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Dos problemas aborda este artículo dedicado al estudio de Coirón (1951): la fascinación y el repudio ante «el placer inusitado de vivir» y la significación del tiempo y la memoria en la escritura novelesca de Daniel Belmar.

César Vallejo es fiel e infiel a la fábula de tradición que ha decidido acoger y mantener con vida. Tal vez por ello en Los heraldos negros se despliega un «verso gris» seducido por la dinámica de los trayectos. Su presencia conecta sugerentemente el primer libro con la obra poética ulterior del poeta legatario.

1. Brown trout ova were imported during the last century from different locations in Europe to establish populations in Chilean rivers (South America). The rivers are currently occupied by naturalized populations that have adapted to very different environmental conditions, such as areas of semi-desert in the north, or rainy and cold areas inthe south. 2. In this first study in this geographical area, electrophoretic variability of proteins encoded by twenty-five loci was screened in seven populations from northern to southern Chile. 3. The results show significant heterogeneity of allelic frequencies between populations in seven of eleven polymorphic loci detected. The estimatedvalue of genetic diversity 0.1274 (HT) is higher than that observed in populations from areas of natural distribution of this species. However, only 12.64% of this genetic diversity was found between samples (GST), indicating a low genetic divergence among Chilean populations. The observed associations among the Chilean and 'modern' group of European populations suggests the probable origin of the new populations. [ABSTRACT FROM AUTHOR]

Introduction: Assessment of body composition is paramount in early assessment of nutritional status impairments due to excess or deficit. There are, however, few field reliable methods for this objective for patients with chronic renal failure (CRF.). Objective: To assess the reliability of the estimations of body composition by different methods as compared to dual energy X-ray absorptiometry (DEXA) as the gold standard method in patients with CRF and on regular chronic haemodialysis. Patients and methods: We assessed body composition in 30 haemodialysis patients (46.9 +/- 15.1 years (18-76); BMI 25.9 +/- 5.7 kg/m(2) (18.1-41.5)), observing agreement in the percentage of fat mass (%FM) between the sum of the 4 folds (SP; calibrator Lange(R)) and bioimpedantiometry by using different equations (BIA; Biodynamics(R) 450) versus DEXA (Lunar DPX-L). Results: (X +/- SD) By BMI, 3 subjects had low weight (10%), 14 normal weight (46.7%), 7 overweight (23.3%), and 6 obesity (20%). The %FM with SP (30.7 +/- 7.1%) significantly differed from DEXA (27.3 +/- 10.3%; p < 0.001). With BIA there was a significant difference in %FM with the Deurenberg and Formica equations. The %FM obtained with the manufacturer's equations (Segal, Lukaski and Kyle) did not show a significant difference from DEXA. With Kyle's equation we observed a better agreement (difference with DEXA: -0.58 +/- 4.2%). Conclusions: We found a low percentage of patients with low weight as compared to previous studies. The skin folds show low reliability to estimate the fat mass. The bioimpedantiometry, using Kile's equation may be a good filed method to assess haemodialysis patients. [ABSTRACT FROM AUTHOR]

Introduction: Assessment of body composition is paramount in early assessment of nutritional status impairments due to excess or deficit. There are, however, few field reliable methods for this objective for patients with chronic renal failure (CRF.) Objective: To assess the reliability of the estimations of body composition by different methods as compared to dual energy X-ray absorptiometry (DEXA) as the gold standard method in patients with CRF and on regular chronic haemodialysis. Patients and methods: We assessed body composition in 30 haemodialysis patients (46.9 ± 15.1 years (18-76); BMI 25.9 ± 5.7 kg/m² (18.1-41.5)), observing agreement in the percentage of fat mass (%FM) between the sum of the 4 folds (SP; calibrator Lange®) and bioimpedantiometry by using different equations (BIA; Biodynamics® 450) versus DEXA (Lunar DPX-L). Results: (X ± SD) By BMI, 3 subjects had low weight (10%), 14 normal weight (46.7%), 7 overweight (23.3%), and 6 obesity (20%). The %FM with SP (30.7 ± 7.1%) significantly differed from DEXA (27.3 ± 10.3%; p < 0.001). With BIA there was a significant difference in %FM with the Deurenberg and Formica equations. The %FM obtained with the manufacturer's equations (Segal, Lukaski and Kyle) did not show a significant difference from DEXA. With Kyle's equation we observed a better agreement (difference with DEXA: -0.58 ± 4.2%). Conclusions: We found a low percentage of patients with low weight as compared to previous studies. The skin folds show low reliability to estimate the fat mass. The bioimpedantiometry, using Kile's equation may be a good filed method to assess haemodialysis patients. [ABSTRACT FROM AUTHOR]

