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A complex link exists between HIV-1 and autophagy, and discordant results have been reported in different in vitro models regarding the way HIV and autophagy modulate each other. Despite this, there is very limited knowledge about the interplay between HIV and autophagy in vivo in lymphoid tissue, due in part by the lack of cell models that recapitulate the in vivo setting. Here, we evaluate the interrelationship between HIV and autophagy using human ex vivo lymphoid tissue cultures as an HIV infection model. Our results showed that human lymphoid aggregated cultures (HLACs) from tonsillar tissue displayed fully functional autophagic activity. In this system, HIV infection resulted in an increase in autophagy. Notably, we observed that both, autophagy-enhancing (rapamycin) or blocking drugs (3-methyladenine, chloroquine and bafilomycin), were able to decrease HIV-DNA levels and HIV replication. Therefore, efficient HIV-1 replication requires a fine-tuned level of autophagy, so modifications of this balance will have a negative impact on its replication. Therefore, targeting the autophagic pathway could be a new therapeutic approach to be explored to treat HIV-1 infection. Ex vivo cultures of human lymphoid tissue are a suitable model to obtain further insights into HIV and its intricate relationship with autophagy. [ABSTRACT FROM AUTHOR]

Introduction: Birdshot chorioretinopathy (BCR) is a bilateral and recurrent posterior uveitis with an uncertain natural history and visual prognosis. Currently, there is no consensus on the best treatment option and its total duration. Clinical Cases: We present a series of three clinical cases of patients with BCR diagnosed in different stages of the disease, which demonstrates the clinical spectrum of this pathology and their treatment with different immunomodulatory drugs. Conclusion: As shown in our series of cases, the early use of immunomodulatory drugs is recommended with a close monitoring and individualized treatment to achieve the best anatomical and functional results. [ABSTRACT FROM AUTHOR]

• Taxonomy of scheduling problem features for eventual classification. • General features related to scheduling problem domain have been mapped. • Support for selecting the best solution approach for scheduling problems. • Multi-label classification for selecting the most suitable scheduling model. • Classification approach consisting of binary optimization and support vector machine. Process scheduling problems have been largely studied in the literature, and a large number of methods and approaches are available and capable of solving them. However, the selection of the best method fitting to a real practical problem at hand, and the limited number of experts in optimization and operations research within industrial environments seriously limit the practical application of the theoretical methods. This work proposes a supporting framework based on a multi-label classification strategy, for selecting those mathematical scheduling models that are more suitable to solve a certain scheduling problem definition. We have decomposed the problem description into binary classification problems, in order to analyze the convenience of each scheduling model for a certain definition. As a result, a systematic approach to scheduling model selection is achieved, facilitating the bridge between theoretical developments and industrial practice. [ABSTRACT FROM AUTHOR]

Waste solvents generated by the process industry are frequently incinerated as a part of their treatment, thus allowing for a partial recovery of their combustion heat. While large chemical sites often have in-house waste incineration facilities, smaller enterprises have to outsource the treatment of their residuals, leading to significant shipments of hazardous substances. In this sense, there is a significant optimization potential to reduce both shipments and the consumption of auxiliary fuels, thus leading to an overall reduction of the primary energy required to produce and deliver chemical products and intermediates. However, inconsistent data systems and incomplete information represent main barriers for investigating the potential of such environmental benefits. As information about waste properties does not need to be reported, it is consequently not possible to rigorously estimate the energetic potential of the hazardous waste produced in a specific area, which would be a crucial first step in the optimization of both design and management of a supply chain network of industrial waste. This work proposes a novel approach for the estimation of hazardous waste properties, combining existing information stemming from industrial and institutional partners. Such framework creates a new waste classification system based on water and pollutant content that links inconsistent data sources with different degrees of detail, and allows for estimating average properties, including the energy content, of different types of primary produced hazardous liquid waste. The validity of the developed methodology for a broad application range is tested with a case study about Switzerland, which, because of its sparse chemical and pharmaceutical industry and an extreme variety in terms of generated waste residues, represents one of the most challenging cases. Such case study investigates the evolution of Swiss industrial waste from 2010 to 2014, determines average properties for 12 different waste classes and their total energy recovery potential. [ABSTRACT FROM AUTHOR]

The introduced work aims to systematic optimize detailed short-term scheduling for industrial waste incineration to support daily decision-making processes. The overall objective is to reduce the utilization of auxiliary fuel used to overcome waste related energy in the incineration process. The reduction is achieved through adequate mixing and scheduling of waste streams with different energy content and improved logistic strategies. With it, regulatory and technical constraints are fulfilled and holdups in production processes derived from bottlenecks in the waste treatment are avoided. The considered system consists of storage tanks, a piping network, tank wagons for waste transportation, unloading pumps and incineration lances. The optimization model is formulated as a mixed-integer linear programming (MILP) problem with a discrete time representation based on a single uniform grid. It consists of two blocks: i) waste transfer and mixing, and ii) the incineration process itself including energy calculations and constraints. The industrial case study of this work shows a saving potential of auxiliary fuel of up to 90%, leading to a reduction of CO 2 emissions of up to 13%. Hence, the systematic scheduling of industrial waste incineration leads to an important reduction of auxiliary fuel consumption, resulting in economic and environmental benefits. [ABSTRACT FROM AUTHOR]

Work in our laboratory has been funded in part by grants from Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS) PI12/02408, PI15/01053 cofinanced by FEDER and by Grifols." now reads: "Cecilia Cabrera is a researcher at the Fundació Institut de Recerca en Ciències de la Salut Germans Trias i Pujol supported by the Health Department of the Catalan Government/Generalitat de Catalunya and ISCIII. "Cecilia Cabrera is a researcher at the Fundació Institut de Recerca en Ciències de la Salut Germans Trias i Pujol supported by the Health Department of the Catalan Government/Generalitat de Catalunya and ISCIII. [Extracted from the article]

