Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria.

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ

Simulation Calculation on the Failure Mode of the Big-size Sandbag Cofferdam on Soft Foundation

The offshore engineering develop fast in recent years, a new method named “big-size sandbag cofferdam” is applied to many practical projects in China. The sandbag is made of geotextile with large sizes in length and width. Sandbags are filled with pumped sea sand and stacked together layer by layer. Many theoretical obstacles remain unsolved, which has restricted the application of this advanced technology. Based on an instability project located in Bohai Bay, the failure mode of the big-size sandbag cofferdam on soft foundation was studied. The results show that the deformation of cofferdam was concentrated on the bottom sandbag, under the action of insufficient foundation bearing capacity and overburden load, the stress of the geotextile at the bottom layer increase sharply during the fast filling, then exceed its ultimate tensile strength, and the cofferdam would be pulled apart from the bottom to top, lead to a continuous penetrating sliding surface failure of big-size sandbag cofferdam

Tree-Ring Based Drought Reconstruction (A.D. 1855-2001) For The Qilian Mountains, Northwestern China

A juniper (Juniperus przewalskii Kom) tree-ring width chronology has been developed from the western-most forest of the Qilian Mountains. Our analyses demonstrate both temperature and precipitation have significant effects on tree growth and that both should be considered in climate reconstruction. Thus a regional drought history (A.D. 1855–2001) is reconstructed by calibrating with a linear interpolation through four Palmer Drought Severity Index (PDSI) grid values nearest the sampling site. Our reconstruction extends the drought history of this area and also reveals that the most severe drought occurred in the 1920s. In the context of the drought history of western China, this extreme drought between 1925–1931 is consistent over a large surrounding region of Northwestern China. Multi-taper spectral analysis reveals the existence of significant 40- to 46-year, 29-year, and 2.1- to 3-year periods of variability. Overall, our study provides reliable information for the research of past drought variability in the Qilian Mountains, Northwestern China.This item is part of the Tree-Ring Research (formerly Tree-Ring Bulletin) archive. For more information about this peer-reviewed scholarly journal, please email the Editor of Tree-Ring Research at [email protected]

Methyl jasmonate- or gibberellins A(3)-induced astaxanthin accumulation is associated with up-regulation of transcription of beta-carotene ketolase genes (bkts) in microalga Haematococcus pluvialis

The microalga Haematococcus pluvialis accumulates astaxanthin in response to abiotic stresses. Since methyl jasmonate (MJ) and gibberellins A(3) (GA(3)) are involved in the stress responses of plants, the impact of these compounds on astaxanthin metabolism was studied. Alga cells treated separately with MJ and GA(3) accumulated more astaxanthin than the controls. MJ and GA(3) treatment increased the transcription of three beta-carotene ketolase genes (bkts). MJ- and GA(3)-responsive cis-acting elements were identified in the 5'-flanking regions of bkt genes. These results suggest that MJ and GA(3) constitute molecular signals in the network of astaxanthin accumulation. Induction of astaxanthin accumulation by MJ or GA(3) without any other stimuli presents an attractive application potential. (C) 2010 Elsevier Ltd. All rights reserved.The microalga Haematococcus pluvialis accumulates astaxanthin in response to abiotic stresses. Since methyl jasmonate (MJ) and gibberellins A(3) (GA(3)) are involved in the stress responses of plants, the impact of these compounds on astaxanthin metabolism was studied. Alga cells treated separately with MJ and GA(3) accumulated more astaxanthin than the controls. MJ and GA(3) treatment increased the transcription of three beta-carotene ketolase genes (bkts). MJ- and GA(3)-responsive cis-acting elements were identified in the 5'-flanking regions of bkt genes. These results suggest that MJ and GA(3) constitute molecular signals in the network of astaxanthin accumulation. Induction of astaxanthin accumulation by MJ or GA(3) without any other stimuli presents an attractive application potential. (C) 2010 Elsevier Ltd. All rights reserved

Double nicking by RNA-directed Cascade-nCas3 for high-efficiency large-scale genome engineering

New CRISPR-based genome editing technologies are developed to continually drive advances in life sciences, which, however, are predominantly derived from systems of Type II CRISPR-Cas9 and Type V CRISPR-Cas12a for eukaryotes. Here we report a novel CRISPR-n(nickase)Cas3 genome editing tool established upon a Type I-F system. We demonstrate that nCas3 variants can be created by alanine-substituting any catalytic residue of the Cas3 helicase domain. While nCas3 overproduction via plasmid shows severe cytotoxicity, an in situ nCas3 introduces targeted double-strand breaks, facilitating genome editing without visible cell killing. By harnessing this CRISPR-nCas3 in situ gene insertion, nucleotide substitution and deletion of genes or genomic DNA stretches can be consistently accomplished with near-100% efficiencies, including simultaneous removal of two large genomic fragments. Our work describes the first establishment of a CRISPR-nCas3-based genome editing technology, thereby offering a simple, yet useful approach to convert the naturally most abundantly occurring Type I systems into advanced genome editing tools to facilitate high-throughput prokaryotic engineering

Construction of a Dengue NanoLuc Reporter Virus for In Vivo Live Imaging in Mice

Since the first isolation in 1943, the dengue virus (DENV) has spread throughout the world, but effective antiviral drugs or vaccines are still not available. To provide a more stable reporter DENV for vaccine development and antiviral drug screening, we constructed a reporter DENV containing the NanoLuc reporter gene, which was inserted into the 5′ untranslated region and capsid junction region, enabling rapid virus rescue by in vitro ligation. In addition, we established a live imaging mouse model and found that the reporter virus maintained the neurovirulence of prototype DENV before engineering. DENV-4 exhibited dramatically increased neurovirulence following a glycosylation site-defective mutation in the envelope protein. Significant mice mortality with neurological onset symptoms was observed after intracranial infection of wild-type (WT) mice, thus providing a visualization tool for DENV virulence assessment. Using this model, DENV was detected in the intestinal tissues of WT mice after infection, suggesting that intestinal lymphoid tissues play an essential role in DENV pathogenesis

Combining intramuscular and intranasal homologous prime-boost with a chimpanzee adenovirus-based COVID-19 vaccine elicits potent humoral and cellular immune responses in mice

The efficacy of many coronavirus disease 2019 (COVID-19) vaccines has been shown to decrease to varying extents against new severe acute respiratory syndrome coronavirus 2 variants, which are responsible for the continuing COVID-19 pandemic. Combining intramuscular and intranasal vaccination routes is a promising approach for achieving more potent immune responses. We evaluated the immunogenicity of prime-boost protocols with a chimpanzee adenovirus serotype 68 vector-based vaccine, ChAdTS-S, administered via both intranasal and intramuscular routes in BALB/c mice. Intramuscular priming followed by an intranasal booster elicited the highest levels of IgG, IgA, and pseudovirus neutralizing antibody titres among all the protocols tested at day 42 after prime immunization compared with the intranasal priming/intramuscular booster and prime-boost protocols using only one route. In addition, intramuscular priming followed by an intranasal booster induced high T-cell responses, measured using the IFN-γ ELISpot assay, that were similar to those observed upon intramuscular vaccination. All ChAdTS-S vaccination groups induced Th1-skewing of the T-cell response according to intracellular cytokine staining and Meso Scale Discovery cytokine profiling assays on day 56 after priming. This study provides reference data for assessing vaccination schemes of adenovirus-based COVID-19 vaccines with high immune efficacy