Expression of TRX1 optimizes the antitumor functions of human CAR T cells and confers resistance to a pro-oxidative tumor microenvironment

Use of chimeric antigen receptor (CAR) T cells to treat B cell lymphoma and leukemia has been remarkably successful. Unfortunately, the therapeutic efficacy of CAR T cells against solid tumors is very limited, with immunosuppression by the pro-oxidative tumor microenvironment (TME) a major contributing factor. High levels of reactive oxygen species are well-tolerated by tumor cells due to their elevated expression of antioxidant proteins; however, this is not the case for T cells, which consequently become hypo-responsive. The aim of this study was to improve CAR T cell efficacy in solid tumors by empowering the antioxidant capacity of CAR T cells against the pro-oxidative TME. To this end, HER2-specific human CAR T cells stably expressing two antioxidant systems: thioredoxin-1 (TRX1), and glutaredoxin-1 (GRX1) were generated and characterized. Thereafter, antitumor functions of CAR T cells were evaluated under control or pro-oxidative conditions. To provide insights into the role of antioxidant systems, gene expression profiles as well as global protein oxidation were analyzed. Our results highlight that TRX1 is pivotal for T cell redox homeostasis. TRX1 expression allows CAR T cells to retain their cytolytic immune synapse formation, cytokine release, proliferation, and tumor cell-killing properties under pro-oxidative conditions. Evaluation of differentially expressed genes and the first comprehensive redoxosome analysis of T cells by mass spectrometry further clarified the underlying mechanisms. Taken together, enhancement of the key antioxidant TRX1 in human T cells opens possibilities to increase the efficacy of CAR T cell treatment against solid tumors

Economía y finanzas sociales: avances en la investigación

Esta obra colectiva propone un cambio de paradigma en la investigación científica, financiera y económica, cuyo centro de atención es reducir las desigualdades sociales y económicas, mejorar la sostenibilidad ambiental y la creación eficiente de valor económico. Desde un punto de vista crítico y mediante diversos enfoques teóricos, metodológicos y disciplinares, los autores analizan el esquema financiero predominante en las economías de mercado, al tiempo que abordan temas como la inclusión financiera, la banca ética o las experiencias e intervenciones en y sobre la economía social.ITESO, A.C

Los bancos extranjeros en México: diversificación de actividades y su efecto en la estructura de ingresos

This paper discusses the profound changes in financial systems that have modified thelinkages between banks, capital markets, businesses, and households. The main impact offinancialization on the banking structure has been the development of large multinationalfinancial corporations that have expanded worldwide and modified their key banking activitiesas well as their income.The main argument of this paper is that although foreign multinational corporationshave become dominant in developing countries, and the banking structure and bank activitieshave been diversified, especially in Mexico, their major income sources still derive frominterest income. It further argues that in Mexico, specific banking activities (although notbank operations overall) have oligopolistic structures. These activities are the major incomesources for banking institutions, and the entrance of foreign multinational corporationsinto the banking market did not change this condition.Este trabajo analiza los profundos cambios ocurridos en el sistema financiero y su impactoen las interrelaciones y el comportamiento de las familias, los mercados de capitales, laestructura bancaria y empresas no financieras. Se destaca que la financiarización modificóla estructura bancaria originando la conformación de corporaciones multinacionales degran tamaño que, a su vez, cambiaron las principales actividades de la banca, así como lafuente de su ingreso. El argumento central de este ensayo es que a pesar que las corporaciones multinacionalesse volvieron dominantes en los países en desarrollo y se diversificó la estructuray las actividades bancarias, en México las principales fuentes de ingresos de estas institucionesno se modificaron, o sea, continuaron proviniendo de los ingresos por concepto deintereses. Se argumenta que ello se explica por las estructuras oligopólicas que dominanalguna actividades bancarias (sin afectar al conjunto de las operaciones); las cuales sehan mantenido como la principal fuente de ingresos para las instituciones bancarias, sinque la dominación de las corporaciones multinacionales haya modificado la fuente deingresos de los principales bancos que operan en México

Site-directed mutagenesis of tyrosine 118 within the central constriction site of the LamB (maltoporin) channel of Escherichia coli. II. Effect on maltose and maltooligosaccharide binding kinetics.

