Anatolii Kulik, Édwin Augusto Tonolo, Alberto Kisner Scortegagna
et al.
The growing environmental impact and rising emission of greenhouse gases have accelerated the research toward renewable energy sources and electric vehicles since one of the main sources of pollution is the CO2 emissions produced by conventional combustion vehicles. This article presents the analysis of the energy balance between a photovoltaic carport with 4.89 kWp installed capacity and an EV, model Renault Fluence ZE DYN, driven in real conditions. The driving tests were performed during the winter season in the city of Curitiba, the capital of the state of Paraná, Brazil, with approximately 1.7 million inhabitants and 1.1 million vehicles. During the test period, we attempt to reproduce the citizen’s daily routes through the city, presenting an average consumption of 15.75 kWh/100 km. The carport PV module’s energy generation and in-plane incident irradiation were acquired to calculate the performance ratio, making a comparison after cleaning maintenance possible. The solar carport system has 4.89 kWp and has generated an average of 465.37 kWh during its 24 months of operation. The analysis scenarios consist of replacing part of the city’s combustion vehicle fleet with the EVs (the same as used in the study) and thus determining how many replicas of the presented photovoltaic systems might be needed, as well as the area required for the installations. In a simulation with 15% of the fleet’s replacement, it would be necessary to generate 17,151.8 MWh, which requires the construction of 36,856 carports, covering an area of approximately 1,105,685 m². Finally, an economic comparison between an internal combustion vehicle and the EV determined that the expenditures involving electric energy to charge the batteries are 3.3 times lower than buying gasoline, assuming the same driving routines.
Lilia Leisle, M. Margreiter, A. Ortega-Ramírez
et al.
Prolonged acidosis, as it occurs during ischemic stroke, induces neuronal death via acid-sensing ion channel 1a (ASIC1a). Concomitantly, it desensitizes ASIC1a, highlighting the pathophysiological significance of modulators of ASIC1a acid sensitivity. One such modulator is the opioid neuropeptide big dynorphin (Big Dyn) which binds to ASIC1a and enhances its activity during prolonged acidosis. The molecular determinants and dynamics of this interaction remain unclear, however. Here, we present a molecular interaction model showing a dynorphin peptide inserting deep into the acidic pocket of ASIC1a. We confirmed experimentally that the interaction is predominantly driven by electrostatic forces, and using noncanonical amino acids as photo-cross-linkers, we identified 16 residues in ASIC1a contributing to Big Dyn binding. Covalently tethering Big Dyn to its ASIC1a binding site dramatically decreased the proton sensitivity of channel activation, suggesting that Big Dyn stabilizes a resting conformation of ASIC1a and dissociates from its binding site during channel opening.
Covering: up to the end of July, 2021Anthraquinone-fused enediynes (AFEs) are a subfamily of enediyne natural products. Dynemicin A (DYN A), the first member of the AFE family, was discovered more than thirty years ago. Subsequently, extensive studies have been reported on the mode of action and the interactions of AFEs with DNA using DYN A as a model. However, progress in the discovery, biosynthesis and clinical development of AFEs has been limited for a long time. In the past five years, four new AFEs have been discovered and significant progress has been made in the biosynthesis of AFEs, especially on the biogenesis of the anthraquinone moiety and their tailoring steps. Moreover, the streamlined total synthesis of AFEs and their analogues boosts the preparation of AFE-based linker-drugs, thus enabling the development of AFE-based antibody-drug conjugates (ADCs). This review summarizes the discovery, mechanism of action, biosynthesis, total synthesis and preclinical studies of AFEs.
The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb intrinsic excitability while blunting the response of LHb neurons to extra hypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn-KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerts differential effects on the excitability of two distinct subpopulations of LHb neurons that differ in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increases neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreases neuronal excitability in small/negative Ih (Ih-) neurons. Additionally, we found that an intact fast-synaptic transmission is required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission. While stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons, we found that U50, 488 either increased or decreased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreased mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. While total p38 MAPK (a downstream signaling pathway driven by KOR activation) expression was elevated in the LHb of MD rats compared to non-MD controls, we found that application of KOR-specific agonist, U50,488, onto LHb slices was still able to alter phosphorylated p38 MAPK (ph-p38) expression in MD rats similar to non-MD controls. Moreover, we found that the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of the functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.
E. Akbari, Griffin B. Spychalski, Kaushik K Rangharajan
et al.
Sprouting angiogenesis, the infiltration and extension of endothelial cells from pre-existing blood vessels, helps orchestrate vascular growth and remodeling. It is now agreed that fluid forces, such as laminar shear stress due to unidirectional flow in straight vessel segments, are important regulators of angiogenesis. However, regulation of angiogenesis by the different flow dynamics that arise due to vessel branching, such as impinging flow stagnation at the base of a bifurcating vessel, are not well understood. Here we used a recently developed 3-D microfluidic model to investigate the role of the flow conditions that occur due to vessel bifurcations on endothelial sprouting. We observed that bifurcating fluid flow located at the vessel bifurcation point suppresses the formation of angiogenic sprouts. Similarly, laminar shear stress at a magnitude of ∼3 dyn/cm2 applied in the branched vessels downstream of the bifurcation point, inhibited the formation of angiogenic sprouts. In contrast, co-application of ∼1 µm/s average transvascular flow across the endothelial monolayer with bifurcating fluid flow and laminar shear stress induced the formation of angiogenic sprouts. These results suggest that transvascular flow imparts a competing effect against bifurcating fluid flow and laminar shear stress in regulating endothelial sprouting. To our knowledge, these findings are the first report on the stabilizing role of bifurcating fluid flow on endothelial sprouting. These results also demonstrate the importance of local flow dynamics due to branched vessel geometry in determining the location of sprouting angiogenesis.
