Aggerkessler3661

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long-term care settings in the SARS-CoV-2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.The Tet-ON system is an important molecular tool for temporally and spatially-controlled inducible gene expression. Here, we developed a Tet-ON system to induce transgene expression specifically in the rod photoreceptors of medaka fish. Our modified reverse tetracycline-controlled transcriptional transactivator (rtTAm) with 5 amino acid substitutions dramatically improved the leakiness of the transgene in medaka fish. Histone Methyltransferase inhibitor We generated a transgenic line carrying a self-reporting vector with the rtTAm gene driven by the Xenopus rhodopsin promoter and a tetracycline response element (TRE) followed by the green fluorescent protein (GFP) gene. We demonstrated that GFP fluorescence was restricted to the rod photoreceptors in the presence of doxycycline in larval fish (9 days post-fertilization). The GFP fluorescence intensity was enhanced with longer durations of doxycycline treatment up to 72 h and in a dose-dependent manner (5-45 μg/ml). These findings demonstrate that the Tet-ON system using rtTAm allows for spatiotemporal control of transgene expression, at least in the rod photoreceptors, in medaka fish.The intestinal immune system maintains intestinal homeostasis in collaboration with diverse immune cell subsets residing at the epithelial layer, lamina propria and gut-associated lymphoid tissue (GALT). Bacterial components and their metabolites are essential for the establishment of the gut immune system. In addition, nutritional signals contribute to maintaining the mucosal immune response. Specialized epithelial microfold (M) cells in GALT facilitate immune surveillance on the mucosal surface by actively taking up external antigens to transport them into the lymphoid follicles. Because hyperplasia of M cells causes an excessive immune response in GALT, there is a self-regulatory mechanism to control the development of M cells appropriately. In this review, we will discuss the molecular mechanisms of mucosal immune regulation and their biological importance.Bleeding associated with endothelial damage is one key feature of severe dengue fever. Here, we investigated whether Notch ligands are associated with bleeding in 115 patients with confirmed dengue infection in Vietnam. Soluble Notch ligands were determined by ELISA. 14.8% (17/115) experienced bleeding manifestations. High soluble DLL1 (sDLL1) plasma levels was associated with bleeding (median 15674 pg/ml vs 7117 pg/ml; p less then 0.001). ROC analysis demonstrated that sDLL1 had the best test performance (AUC=0.852), with 88% sensitivity and 84% specificity. The combination with ALT/AST slightly increased DLL1 performance. sDLL1 may be useful to guide clinical management of dengue patients in endemic settings.Proteins encoded by Antigen Processing Genes (APGs) provide MHC class I (MHC-I) with antigenic peptides. In mammals, polymorphic multigenic MHC-I family is served by monomorphic APGs, whereas in certain non-mammalian species both MHC-I and APGs are polymorphic and coevolve within stable haplotypes. Coevolution was suggested as an ancestral gnathostome feature, presumably enabling only a single highly expressed classical MHC-I gene. In this view coevolution, while optimizing some aspects of adaptive immunity, would also limit its flexibility by preventing the expansion of classical MHC-I into a multigene family. However, some non-mammalian taxa, such as salamanders, have multiple highly expressed MHC-I genes, suggesting either that coevolution is relaxed or that it does not prevent the establishment of multigene MHC-I. To distinguish between these two alternatives we use salamanders (30 species from 16 genera representing six families) to test, within a comparative framework, a major prediction of the coevolution hypothesis the positive correlation between MHC-I and APGs diversity. We found that MHC-I diversity explained both within-individual and species-wide diversity of two APGs, TAP1 and TAP2, supporting their coevolution with MHC-I, while no consistent effect was detected for the other three APGs (PSMB8, PSMB9 and TAPBP). Our results imply that while coevolution occurs in salamanders, it does not preclude the expansion of the MHC-I gene family. Contrary to the previous suggestions, non-mammalian vertebrates thus may be able to accommodate diverse selection pressures with flexibility granted by rapid expansion or contraction of the MHC-I family, while retaining the benefits of coevolution between MHC-I and TAPs.

