RESUMO
Brown and beige adipocytes are specialized cells that express uncoupling protein 1 (UCP1) and dissipate chemical energy as heat. These cells likely possess alternative UCP1-independent thermogenic mechanisms. Here, we identify a secreted enzyme, peptidase M20 domain containing 1 (PM20D1), that is enriched in UCP1(+) versus UCP1(-) adipocytes. We demonstrate that PM20D1 is a bidirectional enzyme in vitro, catalyzing both the condensation of fatty acids and amino acids to generate N-acyl amino acids and also the reverse hydrolytic reaction. N-acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. Mice with increased circulating PM20D1 have augmented respiration and increased N-acyl amino acids in blood. Lastly, administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure. These data identify an enzymatic node and a family of metabolites that regulate energy homeostasis. This pathway might be useful for treating obesity and associated disorders.
Assuntos
Adipócitos/metabolismo , Amidoidrolases/metabolismo , Mitocôndrias/metabolismo , Termogênese , Aminoácidos/sangue , Animais , Respiração Celular , Metabolismo Energético , Ácidos Graxos/sangue , Glucose/metabolismo , Homeostase , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/metabolismoRESUMO
Digital pathology poses unique computational challenges, as a standard gigapixel slide may comprise tens of thousands of image tiles1-3. Prior models have often resorted to subsampling a small portion of tiles for each slide, thus missing the important slide-level context4. Here we present Prov-GigaPath, a whole-slide pathology foundation model pretrained on 1.3 billion 256 × 256 pathology image tiles in 171,189 whole slides from Providence, a large US health network comprising 28 cancer centres. The slides originated from more than 30,000 patients covering 31 major tissue types. To pretrain Prov-GigaPath, we propose GigaPath, a novel vision transformer architecture for pretraining gigapixel pathology slides. To scale GigaPath for slide-level learning with tens of thousands of image tiles, GigaPath adapts the newly developed LongNet5 method to digital pathology. To evaluate Prov-GigaPath, we construct a digital pathology benchmark comprising 9 cancer subtyping tasks and 17 pathomics tasks, using both Providence and TCGA data6. With large-scale pretraining and ultra-large-context modelling, Prov-GigaPath attains state-of-the-art performance on 25 out of 26 tasks, with significant improvement over the second-best method on 18 tasks. We further demonstrate the potential of Prov-GigaPath on vision-language pretraining for pathology7,8 by incorporating the pathology reports. In sum, Prov-GigaPath is an open-weight foundation model that achieves state-of-the-art performance on various digital pathology tasks, demonstrating the importance of real-world data and whole-slide modelling.
Assuntos
Conjuntos de Dados como Assunto , Processamento de Imagem Assistida por Computador , Aprendizado de Máquina , Patologia Clínica , Humanos , Benchmarking , Processamento de Imagem Assistida por Computador/métodos , Neoplasias/classificação , Neoplasias/diagnóstico , Neoplasias/patologia , Patologia Clínica/métodos , Masculino , FemininoRESUMO
Brown fat can reduce obesity through the dissipation of calories as heat. Control of thermogenic gene expression occurs via the induction of various coactivators, most notably PGC-1α. In contrast, the transcription factor partner(s) of these cofactors are poorly described. Here, we identify interferon regulatory factor 4 (IRF4) as a dominant transcriptional effector of thermogenesis. IRF4 is induced by cold and cAMP in adipocytes and is sufficient to promote increased thermogenic gene expression, energy expenditure, and cold tolerance. Conversely, knockout of IRF4 in UCP1(+) cells causes reduced thermogenic gene expression and energy expenditure, obesity, and cold intolerance. IRF4 also induces the expression of PGC-1α and PRDM16 and interacts with PGC-1α, driving Ucp1 expression. Finally, cold, ß-agonists, or forced expression of PGC-1α are unable to cause thermogenic gene expression in the absence of IRF4. These studies establish IRF4 as a transcriptional driver of a program of thermogenic gene expression and energy expenditure.
