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1.
Artigo em Inglês | MEDLINE | ID: mdl-33537929

RESUMO

Hormesis describes a biphasic dose-response relationship generally characterized by a low-dose excitement and a high-dose inhibition. This phenomenon has been observed in the regulation of cell, organ, and organismic level. However, hormesis has not reported in oocytes. In this study, we observed, for the first time, hormetic responses of PIPP levels in oocytes by inhibitor of Akt1 or PKCδ. The expression of PIPP was detected by qPCR, immunofluorescent (IF), and Western Blot (WB). To observe the changes of PIPP levels, we used the inhibitors against pAkt1 (Ser473) or PKCδ, SH-6 or sotrastaurin with low and/or high-dose, treated GV oocytes and cultured for 4 h, respectively. The results showed that PIPP expression was significantly enhanced when oocytes were treated with SH-6 or sotrastaurin 10 µM, but decreased with SH-6 or sotrastaurin 100 µM. We also examined the changes of PIPP levels when GV oocytes were treated with exogenous PtdIns(3,4,5)P3 or LY294002 for 4 h. Our results showed that PIPP level was enhanced much higher under the treatment of 0.1 µM PtdIns(3,4,5)P3 than that of 1 µM PtdIns(3,4,5)P3, which is consistent with the changes of PIPP when oocytes were treated with inhibitors of pAkt1 (Ser473) or PKCδ. In addition, with PIPP siRNA, we detected that down-regulated PIPP may affect distributions of Akt, Cdc25, and pCdc2 (Tyr15). Taken together, these results show that the relationships between PIPP and Akt may follow the principle of hormesis and play a key role during release of diplotene arrest in mouse oocytes.

2.
Nat Commun ; 12(1): 338, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436578

RESUMO

Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7-22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6-33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.


Assuntos
Aberrações Cromossômicas , Evolução Clonal/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Hematológicas/genética , Humanos , Pessoa de Meia-Idade , Mosaicismo , Neoplasias/genética , Medição de Risco , Seleção Genética , Adulto Jovem
3.
Neurosci Lett ; 740: 135461, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33115643

RESUMO

BACKGROUND: Elderly patients receive propofol at regular intervals for sedation during gastrointestinal endoscopy. However, the link between cognition and intermittent propofol exposure remains unclear. Thus, we used aged rats to investigate the effect of propofol on cognition. METHODS: The study included two parts. In the first part, aged (18-20 months old) male Sprague-Dawley rats underwent intermittent intraperitoneal injection of propofol (200 mg/kg) or intralipid, every 9 days or once a day. In the second part, some aged rats received intraperitoneal injection of Bay 11-7082 (1 mg/kg), a specific inhibitor of NF-κB, 30 min before propofol injection. Memory tests were performed to evaluate cognition 24 h after the entire treatment. The hippocampal neuronal damage was assessed by TUNEL staining. The hippocampal levels of p-NF-κB p65, NLRP3, caspase-1 p20, and cleaved caspase-3 were detected by western blotting. The hippocampal and serum levels of IL-1ß, IL-6, and TNF-α were evaluated using ELISA. RESULTS: There were no differences in the behavioral tests, hippocampal neuronal damage, and neuroinflammation between groups given intralipid and propofol treatment every 9 days. However, repeated propofol treatment once a day promoted activation of NF-κB and the NLRP3 inflammasome, inducing cognitive impairment and neuroinflammation. Interestingly, pretreatment with Bay-11-7082 not only inhibited NF-κB/NLRP3 inflammasome activation, but also attenuated neuronal damage and cognitive dysfunction in aged rats exposed to daily propofol treatment. CONCLUSIONS: Intermittent propofol treatment every 9 days may be safe for aged rats. However, propofol treatment once a day could impair the cognition of aged rats, partly through the activation of the NF-κB pathway and NLRP3 inflammasome, which may be a potential targets for the treatment of cognitive impairment in elderly patients.

