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Feng Gao,2 Peng Jing,2 Jian Liu,2 Yuanfei Lu,1 Peicheng Zhang,2 Wei Han,1 Guoliang Liu,1 Ning Ru,2 Guanghui Cui,2 Chenglin Sun,1 Yebing Che,1 Huaming Zhang,1 Qnglong Hu,3 Huan-you Wang,4 Yingli Wu,2 Changjiang Guan,2 Qiang Fu,1 Zhenlu Ma,2 Baofa Yu1–3 1Jinan Baofa Cancer Hospital, Jinan, People's Republic of China; 2TaiMei Baofa Cancer Hospital, Dongping, People's Republic of China; 3Beijing Baofa Cancer Hospital, Beijing, People's Republic of China; 4Department of Pathology, UCSD School of Medicine, La Jolla, CA, USAPurpose: To compare the therapeutic effects of ultra-minimum incision personalized intratumoral chemoimmunotherapy (UMIPIC) with intratumoral chemotherapy (ITCT) in the treatment of advanced hepatocellular carcinomas and to analyze the effect of hapten as an immune booster.Materials and methods: Patients with advanced hepatocellular carcinomas were treated with UMIPIC or ITCT with the same therapeutic procedure; the UMIPIC method had a proprietary regimen including an oxidant, a cytotoxic drug, and hapten, while ITCT delivered the same drug excluding hapten. Of 339 patients in total, 119 of the UMIPIC patients (n=214) had response data and 214 had survival data, and of the ITCT patients (n=125), 61 had response data and 125 had survival data. Tumor response was assessed with a computed tomography scan 6–8 weeks after the initial treatment; the survival rate was evaluated by follow-up visits. Tumor size was classified as small (10 cm); tumor sizes with liver function categorized using Child–Pugh class (A and B) were analyzed by correlation with overall survival.Results: The response rates (complete response + partial response + stable disease) were 78.68% and 81.52% in the UMIPIC and ITCT groups, respectively, with no statistically significant difference; however, the median overall survival was 7 months for UMIPIC (test) and 4 months for ITCT (control), respectively (P

Baofa Yu,1–3 Yuanfei Lu,1 Feng Gao,2 Peng Jing,2 Han Wei,1 Peicheng Zhang,2 Guoliang Liu,1 Ning Ru,2 Guanghui Cui,2 Xinhai Xu,1 Chenglin Sun,1 Changjiang Guan,2 Yebing Che,1 Yingli Wu,2 Zhenlu Ma,2 Qiang Fu,1 Jian Liu,2 Huan-You Wang4 1Jinan Baofa Cancer Hospital, Jinan, 2TaiMei Baofa Cancer Hospital, Dongping, 3Beijing Baofa Cancer Hospital, Beijing, People’s Republic of China; 4Department of Pathology, University of California, San Diego, CA, USAAim: The objective of the study reported here was to evaluate the therapeutic effects of hapten-enhanced chemoimmunotherapy in the treatment of advanced lung cancer by ultra-minimum incision personalized intratumoral chemoimmunotherapy (UMIPIC) and to analyze the effect of this immune booster.Materials and methods: A total of 97 patients with advanced lung cancer were treated with UMIPIC or intratumoral chemotherapy (ITCT). UMIPIC was delivered intratumorally in combination with a proprietary therapeutic regimen composed of three components – an oxidant, a cytotoxic drug, and hapten. ITCT applied using the same procedures and regimen, only without hapten. All data from the two groups were reviewed and analyzed. A total of 55 patients were treated with UMIPIC and 42 with ITCT. Patient responses were assessed with computed tomography scan 4–6 weeks after treatment, and all of the patients were followed until their deaths.Results: Median overall survival was 11.23 months in the UMIPIC (test) group and 5.62 months in the ITCT (control) group (P

Deep space travel presents a number of measurable risks including exposure to a spectrum of radiations of varying qualities, termed galactic cosmic radiation (GCR) that are capable of penetrating the spacecraft, traversing through the body and impacting brain function. Using rodents, studies have reported that exposure to simulated GCR leads to cognitive impairments associated with changes in hippocampus function that can persist as long as one-year post exposure with no sign of recovery. Whether memory can be updated to incorporate new information in mice exposed to GCR is unknown. Further, mechanisms underlying long lasting impairments in cognitive function as a result of GCR exposure have yet to be defined. Here, we examined whether whole body exposure to simulated GCR using 6 ions and doses of 5 or 30 cGy interfered with the ability to update an existing memory or impact hippocampal synaptic plasticity, a cellular mechanism believed to underlie memory processes, by examining long term potentiation (LTP) in acute hippocampal slices from middle aged male mice 3.5-5 months after radiation exposure. Using a modified version of the hippocampus-dependent object location memory task developed by our lab termed "Objects in Updated Locations" (OUL) task we find that GCR exposure impaired hippocampus-dependent memory updating and hippocampal LTP 3.5-5 months after exposure. Further, we find that impairments in LTP are reversed through one-time systemic subcutaneous injection of the histone deacetylase 3 inhibitor RGFP 966 (10 mg/kg), suggesting that long lasting impairments in cognitive function may be mediated at least in part, through epigenetic mechanisms.

