The induced pluripotent stem (iPS) cell field holds promise for in vitro disease modeling. However, identifying innate cellular pathologies, particularly for age-related neurodegenerative diseases, ...has been challenging. Here, we exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to α-synuclein (asyn), a key protein involved in Parkinson's disease (PD). We generated cortical neurons from iPS cells of patients harboring asyn mutations, who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of asyn toxicity led to identification of early pathogenic phenotypes in patient neurons. These included nitrosative stress, accumulation of endoplasmic reticulum (ER)-associated degradation substrates, and ER stress. A small molecule identified in a yeast screen (NAB2), and the ubiquitin ligase Nedd4 it affects, reversed pathologic phenotypes in these neurons.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Several mixed ligand vanadium and copper complexes were synthesized containing 8-hydroxyquinoline (8HQ) and a ligand such as picolinato (pic−), dipicolinato (dipic2−) or a Schiff base. The complexes ...were characterized by spectroscopic techniques and by single-crystal X-ray diffraction in the case of VVO(l-pheolnaph-im)(5-Cl-8HQ) and VVO(OMe)(8HQ)2, which evidenced the distorted octahedral geometry of the complexes. The electronic absorption data showed the presence of strong ligand to metal charge transfer bands, significant solvent effects, and methoxido species in methanol, which was further confirmed by 51V- NMR spectroscopy. The structures of CuII(dipic)(8HQ)Na and VIVO(pic)(8HQ) were confirmed by EPR spectroscopy, showing only one species in solution. The biological activity of the compounds was assessed through the minimal inhibitory concentration (MIC) of the compounds against Mycobacterium tuberculosis (Mtb) and the cytotoxic activity against the cisplatin sensitive/resistant ovarian cells A2780/A2780cisR and the non-tumorigenic HEK cells (IC50 values). Almost all tested vanadium complexes were very active against Mtb and the MICs were comparable to, or better than, the MICs of drugs, such as streptomycin. The activity of the complexes against the A2780 cell line was dependent on incubation time presenting IC50 values in the 3–14μM (at 48h) range. In these conditions, the complexes were significantly (*P<0.05–**P<0.001) more active than cisplatin (22μM), in the A2780 cells and even surpassing its activity in the cisplatin-resistant cells A2780cisR (2.4–8μM vs. 75.4; **P<0.001). In the non-tumorigenic HEK cells poor selectivity toward cancer cells for most of the complexes was observed, as well as for cisplatin.
New vanadium(IV and V) and copper(II) mixed ligand complexes derived from 8-hydroxyquinoline were characterized in solution and solid state and evaluated as potential anti-tuberculosis and anti-cancer drugs. Some vanadium complexes are very active against Mycobacterium tuberculosis and also displayed anti-proliferative activities with low IC50 values. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A major challenge in supramolecular polymerization is controlling the stability of the polymers formed, that is, controlling the rate of monomer exchange in the equilibrium between monomer and ...polymer. The exchange dynamics of supramolecular polymers based on benzene‐1,3,5‐tricarboxamide (BTA) can be regulated by copolymerizing molecules with dendronized (dBTA) and linear (nBTA) ethylene glycol‐based water‐soluble side chains. Whereas nBTAs form long nanofibers in water, dBTAs do not polymerize, forming instead small spherical aggregates. The copolymerization of the two BTAs results in long nanofibers. The exchange dynamics of both the BTA monomers in the copolymer are significantly slowed down in the mixed systems, leading to a more stable copolymer, while the morphology and spectroscopic signature of the copolymers are identical to that of nBTA homopolymer. This copolymerization is the supramolecular counterpart of styrene/ maleic anhydride copolymerization.
