin-3-mediated effects. Papaya fruit has a massive cell wall disassembling during ripening that naturally changes its pectin structure. Our work shows that different points in the ripening time of papaya fruit exhibit pectins (chelate-soluble fractions; CSF) that can or cannot inhibit galectin-3. The fraction that inhibits galectin-3 (3CSF) also diminishes the proliferation of colon cancer cell lines, and it is derived from an intermediate point of papaya ripening. Therefore, we related this to a papaya pectin structure-dependent effect, and the papaya fruit seems to have a pectin structure that is promising in decreasing the risk of colon cancer development.

Bactrocera biguttula is an African olive fruit fly that does not attack cultivated olives but rather develops in the fruits of wild species of Olea and Noronhia. The complete mitochondrial genome of an individual specimen was characterized in comparison to other Bactrocera. The phylogenetic relationships of B. biguttula with other Dacini were investigated, with special focus on B. oleae, an agricultural pest known to attack cultivated and wild olives. The sequence had a total length of 15,829 bp, and included the typical features of insect mitogenomes, similarly to the other Bactrocera analysed. Start codons included ATG, ATC, ATT, and TCG (in COI). The majority of stop codons (TAA) were fully encoded, whereas in some cases only TA or T were present. The complete sequence was biased towards A + T, with a positive AT-skew and a negative GC-skew. The predicted cloverleaf structure of tRNASer1 showed absence of the DHU arm, a common feature in insects and other Metazoans. Phylogenetic reconstruction showed that B. biguttula and B. oleae are sister species, having diverged from a common ancestor < 10 Myr ago. This result warrants future genomic comparisons between these two closely related species for investigating the specific adaptations to the different hosts.

Significant advances have been made in understanding the regulation of inflammasomes and its involvement in innate immunity during pathogenic infections. Inflammasome activation is a tightly regulated process that provides defense against pathogenic infection and important for inflammatory response. Very few studies on the involvement of NLRP3 inflammasome protein complex have been reported in leishmanial infections with contradictory results and without much mechanistic insights. However, the role of NLRP3 inflammasome and its components has not been well deciphered in Leishmania donovani infection. Here we report for the first time a detailed mechanism and plausible impairment of caspase 1 activation during L. donovani infection leading to the survival of these parasites inside the host cells. Low mRNA expression of pro-caspase 1 and lack of caspase 1 maturation were observed after infection, hindering the processing of pro-IL-1β and pro-IL-18 into their mature counter parts. Further, siRNA mediated knock-down of caspase 1 in macrophage cells (THP-1) resulted in significantly higher parasitic burden validating the importance of caspase 1 in the host defense mechanism. Taken together, our data suggests that the parasite inhibits caspase 1 activation to evade the inflammatory nature of pyroptosis.

Fungi under genus Trichoderma as ameliorates of biotic and abiotic stresses in cultivated crops is gaining popularity world-wide and their application in conjunction with seed coating polymers is an attractive proposition to reduce bioagent wastage and harnessing benefits of combined application. The synergistic action of Trichoderma with natural polymers like chitosan can enhance antimicrobial activity. A series of blended film solutions were synthesized by using chitosan, PEG and plasticizer in varying concentrations. The optimization of blended film composition and dose for coating of seeds was done w.r.t seed coating. Studies on compatibility of film forming ingredients with Trichoderma have not shown any inhibition and antimicrobial activity has shown different levels of inhibition of plant pathogens. Films were structurally characterized by XRD, SEM, FT-IR, TGA, DSC. The optimized film solution in combination with different Trichoderma strains improved seed quality parameters in test crop castor (Ricinus communis). Significant increase in vigour index (3110) was observed with Th4d treatment followed by chitosan and Th4d combination formulation (3023). In conclusion, the optimized chitosan-PEG-Th blend was effective in enhancing seed germination and plant growth of castor. The material can be further tested under large field evaluation as a seed coating agent against various plant diseases.

