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1.
PLoS Comput Biol ; 16(9): e1007740, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32881861

RESUMO

The circadian clock is a complex system that plays many important roles in most organisms. Previously, many mathematical models have been used to sharpen our understanding of the Arabidopsis clock, which brought to light the roles of each transcriptional and post-translational regulations. However, the presence of both regulations, instead of either transcription or post-translation, raised curiosity of whether the combination of these two regulations is important for the clock's system. In this study, we built a series of simplified oscillators with different regulations to study the importance of post-translational regulation (specifically, 26S proteasome degradation) in the clock system. We found that a simple transcriptional-based oscillator can already generate sustained oscillation, but the oscillation can be easily destroyed in the presence of transcriptional leakage. Coupling post-translational control with transcriptional-based oscillator in a feed-forward loop will greatly improve the robustness of the oscillator in the presence of basal leakage. Using these general models, we were able to replicate the increased variability observed in the E3 ligase mutant for both plant and mammalian clocks. With this insight, we also predict a plausible regulator of several E3 ligase genes in the plant's clock. Thus, our results provide insights into and the plausible importance in coupling transcription and post-translation controls in the clock system.


Assuntos
Relógios Circadianos/genética , Modelos Biológicos , Processamento de Proteína Pós-Traducional/genética , Transcrição Genética/genética , Arabidopsis/genética , Arabidopsis/fisiologia , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Biologia Computacional , Retroalimentação Fisiológica , Regulação da Expressão Gênica de Plantas/genética , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
2.
PLoS One ; 15(8): e0236731, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866151

RESUMO

Ankle proprioception is crucial for balance and relies upon accurate input from calf muscle spindles. Spindle input, in turn, depends upon the physiological and mechanical properties of surrounding muscle tissue. Altering these properties could affect ankle proprioception, with potential consequences for balance. Here we determine the effects of prior muscle cooling, stretch and contraction upon performance of a contralateral ankle joint matching task. Participants stood passively leaning against a board oriented 22° rearward from vertical. Their right ankle was rotated to a randomised position between ± 6° plantar/dorsiflexion. The task was to align the left ankle to the same position, without vision. In the first experiment, immediately prior to each testing session, participants either produced a strong calf muscle contraction in a fully plantarflexed (tiptoe) posture or underwent 15° dorsiflexion stretch. Contraction had no effect on task performance, whereas stretch produced a significant bias in ankle placement of 0.89 ± 0.6°, indicating that participants perceived their foot to be more plantarflexed compared to a control condition. In the second experiment, the right lower leg was cooled in iced water (≤ 5°C) for 10 minutes. Cooling increased joint matching error by ~0.4°, through a combination of increased bias and variability. These results confirm that conditioning the triceps surae muscles can alter perception of ankle joint position. Since body movement during quiet stance is in the order of 1°, the magnitude of these changes are relevant for balance.


Assuntos
Tornozelo/fisiologia , Músculo Esquelético/fisiologia , Propriocepção , Adulto , Retroalimentação Fisiológica , Feminino , Humanos , Masculino , Contração Muscular , Temperatura Cutânea , Adulto Jovem
3.
EBioMedicine ; 58: 102887, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32736307

RESUMO

The pathogenesis of coronavirus disease 2019 (COVID-19) may be envisaged as the dynamic interaction between four vicious feedback loops chained or happening at once. These are the viral loop, the hyperinflammatory loop, the non-canonical renin-angiotensin system (RAS) axis loop, and the hypercoagulation loop. Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 lights the wick by infecting alveolar epithelial cells (AECs) and downregulating the angiotensin converting enzyme-2 (ACE2)/angiotensin (Ang-1-7)/Mas1R axis. The viral feedback loop includes evading the host's innate response, uncontrolled viral replication, and turning on a hyperactive adaptative immune response. The inflammatory loop is composed of the exuberant inflammatory response feeding back until exploding in an actual cytokine storm. Downregulation of the ACE2/Ang-(1-7)/Mas1R axis leaves the lung without a critical defense mechanism and turns the scale to the inflammatory side of the RAS. The coagulation loop is a hypercoagulable state caused by the interplay between inflammation and coagulation in an endless feedback loop. The result is a hyperinflammatory and hypercoagulable state producing acute immune-mediated lung injury and eventually, adult respiratory distress syndrome.


