Structural basis of amine odorant perception by a mammal olfactory receptor.

Odorants are detected as smell in the nasal epithelium of mammals by two G-protein-coupled receptor families, the odorant receptors and the trace amine-associated receptors1,2 (TAARs). TAARs emerged following the divergence of jawed and jawless fish, and comprise a large monophyletic family of receptors that recognize volatile amine odorants to elicit both intraspecific and interspecific innate behaviours such as attraction and aversion3-5. Here we report cryo-electron microscopy structures of mouse TAAR9 (mTAAR9) and mTAAR9-Gs or mTAAR9-Golf trimers in complex with ß-phenylethylamine, N,N-dimethylcyclohexylamine or spermidine. The mTAAR9 structures contain a deep and tight ligand-binding pocket decorated with a conserved D3.32W6.48Y7.43 motif, which is essential for amine odorant recognition. In the mTAAR9 structure, a unique disulfide bond connecting the N terminus to ECL2 is required for agonist-induced receptor activation. We identify key structural motifs of TAAR family members for detecting monoamines and polyamines and the shared sequence of different TAAR members that are responsible for recognition of the same odour chemical. We elucidate the molecular basis of mTAAR9 coupling to Gs and Golf by structural characterization and mutational analysis. Collectively, our results provide a structural basis for odorant detection, receptor activation and Golf coupling of an amine olfactory receptor.

Simultaneous variable selection and estimation for survival data via the Gaussian seamless- L 0 $$ {L}_0 $$ penalty.

We propose a new simultaneous variable selection and estimation procedure with the Gaussian seamless- L 0 $$ {L}_0 $$ (GSELO) penalty for Cox proportional hazard model and additive hazards model. The GSELO procedure shows good potential to improve the existing variable selection methods by taking strength from both best subset selection (BSS) and regularization. In addition, we develop an iterative algorithm to implement the proposed procedure in a computationally efficient way. Theoretically, we establish the convergence properties of the algorithm and asymptotic theoretical properties of the proposed procedure. Since parameter tuning is crucial to the performance of the GSELO procedure, we also propose an extended Bayesian information criteria (EBIC) parameter selector for the GSELO procedure. Simulated and real data studies have demonstrated the prediction performance and effectiveness of the proposed method over several state-of-the-art methods.

Deep Reinforcement Learning-Based Energy Consumption Optimization for Peer-to-Peer (P2P) Communication in Wireless Sensor Networks.

The fast development of the sensors in the wireless sensor networks (WSN) brings a big challenge of low energy consumption requirements, and Peer-to-peer (P2P) communication becomes the important way to break this bottleneck. However, the interference caused by different sensors sharing the spectrum and the power limitations seriously constrains the improvement of WSN. Therefore, in this paper, we proposed a deep reinforcement learning-based energy consumption optimization for P2P communication in WSN. Specifically, P2P sensors (PUs) are considered agents to share the spectrum of authorized sensors (AUs). An authorized sensor has permission to access specific data or systems, while a P2P sensor directly communicates with other sensors without needing a central server. One involves permission, the other is direct communication between sensors. Each agent can control the power and select the resources to avoid interference. Moreover, we use a double deep Q network (DDQN) algorithm to help the agent learn more detailed features of the interference. Simulation results show that the proposed algorithm can obtain a higher performance than the deep Q network scheme and the traditional algorithm, which can effectively lower the energy consumption for P2P communication in WSN.

Motion opponency at the middle temporal cortex: Preserved motion information and the effect of perceptual learning.

Motion opponency, first observed within the primate middle temporal cortex (MT), refers to the suppressing effect of opposite motion directions on neuronal activity. Namely, when opposing motion directional signals stimulate an MT neuron's receptive field, this neuron's response is comparable with that induced by flicker noise. Under such suppression, it is unknown whether any directional information is still represented at MT. In this study, we applied support vector machine (SVM) learning to human functional magnetic resonance imaging data to investigate if any motion defined orientation information was still available from suppressed MT. We found that, at least at the level of ±45° discrimination, such orientation information was still available. Interestingly, after behavioural perceptual learning that improved human discrimination of fine orientation discrimination (e.g. 42° vs. 48°) using the MT-suppressive motion stimuli, the SVM discrimination of ±45° worsened when functional magnetic resonance imaging (fMRI) signals at post-learning MT were used. This result is consistent with findings in Thompson et al. (2013) that, post-perceptual learning, MT suppression was not released, suggesting that motion opponency was perhaps functionally too important for perceptual learning to overcome.

