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1.
Medicine (Baltimore) ; 99(41): e22610, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031318

RESUMO

BACKGROUND: We systematically evaluated the evidences on oncological and functional outcomes of high-intensity focused ultrasound (HIFU) as the primary treatment for localized prostate cancer (PCa). METHODS: A systematic review was used Medline, Embase, and the Cochrane Library from the inception of each database. The review analyzed the oncological and functional outcomes of HIFU in the treatment of PCa. The RevMan 5.3 software was used for quantity analysis incidence of complications. RESULTS: Twenty-seven articles were included for analysis with a total of 7393 patients. Eighteen studies investigated the whole-gland HIFU, and the duration of follow-up ranged from 2 to 168 months. After whole-gland HIFU, the mean prostate-specific antigen (PSA) nadir was found to be 0.4 to 1.95 ng/mL and the mean time to PSA nadir was 2.4 to 5.4 months. The rate of positive biopsy after HIFU was 4.5% to 91.1%. Meta-analysis revealed the incidences of urinary incontinence, impotence, urinary obstruction, retention, and infection was 10%, 44%, 15%, 11%, 7%, respectively. Nine studies investigated partial-gland HIFU, and the duration of follow-up was 1 to 131 months. After partial-gland HIFU, the mean PSA nadir was 1.9 to 2.7 ng/mL and the mean time to PSA nadir 5.7 to 7.3 months. The rate of positive biopsy after HIFU in the treatment area was 14% to 37.5%. Meta-analysis revealed the incidences of urinary incontinence, impotence, urinary obstruction, retention, and infection was 2%, 21%, 2%, 9%, 11%, respectively. CONCLUSIONS: Early evidence suggested the partial-gland HIFU was safer than whole-gland HIFU, and they had similar oncological outcomes. More prospective randomized controlled trials of whole-gland and partial-gland HIFU for PCa was needed.

2.
Clin Genet ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020905

RESUMO

The subcortical maternal complex (SCMC) is an oocyte-to-embryo-specific maternal functional module. Some variants of SCMC genes that contribute to pre-implantation embryonic arrest have been identified. However, more novel variants should be identified to broaden the phenotypic and genetic spectrum of SCMC genes and establish their roles in embryonic development. We identified 13 novel variants in the SCMC genes, TLE6, NLRP5, NLRP2 and PADI6, from 10 of a total of 50 infertile females with recurrent preimplantation embryonic arrest. Six variants in TLE6 were found in five patients with embryonic arrest, accompanied by direct cleavage and severe fragmentation at the cleavage stage. Three patients carried NLRP5 variants, and one patient each who carried NLRP2 and PADI6 variants had subsequent poor or failed fertilization and cleavage arrest with a relatively lower ratio of severely fragmented embryos. Our findings expand the genetic and phenotypic spectrum of SCMC gene variants associated with human embryogenesis and might help lay the foundation for the genetic diagnosis of female infertility.

3.
Anal Chem ; 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33006882

RESUMO

Thousands of putative microRNA (miRNA)-based cancer biomarkers have been reported, but none has been validated for approval by the Food and Drug Administration. One of the reasons for this alarming discrepancy is the lack of a method that is sufficiently robust for carrying out validation studies, which may require analysis of samples from hundreds of patients across multiple institutions and pooling the results together. The capillary electrophoresis (CE)-based hybridization assay proved to be more robust than reversed transcription polymerase chain reaction (the current standard), but its limit of quantification (LOQ) exceeds 10 pM while miRNA concentrations in cell lysates are below 1 pM. Thus, CE-based separation must be preceded by on-column sample preconcentration. Here, we explain the challenges of sample preconcentration for CE-based miRNA analyses and introduce a preconcentration method that can suit CE-based miRNA analysis utilizing peptide nucleic acid (PNA) hybridization probes. The method combines field-amplified sample stacking (FASS) with isotachophoresis (ITP). We proved that FASS-ITP could retain and concentrate both near-neutral PNA with highly negatively charged PNA-miRNA hybrids. We demonstrated that preconcentration by FASS-ITP could be combined with the CE-based separation of the unreacted PNA probes from the PNA-miRNA hybrids and facilitate improvement in LOQ by a factor of 140, down to 0.1 pM. Finally, we applied FASS-ITP-CE for the simultaneous detection of two miRNAs in crude cell lysates and proved that the method was robust when used in complex biological matrices. The 140-fold improvement in LOQ and the robustness to biological matrices will significantly expand the applicability of CE-based miRNA analysis, bringing it closer to becoming a practical tool for validation of miRNA biomarkers.

