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1.
J Acoust Soc Am ; 146(2): EL151, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31472534

RESUMO

The present work examined factors affecting the intelligibility of high-intensity-level-based speech. Mandarin sentences were processed to contain only high-intensity segments confined by a 5-dB selected intensity range (SIR), with other segments replaced by noise. The processed stimuli were presented to normal-hearing listeners to recognize. The greatest intensity density occurred in the SIR with an upper boundary 3 dB below the peak intensity level, and this SIR yielded the highest intelligibility score in quiet. The SIR with the upper boundary at the peak intensity level yielded better intelligibility performance under noisy conditions, due largely to the relatively high effective signal-to-noise ratio.

2.
J Acoust Soc Am ; 146(2): EL85, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31472565

RESUMO

Dynamic F0 contour plays an important role in recognizing speech. The present work examined the effect of F0 contour on speech intelligibility for hearing-impaired listeners for Mandarin Chinese in quiet, in steady noise, and in two-talker competing speech. The intelligibility of two types of natural speech was measured: single-Tone speech with relatively flat F0 contours and multi-Tone speech with time-varying F0 contours. The speech rate and mean F0 of speech materials were carefully controlled to avoid effects other than F0 contour on the speech intelligibility. Results showed that intelligibility was significantly higher for speech with a flat F0 contour than that with a dynamic F0 contour at a low signal-to-masker ratio in both speech-spectrum noise and two-talker masker.

3.
Hepatology ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31442319

RESUMO

Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult population. A significant subset of patients are lean, but their underlying pathophysiology is not well understood. We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor 19 (FGF19) levels (a surrogate for intestinal farnesoid X receptor [FXR] activity), patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and non-lean NAFLD were investigated in a cohort of Caucasian patients with biopsy-proven NAFLD (n = 538), lean healthy controls (n = 30), and experimental murine models. Patients with lean NAFLD had a more favorable metabolic and histological profile compared to those with non-lean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared to earlier stages of liver fibrosis. Patients with lean NAFLD had higher serum secondary BA and FGF19 levels and reduced 7-alpha-hydroxy-4-cholesten-3-one (C4) levels (P < 0.05 for all). These differences were more profound in early compared to advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and non-lean murine models of NAFLD. Treating mice with an apical sodium-dependent bile acid transporter inhibitor (ASBTi) (SC-435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model. CONCLUSION: Differences in metabolic adaptation between lean and non-lean NAFLD patients, at least in part, explain the pathophysiology and provide novel options for therapy. This article is protected by copyright. All rights reserved.

4.
BMC Neurol ; 19(1): 203, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438897

RESUMO

BACKGROUND: Vanishing white matter disease (VWMD) is one of the most prevalent inherited leukoencephalopathies, which generally presents in childhood as a progressive disorder while less beginning in adulthood. The present report describes the clinical, neuroimaging, and genetic findings of a female patient with adult-onset VWMD. In addition, to provide a clearer delineation of the clinical and genetic characteristics of female adult-onset VWMD patients, 32 genetically confirmed female adult-onset EIF2B-mutated cases are summarized. CASE PRESENTATION: The patient described here suffered from long-term menometrorrhagia prior to manifesting progressive neurological impairments that included tremors, bilateral pyramidal tract injury, cerebellar ataxia, and dementia. To the best of our knowledge, this is the first female patient with adult-onset VWMD suffering from long-term menometrorrhagia attributed to the c.254 T > A and c.496A > G mutations in the EIF2B2 gene; the c.496A > G mutation has not been reported in previous studies. The patient also exhibited metabolic dysfunction. The present findings widen the spectrum of phenotypic heterogeneity observed in VWMD patients. CONCLUSIONS: The present report summarizes 33 female patients with adult-onset VWMD to provide an overview of the clinical and genetic characteristics of this disorder and ovarioleukodystrophy. The mean age of clinical onset in female patients with adult-onset VWMD was 36.8 years and the neurological symptoms primarily included motor and cognitive dysfunction such as paraparesis, cerebellar ataxia, and executive deficits. In addition, ovarian failure occurred in all of these female patients and usually preceded the neurological symptoms. Furthermore, several patients also suffered from metabolic dysfunction. All 33 patients had mutations on EIF2B1-5, and of these, the c.338 G > A mutation in the EIF2B5 gene (p.Arg113His) was the most common. These findings suggest that clinicians should be aware of adult-onset forms of VWMD as well as its typical magnetic resonance imaging (MRI) and clinical characteristics although this pathology is usually recognized as a pediatric disorder. No curative treatment is presently available, and thus early recognition is important to prevent triggering events and to allow for genetic counseling.

