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Anti-IgLON5 disease is a rare neurological disorder characterized by autoantibodies against IgLON5, and pathological evidence of neurodegeneration. IgLON5 is a cell adhesion molecule but its physiological function is unknown. Our aim was to investigate the IgLON5 interactome and to determine if IgLON5 antibodies (IgLON5-abs) affect these protein interactions. IgLON5 interactome was investigated by mass spectrometry sequencing of proteins immunoprecipitated by IgLON5 autoantibodies using cultures of rat cerebellar granular neurons (CGNs). Shedding of IgLON5 was explored using HEK cells transfected with human IgLON5 plasmid and in CGNs. Interactions of IgLON5 with identified binding partners and IgLON5-abs effects were confirmed by immunofluorescence in transfected HEK cells and rat hippocampal neurons. Patients' IgLON5 antibodies co-precipitated all members of the IgLON family and three 3 additional surface proteins. IgLON5 predominantly establishes homomeric and heteromeric (within the cell) and (between cells)-interactions with other IgLON family members and undergoes spontaneous ectodomain shedding. Antibodies from patients with anti-IgLON5 disease prevent trans-interactions in hippocampal neurons independently of the IgLON5 IgG subclass distribution. We show a potentially novel pathogenic mechanism of IgLON5-abs that consists in blocking IgLON5 interactions with its binding partners. These findings extend our knowledge about the physiological role of IgLON5 and pave the way to future understanding of the pathological mechanisms of anti-IgLON5 disease.

Anti-IgLON5 disease is a neurological disorder characterized by autoantibodies against IgLON5 and pathological evidence of neurodegeneration. IgLON5 is a cell adhesion molecule of unknown function that is highly expressed in the brain. Our aim was to investigate the impact of IgLON5 loss-of-function in evaluating brain morphology, social behavior, and the development of symptoms observed in an IgLON5 knockout (IgLON5-KO) mouse model. The IgLON5-KO mice were generated using CRISPR-Cas9 technology. Immunohistochemistry on fixed sagittal brain sections and Western blotting brain lysates were used to confirm IgLON5 silencing and to evaluate the presence of other cell surface proteins. Two- month-old IgLON5-KO and wild-type (WT) mice underwent a comprehensive battery of behavioral tests to assess 1) locomotion, 2) memory, 3) anxiety, 4) social interaction, and 5) depressive-like behavior. Brain sections were examined for the presence of anatomical abnormalities and deposits of hyperphosphorylated tau in young adult (2-month-old) and aged (22-month-old) mice. Mice did not develop neurological symptoms reminiscent of those seen in patients with anti-IgLON5 disease. Behavioral testing revealed that 2-month-old IgLON5-KO mice showed subtle alterations in motor coordination and balance. IgLON5-KO females exhibited hyperactivity during night and day. Males were observed to have depressive-like behavior and excessive nest-building behavior. Neuropathological studies did not reveal brain morphological alterations or hyperphosphorylated tau deposits. IgLON5-KO mice showed subtle alterations in behavior and deficits in fine motor coordination but did not develop the clinical phenotype of anti-IgLON5 disease.

Background Centenarians comprise an age group characterized by exceptional longevity and low age‐associated pathologies. However, they still experience physiological decline, and different studies have linked frailty to this population. Exercise interventions reverse frailty and improve functional capacity, but no studies have addressed the effect of an intervention in centenarians. In this study, we assessed the impact of a 12‐week resistance exercise intervention in a group of centenarians and characterized their functional capacity as well as the expression of several molecular biomarkers associated with frailty. Methods A total of 19 centenarians were enrolled, but 7 of them did not complete the study. The remaining 12 centenarians were randomly assigned to the control or intervention group, which was a 12‐week resistance exercise intervention. Molecular biomarkers were measured by qRT‐PCR and ELISA. Results The intervention group improved their functional capacity measured by Short Physical Performance Battery (SPPB) (post 5.0 vs 2.3 in pre) and Physical Performance and Mobility Examination (PPME) (6.5 vs 3.8), as well as in frailty status studied by Fried Frailty Phenotype (3.0 vs 3.8) and Frailty Trait Scale 5 (FTS5) (post 30.7 vs 34.0 in pre) scales. ANCOVA revealed that the resistance training led to significant improvements in functional capacity scales SPPB (p = 0.01) and PPME (p < 0.001), as well as Fried Frailty Phenotype (p = 0.001) and FTS5 (p = 0.05). Biomarkers related to frailty (EGR1, miR194‐5p, miR125b‐5p and miR454‐3p) and inflammation (IL‐6 and IL‐1β) showed different expression patterns in centenarians (n = 19) compared to both old (n = 44, average of 79 years old) and young adults (n = 34, average of 29 years old) groups. Notably, the intervention was associated with improvements in frailty and inflammation biomarkers expression. Finally, correlation analyses showed significant associations between all functional and frailty variables, with SPPB correlating with miR454‐3p (ρ = 0.73) and FTS5 correlating with miR454‐3p (ρ = −0.83), IL‐6 (ρ = 0.60) and miR125b‐5p (ρ = −0.55). Conclusions Our results revealed that resistance exercise intervention enhances functional status and reduces frailty in centenarians, and this is associated with improvements in frailty and inflammation biomarkers.

