Dissecting the microglial response in transgenic models of amyloidogenesis and tauopathy

Amyloid-beta (Abeta) peptide deposits and hyperphosphorylated tau protein (phospho-tau) accumulate in Alzheimer’s disease (AD) brains. These abnormal protein aggregates leads to glial activation, synaptic dysfunction, neuronal loss and cognitive decline. While microglial response has mostly been analyzed in relation to Abeta accumulation, little is still known about inflammatory processes associated with tau pathology. Microglial reactivity and defective glial responses have been involved in these proteinopathies. Our aim is to clarify the effects of Abeta and tau separately, in order to improve the comprehension of their differential contribution to neuroinflammation and neurodegeneration. We compared the progression of these processes in an amyloidogenic AD model (APPSL/PS1M146L) and two different models of tauopathy (ThyTau22 and hP301S) from 2 to 18 months of age. Accumulation of aggregated proteins was assessed using specific anti- Abeta and phospho-tau antibodies. Inflammatory response was studied using a battery of microglial markers (Iba1, CD45, CD68, Trem2 and Gal-3). In the hippocampus of these models, Tau and Abeta pathologies initiated as early as 2 months of age and increased progressively with aging. Neuritic plaques induced a strong microglial activation associated to plaques in APP/PS1 mice. Interestingly, inflammatory markers and microglial reactivity were barely increased in the hippocampus of ThyTau mice in contrast to not only APP/PS1, but also to P301S mice, which displayed a prominent microglial response. Deciphering the specific effects of Abeta, tau and their different toxic species, would indeed enable the development of novel therapeutic strategies and drugs targeting neuroinflammatory pathways related to these proteinopathies.Universidad de Málaga. Campus de excelencia Andalucía-Tech. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain co-financed by FEDER funds from European Union, and by grant PPIT.UMA.B1.2017/26 (RS-V)

Arabidopsis thaliana bZIP44: a transcription factor affecting seed germination and expression of the mannanase-encoding gene AtMAN7.

Endo-β-mannanases (MAN; EC. 3.2.1.78) catalyze the cleavage of β1[RIGHTWARDS ARROW]4 bonds in mannan polymers and have been associated with the process of weakening the tissues surrounding the embryo during seed germination. In germinating Arabidopsis thaliana seeds, the most highly expressed MAN gene is AtMAN7 and its transcripts are restricted to the micropylar endosperm and to the radicle tip just before radicle emergence. Mutants with a T-DNA insertion in AtMAN7 have a slower germination than the wild type. To gain insight into the transcriptional regulation of the AtMAN7 gene, a bioinformatic search for conserved non-coding cis-elements (phylogenetic shadowing) within the Brassicaceae MAN7 gene promoters has been done, and these conserved motifs have been used as bait to look for their interacting transcription factors (TFs), using as a prey an arrayed yeast library from A. thaliana. The basic-leucine zipper TF AtbZIP44, but not the closely related AtbZIP11, has thus been identified and its transcriptional activation upon AtMAN7 has been validated at the molecular level. In the knock-out lines of AtbZIP44, not only is the expression of the AtMAN7 gene drastically reduced, but these mutants have a significantly slower germination than the wild type, being affected in the two phases of the germination process, both in the rupture of the seed coat and in the breakage of the micropylar endosperm cell walls. In the over-expression lines the opposite phenotype is observed

Conocimiento y práctica sobre prevención de anemia en madres de niños menores de 2 años en el puesto de Salud Villa María, nuevo Chimbote – Perú 2022

El presente trabajo de investigación tuvo como finalidad analiza la relación entre el conocimiento y prácticas sobre prevención de anemia en madres de niños menores a 2 años en el Puesto de Salud de Villa María, Nuevo Chimbote, 2022. Esta investigación fue descriptiva, con enfoque cuantitativo, de corte trasversal y de diseño correlacional; a través de un muestreo probabilístico aplicada a una población de 250 madres de niños menores de 2 años se pudo identificar una muestra de 152 madres. Luego de la aplicación de los instrumentos de conocimiento y practicas sobre prevención de anemia, se logró identificar que, el nivel de conocimiento de la madre respecto a la prevención de anemia estaba en un nivel alto; del mismo modo el nivel de prácticas se encontró en el mismo nivel. Asimismo, a través de la prueba de correlación de Spearman, se logró concluir que existe relación positiva, moderada y significativa entre el conocimiento y la práctica de prevención de anemia con r = 0.710 y p-valor inferior al 5%

SSITA: Seal Serving Institutional Transformation Assessment: Excelencia in Education & Portland State University

In the Spring of 2022, Portland State University was invited to participate in Excelencia in Education’s pilot Seal Serving Institutional Transformation Assessment or SSITA. This SSITA report is a preliminary institutional assessment of Portland State University’s (PSU) efforts to intentionally serve Latiné students and advance degree completion. Between now and June 2023, a committee of faculty, staff, and students will lead the effort to complete a Seal of Excelencia application. We will reach out to all parts of the institution to gather additional information, data, and stories about how units serve our growing Latiné student population. The next round of Seal of Excelencia recipients are announced in the early fall of 2023

