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Serine protease inhibitors (serpins) include thousands of structurally conserved proteins playing key roles in many organisms. Mutations affecting serpins may disturb their conformation, leading to inactive forms. Unfortunately, conformational consequences of serpin mutations are difficult to predict. In this study, we integrate experimental data of patients with mutations affecting one serpin with the predictions obtained by AlphaFold and molecular dynamics. Five SERPINC1 mutations causing antithrombin deficiency, the strongest congenital thrombophilia were selected from a cohort of 350 unrelated patients based on functional, biochemical, and crystallographic evidence supporting a folding defect. AlphaFold gave an accurate prediction for the wild-type structure. However, it also produced native structures for all variants, regardless of complexity or conformational consequences in vivo. Similarly, molecular dynamics of up to 1000 ns at temperatures causing conformational transitions did not show significant changes in the native structure of wild-type and variants. In conclusion, AlphaFold and molecular dynamics force predictions into the native conformation at conditions with experimental evidence supporting a conformational change to other structures. It is necessary to improve predictive strategies for serpins that consider the conformational sensitivity of these molecules.

One of the most common forms of cancer in fair skinned populations is Non-Melanoma Skin Cancer (NMSC), which primarily consists of Basal Cell Carcinoma (BCC), and cutaneous Squamous Cell Carcinoma (SCC). Detecting NMSC early can significantly improve treatment outcomes and reduce medical costs. Similarly, Actinic Keratosis (AK) is a common skin condition that, if left untreated, can develop into more serious conditions, such as SCC. Hyperspectral imagery is at the forefront of research to develop non-invasive techniques for the study and characterisation of skin lesions. This study aims to investigate the potential of near-infrared hyperspectral imagery in the study and identification of BCC, SCC and AK samples in comparison with healthy skin. Here we use a pushbroom hyperspectral camera with a spectral range of ≈ 900 to 1600 nm for the study of these lesions. For this purpose, an ad hoc platform was developed to facilitate image acquisition. This study employed robust statistical methods for the identification of an optimal spectral window where the different samples could be differentiated. To examine these datasets, we first tested for the homogeneity of sample distributions. Depending on these results, either traditional or robust descriptive metrics were used. This was then followed by tests concerning the homoscedasticity, and finally multivariate comparisons of sample variance. The analysis revealed that the spectral regions between 900.66-1085.38 nm, 1109.06-1208.53 nm, 1236.95-1322.21 nm, and 1383.79-1454.83 nm showed the highest differences in this regard, with

Environmental DNA (eDNA) metabarcoding has been increasingly used to monitor the community assemblages of a wide variety of organisms. Here, we test the efficacy of eDNA metabarcoding to assess the composition of Iberian freshwater fishes, one of the most endangered groups of vertebrates in Spain. For this purpose, we sampled 12 sampling sites throughout one of Spain's largest basins, the Duero, which is home to approximately 70% of the genera and 30% of the primary freshwater fish in Spain. We sampled these sampling sites in the summer by using electrofishing, a traditional sampling method, and eDNA metabarcoding of river water samples using the mitochondrial 12S rRNA gene (12S) as a marker. We also resampled four of these sampling sites in autumn by eDNA. We compared the results obtained through eDNA metabarcoding with those of electrofishing surveys (ones conducted for the present study and past ones) and assessed the suitability of 12S as an eDNA metabarcoding marker for this group of freshwater fishes. We found that the 12S fragment, analysed for 25 Iberian species, showed sufficient taxonomic resolution to be useful for eDNA approaches, and even showed population-level differences in the studied populations across the tissue samples for Achondrostoma arcasii. In most cases, a greater number of species was detected through eDNA metabarcoding than through electrofishing. Based on our results, eDNA metabarcoding is a powerful tool to study the freshwater fish composition in the Iberian Peninsula and to unmask cryptic diversity. However, we highlight the need to generate a local genetic database for 12S gene for such studies and to interpret the results with caution when studying only mitochondrial DNA. Finally, our survey shows that the high detection sensitivity of eDNA metabarcoding and the non-invasiveness of this method allows it to act as a detection system for species of low abundance, such as early invasive species or species in population decline, two key aspects of conservation management of Spanish freshwater fishes.

The wild species of the genus Zea commonly named teosintes, comprise nine different taxa, distributed from northern Mexico to Costa Rica. Although this genus of plants has been extensively studied from a morphological, ecogeographical and genetic point of view, most contributions have been limited to the study of a few populations and taxa. To understand the great variability that exists between and within teosinte species, it is necessary to include the vast majority of known populations. In this context, the objective of this work was to evaluate the diversity and genomic structure of 276 teosinte populations. Molecular analyzes were performed with 3,604 plants and with data from 33,929 SNPs. The levels of genetic diversity by taxonomic group show a marked difference between species, races and sections, where the highest values of genomic diversity was found in ssp. parviglumis and ssp. mexicana. The lower values were obtained for the Luxuriantes section as well as ssp. huehuetenagensis of the section Zea. The results of structure show that there is a great genetic differentiation in all the taxonomic groups considered. For ssp. parviglumis and mexicana, which are the taxa with the largest number of populations, a marked genomic differentiation was found that is consistent with their geographic distribution patterns. These results showed a loss of diversity in several teosinte populations, making a strong case for further collection, and ex situ and in situ conservation. Also, this study highlights the importance of integrating genomic diversity and structure for the applications of conservation and management.

Background Several chronic conditions have been identified as risk factors for severe COVID-19 infection, yet the implications of multimorbidity need to be explored. The objective of this study was to establish multimorbidity clusters from a cohort of COVID-19 patients and assess their relationship with infection severity/mortality. Methods The MRisk-COVID Big Data study included 14 286 COVID-19 patients of the first wave in a Spanish region. The cohort was stratified by age and sex. Multimorbid individuals were subjected to a fuzzy c-means cluster analysis in order to identify multimorbidity clusters within each stratum. Bivariate analyses were performed to assess the relationship between severity/mortality and age, sex, and multimorbidity clusters. Results Severe infection was reported in 9.5% (95% CI: 9.0–9.9) of the patients, and death occurred in 3.9% (95% CI: 3.6–4.2). We identified multimorbidity clusters related to severity/mortality in most age groups from 21 to 65 years. In males, the cluster with highest percentage of severity/mortality was Heart-liver-gastrointestinal (81–90 years, 34.1% severity, 29.5% mortality). In females, the clusters with the highest percentage of severity/mortality were Diabetes-cardiovascular (81–95 years, 22.5% severity) and Psychogeriatric (81–95 years, 16.0% mortality). Conclusion This study characterized several multimorbidity clusters in COVID-19 patients based on sex and age, some of which were found to be associated with higher rates of infection severity/mortality, particularly in younger individuals. Further research is encouraged to ascertain the role of specific multimorbidity patterns on infection prognosis and identify the most vulnerable morbidity profiles in the community. Trial registration NCT04981249. Registered 4 August 2021 (retrospectively registered).

