Toll-Like Receptors (TLRs) in Neurodegeneration: Integrative Approach to TLR Cascades in Alzheimer’s and Parkinson’s Diseases

Sterile inflammatory response constitutes a main event in several neurodegenerative disorders. Alzheimer’s disease (AD) and Parkinson’s disease (PD), the leading degenerative pathologies of the central nervous system worldwide, exhibit a strong inflammatory component. Microglial and astrocytic reactivity, increased levels of inflammatory mediators, neuronal damage, and death are part of the pathological scenario leading to the progressive failure of the brain neuronal network. In this regard, the link between the toll-like receptors (TLRs)-mediated inflammatory cascade and the molecular hallmarks of AD and PD have been demonstrated elsewhere. Moreover, the long-lasting exposure to the inflammatory environment is considered one of the key elements leading to the establishment and progression of these pathologies. Accordingly, the modulation of the inflammatory response has emerged as a main target of new therapeutic approaches to fight these diseases. In this regard, and based on our previous works on this subject, we describe the pathological profile of both pathologies but in the inflammatory context. Thus, in the present chapter, we will introduce the main aspects of both diseases and how they interplay with the TLR-mediated response. We believe that this chapter should provide a concise overview of the roles of TLRs in the inflammatory cascades triggered during AD and PD pathophysiology

Apple Production under Protective Netting Systems

Apple crop is more and more cultivated under protective netting systems. Depending on the location and sunlight intensity, apple orchards can benefit from these installations, as they will be protected against extreme weather events. Depending on the technical features of the thread, the nets will be hail-proof, wind-proof, or rain-proof, while having different shading percentages. Modern fruit production faces high pressure also related to biotic stressors; thus, modern protective nets are designed to aid pest management. These protective systems become interesting, as they will induce changes in the orchards’ microenvironment, with consequences on crop physiology. Netting mainly reduces incoming solar radiation and wind speed, altering the heat balance. Leaf gas exchanges and water relations can be positively influenced by netting in apple cultivation areas with extreme solar radiation, high temperatures, and low water availability. These considerations are important, especially if the final yield and quality are not compromised by shading. These protective systems can allow higher sustainability of apple production, lowering resource use, along with crop protection

RHEA v1.0: Enabling fully coupled simulations with hydro-geomechanical heterogeneity

Realistic modelling of tightly coupled hydro-geomechanical processes is relevant for the assessment of many hydrological and geotechnical applications. Such processes occur in geologic formations and are influenced by natural heterogeneity. Current numerical libraries offer capabilities and physics couplings that have proven to be valuable in many geotechnical fields like gas storage, rock fracturing and Earth resources extraction. However, implementation and verification of the full heterogeneity of subsurface properties using high-resolution field data in coupled simulations has not been done before. We develop, verify and document RHEA (Real HEterogeneity App), an open-source, fully coupled, finite-element application capable of including element-resolution hydro-geomechanical properties in coupled simulations. To extend current modelling capabilities of the Multiphysics Object-Oriented Simulation Environment (MOOSE), we added new code that handles spatially distributed data of all hydro-geomechanical properties. We further propose a simple yet powerful workflow to facilitate the incorporation of such data to MOOSE. We then verify RHEA with analytical solutions in one and two dimensions and propose a benchmark semi-analytical problem to verify heterogeneous systems with sharp gradients. Finally, we demonstrate RHEA\u27s capabilities with a comprehensive example including realistic properties. With this we demonstrate that RHEA is a verified open-source application able to include complex geology to perform scalable, fully coupled, hydro-geomechanical simulations. Our work is a valuable tool to assess challenging real-world hydro-geomechanical systems that may include different levels of complexity like heterogeneous geology and sharp gradients produced by contrasting subsurface properties

Descripción anestesiológica del efecto de un protocolo en base a una asociación de tiletamina-zolazepam, incluyendo como preanestésico el butorfanol en el conejo doméstico (Oryctolagus cunículus)