Assuntos
Betacoronavirus/patogenicidade , Coagulação Sanguínea , Infecções por Coronavirus/etiologia , Citocinas/metabolismo , Pneumonia Viral/etiologia , Sistema Renina-Angiotensina , Animais , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Retroalimentação Fisiológica , Humanos , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia
4.
Mol Cell ; 80(1): 29-42.e10, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32857952

RESUMO

(p)ppGpp is a nucleotide messenger universally produced in bacteria following nutrient starvation. In E. coli, ppGpp inhibits purine nucleotide synthesis by targeting several different enzymes, but the physiological significance of their inhibition is unknown. Here, we report the structural basis of inhibition for one target, Gsk, the inosine-guanosine kinase. Gsk creates an unprecedented, allosteric binding pocket for ppGpp by restructuring terminal sequences, which restrains conformational dynamics necessary for catalysis. Guided by this structure, we generated a chromosomal mutation that abolishes Gsk regulation by ppGpp. This mutant strain accumulates abnormally high levels of purine nucleotides following amino-acid starvation, compromising cellular fitness. We demonstrate that this unrestricted increase in purine nucleotides is detrimental because it severely depletes pRpp and essential, pRpp-derived metabolites, including UTP, histidine, and tryptophan. Thus, our results reveal the significance of ppGpp's regulation of purine nucleotide synthesis and a critical mechanism by which E. coli coordinates biosynthetic processes during starvation.


Assuntos
Aminoácidos/biossíntese , Escherichia coli/metabolismo , Guanosina Tetrafosfato/metabolismo , Nucleotídeos/biossíntese , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Retroalimentação Fisiológica , Guanosina Difosfato/metabolismo , Modelos Moleculares , Conformação Proteica , Multimerização Proteica , Purinas/biossíntese , Pirimidinas/biossíntese
5.
PLoS Biol ; 18(8): e3000826, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776935

RESUMO

Ca2+/calmodulin-dependent kinase II (CaMKII) regulates synaptic plasticity in multiple ways, supposedly including the secretion of neuromodulators like brain-derived neurotrophic factor (BDNF). Here, we show that neuromodulator secretion is indeed reduced in mouse α- and ßCaMKII-deficient (αßCaMKII double-knockout [DKO]) hippocampal neurons. However, this was not due to reduced secretion efficiency or neuromodulator vesicle transport but to 40% reduced neuromodulator levels at synapses and 50% reduced delivery of new neuromodulator vesicles to axons. αßCaMKII depletion drastically reduced neuromodulator expression. Blocking BDNF secretion or BDNF scavenging in wild-type neurons produced a similar reduction. Reduced neuromodulator expression in αßCaMKII DKO neurons was restored by active ßCaMKII but not inactive ßCaMKII or αCaMKII, and by CaMKII downstream effectors that promote cAMP-response element binding protein (CREB) phosphorylation. These data indicate that CaMKII regulates neuromodulation in a feedback loop coupling neuromodulator secretion to ßCaMKII- and CREB-dependent neuromodulator expression and axonal targeting, but CaMKIIs are dispensable for the secretion process itself.


Assuntos
Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Cálcio/metabolismo , Neurônios/metabolismo , Subunidades Proteicas/genética , Animais , Astrócitos/citologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/deficiência , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/citologia , Fosforilação , Cultura Primária de Células , Subunidades Proteicas/deficiência , Sinapses/fisiologia , Transmissão Sináptica , Imagem com Lapso de Tempo
6.
DNA Cell Biol ; 39(9): 1558-1572, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32845706

RESUMO

Sarcomas are a broad family of cancers that arise from cells of mesenchymal origin in virtually every tissue of the body. Some transcription factors (TFs) have been reported to be involved in the pathogenesis and metastasis of sarcomas. The expression of certain long noncoding RNAs (lncRNAs) has been correlated with the degree of cancer prognosis. There is an urgent need to effectively integrate TFs and lncRNA/microRNA/mRNA regulatory axis and further identify more key regulators that play crucial roles in sarcomas. We performed a network-based computational analysis to investigate the lncRNA-TF cross talks via integrating lncRNA-TF ceRNA interactions and TF-TF protein-protein interactions. Multiple topology analyses were performed to the sarcomas-related global lncRNA-TF network. Several lncRNAs or TFs with central topology structures were identified as key regulators and used to locate a hub-associated lncRNA-TF subnetwork. Three functional modules were identified from the sarcomas-related global lncRNA-TF network, which have shown significant pathway enrichment and prognosis capability. The lncRNAs and TFs of these modules were shown to participate in sarcoma-related biological phenomena through involving in mitogen-activated protein kinases (MAPK), Jak-STAT, and transforming growth factor (TGF-beta) signaling pathways. More importantly, a subset of core lncRNA-TF cross talks that might form positive feedback loops to control biological processes of sarcomas was identified. These core lncRNA-TF positive feedback loops showed more TF binding affinity than other lncRNAs. All the results can help us uncover the molecular mechanism of sarcomas and provide a novel way for diagnosis biomarker and therapeutic target identification.


