T cell subsets and the outcome of haematopoietic stem cell transplantation

Haematopoietic stem cell transplantation (HSCT) is an effective therapy for many malignant and non‐malignant diseases. However, adverse events such as infections, Graft‐versus‐Host Disease (GvHD) and relapse limit the wider use of HSCT. The identification of factors that predict the outcome of the transplant can be a vital tool to offer patients better options for treatment. Since there is a significant immunological contribution to the outcome of the transplant, it is of interest to ask to what extent the immune status of the patient prior to transplant might influence their subsequent recovery. After transplantation, the reconstitution of the T cell compartment in the patient relies on both expansion of existing T cells and the production of new ones via the thymus; in older patients this latter process is compromised by age‐dependent thymic involution. Improvements in thymus function leading to improvement in immune reconstitution after an HSCT may provide significant benefits, potentially reducing mortality from both infections and GvHD. In one study described in this thesis, an improvement in T cell reconstitution, in particular of the CD4 compartment, could be demonstrated after the administration of an LHRH agonist before transplantation from an allogeneic donor. Such an effect could not be demonstrated in an autologous setting. This may reflect a differential requirement for thymus function in the two transplant settings. In additional studies, various immune parameters including T cell subsets and cytokine profiles from the patient, that could affect the transplant outcome were analysed. The findings indicate that high levels of regulatory T cells (Tregs) as well as high levels of regulatory cytokines in patients pretransplant are factors that predict relapse after transplantation. It is likely that these act by suppressing anti‐tumour responses in the patient. These findings may provide a useful tool to stratify the patients into high and low risk categories prior to transplantation

Local Site Effects in Archaeoseismology: Examples from the Mycenaean Citadels of Tiryns and Midea (Argive Basin, Peloponnese, Greece)

The archaeological community has gained knowledge on how to document and diagnose damage by earthquake shaking to ancient man-made structures and how to estimate the intensity of past earthquakes, but has paid little attention to local site effects and its implications for the dynamic response of those structures. Qualitative studies of damage by earthquakes to ancient constructions surpass the amount of research on local site effects in the archaeoseismological literature. Yet, archaeoseismic observations are often based on a limited part of the mesoseismal area, on loosely constrained dated events, and sometimes on ambiguous evidence of earthquake damage. This mix of factors may lead to imprecise estimates of the size of past earthquakes and/or unrealistic earthquake environmental impacts if local site effects are ignored or over/undervalued. Hence, it is important not to rely solely on intensities based on archaeologically documented coseismic damage without a quantitative estimate of local site effects. The present multidisciplinary study focuses on the Mycenaean citadels of Tiryns and Midea located in the Argive Basin (Peloponnese, Greece). The study is a key contribution to archaeoseismology because it provides a quantitative and deterministic method for estimating ancient local site effects and seismic hazard at an archaeological site. The proposed method permits the calculation of site-specific ground-motions, which are transformable into intensity values. The method requires input from archaeological, geoarchaeological, geophysical, geological, geotechnical, and historical studies. The over-or-underestimation of local site effects is minimized by removing accrued soils younger than the ancient walking horizon of interest. The method is applicable to archaeological sites worldwide with clear or unclear evidence of ancient earthquake damage, is scalable to any area size, and can help to decide on the location of new excavations targeting earthquake damage. The estimation of local site effects is carried out by computing synthetic seismograms for a reference rock-site located at each citadel, which are then used to accelerate regolith models for calculating surface amplifications factors and related ground-motions. Earthquake source parameters of the hypothetical earthquakes are constrained from a seismotectonic model of the area. This study shows how to estimate ancient local site effects to test the Mycenaean earthquake hypothesis, which is based solely on archaeological and geomorphological field observations. The hypothesis suggests repeated earthquake damage to the Cyclopean fortification walls and enclosed buildings of Tiryns, Midea, and Mycenae during the end of the Late Bronze Age (LBA). The hypothesis has lacked evidence of written records of ancient earthquakes and of a town-wide devastation pattern; has left unexplained the strength and location of the potential causative earthquake(s); and has ignored the impact of local site effects. The results of the present study reveal new findings: the Tiryns and Midea citadels settled on weathered hard limestone while the outer constructions settled on cohesive-or-granular soils with variable shear strength and seismic site class categories corresponding to a lower and higher seismic hazard, respectively. Data from two field campaigns during the project coupled with available upfront information from the geophysical, geological, and geotechnical literature and developed subsurface models show that the LBA ground conditions outside the fortification walls had a higher hazard than inside the walls, but archaeological findings do not reflect this. Active seismic sources at a distance greater than 40 km play a minor role. Local seismic sources in the Argolis are however critical, but are not confirmed seismically active. These findings weaken the plausibility of the Mycenaean earthquake hypothesis for Tiryns and Midea