The electrospinning PAN nanofiber membrane (P-CN) was hydrolysed to convert carboxylic groups as reaction sites and covalently graft chitosan molecule. The chitosan derivatives with quaternary ammonium groups exerted greater efficiency against bacteria as compared to pure chitosan. Hence, the chitosan modified membrane (P-CS), can be functionalized with quaternary amine (i.e., glycidyl trimethyl ammonium chloride, GTMAC) to form quaternized chitosan nanofiber membrane (designated as P-HTCC) under various conditions (acidic, neutral, and alkaline). N-quaternized derivatives of chitosan modified membrane (N-HTCC) showed 72% and 60% degree of quaternization (DQ) under acidic and neutral conditions, respectively. Under alkaline condition, additional quaternization of N, O-HTCC via its amino and hydroxyl groups, has improved up to 90% DQ of the chitosan. The antibacterial activity of the quaternized chitosan modified membrane prepared from acetic acid medium is stronger than that prepared from water and alkaline media. Also, antibacterial activity of quaternized chitosan is stronger than chitosan modified membrane against E. coli. The microbiological assessments showed that the water-stable P-HTCC nanofiber membrane under modification in acidic medium exerted antibacterial activity up to 99.95% against E. coli. Therefore, the P-HTCC membrane exhibited high potential to be integrated into microfiltration membrane to effectively disinfect E. coli.

Drought resistance is required in rice breeding to address the challenge of frequent droughts. However, the evolutionary mechanism of rice drought resistance is not fully understood. We investigated the genetic differentiation between upland and lowland rice domesticated in agro-ecosystems with contrasting water-soil conditions using genome-wide SNPs. We estimated morphological differences among upland and lowland rice in drought resistance and productivity through common garden experiments. Upland rice had better drought resistance but poorer productivity. The negative correlations between traits of drought resistance and productivity are attributed to the underlying genetic trade-offs through tight linkages (e.g., DCA1 and OsCesA7) or pleiotropic effects (e.g., LAX1). The genetic trade-offs are common and greatly shape the evolution of drought resistance in upland rice. In genomic regions associated with both productivity and drought resistance, signs of balancing selection were detected in upland rice, while signs of directional selection were detected in lowland rice, potentially contributing to their adaptive differentiation. Signs of balancing selection in upland rice resulted from bi-directional selection during its domestication in drought-prone upland agro-ecosystems. Using genome-wide association analysis, we identified several valuable quantitative trait loci associated with drought resistance, for which highly differentiated genes should be considered candidates. Bi-directional selection breaking tight linkages by accumulating recombination events would be applicable in breeding water-saving and drought-resistance rice.

Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome with uncontrolled inflammation that is a central issue. Its main characteristic is inflammatory mediators and cytokines as well as agglutinating chemokines that injure target cells. Interleukin (IL)-35 is a newly identified IL-12 cytokine family member with structural similarities to other IL-12, IL-23, and IL-27 cytokines but unique immunological functions. How IL-35 functions in ARDS is unclear. The purpose of our study was to determine what role IL-35 played in the development of ARDS. Here we found serum IL-35 concentrations were significantly elevated in patients with ARDS relative to healthy people. Moreover, we established a mouse model of lipopolysaccharide- and cecal ligation and puncture-induced ARDS treated with neutralizing antibodies (anti-IL-35 Ebi3 or anti-IL-35 P35); the results showed that lung injury occurred more often than in untreated models and the inflammatory cytokines CXCL-1, tumor necrosis factor alpha, IL-6, and IL-17A increased significantly after neutralizing antibody treatment in bronchoalveolar lavage fluid and serum. Therefore IL-35 can protect against the development of ARDS. Even more interesting in our study was that we discovered IL-35 expression differed between lung and spleen across different ARDS models, which further demonstrated that the spleen likely has an important role in extrapulmonary ARDS model only, improving the ratio of CD4+/CD4+CD25+Foxp3+(Tregs). Meanwhile in our clinical work, we also found that the concentration of IL-35 and the ratio of CD4+/Treg in the serum are higher and the mortality is lower than those with the spleen deficiency in patients with extrapulmonary ARDS. Therefore, IL-35 is protective in ARDS by promoting the ratio of splenic CD4+/Tregs in extrapulmonary ARDS, and as such, may be a therapeutic target.

