KR-12 Derivatives Endow Nanocellulose with Antibacterial and Anti-Inflammatory Properties: Role of Conjugation Chemistry.

This work combines the wound-healing-related properties of the host defense peptide KR-12 with wood-derived cellulose nanofibrils (CNFs) to obtain bioactive materials, foreseen as a promising solution to treat chronic wounds. Amine coupling through carbodiimide chemistry, thiol-ene click chemistry, and Cu(I)-catalyzed azide-alkyne cycloaddition were investigated as methods to covalently immobilize KR-12 derivatives onto CNFs. The effects of different coupling chemistries on the bioactivity of the KR12-CNF conjugates were evaluated by assessing their antibacterial activities against Escherichia coli and Staphylococcus aureus. Potential cytotoxic effects and the capacity of the materials to modulate the inflammatory response of lipopolysaccharide (LPS)-stimulated RAW 245.6 macrophages were also investigated. The results show that KR-12 endowed CNFs with antibacterial activity against E. coli and exhibited anti-inflammatory properties and those conjugated by thiol-ene chemistry were the most bioactive. This finding is attributed to a favorable peptide conformation and accessibility (as shown by molecular dynamics simulations), driven by the selective chemistry and length of the linker in the conjugate. The results represent an advancement in the development of CNF-based materials for chronic wound care. This study provides new insights into the effect of the conjugation chemistry on the bioactivity of immobilized host defense peptides, which we believe to be of great value for the use of host defense peptides as therapeutic agents.

Remote visualization of large-scale genomic alignments for collaborative clinical research and diagnosis of rare diseases.

The Solve-RD project objectives include solving undiagnosed rare diseases (RD) through collaborative research on shared genome-phenome datasets. The RD-Connect Genome-Phenome Analysis Platform (GPAP), for data collation and analysis, and the European Genome-Phenome Archive (EGA), for file storage, are two key components of the Solve-RD infrastructure. Clinical researchers can identify candidate genetic variants within the RD-Connect GPAP and, thanks to the developments presented here as part of joint ELIXIR activities, are able to remotely visualize the corresponding alignments stored at the EGA. The Global Alliance for Genomics and Health (GA4GH) htsget streaming application programming interface (API) is used to retrieve alignment slices, which are rendered by an integrated genome viewer (IGV) instance embedded in the GPAP. As a result, it is no longer necessary for over 11,000 datasets to download large alignment files to visualize them locally. This work highlights the advantages, from both the user and infrastructure perspectives, of implementing interoperability standards for establishing federated genomics data networks.

A stable cyclized antimicrobial peptide derived from LL-37 with host immunomodulatory effects and activity against uropathogens.

The increasing antibiotic resistance among uropathogenic bacteria warrants alternative therapeutic strategies. We demonstrate the potential of the synthetic peptide CD4-PP, designed by dimerization and backbone cyclization of the shortest antimicrobial region of human cathelicidin, LL-37. CD4-PP is active against clinical and type strains of common uropathogens Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa at concentrations substantially below cellular cytotoxic levels and induced membrane deformation and leakage in E. coli and P. aeruginosa. Furthermore, CD4-PP treatment prevented the formation of new biofilm and dissolved mature biofilm created by E. coli and P. aeruginosa and targeted curli amyloid in E. coli biofilms. In addition, CD4-PP also induced production of LL-37 by uroepithelial cells and increased the expression of tight junction proteins claudin-14 and occludin. During uroepithelial cell infection, CD4-PP significantly reduced uropathogen survival when treatment was given at the start of infection. Low micromolar of CD4-PP treatment initiated after 2 h was successful with all tested species, except P. aeruginosa where CD4-PP was unable to reduce survival, which could be attributed by early biofilm formation. Finally, we demonstrated that urinary catheter pieces coated with saline fluid supplemented with CD4-PP reduced the attachment of E. coli, giving it a potential clinical application.

The influence of shifting perspective on episodic and semantic details during autobiographical memory recall.

Shifting to a novel visual perspective during retrieval influences autobiographical memories (AM) and can lead to persistent changes in memories. Adopting an observer-like compared to an own eyes perspective reduces episodic information during AM recall, but less is known regarding how viewpoint influences semantic information. In the current study, we investigated how shifting from an own eyes to an observer-like perspective during narrative recall of AMs influences episodic and semantic information. Shifting perspective reduced the number of episodic details associated with emotions and thoughts, and also led to similar reductions in personal semantics. We replicated prior research showing that shifting perspective reduces emotional intensity in subsequent memories, but these subjective changes were not coupled with objective changes in a narrative recall. Our findings suggest that shifting perspective influences the interplay between episodic and semantic information during proximate recall and subjective changes when memories are later recalled.

The European Genome-phenome Archive in 2021.

