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The concept of e-learning is a technology-mediated learning approach of great potential from the educational perspective and it has been one of the main research lines of Educational Technology in the last decades. The aim of the present systematic literature review (SLR) was to identify (a) the research topics; (b) the most relevant theories; (c) the most researched modalities; and (d) the research methodologies used. To this end, the PRISMA protocol was followed, and different tools were used for the bibliographic management and text-mining. The literature selection was carried out in three first-quartile journals indexed in JCR-SSCI specialized in Educational Technology. A total of 248 articles composed the final sample. The analysis of the texts identified three main nodes: (a) online students; (b) online teachers; and (c) curriculum-interactive learning environments. It was revealed that MOOC was the most researched e-learning modality. The Community of Inquiry and the Technological Acceptance Model, were the most used theories in the analyzed studies. The most frequent methodology was case study. Finally, the conclusions regarding the objectives of our SRL are presented: Main themes and research sub-themes, most researched e-learning modality, most relevant theoretical frameworks on e-learning, and typologies of research methodologies.

Cells are repeatedly exposed to environmental or endogenous stresses that can alter normal cell behavior and increase cell vulnerability. In order to ensure tissue integrity and function, cells cope with cellular injuries by adapting their metabolism, protecting essential intracellular constituents, inhibiting cell death signaling pathways and activating those devoted to damage repair. The molecular chaperones of the heat-shock protein (HSP) family are critical effectors of this adaptive response. They protect intracellular proteins from misfolding or aggregation, inhibit cell death signaling cascades and preserve the intracellular signaling pathways that are essential for cell survival. Most HSPs are rapidly overexpressed in response to cellular injuries including genotoxic stress. DNA damage can dramatically alter cell behavior and contribute to a number of diseases including developmental defects, neurodegenerative disorders, and cancer. Thus, the ability of cells to repair DNA damage is essential for preserving cell integrity. DNA damage activates a coordinated response that includes detecting DNA lesions before their transmission to daughter cells, blocking cell cycle progression and DNA replication and repairing the damage. Although the role of HSPs in proteins homeostasis and cell death, especially apoptosis has been widely reported, much less is known about their function in DNA repair. This review aims to present the role of HSPs in DNA repair signaling pathways.

Background Breast cancer patients under neoadjuvant chemotherapy includes a heterogeneous group of patients who eventually develop distal disease, not detectable by current methods. We propose the use of exosomal miRNAs and circulating tumor cells as diagnostic and predictive biomarkers in these patients. Methods Fifty-three breast cancer women initially diagnosed with localized breast cancer under neoadjuvant chemotherapy were prospectively enrolled in this study. However, six of them were later re-evaluated and diagnosed as metastatic breast cancer patients by PET-CT scan. Additionally, eight healthy donors were included. Circulating tumor cells and serum exosomal miRNAs were isolated from blood samples before and at the middle of neoadjuvant therapy and exosomal miRNA levels analyzed by qPCR. Results Before neoadjuvant therapy, exosomal miRNA-21 and 105 expression levels were higher in metastatic versus non-metastatic patients and healthy donors. Likewise, higher levels of miRNA-222 were observed in basal-like ( p  = 0.037) and in luminal B versus luminal A ( p  = 0.0145) tumor subtypes. Exosomal miRNA-222 levels correlated with clinical and pathological variables such as progesterone receptor status ( p  = 0.017) and Ki67 ( p  = 0.05). During neoadjuvant treatment, exosomal miRNA-21 expression levels directly correlated with tumor size ( p  = 0.039) and inversely with Ki67 expression ( p  = 0.031). Finally, higher levels of exosomal miRNA-21, miRNA-222, and miRNA-155 were significantly associated with the presence of circulating tumor cells. Conclusion Liquid biopsies based on exosomal miRNAs and circulating tumor cells can be a complementary clinical tool for improving breast cancer diagnosis and prognosis.

The study of anticancer immune responses and in particular the action of immune checkpoint inhibitors that overcome T cell inhibition has revolutionized metastatic patients' care. Unfortunately, many patients are resistant to these innovative immunotherapies. Over the last decade, several immune checkpoint inhibitors, currently available in the clinic, have been developed, such as anti‐PD‐1/PD‐L1 or anti‐CTLA‐4. More recently, other immune checkpoints have been characterized, among them lymphocyte activation gene 3 (LAG‐3). LAG‐3 has been the subject of numerous therapeutic studies and may be involved in cancer‐associated immune resistance phenomena. This review summarizes the latest knowledge on LAG‐3 as an immunotherapeutic target, particularly in combination with standard or innovative therapies. Indeed, many studies are looking at combining LAG‐3 inhibitors with chemotherapeutic, immunotherapeutic, radiotherapeutic treatments, or adoptive cell therapies to potentiate their antitumor effects and/or to overcome patients' resistance. We will particularly focus on the association therapies that are currently in phase III clinical trials and innovative combinations in preclinical phase. These new discoveries highlight the possibility of developing other types of therapeutic combinations currently unavailable in the clinic, which could broaden the therapeutic spectrum of personalized medicine. This review summarizes the latest knowledge on LAG‐3 as an immunotherapeutic target, particularly in combination with standard or innovative therapies.