Análisis funcional de efectores candidatos de Podosphaera xanthii

Los oídios son patógenos biotrofos obligados que requieren células vivas para su desarrollo, por lo que deben eludir o inhibir las respuestas de defensa de la planta mediante la secreción de efectores para completar su ciclo de vida. El haustorio, estructura del hongo especializada en la toma de nutrientes, es también la vía de intercambio de factores con las células huésped. Hasta la fecha, son muy numerosos los efectores identificados en diversos hongos fitopatógenos, sin embargo, los efectores de los oídios están poco caracterizados todavía. En este trabajo hemos desarrollado un método para la identificación y el análisis de efectores candidatos de Podosphaera xanthii (ECP), el principal agente causal del oídio de las cucurbitáceas, mediante silenciamiento génico inducido por hospedador (HIGS) y la sobrexpresión de estos efectores en cotiledones de melón, utilizando para ello Agrobacterium tumefaciens. El silenciamiento de algunos de los ECP analizados provocó la acumulación en las células de la planta de compuestos relacionados con las respuestas de defensa como peróxido de hidrógeno (H2O2) y calosa, lo que sugiere un importante papel en el establecimiento de la infección. En concreto, ECPEc2 parece interferir específicamente con la formación de la papila, primera barrera de defensa de la planta que impide o ralentiza la penetración de la célula vegetal. En el caso de ECP5191, su silenciamiento se traduce un aumento del número de células que acumulaban H2O2 y calosa, así como una disminución en el número de puntos de penetración del hongo, observándose todo lo contrario cuando se sobrexpresa dicho efector. Además, la fusión traduccional CSEP5191-GFP ha permitido localizar este efector en los puntos de penetración y vesículas del haustorio del hongo.Este trabajo ha sido financiado por ayudas del Plan Nacional de I+D+I del anterior Ministerio de Ciencia e Innovación (AGL2010-21848-CO2-01), cofinanciado con fondos FEDER (UE)y una ayuda del Plan Propio de Investigación de la Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Reduced thymic output in elite athletes

Athletes undergoing intensive training schedules have chronic exposure to stress-induced hormones such as cortisol that can depress immune function. We compared the circulating levels of T cell receptor excision circles (TREC), a marker of recent thymic emigrants, as well as the levels of naïve and memory subsets in a group of elite endurance athletes and in controls. The athletes showed a reduction in absolute numbers of naïve T cells, particularly in CD4 T cells. In contrast, memory cells were increased. TREC levels in the athletes were significantly reduced compared to age-matched controls. Such changes resemble premature ageing of the T cell component of the immune system. Since thymic production of T cells naturally decline with age, these results raise the concern that prolonging high intensity exercise into the 4th decade of life may have deleterious consequences for athletes' health. © 2014 Elsevier Inc

Significados funcionales de la fotografía de guerra: las víctimas de Chiapas

Las fotografías que muestran a las víctimas de la guerra, tanto a los combatientes heridos y fallecidos como al pueblo que habita el área de conflicto, guardan diversos significados funcionales. Desde la denuncia social a la intimidación psicológica, las escenas de guerra que se publican en los diarios mundiales ofrecen diferentes lecturas para el espectador común, al que se le muestran a través de un lenguaje espectacular. Analizamos las funciones que residen en algunas imágenes de prensa sobre el conflicto de Chiapas

An empirical and modelling approach to the evaluation of cruise ships' influence on air quality: The case of La Paz, Mexico

Maritime activity has diverse environmental consequences impacts in port areas, especially for air quality, and the post-COVID-19 cruise tourism market's potential to recover and grow is causing new environmental concerns in expanding port cities. This research proposes an empirical and modelling approach for the evaluation of cruise ships' influence on air quality concerning NO2 and SO2 in the city of La Paz (Mexico) using indirect measurements. EPA emission factors and the AERMOD modelling system coupled to WRF were used to model dispersions, while street-level mobile monitoring data of air quality from two days of 2018 were used and processed using a radial base function interpolator. The local differential Moran's Index was estimated at the intersection level using both datasets and a co-location clustering analysis was performed to address spatial constancy and to identify the pollution levels. The modelled results showed that cruise ships' impact on air quality had maximum values of 13.66 µg/m3 for NO2 and 15.71 µg/m3 for SO2, while background concentrations of 8.80 for NOx and 0.05 for SOx (µg/m3) were found by analysing the LISA index values for intersections not influenced by port pollution. This paper brings insights to the use of hybrid methodologies as an approach to studying the influence of multiple-source pollutants on air quality in contexts totally devoid of environmental data.Peer ReviewedPostprint (published version

Neurotoxicity induced by microcystins and cylindrospermopsin: A review

Microcystins (MCs) and cylindrospermopsin (CYN) are among the most frequent toxins produced by cyanobacteria. These toxic secondary metabolites are classified as hepatotoxins and cytotoxin, respectively. Furthermore, both may present the ability to induce damage to the nervous system. In this sense, there are many studies manifesting the potential of MCs to cause neurotoxicity both in vitro and in vivo, due to their probable capacity to cross the blood-brain-barrier through organic anion transporting polypeptides. Moreover, the presence of MCs has been detected in brain of several experimental models. Among the neurological effects, histopathological brain changes, deregulation of biochemical parameters in brain (production of oxidative stress and inhibition of protein phosphatases) and behavioral alterations have been described. It is noteworthy that minority variants such as MC-LF and -LW have demonstrated to exert higher neurotoxic effects compared to the most studied congener, MC-LR. By contrast, the available studies concerning CYN-neurotoxic effects are very scarce, mostly showing inflammation and apoptosis in neural murine cell lines, oxidative stress, and alteration of the acetylcholinesterase activity in vivo. However, more studies are required in order to clarify the neurotoxic potential of both toxins, as well as their possible contribution to neurodegenerative diseases.Ministerio de Economía y Competitividad (AGL2015-64558-R, MINECO/FEDER, UE