Assuntos
Tecido Adiposo Marrom/metabolismo , Fatores Reguladores de Interferon/metabolismo , Termogênese , Fatores de Transcrição/metabolismo , Ativação Transcricional , Adipócitos/metabolismo , Tecido Adiposo Marrom/citologia , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Temperatura Baixa , AMP Cíclico/metabolismo , Metabolismo Energético , Humanos , Canais Iônicos/genética , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Magreza/metabolismo , Ativação Transcricional/efeitos dos fármacos , Proteína Desacopladora 1RESUMO
Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-α (PGC1-α4) as a discovery tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure and improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines. Metrnl stimulates an eosinophil-dependent increase in IL-4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Importantly, blocking Metrnl actions in vivo significantly attenuates chronic cold-exposure-induced alternative macrophage activation and thermogenic gene responses. Thus, Metrnl links host-adaptive responses to the regulation of energy homeostasis and tissue inflammation and has therapeutic potential for metabolic and inflammatory diseases.
Assuntos
Tecido Adiposo Marrom/metabolismo , Fatores de Crescimento Neural/metabolismo , Animais , Glucose/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Fatores de Crescimento Neural/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Termogênese , Fatores de Transcrição/genéticaRESUMO
PGC-1α is a transcriptional coactivator induced by exercise that gives muscle many of the best known adaptations to endurance-type exercise but has no effects on muscle strength or hypertrophy. We have identified a form of PGC-1α (PGC-1α4) that results from alternative promoter usage and splicing of the primary transcript. PGC-1α4 is highly expressed in exercised muscle but does not regulate most known PGC-1α targets such as the mitochondrial OXPHOS genes. Rather, it specifically induces IGF1 and represses myostatin, and expression of PGC-1α4 in vitro and in vivo induces robust skeletal muscle hypertrophy. Importantly, mice with skeletal muscle-specific transgenic expression of PGC-1α4 show increased muscle mass and strength and dramatic resistance to the muscle wasting of cancer cachexia. Expression of PGC-1α4 is preferentially induced in mouse and human muscle during resistance exercise. These studies identify a PGC-1α protein that regulates and coordinates factors involved in skeletal muscle hypertrophy.
Assuntos
Proteínas de Choque Térmico/metabolismo , Músculo Esquelético/metabolismo , Condicionamento Físico Animal , Treinamento Resistido , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Adiposidade , Animais , Glucose/metabolismo , Humanos , Hipertrofia , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Fibras Musculares Esqueléticas/metabolismo , Miostatina/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Isoformas de Proteínas/metabolismoRESUMO
We introduce dynamic predictive coding, a hierarchical model of spatiotemporal prediction and sequence learning in the neocortex. The model assumes that higher cortical levels modulate the temporal dynamics of lower levels, correcting their predictions of dynamics using prediction errors. As a result, lower levels form representations that encode sequences at shorter timescales (e.g., a single step) while higher levels form representations that encode sequences at longer timescales (e.g., an entire sequence). We tested this model using a two-level neural network, where the top-down modulation creates low-dimensional combinations of a set of learned temporal dynamics to explain input sequences. When trained on natural videos, the lower-level model neurons developed space-time receptive fields similar to those of simple cells in the primary visual cortex while the higher-level responses spanned longer timescales, mimicking temporal response hierarchies in the cortex. Additionally, the network's hierarchical sequence representation exhibited both predictive and postdictive effects resembling those observed in visual motion processing in humans (e.g., in the flash-lag illusion). When coupled with an associative memory emulating the role of the hippocampus, the model allowed episodic memories to be stored and retrieved, supporting cue-triggered recall of an input sequence similar to activity recall in the visual cortex. When extended to three hierarchical levels, the model learned progressively more abstract temporal representations along the hierarchy. Taken together, our results suggest that cortical processing and learning of sequences can be interpreted as dynamic predictive coding based on a hierarchical spatiotemporal generative model of the visual world.
Assuntos
Aprendizagem , Neocórtex , Humanos , Aprendizagem/fisiologia , Percepção Visual/fisiologia , Neocórtex/fisiologia , Redes Neurais de Computação , Rememoração MentalRESUMO
PRDM16 is a transcription co-factor that plays critical roles in development of brown adipose tissue, as well as maintenance of adult hematopoietic and neural stem cells. Here we report that PRDM16 is a histone H3K4 methyltransferase on chromatin. Mutation in the N-terminal PR domain of PRDM16 abolishes the intrinsic enzymatic activity of PRDM16. We show that the methyltransferase activity of PRDM16 is required for specific suppression of MLL fusion protein-induced leukemogenesis both in vitro and in vivo. Mechanistic studies show that PRDM16 directly activates the SNAG family transcription factor Gfi1b, which in turn downregulates the HOXA gene cluster. Knockdown Gfi1b represses PRDM16-mediated tumor suppression, while Gfi1b overexpression mimics PRDM16 overexpression. In further support of the tumor suppressor function of PRDM16, silencing PRDM16 by DNA methylation is concomitant with MLL-AF9-induced leukemic transformation. Taken together, our study reveals a previously uncharacterized function of PRDM16 that depends on its PR domain activity.
