Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line

Azacytidine (AzaC) and decitabine (AzadC) are cytosine analogs that covalently trap DNA methyltransferases, which place the important epigenetic mark 5-methyl-2’-deoxycytidine by methylating 2’-deoxycytidine (dC) at the C5 position. AzaC and AzadC are used in the clinic as antimetabolites to treat myelodysplastic syndrome and acute myeloid leukemia and are explored against other types of cancer. Although their principal mechanism of action is known, the downstream effects of AzaC and AzadC treatment are not well understood and the cellular prerequisites that determine sensitivity toward AzaC and AzadC remain elusive. Here, we investigated the effects and phenotype of AzaC and AzadC exposure on the acute myeloid leukemia cell line MOLM-13. We found that while AzaC and AzadC share many effects on the cellular level, including decreased global DNA methylation, increased formation of DNA double-strand breaks, transcriptional downregulation of important oncogenes and similar changes on the proteome level, AzaC failed in contrast to AzadC to induce apoptosis efficiently in MOLM-13. The only cellular marker that correlated with this clear phenotypical outcome was the level of hydroxy-methyl-dC, an additional epigenetic mark that is placed by TET enzymes and repressed in cancer cells. Whereas AzadC increased hmdC substantially in MOLM-13, AzaC treatment did not result in any increase at all. This suggests that hmdC levels in cancer cells should be monitored as a response toward AzaC and AzadC and considered as a biomarker to judge whether AzaC or AzadC treatment leads to cell death in leukemic cells

Epistasis between MicroRNAs 155 and 146a during T Cell-Mediated Antitumor Immunity

An increased understanding of antitumor immunity is necessary for improving cell-based immunotherapies against human cancers. Here, we investigated the roles of two immune system-expressed microRNAs (miRNAs), miR-155 and miR-146a, in the regulation of antitumor immune responses. Our results indicate that miR-155 promotes and miR-146a inhibits interferon γ (IFNγ) responses by T cells and reduces solid tumor growth in vivo. Using a double-knockout (DKO) mouse strain deficient in both miR-155 and miR-146a, we have also identified an epistatic relationship between these two miRNAs. DKO mice had defective T cell responses and tumor growth phenotypes similar to miR-155^(−/−) mice. Further analysis of the T cell compartment revealed that miR-155 modulates IFNγ expression through a mechanism involving repression of Ship1. Our work reveals critical roles for miRNAs in the reciprocal regulation of CD4^+ and CD8^+ T cell-mediated antitumor immunity and demonstrates the dominant nature of miR-155 during its promotion of immune responses

Transport currents and magnetic properties of textured Bi(2223) tape

Magnetic and transport properties of textured Bi(2223) tape with high critical transport current density (jc(77 K, 0 T)=2.8*104 A cm-2) were studied. Magnetic measurements show nongranular behaviour of shielding and transport currents for the magnetic field orientation perpendicular to the tape plane B perpendicular to p at low temperatures and low fields. At high magnetic fields and temperatures, however, quite large differences were observed, which depend on magnetic field sweep rate B and voltage criteria Ec. This is connected with granularity and inhomogeneity of the current flow. It was established that the magnetic field dependence of the critical current has a general scaling behaviour: jc(B, B, T)=jc(0, B, T) f(B/B0(B, T)) where the scaling function f becomes exp(-B/B0) for B/B0>or=1. The scaling parameter B0 is proportional to the irreversibility field Birr. Both B0 and Birr show an exponential temperature dependence

Evidence from heat conductivity for normal-conducting chains in the high T_c super- conductor YBa₂Cu₃O_6.9

The thermal conductivity at T < 0.5K parallel to the CuO2 planes in single crystalline YBa2Cu3O6.9 can be decomposed as kappa-a,b(T) = kappa-phonon(T) + A.T, while kappa-c(T) = kappa-phonon(T). This is explained by a model calculation, assuming that superconductivity is generated in the CuO2 layers and weak superconductivity is induced in the CuO chains by the proximity effect

Anisotropic low-temperature heat transport in YBa₂Cu₃O_6.9 single crystal

We report measurements of the low-temperature thermal conductivity of YBa2Cu3O7-delta (delta congruent-to 0.1) single crystals (T(c) = 84 K) both parallel (kappa(a,b)) and perpendicular (kappa(c)) to the CuO2 planes. Whereas kappa(c) (T) is found to be identical, within experimental resolution, with the phonon contribution kappa(ph) (T), kappa(a,b) (T) contains an additional term linear in temperature, AT. We ascribe AT to the contribution of unpaired electronic carriers residing in the "chain layers". Measurements performed in external magnetic fields B less-than-or-equal-to 8 T support this interpretation. Our observations can be explained by an "internal multilayer" (IML) model in which it is assumed that strong super-conductivity is generated within the CuO2 layers and weak superconductivity is induced in the "chain layers" by the proximity effect. The fit of the experimental results to the IML model reveals that approximately 15% of the electronic carriers remain unpaired in YBa2Cu3O7 below T = 1 K

Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4⁺-T Cell Pathogenicity and Suppresses Autoimmunity

Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate during glycolysis. The PK isoform PKM2 has additional roles in regulation of gene transcription and protein phosphorylation. PKM2 has been shown to control macrophage metabolic remodeling in inflammation, but its role in T cell biology is poorly understood. Here, we report PKM2 upregulation, phosphorylation, and nuclear accumulation in murine and human CD4+ T cells following activation in vitro. Treatment of T cells with TEPP-46, an allosteric activator that induces PKM2 tetramerization and blocks its nuclear translocation, strongly reduces their activation, proliferation, and cytokine production by inhibiting essential signaling pathways and thus preventing the engagement of glycolysis. TEPP-46 limits the development of both T helper 17 (Th17) and Th1 cells in vitro and ameliorates experimental autoimmune encephalomyelitis (EAE) in vivo. Overall, our results suggest that pharmacological targeting of PKM2 may represent a valuable therapeutic approach in T cell-mediated inflammation and autoimmunity

Development of high current capacity mono- and 18-filament in situ MgB2 cables by varying the twist pitch

Undoped and carbon doped magnesium diboride (MgB2) cables have been assembled by braiding six Nb/Monel and Nb/Cu/stainless steel (SS) sheathed mono- and multifilament strands with a central copper stabilizer for improving the operational environment. This paper presents the fabrication and characterization of two types of in situ powder-in-tube processed mono (pure) and multifilament (carbon doped) MgB2 cables with different twist pitch lengths; thereby making them possible candidates for industrial AC applications. Critical current is not influenced by the cabling that results in various twist lengths. The total critical current of the braided cables is obtained by multiplying the critical current of six single wires without any dissipation. The critical current density (Jc) of pure (mono) and carbon doped (18-filament) six stranded cable reached 10000 A/cm2 at 5.5 and 10 T, respectively; without any observable deleterious effect caused by varying the twist pitch. The engineering current density (Je) of both cables reached the same value of 10000 A/cm2 at 3.5 and 6.5 T, respectively. Compared to the literature, this work reports some of the highest Jc and Je values for carbon doped multifilament cables that remain unaffected upon varying the twist pitch. The present results are promising in terms of scaling up these cables to industrial lengths for transformers, fault-current limiters-based applications and paves the way for the development of optimal protocols for practical functionality

Development of high current capacity mono- and 18-filament in situ MgB2 cables by varying the twist pitch

Undoped and carbon doped magnesium diboride (MgB ) cables have been assembled by braiding six Nb/Monel and Nb/Cu/stainless steel (SS) sheathed mono-and multifilament strands with a central copper stabilizer for improving the operational environment. This paper presents the fabrication and characterization of two types of in situ powder-in-tube processed mono (pure) and multi-filament (carbon doped) MgB cables with different twist pitch lengths; thereby making them possible candidates for industrial AC applications. Critical current is not influenced by the cabling that results in various twist lengths. The total critical current of the braided cables is obtained by multiplying the critical current of six single wires without any dissipation. The critical current density (Jc) of pure (mono) and carbon doped (18-filament) six stranded cable reached 10 000 A/cm at 5.5 and 10 T, respectively; without any observable deleterious effect caused by varying the twist pitch. The engineering current density (Je) of both cables reached the same value of 10 000 A/cm at 3.5 and 6.5 T, respectively. Compared to the literature, this work reports some of the highest Jc and Je values for carbon doped multifilament cables that remain unaffected upon varying the twist pitch. The present results are promising in terms of scaling up these cables to industrial lengths for transformers, fault-current limiters-based applications and paves the way for the development of optimal protocols for practical functionality

miR-155 Promotes T Follicular Helper Cell Accumulation during Chronic, Low-Grade Inflammation

Chronic inflammation is a contributing factor to most life-shortening human diseases. However, the molecular and cellular mechanisms that sustain chronic inflammatory responses remain poorly understood, making it difficult to treat this deleterious condition. Using a mouse model of age-dependent inflammation that results from a deficiency in miR-146a, we demonstrate that miR-155 contributed to the progressive inflammatory disease that emerged as Mir146a(-/-) mice grew older. Upon analyzing lymphocytes from inflamed versus healthy middle-aged mice, we found elevated numbers of T follicular helper (Tfh) cells, germinal center (GC) B cells, and autoantibodies, all occurring in a miR-155-dependent manner. Further, Cd4-cre Mir155(fl/fl) mice were generated and demonstrated that miR-155 functions in T cells, in addition to its established role in B cells, to promote humoral immunity in a variety of contexts. Taken together, our study discovers that miR-146a and miR-155 counterregulate Tfh cell development that drives aberrant GC reactions during chronic inflammation