This works aims to demonstrate that hierarchical integration of planning and scheduling of industrial waste incineration improves the energy efficiency of the process, compared to available scheduling approaches. Through the integration with planning models, scheduling models can rely on more far-sighted information; therefore, energy deficits and excesses can be better compensated in the long run. Subsequently, the auxiliary fuel consumption of the incineration process can be further reduced, which leads to an overall increase of the energy efficiency. Planning and scheduling models are formulated as mixed-integer linear programming (MILP) problems with discrete time representation, based on single, uniform grids. The considered waste incineration system consists of storage tanks, a complex piping network, tank wagons for waste transport, unloading stations, and firing lances of incineration units. The conducted industrial case studies reveal substantial improvement potential of daily empirically based waste incineration routines and show that systematic integration of planning and scheduling outperforms consecutive stand-alone scheduling of industrial waste incineration both economically and environmentally by reducing auxiliary fuel usage and CO2 emissions per ton of waste treated, by 16% and 1%, respectively. [ABSTRACT FROM AUTHOR]

Carotenoids refer to a wide class of lipophilic pigments synthesized by plants, exert photoprotective and antioxidant properties that are lost upon carotenoid degradation. Their inclusion into hydrophilic host-molecules could improve their stability. Cyclodextrins, provide a hydrophobic cavity in the core of their structure while the outer configuration is suitable with aqueous environments. Carotenoids can accommodate into the hydrophobic core of cyclodextrins and therefore, they are protected from exogenous stress. Literature reported that carotenoid structure could modulate stability of the complexes, however no conclusions can be drawn as the studies performed so far were not completely analogous. We describe the synthesis of several carotenoids/β-CDs inclusion complexes and provide experimental evidences that β-CDs inclusion renders these compounds more stability towards the oxidizing agents (2,2′-azobis, 2-methylpropionamidine dihydrochloride and hydrogen peroxide). Esterified carotenoids were also used in this work to screen the influence of this particular structural configuration of xanthophylls against oxidation. [ABSTRACT FROM AUTHOR]

Optimizing the scheduling of liquid drug product manufacturing is paramount for pharmaceutical companies in their increasingly competitive environment and requires the modelling of industry-specific constraints. Such constraints include: (i) changing sequence-dependent setup times; (ii) maintaining a sterile production environment (e.g., through sterile holding times); (iii) periods with limited or no plant activity (e.g., no workforce during weekends); and (iv) demand timing (i.e., delivery deadline and release date constraints). In this work, an immediate precedence model is formulated to optimize the scheduling of liquid drug product manufacturing, considering the industry-specific constraints. The primary objective is to minimize the production makespan. Four case studies comprising up to 38 batches from a real multi-product facility illustrate the performance of the rigorous optimization approach. The makespan could be reduced by up to 7.9% compared to expert schedules. [ABSTRACT FROM AUTHOR]

Photoprotection by dietary carotenoids has been linked to their antioxidant properties, in particular quenching of singlet molecular oxygen and scavenging of peroxyl radicals. Here, we compared the DNA-protection and antioxidant effects of selected carotenoids exclusively synthesized in red pepper (capsanthin and capsorubin) to the xanthophyll lutein. Preincubation of human dermal fibroblasts (hdf) with capsanthin and capsorubin significantly counteracted UVB induced cytotoxicity at doses between 0 and 300 mJ cm−2. Pretreatment of hdf with capsanthin, capsorubin or lutein (1 μM) significantly decreased the formation of DNA strand breaks following irradiation with UVB light. All carotenoids studied decreased caspase-3 cleavage (a marker for UVB-induced apoptosis), however, caspase dependent PARP-1 cleavage was not affected suggesting that the remaining caspase activity is sufficient to promote UVB-induced apoptosis. It is conceivable that carotenoids selectively interfere with cellular responses activated by UVB-mediated damage. Our findings indicate that capsanthin and capsorubin exhibit similar properties to lutein and could be used as a dietary supplement to improve natural photoprotection. [ABSTRACT FROM AUTHOR]

The integration of planning and scheduling decisions in rigorous mathematical models usually results in large scale problems. In order to tackle the problem complexity, decomposition techniques based on duality and information flows between a master and a set of subproblems are widely applied. In this sense, ontologies improve information sharing and communication in enterprises and can even represent holistic mathematical models facilitating the use of analytic tools and providing higher flexibility for model building. In this work, we exploit this ontologies’ capability to address the optimal integration of planning and scheduling using a Lagrangian decomposition approach. Scheduling/planning sub-problems are created for each facility/supply chain entity and their dual solution information is shared by means of the ontological framework. Two case studies based on a STN representation of supply chain planning and scheduling models are presented to emphasize the advantages and limitations of the proposed approach. [ABSTRACT FROM AUTHOR]

Highlights: [•] Mathematical ontology for representing engineering systems. [•] Integration of mathematical models using semantic technology. [•] A case study based on supply chain and scheduling levels. [•] Improved modeling understanding, knowledge sharing and data mining. [ABSTRACT FROM AUTHOR]

Highlights: [•] Waste management treatment problem from rigorous multi-objective perspective. [•] We optimize heat integration of Pareto optimal schedules. [•] A case study based on industrial practice is presented. [•] Improved solution quality and efficiency compared non rigorous approaches. [ABSTRACT FROM AUTHOR]

