?This study estimated the number of daily tenofovir disoproxil fumarate/ emtricitabine (TDF/FTC) doses required to achieve and maintain (after discontinuation) intracellular drug concentrations that protect against HIV infection for men who have sex with men (MSM).
Abstract As a highly conserved housekeeping gene, the biological implications of ribosomal protein S15A (RPS15A) during various processes, including carcinogenesis, remain elusive. Herein, the authors reported that knockdown of RPS15A expression significantly inhibited human osteosarcoma U2OS cell proliferation and colony formation in vitro by using a lentivirus-mediated RNA interference (RNAi) system. Moreover, an excess accumulation of cells in the G0/G1 phase was observed in U2OS cells transduced with lentivirus targeting RPS15A, suggesting that the growth inhibition mediated by RPS15A knockdown in osteosarcoma cells was probably due to the induction of cell cycle arrest. Taken together, this study highlights the crucial role of RPS15A in promoting osteosarcoma cell proliferation, and provides a foundation for further study into the clinical potential of inhibition of RPS15A for the treatment of osteosarcoma.
Accurately depicting breast tumors located posteriorly, close to the chest wall musculature, with conventional mammography is a technical challenge.OBJECTIVE: This study demonstrates the proof of concept of an x-ray fluorescence mapping (XFM) technique to address this issue.METHODS: A tissue-equivalent gel phantom is designed to mimic structures in the central part of a compressed breast. The posterior aspect of the breast and adjacent pectoralis major muscle are represented by another 10-mm-thickness breast tissue simulation phantom (BR12) that is attached to the back of the gel phantom as a region of interest (ROI). Two gold nanoparticle (GNP) solutions are embedded into the ROI to simulate varying GNP uptake within breast lesions. The ROI is imaged through performing the XFM technique with an x-ray pencil-beam and a single spectrometer.RESULTS: A 2D mapping of the middle plane in the ROI demonstrates feasibility and matches well the known spatial distribution and different GNP concentrations. 3D reconstruction of the ROI is easily rendered by repeating the 2D mapping process.CONCLUSION: XFM system geometry and its insensitivity to attenuation coefficients of breast tissue components are unique characteristics that may complement conventional mammography and improve the detection of breast cancers located posteriorly, adjacent to or overlying the chest wall musculature.
Although p53 is frequently mutated in human cancers, about 80% of human melanomas retain wild-type p53. Here, we report that PHGDH, the key metabolic enzyme that cata-lyzes the rate-limiting step of serine biosynthesis pathway, is a target of p53 in human melanoma cells. p53 suppresses its expression and inhibits de novo serine biosynthesis. Notably, upon serine starvation, p53-mediated cell death is dramatically enhanced in response to Nutlin-3 treatment. Moreover, PHGDH is recently found to be frequently amplified in human melanomas. We found that PHGDH overexpression significantly suppresses the apoptotic response, whereas RNAi-mediated knock-down of endogenous PHGDH promotes apoptosis under the same treatment. These results demonstrate an important role of p53 in regulating serine biosynthesis pathway through suppressing PHGDH expression and reveal serine deprivation as a novel approach to sensitize p53-mediated apoptotic responses in human melanoma cells.
Objective. Recent studies have shown that dorsal premotor cortex (PMd), a cortical area in the dorsomedial grasp pathway, is involved in grasp movements. However, the neural ensemble firing property of PMd during grasp movements and the extent to which it can be used for grasp decoding are still unclear. Approach. To address these issues, we used multielectrode arrays to record both spike and local field potential (LFP) signals in PMd in macaque monkeys performing reaching and grasping of one of four differently shaped objects. Main results. Single and population neuronal activity showed distinct patterns during execution of different grip types. Cluster analysis of neural ensemble signals indicated that the grasp related patterns emerged soon (200-300 ms) after the go cue signal, and faded away during the hold period. The timing and duration of the patterns varied depending on the behaviors of individual monkey. Application of support vector machine model to stable activity patterns revealed classification accuracies of 94% and 89% for each of the two monkeys, indicating a robust, decodable grasp pattern encoded in the PMd. Grasp decoding using LFPs, especially the high-frequency bands, also produced high decoding accuracies. Significance. This study is the first to specify the neuronal population encoding of grasp during the time course of grasp. We demonstrate high grasp decoding performance in PMd. These findings, combined with previous evidence for reach related modulation studies, suggest that PMd may play an important role in generation and maintenance of grasp action and may be a suitable locus for brain-machine interface applications.
Abstract Simple and reproducible tools to assess antiretroviral adherence are needed. A level of tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) <1,250?fmol/punch is predicted to identify imperfect adherence. Herein we evaluated TFV-DP in DBS as a measure of adherence among HIV-infected women. DBS and peripheral blood mononuclear cells (PBMCs) were collected twice (?1 week apart) in 35 well-controlled HIV-infected women [median age 42 years, 14 African American/black (AA)] receiving daily coformulated tenofovir/emtricitabine and either atazanavir/ritonavir (n=20) or raltegravir (n=16). TFV-DP in DBS and PBMCs was quantified by LC-MS/MS. Six-month adherence was measured as average days between monthly pharmacy refills. Data were loge transformed for analysis and presented as median (range); the correlation between continuous variables was analyzed using the Pearson correlation coefficient. The average TFV-DP between the two visits (aTFV-DP) in DBS and PBMCs was 1,874 (706-3,776) fmol/punch and 125 (1-278) fmol/10(6) cells, respectively. AA women had lower levels of aTFV-DP in DBS compared to whites (1,660 vs. 1,970?fmol/punch; p=0.04), with a viremic patient having the lowest drug levels (706?fmol/punch). Days between pharmacy refills were 34 (30-54) vs. 30 (26-40) in women with TFV-DP in DBS <1,250 vs. ?1,250?fmol/punch (p=0.006). TFV-DP in DBS was negatively correlated with an increasing number of days between refills (r=-0.56, p=0.002). TFV-DP DBS was a reliable and objective measure of adherence in HIV-infected women based on a strong inverse relationship with pharmacy refill adherence.
The purpose of this study is to identify a set of features for optimizing the performance of metaphase chromosome detection under high throughput scanning microscopy. In the development of computer-aided detection (CAD) scheme, feature selection is critically important, as it directly determines the accuracy of the scheme. Although many features have been examined previously, selecting optimal features is often application-oriented.
The use of hydrogel-based cell transport scaffolds holds great promise in regenerative medicine, such as treating osteoarthritis. Gelatin and glucosamine are the ideal materials to be used in the hydrogel scaffolds for cartilage regeneration for they could act as compositions of cartilage. To overcome the weak strength of traditional gelatin hydrogels and down-regulate cell toxicity of glucosamine, gelatin and glucosamine molecules were grafted with acrylate groups and covalently crosslinked under photo-radiation to form hydrogels. Hydrogels with tuning physiochemical properties were produced according to different proportions of methacrylate gelatin (GelMA) and N-acryloyl glucosamine (AGA). The process of photocrosslinking was elaborated, and the hypothesis of increasing AGA concentration leading to higher strength of hydrogels was corroborated by testing rheological property and scanning micro-morphological features. A serial of properties, including smaller swelling ratio, lower gelatin dissolution and slower degradation of GelMA/AGA hydrogels with higher AGA concentration further proved our hypothesis. Moreover, AGA molecules showed less cytotoxicity than unmodified glucosamine molecules and the incorporation of AGA molecules in GelMA/AGA hydrogels upregulated cell adhesion and spreading on the hydrogel surface. All of these results indicated that addition of AGA molecules could significantly alter the physiochemical properties of GelMA/AGA hydrogels, which may have broad application prospects in the future.
The development of a short and efficient synthesis of a complex 6-azaindole, BMS-663068, is described. Construction of the 6-azaindole core is quickly accomplished starting from a simple pyrrole, via a regioselective Friedel-Crafts acylation, Pictet-Spengler cyclization, and a radical-mediated aromatization. The synthesis leverages an unusual heterocyclic N-oxide ?-bromination to functionalize a critical C-H bond, enabling a highly regioselective copper-mediated Ullmann-Goldberg-Buchwald coupling to install a challenging triazole substituent. This strategy resulted in an efficient 11 step linear synthesis of this complex clinical candidate.
The correlation between admission Electrocardiogram (ECG) and coronary angiography findings have the responsibility for culprit vessel in predicting the infarct or multivessel disease (MVD) in acute anterior or anterior-inferior ST segment elevation myocardial infarction.
Ta(V)Cl2Me3 reacts with silica(700) and produces two different [(?SiO)Ta(V)Cl2Me2] surface organometallic species, suggesting a heterogeneity of the highly dehydroxylated silica surface, which was studied with a combined experimental and theoretical approach.
Hippo signaling is a tumor-suppressor pathway involved in organ size control and tumorigenesis through the inhibition of YAP and TAZ. Here, we show that energy stress induces YAP cytoplasmic retention and S127 phosphorylation and inhibits YAP transcriptional activity and YAP-dependent transformation. These effects require the central metabolic sensor AMP-activated protein kinase (AMPK) and the upstream Hippo pathway components Lats1/Lats2 and angiomotin-like 1 (AMOTL1). Furthermore, we show that AMPK directly phosphorylates S793 of AMOTL1. AMPK activation stabilizes and increases AMOTL1 steady-state protein levels, contributing to YAP inhibition. The phosphorylation-deficient S793Ala mutant of AMOTL1 showed a shorter half-life and conferred resistance to energy-stress-induced YAP inhibition. Our findings link energy sensing to the Hippo-YAP pathway and suggest that YAP may integrate spatial (contact inhibition), mechanical, and metabolic signals to control cellular proliferation and survival.
This study aims to investigate whether the nucleoprotein (NP) of severe fever with thrombocytopenia syndrome virus (SFTSV) can impact the cellular immunity of host cells. Gene segments that encode the NP and non-structural protein (NSs) of SFTSV were inserted into eukaryotic expression vector VR1012. Host proteins that interact with NP and affect immunity were identified with co-immunoprecipitation (IP), SDS-PAGE, mass spectrometry (MS), and Western blot. Co-localization of NP and the identified host proteins was confirmed by confocal microscopy. A 60kD SSA/Ro, a protein related to immunity, interacted with NP, as found by IP and MS. Confocal microscopy showed that NP and SSA/Ro were co-localized in cytoplasm. These results indicated that SFTSV NP may specifically bind to 60kD SSA/Ro and cause a series of immune responses and clinical symptoms.
Selecting optimal features from a large image feature pool remains a major challenge in developing computer-aided detection (CAD) schemes of medical images. The objective of this study is to investigate a new approach to significantly improve efficacy of image feature selection and classifier optimization in developing a CAD scheme of mammographic masses.
Reinforcement learning (RL) based brain machine interfaces (BMIs) enable user to learn from environment through interactions to complete the task without desired signals, which is promising for clinical applications. Previous studies exploit Q-learning techniques to discriminate neural states into simple directional actions providing the trial initial timing. However, the movements in BMI applications could be quite complicated, and the action timing explicitly shows the intention when to move. The rich actions and the corresponding neural states form a large state-action space, imposing generalization difficulty on Q-learning. In this paper, we propose to adopt attention-gated reinforcement learning (AGREL) as a new learning scheme for BMIs to adaptively decode high-dimensional neural activities into 7 distinct movements (directional moves, holdings and resting) due to the efficient weight-updating. We apply AGREL on neural data recorded from M1 of a monkey to directly predict a seven-action set in a time sequence to reconstruct the trajectory of a center-out task. Compared to Q-learning techniques, AGREL could improve the target acquisition rate to 90.16% in average with faster convergence and more stability to follow neural activity over multiple days, indicating the potential to achieve better online decoding performance for more complicated BMI tasks.
In this paper, the granted projects of the National Institute of Parasitic Diseases (NIPD), China CDC, was analyzed. The results showed that from 2002 to 2012, 126 projects were granted to NIPD. 28.6% (36/126) of the projects were at the national level; 27% (34/126) were at provincial and ministrerial level. International cooperation projects and those supported by state key laboratory and enterprises accounted for 28.6% (36/126) and 15.8% (20/126), respectively. 94 projects belonged to applied researches and 32 belonged to basic researches. Most project leaders were young and middle-aged researchers with senior professional titles.
This study analyzes the strength, weakness, opportunity and threat (SWOT) of laboratory certification and accreditation on detection of parasitic diseases by SWOT analysis comprehensively, and it puts forward some development strategies specifically, in order to provide some indicative references for the further development.
Introduction. Trajectories of surgical instruments in laparoscopic surgery contain rich information about surgeons' performance. In a simulation environment, instrument trajectories can be taken by motion sensors attached to the instruments. This method is not accepted by surgeons working in the operating room due to safety concerns. In this study, a novel approach of acquiring instrument trajectories from surgical videos is reported. Methods. A total of 12 surgical videos were obtained for this study. The videos were captured during simulated laparoscopic procedures where subjects were required to pick up and transport an object over 3 different targets using a laparoscopic grasper. An algorithm was developed to allow the computer to identify the tip of the grasper on each frame of video, and then compute the trajectories of grasper movement. Results. The newly developed algorithm successfully identified tool trajectories from all 12 surgical videos. To validate the accuracy of this algorithm, the location of the tooltip in these videos were also manually labeled. The rate of accurate matching between these 2 methods was 98.4% of all video frames. Discussion. Identifying tool movement from surgical videos creates an effective way to track instrument trajectories. This builds up the foundation for assessing psychomotor performance of surgeons in the operating room without jeopardizing patient safety.
The high false-positive recall rate is one of the major dilemmas that significantly reduce the efficacy of screening mammography, which harms a large fraction of women and increases healthcare cost. This study aims to investigate the feasibility of helping reduce false-positive recalls by developing a new computer-aided diagnosis (CAD) scheme based on the analysis of global mammographic texture and density features computed from four-view images. Our database includes full-field digital mammography (FFDM) images acquired from 1052 recalled women (669 positive for cancer and 383 benign). Each case has four images: two craniocaudal (CC) and two mediolateral oblique (MLO) views. Our CAD scheme first computed global texture features related to the mammographic density distribution on the segmented breast regions of four images. Second, the computed features were given to two artificial neural network (ANN) classifiers that were separately trained and tested in a ten-fold cross-validation scheme on CC and MLO view images, respectively. Finally, two ANN classification scores were combined using a new adaptive scoring fusion method that automatically determined the optimal weights to assign to both views. CAD performance was tested using the area under a receiver operating characteristic curve (AUC). The AUC = 0.793? ± ?0.026 was obtained for this four-view CAD scheme, which was significantly higher at the 5% significance level than the AUCs achieved when using only CC (p = 0.025) or MLO (p = 0.0004) view images, respectively. This study demonstrates that a quantitative assessment of global mammographic image texture and density features could provide useful and/or supplementary information to classify between malignant and benign cases among the recalled cases, which may eventually help reduce the false-positive recall rate in screening mammography.
