The rising roles of exosomes in the tumor microenvironment reprogramming and cancer immunotherapy.

Exosomes are indispensable for intercellular communications. Tumor microenvironment (TME) is the living environment of tumor cells, which is composed of various components, including immune cells. Based on TME, immunotherapy has been recently developed for eradicating cancer cells by reactivating antitumor effect of immune cells. The communications between tumor cells and TME are crucial for tumor development, metastasis, and drug resistance. Exosomes play an important role in mediating these communications and regulating the reprogramming of TME, which affects the sensitivity of immunotherapy. Therefore, it is imperative to investigate the role of exosomes in TME reprogramming and the impact of exosomes on immunotherapy. Here, we review the communication role of exosomes in regulating TME remodeling and the efficacy of immunotherapy, as well as summarize the underlying mechanisms. Furthermore, we also introduce the potential application of the artificially modified exosomes as the delivery systems of antitumor drugs. Further efforts in this field will provide new insights on the roles of exosomes in intercellular communications of TME and cancer progression, thus helping us to uncover effective strategies for cancer treatment.

Deep Reinforcement Learning for Integration of Train Trajectory Optimization and Timetable Rescheduling Under Disturbances.

High-speed trains are susceptible to unexpected events such as strong winds and equipment failures, which can result in deviations from the scheduled timetable. As the density of traffic increases, these delays can quickly spread to other trains, eventually leading to conflicts in the timetable. To ensure the efficiency of high-speed railways, quickly resolving potential conflicts and generating appropriate rescheduling schemes are essential. The existing hierarchical structure of train control and online rescheduling tends to be inefficient in terms of information communication and can even lead to unfeasible rescheduled timetables and trajectories. To address these issues, an integrated structure of timetable rescheduling and train trajectory optimization is proposed by introducing the train minimum running time into the process of timetable rescheduling and using the adjusted running time as the objective of trajectory optimization. The integration model is formulated by considering the constraints of timetable rescheduling such as the maximum number of trains overtaking trains, platforms at stations, and the priority of the train, as well as the constraints of trajectory optimization. A deep reinforcement learning (DRL)-based approach is proposed to solve the problem. Numerical experiments are conducted on a segment of the Beijing-Shanghai high-speed railway line, using adapted data to demonstrate the effectiveness of the proposed method in rescheduling timetables and optimizing train trajectories. The results show that the integrated rescheduled timetable and the optimized train trajectory can be generated simultaneously and the computation time exhibits a linear increase with respect to the size of the problem.

RNA N6-methyladenosine demethylase FTO targets MOXD1 promoting the malignant phenotype of gastric cancer.

BACKGROUND: The m6A modified demethylase FTO affects the progression of gastric cancer (GC), and the role mechanism of FTO in GC is still unclear. We, here, explored the role of FTO and unrevealed the mechanisms of its function in GC. METHODS: The expression and clinical prognosis of FTO in GC were examined via UALCAN and GEPIA online databases. Effect of FTO shRNA on GC cellular malignant phenotype were proved by CCK-8, Transwell, Wound healing assay and Flow cytometric assay. RNA-sequencing data of FTO depleted AGS cells were downloaded to analyze differentially expressed genes of FTO downstream. The GO and KEGG pathway enrichment were performed for the DEGs by DAVID. RT-qPCR and RIP-qPCR assay were applied to verify the MOXD1 mRNA and methylated mRNA in FTO shRNA group. The expression and clinical prognosis of MOXD1 in GC were explored via UALCAN, GEPIA and Kaplan-Meier plotter. The role and mechanism and of MOXD1 in GC cell lines were detected and analyzed. RESULTS: The expression of FTO was found to be elevated in GC tissues compared with normal tissues, and worse survival were strongly related to high expression of FTO in GC. FTO silencing suppressed the proliferation, migration and promoted apoptosis of GC cells. A total of 5856 DEGs were obtained in between NC and FTO depleted AGS cell groups, and involved in the cancer related pathways. Here, FTO targets MOXD1 mRNA and promotes its expression via m6A methylation. MOXD1 upregulation was associated to poor prognosis of GC. MOXD1 silencing suppressed the malignant phenotype of GC cells. MOXD1 activated cancer -related signaling pathway (MAPK, TGF-ß, NOTCH and JAK/STAT). CONCLUSIONS: Our study demonstrated that FTO silencing decreased MOXD1 expression to inhibit the progression of GC via m6A methylation modification. FTO/MOXD1 may be potential targets for the treatment and prognosis of GC.

Causes of Lower Respiratory Tract Infections and the Use of Diagnostic Biomarkers in Blood Samples from Children in Hohhot, Inner Mongolia, China, Between July 2019 and June 2020.