This study provides the profiles and success predictions of students considering data before, during, and after the COVID-19 pandemic. Using a field experiment of 396 students and more than 7400 instances, we have analyzed students' performance considering the temporal distribution of autonomous learning during courses from 2016/2017 to 2020/2021. After applying unsupervised learning, results show 3 main profiles from the clusters obtained in the simulations: students who work continuously, those who do it in the last-minute, and those with a low performance in the whole autonomous learning. We have found that the highest success ratio is related to students that work in a continuous basis. However, last-minute working is not necessarily linked to failure. We have also found that students' marks can be predicted successfully taking into account the whole data sets. However, predictions are worse when removing data from the month before the final exam. These predictions are useful to prevent students' wrong learning strategies, and to detect malpractices such as copying. We have done all these analyses taking into account the effect of the COVID-19 pandemic, founding that students worked in a more continuous basis in the confinement. This effect was still present one year after. Finally, We have also included an analysis of the techniques that could be more effective to keep in a future non-pandemic scenario the good habits that were detected in the confinement.

Serine protease inhibitors (serpins) include thousands of structurally conserved proteins playing key roles in many organisms. Mutations affecting serpins may disturb their conformation, leading to inactive forms. Unfortunately, conformational consequences of serpin mutations are difficult to predict. In this study, we integrate experimental data of patients with mutations affecting one serpin with the predictions obtained by AlphaFold and molecular dynamics. Five SERPINC1 mutations causing antithrombin deficiency, the strongest congenital thrombophilia were selected from a cohort of 350 unrelated patients based on functional, biochemical, and crystallographic evidence supporting a folding defect. AlphaFold gave an accurate prediction for the wild-type structure. However, it also produced native structures for all variants, regardless of complexity or conformational consequences in vivo. Similarly, molecular dynamics of up to 1000 ns at temperatures causing conformational transitions did not show significant changes in the native structure of wild-type and variants. In conclusion, AlphaFold and molecular dynamics force predictions into the native conformation at conditions with experimental evidence supporting a conformational change to other structures. It is necessary to improve predictive strategies for serpins that consider the conformational sensitivity of these molecules. [ABSTRACT FROM AUTHOR]

Background Current evidence suggests that up to 70% of COVID-19 survivors develop post-COVID symptoms during the following months after infection. Fatigue and dyspnea seem to be the most prevalent post-COVID symptoms. Objective To analyze whether a tele-rehabilitation exercise program is able to improve self-perceived physical exertion in patients with post-COVID fatigue and dyspnea. Methods Sixty-eight COVID-19 survivors exhibiting post-COVID fatigue and dyspnea derived to four Primary Health Care centers located in Madrid were enrolled in this quasi-experimental study. A tele-rehabilitation program based on patient education, physical activity, airway clearing, and breathing exercise interventions was structured on eighteen sessions (3 sessions/week). Self-perceived physical exertion during daily living activities, dyspnea severity, health-related quality of life and distance walked and changes in oxygen saturation and heart rate during the 6-Minute walking test were assessed at baseline, after the program and at 1- and 3-months follow-up periods. Results Daily living activities, dyspnea severity and quality of life improved significantly at all follow-ups (pConclusion Tele-rehabilitation programs could be an effective strategy to reduce post-COVID fatigue and dyspnea in COVID-19 survivors. In addition, it could also reduce the economic burden of acute COVID-19, reaching a greater number of patients and releasing Intensive Unit Care beds for prioritized patients with a severe disease. Study registration The international OSF Registry registration link is https://doi.org/10.17605/OSF.IO/T8SYB.

Agave lechuguilla Torr., of the family Agavaceae, is distributed from southwestern United States to southern Mexico and is one of the most representative species of arid and semiarid regions. Its fiber is extracted for multiple purposes. The objective of this study was to generate a robust model to predict dry fiber yield (Dfw) rapidly, simply, and inexpensively. We used a power model in its linear form and bioclimatic areas as dummy variables. Training, generation (80%) and validation (20%) of the model was performed using machine learning with the package ‘caret’ of R. Using canonical correlation analysis (CCA), we evaluated the relationship of Dwf to bioclimatic variables. The principal components analysis (PCA) generated two bioclimatic zones, each with different A. lechuguilla productivities. We evaluated 499 individuals in four states of Mexico. The crown diameter (Cd) of this species adequately predicts its fiber dry weight (R2 = 0.6327; p < 0.05). The intercept (β0), slope [lnCd (β1)], zone [(β2)] and interaction [lnCd:Zona (β3)] of the dummy model was statistically significant (p < 0.05), giving origin to an equation for each bioclimatic zone. The CCA indicates a positive correlation between minimum temperature of the coldest month (Bio 6) and Dwf (r = 0.84 and p < 0.05). In conclusion, because of the decrease in Bio 6 of more than 0.5°C by 2050, the species could be vulnerable to climate change, and A. lechuguilla fiber production could be affected gradually in the coming years.

Objectives To assess the psychometric characteristics of the Spanish Post-COVID-19 Functional Status (PCFS) scale (web-based and paper-based forms) and the test-retest reliability of the web-based form. Study design and setting Cross-sectional study of 125 COVID-19 survivors. The test-retest reliability of the web-based form was assessed at 7 days after the first evaluation. We collected symptoms, functional status (PCFS scale), health-related quality of life (EuroQol-5D questionnaire, EQ-5D-5L), activities of daily living limitations [Barthel Index and Global Activity Limitation Index, GALI] and psychological state (Hospital Anxiety and Depression Scale, HADS). Results The paper- and web-based forms of the Spanish PCFS scale showed adequate construct validity, and the web-based form provided substantial test-retest reliability (kappa = 0.63). The percentage of agreement between the web-based and paper-based forms was high (88%). Functional status showed a high correlation with EQ-5D-5L (inverse) and GALI (direct) (both; Rho ≥ .743), a moderate correlation with HADS (Rho ≥ .409) and a low correlation with the Barthel Index (Rho < .30). The Kruskal–Wallis test showed statistically significant differences in EQ-5D-5L, GALI and HADS according to the degree of functional status. Conclusion The Spanish version of the PCFS scale (web-based and paper-based forms) showed adequate construct validity, and the web-based form provided substantial test-retest reliability in COVID-19 survivors.

