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1.
Proc Natl Acad Sci U S A ; 121(44): e2415383121, 2024 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-39446389

RESUMO

Phosphoprotein phosphatases (PPPs) are the key serine/threonine phosphatases that regulate all essential signaling cascades. In particular, Protein Phosphatase 1 (PP1) dephosphorylates ~80% of all ser/thr phosphorylation sites. Here, we developed a phosphatase targeting peptide (PhosTAP) that binds all PP1 isoforms and does so with a stronger affinity than any other known PP1 regulator. This PhosTAP can be used as a PP1 recruitment tool for Phosphorylation Targeting Chimera (PhosTAC)-type recruitment in in vitro and cellular experiments, as well as in phosphoproteomics experiments to identify PP1-specific substrates and phosphosites. The latter is especially important to further our understanding of cellular signaling, as the identification of substrates and especially phosphosites that are targeted by specific phosphatases lags behind that of their kinase counterparts. Using PhosTAP-based proteomics, we show that, counter to our current understanding, many PP1 regulators are also substrates, that the number of residues between regulator PP1-binding and phosphosites vary significantly, and that PP1 counteracts the activities of mitotic kinases. Finally, we also found that Haspin kinase is a direct substrate of PP1 and that its PP1-dependent dephosphorylation modulates its activity during anaphase. Together, we show that PP1-specific PhosTAPs are a powerful tool for +studying PP1 activity in vitro and in cells.


Assuntos
Peptídeos , Proteína Fosfatase 1 , Proteína Fosfatase 1/metabolismo , Humanos , Fosforilação , Peptídeos/metabolismo , Peptídeos/química , Proteômica/métodos , Especificidade por Substrato , Células HEK293 , Fosfoproteínas/metabolismo , Células HeLa , Ligação Proteica
2.
Nature ; 583(7814): 55-59, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32612227

RESUMO

Valence electrons contribute a small fraction of the total electron density of materials, but they determine their essential chemical, electronic and optical properties. Strong laser fields can probe electrons in valence orbitals1-3 and their dynamics4-6 in the gas phase. Previous laser studies of solids have associated high-harmonic emission7-12 with the spatial arrangement of atoms in the crystal lattice13,14 and have used terahertz fields to probe interatomic potential forces15. Yet the direct, picometre-scale imaging of valence electrons in solids has remained challenging. Here we show that intense optical fields interacting with crystalline solids could enable the imaging of valence electrons at the picometre scale. An intense laser field with a strength that is comparable to the fields keeping the valence electrons bound in crystals can induce quasi-free electron motion. The harmonics of the laser field emerging from the nonlinear scattering of the valence electrons by the crystal potential contain the critical information that enables picometre-scale, real-space mapping of the valence electron structure. We used high harmonics to reconstruct images of the valence potential and electron density in crystalline magnesium fluoride and calcium fluoride with a spatial resolution of about 26 picometres. Picometre-scale imaging of valence electrons could enable direct probing of the chemical, electronic, optical and topological properties of materials.

3.
J Biol Chem ; 300(1): 105515, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38042495

RESUMO

SDS22 and Inhibitor-3 (I3) are two ancient regulators of protein phosphatase 1 (PP1) that regulate multiple essential biological processes. Both SDS22 and I3 form stable dimeric complexes with PP1; however, and atypically for PP1 regulators, they also form a triple complex, where both proteins bind to PP1 simultaneously (SPI complex). Here we report the crystal structure of the SPI complex. While both regulators bind PP1 in conformations identical to those observed in their individual PP1 complexes, PP1 adopts the SDS22-bound conformation, which lacks its M1 metal. Unexpectedly, surface plasmon resonance (SPR) revealed that the affinity of I3 for the SDS22:PP1 complex is ∼10-fold lower than PP1 alone. We show that this change in binding affinity is solely due to the interaction of I3 with the PP1 active site, specifically PP1's M2 metal, demonstrating that SDS22 likely allows for PP1 M2 metal exchange and thus PP1 biogenesis.


Assuntos
Domínio Catalítico , Proteína Fosfatase 1 , Ubiquitina-Proteína Ligases , Ligação Proteica , Proteína Fosfatase 1/química , Humanos , Ubiquitina-Proteína Ligases/química , Microscopia Crioeletrônica , Metais/química
4.
Mol Cell ; 65(4): 644-658.e5, 2017 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-28212750

RESUMO

Protein function originates from a cooperation of structural rigidity, dynamics at different timescales, and allostery. However, how these three pillars of protein function are integrated is still only poorly understood. Here we show how these pillars are connected in Protein Tyrosine Phosphatase 1B (PTP1B), a drug target for diabetes and cancer that catalyzes the dephosphorylation of numerous substrates in essential signaling pathways. By combining new experimental and computational data on WT-PTP1B and ≥10 PTP1B variants in multiple states, we discovered a fundamental and evolutionarily conserved CH/π switch that is critical for positioning the catalytically important WPD loop. Furthermore, our data show that PTP1B uses conformational and dynamic allostery to regulate its activity. This shows that both conformational rigidity and dynamics are essential for controlling protein activity. This connection between rigidity and dynamics at different timescales is likely a hallmark of all enzyme function.


