Discovering Intrinsic Subgoals for Vision-and-Language Navigation via Hierarchical Reinforcement Learning.

Vision-and-language navigation requires an agent to navigate in a photo-realistic environment by following natural language instructions. Mainstream methods employ imitation learning (IL) to let the agent imitate the behavior of the teacher. The trained model will overfit the teacher's biased behavior, resulting in poor model generalization. Recently, researchers have sought to combine IL and reinforcement learning (RL) to overcome overfitting and enhance model generalization. However, these methods still face the problem of expensive trajectory annotation. We propose a hierarchical RL-based method-discovering intrinsic subgoals via hierarchical (DISH) RL-which overcomes the generalization limitations of current methods and gets rid of expensive label annotations. First, the high-level agent (manager) decomposes the complex navigation problem into simple intrinsic subgoals. Then, the low-level agent (worker) uses an intrinsic subgoal-driven attention mechanism for action prediction in a smaller state space. We place no constraints on the semantics that subgoals may convey, allowing the agent to autonomously learn intrinsic, more generalizable subgoals from navigation tasks. Furthermore, we design a novel history-aware discriminator (HAD) for the worker. The discriminator incorporates historical information into subgoal discrimination and provides the worker with additional intrinsic rewards to alleviate the reward sparsity. Without labeled actions, our method provides supervision for the worker in the form of self-supervision by generating subgoals from the manager. The final results of multiple comparison experiments on the Room-to-Room (R2R) dataset show that our DISH can significantly outperform the baseline in accuracy and efficiency.

Development a high-sensitivity sandwich ELISA for determining antigen content of porcine circovirus type 2 vaccines.

Porcine circovirus type 2 (PCV2) is intensely prevalent in global pig farms. The PCV2 vaccine is an important means of preventing and controlling PCV2. The quality control of PCV2 vaccines is predominantly based on detection techniques such as animal testing and neutralizing antibody titration. Measuring the content of effective proteins in vaccines to measure vaccine efficacy is an excellent alternative to traditional methods, which can greatly accelerate the development speed and testing time of vaccines. In this study, we screened a monoclonal antibody (mAb) that can effectively recognize not only the exogenous expression of PCV2 Cap protein but also PCV2 virus. The double antibody sandwich ELISA (DAS-ELISA) was developed using this mAb that specifically recognize PCV2 Cap. The minimum protein content detected by this method is 3.5 ng/mL. This method can be used for the quality control of PCV2 inactivated vaccine and subunit vaccine, and the detection results are consistent with the results of mice animal experiments. This method has the advantages of simple operation, good sensitivity, high specificity and wide application. It can detect the effective antigen Cap protein content of various types of PCV2 vaccines, which not only shorten the vaccine inspection time but also save costs.

Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developing Drosophila brain.

Glia derived secretory factors play diverse roles in supporting the development, physiology, and stress responses of the central nervous system (CNS). Through transcriptomics and imaging analyses, we have identified Obp44a as one of the most abundantly produced secretory proteins from Drosophila CNS glia. Protein structure homology modeling and Nuclear Magnetic Resonance (NMR) experiments reveal Obp44a as a fatty acid binding protein (FABP) with a high affinity towards long-chain fatty acids in both native and oxidized forms. Further analyses demonstrate that Obp44a effectively infiltrates the neuropil, traffics between neuron and glia, and is secreted into hemolymph, acting as a lipid chaperone and scavenger to regulate lipid and redox homeostasis in the developing brain. In agreement with this essential role, deficiency of Obp44a leads to anatomical and behavioral deficits in adult animals and elevated oxidized lipid levels. Collectively, our findings unveil the crucial involvement of a noncanonical lipid chaperone to shuttle fatty acids within and outside the brain, as needed to maintain a healthy brain lipid environment. These findings could inspire the design of novel approaches to restore lipid homeostasis that is dysregulated in CNS diseases.

Design and Algorithm Integration of High-Precision Adaptive Underwater Detection System Based on MEMS Vector Hydrophone.

