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BackgroundDopamine D1 receptor signaling plays key roles in core domains of neural function, including cognition and reward processing; however, many questions remain about the functions of circuits modulated by dopamine D1 receptor, largely because clinically viable, selective agonists have yet to be tested in humans.MethodsUsing a novel, exploratory neurofunctional domains study design, we assessed the safety, tolerability, pharmacodynamics, and pharmacokinetics of PF-06412562, a selective D1/D5R partial agonist, in healthy male volunteers who met prespecified criteria for low working memory capacity. Functional magnetic resonance imaging, electrophysiologic endpoints, and behavioral paradigms were used to assess working memory, executive function, and motivation/reward processing following multiple-dose administration of PF-06412562. A total of 77 patients were assigned PF-06412562 (3 mg twice daily and 15 mg twice daily) or placebo administered for 5 to 7 days. Due to the exploratory nature of the study, it was neither powered for any specific treatment effect nor corrected for multiple comparisons.ResultsNominally significant improvements from baseline in cognitive endpoints were observed in all 3 groups; however, improvements in PF-06412562–treated patients were less than in placebo-treated participants. Motivation/reward processing endpoints were variable. PF-06412562 was safe and well tolerated, with no serious adverse events, severe adverse events, or adverse events leading to dose reduction or temporary discontinuation except for 1 permanent discontinuation due to increased orthostatic heart rate.ConclusionsPF-06412562, in the dose range and patient population explored in this study, did not improve cognitive function or motivation/reward processing more than placebo over the 5- to 7-day treatment period.ClinicalTrials.gov IdentifierNCT02306876

Quantification of mRNAs in gonads and other tissues at the early critical development stage of sex differentiation may help to provide a global view of regulatory mechanisms underlying sex differentiation. We have recently reported the transcriptomic profiling of fugu gonad associated with sex differentiation. This study attempted to identify the genes in the brain that are involved in gonadal differentiation and development. In this study, a transcriptomic scan of potential candidate genes involved in sex differentiation was conducted in the brains of fugu larvae at 30 and 40 dah (morphological gonadal sex differentiation had not yet occurred). The dimorphic expression patterns of several candidate genes were verified using quantitative PCR. A total of 28.24 Gb of clean reads were obtained and 22,337 genes were identified in the brains of fugu larvae. These included 1008 novel genes that provide abundant data for functional analysis of sex differentiation. 229 genes were identified in the 30 dah larvae that were abundant in the XY brain and 21 that were abundant in the XX brain. In the 40 dah larvae, 325 genes were identified abundant in the XY brain and 174 were identified abundant in the XX brain. This is the first investigation into the transcriptome of the fugu larvae brain at the early sex differentiation stage. The results obtained here will enhance the understanding of molecular mechanisms that underly fugu sex differentiation.

An integrated autonomous relative navigation method based on vision and IMU data fusion was proposed in this paper, which can improve the position accuracy effectively and has strong adaptability to environmental changes. Firstly, IMU pre-integration formula based on Runge Kutta method was derived, which can improve the pre-integration position accuracy and reduce the accumulated error effectively. Secondly, an inverse depth estimation method based on the mixed probability model was proposed during the system initialization process, which can improve the accuracy of camera depth estimation and provide better initial conditions for back-end optimization. Thirdly, a sliding window filtering method based on the probability graph was proposed, which can avoid repeated calculations and improve the sliding window filtering efficiency. Forthly, combined with the advantages of the direct method and the feature point method, a mixed re-projection optimization method was proposed, which can expand the application scope of the method and improve the optimization accuracy effectively. Finally, in the closed-loop optimization, a closed-loop optimization method based on similar transformation is proposed to eliminate the accumulated error. In order to verify the environmental adaptability of the method and the impact of closed-loop detection on the relative navigation system, indoor and outdoor experiments were carried out with a hand-held camera and an IMU. EuRoC dataset was used in the experiments and the proposed method was compared with some classical methods. The experimental results showed that this method has high accuracy and robustness.