Effective seizure detection from long-term EEG is highly important for seizure diagnosis. Existing methods usually design the feature and classifier individually, while little work has been done for the simultaneous optimization of the two parts. This work proposes a deep network to jointly learn a feature and a classifier so that they could help each other to make the whole system optimal. To deal with the challenge of the impulsive noises and outliers caused by EMG artifacts in EEG signals, we formulate a robust stacked autoencoder (R-SAE) as a part of the network to learn an effective feature. In R-SAE, the maximum correntropy criterion (MCC) is proposed to reduce the effect of noise/outliers. Unlike the mean square error (MSE), the output of the new kernel MCC increases more slowly than that of MSE when the input goes away from the center. Thus, the effect of those noises/outliers positioned far away from the center can be suppressed. The proposed method is evaluated on six patients of 33.6 hours of scalp EEG data. Our method achieves a sensitivity of 100% and a specificity of 99%, which is promising for clinical applications.
Both KLF5 and Runx2 are involved in phenotypic switching of vascular smooth muscle cells (VSMC). However, the potential link between KLF5 and Runx2 in mediating vascular calcification remains unclear. The aim of the study was to elucidate the actual relationship between KLF5 and Runx2 in mediating VSMC calcification. We found that high phosphate increased the expression of KLF5, which is accompanied by loss of SM ?-actin and SM22?, as well as gain of Runx2 expression. Overexpression of KLF5 increased, while knockdown of KLF5 decreased, Runx2 expression and calcification. Further study showed that KLF5 bound directly to the Runx2 promoter and activated its transcription. KLF5 was also induced markedly in the calcified aorta of adenine-induced uremic rats. In conclusion, we demonstrate a critical role for KLF5-mediated induction of Runx2 in high phosphate-induced VSMC calcification.
Tongxinluo (TXL), a traditional Chinese medicine, has multiple vasoprotective effects, including anti-inflammation. MicroRNA-155 (miR-155) is involved in vascular inflammation and atherosclerosis. However, a direct relationship between TXL and miR-155 in the development of vascular inflammation and remodeling had not yet been shown. The objective of the present study was to investigate whether TXL exerts an inhibitory effect on the vascular inflammatory response and neointimal hyperplasia by regulating miR-155 expression. Using the carotid artery ligation model in mice, we have shown that TXL dose dependently inhibited neointimal formation and reduced the vascular inflammatory response by inhibiting inflammatory cytokine production and macrophage infiltration. miR-155 was induced by carotid artery ligation, and neointimal hyperplasia was strongly reduced in miR-155(?/?) mice. In contrast, miR-155 overexpression partly reversed the inhibitory effect of TXL on neointimal hyperplasia. In bone marrow-derived macrophages, miR-155 and TNF-? formed a positive feedback loop to promote the inflammatory response, which could be blocked by TXL. Furthermore, TXL increased Akt1 protein expression and phosphorylation in TNF-?-stimulated marrow-derived macrophages, and knockdown of Akt1 abrogated the TXL-induced suppression of miR-155. In conclusion, TXL inhibits the vascular inflammatory response and neointimal hyperplasia induced by carotid artery ligation in mice. Suppression of miR-155 expression mediated by Akt1 and blockade of the feedback loop between miR-155 and TNF-? are important pathways whereby TXL exerts its vasoprotective effects.
The biomechanical property of MGT for patients who underwent partial sacrectomy is not well documented, so this study aimed to investigate biomechanical property of lumbosacral reconstruction after partial sacrectomy.
Skeletal muscle atrophy occurs in response to a variety of conditions including chronic kidney disease, diabetes, cancer, and elevated glucocorticoids. MicroRNAs (miR) may play a role in the wasting process. Activation of the forkhead box O3 (FoxO3) transcription factor causes skeletal muscle atrophy in patients, animals, and cultured cells by increasing the expression of components of the ubiquitin-proteasome and autophagy-lysosome proteolytic systems. To identify microRNAs that potentially modulate the atrophy process, an in silico target analysis was performed and miR-182 was predicted to target FoxO3 mRNA. Using a combination of immunoblot analysis, quantitative real-time RT-PCR, and FoxO3 3'-UTR luciferase reporter genes, miR-182 was confirmed to regulate FoxO3 expression in C2C12 myotubes. Transfection of miR-182 into muscle cells decreased FoxO3 mRNA 30% and FoxO3 protein 67% (P < 0.05) and also prevented a glucocorticoid-induced upregulation of multiple FoxO3 gene targets including MAFbx/atrogin-1, autophagy-related protein 12 (ATG12), cathepsin L, and microtubule-associated protein light chain 3 (LC3). Treatment of C2C12 myotubes with dexamethasone (Dex) (1 ?M, 6 h) to induce muscle atrophy decreased miR-182 expression by 63% (P < 0.05). Similarly, miR-182 was decreased 44% (P < 0.05) in the gastrocnemius muscle of rats injected with streptozotocin to induce diabetes compared with controls. Finally, miR-182 was present in exosomes isolated from the media of C2C12 myotubes and Dex increased its abundance. These data identify miR-182 as an important regulator of FoxO3 expression that participates in the control of atrophy-inducing genes during catabolic diseases.
The differentiation and function of IL-17-producing Th17 cells are tightly regulated by specific transcription factors and cytokines, which are the key participants in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Although specific miRNAs have been shown to be involved in the development of MS and EAE, the potential role of miRNAs in the context of Th17-driven autoimmunity is just beginning to be clarified. miR-20b has been reported as a downregulated miRNA in blood cells of MS patients. In this report, it was further studied in greater detail because we found it was significantly downregulated during EAE, and, in the in vitro differentiation model, Th17 cells had lower expression of miR-20b than did Th1, Th2, or inducible T regulatory cells. Ectopic expression of miR-20b repressed Th17 differentiation in vitro. Using lentiviral vectors for miR-20b overexpression in vivo, we demonstrated that overexpression of miR-20b led to decreased Th17 cells and reduced severity of EAE. Furthermore, we also identified both RAR-related orphan receptor ?t and STAT3 as potential targets of miR-20b. Finally, we confirmed that the mild disease severity and low number of Th17 cells in LV-miR-20b-infected mice were largely reversed by coinfection of these mice with lentivirus-expressing RAR-related orphan receptor ?t or STAT3 3'-untranslated regions. Taken together, our results contribute to the importance of miRNAs in Th17 differentiation and pathogenesis of MS and EAE.
Background. We examined the impact of tool complexity on surgeons' performance and evaluated the value of using a simulation-based program for reducing training cost. Methods. Three pairs of surgical graspers with increasing mechanical complexity, which were designed for open, laparoscopic, and endoscopic procedures, were used in performing a simple object transportation task. Task times and mental workload of 17 surgeons were compared using all 3 variations of the graspers to test the impact of tool complexity on surgical performance. Subsequently, 4 of these surgeons decided to enter a 3-week training phase and practiced with these 3 surgical instruments on a daily basis. Learning curves were plotted to examine the value of using simulation for proficiency training with these tools. Results. Task time was significantly prolonged as tool complexity increased. Practice in a simulated environment shortened the task time significantly and moderately reduced mental workloads. However, the difference in task time varied among the 3 types of tools. Between days 1 and 9, task times for each types of grasper were reduced by 55% (endoscopic), 42% (open), and 22% (laparoscopic). Conclusions. Tool complexity may degrade a surgeon's performance. Extensive simulation training programs are important for surgeons to gain proficiency in handling a tool before they practice on patients.
Many serious concerns exist in the long-term stability of brain-machine interfaces (BMIs) based on spike signals (single unit activity, SUA; multi unit activity, MUA). Some studies showed local field potentials (LFPs) could offer a stable decoding performance. However, the decoding stability of LFPs was examined only when high quality spike signals were recorded. Here we aim to examine the long-term decoding stability of LFPs over a larger time scale when the quality of spike signals was from good to poor or even no spike was recorded.
