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We report a Cu-catalyzed oxidative coupling of aliphatic amines with benzylic and aliphatic boronic esters to give high value alkyl amines, products found widely in applications from medicinal chemistry to materials science. This operationally simple reaction, which can be performed on gram scale, runs under mild conditions and exhibits broad functional group tolerance. The terminal oxidant of the reaction is O2 from the air, avoiding the need for additional chemical oxidants. Investigation into the reaction mechanism suggests that the boronic ester is activated by an aminyl radical, formed through oxidation of the amine by the Cu catalyst, to give a key alkyl radical intermediate. To demonstrate its utility and potential for late-stage functionalization, we showcase the method as the final step in the total synthesis of a TRPV1 antagonist.
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Combining simple amines with the bench-stable sulfinylamine Tr-NSO allows in situ preparation of reactive alkyl sulfinylamines, which when combined with alkyl radicals generated by photocatalytic decarboxylation, provides N-alkyl sulfinamides. The reactions are broad in scope and tolerate a wide variety of functional groups on both the acid and amine components. The sulfinamide products are used to prepare a selection of challenging S(VI) products. The method provides a convenient way to use reactive and unstable alkyl sulfinylamines.
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sulfinamides, sulfonamides, and sulfonimidamides are in-demand motifs in medicinal chemistry, yet methods for the synthesis of alkyl variants that start from simple, readily available feedstocks are scarce. In addition, bespoke syntheses of each class of molecules are usually needed. In this report, we detail the synthesis of these three distinct sulfur functional groups, using readily available and structurally diverse alkyl carboxylic acids as the starting materials. The method harnesses alkyl radical generation from carboxylic acids using acridine photocatalysts and 400 nm light with subsequent radical addition to sulfinylamine reagents, delivering sulfinamide products. Using the N-alkoxy sulfinylamine reagent t-BuO-NSO as the radical trap provides common N-alkoxy sulfinamide intermediates, which can be converted in a divergent manner to either sulfonamides or sulfonimidamides, by treatment with sodium hydroxide, or an amine, respectively. The reactions are scalable, tolerate a broad range of functional groups, and can be used for the diversification of complex biologically active compounds.
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PURPOSE: Myocardin-related transcription factor B (MRTFB) is an important transcriptional regulator, which promotes the activity of an estimated 300 genes but is not known to underlie a Mendelian disorder. METHODS: Probands were identified through the efforts of the Undiagnosed Disease Network. Because the MRTFB protein is highly conserved between vertebrate and invertebrate model organisms, we generated a humanized Drosophila model expressing the human MRTFB protein in the same spatial and temporal pattern as the fly gene. Actin binding assays were used to validate the effect of the variants on MRTFB. RESULTS: Here, we report 2 pediatric probands with de novo variants in MRTFB (p.R104G and p.A91P) and mild dysmorphic features, intellectual disability, global developmental delays, speech apraxia, and impulse control issues. Expression of the variants within wing tissues of a fruit fly model resulted in changes in wing morphology. The MRTFBR104G and MRTFBA91P variants also display a decreased level of actin binding within critical RPEL domains, resulting in increased transcriptional activity and changes in the organization of the actin cytoskeleton. CONCLUSION: The MRTFBR104G and MRTFBA91P variants affect the regulation of the protein and underlie a novel neurodevelopmental disorder. Overall, our data suggest that these variants act as a gain of function.
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Discapacidad Intelectual , Trastornos del Neurodesarrollo , Animales , Niño , Humanos , Drosophila/genética , Actinas/genética , Mutación con Ganancia de Función , Factores de Transcripción/genética , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , FenotipoRESUMEN
WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.
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Trastorno Dismórfico Corporal/patología , Cerebelo/anomalías , Coloboma/patología , Discapacidades del Desarrollo/patología , Epilepsia/patología , Discapacidad Intelectual/patología , Mutación , Malformaciones del Sistema Nervioso/patología , Repeticiones WD40/genética , Adulto , Secuencia de Aminoácidos , Animales , Trastorno Dismórfico Corporal/genética , Cerebelo/patología , Niño , Coloboma/genética , Discapacidades del Desarrollo/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crecimiento & desarrollo , Epilepsia/genética , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Masculino , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Malformaciones del Sistema Nervioso/genética , Fenotipo , Homología de Secuencia , Adulto JovenRESUMEN
Chemosensory pheromonal information regulates aggression and reproduction in many species, but how pheromonal signals are transduced to reliably produce behavior is not well understood. Here we demonstrate that the pheromonal signals detected by Gr32a-expressing chemosensory neurons to enhance male aggression are filtered through octopamine (OA, invertebrate equivalent of norepinephrine) neurons. Using behavioral assays, we find males lacking both octopamine and Gr32a gustatory receptors exhibit parallel delays in the onset of aggression and reductions in aggression. Physiological and anatomical experiments identify Gr32a to octopamine neuron synaptic and functional connections in the suboesophageal ganglion. Refining the Gr32a-expressing population indicates that mouth Gr32a neurons promote male aggression and form synaptic contacts with OA neurons. By restricting the monoamine neuron target population, we show that three previously identified OA-Fru(M) neurons involved in behavioral choice are among the Gr32a-OA connections. Our findings demonstrate that octopaminergic neuromodulatory neurons function as early as a second-order step in this chemosensory-driven male social behavior pathway.