Real-time DOA (direction of arrival) estimation of surface or underwater targets is of great significance to the research of marine environment and national security protection. When conducting real-time DOA estimation of underwater targets, it can be difficult to extract the prior characteristics of noise due to the complexity and variability of the marine environment. Therefore, the accuracy of target orientation in the absence of a known noise is significantly reduced, thereby presenting an additional challenge for the DOA estimation of the marine targets in real-time. Aiming at the problem of real-time DOA estimation of acoustic targets in complex environments, this paper applies the MEMS vector hydrophone with a small size and high sensitivity to sense the conditions of the ocean environment and change the structural parameters in the adaptive adjustments system itself to obtain the desired target signal, proposes a signal processing method when the prior characteristics of noise are unknown. Theoretical analysis and experimental verification show that the method can achieve accurate real-time DOA estimation of the target, achieve an error within 3.1° under the SNR (signal-to-noise ratio) of the X channel of -17 dB, and maintain a stable value when the SNR continues to decrease. The results show that this method has a very broad application prospect in the field of ocean monitoring.

Can Natural Speech Prosody Distinguish Autism Spectrum Disorders? A Meta-Analysis.

Natural speech plays a pivotal role in communication and interactions between human beings. The prosody of natural speech, due to its high ecological validity and sensitivity, has been acoustically analyzed and more recently utilized in machine learning to identify individuals with autism spectrum disorders (ASDs). In this meta-analysis, we evaluated the findings of empirical studies on acoustic analysis and machine learning techniques to provide statistically supporting evidence for adopting natural speech prosody for ASD detection. Using a random-effects model, the results observed moderate-to-large pooled effect sizes for pitch-related parameters in distinguishing individuals with ASD from their typically developing (TD) counterparts. Specifically, the standardized mean difference (SMD) values for pitch mean, pitch range, pitch standard deviation, and pitch variability were 0.3528, 0.6744, 0.5735, and 0.5137, respectively. However, the differences between the two groups in temporal features could be unreliable, as the SMD values for duration and speech rate were only 0.0738 and -0.0547. Moderator analysis indicated task types were unlikely to influence the final results, whereas age groups showed a moderating role in pooling pitch range differences. Furthermore, promising accuracy rates on ASD identification were shown in our analysis of multivariate machine learning studies, indicating averaged sensitivity and specificity of 75.51% and 80.31%, respectively. In conclusion, these findings shed light on the efficacy of natural prosody in identifying ASD and offer insights for future investigations in this line of research.

Mitochondrial Outer Membrane Translocase MoTom20 Modulates Mitochondrial Morphology and Is Important for Infectious Growth of the Rice Blast Fungus Magnaporthe oryzae.

Mitochondria are highly dynamic organelles that constantly change their morphology to adapt to the cellular environment through fission and fusion, which is critical for a cell to maintain normal cellular functions. Despite the significance of this process in the development and pathogenicity of the rice blast fungus Magnaporthe oryzae, the underlying mechanism remains largely elusive. Here, we identified and characterized a mitochondrial outer membrane translocase, MoTom20, in M. oryzae. Targeted gene deletion revealed that MoTom20 plays an important role in vegetative growth, conidiogenesis, penetration, and infectious growth of M. oryzae. The growth rate, conidial production, appressorium turgor, and pathogenicity are decreased in the ΔMotom20 mutant compared with the wild-type and complemented strains. Further analysis revealed that MoTom20 localizes in mitochondrion and plays a key role in regulating mitochondrial fission and fusion balance, which is critical for infectious growth. Finally, we found that MoTom20 is involved in fatty-acid utilization, and its yeast homolog ScTom20 is able to rescue the defects of ΔMotom20 in mitochondrial morphology and pathogenicity. Overall, our data demonstrate that MoTom20 is a key regulator for mitochondrial morphology maintenance, which is important for infectious growth of the rice blast fungus M. oryzae. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Detection of paralytic shellfish toxins by near-infrared spectroscopy based on a near-Bayesian SVM classifier with unequal misclassification costs.

