Involvement of nitric oxide in the mitochondrial action of efavirenz: a differential effect on neurons and glial cells

The anti-human immunodeficiency virus (HIV) drug efavirenz (EFV) alters mitochondrial function in cultured neurons and glial cells. Nitric oxide (NO) is a mediator of mitochondrial dysfunction associated with HIV central nervous system symptoms. We show that EFV promotes inducible nitric oxide synthase (iNOS) expression in cultured glial cells and generated NO undermines their mitochondrial function, as inhibition of NOS partially reverses this effect. EFV inhibits mitochondrial Complex I in both neurons and glia; however, when the latter cells are treated for longer periods, other mitochondrial complexes are also affected in accordance with the increased NO production. These findings shed light on the mechanisms responsible for the frequent EFV-associated neurotoxicity

Neuronal Bioenergetics and Acute Mitochondrial Dysfunction: A Clue to Understanding the Central Nervous System Side Effects of Efavirenz

Background. Neurological pathogenesis is associated with mitochondrial dysfunction and differences in neuronal/glial handling of oxygen and glucose. The main side effects attributed to efavirenz involve the CNS, but the underlying mechanisms are unclear. Methods. Human cell lines and rat primary cultures of neurons and astrocytes were treated with clinically relevant efavirenz concentration. Results. Efavirenz alters mitochondrial respiration, enhances reactive oxygen species generation, undermines mitochondrial membrane potential, and reduces adenosine triphosphate (ATP) levels in a concentration-dependent fashion in both neurons and glial cells. However, it activates adenosine monophosphate–activated protein kinase only in glial cells, upregulating glycolysis and increasing intracellular ATP levels, which do not occur in neurons. To reproduce the conditions that often exist in human immunodeficiency virus–related neuroinflammatory disorders, the effects of efavirenz were evaluated in the presence of exogenous nitric oxide, an inflammatory mediator and mitochondrial inhibitor. The combination potentiated the effects on mitochondrial parameters in both neurons and glial cells, but ATP generation and lactate production were enhanced only in glial cells. Conclusions. Efavirenz affects the bioenergetics of neurons through a mechanism involving acute mitochondrial inhibition, an action exacerbated in neuroinflammatory conditions. A similar scenario of glial cells survival and degeneration of neurons with signs of mitochondrial dysfunction and oxidative stress has been associated with neurocognitive disorders

Bentonite powder XRD quantitative analysis using Rietveld refinement: Revisiting and updating bulk semiquantitative mineralogical compositions

Bentonite is a claystone formed by a complex mineralogical mixture, composed of mont-morillonite, illite, and accessory minerals like quartz, cristobalite, feldspars, carbonates, and minor amounts of iron oxy-hydroxides. Bentonite presents complexity at various scales: (1): a single mineral may present different chemical composition within the same quarry (e.g., feldspars solid solu-tions); (2): montmorillonite presents variability in the cation-exchange distribution while illite may be presented as mixed-layer with smectite sheets; and (3): hardness and crystal size are larger in accessory minerals than in clay minerals, preventing uniform grinding of bentonite. The FEBEX bentonite used is originally from Almería (Spain), and it is a predominantly calcium, magnesium, and sodium bentonite. This Spanish FEBEX bentonite has been hydrothermally altered at laboratory scale for 7–14 years. A thermal gradient was generated by heating a disk of pressed iron powder, simulating the metal waste canister, in contact with the compacted bentonite sample. Hydration was forced from the opposite direction. XRD recorded patterns were very similar. In order to min-imize the bias of XRD semi-quantitative determination methods, Rietveld refinement was per-formed using BGMN software and different structural models. Confidence in the quantification of the main phases allows us to convincingly detect other subtle changes such as the presence of calcite in the hydration front, right at the interface between the saturated and unsaturated bentonite, or the presence of goethite, and not hematite, in the saturated bentonite, near the source of hydration. Smectite component was 72 ± 3% and the refinement was consistent with the presence of ~10% illite, comparable with previous characterization

Tritium permeation experiment at IFMIF Medium Flux Test Module

Tritium release experiments using different breeding material candidates are planned for the medium flux region of the IFMIF Test Cell. Nowadays, only ceramic breeder materials have been suggested to be tested in the Tritium Release Module located in the Medium Flux Test Module of IFMIF. Liquid breeder blankets are very promising and for that reason, several concepts will be tested in ITER. One of the main problems concerning the liquid blankets is the permeation of the generated tritium in the breeder throughout the walls. Since tritium permeation is highly influenced by irradiation conditions, IFMIF is a suitable scenario to perform tritium permeation related experiments. In this paper, a preliminary design of a tritium permeation experiment for the Medium Flux Test Module of IFMIF is proposed, in order to contribute to the progress of the liquid breeder blanket concept validation. The conceptual design of the capsule in which the experiment will be performed is carried out, taking into consideration the experiment necessities and its implementation in the Tritium Release Module. In addition to this, some thermal hydraulic calculations have been performed to evaluate the thermal behaviour of the irradiation capsul