The objective of the study is to analyze the impact of violence on women's health and the feelings generated during the period of exposure to violence. This is a qualitative study with an interpretative phenomenological design in which 16 women participated-4 through interviews and 12 through stories. The data obtained were analyzed using the Colaizzi approach. The results were structured into 3 themes according to how the women interpreted their experiences. The themes were physical consequences: visible traces; psychological consequences: stormy days and sunny days; and social consequences: from loneliness to a new world. In conclusion, the women in this study considered all those (very diverse) physical pathologies to be important. They encompassed a series of psychological disorders that lasted over time, causing considerable suffering and complicating the participants' ability to relate to the rest of society, especially men. Similarly, the participants identified a series of positive consequences when they left the traumatic situation empowered after overcoming gender-based violence.

Objective To describe the impact of different doses of corticosteroids on the evolution of patients with COVID-19 pneumonia, based on the potential benefit of the non-genomic mechanism of these drugs at higher doses. Methods Observational study using data collected from the SEMI-COVID-19 Registry. We evaluated the epidemiological, radiological and analytical scenario between patients treated with megadoses therapy of corticosteroids vs low-dose of corticosteroids and the development of complications. The primary endpoint was all-cause in-hospital mortality according to use of corticosteroids megadoses. Results Of a total of 14,921 patients, corticosteroids were used in 5,262 (35.3%). Of them, 2,216 (46%) specifically received megadoses. Age was a factor that differed between those who received megadoses therapy versus those who did not in a significant manner (69 years [IQR 59–79] vs 73 years [IQR 61–83]; p < .001). Radiological and analytical findings showed a higher use of megadoses therapy among patients with an interstitial infiltrate and elevated inflammatory markers associated with COVID-19. In the univariate study it appears that steroid use is associated with increased mortality (OR 2.07 95% CI 1.91–2.24 p < .001) and megadose use with increased survival (OR 0.84 95% CI 0.75–0.96, p 0.011), but when adjusting for possible confounding factors, it is observed that the use of megadoses is also associated with higher mortality (OR 1.54, 95% CI 1.32–1.80; p < .001). There is no difference between megadoses and low-dose (p .298). Although, there are differences in the use of megadoses versus low-dose in terms of complications, mainly infectious, with fewer pneumonias and sepsis in the megadoses group (OR 0.82 95% CI 0.71–0.95; p < .001 and OR 0.80 95% CI 0.65–0.97; p < .001) respectively. Conclusion There is no difference in mortality with megadoses versus low-dose, but there is a lower incidence of infectious complications with glucocorticoid megadoses.

BackgroundMost patients with COVID-19 receive antibiotics despite the fact that bacterial co-infections are rare. This can lead to increased complications, including antibacterial resistance. We aim to analyze risk factors for inappropriate antibiotic prescription in these patients and describe possible complications arising from their use.MethodsThe SEMI-COVID-19 Registry is a multicenter, retrospective patient cohort. Patients with antibiotic were divided into two groups according to appropriate or inappropriate prescription, depending on whether the patient fulfill any criteria for its use. Comparison was made by means of multilevel logistic regression analysis. Possible complications of antibiotic use were also identified.ResultsOut of 13,932 patients, 3047 (21.6%) were prescribed no antibiotics, 6116 (43.9%) were appropriately prescribed antibiotics, and 4769 (34.2%) were inappropriately prescribed antibiotics. The following were independent factors of inappropriate prescription: February-March 2020 admission (OR 1.54, 95%CI 1.18-2.00), age (OR 0.98, 95%CI 0.97-0.99), absence of comorbidity (OR 1.43, 95%CI 1.05-1.94), dry cough (OR 2.51, 95%CI 1.94-3.26), fever (OR 1.33, 95%CI 1.13-1.56), dyspnea (OR 1.31, 95%CI 1.04-1.69), flu-like symptoms (OR 2.70, 95%CI 1.75-4.17), and elevated C-reactive protein levels (OR 1.01 for each mg/L increase, 95% CI 1.00-1.01). Adverse drug reactions were more frequent in patients who received ANTIBIOTIC (4.9% vs 2.7%, p < .001).ConclusionThe inappropriate use of antibiotics was very frequent in COVID-19 patients and entailed an increased risk of adverse reactions. It is crucial to define criteria for their use in these patients. Knowledge of the factors associated with inappropriate prescribing can be helpful.

Environmental changes can modify the phenotypic characteristics of populations, which in turn can influence their evolutionary trajectories. In ectotherms like fishes, temperature is a particularly important environmental variable that is known to have significant impacts on the phenotype. Here, we raised specimens of the surface ecomorph of Astyanax mexicanus at temperatures of 20°C, 23°C, 25°C, and 28°C to examine how temperature influenced vertebral number and body shape. To increase biological realism, specimens were also subjected to two water turbulence regimes. Vertebral number was counted from x-rays and body shape variation was analysed using geometric morphometric methods. Temperature significantly impacted mean total vertebral number, which increased at the lowest and highest temperatures. Fish reared at lower temperatures had relatively more precaudal vertebrae while fish reared at higher temperatures had relatively more caudal vertebrae. Vertebral anomalies, especially vertebral fusions, were most frequent at the extreme temperature treatments. Temperature significantly impacted body shape as well, with fish reared at 20°C being particularly divergent. Water turbulence also impacted body shape in a generally predictable manner, with specimens reared in high turbulence environments being more streamlined and having extended dorsal and anal fin bases. Variation in environmental variables thus resulted in significant changes in morphological traits known to impact fish fitness, indicating that A. mexicanus has the capacity to exhibit a range of phenotypic plasticity when challenged by environmental change. Understanding the biochemical mechanisms underlying this plasticity and whether adaptive plasticity has influenced the evolutionary radiation of the Characidae, are major directions for future research.

It is well accepted that, at the global scale, the Gutenberg-Richter (GR) law describing the distribution of earthquake magnitude or seismic moment has to be modified at the tail to properly account for the most extreme events. It is debated, though, how much additional time of earthquake recording will be necessary to properly constrain this tail. Using the global CMT catalog, we study how three modifications of the GR law that incorporate a corner-value parameter are compatible with the size of the largest observed earthquake in a given time window. Current data lead to a rather large range of parameter values (e.g., corner magnitude from 8.6 to 10.2 for the so-called tapered GR distribution). Updating this estimation in the future will strongly depend on the maximum magnitude observed, but, under reasonable assumptions, the range will be substantially reduced by the end of this century, contrary to claims in previous literature.