The exchange dynamics of supramolecular polymers based on benzene‐1,3,5‐tricarboxamide (BTA) can be regulated by copolymerizing molecules with dendronized (dBTA) and linear (nBTA) ethylene glycol‐based water‐soluble side chains. Whereas nBTAs form long nanofibers in water, dBTAs do not polymerize. The copolymerization of the two BTAs results in more stable long nanofibers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The opening-angle of quartz c-axis fabrics (OA) is strongly temperature dependent and has proven to be a powerful deformation thermometer for natural metamorphic rocks. Previous considerations of ...empirical data have identified a linear correlation between OA and temperature between 250 and 650°C, and no correlation above 650°C. However, possible effects of pressure have not been investigated. We expanded the data set of OA versus temperature, including data from rocks deformed over 300–1050°C and 2.5–15kbar. Disregarding possible effects of pressure, the OA–temperature relationship can be described by two linear correlations for the intervals ~250–650°C and ~650–1050°C:T°C=6.9OAdegrees+48250°C≤T≤650°CandOA≤87°T°C=4.6OAdegrees+258650°C≤T≤1050°CandOA≥87°
The change on the curve slope of the OA–temperature relationship correlates approximately to the low- to high-quartz transition and to changes in the dynamic recrystallization mechanism from subgrain rotation to grain boundary migration. The available data suggest that pressure has a secondary effect accompanying the major temperature dependence of OA, which is particularly important for temperatures above 650°C, where the correlation between OA and temperature is less pronounced. For fixed pressures, the OA has logarithmic relationships with temperature over the range 250–1050°C. The following thermometer equation is formulated from a multiple regression:T°C=410.44lnOAdegrees+14.22Pkbar−1272
An uncertainty of ±50°C is inherited from the petrological temperature estimates of the natural samples. The data suggest the gradual increasing importance of prism c slip relative to slip in quartz with rising temperature. Under conditions of ‘average’ geological strain rate and water weakening, prism c slip dominates for deformation above ~700°C.
•We improved the quartz c-axis fabric opening-angle deformation thermometer.•We extended the thermometer to higher deformation temperatures (up to 1050°C).•The opening-angle has logarithmic relationships with temperature for fixed pressures.•Pressure has a secondary effect on the opening-angle over the range of 2.5–15kbar.•The data yielded the fit: T (°C)=410.44 ln (opening-angle)+14.22 P (kbar)−1272.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Rifampicin, discovered more than 50 years ago, represents the last novel class of antibiotics introduced for the first-line treatment of tuberculosis. Drugs in this class form part of a 6-month ...regimen that is ineffective against MDR and XDR TB, and incompatible with many antiretroviral drugs. Investments in R&D strategies have increased substantially in the last decades. However, the number of new drugs approved by drug regulatory agencies worldwide does not increase correspondingly. Ruthenium complexes (SCAR) have been tested in our laboratory and showed promising activity against Mycobacterium tuberculosis. These complexes showed up to 150 times higher activity against MTB than its organic molecule without the metal (free ligand), with low cytotoxicity and high selectivity. In this study, promising results inspired us to seek a better understanding of the biological activity of these complexes. The in vitro biological results obtained with the SCAR compounds were extremely promising, comparable to or better than those for first-line drugs and drugs in development. Moreover, SCAR 1 and 4, which presented low acute toxicity, were assessed by Ames test, and results demonstrated absence of mutagenicity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Taurine is associated with insulin signaling and mitochondrial metabolism in mice.•Taurine doses modulated taurine synthesis and AMP-activated protein kinase pathways in 3T3-L1 cells.•A dose of 0.5 ...mM of taurine upregulated insulin pathways in 3T3-L1 cells.•Taurine did not modulate markers of mitochondrial function in subcutaneous white adipose tissue of obese women.•Taurine did not modulate taurine or insulin pathways in subcutaneous white adipose tissue of obese women.
Based on taurine's beneficial roles in metabolic diseases in rodents and obese individuals, we investigated the effects of taurine supplementation on adipose tissue using transcriptome analysis, 3T3-L1 adipocytes, and subcutaneous white adipose tissue (scWAT) of obese women.
First, we applied bioinformatics analysis to evaluate the effect of the taurine synthesis pathway on the adipose tissue of several BXD mice strains. After that, using 3T3-L1 adipocytes, we investigated the effects of different taurine doses in proteins related to insulin signaling, lipid oxidation, and mitochondrial function. Finally, we evaluated the effects of taurine supplementation (3 grams, 8 wk) on the same proteins in the scWAT of obese women.
The transcriptome analysis showed that the taurine biosynthesis pathway was positively associated with insulin signaling and mitochondrial metabolism in the scWAT of BXD mice. The experiments using 3T3-L1 cells highlighted that the taurine dosage has an essential function in taurine synthesis, insulin, and mitochondrial markers. In contrast, the 8-wk taurine administration did not change the basal insulin, proteins of the taurine synthesis or insulin pathways, lipid oxidation, or mitochondrial metabolism in the scWAT of obese women.