RESUMO
There is growing interest in predictive coding as a model of how the brain learns through predictions and prediction errors. Predictive coding models have traditionally focused on sensory coding and perception. Here we introduce active predictive coding (APC) as a unifying model for perception, action, and cognition. The APC model addresses important open problems in cognitive science and AI, including (1) how we learn compositional representations (e.g., part-whole hierarchies for equivariant vision) and (2) how we solve large-scale planning problems, which are hard for traditional reinforcement learning, by composing complex state dynamics and abstract actions from simpler dynamics and primitive actions. By using hypernetworks, self-supervised learning, and reinforcement learning, APC learns hierarchical world models by combining task-invariant state transition networks and task-dependent policy networks at multiple abstraction levels. We illustrate the applicability of the APC model to active visual perception and hierarchical planning. Our results represent, to our knowledge, the first proof-of-concept demonstration of a unified approach to addressing the part-whole learning problem in vision, the nested reference frames learning problem in cognition, and the integrated state-action hierarchy learning problem in reinforcement learning.
Assuntos
Cognição , Aprendizado Profundo , Encéfalo , Reforço Psicológico , PercepçãoRESUMO
The evolutionary conserved Foxo transcription factors are important regulators of quiescence and longevity. Although, Foxo1 is known to be important in regulating CD8(+) T cell trafficking and homeostasis, its role in functional differentiation of antigen-stimulated CD8(+) T cells is unclear. Herein, we demonstrate that inactivation of Foxo1 was essential for instructing T-bet transcription factor-mediated effector differentiation of CD8(+) T cells. The Foxo1 inactivation was dependent on mTORC1 kinase, given that blockade of mTORC1 abrogated mTORC2-mediated Akt (Ser473) kinase phosphorylation, resulting in Foxo1-dependent switch from T-bet to Eomesodermin transcription factor activation and increase in memory precursors. Silencing Foxo1 ablated interleukin-12- and rapamycin-enhanced CD8(+) T cell memory responses and restored T-bet-mediated effector functions. These results demonstrate an essential role of Foxo1 in actively repressing effector or terminal differentiation processes to promote memory CD8(+) T cell development and identify the functionally diverse mechanisms utilized by Foxo1 to promote quiescence and longevity.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Fatores de Transcrição Forkhead/imunologia , Memória Imunológica , Proteínas com Domínio T/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/antagonistas & inibidores , Fatores de Transcrição Forkhead/genética , Interleucina-12/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Complexos Multiproteicos , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR , Transativadores/metabolismo , Fatores de TranscriçãoRESUMO
Left hepatic vein draining into coronary sinus is a rare systemic vascular anomaly. Its presence is significant when it is associated with other cardiac lesions requiring surgery. We report technical challenges in a case of persistent left superior vena cava and left hepatic vein draining into coronary sinus in an adult with ostium secundum atrial septal defect, which was repaired through minimally invasive approach. The main technical challenge in this case was to achieve adequate venous drainage, which was achieved by vacuum assistance and by manipulating the position of femoral venous cannula. We approached through a right anterolateral thoracotomy and adequate venous drainage was achieved without cannulating left hepatic vein or left superior vena cava.
