Tet-mediated DNA oxidation is a recently identified mammalian epigenetic modification, and its functional role in cell-fate transitions remains poorly understood. Here, we derive mouse embryonic ...fibroblasts (MEFs) deleted in all three Tet genes and examine their capacity for reprogramming into induced pluripotent stem cells (iPSCs). We show that Tet-deficient MEFs cannot be reprogrammed because of a block in the mesenchymal-to-epithelial transition (MET) step. Reprogramming of MEFs deficient in TDG is similarly impaired. The block in reprogramming is caused at least in part by defective activation of key miRNAs, which depends on oxidative demethylation promoted by Tet and TDG. Reintroduction of either the affected miRNAs or catalytically active Tet and TDG restores reprogramming in the knockout MEFs. Thus, oxidative demethylation to promote gene activation appears to be functionally required for reprogramming of fibroblasts to pluripotency. These findings provide mechanistic insight into the role of epigenetic barriers in cell-lineage conversion.
Display omitted
•Tet dioxygenases and TDG glycosylase are essential for fibroblast reprogramming•Tet and TDG mediate demethylation and reactivation of miRNAs critical for MET•Tet enzymes are not required for the reactivation of pluripotency loci
Using triple Tet gene knockout cells, Hu et al. show that Tet activity is required for reprogramming of fibroblasts to iPSCs for activation of key miRNA expression during the MET step.
The DArk Matter Particle Explorer (DAMPE) experiment has recently announced the first results for the measurement of total electron plus positron fluxes between 25 GeV and 4.6 TeV. A spectral break ...at about 0.9 TeV and a tentative peak excess around 1.4 TeV have been found. However, it is very difficult to reproduce both the peak signal and the smooth background including spectral break simultaneously. We point out that the numbers of events in the two energy ranges (bins) close to the 1.4 TeV excess have
1
σ
deficits. With the basic physics principles such as simplicity and naturalness, we consider the
-
2
σ
,
+
2
σ
, and
-
1
σ
deviations due to statistical fluctuations for the 1229.3 GeV bin, 1411.4 GeV bin, and 1620.5 GeV bin. Interestingly, we show that all the DAMPE data can be explained consistently via both the continuous distributed pulsar and dark matter interpretations, which have
χ
2
≃
17.2
and
χ
2
≃
13.9
(
for all the 38 points in DAMPE electron/positron spectrum with 3 of them revised
), respectively. These results are different from the previous analysis by neglecting the 1.4 TeV excess. At the same time, we do a similar global fitting on the newly released CALET lepton data, which could also be interpreted by such configurations. Moreover, we present a
U
(
1
)
D
dark matter model with the Breit–Wigner mechanism, which can provide the proper dark matter annihilation cross section and escape the CMB constraint. Furthermore, we suggest a few ways to test our proposal.
Uniform experimental design in chemometrics Xu, Qing‐Song; Xu, Yuan‐Da; Li, Lan ...
Journal of chemometrics,
November 2018, 2018-11-00, 20181101, Volume:
32, Issue:
11
Journal Article
Peer reviewed
Experimental designs and modeling are very important in chemometrics and chemical engineering. There are many kinds of experimental designs, which include the fractional factorial design (including ...the orthogonal design), the optimal regression design, and the uniform design. The uniform experimental design can be regarded as a fractional factorial design with model uncertainty, a space filling design for computer experiments, a robust design against model specification, and a supersaturated design. This paper gives a brief introduction to the recent theoretical developments on uniform experimental design as well as its applications in chemometrics.
This paper gives a brief introduction to the recent theoretical developments on uniform experimental design as well as its applications in chemometrics.
