Autologous hematopoietic SCT (AHSCT) has been investigated in the past as a therapeutic alternative for multiple sclerosis (MS). Despite advances in clinical management, knowledge about mechanisms ...involved with clinical remission post transplantation is still limited. Abnormal microRNA and gene expression patterns were described in MS and have been suggested as disease biomarkers and potential therapeutic targets. Here we assessed T- and B-cell reconstitution, microRNAs and immunoregulatory gene expression after AHSCT. Early immune reconstitution was mainly driven by peripheral homeostatic proliferation. AHSCT increased CD4(+)CD25(hi)FoxP3(+) regulatory T-cell counts and expression of CTLA-4 and GITR (glucocorticoid-induced TNFR) on CD4(+)CD25(hi) T cells. We found transient increase in exhausted PD-1(+) T cells and of suppressive CD8(+)CD28(-)CD57(+) T cells. At baseline, CD4(+) and CD8(+) T cells from MS patients presented upregulated miR-16, miR-155 and miR-142-3p and downregulated FOXP3, FOXO1, PDCD1 and IRF2BP2. After transplantation, the expression of FOXP3, FOXO1, PDCD1 and IRF2BP2 increased, reaching control levels at 2 years. Expression of miR-16, miR-155 and miR-142-3p decreased towards normal levels at 6 months post therapy, remaining downregulated until the end of follow-up. These data strongly suggest that AHSCT normalizes microRNA and gene expression, thereby improving the immunoregulatory network. These mechanisms may be important for disease control in the early periods after AHSCT.
Since the 1990s, a large number of studies around the world have reported the presence of perchlorate in different types of environmental matrices. In view of their inherent characteristics, such as ...high solubility, mobility, persistence, and low affinity for the surface of soil, perchlorates are mobilized through the water-soil system and accumulate in edible plant species of high human consumption. However, the ingestion of food products containing perchlorate represents a potential health risk to people due to their adverse effects on thyroid, hormone, and neuronal development, mainly in infants and fetuses. At present, research has been centered on determining sources, fates, and remediation methods and not on its real extension in vegetables under farming conditions. This review presents a comprehensive overview and update of the frequent detection of perchlorate in fruits and vegetables produced and marketed around the world. Additionally, the impact of fertilizer on the potential addition of perchlorate to soil and its mobility in the water-soil-plant system is discussed. This review is organized into the following sections: sources of perchlorate, mobility in the water-soil system, presence in fruits and vegetables in different countries, international regulations, and toxicological studies. Finally, recommendations for future studies concerning perchlorate in fruits and vegetables are presented.
Progress in understanding tumor stromal biology has been constrained in part because cancer-associated fibroblasts (CAF) are a heterogeneous population with limited cell-type-specific protein ...markers. Using RNA expression profiling, we identified the membrane protein leucine-rich repeat containing 15 (LRRC15) as highly expressed in multiple solid tumor indications with limited normal tissue expression. LRRC15 was expressed on stromal fibroblasts in many solid tumors (e.g., breast, head and neck, lung, pancreatic) as well as directly on a subset of cancer cells of mesenchymal origin (e.g., sarcoma, melanoma, glioblastoma). LRRC15 expression was induced by TGFβ on activated fibroblasts (αSMA
) and on mesenchymal stem cells. These collective findings suggested LRRC15 as a novel CAF and mesenchymal marker with utility as a therapeutic target for the treatment of cancers with LRRC15-positive stromal desmoplasia or cancers of mesenchymal origin. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) directed against LRRC15, and it demonstrated robust preclinical efficacy against LRRC15 stromal-positive/cancer-negative, and LRRC15 cancer-positive models as a monotherapy, or in combination with standard-of-care therapies. ABBV-085's unique mechanism of action relied upon the cell-permeable properties of MMAE to preferentially kill cancer cells over LRRC15-positive CAF while also increasing immune infiltrate (e.g., F4/80
macrophages) in the tumor microenvironment. In summary, these findings validate LRRC15 as a novel therapeutic target in multiple solid tumor indications and support the ongoing clinical development of the LRRC15-targeted ADC ABBV-085.