Assuntos
Seio Coronário , Comunicação Interatrial , Malformações Vasculares , Adulto , Seio Coronário/diagnóstico por imagem , Seio Coronário/cirurgia , Comunicação Interatrial/complicações , Comunicação Interatrial/diagnóstico por imagem , Comunicação Interatrial/cirurgia , Veias Hepáticas/diagnóstico por imagem , Veias Hepáticas/cirurgia , Humanos , Veia Cava Superior/diagnóstico por imagem , Veia Cava Superior/cirurgiaRESUMO
Primary Central Nervous System Lymphoma (PCNSL) is a lymphoid malignancy of the brain that occurs in ~1500 patients per year in the US. PCNSL can spread to the vitreous and retina, where it is known as vitreoretinal lymphoma (VRL). While confirmatory testing for diagnosis is dependent on invasive brain tissue or cerebrospinal fluid sampling, the ability to access the vitreous as a proximal biofluid for liquid biopsy to diagnose PCNSL is an attractive prospect given ease of access and minimization of risks and complications from other biopsy strategies. However, the extent to which VRL, previously considered genetically identical to PCNSL, resembles PCNSL in the same individual with respect to genetic alterations, diagnostic strategies, and precision-medicine based approaches has hitherto not been explored. Furthermore, the degree of intra-patient tumor genomic heterogeneity between the brain and vitreous sites has not been studied. In this work, we report on targeted DNA next-generation sequencing (NGS) of matched brain and vitreous samples in two patients who each harbored VRL and PCSNL. Our strategy showed enhanced sensitivity for molecular diagnosis confirmation over current clinically used vitreous liquid biopsy methods. We observed a clonal relationship between the eye and brain samples in both patients, which carried clonal CDKN2A deep deletions, a highly recurrent alteration in VRL patients, as well as MYD88 p.L265P activating mutation in one patient. Several subclonal alterations, however, in the genes SETD2, BRCA2, TERT, and broad chromosomal regions showed heterogeneity between the brain and the eyes, between the two eyes, and among different regions of the PCNSL brain lesion. Taken together, our data show that NGS of vitreous liquid biopsies in PCNSL patients with VRL highlights shared and distinct genetic alterations that suggest a common origin for these lymphomas, but with additional site-specific alterations. Liquid biopsy of VRL accurately replicates the findings for PCNSL truncal (tumor-initiating) genomic alterations; it can also nominate precision medicine interventions and shows intra-patient heterogeneity in subclonal alterations. To the best of our knowledge, this study represents the first interrogation of genetic underpinnings of PCNSL with matched VRL samples. Our findings support continued investigation into the utility of vitreous liquid biopsy in precision diagnosis and treatment of PCNSL/VRL.
Assuntos
Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias da Retina/metabolismo , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias Oculares/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Linfoma não Hodgkin/metabolismo , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Neoplasias da Retina/tratamento farmacológico , Rituximab/uso terapêutico , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/metabolismoRESUMO
Vitreoretinal lymphoma (VRL) is an uncommon eye malignancy, and VRLs of T cell origin are rare. They are difficult to treat, and their molecular underpinnings, including actionable genomic alterations, remain to be elucidated. At present, vitreous fluid liquid biopsies represent a valuable VRL sample for molecular analysis to study VRLs. In this study, we report the molecular diagnostic workup of a rare case of bilateral T cell VRL and characterize its genomic landscape, including identification of potentially targetable alterations. Using next-generation sequencing of vitreous-derived DNA with a pan-cancer 126-gene panel, we found a copy number gain of BRAF and copy number loss of tumor suppressor DNMT3A. To the best of our knowledge, this represents the first exploration of the T cell VRL cancer genome and supports vitreous liquid biopsy as a suitable approach for precision oncology treatments.
Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Linfoma de Células T/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Retina/genética , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA/genética , DNA Metiltransferase 3A , Regulação Neoplásica da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Neoplasias da Retina/patologia , Corpo Vítreo/metabolismo , Corpo Vítreo/patologiaRESUMO
Although squamous cell carcinomas (SCC) are the most frequent human solid tumor at many anatomic sites, the driving molecular alterations underlying their progression from precursor lesions are poorly understood, especially in the context of photodamage. Therefore, we used high-depth, targeted next-generation sequencing (NGS) of RNA and DNA from routine tissue samples to characterize the progression of both well- (cutaneous) and poorly (ocular) studied SCCs. We assessed 56 formalin-fixed paraffin-embedded (FFPE) cutaneous lesions (n = 8 actinic keratosis, n = 30 carcinoma in situ [CIS], n = 18 invasive) and 43 FFPE ocular surface lesions (n = 2 conjunctival/corneal intraepithelial neoplasia, n = 20 CIS, n = 21 invasive), from institutions in the US and Brazil. An additional seven cases of advanced cutaneous SCC were profiled by hybrid capture-based NGS of >1500 genes. The cutaneous and ocular squamous neoplasms displayed a predominance of UV-signature mutations. Precursor lesions had highly similar somatic genomic landscapes to SCCs, including chromosomal gains of 3q involving SOX2, and highly recurrent mutations and/or loss of heterozygosity events affecting tumor suppressors TP53 and CDKN2A. Additionally, we identify a novel molecular subclass of CIS with RB1 mutations. Among TP53 wild-type tumors, human papillomavirus transcript was detected in one matched pair of cutaneous CIS and SCC. Amplicon-based whole-transcriptome sequencing of select 20 cutaneous lesions demonstrated significant upregulation of pro-invasion genes in cutaneous SCCs relative to precursors, including MMP1, MMP3, MMP9, LAMC2, LGALS1, and TNFRSF12A. Together, ocular and cutaneous squamous neoplasms demonstrate similar alterations, supporting a common model for neoplasia in UV-exposed epithelia. Treatment modalities useful for cutaneous SCC may also be effective in ocular SCC given the genetic similarity between these tumor types. Importantly, in both systems, precursor lesions possess the full complement of major genetic changes seen in SCC, supporting non-genetic drivers of invasiveness.
