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1.
Genes (Basel) ; 12(4)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33806076

RESUMO

Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.

2.
Elife ; 102021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33666173

RESUMO

In utero exposure to maternal immune activation (MIA) is an environmental risk factor for neurodevelopmental and neuropsychiatric disorders. Animal models provide an opportunity to identify mechanisms driving neuropathology associated with MIA. We performed time-course transcriptional profiling of mouse cortical development following induced MIA via poly(I:C) injection at E12.5. MIA-driven transcriptional changes were validated via protein analysis, and parallel perturbations to cortical neuroanatomy were identified via imaging. MIA-induced acute upregulation of genes associated with hypoxia, immune signaling, and angiogenesis, by 6 hr following exposure. This acute response was followed by changes in proliferation, neuronal and glial specification, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cells in germinal zones and alterations in neuronal and glial populations were identified in the MIA-exposed cortex. Overall, paired transcriptomic and neuroanatomical characterization revealed a sequence of perturbations to corticogenesis driven by mid-gestational MIA.

3.
eNeuro ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199411

RESUMO

Cortical interneuron (CIN) dysfunction is thought to play a major role in neuropsychiatric conditions like epilepsy, schizophrenia and autism. It is therefore essential to understand how the development, physiology and functions of CINs influence cortical circuit activity and behavior in model organisms such as mice and primates. While transgenic driver lines are powerful tools for studying CINs in mice, this technology is limited in other species. An alternative approach is to use viral vectors such as AAV, which can be used in multiple species including primates and also have potential for therapeutic use in humans. Thus, we sought to discover gene regulatory enhancer elements (REs) that can be used in viral vectors to drive expression in specific cell types. The present study describes the systematic genome-wide identification of putative REs (pREs) that are preferentially active in immature CINs by histone modification ChIP-seq. We evaluated two novel pREs in AAV vectors, alongside the well-established Dlx I12b enhancer, and found that they drove CIN-specific reporter expression in adult mice. We also showed that the identified Arl4d pRE could drive sufficient expression of channelrhodopsin for optogenetic rescue of behavioral deficits in the Dlx5/6+/- mouse model of fast-spiking CIN dysfunction.Significance Statement Uncovering the contribution of cortical interneuron (CIN) dysfunction to neuropsychiatric conditions is pivotal to generating therapies for these debilitating disorders. To this end, it is important to study the development, physiology and function of CINs in model organisms. While transgenic driver lines are powerful tools to study CINs in mice, this technology is limited in other species. As an alternative, gene regulatory enhancer elements (REs) can be used in viral vectors to drive expression in multiple species including primates. The present study describes the genome-wide identification of REs preferentially active in CINs and the use of these RE AAVs for CIN-specific targeting in adult mice. The methodology and novel REs described here provide new tools for studying and targeting CINs.

4.
Front Mol Neurosci ; 13: 573409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33071758

RESUMO

The TSC1 and TSC2 genes are connected to multiple syndromes from Tuberous Sclerosis Complex (TSC) to autism spectrum disorder (ASD), with uncertainty if genetic variants cause all or subsets of phenotypes based on the location and type of change. For TSC1, few have addressed if non-TSC associated genetic variants have direct contributions to changes in neurological genotype-to-phenotype impacts, including elevated rates of ASD and seizures. Dominant variants cause TSC, yet TSC1 has many heritable variants not dominant for TSC that are poorly understood in neurological function, with some associated with ASD. Herein, we examined how missense variants in TSC1, R336W, T360N, T393I, S403L, and H732Y, impacted the development of cortical inhibitory interneurons, cell-types whose molecular, cellular, and physiological properties are altered after the loss of mouse TSC1. We found these variants complemented a known phenotype caused by loss of TSC1, increased cell size. However, distinct variants, particularly S403L showed deficits in complementing an increase in parvalbumin levels and exhibited smaller amplitude after hyperpolarizations. Overall, these data show that subtle phenotypes can be induced by some TSC1 missense variants and provide an in vivo system to assess TSC1 variants' neurological impact better.