The developing mammalian heart undergoes an important metabolic shift from glycolysis towards mitochondrial oxidation that is critical to support the increasing energetic demands of the maturing heart. Here, we describe a new mechanistic link between mitochondria and cardiac morphogenesis, uncovered by studying mitochondrial citrate carrier (SLC25A1) knockout mice. Slc25a1 null embryos displayed impaired growth, mitochondrial dysfunction and cardiac malformations that recapitulate the congenital heart defects observed in 22q11.2 deletion syndrome, a microdeletion disorder involving the SLC25A1 locus. Importantly, Slc25a1 heterozygous embryos, while overtly indistinguishable from wild type, exhibited an increased frequency of these defects, suggesting Slc25a1 haploinsuffiency and dose-dependent effects. Mechanistically, SLC25A1 may link mitochondria to transcriptional regulation of metabolism through epigenetic control of gene expression to promote metabolic remodeling in the developing heart. Collectively, this work positions SLC25A1 as a novel mitochondrial regulator of cardiac morphogenesis and metabolic maturation, and suggests a role in congenital heart disease., (© 2024. The Author(s).)

The emerging picture of G protein-coupled receptor function suggests that the global signaling response is an integrated sum of a multitude of individual receptor responses, each regulated by their local protein environment. The beta 2 adrenergic receptor (B2AR) has long served as an example receptor in the development of this model. But the mechanism and the identity of the protein-protein interactions that govern the availability of receptors competent for signaling remains incompletely characterized. To address this question, we characterized the interactome of agonist-stimulated B2AR in HEK293 cells using FLAG co-immunoprecipitation coupled to SILAC labeling and mass spectrometry. Our B2AR cross-linked interactome identified 190 high-confidence proteins, including almost all known interacting proteins and six out of seven isoforms of the 14-3-3 family of scaffolding proteins. Inhibiting 14-3-3 proteins with the peptide difopein enhanced isoproterenol-stimulated adrenergic signaling via cAMP approximately three-fold, and increased both miniGs and arrestin recruitment to B2AR more than two fold each, without noticeably changing EC50 with respect to cAMP signaling or effector recruitment upon stimulation. Our results show that 14-3-3 proteins negatively regulate downstream signaling by inhibiting access of B2AR to effector proteins. We propose that 14-3-3 proteins maintain a dynamic pool of B2AR that has reduced signaling efficacy in response to acute agonist stimulation, limiting the amount of signaling-competent receptors at the plasma membrane. Significance Statement This study presents a new interactome of the agonist-stimulated beta 2 adrenergic receptor (B2AR), a paradigmatic GPCR that is both a model system for members of this class and an important signaling protein in respiratory, cardiovascular, and metabolic regulation. We identify 14-3-3 proteins as responsible for restricting B2AR access to signaling effectors and maintaining a receptor population that is insensitive to acute stimulation by agonists., (© 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.)