Advances in new technologies are allowing any field of real life to benefit from using these ones. Among of them, we can highlight the IoT ecosystem making available large amounts of information, cloud computing allowing large computational capacities, and Machine Learning techniques together with the Soft Computing framework to incorporate intelligence. They constitute a powerful set of tools that allow us to define Decision Support Systems that improve decisions in a wide range of real-life problems. In this paper, we focus on the agricultural sector and the issue of sustainability. We propose a methodology that, starting from times series data provided by the IoT ecosystem, a preprocessing and modelling of the data based on machine learning techniques is carried out within the framework of Soft Computing. The obtained model will be able to carry out inferences in a given prediction horizon that allow the development of Decision Support Systems that can help the farmer. By way of illustration, the proposed methodology is applied to the specific problem of early frost prediction. With some specific scenarios validated by expert farmers in an agricultural cooperative, the benefits of the methodology are illustrated. The evaluation and validation show the effectiveness of the proposal.

Strong evidence suggests that differences in the molecular composition of lipids in exosomes depend on the cell type and has an influence on cancer initiation and progression. Here, we analyzed by liquid chromatography–mass spectrometry (LC‐MS) the lipidomic signature of exosomes derived from the human cell lines normal colon mucosa (NCM460D), and colorectal cancer (CRC) nonmetastatic (HCT116) and metastatic (SW620), and exosomes isolated from the plasma of nonmetastatic and metastatic CRC patients and healthy donors. Analysis of this exhaustive lipid study highlighted changes in some molecular species that were found in the cell lines and confirmed in the patients. For example, exosomes from primary cancer patients and nonmetastatic cells compared with healthy donors and control cells displayed a common marked increase in phosphatidylcholine (PC) 34 : 1, phosphatidylethanolamine (PE) 36 : 2, sphingomyelin (SM) d18 : 1/16 : 0, hexosylceramide (HexCer) d18 : 1/24 : 0 and HexCer d18 : 1/24 : 1. Interestingly, these same lipids species were decreased in the metastatic cell line and patients. Further, levels of PE 34 : 2, PE 36 : 2, and phosphorylated PE p16 : 0/20 : 4 were also significantly decreased in metastatic conditions when compared to the nonmetastatic counterparts. The only molecule species found markedly increased in metastatic conditions (in both patients and cells) when compared to controls was ceramide (Cer) d18 : 1/24 : 1. These decreases in lipid species in the extracellular vesicles might reflect function‐associated changes in the metastatic cell membrane. Although these potential biomarkers need to be validated in a larger cohort, they provide new insight toward the use of clusters of lipid biomarkers rather than a single molecule for the diagnosis of different stages of CRC. Lipid dysregulation‐induced structural changes of the plasma membrane in cancer modulate cellular homeostasis, signaling pathways, and can affect colorectal cancer (CRC) initiation and progression. Since these changes are also found in the membrane lipid bilayer of the tumor‐released exosomes, mass spectroscopy can help to define an exosomal lipidomic signature to find noninvasive circulant diagnostic/prognostic biomarkers for different CRC stages.

BackgroundWe previously showed that supernatants of Lactobacillus biofilms induced an anti-inflammatory response by affecting the secretion of macrophage-derived cytokines, which was abrogated upon immunodepletion of the stress protein GroEL.MethodsWe purified GroEL from L. reuteri and analysed its anti-inflammatory properties in vitro in human macrophages isolated from buffy coats, ex vivo in explants from human biopsies and in vivo in a mouse model of DSS induced intestinal inflammation. As a control, we used GroEL purified (LPS-free) from E. coli.ResultsWe found that L. reuteri GroEL (but not E. coli GroEL) inhibited pro-inflammatory M1-like macrophages markers, and favored M2-like markers. Consequently, L. reuteri GroEL inhibited pro-inflammatory cytokines (TNFα, IL-1β, IFNγ) while favouring an anti-inflammatory secretome. In colon tissues from human biopsies, L. reuteri GroEL was also able to decrease markers of inflammation and apoptosis (caspase 3) induced by LPS. In mice, we found that rectal administration of L. reuteri GroEL (but not E. coli GroEL) inhibited all signs of haemorrhagic colitis induced by DSS including intestinal mucosa degradation, rectal bleeding and weight loss. It also decreased intestinal production of inflammatory cytokines (such as IFNγ) while increasing anti-inflammatory IL-10 and IL-13. These effects were suppressed when animals were immunodepleted in macrophages. From a mechanistic point of view, the effect of L. reuteri GroEL seemed to involve TLR4, since it was lost in TRL4−/− mice, and the activation of a non-canonical TLR4 pathway.ConclusionsL. reuteri GroEL, by affecting macrophage inflammatory features, deserves to be explored as an alternative to probiotics.