Abstract: During batch process scheduling, products' batch size, processing conditions as well as operating times are usually established offline and considered out of the scope of the decision making stage. In practice, process dynamics may vary from the ones forecasted, in such a manner that the predicted optimal conditions will not be the best in practice. As a result of this mismatch, the plant usually operates under sub-optimal conditions, but if the process is flexible, its processing conditions can still be adapted to the actual plant needs in order to improve the overall performance. Given this situation, there is a strong motivation for developing models and optimization tools to fully integrate process dynamics into batch scheduling. In this work, the potential of directly including control variables with time varying values and variable batch sizes in the scheduling of batch plants is explored. The optimization of process dynamics, which is time varying, along with scheduling tasks is accomplished using rigorous mixed-integer dynamic optimization techniques. Through several examples, we show that integrating both decision-making levels can lead to significant economic savings. [Copyright &y& Elsevier]

Abstract: Enterprises comprise several functions, such as production, marketing, sales, human resources, logistics, safety and environment, which interact with each other. As a result, decision-making becomes highly challenging in the alignment of decisions to support the success of business goals. Specifically, environmental management is closely related to several levels in the enterprise structure, since they share a large amount of data and information. Hence, effective integration of environmental issues by means of tools improving information sharing and communication, may play a crucial role for the enhanced enterprise operation from an environmental perspective. In this sense, knowledge management technologies have proved to be highly promising for supporting this integration task. In this work, an ontological framework is developed as the technology for information and knowledge models sharing for the environmental assessment of the enterprise. The ontological model is applied to a case study considering a supply chain network design-planning and a process scheduling problem. The ontology provides an enterprise decision-making supporting tool by combining different information systems, which adapts and recognizes the different elements associated with the enterprise functions, and facilitates assessing the environmental performance of enterprises. [Copyright &y& Elsevier]

Abstract: In the domain of chemical process engineering, there is an increased interest in the integration of the enterprise hierarchical levels for decision-making purposes. At the scheduling level, decisions on the allocation of tasks to resources, sequencing and timing of tasks must be managed. However, such decisions are directly related to other enterprise actions, such as control and planning, but they are difficult to coordinate because they are modeled at different time and space scales, and their goals are not the same. In order to achieve integrated decisions supported by high quality information, there is a need to improve and develop robust computational tools and consistent models. In general, scheduling optimization approaches for decision-making differ depending on problem features, such as physical layout or time representation. Therefore, this work focuses on providing a framework based on a semantic model that captures the diversity in scheduling problem representation. Such semantic model uses the master recipe concept from the ANSI/ISA-88 standard perspective and encapsulates the scheduling decision task features. As a result, by the use of a single representation approach, any scheduling problem can be modeled and solved by its adequate optimization tool. The potential of a general model representation is presented by means of several case studies related to the scheduling function. Such case studies shed light to the model capabilities to represent different kinds and particular scheduling problems, achieving integration at the different decision support levels. [Copyright &y& Elsevier]

Abstract: Carotenoid pigments are a group of bioactive compounds that are of interest to the food scientists, nutritionists and food industries due to their positive impact on human health and their economic benefits. Carotenoids are responsible for the attractive colour of many plant food (mainly fruit and vegetables), which is perhaps the first attribute that consumers assess when determining the quality and appearance of a product, and therefore conditions its acceptability. In addition, carotenoids have diverse biological functions and activities, such as the well known provitamin A activity, antioxidant capacity and enhancement of the immune system. There are an extensive number of factors affecting the efficient incorporation of these phytochemicals from the diet, although in many cases no biological activity will be put in action within the consumer body (animal or human) without a first visual attraction. The term bioaccessibility is used to evaluate the amount of a nutrient that is released from a food during the digestion process. The bioaccessibility of lipophilic compounds, such as carotenoids, in natural foods (mainly fruits and vegetables) is usually fairly low and is constrained by various factors, particularly the degree of food processing and matrix composition. There are evidences that homogenisation and thermal treatment have positive effects on the bioaccessibility of these compounds, whereas the presence of dietary fibre has a negative effect. The presence and co-ingestion of fat in the diet are a key factor, with a minimum quantity needed to facilitate carotenoid absorption, and this seems to be one of the advantages of the Mediterranean diet. Most of the relevant data on the bioaccessibility of carotenoids from natural or processed foods has been obtained in postprandial absorption studies and supplementation studies. This approach, although highly valuable, is insufficient for a detailed analysis of the food matrix composition effects, and also it does not take into consideration other factors that may be involved in carotenoid absorption in each stage of the bioaccessibility process (digestibility and absorption). In vitro experimental processes that reproduce the physiological conditions and events that take place in the human gastrointestinal tract during digestion have been developed and fine-tuned in recent years. These digestion models become an excellent analytical resource to establish both the significance and scope of diverse factors in the efficiency of digestibility of carotenoids allowing a detailed analysis of the influence of the food matrix composition on the digestive process. [Copyright &y& Elsevier]

Abstract: The complexity of decision-making in process industries and the need of highly competitive organizations require new supporting tools to coordinate and optimize the information flow among decision levels. This work presents a framework for integrating the scheduling and control decision levels by means of an ontology, which allows and coordinates the information exchange among the different modeling paradigms/conventions currently used for the enterprise-wide optimization (EWO). The scheduling of two multiproduct batch plants with increasing complexity is presented for illustrating the proposed working procedure. [Copyright &y& Elsevier]

Batch scheduling and control decision levels are usually optimized separately, even though integrated decisions would potentially increase the overall performance of the plant. This work aims at including in the scheduling problem the operating conditions related to the control function, which are traditionally optimized and fixed beforehand, to shed light to the benefits that may be obtained when using variable recipes in contrast to fixed nominal recipes. A multiproduct and a multipurpose plant illustrate the proposed approach. In both cases, the potential benefits are confirmed resulting in clear advantages regarding overall economic benefit, when the variable recipes are introduced. Thus, the presented approach gives rise to new tradeoffs, since it allows new improvement opportunities associated with quality, safety, or changing operating policies, which are usually considered separately. [ABSTRACT FROM AUTHOR]