The 3-D structure of the maltooligosaccharide-specific LamB channel of Escherichia coli (also called maltoporin) is known from x-ray crystallography. The central constriction of the channel formed by the external loop 3 is controlled by tyrosine 118. Y118 was replaced by site-directed mutagenesis by 10 other amino acids (alanine (A), isoleucine (I), asparagine (N), serine (S), cysteine (C), aspartic acid (D), arginine (R), histidine (H), phenylalanine (F), and tryptophan (W)) including neutral ones, negatively and positively charged amino acids to study the effect of their size, their hydrophobicity index, and their charge on maltose and maltooligosaccharide binding to LamB. The mutants were reconstituted into lipid bilayer membranes and the stability constants for binding of maltose, maltotriose, maltopentaose, and maltoheptaose to the channel were measured using titration experiments. The mutation of Y118 to any other non-aromatic amino acid led to a substantial decrease of the stability constant of binding by factors between about two and six. The highest effect was observed for the mutant Y118A. Replacement of Y118 by the two other aromatic amino acids, phenylalanine (F) and tryptophan (W), resulted in a substantial increase of the stability constant maximally by a factor of almost 400 for the Y118W mutant. The carbohydrate-induced block of the channel function was used for the study of current noise through the different mutant LamB channels. The analysis of the power density spectra allowed the evaluation of the on- and off-rate constants (k(1) and k(-1)) of sugar binding. The results suggest that both rate constants were affected by the mutations. For most mutants, with the exception of Y118F and Y118W, k(1) decreased and k(-1) increased, whereas the opposite was found for the aromatic amino acid mutants. The results suggest that tyrosine 118 has a crucial effect on carbohydrate transport through LamB

Site-directed mutagenesis of tyrosine 118 within the central constriction site of the LamB (Maltoporin) channel of Escherichia coli. I. Effect on ion transport.

The three-dimensional structure of the malto-oligosaccharide-specific LamB-channel of Escherichia coli (also called maltoporin) is known from x-ray crystallography. The central constriction of the channel formed by the external loop 3 is controlled by a tyrosine residue (Y118). Y118 was replaced by site-directed mutagenesis by ten other amino acids (alanine, isoleucine, asparagine, serine, cysteine, aspartic acid, arginine, histidine, phenylalanine, and tryptophane) including neutral ones, negatively and positively charged amino acids to study the effect of their size, hydrophobicity, and charge on ion transport through LamB. The mutant proteins were purified to homogeneity. They were reconstituted into lipid bilayer membranes and single-channel conductance and ion selectivity were measured to get insight into the mechanism of ion transport through LamB. The mutation of Y118 to any other nonaromatic amino acid led to a substantial increase of the single-channel conductance by more than a factor of six at maximum. The highest effect was observed for Y118D. Additionally, a nonlinear relationship between the salt concentration in the aqueous phase and the channel conductance was observed for this mutant, indicating strong discrete charge effects on ion conductance. For all other mutants, with the exception of Y118R, linear relationships were found between single-channel conductance and bulk aqueous concentration. The individual hydrophobicity indices of the amino acids introduced inside the central constriction of the LamB channel had a somewhat smaller effect on the single-channel conductance as compared with the effect of their size and charge

Influence of microwave sintering on electrical properties of BCTZ lead free piezoelectric ceramics

