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Abstract Background One of the most unusual sources of phylogenetically restricted genes is the molecular domestication of transposable elements into a host genome as functional genes. Although these kinds of events are sometimes at the core of key macroevolutionary changes, their origin and organismal function are generally poorly understood. Results Here, we identify several previously unreported transposable element domestication events in the human and mouse genomes. Among them, we find a remarkable molecular domestication that gave rise to a multigenic family in placental mammals, the Bex/Tceal gene cluster. These genes, which act as hub proteins within diverse signaling pathways, have been associated with neurological features of human patients carrying genomic microdeletions in chromosome X. The Bex/Tceal genes display neural-enriched patterns and are differentially expressed in human neurological disorders, such as autism and schizophrenia. Two different murine alleles of the cluster member Bex3 display morphological and physiopathological brain modifications, such as reduced interneuron number and hippocampal electrophysiological imbalance, alterations that translate into distinct behavioral phenotypes. Conclusions We provide an in-depth understanding of the emergence of a gene cluster that originated by transposon domestication and gene duplication at the origin of placental mammals, an evolutionary process that transformed a non-functional transposon sequence into novel components of the eutherian genome. These genes were integrated into existing signaling pathways involved in the development, maintenance, and function of the CNS in eutherians. At least one of its members, Bex3, is relevant for higher brain functions in placental mammals and may be involved in human neurological disorders.

Abstract Background Comminuted proximal ulna fractures are severe injuries with a high degree of instability. These injuries require surgical treatment, usually angular stable plating or double plating is performed. Nailing of proximal ulna fracture is described but not performed regularly. The aim of this study was to compare a newly developed, locked proximal ulna nail with an angular stable plate in an unstable fracture of the proximal ulna. We hypothesize, that locked nailing of the proximal ulna will provide non-inferior stability compared to locked plating. Methods A defect fracture distal to the coronoid was simulated in 20 sawbones. After nailing or plate osteosynthesis the constructs were tested in a servo-pneumatic testing machine under physiological joint motion (0°-90°) and cyclic loading (30 N – 300 N). Intercyclic osteotomy gap motion and plastic deformation of the constructs were analyzed using micromotion video-analysis. Results The locked nail showed lower osteotomy gap motion (0.50 ± 0.15 mm) compared to the angular stable plate (1.57 ± 0.37 mm, p

Abstract Background Non-communicable Diseases (NCDs) are the leading cause of global mortality and disability with a rising burden in low- and middle-income countries. Their multifactorial aetiology, and their requirement of long-term care, implies the need for comprehensive approaches. From 2009, the Ministry of Health (MoH) in El Salvador has developed a national public health system based on comprehensive primary health care. This study aims to describe the different stakeholders’ perceptions about the management of NCDs along the pathways of care in this health system. Methods During three fieldwork periods in 2018, three complementary qualitative data collection methods were deployed and conducted in settings with high prevalence of NCDs within El Salvador. First, illness narrative methodology was used to document the life histories of people living with a chronic disease and being treated in second and third level health facilities. Second, through social mapping, support resources that NCD patients used throughout the process of their illness within the same settings were analysed. Third, semi-structured interviews were conducted in the same locations, with both chronic patients and health personnel working at different levels of the primary health care setting. Participants were recruited through purposive and snowball sampling, and a deductive approach was implemented for coding during the analysis phase. After grouping codes into potential themes, a thematic framework was developed using a reflexive approach and following triangulation of the data. Results This innovative approach of combining three well-defined qualitative methods identified key implications for the implementation of a comprehensive approach to NCD management in resource-poor settings. The following elements are identified: 1) social risk factors and barriers to care; 2) patient pathways to NCD care; 3) available resources identified through social connections mapping; 4) trust in social connections; and 5) community health promotion and NCD prevention management. Conclusions The Salvadoran public health system has been able to strengthen its comprehensive approach to NCDs, combining a clinical approach – including long-term follow-up – with a preventive community-based strategy. The structural collaboration between the health system and the (self-) organised community has been essential for identifying failings, discuss tensions and work out adapted solutions.

Abstract The synthesis of a foldable viologen-functionalized peptide–polymer conjugate is presented. The ABA-type triblock conjugate with a PEG polymer was capped with a FHFHF pentapeptide sequence and further modified with a viologen building block at both chain ends. The pH-responsive peptide domains fold into an intermediate structure inducing close proximity of the viologen units, which upon a reduction step form π-dimers of the radical cation. Overall the intramolecular folding and intermolecular self-assembly process leads to the formation of supramolecular nanorods. Mixing of viologen-peptide–polymer conjugates with unfunctionalized conjugates leads to crosslinking of the nanorods and hydrogels with a tunable content of viologen end groups. π-Dimerization in the gels induces a deep purple color, which is used as an optical probe to monitor the diffusion of molecular oxygen through the hydrogel matrix.

