Glioblastoma patients have a poor prognosis mainly due to temozolomide (TMZ) resistance. NRF2 is an important transcript factor involved in chemotherapy resistance due to its protective role in the ...transcription of genes involved in cellular detoxification and prevention of cell death processes, such as ferroptosis. However, the relation between NRF2 and iron-dependent cell death in glioma is still poorly understood. Therefore, in this study, we analyzed the role of NRF2 in ferroptosis modulation in glioblastoma cells. Two human glioblastoma cell lines (U251MG and T98G) were examined after treatment with TMZ, ferroptosis inducers (Erastin, RSL3), and ferroptosis inhibitor (Ferrostatin-1). Our results demonstrated that T98G was more resistant to chemotherapy compared to U251MG and showed elevated levels of NRF2 expression. Interestingly, T98G revealed higher sensitivity to ferroptosis, and significant GSH depletion upon system xc
blockage. NRF2 silencing in T98G cells (T98G-shNRF2) significantly reduced the viability upon TMZ treatment. On the other hand, T98G-shNRF2 was resistant to ferroptosis and reverted intracellular GSH levels, indicating that NRF2 plays a key role in ferroptosis induction through GSH modulation. Moreover, silencing of ABCC1, a well-known NRF2 target that diminishes GSH levels, has demonstrated a similar collateral sensitivity. T98G-siABCC1 cells were more sensitive to TMZ and resistant to Erastin. Furthermore, we found that NRF2 positively correlates with ABCC1 expression in tumor tissues of glioma patients, which can be associated with tumor aggressiveness, drug resistance, and poor overall survival. Altogether, our data indicate that high levels of NRF2 result in collateral sensitivity on glioblastoma via the expression of its pro-ferroptotic target ABCC1, which contributes to GSH depletion when the system xc
is blocked by Erastin. Thus, ferroptosis induction could be an important therapeutic strategy to reverse drug resistance in gliomas with high NRF2 and ABCC1 expression.
Laser spectroscopy of muonic deuterium Pohl, Randolf; Nez, François; Fernandes, Luis M. P. ...
Science (American Association for the Advancement of Science),
08/2016, Letnik:
353, Številka:
6300
Journal Article
Recenzirano
Odprti dostop
The deuteron is the simplest compound nucleus, composed of one proton and one neutron. Deuteron properties such as the root-mean-square charge radius rd and the polarizability serve as important ...benchmarks for understanding the nuclear forces and structure. Muonic deuterium μd is the exotic atom formed by a deuteron and a negative muon μ⁻. We measured three 2S-2P transitions in μd and obtain rd = 2.12562(78) fm, which is 2.7 times more accurate but 7.5σ smaller than the CODATA-2010 value rd = 2.1424(21) fm. The μd value is also 3.5σ smaller than the rd value from electronic deuterium spectroscopy. The smaller rd, when combined with the electronic isotope shift, yields a "small" proton radius rp, similar to the one from muonic hydrogen, amplifying the proton radius puzzle.
Accurate knowledge of the charge and Zemach radii of the proton is essential, not only for understanding its structure but also as input for tests of bound-state quantum electrodynamics and its ...predictions for the energy levels of hydrogen. These radii may be extracted from the laser spectroscopy of muonic hydrogen (μp, that is, a proton orbited by a muon). We measured the $2{\mathrm{S}}_{1/2}^{\mathrm{F}=0}-2{\mathrm{P}}_{3/2}^{\mathrm{F}=1}$ transition frequency in μp to be 54611.16(1.05) gigahertz (numbers in parentheses indicate one standard deviation of uncertainty) and reevaluated the $2{\mathrm{S}}_{1/2}^{\mathrm{F}=1}-2{\mathrm{P}}_{3/2}^{\mathrm{F}=1}$ transition frequency, yielding 49881.35(65) gigahertz. From the measurements, we determined the Zemach radius, r Z = 1.082(37) femtometers, and the magnetic radius, r M = 0.87(6) femtometer, of the proton. We also extracted the charge radius, r E = 0.84087(39) femtometer, with an order of magnitude more precision than the 2010-CODATA value and at 7σ variance with respect to it, thus reinforcing the proton radius puzzle.
