A small TAT-TrkB peptide prevents BDNF receptor cleavage and restores synaptic physiology in Alzheimer's disease

In Alzheimer's disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD

A small TAT-TrkB peptide prevents BDNF receptor cleavage and restores synaptic physiology in Alzheimer\u27s disease

Copyright \ua9 2024 The Author(s). Published by Elsevier Inc. All rights reserved. In Alzheimer\u27s disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD

A small TAT-TrkB peptide prevents BDNF receptor cleavage and restores synaptic physiology in Alzheimer's disease

Publisher Copyright: Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.In Alzheimer's disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD.publishersversionpublishe

IRIS Reactor a Suitable Option to Provide Energy and Water Desalination for the Mexican Northwest Region

The Northwest region of Mexico has a deficit of potable water, along this necessity is the region growth, which requires of additional energy capacity. The IRIS reactor offers a very suitable source of energy given its modular size of 300 MWe and it can be coupled with a desalination plant to provide the potable water for human consumption, agriculture and industry. The present paper assess the water and energy requirements for the Northwest region of Mexico and how the deployment of the IRIS reactor can satisfy those necessities. The possible sites for deployment of Nuclear Reactors are considered given the seismic constraints and the closeness of the sea for external cooling. And in the other hand, the size of the desalination plant and the type of desalination process are assessed accordingly with the water deficit of the region

FUZZY MODELING OF THE EFFECTS OF IRRIGATION AND WATER SALINITY IN HARVEST POINT OF TOMATO CROP. PART I: DESCRIPTION OF THE METHOD

ABSTRACT It was used statistical techniques for the evaluation of agricultural experiments, but there are mathematical theories that allow finer adjustments, highlighting among them, the fuzzy logic. The objective of the study was characterizing a method of fuzzy modeling from an agronomic experiment. For this study it was used data from an experiment conducted at the School of Agriculture of São Paulo State University (UNESP) in Botucatu-SP. The system input variables based in fuzzy rules were soil water tension and doses of water salinity, being defined three fuzzy sets. The output variables was elected from the biometric and productivity analysis that showed statistically significant differences, namely, plant height, stem diameter, leaf area, green biomass, dry weight, number of fruits, average fruit weight and percentage of disabled fruits. For output variables 9 fuzzy sets were defined. From the adopted methodology, the model allowed extract directly from the data set a base of rules without the use of questionnaires to experts for its preparation. In addition, it will analyze intermediate regions at trial levels and weave other conclusions of the tomato growth and productivity, not limiting in this way only those observed with statistical analysis.</div

FUZZY MODELING OF THE EFFECTS OF IRRIGATION AND WATER SALINITY IN HARVEST POINT OF TOMATO CROP. PART II: APPLICATION AND INTERPRETATION

ABSTRACT Tomato, the most popular greenery, is characterized by being a demanding crop in water and when in prolonged and severe drought, has limitations in its growth and reduction in productivity. In addition, this vegetable is affected by excess salinity in the water, which causes leaf wilting, apex and leaf edges burn until their death. Such effects generally are studied using statistical analysis, but there are mathematical theories that allow finer adjustments, highlighting among them, the fuzzy logic. The objective of this study was to evaluate the effects on the growth and yield of hybrid tomato from different water tensions in the soil and different salinity doses in the irrigation at 120 days after sowing using fuzzy modeling. It was used data from an experiment that was conducted in the experimental area at the School of Agriculture of São Paulo State University (UNESP) in Botucatu-SP. The input variables of the fuzzy systems were irrigation and salinity, while the output variables elected were the biometric analysis and productivity that showed statistically significant differences. Analyses of the effects of irrigation and salinity were performed by means of three-dimensional graphics and the output variables contour maps. The variables studied here showed higher values, with exception of plant height for treatment with irrigation in field capacity and water salinity zero.</div

Mathematical analysis of maximum power generated by photovoltaic systems and fitting curves for standard test conditions Modelo matemático da potência máxima gerada por sistemas fotovoltaicos e curvas de ajuste às condições de teste em campo