Abstract Background One of today’s greatest challenges in public health worldwide - and especially its key management from Primary Health Care (PHC) - is the growing burden of non-communicable diseases (NCDs). In El Salvador, since 2009 the Minister of Health (MoH) has scaled up a national public health system based on a comprehensive PHC approach. A national multi-sectorial strategic plan for a comprehensive approach to NCDs has also been developed. This analysis explores stakeholders’ perceptions related to the management of NCDs in PHC and, in particular, the role of social participation. Methods A case-study was developed consisting of semi structured interviews and official document reviews. Semi-structured interviews were developed with chronic patients (14) and PHC professionals working in different levels within PHC (12). Purposive sampling was used to recruit participants. A non-pure, deductive approach was implemented for coding. After grouping codes into potential themes, a thematic framework was elaborated through a reflexive approach and the triangulation of the data. The research was conducted between March and August of 2018 in three different departments of El Salvador. Results The structure and the functioning of the Salvadoran PHC system and its intersectoral approach is firstly described. The interdisciplinary PHC-team brings holistic health care closer to the communities in which health promoters play a key role. The findings reflect the generally positive perception of the PHC system in terms of accessibility, quality and continuity of care by chronic patients. Community engagement and the National Health Forum are ensuring accountability through social controllership mechanisms. However, certain challenges were also noted during the interviews related to the shortage of medication and workforce; coordination between the levels of care and the importance of prevention and health promotion programmes for NCDs. Conclusions The Salvadoran PHC and its comprehensive approach to NCDs with an emphasis on intersectoral participation has been positively perceived by the range of stakeholders interviewed. Social engagement and the NHF works as a driving force to ensure accountability as well as in the promotion of a preventive culture. The challenges identified provide keys to amplify knowledge for addressing inequalities in health by strengthening PHC and its NCDs management.

This article empirically tests the role of legacy and digital-born news media, mapping the patterns of audience navigation across news sources and the relationship between news providers. We borrow tools from network science to bring evidence that suggest legacy news media retain control of the most central positions in the online news domain. Great progress has been made in discussing theoretically the impact of the Internet on the news media ecology. Less research attention, however, has been given to empirically testing changes in the role of legacy media and the rising prominence of digital-born outlets. To fill this gap, in this study we use the hyperlink-induced topic search algorithm, which identifies authorities by means of a hyperlink network, to show that legacy media are still the most authoritative sources in the media ecology. To further substantiate their dominant role, we also examine the structural position of news providers in the audience network. We gather navigation data from a panel of 30,000 people and use it to reproduce the network of patterns of news consumption. While legacy news media retain control of the brokerage positions for the general population, our analysis—focused on patterns of young news consumers—reveals that new digital outlets also occupy relevant positions to control the audience flow. The results of this study have substantive implications for our understanding of news organizations’ roles and how they attain authority in the digital age.

Abstract Background Adult forearm fractures require surgical treatment in most cases. Open reduction and internal fixation with plate osteosynthesis is the therapy of choice. Intramedullary fixation offers several advantages compared to plate fixation but is not routinely used. The aim of our study was to compare a newly designed ulna nail with angular stable plating in a biomechanical testing setup of an ulna shaft fracture with a diaphyseal defect. Methods Ten pairs of sawbones with a defect osteotomy of the ulna shaft (OTA 2U2C3) were fixed with an interlocked nail or locked plate osteosynthesis. The constructs were tested under four-point bending, torsional loading and axial loading in a servo-pneumatic testing machine to compare the stiffness of both stabilization methods. Results The nail constructs show lower yet sufficient bending stiffness (62.25 ± 6.64 N/mm) compared to the plate constructs (71.2 ± 5.98 N/mm, p = 0.005). The torsional loading test shows superior stiffness of the plate constructs (0.24 ± 0.03 Nm/deg vs. 0.1 ± 0.01 Nm/deg; p < 0.001), while the axial loading shows superior stiffness of the nail constructs (1028.9 ± 402.1 N/mm vs. 343.9 ± 112.6 N/mm; p < 0.001). Conclusions Intramedullary nailing of ulna shaft fractures obtains sufficient but lower stability in bending and torsional loading when compared to rigid angular stable plating and could be an alternative technique to plate fixation. The lower stability and the closed stabilization technique allow for a rapid periosteal healing, which is not present in stiffer constructs.

Abstract Background Dysphagia is a common and serious complication after (chemo)radiotherapy (CRT) for head-and-neck cancer (HNC) patients. Prophylactic swallowing exercises (PSE) can have a significantly positive effect on post-treatment swallowing function. However, low adherence rates are a key issue in undermining this positive effect. This current randomized trial will investigate the effect of adherence-improving measures on patients’ swallowing function, adherence and quality of life (QOL). Methods This ongoing trial will explore the difference in adherence and swallowing-related outcome variables during and after PSE in HNC patients performing the same therapy schedule, receiving different delivery methods. One hundred and fifty patients treated in various hospitals will be divided into three groups. Group 1 performs PSE at home, group 2 practices at home with continuous counseling through an app and group 3 receives face-to-face therapy by a speech and language pathologist. The exercises consist of tongue-strengthening exercises and chin-tuck against resistance with effortful swallow. The Iowa Oral Performance Instrument and the Swallowing Exercise Aid are used for practicing. Patients are evaluated before, during and after treatment by means of strength measurements, swallowing and QOL questionnaires. Discussion Since low adherence rates undermine the positive impact of PSE on post-treatment swallowing function, there is need to develop an efficient PSE protocol maximizing adherence rates. Trial registration ISRCTN, ID: ISRCTN98243550. Registered retrospectively on 21 December 2018.

