The insulin-like growth factor 1 receptor is essential for axonal regeneration in adult central nervous system neurons

Axonal regeneration is an essential condition to re-establish functional neuronal connections in the injured adult central nervous system (CNS), but efficient regrowth of severed axons has proven to be very difficult to achieve. Although significant progress has been made in identifying the intrinsic and extrinsic mechanisms involved, many aspects remain unresolved. Axonal development in embryonic CNS (hippocampus) requires the obligate activation of the insulin-like growth factor 1 receptor (IGF-1R). Based on known similarities between axonal growth in fetal compared to mature CNS, we decided to examine the expression of the IGF-1R, using an antibody to the βgc subunit or a polyclonal anti-peptide antibody directed to the IGF-R (C20), in an in vitro model of adult CNS axonal regeneration, namely retinal ganglion cells (RGC) derived from adult rat retinas. Expression of both βgc and the β subunit recognized by C20 antibody were low in freshly isolated adult RGC, but increased significantly after 4 days in vitro. As in embryonic axons, βgc was localised to distal regions and leading growth cones in RGC. IGF-1R-βgc co-localised with activated p85 involved in the phosphatidylinositol-3 kinase (PI3K) signaling pathway, upon stimulation with IGF-1. Blocking experiments using either an antibody which neutralises IGF-1R activation, shRNA designed against the IGF-1R sequence, or the PI3K pathway inhibitor LY294002, all significantly reduced axon regeneration from adult RGC in vitro (∼40% RGC possessed axons in controls vs 2-8% in the different blocking studies). Finally, co-transfection of RGC with shRNA to silence IGF-1R together with a vector containing a constitutively active form of downstream PI3K (p110), fully restored axonal outgrowth in vitro. Hence these data demonstrate that axonal regeneration in adult CNS neurons requires re-expression and activation of IGF-1R, and targeting this system may offer new therapeutic approaches to enhancing axonal regeneration following trauma.Fil: Dupraz, Sebastian, Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Córdoba. Centro de Investigaciones en Química Biológica de Cordoba (p); Argentina;Fil: Grassi, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Córdoba. Centro de Investigaciones en Química Biológica de Cordoba (p); Argentina;Fil: Karnas, Diana. Rhythms, Life and Death in the Retina. Centre National de la Recherche Scientifique (CNRS). Université de Strasbourg. Institut des Neurosciences Cellulaires et Intégratives; France;Fil: Nieto Guil, Alvaro Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Córdoba. Centro de Investigaciones en Química Biológica de Cordoba (p); Argentina;Fil: Hicks, David. Rhythms, Life and Death in the Retina. Centre National de la Recherche Scientifique (CNRS). Université de Strasbourg. Institut des Neurosciences Cellulaires et Intégratives; France;Fil: Quiroga, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Córdoba. Centro de Investigaciones en Química Biológica de Cordoba (p); Argentina

Lymphocyte Subpopulation Number and Function in Infancy

Normal values for percentages of lymphocyte subpopulations and functional responses to mitogen stimulation in infancy are not well established. In the present study, lymphocyte subpopulations were examined in umbilical cord blood samples and in peripheral blood samples drawn before 7 and 24 months of age (mean age 10.4 months) from a healthy population of infants born in Tucson, Arizona. Results indicate significant increases occurred from birth to later infancy in the percentages of total T cells (CD3), T-cell subsets (CD4, CD8) and B cells (CD20). The CD4/CD8 ratio and the functional responses to ConA and PWM mitogens significantly decreased from birth to later infancy. PHA responsiveness did not show a significant change. Results from cross-sectional analyses (n=271) were supported in a smaller longitudinal subset (n=37). There were no detectable ethnic- or gender-related differences in cord blood or samples obtained in later infancy. The normal values established in this study will be useful in studies of immune-system maturation and in the clinical evaluation of newborns, infants, and toddlers suspected of either acquired or congenital immune-deficiency states

PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage

Amyotrophic lateral sclerosis (ALS) is associated with progressive degeneration of motor neurons. Several of the genes associated with this disease encode proteins involved in RNA processing, including fused-in-sarcoma/translocated-in-sarcoma (FUS/TLS). FUS is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins that bind thousands of pre-mRNAs and can regulate their splicing. Here, we have examined the possibility that FUS is also a component of the cellular response to DNA damage. We show that both GFP-tagged and endogenous FUS re-localize to sites of oxidative DNA damage induced by UVA laser, and that FUS recruitment is greatly reduced or ablated by an inhibitor of poly (ADP-ribose) polymerase activity. Consistent with this, we show that recombinant FUS binds directly to poly (ADP-ribose) in vitro, and that both GFP-tagged and endogenous FUS fail to accumulate at sites of UVA laser induced damage in cells lacking poly (ADP-ribose) polymerase-1. Finally, we show that GFP-FUS(R521G), harbouring a mutation that is associated with ALS, exhibits reduced ability to accumulate at sites of UVA laser-induced DNA damage. Together, these data suggest that FUS is a component of the cellular response to DNA damage, and that defects in this response may contribute to ALS

SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes

Diabetic kidney disease (DKD) is a topic of increasing concern among clinicians involved in the management of type 2 diabetes mellitus (T2DM). It is a progressive and costly complication associated with increased risk of adverse cardiovascular (CV) and renal outcomes and mortality. Ongoing monitoring of the estimated glomerular filtration (eGFR) rate alongside the urine albumin:creatinine ratio (ACR) is recommended during regular T2DM reviews to enable a prompt DKD diagnosis or to assess disease progression, providing an understanding of adverse risk for each individual. Many people with DKD will progress to end-stage kidney disease (ESKD), requiring renal replacement therapy (RRT), typically haemodialysis or kidney transplantation. A range of lifestyle and pharmacological interventions is recommended to help lower CV risk, slow the advancement of DKD and prevent or delay the need for RRT. Emerging evidence concerning sodium-glucose co-transporter-2 inhibitor (SGLT2i) agents suggests a role for these medicines in slowing eGFR decline, enabling regression of albuminuria and reducing progression to ESKD. Improvements in renal end points observed in SGLT2i CV outcome trials (CVOTs) highlighted the possible impact of these agents in the management of DKD. Data from the canagliflozin CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) have since demonstrated the effectiveness of this medicine in reducing the risk of kidney failure and CV events in a population comprising individuals with T2DM and renal disease. CREDENCE was the first SGLT2i study to examine renal outcomes as the primary end point. Real-world studies have reaffirmed these outcomes in routine clinical practice. This article summarises the evidence regarding the use of SGLT2i medicines in slowing the progression of DKD and examines the possible mechanisms underpinning the renoprotective effects of these agents. The relevant national and international guidance for monitoring and treatment of DKD is also highlighted to help clinicians working to support this vulnerable group

Evaluación de riesgo de intoxicación por plomo en la zona urbana aledaña a una fundidora en Chihuahua, México

El objetivo fue evaluar el riesgo de intoxicación con plomo en tres estratos (E1, E2 y E3) urbanos cercanos a una industria que operó por alrededor de 90 años. En cada estrato se seleccionó una muestra aleatoria de madres en edad reproductiva así como de sus hijos con edades entre 1-5 años. Se obtuvieron muestras de sangre capilar de madres e hijos y se analizaron por voltametría. En cada vivienda muestreada se tomaron muestras de suelo, pintura, polvo y agua para su análisis por voltametría anódica. En forma adicional, se seleccionaron escuelas preescolares, y se obtuvieron muestras de sangre de niños menores de 6 años. Los modelos predictivos se realizaron mediante regresión lineal simple y regresión múltiple. La evaluación se ejecutó con la metodología de evaluación de riesgo de la EPA (Environmental Protection Agency). De un total de 324 niños examinados, el rango de valores de plomo en sangre osciló entre 2.8-50.2 μg/dL con una media geométrica de 11.4 μg/dL (s±8.2), el 32% >10 μg/dL, 4% > 25 μg/dL, 1% > 45 μg/dL. Se encontró una zona de alto riesgo en E1 y de mediano riesgo en E2 (75% y 40% de niños con > 10 μg/dL; norma SSA). Las concentraciones de plomo presentaron una relación inversa con la distancia. Las muestras de suelo superficial mostraron un rango de 100 a > 9,000 ppm. Los valores de plomo en madres se encontraron dentro de la norma. Los predictores de plomo en niños se relacionaron con la exposición a suelo, el cual aporta más del 90% como fuente de exposición. Se concluye que existe una contaminación residual en la zona aledaña a la fundidora, la cual debe remediarse antes de seguir realizando actividades recreativas y culturales. DOI: https://doi.org/10.54167/tecnociencia.v1i1.3

The Place and Value of Sodium-Glucose Cotransporter 2 Inhibitors in the Evolving Treatment Paradigm for Type 2 Diabetes Mellitus: A Narrative Review