A method of determining unknown phase-shifts between elementary images in two-dimensional Structured Illumination Microscopy (2D-SIM) is presented. The proposed method is based on the comparison of the peak intensity of spectral components. These components correspond to the inherent structured illumination spectral content and the residual component that appears from wrongly estimated phase-shifts. The estimation of the phase-shifts is carried out by finding the absolute maximum of a function defined as the normalized peak intensity difference in the Fourier domain. This task is performed by an optimization method providing a fast estimation of the phase-shift. The algorithm stability and robustness are tested for various levels of noise and contrasts of the structured illumination pattern. Furthermore, the proposed approach reduces the number of computations compared to other existing techniques. The method is supported by the theoretical calculations and validated by means of simulated and experimental results.

IntroductionPositron Emission Tomography (PET) imaging with selective 18 kDa translocator protein (TSPO) radiotracers has contributed to our understanding on the role of inflammation in disease development and progression. With an increasing number of rodent models of human disease and expansion of the preclinical PET imaging base worldwide, accurate quantification of longitudinal rodent TSPO PET datasets is necessary. This is particularly relevant as TSPO PET quantification relies on invasive blood sampling due to lack of a suitable tissue reference region. Here we investigate the kinetics and quantification bias of a novel TSPO radiotracer [18F]AB5186 in rats using automatic, manual and image derived input functions.Methods[18F]AB5186 was administered intravenously and dynamic PET imaging was acquired over 2 hours. Arterial blood was collected manually to derive a population based input function or using an automatic blood sampler to derive a plasma input function. Manually sampled blood was also used to analyze the [18F]AB5186 radiometabolite profile in plasma and applied to all groups as a population based dataset. Kinetic models were used to estimate distribution volumes (VT) and [18F]AB5186 outcome measure bias was determined.Results[18F]AB5186 distribution in rats was consistent with TSPO expression and at 2 h post-injection 50% of parent compound was still present in plasma. Population based manual sampling methods and image derived input function (IDIF) underestimated VT by ~50% and 88% compared with automatic blood sampling, respectively. The VT variability was lower when using IDIF versus arterial blood sampling methods and analysis of the Bland-Altman plots showed a good agreement between methods of analysis.ConclusionQuantification of TSPO PET rodent data using image-derived methods, which are more amenable for longitudinal scanning of small animals, yields outcome measures with reduced variability and good agreement, albeit biased, compared with invasive blood sampling methods.

In 1994, the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) included "culture-bound syndromes" in its classification of psychiatric disorders and associated them with disease processes that manifest in behavioural or thought disorders that develop within a given cultural context. This study examines the definitions, explanatory models, signs and symptoms, and healthcare-seeking behaviours common to Fang culture-bound syndromes (i.e., kong, eluma, witchcraft, mibili, mikug, and nsamadalu). The Fang ethnic group is the majority ethnic group in Equatorial Guinea. From September 2012 to January 2013, 45 key Fang informants were selected, including community leaders, tribal elders, healthcare workers, traditional healers, and non-Catholic pastors in 39 of 724 Fang tribal villages in 6 of 13 districts in the mainland region of Equatorial Guinea. An ethnographic approach with an emic-etic perspective was employed. Data were collected using semi-structured interviews, participant observation and a questionnaire that included DHS6 key indicators. Interviews were designed based on the Cultural Formulation form in the DSM-5 and explored the definition of Fang cultural syndromes, symptoms, cultural perceptions of cause, and current help-seeking. Participants defined "Fang culture-bound syndromes" as those diseases that cannot be cured, treated, or diagnosed by science. Such syndromes present with the same signs and symptoms as diseases identified by Western medicine. However, they arise because of the actions of enemies, because of the actions of spirits or ancestors, as punishments for disregarding the law of God, because of the violation of sexual or dietary taboos, or because of the violation of a Fang rite of passage, the dzas, which is celebrated at birth. Six Fang culture-bound syndromes were included in the study: 1) Eluma, a disease that is targeted at the victim out of envy and starts out with sharp, intense, focussed pain and aggressiveness; 2) Witchcraft, characterized by isolation from the outside, socially maladaptive behaviour, and the use of hallucinogenic substances; 3) Kong, which is common among the wealthy class and manifests as a disconnection from the environment and a lack of vital energy; 4) Mibili, a possession by evil spirits that manifests through visual and auditory hallucinations; 5) Mikug, which appears after a person has had contact with human bones in a ritual; and 6) Nsamadalu, which emerges after a traumatic process caused by violating traditions through having sexual relations with one's sister or brother. The therapeutic resources of choice for addressing Fang culture-bound syndromes were traditional Fang medicine and the religious practices of the Bethany and Pentecostal churches, among others. Among African ethnic groups, symbolism, the weight of tradition, and the principle of chance in health and disease are underlying factors in the presentation of certain diseases, which in ethno-psychiatry are now referred to as culture-bound syndromes. In this study, traditional healers, elders, healthcare professionals, religious figures, and leaders of the Fang community in Equatorial Guinea referred to six such cultural syndromes: eluma, witchcraft, kong, mibili, mikug, and nsamadalu. In the absence of a multidisciplinary approach to mental illness in the country, the Fang ethnic group seeks healthcare for culture-bound syndromes from traditional healing and religious rites in the Evangelical faiths.

To identify differences in Risky Consumption (RC) and Binge drinking (BD) trends in students who already followed these patterns of alcohol consumption on starting university and those who did not, and also to try to understand what leads students to engage in these types of behaviour at university.Cohort study among university students in Spain (n = 1382). BD and RC were measured with the Alcohol Use Disorders Identification Test at ages 18, 20, 22, 24 and 27 years. Multilevel logistic regression for repeated measures was used to calculate the adjusted Odds Ratios (ORs).The prevalence rates of RC and BD were lower throughout the study in students who did not follow these patterns of consumption at age 18. For RC and BD, the differences at age 27 years, expressed as percentage points (pp), were respectively 24 pp and 15 pp in women and 29 pp and 25 pp in men. Early age of onset of alcohol use increased the risk of engaging in RC and BD patterns at university, for men (OR = 2.91 & 2.80) and women (OR = 8.14 & 5.53). The same was observed in students living away from the parental home for BD (OR = 3.43 for men & 1.77 for women). Only women were influenced by having positive expectancies for engaging in RC (OR = 1.82) and BD (OR = 1.96).The prevalence rates of both RC and BD at age 27 years were much higher among university students who already followed these patterns of consumption at age 18 years, with the differences being proportionally higher among women. Focusing on the age of onset of alcohol consumption and hindering access to alcohol by minors should be priority objectives aimed at preventing students from engaging in these patterns of alcohol consumption at university.

