Further Studies on the Highly Active Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D3 (Calcitriol): Refinement of the Side Chain.

Current efforts in the vitamin D field are directed toward the development of highly antiproliferative yet noncalcemic analogues of the natural hormone 1α,25-dihydroxyvitamin D3 (1,25D3). We have recently reported the design, synthesis, biological evaluation, and crystal structures of a series of novel analogues that both lack the steroidal C-ring and have an m-phenylene ring replacing the steroidal cyclopentane D-ring. We have now investigated the potentiating effects of incorporating selected modifications (hexafluorination and/or an internal triple bond) within the steroidal side chain in our series. An alternative synthetic strategy (Wittig-Horner approach instead of our previously used Pd-catalyzed tandem cyclization/cross-coupling) for the construction of the vitamin D triene system was found convenient for the target compounds 2, 3a, 3b, and 3c of this report. These modifications enhance vitamin D nuclear receptor (VDR) interactions and consequently VDR-associated biological properties compared to parental PG-136 compound while maintaining normal calcium levels.

[The reception of Freudo-Marxism in the Spain of late Francoism and the Transition, 1975-1978]. / La recepción del freudomarxismo en la España del tardofranquismo y de la Transición, 1975-1978.

Our objective is to show the roots of Freudo-Marxism as a specific form of contact between Marxism and psychoanalysis in the Spain of late Francoism and the Transition (1975-1978). We analyze the relevance of the term "Freudo-Marxism", its differences with Argentine militant psychoanalysis influential in social currents of psychoanalysis in Spain, and the historical review of the movement carried out by a relevant figure for Spanish psychology such as Antonio Caparrós i Benedicto. Finally, we address the relative reception of the work of Wilhelm Reich through the dissemination effort of Ramón García and the figure of Carlos Frigola, Eva Reich's apprentice and creator of the Reich Foundation.

Nuestro objetivo es mostrar el arraigo que tuvo el freudomarxismo, como forma específica de contacto entre marxismo y psicoanálisis, en la España del franquismo tardío y de la Transición (1975-1978). Analizamos la pertinencia del término "freudomarxismo", sus diferencias con un psicoanálisis militante argentino influyente en corrientes sociales del psicoanálisis en España, y la revisión histórica del movimiento que realiza una figura relevante para la psicología española como es Antonio Caparrós i Benedicto. Finalmente abordamos la acogida relativa de la obra de Wilhelm Reich a través del esfuerzo de difusión de Ramón García y de la figura de Carlos Frigola, aprendiz de Eva Reich y creador de la Fundación Reich.

Matters arising: Insufficient evidence that pancreatic ß cells are derived from adult ductal Neurog3-expressing progenitors.

Understanding the origin of pancreatic ß cells has profound implications for regenerative therapies in diabetes. For over a century, it was widely held that adult pancreatic duct cells act as endocrine progenitors, but lineage-tracing experiments challenged this dogma. Gribben et al. recently used two existing lineage-tracing models and single-cell RNA sequencing to conclude that adult pancreatic ducts contain endocrine progenitors that differentiate to insulin-expressing ß cells at a physiologically important rate. We now offer an alternative interpretation of these experiments. Our data indicate that the two Cre lines that were used directly label adult islet somatostatin-producing ∂ cells, which precludes their use to assess whether ß cells originate from duct cells. Furthermore, many labeled ∂ cells, which have an elongated neuron-like shape, were likely misclassified as ß cells because insulin-somatostatin coimmunolocalizations were not used. We conclude that most evidence so far indicates that endocrine and exocrine lineage borders are rarely crossed in the adult pancreas.

La recepción del freudomarxismo en la España del tardofranquismo y de la Transición, 1975-1978 / The reception of Freudo-Marxism in the Spain of late Francoism and the Transition, 1975-1978

Resumen Nuestro objetivo es mostrar el arraigo que tuvo el freudomarxismo, como forma específica de contacto entre marxismo y psicoanálisis, en la España del franquismo tardío y de la Transición (1975-1978). Analizamos la pertinencia del término "freudomarxismo", sus diferencias con un psicoanálisis militante argentino influyente en corrientes sociales del psicoanálisis en España, y la revisión histórica del movimiento que realiza una figura relevante para la psicología española como es Antonio Caparrós i Benedicto. Finalmente abordamos la acogida relativa de la obra de Wilhelm Reich a través del esfuerzo de difusión de Ramón García y de la figura de Carlos Frigola, aprendiz de Eva Reich y creador de la Fundación Reich.