Many patients suffer from chronic postsurgical pain (CPSP) following surgery, and the underlying mechanisms are poorly understood. In the present work, with use of the skin/muscle incision and retraction (SMIR) model, the role of P2X7 receptors (P2X7Rs) in spinal glial cells in the development of CPSP was evaluated. Consistent with previous reports, we found that SMIR decreased the ipsilateral 50% paw withdrawal threshold (PWT), lasting for at least 2weeks. No injury was done to L3 dorsal root ganglia (DRG) neurons and no axonal or Schwann cell damage at the retraction site in the saphenous nerve was observed 7days after SMIR. The results of immunofluorescence showed that both microglia and astrocytes were activated in the spinal dorsal horn following SMIR. In addition, both P2X7Rs and tumor necrosis factor-alpha (TNF-?) were up-regulated following SMIR. Double immunofluorescence staining revealed that the up-regulated P2X7R immunoreactivity was mainly located in microglia, and to a lesser extent in astrocytes, but not in neurons. Intrathecal delivery of specific P2X7R antagonist BBG (10?M in 10?l volume) or A438079 (10?M in 10?l volume), started 30min before the surgery and once daily thereafter for 7days, prevented the mechanical allodynia. Intrathecal injection of BBG inhibited the activation of microglia and astrocytes, and the up-regulation of TNF-? induced by SMIR. These data suggest that P2X7Rs in the spinal dorsal horn might mediate the development of CPSP via activation of glial cells and up-regulation of TNF-?.
Thoracolumbar vertebral metastasis (TVM) affects a large number of cancer patients. However, safe and effective palliative care remains controversial. The aim of the present study was to investigate the safety and efficacy of minimally invasive image-guided radiofrequency ablation (RFA) with percutaneous kyphoplasty (PKP) for TVM treatment.
Polycyclic hydrocarbon compounds with a singlet biradical ground state show unique physical properties and promising material applications; therefore, it is important to understand the fundamental structure/biradical character/physical properties relationships. In this study, para-quinodimethane (p-QDM)-bridged quinoidal perylene dimers 4 and 5 with different fusion modes and their corresponding aromatic counterparts, the pericondensed quaterrylenes 6 and 7, were synthesized. Their ground-state electronic structures and physical properties were studied by using various experiments assisted with DFT calculations. The proaromatic p-QDM-bridged perylene monoimide dimer 4 has a singlet biradical ground state with a small singlet/triplet energy gap (-2.97?kcal?mol(-1)), whereas the antiaromatic s-indacene-bridged N-annulated perylene dimer 5 exists as a closed-shell quinoid with an obvious intramolecular charge-transfer character. Both of these dimers showed shorter singlet excited-state lifetimes, larger two-photon-absorption cross sections, and smaller energy gaps than the corresponding aromatic quaterrylene derivatives 6 and 7, respectively. Our studies revealed how the fusion mode and aromaticity affect the ground state and, consequently, the photophysical properties and electronic properties of a series of extended polycyclic hydrocarbon compounds.
Performing laparoscopic procedures requires different skill sets and team dynamics compared with open procedures. We evaluated team composition and procedure time between these two surgical approaches using data collected from hospitals in the United State and Canada.
The aim of this study was to improve cage systems for maintaining adult honey bee (Apis mellifera L.) workers under in vitro laboratory conditions. To achieve this goal, we experimentally evaluated the impact of different cages, developed by scientists of the international research network COLOSS (Prevention of honey bee COlony LOSSes), on the physiology and survival of honey bees. We identified three cages that promoted good survival of honey bees. The bees from cages that exhibited greater survival had relatively lower titers of deformed wing virus, suggesting that deformed wing virus is a significant marker reflecting stress level and health status of the host. We also determined that a leak- and drip-proof feeder was an integral part of a cage system and a feeder modified from a 20-ml plastic syringe displayed the best result in providing steady food supply to bees. Finally, we also demonstrated that the addition of protein to the bees' diet could significantly increase the level ofvitellogenin gene expression and improve bees' survival. This international collaborative study represents a critical step toward improvement of cage designs and feeding regimes for honey bee laboratory experiments.
Saturated fatty acids like palmitate contribute to muscle atrophy in a number of conditions (e.g., type II diabetes) by altering insulin signaling. Akt is a key modulator of protein balance that inhibits the FoxO transcription factors (e.g., FoxO3) which selectively induce the expression of atrophy-inducing genes (atrogenes) in the ubiquitin-proteasome and autophagy-lysosome systems. Conversely, omega-3 polyunsaturated fatty acids have beneficial effects on insulin signaling and may preserve muscle mass. In an earlier report, the omega-3 fatty acid docosahexaenoic acid (DHA) protected myotubes from palmitate-induced atrophy; the mechanisms underlying the alterations in protein metabolism were not identified. This study investigated whether DHA prevents a palmitate-induced increase in proteolysis by restoring Akt/FoxO signaling. Palmitate increased the rate of protein degradation, while cotreatment with DHA prevented the response. Palmitate reduced the activation state of Akt and increased nuclear FoxO3 protein while decreasing its cytosolic level. Palmitate also increased the messenger RNAs (mRNAs) of two FoxO3 atrogene targets, the E3 ubiquitin ligase atrogin-1/MAFbx and the autophagy mediator Bnip3. DHA attenuated the effects of palmitate on Akt activation, FoxO3 localization and atrogene mRNAs. DHA, alone or in combination with palmitate and decreased the ratio of LC3B-II:LC3B-I protein as well as the rate of autophagosome formation, as indicated by reduced LC3B-II protein in the presence of 10 mmol/L methylamine, suggesting an independent effect of DHA on the macroautophagy pathway. These data indicate that palmitate induces myotube atrophy, at least in part, by activating multiple proteolytic systems and that DHA counters the catabolic effects of palmitate by restoring Akt/FoxO signaling.
Sequential Monte Carlo estimation on point processes has been successfully applied to predict the movement from neural activity. However, there exist some issues along with this method such as the simplified tuning model and the high computational complexity, which may degenerate the decoding performance of motor brain machine interfaces. In this paper, we adopt a general tuning model which takes recent ensemble activity into account. The goodness-of-fit analysis demonstrates that the proposed model can predict the neuronal response more accurately than the one only depending on kinematics. A new sequential Monte Carlo algorithm based on the proposed model is constructed. The algorithm can significantly reduce the root mean square error of decoding results, which decreases 23.6% in position estimation. In addition, we accelerate the decoding speed by implementing the proposed algorithm in a massive parallel manner on GPU. The results demonstrate that the spike trains can be decoded as point process in real time even with 8000 particles or 300 neurons, which is over 10 times faster than the serial implementation. The main contribution of our work is to enable the sequential Monte Carlo algorithm with point process observation to output the movement estimation much faster and more accurately.
Autophagy is a lysosomal degradative process essential for neuronal homeostasis, whereas autophagic failure has been linked to accumulating neurodegenerative disorders. However, the precise role of autophagy in axonal and dendritic degeneration in Alzheimer's disease (AD) remains unclear. In this study, we aim to investigate the precise effect of autophagy in amyloid-? peptide (A?)25-35-mediated neurite degeneration. A?35-25, the non-neurotoxic reverse sequence analogue of A?25-35, was used as a negative control. Our results showed that A?25-35 dose-dependently suppressed PC12 proliferation and induced autophagy induction in neurites (axons and dendrites). A high proportion of autophagic structures in PC12 neurites were autolysosomes after 24 h of A?25-35 treatment. Autophagy inhibition by 3-methyladenine (3MA), LY294002, and chloroquine (CQ) could not relieve the A?25-35-induced neurite degeneration, while administration of autophagy stimulator rapamycin or AR-12 efficiently suppressed neurite degeneration. Autophagosomes colocalized with fragmented mitochondria after A?25-35 treatment. Similar results were obtained using in vitro cultured superior cervical ganglion neurons. These findings demonstrate that autophagy stimulation may prevent neuritic degeneration following A?25-35 treatment. Upregulation of autophagic activity may provide a valuable approach for the treatment of axonal and dendritic dystrophy in AD patients.