The European Genome-phenome Archive (EGA - https://ega-archive.org/) is a resource for long term secure archiving of all types of potentially identifiable genetic, phenotypic, and clinical data resulting from biomedical research projects. Its mission is to foster hosted data reuse, enable reproducibility, and accelerate biomedical and translational research in line with the FAIR principles. Launched in 2008, the EGA has grown quickly, currently archiving over 4,500 studies from nearly one thousand institutions. The EGA operates a distributed data access model in which requests are made to the data controller, not to the EGA, therefore, the submitter keeps control on who has access to the data and under which conditions. Given the size and value of data hosted, the EGA is constantly improving its value chain, that is, how the EGA can contribute to enhancing the value of human health data by facilitating its submission, discovery, access, and distribution, as well as leading the design and implementation of standards and methods necessary to deliver the value chain. The EGA has become a key GA4GH Driver Project, leading multiple development efforts and implementing new standards and tools, and has been appointed as an ELIXIR Core Data Resource.

In Vitro Investigation of Thiol-Functionalized Cellulose Nanofibrils as a Chronic Wound Environment Modulator.

There is currently a huge need for new, improved therapeutic approaches for the treatment of chronic wounds. One promising strategy is to develop wound dressings capable of modulating the chronic wound environment (e.g., by controlling the high levels of reactive oxygen species (ROS) and proteases). Here, we selected the thiol-containing amino acid cysteine to endow wood-derived cellulose nanofibrils (CNF) with bioactivity toward the modulation of ROS levels and protease activity. Cysteine was covalently incorporated into CNF and the functionalized material, herein referred as cys-CNF, was characterized in terms of chemical structure, degree of substitution, radical scavenging capacity, and inhibition of protease activity. The stability of the thiol groups was evaluated over time, and an in vitro cytotoxicity study with human dermal fibroblasts was performed to evaluate the safety profile of cys-CNF. Results showed that cys-CNF was able to efficiently control the activity of the metalloprotease collagenase and to inhibit the free radical DPPH (1,1-Diphenyl-2-picrylhydrazyl radical), activities that were correlated with the presence of free thiol groups on the nanofibers. The stability study showed that the reactivity of the thiol groups challenged the bioactivity over time. Nevertheless, preparing the material as an aerogel and storing it in an inert atmosphere were shown to be valid approaches to increase the stability of the thiol groups in cys-CNF. No signs of toxicity were observed on the dermal fibroblasts when exposed to cys-CNF (concentration range 0.1-0.5 mg/mL). The present work highlights cys-CNF as a promising novel material for the development of bioactive wound dressings for the treatment of chronic wounds.

Besnoitia besnoiti seroprevalence in beef, dairy and bullfighting cattle in Catalonia (north-eastern Spain): A cross-sectional study.

Besnoitia besnoiti is the causative agent of bovine besnoitiosis, a chronic and debilitating disease of cattle that recently re-emerged and seems to be spreading in Europe. A cross-sectional serological study was carried out in different cattle herds in Catalonia, north-eastern Spain, to determine the seroprevalence of B. besnoiti in the region. A total of 791 serum samples (beef cattle n = 338, dairy cattle n = 291; bullfighting cattle n = 162) were tested. Sera were first screened for antibodies against Besnoitia using a commercial Enzyme-Linked Immunosorbent Assay (ELISA) applying a cut-off that was lower than that recommended by the manufacturer in order to reach highest sensitivity. Sera above the chosen cut-off of 15% positivity (PP) were further tested by the Indirect Fluorescent Antibody Test (IFAT) and respectively positive results were confirmed by a B. besnoiti tachyzoite-based immunoblot. A total of 504/791 (63.7%) sera showed ELISA values above the selected cut-off, and 91 of these samples also yielded positive results in IFAT (cut-off titre 1:200). By immunoblot, a positive result was obtained in 93.4% (85 out of the 91) of the IFAT-positive samples. Interestingly, all confirmed Besnoitia-seropositive cases corresponded exclusively to beef cattle from the Pyrenees area, resulting in a prevalence of 25.1% (85/338) at the animal level and of 46% (36/78) at the herd level in this cattle group. No specific antibodies against Besnoitia could be detected in dairy and bullfighting cattle. The obtained results suggested that Besnoitia infections are present in Catalonia, consequently, diagnosis of this parasitic infection should be included in the sanitary control and before trading and movement of animals.

Light-activatable prodrugs based on hyaluronic acid biomaterials.

Photosensitive in situ cross-linked hyaluronan (HA) hydrogels are prepared by modular chemoselective assembly from the biopolymer precursors and novel heterobifunctional linkers with middle photo-labile ortho-nitrobenzyl group and orthogonally reactive terminals. Starting from the thiol-modified HA and a linker with activated disulfide and hydrazide terminals, a photo-degradable HA hydrogel was prepared by the hydrazone cross-linking reaction. Moreover, a light-triggered drug-releasing hydrogel prodrug was constructed by an orthogonal conjugation of dopamine (DA) via a photo-labile linker to HA dually modified with thiol and hydrazide groups (hy-HA-SH) and a subsequent cross-linking with aldehyde-derivatized HA (HA-al). On-demand release of DA from the hydrogel was achieved upon exposure of the hydrogel to UV light whereas 11-fold less release of the drug was observed in the absence of light. The mechanical properties of the hydrogels, photodegradation kinetics, photorelease of the model drugs were studied by rheology, spectrophotometry, chromatography, and mass spectrometry. For the first time, integration of photolabile components into an actual polysaccharide of extracellular matrix was implemented for the light-controlled release of drug molecules.