Zeolite Imidazolate Frameworks (ZIFs) Derived Nanomaterials and their Hybrids for Advanced Secondary Batteries and Electrocatalysis.

Zeolite imidazolate frameworks (ZIFs), as a typical class of metal-organic frameworks (MOFs), have attracted a great deal of attention in the field of energy storage and conversation due to their chemical structure stability, facile synthesis and environmental friendliness. Among of ZIFs family, the zinc-based imidazolate framework (ZIF-8) and cobalt-based imidazolate framework (ZIF-67) have considered as promising ZIFs materials, which attributed to their tunable porosity, stable structure, and desirable electrical conductivity. To date, various ZIF-8 and ZIF67 derived materials, including carbon materials, metal oxides, sulfides, selenides, carbides and phosphides, have been successfully synthesized using ZIFs as templates and evaluated as promising electrode materials for secondary batteries and electrocatalysis. This review provides an effective guide for the comprehension of the performance optimization and application prospects of ZIFs derivatives, specifically focusing on the optimization of structure and their application in secondary batteries and electrocatalysis. In detail, we present recent advances in the improvement of electrochemical performance of ZIF-8, ZIF-67 and ZIF-8@ZIF-67 derived nanomaterials and their hybrids, including carbon materials, metal oxides, carbides, oxides, sulfides, selenides, and phosphides for high-performance secondary batteries and electrocatalysis.

Motion opponency examined throughout visual cortex with multivariate pattern analysis of fMRI data.

This study explores how the human brain solves the challenge of flicker noise in motion processing. Despite providing no useful directional motion information, flicker is common in the visual environment and exhibits omnidirectional motion energy which is processed by low-level motion detectors. Models of motion processing propose a mechanism called motion opponency that reduces flicker processing. Motion opponency involves the pooling of local motion signals to calculate an overall motion direction. A neural correlate of motion opponency has been observed in human area MT+/V5, whereby stimuli with perfectly balanced motion energy constructed from dots moving in counter-phase elicit a weaker response than nonbalanced (in-phase) motion stimuli. Building on this previous work, we used multivariate pattern analysis to examine whether the activation patterns elicited by motion opponent stimuli resemble that elicited by flicker noise across the human visual cortex. Robust multivariate signatures of opponency were observed in V5 and in V3A. Our results support the notion that V5 is centrally involved in motion opponency and in the reduction of flicker. Furthermore, these results demonstrate the utility of multivariate analysis methods in revealing the role of additional visual areas, such as V3A, in opponency and in motion processing more generally.

Prevalence of and risk factors for metabolic associated fatty liver disease in an urban population in China: a cross-sectional comparative study.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD) is a new definition for liver disease associated with known metabolic dysfunction. Based on new diagnostic criteria, we aimed to investigate its prevalence and risk factors in Chinese population. METHODS: We conducted this study in a health examination population who underwent abdominal ultrasonography in China. The diagnosis of MAFLD was based on the new diagnostic criteria. The characteristics of the MAFLD population, as well as the associations between MAFLD and metabolic abnormalities, were explored. Mann-Whitney U test and chi-square test were performed to compare different variables. Binary logistic regression was used to determine the risk factors for MAFLD. RESULTS: Among 139,170 subjects, the prevalence of MAFLD was 26.1% (males: 35.4%; females: 14.1%). The prevalence based on female menopausal status, that is, premenopausal, perimenopausal, and postmenopausal, was 6.1%, 16.8%, and 30.2%, respectively. In different BMI groups (underweight, normal, overweight and obese), the prevalence was 0.1%, 4.0%, 27.4% and 59.8%, respectively. The proportions of abnormal metabolic features in the MAFLD group were significantly higher than those in the non-MAFLD group, as was the proportion of elevated alanine aminotransferase (ALT) (42.5% vs. 11%, P < 0.001). In nonobese individuals with MAFLD, the proportions of abnormal metabolic features were also all significantly higher than those in nonobese individuals without MAFLD. The prevalence of metabolic syndrome (MS), dyslipidaemia, and hyperuricaemia, respectively, in the MAFLD group (53.2%, 80.0%, and 45.0%) was significantly higher than that in the non-MAFLD group (10.1%, 41.7%, and 16.8%). Logistic regression revealed that age, BMI, waist circumference, ALT, triglycerides, fasting glucose, uric acid and platelet count were associated with MAFLD. CONCLUSIONS: MAFLD is prevalent in China and varies considerably among different age, sex, BMI, and female menopausal status groups. MAFLD is related to metabolic disorders, especially obesity, while metabolic disorders also play important roles in the occurrence of MAFLD in nonobese individuals. MAFLD patients exhibit a high prevalence of MS, dyslipidaemia, hyperuricaemia, and elevated liver enzymes. MAFLD tends to coexist with systemic metabolic disorders, and a deep inner relationship may exist between MAFLD and MS. Metabolic disorders should be considered to improve the management of MAFLD.

LysR-type transcriptional regulator FinR is required for phenazine and pyrrolnitrin biosynthesis in biocontrol Pseudomonas chlororaphis strain G05.

Phenazine-1-carboxylic acid and pyrrolnitrin, the two secondary metabolites produced by Pseudomonas chlororaphis G05, serve as biocontrol agents that mainly contribute to the growth repression of several fungal phytopathogens. Although some regulators of phenazine-1-carboxylic acid biosynthesis have been identified, the regulatory pathway involving phenazine-1-carboxylic acid synthesis is not fully understood. We isolated a white conjugant G05W03 on X-Gal-containing LB agar during our screening of novel regulator candidates using transposon mutagenesis with a fusion mutant G05Δphz::lacZ as a recipient. By cloning of DNA adjacent to the site of the transposon insertion, we revealed that a LysR-type transcriptional regulator (LTTR) gene, finR, was disrupted in the conjugant G05W03. To confirm the regulatory function of FinR, we constructed the finR-knockout mutant G05ΔfinR, G05Δphz::lacZΔfinR, and G05Δprn::lacZΔfinR, using the wild-type strain G05 and its fusion mutant derivatives as recipient strains, respectively. We found that the expressions of phz and prn operons were dramatically reduced in the finR-deleted mutant. With quantification of the production of antifungal metabolites biosynthesized by the finR-negative strain G05ΔfinR, it was shown that FinR deficiency also led to decreased yield of phenazine-1-carboxylic acid and pyrrolnitrin. In addition, the pathogen inhibition assay confirmed that the production of phenazine-1-carboxylic acid was severely reduced in the absence of FinR. Transcriptional fusions and qRT-PCR verified that FinR could positively govern the transcription of the phz and prn operons. Taken together, FinR is required for antifungal metabolite biosynthesis and crop protection against some fungal pathogens.Key points• A novel regulator FinR was identified by transposon mutagenesis.• FinR regulates antifungal metabolite production.• FinR regulates the phz and prn expression by binding to their promoter regions.

Relationship between the Metabolic Associated Fatty Liver Disease and Endometrial Thickness in Postmenopausal Women: A Cross-sectional Study in China.

Objectives: To determine the relationship between the endometrial thickness (ET) and metabolic associated fatty liver disease (MAFLD) in the postmenopausal women who have a comprehensive health examination. Methods: This was a population-based, retrospective observational study of the prevalence of MAFLD in 8594 postmenopausal women with different ET in the Quality Control Center of Health Examination in Chongqing, China. Binary and multivariable logistic regression analyses were used to obtain odds ratios and 95% confidence intervals for patients of different ET with MAFLD after adjusting for age. Results: The incidences of MAFLD were 28.6% (1352), 30.3% (1058), 34.9% (133) in postmenopausal women with ET of < 3 mm, 3 mm ≤ & < 5 mm, and ≥ 5 mm, respectively. Compared with a baseline ET of less than 5.0 mm, the risk of MAFLD in patients with ET of ≥5.0 mm is higher (OR=1.291, 95% CI: 1.041-1.603, P<0.05). After adjustment for age, a statistically significant positive correlation was still observed. The increased prevalence of MAFLD in patients with ET of 3 mm ≤ &<5 mm (OR=1.110, 95% CI: 1.008-1.223) and ≥5 mm (OR=1.383, 95% CI: 1.109-1.724) achieved statistical significance, respectively. In addition, multiple logistic analyses controlling for age also confirmed the finding of positive correlation among body mass index (BMI) and ET. Conclusion: Our results suggest that there is a positive correlation between MAFLD and ET in postmenopausal women. In addition, increased BMI is also associated with an increased risk of thickened endometrium.

Patient-derived xenografts of different grade gliomas retain the heterogeneous histological and genetic features of human gliomas.

BACKGROUND: Gliomas account for the major part of primary brain tumors. Based on their histology and molecular alternations, adult gliomas have been classified into four grades, each with distinct biology and outcome. Previous studies have focused on cell-line-based models and patient-derived xenografts (PDXs) from patient-derived glioma cultures for grade IV glioblastoma. However, the PDX of lower grade diffuse gliomas, particularly those harboring the endogenous IDH mutation, are scarce due to the difficulty growing glioma cells in vitro and in vivo. The purpose of this study was to develop a panel of patient-derived subcutaneous xenografts of different grade gliomas that represented the heterogeneous histopathologic and genetic features of human gliomas. METHODS: Tumor pieces from surgical specimens were subcutaneously implanted into flanks of NOD-Prkdcscid ll2rgnull mice. Then, we analyzed the association between the success rate of implantation with clinical parameters using the Chi square test and resemblance to the patient's original tumor using immunohistochemistry, immunofluorescence, short tandem repeat analysis, quantitative real-time polymerase chain reaction, and whole-exome sequencing. RESULTS: A total of 11 subcutaneous xenografts were successfully established from 16 surgical specimens. An increased success rate of implantation in gliomas with wild type isocitrate dehydrogenase (IDH) and high Ki67 expression was observed compared to gliomas with mutant IDH and low Ki67 expression. Recurrent and distant aggressive xenografts were present near the primary implanted tumor fragments from WHO grades II to IV. The xenografts histologically represented the corresponding patient tumor and reconstituted the heterogeneity of different grade gliomas. However, increased Ki67 expression was found in propagated xenografts. Endothelial cells from mice in patient-derived xenografts over several generations replaced the corresponding human tumor blood vessels. Short tandem repeat and whole-exome sequencing analyses indicated that the glioma PDX tumors maintained their genomic features during engraftments over several generations. CONCLUSIONS: The panel of patient-derived glioma xenografts in this study reproduced the diverse heterogeneity of different grade gliomas, thereby allowing the study of the growth characteristics of various glioma types and the identification of tumor-specific molecular markers, which has applications in drug discovery and patient-tailored therapy.

AKT/GSK-3ß/ß-catenin signaling pathway participates in erythropoietin-promoted glioma proliferation.

PURPOSE: Although erythropoietin (EPO) has been proven to significantly promote the proliferation of cancer cells, the mechanism for promoting glioma proliferation is poorly understood. Here, we examined the functional role of the AKT/GSK-3ß/ß-catenin signaling pathway in the EPO-mediated proliferation of glioma. METHODS: The distribution of EPO and Ki-67 among clinical samples with different WHO grades was plotted by Immunological Histological Chemistry analysis. U87 and U251 glioma cell lines were treated with short hairpin RNA targeting (shEPO), recombinant human erythropoietin (rhEPO) and/or AKT-specific inhibitor (MK-2206). The changes in phosphorylated AKT, nuclear ß-catenin, cyclin D1 and p27kip1 expression were detected. Cell cycle distributions and glioma proliferation in vitro and in vivo were analyzed. RESULTS: The expression level of EPO was significantly elevated with the increase of WHO grade and Ki67 in clinical glioma specimens. In vitro, knockdown of endogenous EPO in U87 and U251 cells effectively block the phosphorylation of AKT and GSK-3ß and the expression of nuclear ß-catenin. shEPO treatment also significantly decreased the expression of cyclin D1 and increased the expression of p27kip1. The cell cycle transition then slowed down and the proliferation of glioma cells or mouse xenograft tumors both decreased. Treatment of cells or tumors with extra rhEPO reversed the above biological effects mediated by shEPO. rhEPO-induced activation of the AKT/GSK-3ß/ß-catenin pathway and proliferation were abolished by MK-2206. CONCLUSIONS: Our study identified the AKT/GSK-3ß/ß-catenin axis as a critical mediator of EPO-induced glioma proliferation and further provided a clinically significant dimension to the biology of EPO.