Assuntos
Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , RNA Longo não Codificante/genética , Sarcoma/genética , Fatores de Transcrição/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Retroalimentação Fisiológica , Humanos , Sistema de Sinalização das MAP Quinases , RNA Longo não Codificante/metabolismo , Sarcoma/patologia , Fatores de Transcrição/metabolismo
7.
Nat Commun ; 11(1): 3925, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764538

RESUMO

Adaptation is a ubiquitous property of sensory systems. It is typically considered that neurons adapt to dominant energy in the ambient environment to function optimally. However, perceptual representation of the stimulus, often modulated by feedback signals, sometimes do not correspond to the input state of the stimulus, which tends to be more linked with feedforward signals. Here we investigated the relative contributions to cortical adaptation from feedforward and feedback signals, taking advantage of a visual illusion, the Flash-Grab Effect, to disassociate the feedforward and feedback representation of an adaptor. Results reveal that orientation adaptation is exclusively dependent on the perceived rather than the retinal orientation of the adaptor. Combined fMRI and EEG measurements demonstrate that the perceived orientation of the Flash-Grab Effect is indeed supported by feedback signals in the cortex. These findings highlight the important contribution of feedback signals for cortical neurons to recalibrate their sensitivity.


Assuntos
Adaptação Fisiológica , Ilusões/fisiologia , Orientação Espacial/fisiologia , Adulto , Eletroencefalografia , Potenciais Evocados Visuais , Retroalimentação Fisiológica , Feminino , Neuroimagem Funcional , Humanos , Imagem por Ressonância Magnética , Masculino , Ilusões Ópticas/fisiologia , Estimulação Luminosa , Psicofísica , Retina/fisiologia , Córtex Visual/fisiologia , Percepção Visual/fisiologia , Adulto Jovem
8.
PLoS One ; 15(8): e0238223, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853260

RESUMO

Being delivered as a low birthweight (LBW) infant is a risk factor for elevated blood pressure and future problems with cardiovascular and cerebellar diseases. Although premature babies are reported to have low numbers of nephrons, some unclear questions remain about the mechanisms underlying elevated blood pressure in full-term LBW infants. We previously reported that glucocorticoids increased miR-449a expression, and increased miR-449a expression suppressed Crhr1 expression and caused negative glucocorticoid feedback. Therefore, we conducted this study to clarify the involvement of pituitary miR-449a in the increase in blood pressure caused by higher glucocorticoids in LBW rats. We generated a fetal low-carbohydrate and calorie-restricted model rat (60% of standard chow), and some individuals showed postnatal growth failure caused by growth hormone receptor expression. Using this model, we examined how a high-fat diet (lard-based 45kcal% fat)-induced mismatch between prenatal and postnatal environments could elevate blood pressure after growth. Although LBW rats fed standard chow had slightly higher blood pressure than control rats, their blood pressure was significantly higher than controls when exposed to a high-fat diet. Observation of glomeruli subjected to periodic acid methenamine silver (PAM) staining showed no difference in number or size. Aortic and cardiac angiotensin II receptor expression was altered with compensatory responses. Blood aldosterone levels were not different between control and LBW rats, but blood corticosterone levels were significantly higher in the latter with high-fat diet exposure. Administration of metyrapone, a steroid synthesis inhibitor, reduced blood pressure to levels comparable to controls. We showed that high-fat diet exposure causes impairment of the pituitary glucocorticoid negative feedback via miR-449a. These results clarify that LBW rats have increased blood pressure due to high glucocorticoid levels when they are exposed to a high-fat diet. These findings suggest a new therapeutic target for hypertension of LBW individuals.