Assuntos
Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Regulação Alostérica , Sequência de Aminoácidos , Sítios de Ligação , Catálise , Domínio Catalítico , Sequência Conservada , Cristalografia , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Genótipo , Humanos , Cinética , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Mutação , Ressonância Magnética Nuclear Biomolecular , Fenótipo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Domínios Proteicos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Relação Estrutura-Atividade
5.
Zhonghua Yan Ke Za Zhi ; 59(1): 20-25, 2023 Jan 11.
Artigo em Zh | MEDLINE | ID: mdl-36631053

RESUMO

Objective: To investigate the histopathological classification of orbital space-occupying lesions. Methods: This is a retrospective case series study. The clinical and pathological data of 1 913 tissue specimens from 1 913 patients with space-occupying lesions of the orbit which were examined in the Second Affiliated Hospital, Zhejiang University School of Medicine from January 2000 to December 2021 were collected. The mass lesions were classified based on histogenesis, pathological nature and age. Results: There were 913 males (47.7%) and 1 000 females (52.3%). The lesions were benign in 1 489 patients (77.8%) and malignant in 424 patients (22.2%). Based on histogenesis, there were 521 vasculogenic lesions (27.2%), which rancked first, 407 cystoid lesions (21.3%), 277 lymphoproliferative lesions (14.5%), 182 lacrimal gland lesions (9.5%) and 121 inflammatory lesions (6.3%). By pathological nature, there were 1 489 benign lesions, including cavernous hemangioma (275, 14.4%), dermoid cyst (225, 11.8%), other hemangiomas (199, 10.4%), epidermoid cyst (136, 7.1%) and benign mixed tumor of the lacrimal gland (134, 7.0%), and 257 malignant lesions, including lymphoma (210, 11.0%) and sebaceous gland carcinoma (47, 2.5%). The age of all patients ranged from 0 to 90 years, while 247 lesions (12.9%) occurred in patients aged 0 to18 years, 1 270 lesions (66.4%) in patients aged 19 to 59 years, and 396 lesions (20.7%) in patients aged 60 to 90 years. Conclusions: In 22 years, almost 2/3 benign orbital lesions in the Second Affiliated Hospital, Zhejiang University School of Medicine occurred in young and middle-aged patients, and males were fewer than females. The most common benign orbital tumors was cavernous hemangioma, followed by dermoid cyst and epidermoid cyst. And the most common malignant orbital tumor was lymphoma, which occurred more frequently in older patients.


Assuntos
Cisto Dermoide , Cisto Epidérmico , Hemangioma Cavernoso , Linfoma , Neoplasias Orbitárias , Masculino , Pessoa de Meia-Idade , Feminino , Humanos , Idoso , Órbita , Cisto Dermoide/patologia , Estudos Retrospectivos , Neoplasias Orbitárias/patologia , Linfoma/patologia , Hemangioma Cavernoso/patologia
6.
J Endocrinol Invest ; 45(6): 1201-1208, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35157251

RESUMO

PURPOSE: The pyramidal lobe (PL) is an ancillary lobe of the thyroid gland that can be affected by the same pathologies as the rest of the gland. We aimed to assess the diagnostic performance of high-resolution sonography in the detection of the PL with verification by dissection and histological examination. METHODS: In a prospective, cross-sectional mono-center study, 50 fresh, non-embalmed cadavers were included. Blinded ultrasound examination was performed to detect the PL by two investigators of different experience levels. If the PL was detected with ultrasound, dissection was performed to expose the PL and obtain a tissue sample. When no PL was detected with ultrasound, a tissue block of the anterior cervical region was excised. An endocrine pathologist microscopically examined all tissue samples and tissue blocks for the presence of thyroid parenchyma. RESULTS: The prevalence of the PL was 80% [40/50; 95% CI (68.9%; 91.1%)]. Diagnostic performance for both examiners was: sensitivity (85.0%; 42.5%), specificity (50.0%; 60.0%), positive predictive value (87.2%; 81.0%), negative predictive value (45.5%; 21.0%) and accuracy (78.0%; 46.0%). Regression analysis demonstrated that neither thyroid parenchyma echogenicity, thyroid gland volume, age nor body size proved to be covariates in the accurate detection of a PL (p > .05). CONCLUSION: We report that high-resolution ultrasound is an adequate examination modality to detect the PL. Our findings indicate a higher prevalence than previously reported. Therefore, the PL may be regarded as a regular part of the thyroid gland. We also advocate a dedicated assessment of the PL in routine thyroid ultrasound.