Increased antioxidative capacity and decreased cadmium uptake contribute to hemin-induced alleviation of cadmium toxicity in Chinese cabbage seedlings.

Hemin (ferroprotoporphyrin IX), a compound derivative of heme, has been shown to exert numerous beneficial physiological functions in the resistance of plant to various abiotic stresses. This work investigated the effects of hemin on ameliorating Cd toxicity in Chinese cabbage (Brassica chinensis L.). Our results showed that leaf chlorosis, growth inhibition, root morphology and photosynthetic activity were significantly improved by the addition of hemin in Cd-stressed plants. Meanwhile, Cd-induced oxidative damage was also alleviated by hemin, which was supported by the decreased level of malondialdehyde (MDA) in roots of the seedlings treated with hemin. In the same time, the activities of antioxidative enzymes, including superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), as well as the concentrations of ascorbic acid (AsA) and glutathione (GSH) were elevated by hemin, which contributed to the scavenging of Cd-elicited H2O2 and O2•－ within the roots of Chinese cabbage seedlings. Furthermore, compared with Cd stressed plants, Cd concentrations in both shoots and roots were markedly decreased by exogenous hemin. Hence, it can be speculated that hemin-mediated tolerance to Cd stress may be associated with the inhibition of Cd uptake in Chinese cabbage. This hypothesis was supported by the down-regulated expressions of transporter genes, including BcIRT1, BcIRT2, BcNramp1 and BcZIP2 caused by hemin addition in Chinese cabbage seedlings under Cd treatment. Taken together, these results suggested that hemin alleviated Cd toxicity probably through increasing antioxidative capacities and inhibiting Cd uptake of Chinese cabbage.

Status of lipid and lipoprotein in female breast cancer patients at initial diagnosis and during chemotherapy.

BACKGROUND: The lipid profile status among breast cancer patients at initial diagnosis and during chemotherapy remain controversial. The aim of this study is to study the status of lipid and lipoprotein in female breast cancer patients at initial diagnosis and during chemotherapy. METHODS: We conducted a retrospective cohort study of the status of the lipid and lipoprotein in 1054 primarily diagnosed breast cancer patients and 2483 normal controls with age stratification, from July 2015 to October 2016. At the same time, the status of lipid and lipoprotein were also analyzed among 394 breast cancer patients before and after adjuvant chemotherapy. RESULTS: The incidence of dyslipidemia was significantly lower in breast cancer group(42.98%) compared to normal group(58.28%)(P < 0.001). The levels of total cholesterol (TC), triglycerides (TG), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C) among breast cancer group were significantly lower compared to normal control group (P < 0.05). With age stratification, the levels of TC and LDL-C in breast cancer group were still significantly lower than those in control group (P < 0.001). And the levels of TC, TG, LDL-C, apolipoprotein B were significantly higher among post chemotherapeutic patients compared to prechemotherapeutic patients, however HDL-C and Apo-A1 levels were contrary. CONCLUSIONS: Breast cancer patients have lower incidence of dyslipidemia compared to normal populations. However, the situation of dyslipidemia may become worsened after chemotherapy. Therefore, lipid monitoring and dyslipidemia prevention and treatment should be conducted for breast cancer patients at initial diagnosis and during chemotherapy.

Human efficiency in detecting and discriminating biological motion.

Using an "information meter" provided by ideal observer analysis, we measured the efficiency with which human observers processed different walking stimuli against luminance noise and spatial uncertainty to either detect the presence of a walker or to discriminate the walking direction. Human efficiency was examined across four renderings of a human walker: contour, point lights, silhouette, and skeleton. We replicated the previous finding of low discrimination efficiency in biological motion (Gold, Tadin, Cook, & Blake, 2008) and also found low detection efficiency for biological motion. Interestingly, in both detection and discrimination tasks, the skeleton display was among those yielding the highest level of efficiency in processing visual information. This finding suggests that structural information about the relative position of joints, highlighted in the skeleton display, provides a critical component of the internal representation for biological motion.

