Self-assembly of Fmoc-tetrapeptides based on the RGDS cell adhesion motif

Self-assembly in aqueous solution has been investigated for two Fmoc [Fmoc ¼ N-(fluorenyl)-9-methoxycarbonyl] tetrapeptides comprising the RGDS cell adhesion motif from fibronectin or the scrambled sequence GRDS. The hydrophobic Fmoc unit confers amphiphilicity on the molecules, and introduces aromatic stacking interactions. Circular dichroism and FTIR spectroscopy show that the self-assembly of both peptides at low concentration is dominated by interactions among Fmoc units, although Fmoc-GRDS shows b-sheet features, at lower concentration than Fmoc-RGDS. Fibre X-ray diffraction indicates b-sheet formation by both peptides at sufficiently high concentration. Strong alignment effects are revealed by linear dichroism experiments for Fmoc-GRDS. Cryo-TEM and smallangle X-ray scattering (SAXS) reveal that both samples form fibrils with a diameter of approximately 10 nm. Both Fmoc-tetrapeptides form self-supporting hydrogels at sufficiently high concentration. Dynamic shear rheometry enabled measurements of the moduli for the Fmoc-GRDS hydrogel, however syneresis was observed for the Fmoc-RGDS hydrogel which was significantly less stable to shear. Molecular dynamics computer simulations were carried out considering parallel and antiparallel b-sheet configurations of systems containing 7 and 21 molecules of Fmoc-RGDS or Fmoc-GRDS, the results being analyzed in terms of both intermolecular structural parameters and energy contributions

Comparación de las escalas APACHE II y BISAP en el pronóstico de pancreatitis aguda en un hospital del Perú: Comparison of the APACHE II and BISAP scales in the prognosis of acute pancreatitis in a hospital of Peru

Introduction:  Acute pancreatitis continue to be a disease with significant morbidity and mortality. It is diagnosed by clinical criteria and the inflammatory process can lead to organ failure. The objective of the present study was to compare the scales of APACHE II and BISAP in the development of organic failure in acute pancreatitis from a public hospital of Perú. Pacients and methods: An analytical from validation of a diagnostic test. There were clinical records of patients who were hospitalized with the diagnosis of acute pancreatitis in the Internal Medicine service and the Intensive Care Unit were evaluated. The APACHE II and BISAP scales were applied and the ROC curve, the sensitivity, the specificity, the positive and negative predictive value was calculated for each one. SPSSv23 was used for statistical analysis. Results: Were reviewed 146 stories that met the inclusion criteria. An area under the curve of 0.957 was obtained for BISAP and 0.996 for APACHE II; with a sensitivity and specificity for APACHE II of 83% and  99%,  for BISAP of 66% and 99%. In addition, the positive and negative predictive value for APACHE II is 83% and 99% ,  for BISAP 80% and 98% . Conclusion: The APACHE II scale was superior for detecting organ failure. It was determined that both scales have high specificity, however the APACHE II scale presented a higher sensitivity than the BISAP scale.Introducción: La pancreatitis aguda continúa siendo una enfermedad con morbilidad y mortalidad significativas. Se diagnostica mediante criterios clínicos y el proceso inflamatorio puede llegar hasta una falla de órganos. El objetivo del presente estudio fue comparar las escalas de APACHE II y BISAP en el desarrollo de falla orgánica en pacientes con pancreatitis aguda de un hospital público del Perú. Pacientes y métodos: Se realizó un estudio de validación de prueba diagnóstica. Se evaluaron las historias clínicas de pacientes que estuvieron hospitalizados con el diagnostico de pancreatitis aguda en el servicio de Medicina Interna y la Unidad de Cuidados Intensivos. Se aplicó las escalas APACHE II y BISAP, se calculó la curva ROC, sensibilidad, especificidad, valor predictivo positivo y negativo. Para el análisis estadístico se utilizó el SPSSv23. Resultados: Se evaluaron 146 historias de pacientes que cumplían con los criterios de inclusión. Se obtuvo un área bajo la curva de 0.957 para BISAP y 0.996 para APACHE II; con una sensibilidad y especificidad para APACHE II de 83% y 99%,  para BISAP de 66% y 99%. El valor predictivo positivo y negativo para APACHE II es 83% and 99% y para BISAP 80% y 98%. Conclusiones: La escala de APACHE II fue superior para detectar falla de órganos. Se determinó que ambas escalas poseen alta especificidad, siendo mayor la sensibilidad en la escala BISAP