Rare inherited diseases caused by mutations in the copper transporters SLC31A1 (CTR1) or ATP7A induce copper deficiency in the brain and throughout the body, causing seizures and neurodegeneration in infancy. The mechanistic underpinnings of such neuropathology remains unclear. Here, we characterized the molecular mechanisms by which neuronal cells respond to copper depletion in multiple genetic model systems. Targeted deletion of CTR1 in neuroblastoma clonal cell lines produced copper deficiency that was associated with compromised copper-dependent Golgi and mitochondrial enzymes and a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis revealed simultaneous upregulation of mTORC1 and S6K signaling, along with reduced PERK signaling in CTR1 KO cells. Patterns of gene and protein expression and pharmacogenomics show increased activation of the mTORC1-S6K pathway as a pro-survival mechanism, ultimately resulting in increased protein synthesis as measured by puromycin labeling. These effects of copper depletion were corroborated by spatial transcriptomic profiling of the cerebellum of Atp7a flx/Y :: Vil1 Cre/+ mice, in which copper-deficient Purkinje cells exhibited upregulated protein synthesis machinery and expression of mTORC1-S6K pathway genes. We tested whether increased activity of mTOR in copper-deficient neurons was adaptive or deleterious by genetic epistasis experiments in Drosophila . Copper deficiency dendritic phenotypes in class IV neurons are partially rescued by increased S6k expression or 4E-BP1 (Thor) RNAi, while epidermis phenotypes are exacerbated by Akt, S6k, or raptor RNAi. Overall, we demonstrate that increased mTORC1-S6K pathway activation and protein synthesis is an adaptive mechanism by which neuronal cells respond to copper depletion., Competing Interests: Competing Interest Statement: N/A

Microglia are resident immune cells of the brain and regulate its inflammatory state. In neurodegenerative diseases, microglia transition from a homeostatic state to a state referred to as disease-associated microglia (DAM). DAM express higher levels of proinflammatory signaling molecules, like STAT1 and TLR2, and show transitions in mitochondrial activity toward a more glycolytic response. Inhibition of Kv1.3 decreases the proinflammatory signature of DAM, though how Kv1.3 influences the response is unknown. Our goal was to identify the potential proteins interacting with Kv1.3 during transition to DAM. We utilized TurboID, a biotin ligase, fused to Kv1.3 to evaluate potential interacting proteins with Kv1.3 via mass spectrometry in BV-2 microglia following TLR4-mediated activation. Electrophysiology, Western blotting, and flow cytometry were used to evaluate Kv1.3 channel presence and TurboID biotinylation activity. We hypothesized that Kv1.3 contains domain-specific interactors that vary during a TLR4-induced inflammatory response, some of which are dependent on the PDZ-binding domain on the C terminus. We determined that the N terminus of Kv1.3 is responsible for trafficking Kv1.3 to the cell surface and mitochondria (e.g., NUDC, TIMM50). Whereas, the C terminus interacts with immune signaling proteins in a lipopolysaccharide-induced inflammatory response (e.g., STAT1, TLR2, and C3). There are 70 proteins that rely on the C-terminal PDZ-binding domain to interact with Kv1.3 (e.g., ND3, Snx3, and Sun1). Furthermore, we used Kv1.3 blockade to verify functional coupling between Kv1.3 and interferon-mediated STAT1 activation. Overall, we highlight that the Kv1.3 potassium channel functions beyond conducting the outward flux of potassium ions in an inflammatory context and that Kv1.3 modulates the activity of key immune signaling proteins, such as STAT1 and C3., Competing Interests: Conflict of interest H. W. is an inventor on a University of California patent claiming PAP-1 for immunosuppression. This patent has been abandoned because of its short remaining patent life. The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

How are human-specific brain bioenergetics and excitability connected? In this Neuron issue, Shen et al. 1 reveal a human-specific interaction between RACK1 mRNA and FMRP. Reducing RACK1 mimics FMRP-dependent excitability and mitochondrial phenotypes, which can be reversed with mitochondrial-protective drugs. These findings suggest that FMRP-mediated translation adapts mitochondria to excitability energy demands., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Genes mutated in monogenic neurodevelopmental disorders are broadly expressed. This observation supports the concept that monogenic neurodevelopmental disorders are systemic diseases that profoundly impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations in MECP2. Transcriptomes and proteomes of organs and brain regions from Mecp2-null mice as well as diverse MECP2-null male and female human cells were assessed. Widespread changes in the steady-state transcriptome and proteome were identified in brain regions and organs of presymptomatic Mecp2-null male mice as well as mutant human cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular, Mecp2- and MECP2-sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid metabolism and mitochondrial pathways. MECP2 mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations in Mecp2/MECP2 perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The 1.6-megabase deletion at chromosome 3q29 (3q29Del) is the strongest identified genetic risk factor for schizophrenia, but the effects of this variant on neurodevelopment are not well understood. We interrogated the developing neural transcriptome in two experimental model systems with complementary advantages: isogenic human cortical organoids and isocortex from the 3q29Del mouse model. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 and 12 months, as well as perinatal mouse isocortex, all at single-cell resolution. Systematic pathway analysis implicated dysregulation of mitochondrial function and energy metabolism. These molecular signatures were supported by analysis of oxidative phosphorylation protein complex expression in mouse brain and assays of mitochondrial function in engineered cell lines, which revealed a lack of metabolic flexibility and a contribution of the 3q29 gene PAK2. Together, these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species.

Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimer's disease risk factor apolipoprotein E (APOE) and other secretome components. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease., Competing Interests: MW, OO, AL, AG, SZ, CX, ZW, DD, SR, AI, EO, ED, NS, BR, AC, VS, MP, NS, SK, SC, AB, AW, TW, SR, AL, EW, VF No competing interests declared, (© 2023, Wynne et al.)

MECP2 loss-of-function mutations cause Rett syndrome, a neurodevelopmental disorder resulting from a disrupted brain transcriptome. How these transcriptional defects are decoded into a disease proteome remains unknown. We studied the proteome of Rett cerebrospinal fluid (CSF) to identify consensus Rett proteome and ontologies shared across three species. Rett CSF proteomes enriched proteins annotated to HDL lipoproteins, complement, mitochondria, citrate/pyruvate metabolism, synapse compartments, and the neurosecretory protein VGF. We used shared Rett ontologies to select analytes for orthogonal quantification and functional validation. VGF and ontologically selected CSF proteins had genotypic discriminatory capacity as determined by receiver operating characteristic analysis in Mecp2 -/y and Mecp2 -/+ . Differentially expressed CSF proteins distinguished Rett from a related neurodevelopmental disorder, CDKL5 deficiency disorder. We propose that Mecp2 mutant CSF proteomes and ontologies inform putative mechanisms and biomarkers of disease. We suggest that Rett syndrome results from synapse and metabolism dysfunction., Competing Interests: Mustafa Sahin reports grant support from Novartis, Biogen, Astellas, Aeovian, Bridgebio, and Aucta. He has served on Scientific Advisory Boards for Novartis, Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics and Alkermes. James J. Fink is an employee of Q-State Biosciences. VF is a member of the iScience editorial board., (© 2022 The Author(s).)

The human brain consumes five orders of magnitude more energy than the sun by unit of mass and time. This staggering bioenergetic cost serves mostly synaptic transmission and actin cytoskeleton dynamics. The peak of both brain bioenergetic demands and the age of onset for neurodevelopmental disorders is approximately 5 years of age. This correlation suggests that defects in the machinery that provides cellular energy would be causative and/or consequence of neurodevelopmental disorders. We explore this hypothesis from the perspective of the machinery required for the synthesis of the electron transport chain, an ATP-producing and NADH-consuming enzymatic cascade. The electron transport chain is constituted by nuclear- and mitochondrial-genome-encoded subunits. These subunits are synthesized by the 80S and the 55S ribosomes, which are segregated to the cytoplasm and the mitochondrial matrix, correspondingly. Mitochondrial protein synthesis by the 55S ribosome is the rate-limiting step in the synthesis of electron transport chain components, suggesting that mitochondrial protein synthesis is a bottleneck for tissues with high bionergetic demands. We discuss genetic defects in the human nuclear and mitochondrial genomes that affect these protein synthesis machineries and cause a phenotypic spectrum spanning autism spectrum disorders to neurodegeneration during neurodevelopment. We propose that dysregulated mitochondrial protein synthesis is a chief, yet understudied, causative mechanism of neurodevelopmental and behavioral disorders., Competing Interests: The authors declare no competing interests. Author V.F. is a member of the iScience Editorial Board., (© 2022 The Author(s).)