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The potassium–chloride cotransporter KCC2 is the main extruder of Cl- in neurons. It plays a fundamental role in the activity of the inhibitory neurotransmitters (GABA and glycine) since low levels of KCC2 promote intracellular Cl- accumulation, leading to the depolarizing activity of GABA and glycine. The downregulation of this cotransporter occurs in neurological disorders characterized by hyperexcitability, such as epilepsy, neuropathic pain, and spasticity. KCC2 is also downregulated after axotomy. If muscle reinnervation is allowed, the KCC2 levels recover in motoneurons. Therefore, we argued that target-derived neurotrophic factors might be involved in the regulation of KCC2 expression. For this purpose, we performed the axotomy of extraocular motoneurons via the monocular enucleation of adult rats, and a pellet containing either VEGF or BDNF was chronically implanted in the orbit. Double confocal immunofluorescence of choline acetyl-transferase (ChAT) and KCC2 was carried out in the brainstem sections. Axotomy led to a KCC2 decrease in the neuropil and somata of extraocular motoneurons, peaking at 15 days post-lesion, with the exception of the abducens motoneuron somata. VEGF administration prevented the axotomy-induced KCC2 downregulation. By contrast, BDNF either maintained or reduced the KCC2 levels following axotomy, suggesting that BDNF is involved in the axotomy-induced KCC2 downregulation in extraocular motoneurons. The finding that VEGF prevents KCC2 decrease opens up new possibilities for the treatment of neurological disorders coursing with neuronal hyperactivity due to KCC2 downregulation. [ABSTRACT FROM AUTHOR]

The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological ecosystem. Most of the diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in the variable domain of antibodies, mostly in the regions that form the paratope, yielding antibodies with higher antigen binding affinity. However, antigen recognition is only possible if the antibody folds into a stable functional conformation. Therefore, a key force determining the survival of B cell clones undergoing somatic hypermutation is the ability of the mutated heavy and light chains to efficiently fold and assemble into a functional antibody. The antibody is the structural context where the selection of the somatic mutations occurs, and where both the heavy and light chains benefit from protectivemechanisms that counteract the potentially deleterious impact of the changes. However, in patients with monoclonal gammopathies, the proliferating plasma cell clone may overproduce the light chain, which is then secreted into the bloodstream. This places the light chain out of the protective context provided by the quaternary structure of the antibody, increasing the risk of misfolding and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma (cast) nephropathy are a diverse group of diseases derived from the pathologic aggregation of light chains, in which somatic mutations are recognized to play a role. In this review, we address the mechanisms by which somatic mutations promote the misfolding and pathological aggregation of the light chains, with an emphasis on AL amyloidosis. We also analyze the contribution of the variable domain (VL) gene segments and somatic mutations on light chain cytotoxicity, organ tropism, and structure of the AL fibrils. Finally, we analyze the most recent advances in the development of computational algorithms to predict the role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and discuss the challenges and perspectives that this approach faces. [ABSTRACT FROM AUTHOR]

The iridium(III) complexes [Ir(H)(Cl)(κ2-NSitBu2)(κ2-bipyMe2)] (2) and [Ir(H)(OTf)(κ2-NSitBu2)(κ2-bipyMe2)] (3) (NSitBu2 = {4-methylpyridine-2-yloxy}ditertbutylsilyl) have been synthesized and characterized including X-ray studies of 3. A comparative study of the catalytic activity of complexes 2, 3, [Ir(H)(OTf)(κ2-NSitBu2)(coe)] (4), and [Ir(H)(OTf)(κ2-NSitBu2)(PCy3)] (5) (0.1 mol%) as catalysts precursors for the solventless formic acid dehydrogenation (FADH) in the presence of Et3N (40 mol%) at 353 K has been performed. The highest activity (TOF5 min ≈ 3260 h−1) has been obtained with 3 at 373 K. However, at that temperature the FTIR spectra show traces of CO together with the desired products (H2 and CO2). Thus, the best performance was achieved at 353 K (TOF5 min ≈ 1210 h−1 and no observable CO). Kinetic studies at variable temperature show that the activation energy of the 3-catalyzed FADH process is 16.76 kcal mol−1. Kinetic isotopic effect (5 min) values of 1.6, 4.5, and 4.2 were obtained for the 3-catalyzed dehydrogenation of HCOOD, DCOOH, and DCOOD, respectively, at 353 K. The strong KIE found for DCOOH and DCOOD evidenced that the hydride transfer from the C–H bond of formic acid to the metal is the rate-determining step of the process. [ABSTRACT FROM AUTHOR]

Our aim was to develop a computerized system for real-time monitoring of lung mechanics measurements during both gas and liquid ventilation. System accuracy was demonstrated by calculating regression and percent error of the following parameters compared to standard device: airway pressure difference ([DELTA][P.sub.aw]), respiratory frequency ([f.sub.R]), tidal volume ([V.sub.T]), minute ventilation ([V'.sub.E]), inspiratory and expiratory maximum flows ([V'.sub.ins, max], [V'.sub.exp, max]), dynamic lung compliance ([C.sub.L,dyn]), resistance of the respiratory system calculated by method of Mead-Whittenberger ([R.sub.rs,MW]) and by equivalence to electrical circuits ([R.sub.rs, ele]), work of breathing ([W.sub.OB]), and overdistension. Outcome measures were evaluated as function of gas exchange, cardiovascular parameters, and lung mechanics including mean airway pressure ([mP.sub.aw]). [DELTA][P.sub.aw], [V.sub.T], [V'.sub.ins, max], [V'.sub.exp, max], and [V'.sub.E] measurements had correlation coefficients r = 1.00, and %error < 0.5%. [f.sub.R], [C.sub.L,dyn], [R.sub.rs,MW], [R.sub.rs, ele], and [W.sub.OB] showed r [greater than or equal to] 0.98 and %error < 5%. Overdistension had r = 0.87 and %error < 15%. Also, resistance was accurately calculated by a new algorithm. The system was tested in rats in which lung lavage was used to induce acute respiratory failure. After lavage, both gas- and liquid-ventilated groups had increased [mP.sub.aw] and [W.sub.OB], with decreased [V.sub.T], [V'.sub.E], [C.sub.L,dyn], [R.sub.rs,MW] , and [R.sub.rs,ele] compared to controls. After 1-h ventilation, both injured group had decreased [V.sub.T], [V'.sub.E], and [C.sub.L,dyn], with increased [mP.sub.aw], [R.sub.rs,MW], [R.sub.rs,ele], and [W.sub.OB]. In lung-injured animals, liquid ventilation restored gas exchange, and cardiovascular and lung functions. Our lung mechanics system was able to closely monitor pulmonary function, including during transitions between gas and liquid phases. Index Terms--Compliance, dynamic lung mechanics, inertance, quasi-static lung mechanics, resistance, total liquid ventilation (TLV).