A new schiff base cobalt(III) complex
N
,
N
′-bis(2′-hydroxyphenylacetone)-o-ethanediamine cobalt(III) (
M3
) has been synthesized and characterized by single X-ray crystallography. The cytotoxicity ...of complex
M3
was evaluated against HeLa, LoVo, A549, A549/cis cancer cell lines, and the normal cell lines LO2 by MTT assays. The IC
50
is in the range of 6.27-22.68 μM, which is somewhat lower than cisplatin on the basis of platinum molar concentration. Furthermore, anticancer mechanistic studies showed that the complex
M3
inhibited cell proliferation by blocking DNA synthesis and then acted on nuclear division of HeLa cells over time. Moreover, western blot analysis indicated
M3
dramatically decreased the target protein c-Myc and KLF5 expression levels, and activated many signaling pathways including ER stress, apoptosis, cell cycle and DNA damage in HeLa.
M3
did not affect proteasomal activity.
Cells respond to and actively remodel the extracellular matrix (ECM). The dynamic and bidirectional interaction between cells and ECM, especially their mechanical interactions, has been found to play ...an essential role in triggering a series of complex biochemical and biomechanical signal pathways and in regulating cellular functions and behaviours. The collagen gel contraction assay (CGCA) is a widely used method to investigate cell–ECM interactions in 3D environments and provides a mechanically associated readout reflecting 3D cellular contractility. In this review, we summarize various versions of CGCA, with an emphasis on recent high-throughput and low-consumption CGCA techniques. More importantly, we focus on the technique of force monitoring during the contraction of collagen gel, which provides a quantitative characterization of the overall forces generated by all the resident cells in the collagen hydrogel. Accordingly, we present recent biological applications of the CGCA, which have expanded from the initial wound healing model to other studies concerning cell–ECM interactions, including fibrosis, cancer, tissue repair and the preparation of biomimetic microtissues.
•Collagen gel contraction assay reflects the dynamical cell-ECM interactions and the 3D cellular contractility.•Various techniques have been proposed to improve the throughput of collagen gel contraction assay.•Monitoring the contractile force of collagen gel provides a readout for the overall force generated by resident cells.•Various mathematical models have been proposed to simulate the collagen hydrogel contraction.•Collagen gel contraction assay has been widely used in various biological researches involving cell-ECM interactions.
Background and Aims
Coronavirus disease 2019 (COVID‐19) is a new infectious disease. To reveal the hepatic injury related to this disease and its clinical significance, we conducted a multicenter ...retrospective cohort study that included 5,771 adult patients with COVID‐19 pneumonia in Hubei Province.
Approach and Results
We reported the distributional and temporal patterns of liver injury indicators in these patients and determined their associated factors and death risk. Longitudinal liver function tests were retrospectively analyzed and correlated with the risk factors and death. Liver injury dynamic patterns differed in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL). AST elevated first, followed by ALT, in severe patients. ALP modestly increased during hospitalization and largely remained in the normal range. The fluctuation in TBIL levels was mild in the non‐severe and the severe groups. AST abnormality was associated with the highest mortality risk compared with the other indicators of liver injury during hospitalization. Common factors associated with elevated liver injury indicators were lymphocyte count decrease, neutrophil count increase, and male gender.
Conclusion
The dynamic patterns of liver injury indicators and their potential risk factors may provide an important explanation for the COVID‐19‐associated liver injury. Because elevated liver injury indicators, particularly AST, are strongly associated with the mortality risk, our study indicates that these parameters should be monitored during hospitalization.
Our current understanding of how sugar metabolism affects inflammatory pathways in macrophages is incomplete. Here, we show that glycogen metabolism is an important event that controls ...macrophage-mediated inflammatory responses. IFN-γ/LPS treatment stimulates macrophages to synthesize glycogen, which is then channeled through glycogenolysis to generate G6P and further through the pentose phosphate pathway to yield abundant NADPH, ensuring high levels of reduced glutathione for inflammatory macrophage survival. Meanwhile, glycogen metabolism also increases UDPG levels and the receptor P2Y
in macrophages. The UDPG/P2Y
signaling pathway not only upregulates the expression of STAT1 via activating RARβ but also promotes STAT1 phosphorylation by downregulating phosphatase TC45. Blockade of this glycogen metabolic pathway disrupts acute inflammatory responses in multiple mouse models. Glycogen metabolism also regulates inflammatory responses in patients with sepsis. These findings show that glycogen metabolism in macrophages is an important regulator and indicate strategies that might be used to treat acute inflammatory diseases.