Assuntos
Pescoço , Glândula Tireoide , Estudos Transversais , Humanos , Estudos Prospectivos , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/patologia , Ultrassonografia
7.
Proc Natl Acad Sci U S A ; 116(41): 20472-20481, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31548429

RESUMO

The metalloenzyme protein phosphatase 1 (PP1), which is responsible for ≥50% of all dephosphorylation reactions, is regulated by scores of regulatory proteins, including the highly conserved SDS22 protein. SDS22 has numerous diverse functions, surprisingly acting as both a PP1 inhibitor and as an activator. Here, we integrate cellular, biophysical, and crystallographic studies to address this conundrum. We discovered that SDS22 selectively binds a unique conformation of PP1 that contains a single metal (M2) at its active site, i.e., SDS22 traps metal-deficient inactive PP1. Furthermore, we showed that SDS22 dissociation is accompanied by a second metal (M1) being loaded into PP1, as free metal cannot dissociate the complex and M1-deficient mutants remain constitutively trapped by SDS22. Together, our findings reveal that M1 metal loading and loss are essential for PP1 regulation in cells, which has broad implications for PP1 maturation, activity, and holoenzyme subunit exchange.


Assuntos
Metais/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Proteína Fosfatase 1/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Domínio Catalítico , Metais/química , Modelos Moleculares , Proteínas Nucleares/química , Fosfoproteínas Fosfatases/química , Fosforilação , Conformação Proteica , Proteína Fosfatase 1/química , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/química
8.
Zhonghua Yi Xue Za Zhi ; 102(26): 2033-2036, 2022 Jul 12.
Artigo em Zh | MEDLINE | ID: mdl-35817730

RESUMO

To investigate the feasibility and safety of total laparoscopic cardia function preserving gastrectomy for gastric carcinoma. Clinical data of 10 patients undergoing total laparoscopic cardia function preserving gastrectomy for gastric carcinoma from November 2020 to December 2021 were retrospectively collected. There were 7 males and 3 females. The mean age was (66.1±12.9) years (ranged from 38 to 86 years). All of the 10 patients were successfully performed total laparoscopic cardia function preserving gastrectomy without conversion to laparotomy. The time of digestive tract reconstruction was (24.8±3.3) min (20-30 min), and the intraoperative blood loss was (35±24) ml(20-100 ml). The time of postoperative exhaust was (2.5±0.9) days(2-3 d), the time of postoperative liquid diet was (2.25±0.87) days(2-3 d), postoperative hospital stay was (9.5±2.1) days(6-13 d). No surgical complications such as bleeding, anastomotic fistula or anastomotic stenosis occurred. Postoperative pathology showed that the proximal and distal margins of resected specimens were negative. Patients were followed up for 2 to 15 months, respectively. No death or tumor recurrence and metastasis occurred during the follow-up period. There were no symptoms of reflux after operation. Compared with total gastrectomy and proximal gastrectomy, total laparoscopic cardia function preserving gastrectomy can theoretically reduce the incidence of reflux esophagitis. We used manual suture method for digestive tract reconstruction, which can reduce the application of 2-3 stapling studs and reduce the cost of surgical materials. Compared with subtotal gastrectomy, total laparoscopic cardia function preserving gastrectomy has the advantages of more thorough lymph node dissection, with little residual gastric tissue; therefore, the blood supply is relatively better. The incidence of reflux esophagitis of total laparoscopic cardia function preserving gastrectomy for gastric cancer may was lower than total gastrectomy.


Assuntos
Carcinoma , Esofagite Péptica , Laparoscopia , Neoplasias Gástricas , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/cirurgia , Cárdia/patologia , Esofagite Péptica/cirurgia , Feminino , Gastrectomia/métodos , Humanos , Laparoscopia/métodos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia
9.
Zhonghua Wai Ke Za Zhi ; 60(1): 39-45, 2022 Jan 01.
Artigo em Zh | MEDLINE | ID: mdl-34954945

RESUMO

Objective: To examine the clinical effect of minimally invasive duodenum preserving pancreatic head resection(DPPHR) for benign and pre-malignant lesions of pancreatic head. Methods: The clinical data of patients with diagnosis of benign or pre-malignant pancreatic head tumor were retrospectively collected and analyzed,all of them underwent laparoscopic or robotic DPPHR between October 2015 and September 2021 at Division of Gastrointestinal and Pancreatic surgery,Zhejiang Provincial People's Hospital. Thirty-three patients were enrolled with 10 males and 23 females. The age(M(IQR)) was 54(32) years old(range: 11 to 77 years old) and the body mass index was 21.9(2.9)kg/m2(range: 18.1 to 30.1 kg/m2). The presenting symptoms included abdominal pain(n=12), Whipple triad(n=2), and asymptomatic(n=19). There were 7 patients with hypertension and 1 patient with diabetes mellitus. There were 19 patients who were diagnosed as American Society of Anesthesiologists class Ⅰ and 14 patients who were diagnosed as class Ⅱ. The student t test,U test, χ2 test or Fisher exact test was used to compare continuous data or categorized data,respectively. All the perioperative data and metabolic morbidity were analyzed and experiences on minimally invasive DPPHR were concluded. Results: Fourteen patients underwent laparoscopic DPPHR,while the rest of 19 patients received robotic DPPHR. Indocyanine green fluorescence imaging was used in 19 patients to guide operation. Five patients were performed pancreatico-gastrostomy and the rest 28 patients underwent pancreaticojejunostomy. Pathological outcomes confirmed 9 solid pseudo-papillary neoplasms, 9 intraductal papillary mucinous neoplasms, 7 serous cystic neoplasms, 6 pancreatic neuroendocrine tumors, 1 mucous cystic neoplasm, 1 chronic pancreatitis. The operative time was (309.4±50.3) minutes(range:180 to 420 minutes),and the blood loss was (97.9±48.3)ml(range:20 to 200 ml). Eighteen patients suffered from postoperative complications,including 3 patients experienced severe complications(Clavien-Dindo Grade ≥Ⅲ). Pancreatic fistula occurred in 16 patients,including 8 patients with biochemical leak,7 patients with grade B pancreatic fistula and 1 patient with grade C pancreatic fistula. No one suffered from the duodenal necrosis and none perioperative death was occurred. The length of hospital stay was 14(7) days (range:6 to 87 days). The follow-up was 22.6(24.5)months(range:2 to 74 months). None suffered from recurrence or metastasis. During the follow-up,all the patients were free of refractory cholangitis. Moreover,in the term of endocrine dysfunction,no postoperative new onset of diabetes mellitus were observed in the long-term follow-up. However,in the view of exocrine insufficiency,pancreatic exocrine insufficiency and non-alcoholic fatty liver disease (NAFLD) was complicated in 2 and 1 patient,respectively,with the supplement of pancreatic enzyme,steatorrhea and weight loss relieved,but NAFLD was awaited to be seen. Conclusions: Minimally invasive DPPHR is feasible and safe for benign or pre-malignant lesions of pancreatic head. Moreover,it is oncological equivalent to pancreaticoduodenectomy with preservation of metabolic function without refractory cholangitis.


Assuntos
Pancreatectomia , Neoplasias Pancreáticas , Adolescente , Adulto , Idoso , Criança , Duodeno/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/cirurgia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Complicações Pós-Operatórias , Estudos Retrospectivos , Adulto Jovem
10.
Anim Genet ; 52(1): 47-54, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33200847

RESUMO

Genomic imprinting is a rare epigenetic process in mammalian cells that leads to monoallelic expression of a gene with a parent-specific pattern. The UBE3A (ubiquitin protein ligase E3A) gene is imprinted with maternal allelic expression in the brain but biallelically expressed in all other tissues in humans. The silencing of the paternal UBE3A allele is thought to be caused by the paternally expressed antisense RNA transcript of UBE3A-ATS. The aberrant imprinted expression of the UBE3A is associated with several neurodevelopmental syndromes and psychological disorders. Cattle are a valuable model species in determining the genetic etiology of sporadic human disorder, and maternal expression of UEB3A has been revealed by next-generation sequencing study in the bovine conceptus. In this study, we investigated the allelic expression of UBE3A and UBE3A-ATS in adult bovine somatic tissues. To confirm the splicing pattern of bovine UBE3A, five 5' alternative transcripts (MT210534-MT210538) were first obtained from bovine brain tissue by RT-PCR. Based on 10 SNP genotypes, we found that the brain-specific monoallelic expression of bovine UBE3A did not occur along the entire locus, and there was a shift from biallelic expression to monoallelic expression in exon 14 of the UBE3A gene. However, the brain-specific monoallelic expression of bovine UBE3A-ATS occurred in the entire gene. These observations demonstrated that the monoallelic expression did not occur along the bovine UBE3A entire locus and was associated with the genomic position.