5.
Medicine (Baltimore) ; 98(33): e16799, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415388

RESUMO

To investigate the characteristics of recurrent branchial cleft anomalies (BCAs) and to evaluate the surgical technique and outcomes of patients undergoing reoperation.From January 2005 to August 2018, the clinical data of 216 patients with recurrent second, third, and fourth BCAs were retrospectively analyzed. According to the embryological and anatomical features of the cleft palate and recurrence site, selective neck dissection techniques were used for surgical treatment.Among all 216 patients, 203 healed by primary healing. Twelve patients with local infections and 1 patient with a pharyngeal fistula healed after dressing changes. Eleven patients experienced transient hoarseness and recovered after a few months. Three patients developed permanent hoarseness, and 5 patients developed coughing after eating and drinking. Three patients underwent internal jugular vein ligation. Only 4 recurrences occurred during a follow-up period of more than 1 year. The total cure rate was 98.15%.Selective neck dissection is an effective and safe surgical treatment for recurrent second, third, and fourth branchial cleft anomalies.


Assuntos
Região Branquial/anormalidades , Anormalidades Craniofaciais/cirurgia , Esvaziamento Cervical/métodos , Doenças Faríngeas/cirurgia , Adolescente , Adulto , Região Branquial/patologia , Região Branquial/cirurgia , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Faríngeas/patologia , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
6.
Medicine (Baltimore) ; 98(33): e16828, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415402

RESUMO

RATIONALE: Congenital glucose-galactose malabsorption (CGGM) is a rare, autosomal recessive, hereditary disease that usuallypresents in newborns. CGGM manifests as severe diarrhea, hyperosmolar dehydration, and malnutrition. It does not respond to routine treatment and often is life-threatening. PATIENT CONCERNS: We described a Chinese infant girl with refractory diarrhea, who suffered from severe dehydration and malnutrition even if with fluid replacement therapy and fed with several special formulas. DIAGNOSES: The genetic analysis identified CGGM with SLC5A1 mutations. c.1436G > C (p.R479T) was a novel mutation. INTERVENTIONS: The patient was managed by free-glucose and galactose formula, and then special low-carbohydrate dietary therapy. OUTCOMES: The patient improved immediately after starting a free-glucose and galactose formula, and kept healthy with special low-carbohydrate diet. She had been followed up with nutritional management for 20 months. LESSONS: This report highlights the importance of differential diagnosis of congenital diarrhea and enteropathies. For CGGM, free-glucose and galactose milk powder was the most effective treatment. Low-carbohydrate diet gradually introduced was still a great challenge that requires continuing guidance from child nutritionists and dietitians. Long-term nutrition management was extremely important to ensure the normal growth and development of children.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/tratamento farmacológico , Dieta com Restrição de Carboidratos/métodos , Fórmulas Infantis , Síndromes de Malabsorção/tratamento farmacológico , Erros Inatos do Metabolismo dos Carboidratos/genética , China , Feminino , Galactose , Glucose , Humanos , Recém-Nascido , Síndromes de Malabsorção/genética , Mutação , Transportador 1 de Glucose-Sódio/genética
7.
Oncogene ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420604