4.
J Hazard Mater ; 404(Pt A): 124035, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-33035907

RESUMO

Efficient removal of Hg2+ from aqueous solution is key for environmental protection and human health. Herein, a novel composite of nano humboldtine decorated almandine was synthesized from almandine for the removal of Hg2+. Results showed that the Hg2+ removal process followed pseudo-second-order kinetic model and Langmuir equation, and the maximum adsorption capacity was 575.17 mg/g. Furthermore, Hg2+ removal by the composite was pH-dependent and low pH value facilitated the removal of Hg2+. SEM and HADDF-STEM results suggested a new rod morphology was generated and the adsorbed mercury was mainly enriched into this structure after reaction with Hg2+ solution. The removal mechanisms of Hg2+ by the composite was pH dependent, and included ion exchange, surface complexation, reduction and oxidation. Our results demonstrated that the composite was an ideal material for Hg2+ removal and the transformation ways of mercury related species could be a significant but currently underestimated pathway in natural and engineered systems.

5.
Comput Biol Med ; 125: 104015, 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33035961

RESUMO

Despite great progress in nitric oxide (NO) controlled releasing strategies, the in vivo spatiotemporal NO distribution of arteries is still unclear, which makes it impossible to assess the status of arteries and render NO-based therapies in vivo largely fruitless. Here, we presented personalized computational modelling to calculate the NO distribution on the endothelial surface and in the arterial wall of human atherosclerotic carotid artery bifurcations using models constructed from MRI. The computational results indicated the distribution of NO in the atherosclerotic artery is highly uneven. The volume-weighted average NO concentration (CV) in regions with lipid plaques (9.76 ± 2.82 nM) was about 22 times higher than that in the plaque-free regions. Regions where also the calcified plaque components and the intraplaque hemorrhages are present would increase and abate the CV, respectively. The dynamic blood flow during the cycle would directly affect the distribution of NO on the endothelial surface. The luminal NO distribution is closely related to hemodynamic indicators, including wall shear stress (WSS), time averaged wall shear stress (TAWSS), oscillating shear index (OSI) and relative residence time (RRT). In conclusion, atherosclerotic components determine the space-averaged NO concentration in arterial wall and blood flow controls the luminal NO concentration.

6.
Fertil Steril ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33039126

RESUMO

OBJECTIVE: To measure free and total 25-hydroxyvitamin D [25(OH)D] immediately before embryo transfer and analyze its association with early pregnancy outcome parameters such as biochemical pregnancy, implantation rate, and clinical pregnancy rates in women undergoing fresh embryo transfer after their first ovarian hyperstimulation. DESIGN: Prospective cohort study. SETTING: Academically affiliated private fertility center. PATIENT(S): A total of 2,569 women undergoing fresh embryo transfer after ovarian hyperstimulation. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): The study end points were biochemical pregnancy rate, implantation rate, clinical pregnancy rate, ectopic pregnancy rate, early miscarriages, and ongoing pregnancy rate. Free and total 25(OH)D concentrations were measured 1 day before embryo transfer. RESULT(S): Total 25(OH)D correlated with free 25(OH)D. Total and free 25(OH)D serum concentrations were similar in those patients reaching and not reaching the study outcomes (biochemical pregnancy rate, implantation rate, clinical pregnancy rate, ectopic pregnancy rate, early miscarriages, and ongoing pregnancy rate). There was likewise no statistical difference when analyzing the frequency of all study outcomes in quintiles of either total or free 25(OH)D. In addition, the study population was divided into three groups according to the total vitamin D status based on clinical practice guideline. All outcomes were similar in women with adequate, insufficient, and deficient total 25(OH)D. Multiple linear regression analysis considering confounding likewise indicated no association of free or total vitamin D with any of the study outcomes. CONCLUSION(S): Neither free nor total 25(OH)D concentration at embryo transfer was associated with successful embryo implantation in women undergoing fresh transfer after ovarian hyperstimulation.