Proton-pump inhibitors (PPI), e.g., omeprazole or pantoprazole, are the most widely used drugs for various gastrointestinal diseases. However, more and more side effects, especially an increased risk of infections, have been reported in recent years. The underlying mechanism has still not yet been fully uncovered. Hence, in this study, we analyzed the T cell response after treatment with pantoprazole in vitro. Pantoprazole preincubation reduced the production and secretion of interferon (IFN)-γ and interleukin (IL)-2 after the T cells were activated with phytohemagglutinin (PHA)-L or toxic shock syndrome toxin-1 (TSST-1). Moreover, a lower zinc concentration in the cytoplasm and a higher concentration in the lysosomes were observed in the pantoprazole-treated group compared to the untreated group. We also tested the expression of the zinc transporter Zrt- and Irt-like protein (Zip)8, which is located in the lysosomal membrane and plays a key role in regulating intracellular zinc distribution after T cell activation. Pantoprazole reduced the expression of Zip8. Furthermore, we measured the expression of cAMP-responsive element modulator (CREM) α, which directly suppresses the expression of IL-2, and the expression of the phosphorylated cAMP response element-binding protein (pCREB), which can promote the expression of IFN-γ. The expression of CREMα was dramatically increased, and different isoforms appeared, whereas the expression of pCREB was downregulated after the T cells were treated with pantoprazole. In conclusion, pantoprazole downregulates IFN-γ and IL-2 expression by regulating the expression of Zip8 and pCREB or CREMα, respectively.

Due to the rapid degradation of conventional biopolymer or synthetic polymeric additives at high temperature (HT) or ultra-high temperatures (ultra-HT), effective control of water-based drilling fluid filtration in HT or Ultra-HT environment is still a great challenge in drilling operation. β-cyclodextrin polymer microspheres (β-CPMs), generally using for drug release and waste water treatment, are evaluated as environmentally friendly ultra-HT filtration reducer. The impact of the microspheres on water-based drilling fluids’ properties including rheology and filtration prior to and after hot rolling at different temperatures ranging from 120 to 240°C was investigated. The high temperature and high pressure (HTHP) filtration properties of the microspheres compared to several commercial high temperature filtration reducers were conducted according to the API recommended procedures. The filtration controlling mechanism was analyzed from zeta potential measurement, particle size distribution measurement, and scanning electron microscope observation of filter cake. The results indicated that the β-CPMs exhibited peculiar filtration behavior differently from conventional additives. When the hot rolling temperature was below 160℃, β-CPMs performed a 30% filtration reduction at 1 w/v% content in comparison with control sample. Once the hot rolling temperature was above 160℃, the capacity of filtration control was further improved with increasing temperatures. This is contrast with conventional filtration reducers that the filtration control capacity deteriorate with increasing temperatures. The microspheres still exhibited superior filtration control after exposure to 240℃. Furthermore, β-CPMs showed little effect on the drilling fluid's rheology. When the temperature was below 160℃, the filtration reduction was obtained by water absorption and swelling of β-CPMs. When the temperature was above 160℃, hydrothermal reaction occurred for β-CPMs. Numerous micro- and nano-sized carbon spheres formed, which bridge across micro and nanopores within filter cake and reduce the filter cake permeability effectively. When the temperature was higher than 160℃, hydrothermal reaction occurs. Carbon spheres generated by the hydrothermal degradation of the β-CPMs, which are responsible for the effective filtration control. The hydrothermal reaction changes the adverse effect of high temperature into favorable improvement of filtration control, which provides a novel avenue for HT and ultra-HT filtration control. The β-CPMs show potential application in deep well drilling as environmental friendly and high temperature filtration reducers.