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Agresión , Conducta Animal/fisiología , Proteínas de Drosophila/fisiología , Drosophila/fisiología , Neuronas/fisiología , Octopamina/fisiología , Receptores de Superficie Celular/fisiología , Conducta Sexual Animal , Animales , Animales Modificados Genéticamente , Secuencia de Bases , Cartilla de ADN , Proteínas de Drosophila/genética , Masculino , Reacción en Cadena de la Polimerasa , Receptores de Superficie Celular/genética , Transducción de SeñalRESUMEN
This paper introduces a special issue on 'Histories of asylums, insanity and psychiatry in Scotland', situating the papers that follow in an outline historiography of work in this field. Using Allan Beveridge's claims in 1993 about the relative lack of research on the history of psychiatry in Scotland, the paper reviews a range of contributions that have emerged since then, loosely distinguishing between 'overviews' - work addressing longer-term trends and broader periods and systems - and more detailed studies of particular 'individuals and institutions'. There remains much still to do, but the present special issue signals what is currently being achieved, not least by a new generation of scholars in and on Scotland.
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Hospitales Psiquiátricos/historia , Psiquiatría/historia , Trastornos Psicóticos/historia , Historia del Siglo XX , Humanos , EscociaRESUMEN
Our aim in presenting this Classic Text is to foster wider analytical attention to a fascinating commentary on insanity by a former inmate of Glasgow Royal Asylum, Gartnavel, James Frame. Despite limited coverage in existing literature, his text (and other writings) have been surprisingly neglected by modern scholars. Frame's Philosophy presents a vivid, affecting, often destigmatizing account of the insane and their institutional provision in Scotland. Derived from extensive first-hand experience, Frame's chronicle eloquently and graphically delineates his own illness and the roles and perspectives of many other actors, from clinicians and managers to patients and relations. It is also valuable as a subjective, but heavily mediated, kaleidoscopic view of old and new theories concerning mental afflictions, offering many insights about the medico-moral ethos and milieu of the mid-Victorian Scottish asylum. Alternating as consolatory and admonitory illness biography, insanity treatise, mental health self-help guide, and asylum reform and promotion manual, it demands scrutiny for both its more progressive views and its more compromised and prejudicial attitudes.
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Hospitales Psiquiátricos/historia , Filosofía/historia , Trastornos Psicóticos/historia , Trastornos Psicóticos/terapia , Historia del Siglo XIX , Humanos , EscociaRESUMEN
Johnston's organ, the Drosophila auditory organ, is anatomically very different from the mammalian organ of Corti. However, recent evidence indicates significant cellular and molecular similarities exist between vertebrate and invertebrate hearing, suggesting that Drosophila may be a useful platform to determine the function of the many mammalian deafness genes whose underlying biological mechanisms are poorly characterized. Our goal was a comprehensive screen of all known orthologues of mammalian deafness genes in the fruit fly to better understand conservation of hearing mechanisms between the insect and the fly and ultimately gain insight into human hereditary deafness. We used bioinformatic comparisons to screen previously reported human and mouse deafness genes and found that 156 of them have orthologues in Drosophila melanogaster. We used fluorescent imaging of T2A-GAL4 gene trap and GFP or YFP fluorescent protein trap lines for 54 of the Drosophila genes and found 38 to be expressed in different cell types in Johnston's organ. We phenotypically characterized the function of strong loss-of-function mutants in three genes expressed in Johnston's organ (Cad99C, Msp-300, and Koi) using a courtship assay and electrophysiological recordings of sound-evoked potentials. Cad99C and Koi were found to have significant courtship defects. However, when we tested these genes for electrophysiological defects in hearing response, we did not see a significant difference suggesting the courtship defects were not caused by hearing deficiencies. Furthermore, we used a UAS/RNAi approach to test the function of seven genes and found two additional genes, CG5921 and Myo10a, that gave a statistically significant delay in courtship but not in sound-evoked potentials. Our results suggest that many mammalian deafness genes have Drosophila homologues expressed in the Johnston's organ, but that their requirement for hearing may not necessarily be the same as in mammals.
