Dimensionality and optimal combination of autonomic fear-conditioning measures in humans.

Fear conditioning, also termed threat conditioning, is a commonly used learning model with clinical relevance. Quantification of threat conditioning in humans often relies on conditioned autonomic responses such as skin conductance responses (SCR), pupil size responses (PSR), heart period responses (HPR), or respiration amplitude responses (RAR), which are usually analyzed separately. Here, we investigate whether inter-individual variability in differential conditioned responses, averaged across acquisition, exhibits a multi-dimensional structure, and the extent to which their linear combination could enhance the precision of inference on whether threat conditioning has occurred. In a mega-analytic approach, we re-analyze nine data sets including 256 individuals, acquired by the group of the last author, using standard routines in the framework of psychophysiological modeling (PsPM). Our analysis revealed systematic differences in effect size between measures across datasets, but no evidence for a multidimensional structure across various combinations of measures. We derive the statistically optimal weights for combining the four measures and subsets thereof, and we provide out-of-sample performance metrics for these weights, accompanied by bias-corrected confidence intervals. We show that to achieve the same statistical power, combining measures allows for a relevant reduction in sample size, which in a common scenario amounts to roughly 24%. To summarize, we demonstrate a one-dimensional structure of threat conditioning measures, systematic differences in effect size between measures, and provide weights for their optimal linear combination in terms of maximal retrodictive validity.

Structural optimization method of rice precision direct seed-metering device based on multi-index orthogonal experimental.

Introduction: To improve the mechanization level of rice planting, a new type of direct seeding device for rice was designed. The device's structural properties will be crucial in determining its seeding performance. Structure optimization in the current seed metering device design process focuses on a single or few indexes, resulting in improved individual performance but imbalanced overall performance. Therefore, a structure optimization method of the direct seeding device based on a multi-index orthogonal experiment was proposed in this study. Methods: First, the DEM-MBD coupling method observed the factors and levels that affected the performance overall. Second, a test platform based on the electric drive control model was constructed, and a multi-index orthogonal test was devised. Finally, the structural parameters of the seed metering devices were optimized based on matrix analysis. Results: From the results, the primary and secondary levels of significance of factors were just as follows: hole diameter > hole number > adjustment angle. The following are the optimal parameters found by optimization analysis: the diameter of the hole was 12 mm, the number of holes was 10, and the adjustment angle was 80°. Validation tests were carried out and analyzed based on the optimal structural parameter combination. The qualification rate of seeds per hole, empty hole rate, average seed number, coefficient of variation of seed number, average hole spacing, and the variance coefficient of hole spacing are 93.07%, 0%, 9.39,14.04%, 22.84 cm, and 9.14%, respectively. Discussion: In comparison to traditional design and structural parameter optimization methods for rice precision seed metering device, this study not just to provides an optimization scheme for improving the overall performance of rice precision seed metering device, but also serves as a technical reference for the development and design of new rice precision seed metering device.

When not responding to food changes food value: The role of timing.

Establishing behavior change toward appetitive foods can be crucial to improve people's health. Food go/no-go training (GNG), in which people respond to some food items and not to other food items depending on the presentation of a go or no-go cue, is a means to establish behavior change. GNG changes the perceived value of food items and food consumption. After GNG, no-go items are rated as less attractive than go and/or untrained items, an empirical phenomenon called the NoGo-devaluation-effect. This effect is not always found, however. One theory-based explanation for these inconsistent results may be found in the timing of the go and no-go cues, which is also inconsistent across studies. Hence, in the present work we conducted two experiments to examine the possible role of go and no-go cue presentation timing in eliciting the NoGo-devaluation-effect. In Experiment 1, we presented the food items before the presentation of go/no-go cues, whereas we reversed this order in Experiment 2. As predicted, the NoGo-devaluation-effect was obtained in Experiment 1. This effect was absent in Experiment 2. Moreover, recognition memory for stimulus-action contingencies moderated the devaluation effect in Experiment 1, but not in Experiment 2. These results show that NoGo devaluation is dependent on the timing of the NoGo cue, which has theoretical and applied implications for understanding how and when go/no-go training influences food consumption. We propose that the value of food items is updated during go/no-go training to minimize prediction errors, and that this updating process is boosted by attention.