Assuntos
Pressão Sanguínea/fisiologia , Retroalimentação Fisiológica/fisiologia , Glucocorticoides/sangue , Doenças da Hipófise/sangue , Doenças da Hipófise/fisiopatologia , Hipófise/fisiologia , Animais , Peso ao Nascer/efeitos dos fármacos , Peso ao Nascer/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Corticosterona/sangue , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Recém-Nascido de Baixo Peso/sangue , Recém-Nascido de Baixo Peso/fisiologia , Recém-Nascido , Masculino , Metirapona/uso terapêutico , Doenças da Hipófise/tratamento farmacológico , Hipófise/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar
9.
PLoS Comput Biol ; 16(8): e1008033, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776924

RESUMO

Transient oscillations in network activity upon sensory stimulation have been reported in different sensory areas of the brain. These evoked oscillations are the generic response of networks of excitatory and inhibitory neurons (EI-networks) to a transient external input. Recently, it has been shown that this resonance property of EI-networks can be exploited for communication in modular neuronal networks by enabling the transmission of sequences of synchronous spike volleys ('pulse packets'), despite the sparse and weak connectivity between the modules. The condition for successful transmission is that the pulse packet (PP) intervals match the period of the modules' resonance frequency. Hence, the mechanism was termed communication through resonance (CTR). This mechanism has three severe constraints, though. First, it needs periodic trains of PPs, whereas single PPs fail to propagate. Second, the inter-PP interval needs to match the network resonance. Third, transmission is very slow, because in each module, the network resonance needs to build up over multiple oscillation cycles. Here, we show that, by adding appropriate feedback connections to the network, the CTR mechanism can be improved and the aforementioned constraints relaxed. Specifically, we show that adding feedback connections between two upstream modules, called the resonance pair, in an otherwise feedforward modular network can support successful propagation of a single PP throughout the entire network. The key condition for successful transmission is that the sum of the forward and backward delays in the resonance pair matches the resonance frequency of the network modules. The transmission is much faster, by more than a factor of two, than in the original CTR mechanism. Moreover, it distinctly lowers the threshold for successful communication by synchronous spiking in modular networks of weakly coupled networks. Thus, our results suggest a new functional role of bidirectional connectivity for the communication in cortical area networks.


Assuntos
Potenciais de Ação/fisiologia , Retroalimentação Fisiológica/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Animais , Encéfalo/fisiologia , Biologia Computacional , Rede Nervosa/fisiologia
10.
Cells ; 9(7)2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32708755

RESUMO

The article describes the rationale for inhibition of the renin-angiotensin system (RAS) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent positive feedback-loop mechanisms. Based purely on experimental studies in which RAS pathway inhibitors were administered in vivo to humans/rodents, a reasonable hypothesis of using inhibitors that block both ACE and ACE2 zinc metalloproteases and their downstream pathways in COVID-19 patients will be proposed. In particular, metal (zinc) chelators and renin inhibitors may work alone or in combination to inhibit the positive feedback loops (initially triggered by SARS-CoV-2 and subsequently sustained by hypoxia independently on viral trigger) as both arms of renin-angiotensin system are upregulated, leading to critical, advanced and untreatable stages of the disease.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Angiotensinas/metabolismo , Infecções por Coronavirus/metabolismo , Retroalimentação Fisiológica/efeitos dos fármacos , Humanos , Pandemias , Peptidil Dipeptidase A/efeitos adversos , Peptidil Dipeptidase A/genética , Pneumonia Viral/metabolismo , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco
11.
DNA Cell Biol ; 39(9): 1506-1512, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32635763

RESUMO

Osteoarthritis (OA) acts as the most common type of degenerative joint disease. Long noncoding RNA (lncRNA) has been identified to regulate the apoptosis and proliferation of chondrocyte. However, the deepgoing mechanism involved in the regulation is still unclear. This research aims to investigate the role and molecular mechanism by which lncRNA LINC00511 regulates the OA biology. Functionally, the functional experiments found that LINC00511 expression was upregulated in the IL-1ß-stimulated chondrocyte (ATDC5). Knockdown of LINC00511 facilitated proliferation, and repressed the apoptosis and extracellular matrix (ECM) synthesis of chondrocyte. Mechanically, LINC00511 functioned as sponge of miR-150-5p and then interacted with the 3'-UTR of transcription factor (SP1). In turn, transcription factor SP1 bound with the promoter region of LINC00511 and thus upregulated LINC00511 expression. In conclusion, our findings highlight the function and prognostic value of LINC00511/miR-150-5p/SP1 feedback loop in OA and extend the importance of lncRNA epigenetics in OA biology.