Abstract Our objective is to show the roots of Freudo-Marxism as a specific form of contact between Marxism and psychoanalysis in the Spain of late Francoism and the Transition (1975-1978). We analyze the relevance of the term "Freudo-Marxism", its differences with Argentine militant psychoanalysis influential in social currents of psychoanalysis in Spain, and the historical review of the movement carried out by a relevant figure for Spanish psychology such as Antonio Caparrós i Benedicto. Finally, we address the relative reception of the work of Wilhelm Reich through the dissemination effort of Ramón García and the figure of Carlos Frigola, Eva Reich's apprentice and creator of the Reich Foundation.

Psychoanalysis and academia: the case of Angel Garma and the university of Buenos Aires.

The Spanish psychiatrist and psychoanalyst Ángel Garma-exiled in Argentina after the Spanish Civil War-was one of the founders and the first president of the Argentinian Psychoanalytical Association. Garma unsuccessfully tried to become a university lecturer on three occasions. His final attempt was in 1965, when he applied for a professorship in deep psychology at the Faculty of Philosophy and Literature of the University of Buenos Aires. The application he submitted for this professorship position has been located in Ángel Garma's personal archive. The aim of this article is to analyse this manuscript to search for clues about the author's relationship with his own work and to explain the priorities and interests he intended to explore in the university environment. The first part of the article analyses the content of his application for the professorship, contrasting this content with published work and reviewing the fundamental lines of Garma's psychoanalytical thought (child sexuality, psychoanalysis and psychosomatic medicine, the psychoanalytical institution, etc.). The second part suggests the main reasons why Garma failed in his attempts to become a university lecturer.

The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands.

Since the discovery of vitamin D a century ago, a great number of metabolites, analogs, hybrids and nonsteroidal VDR ligands have been developed. An enormous effort has been made to synthesize compounds which present beneficial properties while attaining lower calcium serum levels than calcitriol. This structural review covers VDR ligands published to date.

The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A.

The biological purpose of long non-coding RNAs (lncRNAs) is poorly understood. Haploinsufficient mutations in HNF1A homeobox A (HNF1A), encoding a homeodomain transcription factor, cause diabetes mellitus. Here, we examine HASTER, the promoter of an lncRNA antisense to HNF1A. Using mouse and human models, we show that HASTER maintains cell-specific physiological HNF1A concentrations through positive and negative feedback loops. Pancreatic ß cells from Haster mutant mice consequently showed variegated HNF1A silencing or overexpression, resulting in hyperglycaemia. HASTER-dependent negative feedback was essential to prevent HNF1A binding to inappropriate genomic regions. We demonstrate that the HASTER promoter DNA, rather than the lncRNA, modulates HNF1A promoter-enhancer interactions in cis and thereby regulates HNF1A transcription. Our studies expose a cis-regulatory element that is unlike classic enhancers or silencers, it stabilizes the transcription of its target gene and ensures the fidelity of a cell-specific transcription factor program. They also show that disruption of a mammalian lncRNA promoter can cause diabetes mellitus.

Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D3.

The toxic calcemic effects of the natural hormone 1α,25-dihydroxyvitamin D3 (1,25D3, 1,25-dihydroxycholecalciferol) in the treatment of hyperproliferative diseases demand the development of highly active and noncalcemic vitamin D analogues. We report the development of two highly active and noncalcemic analogues of 1,25D3 that lack the C-ring and possess an m-phenylene ring that replaces the natural D-ring. The new analogues (3a, 3b) are characterized by an additional six-carbon hydroxylated side chain attached either to the aromatic nucleus or to the triene system. Both compounds were synthesized by the Pd-catalyzed tandem cyclization/cross coupling approach starting from alkyne 6 and diphenol 8. Key steps include a stereoselective Cu-assisted addition of a Grignard reagent to an aromatic alkyne and a Takai olefination of an aromatic aldehyde. The new compounds are noncalcemic and show transcriptional and antiproliferative activities similar to 1,25D3. Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6.

Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster.