Abstract Background Impulsivity and compulsivity are related to emotional and social maladjustment and often underlie psychiatric disorders. Recently, alterations in microbiota composition have been shown to have implications for brain development and social behavior via the microbiota–gut–brain axis. However, the exact mechanisms are not fully identified. Recent evidence suggests the modulatory effect of synbiotics on gut microbiota and the contribution of these agents in ameliorating symptoms of many psychiatric diseases. To date, no randomized controlled trial has been performed to establish the feasibility and efficacy of this intervention targeting the reduction of impulsivity and compulsivity. We hypothesize that supplementation with synbiotics may be an effective treatment in adults with high levels of impulsivity and/or compulsivity. Methods/design This is a prospective, multicenter, double-blind, randomized controlled trial with two arms: treatment with a synbiotic formula versus placebo treatment. The primary outcome is the response rate at the end of the placebo-controlled phase (response defined as a Clinical Global Impression–Improvement Scale score of 1 or 2 = very much improved or much improved, plus a reduction in the Affective Reactivity Index total score of at least 30% compared with baseline). A total of 180 participants with highly impulsive behavior and a diagnosis of attention deficit/hyperactivity disorder (ADHD) and/or borderline personality disorder, aged 18–65 years old, will be screened at three study centers. Secondary outcome measures, including changes in general psychopathology, ADHD symptoms, neurocognitive function, somatic parameters, physical activity, nutritional intake, and health-related quality of life, will be explored at assessments before, during, and at the end of the intervention. The effect of the intervention on genetics, microbiota, and several blood biomarkers will also be assessed. Gastrointestinal symptoms and somatic complaints will additionally be explored at 1-week follow-up. Discussion This is the first randomized controlled trial to determine the effects of supplementation with synbiotics on reducing impulsive and compulsive behavior. This clinical trial can contribute to explaining the mechanisms involved in the crosstalk between the intestinal microbiome and the brain. If effects can be established by reducing impulsive and compulsive behavior, new cost-effective treatments might become available to these patients. Trial registration ClinicalTrials.gov, NCT03495375 . Registered on 26 February 2018.

Resumen: Introducción: Los grupos de morbilidad ajustados (GMA) y los clinical risk groups (CRG) son herramientas de estratificación poblacional basada en la morbilidad que permiten clasificar a los pacientes en categorías mutuamente excluyentes. Objetivo: Comparar la estratificación, según niveles de complejidad, proporcionada por los GMA con la de los CRG y con la realizada ad-hoc por los evaluadores. Diseño: Muestra aleatoria por estratos de riesgo de morbilidad. Emplazamiento: Cataluña. Participantes: Cuarenta médicos de atención primaria emparejados 2 a 2. Intervenciones: Cada pareja de evaluadores tuvo que validar 25 historias. Mediciones principales: Se evaluó la concordancia entre evaluadores, y entre los evaluadores y los resultados obtenidos por los 2 agrupadores de morbilidad con el índice kappa, la sensibilidad, la especificidad, el valor predictivo positivo y el negativo. Resultados: La concordancia entre evaluadores se situó alrededor del valor kappa 0,75 (valor medio = 0,67), entre los GMA y los evaluadores fue similar (valor medio = 0,63), y más elevada que para los CRG (valor medio = 0,35). Los profesionales otorgaron una puntuación de 7,5 a la bondad de ambos agrupadores, aunque para los estratos de mayor complejidad, según asignación de los profesionales, los GMA obtuvieron mejores puntuaciones que los CRG. Los profesionales prefirieron mayoritariamente los GMA frente a los CRG. Estas diferencias se incrementaron con el aumento de la complejidad de los pacientes según el criterio clínico.Globalmente, se encontró menos de un 2% de errores graves de clasificación proporcionada por ambos agrupadores. Conclusión: Los profesionales consideraron que ambos agrupadores clasificaban adecuadamente a la población, aunque los GMA tienen un mejor comportamiento en los estratos que los profesionales identifican como de mayor complejidad. Además, en la mayoría de los casos, los evaluadores clínicos prefirieron los GMA. Abstract: Introduction: Adjusted Morbidity Groups (GMAs) and the Clinical Risk Groups (CRGs) are population morbidity based stratification tools which classify patients into mutually exclusive categories. Objetive: To compare the stratification provided by the GMAs, CRGs and that carried out by the evaluators according to the levels of complexity. Design: Random sample stratified by morbidity risk. Location: Catalonia. Participants: Forty paired general practitioners in the primary care, matched pairs. Interventions: Each pair of evaluators had to review 25 clinical records. Main outputs: The concordance by evaluators, and between the evaluators and the results obtained by the 2 morbidity tools were evaluated according to the kappa index, sensitivity, specificity, and positive and negative predicted values. Results: The concordance between general practitioners pairs was around the kappa value 0.75 (mean value = 0.67), between the GMA and the evaluators was similar (mean value = 0.63), and higher than for the CRG (mean value = 0.35). The general practitioners gave a score of 7.5 over 10 to both tools, although for the most complex strata, according to the professionals’ assignment, the GMA obtained better scores than the CRGs. The professionals preferred the GMAs over the CRGs. These differences increased with the complexity level of the patients according to clinical criteria.Overall, less than 2% of serious classification errors were found by both groupers. Conclusion: The evaluators considered that both grouping systems classified the studied population satisfactorily, although the GMAs showed a better performance for more complex strata. In addition, the clinical raters preferred the GMAs in most cases. Palabras clave: Agrupador de morbilidad, Multimorbilidad, Validación clínica, Keywords: Morbidity grouper, Multimorbidity, Clinical Validation

In this paper, we analyze the two-node joint clock synchronization and ranging problem. We focus on the case of nodes that employ time-to-digital converters to determine the range between them precisely. This specific design choice leads to a sawtooth model for the captured signal, which has not been studied before from an estimation theoretic standpoint. In the study of this model, we recover the basic conclusion of a well-known article by Freris, Graham, and Kumar in clock synchronization. More importantly, we discover a surprising identifiability result on the sawtooth signal model: noise improves the theoretical condition of the estimation of the phase and offset parameters. To complete our study, we provide performance references for joint clock synchronization and ranging using the sawtooth signal model by presenting an exhaustive simulation study on basic estimation strategies under different realistic conditions. With our contributions in this paper, we enable further research in the estimation of sawtooth signal models and pave the path towards their industrial use for clock synchronization and ranging.