7.
Aging Cell ; : e13252, 2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33040455

RESUMO

The risk of colitis and colorectal cancer increases markedly throughout adult life, endangering the health and lives of elderly individuals. Previous studies have proposed that bacterial translocation and infection are the main risk factors for these diseases. Therefore, in the present study, we aimed to identify the underlying mechanism by focusing on the mucus barrier function and mucin-type O-glycosylation. We evaluated alterations in the colon mucus layer in 2-, 16-, and 24-month-old mice and aged humans. Aged colons showed defective intestinal mucosal barrier and changed mucus properties. The miR-124-3p expression level was significantly increased in the aged distal colonic mucosa, which was accompanied by an increase in pathogens and bacterial translocation. Meanwhile, T-synthase, the rate-limiting enzyme in O-glycosylation, displayed an age-related decline in protein expression. Further experiments indicated that miR-124-3p modulated O-glycosylation by directly targeting T-synthase. Moreover, young mice overexpressing miR-124-3p exhibited abnormal glycosylation, early-onset, and more severe colitis. These data suggest that miR-124-3p predisposes to senile colitis by reducing T-synthase, and the miR-124-3p/T-synthase/O-glycans axis plays an essential role in maintaining the physiochemical properties of colonic mucus and intestinal homeostasis.

8.
J Int Med Res ; 48(9): 300060520952279, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32883134

RESUMO

Visual loss after spine surgery in the prone position is a disastrous postoperative complication because it is almost irreversible. Additionally, the optimal treatments and recommended professional guidelines for visual loss after spine surgery are deficient. A 43-year-old man developed visual loss after spine surgery in the prone position. Immediate ophthalmic consultation confirmed central retinal artery occlusion. Therefore, combined therapies were administered, including neurotrophy, anticoagulation, vasodilation, and adequate fluid infusion, followed by hyperbaric oxygen treatment. After active treatment, his visual acuity gradually recovered from 5 hours postoperatively and continued to improve thereafter. We reviewed the literature on postoperative visual loss with a focus on spine surgery in the prone position. Because the etiology of this complication is complex and has few effective treatments, the best method for its avoidance is to pay close attention to preventing it during surgery.

9.
Medicine (Baltimore) ; 99(35): e21758, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871896

RESUMO

INTRODUCTION: Gastroesophageal reflux disease is a common and troublesome condition. This paper reports a rare case of gastroesophageal reflux disease caused by ectopic biliary drainage accompanying the absence of a pyloric channel and duodenal bulb in a female patient with multiple underlying malformations. PATIENT CONCERNS: A 24-year-old female presented with acid regurgitation and abdominal pain for one month. She was born two weeks premature and with blindness of the right eye. Cardiac murmur was detected in the physical examination. DIAGNOSIS: Gastroendoscopy was performed, and a class D reflux esophagitis and ectopic papilla complicated with the absence of a pyloric channel and duodenal bulb were found. Doppler echocardiography further confirmed the defects of atrial and ventricular septa. Trio-based whole exome sequencing was performed on the proband and her family to find the potential association of multiple variations. However, no putative pathogenic mutations were found. INTERVENTIONS: The patient received proton pump inhibitors and prokinetic treatment and underwent surgical repair of septal defects. OUTCOMES: The symptoms were quickly relieved, and the patient was kept stable upon follow-up. CONCLUSION: The combination of an absent pylorus and ectopic papilla is a rare cause of reflux esophagitis. Unusual gastrointestinal anatomical variations may be accompanied by other malformations. Though no remarkable mutation were detected in this case, sequencing is an efficient technique worth full consideration.


Assuntos
Ampola Hepatopancreática/anormalidades , Esofagite Péptica/etiologia , Anormalidades Múltiplas , Cegueira/congênito , Esofagite Péptica/tratamento farmacológico , Feminino , Gastroscopia , Comunicação Interatrial/diagnóstico por imagem , Comunicação Interatrial/cirurgia , Comunicação Interventricular/diagnóstico por imagem , Comunicação Interventricular/cirurgia , Humanos , Inibidores da Bomba de Prótons/uso terapêutico , Sequenciamento Completo do Exoma , Adulto Jovem
10.
Mol Cell Biochem ; 2020 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-32918705