Assuntos
Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias da Túnica Conjuntiva/patologia , Neoplasias Oculares/patologia , Mutação , Neoplasias Cutâneas/patologia , Pele/patologia , Idoso , Carcinoma in Situ/genética , Carcinoma de Células Escamosas/genética , Neoplasias da Túnica Conjuntiva/genética , Neoplasias Oculares/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ceratose Actínica/genética , Ceratose Actínica/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/genéticaRESUMO
The cell-intrinsic mechanisms guiding naive CD8+ T cells for clonal expansion and memory generation via homeostatic proliferation (HP) are unclear. Here, we have shown that HP of naive CD8+ T cells requires IL-7-, but not IL-15-induced mTOR kinase activation. HP-induced mTOR enhances transcription factor T-bet for functional maturation and CD122 expression, which sensitizes for an IL-15-dependent memory transition by favoring transcription factor Eomesodermin over T-bet. Inhibition of mTOR blocks T-bet and CD122 expression but preserves memory in an IL-15-independent manner by promoting Eomesodermin expression. The ability of rapamycin to augment HP-induced memory was cell-intrinsic given that silencing mTOR in CD8+ T cells generated identical outcomes. Strikingly, HP-induced CD8+ T cell memory generated by IL-15-dependent or -independent mechanisms demonstrated identical tumor efficacy. These results indicate a central role for mTOR in HP-induced CD8+ T cell responses and demonstrate the importance for CD8+ memory in HP-induced tumor efficacy.
Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Homeostase , Memória Imunológica , Neoplasias/imunologia , Serina-Treonina Quinases TOR/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Progressão da Doença , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias/patologiaRESUMO
The mechanisms underpinning integration of instructions that program naive CD8+ T cells for effector and/or memory differentiation are not well understood. Herein, we demonstrate that interleukin-12 (IL-12) enhanced and sustained antigen and costimulatory molecule (B7.1)-induced mTOR kinase activity in naive CD8+ (OT-I) T cells via phosphoinositide 3-kinase and STAT4 transcription factor pathways. Blocking mTOR activity by rapamycin reversed IL-12-induced effector functions because of loss of persistent expression of the transcription factor T-bet. Rapamycin treatment of IL-12-conditioned OT-I cells promoted persistent Eomesodermin expression and produced memory cell precursors that demonstrated enhanced sustenance and antigen-recall responses upon adoptive transfer. The memory cell precursors showed greater tumor efficacy than IL-12-conditioned effector OT-I cells. These results identify mTOR as the central regulator of transcriptional programs that determine effector and/or memory cell fates in CD8+ T cells. Targeting mTOR activity offers new opportunities to regulate CD8+ T cell-mediated immunity.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Proteínas com Domínio T/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Memória Imunológica/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/imunologia , Proteínas com Domínio T/biossíntese , Subpopulações de Linfócitos T/metabolismo , Serina-Treonina Quinases TOR , Transdução GenéticaRESUMO
The link between object perception and neural activity in visual cortical areas is a problem of fundamental importance in neuroscience. Here we show that electrical potentials from the ventral temporal cortical surface in humans contain sufficient information for spontaneous and near-instantaneous identification of a subject's perceptual state. Electrocorticographic (ECoG) arrays were placed on the subtemporal cortical surface of seven epilepsy patients. Grayscale images of faces and houses were displayed rapidly in random sequence. We developed a template projection approach to decode the continuous ECoG data stream spontaneously, predicting the occurrence, timing and type of visual stimulus. In this setting, we evaluated the independent and joint use of two well-studied features of brain signals, broadband changes in the frequency power spectrum of the potential and deflections in the raw potential trace (event-related potential; ERP). Our ability to predict both the timing of stimulus onset and the type of image was best when we used a combination of both the broadband response and ERP, suggesting that they capture different and complementary aspects of the subject's perceptual state. Specifically, we were able to predict the timing and type of 96% of all stimuli, with less than 5% false positive rate and a ~20ms error in timing.