Sequence variants in cis-acting enhancers are important for polygenic disease, but their role in Mendelian disease is poorly understood. Redundancy between enhancers that regulate the same gene is thought to mitigate the pathogenic impact of enhancer mutations. Recent findings, however, have shown that loss-of-function mutations in a single enhancer near PTF1A cause pancreas agenesis and neonatal diabetes. Using mouse and human genetic models, we show that this enhancer activates an entire PTF1A enhancer cluster in early pancreatic multipotent progenitors. This leading role, therefore, precludes functional redundancy. We further demonstrate that transient expression of PTF1A in multipotent progenitors sets in motion an epigenetic cascade that is required for duct and endocrine differentiation. These findings shed insights into the genome regulatory mechanisms that drive pancreas differentiation. Furthermore, they reveal an enhancer that acts as a regulatory master key and is thus vulnerable to pathogenic loss-of-function mutations.

The reception of psychodrama in Spain: Correspondence between Jacob Levy Moreno and Ramón Sarró.

Jacob Levy Moreno, the well-known creator of psychodrama, had a close epistolary relationship with the Spanish psychiatrist Ramón Sarró; a collection of these letters has been located in the Sarró personal archive, deposited in the Library of Catalonia. After locating and arranging this correspondence, we proceeded to analyze and contextualize its contents. The analysis of this collection serves as a basis to outline the context in which the relationship between Moreno and Sarró developed, the role played by certain psychotherapy congresses in strengthening their relationships, and the process that resulted in the University of Barcelona awarding Moreno Doctor Honoris Causa. This study has allowed us to identify certain areas of how psychodrama was received in Spain during the 1960s and reflect on the creation of international collaboration networks and the creation of schools and professional and academic legitimation strategies in the wake of the approaches to group psychotherapy and psychodrama that Moreno developed while based in New York. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

La conexión francesa de Ángel Garma: psicología y psicoanálisis en la correspondencia con Daniel Lagache / The French connection of Angel Garma: psychology and psychoanalysis in correspondence with Daniel Lagache

El español Ángel Garma (1904-1993) y el francés Daniel Lagache (1903-1972) son dos figuras clave para la psicología y el psicoanálisis del siglo XX. Hemos localizado parte de su relación epistolar en el Archivo Ángel Garma, conservado en Centro de Ciencias Humanas y Sociales del Consejo Superior de Investigaciones Científicas. El análisis de esta colección nos permite reconstruir la poca conocida relación entre Garma y Lagache, así como profundizar en aspectos biográficos, personales y emocionales de ambos autores. En concreto, buscamos determinar en qué términos personales y profesionales se desarrollaron sus contactos, el nivel de colaboración que establecieron y los resultados científicos y profesionales que pueden identificarse como consecuencia de dicha relación. También nos ha permitido examinar y contextualizar los principales temas de su correspondencia: el intercambio de conocimientos, estrategias de difusión y docencia científica, la relación con colegas y discípulos, y la institu-cionalización del psicoanálisis. Las diferencias que existen entre ambos autores, detectables tanto en sus elaboraciones teóricas, como en su práctica docente y clínica, no les impidió mantener un mutuo respeto intelectual que les llevó a colaborar y brindarse apoyo en la difusión de sus obras respectivas (AU)

Psicoanálisis y marxismo en el tardofranquismo y la Transición. La influencia del pensamiento latinoamericano / Psychoanalysis and marxism in the late-francoism and democratic transition. The influence of Latin American thought

Las ideas de los psicoanalistas del Cono Sur, fundamentalmente argentinos, que llegaron a España en la década de los setenta, encontraron suelo fértil en un contexto politizado y con un fuerte activismo social. Este trabajo se centra en las aportaciones de un grupo de analistas que entendían el psicoanálisis desde una óptica marxista y que influirían en la conformación de la perspectiva social y relacional del psicoanálisis en nuestro país. Para ello, se aborda la conexión entre psicoanálisis y marxismo en la obra de Castilla del Pino, el intento de actualización de la praxis psicoanalítica de José Bleger desde un tenso contexto argentino en el que también destacarán Marie Langer y Antonio Caparrós, y la acogida de dichas propuestas en el ámbito español a través de la revista Clínica y Análisis Grupal. (AU)