RESUMO

Liver sinusoidal endothelial cells (LSECs) play a key role in the initiation and neoangiogenesis of liver regeneration. We presume that the abnormity of the VEGF/VEGFR2 and its pathway gene Id1, Wnt2 and HGF expression in aged LSECs may be an important mechanism to affect liver regeneration of the elderly. LSECs from two different groups (adult and old) were isolated in a rodent model, and observed by SEM and TEM. The adult and old rats were underwent 70% partial hepatectomy. The proliferation of hepatocytes and LSECs were analyzed by Immunofluorescence staining. The expression of VEGF/VEGFR2 and its pathway gene in isolated LSECs and liver tissue after hepatectomy were detected by qRT-PCR and Western blot. There is a decreased number of endothelial fenestrae in the LSECs of the old group, compared to the adult group. The old group had a lower expression of VEGF/VEGFR2 and its pathway gene than the adult groups (p < 0.01). The results of western blot were consistent with those of qRT-PCR. The hepatocytes had a high proliferation rate at first 4 days after hepatectomy, and a significantly higher proliferation rate in the adult group. The LSECs began to proliferate after 4 days of hepatectomy, and showed a quantity advantage in the adult group. The adult group had a significantly higher expression of VEGF/VEGFR2 and its pathway gene after hepatectomy than the old group (p < 0.01). LSCEs turn to be defenestration in structure and have a low expression of VEGF/VEGFR2 and its pathway gene with aging.

11.
Reg Anesth Pain Med ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963077

RESUMO

BACKGROUND AND OBJECTIVES: Gap junctions play a pivotal role in contributing to the formation of astroglial networks and in chronic pain. However, the mechanisms underlying the dysfunction of astroglial gap junctions in chronic pain have not been fully elucidated. METHODS: Chronic constriction injury (CCI) of the sciatic nerve was used to establish rat neuropathic pain model. C6 cells were used to perform experiments in vitro. Von Frey hairs and Hargreave's method were used to determine the withdrawal threshold of rats. Protein expression was detected by immunofluorescence and western blotting. RESULTS: Astragaloside IV (AST IV) significantly attenuated neuropathic pain and suppressed the excitation of spinal astrocytes in rats with CCI. The antinociceptive effect of AST IV was reversed by the gap junction decoupler carbenoxolone (CBX). AST IV inhibited the high expression of phosphorylated connexin 43 (p-Cx43) and p-c-Jun N-terminal kinase (p-JNK) in spinal cord of rats with CCI. JNK inhibitor alleviated neuropathic pain, which was reversed by CBX. JNK inhibitor decreased the high expression of p-Cx43 in both rats with CCI and tumor necrosis factor-alpha (TNF-α)-treated C6 cells. Additionally, the analgesic effect of AST IV was reversed by the adenosine triphosphate-sensitive potassium (KATP) channel blocker, glibenclamide (Glib). Glib abolished the inhibitory effects of AST IV on p-JNK and p-Cx43 both in vivo and in vitro. KATP channel opener (KCO) mimicked the inhibitory effects of AST IV on p-JNK and p-Cx43 in TNF-α-treated C6 cells. CONCLUSION: Our results indicate that the sciatic nerve CCI induces the dysfunction of gap junctions in the spinal cord by activating KATP/JNK signaling to contribute to neuropathic pain. AST IV attenuates neuropathic pain via regulating the KATP-JNK gap junction axis.

12.
J Int Med Res ; 48(9): 300060520951418, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32951504

RESUMO

BACKGROUND: Over 90% of pancreatic stones are radiopaque and can be treated with endoscopy or surgery. However, radiolucent stones are different than radiopaque stones in nature and formation, and therefore, treatment varies.Case presentation: A 25-year-old woman was admitted because of recurrent acute pancreatitis. Imaging examinations confirmed the diagnosis of chronic pancreatitis (CP), and which revealed the existence of radiolucent stones. Endoscopic retrograde cholangiopancreatography (ERCP) was performed and abundant protein-like radiolucent stones were extracted. Three 10F, 7-cm plastic stents were placed. However, the stents were completely occluded by radiolucent stones 1 month later. A nasopancreatic tube was then inserted and flushed regularly, but protein-like stones formed continuously. After multidisciplinary consultation, the following conservative treatment strategy was applied: 1) no more endotherapy; 2) a diet with 40% to 50% of calories from fat was recommended; 3) no pancreatic enzyme replacement therapy; and 4) regular exercise. The above advice aimed to stimulate the secretion of pancreatic fluid to achieve auto-flushing of the pancreatic duct and prevent protein-like stones from depositing. No acute pancreatitis recurred during the 5-year follow-up. CONCLUSIONS: This strategy was effective for auto-flushing the pancreatic duct in patients with radiolucent pancreatic stones after the main pancreatic duct stricture was resolved.