Particulate matter (PM) increases levels of pro-inflammatory cytokines, but its effects on the skin remain largely unknown. We investigated the signal transduction pathway and epigenetic regulatory mechanisms underlying cellular inflammation induced by PM with a diameter of ≤ 2.5 (PM2.5) in vitro and in vivo. PM2.5-treated skin keratinocytes produced various inflammatory cytokines, including IL-6. The binding of PM2.5 to TLR5 initiated intracellular signaling through MyD88, and led to the translocation of NFκB to the nucleus, where it bound the NFκB site within IL-6 promoter. Furthermore, PM2.5 induced a direct interaction between TLR5 and NOX4, and in turn induced the production of ROS and activated NFκB-IL-6 downstream, which was prevented by siRNA-mediated knockdown of NOX4 or antioxidant treatment. Furthermore, expression of TLR5, MyD88, NOX4, phospho-NFκB, and IL-6 was increased in skin tissue of PM2.5-treated flaky tail mice. PM2.5-induced increased transcription of IL-6 was regulated via DNA methylation and histone methylation by epigenetic modification; the binding of DNA demethylase and histone methyltransferase to the IL-6 promoter regions resulted in increased IL-6 mRNA expression. Our findings provide deep insight into the pathogenesis of PM2.5 exposure and can be used as a therapeutic strategy to treat inflammatory skin diseases caused by PM2.5 exposure.

The E3 ubiquitin (Ub) ligase gp78 plays an important role in endoplasmic reticulum (ER)-associated degradation (ERAD) and regulation of lipid biogenesis. Although a variety of substrates of gp78 have been described, the regulation of the degradation of gp78 itself remains poorly understood. To address this problem, we used co-immunoprecipitation-coupled liquid chromatography-tandem mass spectrometry (Co-IP/LC-MS/MS) to identify novel proteins interacting with gp78. One of the proteins identified in this study is the deubiquitylating (DUB) enzyme USP34 (Ub-specific protease 34). We demonstrate that knockdown of USP34 facilitates proteasomal degradation of gp78 and consequently impairs the function of gp78 in regulating lipid droplet formation. This study unveils a previously unknown function of USP34 in regulating the metabolic stability of gp78 and adds to our understanding of the relevance of partnering of DUBs and E3s in regulation of protein ubiquitylation.

Patients harbouring the UGT1A1*28/*28 genotype are at risk of severe toxicity with the standard irinotecan dose. However, this dose is considerably lower than the dose that can be tolerated by UGT1A1*1/*1 and *1/*28 patients. This randomised phase II trial evaluated the efficacy and safety of the FOLFIRI regimen with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients.

Background Medication-related hospital admissions (MRAs) are frequently used to measure outcomes in studies involving medication reviews. The process of identifying MRAs is subjective and time-consuming, and practical, validated alternatives are required. Objective The aim of this study was to develop and validate a practical tool to identify MRAs. Setting Uppsala University Hospital, Sweden. Method We reviewed existing literature on methods to identify MRAs. The tool AT-HARM10 was developed using an iterative process including content validity and feasibility testing. The tool's inter-rater reliability (IRR) and criterion-related validity (CRV) were assessed: four pairs of either final-year undergraduate or postgraduate pharmacy students applied the tool to one of two batches of 50 older patients' hospital admissions. Assessment of the same 100 admissions by two experienced clinicians acted as gold standard. Main outcome measure Cohen's and Fleiss' kappa for IRR, and sensitivity, specificity, and positive and negative predictive value for CRV. Results AT-HARM10 consists of ten closed questions to distinguish between admissions that are unlikely to be and those that are possibly medication-related. The IRR was moderate to substantial (Cohen's kappa values were 0.45-0.75 and Fleiss' kappa values were 0.46 and 0.58). The sensitivity and specificity values were 70/86% and 74/70%, positive and negative predictive values were 73/74% and 71/83% respectively. Both AT-HARM10 and the gold standard identified approximately 50% of the admissions as MRAs. Conclusion AT-HARM10 has been developed as a practical tool to identify MRAs and the tool is valid for use in older patients by final-year undergraduate and postgraduate pharmacy students.