Development of a Prodrug of Camptothecin for Enhanced Treatment of Glioblastoma Multiforme

[EN] A novel therapeutic approach for glioblastoma multiforme (GBM) therapy has been carried out through in vitro and in vivo testing by using the prodrug camptothecin-20-O-(5-aminolevulinate) (CPT-ALA). The incorporation of ALA to CPT may promote uptake of the cytotoxic molecule by glioblastoma cells where the heme synthesis pathway is active, improving the therapeutic action and reducing the side effects over healthy tissue. The antitumor properties of CPT-ALA have been tested on different GBM cell lines (U87, U251, and C6) as well as in an orthotopic GBM model in rat, where potential toxicity in central nervous system cells was analyzed. In vitro results indicated no significant differences in the cytotoxic effect over the different GBM cell lines for CPT and CPT-ALA, albeit cell mortality induced by CPT over normal cell lines was significantly higher than CPT-ALA. Moreover, intracranial GBM in rat was significantly reduced (30% volume) with 2 weeks of CPT-ALA treatment with no significant side effects or alterations to the well-being of the animals tested. 5-ALA moiety enhances CPT diffusion into tumors due to solubility improvement and its metabolic-based targeting, increasing the CPT cytotoxic effect on malignant cells while reducing CPT diffusion to other proliferative healthy tissue. We demonstrate that CPT-ALA blocks proliferation of GBM cells, reducing the infiltrative capacity of GBM and promoting the success of surgical removal, which improves life expectancy by reducing tumor recurrence.Financial support from Spanish Ministry of Economy and Competitiveness (Projects PID2019-111436RB-C21 and SEV2016-0683) and the Generalitat Valenciana (Project PROMETEO/2017/060) is gratefully acknowledged. We thank Prof. Luis Fernandez (Group of Structural Mechanics and Materials Modellings-GEMM, University of Zaragoza, Spain) for donation of human GBM cell lines. We are grateful to Dr. Lawrence Humphreys (CIBER-BBN) for critical reading of the manuscriptCheca-Chavarria, E.; Rivero-Buceta, EM.; Sanchez Martos, MA.; Martinez Navarrete, G.; Soto-Sanchez, C.; Botella Asuncion, P.; Fernandez Jover, E. (2021). Development of a Prodrug of Camptothecin for Enhanced Treatment of Glioblastoma Multiforme. Molecular Pharmaceutics. 18(4):1558-1572. https://doi.org/10.1021/acs.molpharmaceut.0c009681558157218

Underdosing of Surfactant for Preterm Babies with Respiratory Distress Syndrome in Clinical Practice : A Retrospective Cohort Study

This study was supported by Chiesi España, S.A.U., Barcelona, Spain.Objective: To evaluate the initial doses of surfactant administered to preterm infants with respiratory distress syndrome. Study Design: This is a retrospective cohort study of 206 preterm infants admitted in four level III neonatal intensive care units of acute tertiary care hospitals in Spain between 2013 and 2015. Results: The mean initial dose of surfactant was 173.9 (37.3) mg/kg, and 47.5% of infants received a dose of 200 mg/kg ± 10% (180-220 mg/kg), 47% less than 180 mg/kg (-10%), and 5.4% more than 220 mg/kg (+10%). Very preterm infants (32 weeks). Conclusion: Administration of surfactant below the prescribed dose is a frequent error in clinical practice. Inadvertently rounding down doses seems a plausible explanation

Comparative study of extracellular recording methods for analysis of afferent sensory information: Empirical modeling, data analysis and interpretation

Background: Physiological studies of sensorial systems often require the acquisition and processing of data extracted from their multiple components to evaluate how the neural information changes in relation to the environment changes. In this work, a comparative study about methodological aspects of two electrophysiological approaches is described. New method: Extracellular recordings from deep vibrissal nerves were obtained by using a customized microelectrode Utah array during passive mechanical stimulation of rat´s whiskers. These recordings were compared with those obtained with bipolar electrodes. We also propose here a simplified empirical model of the electrophysiological activity obtained from a bundle of myelinated nerve fibers. Results: The peripheral activity of the vibrissal system was characterized through the temporal and spectral features obtained with both recording methods. The empirical model not only allows the correlation between anatomical structures and functional features, but also allows to predict changes in the CAPs morphology when the arrangement and the geometry of the electrodes changes. Comparison with existing method(s): This study compares two extracellular recording methods based on analysis techniques, empirical modeling and data processing of vibrissal sensory information. Conclusions: This comparative study reveals a close relationship between the electrophysiological techniques and the processing methods necessary to extract sensory information. This relationship is the result of maximizing the extraction of information from recordings of sensory activity.Fil: Farfan, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Bioingeniería. Laboratorio de Medios e Interfases; ArgentinaFil: Soto Sanchez, Cristina. Universidad de Miguel Hernández; España. Consorcio Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina; EspañaFil: Pizá, Alvaro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Bioingeniería. Laboratorio de Medios e Interfases; ArgentinaFil: Albarracin, Ana Lia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Bioingeniería. Laboratorio de Medios e Interfases; ArgentinaFil: Soletta, Jorge Humberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Bioingeniería. Laboratorio de Medios e Interfases; ArgentinaFil: Lucianna, Facundo Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Bioingeniería. Laboratorio de Medios e Interfases; ArgentinaFil: Fernandez, Esteve. Universidad de Miguel Hernández; España. Consorcio Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina; Españ