BackgroundDialysis patients have been shown to have low serum carnitine due to poor nutrition, deprivation of endogenous synthesis from kidneys, and removal by hemodialysis. Carnitine deficiency leads to impaired cardiac function and dialysis-related hypotension which are associated with increased mortality. Supplementing with levocarnitine among hemodialysis patients may diminish incidence of intradialytic hypotension. Data on this topic, however, lacks consensus.MethodsWe conducted electronic searches in PubMed, Embase and Cochrane Central Register of Controlled Trials from January 1960 to 19th November 2021 to identify randomized controlled studies (RCTs), which examined the effects of oral or intravenous levocarnitine (L-carnitine) on dialysis-related hypotension among hemodialysis patients. The secondary outcome was muscle cramps. Study results were pooled and analyzed utilizing the random-effects model. Trial sequential analysis (TSA) was performed to assess the strength of current evidence.ResultsEight trials with 224 participants were included in our meta-analysis. Compared to control group, L-carnitine reduced the incidence of dialysis-related hypotension among hemodialysis patients (pooled OR = 0.26, 95% CI [0.10-0.72], p = 0.01, I2 = 76.0%). TSA demonstrated that the evidence was sufficient to conclude the finding. Five studies with 147 participants showed a reduction in the incidence of muscle cramps with L-carnitine group (pooled OR = 0.22, 95% CI [0.06-0.81], p = 0.02, I2 = 74.7%). However, TSA suggested that further high-quality studies were required. Subgroup analysis on the route of supplementation revealed that only oral but not intravenous L-carnitine significantly reduced dialysis-related hypotension. Regarding dose and duration of L-carnitine supplementation, the dose > 4,200 mg/week and duration of at least 12 weeks appeared to prevent dialysis-related hypotension.ConclusionSupplementing oral L-carnitine for at least three months above 4,200 mg/week helps prevent dialysis-related hypotension. L-carnitine supplementation may ameliorate muscle cramps. Further well-powered studies are required to conclude this benefit.

Functional gastrointestinal disorders (FGIDs) are a common concern during the first year of life. Recognized as gut-brain axis disorders by Rome IV criteria, FGIDs etiology is linked to altered gut-brain interaction, intestinal physiology, and microbiota. In this regard, probiotics have emerged as a promising therapy for infant FGIDs. In this study, we have investigated the probiotic potential of the strains Bifidobacterium longum KABP042 and Pediococcus pentosaceus KABP041—isolated from healthy children’s feces—in the treatment of FGIDs. To this scope, genome sequences of both strains were obtained and subjected to in silico analyses. No virulence factors were detected for any strain and only the non-transferable erm(49) gene, which confers resistance to erythromycin and clindamycin, was identified in the genome of B. longum KABP042. Safety of both strains was confirmed by acute oral toxicity in rats. In vitro characterization revealed that the strains tolerate gastric and bile challenges and display a great adhesion capacity to human intestinal cells. The two strains mediate adhesion by different mechanisms and, when combined, synergically induce the expression of Caco-2 tight junction proteins. Moreover, growth inhibition experiments demonstrated the ability of the two strains alone and in combination to antagonize diverse Gram-negative and Gram-positive bacterial pathogens during sessile and planktonic growth. Pathogens’ inhibition was mostly mediated by the production of organic acids, but neutralization experiments strongly suggested the presence of additional antimicrobial compounds in probiotic culture supernatants such as the bacteriocin Lantibiotic B, whose gene was detected in the genome of B. longum KABP042. Finally, an exploratory, observational, pilot study involving 36 infants diagnosed with at least one FGID (infant colic and/or functional constipation) showed the probiotic formula was well tolerated and FGID severity was significantly reduced after 14 days of treatment with the 2 strains. Overall, this work provides evidence of the probiotic and synergic properties of strains B. longum KABP042 and P. pentosaceus KABP041, and of their potential to treat pediatric FGIDs.Clinical Trial Registration: [www.ClinicalTrials.gov], [identifier NCT04944628].

The intense nature of pig production has increased the animals' exposure to stressful conditions, which may be detrimental to their welfare and productivity. Some of the most common sources of stress in pigs are extreme thermal conditions (thermal stress), density and mixing during housing (social stress), or exposure to pathogens and other microorganisms that may challenge their immune system (immune-related stress). The stress response can be monitored based on the animals' coping mechanisms, as a result of specific environmental, social, and health conditions. These animal-based indicators may support decision making to maintain animal welfare and productivity. The present study aimed to systematically review animal-based indicators of social, thermal, and immune-related stresses in farmed pigs, and the methods used to monitor them. Peer-reviewed scientific literature related to pig production was collected using three online search engines: ScienceDirect, Scopus, and PubMed. The manuscripts selected were grouped based on the indicators measured during the study. According to our results, body temperature measured with a rectal thermometer was the most commonly utilized method for the evaluation of thermal stress in pigs (87.62%), as described in 144 studies. Of the 197 studies that evaluated social stress, aggressive behavior was the most frequently-used indicator (81.81%). Of the 535 publications examined regarding immune-related stress, cytokine concentration in blood samples was the most widely used indicator (80.1%). Information about the methods used to measure animal-based indicators is discussed in terms of validity, reliability, and feasibility. Additionally, the introduction and wide spreading of alternative, less invasive methods with which to measure animal-based indicators, such as cortisol in saliva, skin temperature and respiratory rate via infrared thermography, and various animal welfare threats via vocalization analysis are highlighted. The information reviewed was used to discuss the feasible and most reliable methods with which to monitor the impact of relevant stressors commonly presented by intense production systems on the welfare of farmed pigs.

We aimed to assess the feasibility of TESTA’T COVID strategy among healthcare and education professionals.in Spain during the peak of the 6th wave caused by Omicron variant. Kits were ordered online and sent by mail, participants answered an online acceptability/usability survey and uploaded the picture of results. 492 participants ordered a test, 304 uploaded the picture (61.8%). Eighteen positive cases were detected (5.9%). 92.2% were satisfied/very satisfied with the intervention; and 92.5% found performing the test easy/very easy. We demonstrated that implementing online COVID-19 self-testing in schools and healthcare settings in Spain is feasible.

