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Bone marrow-derived cells (BMDCs) infiltrate hypoxic tumors at a pre-angiogenic state and differentiate into mature macrophages, thereby inducing pro-tumorigenic immunity. A critical factor regulating this differentiation is activation of SREBP2-a well-known transcription factor participating in tumorigenesis progression-through unknown cellular mechanisms. Here, we show that hypoxia-induced Golgi disassembly and Golgi-ER fusion in monocytic myeloid cells result in nuclear translocation and activation of SREBP2 in a SCAP-independent manner. Notably, hypoxia-induced SREBP2 activation was only observed in an immature lineage of bone marrow-derived cells. Single-cell RNA-seq analysis revealed that SREBP2-mediated cholesterol biosynthesis was upregulated in HSCs and monocytes but not in macrophages in the hypoxic bone marrow niche. Moreover, inhibition of cholesterol biosynthesis impaired tumor growth through suppression of pro-tumorigenic immunity and angiogenesis. Thus, our findings indicate that Golgi-ER fusion regulates SREBP2-mediated metabolic alteration in lineage-specific BMDCs under hypoxia for tumor progression.
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Monócitos , Neoplasias , Humanos , Monócitos/metabolismo , Medula Óssea , Colesterol/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , HipóxiaRESUMO
In eukaryotic cells, the ribosome-Sec61 translocon complex (RTC) establishes membrane protein topology by cotranslationally partitioning nascent polypeptides into the cytosol, ER lumen, and lipid bilayer. Using photocrosslinking, collisional quenching, cysteine accessibility, and protease protection, we show that a canonical type II signal anchor (SA) acquires its topology through four tightly coupled and mechanistically distinct steps: (1) head-first insertion into Sec61α, (2) nascent chain accumulation within the RTC, (3) inversion from type I to type II topology, and (4) stable translocation of C-terminal flanking residues. Progression through each stage is induced by incremental increases in chain length and involves abrupt changes in the molecular environment of the SA. Importantly, type II SA inversion deviates from a type I SA at an unstable intermediate whose topology is controlled by dynamic interactions between the ribosome and translocon. Thus, the RTC coordinates SA topogenesis within a protected environment via sequential energetic transitions of the TM segment.
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Proteínas de Membrana/metabolismo , Biossíntese de Proteínas , Ribossomos/metabolismo , Animais , Sistema Livre de Células , Cães , Retículo Endoplasmático/metabolismo , Microssomos/metabolismo , Sinais Direcionadores de Proteínas , Coelhos , Canais de Translocação SECRESUMO
Organisms must adapt to environmental stresses to ensure their survival and prosperity. Different types of stresses, including thermal, mechanical, and hypoxic stresses, can alter the cellular state that accompanies changes in gene expression but not the cellular identity determined by a chromatin state that remains stable throughout life. Some tissues, such as adipose tissue, demonstrate remarkable plasticity and adaptability in response to environmental cues, enabling reversible cellular identity changes; however, the mechanisms underlying these changes are not well understood. We hypothesized that positive and/or negative "Integrators" sense environmental cues and coordinate the epigenetic and transcriptional pathways required for changes in cellular identity. Adverse environmental factors such as pollution disrupt the coordinated control contributing to disease development. Further research based on this hypothesis will reveal how organisms adapt to fluctuating environmental conditions, such as temperature, extracellular matrix stiffness, oxygen, cytokines, and hormonal cues by changing their cellular identities.
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Cromatina , Estresse Fisiológico , Cromatina/genética , Temperatura , Epigênese GenéticaRESUMO
Sequential optimization is one of the promising approaches in identifying the optimal candidate(s) (molecules, reactants, drugs, etc.) with desired properties (reaction yield, selectivity, efficacy, etc.) from a large set of potential candidates, while minimizing the number of experiments required. However, the high dimensionality of the feature space (e.g., molecular descriptors) makes it often difficult to utilize the relevant features during the process of updating the set of candidates to be examined. In this article, we developed a new sequential optimization algorithm for molecular problems based on reinforcement learning, multi-armed linear bandit framework, and online, dynamic feature selections in which relevant molecular descriptors are updated along with the experiments. We also designed a stopping condition aimed to guarantee the reliability of the chosen candidate from the dataset pool. The developed algorithm was examined by comparing with Bayesian optimization (BO), using two synthetic datasets and two real datasets in which one dataset includes hydration free energy of molecules and another one includes a free energy difference between enantiomer products in chemical reaction. We found that the dynamic feature selection in representing the desired properties along the experiments provides a better performance (e.g., time required to find the best candidate and stop the experiment) as the overall trend and that our multi-armed linear bandit approach with a dynamic feature selection scheme outperforms the standard BO with fixed feature variables. The comparison of our algorithm to BO with dynamic feature selection is also addressed.
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Bivalent H3K4me3 and H3K27me3 chromatin domains in embryonic stem cells keep active developmental regulatory genes expressed at very low levels and poised for activation. Here, we show an alternative and previously unknown bivalent modified histone signature in lineage-committed mesenchymal stem cells and preadipocytes that pairs H3K4me3 with H3K9me3 to maintain adipogenic master regulatory genes (Cebpa and Pparg) expressed at low levels yet poised for activation when differentiation is required. We show lineage-specific gene-body DNA methylation recruits H3K9 methyltransferase SETDB1, which methylates H3K9 immediately downstream of transcription start sites marked with H3K4me3 to establish the bivalent domain. At the Cebpa locus, this prevents transcription factor C/EBPß binding, histone acetylation, and further H3K4me3 deposition and is associated with pausing of RNA polymerase II, which limits Cebpa gene expression and adipogenesis.
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Adipócitos/citologia , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Metilação de DNA , Histonas/genética , PPAR gama/metabolismo , Células 3T3 , Adipócitos/fisiologia , Animais , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Cromatina/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/química , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Camundongos , Estrutura Terciária de ProteínaRESUMO
The lysine methyltransferase SETDB1, an enzyme responsible for methylation of histone H3 at lysine 9, plays a key role in H3K9 tri-methylation-dependent silencing of endogenous retroviruses and developmental genes. Recent studies have shown that ubiquitination of human SETDB1 complements its catalytic activity and the silencing of endogenous retroviruses in human embryonic stem cells. However, it is not known whether SETDB1 ubiquitination is essential for its other major role in epigenetic silencing of developmental gene programs. We previously showed that SETDB1 contributes to the formation of H3K4/H3K9me3 bivalent chromatin domains that keep adipogenic Cebpa and Pparg genes in a poised state for activation and restricts the differentiation potential of pre-adipocytes. Here, we show that ubiquitin-resistant K885A mutant of SETDB1 represses adipogenic genes and inhibits pre-adipocyte differentiation similar to wild-type SETDB1. We show this was due to a compensation mechanism for H3K9me3 chromatin modifications on the Cebpa locus by other H3K9 methyltransferases Suv39H1 and Suv39H2. In contrast, the K885A mutant did not repress other SETDB1 target genes such as Tril and Gas6 suggesting SETDB1 represses its target genes by two mechanisms; one that requires its ubiquitination and another that still requires SETDB1 but not its enzyme activity.
Assuntos
Adipogenia , Epigênese Genética , Histona-Lisina N-Metiltransferase/metabolismo , Ubiquitinação , Células 3T3-L1 , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Células HEK293 , Código das Histonas , Histona-Lisina N-Metiltransferase/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Mutação de Sentido IncorretoRESUMO
Understanding the dynamic disorder behind a process, i.e., the dynamic effect of fluctuations that occur on a timescale slower or comparable with the timescale of the process, is essential for elucidating the dynamics and kinetics of complicated molecular processes in biomolecules and liquids. Despite numerous theoretical studies of single-molecule kinetics, our microscopic understanding of dynamic disorder remains limited. In the present study, we investigate the microscopic aspects of dynamic disorder in the isomerization dynamics of the Cys14-Cys38 disulfide bond in the protein bovine pancreatic trypsin inhibitor, which has been observed by nuclear magnetic resonance. We use a theoretical model with a stochastic transition rate coefficient, which is calculated from the 1-ms-long time molecular dynamics trajectory obtained by Shaw et al. [Science 330, 341-346 (2010)]. The isomerization dynamics are expressed by the transitions between coarse-grained states consisting of internal states, i.e., conformational sub-states. In this description, the rate for the transition from the coarse-grained states is stochastically modulated due to fluctuations between internal states. We examine the survival probability for the conformational transitions from a coarse-grained state using a theoretical model, which is a good approximation to the directly calculated survival probability. The dynamic disorder changes from a slow modulation limit to a fast modulation limit depending on the aspects of the coarse-grained states. Our analysis of the rate modulations behind the survival probability, in relation to the fluctuations between internal states, reveals the microscopic origin of dynamic disorder.
Assuntos
Aprotinina/química , Microscopia/métodos , Isomerismo , Cinética , Modelos Teóricos , Ressonância Magnética Nuclear Biomolecular , Conformação ProteicaRESUMO
Endothelial cell (EC) plasticity in pathological settings has recently been recognized as a driver of disease progression. Endothelial-to-mesenchymal transition (EndMT), in which ECs acquire mesenchymal properties, has been described for a wide range of pathologies, including cancer. However, the mechanism regulating EndMT in the tumor microenvironment and the contribution of EndMT in tumor progression are not fully understood. Here, we found that combined knockdown of two ETS family transcription factors, ERG and FLI1, induces EndMT coupled with dynamic epigenetic changes in ECs. Genome-wide analyses revealed that ERG and FLI1 are critical transcriptional activators for EC-specific genes, among which microRNA-126 partially contributes to blocking the induction of EndMT. Moreover, we demonstrated that ERG and FLI1 expression is downregulated in ECs within tumors by soluble factors enriched in the tumor microenvironment. These data provide new insight into the mechanism of EndMT, functions of ERG and FLI1 in ECs, and EC behavior in pathological conditions.
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Transição Epitelial-Mesenquimal/genética , Proteína Proto-Oncogênica c-fli-1/genética , Animais , Regulação para Baixo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epigênese Genética , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Prognóstico , Proteína Proto-Oncogênica c-fli-1/antagonistas & inibidores , Proteína Proto-Oncogênica c-fli-1/metabolismo , Regulador Transcricional ERG/antagonistas & inibidores , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo , Microambiente Tumoral/genéticaRESUMO
The kinetics on a basic ligand substitution reaction on dinuclear platinum complexes [Pt(PEt3 )2 PhPt(PEt3 )2 ]2+ and [Pt(PEt3 )2 PhCOPhPt(PEt3 )2 ]2+ , with the ligands pyridine and 3-chloropyridine, is studied. This is a fundamental step in a self-assembly, and the time evolution has been observed with a new experimental technique, QASAP (quantitative analysis of self-assembly process), which is recently developed by Hiraoka's group. As a result of numerical calculations based on master equation, we succeed in specifying the reaction rate constants with a simple reaction model. In addition, the time evolutions of all the intermediate components produced and consumed in chemical reaction are revealed, including those unobserved in the experiments. The convergence behavior of the existence ratios of specific chemical species calculated with the stochastic algorithm method is compared with those obtained from deterministic formalism based on rate equations, revealing a clear dependence on the number of constituent molecules. © 2018 Wiley Periodicals, Inc.
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Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces HMGCS2 and PDK4, which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes. This suggests that PPARα plays a crucial role in nutrient flux in the human liver. Additionally, pemafibrate induces clinically favorable genes, such as ABCA1, FGF21, and VLDLR. Furthermore, pemafibrate shows anti-inflammatory effects in vascular endothelial cells. Pemafibrate is predicted to exhibit beneficial effects in patients with atherogenic dyslipidemia and diabetic microvascular complications.
Assuntos
Benzoxazóis/farmacologia , Butiratos/farmacologia , PPAR alfa/metabolismo , Transcriptoma/efeitos dos fármacos , Animais , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Modelos Moleculares , Oxirredução/efeitos dos fármacos , PPAR alfa/agonistas , PPAR alfa/químicaRESUMO
A model electronic Hamiltonian to describe ligand exchange reactions of palladium(ii) complexes with pyridine (Py) and tridentate (L) ligands was developed. It was shown that the model Hamiltonian can adequately reproduce the structures and potential energies of the reactant/product, intermediate, and transition state of the ligand exchange reaction of [PdPy4]2+ with free Py. The model Hamiltonian was extended to describe reactions of multi-metal complexes and was adequately applied to describe various clusters, [PdaLbPyc]2a+, in the self-assembly of an octahedron-shaped coordination capsule, [Pd6L8]12+. The heterogeneity in the energetics of intermediate species [PdaLbPyc]2a+ was strongly suggested by the calculations, and the underlying microscopic interactions were clarified with the geometrical motif. The present framework provides a way to examine the reaction mechanisms of complex metal ligand self-assembly, which can be complementary microscopic information to the recently investigated novel experimental results for the real time evolutions.
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Herein, the self-assembly process of an octahedron-shaped coordination capsule was analyzed based on a master equation approach using a reaction network model. This model was found to adequately reproduce the overall experimentally observed time evolutions and enabled us to trace the real-time evolution of transient intermediates, ranging from milli-second to hours. The time evolution of the distribution of individual intermediates species was obtained; a few linear-oligomers located near the reactant were produced at first, followed by an explosive increase in several types of intermediates. All of them were then consolidated into a few species just before the formation of the final product. A long-lived [Pd618Py]12+ is a key compound, which acts as a kinetic trap in the reaction dynamics.