Devaluation of NoGo stimuli is both robust and fragile.

Consistently not responding to stimuli during go/no-go training leads to lower evaluations of these NoGo stimuli. How this NoGo-devaluation-effect can be explained has remained unclear. Here, we ran three experiments to test the hypothesis that people form stimulus-stop-associations during the training, which predict the strength of the devaluation-effect. In Experiment 1, we tried to simultaneously measure the stimulus-stop-associations and NoGo-devaluation, but we failed to find these effects. In Experiment 2, we measured NoGo-devaluation with established procedures from previous work, and stimulus-stop-associations with a novel separate task. Results revealed a clear NoGo-devaluation-effect, which remained visible across multiple rating blocks. Interestingly, this devaluation-effect disappeared when stimulus-stop-associations were measured before stimulus evaluations, and there was no evidence supporting the formation of the stimulus-stop-associations. In Experiment 3, we found evidence for the acquisition of stimulus-stop-associations using an established task from previous work, but this time we found no subsequent NoGo-devaluation-effect. The present research suggests that the NoGo-devaluation-effect and stimulus-stop-associations can be found with standard established procedures, but that these effects are very sensitive to alterations of the experimental protocol. Furthermore, we failed to find evidence for both effects within the same experimental protocol, which has important theoretical and applied implications.

Novel meta-diamide insecticide, broflanilide, suppresses the population of common cutworm Spodoptera litura through its lethal and sublethal effects.

BACKGROUND: Broflanilide has been registered in China for the control of Lepidoptera and Coleoptera pests, and is widely used to control the target pests at lethal and sublethal levels. The lethal and sublethal effects of broflanilide on the common cutworm (CCW) Spodoptera litura Fabricius, a representative Lepidopteran pest in agricultural crops, were examined to explore its ecological influence on pests. RESULTS: In F0 , broflanilide had little influence on the hatchability of eggs, but significantly reduced the neonate survival rate. The lethal activity of broflanilide towards third-instar larvae and adults was 0.13 mg kg-1 (LD50 ) and 3.59 mg L-1 (LC50 ) respectively at 48 h. After being treated with a sublethal dose (LD10 and LD30 ) of broflanilide, the duration of third- to sixth-instar larvae and the mean fecundity of reproductive females were significantly increased, but pupation rate, weight of pupae and life-cycle rate were significantly decreased. In F1 , the duration of F1 larvae and the doubling time were prolonged, whereas the rates of pupation and the life cycle were decreased by 14.92% and 18.00%, respectively. The intrinsic rate of increase, finite rate of increase and net reproductive rate in the sublethal group were lower than in the control group. The relative fitness of F1 treated by LD10 and LD30 was 0.81 and 0.66, respectively. CONSLUSION: Broflanilide not only has highly lethal activity, but also suppresses the population growth and progeny of CCW, as a critical factor for guidelines of its usage in the field.

ZNRF1 Mediates Epidermal Growth Factor Receptor Ubiquitination to Control Receptor Lysosomal Trafficking and Degradation.

Activation of the epidermal growth factor receptor (EGFR) is crucial for development, tissue homeostasis, and immunity. Dysregulation of EGFR signaling is associated with numerous diseases. EGFR ubiquitination and endosomal trafficking are key events that regulate the termination of EGFR signaling, but their underlying mechanisms remain obscure. Here, we reveal that ZNRF1, an E3 ubiquitin ligase, controls ligand-induced EGFR signaling via mediating receptor ubiquitination. Deletion of ZNRF1 inhibits endosome-to-lysosome sorting of EGFR, resulting in delayed receptor degradation and prolonged downstream signaling. We further demonstrate that ZNRF1 and Casitas B-lineage lymphoma (CBL), another E3 ubiquitin ligase responsible for EGFR ubiquitination, mediate ubiquitination at distinct lysine residues on EGFR. Furthermore, loss of ZNRF1 results in increased susceptibility to herpes simplex virus 1 (HSV-1) infection due to enhanced EGFR-dependent viral entry. Our findings identify ZNRF1 as a novel regulator of EGFR signaling, which together with CBL controls ligand-induced EGFR ubiquitination and lysosomal trafficking.