These findings identify LRRC15 as a new marker of cancer-associated fibroblasts and cancers of mesenchymal origin and provide preclinical evidence for the efficacy of an antibody-drug conjugate targeting the tumor stroma.
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Triggering is the process by which a linearly stable thermoacoustic system can reach self-sustained oscillations. This nonlinear phenomenon is activated only for sufficiently large amplitudes of ...perturbations to the equilibrium state. In this work, using a nonlinear variational optimisation method coupled with energy bisection, we compute the minimal thresholds for triggering in the Rijke tube. In particular, extending previous works, we take into account the effect of the time delay by optimising not only the perturbations at initial time, but also the velocity at the hot-wire position in the time-delay interval. We found that, for sufficiently large time delays, the nonlinearity linked to the delayed flow velocity bears a strong potential for energy growth, leading to transient amplifications of the energy reaching ${O}(10^{2})$, two orders of magnitude larger than those reported in previous studies. Notably, the gain increases with the time delay, but decreases with the initial energy of the perturbation, thus reaching very high values close to the triggering threshold of the system. The minimal energy for triggering self-sustained oscillations achieves energy values as low as ${O}(10^{-4})$, two orders of magnitude smaller than previous estimates. This indicates that, for thermoacoustic systems characterised by a non-negligible time delay, taking into account the effect of the time-delayed variables, as well as the system nonlinearity, is crucial for correctly evaluating the triggering energy thresholds.
The increment of world's Human population, with the consequent demand for water supply, plus the need for sustainable development and the conservation of water resources, highlights the urgency of ...improving water treatment technologies and management actions.
The aim of the present study was to characterize and evaluate the efficiency of nanofiltration (NF90, NF270) and reverse osmosis (SW30) membranes, in improving the quality of three types of waters: irrigation, municipal supply and wastewater. The efficiency of using this technology was assessed by: (i) the study of water permeability and rejection of some chemical parameters, such as total nitrogen, total phosphorus, chemical oxygen demand (COD), biochemical oxygen demand (BOD5), feacal coliforms, nitrates, chlorides, iron and manganese; and (ii) the evaluation of their ecotoxicological effects, through the use of representative species of different taxonomic and functional groups (Vibrio fischeri, Thamnocephalus platyurus, Daphnia magna, and Pseudokirchneriella subcapitata). Results indicated that all three membranes have high rejection percentages for the majority of the studied parameters (>90%). All parameters concentrations in the permeate stream were below the limit values from Portuguese legislation and European Directives. With respect to the ecotoxicological effects, in general, the use of membranes removed the toxicity detected in the initial samples (which exhibited significant toxicity). The SW30 membrane showed a greater efficiency for toxicity removal, comparing with the nanofiltration membranes. Further, among the nanofiltration membranes used, the NF90 promoted a greater decrease in the toxicity of the samples. Thus, treatment with the membranes NF90 and SW30 allowed obtaining waters with high quality and low ecotoxicological potential, without risks for human populations and endangering the environmental balance.
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•Membrane removal efficiency was evaluated with ecotoxicological endpoints.•Permeate waters achieved good chemical status, complying with legal limits.•Depending on the water end-use, disinfection is recommended after membrane use.•Membrane processing enable the depletion of water toxicity, mainly with RO and NF90.•Wastewater sublethal toxicity was more difficult to treat due to fouling process.
