Inactivation of the Caenorhabditis elegans gene clk-1, which is required for ubiquinone biosynthesis, increases lifespan by an insulin signaling-independent mechanism. We find that homozygous inactivation of mclk1, the mouse ortholog of clk-1, yields ES cells that are protected from oxidative stress and damage to DNA. Moreover, in the livers of old mclk1 +/− mice, hepatocytes that have lost mclk1 expression by loss of heterozygosity undergo clonal expansion, suggesting that their resistance to stress allows them to outcompete cells that still express the gene. mclk1 +/− mice, whose growth and fertility are normal, also display a substantial increase in lifespan in each of three different genetic backgrounds. These observations indicate that the distinct mechanism by which clk-1/mclk1 affects lifespan is evolutionarily conserved from nematodes to mammals and is not tied to a particular anatomy or physiology.[Keywords: clk-1; mclk1; aging; loss of heterozygosity; reactive oxygen species; ubiquinone] Supplemental material is available at http://www.genesdev.org.

The administration of bone mesenchymal stem cells (BMSCs) could reverse experimental colitis, and the predominant mechanism in tissue repair seems to be related to their paracrine activity. BMSCs derived extracellular vesicles (BMSC-EVs), including mcirovesicles and exosomes, containing diverse proteins, mRNAs and micro-RNAs, mediating various biological functions, might be a main paracrine mechanism for stem cell to injured cell communication. We aimed to investigate the potential alleviating effects of BMSC-EVs in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model. Intravenous injection of BMSC-EVs attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI) and histological colonic damage. In inflammation response, the BMSC-EVs treatment significantly reduced both the mRNA and protein levels of nuclear factor kappaBp65 (NF-κBp65), tumor necrosis factor-alpha (TNF-α), induciblenitric oxidesynthase (iNOS) and cyclooxygenase-2 (COX-2) in injured colon. Additionally, the BMSC-EVs injection resulted in a markedly decrease in interleukin-1β (IL-1β) and an increase in interleukin-10 (IL-10) expression. Therapeutic effect of BMSC-EVs associated with suppression of oxidative perturbations was manifested by a decrease in the activity of myeloperoxidase (MPO) and Malondialdehyde (MDA), as well as an increase in superoxide dismutase (SOD) and glutathione (GSH). BMSC-EVs also suppressed the apoptosis via reducing the cleavage of caspase-3, caspase-8 and caspase-9 in colitis rats. Data obtained indicated that the beneficial effects of BMSC-EVs were due to the down regulation of pro-inflammatory cytokines levels, inhibition of NF-κBp65 signal transduction pathways, modulation of anti-oxidant/ oxidant balance, and moderation of the occurrence of apoptosis.

Background Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) induced Coronavirus Disease 2019 (COVID-19) has posed a global threat to public health. The immune system is crucial in defending and eliminating the virus and infected cells. However, immune dysregulation may result in the rapid progression of COVID-19. Here, we evaluated the subsets, phenotypic and functional characteristics of natural killer (NK) and T cells in patients with COVID-19 and their associations with disease severity. Methods Demographic and clinical data of COVID-19 patients enrolled in Wuhan Union Hospital from February 25 to February 27, 2020, were collected and analyzed. The phenotypic and functional characteristics of NK cells and T cells subsets in circulating blood and serum levels of cytokines were analyzed via flow cytometry. Then the LASSO logistic regression model was employed to predict risk factors for the severity of COVID-19. Results The counts and percentages of NK cells, CD4 + T cells, CD8 + T cells and NKT cells were significantly reduced in patients with severe symptoms. The cytotoxic CD3 - CD56 dim CD16 + cell population significantly decreased, while the CD3 - CD56 dim CD16 - part significantly increased in severe COVID-19 patients. More importantly, elevated expression of regulatory molecules, such as CD244 and programmed death-1 (PD-1), on NK cells and T cells, as well as decreased serum cytotoxic effector molecules including perforin and granzyme A, were detected in patients with COVID-19. The serum IL-6, IL-10, and TNF-α were significantly increased in severe patients. Moreover, the CD3 - CD56 dim CD16 - cells were screened out as an influential factor in severe cases by LASSO logistic regression. Conclusions The functional exhaustion and other subset alteration of NK and T cells may contribute to the progression and improve the prognosis of COVID-19. Surveillance of lymphocyte subsets may in the future enable early screening for signs of critical illness and understanding the pathogenesis of this disease.

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Cancer is one of the leading causes of human death, despite enormous efforts to explore cancer biology and develop anticancer therapies. The main challenges in cancer research are establishing an efficient tumor microenvironment in vitro and exploring efficient means for screening anticancer drugs to reveal the nature of cancer and develop treatments. The tumor microenvironment possesses human-specific biophysical and biochemical factors that are difficult to recapitulate in conventional in vitro planar cell models and in vivo animal models. Therefore, model limitations have hindered the translation of basic research findings to clinical applications. In this review, we introduce the recent progress in tumor-on-a-chip devices for cancer biology research, medicine assessment, and biomedical applications in detail. The emerging tumor-on-a-chip platforms integrating 3D cell culture, microfluidic technology, and tissue engineering have successfully mimicked the pivotal structural and functional characteristics of the in vivo tumor microenvironment. The recent advances in tumor-on-a-chip platforms for cancer biology studies and biomedical applications are detailed and analyzed in this review. This review should be valuable for further understanding the mechanisms of the tumor evolution process, screening anticancer drugs, and developing cancer therapies, and it addresses the challenges and potential opportunities in predicting drug screening and cancer treatment.

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Grain-size compositions of lake sediments can provide direct information on changes in 13 transporting mechanism and sedimentary environment. Various grain-size parameters have been 14 employed to reconstruct hydrological conditions within the lake and dust influx from outside the lake. 15Here we present the grain-size results of a 5-m core retrieved from Lake Qinghai, northeastern Tibetan 16Plateau in order to address the links between Holocene depositional process and climatic change. Our 17 results indicate that two parameters (skewness and grain-size ratio of 8~50/2~8 μm) are sensitive to 18 hydrodynamic changes in Lake Qinghai, which are further linked to the strength of the Asian summer 19 monsoon. Variations of these two parameters reveal that summer monsoon intensity weakened 20 gradually from early to late Holocene, superimposed by persistent centennial variability with 21 dominant periods at 0.35, 0.23 and 0.12 kyr. Comparison of grain-size variations with solar activities 22and North Atlantic cooling events reveals that solar forcing likely plays an important role in driving 23 centennial monsoon variability. 24 25

Aeolian deposits at four sites in the Gonghe Basin were used to reconstruct the history of aeolian activity over the late Quaternary. These deposits include well-sorted aeolian sand, paleosols and/or loess. Aeolian sand represents dune-field expansion and/or dune buildup, whereas paleosols indicate stabilization of dunes, accompanying ameliorated vegetation cover. On the basis of 25 dates by optically stimulated luminescence (OSL), it appears that aeolian activities occurred episodically at 33.5, 20.3, 13.9, 11.8–11.0, 9.4, 7.8, and 5.7 (5.5) ka, which is largely consistent with the recent findings from the adjacent semi-arid areas. Aeolian sand mobility occurring during the early to mid Holocene conflicts with a climatic optimum inferred from lacustrine records in the northeastern Qinghai-Tibetan Plateau. This inconsistency may be resolved by interpreting aeolian activity as a response to decreased effective moisture due to enhanced evaporation, induced by higher summer insolation at that time, together with local terrain and its effects on moisture. Our results suggest that aeolian sand and paleosol cannot be simply ascribed to regional dry and wet climates, respectively, and they most likely reflect changes in effective moisture.