How can food choice best be trained? Approach-avoidance versus go/no-go training.

Behavior toward appetitive stimuli can be changed by motor response training procedures in which participants approach or respond to some stimuli and avoid or inhibit behavior to other stimuli. There is discussion in the literature whether effects are different when participants approach versus avoid stimuli during approach-avoidance training compared to when they respond versus not respond to stimuli during go/no-go training. Here, we directly compared effects of approach-avoidance training and go/no-go training on food choice within the same rigorous experimental protocol. Results showed that both training procedures influence food choice such that participants preferred Approach over Avoidance food items, and Go over NoGo food items, and these training effects were not statistically different. The present work suggests any inconsistencies in the literature on possible differences in effectiveness of these training procedures may be explained by differences in methods employed. The present work also raises new theoretical and applied questions about motor response training as a means to change behavior.

Development and validation of screening scores of non-alcoholic fatty liver disease in middle-aged and elderly Chinese.

AIM: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease and also closely related to cardiometabolic disease. Its prevalence was estimated at over one-fourth in the general population in China. We aimed to develop effective score tools for detecting NAFLD. METHODS: A total of 17,212 participants aged 45-70 years old were surveyed in Shanghai between 2013 and 2014, and 13,293 participants were included in this analysis. All participants were randomly classified into the exploratory group or the validation group. Candidate categorical variables were selected using a logistic regression model. The score points were generated according to the ß-coefficients. RESULTS: We developed the Shanghai Nicheng NAFLD Score I (SHNC NAFLD Score I), which included body mass index and waist circumference with an area under the receiver-operating characteristic curve (AUC) of 0.802 (95% CI 0.792-0.811) in the exploratory group and 0.802 (95% CI 0.793-0.812) in the validation group. We further developed the SHNC NAFLD Score II by adding fasting plasma glucose, triglyceride, and alanine aminotransferase/aspartate aminotransferase ratio to the SHNC NAFLD Score I, achieving an AUC of 0.852 (95% CI 0.843-0.861) in the exploratory group and 0.843 (95% CI 0.834-0.852) in the validation group. The two score tools also performed well in subjects with normal alanine aminotransferase (ALT) levels. CONCLUSIONS: Based on anthropometric and clinical categorical variables, our two scores are effective tools for detecting NAFLD in both this southern Chinese population and their subpopulation with normal ALT levels.

Inhibiting Solid Tumor Growth In Vivo by Non-Tumor-Penetrating Nanomedicine.

Nanomedicine (NM) cannot penetrate deeply into solid tumors, which is partly attributed to the heterogeneous microenvironment and high interstitial fluid pressure of solid tumors. To improve NM efficacy, there has been tremendous effort developing tumor-penetrating NMs by miniaturizing NM sizes or controlling NM surface properties. But progress along the direction of developing tumor penetrating nanoparticle has been slow and improvement of the overall antitumor efficacy has been limited. Herein, a novel strategy of inhibiting solid tumor with high efficiency by dual-functional, nontumor-penetrating NM is demonstrated. The intended NM contains 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a vascular-disrupting agent, and doxorubicin (DOX), a cytotoxic drug. Upon arriving at the target tumor site, sustained release of DMXAA from NMs results in disruption of tumor vessel functions, greatly inhibiting the interior tumor cells by cutting off nutritional supply. Meanwhile, the released DOX kills the residual cells at the tumor exterior regions. The in vivo studies demonstrate that this dual-functional, nontumor penetrating NM exhibits superior anticancer activity, revealing an alternative strategy of effective tumor growth inhibition.

Doxorubicin-loaded polysaccharide nanoparticles suppress the growth of murine colorectal carcinoma and inhibit the metastasis of murine mammary carcinoma in rodent models.