Grass management technologies (grass measuring devices and grassland management decision support tools) have been identified as important tools to improve the performance of pasture-based dairy ...farms. They have the potential to significantly improve the efficiency and sustainability of dairy systems by increasing milk production through enhanced pasture growth and utilization, which would reduce the need for supplementary feeds, along with increased output, therefore increasing farm profitability and environmental sustainability. Despite the several potential benefits of grass management technologies, there is a lack of empirical research around the effects of these technologies on the performance of pasture-based dairy systems. The current study aimed to fill this knowledge gap by using a 2018 nationally representative survey of Irish dairy farms and a propensity score matching approach to determine the effects of adopting grass management technologies on the physical, environmental, and financial performance of Irish pasture-based dairy farms. The findings showed that dairy farms utilizing grass management technologies had, on average, higher farm physical, environmental, and financial performance (in terms of grazed pasture use, total pasture use, length of the grazing season, milk yield, milk solids, greenhouse gas emissions per kilogram of fat- and protein-corrected milk, gross output, and gross margin) compared with dairy farms not utilizing these technologies. However, when controlling for selection bias, we can only attribute a positive causal effect of grass management technology adoption on the use of grazed pasture per cow, grazing season length, milk yield per cow, and milk solids per cow. This might be due to dairy farmers not yet using the technologies to their full potential, 2018 being an unusual year in terms of weather (and therefore not being able to capture the full range of farm performance benefits), or because grass management technologies need to be adopted in association with other technologies and practices to achieve their expected performance outcomes. Future research should include updated farm-level data to capture the weather and learning effects and so be able to determine the impact of grass management technologies on a wider range of performance indicators.
Recently, many authors have investigated the origin and growth of turbulent bands in shear flows, highlighting the role of streaks and their inflectional instability in the process of band generation ...and sustainment. Recalling that streaks are created by an optimal transient growth mechanism, and motivated by the observation of a strong increase of the disturbance kinetic energy corresponding to the creation of turbulent bands, we use linear and nonlinear energy optimisations in a tilted domain to unveil the main mechanisms allowing the creation of a turbulent band in a channel flow. Linear transient growth analysis shows an optimal growth for wavenumbers having an angle of approximately $35^\circ$, close to the peak values of the premultiplied energy spectra of direct numerical simulations. This linear optimal perturbation generates oblique streaks, which, for a sufficiently large initial energy, induce turbulence in the whole domain, due to the lack of spatial localisation. However, spatially localised perturbations obtained by adding nonlinear effects to the optimisation or by artificially confining the linear optimal to a localised region in the transverse direction are characterised by a large-scale flow and lead to the generation of a localised turbulent band. These results suggest that two main elements are needed for inducing turbulent bands in a tilted domain: (i) a linear energy growth mechanism, such as the lift-up, for generating large-amplitude flow structures, which produce inflection points; (ii) spatial localisation, linked to the presence or generation of large-scale vortices. We show that these elements alone generate isolated turbulent bands also in large non-tilted domains.
The purpose of this study was to evaluate the potential impact of the pesticides detected in the Alqueva reservoir (Guadiana Basin, South Iberian Peninsula) on the aquatic organisms belonging to this ...ecosystem. For this purpose, the occurrence and risk assessment of 25 pesticides and of a number of their degradation products were determined in the Alqueva surface waters. The areas (sampling stations) most polluted by pesticides were Sra. Ajuda, Lucefecit and Álamos in the northern and in the middle portions of the reservoir, respectively. The aquatic risk assessment revealed that from the various compounds analysed terbuthylazine, chlorfenvinphos and diazinon presented non-acceptable risk when maximum concentrations were used as the measured environmental concentrations (MEC). The locations that had more samples with risk quotients higher than 1 (high risk) were Sra. Ajuda followed by Lucefécit. The use of risk assessment allowed us to conclude that, despite that the pesticides' concentrations in the water column fulfil the European environmental quality standards, a number of the compounds show a high ecotoxicological risk for the aquatic organisms in the Alqueva ecosystem. The results thereby demonstrate that to have an efficient risk management process, the regulatory authorities of each country must consider an integrative chemical and ecotoxicological approach.
•Increasing amounts of bentazone, terbuthylazine and metolachlor•The north part of the reservoir is the most contaminated•All pesticides concentrations complied with the EQS•Terbuthylazine, chlorfenvinphos and diazinon showed high risk for aquatic species•Water resource management must integrate chemical and ecotoxicological evaluation.