Methods to induce analgesia and anesthesia for research purposes, handling, transport, or stunning have been used in 71 species of crustaceans. A non-systematic literature search was conducted on crustacean anesthetic methods. This review presents a comprehensive evaluation of drugs and non-chemical methods used to provide analgesia and anesthesia in many crustacean species rather than just decapod crustaceans. This information allows users to select an appropriate method or agent for their species of interest. We prepared an on-line tool based on datasette, a no-code open-source solution for simple web-based database frontends that allows exploration and downloading data by method, analgesic/anesthetic, species, life stage, or sex, as well as other data including environmental conditions (temperature, salinity, light), route of administration, dosage, and induction and recovery times. These values can be selected to filter the dataset and export it to CSV or JSON formats. Currently, several techniques and chemicals are, in our opinion, unsuitable for use as anesthetics in crustaceans, and the basis for these opinions are presented. Given the evidence of a pain-like experience in crustaceans, we propose that researchers should treat crustaceans humanely, applying the principles of good handling, care, and the management of stress and pain to safeguard their welfare.

The design, synthesis, and initial study of amino-functionalized porphyrins as a new class of bifunctional catalysts for asymmetric organophotocatalysis is described. Two new types of amine–porphyrin hybrids derived from 5,10,15,20-tetraphenylporphyrin (TPPH2), in which a cyclic secondary amine moiety is covalently linked either to a β-pyrrolic position (Type A) or to the p-position of one of the meso phenyl groups (Type B), were prepared by condensation, reductive amination, or amidation reactions from the suitable porphyrins (either formyl or methanamine derivatives) with readily available chiral amines. A preliminary study of the possible use of Type A amine–porphyrin hybrids as asymmetric, bifunctional organophotocatalysts was performed using the chiral, imidazolidinone-catalyzed Diels–Alder cycloaddition between cyclopentadiene 28 and trans-cinnamaldehyde 29 as a benchmark reaction. The yield and the stereochemical outcome of this process, obtained under purely organocatalytic conditions, under dual organophocatalysis, and under bifunctional organophotocatalysis, were compared.

Bone fracture healing is a multistep process, including early immunological reactions, osteogenesis, and as a key factor, angiogenesis. Molecules inducing osteogenesis as well as angiogenesis are rare, but hold promise to be employed in bone tissue engineering. It has been demonstrated that the bone sialoprotein (BSP) can induce bone formation when immobilized in collagen type I, but its effect on angiogenesis still has to be characterized in detail. Therefore, the aim of this study was to analyse the effects of BSP immobilized in a collagen type I gel on angiogenesis. First, in vitro analyses with endothelial cells (HUVECs) were performed detecting enhancing effects of BSP on proliferation and gene expression of endothelial markers. A spheroid model was employed confirming these results. Finally, the inducing impact of BSP-collagen on vascular density was proved in a yolk sac membrane assay. Our results demonstrate that BSP is capable of inducing angiogenesis and confirm that collagen type I is the optimal carrier for this protein. Taking into account former results, and literature showing that BSP also induces osteogenesis, one can hypothesize that BSP couples angiogenesis and osteogenesis, making it a promising molecule to be used in bone tissue regeneration.

Owing to the high risk of recurrence, identifying indicators of carotid plaque vulnerability in atherothrombotic ischemic stroke is essential. In this study, we aimed to identify modified LDLs and antioxidant enzymes associated with plaque vulnerability in plasma from patients with a recent ischemic stroke and carotid atherosclerosis. Patients underwent an ultrasound, a CT-angiography, and an 18F-FDG PET. A blood sample was obtained from patients (n = 64, 57.8% with stenosis ≥50%) and healthy controls (n = 24). Compared to the controls, patients showed lower levels of total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein B (apoB), apoA-I, apoA-II, and apoE, and higher levels of apoJ. Patients showed lower platelet-activating factor acetylhydrolase (PAF-AH) and paraoxonase-1 (PON-1) enzymatic activities in HDL, and higher plasma levels of oxidized LDL (oxLDL) and electronegative LDL (LDL(−)). The only difference between patients with stenosis ≥50% and p < 0.033), the presence of hypoechoic plaque (OR: 7.52, CI: 1.26–44.83, p < 0.027), and of diffuse neovessels (OR: 10.77, CI: 1.21–95.93, p < 0.033), indicating that an increased proportion of LDL(−) is associated with vulnerable atherosclerotic plaque.

Plastic crystals have emerged as benchmark barocaloric (BC) materials for potential solid-state cooling and heating applications due to huge isothermal entropy changes and adiabatic temperature changes driven by pressure. In this work we investigate the BC response of the neopentane derivative 2-methyl-2-nitro-1-propanol (NO _2 C(CH _3 ) _2 CH _2 OH) in a wide temperature range using x-ray diffraction, dilatometry and pressure-dependent differential thermal analysis. Near the ordered-to-plastic transition, we find colossal BC effects of $\simeq$ 400 J K ^−1 kg ^−1 and $\simeq$ 5 K upon pressure changes of 100 MPa. Although reversible effects at the transition are obtained only from higher pressure changes due to hysteretic effects, we do obtain fully reversible BC effects from any pressure change in individual phases, that become giant at moderate pressures due to very large thermal expansion, especially in the plastic phase. From our measurements, we also determine the crystal structure of the low-temperature phase and estimate the contribution of the configurational disorder and the volume change to the total transition entropy change.