BACKGROUND: Paralytic shellfish poisoning caused by human consumption of shellfish fed on toxic algae is a public health hazard. It is essential to implement shellfish monitoring programs to minimize the possibility of shellfish contaminated by paralytic shellfish toxins (PST) reaching the marketplace. RESULTS: This paper proposes a rapid detection method for PST in mussels using near-infrared spectroscopy (NIRS) technology. Spectral data in the wavelength range of 950-1700 nm for PST-contaminated and non-contaminated mussel samples were used to build the detection model. Near-Bayesian support vector machines (NBSVM) with unequal misclassification costs (u-NBSVM) were applied to solve a classification problem arising from the fact that the quantity of non-contaminated mussels was far less than that of PST-contaminated mussels in practice. The u-NBSVM model performed adequately on imbalanced datasets by combining unequal misclassification costs and decision boundary shifts. The detection performance of the u-NBSVM did not decline as the number of PST samples decreased due to adjustments to the misclassification costs. When the number of PST samples was 20, the G-mean and accuracy reached 0.9898 and 0.9944, respectively. CONCLUSION: Compared with the traditional support vector machines (SVMs) and the NBSVM, the u-NBSVM model achieved better detection performance. The results of this study indicate that NIRS technology combined with the u-NBSVM model can be used for rapid and non-destructive PST detection in mussels. © 2023 Society of Chemical Industry.

The natural compound Sanggenon C inhibits PRRSV infection by regulating the TRAF2/NF-κB signalling pathway.

Porcine reproductive and respiratory syndrome (PRRS) is a serious infectious disease and one of the major causes of death in the global pig industry. PRRS virus (PRRSV) strains have complex and diverse genetic characteristics and cross-protection between strains is low, which complicates vaccine selection; thus, the current vaccination strategy has been greatly compromised. Therefore, it is necessary to identify effective natural compounds for the clinical treatment of PRRS. A small molecule library composed of 720 natural compounds was screened in vitro, and we found that Sanggenon C (SC) was amongst the most effective natural compound inhibitors of PRRSV infection. Compared with ribavirin, SC more significantly inhibited PRRSV infection at both the gene and protein levels and reduced the viral titres and levels of protein expression and inflammatory cytokine secretion to more effectively protect cells from PRRSV infection and damage. Mechanistically, SC inhibits activation of the NF-κB signalling pathway by promoting TRAF2 expression, thereby reducing PRRSV replication. In conclusion, by screening natural compounds, we found that SC suppresses PRRSV infection by regulating the TRAF2/NF-κB signalling pathway. This study contributes to a deeper understanding of the therapeutic targets and pathogenesis of PRRSV infection. More importantly, our results demonstrate that SC has potential as a candidate for the treatment of PRRS.

Strong Connection of Single-Wall Carbon Nanotube Fibers with a Copper Substrate Using an Intermediate Nickel Layer.

Lightweight carbon nanotube fibers (CNTFs) with high electrical conductivity and high tensile strength are considered to be an ideal wiring medium for a wide range of applications. However, connecting CNTFs with metals by soldering is extremely difficult due to the nonreactive nature and poor wettability of CNTs. Here we report a strong connection between single-wall CNTFs (SWCNTFs) and a Cu matrix by introducing an intermediate Ni layer, which enables the formation of mechanically strong and electrically conductive joints between SWCNTFs and a eutectic Sn-37Pb alloy. The electrical resistance change rate (ΔR/R0) of Ni-SWCNTF/solder-Cu interconnects only decreases ∼29.8% after 450 thermal shock cycles between temperatures of -196 and 150 °C, which is 8.2 times lower than that without the Ni layer. First-principles calculations indicate that the introduction of the Ni layer significantly improves the heterogeneous interfacial bond strength of the Ni-SWCNTF/solder-Cu connections.

Deletion of a 7-amino-acid region in the porcine epidemic diarrhea virus envelope protein induces higher type I and III interferon responses and results in attenuation in vivo.

