IL-10 indirectly modulates functional activity of CD4+CD28null T-lymphocytes through LFA-3 and HLA class II inhibition.

Expansion of CD4+CD28null T-lymphocytes is common in chronic heart failure (CHF) patients. Its ability to produce high levels of proinflammatory cytokines is probably the key role of these cells in CHF. IL-10 is a candidate for limiting CD4+CD28null T-lymphocyte responses, whereas tumour necrosis factor (TNF) is the cytokine most closely involved in the loss of CD28 expression. Serum levels of TNF and IL-10 were measured in 65 CHF patients (mean age, 65.2 ± 13.84 years). Patients with an IL-10/TNF ratio ≥1 had significantly lower levels of CD4+CD28null T-lymphocytes than those with a ratio <1. In vitro, IL-10 reduced the frequency of proliferative CD4+CD28null T-lymphocytes stimulated with anti-CD3. Pre-treatment with IL-10 before anti-CD3 stimulation was required for the cytokine to inhibit TNF production by CD4+CD28null T-lymphocytes. In addition to the previously described effect of IL-10 on HLA-DR and ICAM-1 expression, LFA-3 protein and mRNA levels were reduced in the presence of the cytokine in monocytes. IL-10 inhibition on CD4+CD28null T-lymphocytes may be mediated by a reduction in HLA class II and LFA-3 expression because blocking interactions with these costimulators has similar effects to those of IL-10 treatment. Moreover, costimulation through CD2/LFA-3 interaction is enough to induce proliferation and cytokine production in CD4+CD28null T-lymphocytes.

Single-cell analysis of the epitranscriptome: RNA modifications under the microscope.

The identification of mechanisms capable of modifying genetic information by the addition of covalent RNA modifications distinguishes a level of complexity in gene expression which challenges key long-standing concepts of RNA biology. One of the current challenges of molecular biology is to properly understand the molecular functions of these RNA modifications, with more than 170 different ones having been identified so far. However, it has not been possible to map specific RNA modifications at a single-cell resolution until very recently. This review will highlight the technological advances in single-cell methodologies aimed at assessing and testing the biological function of certain RNA modifications, focusing on m6A. These advances have allowed for the development of novel strategies that enable the study of the 'epitranscriptome'. Nevertheless, despite all these improvements, many challenges and difficulties still need fixing for these techniques to work efficiently.

ANCUT1, a novel thermoalkaline cutinase from Aspergillus nidulans and its application on hydroxycinnamic acids lipophilization.

One of the four cutinases encoded in the Aspergillus nidulans genome, ANCUT1, is described here. Culture conditions were evaluated, and it was found that this enzyme is produced only when cutin is present in the culture medium, unlike the previously described ANCUT2, with which it shares 62% amino acid identity. The differences between them include the fact that ANCUT1 is a smaller enzyme, with experimental molecular weight and pI values of 22 kDa and 6, respectively. It shows maximum activity at pH 9 and 60 °C under assayed conditions and retains more than 60% of activity after incubation for 1 h at 60 °C in a wide range of pH values (6-10) after incubations of 1 or 3 h. It has a higher activity towards medium-chain esters and can modify long-chain length hydroxylated fatty acids constituting cutin. Its substrate specificity properties allow the lipophilization of alkyl coumarates, valuable antioxidants and its thermoalkaline behavior, which competes favorably with other fungal cutinases, suggests it may be useful in many more applications.

Preoperative MRSA screening using a simple questionnaire prior elective total joint replacement.

