Myc controls a distinct transcriptional program in fetal thymic epithelial cells that determines thymus growth

Interactions between thymic epithelial cells (TEC) and developing thymocytes are essential for T cell development, but molecular insights on TEC and thymus homeostasis are still lacking. Here we identify distinct transcriptional programs of TEC that account for their age-specific properties, including proliferation rates, engraftability and function. Further analyses identify Myc as a regulator of fetal thymus development to support the rapid increase of thymus size during fetal life. Enforced Myc expression in TEC induces the prolonged maintenance of a fetal-specific transcriptional program, which in turn extends the growth phase of the thymus and enhances thymic output; meanwhile, inducible expression of Myc in adult TEC similarly promotes thymic growth. Mechanistically, this Myc function is associated with enhanced ribosomal biogenesis in TEC. Our study thus identifies age-specific transcriptional programs in TEC, and establishes that Myc controls thymus size

Bid activates multiple mitochondrial apoptotic mechanisms in primary hepatocytes after death receptor engagement

: Activation of Fas or tumor necrosis factor receptor 1 (TNF-R1) on hepatocytes leads to apoptosis, which requires mitochondria activation. The pro-death Bcl-2 family protein, Bid, mediates this pathway by inducing mitochondrial releases of cytochrome c and other apoptotic factors. How Bid activates mitochondria has been studied in vitro with isolated mitochondria. We intended to study the mechanisms in intact hepatocytes so that findings could be made in a proper cellular context and would be more physiologically relevant. : Hepatocytes were isolated from wild-type and bid-deficient mice and treated with anti-Fas or TNF-α. Mechanisms of mitochondria activation were dissected with genetic, biochemical, and morphologic approaches. :bid-deficient hepatocytes were much more resistant to apoptosis. Bid was required for permeability transition and mitochondria depolarization in addition to the previously defined release of cytochrome c. Permeability transition inhibitors cyclosporin A and aristolochic acid could inhibit mitochondria activation effectively, but not as much as the deletion of the bid gene, and they could not inhibit Bak oligomerization. In addition, mitochondria depolarization also could be induced by caspases, whose activation was mainly dependent on Bid. : Bid may activate mitochondria by 2 mechanisms, one is related to permeability transition and the other is related to Bak oligomerization. Bid can further affect mitochondria potentials by indirectly regulating caspase activity. This in vivo study provides novel findings not previously disclosed by in vitro studies, and indicates the importance of several mechanisms in contributing Bid-mediated mitochondria dysfunction that could be potential cellular targets of intervention

Loss of Zbtb32 in NOD mice does not significantly alter T cell responses. [version 2; referees: 2 approved]

Background: We previously identified the transcriptional regulator Zbtb32 as a factor that can promote T cell tolerance in the Non-Obese Diabetic (NOD) mouse, a model of Type 1 diabetes. Antigen targeted to DCIR2+ dendritic cells (DCs) in vivo inhibited both diabetes and effector T cell expansion in NOD mice. Furthermore, Zbtb32 was preferentially induced in autoreactive CD4 T cells stimulated by these tolerogenic DCIR2+ DCs, and overexpression of Zbtb32 in islet-specific T cells inhibited the diabetes development by limiting T cell proliferation and cytokine production. Methods: To further understand the role of Zbtb32 in T cell tolerance induction, we have now used CRISPR to target the Zbtb32 gene for deletion directly in NOD mice and characterized the mutant mice. We hypothesized that the systemic loss of Zbtb32 in NOD mice would lead to increased T cell activation and increased diabetes pathogenesis. Results: Although NOD.Zbtb32-/- male NOD mice showed a trend towards increased diabetes incidence compared to littermate controls, the difference was not significant. Furthermore, no significant alteration in lymphocyte number or function was observed. Importantly, in vitro stimulation of lymphocytes from NOD.Zbtb32-/- mice did not produce the expected hypersensitive phenotype observed in other genetic strains, potentially due to compensation by homologous genes. Conclusions: The loss of Zbtb32 in the NOD background does not result in the expected T cell activation phenotype

Determining the lower limit of Liangzhu culture based on black carbon purification with hydropyrolysis technique