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Sordera , Drosophila , Animales , Humanos , Ratones , Drosophila/genética , Drosophila melanogaster/genética , Audición/genética , Vertebrados , MamíferosRESUMEN
EZH1 ( Enhancer of Zeste, homolog 1) , a Polycomb Repressive Complex-2 (PRC2) component, is involved in a myriad of cellular processes through modifying histone 3 lysine27 (H3K27) residues. EZH1 represses transcription of downstream target genes through H3K27 trimethylation (H3K27me3). Genetic mutations in histone modifiers have been associated with developmental disorders, while EZH1 has not yet been linked to any human disease. However, the paralog EZH2 is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a de novo variant in EZH1 , p.Ala678Gly, through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and was the best candidate variant found in the exome. Human EZH1 / 2 are homologous to fly Enhancer of zeste E(z) , an essential gene in flies, and the residue (A678 in humans, A691 in Drosophila ) is conserved. To further study this variant, we obtained Drosophila null alleles and generated transgenic flies expressing wild-type (E(z) WT ) and the variant (E(z) A691G ) . The E(z) A691G variant led to hyper H3K27me3 while the E(z) WT did not, suggesting this is as a gain-of-function allele. When expressed under the tubulin promotor in vivo the variant rescued null-lethality similar to wild-type but the E(z) A691G flies exhibit bang sensitivity and shortened lifespan. In conclusion, here we present a novel EZH1 de novo variant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact in Drosophila . Biochemically this allele leads to increased H3K27me3 suggesting gain-of-function, but when expressed in adult flies the E(z) A691G has some characteristics of partial loss-of-function which may suggest it is a more complex allele in vivo .
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EZH1, a polycomb repressive complex-2 component, is involved in a myriad of cellular processes. EZH1 represses transcription of downstream target genes through histone 3 lysine27 (H3K27) trimethylation (H3K27me3). Genetic variants in histone modifiers have been associated with developmental disorders, while EZH1 has not yet been linked to any human disease. However, the paralog EZH2 is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a de novo missense variant in EZH1 through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and an analogous somatic or germline mutation in EZH2 has been reported in patients with B-cell lymphoma or Weaver syndrome, respectively. Human EZH1/2 are homologous to fly Enhancer of zeste (E(z)), an essential gene in Drosophila, and the affected residue (p.A678 in humans, p.A691 in flies) is conserved. To further study this variant, we obtained null alleles and generated transgenic flies expressing wildtype [E(z)WT] and the variant [E(z)A691G]. When expressed ubiquitously the variant rescues null-lethality similar to the wildtype. Overexpression of E(z)WT induces homeotic patterning defects but notably the E(z)A691G variant leads to dramatically stronger morphological phenotypes. We also note a dramatic loss of H3K27me2 and a corresponding increase in H3K27me3 in flies expressing E(z)A691G, suggesting this acts as a gain-of-function allele. In conclusion, here we present a novel EZH1 de novo variant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact in Drosophila.
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Drosophila melanogaster , Histonas , Animales , Humanos , Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Histonas/genética , Complejo Represivo Polycomb 2RESUMEN
Development of effective therapies against SARS-CoV-2 infections relies on mechanistic knowledge of virus-host interface. Abundant physical interactions between viral and host proteins have been identified, but few have been functionally characterized. Harnessing the power of fly genetics, we develop a comprehensive Drosophila COVID-19 resource (DCR) consisting of publicly available strains for conditional tissue-specific expression of all SARS-CoV-2 encoded proteins, UAS-human cDNA transgenic lines encoding established host-viral interacting factors, and GAL4 insertion lines disrupting fly homologs of SARS-CoV-2 human interacting proteins. We demonstrate the utility of the DCR to functionally assess SARS-CoV-2 genes and candidate human binding partners. We show that NSP8 engages in strong genetic interactions with several human candidates, most prominently with the ATE1 arginyltransferase to induce actin arginylation and cytoskeletal disorganization, and that two ATE1 inhibitors can reverse NSP8 phenotypes. The DCR enables parallel global-scale functional analysis of SARS-CoV-2 components in a prime genetic model system.