5.
Proc Natl Acad Sci U S A ; 117(45): 28384-28392, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33122441

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The main proliferating component of KS tumors is a cell of endothelial origin termed the spindle cell. Spindle cells are predominantly latently infected with only a small percentage of cells undergoing viral replication. As there is no direct treatment for latent KSHV, identification of host vulnerabilities in latently infected endothelial cells could be exploited to inhibit KSHV-associated tumor cells. Using a pooled CRISPR-Cas9 lentivirus library, we identified host factors that are essential for the survival or proliferation of latently infected endothelial cells in culture, but not their uninfected counterparts. Among the many host genes identified, there was an enrichment in genes localizing to the mitochondria, including genes involved in mitochondrial translation. Antibiotics that inhibit bacterial and mitochondrial translation specifically inhibited the expansion of latently infected endothelial cells and led to increased cell death in patient-derived PEL cell lines. Direct inhibition of mitochondrial respiration or ablation of mitochondrial genomes leads to increased death in latently infected cells. KSHV latent infection decreases mitochondrial numbers, but there are increases in mitochondrial size, genome copy number, and transcript levels. We found that multiple gene products of the latent locus localize to the mitochondria. During latent infection, KSHV significantly alters mitochondrial biology, leading to enhanced sensitivity to inhibition of mitochondrial respiration, which provides a potential therapeutic avenue for KSHV-associated cancers.

6.
PLoS Pathog ; 16(6): e1008634, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32555637

RESUMO

Kaposi's Sarcoma Herpesvirus (KSHV) is present in the main tumor cells of Kaposi's Sarcoma (KS), the spindle cells, which are of endothelial origin. KSHV is also associated with two B-cell lymphomas, Primary Effusion Lymphoma (PEL) and Multicentric Castleman's Disease. In KS and PEL, KSHV is primarily latent in the infected cells, expressing only a few genes. Although KSHV infection is required for KS and PEL, it is unclear how latent gene expression contributes to their formation. Proliferation of cancer cells occurs despite multiple checkpoints intended to prevent dysregulated cell growth. The first of these checkpoints, caused by shortening of telomeres, results in replicative senescence, where cells are metabolically active, but no longer divide. We found that human dermal lymphatic endothelial cells (LECs) are more susceptible to KSHV infection than their blood-specific endothelial cell counterparts and maintain KSHV latency to higher levels during passage. Importantly, KSHV infection of human LECs but not human BECs promotes their continued proliferation beyond this first checkpoint of replicative senescence. The latently expressed viral cyclin homolog is essential for KSHV-induced bypass of senescence in LECs. These data suggest that LECs may be an important reservoir for KSHV infection and may play a role during KS tumor development and that the viral cyclin is a critical oncogene for this process.


Assuntos
Senescência Celular , Ciclinas/metabolismo , Células Endoteliais/metabolismo , Infecções por Herpesviridae/metabolismo , Herpesvirus Humano 8/metabolismo , Proteínas Virais/metabolismo , Ciclinas/genética , Células Endoteliais/patologia , Células Endoteliais/virologia , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/patologia , Herpesvirus Humano 8/genética , Humanos , Proteínas Virais/genética
7.
Development ; 147(14)2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32586977

RESUMO

Cortical interneurons (CINs) originate in the ganglionic eminences (GEs) and migrate tangentially to the cortex guided by different attractive and repulsive cues. Once inside the cortex, the cellular and molecular mechanisms determining the migration of CINs along the rostrocaudal axis are less well understood. Here, we investigated the cortical distribution of CINs originating in the medial and caudal GEs at different time points. Using molecular and genetic labeling, we showed that, in the mouse, early- and late-born CINs (E12 versus E15) are differentially distributed along the rostrocaudal axis. Specifically, late-born CINs are preferentially enriched in cortical areas closer to their respective sites of origin in the medial or caudal GE. Surprisingly, our in vitro experiments failed to show a preferential migration pattern along the rostrocaudal axis for medial- or caudal-born CINs. Moreover, in utero transplantation experiments suggested that the rostrocaudal dispersion of CINs depends on the developmental stage of the host brain and is limited by the migration time and the increasing size of the developing brain. These data suggest that the embryonic expansion of the cortex contributes to the rostrocaudal distribution of CINs.