Programmed death 1 (PD-1) and its two natural ligands PD-L1 and PD-L2 are responsible for delivering inhibitory signals that regulate the balance between T cell activation, tolerance, and ...immunopathology. In previous studies, PD-1 was found only expressed on the surface of immune cells, such as T cells and B cells while PD-1's ligands PD-L1 and PD-L2 were found expressed in some tumor cells. However, recent studies revealed intrinsic expression of PD-1 in melanoma and some other cancers. In melanoma cells, PD-1 can be activated by its ligand PD-L1 expressed by tumor cells, modulating downstream mammalian target of rapamycin signaling and promoting tumor growth independent of adaptive immunity. In addition to melanoma, PD-1 was also detected in liver cancer cells as well as in non-small lung cancer cells. Unlike its oncogenic functions in melanoma and hepatic carcinoma cells, PD-1 seemed to play a distinct role in lung cancer, as blockade of PD-1 instead promoted tumor cells proliferation. Tumor-intrinsic PD-1 expression seems to be widespread in many tumor types, according to our reanalysis on cancer transcriptomic and proteomic data. The multifaceted roles of PD-1 in tumor cells beyond immune checkpoint signaling may explain the differential therapeutic effects of anti-PD-1 and anti-PD-L1 drugs and provide crucial information when developing combinatorial approaches to enhance antitumor immunity.
Given the powerful potential of chiral-at-silicon chemistry, enantioselective synthesis of Si-stereogenic centers has attracted substantial research interest in recent years. However, the catalytic ...asymmetric synthesis of Si-stereogenic organosilicon compounds remains an appealing venture and is a challenging subject because of the difficulty in achieving high reactivity and stereoselectivity for "silicon-center" transformations. Herein, we disclose a highly enantioselective palladium-catalyzed hydrosilylation of 1,3-diynes with dihydrosilanes, which enables the facile preparation of Si-stereogenic enynes and an enyne-linked chiral polymer (polyenyne) in good yields and excellent ees (up to >99%) by desymmetrization. The unusual stereoselectivity in this reaction is achieved by precisely controlling the steric hindrance and electronic effect of the newly developed chiral ligands, resulting in a wide range of chiral silanes and a Si-containing polymer bearing a Si-stereogenic center which is otherwise difficult to access. The key to the high enantioselectivity relies on catalyst aggregation-induced non-covalent interaction, which exerts a remarkably positive influence on the Si-H bond activation and enhancement of enantioselectivity, in which the palladium/P-ligand complex was proved to be air-stable and moisture-insensitive in this reaction.
A highly enantioselective palladium-catalyzed hydrosilylation of 1,3-diynes with dihydrosilanes was established for the facile preparation of Si-stereogenic enynes and an enyne-linked chiral polymer (polyenyne) in good yields with excellent ees.
Abstract
Thermoelectrics enable waste heat recovery, holding promises in relieving energy and environmental crisis. Lillianite materials have been long-term ignored due to low thermoelectric ...efficiency. Herein we report the discovery of superior thermoelectric performance in Pb
7
Bi
4
Se
13
based lillianites, with a peak figure of merit,
zT
of 1.35 at 800 K and a high average
zT
of 0.92 (450–800 K). A unique quality factor is established to predict and evaluate thermoelectric performances. It considers both band nonparabolicity and band gaps, commonly negligible in conventional quality factors. Such appealing performance is attributed to the convergence of effectively nested conduction bands, providing a high number of valley degeneracy, and a low thermal conductivity, stemming from large lattice anharmonicity, low-frequency localized Einstein modes and the coexistence of high-density moiré fringes and nanoscale defects. This work rekindles the vision that Pb
7
Bi
4
Se
13
based lillianites are promising candidates for highly efficient thermoelectric energy conversion.
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