RESUMO

Pancreatic cancer is a deadliest type of malignancy and lacks effective intervention. We here report a potential strategy for treatment of this malignancy by the combination of arsenic trioxide (ATO) and BET bromodomain inhibitor JQ1. These two agents synergistically modulate multistages of autophagy and thus induce apoptosis effectively in pancreatic cancer cells. Our genomic and biochemical data have demonstrated that crosstalks between ER stress and autophagy play crucial roles during ATO-induced apoptosis, in which NRF2 may stand at the crossroad between cell death and survival. This has been further strengthened by our finding that NRF2 depletion renders insensitive cells into sensitive ones in regard to ATO treatment-caused cell death. The knockdown of NRF2 and the addition of JQ1 result in similar molecular/cellular effects in promoting effective ATO-induced apoptosis in cells that are insensitive to ATO treatment alone. Thus, the combination of ATO and JQ1 may represent a new treatment strategy for pancreatic cancer.

8.
World J Gastroenterol ; 25(29): 3972-3984, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31413531

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the third most prevalent malignancy and has the fourth highest global cancer mortality rate. Early diagnosis and prompt medical attention can improve quality of life and the prognosis of CRC patients. Accumulating evidence reveals that long non-coding RNAs (lncRNAs) function as oncogenes or anti-oncogenes, as well as biomarkers in various cancers. AIM: To investigate the levels and molecular mechanism of the lncRNA maternally expressed gene 3 (MEG3) in CRC. METHODS: The levels of lncRNA MEG3 in CRC tissue, serum and cell line samples were explored via qRT-PCR. The relationship between MEG3 levels and clinicopathological features in CRC was investigated. The diagnostic and prognostic values of serum MEG3 levels were analyzed with ROC curves and Kaplan­Meier survival curves, respectively. RESULTS: Significant decreased levels of MEG3 existed in CRC tissue, cell lines and serum. CRC patients with down-regulated serum MEG3 levels had larger tumor sizes, and advanced clinical stages. The sensitivity and specificity of serum MEG3 levels in CRC detection was 0.667 and 0.875, respectively. Tumor size, T stages, and serum MEG3 levels are indie factors that produce an effect on CRC patients' prognosis. Kaplan­Meier survival curves suggested that CRC patients with high levels of MEG3 had a remarkably better overall survival rate. CONCLUSION: LncRNA MEG3 is down-regulated in CRC, and regulates cell functions by targeting adenosine deaminase's effect on RNA 1 in CRC.

9.
J Phys Chem Lett ; : 5105-5110, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31419133

RESUMO

Three Pt(II) complexes, Pt(czpyOczpy), Pt(czpyOczpy-Me), and Pt(czpyOczpy-OMe), are designed to elucidate the inherent relationship between electronically excited-state and photo- and electroluminescent properties. These complexes showed a blue-shifted phosphorescence with a narrowing spectral profile, which are interrelated with the variation of T1 states from the 3MLCT, hybridized 3(MLCT/LC) to 3LC transition. This change is ascribed to the destabilization of LUMO energy levels on the pyridinyl site, leading to more electron distribution on the carbazolide unit in T1. Moreover, the solution-processed device of Pt(czpyOczpy-OMe), featuring a 3LC transition, shows the best color purity of blue light. Compared to the device of Pt(czpyOczpy) with 3MLCT character, the device of Pt(czpyOczpy-Me) with hybridized 3(MLCT/LC) exhibits improved color purity and external quantum efficiency (10.2%) at a luminance of 1000 cd/m2. Therefore, this work gives a mechanistic interpretation of the phosphorescent properties of tetradentate Pt(II) complexes derived from the manageable lowest triplet excited states.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31424964