Porcine epidemic diarrhea virus (PEDV) leads to enormous economic losses for the pork industry. However, the commercial vaccines failed to fully protect against the epidemic strains. Previously, the rCH/SX/2016-SHNXP strain with the entire E protein and the rCH/SX/2015 strain with the deletion of 7-amino-acid (7-aa) at positions 23-29 in E protein were constructed and rescued. The pathogenicity assay indicated that rCH/SX/2015 is an attenuated strain, but rCH/SX/2016-SHNXP belongs to the virulent strains. Then, the recombination PEDV (rPEDV-EΔaa23-aa29)strain with a 7-aa deletion in the E protein was generated, using the highly virulent rCH/SX/2016-SHNXP strain (rPEDV-Ewt) as the backbone. Compared with the rPEDV-Ewt strain, the release and infectivity of the rPEDV-EΔaa23-aa29 strain were significantly reduced in vitro, but stronger interferon (IFN) responses were triggered both in vitro and in vivo. The pathogenicity assay showed that the parental strain resulted in severe diarrhea (100%) and death (100%) in all piglets. Compared with the parental strain group, rPEDV-EΔaa23-aa29 caused lower mortality (33%) and diminished fecal PEDV RNA shedding. At 21 days, all surviving pigs were challenged orally with rPEDV-Ewt. No pigs died in the two groups. Compared with the mock group, significantly delayed and milder diarrhea and reduced fecal PEDV RNA shedding were detected in the rPEDV-EΔaa23-aa29 group. In conclusion, the deletion of a 7-aa fragment in the E protein (EΔaa23-aa29) attenuated PEDV but retained its immunogenicity, which can offer new ideas for the design of live attenuated vaccines and provide new insights into the attenuated mechanism of PEDV. IMPORTANCE Porcine epidemic diarrhea virus (PEDV) causes high mortality in neonatal piglets and remains a large challenge to the pork industry. Unfortunately, no safe and effective vaccines are available yet. The pathogenesis and molecular basis of the attenuation of PEDV remain unclear, which seriously hinders the development of PEDV vaccines. This study found that the rPEDV carrying EΔaa23-aa29 mutation in the E protein induced significantly higher IFN responses than the parental virus, partially attenuated, and remained immunogenic in piglets. For the first time, PEDV E was verified as an IFN antagonist in the infection context and identified as a virulence factor of PEDV. Our data also suggested that EΔaa23-aa29 mutation can be a good target for the development of live attenuated vaccines for PEDV and also provide new perspectives for the attenuated mechanism of PEDV.

Genomic similarity and antibody-dependent enhancement of immune serum potentially affect the protective efficacy of commercial MLV vaccines against NADC30-like PRRSV.

Porcine reproductive and respiratory syndrome (PRRS) is one of the most significant diseases affecting the pig industry worldwide. The PRRSV mutation rate is the highest among the RNA viruses. To date, NADC30-like PRRSV and highly pathogenic PRRSV (HP-PRRSV) are the dominant epidemic strains in China; however, commercial vaccines do not always provide sufficient cross-protection, and the reasons for insufficient protection are unclear. This study isolated a wild-type NADC30-like PRRSV, SX-YL1806, from Shaanxi Province. Vaccination challenge experiments in piglets showed that commercial modified live virus (MLV) vaccines provided good protection against HP-PRRSV. However, it could not provide sufficient protection against the novel strain SX-YL1806. To explore the reasons for this phenomenon, we compared the genomic homology between the MLV strain and HP-PRRSV or NADC30-like PRRSV and found that the MLV strain had a lower genome similarity with NADC30-like PRRSV. Serum neutralization assay showed that MLV-immune serum slightly promoted the homologous HP-PRRSV replication and significantly promoted the heterologous NADC30-like PRRSV strain replication in vitro, suggesting that antibody-dependent enhancement (ADE) might also play a role in decreasing MLV protective efficacy. These findings expand our understanding of the potential factors affecting the protective effect of PRRSV MLV vaccines against the NADC30-like strains.

Inhibitory Effects of Epithelial Cells on Fibrosis Mechanics of Microtissue and Their Spatiotemporal Dependence on the Epithelial-Fibroblast Interaction.

Cell-generated contraction force is the primary physical drive for fibrotic densification of biological tissues. Previous studies using two-dimensional culture models have shown that epithelial cells inhibit the myofibroblast-derived contraction force via the regulation of the fibroblast/myofibroblast transition (FMT). However, it remains unclear how epithelial cells interact with fibroblasts and myofibroblasts to determine the mechanical consequences and spatiotemporal regulation of fibrosis development. In this study, we established a three-dimensional microtissue model using an NIH/3T3 fibroblast-laden collagen hydrogel, incorporated with a microstring-based force sensor, to assess fibrosis mechanics. When Madin-Darby canine kidney epithelial cells were cocultured on the microtissue's surface, the densification, stiffness, and contraction force of the microtissue greatly decreased compared to the monocultured microtissue without epithelial cells. The key fibrotic features, such as enhanced protein expression of α-smooth muscle actin, fibronectin, and collagen indicating FMT and matrix deposition, respectively, were also significantly reduced. The antifibrotic effects of epithelial cells on the microtissue were dependent on the intercellular signaling molecule prostaglandin E2 (PGE2) with an effective concentration of 10 µM and their proximity to the fibroblasts, indicating paracrine cellular signaling between the two types of cells during tissue fibrosis. The effect of PGE2 on microtissue contraction was also dependent on the time point when PGE2 was delivered or blocked, suggesting that the presence of epithelial cells at an early stage is critical for preventing or treating advanced fibrosis. Taken together, this study provides insights into the spatiotemporal regulation of mechanical properties of fibrosis by epithelial cells, and the cocultured microtissue model incorporated with a real-time and sensitive force sensor will be a suitable system for evaluating fibrosis and drug screening.