4.
medRxiv ; 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33269365

RESUMO

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. 1-4 These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. 2,5,6 A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. 7,8 Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of Clostridium Difficile (HR=2.0, 95% CI: 1.2-3.3, p=6×10 -3 ) and Streptococcus/Enterococcus infections (HR=1.5, 95% CI=1.1-2.1, p=5×10 -3 ). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

5.
Nat Genet ; 52(11): 1219-1226, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33106634

RESUMO

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.

6.
Mol Cell ; 80(3): 512-524.e5, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33049228

RESUMO

CRISPR-Cas systems are bacterial anti-viral systems, and phages use anti-CRISPR proteins (Acrs) to inactivate these systems. Here, we report a novel mechanism by which AcrIF11 inhibits the type I-F CRISPR system. Our structural and biochemical studies demonstrate that AcrIF11 functions as a novel mono-ADP-ribosyltransferase (mART) to modify N250 of the Cas8f subunit, a residue required for recognition of the protospacer-adjacent motif, within the crRNA-guided surveillance (Csy) complex from Pseudomonas aeruginosa. The AcrIF11-mediated ADP-ribosylation of the Csy complex results in complete loss of its double-stranded DNA (dsDNA) binding activity. Biochemical studies show that AcrIF11 requires, besides Cas8f, the Cas7.6f subunit for binding to and modifying the Csy complex. Our study not only reveals an unprecedented mechanism of type I CRISPR-Cas inhibition and the evolutionary arms race between phages and bacteria but also suggests an approach for designing highly potent regulatory tools in the future applications of type I CRISPR-Cas systems.

7.
BMC Anesthesiol ; 20(1): 197, 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32781985

RESUMO

BACKGROUND: Rectus sheath block (RSB) is known to attenuate postoperative pain and reduce perioperative opioid consumption. Thus, a retrospective study was performed to examine the effects of bilateral rectus sheath block (BRSB) in cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A total of 178 patients undergoing CRS/HIPEC at our hospital were included. Patient information and anaesthesia-related indicators were collected from the electronic medical record (EMR) system. All subjects were divided into the following two groups: the G group (general anaesthesia) and the GR group (RSB combined with general anaesthesia). Patients in the GR group received 0.375% ropivacaine for BRSB before surgery. The primary outcomes included the total amount of remifentanil and rocuronium, the total consumption of dezocine after surgery, the visual analogue scale (VAS) score and the patient-controlled intravenous analgesia (PCIA) input dose at 1 h (T6), 6 h (T7), 12 h (T8), 24 h (T9) and 48 h (T10) after surgery. Other outcomes were also recorded, such as patient demographic data, the intraoperative heart rate (HR) and mean arterial pressure (MAP), and postoperative complications. RESULTS: Compared with the G group, the GR group showed a shorter time to tracheal extubation (P < 0.05), a decreased total amount of remifentanil and rocuronium (P < 0.05), and a reduced VAS score, PCIA input dose and number of PCIA boluses at 1 h, 6 h and 12 h after surgery (P < 0.05). However, at 24 h and 48 h after surgery, there were no differences in the VAS score of pain at rest or during motion between the two groups (P > 0.05). Moreover, the incidence of hypertension, emergence agitation, delayed recovery, hypercapnia, and nausea and vomiting was lower in the GR group than in the G group (P < 0.05). There were no differences in the changes in MAP and HR during the surgery between the two groups (P > 0.05). No complications associated with nerve block occurred. CONCLUSION: BRSB could provide short-term postoperative analgesia, reduce perioperative opioid consumption and reduce the incidence of postoperative complications. It is an effective and safe procedure in CRS/HIPEC.