Essential foods as part of a daily meal may include numerous kinds of biogenic amines (BAs) at various concentrations. BAs have a variety of toxicological effects on human health and have been linked to multiple outbreaks of foodborne disease. BAs also are known to cause cancer based on their ability to react with nitrite salts, resulting in the production of carcinogenic organic compounds (nitrosamines). Ingestion of large quantities of BAs in food causes toxicological effects and health disorders, including psychoactive, vasoactive, and hypertensive effects and respiratory, gastrointestinal, cardiovascular, and neurological disorders. The toxicity of BAs is linked closely to the BAs histamine and tyramine. Other amines, such as phenylethylamine, putrescine, and cadaverine, are important because they can increase the negative effects of histamine. The key method for reducing BA concentrations and thus foodborne illness is management of the bacterial load in foods. Basic good handling and hygiene practices should be used to control the formation of histamine and other BAs and reduce the toxicity histamine and tyramine. A better understanding of BAs is essential to enhance food safety and quality. This review also includes a discussion of the public health implications of BAs in foods.

The insecticidal activity of a Ricinus communis leaf hexane extract and its fractions against adult yellow sugarcane aphids (Sipha flava) was evaluated using a contact bioassay after fumigation. The n-hexane extract at 10,000 ppm achieved the highest mortality (80%); the positive control had 100% mortality and the negative control had only 4% mortality over the 72-h experiment time. Chemical fractionation of the hexane extract of R. communis leaves produced multiple fractions, and 10,000 ppm of the F4 fraction resulted in 92% aphid mortality at 72 h. Gas chromatography-mass spectrometry of the F4 fraction revealed linoleic acid as the major compound (84.5%). The R. communis n-hexane extract and linoleic acid could be used for integrated pest control as an ecologically friendly alternative to synthetic chemical insecticides.

In nature, single-strand breaks (SSBs) in DNA occur more frequently (by orders of magnitude) than double-strand breaks (DSBs). SSBs induced by the CRISPR/Cas9 nickase at a distance of 50 to 100 bp on opposite strands are highly mutagenic, leading to insertions/deletions (InDels), with insertions mainly occurring as direct tandem duplications. As short tandem repeats are overrepresented in plant genomes, this mechanism seems to be important for genome evolution. We investigated the distance at which paired 5' overhanging SSBs are mutagenic and which DNA repair pathways are essential for insertion formation in Arabidopsis thaliana. We were able to detect InDel formation up to a distance of 250 bp, although with much reduced efficiency. Surprisingly, the loss of the classical non-homologous end joining (NHEJ) pathway factors KU70 or DNA ligase 4 (LIG4) completely abolished tandem repeat formation. The microhomology-mediated NHEJ factor POLQ was required only for patch-like insertions, which are well-known from DSB repair as templated insertions from ectopic sites. As SSBs can also be repaired using homology, we furthermore asked whether the classical homologous recombination pathway is involved in this process in plants. The fact that RAD54 is not required for homology-mediated SSB repair demonstrates that the mechanisms for DSB- and SSB-induced homologous recombination differ in plants.

To understand Clonorchis sinensis re-infection and the determinants in endemic areas is important in establishment of control measures.

A prospective cohort study was implemented in Hengxian County, Guangxi, China. Individuals with C. sinensis infection were completely treated, and those cured were enrolled as study subjects and followed up for 3, 6 and 12 months. The re-infection frequency and incidence were calculated, and a multivariable Cox proportional hazard model was constructed to capture re-infection determinants.

Among 635 enrolled subjects, 436 (68.7%) completed follow-up. Of these, 177 (40.6%) were re-infected; 133 (75.1%) were re-infected once, 41 (23.2%) twice and 3 (1.7%) three times. The incidence of re-infection was 64.0 per 100 person-years. Males (aHR 1.67, 95% CI 1.14-2.44), those with underlying diseases (aHR 1.41, 95% CI 1.02-1.95), and those with moderate- and heavy-intensity infections (aHR 1.45, 95% CI 1.14-1.85) had increasing re-infection probabilities.

C. sinensis re-infection is high in endemic areas. Males and high-intensity infection are important determinants of re-infection. Repeated chemotherapy is necessary to control re-infection and its associated morbidities, especially in high-risk individuals. In addition, behavioural education is advised to decrease overall re-infection in endemic areas.

C. sinensis re-infection is high in endemic areas. Males and high-intensity infection are important determinants of re-infection. Repeated chemotherapy is necessary to control re-infection and its associated morbidities, especially in high-risk individuals. In addition, behavioural education is advised to decrease overall re-infection in endemic areas.