Transfer in motion discrimination learning was no greater in double training than in single training.

We investigated the controversy regarding double training in motion discrimination learning. We collected data from 43 participants in a motion direction discrimination learning task with either double training (i.e., training plus exposure) or single training (i.e., no exposure). By pooling these data with those in the literature, we had data in double training from 28 participants and in single training from 36 participants. We found that, in double training, the transfer along the exposed direction was less than that along the trained direction, indicating incomplete transfer. Importantly, the transfer in double training was not reliably greater than that in single training.

Examining the standard model of signal detection theory in motion discrimination.

We studied a fundamental assumption in signal detection theory that is applied to motion discrimination. Using random-dot motion stimuli of 100% coherence, it is natural to represent the two directions as two normal distributions. Then a same-different task and a forced-choice task should give rise to consistent d' estimates, because both tasks share the same underlying signal detection theory model. To verify this prediction, we used 4°, 8°, and 12° as the angular difference in motion discrimination. In a between-subjects design, we found the predicted result only with the 4° angular difference. With 8° and 12°, the estimated same-different d' was 32% greater than the two-alternative forced-choice d'. In a subsequent within-subject design with counterbalancing, the first half of the data confirmed this finding. Interestingly, there was now within-subject consistency. Namely, the second task's d' was comparable to the first task's, as if the first task's discrimination was carried over to the second task. This carryover effect diminished when the time gap between the two tasks was lengthened.

Boundary extension: Insights from signal detection theory.

After viewing a scene, people often remember having seen more of the world than was originally visible, an error referred to as boundary extension. Despite the large number of studies on this phenomenon, performance has never been considered in terms of signal detection theory (SDT). We report two visual memory experiments that allowed us to explore boundary extension in terms of SDT. In our experiments, participants first studied pictures presented as close-up or wide-angle views. At test, either the identical view or a different view (a closer or wider angle version of the same scene) were presented and participants rated the test image as being the same or different than before on a 6-point scale. We found that both discrimination sensitivity and bias contributed to the boundary extension effect. The discrimination sensitivity difference was at least 28%, and its presence refuted the hypothesis that boundary extension was due solely to participants' response bias to label test pictures as more wide-angled. Instead, our results support the idea that participants' responses reflect false memory beyond the view (i.e., a more wide-angle view of the world).

Sharpened cortical tuning and enhanced cortico-cortical communication contribute to the long-term neural mechanisms of visual motion perceptual learning.

Much has been debated about whether the neural plasticity mediating perceptual learning takes place at the sensory or decision-making stage in the brain. To investigate this, we trained human subjects in a visual motion direction discrimination task. Behavioral performance and BOLD signals were measured before, immediately after, and two weeks after training. Parallel to subjects' long-lasting behavioral improvement, the neural selectivity in V3A and the effective connectivity from V3A to IPS (intraparietal sulcus, a motion decision-making area) exhibited a persistent increase for the trained direction. Moreover, the improvement was well explained by a linear combination of the selectivity and connectivity increases. These findings suggest that the long-term neural mechanisms of motion perceptual learning are implemented by sharpening cortical tuning to trained stimuli at the sensory processing stage, as well as by optimizing the connections between sensory and decision-making areas in the brain.

Limited transfer of long-term motion perceptual learning with double training.

A significant recent development in visual perceptual learning research is the double training technique. With this technique, Xiao, Zhang, Wang, Klein, Levi, and Yu (2008) have found complete transfer in tasks that had previously been shown to be stimulus specific. The significance of this finding is that this technique has since been successful in all tasks tested, including motion direction discrimination. Here, we investigated whether or not this technique could generalize to longer-term learning, using the method of constant stimuli. Our task was learning to discriminate motion directions of random dots. The second leg of training was contrast discrimination along a new average direction of the same moving dots. We found that, although exposure of moving dots along a new direction facilitated motion direction discrimination, this partial transfer was far from complete. We conclude that, although perceptual learning is transferrable under certain conditions, stimulus specificity also remains an inherent characteristic of motion perceptual learning.