miRNA profiling during antigen-dependent T cell activation: A role for miR-132-3p

microRNAs (miRNAs) are tightly regulated during T lymphocyte activation to enable the establishment of precise immune responses. Here, we analyzed the changes of the miRNA profiles of T cells in response to activation by cognate interaction with dendritic cells. We also studied mRNA targets common to miRNAs regulated in T cell activation. pik3r1 gene, which encodes the regulatory subunits of PI3K p50, p55 and p85, was identified as target of miRNAs upregulated after T cell activation. Using 3'UTR luciferase reporter-based and biochemical assays, we showed the inhibitory relationship between miR-132-3p upregulation and expression of the pik3r1 gene. Our results indicate that specific miRNAs whose expression is modulated during T cell activation might regulate PI3K signaling in T cells.We thank Miguel Vicente-Manzanares for help with English editing and Almudena R. Ramiro for helpful discussions. We appreciate help from Gloria Martinez del Hoyo on DCs experiments set up. We also thank the CNIC Genomics, Bioinformatics and Cellomics Units for technical support. This work was supported by grants SAF2014-55579R from Ministerio de Economia y Competitividad-Spain, ERC-2011-AdG 294340-GENTRIS, CIBER CARDIOVASCULAR (FEDER and Instituto de Salud Carlos III), PIE-13-00041 and INDISNET S2011-BMD-2332 (F.S.M.). The Centro Nacional de Investigaciones Cardiovasculares (CNIC, Spain) is supported by the Ministerio de Economia y Competitividad-Spain and the Pro-CNIC Foundation.S

Computational study of ligand binding in lipid transfer proteins: Structures, interfaces, and free energies of protein-lipid complexes

Plant nonspecific lipid transfer proteins (nsLTPs) bind a wide variety of lipids, which allows them to perform disparate functions. Recent reports on their multifunctionality in plant growth processes have posed new questions on the versatile binding abilities of these proteins. The lack of binding specificity has been customarily explained in qualitative terms on the basis of a supposed structural flexibility and nonspecificity of hydrophobic protein-ligand interactions. We present here a computational study of protein-ligand complexes formed between five nsLTPs and seven lipids bound in two different ways in every receptor protein. After optimizing geometries inmolecular dynamics calculations, we computed Poisson- Boltzmann electrostatic potentials, solvation energies, properties of the protein-ligand interfaces, and estimates of binding free energies of the resulting complexes. Our results provide the first quantitative information on the ligand abilities of nsLTPs, shed new light into protein-lipid interactions, and reveal new features which supplement commonly held assumptions on their lack of binding specificity

Microtubule stabilization protects cognitive function and slows down the course of Alzheimer's like pathology in an amyloidogenic mouse model

Cognitive decline in Alzheimer's disease (AD) is highly related to synaptic dysfunction and neuronal loss. In AD, the hyperphosphorylation of tau compromises axonal transport and leads to the generation of dystrophic neurites, contributing to synaptic impairment. In addition to phospho-tau, AD brains accumulate amyloid-beta. This study evaluated the effect of the brain-penetrant microtubule-stabilizing agent, Epothilone D (EpoD) in the progression of the disease in a double transgenic mouse model of amyloidosis. Young APP/PS1 mice were weekly treated with intraperitoneal injections of EpoD (2 mg/kg) or vehicle solution for 3 months. Memory performance was tested using object-recognition tasks, Y-maze and Morris water maze. EpoD-treated mice improved their performance of cognitive tests, while hippocampal phospho-tau and Aβ levels, especially soluble oligomers, decreased significantly. β/γ-secretase activities were not affected by EpoD in vitro. A significant amelioration of synaptic/neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. In conclusion, EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Abeta accumulation, and promoting neuronal and cognitive protection. These results underline the crosstalk between cytoskeleton pathology and proteinopathy. Therefore, microtubule-stabilizing drugs could be candidates for slowing AD progression at both tau and Aβ pathologies.Supported by PI18/01557 (to AG) and PI18/01556 (to JV) grants from ISCiii of Spain, co-financed by FEDER funds from European Union, CIBERNED collaborative grant (to AG and JV), and by PPIT.UMA.B1.2017/26 grant (to RSV). Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech