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1.
J Clin Sleep Med ; 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32964831

RESUMO

STUDY OBJECTIVES: Polysomnography is the gold standard in identifying sleep stages; however, there are discrepancies in how technicians use the standards. Because organizing meetings to evaluate this discrepancy and/or reach a consensus among multiple sleep centers is time consuming, we developed an artificial intelligence (AI) system to efficiently evaluate the reliability and consistency of sleep scoring, and hence the sleep center quality. METHODS: An interpretable machine learning algorithm was used to evaluate interrater reliability (IRR) of sleep stage annotation among sleep centers. The AI system was trained to learn raters from one hospital, and applied to subjects from the same or other hospitals. The results were compared with the experts' annotation to determine IRR. Intra-center and inter-center assessments were conducted on 679 subjects without sleep apnea from six sleep centers in Taiwan. Centers with potential quality issues were identified by the estimated IRR. RESULTS: In the intra-center assessment, the median accuracy ranged from 80·3% to 83·3% with the exception of one hospital (designated E) with an accuracy of 72·3%. In the inter-center assessment, the median accuracy ranged from 75·7% to 83·3% when hospital E was excluded from testing and training. The performance of the proposed method was higher for N2, awake, and REM, compared to N1 and N3. The significant IRR discrepancy of hospital E suggested a quality issue. This quality issue is confirmed by the physicians in charge of hospital E. CONCLUSIONS: The proposed AI system proved effective in assessing IRR and hence the sleep center quality.

2.
BMJ Open ; 10(6): e032633, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32546485

RESUMO

OBJECTIVES: The role of faecal haemoglobin as a colorectal cancer screening tool has been demonstrated. However, the association between the faecal haemoglobin concentration and the risk of cardiovascular disease events and deaths is still unclear. DESIGN: Cohort study design. SETTING: Population-based organised integrated service screening in Keelung City, Taiwan PARTICIPANTS: A total of 33 355 healthy individuals aged over 40 years who were free of cardiovascular disease at study entry were followed up. MAIN OUTCOMES AND MEASURES: Newly diagnosed cardiovascular disease events and deaths. RESULTS: After a median follow-up of 2.39 years, a total of 2768 participants developed cardiovascular events, and after a median follow-up of 8.43 years, 317 cases of cardiovascular deaths occurred. The risk of cardiovascular disease increased with baseline faecal haemoglobin in a dose-response manner, yielding a significant elevated risk of cardiovascular disease in parallel with the incremental concentration of faecal haemoglobin (adjusted HRs=1.04, 1.10, 1.40 and 1.23 for faecal haemoglobin concentrations of 1-19, 20-49, 50-99 and ≥100 ng/mL, trend test, p<0.0001, as compared with the reference group with undetectable faecal haemoglobin concentrations). A similar pattern was observed for the risk of cardiovascular disease deaths. In addition, the faecal haemoglobin improved the prediction performance of the model for the risk of cardiovascular diseases; the integrated discrimination improvement was 0.3% (p<0.001) for cardiovascular events and 0.1% (p=0.020) for cardiovascular deaths. CONCLUSIONS: Our data support that faecal haemoglobin concentrations may be associated with the risk of cardiovascular diseases. The biological mechanisms underlying the role of faecal haemoglobin as health outcomes should be investigated.

3.
J Chin Med Assoc ; 2020 May 18.
Artigo em Inglês | MEDLINE | ID: covidwho-338268

RESUMO

The novel coronavirus disease 2019 (COVID-19), with first presentation of atypical pneumonia, has spread rapidly from Wuhan, China on December 12, 2019 to over 200 countries, caused 2310572 infected individuals and 158691 mortalities, updated on 2020/4/19. Many studies have published timely to help global health-care workers to understand and control the disease. Vulnerable patients with risk factors such as elderly, cardiovascular diseases (e.g. hypertension, coronary disease, or cardiomyopathy), diabetes, chronic kidney disease…etc., have worse outcomes after covid-19 infection. COVID-19 could directly cause cardiovascular injuries such as pericarditis, myocarditis, myocardial infarction, heart failure, arrhythmias or thromboembolic events, which urge cardiologists to be involved in the frontline to practice. Here we provide a review of COVID-19 on cardiovascular system to assist clinical cardiologists to better understand the disease and being capable of providing comprehensive medical support.

4.
J Chin Med Assoc ; 83(8): 704-709, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32433342

RESUMO

The novel coronavirus disease 2019 (COVID-19), with first presentation of atypical pneumonia, has spread rapidly from Wuhan, China, on December 12, 2019 to over 200 countries, caused 2 310 572 infected individuals and 158 691 mortalities, updated on April 19, 2020. Many studies have published timely to help global healthcare workers to understand and control the disease. Vulnerable patients with risk factors such as elderly, cardiovascular diseases (eg, hypertension, coronary disease, or cardiomyopathy), diabetes, and chronic kidney disease have worse outcomes after COVID-19 infection. COVID-19 could directly cause cardiovascular injuries such as pericarditis, myocarditis, myocardial infarction, heart failure, arrhythmias, or thromboembolic events, which urge cardiologists to be involved in the frontline to practice. Here, we provide a review of COVID-19 on cardiovascular system to assist clinical cardiologists to better understand the disease and being capable of providing comprehensive medical support.


Assuntos
Betacoronavirus , Doenças Cardiovasculares/etiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pandemias
5.
COPD ; 17(2): 191-196, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131647

RESUMO

The aim of this study was to develop a simplified screening questionnaire to detect the existence of severe obstructive sleep apnea (OSA) in chronic obstructive pulmonary disease (COPD) patients to reduce mortality and hospitalization rates. Seventy-seven stable Asian COPD patients aged 69.2 ± 11.5 years were retrospectively analyzed into the development group. The simplified screening questionnaire was developed from factors identified from sleep surveys and demographic data to predict severe OSA. Receiver operating characteristic (ROC) curve analysis was used to validate the simplified screening questionnaire. Data from another 78 stable COPD patients were used for validation. The apnea-hypopnea index was similar between the development and validation groups (26.3 ± 21.9 and 27.6 ± 21.1, respectively). After logistic regression analysis in the development group, snoring, body mass index ≥27.5 kg/m2, witnessed apnea and coronary artery disease were incorporated into the screening questionnaire to predict OSA. When this questionnaire was applied to the validation group, the results were similar. The simplified screening questionnaire developed is useful in identifying severe OSA in COPD patients.

6.
J Virol ; 94(3)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31723026

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), an AIDS-defining cancer with abnormal angiogenesis. The high incidence of KS in human immunodeficiency virus (HIV)-infected AIDS patients has been ascribed to an interaction between HIV type 1 (HIV-1) and KSHV, focusing on secretory proteins. The HIV-1 secreted protein HIV Tat has been found to synergize with KSHV lytic proteins to induce angiogenesis. However, the impact and underlying mechanisms of HIV Tat in KSHV-infected endothelial cells undergoing viral lytic reactivation remain unclear. Here, we identified LINC00313 as a novel KSHV reactivation-activated long noncoding RNA (lncRNA) that interacts with HIV Tat. We found that LINC00313 overexpression inhibits cell migration, invasion, and tube formation, and this suppressive effect was relieved by HIV Tat. In addition, LINC00313 bound to polycomb repressive complex 2 (PRC2) complex components, and this interaction was disrupted by HIV Tat, suggesting that LINC00313 may mediate transcription repression through recruitment of PRC2 and that HIV Tat alleviates repression through disruption of this association. This notion was further supported by bioinformatics analysis of transcriptome profiles in LINC00313 overexpression combined with HIV Tat treatment. Ingenuity Pathway Analysis (IPA) showed that LINC00313 overexpression negatively regulates cell movement and migration pathways, and enrichment of these pathways was absent in the presence of HIV Tat. Collectively, our results illustrate that an angiogenic repressive lncRNA, LINC00313, which is upregulated during KSHV reactivation, interacts with HIV Tat to promote endothelial cell motility. These results demonstrate that an lncRNA serves as a novel connector in HIV-KSHV interactions.IMPORTANCE KS is a prevalent tumor associated with infections with two distinct viruses, KSHV and HIV. Since KSHV and HIV infect distinct cell types, the virus-virus interaction associated with KS formation has focused on secretory factors. HIV Tat is a well-known RNA binding protein secreted by HIV. Here, we revealed LINC00313, an lncRNA upregulated during KSHV lytic reactivation, as a novel HIV Tat-interacting lncRNA that potentially mediates HIV-KSHV interactions. We found that LINC00313 can repress endothelial cell angiogenesis-related properties potentially by interacting with chromatin remodeling complex PRC2 and downregulation of cell migration-regulating genes. An interaction between HIV Tat and LINC00313 contributed to the dissociation of PRC2 from LINC00313 and the disinhibition of LINC00313-induced repression of cell motility. Given that lncRNAs are emerging as key players in tissue physiology and disease progression, including cancer, the mechanism identified in this study may help decipher the mechanisms underlying KS pathogenesis induced by HIV and KSHV coinfection.

7.
J Clin Monit Comput ; 34(1): 171-179, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30725265

RESUMO

Capnography involves the measurement of end-tidal CO2 (EtCO2) values to detect hypoventilation in patients undergoing sedation. In a previous study, we reported that initiating a flexible bronchoscopy (FB) examination only after detecting signs of hypoventilation could reduce the risk of hypoxemia without compromising the tolerance of the patient for this type of intervention. We hypothesize that hypoventilation status could be determined with greater precision by combining thoracic impedance-based respiratory signals, RESP, and EtCO2 signals obtained from a nasal-oral cannula. Retrospective analysis was conducted on RESP and EtCO2 waveforms obtained from patients during the induction of sedation using propofol for bronchoscopic examination in a previous study. EtCO2 waveforms associated with hypoventilation were then compared with RESP patterns, patient variables, and sedation outcomes. Signals suitable for analysis were obtained from 44 subjects, 42 of whom presented indications of hypoventilation, as determined by EtCO2 waveforms. Two subtypes of hypoventilation were identified by RESP: central-predominant (n = 22, flat line RESP pattern) and non-central-predominant (n = 20, RESP pattern indicative of respiratory effort with upper airway collapse). Compared to cases of non-central-predominant hypoventilation, those presenting central-predominant hypoventilation during induction were associated with a lower propofol dose (40.2 ± 18.3 vs. 60.8 ± 26.1 mg, p = 0.009), a lower effect site concentration of propofol (2.02 ± 0.33 vs. 2.38 ± 0.44 µg/ml, p = 0.01), more rapid induction (146.1 ± 105.5 vs. 260.9 ± 156.2 s, p = 0.01), and lower total propofol dosage (96.6 ± 41.7 vs. 130.6 ± 53.4 mg, p = 0.04). Hypoventilation status (as revealed by EtCO2 levels) could be further classified by RESP into central-predominant or non-central-predominant types. It appears that patients with central-predominant hypoventilation are more sensitive to propofol during the induction of sedation. RESP values could be used to tailor sedation management specifically to individual patients.

8.
PLoS One ; 14(12): e0225423, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31790451

RESUMO

INTRODUCTION: Positive fluid balance is a prognostic factor for mortality in patients with sepsis; however, the association between cumulated fluid balance (CFB) and sepsis-induced multi-organ dysfunction syndrome (MODS) has yet to be elucidated. In this study, we sought to determine whether CFB is correlated with MODS and mortality in cases of septic shock. METHODS: The study retrospectively recruited patients with septic shock from the intensive care unit of a tertiary care hospital. Multiple organ dysfunction syndrome (MODS) was identified as sequential organ failure assessment (SOFA) score ≥ 2 in more than one organ system. The CFB is the sum of all daily intake and output. An independent t-test, single and multivariate logistic regression, the receiver operating characteristic (ROC) curves, and the Pearson correlation coefficient were used to determine whether a relationship exists between CFB and the development of MODS and mortality. RESULTS: Among the 104 patients enrolled in the study, 58 (55.8%) survived more than 28 days, and 73 (70.2%) developed MODS on day 3. The values of CFB in the first 24 hours and 72 hours after diagnosis of septic shock in patients with MODS were higher than these in patients without MODS (1086.6 ± 176.3 vs. 325.5 ± 205.7 ml, p = 0.013 and 2408 ± 361 vs. 873.1 ± 489 ml, p < 0.0001). In a multivariate logistic regression, the independent factors associated with the development of MODS on day 3 were APACHE II score at ICU admission (27.6 ± 7.6 in patients with MODS vs. 20.5 ± 6.4 in those without; O.R. 1.18; 95% C.1 I. 1.08-1.30; p < 0.001), disseminated intravascular coagulopathy (DIC) (n = 28; 38.4% vs. n = 2; 6.5%; O.R. 23.67; 95% C.I. 3.58-156.5; p = 0.001), and CFB in the first 72 hours (72-hr CFB) > median (1767.50ml) (n = 41; 56.2% vs. n = 11; 35.5%; O.R. 3.67; 95% C.I., 1.18-11.40; p = 0.024). Moreover, a multivariate logistic regression also identified neoplasm (n = 25; 54.3% vs. n = 17; 29.3%; O.R. 3.45; 95% C.I. 1.23-10.0; p = 0.019) and 72-hr CFB > median (n = 30; 65.2% vs. n = 21; 36.2%; O.R. 4.13; 95% C.I. 1.34-12.66; p = 0.013) as independent factors associated with 28-day mortality. 72-hr CFB values were strongly correlated with the SOFA score (r = 0.445, p < 0.0001). The area under the ROC curve revealed that 72-hr CFB has good discriminative power in associating the development of MODS (0.644, p = 0.002) and predicting subsequent 28-day mortality (0.704, p < 0.0001). CONCLUSIONS: 72-hr CFB appears to be correlated with the likelihood of developing MODS and mortality in patients with septic shock. Thus, it appears that 72-hr CFB could perhaps be used as an indicator for MODS and a predictor for mortality in those patients.


Assuntos
Insuficiência de Múltiplos Órgãos/epidemiologia , Choque Séptico/epidemiologia , Choque Séptico/mortalidade , Equilíbrio Hidroeletrolítico , APACHE , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Unidades de Terapia Intensiva , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Prognóstico , Curva ROC , Estudos Retrospectivos , Taxa de Sobrevida , Taiwan/epidemiologia , Centros de Atenção Terciária
9.
Pharmaceutics ; 11(11)2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31717826

RESUMO

In recent decades, the decellularized extracellular matrix (ECM) has shown potential as a promising scaffold for tissue regeneration. In this study, an organic acid decellularized lymph node (dLN) was developed as a carrier for dendritic cells (DCs) to induce antitumor immunity. The dLNs were prepared by formic acid, acetic acid, or citric acid treatment. The results showed highly efficient removal of cell debris from the lymph node and great preservation of ECM architecture and biomolecules. In addition, bone marrow dendritic cells (BMDCs) grown preferably inside the dLN displayed the maturation markers CD80, CD86, and major histocompatibility complex (MHC)-II, and they produced high levels of interleukin (IL)-1ß, IL-6, and IL-12 cytokines when stimulated with ovalbumin (OVA) and CpG oligodeoxynucleotides (CPG-ODN). In an animal model, the BMDC-dLN completely rejected the E.G7-OVA tumor. Furthermore, the splenocytes from BMDC-dLN-immunized mice produced more interferon gamma, IL-4, IL-6, and IL-2, and they had a higher proliferation rate than other groups when re-stimulated with OVA. Hence, BMDC-dLN could be a promising DC-based scaffold for in vivo delivery to induce potent antitumor immunity.

10.
Science ; 366(6466): 714-723, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31699932

RESUMO

Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.