Assuntos
Apoptose , Proliferação de Células , Condrócitos/metabolismo , Osteoartrite/genética , Regiões 3' não Traduzidas , Animais , Linhagem Celular , Condrócitos/fisiologia , Retroalimentação Fisiológica , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoartrite/metabolismo , Regiões Promotoras Genéticas , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo
12.
PLoS Genet ; 16(6): e1008715, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32559233

RESUMO

Dysregulation of the Ras oncogene in development causes developmental disorders, "Rasopathies," whereas mutational activation or amplification of Ras in differentiated tissues causes cancer. Rabex-5 (also called RabGEF1) inhibits Ras by promoting Ras mono- and di-ubiquitination. We report here that Rabex-5-mediated Ras ubiquitination requires Ras Tyrosine 4 (Y4), a site of known phosphorylation. Ras substitution mutants insensitive to Y4 phosphorylation did not undergo Rabex-5-mediated ubiquitination in cells and exhibited Ras gain-of-function phenotypes in vivo. Ras Y4 phosphomimic substitution increased Rabex-5-mediated ubiquitination in cells. Y4 phosphomimic substitution in oncogenic Ras blocked the morphological phenotypes associated with oncogenic Ras in vivo dependent on the presence of Rabex-5. We developed polyclonal antibodies raised against an N-terminal Ras peptide phosphorylated at Y4. These anti-phospho-Y4 antibodies showed dramatic recognition of recombinant wild-type Ras and RasG12V proteins when incubated with JAK2 or SRC kinases but not of RasY4F or RasY4F,G12V recombinant proteins suggesting that JAK2 and SRC could promote phosphorylation of Ras proteins at Y4 in vitro. Anti-phospho-Y4 antibodies also showed recognition of RasG12V protein, but not wild-type Ras, when incubated with EGFR. A role for JAK2, SRC, and EGFR (kinases with well-known roles to activate signaling through Ras), to promote Ras Y4 phosphorylation could represent a feedback mechanism to limit Ras activation and thus establish Ras homeostasis. Notably, rare variants of Ras at Y4 have been found in cerebellar glioblastomas. Therefore, our work identifies a physiologically relevant Ras ubiquitination signal and highlights a requirement for Y4 for Ras inhibition by Rabex-5 to maintain Ras pathway homeostasis and to prevent tissue transformation.


Assuntos
Proteínas de Drosophila/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismo , Proteínas ras/metabolismo , Animais , Células Cultivadas , Sequência Conservada , Drosophila , Receptores ErbB/metabolismo , Retroalimentação Fisiológica , Janus Quinase 2/metabolismo , Fosforilação , Tirosina/química , Tirosina/genética , Ubiquitinação , Proteínas ras/química , Proteínas ras/genética , Quinases da Família src/metabolismo
13.
PLoS Genet ; 16(6): e1008829, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32502151

RESUMO

Ion channels are present at specific levels within subcellular compartments of excitable cells. The regulation of ion channel trafficking and targeting is an effective way to control cell excitability. The BK channel is a calcium-activated potassium channel that serves as a negative feedback mechanism at presynaptic axon terminals and sites of muscle excitation. The C. elegans BK channel ortholog, SLO-1, requires an endoplasmic reticulum (ER) membrane protein for efficient anterograde transport to these locations. Here, we found that, in the absence of this ER membrane protein, SLO-1 channels that are seemingly normally folded and expressed at physiological levels undergo SEL-11/HRD1-mediated ER-associated degradation (ERAD). This SLO-1 degradation is also indirectly regulated by a SKN-1A/NRF1-mediated transcriptional mechanism that controls proteasome levels. Therefore, our data indicate that SLO-1 channel density is regulated by the competitive balance between the efficiency of ER trafficking machinery and the capacity of ERAD.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas de Ligação a DNA/metabolismo , Degradação Associada com o Retículo Endoplasmático/genética , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Terminações Pré-Sinápticas/metabolismo , Fatores de Transcrição/metabolismo , Aldicarb/farmacologia , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Acoplamento Excitação-Contração/efeitos dos fármacos , Acoplamento Excitação-Contração/genética , Retroalimentação Fisiológica/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Músculos/inervação , Terminações Pré-Sinápticas/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma , Isoformas de Proteínas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
14.
PLoS Genet ; 16(6): e1008892, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32569316

RESUMO

Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme that has emerged as a central hub linking redox equilibrium and signal transduction in living organisms. The homeostasis of NAD is required for plant growth, development, and adaption to environmental cues. In this study, we isolated a chilling hypersensitive Arabidopsis thaliana mutant named qs-2 and identified the causal mutation in the gene encoding quinolinate synthase (QS) critical for NAD biosynthesis. The qs-2 mutant is also hypersensitive to salt stress and abscisic acid (ABA) but resistant to drought stress. The qs-2 mutant accumulates a reduced level of NAD and over-accumulates reactive oxygen species (ROS). The ABA-hypersensitivity of qs-2 can be rescued by supplementation of NAD precursors and by mutations in the ABA signaling components SnRK2s or RBOHF. Furthermore, ABA-induced over-accumulation of ROS in the qs-2 mutant is dependent on the SnRK2s and RBOHF. The expression of QS gene is repressed directly by ABI4, a transcription factor in the ABA response pathway. Together, our findings reveal an unexpected interplay between NAD biosynthesis and ABA and stress signaling, which is critical for our understanding of the regulation of plant growth and stress responses.