Little is known about role of Nitric Oxide (NO) of ischemic postconditioning in global cerebral ischemia and reperfusion (I/R) injury. In this study, we detected the dynamic change of NO during the ischemic postconditioning against global cerebral I/R in vivo, and compared the effects of six postconditioning conditions with different numbers of cycles and periods for reperfusion/occlusion. The animals underwent postconditioning consisting of 3 or 10 cycles of 15-s reperfusion, followed by 15-s occlusion (post-3-15/15, post-10-15/15), or 3 or 10 cycles of 30-s reperfusion/30-s occlusion (post-3-30/30, post-10-30/30), or 3 or 10 cycles of 60-s reperfusion/15-s occlusion (post-3-60/15, post-10-60/15). The results showed that four groups increased NO concentration, while all groups improved CBF significantly. Different postconditioning groups had different effects on NO and CBF. Post-3-30/30 had the strongest effect on both. Also it reduced infarct size from 33.0% to 24.29%, and downregulated the cell death ratio from 6.71% to 1.04%, showing the strongest protective effect among tested conditions. And we found that post-3-30/30 was an optional method in ischemic postconditioning, which obviously induced a large amount of NO synthesis with a slow speed, increased CBF and reduced the brain injuries. Therefore we concluded that NO is a reliable candidate in mediating ischemic postconditioning neuroprotection.
The ventral tegmental area (VTA) plays an important role in motivation and motor activity of mammals. Previous studies have reported that electrical stimulations of the VTA's neuronal projections were able to upregulate the locomotor activity of behaving rats. However, which types of neurons in the VTA that take part in the activation remain elusive. In this paper we employed optogenetic technique to selectively activate the excitatory neurons expressing CaMKII? in the VTA region and induced a higher locomotor activity for free behaving rats. Further behavioral studies indicated that reward learning mediated in the enhancement of the rat locomotor activity. Finally the immunohistochemistry studies explored that the excitatory neurons under the optogenetic activation in VTA were partly dopaminergic that may participate as a vital role in the optogenetic activation of the locomotor activity. In total, our study provided an optogenetic approach to selectively upregulate the locomotor activity of free behaving rats, thus facilitating both neuroscience researches and neural engineering such as animal robotics in the future.
The insect-machine interface (IMI) is a novel approach developed for man-made air vehicles, which directly controls insect flight by either neuromuscular or neural stimulation. In our previous study of IMI, we induced flight initiation and cessation reproducibly in restrained honeybees (Apis mellifera L.) via electrical stimulation of the bilateral optic lobes. To explore the neuromechanism underlying IMI, we applied electrical stimulation to seven subregions of the honeybee brain with the aid of a new method for localizing brain regions. Results showed that the success rate for initiating honeybee flight decreased in the order: ?-lobe (or ?-lobe), ellipsoid body, lobula, medulla and antennal lobe. Based on a comparison with other neurobiological studies in honeybees, we propose that there is a cluster of descending neurons in the honeybee brain that transmits neural excitation from stimulated brain areas to the thoracic ganglia, leading to flight behavior. This neural circuit may involve the higher-order integration center, the primary visual processing center and the suboesophageal ganglion, which is also associated with a possible learning and memory pathway. By pharmacologically manipulating the electrically stimulated honeybee brain, we have shown that octopamine, rather than dopamine, serotonin and acetylcholine, plays a part in the circuit underlying electrically elicited honeybee flight. Our study presents a new brain stimulation protocol for the honeybee-machine interface and has solved one of the questions with regard to understanding which functional divisions of the insect brain participate in flight control. It will support further studies to uncover the involved neurons inside specific brain areas and to test the hypothesized involvement of a visual learning and memory pathway in IMI flight control.
In the field of computer-aided mammographic mass detection, many different features and classifiers have been tested. Frequently, the relevant features and optimal topology for the artificial neural network (ANN)-based approaches at the classification stage are unknown, and thus determined by trial-and-error experiments. In this study, we analyzed a classifier that evolves ANNs using genetic algorithms (GAs), which combines feature selection with the learning task. The classifier named "Phased Searching with NEAT in a Time-Scaled Framework" was analyzed using a dataset with 800 malignant and 800 normal tissue regions in a 10-fold cross-validation framework. The classification performance measured by the area under a receiver operating characteristic (ROC) curve was 0.856 ± 0.029. The result was also compared with four other well-established classifiers that include fixed-topology ANNs, support vector machines (SVMs), linear discriminant analysis (LDA), and bagged decision trees. The results show that Phased Searching outperformed the LDA and bagged decision tree classifiers, and was only significantly outperformed by SVM. Furthermore, the Phased Searching method required fewer features and discarded superfluous structure or topology, thus incurring a lower feature computational and training and validation time requirement. Analyses performed on the network complexities evolved by Phased Searching indicate that it can evolve optimal network topologies based on its complexification and simplification parameter selection process. From the results, the study also concluded that the three classifiers - SVM, fixed-topology ANN, and Phased Searching with NeuroEvolution of Augmenting Topologies (NEAT) in a Time-Scaled Framework - are performing comparably well in our mammographic mass detection scheme.
MicroRNA-365 (miR-365) plays crucial roles in regulating cell proliferation, apoptosis and differentiation in various cell types. However, its function in vascular smooth muscle cells (VSMCs) is largely unknown. In our study, we found miR-365 was highly expressed in adult rat carotid arteries, but was significantly decreased in rat carotid arteries after balloon injury, a process involving neointima formation and VSMC proliferation. In vitro, the miR-365 significantly inhibited cell proliferation of isolated primary rat aortic VSMCs. Furthermore, we identified that cyclin D1 was a direct target of miR-365 in VSMCs. The miR-365 suppressed cyclin D1 expression on both mRNA and protein level. Luciferase reporter assay demonstrated that miR-365 inhibited cyclin D1 through targeting its 3'UTR. Importantly, cyclin D1 overexpression rescued the inhibitory effect of miR-365 on VSMCs proliferation. Taken together, by our studies, we identified a new MicroRNA, miR-365, involving in the pathological process of vascular injury, which inhibits VSMC proliferation through targeting cyclinD1.
While some probiotics have shown beneficial effects on preventing or treating colitis development, others have shown no effects. In this study, we have assessed the immunomodulating effects of two probiotic strains, Lactobacillus rhamnosus (L. rhamnosus) and Bifidobacterium breve (B. breve) on T cell polarization in vitro, using human peripheral blood mononuclear cells (PBMC), and in vivo, using murine dextran sodium sulfate (DSS) colitis model. With respect to the latter, the mRNA expression of T cell subset-associated transcription factors and cytokines in the colon was measured and the T helper type (Th) 17 and regulatory T cell (Treg) subsets were determined in the Peyer's patches. Both L. rhamnosus and B. breve incubations in vitro reduced Th17 and increased Th2 cell subsets in human PBMCs. In addition, B. breve incubation was also able to reduce Th1 and increase Treg cell subsets in contrast to L. rhamnosus. In vivo intervention with B. breve, but not L. rhamnosus, significantly attenuated the severity of DSS-induced colitis. In DSS-treated C57BL/6 mice, intervention with B. breve increased the expression of mRNA encoding for Th2- and Treg-associated cytokines in the distal colon. In addition, intervention with B. breve led to increases of Treg and decreases of Th17 cell subsets in Peyer's patches of DSS-treated mice. B. breve modulates T cell polarization towards Th2 and Treg cell-associated responses in vitro and in vivo. In vivo B. breve intervention ameliorates DSS-induced colitis symptoms and this protective effect may mediated by its effects on the T-cell composition.
Skeletal muscle atrophy is prevalent in chronic diseases and microRNAs (miRs) may play a key role in the wasting process. miR-23a was previously shown to inhibit the expression of atrogin-1 and MuRF1 in muscle. It also was reported to be regulated by NFATc3 in cardiomyocytes. The objective of this study was to determine if miR-23a is regulated during muscle atrophy and to evaluate the relationship between calcineurin (Cn)/nuclear factor of activated T-cells (NFAT) signaling and miR-23a expression in skeletal muscle cells during atrophy. miR-23a was decreased in the gastrocnemius of rats with acute streptozotocin (STZ)-induced diabetes, a condition known to increase atrogin-1 and MuRF1 expression and cause atrophy. Treatment of C2C12 myotubes with Dexamethasone (Dex) for 48 hours also reduced miR-23a as well as RCAN1.4 mRNA, which is transcriptionally regulated by NFAT. Both NFATc3 nuclear localization and the amount of miR-23a decreased rapidly within 1 hour of Dex administration suggesting a link between Cn signaling and miR-23a. Compared to primary myotubes from wild type mice, myotubes from CnA?-/- or CnA?-/- mice had a lower level of miR-23a. Dex did not further suppress miR-23a in the Cn-deficient myotubes. Overexpression of CnA? in C2C12 myotubes prevented Dex-induced suppression of miR-23a. Finally, miR-23a was present in exosomes isolated from the media of C2C12 myotubes and Dex increased its exosomal abundance. Dex did not alter the number of exosomes released into the media. We conclude that atrophy-inducing conditions down regulate miR-23a in muscle by mechanisms involving attenuated Cn/NFAT signaling and selective packaging into exosomes.
Clars aromatic sextet rule has been widely used for the prediction of the reactivity and stability of polycyclic aromatic hydrocarbons with a closed-shell electronic configuration. Recent advances in open-shell biradicaloids have shown that the number of aromatic sextet rings plays an important role in determination of their ground states. In order to test the validity of this rule in singlet biradicaloids, the two soluble and stable dibenzoheptazethrene isomers DBHZ1 and DBHZ2 were prepared by different synthetic approaches and isolated in crystalline form. These two molecules have different numbers of aromatic sextet rings in their respective biradical resonance forms and thus are expected to exhibit varied singlet biradical character. This assumption was verified by different experimental methods, including nuclear magnetic resonance (NMR), electron spin resonance (ESR), superconducting quantum interference device (SQUID), steady-state and transient absorption spectroscopy (TA), and X-ray crystallographic analysis, assisted by unrestricted symmetry-broken density functional theory (DFT) calculations. DBHZ2, with more aromatic sextet rings in the biradical form, was demonstrated to possess greater biradical character than DBHZ1; as a result, DBHZ2 exhibited an intense one-photon absorption (OPA) in the near-infrared region (?abs(max) = 804 nm) and a large two-photon absorption (TPA) cross-section (?((2))max = 2800 GM at 1600 nm). This investigation together with previous studies indicates that Clars aromatic sextet rule can be further extended to the singlet biradicaloids to predict their ground states and singlet biradical characters.
Peroxisome proliferator activated receptor ? (PPAR-?) plays important roles in cell cycle regulation, differentiation and apoptosis. Krüppel-like factor 4 (KLF4) modulates vascular smooth muscle cell (VSMC) phenotype. Both KLF4 and PPAR-? are involved in VSMC proliferation and differentiation. However, the actual relationship between KLF4 and PPAR-? in VSMCs is not clear. In this study, we found that PPAR-? agonist pioglitazone increases KLF4 protein levels but does not influence KLF4 gene transcription. PPAR-? overexpression increases, while PPAR-? knockdown reduces KLF4 expression, suggesting that the increase in KLF4 protein levels induced by pioglitazone is PPAR-?-dependent. Further study showed that pioglitazone enhances KLF4 protein stability through reducing KLF4 ubiquitination. Furthermore, we demonstrated that stabilization of KLF4 by pioglitazone was related to the activation of Akt signaling pathway. Taken together, we revealed that PPAR-? agonist pioglitazone stabilizes KLF4 protein via activating Akt signaling and reducing KLF4 ubiquitination, providing further insights into PPAR-? and KLF4 in regulating each others expression in VSMCs.
Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated antitumor activity both in vitro and in vivo. The energy-sensing AMP-activated protein kinase (AMPK) is known to be a major cellular target of biguanides. Based on our discovery of cross-talk between the AMPK and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) signaling pathways, we investigated the antitumor effects of combining phenformin with a BRAF inhibitor PLX4720 on the proliferation of BRAF-mutated melanoma cells in vitro and on BRAF-driven tumor growth in vivo. Cotreatment of BRAF-mutated melanoma cell lines with phenformin and PLX4720 resulted in synergistic inhibition of cell viability, compared with the effects of the single agent alone. Moreover, treatment with phenformin significantly delayed the development of resistance to PLX4720 in cultured melanoma cells. Biochemical analyses showed that phenformin and PLX4720 exerted cooperative effects on inhibiting mTOR signaling and inducing apoptosis. Noticeably, phenformin selectively targeted subpopulations of cells expressing JARID1B, a marker for slow cycling melanoma cells, whereas PLX4720 selectively targeted JARID1B-negative cells. Finally, in contrast to their use as single agents, the combination of phenformin and PLX4720 induced tumor regression in both nude mice bearing melanoma xenografts and in a genetically engineered BRAF(V600E)/PTEN(null)-driven mouse model of melanoma. These results strongly suggest that significant therapeutic advantage may be achieved by combining AMPK activators such as phenformin with BRAF inhbitors for the treatment of melanoma.
Bio-robots based on brain computer interface (BCI) suffer from the lack of considering the characteristic of the animals in navigation. This paper proposed a new method for bio-robots automatic navigation combining the reward generating algorithm base on Reinforcement Learning (RL) with the learning intelligence of animals together. Given the graded electrical reward, the animal e.g. the rat, intends to seek the maximum reward while exploring an unknown environment. Since the rat has excellent spatial recognition, the rat-robot and the RL algorithm can convergent to an optimal route by co-learning. This work has significant inspiration for the practical development of bio-robots navigation with hybrid intelligence.
Seizure detection from electroencephalogram (EEG) plays an important role for epilepsy therapy. Due to the diversity of seizure EEG patterns between different individuals, multiple features are necessary for high accuracy since a single feature could hardly encode all types of epileptiform discharges. However, a large feature set inevitably causes the increase of the computational cost. This paper proposes a boosted cascade chain to obtain both high detection performance and high computational efficiency. Sixteen features that are widely used in seizure detection are implemented. Considering the sequential characteristics of EEG signals, the features are extracted on each 1-second segment and its former three segments. Thus, a total of 64 features are used to construct a feature pool. Based on the feature pool, Real AdaBoost is used to select a group of effective features, on which weak classifiers are learned to assemble a strong classifier. The strong classifier is transformed to a cascade classifier by reordering the weak classifiers and learning a threshold for each weak classifier. The cascade classifier still has the similar classification strength to the original strong classifier. More importantly, it is able to reject easy non-seizure samples by the first a few weak classifiers in the cascade, thus high computational efficiency can be obtained. To evaluate our method, 90.6-hour EEG signals from four patients are tested. The experimental results show that our method can achieve an average accuracy of 95.31% and an average detection rate of 91.29% with the false positive rate of 4.68%. On average, only about 4 features are used. Compared with support vector machine (SVM), our method is much more efficient with the similar detection performance.