For the first time, to our knowledge, we showed that supplementation with 3 g of taurine for 8 wk promoted no effect in the insulin signaling pathway in the scWAT of obese women. These findings bring new perspectives to investigate different taurine doses and the intervention period for human studies owing to the potential antiobesity activity of taurine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Understanding the short-range molecular motions of organic ionic plastic crystals is critical for the application of these materials as solid-state electrolytes in electrochemical devices such as ...lithium batteries. However, the theory of short-range-motions was originally developed for simple molecular plastic crystals and does not take account of strong interionic interactions that are present in organic ionic plastic crystals. Here we report a fundamental investigation of the dynamic behavior of an archetypal example triethyl(methyl)phosphonium bis(fluorosulfonyl)amide (P1222FSI) through calorimetry, impedance spectroscopy, synchrotron X-ray diffraction, and solid-state NMR and Raman spectroscopies. For the first time, we show the presence of conformational dynamics in the solid state for the FSI anion. We relate the dynamics to a unique second-order displacive phase transition of P1222FSI. This detailed analysis suggests a new disorder mechanism involving cooperative motion between the cation and FSI anion in the plastic crystal due to strong interionic interactions.
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IJS, KILJ, NUK, PNG, UL, UM
The aim of this study was to identify a candidate drug for the development of anti-tuberculosis therapy from previously synthesized compounds based on the thiosemicarbazones, semicarbazones, ...dithiocarbazates and hydrazide/hydrazones compounds. The minimal inhibitory concentration (MIC) of these compounds against
Mycobacterium tuberculosis was determined. Their
in vitro cytotoxicity to J774 cells (IC
50) was determined to establish a selectivity index (SI) (SI
=
IC
50/MIC). The best compounds were the thiosemicarbazones (
2,
3 and
4) and the hydrazide/hydrazones (
14,
15,
16 and
18). The results are comparable to or better than those of “first line” or “second line” drugs commonly used to treat TB, suggesting these compounds as anti-TB drug candidates.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Fibroblast growth factor 21 (FGF21) signaling and genetic factors are involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. However, these factors have rarely been studied in type 2 ...diabetes mellitus (T2D) patients from admixed populations such as in those of Brazil. Therefore, we aimed to evaluate rs738409 patanin-like phospholipase domain-containing protein (
) and rs499765
polymorphisms in T2D, and their association with NAFLD, liver fibrosis, and serum biomarkers (FGF21 and cytokeratin 18 levels). A total of 158 patients were included, and the frequency of NAFLD was 88.6%, which was independently associated with elevated body mass index. Significant liver fibrosis (≥F2) was detected by transient elastography (TE) in 26.8% of NAFLD patients, and was independently associated with obesity, low density lipoprotein, and gamma-glutamyl transferase (GGT).
GG genotype and GGT were independently associated with cirrhosis.
GG genotype patients had higher GGT and AST levels;
GG carriers had higher TE values than CG patients, and
CG genotype patients showed lower gamma-GT values than CC patients. No differences were found in serum values of FGF21 and CK18 in relation to the presence of NAFLD or liver fibrosis. The proportion of NAFLD patients with liver fibrosis was relevant in the present admixed T2D population, and was associated with
polymorphisms.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
ABSTRACT The plasma emission, or electromagnetic (EM) radiation at the plasma frequency and/or its harmonic(s), is generally accepted as the radiation mechanism responsible for solar type II and III ...radio bursts. Identification and characterization of these solar radio burst phenomena were done in the 1950s. Despite many decades of theoretical research since then, a rigorous demonstration of the plasma emission process based upon first principles was not available until recently, when, in a recent Letter, Ziebell et al. reported the first complete numerical solution of EM weak turbulence equations; thus, quantitatively analyzing the plasma emission process starting from the initial electron beam and the associated beam-plasma (or Langmuir wave) instability, as well as the subsequent nonlinear conversion of electrostatic Langmuir turbulence into EM radiation. In the present paper, the same problem is revisited in order to elucidate the detailed physical mechanisms that could not be reported in the brief Letter format. Findings from the present paper may be useful for interpreting observations and full-particle numerical simulations.
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