Assuntos
Encéfalo/metabolismo , Bovinos/genética , Epigênese Genética , Impressão Genômica , Ubiquitina-Proteína Ligases/genética , Alelos , Animais , Feminino , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/genética , RNA Antissenso/genética
11.
Epidemiol Infect ; 148: e84, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32234104

RESUMO

The aim of this study was to develop and externally validate a simple-to-use nomogram for predicting the survival of hospitalised human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients (hospitalised person living with HIV/AIDS (PLWHAs)). Hospitalised PLWHAs (n = 3724) between January 2012 and December 2014 were enrolled in the training cohort. HIV-infected inpatients (n = 1987) admitted in 2015 were included as the external-validation cohort. The least absolute shrinkage and selection operator method was used to perform data dimension reduction and select the optimal predictors. The nomogram incorporated 11 independent predictors, including occupation, antiretroviral therapy, pneumonia, tuberculosis, Talaromyces marneffei, hypertension, septicemia, anaemia, respiratory failure, hypoproteinemia and electrolyte disturbances. The Likelihood χ2 statistic of the model was 516.30 (P = 0.000). Integrated Brier Score was 0.076 and Brier scores of the nomogram at the 10-day and 20-day time points were 0.046 and 0.071, respectively. The area under the curves for receiver operating characteristic were 0.819 and 0.828, and precision-recall curves were 0.242 and 0.378 at two time points. Calibration plots and decision curve analysis in the two sets showed good performance and a high net benefit of nomogram. In conclusion, the nomogram developed in the current study has relatively high calibration and is clinically useful. It provides a convenient and useful tool for timely clinical decision-making and the risk management of hospitalised PLWHAs.


Assuntos
Infecções por HIV/epidemiologia , Infecções por HIV/mortalidade , Nomogramas , Adulto , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto Jovem
12.
Mol Cell Proteomics ; 17(12): 2448-2461, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30228194

RESUMO

A "tug-of-war" between kinases and phosphatases establishes the phosphorylation states of proteins. While serine and threonine phosphorylation can be catalyzed by more than 400 protein kinases, the majority of serine and threonine dephosphorylation is carried out by seven phosphoprotein phosphatases (PPPs). The PPP family consists of protein phosphatases 1 (PP1), 2A (PP2A), 2B (PP2B), 4 (PP4), 5 (PP5), 6 (PP6), and 7 (PP7). The imbalance in numbers between serine- and threonine-directed kinases and phosphatases led to the early belief that PPPs are unspecific and that kinases are the primary determinants of protein phosphorylation. However, it is now clear that PPPs achieve specificity through association with noncatalytic subunits to form multimeric holoenzymes, which expands the number of functionally distinct signaling entities to several hundred. Although there has been great progress in deciphering signaling by kinases, much less is known about phosphatases.We have developed a chemical proteomic strategy for the systematic interrogation of endogenous PPP catalytic subunits and their interacting proteins, including regulatory and scaffolding subunits (the "PPPome"). PP1, PP2A, PP4, PP5, and PP6 were captured using an immobilized, specific but nonselective PPP inhibitor microcystin-LR (MCLR), followed by protein identification by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in a single analysis. Here, we combine this approach of phosphatase inhibitor bead profiling and mass spectrometry (PIB-MS) with label-free and tandem mass tag (TMT) quantification to map the PPPome in human cancer cell lines, mouse tissues, and yeast species, through which we identify cell- and tissue-type-specific PPP expression patterns and discover new PPP interacting proteins.


Assuntos
Domínio Catalítico , Microcistinas/farmacologia , Neoplasias/enzimologia , Fosfoproteínas Fosfatases/antagonistas & inibidores , Proteômica/métodos , Saccharomyces cerevisiae/enzimologia , Animais , Cromatografia Líquida , Células HeLa , Humanos , Células MCF-7 , Toxinas Marinhas , Camundongos , Fosfoproteínas Fosfatases/classificação , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Ligação Proteica , Transdução de Sinais , Espectrometria de Massas em Tandem
13.
Zhonghua Yi Xue Za Zhi ; 100(27): 2116-2120, 2020 Jul 21.
Artigo em Zh | MEDLINE | ID: mdl-32689752