Located in the middle and lower reaches of the Yangtze River, the Liangzhu Culture was one of the most important Neolithic cultures at the dawn of Chinese civilization. However, uncertainty over the lower age limit ending the Liangzhu Culture has resulted in a lack of consensus in defining its timespan. In order to establish the lower age limit, a representative site of late Liangzhu Culture, the Bianjiashan wharf, located in Hangzhou City, Zhejiang Province, Eastern China, was selected for investigation. Wooden stakes in the wharf and charcoals in the sediment profile near to the wharf site were collected for 14C AMS dating. To remove any contaminants, the charcoals were pre-treated by catalytic hydropyrolysis (HyPy) to isolate black carbon fractions (BCHyPy). The continuous charcoal age distribution along the vertical profile of the silt core suggests the continual occupation of the Bianjiashan Site and that the site was developed soon after the river formed. The end of river sedimentation indicates that the demise of the Bianjiashan Site occurred no later than Cal BC 2470 (95% probability). The mean age of the more recent calendar calibrated age range BC 2525 for the BCHyPy residue is consistent with earlier evidence. The wharf, as a typical structure of the late Liangzhu Culture, was established between Cal BC 2635 and 2890 (95% probability). The start of the river charcoal sedimentation was found to have a very similar overall age span and, therefore, the river existed at the Bianjiasha Site for no more than a maximum of just over 400 years, which is taken as the maximum period, it was occupied by the Liangzhu population. In comparison to the fresh charcoal samples, the BCHyPy fractions and products were generally found to have similar probability age distributions. GC-MS analysis of the products (non-BCHyPy fractions) released by HyPy indicated that . Tthe exogenous carbon from plants in the charcoal is present as both covalently bonded and adsorbed species, and was deposited at the same time as the charcoal, suggesting that the sediments have been preserved in a closed environment without disturbance as soon as the river ceased to exist. Thus, HyPy has confirms that there was no significant bias in the charcoal radiocarbon ages from more recent sedimentary organic matter

Low content of highly reactive iron in sediments from Prydz Bay and the adjacent Southern Ocean: Controlling factors and implications for sedimentary organic carbon preservation

Examining iron (Fe) speciation in marine sediments is critical to understand Fe and carbon biogeochemical cycling in polar regions. In this study, we investigated the speciation of Fe in sediments from Prydz Bay and the adjacent Southern Ocean, and examined the factors controlling Fe speciation and its relationship with total organic carbon (TOC). Our results reveal that unreactive silicate Fe (FeU) is the dominant pool of total Fe (FeT), followed by poorly reactive sheet silicate Fe (FePRS), reducible crystalline Fe oxides (Feox2), easily reducible amorphous/poorly crystalline Fe oxides (Feox1), and magnetite (Femag), with carbonate-associated ferrous Fe (Fecarb) being the smallest pool. The highly reactive Fe (FeHR)/FeT ratios (0.13 ± 0.06) in our study area are among the lowest end-member globally, primarily due to weak bedrock weathering and slow glacier melting. The Feox1/FeT ratios are similar to those in continental shelf and marginal seas containing highly weathered materials, while the Feox2/FeT ratios are significantly lower. This result implicates that low temperature inhibits the aging of iceberg melting-sourced Feox1 potentially, and accordingly the regulation of weathering on the FeHR/FeT ratio is mainly reflected in Feox2/FeT ratio. There are no significant correlations between TOC and FeHR, Fecarb, Feox1 or Feox2 in the research region. Four distinct patterns of TOC/FeHR ratio can be discerned by summarizing the global data set: (a) high TOC/FeHR ratios (> 2.5) are likely the result of high marine primary productivity and low chemically weathered source materials; (b) low TOC/FeHR ratios (< 0.6) are caused by high rates of FeHR inputs and OC remineralization; (c) mid-range TOC/FeHR ratios (0.6 – 2.5) typical of most river particulates and marginal sea sediments indicate the same FeHR and OC sources and/or interactions between each other; (d) both low TOC and FeHR content is the result of low marine primary productivity and weak chemical weathering. Our findings provide new insights into the relationship between FeHR and TOC in polar sediments

Non-Canonical NF-κB Activation and Abnormal B Cell Accumulation in Mice Expressing Ubiquitin Protein Ligase-Inactive c-IAP2

Loss of c-IAP2 ubiquitin ligase activity, which occurs in the lymphoma-causing c-IAP2/MALT1 fusion protein, activates non-canonical NF-κB signaling and results in B cell abnormalities characteristic of MALT lymphoma

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Parasitism Shifts the Effects of Native Soil Microbes on the Growth of the Invasive Plant <i>Alternanthera philoxeroides</i>

Soil microbes play an important role in plant invasion, and parasitic plants regulate the growth of invasive plants. However, the mechanisms by which parasitic plants regulate the effects of soil microbes on invasive plants have not been investigated. Here, we used the invasive plant Alternanthera philoxeroides and the holoparasitic plant Cuscuta grovonii to test whether and how C. grovonii parasitism shifts the effect of native soil microbes on the growth of A. philoxeroides. In a factorial setup, A. philoxeroides was grown in pots with the presence versus absence of parasitism and the presence versus absence of native soil microbes. The findings showed that native soil microbes increased the biomass and clonal growth of A. philoxeroides only in the absence of a parasite, whereas parasitism decreased the biomass and clonal growth of A. philoxeroides only in the presence of soil microbes. In addition, the presence of soil microbes increased the deleterious effects of the parasite on A. philoxeroides. These results indicate that parasitism can shift the effects of native soil microbes on the growth of the invasive plant A. philoxeroides. Our results enrich the understanding of the mechanisms underlying the success of plant invasion