Immunoanalytical Detection of Conserved Peptides: Refining the Universe of Biomarker Targets in Planetary Exploration.

Ancient peptides are remnants of early biochemistry that continue to play pivotal roles in current proteins. They are simple molecules yet complex enough to exhibit independent functions, being products of an evolved biochemistry at the interface of life and nonlife. Their adsorption to minerals may contribute to their stabilization and preservation over time. To investigate the feasibility of conserved peptide sequences and structures as target biomarkers for the search for life on Mars or other planetary bodies, we conducted a bioinformatics selection of well-conserved ancient peptides and produced polyclonal antibodies for their detection using fluorescence microarray immunoassays. Additionally, we explored how adsorbing peptides to Mars-representative minerals to form organomineral complexes could affect their immunological detection. The results demonstrated that the selected peptides exhibited autonomous folding, with some of them regaining their structure, even after denaturation. Furthermore, their cognate antibodies detected their conformational features regardless of amino acid sequences, thereby broadening the spectrum of target peptide sequences. While certain antibodies displayed unspecific binding to bare minerals, we validated that peptide-mineral complexes can be detected using sandwich immunoassays, as confirmed through desorption and competitive assays. Consequently, we conclude that the diversity of peptide sequences and structures suitable for use as target biomarkers in astrobiology can be constrained to a few well conserved sets, and they can be detected even if they are adsorbed in organomineral complexes.

Contingency learning and episodic contributions to the item-specific proportion congruent effect.

Several studies have challenged the conflict adaptation account of cognitive control effects, suggesting that they are the result of learning/memory processes independent from control modulation. Some authors have suggested that the item-specific proportion congruent (ISPC) effect (i.e., the smaller congruency effect on items presented frequently in an incongruent combination) is driven by colour-word contingency learning (CL). However, it has recently been suggested that CL can be explained in terms of episodic retrieval of the response given to the last encounter with the same stimulus, with no role of associative learning. This study aims to analyse the independent role of CL and episodic retrieval on the ISPC effect. Experiment 1 showed no effect of control modulation and indicated that, when manipulated independently, learning-driven contingency is modulated by the episodic factor, but it remains significant. Experiments 2 and 3 extended the study of the interplay between learning and recency to the colour-word CL paradigm, finding larger contingency effects on colour words compared with neutral ones and replicating the interaction between CL and episodic retrieval from Experiment 1. Surprisingly, these two experiments also showed control modulation apart from contingency and recency effects in colour words. In sum, our study reveals that the ISPC effect results from the joint contribution of cognitive control, associative learning, and episodic effects.

DOCU-CLIM: A global documentary climate dataset for climate reconstructions.

Documentary climate data describe evidence of past climate arising from predominantly written historical documents such as diaries, chronicles, newspapers, or logbooks. Over the past decades, historians and climatologists have generated numerous document-based time series of local and regional climates. However, a global dataset of documentary climate time series has never been compiled, and documentary data are rarely used in large-scale climate reconstructions. Here, we present the first global multi-variable collection of documentary climate records. The dataset DOCU-CLIM comprises 621 time series (both published and hitherto unpublished) providing information on historical variations in temperature, precipitation, and wind regime. The series are evaluated by formulating proxy forward models (i.e., predicting the documentary observations from climate fields) in an overlapping period. Results show strong correlations, particularly for the temperature-sensitive series. Correlations are somewhat lower for precipitation-sensitive series. Overall, we ascribe considerable potential to documentary records as climate data, especially in regions and seasons not well represented by early instrumental data and palaeoclimate proxies.

Medical mistakes and their absence in medical schools

Medical mistakes are any unintentional acts which are detrimental to patients' health, most of which have multiple causes or arise from the complexity of modern healthcare systems. Since no medical specialty is free of mistakes, training is needed beginning in undergraduate school to learn how to deal with them. (Acta Med Colomb 2022; 48. DOI:https://doi.org/10.36104/amc.2023.2522).

Aripiprazole for the treatment of schizophrenia: Recommendations of a panel of Spanish experts on its use in clinical practice.