RESUMO

Objective: To investigate the value of non-invasive ventilation (NIV) combined with high flow nasal cannula oxygen therapy (HFNCO) in sequential treatment of patients with chronic obstructive pulmonary disease after mechanical ventilation. Methods: Chronic obstructive pulmonary disease with acute exacerbation (AECOPD) patients with invasive mechanical ventilation (MV) and successful withdrawal admitted into Huxi Affiliated Hospital of Jining Medical College from January 2018 to December 2019 were enrolled for perspective study. The patients were divided into treatment group (n=40) and control group (n=33) by random number table method. The treatment group was given NIV and HFNCO, the control group was given NIV treatment alone. Bedside ultrasound was used to measure the patients' diaphragmatic motion, and the differences between the two groups of patients before treatment, 24, 48 and 72 h after treatment were compared in diaphragmatic excursions during quiet breathing (DEq), diaphragmatic excursions during deep breathing(DEd), diaphragmatic shallow fast breathing index (D-RSBI), arterial oxygen partial pressure (PaO(2)), arterial partial pressure of carbon dioxide (PaCO(2)), re-tracheal intubation rate, mortality rate for 28 days and average duration of NPPV treatment within 3 days. Results: There were no statistically significant differences in DEq, DEd, D-RSBI, PaO(2) and PaCO(2) between the two groups before treatment (all P>0.05). After 24 h treatment, DEd decreased in both groups, D-RSBI increased in both groups, However, D-RSBI [(1.33±0.56) vs (1.62±0.59) times·min(-1)·mm(-1)] in the treatment group was significantly lower than the control group, P=0.034. After 72 h treatment, DEd [(41.4±8.1) vs (37.8±6.0) mm] was significantly higher than the control group, D-RSBI [(1.02±0.27) vs (1.22±0.43) times·min(-1)·mm(-1)] was significantly lower than the control group (all P<0.05). The average duration of NIV treatment time [(7.5±1.2) vs (9.3±2.6) h] in the treatment group was significantly shorter than that in the control group (P<0.01). There were no statistically significant differences in PaO(2), PCO(2), re-tracheal intubation rate and the mortality rate of 28 days. Conclusion: NIV combined with HFNCO sequential therapy can effectively relieve diaphragm fatigue and promote recovery of respiratory muscle strength, and it's better than NIV alone.


Assuntos
Ventilação não Invasiva , Oxigenoterapia/métodos , Oxigênio/administração & dosagem , Doença Pulmonar Obstrutiva Crônica , Extubação , Cânula , Humanos , Doença Pulmonar Obstrutiva Crônica/terapia , Respiração Artificial , Resultado do Tratamento
14.
J Biol Chem ; 293(20): 7766-7776, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29618508

RESUMO

The integrated stress response (ISR) is regulated by kinases that phosphorylate the α subunit of translation initiation factor 2 and phosphatases that dephosphorylate it. Genetic and biochemical observations indicate that the eIF2αP-directed holophosphatase, a therapeutic target in diseases of protein misfolding, is comprised of a regulatory subunit, PPP1R15, and a catalytic subunit, protein phosphatase 1 (PP1). In mammals, there are two isoforms of the regulatory subunit, PPP1R15A and PPP1R15B, with overlapping roles in the essential function of eIF2αP dephosphorylation. However, conflicting reports have appeared regarding the requirement for an additional co-factor, G-actin, in enabling substrate-specific dephosphorylation by PPP1R15-containing PP1 holoenzymes. An additional concern relates to the sensitivity of the holoenzyme to the [(o-chlorobenzylidene)amino]guanidines Sephin1 or guanabenz, putative small-molecule proteostasis modulators. It has been suggested that the source and method of purification of the PP1 catalytic subunit and the presence or absence of an N-terminal repeat-containing region in the PPP1R15A regulatory subunit might influence the requirement for G-actin and sensitivity of the holoenzyme to inhibitors. We found that eIF2αP dephosphorylation by PP1 was moderately stimulated by repeat-containing PPP1R15A in an unphysiological low ionic strength buffer, whereas stimulation imparted by the co-presence of PPP1R15A and G-actin was observed under a broad range of conditions, low and physiological ionic strength, regardless of whether the PPP1R15A regulatory subunit had or lacked the N-terminal repeat-containing region and whether it was paired with native PP1 purified from rabbit muscle or recombinant PP1 purified from bacteria. Furthermore, none of the PPP1R15A-containing holophosphatases tested were inhibited by Sephin1 or guanabenz.


Assuntos
Actinas/metabolismo , Resistência a Medicamentos , Fator de Iniciação 2 em Eucariotos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Guanabenzo/análogos & derivados , Proteína Fosfatase 1/antagonistas & inibidores , Animais , Domínio Catalítico , Guanabenzo/farmacologia , Células HeLa , Humanos , Fosforilação , Isoformas de Proteínas , Proteólise , Coelhos
15.
Mol Psychiatry ; 23(3): 597-608, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28439098

