RESUMEN
The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes'1-3, with a proposed role in contributing to human bipedalism4-6. Yet, the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution. We demonstrate that this Alu element-inserted into an intron of the TBXT gene7-9-pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt, mimicking the expression pattern of its hominoid orthologue TBXT. Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud. These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. Moreover, mice expressing the exon-skipped Tbxt isoform develop neural tube defects, a condition that affects approximately 1 in 1,000 neonates in humans10. Thus, tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects, which continue to affect human health today.
Asunto(s)
Empalme Alternativo , Evolución Molecular , Hominidae , Proteínas de Dominio T Box , Cola (estructura animal) , Animales , Humanos , Ratones , Empalme Alternativo/genética , Elementos Alu/genética , Modelos Animales de Enfermedad , Genoma/genética , Hominidae/anatomía & histología , Hominidae/genética , Intrones/genética , Defectos del Tubo Neural/genética , Defectos del Tubo Neural/metabolismo , Fenotipo , Isoformas de Proteínas/deficiencia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Cola (estructura animal)/anatomía & histología , Cola (estructura animal)/embriología , Exones/genéticaRESUMEN
The chromosomally-arrayed Hox gene family plays central roles in embryonic patterning and the specification of cell identities throughout the animal kingdom. In vertebrates, the relatively large number of Hox genes and pervasive expression throughout the body has hindered understanding of their biological roles during differentiation. Studies on the subtype diversification of spinal motor neurons (MNs) have provided a tractable system to explore the function of Hox genes during differentiation, and have provided an entry point to explore how neuronal fate determinants contribute to motor circuit assembly. Recent work, using both in vitro and in vivo models of MN subtype differentiation, have revealed how patterning morphogens and regulation of chromatin structure determine cell-type specific programs of gene expression. These studies have not only shed light on basic mechanisms of rostrocaudal patterning in vertebrates, but also have illuminated mechanistic principles of gene regulation that likely operate in the development and maintenance of terminal fates in other systems.
Asunto(s)
Proteínas de Homeodominio , Médula Espinal , Animales , Proteínas de Homeodominio/metabolismo , Médula Espinal/metabolismo , Regulación del Desarrollo de la Expresión Génica , Diferenciación Celular/genética , Neuronas Motoras/metabolismo , VertebradosRESUMEN
Hydrogen bonding networks are ubiquitous in biological systems and play a key role in controlling the conformational dynamics and allosteric interactions of enzymes. Yet in small organometallic catalysts, hydrogen bonding rarely controls ligand binding to the metal center. In this work, a hydrogen bonding network within a well-defined organometallic catalyst works in concert with cation-dipole interactions to gate substrate access to the active site. An ammine ligand acts as one cofactor, templating a hydrogen bonding network within a pendent crown ether and preventing the binding of strong donor ligands, such as nitriles, to the nickel center. Sodium ions are the second cofactor, disrupting hydrogen bonding to enable switchable ligand substitution reactions. Thermodynamic analyses provide insight into the energetic requirements of the different supramolecular interactions that enable substrate gating. The dual cofactor approach enables switchable catalytic hydroamination of crotononitrile. Systematic comparisons of catalysts with varying structural features provide support for the critical role of the dual cofactors in achieving on/off catalysis with substrates containing strongly donating functional groups that might otherwise interfere with switchable catalysts.
RESUMEN
The Baeyer-Villiger oxidation of ketones is a crucial oxygen atom transfer (OAT) process used for ester production. Traditionally, Baeyer-Villiger oxidation is accomplished by thermally oxidizing the OAT from stoichiometric peroxides, which are often difficult to handle. Electrochemical methods hold promise for breaking the limitation of using water as the oxygen atom source. Nevertheless, existing demonstrations of electrochemical Baeyer-Villiger oxidation face the challenges of low selectivity. We report in this study a strategy to overcome this challenge. By employing a well-known water oxidation catalyst, Fe2O3, we achieved nearly perfect selectivity for the electrochemical Baeyer-Villiger oxidation of cyclohexanone. Mechanistic studies suggest that it is essential to produce surface hydroperoxo intermediates (M-OOH, where M represents a metal center) that promote the nucleophilic attack on ketone substrates. By confining the reactions to the catalyst surfaces, competing reactions (e.g., dehydrogenation, carboxylic acid cation rearrangements, and hydroxylation) are greatly limited, thereby offering high selectivity. The surface-initiated nature of the reaction is confirmed by kinetic studies and spectroelectrochemical characterizations. This discovery adds nucleophilic oxidation to the toolbox of electrochemical organic synthesis.