Assuntos
Mapeamento Encefálico/métodos , Eletroencefalografia/métodos , Potenciais Evocados/fisiologia , Lobo Temporal/fisiologia , Percepção Visual/fisiologia , Biologia Computacional , Epilepsia/fisiopatologia , Humanos , Processamento de Sinais Assistido por ComputadorRESUMO
A motor cortex-based brain-computer interface (BCI) creates a novel real world output directly from cortical activity. Use of a BCI has been demonstrated to be a learned skill that involves recruitment of neural populations that are directly linked to BCI control as well as those that are not. The nature of interactions between these populations, however, remains largely unknown. Here, we employed a data-driven approach to assess the interaction between both local and remote cortical areas during the use of an electrocorticographic BCI, a method which allows direct sampling of cortical surface potentials. Comparing the area controlling the BCI with remote areas, we evaluated relationships between the amplitude envelopes of band limited powers as well as non-linear phase-phase interactions. We found amplitude-amplitude interactions in the high gamma (HG, 70-150 Hz) range that were primarily located in the posterior portion of the frontal lobe, near the controlling site, and non-linear phase-phase interactions involving multiple frequencies (cross-frequency coupling between 8-11 Hz and 70-90 Hz) taking place over larger cortical distances. Further, strength of the amplitude-amplitude interactions decreased with time, whereas the phase-phase interactions did not. These findings suggest multiple modes of cortical communication taking place during BCI use that are specialized for function and depend on interaction distance.
Assuntos
Interfaces Cérebro-Computador , Aprendizagem/fisiologia , Córtex Motor/fisiologia , Adolescente , Adulto , Criança , Biologia Computacional , Eletrocorticografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Rede Nervosa/fisiologia , Análise e Desempenho de Tarefas , Adulto JovemRESUMO
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha 4 (PGC-1α4) is a protein isoform derived by alternative splicing of the PGC1α mRNA and has been shown to promote muscle hypertrophy. We show here that G protein-coupled receptor 56 (GPR56) is a transcriptional target of PGC-1α4 and is induced in humans by resistance exercise. Furthermore, the anabolic effects of PGC-1α4 in cultured murine muscle cells are dependent on GPR56 signaling, because knockdown of GPR56 attenuates PGC-1α4-induced muscle hypertrophy in vitro. Forced expression of GPR56 results in myotube hypertrophy through the expression of insulin-like growth factor 1, which is dependent on Gα12/13 signaling. A murine model of overload-induced muscle hypertrophy is associated with increased expression of both GPR56 and its ligand collagen type III, whereas genetic ablation of GPR56 expression attenuates overload-induced muscle hypertrophy and associated anabolic signaling. These data illustrate a signaling pathway through GPR56 which regulates muscle hypertrophy associated with resistance/loading-type exercise.