8.
Elife ; 92020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32452758

RESUMO

​Maf (c-Maf) and Mafb transcription factors (TFs) have compensatory roles in repressing somatostatin (SST+) interneuron (IN) production in medial ganglionic eminence (MGE) secondary progenitors in mice. Maf and Mafb conditional deletion (cDKO) decreases the survival of MGE-derived cortical interneurons (CINs) and changes their physiological properties. Herein, we show that (1) Mef2c and Snap25 are positively regulated by Maf and Mafb to drive IN morphological maturation; (2) Maf and Mafb promote Mef2c expression which specifies parvalbumin (PV+) INs; (3) Elmo1, Igfbp4 and Mef2c are candidate markers of immature PV+ hippocampal INs (HIN). Furthermore, Maf/Mafb neonatal cDKOs have decreased CINs and increased HINs, that express Pnoc, an HIN specific marker. Our findings not only elucidate key gene targets of Maf and Mafb that control IN development, but also identify for the first time TFs that differentially regulate CIN vs. HIN production.

9.
Proc Natl Acad Sci U S A ; 117(11): 6189-6195, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123116

RESUMO

Neurofibromatosis 1 (NF1) is caused by mutations in the NF1 gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouse Nf1 from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Nf1 loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss of Nf1, without changes in somatostatin (SST)-positive CINs. We discovered that loss of Nf1 results in a dose-dependent decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone.


Assuntos
Córtex Cerebral/patologia , Neurônios GABAérgicos/patologia , Interneurônios/patologia , Proteínas com Homeodomínio LIM/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurofibromatose 1/patologia , Neurofibromina 1/genética , Fatores de Transcrição/metabolismo , Aminoacetonitrila/administração & dosagem , Aminoacetonitrila/análogos & derivados , Animais , Células Cultivadas , Córtex Cerebral/citologia , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Neurônios GABAérgicos/metabolismo , Humanos , Interneurônios/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Eminência Mediana/citologia , Camundongos , Camundongos Knockout , Neurofibromatose 1/genética , Neurofibromina 1/metabolismo , Neuroglia/citologia , Parvalbuminas/metabolismo , Cultura Primária de Células , Somatostatina/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo
10.
Curr Biol ; 30(4): R157-R158, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32097639

RESUMO

Tessler et al. demonstrate that a 'soft' robot causes less stress to a jellyfish while handling compared to a traditional 'hard' robot.

11.
J Neurosci ; 40(11): 2215-2227, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-31988060

RESUMO

Manipulations that enhance GABAergic inhibition have been associated with improved behavioral phenotypes in autism models, suggesting that autism may be treated by correcting underlying deficits of inhibition. Interneuron transplantation is a method for increasing recipient synaptic inhibition, and it has been considered a prospective therapy for conditions marked by deficient inhibition, including neuropsychiatric disorders. It is unknown, however, whether interneuron transplantation may be therapeutically effective only for conditions marked by reduced inhibition, and it is also unclear whether transplantation improves behavioral phenotypes solely by normalizing underlying circuit defects. To address these questions, we studied the effects of interneuron transplantation in male and female mice lacking the autism-associated gene, Pten, in GABAergic interneurons. Pten mutant mice exhibit social behavior deficits, elevated synaptic inhibition in prefrontal cortex, abnormal baseline and social interaction-evoked electroencephalogram (EEG) signals, and an altered composition of cortical interneuron subtypes. Transplantation of wild-type embryonic interneurons from the medial ganglionic eminence into the prefrontal cortex of neonatal Pten mutants rescued social behavior despite exacerbating excessive levels of synaptic inhibition. Furthermore, transplantation did not normalize recipient EEG signals measured during baseline states. Interneuron transplantation can thus correct behavioral deficits even when those deficits are associated with elevated synaptic inhibition. Moreover, transplantation does not exert therapeutic effects solely by restoring wild-type circuit states. Our findings indicate that interneuron transplantation could offer a novel cell-based approach to autism treatment while challenging assumptions that effective therapies must reverse underlying circuit defects.SIGNIFICANCE STATEMENT Imbalances between neural excitation and inhibition are hypothesized to contribute to the pathophysiology of autism. Interneuron transplantation is a method for altering recipient inhibition, and it has been considered a prospective therapy for neuropsychiatric disorders, including autism. Here we examined the behavioral and physiological effects of interneuron transplantation in a mouse genetic model of autism. They demonstrate that transplantation rescues recipient social interaction deficits without correcting a common measure of recipient inhibition, or circuit-level physiological measures. These findings demonstrate that interneuron transplantation can exert therapeutic behavioral effects without necessarily restoring wild-type circuit states, while highlighting the potential of interneuron transplantation as an autism therapy.