Assuntos
Carcinogênese/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/genética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/química , Classe Ia de Fosfatidilinositol 3-Quinase/química , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Feminino , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Ligação Proteica , Domínios Proteicos , Tiazóis/farmacologia
11.
Nat Commun ; 10(1): 4180, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519888

RESUMO

Algae produce the largest amount of oxygen on earth and are invaluable for human nutrition and biomedicine, as well as for the chemical industry, energy production and agriculture. The mechanisms by which algae can detect and respond to changes in their environments can rely on membrane receptors, including TRP ion channels. Here we present a 3.5-Å resolution cryo-EM structure of the transient receptor potential (TRP) channel crTRP1 from the alga Chlamydomonas reinhardtii that opens in response to increased temperature and is positively regulated by the membrane lipid PIP2. The structure of crTRP1 significantly deviates from the structures of other TRP channels and has a unique 2-fold symmetrical rose-shape architecture with elbow domains and ankyrin repeat domains submerged and dipping into the membrane, respectively. Our study provides a structure of a TRP channel from a micro-organism and a structural framework for better understanding algae biology and TRP channel evolution.


Assuntos
Chlamydomonas reinhardtii/metabolismo , Proteínas de Plantas/metabolismo , Canais de Receptores Transientes de Potencial/metabolismo , Repetição de Anquirina/genética , Repetição de Anquirina/fisiologia , Chlamydomonas reinhardtii/genética , Microscopia Crioeletrônica , Células HEK293 , Humanos , Proteínas de Plantas/genética , Estrutura Secundária de Proteína , Canais de Receptores Transientes de Potencial/genética
12.
Cancer Sci ; 110(10): 3204-3214, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385416

RESUMO

Peritoneal dissemination is the most frequent metastatic route of ovarian cancer. However, due to the high heterogeneity in ovarian cancer, most conventional studies lack parental tumor controls relevant to metastases and, thus, it is difficult to trace the molecular changes of cancer cells along with the selection by the abdominal microenvironment. Here, we established an in vivo mouse peritoneal dissemination scheme that allowed us to select more aggressive sublines from parental ovarian cancer cells, including A2780 and SKOV-3. Microarray and gene profiling analyses indicated that autophagy-related genes were enriched in selected malignant sublines. Detection of LC3-II, p62 and autophagic puncta demonstrated that these malignant variants were more sensitive to autophagic induction when exposed to diverse stress conditions, such as high cell density, starvation and drug treatment. As compared with parental A2780, the selected variant acquired the ability to grow better under high-density stress; however, this effect was reversed by addition of autophagic inhibitors or knockdown of ATG5. When analyzing the clinical profiles of autophagy-related genes identified to be enriched in malignant A2780 variant, 73% of them had prognostic significance for the survival of ovarian cancer patients. Taken together, our findings indicate that an increase in autophagic potency among ovarian cancer cells is crucial for selection of metastatic colonies in the abdominal microenvironment. In addition, the derived autophagic gene profile can not only predict prognosis well but can also be potentially applied to precision medicine for identifying those ovarian cancer patients suitable for taking anti-autophagy cancer drugs.


Assuntos
Proteínas Relacionadas à Autofagia/genética , Perfilação da Expressão Gênica/métodos , Proteínas Associadas aos Microtúbulos/genética , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Proteínas de Ligação a RNA/genética , Animais , Autofagia , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Humanos , Camundongos , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/patologia , Medicina de Precisão , Prognóstico , Microambiente Tumoral
13.
Sci Adv ; 5(7): eaaw2326, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31309145

RESUMO

The highly conserved Elongator complex modifies transfer RNAs (tRNAs) in their wobble base position, thereby regulating protein synthesis and ensuring proteome stability. The precise mechanisms of tRNA recognition and its modification reaction remain elusive. Here, we show cryo-electron microscopy structures of the catalytic subcomplex of Elongator and its tRNA-bound state at resolutions of 3.3 and 4.4 Å. The structures resolve details of the catalytic site, including the substrate tRNA, the iron-sulfur cluster, and a SAM molecule, which are all validated by mutational analyses in vitro and in vivo. tRNA binding induces conformational rearrangements, which precisely position the targeted anticodon base in the active site. Our results provide the molecular basis for substrate recognition of Elongator, essential to understand its cellular function and role in neurodegenerative diseases and cancer.