Traditional automatic navigation methods for bio-robots are constrained to configured environments and thus cant be applied to tasks in unknown environments. With no consideration of bio-robots own innate living ability and treating bio-robots in the same way as mechanical robots, those methods neglect the intelligence behavior of animals. This paper proposes a novel ratbot automatic navigation method in unknown environments using only reward stimulation and distance measurement. By utilizing rats habit of thigmotaxis and its reward-seeking behavior, this method is able to incorporate rats intrinsic intelligence of obstacle avoidance and path searching into navigation. Experiment results show that this method works robustly and can successfully navigate the ratbot to a target in the unknown environment. This work might put a solid base for application of ratbots and also has significant implication of automatic navigation for other bio-robots as well.
Event-related potentials (ERP)-based image triage (or search) in the context of Rapid Serial Visual Presentation (RSVP) exploits difference in the human brain response to target and distracted stimuli in the form of an image. So far, most paradigms focus on image triage (or search) among rough object categories. In this paper, we explored the possibility and effectiveness of target detection among finer categories like different animals. We analyzed on the difference of ERP components in two image search tasks, a simple-recognition task in which all images of a target are the same and a discriminative-recognition task in which all images are randomly different but belong to the same target category (the same kind of animal). We observed that the P3 amplitude reduced and the P3 latency delayed on the discriminative-recognition condition due to the increased difficulty of identifying different images belonging to the same category. But the average area under ROC curve reached 0.82 which indicated that rapid target detection among finer categories by single-trial ERP were feasible with trivial contribution of N1 and stable contribution of N2 and P3.
"Semantic gap" is the major bottleneck of semantic-based multimedia retrieval technique in the field of information retrieval. Studies have shown that robust semantic-based image retrieval can be achieved by single-trial visual evoked event related potential (ERP) detection. However, the question remains whether auditory evoked ERP can be utilized to achieve semantic-based sound retrieval. In this paper, we investigated this question in the rapid serial auditory presentation (RSAP) paradigm. Eight BCI-naïve participants were instructed to perform target detection in RSAP sequences with the vocalizations of 8 familiar animals as sound stimuli, and we compared ERP components and single-trial ERP classification performance between two conditions, the target was a predefined specific one, and the targets were different but belonged to the same semantic category (i.e., semantic-based sound retrieval). Although the amplitudes of ERP components (e.g., N2 and P3) and classification performance decreased a little due to the difficulty of the semantic-based sound retrieval tasks, the best two participants still achieved the area under the receive operating characteristic curve (AUC) of single-trial ERP detection more than 0.77. It suggested that semantic-based sound retrieval by auditory evoked ERP was potentially feasible.
In this paper we developed an integrated device comprised of a multi-electrode array coupled with optical fiber for deep-brain optical stimulation and electrical recording. We characterized the array device both electrically and optically, and conducted in vivo experiments on free moving rats for validation. This design of array device provides a viable tool for neuromodulation and neural signal acquisition in optogenetics and in other fields of neuroscience studies perspectively.
Studies on behavior control are important for bio-robots designation. For auto or manual navigation of the bio-robots, the accuracy of the command execution is especially critical. In this paper, we reported a precise "STOP" command for the rat-robots by optical stimulation of the central nervous system (CNS). We labeled dorsolateral periaqueductal gray (dlPAG) neurons with light sensitive channelrhodopsin-2 (ChR2) and directly probed the optical fiber to reactivate these neurons. The rats showed freezing behavior only upon the optical stimulation with an appropriate range of laser intensity and stimulation frequency. Neuron spikes and local field potential (LFP) were simultaneously recorded with optical stimulation by optrodes on free moving rat-robots. Together, our findings demonstrated the utility of deep brain optical stimulation for the stopping behavior of rat-robot control and indicated a potential application of optogenetics for precise control of bio-robots in further work.
In this paper, a remote stimulator is developed for rat-robot navigation based on the technique of Brain-Computer-Interface (BCI). The stimulator can output constant current from 0 to 1000 µA, which overcome several shortages of our previous constant voltage stimulator. The constant current stimulator consists of four major components, including power supply, micro control unit (MCU), constant current source and bluetooth transceiver for downloading stimulation commands. The stimulator has a weight of about 20g and size of 32mm*25mm*6mm. It has five channels of stimulation, which are connected with implanted microelectrodes in rat brain. The electrical parameters were characterized on three rats with different recovery time after brain surgery. Increasing current stimulations were applied on the dorsolateral periaqueductal gray (dlPAG) area to prove the effect of current stimulation on rat behavior.
Previous studies have demonstrated that both retinoids and apelin possess potent cardiovascular properties and that retinoids can mediate the expression of many genes in the cardiovascular system. However, it is not clear whether and how retinoids regulate apelin expression in rat VSMCs (vascular smooth muscle cells). In the present study, we investigated the molecular mechanism of apelin expression regulation by the synthetic retinoid Am80 in VSMCs. The results showed that Am80 markedly up-regulated apelin mRNA and protein levels in VSMCs. Furthermore, KLF5 (Krüppel-like factor 5) and Sp1 (stimulating protein-1) co-operatively mediated Am80-induced apelin expression through their direct binding to the TCE (transforming growth factor-? control element) on the apelin promoter. Interestingly, upon Am80 stimulation, the RAR? (retinoic acid receptor ?) was recruited to the apelin promoter by interacting with KLF5 and Sp1 prebound to the TCE site of the apelin promoter to form a transcriptional activation complex, subsequently leading to the up-regulation of apelin expression in VSMCs. An in vivo study indicated that Am80 increased apelin expression in balloon-injured arteries of rats, consistent with the results from the cultured VSMCs. Thus the results of the present study describe a novel mechanism of apelin regulation by Am80 and further expand the network of RAR? in the retinoid pathway.
The adsorption of DNAs in G-quadruplex solution onto 13nm gold nanoparticles (AuNPs) was studied through monitoring of the localized surface plasmon resonance (LSPR) absorbance of 13nm AuNPs at 520 and 650nm (A650/A520) in the solutions of three widely studied guanine-rich sequences, TBA(5-GGTTGGTGTGGTTGG-3), PW17(5-GGGTAGGGCGGGTTGGG-3), and PSO (5-GGGTTAGGGTTAGGGTTAGGG-3). It was found that the degree of adsorption of DNAs in Pb(2+) stabilized G-quadruplex (G-Pb(2+)) solutions is up to 93% after more than 5h of incubation. Furthermore, the lead concentrations in the solutions containing G-quadruplex and AuNP were analyzed by an inductively coupled plasma atomic emission spectrometer. The results showed that Pb(2+) had been released from the G-quadruplexes, which means the G-quadruplexes may be unfolded in the presence of AuNP. This interaction between G-quadruplexes and AuNP demonstrated that long time incubation between DNAs and AuNPs would possibly make it unable to distinguish G-quadruplex from ssDNA. Thus, a biosensing system consisting of PW17 and AuNPs was developed to detect Pb(2+). It was found that the LSPR responses at A650/A520 were sensitive to [Pb(2+)]. However, the sensitivity of the system was interfered by the potential unfolding of PW17-Pb(2+) in the presence of AuNPs. This unexpected adverse effect of AuNPs on DNA-based biosensors should be taken into consideration in the future development of biosensing systems that are based on ssDNA aptamers and unmodified AuNPs.