RESUMO

Expansion microscopy (ExM) is a physical form of magnification that increases the effective resolving power of any microscope. Here, we describe the fundamental principles of ExM, as well as how recently developed ExM variants build upon and apply those principles. We examine applications of ExM in cell and developmental biology for the study of nanoscale structures as well as ExM's potential for scalable mapping of nanoscale structures across large sample volumes. Finally, we explore how the unique anchoring and hydrogel embedding properties enable postexpansion molecular interrogation in a purified chemical environment. ExM promises to play an important role complementary to emerging live-cell imaging techniques, because of its relative ease of adoption and modification and its compatibility with tissue specimens up to at least 200 µm thick. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 35 is October 7, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

11.
Ear Hear ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31369470

RESUMO

OBJECTIVES: Lexical tone information provides redundant cues for the recognition of Mandarin sentences in listeners with normal hearing in quiet conditions. The contribution of lexical tones to Mandarin sentence recognition in listeners with hearing aids (HAs) is unclear. This study aimed to remove lexical tone information and examine the effects on Mandarin sentence intelligibility in HA users. The second objective was to investigate the contribution of cognitive abilities (i.e., general cognitive ability, working memory, and attention) on Mandarin sentence perception when the presentation of lexical tone information was mismatched. DESIGN: A text-to-speech synthesis engine was used to manipulate Mandarin sentences into three test conditions: (1) a Normal Tone test condition, where no alterations were made to lexical tones within sentences; (2) a Flat Tone test condition, where lexical tones were all changed into tone 1 (i.e., the flat tone); and (3) a Random Tone test condition, where each word in test sentences was randomly assigned one of four Mandarin lexical tones. The manipulated sentence signals were presented to 32 listeners with HAs in both quiet and noisy environments at an 8 dB signal to noise ratio. RESULTS: Speech intelligibility was reduced significantly (by approximately 40 percentage points) in the presence of mismatched lexical tone information in both quiet and noise. The difficulty in correctly identifying sentences with mismatched lexical tones among adults with hearing loss was significantly greater than that of adults with normal hearing. Cognitive function was not significantly related to a decline in speech recognition scores. CONCLUSIONS: Contextual and other phonemic cues (i.e., consonants and vowels) are inadequate for HA users to perceive sentences with mismatched lexical tone contours in quiet or noise. Also, HA users with better cognitive function could not compensate for the loss of lexical tone information. These results highlight the importance of accurately representing lexical tone information for Mandarin speakers using HAs.

12.
J Acoust Soc Am ; 146(1): EL52, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31370567

RESUMO

The present work assesses the effect of low-pass filtering on masking release in Mandarin sentence recognition. Mandarin sentences were masked by steady-state noise and two-talker masker, processed by low-pass filtering, and presented to normal-hearing listeners to recognize. Negative release was observed at low-pass filtering cutoff frequencies ≤750 Hz, with listeners showing better performance under the steady-state noise condition than under the two-talker masker condition. The negative release was affected by the input signal-to-noise ratio. Language characteristics might partially account for the negative release observed with Mandarin speech.