Autophagy plays a crucial role in the physiopathological mechanisms of diseases by regulating cellular functions and maintaining cellular homeostasis, which has garnered extensive attention from researchers worldwide. The holistic regulation and bidirectional regulation effects of acupuncture can modulate cellular autophagy, promoting or restoring the homeostasis of the body’s internal environment to achieve therapeutic outcomes. This paper systematically reviews the research progress on the use of acupuncture for treating various diseases via the autophagy pathway, summarizes signal pathways related to acupuncture regulating autophagy, and analyzes the deficiencies present in the existing research. The review results indicate that the mechanism of action of acupuncture on autophagy dysfunction is reflected in the changes in LC3, Beclin1, p53, and autophagy-associated (ATG) protein expression, and regulates signaling pathways and key proteins or genes. The regulatory effect of acupuncture on autophagy capacity is bidirectional: it inhibits the abnormal activation of autophagy to prevent exacerbation of injury and reduce apoptosis, while also activating or enhancing autophagy to promote the elimination of inflammation and reduce oxidative stress. Further analysis suggests that the mechanisms of acupuncture regulating autophagy are insufficiently explored. Future research should prioritize the development of more appropriate animal models, analyzing the accuracy of relevant pathways and the specificity of indicators, exploring the synergistic effects among targets and signaling pathways, clarifying the regulatory mechanisms of acupuncture at various stages of autophagy, and evaluating the efficacy of acupuncture in autophagy modulating. This paper offers valuable insights into the regulation of autophagy by acupuncture.

Abstract In the last three years, the capacity of health care systems and the public health policies of governments worldwide were challenged by the spread of SARS-CoV-2. Mortality due to SARS-CoV-2 mainly resulted from the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Moreover, millions of people who survived ALI/ARDS in SARS-CoV-2 infection suffer from multiple lung inflammation-induced complications that lead to disability and even death. The lung-bone axis refers to the relationship between lung inflammatory diseases (COPD, asthma, and cystic fibrosis) and bone diseases, including osteopenia/osteoporosis. Compared to chronic lung diseases, the influence of ALI on the skeleton has not been investigated until now. Therefore, we investigated the effect of ALI on bone phenotypes in mice to elucidate the underlying mechanisms. In vivo bone resorption enhancement and trabecular bone loss were observed in LPS-induced ALI mice. Moreover, chemokine (C-C motif) ligand 12 (CCL12) accumulated in the serum and bone marrow. In vivo global ablation of CCL12 or conditional ablation of CCR2 in bone marrow stromal cells (BMSCs) inhibited bone resorption and abrogated trabecular bone loss in ALI mice. Furthermore, we provided evidence that CCL12 promoted bone resorption by stimulating RANKL production in BMSCs, and the CCR2/Jak2/STAT4 axis played an essential role in this process. Our study provides information regarding the pathogenesis of ALI and lays the groundwork for future research to identify new targets to treat lung inflammation-induced bone loss.

ObjectiveThe purpose of this study was to analyze the clinical effect of percutaneous endoscopic medial foraminal discectomy (PEMFD) in the treatment of lumbar disc herniation (LDH).MethodsWe retrospectively examined and compared clinical data from 39 single-level LDH patients who underwent PEID and 47 who underwent PEMFD. All the patients were diagnosed with single-level LDH and were treated in Xuzhou Central Hospital for single-segmental lumbar disc herniation between June 2017 and December 2019. Collect and count surgical-related indicators, intraoperative bleeding volume and 24-hour postoperative drainage volume, lower extremity numbness Visual Analogue Scale (VAS), the pain VAS and lumbar Oswestry Disability Index (ODI) scores.ResultsIntraoperative bleeding volume and 24-hour postoperative drainage volume were significantly lower in the PEMFD group (p