The rural electrification is characterized by geographical dispersion of the population, low consumption, high investment by consumers and high cost. Moreover, solar radiation constitutes an inexhaustible source of energy and in its conversion into electricity photovoltaic panels are used. In this study, equations were adjusted to field conditions presented by the manufacturer for current and power of small photovoltaic systems. The mathematical analysis was performed on the photovoltaic rural system I-100 from ISOFOTON, with power 300 Wp, located at the Experimental Farm Lageado of FCA/UNESP. For the development of such equations, the circuitry of photovoltaic cells has been studied to apply iterative numerical methods for the determination of electrical parameters and possible errors in the appropriate equations in the literature to reality. Therefore, a simulation of a photovoltaic panel was proposed through mathematical equations that were adjusted according to the data of local radiation. The results have presented equations that provide real answers to the user and may assist in the design of these systems, once calculated that the maximum power limit ensures a supply of energy generated. This real sizing helps establishing the possible applications of solar energy to the rural producer and informing the real possibilities of generating electricity from the sun.<br>A eletrificação rural é caracterizada pela dispersão geográfica da população, baixo consumo, alto investimento por consumidor e elevado custo operacional. Por outro lado, a radiação solar constitui-se numa inesgotável fonte energética, e para sua conversão em energia elétrica são utilizados painéis fotovoltaicos. Neste trabalho, foram determinadas equações ajustadas às condições de campo apresentadas pelo fabricante para corrente e potência de sistemas fotovoltaicos de pequeno porte. A análise matemática foi feita sobre o sistema fotovoltaico rural I-100 da ISOFOTON, com potência de 300 Wp, localizado na Fazenda Experimental Lageado da FCA/UNESP. Para o desenvolvimento de tais equações, procurou-se estudar o circuito elétrico de células fotovoltaicas, aplicar os métodos numéricos iterativos para a determinação de parâmetros elétricos e analisar possíveis erros na adequação das equações existentes da literatura à realidade. Sendo assim, foi proposta a simulação de um painel fotovoltaico por meio de equações matemáticas que foram ajustadas segundo os dados de radiação locais. Os resultados apresentam equações que fornecem respostas reais para o usuário e podem auxiliar no dimensionamento destes sistemas, uma vez que a potência máxima calculada garante um limite de fornecimento da energia gerada. Este real dimensionamento auxilia a determinação das possíveis aplicações da energia solar para o produtor rural, informando as possibilidades reais de geração de energia elétrica pelo Sol

Cleavage of the TrkB-FL receptor during epileptogenesis: insights from a kainic acid-induced model of epilepsy and human samples

Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, differentiation, and plasticity. In epilepsy, BDNF exhibits a dual role, exerting both antiepileptic and pro-epileptic effects. The cleavage of its main receptor, full-length tropomyosin-related kinase B (TrkB-FL), was suggested to occur in status epilepticus (SE) in vitro. Moreover, under excitotoxic conditions, TrkB-FL was found to be cleaved, resulting in the formation of a new intracellular fragment, TrkB-ICD. Thus, we hypothesized that TrkB-FL cleavage and TrkB-ICD formation could represent an uncovered mechanism in epilepsy. We used a rat model of mesial temporal lobe epilepsy (mTLE) induced by kainic acid (KA) to investigate TrkB-FL cleavage and TrkB-ICD formation during SE (∼3 h after KA) and established epilepsy (EE) (4–5 weeks after KA). Animals treated with 10 mg/kg of KA exhibited TrkB-FL cleavage during SE, with hippocampal levels of TrkB-FL and TrkB-ICD correlating with seizure severity. Notably, TrkB-FL cleavage and TrkB-ICD formation were also detected in animals with EE, which exhibited spontaneous recurrent convulsive seizures, neuronal death, mossy fiber sprouting, and long-term memory impairment. Importantly, hippocampal samples from patients with refractory epilepsy also showed TrkB-FL cleavage with increased TrkB-ICD levels. Additionally, lentiviral-mediated overexpression of TrkB-ICD in the hippocampus of healthy mice and rats resulted in long-term memory impairment. Our findings suggest that TrkB-FL cleavage and the subsequent TrkB-ICD production occur throughout epileptogenesis, with the extent of cleavage correlating positively with seizure occurrence. Moreover, we found that TrkB-ICD overexpression impairs memory. This work uncovers a novel mechanism in epileptogenesis that could serve as a potential therapeutic target in mTLE, with implications for preserving cognitive function