RESUMO

Several preclinical studies have reported the rapid antidepressant effects of N-methyl-D-aspartate receptor (NMDAR) antagonists, although the underlying mechanisms are still unclear. Death-associated protein kinase 1 (DAPK1) couples GluN2B subunits at extrasynaptic sites to regulate NMDAR channel conductance. In the present study, we found that chronic unpredictable stress (CUS) induced extracellular glutamate accumulation, accompanied by an increase in the DAPK1-NMDAR interaction, the high expression of DAPK1 and phosphorylated GluN2B at Ser1303, a decrease in phosphorylated DAPK1 at Ser308 and synaptic protein deficits in the rat medial prefrontal cortex (mPFC). CUS also enhanced GluN2B-mediated NMDA currents and extrasynaptic responses that were induced by bursts of high-frequency stimulation, which may be associated with the loss of astrocytes and low expression of glutamate transporter-1 (GLT-1). The blockade of GLT-1 in the mPFC was sufficient to induce depressive-like behavior and cause similar molecular changes. Selective GluN2B antagonist, DAPK1 knockdown by adeno-associated virus-mediated short-hairpin RNA or a pharmacological inhibitor, and the uncoupling of DAPK1 from the NMDAR GluN2B subunit produced rapid antidepressant-like effects and reversed CUS-induced alterations in the mPFC. The inhibition of DAPK1 and its interaction with GluN2B subunit in the mPFC also rescued CUS-induced depressive-like behavior 7 days after treatment. A selective GluN2B antagonist did not have rewarding effects in the conditioned place preference paradigm. Altogether, our findings suggest that the DAPK1 interaction with the NMDAR GluN2B subunit acts as a critical component in the pathophysiology of depression and is a potential target for new antidepressant treatments.


Assuntos
Proteínas Quinases Associadas com Morte Celular/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Antidepressivos/farmacologia , Doença Crônica , Depressão/fisiopatologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ácido Glutâmico/metabolismo , Masculino , Fosforilação , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/metabolismo
16.
Radiologe ; 59(4): 328-337, 2019 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-30789997

RESUMO

CLINICAL ISSUE: Due to the high prevalence of clinically suspected cholecystitis or cholecystolithiasis the gallbladder is one of the organs examined the most by imaging. STANDARD RADIOLOGICAL METHODS: In most clinical settings ultrasound is the primary imaging method because of its wide availability, speed and superior spatial resolution. In cases of ambiguous findings or potential complications computed tomography (CT) and magnetic resonance imaging (MRI) are used. METHODICAL INNOVATIONS: When specific problems arise these imaging modalities may be enhanced by special techniques, e. g. contrast-enhanced ultrasound or dual-energy CT, and specific MRI sequences. PERFORMANCE: Special variants of cholecystitis, such as xanthogranulomatous cholecystitis and adenomyomatosis, may pose a particularly difficult diagnostic problem as they may resemble other diseases. Sequelae of cholecystolithiasis, such as the Mirizzi syndrome and acute bowel obstruction, may complicate the imaging algorithm as the location and the symptoms shift. Cases of neoplastic diseases of gallbladder cancer and other malignancies require a broad spectrum of imaging modalities. ACHIEVEMENTS: Although the gallbladder can easily be examined with ultrasound, some cases require a more thorough ultrasound examination. In some cases only a combination of multiple imaging modalities yield the diagnosis. Further developments regarding technical issues and the diagnostic algorithm can be expected. PRACTICAL RECOMMENDATIONS: Ultrasound is the best first imaging modality. In cases of ambiguous findings or clinical complications CT or MRI are recommended.


Assuntos
Doenças da Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar , Tomografia Computadorizada por Raios X , Diagnóstico Diferencial , Imageamento por Ressonância Magnética , Ultrassonografia
18.
Zhonghua Yu Fang Yi Xue Za Zhi ; 53(3): 330-333, 2019 Mar 06.
Artigo em Zh | MEDLINE | ID: mdl-30841678

RESUMO

In this study, 1 065 infants and young children aged 24 months below in ethnic minorities gathering in poor rural areas in poor rural areas of Liangshan Yi Autonomous Prefecture of Sichuan Province and Gannan Tibetan Autonomous Prefecture of Gansu Province were investigated for their anemia status from October to November 2014, and the association between anemia and the utilization of maternal and child health services was analyzed. The prevalence of anemia in this area was 52.68%(561/1 065). After the adjustment of socio-demographic characteristics of mothers and infants, compared with infants aged 2-5 months, Han ethnic group, and infants whose mother was not anemic, the OR(95%CI) values of infant anemia for infants aged 6-12 months, 13-8 months, 19-24 months, ethnic minorities group, and infants whose mother was anemic were 11.65 (7.09-19.14), 9.91 (5.99-16.38), 5.87 (3.39-10.16), 1.55 (1.10-2.18) and 1.52 (1.14-2.04), respectively; Compared with infants whose child examination times not up to standard, and who were not only non-hospital delivered but also received inadequate number of inoculation, the OR (95%CI) values of infant anemia for infants whose child examination times up to standard, and who were not only hospital delivered but also received adequate number of inoculation were 0.60 (0.38-0.94) and 0.71 (0.52-0.98), respectively. The infants anemia is associated with the utilization of maternal and child health services.