As a synergistic drug combination, doxorubicin-loaded cisplatin crosslinked polysaccharide-based nanoparticles (Dex-SA-DOX-CDDP) have demonstrated enhanced antitumor efficacy and reduced systemic toxicity via optimized biodistribution, controlled drug release, prolonged blood circulation, and improved tolerability, compared to the non-crosslinked nanoparticles or free doxorubicin. Herein, we apply the Dex-SA-DOX-CDDP nanoparticles as an efficient antitumor agent to treat colorectal and breast tumors in three different in vivo models, i.e. subcutaneously implanted colorectal carcinoma, dimethylhydrazine-induced autochthonous colorectal carcinoma, and metastatic mammary carcinoma, which more closely simulate the natural milieu of the original tumor with intact pathological and immunological responses. Based on the properties of this combination in higher tumor accumulation and penetrating efficiency, the Dex-SA-DOX-CDDP nanoparticles significantly decreased the tumor sizes in CT26 cell line xenograft tumors compared to control. In addition, the affected animals' lifespan was significantly extended after the Dex-SA-DOX-CDDP treatment, in the autochthonous colon cancer model. Moreover, with the aid of iRGD, Dex-SA-DOX-CDDP could effectively block primary tumor growth and prevent the metastasis of 4T1 murine mammary carcinoma. In conclusion, Dex-SA-DOX-CDDP nanoparticles remarkably inhibit growth of colorectal carcinoma and metastasis of mammary carcinoma in vivo, which provides potential application as a safe and efficient antitumor agent in treatment of these cancers.

Well-defined polymer-drug conjugate engineered with redox and pH-sensitive release mechanism for efficient delivery of paclitaxel.

The synthesis of polymer-drug conjugate (PDC) capable of convenient preparation and controlled release of therapeutic agents is still an urgent requirement in drug delivery field. Herein, we develop a novel anti-cancer PDC engineered with side groups of disulfide and ester bonds for on-demand delivery of paclitaxel (PTX) with redox and pH dual sensitive behaviors. A simple polymer, 3,3'-dithiodipropionic acid functionalized poly(ethylene glycol)-b-poly(l-lysine) (mPEG-b-P(LL-DTPA)), was synthesized and PTX was directly conjugated to the carboxyl groups of mPEG-b-P(LL-DTPA) to obtain the disulfide-containing polymer-PTX conjugate (P(L-SS-PTX)). Another structural similar polymer-PTX conjugate without disulfide bonds (P(L-PTX)) was also prepared to verify the function of disulfide linkages. The P(L-SS-PTX) micelles showed rapid drug release under tumor-relevant reductive conditions as designed. Interestingly, the PTX release from P(L-SS-PTX) micelles could also be promoted by the increased acidity (pH ≈ 5). In vitro cytotoxicity study showed that the P(L-SS-PTX) micelles exhibited significantly enhanced cytotoxicity against a variety of tumor cells compared to the non-sensitive P(L-PTX) micelles. The in vivo studies on B16F1 melanoma bearing C57BL/6 mice demonstrated the superior antitumor activity of P(L-SS-PTX) over both free PTX and P(L-PTX). This dual-sensitive prodrug provides a useful strategy for anti-tumor drug delivery.

Co-delivery of doxorubicin and paclitaxel by PEG-polypeptide nanovehicle for the treatment of non-small cell lung cancer.

Despite progress, combination therapy of different functional drugs to increase the efficiency of anticancer treatment still remains challenges. An amphiphilic methoxy poly(ethylene glycol)-b-poly(l-glutamic acid)-b-poly(l-lysine) triblock copolymer decorated with deoxycholate (mPEsG-b-PLG-b-PLL/DOCA) was synthesized and developed as a nanovehicle for the co-delivery of anticancer drugs: doxorubicin (DOX) and paclitaxel (PTX). The amphiphilic copolymer spontaneously self-assembled into micellar-type nanoparticles in aqueous solutions and the blank nanoparticles possessed excellent stability. Three different domains of the copolymer performed distinct functions: PEG outer corona provided prolonged circulation, middle biodegradable and hydrophilic PLG shell was designed for DOX loading through electrostatic interactions, and hydrophobic deoxycholate modified PLL served as the container for PTX. In vitro cytotoxicity assays against A549 human lung adenocarcinoma cell line demonstrated that the DOX + PTX co-delivered nanoparticles (Co-NPs) exhibited synergistic effect in inducing cancer cell apoptosis. Ex vivo DOX fluorescence imaging revealed that Co-NPs had highly efficient targeting and accumulation at the implanted site of A549 xenograft tumor in vivo. Co-NPs exhibited significantly higher antitumor efficiency in reducing tumor size compared to free drug combination or single drug-loaded nanoparticles, while no obvious side effects were observed during the treatment, indicating this co-delivery system with different functional antitumor drugs provides the clinical potential in cancer therapy.