8.
Sensors (Basel) ; 20(12)2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32575841

RESUMO

Human-vehicle classification is an essential component to avoiding accidents in autonomous driving. The classification technique based on the automotive radar sensor has been paid more attention by related researchers, owing to its robustness to low-light conditions and severe weather. In the paper, we propose a hybrid support vector machine-convolutional neural network (SVM-CNN) approach to address the class-imbalance classification of vehicles and pedestrians with limited experimental radar data available. A two-stage scheme with the combination of feature-based SVM technique and deep learning-based CNN is employed. In the first stage, the modified SVM technique based on these distinct physical features is firstly used to recognize vehicles to effectively alleviate the imbalance ratio of vehicles to pedestrians in the data level. Then, the residual unclassified images will be used as inputs to the deep network for the subsequent classification, and we introduce a weighted false error function into deep network architectures to enhance the class-imbalance classification performance at the algorithm level. The proposed SVM-CNN approach takes full advantage of both the locations of underlying class in the entire Range-Doppler image and automatical local feature learning in the CNN with sliding filter bank to improve the classification performance. Experimental results demonstrate the superior performances of the proposed method with the F 1 score of 0.90 and area under the curve (AUC) of the receiver operating characteristic (ROC) of 0.99 over several state-of-the-art methods with limited experimental radar data available in a 77 GHz automotive radar.

9.
J Phys Chem Lett ; 11(3): 1087-1092, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31957440

RESUMO

We develop a spin diffusion theory based on the exchange mechanism among polarons to understand the organic pure spin current. It is demonstrated that the exchange coupling is strong enough to induce spin transport within the organic layer with impurity concentrations higher than 1018 cm-3. By calculating the inverse spin Hall voltage in an organic spin device, we predict that the voltage depends nonmonotonically on the impurity concentration of the organic material. By tuning the doping concentration, one can achieve a maximum inverse spin Hall voltage. Our results not only explain some recent experimental data but also inspire further experimental investigation on pure spin current in organic devices with variable impurity doping.

10.
Int J Oncol ; 55(5): 988-1002, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31485599

RESUMO

Anaplastic thyroid carcinoma (ATC) has a poor prognosis due to its resistance to all conventional treatments. The long non­coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) serves a critical role in cancer chemoresistance; however, whether NEAT1 is associated with chemoresistance of ATC remains unclear. In the present study, reverse transcription­quantitative PCR assays were performed to detect the expression levels of NEAT1, microRNA (miR)­9­5p and sperm­associated antigen 9 (SPAG9). Western blot analysis was conducted to assess the protein expression levels of p62, microtubule­associated proteins 1A/1B light chain 3B and SPAG9. Cell proliferation was detected using the Cell Counting kit­8 assay, and cell apoptosis was determined by flow cytometry. Dual­luciferase reporter and RNA immunoprecipitation assays were performed to verify the interaction between NEAT1 and miR­9­5p, or miR­9­5p and SPAG9. Furthermore, an animal model was used to investigate the regulatory effects of NEAT1 on cisplatin (DDP)­resistance in tumors in vivo. The present results demonstrated that NEAT1 was upregulated in ATC tissues and cell lines, and NEAT1 silencing resulted in decreased DDP­resistance of ATC cells. In addition, NEAT1 suppressed miR­9­5p expression by binding to miR­9­5p and SPAG9 was a direct target of miR­9­5p. miR­9­5p overexpression sensitized ATC cells to DDP. Notably, NEAT1 silencing exerted its inhibitory effect on DDP­resistance of ATC via the miR­9­5p/SPAG9 axis in vitro and in vivo. In conclusion, the present study demonstrated that NEAT1 silencing ameliorated DDP­resistance of ATC, at least in part by reducing miR­9­5p sponging and regulating SPAG5 expression; therefore, NEAT1 may be considered a potential therapeutic target of ATC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , Carcinoma Anaplásico da Tireoide/secundário , Neoplasias da Glândula Tireoide/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Cisplatino/farmacologia , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Transl Neurosci ; 10: 180-186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410301

RESUMO

Background: General anesthesia and increasing age are two main risk factors for postoperative cognitive dysfunction (POCD). Effective agents for the prevention or treatment of POCD are urgently needed. L-655,708, an inverse agonist of α5 subunit-containing γ-aminobutyric acid subtype A (α5GABAA) receptors, can prevent anesthesia-induced memory deficits in young animals. However, there is a lack of evidence of its efficacy in old animals. Methodology: Young (3- to 5-month-old) and old (18- to 20-month-old) mice were given an inhalation of 1.33% isoflurane for 1 hour and their associative memory was evaluated 24 hours after anesthesia using fear-conditioning tests (FCTs). To evaluate the effect of L-655,708, mice received intraperitoneal injections of L-655,708 (0.7 mg/kg) or vehicle 30 minutes before anesthesia. Results: Old mice exhibited impaired memory and lower hippocampal α5GABAA levels than young mice under physiological conditions. Pre-injections of L-655,708 significantly alleviated isoflurane-induced memory decline in young mice, but not in old mice. Conclusions: L-655,708 is not as effective for the prevention of POCD in old mice as it is in young mice. The use of inverse agonists of α5GABAA in preventing POCD in old patients should be carefully considered.

12.
Phys Chem Chem Phys ; 21(24): 12924-12930, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31165113

RESUMO

We report a comprehensive theory based on the extended Su-Schrieffer-Heeger (SSH) model to study the interconversion from the dark triplet exciton state to a bright singlet one in molecular heterojunctions, containing both intrachain and interchain excitons. By studying the spin mixing and the projection of excitons onto the pure singlet and triplet excitons, unlike usual methods, we found that the internal electroluminescent quantum efficiency, which is largely determined by the singlet fraction, can be widely tuned by the spin-orbit coupling strength, the intensity of hyperfine interaction, electron-phonon coupling and the site energy offset of the two chains constituting the molecular heterojunctions. In addition, the interchain excitons possess a higher fraction of singlet states in comparison with the intrachain excitons. Remarkably, it can reach up to 52% by proper choice of the above-mentioned physical parameters. Our results outline a novel approach to further improve the luminous efficiency of organic light emitting diodes.

13.
Neural Regen Res ; 14(6): 1029-1036, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30762015

RESUMO

The α5 subunit-containing gamma-amino butyric acid type A receptors (α5 GABAARs) are a distinct subpopulation that are specifically distributed in the mammalian hippocampus and also mediate tonic inhibitory currents in hippocampal neurons. These tonic currents can be enhanced by low-dose isoflurane, which is associated with learning and memory impairment. Inverse agonists of α5 GABAARs, such as L-655,708, are able to reverse the short-term memory deficit caused by low-dose isoflurane in young animals. However, whether these negative allosteric modulators have the same effects on aged rats remains unclear. In the present study, we mainly investigated the effects of L-655,708 on low-dose (1.3%) isoflurane-induced learning and memory impairment in elderly rats. Young (3-month-old) and aged (24-month-old) Wistar rats were randomly assigned to receive L-655,708 0.5 hour before or 23.5 hours after 1.3% isoflurane anesthesia. The Morris Water Maze tests demonstrated that L-655,708 injected before or after anesthesia could reverse the memory deficit in young rats. But in aged rats, application of L-655,708 only before anesthesia showed similar effects. Reverse transcription-polymerase chain reaction showed that low-dose isoflurane decreased the mRNA expression of α5 GABAARs in aging hippocampal neurons but increased that in young animals. These findings indicate that L-655,708 prevented but could not reverse 1.3% isoflurane-induced spatial learning and memory impairment in aged Wistar rats. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Academy of Military Medical Science of China (approval No. NBCDSER-IACUC-2015128) in December 2015.