Assuntos
Anemia/etnologia , Etnicidade/estatística & dados numéricos , Serviços de Saúde Materno-Infantil/estatística & dados numéricos , Grupos Minoritários/estatística & dados numéricos , Áreas de Pobreza , População Rural/estatística & dados numéricos , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Lactente , Gravidez , Prevalência
19.
Morphologie ; 103(341): 37-47, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30638803

RESUMO

BACKGROUND: The kangaroo pericardium might be considered to be a good candidate material for use in the manufacture of the leaflets of percutaneous heart valves based upon the unique lifestyle. The diet consists of herbs, forbs and strubs. The kangaroo pericardium holds an undulated structure of collagen. MATERIAL AND METHOD: A Red Kangaroo was obtained after a traffic fatality and the pericardium was dissected. Four compasses were cut from four different sites: auricular (AUR), atrial (ATR), sternoperitoneal (SPL) and phrenopericardial (PPL). They were investigated by means of scanning electron microscopy, light microscopy and transmission electron microscopy. RESULTS: All the samples showed dense and wavy collagen bundles without vascularisation from both the epicardium and the parietal pericardium. The AUR and the ATR were 150±25µm thick whereas the SPL and the PPL were thinner at 120±20µm. The surface of the epicardium was smooth and glistening. The filaments of collagen were well individualized without any aggregation, but the banding was poorly defined and somewhat blurry. CONCLUSION: This detailed morphological analysis of the kangaroo pericardium illustrated a surface resistant to thrombosis and physical characteristics resistant to fatigue. The morphological characteristics of the kangaroo pericardium indicate that it represents an outstanding alternative to the current sources e.g., bovine and porcine. However, procurement of tissues from the wild raises supply and sanitary issues. Health concerns based upon sanitary uncertainty and reliability of supply of wild animals remain real problems.


Assuntos
Bioprótese , Próteses Valvulares Cardíacas , Ligamentos/ultraestrutura , Macropodidae/anatomia & histologia , Pericárdio/ultraestrutura , Animais , Austrália , Doenças das Valvas Cardíacas/cirurgia , Humanos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão
20.
Zhonghua Gan Zang Bing Za Zhi ; 27(1): 51-55, 2019 Jan 20.
Artigo em Zh | MEDLINE | ID: mdl-30685924

RESUMO

Objective: To investigate the effects of two different sorbents(Carbon perfusion apparatus and Resin perfusion apparatus)in Double plasma molecular absorb syetem for liver failure treatment. Methods: A total of 152 cases with liver failure who were admitted to The Sixth People's Hospital of Zhengzhou, from June 2016 to May 2018 were selected and divided into DPMARS Carbon group (77 cases) and Resin group (75 cases). The two groups were observed in terms of liver function, prothrombin activity(PTA),Plasma albumin ,tumor necrosis factor alpha and interleukin-6 were detected and compared between the two groups before and after treatment. Results: ①The clinical symptoms improved in different degree in two groups, the recovery rate of Carbon cans Carbon perfusion apparatus group and Resin group separately were89.6% (69/77)、90.7% (68/75)(χ(2) = 0.048, P = 0.975), there were no statistical differences. There were no statistical differences between the two groups in untoward reactions(χ(2) = 0.235, P = 0.995), ②Compared with before treatment, TBil(t = 3.735, 3.728; P = 0.000, 0.000)、ALT(t = 5.117, 5.203; P = 0.000, 0.000)、TNF-α (t = 3.158, 3.094; P = 0.000, 0.002)、IL-6(t = 3.647, 3.559; P = 0.002, 0.003)decreased and ALB (t = 2.300, 3.065; P = 0.024, 0.003) increased significantly after treatment in both groups, and there were statistical differences. There were no signifiant differences in the changes in ALB(t = 0.316, 0.209; P = 0.657, 0.720) and PTA(t = 0.810, 0.843; P = 0.429, 0.516). ③After treatment, there were no signifiant differences in the changes in TBil、ALT、ALB、PTA、TNF-α、IL-6(t = 0.377、0.904、-1.133、-1.552、0.841、0.401; P = 0.952、0.283、0.826、0.094、0.154、0.457). Conclusion: Double plasma molecular absorb syetem is effective in treating liver failure. Carbon perfusion apparatus or Resin perfusion apparatus can be combined with Specific bilirubin adsorption column for DPMARS in clinical treatment,and their effects are similar.


Assuntos
Hemoperfusão/métodos , Falência Hepática/terapia , Troca Plasmática , Adsorção , Humanos , Interleucina-6
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