OBJECTIVES: Aripiprazole is an antipsychotic with a partial agonism of dopamine D2 and D3 receptors. This differential mechanism implies a rigorous appraisal of the appropriate therapeutic strategies in certain situations. To answer currently unsolved clinical questions about the use of oral and long-acting injectable (LAI) aripiprazole, we present here an expert consensus from 12 Spanish psychiatrists and a pharmacologist with extensive experience in the use of this antipsychotic. METHODS: Through one face-to-face session and online collaboration, we reached consensus and established practical recommendations based on scientific evidence and clinical experience. We classified the available scientific literature according to SIGN system and attributed a level of evidence to each reviewed article. RESULTS: The recommendations were divided according to (i) chronological dimension (based on previous treatments, including patients naïve or not to antipsychotic treatment and maintenance regimen), and (ii) dimension related to therapeutic options, comprising switches to aripiprazole and the most used combinations with this antipsychotic. CONCLUSIONS: We recommend considering aripiprazole as first treatment option in the early stages of schizophrenia and in patients with affective symptoms and contemplating a switch to aripiprazole LAI in all candidate patients. Importantly, switches from other antipsychotics should consider previous antipsychotic history and exposure to aripiprazole. KEYPOINTSAripiprazole can be considered as first treatment option in early stages of schizophrenia and in patients with significant affective symptoms.Aripiprazole LAI shows better adherence than oral aripiprazole and could be considered in all candidate patients.Before switching to aripiprazole, detailed information about previous antipsychotic history should be gathered.Switch to aripiprazole should be managed differently for aripiprazole naïve and non-naïve patients.Rigorous and controlled studies on antipsychotics in real clinical practice should be carried out.

Targeted bacterial conjugation mediated by synthetic cell-to-cell adhesions.

Genetic interventions on microbiomes, for clinical or biotechnological purposes, remain challenging. Conjugation-based delivery of genetic cargo is still unspecific and limited by low conjugation rates. Here we report an approach to overcome these problems, based on a synthetic bacterial adhesion system. Mating assemblers consist on a synthetic adhesion formed by the expression on the surface of donor and target cells of specific nanobodies (Nb) and their cognate antigen (Ag). The Nb-Ag bridge increased 1-3 logs transfer of a variety of plasmids, especially in liquid media, confirming that cell-cell docking is a main determinant limiting mating efficiency. Synthetic cell-to-cell adhesion allows efficient conjugation to targeted recipients, enhancing delivery of desired genes to a predefined subset of prey species, or even specific pathogenic strains such as enterohemorrhagic Escherichia coli (EHEC), within a bacterial community. The synthetic conjugation enhancer presented here optimizes plasmid delivery by selecting the target hosts with high selectivity.

Intestinal parasitosis in children from a rural Caribbean area in Colombia / Parasitosis intestinal en niños de una zona rural del Caribe de Colombia

Abstract In Colombia, the prevalence of intestinal parasitosis varies throughout its regions, social classes, and living conditions. We performed a cohort study (2017-2018) on children from 1-10 years old in El Cedro, Ayapel, Colombia. We tested a convenience sampling of those who accepted and signed the consent form. The National Intestinal Parasite Survey was applied; feces and water source sampling were tested for coprological and microbiology analysis, respectively. Education and pharmacologic treatment to the minor and co-inhabitants were performed. After the recruiting, we followed up at 7 and 12 months. Statistical analysis was performed using IBM® SPSS22. Participants 47, 61,7% male, average age 5,7 years. The caretakers had a low educational background. The monthly income of 72,3% of households was < USD 87. The coprological test showed 61,7% with at least one type of parasite; 32,2% with two or more. Trichuris trichiura was the most frequent. Water sources were positive for Escherichia coli. The population tested showed a high frequency of parasitic infection. We did not find a reduction of intestinal parasitosis with educa tion and pharmacologic treatment at the end of the follow-up. It must be necessary to impact social determinants of public health to achieve intestinal parasitosis control.