Polypeptide-based combination of paclitaxel and cisplatin for enhanced chemotherapy efficacy and reduced side-effects.

A novel methoxy poly(ethylene glycol)-b-poly(l-glutamic acid)-b-poly(l-phenylalanine) (mPEG-b-P(Glu)-b-P(Phe)) triblock copolymer was prepared and explored as a micelle carrier for the co-delivery of paclitaxel (PTX) and cisplatin (cis-diamminedichlo-platinum, CDDP). PTX and CDDP were loaded inside the hydrophobic P(Phe) inner core and chelated to the middle P(Glu) shell, respectively, while mPEG provided the outer corona for prolonged circulation. An in vitro release profile of the PTX+CDDP-loaded micelles showed that the CDDP chelation cross-link prevented an initial burst release of PTX. The PTX+CDDP-loaded micelles exhibited a high synergism effect in the inhibition of A549 human lung cancer cell line proliferation over 72 h incubation. For the in vivo treatment of xenograft human lung tumor, the PTX+CDDP-loaded micelles displayed an obvious tumor inhibiting effect with a 83.1% tumor suppression rate (TSR%), which was significantly higher than that of a free drug combination or micelles with a single drug. In addition, more importantly, the enhanced anti-tumor efficacy of the PTX+CDDP-loaded micelles came with reduced side-effects. No obvious body weight loss occurred during the treatment of A549 tumor-bearing mice with the PTX+CDDP-loaded micelles. Thus, the polypeptide-based combination of PTX and CDDP may provide useful guidance for effective and safe cancer chemotherapy.

Doxorubicin-loaded amphiphilic polypeptide-based nanoparticles as an efficient drug delivery system for cancer therapy.

An amphiphilic anionic copolymer, methoxy poly(ethylene glycol)-b-poly(l-glutamic acid-co-l-phenylalanine) (mPEG-b-P(Glu-co-Phe)), with three functionalized domains, was synthesized and used as a nanovehicle for cationic anticancer drug doxorubicin hydrochloride (DOX·HCl) delivery via electrostatic interactions for cancer treatment. The three domains displayed distinct functions: PEG block chain for prolonged circulation; poly(phenylalanine) domain for stabilizing the nanoparticle construct through hydrophobic/aromatic interactions; and the poly(glutamic acid) domain for providing electrostatic interactions with the cationic drug to be loaded. The copolymer could self-assemble into micellar-type nanoparticles, and DOX was successfully loaded into the interior of nanoparticles by simple mixing of DOX·HCl and the copolymer in the aqueous phase. DOX-loaded mPEG-b-P(Glu-co-Phe) nanoparticles (DOX-NP) had a superior drug-loading content (DLC) (21.7%), a high loading efficiency (almost 98%) and a pH-triggered release of DOX. The size of DOX-NP was ∼140 nm, as determined by dynamic light scattering measurements and transmission electron microscopy. In vitro assays showed that DOX-NP exhibited higher cell proliferation inhibition and higher cell uptake in A549 cell lines compared with free DOX·HCl. Maximum tolerated dose (MTD) studies showed that DOX-NP demonstrated an excellent safety profile with a significantly higher MTD (15 mg DOX kg(-1)) than that of free DOX·HCl (5 mg DOX kg(-1)). The in vivo studies on the subcutaneous non-small cell lung cancer (A549) xenograft nude mice model confirmed that DOX-NP showed significant antitumor activity and reduced side effects, and then enhanced tumor accumulation as a result of the prolonged circulation in blood and the enhanced permeation and retention effect, compared with free DOX, indicating its great potential for cancer therapy.

Polypeptide/doxorubicin hydrochloride polymersomes prepared through organic solvent-free technique as a smart drug delivery platform.