Abstract Background Accumulating studies indicates that microRNAs (miRNAs) play vital roles in the process of development and progression of many human complex diseases. However, traditional biochemical experimental methods for identifying disease-related miRNAs cost large amount of time, manpower, material and financial resources. Methods In this study, we developed a framework named hybrid collaborative filtering for miRNA-disease association prediction (HCFMDA) by integrating heterogeneous data, e.g., miRNA functional similarity, disease semantic similarity, known miRNA-disease association networks, and Gaussian kernel similarity of miRNAs and diseases. To capture the intrinsic interaction patterns embedded in the sparse association matrix, we prioritized the predictive score by fusing three types of information: similar disease associations, similar miRNA associations, and similar disease-miRNA associations. Meanwhile, singular value decomposition was adopted to reduce the impact of noise and accelerate predictive speed. Results We then validated HCFMDA with leave-one-out cross-validation (LOOCV) and two types of case studies. In the LOOCV, we achieved 0.8379 of AUC (area under the curve). To evaluate the performance of HCFMDA on real diseases, we further implemented the first type of case validation over three important human diseases: Colon Neoplasms, Esophageal Neoplasms and Prostate Neoplasms. As a result, 44, 46 and 44 out of the top 50 predicted disease-related miRNAs were confirmed by experimental evidence. Moreover, the second type of case validation on Breast Neoplasms indicates that HCFMDA could also be applied to predict potential miRNAs towards those diseases without any known associated miRNA. Conclusions The satisfactory prediction performance demonstrates that our model could serve as a reliable tool to guide the following research for identifying candidate miRNAs associated with human diseases.

To respond to emergencies in a timely manner, emergency engineering equipment has been an important tool to implement emergency strategies. However, random failures of the equipment may occur during operation. Therefore, appropriate maintenance and spare parts inventory strategies are crucial to ensure the smooth operation of the equipment. Furthermore, the urgency degree of emergencies varies in practice. Nevertheless, existing studies rarely consider the impact of urgency degree and demand priorities on the service order of the equipment. To bridge the research gaps, this paper establishes a joint optimization model of maintenance and spare parts inventory strategies for emergency engineering equipment considering demand priorities. The proposed model includes two types of emergency engineering equipment with different service rates. The more urgent demand can be fulfilled by the equipment with a higher priority. Corrective maintenance and spare parts inventory policies are simultaneously performed for the equipment. The Markov process imbedding method is utilized to derive the probabilistic indexes of the system. To maximize the system availability, the number of maintenance engineers and the spare parts inventory strategy is optimized via the construction of the joint optimization model. The optimal solution for the optimization problem is obtained using the branch-and-bound method. Finally, this study presents practical examples to verify the effectiveness of the model and methods.

Abstract Background Trachypithecus leucocephalus, the white-headed langur, is a critically endangered primate that is endemic to the karst mountains in the southern Guangxi province of China. Studying the genomic and transcriptomic mechanisms underlying its local adaptation could help explain its persistence within a highly specialized ecological niche. Results In this study, we used PacBio sequencing and optical assembly and Hi-C analysis to create a high-quality de novo assembly of the T. leucocephalus genome. Annotation and functional enrichment revealed many genes involved in metabolism, transport, and homeostasis, and almost all of the positively selected genes were related to mineral ion binding. The transcriptomes of 12 tissues from three T. leucocephalus individuals showed that the great majority of genes involved in mineral absorption and calcium signaling were expressed, and their gene families were significantly expanded. For example, FTH1 primarily functions in iron storage and had 20 expanded copies. Conclusions These results increase our understanding of the evolution of alkali tolerance and other traits necessary for the persistence of T. leucocephalus within an ecologically unique limestone karst environment.

Accident causal scenario can describe the process logic of the accident clearly and concretely from the perspective of the control mechanism. Only by improving the quality of the causal scenario can the effective control measures be taken. Combining the technical characteristics of the fully automatic operation (FAO) system, the paper proposes an automated accident causal scenario identification method for FAO system based on the System-Theoretic Process Analysis (STPA) method. Aiming at the problem that there are too many layers in the hierarchical control structure diagram of STPA method, which makes it impossible to effectively trace the cause and the problem that the basic control structure model only contains the control structural information and lacks the cause information, a new basic control structure model is defined to model multiple control processes in time sequence, and then the paper extends it from four aspects: control action, input variables, external disturbance, and synchronous timing to add more system cause information. For the lack of a unified standard description problem for the causal scenario, a four-stage causal scenario description method is defined, this paper has developed the first timing, non-first timing, synchronous timing, and external disturbance causal scenario search rules to ensure the automatic identification of the causal scenarios. Applying the automated safety analysis method to the case study of the operational scenarios of parking in a station of Beijing Yanfang Line, the automated identification of related causal scenarios is successfully completed through the Auto-STPA platform, and corresponding safety requirements are added. The feasibility of the method and the applicability to the analysis of operational scenarios are verified.