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COVID-19 , SARS-CoV-2 , Humanos , Animales , SARS-CoV-2/genética , Drosophila , Actinas , Animales Modificados GenéticamenteRESUMEN
This article examines the management and meaning of post-mortem examinations, and the spatial ordering of patients' death, dissection and burial at the Victorian asylum, referencing a range of institutional contexts and exploiting a case study of the Royal Edinburgh Asylum. The routinizing of dissection and the development of the dead-house from a more marginal asylum sector to a lynchpin of laboratory medicine is stressed. External and internal pressure to modernize pathological research facilities is assessed alongside governmental, public and professional critiques of variable necroscopy practices. This is contextualized against wider issues and attitudes surrounding consent and funereal rituals. Onus is placed on tendencies in anatomizing insanity towards the conversion of deceased lunatics--pauper lunatics especially--into mere pathological specimens. On the other hand, significant but compromised resistance on the part of a minority of practitioners, relatives and the wider public is also identified.
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Autopsia/historia , Entierro/historia , Pesar , Hospitales Psiquiátricos/historia , Trastornos Mentales/historia , Prácticas Mortuorias/historia , Historia del Siglo XIX , Historia del Siglo XX , Humanos , EscociaRESUMEN
Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through "humanization" rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes points to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.
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Trastorno del Espectro Autista , Trastorno Autístico , Drosophila , Trastornos del Neurodesarrollo , Receptores de Glicina , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Trastorno Autístico/genética , Drosophila/genética , Predisposición Genética a la Enfermedad , Humanos , Trastornos del Neurodesarrollo/genética , Receptores de Glicina/genéticaRESUMEN
Using a 15.9 m baseline at the Navy Prototype Optical Interferometer (NPOI), we have successfully detected interferometric fringes in observations of the geosynchronous satellite (geosat) DirecTV-9S while it glinted on two nights in March 2009. The fringe visibilities can be fitted by a model consisting of two components, one resolved (â³3.7 m) and one unresolved (â¼1.1 m). Both the length of the glint and the specular albedos are consistent with the notion that the glinting surfaces are not completely flat and scatter reflected sunlight into an opening angle of roughly 15°. Enhancements to the NPOI that would improve geosat observations include adding an infrared capability, which could extend the glint season, and adding larger, adaptive-optics equipped telescopes. Future work may test the feasibility of observing geosats with aperture-masked large telescopes and of developing an array of six to nine elements.
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Synthetically versatile alkyl sulfinates can be prepared from readily available amines, using Katritzky pyridinium salt intermediates. In a catalyst-free procedure, primary, secondary, and benzylic alkyl radicals are generated by photoinduced or thermally induced single-electron transfer (SET) from an electron donor-acceptor (EDA) complex, and trapped by SO2 to generate sulfonyl radicals. Hydrogen atom transfer (HAT) from Hantzsch ester gives alkyl sulfinate products, which are used to prepare a selection of medicinal chemistry relevant sulfonyl-containing motifs.
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The second part of this paper explores deepening doubts about pyromania as a special insanity, British debates post-1890, and pyromania's supplanting with the broader diagnostic category of insane incendiarism. It assesses the conceptual importance of revenge and morbid-motivations for arson, and the relationship of Victorian and Edwardian concepts of arson to more modern psychiatric research.The main objective is to ascertain the extent to which Victorian and Edwardian medico-psychologists and medical legists arrived at meaningful and workable definitions of criminal insanity linked to arson. It concludes by emphasizing the limitations, contentiousness and inconsistencies in the use of technical terms such as'pyromania', contrasted with the qualified success of authorities in arriving at more viable and broadly acceptable explanations of insane firesetting.
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Piromanía/historia , Psiquiatría Forense/historia , Defensa por Insania/historia , Trastornos Mentales/historia , Europa (Continente) , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Reino Unido , Estados UnidosRESUMEN
This article surveys evolving and competing medico-legal concepts of pyromania and insane arson. Exploiting evidence from medical jurisprudence, medico-legal publications, medical lexicography and case histories, it seeks to explicate the key positions in contemporary professional debates concerning arson and mental derangement. A major focus is the application of the doctrines of moral and partial insanity, monomania, instinctive insanity and irresistible impulse to understandings of pyromania and insane arson. The limited extent to which mental defect provided a satisfactory diagnosis and exculpatory plea for morbid arson is also explored. Additionally, this article compares and contrasts contemporary debates about other special manias, especially kleptomania. Part 2 will be published in the next issue, History of Psychiatry 21 (4).
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Piromanía/historia , Psiquiatría Forense/historia , Trastornos Mentales/historia , Principios Morales , Adulto , Niño , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Defensa por Insania , Reino Unido , Estados UnidosRESUMEN
Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.