Research on the Nile crocodile and five birds shows that limb evolution is shaped by an interplay between natural selection and developmental constraints, the outcome varying between different digits, and between embryos and adults. Developmental consequences of selection for digit loss The archosaurs are a group of land vertebrates that included the dinosaurs; birds and crocodiles are their only living representatives. Throughout their history, archosaurs show a persistent pattern of digit loss from the ancestral condition of five digits per limb. In all cases, however, rudiments for digits persist in the embryo even though they are not present in the adult, and the most persistent is digit five. Looking at embryology in crocodiles and five bird species, Michael Richardson and colleagues show that from the Nile crocodile (where adults have all five digits) to the emu (with a rudimentary wing containing just one digit) the signs for digit five are always present, if transiently. The authors suggest that this persistence might be a developmental constraint resulting from the association between digit five and the zone of polarizing activity, the region of the embryonic limb that governs digit development as a whole. Evolution involves interplay between natural selection and developmental constraints 1 , 2 , 3 . This is seen, for example, when digits are lost from the limbs during evolution 1 , 3 , 4 . Extant archosaurs (crocodiles and birds) show several instances of digit loss 3 , 5 , 6 under different selective regimes, and show limbs with one, two, three, four or the ancestral number of five digits. The ‘lost’ digits sometimes persist for millions of years as developmental vestiges 7 , 8 , 9 , 10 . Here we examine digit loss in the Nile crocodile and five birds, using markers of three successive stages of digit development. In two independent lineages under different selection, wing digit I and all its markers disappear. In contrast, hindlimb digit V persists in all species sampled, both as cartilage, and as Sox9 - expressing precartilage domains, 250 million years after the adult digit disappeared. There is therefore a mismatch between evolution of the embryonic and adult phenotypes. All limbs, regardless of digit number, showed similar expression of sonic hedgehog ( Shh ). Even in the one-fingered emu wing, expression of posterior genes Hoxd11 and Hoxd12 was conserved, whereas expression of anterior genes Gli3 and Alx4 was not. We suggest that the persistence of digit V in the embryo may reflect constraints, particularly the conserved posterior gene networks associated with the zone of polarizing activity (ZPA 11 ). The more rapid and complete disappearance of digit I may reflect its ZPA-independent specification, and hence, weaker developmental constraints. Interacting with these constraints are selection pressures for limb functions such as flying and perching. This model may help to explain the diverse patterns of digit loss in tetrapods. Our study may also help to understand how selection on adults leads to changes in development.

The NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome is a multi-protein complex, aimed at producing IL-1β in response to danger signals which must be tightly regulated. Here we investigated the importance of the stress sensor, Heat Shock Protein 70 (HSP70) on NLRP3 inflammasome activation. HSP70 deficiency leads to the worsening of NLRP3-dependent peritonitis in mice. HSP70 deficiency also enhances caspase-1 activation and IL-1β production in murine Bone Marrow-Derived Macrophages (BMDMs) under NLRP3 activator treatment in vitro. This observation is associated with an increased number and size of Apoptosis associated Speck-like protein containing a CARD domain (ASC)/NLRP3 specks. Conversely, the overexpression of HSP70 in BMDMs decreases caspase-1 activation and IL-1β production under NLRP3 activator treatment. HSP70 interacts with NLRP3 and this interaction is lost upon NLRP3 inflammasome activation. Heat shock inhibits NLRP3 inflammasome activation in vitro and inhibits peritonitis in mice. Therefore this study provides evidence on the inhibitory role of HSP70 on NLRP3 inflammasome and open the possibility of treating inflammatory diseases via HSP70 induction and/or by hyperthermia.

Transforming growth factor-beta (TGFβ) is a major immunosuppressive cytokine produced by various cell types, including regulatory T cells (Tregs) and M2 macrophages. In Tregs, GRP94 is known as a key protein regulating TGFβ expression by chaperoning both the TGFβ docking receptor, GARP, and the integrin αvβ8. We previously reported that GRP94 inhibition in a triple-negative breast cancer (TNBC) murine model induced a decrease in intra-tumoral CD206 + M2-like macrophages that correlated with a decrease in collagen content, an increase in CD8+ cells in tumors and a reduced tumor volume. Here, we investigated the impact of GRP94 inhibition on TGFβ expression focusing on a possible interaction with furin, a proprotein convertase responsible for the first step in TGFβ maturation. We demonstrated in human primary M2 macrophages that GRP94 interacted with furin and that GRP94 inhibition by its selective inhibitor PU-WS13 led to a decrease in furin enzymatic activity, which was associated with a decrease in TGFβ secretion. Similar results were obtained in the human TNBC cell line MDA-MB-231 using PU-WS13 and GRP94 inhibitor- 1, suggesting that our findings are not cell type-specific. Finally, we showed that GRP94 associated with LRRC33, a GARP paralog in macrophages. Together, these findings support the hypothesis that GRP94 plays a key role in regulating the TGFβ maturation pathway, not only in Tregs as previously reported, but also in M2 macrophages and tumor cells.