Assuntos
Arabidopsis/fisiologia , Regulação da Expressão Gênica de Plantas , Complexos Multienzimáticos/genética , Reguladores de Crescimento de Planta/metabolismo , Estresse Fisiológico/genética , Ácido Abscísico/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/isolamento & purificação , Proteínas de Arabidopsis/metabolismo , Retroalimentação Fisiológica , Perfilação da Expressão Gênica , Complexos Multienzimáticos/isolamento & purificação , Complexos Multienzimáticos/metabolismo , Mutação , NAD/biossíntese , NADPH Oxidases/metabolismo , Plantas Geneticamente Modificadas , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/isolamento & purificação , Fatores de Transcrição/metabolismo
15.
Restor Neurol Neurosci ; 38(4): 343-354, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32597823

RESUMO

Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into cells, corona viruses (CoV) activate aryl hydrocarbon receptors (AhRs) by an indoleamine 2,3-dioxygenase (IDO1)-independent mechanism, bypassing the IDO1-kynurenine-AhR pathway. The IDO1-kynurenine-AhR signaling pathway is used by multiple viral, microbial and parasitic pathogens to activate AhRs and to establish infections. AhRs enhance their own activity through an IDO1-AhR-IDO1 positive feedback loop prolonging activation induced by pathogens. Direct activation of AhRs by CoV induces immediate and simultaneous up-regulation of diverse AhR-dependent downstream effectors, and this, in turn, results in a "Systemic AhR Activation Syndrome" (SAAS) consisting of inflammation, thromboembolism, and fibrosis, culminating in multiple organ injuries, and death. Activation of AhRs by CoV may lead to diverse sets of phenotypic disease pictures depending on time after infection, overall state of health, hormonal balance, age, gender, comorbidities, but also diet and environmental factors modulating AhRs. We hypothesize that elimination of factors known to up-regulate AhRs, or implementation of measures known to down-regulate AhRs, should decrease severity of infection. Although therapies selectively down-regulating both AhR and IDO1 are currently lacking, medications in clinical use such as dexamethasone may down-regulate both AhR and IDO1 genes, as calcitriol/vitamin D3 may down-regulate the AhR gene, and tocopherol/vitamin E may down-regulate the IDO1 gene. Supplementation of calcitriol should therefore be subjected to epidemiological studies and tested in prospective trials for prevention of CoV infections, as should tocopherol, whereas dexamethasone could be tried in interventional trials. Because lack of physical exercise activates AhRs via the IDO1-kynurenine-AhR signaling pathway increasing risk of infection, physical exercise should be encouraged during quarantines and stay-at-home orders during pandemic outbreaks. Understanding which factors affect gene expression of both AhR and IDO1 may help in designing therapies to prevent and treat humans suffering from Covid-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/fisiopatologia , Indolamina-Pirrol 2,3,-Dioxigenase/fisiologia , Pandemias , Pneumonia Viral/fisiopatologia , Receptores de Hidrocarboneto Arílico/fisiologia , Poluentes Atmosféricos/efeitos adversos , Calcitriol/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Dexametasona/uso terapêutico , Exercício Físico , Retroalimentação Fisiológica , Feminino , Fibrose/etiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Inflamação/etiologia , Cinurenina/fisiologia , Masculino , Terapia de Alvo Molecular , Insuficiência de Múltiplos Órgãos/etiologia , Trabalho de Parto Prematuro/etiologia , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Gravidez , Complicações Infecciosas na Gravidez/fisiopatologia , Receptores de Hidrocarboneto Arílico/biossíntese , Receptores de Hidrocarboneto Arílico/genética , Transtornos das Sensações/etiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tromboembolia/etiologia , Tocoferóis/uso terapêutico
16.
Proc Natl Acad Sci U S A ; 117(24): 13447-13456, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32482854