Light is a key environmental parameter known to influence fish throughout various stages of their life, from embryonic development to sexually mature adults. In a recent study, the effects of different light conditions on the growth of Dicentrarchus labrax larvae were investigated using light-emitting diodes (LEDs) as a light source. Here, pathological examinations were carried out to assess whether variations in light affected the visual system of the larvae, including any negative impacts on the retina or the growth rate. Although light did not affect the total thickness (TT) of the retina, the thickness of the retinal pigment epithelium layer (PRE), photoreceptor layer (PRos/is), outer nuclear layer (ONL), and inner nuclear layer (INL), and the PRE/TT and ONL/TT ratios were all significantly higher in larvae exposed to blue light than in larvae exposed to white light. Additionally, the thickness of PRE and the outer nuclear layer and the RPE/TT and ONL/TT ratios of larvae exposed to 2.0 W m-2 were significantly lower than in larvae exposed to 0.3 W m-2. By contrast, the INL/TT ratio in larvae exposed to 2.0 W m-2 was significantly higher than in larvae exposed to 0.3 W m-2. Additionally, the INL and ganglion cell layer nuclei density of larvae exposed to 2.0 W m-2 were significantly higher than in those exposed to 0.3 W m-2 (p < 0.05). Transmission electron microscopy revealed different levels of abnormalities in the photoreceptor layers in all treatment groups. Considering the growth of the larvae, the results of the study suggest that continuous LED exposure induced damage to photoreceptor cells but was not relevant to the growth performance of D. labrax larvae. Moreover, the results obtained here also support the high plasticity of retinal development in response to altered environmental light conditions.

We assessed the effects of light intensity and spectrum on the growth, development and survival of Dicentrarchus labrax larvae from 30 to 96 days after hatching. Twelve lighting regimes were applied using 0.3, 1 and 2 W/m² full spectrum white, blue, red and green light. By day 66 of exposure, growth performance was significantly better in larvae reared under green or red light compared with white or blue light (p

We assessed the effects of light intensity and spectrum on the growth and survival of Takifugu rubripes larvae from 30 to 69 days after hatching. Five lighting regimes were applied using 0.5, 1.5, and 3.0 W m−2 full spectrum white (W0.5, W1.5, W3.0), 0.5 W m−2 yellow (Y0.5), and 0.5 W m−2 blue light (B0.5). At the end of the experiment, body length, wet weight, and specific growth rate from day 0 to day 39 were significantly greater in larvae reared under W3.0 than under B0.5 (P ˂ 0.05). No significant differences were observed among W0.5, W1.5, and W3.0, or among W0.5, Y0.5, and B0.5 (P > 0.05). Survival rate was significantly higher in larvae reared under W1.5 than W0.5 (P ˂ 0.05), but no significant differences were observed among W0.5, Y0.5, and B0.5 (P > 0.05). Additionally, light conditioning did not affect the total thickness of the retina. Although the ratio of the thickness of the retinal pigment epithelium layer/total thickness (TT) was significantly higher in larvae exposed to W3.0 compared with those exposed to other light conditions, and the thickness of the outer nuclear layer/TT was significantly lower in larvae exposed to W3.0 compared with those exposed to W0.5 (P

Purpose To evaluate the clinical safety and efficacy of povidone-iodine (PVP-I) 0.6%/dexamethasone (DEX) 0.1% ophthalmic suspension vs vehicle in patients with clinically suspected acute viral conjunctivitis. Patients and methods This was a randomized, double-masked, parallel-group, vehicle-controlled study. Adults with a clinical diagnosis of suspected acute viral conjunctivitis were randomized 1:1 to PVP-I/DEX ophthalmic suspension or vehicle bilaterally four times daily for 5 days (Days 1-5). Evaluation was on Days 1, 3 (+1-day window), and 6 (+1). Patients with signs of acute viral conjunctivitis at the Day 6 visit received open-label PVP-I/DEX for five additional days and were evaluated on Day 11-14. The primary efficacy endpoint was clinical resolution of acute viral conjunctivitis in the study eye at the Day 6 visit. Results Overall, 132 patients were randomized and received treatment (PVP-I/DEX, n=66; vehicle, n=66); 38 patients continued into the open-label portion of the study. Not enough patients with confirmed adenoviral conjunctivitis (n=32/132) were enrolled to assess the primary endpoint, although there were some efficacy trends in the PVP-I/DEX group for global clinical score (sum of watery conjunctival discharge and bulbar conjunctival redness). There were no serious treatment-emergent adverse events (TEAEs) and no patients discontinued due to a TEAE. In the masked phase, 56.1% of patients receiving PVP-I/DEX experienced at least one TEAE vs 43.9% in the vehicle group; 78.9% of patients in the open-label phase experienced at least one TEAE. Most TEAEs were mild in severity. Conclusion PVP-I/DEX ophthalmic suspension administered for ≤14 days had a favorable safety profile and was generally well tolerated.