Abstract: The term “bioaccessibility” is a key concept to ascertain nutritional efficiency of food and food formula developed with the aim of improving human health. In this review, working definitions of bioavailability, bioaccessibility, and bioactivity are examined, taking into account the complete sequence of events that take place during the digestive transformation of food into material that can be assimilated by the body, the absorption/assimilation into the cells of the intestinal epithelium, the presystemic metabolism, and, lastly, the development of biologic actions. Comparison among in vivo and in vitro techniques to assess bioaccessibility is accomplished, considering the strengths and limitations of each experimental approach, with a complete description of in vitro procedures applied to determine bioaccessibility of carotenoids. Although a great development has been achieved on the in vitro approaches, these are especially intended for initial screening and should be complemented with in vivo studies, which will remain as the criterion standard for bioaccessibility of nutrients and bioactive compounds at specific target populations. Application of bioaccessibility assessment in foods claiming a health benefit because of their nutrients or bioactive compounds content is described. Measurement of bioaccessibility provides valuable information to select the appropriate dosage and source of food matrices to ensure nutritional efficacy of food products. In addition, in vitro bioactivity measurements to support health benefits of bioactive compounds should be accomplished with estimation of their bioaccessibility, to adequately give nutritional significance to health claims. [Copyright &y& Elsevier]

Abstract: The blanketing process consists of creating and maintaining an inert atmosphere inside a closed equipment to prevent the contained product from mixing with oxygen. This technique is widely used in chemical, pharmaceutical and food industries operations, to avoid the ignition, degradation or evaporation losses of their products. This work deals with the design process of an optimal blanketing system in terms of cost, safety and environmental issues, for a multiple-tank storage facility. With this objective, the feasibility of installing a manifold in the system as an alternative to the traditional approach of an individual component in each tank has been technically studied by means of statistical analysis and fluid flow simulation. Moreover, economical, environmental and safety analyses have been performed. The reported results shed light to a more economical solution, which entails a decrease in atmospheric emissions and offers an even higher reliability than traditional systems. [Copyright &y& Elsevier]

Abstract: Here we describe the profiles of volatile compounds from the thermal degradation of carotenoids present in oleoresins of marigold, tomato and paprika. The profiles obtained by SPME-GC were complex, with identical compounds, such as toluene and m-xylene, being detected in all three oleoresins. Intramolecular cyclisation is proposed as the main reaction mechanism in the formation of the volatile compounds detected; this process is activated by the thermal impact generated during the processing and is followed by a reaction of elimination in the chain or a heterolytic fragmentation reaction. The presence of other compounds, such as various methyl benzaldehydes or isophorone (1,1,3-trimethyl-3-cyclohexene-5-one), also indicates the concurrence of carotenoid oxidation reactions that affect either the central polyenoic chain or the end-groups (β or ε rings). Ethanone,1-(methylphenyl), (4prime-methylacetophenone) not previously reported as a compound resulting from the thermal degradation of carotenoids, was also characterised and the same mechanism is proposed for its formation. [Copyright &y& Elsevier]

Abstract: Efficiency of the micellar incorporation of carotenoids was determined through the application of an in vitro digestion procedure, and in function of the composition of the lipophilic environment, where digestion was carried out. Analysed factors affecting micellization level were presence of oil in the digestion mixture, class of pigment, and cholesterol. The addition of oil to the digestion mixture caused changes of different extent in function of the class of pigment, and significant interactions between the factors presence of oil and class of pigment were detected. Accessibility of lycopene was affected negatively by an increase of the amount of vegetable oil, while lutein ester increased its presence in micelles. Although cholesterol was not a significant factor affecting the micellization efficiency, when cholesterol and oil were added to the digestion process, the amount of micellarized pigment was significantly affected, positively or negatively depending on lipophilic characteristics of the pigment. Therefore, an interaction between the factors cholesterol and presence of oil with different effects on the micellization of pigments was analysed. The physical–chemical differences of carotenoids, that are consequence of their structural features, generated diverse requirements of the lipophilic environment to facilitate their emulsion and subsequent incorporation into micelles. Industrial relevance: Carotenoid pigments are widely used by the food industry as colorants, although nutritional and functional properties make them to be applied for other purposes, as in the enhancement of functional foods. The physico-chemical characteristics of carotenoids make them to be low bioavailable, so that a correct formulation of the food matrix is required in order to achieve an appropriate bioavailability. The development of in vitro digestion methods, which allow the measurement of the potential bioavailability of carotenoids, could be considered as a useful tool to screen those factors and components that modify the bioavailability of these compounds in a given matrix composition so selection of the formulation conditions that gives the higher availability may be performed. The aim of this work was the development and application of an in vitro method to measure the potential bioavailability of carotenoids considering several factors that modulate it. [Copyright &y& Elsevier]

The lung is prone to infections from respiratory viruses such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). A challenge in combating these infections is the difficulty in targeting antiviral activity directly at the lung mucosal tract. Boosting the capability of the respiratory mucosa to trigger a potent immune response at the onset of infection could serve as a potential strategy for managing respiratory infections. This study focused on screening immunomodulators to enhance innate immune response in lung epithelial and immune cell models. Through testing various subfamilies and pathways of pattern recognition receptors (PRRs), the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family was found to selectively activate innate immunity in lung epithelial cells. Activation of NOD1 and dual NOD1/2 by the agonists TriDAP and M-TriDAP, respectively, increased the number of IL-8+ cells by engaging the NF-κB and interferon response pathways. Lung epithelial cells showed a stronger response to NOD1 and dual NOD1/2 agonists compared to control. Interestingly, a less-pronounced response to NOD1 agonists was noted in PBMCs, indicating a tissue-specific effect of NOD1 in lung epithelial cells without inducing widespread systemic activation. The specificity of the NOD agonist pathway was confirmed through gene silencing of NOD1 (siRNA) and selective NOD1 and dual NOD1/2 inhibitors in lung epithelial cells. Ultimately, activation induced by NOD1 and dual NOD1/2 agonists created an antiviral environment that hindered SARS-CoV-2 replication in vitro in lung epithelial cells. [ABSTRACT FROM AUTHOR]