Resumen En Colombia, la prevalencia de parasitosis intestinal varía por regiones, clases sociales, condiciones de vida. Realizamos estudio de cohorte (2017-2018) en niños de 1-10 años en El Cedro, Ayapel, Colombia. Muestra por conveniencia, se incluyeron aquellos que aceptaron y firmaron el consentimiento. Se aplicó la Encuesta Nacional de Parásitos Intestinales; se analizaron muestras de heces y fuentes de agua para análisis coprológico y microbiológico, respectivamente. Se realizó educación y tratamiento farmacológico al menor y cohabitantes. Después del reclutamiento, seguimiento a los 7 y 12 meses. El análisis estadístico se realizó con IBM® SPSS22. Participantes 47, 61,7% hombres, promedio de edad 5,7 años. Cuidadores con bajo nivel educativo, ingreso mensual del 72,3% de los hogares fue <USD 87. La población analizada mostró una alta frecuencia de infección parasitaria, un 61,7% con al menos un tipo de parásito; 32,2% con dos o más. Trichuris trichiura fue el más frecuente. Las fuentes de agua fueron positivas para Escherichia coli. Al final del seguimiento, no se redujo la frecuencia de la parasitosis intestinal a pesar de educación y tratamiento farmacológico. Se requiere incidir en los determinantes sociales y de salud pública para lograr el control de las parasitosis intestinales.

Proportion of conflict, contingency learning, and recency effects in a Stroop task.

Recent research on the relation between learning and cognitive control has assumed that conflict modulates learning, either by increasing arousal and hence improving learning in high-conflict situations, or by inducing control, and hence inhibiting the processing of distracters and their eventual association with the imperative responses. We analyse whether the amount of conflict, manipulated through the proportion of congruency in a set of Stroop inducer trials, affects learning of contingencies established on diagnostic trials composed by neutral words associated with colour responses. The results reproduced the list-wide proportion of congruency effect on the inducer trials, and showed evidence of contingency learning on the diagnostic trials, but provided no indication that this learning was modulated by the level of conflict. Specific analyses conducted to control for the impact of episodic effects on the expression of learning indicated that contingency effects were not driven by the incremental processes that could be expected by associative learning, but rather they were due to the impact of the most recent trial involving the same distracter. Accordingly, these effects disappeared when tested selectively on trials that required a non-matching response with respect to the previous occurrence of the distracter. We interpret this result in the context of the debate on how learning and memory interact with the processes of cognitive control.

The type III secretion system effector network hypothesis.

Type III secretion system (T3SS) effectors are key virulence factors that underpin the infection strategy of many clinically important Gram-negative pathogens, including Salmonella enterica, Shigella spp., enteropathogenic and enterohemorrhagic Escherichia coli and their murine equivalent, Citrobacter rodentium. The cellular processes or proteins targeted by the effectors can be common to multiple pathogens or pathogen-specific. The main approach to understanding T3SS-mediated pathogenesis has been to determine the contribution of one effector at a time, with the aim of piecing together individual functions and unveiling infection mechanisms. However, in contrast to this prevailing approach, simultaneous deletion of multiple effectors revealed that they function as an interconnected network in vivo, uncovering effector codependency and context-dependent effector essentiality. This paradigm shift in T3SS biology is at the heart of this opinion article.

Effects on Respiratory Pressures, Spirometry Biomarkers, and Sports Performance after Inspiratory Muscle Training in a Physically Active Population by Powerbreath®: A Systematic Review and Meta-Analysis.

Sports performance in athletes can be limited by respiratory factors, so it is understandable to propose that inspiratory muscle training (IMT) can improve respiratory function and exercise performance. Power-Breathe® (PwB) is a sectorized respiratory muscle training tool that uses a resistive load to train IMT. There is currently a growing interest in respiratory muscle training, so we set out to systematically assess the effects of IMT with PwB on respiratory parameters and athletic performance in physically active, healthy adults. Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, the Cochrane and PEDro scales to assess methodological quality, effect size using the Rosenthal formula, and the Cochrane tool for estimation of risk of bias, studies searchable in Medline, Web of Science, and Cochrane. In addition, for the performance of the meta-analysis, the documentation and quantification of the heterogeneity in each meta-analysis were directed through the Cochran's Q test and the I2 statistic; in addition, a publication bias analysis was performed using funnel plots. Of the total of 241 studies identified in the search, 11 studies for the systematic review and nine for the meta-analysis met the exclusion and/or inclusion criteria. IMT, with PwB, showed significant improvements in maximal inspiratory pressure (MIP) and substantial improvements in forced vital capacity (FVC) in the meta-analysis results. Also, sports performance was significantly increased by IMT with PwB. In conclusion, the use of PwB is an IMT tool that improves respiratory and sports performance.