International audienceBarium titanate doped with calcium and zirconium (BCTZ) could be used at low temperature to replace lead based piezoelectric ceramics (PZT). The classical way to obtain BCTZ is the solid-state route coupled with conventional sintering, but this step is time-consuming. To reduce the duration of this process, microwave heating was used for sintering. It is a fast sintering method and the heating rate was around 200 °C/min in this study. Slightly better electrical properties with finer microstructures (d33* = 706 pm/V, grain size about 42.1 ± 14.2 μm) were obtained for samples sintered by microwave heating during 50 min compared to the conventional sintering (d33* = 622 pm/V, 22.6 ± 4.4 μm). The main result of this study is that by using microwave heating, the sintering step duration (including heating, dwell time and cooling) was drastically reduced: 1.5 h for microwave sintering against 12.5 h for conventional sintering

Influence of microwave sintering on electrical properties of BCTZ lead free piezoelectric ceramics

International audienceBarium titanate doped with calcium and zirconium (BCTZ) could be used at low temperature to replace lead based piezoelectric ceramics (PZT). The classical way to obtain BCTZ is the solid-state route coupled with conventional sintering, but this step is time-consuming. To reduce the duration of this process, microwave heating was used for sintering. It is a fast sintering method and the heating rate was around 200 °C/min in this study. Slightly better electrical properties with finer microstructures (d33* = 706 pm/V, grain size about 42.1 ± 14.2 μm) were obtained for samples sintered by microwave heating during 50 min compared to the conventional sintering (d33* = 622 pm/V, 22.6 ± 4.4 μm). The main result of this study is that by using microwave heating, the sintering step duration (including heating, dwell time and cooling) was drastically reduced: 1.5 h for microwave sintering against 12.5 h for conventional sintering

CymA of Klebsiella oxytoca Outer Membrane: Binding of Cyclodextrins and Study of the Current Noise of the Open Channel

CymA, the outer membrane component of the cyclodextrin (CD) uptake and metabolism system of Klebsiella oxytoca, was reconstituted into lipid bilayer membranes. The channel properties of this unusual porin were studied in detail. The binding of CDs to the channel resulted in its complete block for ion transport. This result allowed the detailed investigation of carbohydrate binding, and the stability constants for the binding of cyclic and linear carbohydrates to the binding site inside the channel were calculated from titration experiments of the membrane conductance with the carbohydrates. Highest stability constant was observed for α-cyclodextrin (α-CD; K = 32,000 1/M) followed by β-cyclodextrin (β-CD; K = 1970 1/M) and γ-cyclodextrin (γ-CD; K = 310 1/M). Linear maltooligosaccharides bound also to CymA but with much smaller stability constants as compared to cyclic ones. The noise of the current through CymA in multi- and single-channel experiments was investigated using fast Fourier transformation. The current through the open channels had a rather high spectral density, which was a Lorentzian function of the frequency up to 2000 Hz. Upon addition of cyclic dextrins to the aqueous phase the spectral density decreased in a dose-dependent manner, which made it impossible to evaluate the binding kinetics. Experiments with single CymA-channels demonstrated the channel is highly asymmetric concerning channel flickers and current noise

microRNA-122 amplifies hepatitis C virus translation by shaping the structure of the internal ribosomal entry site

International audienceThe liver-specific microRNA-122 (miR-122) recognizes two conserved sites at the 5' end of the hepatitis C virus (HCV) genome and contributes to stability, translation, and replication of the viral RNA. We show that stimulation of the HCV internal ribosome entry site (IRES) by miR-122 is essential for efficient viral replication. The mechanism relies on a dual function of the 5' terminal sequence in the complementary positive (translation) and negative strand (replication), requiring different secondary structures. Predictions and experimental evidence argue for several alternative folds involving the miR-binding region (MBR) adjacent to the IRES and interfering with its function. Mutations in the MBR, designed to suppress these dysfunctional structures indeed stimulate translation independently of miR-122. Conversely, MBR mutants favoring alternative folds show impaired IRES activity. Our results therefore suggest that miR-122 binding assists the folding of a functional IRES in an RNA chaperone-like manner by suppressing energetically favorable alternative secondary structures

Microwave sintering: Improvement of the electrical properties of barium titanate doped with calcium and zirconia

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