Some HIV-infected c-ART-suppressed individuals show incomplete CD4+ T-cell recovery, abnormal T-cell activation and higher mortality. One potential source of immune activation could be coinfection with cytomegalovirus (CMV). IgG and IgM levels, immune activation, inflammation and T-cell death in c-ART-suppressed individuals with CD4+ T-cell counts >350 cells/μL (immunoconcordant, n = 133) or <350 cells/μL (immunodiscordant, n = 95) were analyzed to evaluate the effect of CMV humoral response on immune recovery. In total, 27 HIV-uninfected individuals were included as controls. In addition, the presence of CMV IgM antibodies was retrospectively analyzed in 58 immunoconcordant individuals and 66 immunodiscordant individuals. Increased CMV IgG levels were observed in individuals with poor immune reconstitution (p = 0.0002). Increased CMV IgG responses were significantly correlated with lower nadir and absolute CD4+ T-cell counts. In contrast, CMV IgG responses were positively correlated with activation (HLA-DR+) and death markers in CD4+ T-cells and activated memory CD8+ T-cells (CD45RA-CD38+). Longitudinal subanalysis revealed an increased frequency of IgM+ samples in individuals with poor CD4+ T-cell recovery, and an association was observed between retrospective IgM positivity and the current level of IgG. The magnitude of the humoral immune response to CMV is associated with nadir CD4+ T-cell counts, inflammation, immune activation and CD4+ T-cell death, thus suggesting that CMV infection may be a relevant driving force in the increased morbidity/mortality observed in HIV+ individuals with poor CD4+ T-cell recovery. [ABSTRACT FROM AUTHOR]

Autophagy restricts infection of CD4 T lymphocytes by HIV-1, but little is known about autophagy in treated HIV-1–infected individuals. We have analyzed the capability of CD4 T cells from aviremic-treated individuals to trigger autophagy and correlated this response with parameters known to be important for immunological recovery. Autophagy was significantly decreased in CD4 T cells from HIV-1–treated individuals compared with uninfected controls, and this defective autophagic response was more pronounced in individuals with poor CD4 T-cell recovery, suggesting a link between impaired autophagy in CD4 T cells and chronic immunological defects that remain in treated HIV infection. [ABSTRACT FROM AUTHOR]

Background: HIV-1 Rev response element (RRE) is a functional region of viral RNA lying immediately downstream to the junction of gp120 and gp41 in the env coding sequence. The RRE is essential for HIV replication and binds with the Rev protein to facilitate the export of viral mRNA from nucleus to cytoplasm. It has been suggested that changes in the predicted secondary structure of primary RRE sequences impact the function of the RREs; however, functional assays have not yet been performed. The aim of this study was to characterize the genetic, structural and functional variation in the RRE primary sequences selected in vivo by Enfuvirtide pressure. Results: Multiple RRE variants were obtained from viruses isolated from patients who failed an Enfuvirtide-containing regimen. Different alterations were observed in the predicted RRE secondary structures, with the abrogation of the primary Rev binding site in one of the variants. In spite of this, most of the RRE variants were able to bind Rev and promote the cytoplasmic export of the viral mRNAs with equivalent efficiency in a cell-based assay. Only RRE45 and RRE40-45 showed an impaired ability to bind Rev in a gel-shift binding assay. Unexpectedly, this impairment was not reflected in functional capacity when RNA export was evaluated using a reporter assay, or during virus replication in lymphoid cells, suggesting that in vivo the RRE would be highly malleable. Conclusions: The Rev-RRE functionality is unaffected in RRE variants selected in patients failing an ENF-containing regimen. Our data show that the current understanding of the Rev-RRE complex structure does not suffice and fails to rationally predict the function of naturally occurring RRE mutants. Therefore, this data should be taken into account in the development of antiviral agents that target the RRE-Rev complex. [ABSTRACT FROM AUTHOR]

Background: In 2015, a specific health-related quality of life questionnaire for sarcopenia, SarQoL®, was developed and validated in French. Since then, SarQoL® has been adapted and validated in different languages. We prepared a translation, cultural adaptation and validation of the psychometric properties of the SarQoL® into Spanish.Methods: A cross-sectional study with 86 participants. The translation and adaptation followed international guidelines with two direct translations, a synthesized version of the direct translations, two reverse translations, consensus by an expert committee of a pre-final version, pre-test by end users and final version. The discriminative power (logistic regression analyses), construct validity (Pearson and Spearman´s correlation), internal consistency (Cronbach´s alpha coefficient), test-retest reliability (intraclass correlation coefficient) and ceiling and floor effects were analyzed.Results: The Spanish version showed good construct validity (high correlation with comparable domains of the SF-36), high internal consistency (Cronbach's alpha coefficient: 0.84) and excellent test-retest reliability (ICC: 0.967, 95%, CI 0.917 - 0.989). However, it had no discriminative power between sarcopenic and non-sarcopenic participants defined with the EWGSOP and FNIH diagnostic criteria of sarcopenia. It did show discriminative power between patients with decreased vs normal muscle strength (54.9 vs. 62.6, p 0.009) and low vs. normal physical performance (57.3 vs. 70.2; p 0.005). No ceiling or floor effect was found.Conclusions: The Spanish version of SarQoL® has similar psychometric properties to those of the original version of the instrument. It did not discriminate between sarcopenic and non-sarcopenic patients diagnosed according to the EWGSOP or FNIH criteria, but it did with those with low muscle strength and low physical performance. [ABSTRACT FROM AUTHOR]