Neurogenesis in the adult dentate gyrus (DG) of the hippocampus allows the continuous generation of new neurons. This cellular process can be disturbed under specific environmental conditions, such as epileptic seizures; however, the underlying mechanisms responsible for their control remain largely unknown. Although different studies have linked the JNK (c-Jun-N-terminal-kinase) activity with the regulation of cell proliferation and differentiation, the specific function of JNK in controlling adult hippocampal neurogenesis is not well known. The purpose of this study was to analyze the role of JNK isoforms (JNK1/JNK2/JNK3) in adult-hippocampal neurogenesis. To achieve this goal, we used JNK-knockout mice ( Jnk1 −/− , Jnk2 −/− , and Jnk3 −/− ), untreated and treated with intraperitoneal injections of kainic acid (KA), as an experimental model of epilepsy. In each condition, we identified cell subpopulations at different stages of neuronal maturation by immunohistochemical specific markers. In physiological conditions, we evidenced that JNK1 and JNK3 control the levels of one subtype of early progenitor cells (GFAP + /Sox2 + ) but not the GFAP + /Nestin + cell subtype. Moreover, the absence of JNK1 induces an increase of immature neurons (Doublecortin + ; PSA-NCAM + cells) compared with wild-type (WT). On the other hand, Jnk1 −/− and Jnk3 −/− mice showed an increased capacity to maintain hippocampal homeostasis, since calbindin immunoreactivity is higher than in WT. An important fact is that, after KA injection, Jnk1 −/− and Jnk3 −/− mice show no increase in the different neurogenic cell subpopulation analyzed, in contrast to what occurs in WT and Jnk2 −/− mice. All these data support that JNK isoforms are involved in the adult neurogenesis control.

[This corrects the article DOI: 10.3389/fimmu.2023.1151574.].

Background: Anti-IgLON5 disease is a rare late-onset neurological disease associated with autoantibodies against IgLON5, neuronal accumulation of phosphorylated Tau protein (p-Tau), and sleep, respiratory, and motor alterations. Purpose: We performed a pilot study of whether the neuropathological and clinical features of anti-IgLON5 disease may be recapitulated in mice with chronic intracerebroventricular infusion of human anti-IgLON5 disease IgG (Pt-IgG). Methods: Humanized transgenic hTau mice expressing human Tau protein and wild-type (WT) control mice were infused intracerebroventricularly with Pt-IgG or with antibodies from a control subject for 14 days. The sleep, respiratory, and motor phenotype was evaluated at the end of the antibody infusion and at least 30 days thereafter, followed by immunohistochemical assessment of p-Tau deposition. Results: In female hTau and WT mice infused with Pt-IgG, we found reproducible trends of diffuse neuronal cytoplasmic p-Tau deposits in the brainstem and hippocampus, increased ventilatory period during sleep, and decreased inter-lick interval during wakefulness. These findings were not replicated on male hTau mice. Conclusion: The results of our pilot study suggest, but do not prove, that chronic ICV infusion of mice with Pt-IgG may elicit neuropathological, respiratory, and motor alterations. These results should be considered as preliminary until replicated in larger studies taking account of potential sex differences in mice.

El delito de incitación al odio del artículo 510 del Código penal español está inmerso en un debate doctrinal y jurisprudencial que no ha hecho sino agudizarse después de su última reforma en el año 2015. En esta contribución se hace una propuesta para su cabal interpretación en clave de protección de colectivos; se intenta diagnosticar en qué punto se encuentra la jurisprudencia a la hora de señalar los límites del ámbito de prohibición y, por último, se sugiere una orientación de futuro que pueda neutralizar los riesgos de una expansión sin límites de este precepto. Incitement to hatred (article 510 of the Spanish Criminal Code) remains in the middle of a doctrinal and jurisprudential turnoil that has only intensified since the latest reform in 2015. This contribution makes a proposal for its proper interpretation in terms of the protection of groups; it attempts to diagnose where the case law stands when it comes to indicating the limits of the scope of prohibition and, finally, it suggests a future direction that could neutralise the risks of an unrestricted expansion of this precept.

