Notes

Made easier Assessment with the Catalog of Microvascular Level of resistance.
Propofol is the most commonly used intravenous anesthetic worldwide. It can induce loss of consciousness prior to the occurrence of severe respiratory suppression, which is also a pharmacodynamic feature of all general anesthetics. However, the neural mechanisms underlying this natural phenomenon are controversial and highly related to patient safety. In the present study, we demonstrated that the pharmacodynamic effects of propofol (50 and 100 μM) on suppression of consciousness-related excitatory postsynaptic currents in the medial prefrontal cortex (mPFC) and centromedian nucleus of the thalamus (CMT) were lower than those in the kernel respiratory rhythmogenesis nucleus pre-Bötzinger complex (PrBo). Furthermore, we unexpectedly found that the GABAA receptor β3 subunit is the key target for propofol's action and that it is mutually and exclusively expressed in GABAergic neurons. It is also more abundant in the mPFC and CMT, but mainly co-localized with GABAergic neurons in the PrBo. As a result, the differentiated expression pattern should mediate more neuron suppression through the activation of GABAergic neurons in the mPFC and CMT at low doses of propofol (50 μM). However, PrBo GABAergic neurons were only activated by propofol at a high dose (100 μM). These results highlight the detailed pharmacodynamic effects of propofol on consciousness-related and respiration-related nuclei and provide the distinct interaction mechanism between the β3 subunit and GABAergic neurons in mediating the suppression of consciousness compared to the inhibition of respiration.Nervous system development and plasticity involve changes in cellular morphology, making morphological analysis a valuable exercise in the study of nervous system development, function and disease. Morphological analysis is a time-consuming exercise requiring meticulous manual tracing of cellular contours and extensions. We have developed a software tool, called SMorph, to rapidly analyze the morphology of cells of the nervous system. SMorph performs completely automated Sholl analysis. It extracts 23 morphometric features based on cell images and Sholl analysis parameters, followed by principal component analysis (PCA). SMorph was tested on neurons, astrocytes and microglia and reveals subtle changes in cell morphology. Using SMorph, we found that chronic 21-day treatment with the antidepressant desipramine results in a significant structural remodeling in hippocampal astrocytes in mice. Given the proposed involvement of astroglial structural changes and atrophy in major depression in humans, our results reveal a novel kind of structural plasticity induced by chronic antidepressant administration.The Kv2 channels encode delayed rectifier currents that regulate membrane potential in many tissues. They also have a non-conducting function to form stable junctions between the endoplasmic reticulum and plasma membranes, creating membrane contact sites that mediate functions distinct from membrane excitability. Therefore, proteins that interact with Kv2.1 and Kv2.2 channels can alter conducting and/or non-conducting channel properties. One member of the AMIGO family of proteins is an auxiliary β-subunit for Kv2 channels and modulates Kv2.1 electrical activity. However, the AMIGO family has two additional members of ∼50% similarity that have not yet been characterized as Kv2 β-subunits. In this work, we show that the surface trafficking and localization of all three AMIGOs are controlled by their assembly with both Kv2 channels. Additionally, assembly of each AMIGO with either Kv2.1 or Kv2.2 hyperpolarizes the channel activation midpoint by -10 mV. However, only AMIGO2 significantly slows inactivation and deactivation, leading to a prolonged open state of Kv2 channels. The co-regulatory effects of Kv2s and AMIGOs likely fine-tune both the electrical and non-electrical properties of the cells in which they are expressed.UVBR-induced photolesions in genomic DNA of keratinocytes impair cellular functions and potentially determine the cell fate post-irradiation. The ability of insulin-like growth factor-I (IGF-I) to rescue epidermal keratinocytes after photodamage via apoptosis prevention and photolesion removal was recently demonstrated using in vitro two-dimensional and three-dimensional skin models. JAK inhibitor Given the limited knowledge of specific signalling cascades contributing to post-UVBR IGF-I effects, we used inhibitors to investigate the impact of blockade of various signalling mediators on IGF-I photoprotection. IGF-I treatment, in the presence of signalling inhibitors, particularly TDRL-505, which targets replication protein A (RPA), impaired activation of IGF-1R downstream signalling, diminished cyclobutane pyrimidine dimer removal, arrested growth, reduced cell survival and increased apoptosis. Further, the transient partial knockdown of RPA was found to abrogate IGF-I-mediated responses in keratinocytes, ultimately affecting photoprotection and, thereby, establishing that RPA is required for IGF-I function. Our findings thus elucidate the importance of RPA in linking the damage response activation, cell cycle regulation, repair and survival pathways, separately initiated by IGF-I upon UVBR-induced damage. This information is potentially imperative for the development of effective sunburn and photodamage repair strategies. This article has an associated First Person interview with the first author of the paper.Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of both upper and lower motor neurons (MNs). The main clinical features of ALS are motor function impairment, progressive muscle weakness, muscle atrophy and, ultimately, paralysis. Intrinsic skeletal muscle deterioration plays a crucial role in the disease and contributes to ALS progression. Currently, there are no effective treatments for ALS, highlighting the need to obtain a deeper understanding of the molecular events underlying degeneration of both MNs and muscle tissue, with the aim of developing successful therapies. Muscle tissue is enriched in a group of microRNAs called myomiRs, which are effective regulators of muscle homeostasis, plasticity and myogenesis in both physiological and pathological conditions. After providing an overview of ALS pathophysiology, with a focus on the role of skeletal muscle, we review the current literature on myomiR network dysregulation as a contributing factor to myogenic perturbations and muscle atrophy in ALS.
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