Significance Mammalian chromatin is compartmentalized in topologically associating domains (TADs), genomic regions within which sequences preferentially contact each other. This organization has been ...proposed to be essential to organize the regulatory information contained in mammalian genomes. We show that Six homeobox genes, essential developmental regulators organized in gene clusters across different animal phyla, share a deeply conserved chromatin organization formed by two abutting TADs that predates the Cambrian explosion. This organization is required to generate separate regulatory landscapes for neighboring genes within the cluster, resulting in very different gene expression patterns. Finally, we show that this extremely conserved 3D architecture is associated with a characteristic arrangement of CCCTC-binding factor (CTCF) binding sites in diverging orientations, revealing a genome-wide conserved signature for TAD borders.
Increasing evidence in the last years indicates that the vast amount of regulatory information contained in mammalian genomes is organized in precise 3D chromatin structures. However, the impact of this spatial chromatin organization on gene expression and its degree of evolutionary conservation is still poorly understood. The Six homeobox genes are essential developmental regulators organized in gene clusters conserved during evolution. Here, we reveal that the Six clusters share a deeply evolutionarily conserved 3D chromatin organization that predates the Cambrian explosion. This chromatin architecture generates two largely independent regulatory landscapes (RLs) contained in two adjacent topological associating domains (TADs). By disrupting the conserved TAD border in one of the zebrafish Six clusters, we demonstrate that this border is critical for preventing competition between promoters and enhancers located in separated RLs, thereby generating different expression patterns in genes located in close genomic proximity. Moreover, evolutionary comparison of Six-associated TAD borders reveals the presence of CCCTC-binding factor (CTCF) sites with diverging orientations in all studied deuterostomes. Genome-wide examination of mammalian HiC data reveals that this conserved CTCF configuration is a general signature of TAD borders, underscoring that common organizational principles underlie TAD compartmentalization in deuterostome evolution.
Fossil data suggest that limbs evolved from fish fins by sequential elaboration of their distal endoskeleton, giving rise to the autopod close to the tetrapod origin. This elaboration may have ...occurred by a simultaneous reduction of the distal ectodermal fold of fish fins. Modulation of 5′Hoxd gene transcription, through tetrapod-specific digit enhancers, has been suggested as a possible evolutionary mechanism involved in these morphological transformations. Here, we overexpress hoxd13a in zebrafish to investigate the impact of increasing 5′Hoxd expression during fin development. This overexpression causes increased proliferation, distal expansion of chondrogenic tissue and finfold reduction. In addition, we also show that the tetrapod-specific 5′Hoxd enhancer CsC promotes similar expression in zebrafish fins and mouse limbs. Our results support the idea that modulation of 5′Hoxd gene expression, by acquisition of novel enhancer elements, offered the substrate for the evolution of fins and the origin of tetrapod limbs.
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► hox13a overexpression induces distal expansion and finfold reduction in fish fins ► The distal proliferative tissue induced by hoxd13a is chondrogenic ► The gene expression in this distal tissue is analogous to autopod/digit identity ► A tetrapod hoxd13 digit enhancer drives distal-specific expression in zebrafish fins
Freitas et al. provide functional evidence supporting the hypothesis that modulation of 5′Hoxd transcription, through the addition of novel enhancer elements, was a key evolutionary mechanism for the distal elaboration of vertebrate appendages. This elaboration evolved into the distal limbs of tetrapods and allowed the colonization of land by vertebrates.
Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking ...these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. However, no direct connection between the obesity-associated variants and FTO expression or function has been made. Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.
El actual desarrollo científico y tecnológico, que ha permitido aumentar el tiempo de vida en condiciones saludables, ha conducido a una reconfiguración de la vida y la vejez. Esto ha generado nuevas ...preguntas sobre el sentido de esa vida alargada en el tiempo. El artículo analiza cómo, a través del jovenismo y el consumismo, se ha entronizado el ideal de eterna juventud, denigrando la vejez, medicalizando la vida y creando una obsesión por la cosmética y la estética. En últimas, se evidencia que la búsqueda de la abolición de la vejez responde al intento de disolver la muerte.
Introduction There are several risk factors associated with developing mental disorders among people over 60 years of age. Mental health encompasses multiple domains or capacities, which can comprise ...the psychological wellbeing of older people. Therefore, resilient coping, self-compassion, self-esteem, hopelessness, quality of life, and depression are considered the characteristics and adaptive mechanisms that bring together the main risk and protective factors for imbalance in mental wellbeing. Objective This study aimed to establish the demographic, social, and family factors, as well as the clinical characteristics and lifestyle habits that influence the mental health of the elderly people in the city of Medellín, in the year 2021, to build a mental health index. Methodology This study adopts a quantitative approach, employs retrospective temporality, and utilizes secondary sources. A cross-sectional survey was carried out with the SABAM Project (health and mental wellbeing of older adults from five cities in Colombia in 2021 by its Spanish acronym) database (secondary source), which is part of the research group “Public Health Observatory” of CES University (Medellín, Colombia). The database comprised 500 records of people aged over 60 years from the city of Medellín in 2021. While constructing the index, a principal component analysis was used, along with the Varimax method for factor analysis rotation. Results The median age of the general population was 67 years (IQR 63–72); for men, the median age was 66 years (IQR 63–71) and for women, the median age was 67 years (IQR 63–72). An association was found between low socioeconomic levels, alcohol consumption, and the level of higher education (university—postgraduate) with low levels of the Mental Health Index in people over 60 years of age in Medellín during the year 2021. Conclusion A quantitative model was developed to predict either a positive or negative prognosis in the mental wellbeing of the population over 60 years of age in the city of Medellín. The model was also used for the development of a sociodemographic profile highlighting the impact on mental health among people over 60 years of age with limited economic resources.