RESUMO

Precisely controlling the activation of transcription factors is crucial for physiology. After a transcription factor is activated and carries out its transcriptional activity, it also needs to be properly deactivated. Here, we report a deactivation mechanism of HIF-1 and several other oncogenic transcription factors. HIF-1 promotes the transcription of an ADP ribosyltransferase, TiPARP, which serves to deactivate HIF-1. Mechanistically, TiPARP forms distinct nuclear condensates or nuclear bodies in an ADP ribosylation-dependent manner. The TiPARP nuclear bodies recruit both HIF-1α and an E3 ubiquitin ligase HUWE1, which promotes the ubiquitination and degradation of HIF-1α. Similarly, TiPARP promotes the degradation of c-Myc and estrogen receptor. By suppressing HIF-1α and other oncogenic transcription factors, TiPARP exerts strong antitumor effects both in cell culture and in mouse xenograft models. Our work reveals TiPARP as a negative-feedback regulator for multiple oncogenic transcription factors, provides insights into the functions of protein ADP-ribosylation, and suggests activating TiPARP as an anticancer strategy.


Assuntos
Núcleo Celular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , ADP-Ribosilação , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Receptor alfa de Estrogênio/metabolismo , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/genética , Domínios e Motivos de Interação entre Proteínas , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
17.
Nature ; 582(7813): 545-549, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499655

RESUMO

Animals sense the environment through pathways that link sensory organs to the brain. In the visual system, these feedforward pathways define the classical feedforward receptive field (ffRF), the area in space in which visual stimuli excite a neuron1. The visual system also uses visual context-the visual scene surrounding a stimulus-to predict the content of the stimulus2, and accordingly, neurons have been identified that are excited by stimuli outside their ffRF3-8. However, the mechanisms that generate excitation to stimuli outside the ffRF are unclear. Here we show that feedback projections onto excitatory neurons in the mouse primary visual cortex generate a second receptive field that is driven by stimuli outside the ffRF. The stimulation of this feedback receptive field (fbRF) elicits responses that are slower and are delayed in comparison with those resulting from the stimulation of the ffRF. These responses are preferentially reduced by anaesthesia and by silencing higher visual areas. Feedback inputs from higher visual areas have scattered receptive fields relative to their putative targets in the primary visual cortex, which enables the generation of the fbRF. Neurons with fbRFs are located in cortical layers that receive strong feedback projections and are absent in the main input layer, which is consistent with a laminar processing hierarchy. The observation that large, uniform stimuli-which cover both the fbRF and the ffRF-suppress these responses indicates that the fbRF and the ffRF are mutually antagonistic. Whereas somatostatin-expressing inhibitory neurons are driven by these large stimuli, inhibitory neurons that express parvalbumin and vasoactive intestinal peptide have mutually antagonistic fbRF and ffRF, similar to excitatory neurons. Feedback projections may therefore enable neurons to use context to estimate information that is missing from the ffRF and to report differences in stimulus features across visual space, regardless of whether excitation occurs inside or outside the ffRF. By complementing the ffRF, the fbRF that we identify here could contribute to predictive processing.


Assuntos
Retroalimentação Fisiológica , Neurônios/fisiologia , Estimulação Luminosa , Córtex Visual/citologia , Córtex Visual/fisiologia , Vias Visuais , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Fatores de Tempo
18.
Med Hypotheses ; 143: 109906, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32505910

RESUMO

Most COVID-19 infected individuals present with mild flu-like symptoms; however, 5-10% of cases suffer from life-threatening pneumonia and respiratory failure. The pathogenesis of SARS-CoV-2 and its pathology of associated acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, coagulopathy and multiorgan failure is not known. SARS-CoV-2 is an envelope virus with S (spike), M (membrane), N (nucleocapsid) and E (envelop) proteins. In a closely related coronavirus (SARS-CoV), the transmembrane E protein exerts an important role in membrane-ionic transport through viroporins, deletion of which reduced levels of IL-1ß and a remarkably reduced lung edema compared to wild type. IL-1ß is generated by macrophages upon activation of intracellular NLRP3 (NOD-like, leucine rich repeat domains, and pyrin domain-containing protein 3), part of the functional NLRP3 inflammasome complex that detects pathogenic microorganisms and stressors, while neutrophils are enhanced by increasing levels of IL-1ß. Expiring neutrophils undergo "NETosis", producing thread-like extracellular structures termed neutrophil extracellular traps (NETs), which protect against mild infections and microbes. However, uncontrolled NET production can cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), coagulopathy, multiple organ failure, and autoimmune disease. Herein, we present arguments underlying our hypothesis that IL-1ß and NETs, mediated via NLRP3 inflammasomes, form a feed-forward loop leading to the excessive alveolar and endothelial damage observed in severe cases of COVID-19. Considering such assertions, we propose potential drug candidates that could be used to alleviate such pathologies. Considering that recent efforts to ascertain effective treatments of COVID-19 in severe patients has been less than successful, investigating novel avenues of treating this virus are essential.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Armadilhas Extracelulares/efeitos dos fármacos , Interleucina-1beta/antagonistas & inibidores , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Infecções por Coronavirus/imunologia , Armadilhas Extracelulares/imunologia , Retroalimentação Fisiológica , Humanos , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Modelos Biológicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pandemias , Pneumonia Viral/imunologia
19.
Jpn J Clin Oncol ; 50(8): 839-846, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32577751