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Polycomb repressive complex 1 (PRC1) plays an essential role in the epigenetic repression of gene expression during development and cellular differentiation via multiple effector mechanisms, including ubiquitination of H2A and chromatin compaction. However, whether it regulates the stepwise progression of adipogenesis is unknown. Here, we show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. Knockdown of either RING1B or SKP1 prevented FBXL10-mediated repression of 3T3-L1 preadipocyte differentiation indicating that PRC1 formation mediates the inhibitory effect of FBXL10 on adipogenesis. Using ChIP-seq, we show that FBXL10 recruits RING1B to key specific genomic loci surrounding the key cell cycle and the adipogenic genes Cdk1, Uhrf1, Pparg1, and Pparg2 to repress adipogenesis. These results suggest that FBXL10 represses adipogenesis by targeting a noncanonical PRC1 complex to repress key genes (e.g. Pparg) that control conversion of pluripotent cells into the adipogenic lineage.
Assuntos
Adipócitos/metabolismo , Adipogenia/fisiologia , Proteínas F-Box/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Animais , Biomarcadores/metabolismo , Western Blotting , Ciclo Celular , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Imunoprecipitação da Cromatina , Proteínas F-Box/antagonistas & inibidores , Proteínas F-Box/genética , Perfilação da Expressão Gênica , Histonas/metabolismo , Técnicas Imunoenzimáticas , Imunoprecipitação , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Proteínas de Repetições Ricas em Leucina , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , PPAR gama/genética , PPAR gama/metabolismo , Complexo Repressor Polycomb 1/genética , Isoformas de Proteínas , Estrutura Terciária de Proteína , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , UbiquitinaçãoRESUMO
A new integral equation theory is proposed, which enables us to efficiently compute conformational distribution of a polyatomic molecule in solution phase. The solvation effect on the intramolecular correlation function is evaluated through a self-consistent procedure. In addition, the analytical expression of solvation free energy is derived, explicitly taking into account the molecular structural fluctuation. The derived equation establishes a direct route between the structural fluctuation and free energy of the molecule. The method was successfully applied to a series of n-alkanes in aqueous solutions to demonstrate the superiority of the proposed theory.
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The C terminus of Hsp70 interacting protein (CHIP) E3 ligase functions as a key regulator of protein quality control by binding the C-terminal (M/I)EEVD peptide motif of Hsp/c70(90) with its N-terminal tetratricopeptide repeat (TPR) domain and facilitating polyubiquitination of misfolded client proteins via its C-terminal catalytic U-box. Using CFTR as a model client, we recently showed that the duration of the Hsc70-client binding cycle is a primary determinant of stability. However, molecular features that control CHIP recruitment to Hsp/c70, and hence the fate of the Hsp/c70 client, remain unknown. To understand how CHIP recognizes Hsp/c70, we utilized a dominant negative mutant in which loss of a conserved proline in the U-box domain (P269A) eliminates E3 ligase activity. In a cell-free reconstituted ER-associated degradation system, P269A CHIP inhibited Hsc70-dependent CFTR ubiquitination and degradation in a dose-dependent manner. Optimal inhibition required both the TPR and the U-box, indicating cooperativity between the two domains. Neither the wild type nor the P269A mutant changed the extent of Hsc70 association with CFTR nor the dissociation rate of the Hsc70-CFTR complex. However, the U-box mutation stimulated CHIP binding to Hsc70 while promoting CHIP oligomerization. CHIP binding to Hsc70 binding was also stimulated by the presence of an Hsc70 client with a preference for the ADP-bound state. Thus, the Hsp/c70 (M/I)EEVD motif is not a simple anchor for the TPR domain. Rather CHIP recruitment involves reciprocal allosteric interactions between its TPR and U-box domains and the substrate-binding and C-terminal domains of Hsp/c70.