Assuntos
Transtorno Autístico/cirurgia , Transplante de Tecido Encefálico , Transplante de Tecido Fetal , Neurônios GABAérgicos/fisiologia , Interneurônios/transplante , Inibição Neural/fisiologia , PTEN Fosfo-Hidrolase/deficiência , Comportamento Social , Animais , Transtorno Autístico/fisiopatologia , Transtorno Autístico/psicologia , Modelos Animais de Doenças , Eletroencefalografia , Comportamento Exploratório , Feminino , Masculino , Aprendizagem em Labirinto , Eminência Mediana/citologia , Eminência Mediana/embriologia , Camundongos , Camundongos Knockout , PTEN Fosfo-Hidrolase/fisiologia , Técnicas de Patch-Clamp , Fenótipo , Córtex Pré-Frontal/fisiopatologia , Distribuição Aleatória , Sinapses/fisiologia
12.
Virology ; 540: 150-159, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31928996

RESUMO

During DNA virus infections, detection of cytosolic DNA by the cGAS-STING pathway leads to activation of IFN-ß. Kaposi's Sarcoma Herpesvirus (KSHV), an oncogenic DNA virus, is the etiological agent of Kaposi's Sarcoma, an endothelial cell (EC)-based tumor. To investigate the role of STING during KSHV infection of primary ECs we identified a primary lymphatic EC sample that is defective for STING activation and we also knocked out STING in blood ECs. Ablation of STING in EC does not increase susceptibility to KSHV latent infection nor does it increase KSHV spread after lytic reactivation indicating STING signaling does not restrict KSHV. In contrast, STING ablation increases Adenovirus spread at low MOI, but STING is dispensable for blocking replication. These experiments reveal that the importance of STING depends on the DNA virus and that STING appears more important for restricting spread to bystander cells than for inhibition of viral replication.


Assuntos
Células Endoteliais/virologia , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/virologia , Herpesvirus Humano 8/fisiologia , Proteínas de Membrana/metabolismo , DNA Viral , Suscetibilidade a Doenças , Humanos , Imunidade Inata , Nucleotidiltransferases/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais , Replicação Viral
13.
Soft Robot ; 7(4): 451-461, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31923364

RESUMO

Dielectric elastomer actuators exhibit an unusual combination of large displacements, moderate bandwidth, low power consumption, and mechanical impedance comparable with human skin, making them attractive for haptic devices. In this article, we propose a wearable haptic communication device based on a two-by-two array of dielectric elastomer linear actuators. We briefly describe the architecture of the actuators and their mechanical and electrical integration into a wearable armband. We then characterize the actuators' force, displacement, and thermal properties in a bench-top configuration. We also report on the power and drive circuit design. Finally, we perform a set of preliminary perception evaluations on participants using our haptic device, including detection threshold tests and identification tests for locations and directions on the forearm. Human testing with individual actuators demonstrates that the broadband actuation can be easily perceived on the forearm, providing the basis for both the development of a wearable actuator array and its use in more extensive perception evaluation as described herein.

14.
Biotechniques ; 68(2): 72-78, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31849245

RESUMO

The Oxford Nanopore Technologies MinION™ sequencer holds the capability to generate long amplicon reads; however, only a small amount of information is available regarding methodological approaches and the ability to identify a broad diversity of fungal taxa. To assess capabilities, three fungal mock communities were sequenced, each of which had varying ratios of 16 taxa. The data were processed through our selected pipeline. The MinION recovered all mock community members, when mixed at equal ratios. When a taxon was represented at a lower ratio, it was not recovered or decreased in relative abundance. Despite high error rates, highly accurate consensus sequences can be derived. This methodological approach identified all mock community taxa, demonstrating the MinION can be used as a practical alternative to profile fungal communities.