Precision livestock farming (PLF) technologies have been widely promoted as important tools to improve the sustainability of dairy systems due to perceived economic, social, and environmental ...benefits. However, there is still limited information about the level of adoption of PLF technologies (percentage of farms with a PLF technology) and the factors (farm and farmer characteristics) associated with PLF technology adoption in pasture-based dairy systems. The current research aimed to address this knowledge gap by using a representative survey of Irish pasture-based dairy farms from 2018. First, we established the levels of adoption of 9 PLF technologies (individual cow activity sensors, rising plate meters, automatic washers, automatic cluster removers, automatic calf feeders, automatic parlor feeders, automatic drafting gates, milk meters, and a grassland management decision-support tool) and grouped them into 4 PLF technology clusters according to the level of association with each other and the area of dairy farm management in which they are used. The PLF technology clusters were reproductive management technologies, grass management technologies, milking management technologies, and calf management technologies. Additionally, we classified farms into 3 categories of intensity of technology adoption based on the number of PLF technologies they have adopted (nonadoption, low intensity of adoption, and high intensity of adoption). Second, we determined the factors associated with the intensity of technology adoption and with the adoption of the PLF technology clusters. A multinomial logistic regression model and 4 logistic regressions were used to determine the factors associated with intensity of adoption (low and high intensity of adoption compared with nonadoption) and with the adoption of the 4 PLF technology clusters, respectively. Adoption levels varied depending on PLF technology, with the most adopted PLF technologies being those related to the milking process (e.g., automatic parlor feeders and milk meters). The results of the multinomial logistic regression suggest that herd size, proportion of hired labor, agricultural education, and discussion group membership were positively associated with a high intensity of adoption, whereas age of farmer and number of household members were negatively associated with high intensity of adoption. However, when analyzing PLF technology clusters, the magnitude and direction of the influence of the factors in technology adoption varied depending on the PLF technology cluster being investigated. By identifying the PLF technologies in which pasture-based dairy farmers are investing more and by detecting potential drivers and barriers for the adoption of PLF technologies, the current study could allow PLF technology companies, practitioners, and researchers to develop and target strategies that improve future adoption of PLF technologies in pasture-based dairy settings.
•A reduced reaction mechanism is developed to predict pre-ignition in modern gasoline engines.•This so-called “GasLube” mechanism is validated for a wide range of operating conditions.•A detailed ...study of the auto-ignition process of gasoline/oil mixtures is performed.•A single pure species, n-Hexadecane, can serve as surrogate species for lubricant oil.•The “GasLube” mechanism accurately predicts the reduction of gasoline ignition delay due to lubricant oil.
Recent research highlights the influence of the presence of lubricant oil droplets on the combustion process in Direct Injection Spark Ignition (DISI) engines. Lubricant oil is considered to be the main responsible agent for the onset of pre-ignition phenomena, which can escalate highly undesired super-knock events. Moreover, lubricant oil plays a primary role in the generation of very fine soot particle emissions. In the present work, a reduced reaction mechanism is developed for modeling the combustion of gasoline-oil mixtures, allowing one to simulate the variation in ignitability of gasoline-like fuels induced by the presence of lubricant oil. In this study, a single hydrocarbon species, namely n-Hexadecane (n-C16H34), is shown to reproduce lubricant oil chemical and physical characteristics. Great effort has been performed to identify the most significant reaction pathways to reduce the complexity of the chemistry mechanism and the number of variables, while maintaining the important features of detailed mechanisms, for the highest computational efficiency. The proposed reduced mechanism has been validated for a wide range of operating conditions. It is employed for 3D simulations of experimental measurements in which iso-Octane was blended with different percentages of lubricant oil and its surrogates. Operating conditions representative of those of a typical turbocharged DISI engine are considered. The very good agreement obtained in the comparison with the experimental data confirms the effectiveness of the proposed “GasLube” mechanism in reproducing lubricant oil’s influence on ignition propensity of gasoline-like fuels. Furthermore, the 3D numerical simulations allowed a detailed analysis of the ignition phenomenon, providing more insight into the basic processes of lubricant oil induced pre-ignition events in DISI gasoline engines.
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