Adaptation of crops to climate change has motivated an increasing interest in the potential value of novel traits from wild species; maize wild relatives, the teosintes, harbor traits that may be useful to maize breeding. To study the ecogeographic distribution of teosinte we constructed a robust database of 2363 teosinte occurrences from published sources for the period 1842-2016. A geographical information system integrating 216 environmental variables was created for Mexico and Central America and was used to characterize the environment of each teosinte occurrence site. The natural geographic distribution of teosinte extends from the Western Sierra Madre of the State of Chihuahua, Mexico to the Pacific coast of Nicaragua and Costa Rica, including practically the entire western part of Mesoamerica. The Mexican annuals Zea mays ssp. parviglumis and Zea mays ssp. mexicana show a wide distribution in Mexico, while Zea diploperennis, Zea luxurians, Zea perennis, Zea mays ssp. huehuetenangensis, Zea vespertilio and Zea nicaraguensis had more restricted and distinct ranges, representing less than 20% of the total occurrences. Only 11.2% of teosinte populations are found in Protected Natural Areas in Mexico and Central America. Ecogeographical analysis showed that teosinte can cope with extreme levels of precipitation and temperatures during growing season. Modelling teosinte geographic distribution demonstrated congruence between actual and potential distributions; however, some areas with no occurrences appear to be within the range of adaptation of teosintes. Field surveys should be prioritized to such regions to accelerate the discovery of unknown populations. Potential areas for teosintes Zea mays ssp. mexicana races Chalco, Nobogame, and Durango, Zea mays ssp. huehuetenangensis, Zea luxurians, Zea diploperennis and Zea nicaraguensis are geographically separated; however, partial overlapping occurs between Zea mays ssp. parviglumis and Zea perennis, between Zea mays ssp. parviglumis and Zea diploperennis, and between Zea mays ssp. mexicana race Chalco and Zea mays ssp. mexicana race Central Plateau. Assessing priority of collecting for conservation showed that permanent monitoring programs and in-situ conservation projects with participation of local farmer communities are critically needed; Zea mays ssp. mexicana (races Durango and Nobogame), Zea luxurians, Zea diploperennis, Zea perennis and Zea vespertilio should be considered as the highest priority taxa.

Mutations in eyes shut homolog (EYS), a gene predominantly expressed in the photoreceptor cells of the retina, are among the most frequent causes of autosomal recessive (ar) retinitis pigmentosa (RP), a progressive retinal disorder. Due to the absence of EYS in several rodent species and its retina-specific expression, still little is known about the exact function of EYS and the pathogenic mechanism underlying EYS-associated RP. We characterized eys in zebrafish, by RT-PCR analysis on zebrafish eye-derived RNA, which led to the identification of a 8,715 nucleotide coding sequence that is divided over 46 exons. The transcript is predicted to encode a 2,905-aa protein that contains 39 EGF-like domains and five laminin A G-like domains, which overall shows 33% identity with human EYS. To study the function of EYS, we generated a stable eysrmc101/rmc101 mutant zebrafish model using CRISPR/Cas9 technology. The introduced lesion is predicted to result in premature termination of protein synthesis and lead to loss of Eys function. Immunohistochemistry on retinal sections revealed that Eys localizes at the region of the connecting cilium and that both rhodopsin and cone transducin are mislocalized in the absence of Eys. Electroretinogram recordings showed diminished b-wave amplitudes in eysrmc101/rmc101 zebrafish (5 dpf) compared to age- and strain-matched wild-type larvae. In addition, decreased locomotor activity in response to light stimuli was observed in eys mutant larvae. Altogether, our study shows that absence of Eys leads to a disorganized retinal architecture and causes visual dysfunction in zebrafish.

Binge drinking (BD), a harmful pattern of alcohol consumption, is common during adolescence. Young adults with alcohol use disorders exhibit hippocampal alterations and episodic memory deficits. However, it is not known how these difficulties progress in community BD adolescents. Our objective was to analyze the relationship between BD trajectory and verbal episodic memory during the developmental period spanning from adolescence and to early adulthood. An initial sample of 155 male and female first-year university students with no other risk factors were followed over six years. Participants were classified as stable non-BDs, stable BDs and ex-BDs according to the third AUDIT item. At baseline, participants comprised 36 ♂/ 40 ♀ non-BDs (18.58 years), 40 ♂/ 39 ♀ BDs (18.87 years), and at the third follow-up, they comprised 8 ♂/ 8 ♀ stable non-BDs (25.49 years), 2 ♂/ 2 ♀ stable BDs (25.40) and 8 ♂/ 12 ♀ ex-BDs (24.97 years). Episodic memory was assessed four times with the Logical Memory subtest (WMS-III) and the Rey Auditory Verbal Learning Test (RAVLT). Generalized linear mixed models were applied. The results showed that, relative to non-BDs, stable BDs presented difficulties in immediate and delayed recall in the Logical Memory subtest. These difficulties remained stable over time. The short-term ex-BDs continued to display difficulties in immediate and delayed recall in the Logical Memory subtest, but long-term ex-BDs did not. The effects were not influenced by age of alcohol onset, frequency of cannabis use, tobacco use or psychopathological distress. In conclusion, BD during adolescence and young adulthood is associated with episodic memory deficits. Abandoning the BD pattern may lead to partial recovery. These findings are consistent with the vulnerability of the adolescent hippocampus to the neurotoxic effects of alcohol.

INTRODUCTION:The mechanisms of mononuclear phagocyte death have been associated with the permissiveness and resistance to mycobacterial replication, but it remains unknown whether or not they help predict the risk of developing TB. OBJECTIVE:To describe the factors associated with the induction of monocyte mitochondrial and membrane damage in response to PPD as well as determine if this type of damage might predict the susceptibility of developing active tuberculosis in a cohort of household contacts (HHCs) from Medellin, Colombia from 2005 to 2008. METHODS:The prospective cohort study contains 2060 HHCs patients with pulmonary tuberculosis who were meticulously followed for two years. A survey of the socio-demographic, clinical, epidemiological factors and blood samples were collected. Mononuclear cell cultures were stimulated with or without PPD and the type of monocyte death was determined by the flow of cytometry, an indicator was also used for its analysis. Logistic regression was adjusted by the Generalized Estimations Equations and the survival was estimated with the Kaplan-Meier and Cox regression. Confidence intervals were used for estimating the association. RESULTS:1,859 out of 2,060 blood samples of the HHCs patients analyzed showed monocyte death. In response to PPD, 83.4% underwent mitochondrial damage while 50.9% had membrane damage. The membrane damage in response to PPD was higher in children under 4 years (OR: 1.57; (95% CI: 1.1 to 2.4) and the HHCs who slept regularly in the same household has an index case of (OR: 1.54; 95% CI: 1.0 to 2.3). After adjustment by age, comorbidities, nutritional status, proximity to index case and overcrowding, the risk of developing active TB among BCG vaccinated HHCs individuals with induction of mitochondrial damage was HR = 0.19 (95% CI: 0.1 to 0.5). CONCLUSIONS:The induction of monocytes mitochondrial damage by PPD stimulation correlates with protection of TB disease development in BCG-vaccinated HHCs. This represents a potential tool to predict susceptibility of developing active disease in this population.