Leprosy is caused by Mycobacterium leprae infection and remains a major public health problem in many areas of the world. Challenges to its timely diagnosis result in delay in treatment, which is ...usually associated with severe disability. Although phenolic glycolipid (PGL)-I has been reported as auxiliary diagnostic tool, currently there is no serological assay routinely used in leprosy diagnosis. The aim of this study was to evaluate the effectiveness of two related reagents, LID-1 and LID-NDO, for the detection of M. leprae infection. Sera from 98 leprosy patients, 365 household contacts (HHC) and 98 endemic controls from Rio Grande do Norte, Brazil, were evaluated. A subgroup of the HHC living in a hyperendemic area was followed for 7-10 years. Antigen-specific antibody responses were highest in multibacillary (MB) at the lepromatous pole (LL/BL) and lowest in paucibacillary (PB) at the tuberculoid pole (TT/BT). A positive correlation for both anti-LID-1 and anti-LID-NDO antibodies was found with bacterial burden (LID-1, r = 0.84, p<0.001; LID-NDO, r = 0.82, p<0.001), with higher sensitivity than bacilloscopy. According to Receiver Operating Curve, LID-1 and LID-NDO performed similarly. The sensitivity for MB cases was 89% for LID-1 and 95% for LID-NDO; the specificity was 96% for LID-1 and 88% for LID-NDO. Of the 332 HHC that were followed, 12 (3.6%) were diagnosed with leprosy in a median time of 31 (3-79) months after recruitment. A linear generalized model using LID-1 or LID-NDO as a predictor estimated that 8.3% and 10.4% of the HHC would become a leprosy case, respectively. Together, our findings support a role for the LID-1 and LID-NDO antigens in diagnosing MB leprosy and identifying people at greater risk of developing clinical disease. These assays have the potential to improve the diagnostic capacity at local health centers and aid development of strategies for the eventual control and elimination of leprosy from endemic areas.
The size of the proton dos Santos, Joaquim M. F; Fernandes, Luis M. P; Liu, Yi-Wei ...
Nature (London),
07/2010, Letnik:
466, Številka:
7303
Journal Article
Recenzirano
The proton is the primary building block of the visible Universe, but many of its properties—such as its charge radius and its anomalous magnetic moment—are not well understood. The root-mean-square ...charge radius, rp, has been determined with an accuracy of 2 per cent (at best) by electron–proton scattering experiments. The present most accurate value of rp (with an uncertainty of 1 per cent) is given by the CODATA compilation of physical constants. This value is based mainly on precision spectroscopy of atomic hydrogen and calculations of bound-state quantum electrodynamics (QED; refs 8, 9). The accuracy of rp as deduced from electron–proton scattering limits the testing of bound-state QED in atomic hydrogen as well as the determination of the Rydberg constant (currently the most accurately measured fundamental physical constant). An attractive means to improve the accuracy in the measurement of rp is provided by muonic hydrogen (a proton orbited by a negative muon); its much smaller Bohr radius compared to ordinary atomic hydrogen causes enhancement of effects related to the finite size of the proton. In particular, the Lamb shift (the energy difference between the 2S1/2 and 2P1/2 states) is affected by as much as 2 per cent. Here we use pulsed laser spectroscopy to measure a muonic Lamb shift of 49,881.88(76) GHz. On the basis of present calculations of fine and hyperfine splittings and QED terms, we find rp = 0.84184(67) fm, which differs by 5.0 standard deviations from the CODATA value of 0.8768(69) fm. Our result implies that either the Rydberg constant has to be shifted by −110 kHz/c (4.9 standard deviations), or the calculations of the QED effects in atomic hydrogen or muonic hydrogen atoms are insufficient.