Prognostic significance of amino acid and biogenic amines profiling in chronic kidney disease

Producción CientíficaThere is a pressing need for more precise biomarkers of chronic kidney disease (CKD). Plasma samples from 820 subjects [231 with CKD, 325 with end-stage kidney disease (ESKD) and 264 controls] were analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) to determine a metabolic profile of 28 amino acids (AAs) and biogenic amines to test their value as markers of CKD risk and progression. The kynurenine/tryptophan ratio showed the strongest correlation with estimated glomerular filtration rate values (coefficient = −0.731, p < 0.0001). Models created with orthogonal partial least squares-discriminant analysis (OPLS-DA) containing the metabolic signature showed a high goodness of fit and predictability for controls/CKD (R2X:0.73:R2Y:0.92:Q2:0.92, p < 0.0001) and lower values for CKD/ESKD (R2X:0.56:R2Y:0.59:Q2:0.55, p < 0.0001). Based on generated VIP scores, the most relevant markers for segregating samples into control/CKD and CKD/ESKD groups were citrulline (1.63) and tryptophan (1.47), respectively. ROC analysis showed that the addition of the metabolic profile to a model including CKD classic risk factors improved the AUC from 86.7% (83.6–89.9) to 100% (100–100) for CKD risk (p < 0.0001) and from 63.0% (58.2–67.8) to 96.5% (95.3–97.8) for the risk of progression from CKD to ESKD (p < 0.0001). Plasma concentrations of AAs and related amines may be useful as diagnostic biomarkers of kidney disease, both for CKD risk and for progression of CKD patients to ESKD.Instituto de Salud Carlos III y Unión Europea (NextGeneration UE) - (grant RD21/0005/0031)Instituto de Salud Carlos III y Unión Europea - (grant PI22/00181 )Junta de Extremadura y Fondo Europeo de Desarrollo Regional (FEDER) - (grant GR21026

Present status of the Liquid Breeder Validation

One of the objectives of IFMIF (International Fusion Materials Irradiation Facility), as stated in its specifications, is the validation of breeder blanket concepts for DEMO design. The so-called Liquid Breeder Validation Module (LBVM) will be used in IFMIF to perform experiments under irradiation on functional materials related to liquid breeder concepts for future fusion reactors. This module, not considered in previous IFMIF design phases, is currently under design by CIEMAT in the framework of the IFMIF/EVEDA project. In this paper, the present status of the design of the LBVM is presented

Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: the PROLUNG Phase 2 randomized clinical trial

Importance: Because of socioeconomic factors, many patients with advanced non-small cell lung cancer (NSCLC) do not receive immunotherapy in the first-line setting. It is unknown if the combination of immunotherapy with chemotherapy can provide clinical benefits in immunotherapy-naive patients with disease progression after treatment with platinum-based chemotherapy. Objective: To evaluate the safety and efficacy of the combination of pembrolizumab plus docetaxel in patients with previously treated advanced NSCLC following platinum-based chemotherapy regardless of EGFR variants or programmed cell death ligand 1 status. Design, Setting, and Participants: The Pembrolizumab Plus Docetaxel for Advanced Non-Small Cell Lung Cancer (PROLUNG) trial randomized 78 patients with histologically confirmed advanced NSCLC in a 1:1 ratio to receive either pembrolizumab plus docetaxel or docetaxel alone from December 2016 through May 2019. Interventions: The experimental arm received docetaxel on day 1 (75 mg/m2) plus pembrolizumab on day 8 (200 mg) every 3 weeks for up to 6 cycles followed by pembrolizumab maintenance until progression or unacceptable toxic effects. The control arm received docetaxel monotherapy. Main Outcomes and Measures: The primary end point was overall response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival, and safety. Results: Among 78 recruited patients, 32 (41%) were men, 34 (44%) were never smokers, and 25 (32%) had an EGFR/ALK alteration. Forty patients were allocated to receive pembrolizumab plus docetaxel, and 38 were allocated to receive docetaxel. A statistically significant difference in ORR, assessed by an independent reviewer, was found in patients receiving pembrolizumab plus docetaxel vs patients receiving docetaxel (42.5% vs 15.8%; odds ratio, 3.94; 95% CI, 1.34-11.54; P =.01). Patients without EGFR variations had a considerable difference in ORR of 35.7% vs 12.0% (P =.06), whereas patients with EGFR variations had an ORR of 58.3% vs 23.1% (P =.14). Overall, PFS was longer in patients who received pembrolizumab plus docetaxel (9.5 months; 95% CI, 4.2-not reached) than in patients who received docetaxel (3.9 months; 95% CI, 3.2-5.7) (hazard ratio, 0.24; 95% CI, 0.13-0.46; P <.001). For patients without variations, PFS was 9.5 months (95% CI, 3.9-not reached) vs 4.1 months (95% CI, 3.5-5.3) (P <.001), whereas in patients with EGFR variations, PFS was 6.8 months (95% CI, 6.2-not reached) vs 3.5 months (95% CI, 2.3-6.2) (P =.04). In terms of safety, 23% (9 of 40) vs 5% (2 of 38) of patients experienced grade 1 to 2 pneumonitis in the pembrolizumab plus docetaxel and docetaxel arms, respectively (P =.03), while 28% (11 of 40) vs 3% (1 of 38) experienced any-grade hypothyroidism (P =.002). No new safety signals were identified. Conclusions and Relevance: In this phase 2 study, the combination of pembrolizumab plus docetaxel was well tolerated and substantially improved ORR and PFS in patients with advanced NSCLC who had previous progression after platinum-based chemotherapy, including NSCLC with EGFR variations. Trial Registration: ClinicalTrials.gov Identifier: NCT02574598