Abstract: Background: Numerous studies have analyzed the effects of raltegravir intensification on HIV-1 viral replication in infected individuals receiving suppressive combined antiretroviral treatment (cART). Nevertheless, there are only two studies on the effect of raltegravir in HTLV-1 infection, and none in HTLV-2. Objective: To study the effect of raltegravir on HTLV-2 infection in HIV-1-co-infected individuals. Study design: This retrospective longitudinal study included four HTLV-2-HIV-1-co-infected individuals who received raltegravir-based cART during 48 weeks and 11 HTLV-2-HIV-1-co-infected individuals under cART without raltegravir during 48 weeks. HTLV-2 proviral load, CD4 and CD8 count and frequency were analyzed. Results: HTLV-2 proviral load significantly increased at week 24 compared to baseline among all the patients who received raltegravir (p =0.003), while no significant increases were found in the control group. No significant variation in either CD8 or CD4 counts was found during the follow up in both groups. Conclusions: Raltegravir induced a transient increment on total HTLV-2 DNA proviral load in HTLV-2/HIV-1-coinfected individuals on suppressive cART after 24 weeks. [Copyright &y& Elsevier]

During the SARS-CoV-2 pandemic, hospital-based liaison geriatric units (LGUs) were created in Spanish hospitals with the aim to improve health care coordination between nursing homes (NHs) and hospitals. Our university hospital created a comprehensive, proactive LGU serving 31 public and private NHs of different sizes and characteristics to offer support to more than 2500 residents. In the first 3 months of 2021, this LGU performed 1252 assessments (81% as outpatients, 12% at the emergency department, and 7% during hospitalization), avoiding an estimated 49 hospital transfers and 29 hospitalizations. Other activities included giving NHs support and advice during COVID-19 outbreaks, comanagement of selected residents with other hospital-based specialists (implementing telemedicine), and implementation of a protocol that allowed using drugs only approved for hospital use in selected NHs. This model of LGU has been shown to be feasible, to improve residents' health care, and avoid hospital referrals. Long-term care needs to be re-imagined, and hospital geriatric departments need to prove that they are able to offer expertise to support NH health care professionals. [ABSTRACT FROM AUTHOR]

Dry eye disease is one of the most frequent pathological events that take place in the course of the graft versus host disease (GVHD), and is the main cause of deterioration in quality of life for patients. Thus, demonstration of dry eye signs in murine models of oGVHD is crucial for the validation of these models for the study of the disease. Given the increasing evidence that tear osmolarity is an important player of dry eye disease, our purpose in this study was to validate the use of a reliable method to assess tear osmolarity in mice: the electrical impedance method. Then, we wanted to test its utility with an oGVHD model. Tear volume assessment was also performed, using the phenol red thread test. We found differences in tear osmolarity in mice that received a transplant with cells from bone marrow and spleen (the GVHD group ) when compared with mice that only received bone marrow cells (the BM group ) at day 7 (362 ± 8 mOsm/l and 345 ± 9 mOsm/l respectively; P < 0.01) and day 21 (348 ± 19 mOsm/l vs. 326 ± 15 mOsm/l; P < 0.05). We found also differences in tear volume at day 14 (2.30 ± 0.61 mm in oGVHD group and 2.89 ± 0.62 mm in BM group ; P = 0.06) and at day 21 (2.10 ± 0.30 mm in oGVHD group and 2.89 ± 0.32 mm in BM group ; P < 0.01). Besides this, we observed reduction in epithelial thickness between the GVHD and BM groups (37.0 ± 6.2 μm and 43.6 ± 3.3 μm respectively; P < 0.05). These data show the usefulness of the electrical impedance method to measure tear osmolarity in mice. We can also conclude that this oGVHD model mimics the tear film alterations found in human dry eye disease, what contributes to give relevance to this model for the study of GVHD. [ABSTRACT FROM AUTHOR]

Objective: Prognostic stratification of patients with cirrhosis is common clinical practice. This study compares the prognostic accuracy (28-day and 90-day transplantfree mortality) of the acute-on-chronic liver failure (ACLF) classification (no ACLF, ACLF grades 1, 2 and 3) with that of acute kidney injury (AKI) classification (no AKI, AKI stages 1, 2 and 3). Design:The study was performed in 510 patients with an acute decompensation of cirrhosis previously included in the European Association for the Study of the Liver- Chronic Liver Failure consortium CANONIC study. ACLF was evaluated at enrolment and 48 h after enrolment, and AKI was evaluated at 48 h according to Acute Kidney Injury Network criteria. Results: 240 patients (47.1%) met the criteria of ACLF at enrolment, while 98 patients (19.2%) developed AKI. The presence of ACLF and AKI was strongly associated with mortality. 28-day transplant-free mortality and 90- day transplant-free mortality of patients with ACLF (32% and 49.8%, respectively) were significantly higher with respect to those of patients without ACLF (6.2% and 16.4%, respectively; both p<0.001). Corresponding values in patients with and without AKI were 46% and 59%, and 12% and 25.6%, respectively (p<0.0001 for both). ACLF classification was more accurate than AKI classification in predicting 90-day mortality (area under the receiving operating characteristic curve=0.72 vs 0.62; p<0.0001) in the whole series of patients. Moreover, assessment of ACLF classification at 48 h had significantly better prognostic accuracy compared with that of both AKI classification and ACLF classification at enrolment. Conclusions: ACLF stratification is more accurate than AKI stratification in the prediction of short-term mortality in patients with acute decompensation of cirrhosis. [ABSTRACT FROM AUTHOR]