Design of New Dispersants Using Machine Learning and Visual Analytics

Artificial intelligence (AI) is an emerging technology that is revolutionizing the discovery of new materials. One key application of AI is virtual screening of chemical libraries, which enables the accelerated discovery of materials with desired properties. In this study, we developed computational models to predict the dispersancy efficiency of oil and lubricant additives, a critical property in their design that can be estimated through a quantity named blotter spot. We propose a comprehensive approach that combines machine learning techniques with visual analytics strategies in an interactive tool that supports domain experts’ decision-making. We evaluated the proposed models quantitatively and illustrated their benefits through a case study. Specifically, we analyzed a series of virtual polyisobutylene succinimide (PIBSI) molecules derived from a known reference substrate. Our best-performing probabilistic model was Bayesian Additive Regression Trees (BART), which achieved a mean absolute error of (Formula presented.) and a root mean square error of (Formula presented.), as estimated through 5-fold cross-validation. To facilitate future research, we have made the dataset, including the potential dispersants used for modeling, publicly available. Our approach can help accelerate the discovery of new oil and lubricant additives, and our interactive tool can aid domain experts in making informed decisions based on blotter spot and other key propertie

The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior

In the last decade, new non-apoptotic roles have been ascribed to apoptotic caspases. This family of proteins plays an important role in the sculpting of the brain in the early stages of development by eliminating excessive and nonfunctional synapses and extra cells. Consequently, impairments in this process can underlie many neurological and mental illnesses. This view is particularly relevant to dopamine because it plays a pleiotropic role in motor control, motivation, and reward processing. In this study, we analyze the effects of the elimination of caspase-8 (CASP8) on the development of catecholaminergic neurons using neurochemical, ultrastructural, and behavioral tests. To do this, we selectively delete the CASP8 gene in cells that express tyrosine hydroxylase with the help of recombination through the Cre-loxP system. Our results show that the number of dopaminergic neurons increases in the substantia nigra. In the striatum, the basal extracellular level of dopamine and potassium-evoked dopamine release decreased significantly in mice lacking CASP8, clearly showing the low dopamine functioning in tissues innervated by this neurotransmitter. This view is supported by electron microscopy analysis of striatal synapses. Interestingly, behavioral analysis demonstrates that mice lacking CASP8 show changes reminiscent of autism spectrum disorders (ASD). Our research reactivates the possible role of dopamine transmission in the pathogenesis of ASD and provides a mild model of autism.Ministerio de Economía y Competitividad RTI2018-098645-B-I00, PID2019-109569GB-I00, RTI2018-099778-B-I00Junta de Andalucía P18-RT-1372, US-1264806, PI-0080-2017, PI-0009-2017, PI-0134-2018, PEMP-0008-2020, P20_00958, CTS-510Instituto de Salud Carlos III PI18/01691Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz-INiBICA LI19/06IN-CO22, IN-C09European Union 95568