The effects of the anaesthetic protocol, based on a premedication with atropine and butorphanol (Torbugesic®) and the anesthetic induction with a Tiletamine-Zolazepam asociation, were studied in 27 healthy adults rabbits. Each animal was premedicated with 0.04 mg/kg b.w. atropine, to counteract the vagal effects derivated from general anesthesia and 0.5 mg/kg butorphanol to provide analgesia. After each drug administration, the physiologic parameter measure was registered. The induction was done with a Tiletamine Zolazepam asociation, and was determined by the lost of both, the straight head and the righting reflex. The heart rate, respiratory rate and arterial blood pressure were determined and registered every 5 minutes, the body temperature was controlled every 15 minutes, every measurement was done until the moment of recovery of the both previously mentioned reflex. The average dose of Tiletamina-zolazepam injected to achieve the induction anesthetic state, the time it takes the administration of that asociattion dose, the resultant surgical anesthetic period in minutes, the post anesthetic motor depression time, and total anesthesia time, were also determined and recorded. The average i.v. dose induction of Tiletamine-Zolazepam asociation was 9,08 mg/kg of body weigh, injected in a average time of 18,5 seconds, providing a surgical anesthetic period of 17,4 minutes followed by a post anesthetic motor depression period of 20,6 minutes, resulting in a total anesthesia time of 37 minutes. The changes in the physiological parameters, under the effects of this protocol, remains in the normal physiological ranges described for the specie, demonstrating the safety of this pharmacological association.    Se estudiaron los efectos de un protocolo anestésico basado en una premedicación con atropina y butorfanol, e inducción con tiletamina-zolazepam en 27 conejos adultos y sanos. Los animales fueron premedicados con atropina en una dosis de 0,04 mg/kg para contrarrestar los efectos de predominio vagal derivados de la anestesia y butorfanol en dosis de 0,5 mg/kg, para proveer analgesia durante el procedimiento. Posterior a la aplicación de cada uno de los fármacos se midieron las variables fisiológicas. La inducción con tiletamina-zolazepam se realizó hasta observar la pérdida del reflejo de cabeza erguida y estación. Se midieron cada 5 minutos la frecuencia cardíaca, frecuencia respiratoria y presión arterial, y cada 15 minutos la temperatura corporal, hasta la recuperación de los reflejos anteriormente descritos. Se registró además, la dosis de tiletamina-zolazepam necesaria para la inducción, el tiempo empleado en la administración del fármaco, el tiempo de anestesia quirúrgica, el tiempo de depresión motora pos anestésica y el tiempo de anestesia total. En el conejo doméstico la dosis promedio de inducción endovenosa de la asociación de tiletamina-zolazepam fue de 9,06 mg/ kg, administrado en un tiempo promedio de 18,52 segundos, proporcionando un período de anestesia quirúrgica de 17,40 minutos, con un período de depresión pos anestésica de 20,59 minutos promedio y un tiempo de anestesia total de 37,0 minutos. Los cambios en las variables fisiológicas, bajo la acción del protocolo estudiado, se mantienen dentro de los rangos fisiológicos normales para la especie, lo que demuestra la seguridad anestésica de esta asociación farmacológica.  

Wnt Signaling Upregulates Teneurin-3 Expression via Canonical and Non-canonical Wnt Pathway Crosstalk

Teneurins (Tens) are a highly conserved family of proteins necessary for cell-cell adhesion. Tens can be cleaved, and some of their proteolytic products, such as the teneurin c-terminal associated-peptide (TCAP) and the intracellular domain (ICD), have been demonstrated to be biologically active. Although Tens are considered critical for central nervous system development, they have also been demonstrated to play important roles in adult tissues, suggesting a potential link between their deregulation and various pathological processes, including neurodegeneration and cancer. However, knowledge regarding how Ten expression is modulated is almost absent. Relevantly, the functions of Tens resemble several of the effects of canonical and non-canonical Wnt pathway activation, including the effects of the Wnt pathways on neuronal development and function as well as their pivotal roles during carcinogenesis. Accordingly, in this initial study, we decided to evaluate whether Wnt signaling can modulate the expression of Tens. Remarkably, in the present work, we used a specific inhibitor of porcupine, the key enzyme for Wnt ligand secretion, to not only demonstrate the involvement of Wnt signaling in regulating Ten-3 expression for the first time but also reveal that Wnt3a, a canonical Wnt ligand, increases the expression of Ten-3 through a mechanism dependent on the secretion and activity of the non-canonical ligand Wnt5a. Although our work raises several new questions, our findings seem to demonstrate the upregulation of Ten-3 by Wnt signaling and also suggest that Ten-3 modulation is possible because of crosstalk between the canonical and non-canonical Wnt pathways

Implantation of CPT1AM-expressing adipocytes reduces obesity and glucose intolerance in mice

Obesity and its associated metabolic comorbidities are a rising global health and social issue, with novel therapeutic approaches urgently needed. Adipose tissue plays a key role in the regulation of energy balance and adipose tissue-derived mesenchymal stem cells (AT-MSCs) have gained great interest in cell therapy. Carnitine palmitoyltransferase 1A (CPT1A) is the gatekeeper enzyme for mitochondrial fatty acid oxidation. Here, we aimed to generate adipocytes expressing a constitutively active CPT1A form (CPT1AM) that can improve the obese phenotype in mice after their implantation. AT-MSCs were differentiated into mature adipocytes, subjected to lentivirus-mediated expression of CPT1AM or the GFP control, and subcutaneously implanted into mice fed a high-fat diet (HFD). CPT1AM-implanted mice showed lower body weight, hepatic steatosis and serum insulin and cholesterol levels alongside improved glucose tolerance. HFD-induced increases in adipose tissue hypertrophy, fibrosis, inflammation, endoplasmic reticulum stress and apoptosis were reduced in CPT1AM-implanted mice. In addition, the expression of mitochondrial respiratory chain complexes was enhanced in the adipose tissue of CPT1AM-implanted mice. Our results demonstrate that implantation of CPT1AM-expressing AT-MSC-derived adipocytes into HFD-fed mice improves the obese metabolic phenotype, supporting the future clinical use of this ex vivo gene therapy approach