In this work, we present a numerical study of a granular collapse in a viscous fluid adopting a DEM-PFV (Pore Finite Volume) coupled model. We analyze the time evolution of the collapse and the final morphology of the deposit (triangular or trapezoidal) as a function of the initial solid fraction and column aspect ratio. Finally, we discuss the role of the initial packing fraction of the granular material on the time evolution of the pore pressure. The numerical results are consistent with experimental observation [3] showing the capability of the DEM-PFV coupled model to simulate saturated granular media from triggering to flowing and stopping conditions.

The magnetically frustrated manganese nitride antiperovskite family displays significant changes of entropy under changes in hydrostatic pressure near a first-order antiferromagnetic to paramagnetic phase transition that can be useful for the emerging field of solid-state barocaloric cooling. In previous studies, the transition hysteresis has significantly reduced the reversible barocaloric effects (BCE). Here we show that the transition hysteresis can be tailored through quaternary alloying in the Mn _3 Cu $_{1-x}$ Sn $_{x}$ N system. We find the magnitude of hysteresis is minimised when Cu and Sn are equiatomic ( x = 0.5) reaching values far less than previously found for Mn _3 A N ( $A = $ Pd, Ni, Ga, Zn), whilst retaining entropy changes of the same order of magnitude. These results demonstrate that reversible BCE are achievable for p

Abstract Background Transposable elements (TEs) are an important source of genomic variability in eukaryotic genomes. Their activity impacts genome architecture and gene expression and can lead to drastic phenotypic changes. Therefore, identifying TE polymorphisms is key to better understand the link between genotype and phenotype. However, most genotype-to-phenotype analyses have concentrated on single nucleotide polymorphisms as they are easier to reliable detect using short-read data. Many bioinformatic tools have been developed to identify transposon insertions from resequencing data using short reads. Nevertheless, the performance of most of these tools has been tested using simulated insertions, which do not accurately reproduce the complexity of natural insertions. Results We have overcome this limitation by building a dataset of insertions from the comparison of two high-quality rice genomes, followed by extensive manual curation. This dataset contains validated insertions of two very different types of TEs, LTR-retrotransposons and MITEs. Using this dataset, we have benchmarked the sensitivity and precision of 12 commonly used tools, and our results suggest that in general their sensitivity was previously overestimated when using simulated data. Our results also show that, increasing coverage leads to a better sensitivity but with a cost in precision. Moreover, we found important differences in tool performance, with some tools performing better on a specific type of TEs. We have also used two sets of experimentally validated insertions in Drosophila and humans and show that this trend is maintained in genomes of different size and complexity. Conclusions We discuss the possible choice of tools depending on the goals of the study and show that the appropriate combination of tools could be an option for most approaches, increasing the sensitivity while maintaining a good precision.

By analyzing longitudinal data from the start to the end of primary education, we aimed to investigate whether symbolic numerical magnitude processing at the start of primary education predicted arithmetic at the end, and whether arithmetic at the start of primary education predicted later symbolic numerical magnitude processing skills at the end. In the first grade (start) and sixth grade (end) of primary education, the same group of children’s symbolic numerical magnitude processing skills and arithmetic competence were assessed. We were particularly interested in exploring the direction of the association between symbolic numerical magnitude processing and arithmetic and observed that this association was bi-directional across primary education. Symbolic numerical magnitude processing skills in first grade predicted arithmetic in sixth grade; but also the reversed direction turned out significant: Early arithmetic predicted later symbolic numerical magnitude processing skills. Both directions remained significant after controlling for motor speed and nonverbal reasoning. Critically, when controlling for auto-regressive effects of prior abilities, the symbolic comparison-arithmetic association was no longer significant, the reversed direction became marginally significant. This suggests that children’s arithmetic development across primary education to some extent strengthens their ability to process the numerical meaning of Arabic digits.

ABSTRACT: Background: Reducing the alcohol-attributable cancer burden in the WHO European Region is a public health priority. This study aims to estimate the number of potentially avoidable cancers in countries of the WHO European Region in 2019 for three scenarios in which current excise duties on alcoholic beverages were increased by 20%, 50%, or 100%. Methods: Mean prices and excise duties for beer, wine, and spirits in the Member States of the WHO European Region in 2020 were used as the baseline scenario. We assumed that increases in excise duties (20%, 50%, and 100%) were fully incorporated into the consumer price. Beverage-specific price elasticities of demand, with lower elasticities for heavy drinkers, were obtained from a meta-analysis. Model estimates were applied to alcohol exposure data for 2009 and cancer incidence and mortality rates for 2019, assuming a 10-year lag time between alcohol intake and cancer development and mortality. Findings: Of 180,887 (95% Confidence interval [CI]: 160,595-201,705) new alcohol-attributable cancer cases and 85,130 (95% CI: 74,920-95,523) deaths in the WHO European Region in 2019, 5·9% (95% CI: 5·6-6·4) and 5·7% (95% CI: 5·4-6·1), respectively, could have been avoided by increasing excise duties by 100%. According to our model, alcohol-attributable female breast cancer and colorectal cancer contributed most to the avoidable cases and deaths. Interpretation: Doubling current alcohol excise duties could avoid just under 6% (or 10,700 cases and 4,850 deaths) of new alcohol-attributable cancers within the WHO European Region, particularly in Member States of the European Union where excise duties are in many cases very low. Funding: None.