13.
Autophagy ; : 1-16, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31373534

RESUMO

The roles of SUMOylation and the related enzymes in autophagic regulation are unclear. Based on our previous studies that identified the SUMO2/3-specific peptidase SENP3 as an oxidative stress-responsive molecule, we investigated the correlation between SUMOylation and macroautophagy/autophagy. We found that Senp3± mice showed increased autophagy in the liver under basal and fasting conditions, compared to Senp3+/+ mice. We constructed a liver-specific senp3 knockout mouse; these Senp3-deficient liver tissues showed increased autophagy as well. Autophagic flux was accelerated in hepatic and other cell lines following knockdown of SENP3, both before and after the cells underwent starvation in the form of the serum and amino acid deprivation. We demonstrated that BECN1/beclin 1, the core molecule of the BECN1-PIK3C3 complex, could be SUMO3-conjugated by PIAS3 predominantly at K380 and deSUMOylated by SENP3. The basal SUMOylation of BECN1 was increased upon cellular starvation, which enhanced autophagosome formation by facilitating BECN1 interaction with other complex components UVRAG, PIK3C3 and ATG14, thus promoting PIK3C3 activity. In contrast, SENP3 deSUMOylated BECN1, which impaired BECN1-PIK3C3 complex formation or stability to suppress the PIK3C3 activity. DeSUMOylation of BECN1 restrained autophagy induction under basal conditions and especially upon starvation when SENP3 had accumulated in response to the increased generation of reactive oxygen species. Thus, while reversible SUMOylation regulated the degree of autophagy, SENP3 provided an intrinsic overflow valve for fine-tuning autophagy induction. Abbreviations: AL: autolysosome; AP: autophagosome; ATG: autophagy related; ATG14: autophagy related 14; BECN1: beclin 1, autophagy related; cKO: conditional knockout; co-IP: co-immunoprecipitation; CQ: chloroquine; EBSS: Earle's balanced salt solution; GFP: green fluorescent protein; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PTM: post-translational modification; RFP: red fluorescent protein; ROS: reactive oxygen species; RUBCN/rubicon: RUN domain and cysteine-rich domain containing, BECN1-interacting protein; SENP3: SUMO specific peptidase 3; shRNA: small hairpin RNA; siRNA: small interfering RNA; SQSTM1: sequestosome 1; SUMO: small ubiquitin-like modifier; UVRAG: UV radiation resistance associated gene.

14.
Anesthesiology ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31365369

RESUMO

Anesthesiologists are both teachers and learners and alternate between these roles throughout their careers. However, few anesthesiologists have formal training in the methodologies and theories of education. Many anesthesiology educators often teach as they were taught and may not be taking advantage of current evidence in education to guide and optimize the way they teach and learn. This review describes the most up-to-date evidence in education for teaching knowledge, procedural skills, and professionalism. Methods such as active learning, spaced learning, interleaving, retrieval practice, e-learning, experiential learning, and the use of cognitive aids will be described. We made an effort to illustrate the best available evidence supporting educational practices while recognizing the inherent challenges in medical education research. Similar to implementing evidence in clinical practice in an attempt to improve patient outcomes, implementing an evidence-based approach to anesthesiology education may improve learning outcomes.

15.
BMC Nephrol ; 20(1): 311, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395027

RESUMO

BACKGROUND: Patients suffering from acute kidney injury (AKI) were associated with impaired sodium and potassium homeostasis. We aimed to investigate how admission serum sodium and potassium independently and jointly modified adverse clinical outcomes among AKI patients. METHODS: Patient data were extracted from the Multiparameter Intelligent Monitoring in Intensive Care Database III. Participants were categorized into three groups according to admission serum sodium and potassium, and the cut-off values were determined using smooth curve fitting. The primary outcome was 90-day mortality in the intensive care unit (ICU). Cox proportional hazards models were used to evaluate the prognostic effects of admission serum sodium and potassium levels. RESULTS: We included 13,621 ICU patients with AKI (mean age: 65.3 years; males: 55.4%). The middle category of admission serum sodium and potassium levels were 136.0-144.9 mmol/L and 3.7-4.7 mmol/L through fitting smooth curve. In multivariable Cox models, compared with the middle category, patients with hyponatremia or hypernatremia were associated with excess mortality and the HRs and its 95%CIs were 1.38 (1.27, 1.50) and 1.56 (1.36, 1.79), and patients with either hypokalemia or hyperkalemia were associated with excess mortality and the hazard ratios (HRs) and its 95% confidential intervals (95% CIs) were 1.12 (1.02, 1.24) and 1.25 (1.14, 1.36), respectively. Significant interactions were observed between admission serum sodium and potassium levels (P interaction = 0.001), with a higher serum potassium level associated with increased risk of 90-day mortality among patients with hyponatremia, whereas the effects of higher sodium level on prognostic effects of potassium were subtle. CONCLUSIONS: Admission serum sodium and potassium were associated with survival in a U-shaped pattern among patients with AKI, and hyperkalemia predict a worse clinical outcome among patients with hyponatremia.