RESUMEN
The 1,2-insertion reaction of CO2 into metal-hydride bonds of d6-octahedral complexes to give κ1-O-metal-formate products is the key step in various CO2 reduction schemes and as a result has attracted extensive mechanistic investigations. For many octahedral catalysts, CO2 insertion follows an associative mechanism in which CO2 interacts directly with the coordinated hydride ligand instead of the more classical dissociative mechanism that opens an empty coordination site to bind the substrate to the metal prior to a hydride migration step. To better understand the associative mechanism, we conducted a systematic quantum chemical investigation on the reaction between CO2 and fac-(bpy)Re(CO)3H (1-Re-H; bpy = 2,2'-bipyridine) starting with the gas phase and then moving to THF and other solvents with increased dielectric constants. Detailed analyses of the potential energy surfaces (PESs) and intrinsic reaction coordinates (IRCs) reveal that the reaction is enabled in all media by an initial stage of making a 3c-2e bond between the carbon of CO2 and the metal-hydride bond that is most consistent with an organometallic bridging hydride Re-H-CO2 species. Once CO2 is bent and anchored to the metal-hydride bond, the reaction proceeds by a rotation motion via a cyclic transition state TS2 that interchanges Re-H-CO2 and Re-O-CHO coordination. The combined stages provide an asynchronous-concerted pathway for CO2 insertion on the Gibbs free energy surface with TS2 as the highest energy point. Consideration of TS2 as a rate-determining TS gives activation barriers, inverse KIEs, substituent effects, and solvent effects that agree with the experimental data available in this system. An important new insight revealed by the analyses of the results is that the initial stage of the reaction is not a hydride transfer step as has been assumed in some studies. In fact, the loose vibration of the TS that can be identified for the first stage of the reaction in solution (TS1) does not involve the Re-H stretching vibrational mode. Accordingly, the imaginary frequency of TS1 is insensitive to deuteration, and therefore, TS1 leads to no significant KIE.
RESUMEN
Correct coding is an important component of effective dermatology practice management. Over the past several years there have been updates to many commonly used codes within dermatology. This review highlights many of these updates, such as: the skin biopsy codes have been subdivided to reflect the different biopsy techniques. The definition of complex linear repairs has been updated and clarified. Outpatient and inpatient evaluation and management visits have new coding guidelines to determine level of care. Dermatopathology consultation codes have been updated and category III codes related to digital pathology have been created. Understanding the details and nuances of each of these categories of codes is vital to ensuring appropriate coding is performed.
Asunto(s)
Codificación Clínica , Dermatología , Dermatología/normas , Dermatología/métodos , Humanos , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/patología , Enfermedades de la Piel/terapia , Biopsia , Clasificación Internacional de EnfermedadesRESUMEN
A 69-year-old had fever, fatigue, rash, right periorbital swelling, and shortness of breath. Chest computed tomography revealed numerous small, bilateral pulmonary nodules; laboratory testing revealed mean corpuscular volume, 96.1 fL; hemoglobin level, 12.4 mg/dL; and leukopenia. What is the diagnosis and what would you do next?
Asunto(s)
Disnea , Exantema , Fiebre , Anciano , Humanos , Disnea/etiología , Exantema/etiología , Fiebre/etiologíaRESUMEN
Esophageal cancer is frequently treated with esophagectomy, which is associated with distinct complications. Delayed gastric conduit emptying is a well-recognized complication that usually occurs within the postoperative period. By contrast, gastric tube volvulus is a rarer complication with a more variable time course of onset after esophagectomy and can be mistaken for delayed gastric conduit emptying. We describe the fifth reported case of gastric tube volvulus occurring years after esophagectomy and its successful treatment via endoscopic stenting.