14.
Nat Mater ; 18(5): 510-517, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30804509

RESUMO

As an important application of functional biomaterials, neural probes have contributed substantially to studying the brain. Bioinspired and biomimetic strategies have begun to be applied to the development of neural probes, although these and previous generations of probes have had structural and mechanical dissimilarities from their neuron targets that lead to neuronal loss, neuroinflammatory responses and measurement instabilities. Here, we present a bioinspired design for neural probes-neuron-like electronics (NeuE)-where the key building blocks mimic the subcellular structural features and mechanical properties of neurons. Full three-dimensional mapping of implanted NeuE-brain interfaces highlights the structural indistinguishability and intimate interpenetration of NeuE and neurons. Time-dependent histology and electrophysiology studies further reveal a structurally and functionally stable interface with the neuronal and glial networks shortly following implantation, thus opening opportunities for next-generation brain-machine interfaces. Finally, the NeuE subcellular structural features are shown to facilitate migration of endogenous neural progenitor cells, thus holding promise as an electrically active platform for transplantation-free regenerative medicine.


Assuntos
Materiais Biocompatíveis/química , Interfaces Cérebro-Computador , Eletrodos Implantados , Eletrônica , Neurônios/fisiologia , Animais , Animais Recém-Nascidos , Astrócitos/citologia , Biomimética , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Mapeamento Encefálico , Fenômenos Eletrofisiológicos , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/diagnóstico por imagem , Humanos , Imageamento Tridimensional , Inflamação , Masculino , Teste de Materiais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nanomedicina , Neuritos , Refratometria , Projetos de Pesquisa , Técnicas Estereotáxicas , Estresse Mecânico
15.
Biofabrication ; 10(3): 034106, 2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29923501

RESUMO

Three-dimensional bioprinting has emerged as a promising technique in tissue engineering applications through the precise deposition of cells and biomaterials in a layer-by-layer fashion. However, the limited availability of hydrogel bioinks is frequently cited as a major issue for the advancement of cell-based extrusion bioprinting technologies. It is well known that highly viscous materials maintain their structure better, but also have decreased cell viability due to the higher forces which are required for extrusion. However, little is known about the effect of the two distinct components of dynamic modulus of viscoelastic materials, storage modulus (G') and loss modulus (G″), on the printability of hydrogel-based bioinks. Additionally, 'printability' has been poorly defined in the literature, mostly consisting of gross qualitative measures which do not allow for direct comparison of bioinks. This study developed a framework for evaluating printability and investigated the effect of dynamic modulus, including storage modulus (G'), loss modulus (G″), and loss tangent (G″/G') on the printing outcome. Gelatin and alginate as model hydrogels were mixed at various concentrations to obtain hydrogel formulations with a wide range of storage and loss moduli. These formulations were then evaluated for the quantitatively defined values of extrudability, extrusion uniformity, and structural integrity. For extrudability, increasing either the loss or storage modulus increased the pressure required to extrude the bioink. A mathematical model relating the G' and G″ to the required extrusion pressure was derived based on the data. A lower loss tangent was correlated with increased structural integrity while a higher loss tangent correlated with increased extrusion uniformity. Gelatin-alginate composite hydrogels with a loss tangent in the range of 0.25-0.45 exhibited an excellent compromise between structural integrity and extrusion uniformity. In addition to the characterization of a common bioink, the methodology introduced in this paper could also be used to evaluate the printability of other bioinks in the future.


Assuntos
Alginatos/química , Bioimpressão/métodos , Gelatina/química , Teste de Materiais/métodos , Elasticidade , Reologia , Engenharia Tecidual , Viscosidade
16.
Proteins ; 86(8): 882-891, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29726048

