Galectins in epithelial-mesenchymal transition: roles and mechanisms contributing to tissue repair, fibrosis and cancer metastasis.

Galectins are soluble glycan-binding proteins that interact with a wide range of glycoproteins and glycolipids and modulate a broad spectrum of physiological and pathological processes. The expression and subcellular localization of different galectins vary among tissues and cell types and change during processes of tissue repair, fibrosis and cancer where epithelial cells loss differentiation while acquiring migratory mesenchymal phenotypes. The epithelial-mesenchymal transition (EMT) that occurs in the context of these processes can include modifications of glycosylation patterns of glycolipids and glycoproteins affecting their interactions with galectins. Moreover, overexpression of certain galectins has been involved in the development and different outcomes of EMT. This review focuses on the roles and mechanisms of Galectin-1 (Gal-1), Gal-3, Gal-4, Gal-7 and Gal-8, which have been involved in physiologic and pathogenic EMT contexts.

Association of LIfestyle for BRAin health risk score (LIBRA) and genetic susceptibility with incident dementia and cognitive decline.

INTRODUCTION: Evaluating whether genetic susceptibility modifies the impact of lifestyle-related factors on dementia is critical for prevention. METHODS: We studied 5170 participants from a French cohort of older persons free of dementia at baseline and followed for up to 17 years. The LIfestyle for BRAin health risk score (LIBRA) including 12 modifiable factors was constructed at baseline (higher score indicating greater risk) and was related to both subsequent cognitive decline and dementia incidence, according to genetic susceptibility to dementia (reflected by the apolipoprotein E [APOE] ε4 allele and a genetic risk score [GRS]). RESULTS: The LIBRA was associated with higher dementia incidence, with no significant effect modification by genetics (hazard ratio for one point score = 1.09 [95% confidence interval, 1.05; 1.13]) in APOE ε4 non-carriers and = 1.15 [1.08; 1.22] in carriers; P = 0.15 for interaction). Similar findings were obtained with the GRS and with cognitive decline. DISCUSSION: Lifestyle-based prevention may be effective whatever the genetic susceptibility to dementia.

Anastomotic leak in colorectal cancer surgery: Contribution of gut microbiota and prediction approaches.

AIM: To monitor prospectively the occurrence of colorectal anastomotic leakage (CAL) in patients with colon cancer undergoing resectional surgery, characterizing the microbiota in both faeces and mucosal biopsies of anastomosis. In a second stage, we investigated the ability to predict CAL using machine learning models based on clinical data and microbiota composition. METHOD: A total of 111 patients were included, from whom a faecal sample was obtained, as well as biopsy samples from proximal and distal sites in the healthy margins of the tumour piece. The microorganisms present in the samples were investigated using microbial culture and 16S rDNA massive sequencing. Collagenase and protease production was determined, as well as the presence of genes responsible for expressing enzymes with these activities. Machine learning analyses were developed using clinical and microbiological data. RESULTS: The incidence of CAL was 9.0%, and CAL was associated with collagenase/protease-producing Enterococcus. Significant differences were found in the microbiota composition of proximal and distal biopsy samples, but not in faecal samples, among patients who developed CAL. Clinical predictors of CAL were 5-day C-reactive protein and heart disease, whereas 3-day C-reactive protein and diabetes were negative predictors. CONCLUSION: Biopsy samples from surgical margins, rather than faecal samples, are the most appropriate samples for exploring the contribution of the intestinal microbiota to CAL. Enterococci are only enriched in the anastomosis after surgery, and their collagenases and proteases are involved in the degradation of the anastomotic scar.

Driver Monitoring for a Driver-Centered Design and Assessment of a Merging Assistance System Based on V2V Communications.

Merging is one of the most critical scenarios that can be found in road transport. In this maneuver, the driver is subjected to a high mental load due to the large amount of information he handles, while making decisions becomes a crucial issue for their safety and those in adjacent vehicles. In previous works, it was studied how the merging maneuver affected the cognitive load required for driving by means of an eye tracking system, justifying the proposal of a driver assistance system for the merging maneuver on highways. This paper presents a merging assistance system based on communications between vehicles, which allows vehicles to share internal variables of position and speed and is implemented on a mobile device located inside the vehicle. The system algorithm decides where and when the vehicle can start the merging maneuver in safe conditions and provides the appropriate information to the driver. Parameters and driving simulator tests are used for the interface definition to develop the less intrusive and demanding one. Afterward, the system prototype was installed in a real passenger car and tests in real scenarios were conducted with several drivers to assess usability and mental load. Comparisons among alternative solutions are shown and effectiveness is assessed.