Molecular alterations leading progression of asymptomatic CLL-like high-count monoclonal B lymphocytosis (hiMBL) to chronic lymphocytic leukemia (CLL) remain poorly understood. Recently, genome-wide association studies have found 6p21.3, where the human leukocyte antigen (HLA) system is coded, to be a susceptibility risk region for CLL. Previous studies have produced discrepant results regarding the association between HLA and CLL development and outcome, but no studies have been performed on hiMBL.We evaluated the role of HLA class I (-A, -B and -C) and class II (-DRB1 and -DQB1) in hiMBL/CLL susceptibility, hiMBL progression to CLL, and treatment requirement in a large series of 263 patients diagnosed in our center with hiMBL (n = 156) or Binet A CLL (n = 107).No consistent association between HLA specificities and hiMBL or CLL susceptibility was found. With a median follow-up of 7.7 years, 48/156 hiMBLs (33%) evolved to asymptomatic CLLs, while 16 hiMBLs (10%) and 44 CLLs (41%) required treatment. No HLA specificities were found to be significantly associated with hiMBL progression or treatment in the whole cohort. However, within antigen-experienced immunoglobulin heavy-chain (IGHV)-mutated hiMBLs, which represents the highest proportion of hiMBL cases (81%), the presence of HLA-DQB1*03 showed a trend to a higher risk of progression to CLL (60% vs. 26%, P = 0.062). Moreover, HLA-DQB1*02 specificity was associated with a lesser requirement for 15-year treatment (10% vs. 36%, P = 0.012).In conclusion, our results suggest a role for HLA in IGHV-mutated hiMBL prognosis, and are consistent with the growing evidence of the influence of 6p21 on predisposition to CLL. Larger non-biased series are required to enable definitive conclusions to be drawn.

Our main objective was to analyse the different contributions of relational verbal reasoning (analogical and class inclusion) and executive functioning to metaphor comprehension across development. We postulated that both relational reasoning and executive functioning should predict individual and developmental differences. However, executive functioning would become increasingly involved when metaphor comprehension is highly demanding, either because of the metaphors' high difficulty (relatively novel metaphors in the absence of a context) or because of the individual's special processing difficulties, such as low levels of reading experience or low semantic knowledge. Three groups of participants, 11-year-olds, 15-year-olds and young adults, were assessed in different relational verbal reasoning tasks-analogical and class-inclusion-and in executive functioning tasks-updating information in working memory, inhibition, and shifting. The results revealed clear progress in metaphor comprehension between ages 11 and 15 and between ages 15 and 21. However, the importance of executive function in metaphor comprehension was evident by age 15 and was restricted to updating information in working memory and cognitive inhibition. Participants seemed to use two different strategies to interpret metaphors: relational verbal reasoning and executive functioning. This was clearly shown when comparing the performance of the "more efficient" participants in metaphor interpretation with that of the "less efficient" ones. Whereas in the first case none of the executive variables or those associated with relational verbal reasoning were significantly related to metaphor comprehension, in the latter case, both groups of variables had a clear predictor effect.

The theory of finite-size scaling explains how the singular behavior of thermodynamic quantities in the critical point of a phase transition emerges when the size of the system becomes infinite. Usually, this theory is presented in a phenomenological way. Here, we exactly demonstrate the existence of a finite-size scaling law for the Galton-Watson branching processes when the number of offsprings of each individual follows either a geometric distribution or a generalized geometric distribution. We also derive the corrections to scaling and the limits of validity of the finite-size scaling law away the critical point. A mapping between branching processes and random walks allows us to establish that these results also hold for the latter case, for which the order parameter turns out to be the probability of hitting a distant boundary.

Despite being a paradigm of quantitative linguistics, Zipf's law for words suffers from three main problems: its formulation is ambiguous, its validity has not been tested rigorously from a statistical point of view, and it has not been confronted to a representatively large number of texts. So, we can summarize the current support of Zipf's law in texts as anecdotic. We try to solve these issues by studying three different versions of Zipf's law and fitting them to all available English texts in the Project Gutenberg database (consisting of more than 30 000 texts). To do so we use state-of-the art tools in fitting and goodness-of-fit tests, carefully tailored to the peculiarities of text statistics. Remarkably, one of the three versions of Zipf's law, consisting of a pure power-law form in the complementary cumulative distribution function of word frequencies, is able to fit more than 40% of the texts in the database (at the 0.05 significance level), for the whole domain of frequencies (from 1 to the maximum value), and with only one free parameter (the exponent).

Antithrombin is a crucial anticoagulant serpin whose even moderate deficiency significantly increases the risk of thrombosis. Most cases with antithrombin deficiency carried genetic defects affecting exons or flanking regions of SERPINC1.We aimed to identify regulatory mutations inSERPINC1 through sequencing the promoter, intron 1 and 2 of this gene in 23 patients with antithrombin deficiency but without known genetic defects. Three cases with moderate antithrombin deficiency (63-78%) carried potential regulatory mutations. One located 200 bp before the initiation ATG and two in intron 1. These mutations disrupted two out of five potential vitamin D receptor elements (VDRE) identified in SERPINC1 with different software. One genetic defect, c.42-1060_-1057dupTTGA, was a new low prevalent polymorphism (MAF: 0.01) with functional consequences on plasma antithrombin levels. The relevance of the vitamin D pathway on the regulation of SERPINC1 was confirmed in a cell model. Incubation of HepG2 with paricalcitol, a vitamin D analog, increased dose-dependently the levels of SERPINC1transcripts and antithrombin released to the conditioned medium. This study shows further evidence of the transcriptional regulation of SERPINC1 by vitamin D and first describes the functional and pathological relevance of mutations affecting VDRE of this gene. Our study opens new perspectives in the search of new genetic defects involved in antithrombin deficiency and the risk of thrombosis as well as in the design of new antithrombotic treatments.