Corrector atmosférico en imágenes Landsat

Los efectos atmosféricos en las imágenes satelitales distorsionan la información disponible y originan errores en la estimación de las variables biofísicas provenientes de los datos espectrales. En este trabajo se desarrolló un algoritmo de corrección atmosférica que se basó en la correlación existente entre la reflectancia de la banda 7 (infrarrojo medio, 2.2 μm) y la banda 1 (Azul, 0.485 μm) de la vegetación, para los sensores TM y ETM+. La ordenada al origen de la regresión entre la banda 7 y la banda 1 de imágenes Landsat es un estimador de la reflectancia de trayectoria en la banda 1. Con esta reflectancia de trayectoria y un modelo de atmósfera y aerosol definido, es posible estimar el espesor óptico de los aerosoles centrado en 0.55 μm. El algoritmo se apoyó en el acoplamiento de varios modelos de simulación y bibliotecas de datos espectrales para la representación del sistema óptico suelo–vegetación–atmósfera. La vegetación en una imagen se identifica mediante un clasificador genérico de objetos en cuatro variantes: oscura densa, cobertura alta, media y baja. El algoritmo se probó en dos fases, la primera se basó en un análisis empírico sobre los resultados de la simulación del sistema óptico suelo–vegetación–atmósfera, en el que se tenían condiciones controladas. En la segunda fase se validó el algoritmo con 7 imágenes ETM+ cuyas escenas contenían un sitio de la red robótica de aerosoles (AERONET), la cual mide con gran precisión el espesor óptico de los aerosoles en diferentes intervalos de longitud de onda. El análisis de los resultados mostró que el corrector estima el espesor óptico de la escena con un ajuste: R2 = 0.97, error típico de 0.059 (20.3%) y que representa bien la variabilidad espacial de carga de aerosoles en imágenes Landsat

Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile

[EN]Circulating myeloma tumor cells (CTCs) as defined by the presence of peripheral blood (PB) clonal plasma cells (PCs) are a powerful prognostic marker in multiple myeloma (MM). However, the biological features of CTCs and their pathophysiological role in MM remains unexplored. Here, we investigate the phenotypic, cytogenetic, and functional characteristics as well as the circadian distribution of CTCs vs paired bone marrow (BM) clonal PCs from MM patients. Our results show that CTCs typically represent a unique subpopulation of all BM clonal PCs, characterized by downregulation (P < .05) of integrins (CD11a/CD11c/CD29/CD49d/CD49e), adhesion (CD33/CD56/CD117/CD138), and activation molecules (CD28/CD38/CD81). Fluorescence in situ hybridization analysis of fluorescence-activated cell sorter-sorted CTCs also unraveled different cytogenetic profiles vs paired BM clonal PCs. Moreover, CTCs were mostly quiescent and associated with higher clonogenic potential when cocultured with BM stromal cells. Most interestingly, CTCs showed a circadian distribution which fluctuates in a similar pattern to that of CD34(+) cells, and opposite to stromal cell-derived factor 1 plasma levels and corresponding surface expression of CXC chemokine receptor 4 on clonal PCs, suggesting that in MM, CTCs may egress to PB to colonize/metastasize other sites in the BM during the patients' resting period

Update of the 5 MW Beam-on-Target Requirements for improvement of the materials irradiation performance at IFMIF-DONES

IFMIF-DONES is a facility under construction in Granada, whose main goal is the validation and characterization of materials under a fusion prototypic irradiation field. This field is created by the interaction of a high energy intense continuous deuteron beam and a flowing liquid lithium target. The requirements imposed on the beam at the interaction point are a complex trade-off among the scientific experimental needs for the materials irradiation defined at the top-level requirements (20 dpa in a volume of 0.3 dm3 and 50 dpa in 0.1 dm3), and the technical constraints of several systems such as the Accelerator Systems, the Lithium Systems, and the Test Systems. Recent simulations with the initial definition of beam-on-target requirements showed the necessity of redefining them in order to fulfill the irradiation needs. This contribution will address the main challenges to gather the inputs for the definition and reassessment of the beam-on-target requirements. A comparison detailing the main changes compared to the previous ones will be given, together with a short overview of the studies ongoing by different systems to analyze the impact of each beam-on-target requirements on the performance of the whole facility