Ethics of organ procurement from the unrepresented patient population.

The shortage of organs for transplantation by its nature prompts ethical dilemmas. For example, although there is an imperative to save human life and reduce suffering by maximising the supply of vital organs, there is an equally important obligation to ensure that the process by which we increase the supply respects the rights of all stakeholders. In a relatively unexamined practice in the USA, organs are procured from unrepresented decedents without their express consent. Unrepresented decedents have no known healthcare wishes or advance care planning document; they also lack a surrogate. The Revised Uniform Anatomical Gift Act (RUAGA) of 2006 sends a mixed message about the procurement of organs from this patient population and there are hospitals that authorise donation. In addition, in adopting the RUAGA, some states included provisions that clearly allow organ procurement from unrepresented decedents. An important unanswered question is whether this practice meets the canons of ethical permissibility. The current Brief Report presents two principled approaches to the topic as a way of highlighting some of the complexities involved. Concluding remarks offer suggestions for future research and discussion.

Quantitative determination of five hydroxy acids, precursors of relevant wine aroma compounds in wine and other alcoholic beverages.

A method for the quantitative determination of 2-hydroxy-2-methylbutanoic (2OH2MB), 2-hydroxy-3-methylbutanoic (2OH3MB), 3-hydroxy-3-methylbutanoic (3OH3MB), 2-hydroxy-4-methylpentanoic (2OH4MP) and 3-hydroxybutanoic (3OHB) acids has been optimized, validated and applied to a set of wines and other alcoholic beverages. The analytes were preconcentrated in a solid phase extraction cartridge and derivatized with 2,3,4,5,6-pentafluorobenzyl bromide at room temperature for 30 min, followed by GC-MS analysis. Detection limits were between 0.5 and 29 µg L(-1), and linearity was maintained up to 3 or 12 mg L(-1), depending on the analyte. Recovery values were between 85 and 106 %, and reproducibility was better than 12 % RSD in most cases. The first specific study of these analytes in wine and other alcoholic beverages is herein reported. Concentrations ranged from the method detection limits to 7820, 519, 8510, 3470 and 2500 µg L(-1) for 2OH2MB, 2OH3MB, 3OH3MB, 2OH4MP and 3OHB, respectively, which may have relevant sensory effects. These products were not found in distillates (except 3OHB) but were all present in beer. 2OH2MB, 3OH3MB and 3OHB were found in unfermented grape derivatives. Sherry wines had the highest levels of all except for 3OHB.

An overview of psychosocial assessment procedures in reconstructive hand transplantation.

There have been more than 90 hand and upper extremity transplants performed worldwide. Functional and sensory outcomes have been reported in several studies, but little is known about the psychosocial outcomes. A comprehensive systematic literature review was performed, addressing the psychosocial impact of reconstructive hand transplantation. This review provides an overview of psychosocial evaluation protocols and identifies standards in this novel and exciting field. Essentials of the psychosocial assessment are discussed and a new protocol, the 'Chauvet Protocol', representing a standardized assessment protocol for future multicenter psychosocial trials is being introduced.

Psychometric properties of the eight-item modified Medical Outcomes Study Social Support Survey based on Spanish outpatients.