In this paper, a new camera calibration method based on the image of the absolute quadratic curve (IAC) is proposed, and a new target is designed for this method, which is both convenient and flexible. It first extracts the characteristic points and the characteristic lines of the target and finds out the vanishing point and the vanishing line. The radial and tangential distortion coefficients are obtained by using the cross ratio invariance to correct the target image distortion. Then, the four internal parameters of the camera are obtained by IAC. The influence of the skew parameters is ignored. The rotation matrix is then calculated by the orthogonal characteristic of the coordinate system, and the translation vector is calculated by the center coordinates of the camera. In this way, the internal and external parameters of the camera can be obtained. The internal and external parameters are taken as initial values, and the optimal results are obtained by nonlinear optimization using the reprojection method. Finally, the relative position between different target images can be obtained by using the fundamental matrix, namely, the rotation angle. In the process of solving, the normalization method is used to improve the accuracy of data processing. Not requiring any prior information of the camera, the method has a wide range of applications.

Although Low-dose computed tomography (LDCT) is the most effective way for early lung cancer screening, it's still a challenge to further reduce radiation dose on the premise of ensuring image quality. Penalized weighted least-squares (PWLS) image reconstruction with nonlocal means (NLM) prior has shown excellent performance to improve the image quality for LDCT, especially when the nonlocal weights are calculated from previous full-dose CT (FDCT) image. However, the previous FDCT image of the same patient is not readily available, and registration between the LDCT and FDCT images must be considered because of the scanning misalignment. This paper proposed a new NLM prior model to reconstruct high quality LDCT image without image registering. In order to estimate the nonlocal weights of NLM prior, a database was trained from FDCT images of different patients, from which the patch samples similar to each target patch of the LDCT were extracted. Then the nonlocal weights were determined by the patch samples, and integrated into PWLS reconstruction with the priori information of local structures from FDCT. Experiments with 10mAs LDCT data have shown its superiority in reducing noise, streaking artifacts and preserving structure detail, indicating the potential of further dose reduction in ultra-LDCT lung screening.

In this paper, a mixed probability inverse depth estimation method based on probabilistic graph model is proposed, which can effectively solve the problems of far distance from the camera center and long data tail in depth estimation. At the same time, not only the accuracy can be improved but also the robustness of inverse depth estimation can be developed. First, the triangle method was used to find the depth information and location of a point in space, and the inverse depth information was obtained as the initial information of inverse depth estimation. Then, the basic matrix in epipolar geometry was obtained by using the normalized eight-point algorithm, and the pose of a camera was obtained as the initial information of optimization. Next, the pose of the monocular camera was modeled by a factor graph model, and the pose estimation was transformed into an unconstrained optimization problem by using the transformation relationship between Lie group and Lie algebra to obtain the pose of the camera. Finally, the inverse depth obtained by using the Gauss-uniform mixed probability distribution based on the probability graph model was used to calculate the recurrence formula by approximate inference, which can facilitate the sequential processing of multiple images. The depth information was quantitatively measured and compared by using TUM datasets, and the length of space object was measured by using inverse depth information, thus the measurement accuracy of this method was indirectly verified. This method is characterized by strong robustness and high measurement accuracy in the environments with random interferences.