Assuntos
Complexos Multiproteicos/metabolismo , Fatores de Alongamento de Peptídeos/metabolismo , RNA de Transferência/genética , Anticódon/química , Sítios de Ligação , Domínio Catalítico , Histona Acetiltransferases/química , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Modelos Moleculares , Conformação Molecular , Complexos Multiproteicos/química , Fatores de Alongamento de Peptídeos/química , Fatores de Alongamento de Peptídeos/genética , Ligação Proteica , RNA de Transferência/química , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
14.
Toxins (Basel) ; 11(5)2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072027

RESUMO

Aflatoxins are carcinogenic secondary metabolites of fungi that contaminate many staple crops and foods. Aflatoxin contamination is a worldwide problem, especially in developing countries, posing health hazards, e.g., causing aflatoxicosis and hepatocellular carcinoma, and even death. Biological solutions for aflatoxin detoxification are environmentally friendly and a cheaper alternative than chemical methods. The aims of the current study were to investigate: (1) the ability of MSMEG_5998, an aflatoxin-degrading F420H2-dependent reductase from Mycobacterium smegmatis, to degrade aflatoxin B1 (AFB1) and reduce AFB1-caused damage in HepG2 cell culture model; and (2) whether a thioredoxin (Trx) linkage of MSMEG_5998 enhanced the enzyme activity. We show that Trx-linked MSMEG_5998 degraded 63% AFB1 and native MSMEG_5998 degraded 31% after 4 h at 22 °C, indicating that the Trx-linked enzyme had a better AFB1-degrading ability. In a HepG2 cell culture model, Trx-linked MSMEG_5998 reduced DNA damage and p53-mediated apoptosis caused by AFB1 to a greater extent than the native enzyme. These findings suggest that Trx-linked MSMEG_5998 could potentially be developed to protect the liver from AFB1 damage, or as a candidate protein to reduce AFB1-related toxicity in animals.


Assuntos
Aflatoxinas/toxicidade , Mycobacterium smegmatis/enzimologia , Oxirredutases/farmacologia , Substâncias Protetoras/farmacologia , Apoptose/efeitos dos fármacos , Dano ao DNA , Estabilidade Enzimática , Células Hep G2 , Humanos , Proteínas Recombinantes/farmacologia
15.
Taiwan J Ophthalmol ; 9(1): 43-45, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30993067

RESUMO

Traditional hydrodissection may cause posterior capsule rupture (PCR) if excessive fluid accumulates. In this study, we describe the successful application of a novel minimal fluid hydrodissection technique in 100 consecutive cataract surgery cases. This technique separates the nucleus from the capsule utilizing low hydrostatic pressure and precise kinetic movement of a small volume (around 0.2 cc) of balanced salt solution. There were no instances of PCR. This technique is suitable for a range of cases, including femtosecond laser-assisted cataract surgery and posterior subcapsular cataract.

16.
Nat Commun ; 10(1): 625, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30733442

RESUMO

The Elongator complex catalyzes posttranscriptional tRNA modifications by attaching carboxy-methyl (cm5) moieties to uridine bases located in the wobble position. The catalytic subunit Elp3 is highly conserved and harbors two individual subdomains, a radical S-adenosyl methionine (rSAM) and a lysine acetyltransferase (KAT) domain. The details of its modification reaction cycle and particularly the substrate specificity of its KAT domain remain elusive. Here, we present the co-crystal structure of bacterial Elp3 (DmcElp3) bound to an acetyl-CoA analog and compare it to the structure of a monomeric archaeal Elp3 from Methanocaldococcus infernus (MinElp3). Furthermore, we identify crucial active site residues, confirm the importance of the extended N-terminus for substrate recognition and uncover the specific induction of acetyl-CoA hydrolysis by different tRNA species. In summary, our results establish the clinically relevant Elongator subunit as a non-canonical acetyltransferase and genuine tRNA modification enzyme.