PURPOSE: The aim of this study was to examine the psychometric properties of the modified Medical Outcomes Study Social Support Survey (mMOS-SS) in a primary healthcare setting (PHCS). METHODS: A cross-sectional descriptive study was carried out with Spanish outpatients (N = 903) from a PHCS. Subjects responded to the first eight items of the classic Medical Outcomes Study-Social Support Survey (MOS-SS), in effect the mMOS-SS, and immediately proceeded to give answers to the rest of the scale. Also, sociodemographic, self-reported health status and mood/anxiety disorders data were collected. Factor structure was analyzed using exploratory and confirmatory analysis, internal reliability was determined by Cronbach's standardized alpha, and consistency was evaluated by item-to-total score correlations. Evidences of validity were assessed by Spearman's rank correlations, and using the Mann-Whitney test or Kruskal-Wallis test as appropriate, of differences between the mMOS-SS and the MOS-SS. RESULTS: Mean scores for the MOS-SS (mean = 4.26, SD = 0.78) and mMOS-SS (mean = 4.34, SD = 0.74) are similar. Cronbach's alpha was 0.96 and 0.91, for the MOS-SS and mMOS-SS, respectively. Item-to-total score correlations of the MOS-SS and mMOS-SS are ≥0.64 and ≥0.70, respectively. Exploratory factor analysis (EFA) [56.63% variance, KMO=0.904; χ2=4396.27], and confirmatory factor analysis (CFA) [CFI=0.95; NNFI(TLI)=0.97; SRMR=0.05; χ2=296.81; RMSEA=0.17] showed a one-factor structure. CONCLUSIONS: Psychometric properties of the Spanish version of the mMOS-SS in outpatients attending a PHCS are adequate. Factor analysis confirmed a one-factor model with acceptable fit indices.

Galectin-8 counteracts folic acid-induced acute kidney injury and prevents its transition to fibrosis.

Acute kidney injury (AKI), characterized by a sudden decline in kidney function involving tubular damage and epithelial cell death, can lead to progressive tissue fibrosis and chronic kidney disease due to interstitial fibroblast activation and tissue repair failures that lack direct treatments. After an AKI episode, surviving renal tubular cells undergo cycles of dedifferentiation, proliferation and redifferentiation while fibroblast activity increases and then declines to avoid an exaggerated extracellular matrix deposition. Appropriate tissue recovery versus pathogenic fibrotic progression depends on fine-tuning all these processes. Identifying endogenous factors able to affect any of them may offer new therapeutic opportunities to improve AKI outcomes. Galectin-8 (Gal-8) is an endogenous carbohydrate-binding protein that is secreted through an unconventional mechanism, binds to glycosylated proteins at the cell surface and modifies various cellular activities, including cell proliferation and survival against stress conditions. Here, using a mouse model of AKI induced by folic acid, we show that pre-treatment with Gal-8 protects against cell death, promotes epithelial cell redifferentiation and improves renal function. In addition, Gal-8 decreases fibroblast activation, resulting in less expression of fibrotic genes. Gal-8 added after AKI induction is also effective in maintaining renal function against damage, improving epithelial cell survival. The ability to protect kidneys from injury during both pre- and post-treatments, coupled with its anti-fibrotic effect, highlights Gal-8 as an endogenous factor to be considered in therapeutic strategies aimed at improving renal function and mitigating chronic pathogenic progression.

Surgical Interest of an Accurate Real-World Prediction of Primary Systemic Therapy Response in HER2 Breast Cancers.

Human epidermal growth factor receptor 2 (HER2)-enriched breast cancers (BC) present the highest rates of pathological response to primary systemic therapy (PST), but they are also the ones that tend to be larger at diagnosis, with microcalcifications and, often, with axillary involvement. If we do not have a reliable method to predict the degree of response, we may not be able to transfer the benefits of PST to surgery. The post-PST surgery planning is guided by the findings in the magnetic resonance imaging (MRI), whose predictive capacity, although high, is far from optimal. Thus, it seems interesting to find other variables to improve it. A retrospective observational study including women with HER2 BC treated with PST and further surgery was conducted. Information regarding clinical, radiological, and histopathological variables was gathered from a total of 132 patients included. Radiological complete response (rCR) was achieved in 65.9% of the sample, and pathological complete response (pCR), according to Miller and Payne criteria, in 58.3% of cases. A higher Ki67 value, the absence of Hormonal Receptors expression, and an rCR was significantly related to a pCR finding. This information impacts directly in surgery planning, as it permits adjustment of the breast resection volume.

The Clinical Impact of Neoadjuvant Endocrine Treatment on Luminal-like Breast Cancers and Its Prognostic Significance: Results from a Single-Institution Prospective Cohort Study.