Biomass-based, small-scale Combined Cooling, Heating and Power (CCHP) systems can increase the energy autonomy of building complexes while reducing their Greenhouse Gases (GHG) emissions. In combination with air-to-water Heat Pumps (HP), highly efficient energy systems can be designed, which allow for high flexibility in serving thermal and electric demands. This study presents an exergy evaluation of such a small-scale CCHP/HP system using a dynamic modelling approach based on gasification of various types of woody biomass. The transient model takes into account the effects of the biomass chemical composition as well as of ambient temperatures on the exergy performance of all key components for various CCHP system sizes supporting an HP system. The model has been applied in a case study for a historic building complex, where the CCHP sub-system would support an HP-subsystem allowing for downsizing the latter. The results show that smaller CCHP systems operate with higher exergy efficiency, because for larger systems the heat transfer from the engine and the operation of the absorption chiller are less exergy efficient. The electric load-following CCHP subsystem reaches exergy efficiencies of up to 13.3%, indicating huge improvement potential for system and sub-system design. It was also found that the biomass composition heavily influences the exergy efficiency of the gasifier and in turn changes the exergy efficiency of the syngas engine and the entire CCHP sub-system.

ABSTRACT The reproductive biology of thresher shark species of the Ecuadorian Pacific was analysed based on 1236 specimens of Alopias pelagicus (711 females and 525 males) and 354 of A. superciliosus (164 females and 190 males) landed in “Playita Mía”, from January to December of 2019. The length of A. pelagicus females ranged between 67.2 and 184 cm PCL (precaudal length) and the males between 69.0 and 178.4 cm PCL, A. superciliosus registered a minimum and maximum size of 76.0 and 202.2 cm PCL for females and 94.0 and 204.8 cm PCL for males. The most frequently captured size class for A. pelagicus was 147.2−157.2 cm PCL and for A. superciliosus was 156.0-166.0 cm PCL. The sex ratio (F:M) for A. pelagicus and A. superciliosus was 1.35F:1M and 0.86F:1M respectively. For A. pelagicus males the inflection point of the clasper length adjustment, was 134.2 cm PCL and size at first sexual maturity (L 50 ) was estimated at 136.0 cm PCL. For A. superciliosus males the inflection point of the clasper length adjustment, was 136.8 cm PCL, and the first sexual maturity (L 50 ) was estimated at 138.7 cm PCL.

The increase in emissions associated with aviation requires deeper research into novel sensing and flow-control strategies to obtain improved aerodynamic performances. In this context, data-driven methods are suitable for exploring new approaches to control the flow and develop more efficient strategies. Deep artificial neural networks (ANNs) used together with reinforcement learning, i.e., deep reinforcement learning (DRL), are receiving more attention due to their capabilities of controlling complex problems in multiple areas. In particular, these techniques have been recently used to solve problems related to flow control. In this work, an ANN trained through a DRL agent, coupled with the numerical solver Alya, is used to perform active flow control. The Tensorforce library was used to apply DRL to the simulated flow. Two-dimensional simulations of the flow around a cylinder were conducted and an active control based on two jets located on the walls of the cylinder was considered. By gathering information from the flow surrounding the cylinder, the ANN agent is able to learn through proximal policy optimization (PPO) effective control strategies for the jets, leading to a significant drag reduction. Furthermore, the agent needs to account for the coupled effects of the friction- and pressure-drag components, as well as the interaction between the two boundary layers on both sides of the cylinder and the wake. In the present work, a Reynolds number range beyond those previously considered was studied and compared with results obtained using classical flow-control methods. Significantly different forms of nature in the control strategies were identified by the DRL as the Reynolds number Re increased. On the one hand, for Re≤1000, the classical control strategy based on an opposition control relative to the wake oscillation was obtained. On the other hand, for Re=2000, the new strategy consisted of energization of the boundary layers and the separation area, which modulated the flow separation and reduced the drag in a fashion similar to that of the drag crisis, through a high-frequency actuation. A cross-application of agents was performed for a flow at Re=2000, obtaining similar results in terms of the drag reduction with the agents trained at Re=1000 and 2000. The fact that two different strategies yielded the same performance made us question whether this Reynolds number regime (Re=2000) belongs to a transition towards a nature-different flow, which would only admits a high-frequency actuation strategy to obtain the drag reduction. At the same time, this finding allows for the application of ANNs trained at lower Reynolds numbers, but are comparable in nature, saving computational resources.

A Correction to this paper has been published: https://doi.org/10.1038/s42003-021-01894-9

Hyperthermia is a common confounding factor for assessing the neurotoxic effects of methamphetamine (METH) in mammalian models. The development of new models of methamphetamine neurotoxicity using vertebrate poikilothermic animals should allow to overcome this problem. The aim of the present study was to develop a zebrafish model of neurotoxicity by binge-like methamphetamine exposure. After an initial testing at 20 and 40 mg/L for 48 h, the later METH concentration was selected for developing the model and the effects on the brain monoaminergic profile, locomotor, anxiety-like and social behaviors as well as on the expression of key genes of the catecholaminergic system were determined. A concentration- and time-dependent decrease in the brain levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) was found in METH-exposed fish. A significant hyperactivity was found during the first hour of exposure, followed 3 h after by a positive geotaxis and negative scototaxis in the novel tank and in the light/dark paradigm, respectively. Moreover, the behavioral phenotype in the treated fish was consistent with social isolation. At transcriptional level, th1 and slc18a2 (vmat2) exhibited a significant increase after 3 h of exposure, whereas the expression of gfap, a marker of astroglial response to neuronal injury, was strongly increased after 48 h exposure. However, no evidences of oxidative stress were found in the brain of the treated fish. Altogether, this study demonstrates the suitability of the adult zebrafish as a model of METH-induced neurotoxicity and provides more information about the biochemical and behavioral consequences of METH abuse.