Thermodynamic Performance of a Brayton Pumped Heat Energy Storage System: Influence of Internal and External Irreversibilities.

A model for a pumped thermal energy storage system is presented. It is based on a Brayton cycle working successively as a heat pump and a heat engine. All the main irreversibility sources expected in real plants are considered: external losses arising from the heat transfer between the working fluid and the thermal reservoirs, internal losses coming from pressure decays, and losses in the turbomachinery. Temperatures considered for the numerical analysis are adequate for solid thermal reservoirs, such as a packed bed. Special emphasis is paid to the combination of parameters and variables that lead to physically acceptable configurations. Maximum values of efficiencies, including round-trip efficiency, are obtained and analyzed, and optimal design intervals are provided. Round-trip efficiencies of around 0.4, or even larger, are predicted. The analysis indicates that the physical region, where the coupled system can operate, strongly depends on the irreversibility parameters. In this way, maximum values of power output, efficiency, round-trip efficiency, and pumped heat might lay outside the physical region. In that case, the upper values are considered. The sensitivity analysis of these maxima shows that changes in the expander/turbine and the efficiencies of the compressors affect the most with respect to a selected design point. In the case of the expander, these drops are mostly due to a decrease in the area of the physical operation region.

Changes in severity, mortality, and virus genome among a Spanish cohort of patients hospitalized with SARS-CoV-2.

Comparing pandemic waves could aid in understanding the evolution of COVID-19. The objective of the present study was to compare the characteristics and outcomes of patients hospitalized for COVID-19 in different pandemic waves in terms of severity and mortality. We performed an observational retrospective cohort study of 5,220 patients hospitalized with SARS-CoV-2 infection from February to September 2020 in Aragon, Spain. We compared ICU admissions and 30-day mortality, clinical characteristics, and risk factors of the first and second waves of COVID-19. The SARS-CoV-2 genome was also analyzed in 236 samples. Patients in the first wave (n = 2,547) were older (median age 74 years [IQR 60-86] vs. 70 years [53-85]; p < 0.001) and had worse clinical and analytical parameters related to severe COVID-19 than patients in the second wave (n = 2,673). The probability of ICU admission at 30 days was 16% and 10% (p < 0.001) and the cumulative 30-day mortality rates 38% and 32% in the first and second wave, respectively (p = 0.007). Survival differences were observed among patients aged 60 to 80 years. We also found some variability among death risk factors and the viral genome between waves. Therefore, the two analyzed COVID-19 pandemic waves were different in terms of disease severity and mortality.

A Clinical Decision Web to Predict ICU Admission or Death for Patients Hospitalised with COVID-19 Using Machine Learning Algorithms.

The purpose of the study was to build a predictive model for estimating the risk of ICU admission or mortality among patients hospitalized with COVID-19 and provide a user-friendly tool to assist clinicians in the decision-making process. The study cohort comprised 3623 patients with confirmed COVID-19 who were hospitalized in the SALUD hospital network of Aragon (Spain), which includes 23 hospitals, between February 2020 and January 2021, a period that includes several pandemic waves. Up to 165 variables were analysed, including demographics, comorbidity, chronic drugs, vital signs, and laboratory data. To build the predictive models, different techniques and machine learning (ML) algorithms were explored: multilayer perceptron, random forest, and extreme gradient boosting (XGBoost). A reduction dimensionality procedure was used to minimize the features to 20, ensuring feasible use of the tool in practice. Our model was validated both internally and externally. We also assessed its calibration and provide an analysis of the optimal cut-off points depending on the metric to be optimized. The best performing algorithm was XGBoost. The final model achieved good discrimination for the external validation set (AUC = 0.821, 95% CI 0.787-0.854) and accurate calibration (slope = 1, intercept = -0.12). A cut-off of 0.4 provides a sensitivity and specificity of 0.71 and 0.78, respectively. In conclusion, we built a risk prediction model from a large amount of data from several pandemic waves, which had good calibration and discrimination ability. We also created a user-friendly web application that can aid rapid decision-making in clinical practice.

Deep Learning for Walking Behaviour Detection in Elderly People Using Smart Footwear.