Purpose: Neoadjuvant endocrine treatment (NET) has become a useful tool for the downstaging of luminal-like breast cancers in postmenopausal patients. It enables us to increase breast- conserving surgery (BCS) rates, provides an opportunity for us to assess in vivo NET effectiveness, and allows us to study any biological changes that may act as valid biomarkers. The purpose of this study was to evaluate the safety and effectiveness of NET, and to assess the role of Ki67 proliferation rate changes as an indicator of endocrine responsiveness. Methods: From 2016 to 2020, a single-institution cohort of patients, treated with NET and further surgery, was evaluated. In patients with Ki67 ≥ 10%, a second core biopsy was performed after four weeks. Information regarding histopathological and clinical changes was gathered. Results: A total of 115 estrogen receptor-positive (ER+)/HER2-negative patients were included. The median treatment duration was 5.0 months (IQR: 2.0−6.0). The median maximum size in the surgical sample was 40% smaller than the pretreatment size measured by ultrasound (p < 0.0001). The median pretreatment Ki67 expression was 20.0% (IQR: 12.0−30.0), and was reduced to 5.0% (IQR: 1.8−10.0) after four weeks, and to 2.0% (IQR: 1.0−8.0) in the surgical sample (p < 0.0001). BCS was performed on 98 patients (85.2%). No pathological complete responses were recorded. A larger Ki67 fold change after four weeks was significantly related to a PEPI score of zero (p < 0.002). No differences were observed between luminal A- and B-like tumors, with regard to fold change and PEPI score. Conclusions: In our cohort, NET was proven to be effective for tumor size and Ki67 downstaging. This resulted in a higher rate of conservative surgery, aided in therapeutic decision making, provided prognostic information, and constituted a safe and well-tolerated approach.

Paleomagnetic techniques can date speleothems with high concentrations of detrital material.

The U-series dating of young and 'dirty' speleothems is challenging due to difficulties in assessing the isotopic composition of detrital contaminants and the low-abundance of 230Th generated in situ. Here we propose a new dating approach based on the comparison of a speleothem's paleomagnetic directions to reference curves from global paleomagnetic reconstructions. This approach is demonstrated on a stalagmite collected from the Soprador do Carvalho cave in the Central Region of Portugal. A radioisotopic age model, built using four U-series ages and three 14C, suggests relatively steady carbonate precipitation from ~ 5760 BCE until ~ 1920 CE. Forty-five 6 mm-thick subsamples were analyzed using alternating field and thermal demagnetization protocols, providing well-defined, primary magnetic directions. An age model of the stalagmite was obtained by fitting its paleomagnetic record with the reference paleosecular variation curves obtained by previous paleo-reconstruction models, applying statistical bootstrapping analysis to define their best fit. The resulting age models fit closely with the radioisotopic age model but provide a significantly higher time resolution. We reach the same conclusion when applying this approach to another stalagmite from the Algarve region of Portugal. Our approach thus appears a promising alternative to date young speleothems with high detrital contents.

Interference in visual perception by verbal and spatial cognitive activity.

In two experiments we tested the hypothesis that cognitive processing based on spatial imagery produces more deterioration of visual perception than cognitive processing based on verbal codes. So, we studied the effect on visual perception of two cognitive tasks, one of spatial imagery and the other a verbal task. In the first one, with 30 participants, we analyzed the mental load and ocular behaviors in both cognitive tasks. In the second experiment, with 29 participants, we studied the effect of both tasks on a visual search task, using a dual-task experimental paradigm. The verbal task presented higher mental load than the imagery task when both tasks were carried out with visual search task, and there was more deterioration in stimulus detection with the verbal task. We can conclude that: (1) cognitive tasks produce important deterioration in the capacities of visual search and identification of stimuli; (2) this deterioration has two components: (a) an inefficient search, associated with alterations of the gaze patterns while performing cognitive tasks, and (b) a general interference, nonspecific to spatial codes, in the process of identification of looked-at stimuli; (3) this cognitive interference is related to the mental load or effort required by the cognitive task.

Single-colony sequencing reveals microbe-by-microbiome phylosymbiosis between the cyanobacterium Microcystis and its associated bacteria.