Deoxyribonucleic acid (DNA) methylation is an important epigenetic mark involved in diverse biological processes. Here, we report the critical function of tomato (Solanum lycopersicum) Domains Rearranged Methyltransferase7 (SlDRM7) in plant growth and development, especially in leaf interveinal chlorosis and senescence. Using a hairpin RNA-mediated RNA interference (RNAi), we generated SlDRM7-RNAi lines and observed pleiotropic developmental defects including small and interveinal chlorosis leaves. Combined analyses of whole genome bisulfite sequence (WGBS) and RNA-seq revealed that silencing of SlDRM7 caused alterations in both methylation levels and transcript levels of 289 genes, which are involved in chlorophyll synthesis, photosynthesis, and starch degradation. Furthermore, the photosynthetic capacity decreased in SlDRM7-RNAi lines, consistent with the reduced chlorophyll content and repression of genes involved in chlorophyll biosynthesis, photosystem, and photosynthesis. In contrast, starch granules were highly accumulated in chloroplasts of SlDRM7-RNAi lines and associated with lowered expression of genes in the starch degradation pathway. In addition, SlDRM7 was activated by aging- and dark-induced senescence. Collectively, these results demonstrate that SlDRM7 acts as an epi-regulator to modulate the expression of genes related to starch and chlorophyll metabolism, thereby affecting leaf chlorosis and senescence in tomatoes.

The mechanisms associated with the regulation of iron (Fe) homeostasis have been extensively examined, however, epigenetic regulation of these processes remains largely unknown. Here, we report that a naturally occurring epigenetic mutant, Colorless non-ripening (Cnr), displayed increased Fe-deficiency responses compared to its wild-type Ailsa Craig (AC). RNA-sequencing revealed that a total of 947 and 1,432 genes were up-regulated by Fe deficiency in AC and Cnr roots, respectively, while 923 and 1,432 genes were, respectively, down-regulated. Gene ontology analysis of differentially expressed genes showed that genes encoding enzymes, transporters, and transcription factors were preferentially affected by Fe deficiency. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed differential metabolic responses to Fe deficiency between AC and Cnr. Based on comparative transcriptomic analyses, 24 genes were identified as potential targets of Cnr epimutation, and many of them were found to be implicated in Fe homeostasis. By developing CRISPR/Cas9 genome editing SlSPL-CNR knockout (KO) lines, we found that some Cnr-mediated Fe-deficiency responsive genes showed similar expression patterns between SlSPL-CNR KO plants and the Cnr epimutant. Moreover, both two KO lines displayed Fe-deficiency-induced chlorosis more severe than AC plants. Additionally, the Cnr mutant displayed hypermethylation in the 286-bp epi-mutated region on the SlSPL-CNR promoter, which contributes to repressed expression of SlSPL-CNR when compared with AC plants. However, Fe-deficiency induced no change in DNA methylation both at the 286-bp epi-allele region and the entire region of SlSPL-CNR gene. Taken together, using RNA-sequencing and genetic approaches, we identified Fe-deficiency responsive genes in tomato roots, and demonstrated that SlSPL-CNR is a novel regulator of Fe-deficiency responses in tomato, thereby, paving the way for further functional characterization and regulatory network dissection.

In order to understand the new-old asphalt diffusion behavior, use the Materials Studio (MS) molecular dynamic simulation software to build a matrix asphalt and aging asphalt molecular model based on the average molecular model of the asphalt, and select the appropriate force field and potential energy function. As well as parameters such as boundary conditions, set up as-phalt-regenerative dot-shaped contact models and laminar contact models. From the perspective of molecular perspectives, the diffusion behavior between the old and new asphalt and the re-generative agent is analyzed. The promotion effect of the asphalt diffusion behavior, the simulation results show that the asphalt's internal diffusion process is mutual, and the promotion effect of aromatherapy regeneratives on the spread of new and old asphalt under the same conditions is better than chain regenerative agents and waste oil regeneration agents.

Abstract Background The interactions among proteins act as crucial roles in most cellular processes. Despite enormous effort put for identifying protein-protein interactions (PPIs) from a large number of organisms, existing firsthand biological experimental methods are high cost, low efficiency, and high false-positive rate. The application of in silico methods opens new doors for predicting interactions among proteins, and has been attracted a great deal of attention in the last decades. Results Here we present a novelty computational model with the adoption of our proposed Discriminative Vector Machine (DVM) model and a 2-Dimensional Principal Component Analysis (2DPCA) descriptor to identify candidate PPIs only based on protein sequences. To be more specific, a 2DPCA descriptor is employed to capture discriminative feature information from Position-Specific Scoring Matrix (PSSM) of amino acid sequences by the tool of PSI-BLAST. Then, a robust and powerful DVM classifier is employed to infer PPIs. When applied on both gold benchmark datasets of Yeast and H. pylori, our model obtained mean prediction accuracies as high as of 97.06 and 92.89%, respectively, which demonstrates a noticeable improvement than some state-of-the-art methods. Moreover, we constructed Support Vector Machines (SVM) based predictive model and made comparison it with our model on Human benchmark dataset. In addition, to further demonstrate the predictive reliability of our proposed method, we also carried out extensive experiments for identifying cross-species PPIs on five other species datasets. Conclusions All the experimental results indicate that our method is very effective for identifying potential PPIs and could serve as a practical approach to aid bioexperiment in proteomics research.