The Basque Region has experienced politically-motivated violence in different forms for decades. However, public policies and legal tools utilized in addressing this violence have centered on counterterrorism strategies, while bypassing, or even covering up, the occurrence of serious human rights violations committed by, or in collusion with, State representatives. This contribution identifies different forms of politically-motivated violence that have taken place from the period of the civil war in Spain onwards, offering an up-to-date map of the most serious violations of human rights related to the Basque Country. Thereafter, it briefly presents the legal framework addressing human rights violations, highlighting its strengths and weaknesses. The central thesis points out that double standards are being applied when legally acknowledging victims of human rights violations resulting from political violence. It leads to victims of terrorism being adequately and fairly considered, while other victims of the State or actors connected to the State are subject to non-recognition and even discrimination. Adapted from the source document.

Brain aging consists of a progressive loss of functional capacities, which is associated with a progressive cognitive decline and can lead to neurodegenerative diseases. Studies comparing the underlying molecular mechanisms of the human hippocampus between young and older adults remain scarce. In our study, we completed a transcriptomic analysis from hippocampal samples of different ages and performed 2 complementary analyses. A comparison between young and old groups revealed a set of genes differentially expressed in aged individuals linked to inflammation and immune system pathways, DNA repair, metabolism, or neural activity. Correlation analysis showed that the expression of an additional subset of 6 genes was associated with chronological aging. Among them, further analysis identified RAD23B as the most significant gene with a negative correlation of its mRNA and protein expression with age in the human hippocampus. Its expression was even lower in patients with Alzheimer's disease. RAD23B was mostly expressed in neurons and astrocytes, where studies in human primary cultures uncovered that it is required for cell survival and function. In summary, these results unravel dynamic gene expression changes that distinguish young from older adults and identify RAD23B as a putative biomarker and regulator of cell aging in the brain. 2 complementary analysis from a transcriptome study in human hippocampal samples of different ages revealed a set of genes differentially expressed in aged individuals linked to inflammation and immune system pathways, DNA repair (RAD23) or neural activity.

Este libro tiene como objetivo el estudio y discusión de una parte central —la relativa a la penas— de las novedades introducidas por las LO 1/2015 y LO 2/2015 de reforma del Código Penal y de los delitos de terrorismo, respectivamente, que ya entraron en vigor el 1 de julio de 2015. El derecho penal se encuentra sometido a un proceso de cambio permanente que, si bien hace tan sólo unas décadas era de índole excepcional, se ha convertido en una característica estructural y permanente. Los cambios legislativos se multiplican y se aceleran con cada elección de un nuevo gobierno, convirtiéndose la política criminal en una de las principales políticas simbólicas como instrumento primario de comunicación con el electorado. El primado de la voluntad comunicativa de los procesos de reforma ha desplazado el papel y la dimensión técnica hasta el punto de que las reformas, al menos en el Estado español, prescinden de un análisis detenido de los cambios propuestos y su contraste con —inexistentes— evaluaciones de otras reformas previamente realizadas. El objetivo de esta contribución es precisamente analizar los cambios que se impulsan a través de las citadas LO 1 y 2/2015, con particular atención a todo lo que tiene que ver con el nuevo diseño de la regulación de las penas. Serán por ello objeto de estudio el propio proceso legislativo de reforma, la prisión permanente revisable –desde una óptica comparada, con especial atención a la regulación austríaca y a la jurisprudencia del Tribunal Europeo de Derechos Humanos–, la libertad vigilada, las medidas de seguridad y los pronósticos de peligrosidad, la suspensión de la ejecución de la pena privativa de libertad y otras alternativas a la prisión, la supresión de las faltas y las últimas modificaciones en materia de responsabilidad de las personas jurídicas. Jon-Mirena Landa Gorostiza es catedrático –acreditado– de Derecho Penal en la Facultad de Derecho –Bizkaia– de la Universidad del País Vasco (UVP-EHU) y es director de la Cátedra de Derechos Humanos y Poderes Públicos de la UPV/EHU. Sus principales líneas de investigación tienen que ver con el racismo, la xenofobia, la discriminación, así como con los delitos de odio, terrorismo, crímenes contra la humanidad y penología. En la actualidad dirige un grupo de investigación financiado por el Gobierno español (I+D+I DER 2015-64599-P) en materia de sanciones penales desde una óptica comparada con especial atención a los delitos de odio y de terrorismo.