13.
J Hematol Oncol ; 13(1): 120, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887634

RESUMO

BACKGROUND: Critically ill patients diagnosed with COVID-19 may develop a pro-thrombotic state that places them at a dramatically increased lethal risk. Although platelet activation is critical for thrombosis and is responsible for the thrombotic events and cardiovascular complications, the role of platelets in the pathogenesis of COVID-19 remains unclear. METHODS: Using platelets from healthy volunteers, non-COVID-19 and COVID-19 patients, as well as wild-type and hACE2 transgenic mice, we evaluated the changes in platelet and coagulation parameters in COVID-19 patients. We investigated ACE2 expression and direct effect of SARS-CoV-2 virus on platelets by RT-PCR, flow cytometry, Western blot, immunofluorescence, and platelet functional studies in vitro, FeCl3-induced thrombus formation in vivo, and thrombus formation under flow conditions ex vivo. RESULTS: We demonstrated that COVID-19 patients present with increased mean platelet volume (MPV) and platelet hyperactivity, which correlated with a decrease in overall platelet count. Detectable SARS-CoV-2 RNA in the blood stream was associated with platelet hyperactivity in critically ill patients. Platelets expressed ACE2, a host cell receptor for SARS-CoV-2, and TMPRSS2, a serine protease for Spike protein priming. SARS-CoV-2 and its Spike protein directly enhanced platelet activation such as platelet aggregation, PAC-1 binding, CD62P expression, α granule secretion, dense granule release, platelet spreading, and clot retraction in vitro, and thereby Spike protein enhanced thrombosis formation in wild-type mice transfused with hACE2 transgenic platelets, but this was not observed in animals transfused with wild-type platelets in vivo. Further, we provided evidence suggesting that the MAPK pathway, downstream of ACE2, mediates the potentiating role of SARS-CoV-2 on platelet activation, and that platelet ACE2 expression decreases following SARS-COV-2 stimulation. SARS-CoV-2 and its Spike protein directly stimulated platelets to facilitate the release of coagulation factors, the secretion of inflammatory factors, and the formation of leukocyte-platelet aggregates. Recombinant human ACE2 protein and anti-Spike monoclonal antibody could inhibit SARS-CoV-2 Spike protein-induced platelet activation. CONCLUSIONS: Our findings uncovered a novel function of SARS-CoV-2 on platelet activation via binding of Spike to ACE2. SARS-CoV-2-induced platelet activation may participate in thrombus formation and inflammatory responses in COVID-19 patients.


Assuntos
Betacoronavirus/metabolismo , Plaquetas/metabolismo , Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Trombose/metabolismo , Adulto , Idoso , Animais , Betacoronavirus/genética , Células CACO-2 , Infecções por Coronavirus/virologia , Feminino , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Células PC-3 , Pandemias , Peptidil Dipeptidase A/genética , Agregação Plaquetária/imunologia , Contagem de Plaquetas , Pneumonia Viral/virologia , RNA Viral/sangue , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Trombose/virologia
14.
Int J Med Sci ; 17(15): 2373-2378, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922203

RESUMO

Background: In patients with coronavirus disease 2019 (COVID-19) pneumonia, whether new pulmonary lesions will continue to develop after treatment was unknown. This study aimed to determine whether new pulmonary lesions will develop after treatment in patients with COVID-19 pneumonia, and investigate their CT features and outcomes. Methods: This retrospective study included 56 consecutive patients with confirmed COVID-19 pneumonia from January 20 to March 5, 2020. Their initial and follow-up CT images and clinical data were reviewed. The CT manifestations of primary and newly developed pulmonary lesions and their changes after treatment were mainly evaluated. Results: Among the 56 patients (mean age: 48±15 years, 35 men) with COVID-19 pneumonia, 42 (75.0%) patients developed new pulmonary lesions during treatment. All new lesions developed before the nucleic acid test turned negative. Patients with new lesions were more likely to have lymphopenia (P=0.041) or increased C-reactive protein (CRP) levels (P<0.001) than those without new lesions. Of the 42 patients, 30 (71.4%) patients developed new lesions once, and 12 (28.6%) twice or thrice, which usually appeared when primary lesions were progressing (37, 88.1%) and 1-15 days after treatment. The newly developed lesions were usually multiple (38, 90.5%), distributed in the previously involved (39, 92.9%) or uninvolved (27, 64.3%) lobes, and manifested as ground-glass opacities (GGOs) with consolidation (23, 54.8%) or pure GGOs (19, 45.2%). After their occurrence, the new lesions in most patients (32, 76.2%) showed direct absorption, whereas those in some patients (10, 23.8%) progressed before absorption. Conclusion: During treatment, most patients with COVID-19 pneumonia will develop new pulmonary lesions, which usually manifest as multiple GGOs distributed around the primary lesions or in previously uninvolved lobes, and are subsequently absorbed directly.