RESUMO

NCYM is an antisense transcript of MYCN oncogene and promotes tumor progression. NCYM encodes a de novo protein whose open reading frame evolved from noncoding genomic regions in the ancestor of Homininae. Because of its topology, NCYM is always co-amplified with MYCN oncogene, and the mutual regulations between NCYM and MYCN maintain their expressions at high levels in MYCN-amplified tumors. NCYM stabilizes MYCN by inhibiting GSK3ß, whereas MYCN stimulates transcription of both NCYM and MYCN. NCYM mRNA and its noncoding transcript variants MYCNOS have been shown to stimulate MYCN expression via direct binding to MYCN promoter, indicating that both coding and noncoding transcripts of NCYM induce MYCN expression. In contrast to the noncoding functions of NCYM, NCYM protein also promotes calpain-mediated cleavage of c-MYC. The cleaved product called Myc-nick inhibits cell death and promotes cancer cell migration. Furthermore, NCYM-mediated inhibition of GSK3ß results in the stabilization of ß-catenin, which promotes aggressiveness of bladder cancers. These MYCN-independent functions of NCYM showed their clinical significance in MYCN-non-amplified tumors, including adult tumors. This year is the 30th anniversary of the identification of NCYM/MYCNOS gene. On this special occasion, we summarize the current understanding of molecular functions and the clinical significance of NCYM and discuss future directions to achieve therapeutic strategies targeting NCYM.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Neuroblastoma/genética , Reprogramação Celular/genética , Retroalimentação Fisiológica , Humanos , Neuroblastoma/patologia , Resultado do Tratamento
20.
Proc Natl Acad Sci U S A ; 117(21): 11811-11819, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32393641

RESUMO

"Growing old" is the most common cause of hearing loss. Age-related hearing loss (ARHL) (presbycusis) first affects the ability to understand speech in background noise, even when auditory thresholds in quiet are normal. It has been suggested that cochlear denervation ("synaptopathy") is an early contributor to age-related auditory decline. In the present work, we characterized age-related cochlear synaptic degeneration and hair cell loss in mice with enhanced α9α10 cholinergic nicotinic receptors gating kinetics ("gain of function" nAChRs). These mediate inhibitory olivocochlear feedback through the activation of associated calcium-gated potassium channels. Cochlear function was assessed via distortion product otoacoustic emissions and auditory brainstem responses. Cochlear structure was characterized in immunolabeled organ of Corti whole mounts using confocal microscopy to quantify hair cells, auditory neurons, presynaptic ribbons, and postsynaptic glutamate receptors. Aged wild-type mice had elevated acoustic thresholds and synaptic loss. Afferent synapses were lost from inner hair cells throughout the aged cochlea, together with some loss of outer hair cells. In contrast, cochlear structure and function were preserved in aged mice with gain-of-function nAChRs that provide enhanced olivocochlear inhibition, suggesting that efferent feedback is important for long-term maintenance of inner ear function. Our work provides evidence that olivocochlear-mediated resistance to presbycusis-ARHL occurs via the α9α10 nAChR complexes on outer hair cells. Thus, enhancement of the medial olivocochlear system could be a viable strategy to prevent age-related hearing loss.


Assuntos
Envelhecimento/fisiologia , Cóclea , Células Ciliadas Auditivas Externas , Presbiacusia , Complexo Olivar Superior , Animais , Cóclea/fisiologia , Cóclea/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Retroalimentação Fisiológica/fisiologia , Células Ciliadas Auditivas Externas/citologia , Células Ciliadas Auditivas Externas/fisiologia , Camundongos , Emissões Otoacústicas Espontâneas/fisiologia , Presbiacusia/fisiopatologia , Presbiacusia/prevenção & controle , Complexo Olivar Superior/citologia , Complexo Olivar Superior/fisiologia
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