Abhishta Abhishta, R. V. Rijswijk-Deij, L. Nieuwenhuis
Distributed Denial-of-Service (DDoS) attacks continue to pose a serious threat to the availability of Internet services. The Domain Name System (DNS) is part of the core of the Internet and a crucial factor in the successful delivery of Internet services. Because of the importance of DNS, specialist service providers have sprung up in the market, that provide managed DNS services. One of their key selling points is that they protect DNS for a domain against DDoS attacks. But what if such a service becomes the target of a DDoS attack, and that attack succeeds? In this paper we analyse two such events, an attack on NS1 in May 2016, and an attack on Dyn in October 2016. We do this by analysing the change in the behaviour of the service's customers. For our analysis we leverage data from the OpenINTEL active DNS measurement system, which covers large parts of the global DNS over time. Our results show an almost immediate and statistically significant change in the behaviour of domains that use NS1 or Dyn as a DNS service provider. We observe a decline in the number of domains that exclusively use NS1 or Dyn as a managed DNS service provider, and see a shift toward risk spreading by using multiple providers. While a large managed DNS provider may be better equipped to protect against attacks, these two case studies show they are not impervious to them. This calls into question the wisdom of using a single provider for managed DNS. Our results show that spreading risk by using multiple providers is an effective countermeasure, albeit probably at a higher cost.
Endothelial cells lining blood vessels are exposed to various hemodynamic forces associated with blood flow. These include fluid shear, the tangential force derived from the friction of blood flowing across the luminal cell surface, tensile stress due to deformation of the vessel wall by transvascular flow, and normal stress caused by the hydrodynamic pressure differential across the vessel wall. While it is well known that these fluid forces induce changes in endothelial morphology, cytoskeletal remodeling, and altered gene expression, the effect of flow on endothelial organization within the context of the tumor microenvironment is largely unknown. Using a previously established microfluidic tumor vascular model, the objective of this study was to investigate the effect of normal (4 dyn/cm2), low (1 dyn/cm2), and high (10 dyn/cm2) microvascular wall shear stress (WSS) on tumor-endothelial paracrine signaling associated with angiogenesis. It is hypothesized that high WSS will alter the endothelial phenotype such that vascular permeability and tumor-expressed angiogenic factors are reduced. Results demonstrate that endothelial permeability decreases as a function of increasing WSS, while co-culture with tumor cells increases permeability relative to mono-cultures. This response is likely due to shear stress-mediated endothelial cell alignment and tumor-VEGF-induced permeability. In addition, gene expression analysis revealed that high WSS (10 dyn/cm2) significantly down-regulates tumor-expressed MMP9, HIF1, VEGFA, ANG1, and ANG2, all of which are important factors implicated in tumor angiogenesis. This result was not observed in tumor mono-cultures or static conditioned media experiments, suggesting a flow-mediated paracrine signaling mechanism exists with surrounding tumor cells that elicits a change in expression of angiogenic factors. Findings from this work have significant implications regarding low blood velocities commonly seen in the tumor vasculature, suggesting high shear stress-regulation of angiogenic activity is lacking in many vessels, thereby driving tumor angiogenesis.
Recent developments in the strength and conditioning field have shown the incorporation of foam rolling self-myofascial release in adjunct with a dynamic warm-up. This is thought to improve overall training performance; however, minimal research exists supporting this theory. Therefore, determining if an acute bout of foam rolling self-myofascial release in addition to a dynamic warm-up could influence performance is of importance. In order to do so, eleven athletically trained male subjects participated in a two condition, counterbalanced, crossover within-subjects study comparing two particular warm-up routines. The two warm-up routines compared were a total-body dynamic warm-up (DYN) and a total-body dynamic warm-up in adjunct with a self-myofascial release, total-body foam rolling session (SMR). Following each warm-up condition, subjects performed tests of flexibility, power, agility, strength, and speed. Paired samples T-tests were utilized to determine if there were any significant differences in test results between conditions (DYN vs. SMR). The data indicated that SMR was effective at improving power, agility, strength, and speed when compared to DYN (P ≤ 0.024). A warm-up routine consisting of both a dynamic warm-up and a self-myofascial release, total-body foam rolling session resulted in overall improvements in athletic performance testing.
Here, we report a pneumatic pressure-driven microfluidic device capable of multi-throughput medium circulation culture. The circulation culture system has the following advantages for application in drug discovery: (i) simultaneous operation of multiple circulation units, (ii) use of a small amount of circulating medium (3.5 mL), (iii) pipette-friendly liquid handling, and (iv) a detachable interface with pneumatic pressure lines via sterile air-vent filters. The microfluidic device contains three independent circulation culture units, in which human umbilical vein endothelial cells (HUVECs) were cultured under physiological shear stress induced by circulation of the medium. Circulation of the medium in the three culture units was generated by programmed sequentially applied pressure from two pressure-control lines. HUVECs cultured in the microfluidic device were aligned under a one-way circulating flow with a shear stress of 10 dyn cm(-2); they exhibited a randomly ordered alignment under no shear stress and under reciprocating flow with a shear stress of 10 dyn cm(-2). We also observed 2.8- to 4.9-fold increases in expression of the mRNAs of endothelial nitric oxide synthase and thrombomodulin under one-way circulating flow with a shear stress of 10 dyn cm(-2) compared with conditions of no shear stress or reciprocating flow.