Assuntos
Betacoronavirus/isolamento & purificação , Técnicas de Laboratório Clínico/estatística & dados numéricos , Infecções por Coronavirus/mortalidade , Pulmão/diagnóstico por imagem , Pneumonia Viral/mortalidade , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Adulto , Betacoronavirus/genética , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Pneumonia Viral/virologia , RNA Viral/isolamento & purificação , Estudos Retrospectivos
15.
Circulation ; 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32988222

RESUMO

Background: Proprotein convertase subtilisin/kexin 9 (PCSK9), mainly secreted by the liver and released into the blood, elevates plasma low-density lipoprotein (LDL) cholesterol by degrading LDL receptor. Pleiotropic effects of PCSK9 beyond lipid-metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, as well as the underlying mechanisms, still remain unclear. Methods: We detected the direct effects of PCSK9 on agonists-induced platelet aggregation, dense granule ATP release, integrin αIIbß3 activation, α granule release, spreading, and clot retraction. These studies were complemented by in vivo analysis of FeCl3-injured mouse mesenteric arteriole thrombosis. We also investigated the underlying mechanisms. Using myocardial infarct (MI) model, we explored the effects of PCSK9 on microvascular obstruction and infarct expansion post-MI. Results: PCSK9 directly enhances agonists-induced platelet aggregation, dense granule ATP release, integrin αIIbß3 activation, P-selection release from α granules, spreading, and clot retraction. In line, PCSK9 enhances in vivo thrombosis in a FeCl3-injured mesenteric arteriole thrombosis mouse model, while PCSK9 inhibitor evolocumab ameliorates its enhancing effects. Mechanism studies revealed that PCSK9 binds to platelet CD36 and thus activates Src kinase and mitogen-activated protein kinase (MAPK)- extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase, increases the generation of reactive oxygen species, as well as activates the p38MAPK/cytosolic phospholipase A2/cyclooxygenase-1/thromboxane A2 signaling pathways downstream of CD36 to enhance platelet activation. Using CD36 knockout mice, we showed the enhancing effects of PCSK9 on platelet activation are CD36 dependent. Consistently and importantly, aspirin abolishes the enhancing effects of PCSK9 on platelet activation and in vivo thrombosis. Finally, we showed that PCSK9 activating platelet CD36 aggravates microvascular obstruction and promotes MI expansion post-MI. Conclusions: PCSK9 in plasma directly enhances platelet activation and in vivo thrombosis, as well as MI expansion post-MI, by binding to platelet CD36 and thus activating the downstream signaling pathways. PCSK9 inhibitors or aspirin abolish the enhancing effects of PCSK9, supporting the use of aspirin in patients with high plasma PCSK9 levels in addition to PCSK9 inhibitors to prevent thrombotic complications.

16.
Opt Lett ; 45(15): 4308-4311, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735285

RESUMO

We report on the realization of an optical phase noise cancellation technique by passively embedding the optical phase noise information into a radio frequency signal and creating a copy of the optical frequency signal, which is pre-corrected by the amount of phase noise introduced by optical phase perturbations. Neither phase discrimination nor an active servo controller is required due to the open-loop design, mitigating some technical problems, such as the limited compensation speed and finite phase/timing jitter, in conventional phase noise cancellation. We experimentally demonstrate that this technique maintains the same delay-limited bandwidth and phase noise suppression capability as in conventional techniques, but significantly shortens the response speed and phase recovery time. Passive decoupling optical phase perturbation represents a powerful technique in the domains of optical frequency standard comparisons and tools for future optical atomic clocks, which are now under investigation for a potential redefinition of the International Time Scale.