Heparanase is an endoglycosidase that participates in morphogenesis, tissue repair, heparan sulphates turnover and immune response processes. It is over-expressed in tumor cells favoring the metastasis as it penetrates the endothelial layer that lines blood vessels and facilitates the metastasis by degradation of heparan sulphate proteoglycans of the extracellular matrix. Heparanase may also affect the hemostatic system in a non-enzymatic manner, up-regulating the expression of tissue factor, which is the initiator of blood coagulation, and dissociating tissue factor pathway inhibitor on the cell surface membrane of endothelial and tumor cells, thus resulting in a procoagulant state. Trying to check the effect of heparanase on heparin, a highly sulphated glycosaminoglycan, when it activates antithrombin, our results demonstrated that heparanase, but not proheparanase, interacted directly with antithrombin in a non-covalent manner. This interaction resulted in the activation of antithrombin, which is the most important endogenous anticoagulant. This activation mainly accelerated FXa inhibition, supporting an allosteric activation effect. Heparanase bound to the heparin binding site of antithrombin as the activation of Pro41Leu, Arg47Cys, Lys114Ala and Lys125Alaantithrombin mutants was impaired when it was compared to wild type antithrombin. Intrinsic fluorescence analysis showed that heparanase induced an activating conformational change in antithrombin similar to that induced by heparin and with a KD of 18.81 pM. In conclusion, under physiological pH and low levels of tissue factor, heparanase may exert a non-enzymatic function interacting and activating the inhibitory function of antithrombin.

The effects produced by transcranial direct current stimulation (tDCS) applied to the motor system have been widely studied in the past, chiefly focused on primary motor cortex (M1) excitability. However, the effects on functional tasks are less well documented.This study aims to evaluate the effect of tDCS-M1 on goal-oriented actions (i.e., arm-reaching movements; ARM), in a reaction-time protocol.13 healthy subjects executed dominant ARM as fast as possible to one of two targets in front of them while surface EMG was recorded. Participants performed three different sessions. In each session they first executed ARM (Pre), then received tDCS, and finally executed Post, similar to Pre. Subjects received three different types of tDCS, one per session: In one session the anode was on right-M1 (AR), and the cathode on the left-M1 (CL), thus termed AR-CL; AL-CR reversed the montage; and Sham session was applied likewise. Real stimulation was 1mA-10min while subjects at rest. Three different variables and their coefficients of variation (CV) were analyzed: Premotor times (PMT), reaction-times (RT) and movement-times (MT).triceps-PMT were significantly increased at Post-Sham, suggesting fatigue. Results obtained with real tDCS were not different depending on the montage used, in both cases PMT were significantly reduced in all recorded muscles. RT and MT did not change for real or sham stimulation. RT-CV and PMT-CV were reduced after all stimulation protocols.tDCS reduces premotor time and fatigability during the execution of fast motor tasks. Possible underlying mechanisms are discussed.

Secondary lymphedema is a common complication of cancer treatment and recent studies have demonstrated that lymph node transplantation (LNT) can decrease swelling, as well as the incidence of infections. However, although these results are exciting, the mechanisms by which LNT improves these pathologic findings of lymphedema remain unknown. Using a transgenic mouse model of lymphedema, this study sought to analyze the effect of LNT on lymphatic regeneration and T cell-mediated immune responses.We used a mouse model in which the expression of the human diphtheria toxin receptor is driven by the FLT4 promoter to enable the local ablation of the lymphatic system through subdermal hindlimb diphtheria toxin injections. Popliteal lymph node dissection was subsequently performed after a two-week recovery period, followed by either orthotopic LNT or sham surgery after an additional two weeks. Hindlimb swelling, lymphatic vessel regeneration, immune cell trafficking, and T cell-mediated immune responses were analyzed 10 weeks later.LNT resulted in a marked decrease in hindlimb swelling, fibroadipose tissue deposition, and decreased accumulation of perilymphatic inflammatory cells, as compared to controls. In addition, LNT induced a marked lymphangiogenic response in both capillary and collecting lymphatic vessels. Interestingly, the resultant regenerated lymphatics were abnormal in appearance on lymphangiography, but LNT also led to a notable increase in dendritic cell trafficking from the periphery to the inguinal lymph nodes and improved adaptive immune responses.LNT decreases pathological changes of lymphedema and was shown to potently induce lymphangiogenesis. Lymphatic vessels induced by LNT were abnormal in appearance, but were functional and able to transport antigen-presenting cells. Animals treated with LNT have an increased ability to mount T cell-mediated immune responses when sensitized to antigens in the affected hindlimb.

[This corrects the article DOI: 10.1371/journal.pone.0152159.].

To evaluate the prevalence of alcohol consumption among university students during late adolescence and young adulthood and to identify the associated factors.Cohort study among university students in Spain (n = 1382). Heavy Episodic Drinking (HED) and Risky Consumption (RC) were measured with the Alcohol Use Disorders Identification Test (AUDIT) at ages 18, 20, 22, 24 and 27 years. Data on potential factors associated with alcohol use were obtained with an additional questionnaire. Multilevel logistic regression for repeated measures was used to obtain adjusted OR (Odds Ratios).The rates of prevalence of RC were lower, but not statistically significant, in women. The age-related changes in these rates were similar in both genders, and the prevalence of RC peaked at 20 years. By contrast, the prevalence of HED was significantly lower in women and peaked at 18 years in women and at 22 years in men. Multivariate models showed that early age of onset of alcohol use (OR = 10.6 and OR = 6.9 for women; OR = 8.3 and OR = 8.2 for men) and positive expectations about alcohol (OR = 7.8 and OR = 4.5 for women; OR = 3.6 and OR = 3.3 for men) were the most important risk factors for RC and HED. Living away from the family home was also a risk factor for both consumption patterns among women (OR = 3.16 and OR = 2.34), while a high maternal education level was a risk factor for RC among both genders (OR = 1.62 for women; OR = 2.49 for men).Alcohol consumption decreases significantly at the end of youth, with higher rates of prevalence and a later peak among men. Prevention strategies should focus on beliefs and expectations about alcohol and on delaying the age of onset. Women are at particular risk for these consumption patterns if they live away from their parents. Belonging to a high-income family is a strong risk factor for RC.

