Human cell dedifferentiation in mesenchymal condensates through controlled autophagy

Tissue and whole organ regeneration is a dramatic biological response to injury that occurs across different plant and animal phyla. It frequently requires the dedifferentiation of mature cells to a condensed mesenchymal blastema, from which replacement tissues develop. Human somatic cells cannot regenerate in this way and differentiation is considered irreversible under normal developmental conditions. Here, we sought to establish in vitro conditions to mimic blastema formation by generating different three-dimensional (3D) condensates of human mesenchymal stromal cells (MSCs). We identified specific 3D growth environments that were sufficient to dedifferentiate aged human MSCs to an early mesendoderm-like state with reversal of age-associated cell hypertrophy and restoration of organized tissue regenerating capacity in vivo. An optimal auophagic response was required to promote cytoplasmic remodeling, mitochondrial regression, and a bioenergetic shift from oxidative phosphorylation to anaerobic metabolism. Our evidence suggests that human cell dedifferentiation can be achieved through autonomously controlled autophagic flux

Synthesis of iron-doped TiO2 nanoparticles by ball-milling process : the influence of process parameters on the structural, optical, magnetic, and photocatalytic properties

Titanium dioxide (TiO2) absorbs only a small fraction of incoming sunlight in the visible region thus limiting its photocatalytic efficiency and concomitant photocatalytic ability. The large-scale application of TiO2 nanoparticles has been limited due to the need of using an ultraviolet excitation source to achieve high photocatalytic activity. The inclusion of foreign chemical elements in the TiO2 lattice can tune its band gap resulting in an absorption edge red-shifted to lower energies enhancing the photocatalytic performance in the visible region of the electromagnetic spectrum. In this research work, TiO2 nanoparticles were doped with iron powder in a planetary ball-milling system using stainless steel balls. The correlation between milling rotation speeds with structural and morphologic characteristics, optical and magnetic properties, and photocatalytic abilities of bare and Fedoped TiO2 powders was studied and discussed.This work was partially financed by FCT-Fundacao para a Ciencia e Tecnologia-under the project PTDC/FIS/120412/2010: "Nanobased concepts for Innovative & Eco-sustainable constructive material's surfaces.

Bacillus anthracis TIR Domain-Containing Protein Localises to Cellular Microtubule Structures and Induces Autophagy

Toll-like receptors (TLRs) recognise invading pathogens and mediate downstream immune signalling via Toll/IL-1 receptor (TIR) domains. TIR domain proteins (Tdps) have been identified in multiple pathogenic bacteria and have recently been implicated as negative regulators of host innate immune activation. A Tdp has been identified in Bacillus anthracis, the causative agent of anthrax. Here we present the first study of this protein, designated BaTdp. Recombinantly expressed and purified BaTdp TIR domain interacted with several human TIR domains, including that of the key TLR adaptor MyD88, although BaTdp expression in cultured HEK293 cells had no effect on TLR4- or TLR2- mediated immune activation. During expression in mammalian cells, BaTdp localised to microtubular networks and caused an increase in lipidated cytosolic microtubule-associated protein 1A/1B-light chain 3 (LC3), indicative of autophagosome formation. In vivo intra-nasal infection experiments in mice showed that a BaTdp knockout strain colonised host tissue faster with higher bacterial load within 4 days post-infection compared to the wild type B. anthracis. Taken together, these findings indicate that BaTdp does not play an immune suppressive role, but rather, its absence increases virulence. BaTdp present in wild type B. anthracis plausibly interact with the infected host cell, which undergoes autophagy in self-defence

Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections

Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. About 1538 participants with active HIV and/or HCV infection in three ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with log IL-18 including HCV and HIV infection status, and HIV RNA in each ancestry group and then meta-analyzed. Eleven highly correlated single-nucleotide polymorphisms (r²=0.98–1) in the IL-18-BCO2 region were significantly associated with log IL-18; each T allele of rs80011693 confers a decrease of 0.06 log pg ml⁻¹ of IL-18 after adjusting for covariates (rs80011693; rs111311302 β=−0.06, P-value=2.7 × 10⁻⁴). In conclusion, genetic variation in IL-18 is associated with IL-18 production in response to HIV and HCV infection, and may explain variability in the inflammatory outcomes of chronic viral infections

Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase

Meiotic crossovers are produced when programmed double-strand breaks (DSBs) are repaired by recombination from homologous chromosomes (homologues). In a wide variety of organisms, meiotic HORMA-domain proteins are required to direct DSB repair towards homologues. This inter-homologue bias is required for efficient homology search, homologue alignment, and crossover formation. HORMA-domain proteins are also implicated in other processes related to crossover formation, including DSB formation, inhibition of promiscuous formation of the synaptonemal complex (SC), and the meiotic prophase checkpoint that monitors both DSB processing and SCs. We examined the behavior of two previously uncharacterized meiosis-specific mouse HORMA-domain proteins-HORMAD1 and HORMAD2-in wild-type mice and in mutants defective in DSB processing or SC formation. HORMADs are preferentially associated with unsynapsed chromosome axes throughout meiotic prophase. We observe a strong negative correlation between SC formation and presence of HORMADs on axes, and a positive correlation between the presumptive sites of high checkpoint-kinase ATR activity and hyper-accumulation of HORMADs on axes. HORMADs are not depleted from chromosomes in mutants that lack SCs. In contrast, DSB formation and DSB repair are not absolutely required for depletion of HORMADs from synapsed axes. A simple interpretation of these findings is that SC formation directly or indirectly promotes depletion of HORMADs from chromosome axes. We also find that TRIP13 protein is required for reciprocal distribution of HORMADs and the SYCP1/SC-component along chromosome axes. Similarities in mouse and budding yeast meiosis suggest that TRIP13/Pch2 proteins have a conserved role in establishing mutually exclusive HORMAD-rich and synapsed chromatin domains in both mouse and yeast. Taken together, our observations raise the possibility that involvement of meiotic HORMA-domain proteins in the regulation of homologue interactions is conserved in mammals

Light and Heavy Fractions of Soil Organic Matter in Response to Climate Warming and Increased Precipitation in a Temperate Steppe

Soil is one of the most important carbon (C) and nitrogen (N) pools and plays a crucial role in ecosystem C and N cycling. Climate change profoundly affects soil C and N storage via changing C and N inputs and outputs. However, the influences of climate warming and changing precipitation regime on labile and recalcitrant fractions of soil organic C and N remain unclear. Here, we investigated soil labile and recalcitrant C and N under 6 years' treatments of experimental warming and increased precipitation in a temperate steppe in Northern China. We measured soil light fraction C (LFC) and N (LFN), microbial biomass C (MBC) and N (MBN), dissolved organic C (DOC) and heavy fraction C (HFC) and N (HFN). The results showed that increased precipitation significantly stimulated soil LFC and LFN by 16.1% and 18.5%, respectively, and increased LFC∶HFC ratio and LFN∶HFN ratio, suggesting that increased precipitation transferred more soil organic carbon into the quick-decayed carbon pool. Experimental warming reduced soil labile C (LFC, MBC, and DOC). In contrast, soil heavy fraction C and N, and total C and N were not significantly impacted by increased precipitation or warming. Soil labile C significantly correlated with gross ecosystem productivity, ecosystem respiration and soil respiration, but not with soil moisture and temperature, suggesting that biotic processes rather than abiotic factors determine variations in soil labile C. Our results indicate that certain soil carbon fraction is sensitive to climate change in the temperate steppe, which may in turn impact ecosystem carbon fluxes in response and feedback to climate change

Arc Discharge Synthesis and Photoluminescence of 3D Feather-like AlN Nanostructures

A complex three-dimensional (3D) feather-like AlN nanostructure was synthesized by a direct reaction of high-purity Al granules with nitrogen using an arc discharge method. By adjusting the discharge time, a coral-like nanostructure, which evolved from the feather-like nanostructure, has also been observed. The novel 3D feather-like AlN nanostructure has a hierarchical dendritic structure, which means that the angle between the trunk stem and its branch is always about 30° in any part of the structure. The fine branches on the surface of the feather-like nanostructure have shown a uniform fish scale shape, which are about 100 nm long, 10 nm thick and several tens of nanometers in width. An alternate growth model has been proposed to explain the novel nanostructure. The spectrum of the feather-like products shows a strong blue emission band centered at 438 nm (2.84 eV), which indicates their potential application as blue light-emitting diodes

Haplotype Estimation from Fuzzy Genotypes Using Penalized Likelihood

The Composite Link Model is a generalization of the generalized linear model in which expected values of observed counts are constructed as a sum of generalized linear components. When combined with penalized likelihood, it provides a powerful and elegant way to estimate haplotype probabilities from observed genotypes. Uncertain (“fuzzy”) genotypes, like those resulting from AFLP scores, can be handled by adding an extra layer to the model. We describe the model and the estimation algorithm. We apply it to a data set of accurate human single nucleotide polymorphism (SNP) and to a data set of fuzzy tomato AFLP scores