INTRODUCTION: The purpose of this study was to evaluate the management and results of our standarized protocol for preoperative identification of MRSA colonisation in patients undergoing primary total hip and knee replacement procedures. METHODS: Following hospital protocol, between January 2016 and June 2019 37,745 patients awaiting elective joint replacement underwent a standardized questionnaire to assess the risk of MRSA infection, identifying patients requiring preoperative MRSA screening. An evaluation of the questionnaire identified effective questions for identifying infected patients. Furthermore, an analysis evaluated the impact of comorbidities or Charlson Comorbidity Index scores on positive MRSA colonization. Additionally, we evaluated the cost savings of targeted testing compared to testing all surgery patients. RESULTS: Of the 37,745 patients, 8.057 (21.3%) were swabbed, with a total of 65 (0.81%) positive tests. From this group 27 (36.48%) who were treated were negative before surgery. Some of the questionnaire results were consistently associated with a higher chance of colonization, including hospitalization during the past year (47,7%), previous history of MRSA (44,6%), and agriculture or cattle farming related work (15,4%). By selectively testing high-risk patients identified through the questionnaire, we achieved a 79% reduction in costs compared to universal MRSA screening. CONCLUSION: Our results suggest that the simple and standardized questionnaire is a valuable tool for preoperative screening, effectively identifying high-risk patients prone to MRSA colonisation. The risk of periprosthetic joint infection (PJI) and its associated sequelae may be reduced by this approach.

Transition from a meiotic to a somatic-like DNA damage response during the pachytene stage in mouse meiosis.

Homologous recombination (HR) is the principal mechanism of DNA repair acting during meiosis and is fundamental for the segregation of chromosomes and the increase of genetic diversity. Nevertheless, non-homologous end joining (NHEJ) mechanisms can also act during meiosis, mainly in response to exogenously-induced DNA damage in late stages of first meiotic prophase. In order to better understand the relationship between these two repair pathways, we studied the response to DNA damage during male mouse meiosis after gamma radiation. We clearly discerned two types of responses immediately after treatment. From leptotene to early pachytene, exogenous damage triggered the massive presence of γH2AX throughout the nucleus, which was associated with DNA repair mediated by HR components (DMC1 and RAD51). This early pathway finished with the sequential removal of DMC1 and RAD51 and was no longer inducible at mid pachytene. However, from mid-pachytene to diplotene, γH2AX appeared as large discrete foci. This late repair pattern was mediated initially by NHEJ, involving Ku70 and XRCC4, which were constitutively present, and 53BP1, which appeared at sites of damage soon after irradiation. Nevertheless, 24 hours after irradiation, a HR pathway involving RAD51 but not DMC1 mostly replaced NHEJ. Additionally, we observed the occurrence of synaptonemal complex bridges between bivalents, most likely representing chromosome translocation events that may involve DMC1, RAD51 or 53BP1. Our results reinforce the idea that the early "meiotic" repair pathway that acts by default at the beginning of meiosis is replaced from mid-pachytene onwards by a "somatic-like" repair pattern. This shift might be important to resolve DNA damage (either endogenous or exogenous) that could not be repaired by the early meiotic mechanisms, for instance those in the sex chromosomes, which lack a homologous chromosome to repair with. This transition represents another layer of functional changes that occur in meiotic cells during mid pachytene, in addition to epigenetic reprograming, reactivation of transcription, changes in the gene expression profile and acquisition of competence to proceed to metaphase.

Novel technique of development of human derived acellular dermal matrix.

Reconstructive surgery techniques have evolved exponentially in last decades. From regional flaps to free tissue transfer, tissue movilization has become the gold standart treatment in many reconstructive procedures. Main disadvantage from these techniques lies in the possibility of sequels in donor zone. Furthermore, raising comorbidities in general population and growing indications for reconstructive surgery in elder people, have triggered the development of new biomaterials which can offer support in the reconstruction while elicit donor zone morbidity. Advances in tissue decellularization techniques have brought numerous matrices which have shown effectivity in many reconstructive procedures. Use of acellular dermal matrices may become an eligible solution for many reconstructive procedures. From breast reconstruction assisted by matrices to complex wound coverage passing throught tendon repair techniques, acellular dermal matrices have shown effectiveness in last studies. Local production of this biomaterial leads to cost minimization derived from harvesting and manufacturing matrices in our centre and avoid out-of-stock and storage issues. Current original protocol proposed by our group include all steps from harvesting samples from cadaveric donors till matrix storage after decellularization proccess. The result is a high valued biomaterial in terms of biocompatibility and security profile available.

New Method for Obtaining a Bioactive Essence Extracted from Iberian Ham Fat Rich in MUFA and Antioxidants.