Contrast-induced nephropathy (CIN) is an iatrogenic medical event for which there is not yet a successful therapy. Increasing evidence in rodents has suggested that this disease is associated with renal tubular and vascular injury that is triggered directly by oxidative stress. In the present study, we evaluated whether the antioxidant resin from Virola oleifera (RV) could attenuate renal damage in an experimental mouse model of CIN. Adult male Swiss mice were divided into six groups and pre-treated orally with RV (10, 100 and 300 mg/kg), N-acetylcysteine (200 mg/kg) or vehicle for 5 days before the induction of CIN and Control group. Renal function was assessed by measuring plasma creatinine and urea levels. Additionally, renal oxidative stress and apoptosis/cell viability were determined with flow cytometry. Finally, kidney tissues were sectioned for histopathological examination. In this CIN model, pre-treatment with RV improved renal function, lowered the mortality rate, and reduced oxidative stress and apoptosis in both the medulla and cortex renal cells in a dose-dependent manner. Moreover, the RV treatment had beneficial effects on kidney histopathology that were superior to the standard treatment with N-acetylcysteine. These data suggest that because of its antioxidative and antiapoptotic effects and its ability to preserve renal function, resin from Virola oleifera may have potential as a new therapeutic approach for preventing CIN.

Zipf's law is a fundamental paradigm in the statistics of written and spoken natural language as well as in other communication systems. We raise the question of the elementary units for which Zipf's law should hold in the most natural way, studying its validity for plain word forms and for the corresponding lemma forms. We analyze several long literary texts comprising four languages, with different levels of morphological complexity. In all cases Zipf's law is fulfilled, in the sense that a power-law distribution of word or lemma frequencies is valid for several orders of magnitude. We investigate the extent to which the word-lemma transformation preserves two parameters of Zipf's law: the exponent and the low-frequency cut-off. We are not able to demonstrate a strict invariance of the tail, as for a few texts both exponents deviate significantly, but we conclude that the exponents are very similar, despite the remarkable transformation that going from words to lemmas represents, considerably affecting all ranges of frequencies. In contrast, the low-frequency cut-offs are less stable, tending to increase substantially after the transformation.

Paget disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. The main alteration resides in osteoclasts that increase in size, number and activity. Many osteoclasts have cytoplasmic inclusions that have been associated with protein aggregates, increasing the evidences of a possible deregulation of autophagy in the development of the PDB. Autophagy starts with encapsulation of the target into a double-membrane-bound structure called an "autophagosome." It has been reported that at least 18 ATG genes (autophagy-related genes) are involved in autophagosome formation. We have studied the distribution of genotypes of the ATG2B rs3759601, ATG16L1 rs2241880, ATG10 rs1864183 and ATG5 rs2245214 polymorphisms in a Spanish cohort of subjects with PDB and compared with healthy subjects. Our results show that being a carrier of the C allele of the ATG16L1 rs2241880 and the G allele of ATG5 rs2245214 polymorphisms were associated with an increased risk of developing PDB, whereas being a carrier of the T allele of ATG10 rs1864183 polymorphism decreased the risk of suffering the disease in our series. This is the first report that shows an association between autophagy and Paget Disease of Bone and requires further confirmation in other series.

The inefficient glycosylation of consensus sequence on N135 in antithrombin explains the two glycoforms of this key anticoagulant serpin found in plasma: α and β, with four and three N-glycans, respectively. The lack of this N-glycan increases the heparin affinity of the β-glycoform. Recent studies have demonstrated that an aromatic sequon (Phe-Y-Asn-X-Thr) in reverse β-turns enhances N-glycosylation efficiency and stability of different proteins. We evaluated the effect of the aromatic sequon in this defective glycosylation site of antithrombin, despite of being located in a loop between the helix D and the strand 2A. We analyzed the biochemical and functional features of variants generated in a recombinant cell system (HEK-EBNA). Cells transfected with wild-type plasmid (K133-Y-N135-X-S137) generated 50% of α and β-antithrombin. The S137T, as previously reported, K133F, and the double mutant (K133F/S137T) had improved glycosylation efficiency, leading to the secretion of α-antithrombin, as shown by electrophoretic and mass analysis. The presence of the aromatic sequon did not significantly affect the stability of this conformationally sensitive serpin, as revealed by thermal denaturation assay. Moreover, the aromatic sequon hindered the activation induced by heparin, in which is involved the helix D. Accordingly, K133F and particularly K133F/S137T mutants had a reduced anticoagulant activity. Our data support that aromatic sequons in a different structural context from reverse turns might also improve the efficiency of N-glycosylation.

Binge drinking or heavy episodic drinking is a high prevalent pattern of alcohol consumption among young people in several countries. Despite increasing evidence that binge drinking is associated with impairments in executive aspects of working memory (i.e. self-ordered working memory), processes known to depend on the mid-dorsolateral prefrontal cortex (Brodmann areas 46 and 9), less is known about the impact of binge drinking on prefrontal gray matter integrity. Here, we investigated the effects of binge drinking on gray matter volume of mid- dorsolateral prefrontal cortex in youths. We used voxel-based morphometry on the structural magnetic resonance images of subjects reporting a persistent (at least three years) binge drinking pattern of alcohol use (n = 11; age 22.43 ± 1.03) and control subjects (n = 21; age 22.18 ± 1.08) to measure differences in gray matter volume between both groups. In a region of interest analysis of the mid-dorsolateral prefrontal cortex, after co-varying for age and gender, we observed significantly larger gray matter volume in the left mid-dorsolateral prefrontal cortex (Brodmann areas 46 and 9) in binge drinkers in comparison with control subjects. Furthermore, there was a significant positive correlation between left mid-dorsolateral prefrontal cortex volume and Self-Ordered Pointing Test (SOPT) total errors score in binge drinkers. The left mid-dorsolateral prefrontal cortex volume also correlated with the quantity and speed of alcohol intake. These findings indicate that a repeated exposure to alcohol -that does not meet criteria for alcohol dependence- throughout post-adolescent years and young adulthood is linked with structural anomalies in mid-dorsolateral prefrontal regions critically involved in executive aspects of working memory.

NK cell effector functions are controlled by a combination of inhibitory receptors, which modulate NK cell activation initiated by stimulatory receptors. Most of the canonical NK cell inhibitory receptors recognize allelic forms of classical and non-classical MHC class I molecules. Furthermore, high expression of MHC-I molecules on effector immune cells is also associated with reverse signaling, giving rise to several immune-regulatory functions. Consequently, the inhibitory function of MHC class I expressed on a human NKL cell line and activated primary NK and T cells on different activating receptors are analyzed in this paper. Our results reveal that MHC-I molecules display specific patterns of "selective" inhibition over cytotoxicity and cytokine production induced by ITAM-dependent receptors and 2B4, but not on NKG2D. This contrasts with the best known "canonical" inhibitory receptors, which constitutively inhibit both functions, regardless of the activating receptor involved. Our results support the existence of a new fine-tuner inhibitory function for MHC-I molecules expressed on cytotoxic effector cells that could be involved in establishing self-tolerance in mature activated NK cells, and could also be important in tumor and infected cell recognition.