17.
J Mater Chem B ; 8(32): 7042-7061, 2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32743631

RESUMO

Stimuli-responsive polymers exhibit properties that make them ideal candidates for biosensing and molecular diagnostics. Through rational design of polymer composition combined with new polymer functionalization and synthetic strategies, polymers with myriad responsivities, e.g., responses to temperature, pH, biomolecules, CO2, light, and electricity can be achieved. When these polymers are specifically designed to respond to biomarkers, stimuli-responsive devices/probes, capable of recognizing and transducing analyte signals, can be used to diagnose and treat disease. In this review, we highlight recent state-of-the-art examples of stimuli-responsive polymer-based systems for biosensing and bioimaging.

18.
Sci Rep ; 10(1): 13626, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788610

RESUMO

This study investigates the effects of aircraft cabin pressure on intracranial pressure (ICP) elevation of a pneumocephalus patient. We propose an experimental setup that simulates the intracranial hydrodynamics of a pneumocephalus patient during flight. It consists of an acrylic box (skull), air-filled balloon [intracranial air (ICA)], water-filled balloon (cerebrospinal fluid and blood) and agarose gel (brain). The cabin was replicated using a custom-made pressure chamber. The setup can measure the rise in ICP during depressurization to levels similar to that inside the cabin at cruising altitude. ΔICP, i.e. the difference between mean cruising ICP and initial ICP, was found to increase with ICA volume and ROC. However, ΔICP was independent of the initial ICP. The largest ΔICP was 5 mmHg; obtained when ICA volume and ROC were 20 ml and 1,600 ft/min, respectively. The postulated ICA expansion and the subsequent increase in ICP in pneumocephalus patients during flight were successfully quantified in a laboratory setting. Based on the quantitative and qualitative analyses of the results, an ICA volume of 20 ml and initial ICP of 15 mmHg were recommended as conservative thresholds that are required for safe air travel among pneumocephalus patients. This study provides laboratory data that may be used by doctors to advise post-neurosurgical patients if they can safely fly.

19.
Cell Rep ; 32(7): 108044, 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32814047

RESUMO

Type I interferon (IFN) plays an essential role in the host innate immune responses. Several ubiquitin-conjugating enzyme (E2) family members were reported to regulate type I IFN production and host antiviral immune responses. However, the molecular mechanisms are still not fully understood. Here, we report that UBE2S acts as a negative regulator in the type I IFN signaling pathway. Ectopic expression of UBE2S inhibits host antiviral immune responses and enhances viral replications, whereas deficiency of UBE2S enhances host antiviral immune responses and suppresses viral replications both in vitro and in vivo. Inhibition of type І IFN production by UBE2S is independent on its E2 and E3 enzymic activity. Mechanistically, UBE2S interacts with TBK1 and recruits ubiquitin-specific protease 15 (USP15) to remove Lys63 (K63)-linked polyubiquitin chains of TBK1. Our findings reveal a role of the UBE2S-USP15-TBK1 axis in the regulation of host antiviral innate immune responses.

20.
Thromb Haemost ; 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32854120

RESUMO

Platelet activation plays a pivotal role in physiological hemostasis and pathological thrombosis causing heart attack and stroke. Previous studies conclude that simultaneous activation of Gi and G12/13 signaling pathways is sufficient to cause platelet aggregation. However, using Gq knockout mice and Gq-specific inhibitors, we here demonstrated that platelet aggregation downstream of coactivation of Gi and G12/13 depends on agonist concentrations; coactivation of Gi and G12/13 pathways only induces platelet aggregation under higher agonist concentrations. We confirmed Gi and G12/13 pathway activation by showing cAMP (cyclic adenosine monophosphate) decrease and RhoA activation in platelets stimulated at both low and high agonist concentrations. Interestingly, we found that though Akt and PAK (p21-activated kinase) translocate to the platelet membrane upon both low and high agonist stimulation, membrane-translocated Akt and PAK only phosphorylate at high agonist concentrations, correlating well with platelet aggregation downstream of concomitant Gi and G12/13 pathway activation. PAK inhibitor abolishes Akt phosphorylation, inhibits platelet aggregation in vitro and arterial thrombus formation in vivo. We propose that the PAK-PI3K/Akt pathway mediates platelet aggregation downstream of Gi and G12/13, and PAK may represent a potential antiplatelet and antithrombotic target.

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