The increase in the proportion of elderly in Europe brings with it certain challenges that society needs to address, such as custodial care. We propose a scalable, easily modulated and live assistive technology system, based on a comfortable smart footwear capable of detecting walking behaviour, in order to prevent possible health problems in the elderly, facilitating their urban life as independently and safety as possible. This brings with it the challenge of handling the large amounts of data generated, transmitting and pre-processing that information and analysing it with the aim of obtaining useful information in real/near-real time. This is the basis of information theory. This work presents a complete system aiming at elderly people that can detect different user behaviours/events (sitting, standing without imbalance, standing with imbalance, walking, running, tripping) through information acquired from 20 types of sensor measurements (16 piezoelectric pressure sensors, one accelerometer returning reading for the 3 axis and one temperature sensor) and warn the relatives about possible risks in near-real time. For the detection of these events, a hierarchical structure of cascading binary models is designed and applied using artificial neural network (ANN) algorithms and deep learning techniques. The best models are achieved with convolutional layered ANN and multilayer perceptrons. The overall event detection performance achieves an average accuracy and area under the ROC curve of 0.84 and 0.96, respectively.

Inspiratory Muscle Training Program Using the PowerBreath®: Does It Have Ergogenic Potential for Respiratory and/or Athletic Performance? A Systematic Review with Meta-Analysis.

This systematic review and meta-analysis aim to provide scientific evidence regarding the effects of training on respiratory muscle training's impact with the PowerBreath®. A systematic analysis based on the PRISMA guides and a conducted research structured around the bases of Web of Science, Scopus, Medline/PubMed, SciELO y Cochrane Library Plus. Six articles published before January 2021 were included. The documentation and quantification of heterogeneity in every meta-analysis were directed through Cochran's Q test and the statistic I2; additionally, a biased publication analysis was made using funnel plots, whose asymmetry was quantified Egger's regression. The methodological quality was assessed through McMaster's. PowerBreath® administering a ≥ 15% resistive load of the maximum inspiratory pressure (PIM) achieves significant improvements (54%) in said pressure within 4 weeks of commencing the inspiratory muscle training. The maximal volume of oxygen (VO2max) considerable enhancements was achieved from the 6 weeks associated with the maximum inspiratory pressure ≥ 21.5% post inspiratory muscle training onwards. Conversely, a significant blood lactate concentration decrement occurred from the 4th week of inspiratory muscle training, after a maximum inspiratory pressure ≥ 6.8% increment. PowerBreath® is a useful device to stimulate sport performance and increase pulmonary function.

A multiplex antigen microarray for simultaneous IgG and IgM detection against SARS-CoV-2 reveals higher seroprevalence than reported.

The surge of SARS-CoV-2 has challenged health systems worldwide and efficient tests to detect viral particles, as well as antibodies generated against them, are needed. Specificity, sensitivity, promptness or scalability are the main parameters to estimate the final performance, but rarely all of them match in a single test. We have developed SCOVAM, a protein microarray with several viral antigens (spike, nucleocapsid, main protease Nsp5) as capturing probes in a fluorescence immunoassay for COVID-19 serological testing. SCOVAM depicts IgG and IgM antibody responses against each of these proteins of 22 individuals in a single microscope slide. It detects specific IgM (0.094 µg ml-1 ) and IgG (~0.017 µg ml-1 ) and is scalable and cost-effective. We validated SCOVAM by comparing with a widely used chemiluminescent commercial serological test (n = 742). SCOVAM showed twice the sensitivity and allowed following seroconversion in a single assay. By analysing the prevalence 4 months later in a subset of 76 positive sera, we still detected 93.42% of positives, almost doubling the detection of the commercial assay. The higher sensitivity of SCOVAM is especially relevant to screen sera for convalescent plasma-based treatments, high-throughput antibody response monitoring after vaccination or evaluation of vaccine efficiency.

Type III secretion system effectors form robust and flexible intracellular virulence networks.