16.
J Cell Biol ; 218(9): 3002-3018, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31387940

RESUMO

The BH3-only pro-apoptotic protein BIK is regulated by the ubiquitin-proteasome system. However, the mechanism of this regulation and its physiological functions remain elusive. Here, we identify Cul5-ASB11 as the E3 ligase targeting BIK for ubiquitination and degradation. ER stress leads to the activation of ASB11 by XBP1s during the adaptive phase of the unfolded protein response, which stimulates BIK ubiquitination, interaction with p97/VCP, and proteolysis. This mechanism of BIK degradation contributes to ER stress adaptation by promoting cell survival. Conversely, genotoxic agents down-regulate this IRE1α-XBP1s-ASB11 axis and stabilize BIK, which contributes in part to the apoptotic response to DNA damage. We show that blockade of this BIK degradation pathway by an IRE1α inhibitor can stabilize a BIK active mutant and increase its anti-tumor activity. Our study reveals that different cellular stresses regulate BIK ubiquitination by ASB11 in opposing directions, which determines whether or not cells survive, and that blocking BIK degradation has the potential to be used as an anti-cancer strategy.

17.
J Proteome Res ; 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31364357

RESUMO

Database searches of MS/MS spectra are the main approach to peptide/protein identification in proteomics. Since most database search engines only utilize a small portion of the original MS/MS signals for peptide detection, how to improve the quality of MS/MS signals is a primary concern for enhancement of the peptide/protein identification rate. A fundamental issue is that some noise MS signals, informative or uninformative, have to be filtered out prior to database searching. Herein, an integrative preprocessing algorithm was designed, termed pClean, which incorporates three modules to preprocess MS/MS spectra, such as the removal of isobaric-labeling related ions, the reduction in isotopic peaks, the deconvolution of ions with higher charges, and the clearance of uninformative MS/MS signals. In contrast to the currently available approaches to MS/MS data preprocessing, pClean enables treatment of MS/MS spectra with high mass accuracy and favors filtering for the labeling or nonlabeling of peptides. Data sets at various scales gained from mass spectrometers with high resolution were used to assess the quality of peptides identified after pClean treatment and to compare the pClean improvement with those of other software programs. On the basis of the analysis of peptides identified and the Mascot ion score, pClean was proven to be effective in the removal of mass spectral noise and the reduction of random matching. Compared with other software programs, pClean appeared to be beneficial in terms of preprocessing performances for the enhancement of confidence scores and the increase in peptides identified. pClean is available at https://github.com/AimeeD90/pClean_release .

18.
Biomed Pharmacother ; 118: 109237, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31376653

RESUMO

Tea consumption has positive effects on the skeletal system and prevents postmenopausal osteoporosis, mainly by inhibiting osteoclastogenesis. In green tea, (-)-epigallocatechin-3-gallate (EGCG) is the most abundant and active compound and has been shown to inhibit RANKL-induced osteoclast formation. Taking into account the highly oxidizable and unstable nature of EGCG, we hypothesized that EGCG oxidation product exhibits greater anti-osteoclastogenesis potential than EGCG. In this study, we successfully isolated and identified an EGCG oxidation derivative, (-)-gallocatechin gallate (compound 2), using a chemical oxidation strategy. We then compared the ability of compound 2 and EGCG to inhibit RANKL-induced osteoclastogenesis in RAW 264.7 cells. The results of TRAP staining and F-actin ring immunofluorescent staining showed that compound 2 exhibits stronger inhibition of RANKL-induced osteoclast differentiation and F-actin ring formation, respectively, than EGCG. Additionally, quantitative real-time PCR (qRT-PCR) and western blotting analyses showed that compound 2 significantly and more strongly inhibited the expression of osteoclastogenesis-related marker genes and proteins, including c-Src, TRAP, cathepsin K, ß3-Integrin, and MMP-9, compared with EGCG. Furthermore, compound 2 significantly suppressed RANKL-induced expression of NFATc1 and c-Fos, the master transcriptional regulators of osteoclastogenesis, more strongly than EGCG. Mechanistically, molecular interaction assays showed that compound 2 binds to RANK with high affinity (KD = 189 nM) and blocks RANKL-RANK interactions, thereby suppressing RANKL-induced early RANK signaling pathways including p65, JNK, ERK, and p38 in osteoclast precursors. Taken together, this study demonstrates for the first time that an oxidation derivative of EGCG (compound 2) inhibits RANKL-induced osteoclastogenesis by suppressing RANK signaling pathways in RAW 264.7 cells.