RESUMEN
Hydrogen evolution is an important fuel-generating reaction that has been subject to mechanistic debate about the roles of monometallic and bimetallic pathways. The molecular iridium catalysts in this study undergo photoelectrochemical dihydrogen (H2) evolution via a bimolecular mechanism, providing an opportunity to understand the factors that promote bimetallic H-H coupling. Covalently tethered diiridium catalysts evolve H2 from neutral water faster than monometallic catalysts, even at lower overpotential. The unexpected origin of this improvement is non-covalent supramolecular self-assembly into nanoscale aggregates that efficiently harvest light and form H-H bonds. Monometallic catalysts containing long-chain alkane substituents leverage the self-assembly to evolve H2 from neutral water at low overpotential and with rates close to the expected maximum for this light-driven water splitting reaction. Design parameters for holding multiple catalytic sites in close proximity and tuning catalyst microenvironments emerge from this work.
RESUMEN
In some contemporary psychoanalytic theories, a thesis has emerged according to which gender transition can constitute a sinthome. But gender remains a much-discussed notion in Lacanian psychoanalysis, especially in France. This article contributes to the debate by questioning the notion of femininity since it seems to be an essential point in how gender studies and Lacanian sexuation theory diverge. First, we clarify the Lacanian notion of femininity and its conceptual link to the notion of sinthome. Then, we discuss the clinical case of a transgender woman for whom the question of femininity was central during her transition. Finally, we argue how gender transition might function as a sinthome and the limits to such an understanding.
Em algumas teorias psicanalíticas contemporâneas, surgiu a tese de que a transição de gênero pode constituir um sinthoma. Mas gênero continua sendo uma noção muito discutida na psicanálise lacaniana, especialmente na França. Este artigo contribui para o debate ao questionar a noção de feminilidade, pois parece ser um ponto essencial na divergência entre os estudos de gênero e a teoria lacaniana da sexuação. Primeiramente, esclarecemos a noção lacaniana de feminilidade e seu vínculo conceitual com a noção de sinthoma. Em seguida, discutimos o caso clínico de uma mulher transgênero para quem a questão da feminilidade foi central durante sua transição. Por fim, discutimos como a transição de gênero pode funcionar como um sinthoma e os limites para tal compreensão.
Dans certaines théories psychanalytiques contemporaines, une thèse a émergé selon laquelle la transition de genre peut constituer un sinthome. Mais le genre reste une notion très discutée dans la psychanalyse lacanienne, notamment en France. Cet article contribue au débat en interrogeant la notion de féminité puisqu'elle semble être un point sur lequel divergent les études de genre et la théorie lacanienne de la sexuation. Pour ce faire, nous clarifions la notion lacanienne de féminité et son lien conceptuel avec la notion de sinthome. Ensuite, nous étudions le cas clinique d'une femme transgenre pour qui la question de la féminité a été centrale lors de sa transition. Enfin, nous discutons de la manière dont la transition de genre peut fonctionner comme un sinthome et des limites de cette thèse.
En algunas teorías psicoanalíticas contemporáneas ha surgido la tesis de que la transición de género puede constituir un sinthome. Pero el género sigue siendo una noción muy discutida en el psicoanálisis lacaniano, especialmente en Francia. Este artículo contribuye al debate cuestionando la noción de feminidad ya que parece ser un punto esencial en la divergencia entre los estudios de género y la teoría lacaniana de la sexuación. Primero, aclaramos la noción lacaniana de feminidad y su vínculo conceptual con la noción de sinthome. Luego, discutimos el caso clínico de una mujer transgénero para quien la cuestión de la feminidad fue central durante su transición. Finalmente, argumentamos cómo la transición de género podría funcionar como un sinthome y los límites de tal comprensión.