Iberian ham is one of the most representative Spanish products and presents an excellent nutritional and sensory quality. Iberian ham trimming fat is considered a by-product and to give a new use to this remaining part could represent a healthy and innovative option for obtaining sustainable foods. The purpose of this work was to obtain a new bioactive ingredient from Iberian ham trimming fat with the highest amount of antioxidants and monounsaturated fatty acids (MUFA), using a new non-invasive solvent-free method. To obtain the essence, two different extraction procedures were carried out. After fatty acid characterization, degree of acidity, peroxide index and a basic sensory analysis were performed. Antioxidant in vitro activity and total phenolic compounds (TPC) were also determined. This new ingredient showed a better sensory profile than raw ham fat, a lower degree of acidity, a higher content of MUFAs, and also showed a higher antioxidant capacity and an increase in phenolic compounds compared to the raw material. This bioactive essence could be used as a food, a cosmetic or a nutraceutical ingredient to prevent certain diseases related to oxidative stress and could also contribute to the maintenance of the circular economy.

Cross-lingual semantic annotation of biomedical literature: experiments in Spanish and English.

MOTIVATION: Biomedical literature is one of the most relevant sources of information for knowledge mining in the field of Bioinformatics. In spite of English being the most widely addressed language in the field; in recent years, there has been a growing interest from the natural language processing community in dealing with languages other than English. However, the availability of language resources and tools for appropriate treatment of non-English texts is lacking behind. Our research is concerned with the semantic annotation of biomedical texts in the Spanish language, which can be considered an under-resourced language where biomedical text processing is concerned. RESULTS: We have carried out experiments to assess the effectiveness of several methods for the automatic annotation of biomedical texts in Spanish. One approach is based on the linguistic analysis of Spanish texts and their annotation using an information retrieval and concept disambiguation approach. A second method takes advantage of a Spanish-English machine translation process to annotate English documents and transfer annotations back to Spanish. A third method takes advantage of the combination of both procedures. Our evaluation shows that a combined system has competitive advantages over the two individual procedures. AVAILABILITY AND IMPLEMENTATION: UMLSMapper (https://snlt.vicomtech.org/umlsmapper) and the annotation transfer tool (http://scientmin.taln.upf.edu/anntransfer/) are freely available for research purposes as web services and/or demos. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Draft Genome Resources Sequences of Six Pseudomonas syringae pv. actinidiae Strains Isolated from Actinidia chinensis var. deliciosa Leaves in Portugal.

Pseudomonas syringae pv. actinidiae is a quarantine bacterium affecting all the Portuguese main areas of kiwifruit production. We report the draft genome of six P. syringae pv. actinidiae strains isolated from symptomatic leaves of Actinidia chinensis var. deliciosa in a study that determined the genetic population structure of the endophytic and epiphytic populations in two consecutive seasons. Average nucleotide identity values were above 99% similarity with reference strains from P. syringae pv. actinidiae biovar 3. The genomic differences found between these strains confirm the genetic diversity described for P. syringae pv. actinidiae population in Portugal. Furthermore, data provide evidence that the initial clonal expansion of P. syringae pv. actinidiae in Europe was followed by a genomic diversification constituting a valuable resource for epidemiological and evolutionary studies, namely when adopting strategies for epidemics management.

The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling.

The tricarboxylic acid cycle enzyme fumarate hydratase (FH) has been identified as a tumor suppressor in a subset of human renal cell carcinomas. Human FH-deficient cancer cells display high fumarate concentration and ROS levels along with activation of HIF-1. The underlying mechanisms by which FH loss increases ROS and HIF-1 are not fully understood. Here, we report that glutamine-dependent oxidative citric acid cycle metabolism is required to generate fumarate and increase ROS and HIF-1 levels. Accumulated fumarate directly bonds the antioxidant glutathione in vitro and in vivo to produce the metabolite succinated glutathione (GSF). GSF acts as an alternative substrate to glutathione reductase to decrease NADPH levels and enhance mitochondrial ROS and HIF-1 activation. Increased ROS also correlates with hypermethylation of histones in these cells. Thus, fumarate serves as a proto-oncometabolite by binding to glutathione which results in the accumulation of ROS.

Recommendations on the pharmacological treatment of epithelial ovarian cancer in Mexico.