19.
PLoS Genet ; 15(8): e1008344, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31469826

RESUMO

Pancreatic adenocarcinoma (PC) is a lethal malignancy that is familial or associated with genetic syndromes in 10% of cases. Gene-based surveillance strategies for at-risk individuals may improve clinical outcomes. However, familial PC (FPC) is plagued by genetic heterogeneity and the genetic basis for the majority of FPC remains elusive, hampering the development of gene-based surveillance programs. The study was powered to identify genes with a cumulative pathogenic variant prevalence of at least 3%, which includes the most prevalent PC susceptibility gene, BRCA2. Since the majority of known PC susceptibility genes are involved in DNA repair, we focused on genes implicated in these pathways. We performed a region-based association study using the Mixed-Effects Score Test, followed by leave-one-out characterization of PC-associated gene regions and variants to identify the genes and variants driving risk associations. We evaluated 398 cases from two case series and 987 controls without a personal history of cancer. The first case series consisted of 109 patients with either FPC (n = 101) or PC at ≤50 years of age (n = 8). The second case series was composed of 289 unselected PC cases. We validated this discovery strategy by identifying known pathogenic BRCA2 variants, and also identified SMG1, encoding a serine/threonine protein kinase, to be significantly associated with PC following correction for multiple testing (p = 3.22x10-7). The SMG1 association was validated in a second independent series of 532 FPC cases and 753 controls (p<0.0062, OR = 1.88, 95%CI 1.17-3.03). We showed segregation of the c.4249A>G SMG1 variant in 3 affected relatives in a FPC kindred, and we found c.103G>A to be a recurrent SMG1 variant associating with PC in both the discovery and validation series. These results suggest that SMG1 is a novel PC susceptibility gene, and we identified specific SMG1 gene variants associated with PC risk.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31441307

RESUMO

Thus far, there is still no study systematically investigating the influence of asymmetric side-chain design on a polymer's stretchability and its associated stretchable device applications. Herein, three kinds of asymmetric side chains consisting of carbosilane side chain (Si-C8), siloxane-terminated side chain (SiO-C8), and decyltetradecane side chain (DT) are engineered in isoindigo-bithiophene (PII2T, P1-P3) and isoindigo-difluorobithiophene (PII2TF, P4-P6) conjugated polymers, and their structure-stretchability correlation is explored in field-effect transistor characterization. It is revealed that owing to the geometric difference between the side chains, different asymmetric side-chain combinations impose distinct influences on the molecular stacking and orientation of the derived polymers. Surprisingly, the combination of asymmetric side chains and backbone fluorination is shown to deliver the best stretchability and mechanical durability of the derived polymer. Consequently, P6 consisting of asymmetric Si-C8/DT side chains and fluorinated backbone possesses the best mobility preservation of 81% at 100% strain with the stretching force perpendicular to the charge-transporting direction. Moreover, it presents 90% mobility retention after 400 stretching-releasing cycles with 60% strain, greatly exceeding the value (36%) of the non-fluorinated counterpart (P3). Our results suggest that the rational design of asymmetric side chains and backbone fluorination provides an efficient way to enhance the intrinsic stretchability of conjugated polymers.

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