Assuntos
Histona Acetiltransferases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Domínio Catalítico , Histona Acetiltransferases/química , Methanocaldococcus/metabolismo , RNA de Transferência/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Especificidade por Substrato
18.
Cell ; 175(6): 1546-1560.e17, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30500537

RESUMO

Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF). This repair capacity is overwhelmed when cytosolic THF hyperaccumulates in the absence of mitochondrially produced formate, leading to THF degradation. Unexpectedly, we also find that the classic antifolate methotrexate, by inhibiting its well-known target DHFR, causes even more extensive folate degradation in nearly all tested cancer cell lines. These findings shed light on design features of folate metabolism, provide a biochemical basis for clinically observed folate deficiency in QDPR-deficient patients, and reveal a hitherto unknown and unexplored cellular effect of methotrexate.


Assuntos
Carbono/metabolismo , Citosol/metabolismo , Formiatos/metabolismo , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Tetra-Hidrofolatos/metabolismo , Citosol/patologia , Células HCT116 , Células HeLa , Humanos , Células MCF-7 , Metotrexato/farmacocinética , Metotrexato/farmacologia , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Tetra-Hidrofolato Desidrogenase/metabolismo
19.
Front Physiol ; 9: 723, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30013479

RESUMO

Purpose: We propose a phenotype-based artificial intelligence system that can self-learn and is accurate for screening purposes and test it on a Level IV-like monitoring system. Methods: Based on the physiological knowledge, we hypothesize that the phenotype information will allow us to find subjects from a well-annotated database that share similar sleep apnea patterns. Therefore, for a new-arriving subject, we can establish a prediction model from the existing database that is adaptive to the subject. We test the proposed algorithm on a database consisting of 62 subjects with the signals recorded from a Level IV-like wearable device measuring the thoracic and abdominal movements and the SpO2. Results: With the leave-one-subject-out cross validation, the accuracy of the proposed algorithm to screen subjects with an apnea-hypopnea index greater or equal to 15 is 93.6%, the positive likelihood ratio is 6.8, and the negative likelihood ratio is 0.03. Conclusion: The results confirm the hypothesis and show that the proposed algorithm has potential to screen patients with SAS.

20.
J Cell Physiol ; 233(1): 497-505, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28294332

RESUMO

The tautomeric pair of garcinielliptone FC (GFC) is a novel tautomeric pair of polyprenyl benzophenonoid isolated from the pericarps of Garcinia subelliptica Merr. (G. subelliptica, Clusiaceae), a tree with abundant sources of polyphenols. Our previous report demonstrated that GFC induced apoptosis on various types of human cancer cell lines including chemoresistant human colorectal cancer HT-29 cells. In the present study, we observed that many autophagy-related genes in GFC-treated HT-29 cells were up- and down-regulated using a cDNA microarray containing oncogenes and kinase genes. GFC-induced autophagy of HT-29 cells was confirmed by observing the formation of acidic vesicular organelles, LC3 puncta, and double-membrane autophagic vesicles using flow cytometry, confocal microscopy, and transmission electron microscopy, respectively. Inhibition of AKT/mTOR/P70S6K signaling as well as formation of Atg5-Atg12 and PI3K/Beclin-1 complexes were observed using Western blot. Administration of autophagy inhibitor (3-methyladenine and shRNA Atg5) and apoptosis inhibitor Z-VAD showed that the GFC-induced autophagy was cytotoxic form and GFC-induced apoptosis enhanced GFC-induced autophagy. Our data suggest the involvement of autophagy and apoptosis in GFC-induced anticancer mechanisms of human colorectal cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Proteína 12 Relacionada à Autofagia/genética , Proteína 12 Relacionada à Autofagia/metabolismo , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/ultraestrutura , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Transfecção
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