Ovarian cancer is the third most frequent gynaecological malignancy worldwide and in Mexico, with a high mortality rate, due to that in many cases its diagnosis is made in advanced stages. Prognosis is important for determining the subtype and the degree of evolution. During lasts years, the management of ovarian cancer has undergone an important evolution with the incorporation of new therapeutic options, which in turn represent an increase in the survival of these patients. We present recommendations for the management of ovarian cancer developed by an expert panel Mexican based on available evidence so far and the characteristics of health care in the country.

El cáncer de ovario es la tercera neoplasia maligna ginecológica más frecuente globalmente y también en México, con una elevada tasa de mortalidad debido a que en muchos casos su diagnóstico se realiza en etapas avanzadas. Para establecer su pronóstico es importante la determinación del subtipo y del grado de evolución. En los últimos años, el manejo del cáncer de ovario ha sufrido una importante evolución con la incorporación de nuevas opciones terapéuticas, que a su vez representan un incremento en la supervivencia de estas pacientes. Se presentan las recomendaciones para el manejo del cáncer de ovario elaboradas por un panel de expertos mexicanos basadas en la evidencia disponible hasta el momento y en las características de la atención sanitaria del país.

In vitro Conversion into CD4+CD25+Foxp3+ Induced Regulatory T Cells Is Reduced in Atopic Dermatitis Patients.

BACKGROUND: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases, with an increasing incidence in clinical practice. AD models have demonstrated that TGF-ß signaling is compromised in regulatory T cells (Tregs). OBJECTIVES: This study aimed to investigate the TGF-ß-dependent in vitro conversion of CD4+CD25- T cells derived from AD-patients into CD4+CD25+Foxp3+ induced Tregs (iTregs) in comparison to healthy controls. METHODS: To analyze in vitro iTreg conversion, human CD4+CD25- T cells were cultured on anti-CD3-coated plates in the presence of TGF-ß and IL-2 for up to 3 days. Consequently, the underlying mechanism of impaired CD4+CD25+Foxp3+ iTreg generation was explored by focusing on TGF-ß signaling. Finally, the functionality of iTregs was investigated. RESULTS: Conversion of CD4+CD25-Foxp3- into CD4+CD25+Foxp3+ iTregs was diminished in AD individuals. Impaired iTreg generation was accompanied by a reduced surface expression of GARP (glycoprotein A repetitions predominant), a marker for activated Tregs. A reduced expression of Smad3 mRNA was revealed in CD4+CD25- T cells. Interestingly, the suppressive quality of iTregs was found to be equal in cells derived from AD and healthy donors. CONCLUSION: The signaling effect of TGF-ß receptors on the suppressor quality of iTreg conversion is conserved. Impaired iTreg generation might be a reason for the lack of immune suppression in AD patients and contributes to the chronicity of the disease.

A Hybrid Metal-Organic Framework-Reduced Graphene Oxide Nanomaterial for Selective Removal of Chromate from Water in an Electrochemical Process.

Hexavalent chromium Cr(VI) is a highly toxic groundwater contaminant. In this study, we demonstrate a selective electrochemical process tailored for removal of Cr(VI) using a hybrid MOF@rGO nanomaterial synthesized by in situ growth of a nanocrystalline, mixed ligand octahedral metal-organic framework with cobalt metal centers, [Co2(btec)(bipy)(DMF)2]n (Co-MOF), on the surface of reduced graphene oxide (rGO). The rGO provides the electric conductivity necessary for an electrode, while the Co-MOF endows highly selective adsorption sites for CrO42-. When used as an anode in the treatment cycles, the MOF@rGO electrode exhibits strong selectivity for adsorption of CrO42- over competing anions including Cl-, SO42-, and As(III) and achieves charge efficiency (CE) >100% due to the strong physisorption of CrO42- by Co-MOF; both electro- and physisorption capacities are regenerated with the reversal of the applied voltage, when highly toxic Cr(VI) is reduced to less toxic reduced Cr species and subsequently released into brine. This approach allows easy regeneration of the nonconducting Co-MOF without any chemical addition while simultaneously transforming Cr(VI), inspiring a novel electrochemical method for highly selective degradation of toxic contaminants using tailor-designed electrodes with high affinity adsorbents.