Expanding the genetic spectrum of TUBB1-related thrombocytopenia

β1-Tubulin plays a major role in proplatelet formation and platelet shape maintenance, and pathogenic variants in TUBB1 lead to thrombocytopenia and platelet anisocytosis (TUBB1-RT). To date, the reported number of pedigrees with TUBB1-RT and of rare TUBB1 variants with experimental demonstration of pathogenicity is limited. Here, we report 9 unrelated families presenting with thrombocytopenia carrying 6 β1-tubulin variants, p.Cys12LeufsTer12, p.Thr107Pro, p.Gln423*, p.Arg359Trp, p.Gly109Glu, and p.Gly269Asp, the last of which novel. Segregation studies showed incomplete penetrance of these variants for platelet traits. Indeed, most carriers showed macrothrombocytopenia, some only increased platelet size, and a minority had no abnormalities. Moreover, only homozygous carriers of the p.Gly109Glu variant displayed macrothrombocytopenia, highlighting the importance of allele burden in the phenotypic expression of TUBB1-RT. The p.Arg359Trp, p.Gly269Asp, and p.Gly109Glu variants deranged β1-tubulin incorporation into the microtubular marginal ring in platelets but had a negligible effect on platelet activation, secretion, or spreading, suggesting that β1-tubulin is dispensable for these processes. Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin incorporation into the microtubular network. In addition, TUBB1 variants markedly impaired proplatelet formation from peripheral blood CD34+ cell-derived megakaryocytes. Our study, using in vitro modeling, molecular characterization, and clinical investigations provides a deeper insight into the pathogenicity of rare TUBB1 variants. These novel data expand the genetic spectrum of TUBB1-RT and highlight a remarkable heterogeneity in its clinical presentation, indicating that allelic burden or combination with other genetic or environmental factors modulate the phenotypic impact of rare TUBB1 variants.This work was partially supported by grants from Instituto de Salud Carlos III (ISCIII) and Feder (PI17/01311, PI17/01966, PI20/00926 and CB15/00055), Fundacion Séneca (19873/ GERM/15), Gerencia Regional de Salud (GRS 2061A/19 and 1647/A/17), Fundacion Mutua Madrile´ña (AP172142019), and ~ Sociedad Espanola de Trombosis y Hemostasia (Premio L ~ opez Borrasca 2019 and Ayuda a Grupos de Trabajo en Patologıa Hemorragica). The authors’ research on inherited platelet disorders is conducted in accordance with the aims of the Functional and Molecular Characterization of Patients with Inherited Platelet Disorders Project, from Grupo Espanol de Alteraciones Plaqueta- ~ rias Congenitas, which is supported by the Spanish Society of Thrombosis and Haemostasis. V.P.-B. has a predoctoral contract from CIBERER. L.B. was supported by a fellowship from Fondazione Umberto Veronesi. M.E.d.l.M.-B. holds a postdoctoral fellowship from the University of Murcia. A.M.-Q. holds a predoctoral grant from the Junta de Castilla y Leon

Oral Anticoagulation and Risk of Symptomatic Hemorrhagic Transformation in Stroke Patients Treated With Mechanical Thrombectomy: Data From the Nordictus Registry

Introduction: We aimed to evaluate if prior oral anticoagulation (OAC) and its type determines a greater risk of symptomatic hemorrhagic transformation in patients with acute ischemic stroke (AIS) subjected to mechanical thrombectomy. Materials and Methods: Consecutive patients with AIS included in the prospective reperfusion registry NORDICTUS, a network of tertiary stroke centers in Northern Spain, from January 2017 to December 2019 were included. Prior use of oral anticoagulants, baseline variables, and international normalized ratio (INR) on admission were recorded. Symptomatic intracranial hemorrhage (sICH) was the primary outcome measure. Secondary outcome was the relation between INR and sICH, and we evaluated mortality and functional outcome at 3 months by modified Rankin scale. We compared patients with and without previous OAC and also considered the type of oral anticoagulants. Results: About 1.455 AIS patients were included, of whom 274 (19%) were on OAC, 193 (70%) on vitamin K antagonists (VKA), and 81 (30%) on direct oral anticoagulants (DOACs). Anticoagulated patients were older and had more comorbidities. Eighty-one (5.6%) developed sICH, which was more frequent in the VKA group, but not in DOAC group. OAC with VKA emerged as a predictor of sICH in a multivariate regression model (OR, 1.89 [95% CI, 1.01–3.51], p = 0.04) and was not related to INR level on admission. Prior VKA use was not associated with worse outcome in the multivariate regression model nor with mortality at 3 months. Conclusions: OAC with VKA, but not with DOACs, was an independent predictor of sICH after mechanical thrombectomy. This excess risk was associated neither with INR value by the time thrombectomy was performed, nor with a worse functional outcome or mortality at 3 months

Competitive Asymmetries in the Use of Supplementary Food by the Endangered Iberian Lynx (Lynx pardinus)