Efficient, inexpensive and sensitive assays for the measurement of drugs are of interest for pharmacokinetic and pharmacodynamics (PK-PD) analysis. Dried blood spots (DBS) are a unique bioanaltyical matrix with the potential to fulfill this interest for the measurement of numerous analytes. Here we describe the development and validation of a reversed-phase high performance liquid chromatographic (LC), tandem mass spectrometry (MS/MS) assay for the determination of ribavirin (RBV) in DBS. A 3mm punch from spotted and dried whole blood was extracted in methanol utilizing isotopically labeled internal standard for LC-MS/MS analysis. Validation was performed over a range of 0.05?g/mL to 10.0?g/mL and the method was shown to be precise (coefficient of variation ?15%) and accurate (within ±15% of control). These acceptance criteria were met for hematocrit ranges of 20-54%, for center versus edge punches and for spot volumes from 10 to 60?L. RBV was stable for up to 140 days at room temperature and -20°C as well as for three freeze/thaw cycles. Correlation of RBV in DBS versus in plasma yielded r(2)?0.98 demonstrating that DBS can be used as an alternative to plasma for PK-PD studies in human subjects.
Computer-aided detection and diagnosis (CAD) systems are increasingly being used as an aid by clinicians for detection and interpretation of diseases. Computer-aided detection systems mark regions of an image that may reveal specific abnormalities and are used to alert clinicians to these regions during image interpretation. Computer-aided diagnosis systems provide an assessment of a disease using image-based information alone or in combination with other relevant diagnostic data and are used by clinicians as a decision support in developing their diagnoses. While CAD systems are commercially available, standardized approaches for evaluating and reporting their performance have not yet been fully formalized in the literature or in a standardization effort. This deficiency has led to difficulty in the comparison of CAD devices and in understanding how the reported performance might translate into clinical practice. To address these important issues, the American Association of Physicists in Medicine (AAPM) formed the Computer Aided Detection in Diagnostic Imaging Subcommittee (CADSC), in part, to develop recommendations on approaches for assessing CAD system performance. The purpose of this paper is to convey the opinions of the AAPM CADSC members and to stimulate the development of consensus approaches and "best practices" for evaluating CAD systems. Both the assessment of a standalone CAD system and the evaluation of the impact of CAD on end-users are discussed. It is hoped that awareness of these important evaluation elements and the CADSC recommendations will lead to further development of structured guidelines for CAD performance assessment. Proper assessment of CAD system performance is expected to increase the understanding of a CAD systems effectiveness and limitations, which is expected to stimulate further research and development efforts on CAD technologies, reduce problems due to improper use, and eventually improve the utility and efficacy of CAD in clinical practice.
The objective of this study is to investigate the feasibility of predicting near-term risk of breast cancer development in women after a negative mammography screening examination. It is based on a statistical learning model that combines computerized image features related to bilateral mammographic tissue asymmetry and other clinical factors.
Reports of recurrence following restructuring of primary giant cell tumor (GCT) defects using polymethyl methacrylate (PMMA) bone cementation or allogeneic bone graft with and without adjuvants for intralesional curettage vary widely. Systematic review and meta-analysis were conducted to investigate efficacy of PMMA bone cementation and allogeneic bone grafting following intralesional curettage for GCT.
Infections with the intracellular protozoan parasite Toxoplasma gondii pose a serious public health problem and are of great economic importance worldwide. The parasite rhoptry protein 5 (ROP5) has been implicated as a major virulence factor that reduces the accumulation of immunity-related GTPases (IRG) in parasitophorous vacuole membrane (PVM), which maintains PVM integrity and evades IFN?-mediated killing by intracellular parasites. To study the immunoprotective value of ROP5, BALB/c mice were immunized with a recombinant form of the protein administered alone or in combination with another promising vaccine antigen, rSAG1. All mice vaccinated with the recombinant antigens developed a high level of specific antibody responses against soluble tachyzoite antigens (STAg), a statistically significant increase of the splenocyte proliferation response, and significant levels of IFN-? and IL-2 production. In contrast to rSAG1, which only stimulated the release of IFN-? and IL-2, rROP5 induced the specific production of IL-10, the Th2-type cytokine, in addition to IFN-? and IL-2. These results demonstrated that rROP5 could induce significant cellular and humoral (Th1/Th2) immune responses. Moreover, mice immunized with rROP5 displayed a prolonged survival time against a lethal challenge with the T. gondii RH strain. Additionally, vaccination with the mixture of rROP5+rSAG1 resulted in higher levels of T. gondii-specific IgG antibodies and lymphocyte proliferative responses and conferred more efficient protection against T. gondii challenge compared to immunization with rROP5 or rSAG1 alone. Our studies show that recombinant ROP5 antigen may be a promising vaccine candidate against toxoplasmosis. To our knowledge, this is the first report to evaluate the immunoprotective value of ROP5.
Establishing a dense vertex-to-vertex anthropometric correspondence between 3D faces is an important and fundamental problem in 3D face research, which can contribute to most applications of 3D faces. This paper proposes a sparse facial deformable model to automatically achieve this task. For an input 3D face, the basic idea is to generate a new 3D face that has the same mesh topology as a reference face and the highly similar shape to the input face, and whose vertices correspond to those of the reference face in an anthropometric sense. Two constraints: 1) the shape constraint and 2) correspondence constraint are modeled in our method to satisfy the three requirements. The shape constraint is solved by a novel face deformation approach in which a normal-ray scheme is integrated to the closest-vertex scheme to keep high-curvature shapes in deformation. The correspondence constraint is based on an assumption that if the vertices on 3D faces are corresponded, their shape signals lie on a manifold and each face signal can be represented sparsely by a few typical items in a dictionary. The dictionary can be well learnt and contains the distribution information of the corresponded vertices. The correspondence information can be conveyed to the sparse representation of the generated 3D face. Thus, a patch-based sparse representation is proposed as the correspondence constraint. By solving the correspondence constraint iteratively, the vertices of the generated face can be adjusted to correspondence positions gradually. At the early iteration steps, smaller sparsity thresholds are set that yield larger representation errors but better globally corresponded vertices. At the later steps, relatively larger sparsity thresholds are used to encode local shapes. By this method, the vertices in the new face approach the right positions progressively until the final global correspondence is reached. Our method is automatic, and the manual work is needed only in training procedure. The experimental results on a large-scale publicly available 3D face data set, BU-3DFE, demonstrate that our method achieves better performance than existing methods.
A reversed-phase high performance liquid chromatographic (LC), tandem mass spectrometry (MS/MS) assay for the determination of tenofovir (TFV) and emtricitabine (FTC) in dried blood spots (DBS) from human whole blood was developed and validated. Whole blood samples were spotted, dried, and a 3mm punch was extracted with methanol for analysis by LC-MS/MS utilizing stable isotope labeled internal standards. The assay was validated over the range of 2.5-1000ng/mL for TFV and 2.5-5000ng/mL for FTC. The method was accurate (within ±15% of control) and precise (coefficient of variation ?15%) for hematocrit concentrations ranging from 25% to 76%; using edge punches vs. center punches; and spot volumes of 10-50?L. Analytes were stable for five freeze/thaw cycles and up to 6 days at room temperature, whereas long-term storage required -20°C or -80°C. Comparison of TFV and FTC in DBS vs. plasma yielded r(2)?0.96, indicating that DBS can be used as a plasma alternative for pharmacokinetic analyses in vivo.
Previous studies on surgical team composition have shown that surgical team size had an independent impact on surgical performance in US and Canadian hospitals. We aimed to investigate the impact of team composition on surgical performance in two Chinese hospitals.
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