Regulation of intracellular ion homeostasis is essential for eukaryotic cell physiology. An example is provided by loss of ATP2C1 function, which leads to skin ulceration, improper keratinocyte adhesion, and cancer formation in Hailey-Hailey patients. The yeast ATP2C1 orthologue PMR1 codes for a Mn2+/Ca2+ transporter that is crucial for cis-Golgi manganese supply. Here, we present evidence that calcium overcomes the lack of Pmr1 through vesicle trafficking-stimulated manganese delivery and requires the endoplasmic reticulum Mn2+ transporter Spf1 and the late endosome/trans-Golgi Nramp metal transporter Smf2. Smf2 co-localizes with the putative Mn2+ transporter Atx2, and ATX2 overexpression counteracts the beneficial impact of calcium treatment. Our findings suggest that vesicle trafficking promotes organelle-specific ion interchange and cytoplasmic metal detoxification independent of calcineurin signaling or metal transporter re-localization. Our study identifies an alternative mode for cis-Golgi manganese supply in yeast and provides new perspectives for Hailey-Hailey disease treatment. [ABSTRACT FROM AUTHOR]

Antibodies with the ability to block the interaction of HIV-1 envelope glycoprotein (Env) gp120 with CD4, including those overlapping the CD4 binding site (CD4bs antibodies), can protect from infection by HIV-1, and their elicitation may be an interesting goal for any vaccination strategy. To identify gp120/CD4 blocking antibodies in plasma samples from HIV-1 infected individuals we have developed a competitive flow cytometry-based functional assay. In a cohort of treatment-naïve chronically infected patients, we showed that gp120/CD4 blocking antibodies were frequently elicited (detected in 97% plasma samples) and correlated with binding to trimeric HIV-1 envelope glycoproteins. However, no correlation was observed between functional CD4 binding blockade data and titer of CD4bs antibodies determined by ELISA using resurfaced gp120 proteins. Consistently, plasma samples lacking CD4bs antibodies were able to block the interaction between gp120 and its receptor, indicating that antibodies recognizing other epitopes, such as PGT126 and PG16, can also play the same role. Antibodies blocking CD4 binding increased over time and correlated positively with the capacity of plasma samples to neutralize the laboratory-adapted NL4.3 and BaL virus isolates, suggesting their potential contribution to the neutralizing workforce of plasma in vivo. Determining whether this response can be boosted to achieve broadly neutralizing antibodies may provide valuable information for the design of new strategies aimed to improve the anti-HIV-1 humoral response and to develop a successful HIV-1 vaccine. [ABSTRACT FROM AUTHOR]

Background The MPER region of the HIV-1 envelope glycoprotein gp41 is targeted by broadly neutralizing antibodies. However, the localization of this epitope in a hydrophobic environment seems to hamper the elicitation of these antibodies in HIV infected individuals. We have quantified and characterized anti-MPER antibodies by ELISA and by flow cytometry using a collection of mini gp41-derived proteins expressed on the surface of 293T 2 cells. Longitudinal plasma samples from 35 HIV-1 infected individuals were assayed for MPER recognition and MPER-dependent neutralizing capacity using HIV-2 viruses engrafted with HIV-1 MPER sequences. Results Miniproteins devoid of the cysteine loop of gp41 exposed the MPER on 293T cell membrane. Anti-MPER antibodies were identified in most individuals and were stable when analyzed in longitudinal samples. The magnitude of the responses was strongly correlated with the global response to the HIV-1 envelope glycoprotein, suggesting no specific limitation for anti- MPER antibodies. Peptide mapping showed poor recognition of the C-terminal MPER moiety and a wide presence of antibodies against the 2F5 epitope. However, antibody titers failed to correlate with 2F5-blocking activity and, more importantly, with the specific neutralization of HIV-2 chimeric viruses bearing the HIV-1 MPER sequence; suggesting a strong functional heterogeneity in anti-MPER humoral responses. Conclusions Anti-MPER antibodies can be detected in the vast majority of HIV-1 infected individuals and are generated in the context of the global anti-Env response. However, the neutralizing capacity is heterogeneous suggesting that eliciting neutralizing anti-MPER antibodies by immunization might require refinement of immunogens to skip nonneutralizing responses. [ABSTRACT FROM AUTHOR]

Objective To assess the extent of exclusion of older individuals from ongoing clinical trials regarding type 2 diabetes mellitus. Design Cohort study. Setting World Health Organization Clinical Trials Registry Platform. Participants Using the Participation of the Elderly in Clinical Trials methodology, data from ongoing clinical trials on type 2 diabetes mellitus were extracted from the platform on July 31, 2011. Measurements Proportion of trials excluding individuals using an arbitrary upper age limit or other exclusion criteria that might indirectly cause limited recruitment of older individuals. Exclusion criteria were classified as justified or poorly justified. Results Of 440 trials investigating treatments for type 2 diabetes mellitus, 289 (65.7%) excluded individuals using an arbitrary upper age limit. Such exclusion was significantly more common in trials with calculated sample sizes of less than 100 subjects (73.6% vs 59.5%; P = .002). Exclusion for comorbidity was present in 338 trials (76.8%); this exclusion was poorly justified in 236 trials (53.6%). Exclusion for polypharmacy (29.5% of trials), cognitive impairment (18.4%), short life expectancy (8.9%), and other poorly justified exclusion criteria that could limit the inclusion of older individuals was also present. Only six trials (1.4%) were designed specifically to study older adults. Conclusion Despite the recommendations of international regulatory agencies, exclusion of older individuals from ongoing trials regarding type 2 diabetes mellitus is frequent-higher than reported for other age-related diseases. This exclusion limits the value of the evidence that clinicians use when treating old, frail, complex patients with diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Despite depression being a common problem among nonprofessional caregivers, no studies of prevention of depression targeting this population exist in the literature. The studies of indicated prevention of depression aim of this study was to assess the efficacy of a problem-solving intervention in preventing clinical depression in a sample of female caregivers. Method: A controlled randomized trial was conducted among 173 participants (mean age 53.9 years), 89 of whom were randomized to the intervention group and 84 (controls) to usual care. The intervention comprised five weekly 90-minute group sessions. Results: At post-treatment, depression symptoms in the intervention group had remitted significantly more than in the control group, with a large effect size (d = 1.54). The proportion of participants showing clinically significant improvement was significantly larger in the intervention group (80.9% vs. 11.9% among controls), and fewer intervention-group participants had progressed to clinical depression during the study period (4.5% vs. 13.1% among controls). The intervention group also exhibited a significantly greater reduction in emotional distress and caregiver burden than the control group. Conclusions: These findings attest to the short-term efficacy of the intervention. [ABSTRACT FROM AUTHOR]