Assuntos
Regulação da Expressão Gênica/fisiologia , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/metabolismo , Condicionamento Físico Animal , Receptores Acoplados a Proteínas G/biossíntese , Transdução de Sinais/fisiologia , Animais , Colágeno Tipo III/biossíntese , Hipertrofia/metabolismo , Fator de Crescimento Insulin-Like I/biossíntese , Masculino , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fatores de Transcrição/metabolismoRESUMO
Non-Hodgkin lymphoma of the orbit and ocular adnexa is the most common primary orbital malignancy. Treatments for low- (extra-nodal marginal zone and follicular lymphomas) and high-grade (diffuse large B-cell lymphoma) are associated with local and vision-threatening toxicities. High-grade lymphomas relapse frequently and exhibit poor survival rates. Despite advances in genomic profiling and precision medicine, orbital and ocular adnexal lymphomas remain poorly characterized molecularly. We performed targeted next-generation sequencing (NGS) profiling of 38 formalin-fixed, paraffin-embedded orbital and ocular adnexal lymphomas obtained from a single-center using a panel targeting near-term, clinically relevant genes. Potentially actionable mutations and copy number alterations were prioritized based on gain- and loss-of-function analyses, and catalogued, approved, and investigational therapies. Of 36 informative samples, including marginal zone lymphomas (n=20), follicular lymphomas (n=9), and diffuse large B-cell lymphomas (n=7), 53% harbored a prioritized alteration (median=1, range 0-5/sample). MYD88 was the most frequently altered gene in our cohort, with potentially clinically relevant hotspot gain-of-function mutations identified in 71% of diffuse large B-cell lymphomas and 25% of marginal zone lymphomas. Prioritized alterations in epigenetic modulators were common and included gain-of-function EZH2 and loss-of-function ARID1A mutations (14% of diffuse large B-cell lymphomas and 22% of follicular lymphomas contained alterations in each of these two genes). Single prioritized alterations were also identified in the histone methyltransferases KMT2B (follicular lymphoma) and KMT3B (diffuse large B-cell lymphoma). Loss-of-function mutations and copy number alterations in the tumor suppressors TP53 (diffuse large B-cell and follicular lymphoma), CDKN2A (diffuse large B-cell and marginal zone lymphoma), PTEN (diffuse large B-cell lymphoma), ATM (diffuse large B-cell lymphoma), and NF1 (diffuse large B-cell lymphoma), and gain-of-function mutations in the oncogenes HRAS (follicular lymphoma) and NRAS (diffuse large B-cell lymphoma) were also observed. Together, our study demonstrates that NGS can be used to profile routine formalin-fixed, paraffin-embedded orbital and ocular adnexal lymphomas for identification of somatic-driving alterations and nomination of potential therapeutic strategies.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Oculares/genética , Perfilação da Expressão Gênica , Linfoma/genética , Idoso , Idoso de 80 Anos ou mais , Inibidor p16 de Quinase Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p18/genética , Proteínas de Ligação a DNA , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Neoplasias Oculares/patologia , Feminino , Genômica , Histona-Lisina N-Metiltransferase/genética , Humanos , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Nucleares/genética , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição/genéticaRESUMO
PURPOSE: To describe the spectral-domain optical coherence tomography (SD OCT) features of peripheral retinal findings using an ultra-widefield (UWF) steering technique to image the retinal periphery. DESIGN: Observational study. PARTICIPANTS: A total of 68 patients (68 eyes) with 19 peripheral retinal features. MAIN OUTCOME MEASURES: Spectral-domain OCT-based structural features. METHODS: Nineteen peripheral retinal features, including vortex vein, congenital hypertrophy of the retinal pigment epithelium, pars plana, ora serrata pearl, typical cystoid degeneration (TCD), cystic retinal tuft, meridional fold, lattice and cobblestone degeneration, retinal hole, retinal tear, rhegmatogenous retinal detachment, typical degenerative senile retinoschisis, peripheral laser coagulation scars, ora tooth, cryopexy scars (retinal tear and treated retinoblastoma scar), bone spicules, white without pressure, and peripheral drusen, were identified by peripheral clinical examination. Near-infrared scanning laser ophthalmoscopy images and SD OCT of these entities were registered to UWF color photographs. RESULTS: Spectral-domain OCT resolved structural features of all peripheral findings. Dilated hyporeflective tubular structures within the choroid were observed in the vortex vein. Loss of retinal lamination, neural retinal attenuation, retinal pigment epithelium loss, or hypertrophy was seen in several entities, including congenital hypertrophy of the retinal pigment epithelium, ora serrata pearl, TCD, cystic retinal tuft, meridional fold, lattice, and cobblestone degenerations. Hyporeflective intraretinal spaces, indicating cystoid or schitic fluid, were seen in ora serrata pearl, ora tooth, TCD, cystic retinal tuft, meridional fold, retinal hole, and typical degenerative senile retinoschisis. The vitreoretinal interface, which often consisted of lamellae-like structures of the condensed cortical vitreous near or adherent to the neural retina, appeared clearly in most peripheral findings, confirming its association with many low-risk and vision-threatening pathologies, such as lattice degeneration, meridional folds, retinal breaks, and rhegmatogenous retinal detachments. CONCLUSIONS: Ultra-widefield steering-based SD OCT imaging of the retinal periphery is feasible with current commercially available devices and provides detailed anatomic information of the peripheral retina, including benign and pathologic entities, not previously imaged. This imaging technique may deepen our structural understanding of these entities and their potentially associated macular and systemic pathologies, and may influence decision-making in clinical practice, particularly in areas with teleretinal capabilities but poor access to retinal specialists.