BACKGROUND: Cyanobacteria from the genus Microcystis can form large mucilaginous colonies with attached heterotrophic bacteria-their microbiome. However, the nature of the relationship between Microcystis and its microbiome remains unclear. Is it a long-term, evolutionarily stable association? Which partners benefit? Here we report the genomic diversity of 109 individual Microcystis colonies-including cyanobacteria and associated bacterial genomes-isolated in situ and without culture from Lake Champlain, Canada and Pampulha Reservoir, Brazil. RESULTS: We identified 14 distinct Microcystis genotypes from Canada, of which only two have been previously reported, and four genotypes specific to Brazil. Microcystis genetic diversity was much greater between than within colonies, consistent with colony growth by clonal expansion rather than aggregation of Microcystis cells. We also identified 72 bacterial species in the microbiome. Each Microcystis genotype had a distinct microbiome composition, and more closely related genotypes had more similar microbiomes. This pattern of phylosymbiosis could be explained by co-phylogeny in only two out of the nine most prevalent associated bacterial genera, Roseomonas and Rhodobacter. These phylogenetically associated genera could enrich the metabolic repertoire of Microcystis, for example by encoding the biosynthesis of complementary carotenoid molecules. In contrast, other colony-associated bacteria showed weaker signals of co-phylogeny, but stronger evidence of horizontal gene transfer with Microcystis. These observations suggest that acquired genes are more likely to be retained in both partners (Microcystis and members of its microbiome) when they are loosely associated, whereas one gene copy is sufficient when the association is physically tight and evolutionarily long-lasting. CONCLUSIONS: We have introduced a method for culture-free isolation of single colonies from nature followed by metagenomic sequencing, which could be applied to other types of microbes. Together, our results expand the known genetic diversity of both Microcystis and its microbiome in natural settings, and support their long-term, specific, and potentially beneficial associations. Video Abstract.

Circulating Extracellular Vesicle Proteins and MicroRNA Profiles in Subcortical and Cortical-Subcortical Ischaemic Stroke.

In order to investigate the role of circulating extracellular vesicles (EVs), proteins, and microRNAs as damage and repair markers in ischaemic stroke depending on its topography, subcortical (SC), and cortical-subcortical (CSC) involvement, we quantified the total amount of EVs using an enzyme-linked immunosorbent assay technique and analysed their global protein content using proteomics. We also employed a polymerase chain reaction to evaluate the circulating microRNA profile. The study included 81 patients with ischaemic stroke (26 SC and 55 CSC) and 22 healthy controls (HCs). No differences were found in circulating EV levels between the SC, CSC, and HC groups. We detected the specific expression of C1QA and Casp14 in the EVs of patients with CSC ischaemic stroke and the specific expression of ANXA2 in the EVs of patients with SC involvement. Patients with CSC ischaemic stroke showed a lower expression of miR-15a, miR-424, miR-100, and miR-339 compared with those with SC ischaemic stroke, and the levels of miR-339, miR-100, miR-199a, miR-369a, miR-424, and miR-15a were lower than those of the HCs. Circulating EV proteins and microRNAs from patients with CSC ischaemic stroke could be considered markers of neurite outgrowth, neurogenesis, inflammation process, and atherosclerosis. On the other hand, EV proteins and microRNAs from patients with SC ischaemic stroke might be markers of an anti-inflammatory process and blood-brain barrier disruption reduction.

[Attention to speed and guide traffic signs with eye movements]. / Atención a señales de velocidad y de orientación mediante movimientos oculares.

The goal of this research is to describe the visual search patterns for diverse traffic signs. Twelve drivers of both genders and different driving experience levels took part in real driving research with an instrumented car provided with an eye-tracking system. Looking at signs has a weak relation with speed reduction in cases where actual driving speed was higher. Nevertheless, among the people who looked at the sign, the percentage of those who reduce the speed below the limit is greater than of those who do not look at the sign. Guide traffic signs, particularly those mounted over the road, are more frequently glanced at than speed limit signs, with a glance duration of more than one second, in sequences of more than two consecutive fixations. Implications for driving and the possibilities and limitations of eye movement analysis for traffic sign research are discussed.

Update on the Effects of Antioxidants on Diabetic Retinopathy: In Vitro Experiments, Animal Studies and Clinical Trials.

Current therapies for diabetic retinopathy (DR) incorporate blood glucose and blood pressure control, vitrectomy, photocoagulation, and intravitreal injections of anti-vascular endothelial growth factors or corticosteroids. Nonetheless, these techniques have not been demonstrated to completely stop the evolution of this disorder. The pathophysiology of DR is not fully known, but there is more and more evidence indicating that oxidative stress is an important mechanism in the progression of DR. In this sense, antioxidants have been suggested as a possible therapy to reduce the complications of DR. In this review we aim to assemble updated information in relation to in vitro experiments, animal studies and clinical trials dealing with the effect of the antioxidants on DR.