Single-Walled Carbon Nanotube/Copper Core-Shell Fibers with a High Specific Electrical Conductivity.

Carbon nanotube (CNT)/Cu core-shell fibers are a promising material for lightweight conductors due to their higher conductivity than pure CNT fibers and lower density than traditional Cu wires. However, the electrical properties of the hybrid fiber have been unsatisfactory, mainly because of the weak CNT-Cu interfacial interaction. Here we report the fabrication of a single-walled CNT (SWCNT)/Cu core-shell fiber that outperforms commercial Cu wires in terms of specific electrical conductivity and current carrying capacity. A dense and uniform Cu shell was coated on the surface of wet-spun SWCNT fibers using a combination of magnetron sputtering and electrochemical deposition. Our SWCNT/Cu core-shell fibers had an ultrahigh specific electrical conductivity of (1.01 ± 0.04) × 104 S m2 kg-1, 56% higher than Cu. Experimental and simulation results show that oxygen-containing functional groups on the surface of a wet-spun SWCNT fiber interact with the sputtered Cu atoms to produce strong bonding. Our hybrid fiber preserved its integrity and conductivity well after more than 5000 bending cycles. Furthermore, the current carrying capacity of the coaxial fiber reached 3.14 × 105 A cm-2, three times that of commercial Cu wires.

Identification of Perna viridis contaminated with diarrhetic shellfish poisoning toxins in vitro using NIRS and a discriminative non-negative representation-based classifier.

Diarrhetic shellfish poisoning (DSP) toxins are one of the most widespread marine biotoxins that affect aquaculture and human health, and their detection has become crucial. In this study, near-infrared reflectance spectroscopy (NIRS) with non-destructive characteristics was used to identify DSP toxins in Perna viridis. The spectral data of the DSP toxin-contaminated and non-contaminated Perna viridis samples were acquired in the 950-1700 nm range. To solve the discrimination of spectra with crossover and overlapping, a discriminative non-negative representation-based classifier (DNRC) has been proposed. Compared with collaborative and non-negative representation-based classifiers, the DNRC model exhibited better performance in detecting DSP toxins, with a classification accuracy of 99.44 %. For a relatively small-scale sample dataset in practical applications, the performance of the DNRC model was compared with those of classical models. The DNRC model achieved the best results for both identification accuracy and F-measure, and its detection performance did not significantly decrease with decreasing sample size. The experimental results validated that a combination of NIRS and the DNRC model can facilitate rapid, convenient, and non-destructive detection of DSP toxins in Perna viridis.

MoLrp1-mediated signaling induces nuclear accumulation of MoMsn2 to facilitate fatty acid oxidation for infectious growth of the rice blast fungus.

Fatty acid ß-oxidation is critical for fatty acid degradation and cellular development. In the rice blast fungus Magnaporthe oryzae, fatty acid ß-oxidation is reported to be important mainly for turgor generation in the appressorium. However, the role of fatty acid ß-oxidation during invasive hyphal growth is rarely documented. We demonstrated that blocking peroxisomal fatty acid ß-oxidation impaired lipid droplet (LD) degradation and infectious growth of M. oryzae. We found that the key regulator of pathogenesis, MoMsn2, which we identified previously, is involved in fatty acid ß-oxidation by targeting MoDCI1 (encoding dienoyl-coenzyme A [CoA] isomerase), which is also important for LD degradation and infectious growth. Cytological observations revealed that MoMsn2 accumulated from the cytosol to the nucleus during early infection or upon treatment with oleate. We determined that the low-density lipoprotein receptor-related protein MoLrp1, which is also involved in fatty acid ß-oxidation and infectious growth, plays a critical role in the accumulation of MoMsn2 from the cytosol to the nucleus by activating the cyclic AMP signaling pathway. Our results provide new insights into the importance of fatty acid oxidation during invasive hyphal growth, which is modulated by MoMsn2 and its related signaling pathways in M. oryzae.