Patterns in medication incidents: A 10-yr experience of a cross-national anaesthesia incident reporting system.

BACKGROUND: Medication-related adverse events (MRE) in anaesthesia care are frequent and require a deeper understanding if we are to prevent medication harm. METHODS: We searched for reported MRE from the Spanish Anaesthesia Incident Reporting System (SENSAR) database over a 10-yr period. SENSAR is a cross-national, multicentre system focused on perioperative and critical care. A descriptive analysis of independent variables, phase of medication process, type of MRE, and medication group involved, and their relationships with morbidity was conducted. RESULTS: A total of 1970 MRE were identified from 7072 reported incidents. Patient harm was reported in 31% of the MRE. The administration phase was more frequent (42%) and showed the highest harm rate (44%) compared with other medication process phases. The most frequent types of MRE were wrong treatment regimen and wrong medication (55% of cases). The medication groups most commonly reported were those that alter haemostasis (18%), vasoconstrictor agents (13%), and opioids (10%). Vasoconstrictor agents, benzodiazepines, and neuromuscular blocking agents were the medication groups involved in patient harm four-fold more, and opioids three-fold more, than medications that alter haemostasis. The 1970 incidents were investigated and led to implementation of 4223 local corrective patient safety and quality improvement measures. CONCLUSIONS: Patient harm in the perioperative setting from medications remains a major issue for patients, hospital leaders, and clinicians. We found patterns and specific causes that can be mitigated through proven systems solutions, and should be taken into consideration in designing sustainable solutions for safe perioperative care. CLINICAL TRIAL REGISTRATION: NCT03615898.

A physical activity program versus usual care in the management of quality of life for pre-frail older adults with chronic pain: randomized controlled trial.

BACKGROUND: Exercise has shown being effective for managing chronic pain and preventing frailty status in older adults but the effect of an exercise program in the quality of life of pre-frail older adults with chronic pain remains unclear. Our objective was to evaluate the effectiveness of multicomponent structured physical exercise program for pre-frail adults aged 65 years or more with chronic pain to improve their perceived health related quality of life, compared with usual care. METHODS: Open label randomized controlled trial. Participants were community-dwelling pre-frail older adults aged 65 years or older with chronic pain and non-dependent for basic activities of daily living attending a Primary Healthcare Centre. Forty-four participants were randomly allocated to a control group (n = 20) that received usual care or an intervention group (n = 24) that received an 8-week physical activity and education program. Frailty status (SHARE Frailty Index), quality of life (EuroQol-5D-5L), pain intensity (Visual Analogue Scale), physical performance (Short Physical Performance Battery) and depression (Yessavage) were assessed at baseline, after the intervention and after 3 months follow-up. The effect of the intervention was analysed by mean differences between the intervention and control groups. RESULTS: The follow-up period (3 months) was completed by 32 patients (73%), 17 in the control group and 15 in the intervention group. Most participants were women (78.1%) with a mean age (standard deviation) of 77.2 (5.9) years and a mean pain intensity of 48.1 (24.4) mm. No relevant differences were found between groups at baseline. After the intervention, mean differences in the EuroQol Index Value between control and intervention groups were significant (- 0.19 95% CI(- 0.33- -0.04)) and remained after 3 months follow-up (- 0.21 95% CI(- 0.37- -0.05)). Participants in the exercise group showed better results in pain intensity and frailty after the intervention, and an improvement in physical performance after the intervention and after 3 months. CONCLUSIONS: An eight-week physical activity and education program for pre-frail older adults with chronic pain, compared with usual care, could be effective to improve quality of life after the intervention and after three-months follow-up. STUDY REGISTRATION DETAILS: This study was retrospectively registered in ClinicalTrials.gov with the identifier NCT04045535 .

Bone impaction grafting with trabecular metal augments in large defects in young patients: unravelling a new perspective in surgical technique.