Similarities and Differences in Extracellular Vesicle Profiles between Ischaemic Stroke and Myocardial Infarction.

Extracellular vesicles (EVs) are involved in intercellular signalling through the transfer of molecules during physiological and pathological conditions, such as ischaemic disease. EVs might therefore play a role in ischaemic stroke (IS) and myocardial infarction (MI). In the present study, we analysed the similarities and differences in the content of circulating EVs in patients with IS and MI. This prospective observational study enrolled 140 participants (81 patients with IS, 37 with MI and 22 healthy controls [HCs]). We analysed the protein and microRNA content from EVs using proteomics and reverse transcription quantitative real-time polymerase chain reaction and compared it between the groups. In the patients with IS and MI, we identified 14 common proteins. When comparing IS and MI, we found differences in the protein profiles (apolipoprotein B, alpha-2-macroglobulin, fibronectin). We also found lower levels of miR-340 and miR-424 and higher levels of miR-29b in the patients with IS and MI compared with the HCs. Lastly, we found higher miR-340 levels in IS than in MI. In conclusion, proteomic and miRNA analyses suggest a relationship between circulating EV content and the patient's disease state. Although IS and MI affect different organs (brain and heart) with distinct histological characteristics, certain EV proteins and miRNAs appear to participate in both diseases, while others are present only in patients with IS.

Galectins in epithelial-mesenchymal transition: roles and mechanisms contributing to tissue repair, fibrosis and cancer metastasis

Galectins are soluble glycan-binding proteins that interact with a wide range of glycoproteins and glycolipids and modulate a broad spectrum of physiological and pathological processes. The expression and subcellular localization of different galectins vary among tissues and cell types and change during processes of tissue repair, fibrosis and cancer where epithelial cells loss differentiation while acquiring migratory mesenchymal phenotypes. The epithelial-mesenchymal transition (EMT) that occurs in the context of these processes can include modifications of glycosylation patterns of glycolipids and glycoproteins affecting their interactions with galectins. Moreover, overexpression of certain galectins has been involved in the development and different outcomes of EMT. This review focuses on the roles and mechanisms of Galectin-1 (Gal-1), Gal-3, Gal-4, Gal-7 and Gal-8, which have been involved in physiologic and pathogenic EMT contexts.

Novel Molecular Characterization of Colorectal Primary Tumors Based on miRNAs.

microRNAs (miRNA) expression in colorectal (CR) primary tumours can facilitate a more precise molecular characterization. We identified and validated a miRNA profile associated with clinical and histopathological features that might be useful for patient stratification. In situ hybridization array using paraffin-embedded biopsies of CR primary tumours were used to screen 1436 miRNAs. 17 miRNAs were selected for validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) (n = 192) and were further correlated with clinical and histopathological data. We demonstrated that miRNAs associated to Colorectal Cancer (CRC) diagnosis age (over 50s and 60s) included miR-1-3p, miR-23b-3p, miR-27b-3p, miR-143-3p, miR-145-5p and miR-193b-5p. miR-23b-3p and miR-24-3p discriminated between Lynch Syndrome and sporadic CRC. miR-10a-5p, miR-20a-5p, miR-642b and Let-7a-5p were associated to stroma abundance. miR-642b and Let-7a-5p were associated with to peritumoral inflammation abundance. miR-1-3p, miR-143-3p and miR-145-5p correlated with mucinous component. miR-326 correlated with tumour location (right or left sided). miR-1-3p associated with tumour grade. miR-20a-5p, miR-193b-5p, miR-320a, miR-326 and miR-642b-3p associated to tumour stage and progression. Remarkably, we also demonstrated that miR-1-3p and miR-326 expression significantly associated with patient overall survival (OS). Hierarchical clustering and bioinformatics analysis indicated that selected miRNAs could re-classify the patients and work cooperatively, modulating common target genes involved in colorectal cancer key signalling pathways. In conclusion, molecular characterization of CR primary tumours based on miRNAs could lead to more accurate patient reclassification and may be useful for efficient patient management.