Efficient Fabrication of High-Quality Single-Walled Carbon Nanotubes and Their Macroscopic Conductive Fibers.

High-purity and well-graphitized single-walled carbon nanotubes (SWCNTs) with excellent physiochemical properties are ideal building blocks for the assembly of various CNT macrostructures for a wide range of applications. We report the preparation of high-quality SWCNTs on a large scale using a floating catalyst chemical vapor deposition (FCCVD) method. Under the optimum conditions, the conversion rate of the carbon source to SWCNTs reached 28.8%, and 20.4% of the metal nanoparticles were active for SWCNT growth, which are 15% and ∼400 times higher than those previously reported for FCCVD synthesis, respectively. As a result, the prepared SWCNTs have a very low residual catalyst content of ∼1.9 wt % and a high rapid oxidation temperature of 717 °C. Using these high-quality SWCNTs, we spun macroscopic SWCNT fibers by a wet-spinning process. The resulting fibers had a high electrical conductivity of 6.67 MS/m, which is 32% higher than the best value previously reported for SWCNT fibers.

Research on the evolution of spatial network structure of tourism eco-efficiency and its influencing factors in China's provinces based on carbon emission accounting.

In the context of global warming, although the coordinated development of tourism has led to regional economic growth, the high energy consumption-driven effects of such development have also led to environmental degradation. This research combines the undesired output of the Super-SBM model and social network analysis methods to determine the eco-efficiency of provincial tourism in China from 2010-2019 and analyzes its spatial correlation characteristics as well as its influencing factors. The aim of the project is to improve China's regional tourism eco-efficiency and promote cross-regional tourism correlation. The results show that (1) the mean value of provincial tourism eco-efficiency in China is maintained at 0.405~0.612, with an overall fluctuating upward trend. The tourism eco-efficiency of eastern China is higher than that of central, western and northeastern China, but the latter three regions have not formed a stable spatial distribution pattern. (2) The spatial network of provincial tourism eco-efficiency in China is multithreaded, dense and diversified. Throughout the network, affiliations are becoming closer, and network structure robustness is gradually improving, although the "hierarchical" spatial network structure remains. In individual networks, Jiangsu, Guangdong and Shandong provinces in eastern China have higher centrality degrees, closeness centrality and betweenness centrality than other provinces, which means they are dominant in the network. Hainan Province, also located in eastern China, has not yet built a "bridge" for tourism factor circulation. In the core-periphery model, the core-periphery areas of China's provincial tourism eco-efficiency are distributed in clusters, and the number of "core members" has increased. (3) The economic development level, information technology development level, and tourism technology level collectively drive the development and evolution of China's provincial tourism eco-efficiency spatial network.

Ryanodine receptor (RYR) mutational status correlates with tumor mutational burden, age and smoking status and stratifies non-small cell lung cancer patient prognosis.

Background: The ryanodine receptors (RYRs) have been implicated in many muscular, cardiac and neurological diseases. However, there are almost no studies so far focusing on RYR genetic alterations and its roles in cancer, especially in non-small cell lung cancer (NSCLC). Methods: The whole-exome sequencing (WES) data, demographic and clinical data of 1,052 NSCLC patients was downloaded from The Cancer Genome Atlas (TCGA) database and analyzed using the corresponding packages of the R software. Mutational profile was established and its correlation with tumor mutational burden (TMB), prognosis, age and smoking status was analyzed and compared. Results: RYR mutations were found in 502 NSCLC patients, in which mutations of RYR1, RYR2 and RYR3 were found in 17.3% (182/1,052), 40.0% (421/1,052) and 21.3% (224/1,052) of patients, respectively. Random distribution of mutations without hotspot mutations were observed with all three RYR isoforms. Significant co-mutations were found between RYR1 and RYR3, while mutual exclusive mutations were found between RYR1 and RYR2, and between RYR2 and RYR3. Significant correlation was found between cumulative number of mutations and cumulative TMB for all three RYR isoforms, and patients with RYR mutations exhibited significantly higher TMB than those without RYR mutations. Significant correlation was also found between mutational status and age in RYR2 and RYR3, and between mutational status and smoking history grading in all three isoforms, and between mutational status and number of pack years in RYR3. More interestingly, significant stratification of patient survival was revealed by RYR2 mutational status, which was found to be one of the independent risk factors for patient prognosis in multivariate Cox analysis. Conclusions: The mutational profile of RYR in NSCLC has been characterized for the first time. Strong correlation was found between RYR mutational status and TMB, age and smoking status. RYR2 mutational status was an independent risk factor for NSCLC patient prognosis.