Infections with many Gram-negative pathogens, including Escherichia coli, Salmonella, Shigella, and Yersinia, rely on type III secretion system (T3SS) effectors. We hypothesized that while hijacking processes within mammalian cells, the effectors operate as a robust network that can tolerate substantial contractions. This was tested in vivo using the mouse pathogen Citrobacter rodentium (encoding 31 effectors). Sequential gene deletions showed that effector essentiality for infection was context dependent and that the network could tolerate 60% contraction while maintaining pathogenicity. Despite inducing very different colonic cytokine profiles (e.g., interleukin-22, interleukin-17, interferon-γ, or granulocyte-macrophage colony-stimulating factor), different networks induced protective immunity. Using data from >100 distinct mutant combinations, we built and trained a machine learning model able to predict colonization outcomes, which were confirmed experimentally. Furthermore, reproducing the human-restricted enteropathogenic E. coli effector repertoire in C. rodentium was not sufficient for efficient colonization, which implicates effector networks in host adaptation. These results unveil the extreme robustness of both T3SS effector networks and host responses.

Identification of Nanobodies Blocking Intimate Adherence of Shiga Toxin-Producing Escherichia coli to Epithelial Cells.

Therapeutic antibodies (Abs) inhibiting bacterial adhesion to host epithelia are an attractive option to reduce the load of Shiga toxin-producing E. coli (STEC) in the intestine of the patient and also in the bovine reservoir, thereby minimizing the risk of STEC contamination in the food chain. Of particular interest are recombinant single-domain Ab fragments called nanobodies (Nbs) derived from the variable domain of camelid heavy chain-only antibodies (VHH). The outer membrane adhesin intimin and the translocated intimin receptor (Tir) are essential for the attachment of STEC to host epithelia. In addition, EspA filaments of the bacterial type III protein secretion system are needed for Tir translocation into the host cell. Given their importance for bacterial adhesion and colonization, we developed Nbs against intimin, Tir and EspA proteins of STEC serotype O157:H7. Here, we report the screening methods used to isolate inhibitory Nbs blocking intimin-Tir protein-protein interaction, actin-pedestal formation, and intimate adhesion of STEC to epithelial cells in vitro. First, we describe how VHH gene repertoires can be produced as Nbs secreted by E. coli using the α-hemolysin (HlyA) protein secretion system. Next, we report the methods for identification of inhibitors of intimin-Tir protein-protein interaction and of STEC intimate adhesion to HeLa cells in culture. These methods can be adapted for the screening of Nbs against different adhesin-receptor complexes to block the adhesion of other pathogens to host cells.

Faecal neutrophil elastase-antiprotease balance reflects colitis severity.

Given the global burden of diarrheal diseases on healthcare it is surprising how little is known about the drivers of disease severity. Colitis caused by infection and inflammatory bowel disease (IBD) is characterised by neutrophil infiltration into the intestinal mucosa and yet our understanding of neutrophil responses during colitis is incomplete. Using infectious (Citrobacter rodentium) and chemical (dextran sulphate sodium; DSS) murine colitis models, as well as human IBD samples, we find that faecal neutrophil elastase (NE) activity reflects disease severity. During C. rodentium infection intestinal epithelial cells secrete the serine protease inhibitor SerpinA3N to inhibit and mitigate tissue damage caused by extracellular NE. Mice suffering from severe infection produce insufficient SerpinA3N to control excessive NE activity. This activity contributes to colitis severity as infection of these mice with a recombinant C. rodentium strain producing and secreting SerpinA3N reduces tissue damage. Thus, uncontrolled luminal NE activity is involved in severe colitis. Taken together, our findings suggest that NE activity could be a useful faecal biomarker for assessing disease severity as well as therapeutic target for both infectious and chronic inflammatory colitis.

A nanobody targeting the translocated intimin receptor inhibits the attachment of enterohemorrhagic E. coli to human colonic mucosa.

Enterohemorrhagic E. coli (EHEC) is a human intestinal pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome. No vaccines or specific therapies are currently available to prevent or treat these infections. EHEC tightly attaches to the intestinal epithelium by injecting the intimin receptor Tir into the host cell via a type III secretion system (T3SS). In this project, we identified a camelid single domain antibody (nanobody), named TD4, that recognizes a conserved Tir epitope overlapping the binding site of its natural ligand intimin with high affinity and stability. We show that TD4 inhibits attachment of EHEC to cultured human HeLa cells by preventing Tir clustering by intimin, activation of downstream actin polymerization and pedestal formation. Furthermore, we demonstrate that TD4 significantly reduces EHEC adherence to human colonic mucosa in in vitro organ cultures. Altogether, these results suggest that nanobody-based therapies hold potential in the development of much needed treatment and prevention strategies against EHEC infection.