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Regulador de Condutância Transmembrana em Fibrose Cística/química , Proteínas de Choque Térmico HSC70/química , Dobramento de Proteína , Ubiquitina-Proteína Ligases/química , Difosfato de Adenosina/química , Difosfato de Adenosina/genética , Difosfato de Adenosina/metabolismo , Motivos de Aminoácidos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Retículo Endoplasmático/química , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Proteínas de Choque Térmico HSC70/genética , Proteínas de Choque Térmico HSC70/metabolismo , Humanos , Mutação , Estrutura Terciária de Proteína , Proteólise , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Proteins exhibit conformational fluctuations and changes over various time scales, ranging from rapid picosecond-scale local atomic motions to slower microsecond-scale global conformational transformations. In the presence of these intricate fluctuations, chemical reactions occur and functions emerge. These conformational fluctuations of proteins are not merely stochastic random motions but possess distinct spatiotemporal characteristics. Moreover, chemical reactions do not always proceed along a single reaction coordinate in a quasi-equilibrium manner. Therefore, it is essential to understand spatiotemporal conformational fluctuations of proteins and the conformational change processes associated with reactions. In this Perspective, we shed light on the complex dynamics of proteins and their role in enzyme catalysis by presenting recent results regarding dynamic couplings and disorder in the conformational dynamics of proteins and rare but rapid enzymatic reaction events obtained from molecular dynamics simulations.
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Simulação de Dinâmica Molecular , Proteínas , Conformação Proteica , CatáliseRESUMO
Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of ß-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to ß-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.
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While epigenetic modifications of DNA and histones play main roles in gene transcription regulation, recently discovered post-transcriptional RNA modifications, known as epitranscriptomic modifications, have been found to have a profound impact on gene expression by regulating RNA stability, localization and decoding efficiency. Importantly, genetic variations or environmental perturbations of epitranscriptome modifiers (that is, writers, erasers and readers) are associated with obesity and metabolic diseases, such as type 2 diabetes. The epitranscriptome is closely coupled to epigenetic signalling, adding complexity to our understanding of gene expression in both health and disease. Moreover, the epitranscriptome in the parental generation can affect organismal phenotypes in the next generation. In this Review, we discuss the relationship between epitranscriptomic modifications and metabolic diseases, their relationship with the epigenome and possible therapeutic strategies.
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Diabetes Mellitus Tipo 2 , Doenças Metabólicas , Humanos , Diabetes Mellitus Tipo 2/genética , Doenças Metabólicas/genética , Epigênese Genética , Regulação da Expressão Gênica , Processamento Pós-Transcricional do RNARESUMO
BACKGROUND: To date, the reliable detection of mild cognitive impairment (MCI) remains a significant challenge for clinicians. Very few studies investigated the sensitivity of acoustic features in detecting Mandarin-speaking elders at risk for MCI, defined as "putative MCI" (pMCI). OBJECTIVE: This study sought to investigate the possibility of using automatically extracted speech acoustic features to detect elderly people with pMCI and reveal the potential acoustic markers of cognitive decline at an early stage. METHODS: Forty-one older adults with pMCI and 41 healthy elderly controls completed four reading tasks (syllable utterance, tongue twister, diadochokinesis, and short sentence reading), from which acoustic features were extracted automatically to train machine learning classifiers. Correlation analysis was employed to evaluate the relationship between classifier predictions and participants' cognitive ability measured by Mini-Mental State Examination 2. RESULTS: Classification results revealed that some temporal features (e.g., speech rate, utterance duration, and the number of silent pauses), spectral features (e.g., variability of F1 and F2), and energy features (e.g., SD of peak intensity and SD of intensity range) were effective predictors of pMCI. The best classification result was achieved in the Random Forest classifier (accuracyâ=â0.81, AUCâ=â0.81). Correlation analysis uncovered a strong negative correlation between participants' cognitive test scores and the probability estimates of pMCI in the Random Forest classifier, and a modest negative correlation in the Support Vector Machine classifier. CONCLUSIONS: The automatic acoustic analysis of speech could provide a promising non-invasive way to assess and monitor the early cognitive decline in Mandarin-speaking elders.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/diagnóstico , Acústica da Fala , Disfunção Cognitiva/diagnóstico , Fala , AcústicaRESUMO
Chemical modulation of histone deacetylase (HDAC) activity by HDAC inhibitors (HDACi) is an increasingly important approach for modifying the etiology of human disease. Loss-of-function diseases arise as a consequence of protein misfolding and degradation, which lead to system failures. The DeltaF508 mutation in cystic fibrosis transmembrane conductance regulator (CFTR) results in the absence of the cell surface chloride channel and a loss of airway hydration, leading to the premature lung failure and reduced lifespan responsible for cystic fibrosis. We now show that the HDACi suberoylanilide hydroxamic acid (SAHA) restores surface channel activity in human primary airway epithelia to levels that are 28% of those of wild-type CFTR. Biological silencing of all known class I and II HDACs reveals that HDAC7 plays a central role in restoration of DeltaF508 function. We suggest that the tunable capacity of HDACs can be manipulated by chemical biology to counter the onset of cystic fibrosis and other human misfolding disorders.