15.
Dev Neurosci ; 42(5-6): 195-207, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33657557

RESUMO

Autism spectrum disorder (ASD) manifests early in childhood. While genetic variants increase risk for ASD, a growing body of literature has established that in utero chemical exposures also contribute to ASD risk. These chemicals include air-based pollutants like diesel particulate matter (DPM). A combination of single-cell and direct transcriptomics of DPM-exposed human-induced pluripotent stem cell-derived cerebral organoids revealed toxicogenomic effects of DPM exposure during fetal brain development. Direct transcriptomics, sequencing RNA bases via Nanopore, revealed that cerebral organoids contain extensive RNA modifications, with DPM-altering cytosine methylation in oxidative mitochondrial transcripts expressed in outer radial glia cells. Single-cell transcriptomics further confirmed an oxidative phosphorylation change in cell groups such as outer radial glia upon DPM exposure. This approach highlights how DPM exposure perturbs normal mitochondrial function and cellular respiration during early brain development, which may contribute to developmental disorders like ASD by altering neurodevelopment.

16.
Nat Commun ; 10(1): 4994, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676823

RESUMO

Medial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties. However, mechanisms regulating their diversity remain poorly understood. Here, we show that conditional loss of the Tuberous Sclerosis Complex (TSC) gene, Tsc1, which inhibits the mammalian target of rapamycin (MTOR), causes a subset of SST+ CINs, to express PV and adopt fast-spiking (FS) properties, characteristic of PV+ CINs. Milder intermediate phenotypes also occur when only one allele of Tsc1 is deleted. Notably, treatment of adult mice with rapamycin, which inhibits MTOR, reverses the phenotypes. These data reveal novel functions of MTOR signaling in regulating PV expression and FS properties, which may contribute to TSC neuropsychiatric symptoms. Moreover, they suggest that CINs can exhibit properties intermediate between those classically associated with PV+ or SST+ CINs, which may be dynamically regulated by the MTOR signaling.


Assuntos
Córtex Cerebral/fisiologia , Interneurônios/fisiologia , Parvalbuminas/metabolismo , Somatostatina/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Potenciais de Ação/fisiologia , Animais , Córtex Cerebral/citologia , Feminino , Interneurônios/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Parvalbuminas/genética , Técnicas de Patch-Clamp , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Somatostatina/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética
17.
Adv Funct Mater ; 29(7)2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-31372108

RESUMO

Fluidic soft sensors have been widely used in wearable devices for human motion capturing. However, thus far, the biocompatibility of the conductive liquid, the linearity of the sensing signal, and the hysteresis between the loading and release processes have limited the sensing quality as well as the applications of these sensors. In this paper, silicone based strain and force sensors composed of a novel biocompatible conductive liquid (potassium iodide and glycerol solution) are introduced. The strain sensors exhibit negligible hysteresis up to 5 Hz, with a gauge factor of 2.2 at 1 Hz. The force sensors feature a novel multi-functional layered structure, with micro-cylinder-filled channels to achieve high linearity, low hysteresis (5.3% hysteresis at 1 Hz), and good sensitivity (100% resistance increase at a 5 N load). The sensors' gauge factors are stable at various temperatures and humidity levels. These bio-compatible, low hysteresis, and high linearity sensors are promising for safe and reliable diagnostic devices, wearable motion capture, and compliant human-computer interfaces.