Neurotoxic assessment of Microcystin-LR, cylindrospermopsin andtheir combination on the human neuroblastoma SH-SY5Y cell line

Microcystin-LR (MC-LR) and Cylindrospermopsin (CYN) are produced by cyanobacteria. Although being considered as a hepatotoxin and a cytotoxin, respectively, different studies have revealed neurotoxic properties for both of them. The aim of the present work was to study their cytotoxic effects, alone and in combination, in the SH-SY5Y cell line. In addition, toxicity mechanisms such as oxidative stress and acetylcholinesterase (AChE) activity, and morphological studies were carried out. Results showed a cytotoxic response of the cells after their exposure to 0–100 μg/mL of MC-LR or 0–10 μg/mL CYN in both differentiated and undifferentiated cells. Thus, CYN resulted to be more toxic than MC-LR. Respect to their combination, a higher cytotoxic effect than the toxins alone in the case of undifferentiated cells, and almost a similar response to the presented by MC-LR in differentiated cells were observed. However, after analyzing this data with the isobolograms method, an antagonistic effect was mainly obtained. The oxidative stress study only showed an affectation of glutathione levels at the highest concentrations assayed of MC-LR and the combination in the undifferentiated cells. A significant increase in the AChE activity was observed after exposure to MC-LR in undifferentiated cells, and after exposure to the combination of both cyanotoxins on differentiated cells. However, CYN decreased the AChE activity only on differentiated cultures. Finally, the morphological study revealed different signs of cellular affectation, with apoptotic processes at all the concentrations assayed. Therefore, both cyanotoxins isolated and in combination, have demonstrated to cause neurotoxic effects in the SH-SY5Y cell line.Ministerio de Economía y Com-petitividad of Spain (AGL2015-64558-R, MINECO/FEDER, UE)Junta de Andalucia for the contact of María Gracia Hinojosa (USE-16667

Toxic Effects of the Cylindrospermopsin and Chlorpyrifos Combination on the Differentiated SH-SY5Y Human Neuroblastoma Cell Line

Due to climate change and anthropogenic activities, the levels of pollution of aquatic and terrestrial environments have increased in the last decades. In this sense, the rise of cyanobacterial blooms, which release secondary metabolites with toxic properties, and the global use of pesticides for agricultural purposes have a negative impact on ecosystems. Thus, it would be interesting to study the concomitance of both types of toxicants in the same sample, since it is possible that they appear together. The aim of the present work was to state the effects of the interaction between the cyanotoxin cylindrospermopsin and the pesticide chlorpyrifos in differentiated SH-SY5Y neuronal cells to assess how they could affect the nervous system. To this end, cytotoxicity, morphological, and acetylcholinesterase activity studies were performed during 24 and 48 h. The results revealed a concentration-dependent decrease in viability and interaction between both toxicants, together with clear signs of apoptosis and necrosis induction. In this sense, different stages on the differentiation process would lead to differences in the toxicity exerted by the compounds both isolated as in combination, which it is not observed in non-differentiated cells. Additionally, the acetylcholinesterase activity appeared not to be affected, which is a clear difference compared to non-differentiated cells. These results show the importance of studying not only the toxicants themselves, but also in combination, to assess their possible effects in a more realistic scenario.Ministerio de Ciencia e Innovación PID 2019-104890RB-I0

Cytotoxicity and Effects on the Synapsis Induced by Pure Cylindrospermopsin in an E17 Embryonic Murine Primary Neuronal Culture in a Concentration-and Time-Dependent Manner

Cylindrospermopsin (CYN) is a cyanotoxin whose incidence has been increasing in the last decades. Due to its capacity to exert damage at different levels of the organism, it is considered a cytotoxin. Although the main target organ is the liver, recent studies indicate that CYN has potential toxic effects on the nervous system, both in vitro and in vivo. Thus, the aim of the present work was to study the effects of this cyanotoxin on neuronal viability and synaptic integrity in murine primary cultures of neurons exposed to environmentally relevant concentrations (0–1 µg/mL CYN) for 12, 24, and 48 h. The results demonstrate a concentration-and time-dependent decrease in cell viability; no cytotoxicity was detected after exposure to the cyanotoxin for 12 h, while all of the concentrations assayed decreased this parameter after 48 h. Furthermore, CYN was also demonstrated to exert damage at the synaptic level in a murine primary neuronal culture in a concentration-and timedependent manner. These data highlight the importance of studying the neurotoxic properties of this cyanotoxin in different experimental models.Ministerio de Economía y Competitividad AGL2015-64558-RMinisterio de Ciencia e Innovación PID2019-104890RB-I00, 10.13039/50110001103