A novel ferroptosis-related gene prognostic index for prognosis and response to immunotherapy in patients with prostate cancer.

Background: Prostate cancer (PCa) is among the leading causes of cancer death worldwide. Ferroptosis refers to an iron-dependent form of regulated cell death and is involved in prostate tumorigenesis. A few ferroptosis-related gene signatures have been developed to predict the prognosis for PCa patients. However, previous signatures were typically established based on biochemical recurrence-free survival, which has proven not to be a good surrogate for overall survival (OS). This study aimed to construct a novel ferroptosis-related gene prognostic index (FRGPI) to predict disease-free survival (DFS) and response to immunotherapy for PCa patients after radical prostatectomy. Methods: Gene expression and clinicopathological data on PCa patients were obtained from the TCGA database. Ferroptosis-related hub genes associated with DFS of PCa patients were identified by an in-depth bioinformatics analysis using a novel and comprehensive algorithm based on functional enrichment, consensus clustering, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) network construction. The FRGPI was established on the basis of the genes selected using multivariate cox regression analysis and further validated in two additional PCa cohorts. Next, the clinicopathological, molecular, and immune profiles were characterized and compared between FRGPI-high and FRGPI-low subgroups. Finally, the predictive role of the FRGPI in response to immunotherapy was estimated using a metastatic urothelial cancer cohort treated with an anti-PD-L1 agent. Results: The FRGPI was constructed based on four genes (E2F1, CDC20, TYMS, and NUP85), and FRGPI-high patients had worse DFS than FRGPI-low patients. Multivariate cox regression analysis revealed that FRGPI could act as an independent prognostic factor for PCa patients after radical prostatectomy. A prognostic nomogram comprising the FRGPI and other clinicopathological parameters was established to predict the DFS for PCa patients quantitatively. In addition, comprehensive results demonstrated that high FRGPI scores showed a significantly positive correlation with worse clinicopathological features, higher mutation counts, increased frequency of copy number variations (CNVs), higher homologous recombination deficiency (HRD) and immune scores, higher mRNAsi, and more importantly, enhanced sensitivity to immunotherapy. Conclusions: FRGPI is not only a promising and robust prognostic biomarker, but also a potential indicator of immunotherapeutic outcomes for PCa patients after radical prostatectomy.

Gene regulation network analyses of pistil development in papaya.

BACKGROUND: The pistil is an essential part of flowers that functions in the differentiation of the sexes and reproduction in plants. The stigma on the pistil can accept pollen to allow fertilization and seed development. Papaya (Carica papaya L.) is a dioecious plant, where female flowers exhibit normal pistil, while the male flowers exhibit aborted pistil at a late stage of pistil development. RESULTS: The developmental stages of papaya pistil were analyzed after first dividing it into slices representing the primordium stage 1 (S1), the pre-meiotic stages S2, post-meiotic stage S3, and the mitotic stage S4. The SS scoring algorithm analysis of genes preferentially expressed at different stages revealed differentially expressed genes between male and female flowers. A transcription factor regulatory network for each stage based on the genes that are differentially expressed between male and female flowers was constructed. Some transcription factors related to pistil development were revealed based on the analysis of regulatory networks such as CpAGL11, CpHEC2, and CpSUPL. Based on the specific expression of genes, constructed a gene regulatory subnetwork with CpAGL11-CpSUPL-CpHEC2 functioning as the core. Analysis of the functionally enriched terms in this network reveals several differentially expressed genes related to auxin/ brassinosteroid signal transduction in the plant hormone signal transduction pathway. At the same time, significant differences in the expression of auxin and brassinosteroid synthesis-related genes between male and female flowers at different developmental stages were detected. CONCLUSIONS: The pistil abortion of papaya might be caused by the lack of expression or decreased expression of some transcription factors and hormone-related genes, affecting hormone signal transduction or hormone biosynthesis. Analysis of aborted and normally developing pistil in papaya provided new insights into the molecular mechanism of pistil development and sex differentiation in dioecious papaya.