Background: As a conservation tool, supplementary feeding programs may be directed to specific individuals or sectors of the target population whose productivity or survival is thought to be limited by food scarcity. However, the use of supplemental food by different sex and age classes has received little attention. We studied individual variation in the access of the endangered Iberian lynx (Lynx pardinus) to supplementary food. Methodology/Principal Findings: From 5349 pictures taken with automatic cameras placed in 25 feeding stations, we identified 28 individuals whose sex and age were known. All individuals known to live in areas subjected to supplementation regularly visited feeding stations. Food consumption was not proportional to expected variations in energy demand within sex and age classes. Food consumption by males was higher than by females, and increased with age, in agreement with a despotic distribution. Food consumption also increased with lynx body mass, and this pattern held for individuals sharing the same breeding territories. The access of inferior competitors increased with the number of feeding stations available within lynx territories. Conclusions/Significance: All lynx exposed to food supplementation made a regular use of extra food but individuals predicted to be competitively dominant visited stations more frequently than subordinates of the same breeding territory. Our results suggest that insufficient provision of supplementary food could restrict the access of juveniles, or even adult females, to feeding stations. Limited consumption by these target individuals may compromise the efficiency of the supplementary feeding programme at the population level, in endangered species that, as the Iberian lynx, exhibit marked sexual dimorphism in body size.Peer reviewe

The CARMENES search for exoplanets around M dwarfs

Context. The CARMENES instrument, installed at the 3.5 m telescope of the Calar Alto Observatory in Almería, Spain, was conceived to deliver high-accuracy radial velocity (RV) measurements with long-term stability to search for temperate rocky planets around a sample of nearby cool stars. Moreover, the broad wavelength coverage was designed to provide a range of stellar activity indicators to assess the nature of potential RV signals and to provide valuable spectral information to help characterise the stellar targets. Aims: We describe the CARMENES guaranteed time observations (GTO), spanning from 2016 to 2020, during which 19 633 spectra for a sample of 362 targets were collected. We present the CARMENES Data Release 1 (DR1), which makes public all observations obtained during the GTO of the CARMENES survey. Methods: The CARMENES survey target selection was aimed at minimising biases, and about 70% of all known M dwarfs within 10 pc and accessible from Calar Alto were included. The data were pipeline-processed, and high-level data products, including 18 642 precise RVs for 345 targets, were derived. Time series data of spectroscopic activity indicators were also obtained. Results: We discuss the characteristics of the CARMENES data, the statistical properties of the stellar sample, and the spectroscopic measurements. We show examples of the use of CARMENES data and provide a contextual view of the exoplanet population revealed by the survey, including 33 new planets, 17 re-analysed planets, and 26 confirmed planets from transiting candidate follow-up. A subsample of 238 targets was used to derive updated planet occurrence rates, yielding an overall average of 1.44 ± 0.20 planets with 1 M⊕ < Mpl sin i < 1000 M⊕ and 1 day < Porb < 1000 days per star, and indicating that nearly every M dwarf hosts at least one planet. All the DR1 raw data, pipeline-processed data, and high-level data products are publicly available online. Conclusions: CARMENES data have proven very useful for identifying and measuring planetary companions. They are also suitable for a variety of additional applications, such as the determination of stellar fundamental and atmospheric properties, the characterisation of stellar activity, and the study of exoplanet atmospheres

Rarity of monodominance in hyperdiverse Amazonian forests.

Tropical forests are known for their high diversity. Yet, forest patches do occur in the tropics where a single tree species is dominant. Such "monodominant" forests are known from all of the main tropical regions. For Amazonia, we sampled the occurrence of monodominance in a massive, basin-wide database of forest-inventory plots from the Amazon Tree Diversity Network (ATDN). Utilizing a simple defining metric of at least half of the trees ≥ 10 cm diameter belonging to one species, we found only a few occurrences of monodominance in Amazonia, and the phenomenon was not significantly linked to previously hypothesized life history traits such wood density, seed mass, ectomycorrhizal associations, or Rhizobium nodulation. In our analysis, coppicing (the formation of sprouts at the base of the tree or on roots) was the only trait significantly linked to monodominance. While at specific locales coppicing or ectomycorrhizal associations may confer a considerable advantage to a tree species and lead to its monodominance, very few species have these traits. Mining of the ATDN dataset suggests that monodominance is quite rare in Amazonia, and may be linked primarily to edaphic factors