Rapid and efficient side-chain functionalization of polypeptide with neighboring carboxylgroups is achieved via the combination of ring-opening polymerization and subsequent thiol-yne click chemistry. The spontaneous formation of polymersomes with uniform size is found to occur in aqueous medium via electrostatic interaction between the anionic polypeptide and cationic doxorubicin hydrochloride (DOX·HCl). The polymersomes are taken up by A549 cells via endocytosis, with a slightly lower cytotoxicity compared with free DOX ·HCl. Moreover, the drug-loaded polymersomes exhibit the enhanced therapeutic efficacy, increase apoptosis in tumor tissues, and reduce systemic toxicity in nude mice bearing A549 lung cancer xenograft, in comparison with free DOX ·HCl.

Poly(ester amide) blend microspheres for oral insulin delivery.

This study developed a novel oral insulin formulation centered on microspheres consisting of a blend of biodegradable poly(ester amide) (PEA). In the formulation, L-lysine-/L-leucine-based PEA with pendant COOH groups (PEA-COOH) was used as a pH-responsive material for the protection of insulin from the harsh environmental conditions of the stomach. Arginine-based PEA (Arg-PEA) was introduced to improve the intestinal absorption of the drug. The influence of both the hydrophobicity of PEA-COOH and the content of Arg-PEA was investigated in detail on microsphere surface morphology, drug loading, and the in vitro release profile of insulin. The PEA-COOH/Arg-PEA blend microspheres protected the loaded insulin in simulated gastric fluid and released insulin in a fast and sustained manner in simulated intestinal fluid. The in vivo test demonstrated that the oral administration of insulin-loaded PEA blend microspheres could effectively suppress the blood glucose level in diabetic rats for 10h, and the oral bioavailability was improved to 5.89+1.84% in healthy rats. These results indicate that the PEA blend microspheres are promising vehicles for the oral delivery of insulin.

Methoxypoly(ethylene glycol)-block-poly(L-glutamic acid)-loaded cisplatin and a combination with iRGD for the treatment of non-small-cell lung cancers.

CDDP is loaded into methoxypoly(ethylene glycol)-block-poly(L-glutamic acid) (mPEG-b-PLG), and a combination with iRGD is applied for NSCLC chemotherapy. The CDDP-loaded micelles show sustained cisplatin release in PBS, dose- and time-dependent inhibition to HeLa and A549 cell proliferation, and no apparent hemolysis activities. In in vivo studies using subcutaneous NSCLC xenograft models (A549), both free CDDP and CDDP-loaded micelles show an evident anti-tumor effect. However, the toxicity of CDDP is significantly reduced in the cases of CDDP-loaded micelles and co-administration with iRGD, and the survival time is prolonged by over 30%. Therefore, mPEG-b-PLG-loaded cisplatin and the combination with iRGD provides a promising new therapy for NSCLC.

Preparation, characterization and related in vivo release, safety and toxicity studies of long acting lanreotide microspheres.

The goal of this project was to prepare long-acting lanreotide acetate poly(lactic-co-glycolic acid) (PLGA) microspheres and to analyze the in vivo and in vitro release, safety and toxicology of these preparations. Long-acting lanreotide acetate PLGA microspheres that exhibited a 5-week slow-release period were prepared by a multiple-emulsion solvent evaporation method. Physical characterization, as well as the analysis of the in vivo and in vitro release, safety, acute toxicity and chronic toxicity of the lanreotide microspheres, were conducted in animal models in rats, guinea pigs, rabbits and beagle dogs. The lanreotide acetate PLGA microspheres prepared by multiple-emulsion solvent evaporation had smooth surfaces, uniform particle size and stable lanreotide loading. In vivo and in vitro experiments showed that the lanreotide acetate PLGA microspheres could continuously release lanreotide for 5 weeks. The safety of these long acting lanreotide microspheres was good in the following animal models: active systemic anaphylaxis test in guinea pigs, passive cutaneous anaphylaxis test in rats, hemolytic test in rabbits, local skin irritation test after subcutaneous administration in rabbits and muscle stimulation test in rabbits. Furthermore, no significant acute toxicity or chronic toxicity was observed after administration of lanreotide acetate PLGA microspheres in beagle dogs at dosages up to 22 mg/kg. The lanreotide acetate PLGA microspheres that were prepared in this study exhibited beneficial characteristics in apparent property and structural stability, as well as in release trends in vivo and in vitro.