TPS2681 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy expressing an affinity-enhanced T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1 and/or LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapy, GSK4427296, utilizes the same TCR as lete-cel, as well as an epigenetic reprogramming process (Epi-R) developed by Lyell Immunopharma to alter the phenotypic T-cell profile of the manufactured product, and is intended to increase the proportion of cells with properties of durable stemness. T cells with properties of durable stemness are able to proliferate, persist, and self-renew with anti-tumor functionality. A first-time-in-human master protocol (NCT04526509) is underway to evaluate the safety, tolerability, and recommended phase II dose (RP2D) of next generation NY-ESO-1 TCR T-cell therapies. Substudy 3 is added to this master protocol to assess GSK4427296 in patients with advanced synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCLS). Methods: This substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage, aiming to dose 10 participants at the RP2D. Key inclusion criteria: age ≥18 years; measurable disease per RECIST v1.1; HLA-A*02:01, A*02:05, or A*02:06 positivity; NY-ESO-1/LAGE-1a tumor expression; advanced (metastatic/unresectable) SS with t(X;18) translocation or MRCLS with a translocation involving DDIT3 and/or FUS and/or EWSR1 genes; and anthracycline-based therapy receipt/completion/intolerance. Key exclusion criteria: prior malignancy that is not in complete remission or clinically significant systemic illness; prior receipt of gene or allogenic stem cell/solid organ transplant; and central nervous system metastases. Primary endpoints: safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints: investigator-assessed overall response rate, duration of response, maximum transgene expansion (Cmax), Tmax, and AUC(0-t). Analyses will be descriptive. The master protocol is open for recruitment. Clinical trial information: NCT04526509.

Many economically important species in demand in the market and with depleted populations have been artificial bred and their seed intensively released into the wild. As one of the most important fishery species in China, the swimming crab Portunus trituberculatus has been stocked in Panjin at a large scale since 2012. Nevertheless, no genetic profile considering genetic effects of these practices has been constructed. The present study traced the crab population enhancement in Panjin. In 2015, a total of 1671 crabs were captured in Panjin and among them 120 individuals were identified as being hatchery-raised, indicating that hatchery-raised seed contributed to the local resource. To address possible genetic effects from the hatchery stock, we compared the genetic characteristic among female broodstock, recaptured hatchery-raised, recaptured non-hatchery-raised and a wild control population based on six microsatellite markers. Results showed obvious reductions in gene diversity and effective population size (Ne) and increased relatedness in recaptured hatchery-raised crabs. Moreover, recaptured non-hatchery-raised – the local population in Panjin – also exhibited similar patterns of dramatic loss of Ne and increased degree of relatedness. The genetic homogeneity involving low Wright's fixation index (Fst), large percentage genetic variance among individuals and strong gene flow appeared in all sample locations distributed in the Bohai Sea and the Yellow Sea. Our data suggest that large-scale stock enhancement of P. trituberculatus presents strong potential genetic risks to the Panjin local population and even the whole waters surrounding the Liaodong Peninsula. Several approaches were proposed to gain better insight into P. trituberculatus enhancement practices in the future.

Purpose To evaluate the efficacy/safety of an ophthalmic suspension of povidone-iodine (PVP-I) 0.6% and dexamethasone 0.1% in patients with acute adenoviral conjunctivitis. Design Multicenter, randomized, vehicle-controlled, double-masked trial. Methods Adults with a positive Rapid Pathogen Screening Adeno-Detector Plus test were randomized 1:1:1 to PVP-I 0.6%/dexamethasone 0.1%, PVP-I 0.6%, or vehicle, bilaterally 4 times daily for 5 days (days 1-5). Patients were evaluated on days 3, 6, and 12 (+1-day window). Efficacy measures included clinical resolution and adenoviral eradication. Results Overall, 144 patients were included in the efficacy analysis (PVP-I/dexamethasone, n = 48; PVP-I, n = 50; vehicle, n = 46). The proportion of patients with clinical resolution (primary study eye with last observation carried forward [LOCF]) at the day 6 visit was higher with PVP-I/dexamethasone (31.3%) than with vehicle (10.9%; P = .0158) and PVP-I (18.0%; P = nonsignificant). The proportion with adenoviral eradication (primary study eye with LOCF) was higher with PVP-I/dexamethasone than with vehicle at the day 3 (35.4% vs 8.7%; P = .0019) and day 6 (79.2% vs 56.5%; P = .0186) visits and vs PVP-I (day 3 visit, 32.0%; day 6 visit, 62.0%; each P = nonsignificant). Treatment-emergent adverse events (AEs) occurred in 69.0% (vehicle), 62.7% (PVP-I), and 53.4% (PVP-I/dexamethasone) of patients in the safety dataset. Discontinuation owing to AEs occurred in 37 patients (vehicle, n = 16; PVP-I, n = 12; PVP-I/dexamethasone, n = 9). Conclusion PVP-I/dexamethasone appeared safe and well tolerated, and significantly improved clinical resolution and adenoviral eradication in patients with acute adenoviral conjunctivitis.