The vicuña (
) is the most representative wild ungulate of the high Andes of South America with two recognized morphological subspecies,
in the north and
in the south of its distribution. Current ...vicuña population size (460,000-520,000 animals) is the result of population recovery programs established in response to 500 years of overexploitation. Despite the vicuña's ecosystemic, economic and social importance, studies about their genetic variation and history are limited and geographically restricted. Here, we present a comprehensive assessment of the genetic diversity of vicuña based on samples collected throughout its distribution range corresponding to eleven localities in Peru and five in Chile representing
, plus four localities each in Argentina and Chile representing
Analysis of mitochondrial DNA and microsatellite markers show contrasting results regarding differentiation between the two vicuña types with mitochondrial haplotypes supporting subspecies differentiation, albeit with only a few mutational steps separating the two subspecies. In contrast, microsatellite markers show that vicuña genetic variation is best explained as an isolation by distance pattern where populations on opposite ends of the distribution present different allelic compositions, but the intermediate populations present a variety of alleles shared by both extreme forms. Demographic characterization of the species evidenced a simultaneous and strong reduction in the effective population size in all localities supporting the existence of a unique, large ancestral population (effective size ∼50,000 individuals) as recently as the mid-Holocene. Furthermore, the genetic variation observed across all localities is better explained by a model of gene flow interconnecting them rather than only by genetic drift. Consequently, we propose space "continuous" Management Units for vicuña as populations exhibit differentiation by distance and spatial autocorrelation linked to sex biased dispersal instead of population fragmentation or geographical barriers across the distribution.
We present a case of intractable dysphagia in a 23-year-old female with type 1 esophageal atresia (EA) and subsequent postsurgical refractory esophageal strictures. The patient was referred due to ...increasing symptomatology and a slight response to balloon dilations. A biodegradable polydioxanone stent (ELLA) was placed, but this did not relieve the dysphagia. After the sequential placement of two siliconated polypropylene stents (Polyflex™, Boston Scientifics), the dysphagia was definitively relieved. To our knowledge, this is the first published case with a full resolution of dysphagia using this strategy in an adult patient.
The HoxA and HoxD gene clusters of jawed vertebrates are organized into bipartite three-dimensional chromatin structures that separate long-range regulatory inputs coming from the anterior and ...posterior Hox-neighboring regions. This architecture is instrumental in allowing vertebrate Hox genes to pattern disparate parts of the body, including limbs. Almost nothing is known about how these three-dimensional topologies originated. Here we perform extensive 4C-seq profiling of the Hox cluster in embryos of amphioxus, an invertebrate chordate. We find that, in contrast to the architecture in vertebrates, the amphioxus Hox cluster is organized into a single chromatin interaction domain that includes long-range contacts mostly from the anterior side, bringing distant cis-regulatory elements into contact with Hox genes. We infer that the vertebrate Hox bipartite regulatory system is an evolutionary novelty generated by combining ancient long-range regulatory contacts from DNA in the anterior Hox neighborhood with new regulatory inputs from the posterior side.
Alzheimer's disease is the main cause of aging-associated dementia, for which there is no effective treatment. In this work, we reanalyze the information of a previous genome wide association study, ...using a new pipeline design to identify novel potential drugs. With this approach, ribonucleoside-diphosphate reductase gene (RRM2B) emerged as a candidate target and its inhibitor, 2', 2'-difluoro 2'deoxycytidine (gemcitabine), as a potential pharmaceutical drug against Alzheimer's disease. We functionally verified the effect of inhibiting the RRM2B homolog, rnr-2, in an Alzheimer's model of Caenorhabditis elegans, which accumulates human Aβ1-42 peptide to an irreversible paralysis. RNA interference against rnr-2 and also treatment with 200 ng/ml of gemcitabine, showed an improvement of the phenotype. Gemcitabine treatment increased the intracellular ATP level 3.03 times, which may point to its mechanism of action. Gemcitabine has been extensively used in humans for cancer treatment but at higher concentrations. The 200 ng/ml concentration did not exert a significant effect over cell cycle, or affected cell viability when assayed in the microglia N13 cell line. Thus, the inhibitory drug of the RRM2B activity could be of potential use to treat Alzheimer's disease and particularly gemcitabine might be considered as a promising candidate to be repurposed for its treatment.
Multiple myeloma is a hematologic neoplasm caused by an uncontrolled clonal proliferation of neoplastic plasma cells (nPCs) in the bone marrow. The development and survival of this disease is tightly ...related to the bone marrow environment. Proliferation and viability of nPCs depend on their interaction with the stromal cells and the extracellular matrix components, which also influences the appearance of drug resistance. Recapitulating these interactions in an in vitro culture requires 3D environments that incorporate the biomolecules of interest. In this work, we studied the proliferation and viability of three multiple myeloma cell lines in a microgel consisting of biostable microspheres with fibronectin (FN) on their surfaces. We also showed that the interaction of the RPMI8226 cell line with FN induced cell arrest in the G0/G1 cell cycle phase. RPMI8226 cells developed a significant resistance to dexamethasone, which was reduced when they were treated with dexamethasone and bortezomib in combination.
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