18.
Mol Autism ; 10: 17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31007884

RESUMO

Background: Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported. Methods: Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer types obtained by differential expression meta-analysis and report gene, pathway, and drug set-based overlaps between them. Results: Four cancer types (brain, thyroid, kidney, and pancreatic cancers) presented a significant overlap in gene expression deregulations in the same direction as ASD whereas two cancer types (lung and prostate cancers) showed differential expression profiles significantly deregulated in the opposite direction from ASD. Functional enrichment and LINCS L1000 based drug set enrichment analyses revealed the implication of several biological processes and pathways that were affected jointly in both diseases, including impairments of the immune system, and impairments in oxidative phosphorylation and ATP synthesis among others. Our data also suggest that brain and kidney cancer have patterns of transcriptomic dysregulation in the PI3K/AKT/MTOR axis that are similar to those found in ASD. Conclusions: Comparisons of ASD and cancer differential gene expression meta-analysis results suggest that brain, kidney, thyroid, and pancreatic cancers are candidates for direct comorbid associations with ASD. On the other hand, lung and prostate cancers are candidates for inverse comorbid associations with ASD. Joint perturbations in a set of specific biological processes underlie these associations which include several pathways previously implicated in both cancer and ASD encompassing immune system alterations, impairments of energy metabolism, cell cycle, and signaling through PI3K and G protein-coupled receptors among others. These findings could help to explain epidemiological observations pointing towards direct and inverse comorbid associations between ASD and specific cancer types and depict a complex scenario regarding the molecular patterns of association between ASD and cancer.


Assuntos
Transtorno Autístico/genética , Encéfalo/metabolismo , Neoplasias/genética , Transcriptoma , Transtorno Autístico/epidemiologia , Humanos , Neoplasias/epidemiologia , Transdução de Sinais/genética
19.
Cell Rep ; 26(5): 1157-1173.e5, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30699346

RESUMO

Mafb and c-Maf transcription factor (TF) expression is enriched in medial ganglionic eminence (MGE) lineages, beginning in late-secondary progenitors and continuing into mature parvalbumin (PV+) and somatostatin (SST+) interneurons. However, the functions of Maf TFs in MGE development remain to be elucidated. Herein, Mafb and c-Maf were conditionally deleted, alone and together, in the MGE and its lineages. Analyses of Maf mutant mice revealed redundant functions of Mafb and c-Maf in secondary MGE progenitors, where they repress the generation of SST+ cortical and hippocampal interneurons. By contrast, Mafb and c-Maf have distinct roles in postnatal cortical interneuron (CIN) morphological maturation, synaptogenesis, and cortical circuit integration. Thus, Mafb and c-Maf have redundant and opposing functions at different steps in CIN development.


Assuntos
Linhagem da Célula , Córtex Cerebral/metabolismo , Interneurônios/metabolismo , Fator de Transcrição MafB/metabolismo , Proteínas Proto-Oncogênicas c-maf/metabolismo , Potenciais de Ação , Animais , Animais Recém-Nascidos , Apoptose , Membrana Celular/metabolismo , Movimento Celular , Proliferação de Células , Hipocampo/metabolismo , Eminência Mediana/metabolismo , Camundongos Knockout , Neuritos/metabolismo , Neurogênese , Parvalbuminas/metabolismo , Somatostatina/metabolismo , Sinapses/metabolismo
20.
Sci Robot ; 4(33)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-33137785

RESUMO

Here, we present ultragentle soft robotic actuators capable of grasping delicate specimens of gelatinous marine life. Although state-of-the-art soft robotic manipulators have demonstrated gentle gripping of brittle animals (e.g., corals) and echinoderms (e.g., sea cucumbers) in the deep sea, they are unable to nondestructively grasp more fragile soft-bodied organisms, such as jellyfish. Through an exploration of design parameters and laboratory testing of individual actuators, we confirmed that our nanofiber-reinforced soft actuators apply sufficiently low contact pressure to ensure minimal harm to typical jellyfish species. We then built a gripping device using several actuators and evaluated its underwater grasping performance in the laboratory. By assessing the gripper's region of acquisition and robustness to external forces, we gained insight into the necessary precision and speed with which grasping maneuvers must be performed to achieve successful collection of samples. Last, we demonstrated successful manipulation of three live jellyfish species in an aquarium setting using a hand-held prototype gripper. Overall, our ultragentle gripper demonstrates an improvement in gentle sample collection compared with existing deep-sea sampling devices. Extensions of this technology may improve a variety of in situ characterization techniques used to study the ecological and genetic features of deep-sea organisms.

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