BACKGROUND: Acetabular reconstruction with bone impaction grafting in large defects has yielded conflicting results. METHODS: This was a retrospective study of a case series of five patients with a young age (≤50 years) at the time of surgery who had large acetabular defects reconstructed by bone impaction grafting and trabecular metal augments. The mean follow-up was 79 months. We describe the surgical technique in detail. RESULTS: Improvement was significant on the WOMAC and SF-36 scales (p < 0.05). The radiographs taken at the last follow-up examination showed no migration of the polyethylene cup (p = 0.31) or differences in the abduction angle (p = 0.27) compared to the radiographs from the immediate postoperative period. One patient presented two dislocation episodes as a complication. CONCLUSION: The combination of trabecular metal augments with the bone impaction grafting technique in young patients with large acetabular defects provides satisfactory results in the long term and restores the bone stock.

Evaluation of Cleaning Processes Using Colorimetric and Spectral Data for the Removal of Layers of Limewash from Medieval Plasterwork.

In the cultural heritage preservation of medieval buildings, it is common to find plaster walls covered in lime, which previously were painted in polychromy. The conservation interventions usually try to remove the whitewash, whilst maintaining the original color of the painted wall as much as possible. However, there is no agreement on which cleaning technique best preserves the original appearance of the colored plaster. Different pigments found below the lime layer may behave differently depending on the cleaning technique used. Usually, colorimetric or photometric area-based measurements are carried out to study the color of the cleaned areas to compare with their original color, obtained from pre-made plaster probes. However, this methodology fails when the mean color difference is not enough to fully characterize the changes in texture and color appearance. This study presents a set of experiments carried out using two different pigments (cinnabar and malachite) covered with lime, and treated with nine different cleaning techniques on plaster probes prepared according to medieval techniques. We have studied the effect of the cleaning process on the color and the homogeneity of the samples using a hyperspectral imaging workflow. Four different analysis methods are presented and discussed. Our results show that the proposed analysis is able to provide a much more comprehensive and diversified characterization of the quality of the cleaning method compared to the commonly used colorimetric or photometric area-based measurements.

Regulation of the cutinases expressed by Aspergillus nidulans and evaluation of their role in cutin degradation.

Four cutinase genes are encoded in the genome of the saprophytic fungus Aspergillus nidulans, but only two of them have proven to codify for active cutinases. However, their overall roles in cutin degradation are unknown, and there is scarce information on the regulatory effectors of their expression. In this work, the expression of the cutinase genes was assayed by multiplex qRT-PCR in cultures grown in media containing both inducer and repressor carbon sources. The genes ancut1 and ancut2 were induced by cutin and its monomers, while ancut3 was constitutively expressed. Besides, cutin induced ancut4 only under oxidative stress conditions. An in silico analysis of the upstream regulatory sequences suggested binding regions for the lipid metabolism transcription factors (TF) FarA for ancut1 and ancut2 while FarB for ancut3. For ancut4, the analysis suggested binding to NapA (the stress response TF). These binding possibilities were experimentally tested by transcriptional analysis using the A. nidulans mutants ANΔfarA, ANΔfarB, and ANΔnapA. Regarding cutin degradation, spectroscopic and chromatographic methods showed similar products from ANCUT1 and ANCUT3. In addition, ANCUT1 produced 9,10-dihydroxy hexadecanoic acid, suggesting an endo-cleavage action of this enzyme. Regarding ANCUT2 and ANCUT4, they produced omega fatty acids. Our results confirmed the cutinolytic activity of the four cutinases, allowed identification of their specific roles in the cutinolytic system and highlighted their differences in the regulatory mechanisms and affinity towards natural substrates. This information is expected to impact the cutinase production processes and broaden their current biotechnological applications.

Penalizing fathers who use family-friendly measures. A comparative study with university students from Ghana and Spain.

This article provides experimental empirical evidence on the penalization of a father of high professional status who decides to use a family friendly measure (FFM) offered by his company. A cross-cultural sample of university students (in the field of Business Administration and Economics) from Ghana and Spain was used to evaluate a hypothetical male employee who after the birth of their child either used a reduction of the working day or worked traditional hours. We compared the results with those obtained for an identical female employee. We considered several variables that mediated the effect of using the FFM on the behavior proxy items. We also considered the participants' (explicit and implicit) attitudes towards fathers caring for their babies. We obtained strong empirical evidence on the penalization of a father who uses a reduction of the working day. However, and contrary to expectations, in Spain this penalty experienced by the father was similar to that experienced by the mother, while in Ghana it was greater.