Mo-CBP3 is a chitin-binding protein from M. oleifera seeds that inhibits the germination and mycelial growth of phytopathogenic fungi. This protein is highly thermostable and resistant to pH changes, ...and therefore may be useful in the development of new antifungal drugs. However, the relationship of MoCBP3 with the known families of carbohydrate-binding domains has not been established. In the present study, full-length cDNAs encoding 4 isoforms of Mo-CBP3 (Mo-CBP3-1, Mo-CBP3-2, Mo-CBP3-3 and Mo-CBP3-4) were cloned from developing seeds. The polypeptides encoded by the Mo-CBP3 cDNAs were predicted to contain 160 (Mo-CBP3-3) and 163 amino acid residues (Mo-CBP3-1, Mo-CBP3-2 and Mo-CBP3-4) with a signal peptide of 20-residues at the N-terminal region. A comparative analysis of the deduced amino acid sequences revealed that Mo-CBP3 is a typical member of the 2S albumin family, as shown by the presence of an eight-cysteine motif, which is a characteristic feature of the prolamin superfamily. Furthermore, mass spectrometry analysis demonstrated that Mo-CBP3 is a mixture of isoforms that correspond to different mRNA products. The identification of Mo-CBP3 as a genuine member of the 2S albumin family reinforces the hypothesis that these seed storage proteins are involved in plant defense. Moreover, the chitin-binding ability of Mo-CBP3 reveals a novel functionality for a typical 2S albumin.
Vector control remains the sole effective method to prevent dengue virus (DENV) transmission, although a vaccine for dengue has recently become available and testing of its efficacy and coverage is ...being performed in multiple places. Entomological surveillance is a key factor in alerting authorities to possible outbreaks, but until now natural DENV infection of mosquito populations has been scarcely used as an early warning system to monitor fluctuating prevalence of infected mosquitoes. The purpose of this study was to determine the burden of adult and larval/pupae of Aedes aegypti and Aedes albopictus with DENV in urban areas in the state of Rio Grande do Norte, Brazil.
Immature insect forms (larvae and pupae) were collected from April 2011 to March 2012, whereas the collection of adults was conducted along 3 years: May 2011 to April 2014. Total RNAs of the samples were extracted and the nested reverse transcriptase PCR assay for detecting and typing DENV was performed. Of the 1333 immature insects collected during the study period, 1186 (89%) were A. aegypti and 147 (11%) A. albopictus. DENV-4 was identified in pools of A. aegypti larvae. The rate of DENV infection in immature A. aegypti was expressed as MIR = 3.37. DENV wasnot detected in immature A. albopictus. A total of 1360 adult female mosquitoes of the Aedes genus were captured from May 2011 to April 2014. Of this total, 1293 were A. aegypti (95%) and 67 were A. albopictus (5%). From the 130 pools studied, 27 (20.7%) were positive for DENV. DENV-1 was identified in 2/27 (7.4%) pools; 1of A. albopictus and 1 of A. aegypti. DENV-2 was identified in only 1/27 (3.7%) A. aegypti pools. DENV-4 was the most prevalent, identified in 24/27 (88.8%) of the positive pools, with 19 being of A. aegypti and 5 of A. albopictus pools. The minimum infection rate for adults of the Aedes genus was 19.8, considering both A. aegypti and A. albopictus.
This work represents the most complete study to date on the interaction between dengue viruses and Aedes mosquitoes in the State of Rio Grande do Norte, and raises important questions about a possible role of A. albopictus in the transmission of dengue virus in Brazil.
•Active MAP was tested on cherry tomatoes during 5°C cold storage.•Firmness was maintained and changes in sugar and organic acid contents were delayed.•Respiration rate and ethylene production rate ...were decreased.•Active MAP reduced weight loss and lycopene biosynthesis and maintained red color.•Active MAP and low temperature were effective in delaying tomato maturation.