Over recent years, the expanding evidence base for sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapies has revealed benefits beyond their glucose-lowering efficacy in the treatment of Type 2 diabetes mellitus (T2DM), resulting in their recognition as cardiorenal medicines. While SGLT2is continue to be recommended among the second-line therapies for the treatment of hyperglycaemia, their true value now extends to the prevention of debilitating and costly cardiovascular and renal events for high-risk individuals, with particular benefit shown in reducing major adverse cardiac events and heart failure (HF) and slowing the progression of chronic kidney disease. However, SGLT2i usage is still suboptimal among groups considered to be at greatest risk of cardiorenal complications. The ongoing coronavirus disease 2019 (COVID-19) pandemic has intensified financial pressures on healthcare systems, which may hamper further investment in newer effective medicines. Emerging evidence indicates that glycaemic control should be prioritised for people with T2DM in the era of COVID-19 and practical advice on the use of T2DM medications during periods of acute illness remains important, particularly for healthcare professionals working in primary care who face multiple competing priorities. This article provides the latest update from the Improving Diabetes Steering Committee, including perspectives on the value of SGLT2is as cost-effective therapies within the T2DM treatment paradigm, with particular focus on the latest published evidence relating to the prevention or slowing of cardiorenal complications. The implications for ongoing and future approaches to diabetes care are considered in the light of the continuing coronavirus pandemic, and relevant aspects of international treatment guidelines are highlighted with practical advice on the appropriate use of SGLT2is in commonly occurring T2DM clinical scenarios. The ‘SGLT2i Prescribing Tool for T2DM Management’, previously published by the Steering Committee, has been updated to reflect the latest evidence and is provided in the Supplementary Materials to help support clinicians delivering T2DM care

Tradespace Investigation of a Telescope Architecture for Next-generation Space Astronomy and Exploration

Humanity’s endeavor to further its scientific understanding of the celestial heavens has led to the creation and evolution of increasingly powerful and complex space telescopes. Space telescopes provide a view of the solar system, galaxy, and universe unobstructed by Earth’s atmosphere and have profoundly changed the way people view space. In an effort to further advance space telescope capability and achieve the accompanying scientific understanding, the Massachusetts Institute of Technology (MIT), specifically, course 16.89 Space Systems Engineering, explored the tradespace of architectural enumerations encompassed within the design of an ultraviolet-optical-infrared (UVOIR) space telescope located at Sun-Earth Lagrangian Point Two (SE-L2). SE-L2 presents several advantages as an operating location for a UVOIR telescope such as a thermally stable environment and an orbit that allows the telescope to maintain a constant orientation with respect to all of the primary sources of heat and light. The main disadvantages associated with SE-L2 are caused by its relatively large distance from Earth, which marginalizes the effectiveness of real-time telerobotics because of latency and increases the cost of communications, launch, and servicing. Course 16.89 believes that, for this UVOIR application, the strengths of this operating location outweigh its weaknesses and therefore decided to explore the family of opportunities associated with SE-L2. This course used appropriate performance and system metrics to quantify the effectiveness of the aforementioned architectures and create a Pareto front of viable architectures. Evaluating the designs along the Pareto front allowed the course to characterize and group architectures and present these group-types to stakeholders for the selection of an optimal space telescope according to stakeholder requirements and resources. This course also developed sensitivity analysis, which allowed for a greater understanding of how architectural decisions affect the performance of the satellite. Segmentation, modularity, assembly, autonomy, and servicing were key aspects of this multidimensional analysis given the 16.8-meter class size and location of the telescope. Within the respective operating environment and for a spacecraft of similar characteristics, this model will allow stakeholders to predict the long-term operational effectiveness of different space telescope architectures and capture the synergistic effects of combining various architectural decisions into a spacecraft design. The following sections step through the aforesaid analysis and design efforts conducted in 16.89 beginning with Section III, which explicitly performs the stakeholder analysis and articulates the requirements of the mission. Section IV gives an overview of past designs and expands upon the architecture enumerations pertinent to this project, while Section V presents the methods and metrics by which those architectures will be evaluated and the system metrics which will be balanced and optimized in the creation of this space telescope. Section VI will present the model validation of this project and Section VII will discuss the results and analyses of the project. Finally, Section VIII will explore the future work opportunities of this project, while Section IX will present the conclusions and recommendations drawn from this project.MIT Department of Aeronautics and Astronautic

SGLT2 Inhibitors in Type 2 Diabetes Management: Key Evidence and Implications for Clinical Practice

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Host-Toxin Interactions Involving EspC and Pet, Two Serine Protease Autotransporters of the Enterobacteriaceae

EspC and Pet are toxins secreted by the diarrheagenic enteropathogenic and enteroaggregative Escherichia coli pathotypes, respectively. Both toxins have a molecular mass around 110 kDa and belong to the same protein family called Serine Protease Autotransporters of the Enterobacteriaceae (SPATE). Furthermore, both toxins act within the cytosol of intoxicated epithelial cells to disrupt the architecture of the actin cytoskeleton. This cytopathic and enterotoxic effect results from toxin cleavage of the actin-binding protein fodrin, although the two toxins recognize different cleavage sites on fodrin. EspC and Pet also have dramatically different mechanisms of entering the target cell which appear dependent upon the E. coli pathotype. In this review, we compare/contrast EspC and Pet in regards to their mode of delivery into the target cell, their effects on fodrin and the actin cytoskeleton, and their possible effects on the physiology of the intestinal epithelial cell