Background: PF-06412562 is a moderately potent, highly selective oral D1/D5 dopamine receptor partial agonist. Objective: To study the efficacy and safety of a single, oral, split dose of PF-06412562 in patients with Parkinson’s disease. Methods: Following overnight levodopa (L-dopa, Sinemet®) washout, subjects received a single dose of levodopa in open-label period 1. Periods 2 and 3 had a double-blinded, sponsor-open, randomized, 2-way cross-over, placebo-controlled design, during which subjects were randomized to PF-06412562 30 mg (+ 20 mg 4 h later) or placebo. Maximum percent improvement from baseline in finger-tapping speed (measure of bradykinesia) measured using KinesiaTM technology (as the primary end point) and change from baseline in the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III) motor section scores (the preferred exploratory end point) were evaluated. Results: Nineteen subjects received levodopa; 13 met the period 2/3 entry criteria and received PF-06412562, 30 + 20 mg, or placebo. The prespecified primary efficacy criterion for significant improvement in finger-tapping was not met due to inconsistencies in the task leading to large between-period fluctuations of within-patient baseline values. Change from baseline in MDS-UPDRS-III score with PF-06412562 resulted in a placebo-adjusted point estimate of –10.59 with a one-sided 90% upper CI of PF-06412562 versus placebo model-based contrast of (–inf, –7.44) at 1.5–2.5 h after the dose (p < 0.0001). All adverse events were mild-to-moderate. Conclusions: We report the first evidence of potential anti-parkinsonian efficacy of the oral selective D1/D5 partial agonist PF-06412562 without the significant acute changes in cardiovascular parameters reported with previous D1 agonists.

The swimming crab is an important commercial fishery species in China, Korea and Japan. Overfishing and destruction of habitats in coastal waters mean that the natural resources cannot meet the swimming crab’s increased demands for food, caused by large-scale stock enhancement in Liaoning, China over the last eight years. The genetic response of the local wild populations to such a large-scale release has not been investigated. Here, we monitored the temporal variations in genetic diversity and structure in Panjin and Yingkou using eighteen microsatellite markers across six years. A high level of genetic diversity was maintained in these populations, but significant deviation from HWE was observed (P

In this paper, a formation collision forecast and coordination algorithm (FCFCA) is proposed to avoid collisions in the configuration control of missile autonomous formation (MAF). First, the conditions are derived to forecast collisions of the MAF. Second, the transition target configuration is designed to coordinate collisions. Third, by minimizing the formation group cost, we obtain the optimal transition vector, which can avoid collisions and guarantee the efficiency, safety, and stability of the MAF. Finally, simulation and experiment results are presented to verify the effectiveness of the FCFCA.

UAV Swarm with high dynamic configuration at a large scale requires a high-precision mathematical model to fully exploit its boundary performance. In order to instruct the engineering application with high confidence, uncertainties induced from either systematic measurement or the environment cannot be ignored. This paper investigates the I t o ^ stochastic model of the UAV Swarm system with multiplicative noises. By combining the cooperative kinematic model with a simplified individual dynamic model of fixed-wing-aircraft for the first time, the configuration control model is derived. Considering the uncertainties in actual flight, multiplicative noises are introduced to complete the I t o ^ stochastic model. Following that, the estimator and controller are designed to control the formation. The mean-square uniform boundedness condition of the proposed stochastic system is presented for the closed-loop system. In the simulation, the stochastic robustness analysis and design (SRAD) method is used to optimize the properties of the formation. More importantly, the effectiveness of the proposed model is also verified using real data of five unmanned aircrafts collected in outfield formation flight experiments.