Este texto analiza el proyecto llamado «católico-industrial» del intelectual argentino Félix Frías, enmarcado en el influyente liberalismo católico latinoamericano de mitad del siglo XIX, para la propagación del catolicismo sobre los pueblos indígenas, como medio necesario para el surgimiento del espíritu liberal entre los neófitos. Se sostiene que, dado su exilio en Bolivia y su cercanía a la Administración de José Ballivián (1841-1847), las nuevas políticas de integración de los Orientes bolivianos en el mercado interior del país llevadas a cabo por ese gobierno recibieron influencias del discurso de Frías y ejercieron peso sobre el mismo. Frías expresó su pensamiento fundamentalmente en dos obras, publicadas en 1844 y 1846. Ambas, junto con la prensa, el diario de debates, la legislación y algunos otros escritos menores constituyen las fuentes utilizadas en este artículo. A través de ellas podremos abordar la intertextualidad entre la obra de Frías y la política de Ballivián.

Familial melanoma accounts for 10% of cases, being CDKN2A the main high-risk gene. However, the mechanisms underlying melanomagenesis in these cases remain poorly understood. Our aim was to analyze the transcriptome of melanocyte-keratinocyte co-cultures derived from healthy skin from familial melanoma patients vs. controls, to unveil pathways involved in melanoma development in at-risk individuals. Accordingly, primary melanocyte-keratinocyte co-cultures were established from the healthy skin biopsies of 16 unrelated familial melanoma patients (8 CDKN2A mutant, 8 CDKN2A wild-type) and 7 healthy controls. Whole transcriptome was captured using the SurePrint G3 Human Microarray. Transcriptome analyses included: differential gene expression, functional enrichment, and protein-protein interaction (PPI) networks. We identified a gene profile associated with familial melanoma independently of CDKN2A germline status. Functional enrichment analysis of this profile showed a downregulation of pathways related to DNA repair and immune response in familial melanoma (P < 0.05). In addition, the PPI network analysis revealed a network that consisted of double-stranded DNA repair genes (including BRCA1, BRCA2, BRIP1, and FANCA), immune response genes, and regulation of chromosome segregation. The hub gene was BRCA1. In conclusion, the constitutive deregulation of BRCA1 pathway genes and the immune response in healthy skin could be a mechanism related to melanoma risk.

Restoration is considered an effective strategy to accelerate the recovery of biological communities at local scale. However, the effects of restoration actions in the marine ecosystems are still unpredictable. We performed a global analysis of published literature to identify the factors increasing the probability of restoration success in coastal and marine systems. Our results confirm that the majority of active restoration initiatives are still concentrated in the northern hemisphere and that most of information gathered from restoration efforts derives from a relatively small subset of species. The analysis also indicates that many studies are still experimental in nature, covering small spatial and temporal scales. Despite the limits of assessing restoration effectiveness in absence of a standardized definition of success, the context (degree of human impact, ecosystem type, habitat) of where the restoration activity is undertaken is of greater relevance to a successful outcome than how (method) the restoration is carried out. Contrary to expectations, we found that restoration is not necessarily more successful closer to protected areas (PA) and in areas of moderate human impact. This result can be motivated by the limits in assessing the success of interventions and by the tendency of selecting areas in more obvious need of restoration, where the potential of actively restoring a degraded site is more evident. Restoration sites prioritization considering human uses and conservation status present in the region is of vital importance to obtain the intended outcomes and galvanize further actions.

Dyslexia is targeted most effectively when (1) interventions are provided preventively, before the onset of reading instruction, and (2) remediation programs combine letter-sound training with phoneme blending. Given the growing potential of technology in educational contexts, there has been a considerable increase of letter-sound trainings embedded in digital serious games. One such intervention is GraphoGame. Yet, current evidence on the preventive impact of GraphoGame is limited by the lack of adaptation of the original learning content to the skills of pre-readers, short training duration, and a restricted focus on explicitly trained skills. Therefore, the current study aims at investigating the impact of a preventive, and pre-reading adapted GraphoGame training (i.e., GraphoGame-Flemish, GG-FL) on explicitly trained skills and non-specifically trained phonological and language abilities. Following a large-scale screening (N = 1225), the current study included 88 pre-reading kindergarteners at cognitive risk for dyslexia who were assigned to three groups training either with GG-FL (n = 31), an active control game (n = 29), or no game (n = 28). Before and after the 12-week intervention, a variety of reading-related skills were assessed. Moreover, receptive letter knowledge and phonological awareness were measured every three weeks during the intervention period. Results revealed significantly larger improvements in the GG-FL group on explicitly trained skills, i.e., letter knowledge and word decoding, without finding transfer-effects to untrained phonological and language abilities. Our findings imply a GG-FL-driven head start on early literacy skills in at-risk children. A follow-up study should uncover the long-term impact and the ability of GG-FL to prevent actual reading failure.

Plant genomes are highly diverse in size and repetitive DNA composition. In the absence of polyploidy, the dynamics of repetitive elements, which make up the bulk of the genome in many species, are the main drivers underpinning changes in genome size and the overall evolution of the genomic landscape. The advent of high-throughput sequencing technologies has enabled investigation of genome evolutionary dynamics beyond model plants to provide exciting new insights in species across the biodiversity of life. Here we analyze the evolution of repetitive DNA in two closely related species of Heloniopsis (Melanthiaceae), which despite having the same chromosome number differ nearly twofold in genome size [i.e., H. umbellata (1C = 4,680 Mb), and H. koreana (1C = 2,480 Mb)]. Low-coverage genome skimming and the RepeatExplorer2 pipeline were used to identify the main repeat families responsible for the significant differences in genome sizes. Patterns of repeat evolution were found to correlate with genome size with the main classes of transposable elements identified being twice as abundant in the larger genome of H. umbellata compared with H. koreana. In addition, among the satellite DNA families recovered, a single shared satellite (HeloSAT) was shown to have contributed significantly to the genome expansion of H. umbellata. Evolutionary changes in repetitive DNA composition and genome size indicate that the differences in genome size between these species have been underpinned by the activity of several distinct repeat lineages.