The ideas of South American psychoanalists, mainly Argentinian, reached Spain in the 70s and grew in a highly-politized context. This work focuses on the contributions of a certain group of clinicians who understood psychoanalysis through the lens of marxism and contributed to develop the social and relational perspective of psychoanalysis in Spain. We examine the link between psychoanalysis and marxism in Castilla del Pino's works and the efforts of José Bleger, Marie Langer, and Antonio Caparrós to update psychoanalytical praxis in a difficult Argentinian context. Finally, we analyse the reception of this line of thought in Spain by the Clínica y Análisis Grupal journal. (AU)

Un nombre en la torre de marfil. Psicoanálisis y psicología profunda a través de La historia interminable de M. Ende (1979) / A name in the ivory tower. Psychoanalysis and depth psychology through michael ende’s the neverending story

El objetivo del artículo es abordar la relación entre psicoanálisis y arte -en este caso, literatura- entendiendo que este último arrastra intuiciones que posterior o paralelamente hipotetizadas por las disciplinas psi. Para ello, se parte del concepto de “arte visionario” de Carl Gustav Jung y de la noción de que el “artista precede” de Jacques Lacan para explorar la manera en la que una obra como La Historia Interminable (M. Ende) permite arrojar luz sobre los desarrollos teóricos de estos dos autores. En el caso de J. Lacan, los registros de lo simbólico, lo imaginario y lo real. En el caso de C. G. Jung, el viaje interior que supone el proceso de individuación y el contacto con arquetipos del inconsciente colectivo.(AU)

The aim of this paper is to address the relation between psychoanalysis and literary art. We assume that art presents intuitions latter developed by PSI theories. On the basis of Visionary Art (Carl Gustav Jung) and “the artist always precedes” (Jacques Lacan) concepts, we explore the way in which The Neverending Story (M. Ende) sheds light on the theories developed by these authors. On one hand, the J. Lacan’s concepts of the Imaginary, the Symbolic and the Real. On the other hand, the inner path of the Individuation Process and the archetypes of the Collective Unconscious of C.G. Jung.(AU)

REST is a major negative regulator of endocrine differentiation during pancreas organogenesis.

Multiple transcription factors have been shown to promote pancreatic ß-cell differentiation, yet much less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrinogenesis in the embryonic pancreas. However, pancreatic Rest knockout mice failed to show abnormal numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we observed a marked increase in pancreatic endocrine cell formation. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts and induced ß-cell-specific genes in human adult duct-derived organoids. We also defined genomic sites that are bound and repressed by REST in the embryonic pancreas. Our findings show that REST-dependent inhibition ensures a balanced production of endocrine cells from embryonic pancreatic progenitors.

Hnf1b-CreER causes efficient recombination of a Rosa26-RFP reporter in duct and islet δ cells.

The Hnf1b-CreERT2 BAC transgenic (Tg(Hnf1b-cre/ERT2)1Jfer) has been used extensively to trace the progeny of pancreatic ducts in developmental, regeneration, or cancer models. Hnf1b-CreERT2 transgenics have been used to show that the cells that form the embryonic pancreas duct-like plexus are bipotent duct-endocrine progenitors, whereas adult mouse duct cells are not a common source of ß cells in various regenerative settings. The interpretation of such genetic lineage tracing studies is critically dependent on a correct understanding of the cell type specificity of recombinase activity with each reporter system. We have reexamined the performance of Hnf1b-CreERT2 with a Rosa26-RFP reporter transgene. This showed inducible recombination of up to 96% adult duct cells, a much higher efficiency than previously used reporter transgenes. Despite this high duct-cell excision, recombination in α and ß cells remained very low, similar to previously used reporters. However, nearly half of somatostatin-expressing δ cells showed reporter activation, which was due to Cre expression in δ cells rather than to duct to δ cell conversions. The high recombination efficiency in duct cells indicates that the Hnf1b-CreERT2 model can be useful for both ductal fate mapping and genetic inactivation studies. The recombination in δ cells does not modify the interpretation of studies that failed to show duct conversions to other cell types, but needs to be considered if this model is used in studies that aim to modify the plasticity of pancreatic duct cells.

Design, Synthesis, Evaluation and Structure of Allenic 1α,25-Dihydroxyvitamin D3 Analogs with Locked Mobility at C-17.

Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue-selective new analogs. We have designed and synthesized the first examples of 1α,25-dihydroxyvitamin D3 analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility. The triene system was constructed by a Pd0 -mediated cyclization/Suzuki-Miyaura cross-coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester-Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)-1α,25-dihydroxy-17,20-dien-24-homo-21-nor-vitamin D3 bound to binding domain of the vitamin D receptor, provide information concerning side-chain conformational requirements for biological activity.

Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene.

Despite the central role of chromosomal context in gene transcription, human noncoding DNA variants are generally studied outside of their genomic location. This limits our understanding of disease-causing regulatory variants. INS promoter mutations cause recessive neonatal diabetes. We show that all INS promoter point mutations in 60 patients disrupt a CC dinucleotide, whereas none affect other elements important for episomal promoter function. To model CC mutations, we humanized an ∼3.1-kb region of the mouse Ins2 gene. This recapitulated developmental chromatin states and cell-specific transcription. A CC mutant allele, however, abrogated active chromatin formation during pancreas development. A search for transcription factors acting through this element revealed that another neonatal diabetes gene product, GLIS3, has a pioneer-like ability to derepress INS chromatin, which is hampered by the CC mutation. Our in vivo analysis, therefore, connects two human genetic defects in an essential mechanism for developmental activation of the INS gene.

HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer.

Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding Lysine-specific demethylase 6A, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutant transcriptomes phenocopy those of Kdm6a mutations, and both defects synergize with KrasG12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic, and biochemical studies to show that HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates differentiated acinar cell programs, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. We also identify a subset of non-classical PDAC samples that exhibit the HNF1A/KDM6A-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A deficiency promotes PDAC. They also connect the tumor-suppressive role of KDM6A deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation.

The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production. Thrombosis is a common causal pathology for three widespread cardiovascular syndromes: acute coronary syndrome (ACS), venous thromboembolism (VTE), and strokes. In this research a series of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitor were designed, synthesized, and evaluated for their FXa inhibitor activity, cytotoxicity activity and coagulation parameters. Rational design for the desired novel molecules was performed through protein-ligand complexes selection and ligand clustering. The microwave-assisted synthetic strategy of selected compounds was carried out by using Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions under microwave irradiation. The microwave methodology proved to be an efficient way to obtain all novel compounds in high yields (73-93%). Furthermore, a thermochemical analysis, optimization and reactivity indexes such as electronic chemical potential (µ), chemical hardness (η), and electrophilicity (ω) were performed to understand the relationship between the structure and the energetic behavior of all the series. Then, in vitro analysis showed that compounds 27, 29-31, and 34 exhibited inhibitory activity against FXa and the corresponding half maximal inhibitory concentration (IC50) values were calculated. Next, a cell viability assay in HEK293 and HepG2 cell lines, and coagulation parameters (anti FXa, Prothrombin time (PT), activated Partial Thromboplastin Time (aPTT)) of the most active novel molecules were performed to determine the corresponding cytotoxicity and possible action on clotting pathways. The obtained results suggest that compounds 27 and 29 inhibited FXa targeting through coagulation factors in the intrinsic and extrinsic pathways. However, compound 34 may target coagulation FXa mainly by the extrinsic and common pathway. Interestingly, the most active compounds in relation to the inhibition activity against FXa and coagulation parameters did not show toxicity at the performed coagulation assay concentrations. Finally, docking studies confirmed the preferential binding mode of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives inside the active site of FXa.

Vitamin D and Its Synthetic Analogs.

For many individuals, in particular during winter, supplementation with the secosteroid vitamin D3 is essential for the prevention of bone disorders, muscle weakness, autoimmune diseases, and possibly also different types of cancer. Vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as potent agonist of the transcription factor vitamin D receptor (VDR). Thus, vitamin D directly affects chromatin structure and gene regulation at thousands of genomic loci, i.e., the epigenome and transcriptome of its target tissues. Modifications of 1,25(OH)2D3 at its side-chain, A-ring, triene system, or C-ring, alone and in combination, as well as nonsteroidal mimics provided numerous potent VDR agonists and some antagonists. The nearly 150 crystal structures of VDR's ligand-binding domain with various vitamin D compounds allow a detailed molecular understanding of their action. This review discusses the most important vitamin D analogs presented during the past 10 years and molecular insight derived from new structural information on the VDR protein.