The effects of active modified atmosphere packaging (MAP) on the postharvest quality of cherry tomatoes stored at cold temperature (5°C) and in bi-oriented polypropylene/low density polyethylene BOPP/LDPE bags were investigated. The atmosphere composition used in the packaging was 5% O2+5% CO2 (MAP), and synthetic air (control). The variables measured were weight loss, firmness, sugar, organic acids, color, lycopene, respiration rate, and ethylene biosynthesis over 25 days. The results showed that active MAP could extend the shelf life of cherry tomatoes to 25 days and the gas concentration could influence the postharvest quality of cherry tomatoes. MAP treatment decreased the respiration rate and ethylene production rate while reducing weight loss, lycopene biosynthesis, and the formation of red color. Through the use of MAP it was possible to maintain firmness and delay changes in sugar and organic acid contents. The combination of active MAP and low temperature treatments was effective with regard to delaying maturity during the storage period, and preserving the quality of cherry tomatoes.
To update the social distribution of women's obesity in the developing world and, in particular, to identify the specific level of economic development at which, if any, women's obesity in the ...developing world starts to fuel inequities in health.
Multilevel logistic regression analyses applied to anthropometric and socioeconomic data collected by nationally representative cross-sectional surveys conducted from 1992 to 2000 in 37 developing countries within a wide range of world regions and stages of economic development (gross national product (GNP) from 190 to 4440 US dollars per capita).
: In total, 148 579 nonpregnant women aged 20-49 y.
Body mass index to assess obesity status; quartiles of years of education to assess woman's socioeconomic status (SES), and GNP per capita to assess country's stage of economic development.
Belonging to the lower SES group confers strong protection against obesity in low-income economies, but it is a systematic risk factor for the disease in upper-middle income developing economies. A multilevel logistic model-including an interaction term between the country's GNP and each woman's SES-indicates that obesity starts to fuel health inequities in the developing world when the GNP reaches a value of about 2500 US dollars per capita.
For most upper-middle income economies and part of the lower-middle income economies, obesity among adult women is already a relevant booster of health inequities and, in the absence of concerted national public actions to prevent obesity, economic growth will greatly expand the list of developing countries where this situation occurs.
Mo-CBP3 is a chitin-binding 2S albumin from Moringa oleifera. This seed storage protein is resistant to thermal denaturation and shows biological activities that might be of practical use, such as ...antifungal properties against Candida sp., a pathogen that causes candidiasis, and against Fusarium solani, a soil fungus that can cause diseases in plants and humans. Previous work has demonstrated that Mo-CBP3 is a mixture of isoforms encoded by members of a small multigene family. Mature Mo-CBP3 is a small protein (∼14 kDa), constituted by a small chain of approximately 4 kDa and a large chain of 8 kDa, which are held together by disulfide bridges. However, a more comprehensive picture on the spectrum of Mo-CBP3 isoforms which are found in mature seeds, is still lacking. In this work, genomic DNA fragments were obtained from M. oleifera leaves, cloned and completely sequenced, thus revealing new genes encoding Mo-CBP3. Moreover, mass spectrometry analysis showed that the mature protein is a complex mixture of isoforms with a remarkable number of molecular mass variants. Using computational predictions and calculations, most (∼86%) of the experimentally determined masses were assigned to amino acid sequences deduced from DNA fragments. The results suggested that the complex mixture of Mo-CBP3 isoforms originates from proteins encoded by closely related genes, whose products undergo different combinations of distinct post-translational modifications, including cleavage at the N- and C-terminal ends of both subunits, cyclization of N-terminal Gln, as well as Pro hydroxylation, Ser/Thr phosphorylation, and Met oxidation.
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•Genomic DNA fragments obtained from leaves and encoding new isoforms of Mo-CBP3 were cloned and sequenced.•Mass spectrometry analysis showed that Mo-CBP3 comprises a remarkable number of molecular mass variants.•Most of the observed molecular masses were satisfactorily assigned to amino acid sequences deduced from DNA clones.•The data suggest that Mo-CBP3 isoforms arise from different combinations of post-translational modifications.
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