¿Debería considerarse la obesidad un factor limitante para el tratamiento con clozapina? / Should obesity be a limiting factor for clozapine treatment?

Objetivo. Clozapina es el fármaco de elección en el tratamiento de la esquizofrenia resistente, pero genera importantes cambios ponderales que pueden disuadir al clínico de utilizarlo, preocupado por los posibles riesgos para la salud del paciente. Para valorar estos aspectos evaluamos los cambios producidos en el índice de masa corporal (IMC) a las 18 y 56 semanas de tratamiento con clozapina. Método. En una muestra de pacientes diagnosticados de esquizofrenia, el peso y la estatura fueron medidos a nivel basal y posteriormente de forma semanal durante las primeras 18 semanas de tratamiento con clozapina. Posteriormente la evaluación fue mensual. Se registraron así mismo las dosis regulares de clozapina, los niveles plasmáticos de clozapina y norclozapina, la medicación concomitante, el género y la edad. Resultados. A las 18 semanas (n=76) el incremento medio en IMC era de 1,83kg/m2. El IMC basal se correlacionaba de forma inversa con el incremento en IMC. A las 56 semanas (n=57) el incremento medio en IMC era 2,67kg/m2 y se correlacionaba de forma inversa con el IMC basal. Análisis de regresión múltiple replicaron estos resultados. Considerando categorías diferentes según el IMC basal, los pacientes que partían de un sobrepeso tenían menor riesgo de incremento ponderal continuado. Conclusiones. La presencia de sobrepeso no debiera disuadir al clínico de considerar el tratamiento con clozapina en pacientes con esquizofrenia resistente(AU)

Objective. Clozapine is the first choice in drug-resistant schizophrenia but also causes important weight changes. This might discourage clinicians who are concerned about the risk of developing health problems. To assess this issue we measured change in body mass index (cBMI) induced by clozapine at 18 and 56 weeks. Methods. Baseline body weight and height were measured and weight weekly thereafter during the first 18 weeks of treatment. After that, measurements were made monthly. Steady clozapine dose, clozapine and norclozapine blood concentrations, concomitant medication, gender and age were recorded. Results. At 18 weeks (n=76) mean cBMI was 1.83kg/m2. Baseline BMI was inversely correlated with cBMI. At 56 weeks (n=57) cBMI was 2.67kg/m2 and was inversely correlated with basal BMI. Multiple regression analysis replicated the results. When split with BMI categories, obese patients had lesser risk for further weight gain. Conclusions. Obesity should not discourage clinicians from starting clozapine in drug-resistant patients(AU)

Should obesity be a limiting factor for clozapine treatment?

OBJECTIVE: Clozapine is the first choice in drug-resistant schizophrenia but also causes important weight changes. This might discourage clinicians concerned about the risk of developing health problems. To assess this issue we measured change in body mass index (cBMI) induced by clozapine at 18 and 56 weeks. METHODS: Baseline body weight and height were measured and weight weekly thereafter during the first 18 weeks of treatment. After that, measurements were made monthly. Steady clozapine dose, clozapine and norclozapine blood concentrations, concomitant medication, gender and age were recorded. RESULTS: At 18 weeks (n=76) mean cBMI was 1.83 kg/m(2). Baseline BMI was inversely correlated with cBMI. At 56 weeks (n=57) cBMI was 2.67 kg/m(2) and was inversely correlated with basal BMI. Multiple regression analysis replicated the results. When split with BMI categories, obese patients had lesser risk for further weight gain. CONCLUSIONS: Obesity should not discourage clinicians from starting clozapine in drug-resistant patients.

Topological visual mapping in robotics.

A key problem in robotics is the construction of a map from its environment. This map could be used in different tasks, like localization, recognition, obstacle avoidance, etc. Besides, the simultaneous location and mapping (SLAM) problem has had a lot of interest in the robotics community. This paper presents a new method for visual mapping, using topological instead of metric information. For that purpose, we propose prior image segmentation into regions in order to group the extracted invariant features in a graph so that each graph defines a single region of the image. Although others methods have been proposed for visual SLAM, our method is complete, in the sense that it makes all the process: it presents a new method for image matching; it defines a way to build the topological map; and it also defines a matching criterion for loop-closing. The matching process will take into account visual features and their structure using the graph transformation matching (GTM) algorithm, which allows us to process the matching and to remove out the outliers. Then, using this image comparison method, we propose an algorithm for constructing topological maps. During the experimentation phase, we will test the robustness of the method and its ability constructing topological maps. We have also introduced new hysteresis behavior in order to solve some problems found building the graph.

Primeras notificaciones espontáneas de sospechas de reacciones adversas a los nuevos antiinflamatorios selectivos sobre la ciclooxigenasa. Respuesta / First spontaneous reports of adverse drug reactions to the new selective COX-2 non-steroideal anti-inflammatory drugs. Reply

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