RESUMO

Current cholesteryl ester transfer protein (CETP) inhibitors are designed based on the unglycosylated crystal structure, and most of them have failed to cure cardiovascular disease (CVD). It is particularly important for us to investigate the glycosylation structure of CETP (CETP-G) and effect of glycans on the structure and function of CETP. Here, we used a total of 3.0-µs molecular dynamics (MD) trajectories of nascent structure of CETP (CETP-N) and CETP-G to study their structural differentiations, to shed new light on the CETP-mediated lipid exchange. In accordance with our simulations and previous mutation studies, relative to CETP-N, CETP-G adopts a more stretched shape with higher hydrophobic and hydrophilic solvent-accessible surface area (SASA) of N-terminal oscillating with larger amplitude, in which Glycan88 provides partial assistance for CEs through the N-terminal. Glycan341 reduces the flexibility of neck flap, with the interference of CEs through the neck region. Besides, Glycan240 reduces the flexibility of Helix-X to interfere the CEs transfer. Glycan396 decreases the flexibility and increases the hydrophobic SASA of C-terminal. Overall, these glycans affect the dynamics and structure of CETP through forming H-bonds with surrounding residues, and the sampled conformations of glycan is also affected by its surrounding residues. Thus, glycans are an integral part of CETP, further studies on the CETP inhibition and treatment of CVD should fully consider the effect of glycans.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/química , Glicoproteínas/química , Simulação de Dinâmica Molecular , Polissacarídeos/química , Sítios de Ligação , Interações Hidrofóbicas e Hidrofílicas , Ligação Proteica , Conformação Proteica , Solventes/química , Relação Estrutura-Atividade
17.
Acc Chem Res ; 51(2): 309-318, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29381054

RESUMO

Nanobioelectronics represents a rapidly developing field with broad-ranging opportunities in fundamental biological sciences, biotechnology, and medicine. Despite this potential, seamless integration of electronics has been difficult due to fundamental mismatches, including size and mechanical properties, between the elements of the electronic and living biological systems. In this Account, we discuss the concept, development, key demonstrations, and future opportunities of mesh nanoelectronics as a general paradigm for seamless integration of electronics within synthetic tissues and live animals. We first describe the design and realization of hybrid synthetic tissues that are innervated in three dimensions (3D) with mesh nanoelectronics where the mesh serves as both as a tissue scaffold and as a platform of addressable electronic devices for monitoring and manipulating tissue behavior. Specific examples of tissue/nanoelectronic mesh hybrids highlighted include 3D neural tissue, cardiac patches, and vascular constructs, where the nanoelectronic devices have been used to carry out real-time 3D recording of electrophysiological and chemical signals in the tissues. This novel platform was also exploited for time-dependent 3D spatiotemporal mapping of cardiac tissue action potentials during cell culture and tissue maturation as well as in response to injection of pharmacological agents. The extension to simultaneous real-time monitoring and active control of tissue behavior is further discussed for multifunctional mesh nanoelectronics incorporating both recording and stimulation devices, providing the unique capability of bidirectional interfaces to cardiac tissue. In the case of live animals, new challenges must be addressed, including minimally invasive implantation, absence of deleterious chronic tissue response, and long-term capability for monitoring and modulating tissue activity. We discuss each of these topics in the context of implantation of mesh nanoelectronics into rodent brains. First, we describe the design of ultraflexible mesh nanoelectronics with size features and mechanical properties similar to brain tissue and a novel syringe-injection methodology that allows the mesh nanoelectronics to be precisely delivered to targeted brain regions in a minimally invasive manner. Next, we discuss time-dependent histology studies showing seamless and stable integration of mesh nanoelectronics within brain tissue on at least one year scales without evidence of chronic immune response or glial scarring characteristic of conventional implants. Third, armed with facile input/output interfaces, we describe multiplexed single-unit recordings that demonstrate stable tracking of the same individual neurons and local neural circuits for at least 8 months, long-term monitoring and stimulation of the same groups of neurons, and following changes in individual neuron activity during brain aging. Moving forward, we foresee substantial opportunities for (1) continued development of mesh nanoelectronics through, for example, broadening nanodevice signal detection modalities and taking advantage of tissue-like properties for selective cell targeting and (2) exploiting the unique capabilities of mesh nanoelectronics for tackling critical scientific and medical challenges such as understanding and potentially ameliorating cell and circuit level changes associated with natural and pathological aging, as well as using mesh nanoelectronics as active tissue scaffolds for regenerative medicine and as neuroprosthetics for monitoring and treating neurological diseases.


Assuntos
Equipamentos e Provisões Elétricas , Eletrônica Médica/instrumentação , Eletrônica Médica/métodos , Engenharia Tecidual/métodos , Animais , Encéfalo/metabolismo , Humanos , Camundongos , Neurônios/metabolismo , Primatas , Ratos
18.
Sci Rep ; 7(1): 17808, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29259323

RESUMO

Despite the increasing quantity of tools for accurately predicting gene fusion candidates from sequencing data, we are still faced with the critical challenge of visualizing the corresponding gene fusion products to infer their biological consequence (i.e. novel protein and increased gene expression). This is currently accomplished by manually inspecting and inferring the biological consequence of top scoring gene fusion candidates. This labor-intensive process could be made easier by automating the annotation of gene fusion products and generating easily interpretable visualizations. We developed a gene fusion visualization tool, called INTEGRATE-Vis, that generates comprehensive, highly customizable, publication-quality graphics focused on annotating each gene fusion at the transcript- and protein-level and assessing expression within an individual sample or across a patient cohort. INTEGRATE-Vis is the first comprehensive gene fusion visualization tool to help a user infer the potential consequence of a gene fusion event. It has potential utility in both research and clinical settings. INTEGRATE-Vis is available at https://github.com/ChrisMaherLab/INTEGRATE-Vis .


Assuntos
Fusão Gênica/genética , Genômica/métodos , Computadores , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Software
19.
Anal Chim Acta ; 983: 173-180, 2017 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-28811024

RESUMO

An aptamer induced "switch on" fluorescence resonance energy transfer (FRET) biosensor for the simultaneous detection of multiple tumor markers (e.g., AFP and CEA) combining molybdenum disulfide (MoS2) nanosheets with multicolored Au NCs by a single excitation was developed for the first time. Here, AFP aptamer functionalized green colored Au NCs (510 nm) and CEA aptamer functionalized red colored Au NCs (650 nm) are used as energy donors, while MoS2 is used as energy receptor. On the basis of recording the change of the recovered fluorescence intensity at 510 nm and 650 nm upon the addition of targets CEA and AFP, these two tumor markers can be simultaneously quantitatively detected, with detection limits of 0.16 and 0.21 ng mL-1 (3σ) for AFP and CEA, respectively. In addition, it is noteworthy that the developed biosensor can not only realize accurate quantitative determination of multiple tumor markers by fluorescent intensity, but also be applied in semi-quantitative determination through photo visualization. More importantly, confocal microscope experiments prove that serums from normal and hepatoma patients can also be visually and qualitatively discriminated by this FRET-based biosensor with a single excitation wavelength, indicating promising potential of this assay for clinical diagnosis.


Assuntos
Biomarcadores Tumorais/análise , Técnicas Biossensoriais , Transferência Ressonante de Energia de Fluorescência , Nanocompostos , Cor , Ouro , Humanos , Limite de Detecção
20.
BMC Bioinformatics ; 18(1): 360, 2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28774262

RESUMO

BACKGROUND: Histopathology images are critical for medical diagnosis, e.g., cancer and its treatment. A standard histopathology slice can be easily scanned at a high resolution of, say, 200,000×200,000 pixels. These high resolution images can make most existing imaging processing tools infeasible or less effective when operated on a single machine with limited memory, disk space and computing power. RESULTS: In this paper, we propose an algorithm tackling this new emerging "big data" problem utilizing parallel computing on High-Performance-Computing (HPC) clusters. Experimental results on a large-scale data set (1318 images at a scale of 10 billion pixels each) demonstrate the efficiency and effectiveness of the proposed algorithm for low-latency real-time applications. CONCLUSIONS: The framework proposed an effective and efficient system for extremely large histopathology image analysis. It is based on the multiple instance learning formulation for weakly-supervised learning for image classification, segmentation and clustering. When a max-margin concept is adopted for different clusters, we obtain further improvement in clustering performance.


Assuntos
Patologia/métodos , Algoritmos , Análise por Conglomerados , Metodologias Computacionais , Humanos , Processamento de Imagem Assistida por Computador , Curva ROC , Estatística como Assunto
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