Background: HIV-1 infection generates numerous abnormalities in the B cell compartment which can be partly reversed by antiretroviral therapy. Our aim was to evaluate the effects that re-exposure to HIV antigens might have on the frequency and functionality of antibody secreting cells (ASC) in patients undergoing structured treatment interruptions (STI). As re-exposure to viral antigens may also boost the production of (neutralizing) antibodies, we also assessed the neutralizing activities during STI cycles. Methods: Retrospective study of 10 patients undergoing 3 cycles of STI with 2 weeks on and 4 weeks off HAART. ASC frequencies were determined by flow cytometry in samples obtained at the beginning and the end of STI. Neutralization capacity, total IgG concentration and anti-gp120-IgG titres were evaluated. Results: As expected, median viral loads were higher at the end of STI compared to on-HAART time points. The level of CD27 and CD38 expressing ACS followed the same pattern; with ASC being elevated up to 16 fold in some patients (median increase of 3.5% ± 4.13). Eight out of 10 patients maintained stable total IgG levels during the study. After purifying IgG fractions from plasma, HIV-neutralizing activity was observed in the two subjects with highest anti-gp120 titers. In one of these patients the neutralizing activity remained constant while the other showed elevated neutralizing Ab after first STI and once treatment was reinitiated after the 2nd STI Conclusions: Our data suggest that STI and its associated transient increases in viral load drive the frequencies of ASC in an antigen-specific manner. In some subjects, this re-exposure to autologous virus boosts the presence of neutralizing antibodies, similar to what is seen after influenza vaccination. STI may not boost clinically beneficial nAb levels but offers opportunities to isolate nAb producing cells at considerably higher levels than in subjects with completely suppressed viral replication. [ABSTRACT FROM AUTHOR]

Intravesical Bacille Calmette-Guérin (BCG) remains the most effective treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), unfortunately there is no validated biomarker to predict clinical outcome. Here we tried to explore the possibility that a combination of the density of peritumoral infiltrating cells (Th1, Th2 and PD-L1) and the composition of peripheral immune cells (neutrophil and lymphocyte counts) could generate a more reliable prognostic biomarker. Twenty-two patients with high-risk NMIBC treated with BCG (10 BCG nonresponders and 12 BCG responders) were selected. BCG responders had significantly lower level of peritumoral T-bet+ cells with an associated higher GATA-3+/T-bet+ ratio (p = 0.04, p = 0.02, respectively). Furthermore, the immune polarization in tissue (GATA-3+/T-bet+ ratio) adjusted for the systemic inflammation (neutrophil-to-lymphocyte ratio) showed a significantly higher association with the BCG response (p = 0.004). A survival analysis demonstrated prolonged recurrence-free survival (RFS) in patients with a lower T-bet+/Lymphocyte ratio and higher GTR/NLR (p = 0.01). No association was observed between peritumoral PD-L1+ expression and the BCG response. In conclusion, alterations in overall immune function, both local and systemic, may influence the therapeutic response to BCG, therefore a combined analysis of tumoral (Th2/Th1 ratio) and peripheral (NLR) immune composition prior to treatment may be a promising approach to predict the BCG response in high-risk NMIBC patients. [ABSTRACT FROM AUTHOR]

The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, cholesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41-MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane-dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants. [ABSTRACT FROM AUTHOR]

Background: HIV-1 infection generates numerous abnormalities in the B cell compartment which can be partly reversed by antiretroviral therapy. Our aim was to evaluate the effects that re-exposure to HIV antigens might have on the frequency and functionality of antibody secreting cells (ASC) in patients undergoing structured treatment interruptions (STI). As re-exposure to viral antigens may also boost the production of (neutralizing) antibodies, we also assessed the neutralizing activities during STI cycles.Methods: Retrospective study of 10 patients undergoing 3 cycles of STI with 2 weeks on and 4 weeks off HAART. ASC frequencies were determined by flow cytometry in samples obtained at the beginning and the end of STI. Neutralization capacity, total IgG concentration and anti-gp120-IgG titres were evaluated.Results: As expected, median viral loads were higher at the end of STI compared to on-HAART time points. The level of CD27 and CD38 expressing ACS followed the same pattern; with ASC being elevated up to 16 fold in some patients (median increase of 3.5% ± 4.13). Eight out of 10 patients maintained stable total IgG levels during the study. After purifying IgG fractions from plasma, HIV-neutralizing activity was observed in the two subjects with highest anti-gp120 titers. In one of these patients the neutralizing activity remained constant while the other showed elevated neutralizing Ab after first STI and once treatment was reinitiated after the 2nd STI.Conclusions: Our data suggest that STI and its associated transient increases in viral load drive the frequencies of ASC in an antigen-specific manner. In some subjects, this re-exposure to autologous virus boosts the presence of neutralizing antibodies, similar to what is seen after influenza vaccination. STI may not boost clinically beneficial nAb levels but offers opportunities to isolate nAb producing cells at considerably higher levels than in subjects with completely suppressed viral replication. [ABSTRACT FROM AUTHOR]