BACKGROUND Lower respiratory tract infection (LRTI) in children is due to various pathogens. Appropriate diagnosis and early treatment are important for reducing the mortality rate of LRTI. Data on the epidemiology profiles of LRTI are scarce in northern China. The aim of this study was to provide data on the pathogen pattern of LRTI in hospitalized children in Hohhot, Inner Mongolia, China. MATERIAL AND METHODS From July 2019 to June 2020, nasopharyngeal swabs were collected from 265 children in Hohhot with LRTI, and pathogens were detected with RT-PCR and PCR. The correlations among procalcitonin (PCT), C-reactive protein (CRP), and white blood cells (WBC) with acute respiratory infections were evaluated. RESULTS The highest prevalence of LRTI was detected in 2- to 6-year-old children (149, 56.2%) in winter. Eleven respiratory pathogens were evaluated, and respiratory syncytial virus, Streptococcus pneumoniae and Haemophilus influenza were the most common pathogens in this region. Single viruses, bacteria, mycoplasma, and multiple pathogens were identified in 24.2, 15.8, 5.3, and 54.7% of patients, respectively. The mean blood biomarker values of patients with LRTI were significantly different from those of healthy children. Furthermore, The AUCs were 0.90, 0.74, and 0.84 for bacteria, virus, and mycoplasma PCT values, which were significantly higher than that of WBC and CRP. CONCLUSIONS This evaluation of the regional pattern of pathogens in children with acute respiratory infections and the correlation with blood biomarkers provides valuable information for the prevention and treatment of LRTI in children.

Consensus for Second-Order Discrete-Time Agents With Position Constraints and Delays.

This article addresses a consensus problem of second-order discrete-time agents in general directed networks with nonuniform position constraints, switching topologies, and communication delays. A projection operation is performed to ensure the agents stay in some given convex sets, and a distributed algorithm is employed for the consensus achievement of all agents. The analysis approach is to use a linear transformation to convert the original system into an equivalent system and then merge the nonlinear error term into the convex null of the agents' states so as to prove the consensus convergence of the system based on the properties of the non-negative matrices. It is shown that all agents finally converge to a consensus point while their positions stay in the corresponding constraint sets as long as the union of the communication graphs among each certain time interval is strongly connected even when the communication delays are considered. Finally, numerical simulation examples are given to show the theoretical results.

Prevalence, awareness, treatment, and control of hypertension in Northern China: a cross-sectional study.

BACKGROUND: Hypertension has always been a worldwide health concern. The purpose of this study was to investigate the prevalence, awareness, treatment, and control rates of hypertension among adult residents of northern China, where people usually have a high-fat, high-salt diet and heavy alcohol consumption. METHODS: Through the Early Screening and Comprehensive Intervention Project for High Risk Groups of Cardiovascular Diseases in the Inner Mongolia of northern China, we collected data of 70,380 residents, from September 2015 to June 2017. We assessed the prevalence, awareness, treatment, and control of hypertension in the total population and sub-populations. Multivariable logistic regression analyses were used to identify the factors associated with the prevalence and control of hypertension. RESULTS: Among participants, only 13.4% had optimal blood pressure levels. About 55.7% (95% confidence interval (CI) = 55.3-56.1%) of the participants had hypertension. In addition, the awareness, treatment, control and control under-treatment rate of hypertension were 52.8% (95%CI = 52.3-53.3%), 43.3% (95%CI = 42.8-43.8%), 8.6% (95%CI = 8.3-8.9%) and 19.8% (95%CI = 19.2-20.4%), respectively. Multivariable logistic regression showed that older, male, Han, living in rural areas, current drinker, not married, lower educational level, lower annual income, diabetes, obesity, and dyslipidemia were more likely to be suffered from hypertension (P < 0.05). Controlled hypertension was less common in those younger, Mongol, not married, farmer, current drinker, lower educational level, obesity, diabetes, without prior CHD, and without prior CVD (P < 0.05). CONCLUSION: Among populations aged 35-75 years in Northern China, more than half have hypertension, fewer than one-tenth have successfully controlled hypertension, and fewer than one-fifth of hypertension patients receiving treatment have controlled hypertension.

The complete mitochondrial genome of Metidiocerus sp. (Hemiptera: Cicadellidae: Idiocerinae).

The species Metidiocerus sp. belonging to the subfamily Idiocerinae (Hemiptera, Cicadellidae). Here, we sequenced and annotated the mitochondrial genome (mitogenome) of Metidiocerus sp. This mitogenome was 15,079 bp long and encoded 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), and 2 ribosomal RNA unit genes (rRNAs), and one non-coding region. The nucleotide composition biases toward A and T, which together made up 77.4% of the entirety. All 13 PCGs were initiated by the ATN (ATG, ATT, ATA, and ATC) codon. All PCGs terminate with the stop codons TAA except for COX2, ND4, and ND1 ended with single T. A phylogenetic tree generated by the Bayesian method showed that Metidiocerus sp. is closely related to Idiocerus salicis and Idiocerus herrichii which enriched the mitochondrial genome data of Idiocerinae.

Complete mitochondrial genome of Populicerus confusus (Hemiptera: Cicadellidae: Idiocerinae).

In this study, we firstly reported the complete mitochondrial genome of Populicerus confuses. The complete mitochondrial genome was 16,395 bp in length which overall base composition was 41.43% A, 36.30% T, 11.54% C, and 10.73% G. It consisted of 13 protein-coding genes (PCGs), 22 tRNA genes, 2 rRNA genes (12S and 16S rRNA), and a control region (D-loop region). The complete mitochondrial genomes of P. confuses and other 9 species were used for phylogenetic analysis using the Bayesian method. The resulting phylogenetic tree confirms that the Populicerus populi is most closely related to P. confuses. The mitogenome provided the valuable evidence on phylogenetic relationship of the Idiocerinae at the molecular level.

Association between carotid plaque and Parkinson's disease.

BACKGROUND: Epidemiological studies show that patients with Parkinson's disease (PD) are prone to have a reduced incidence of ischemic cerebrovascular disease. Previous studies show the correlation between PD and the lipids serum levels. The PD,s patients are found with a reduced serum level of triglyceride and low-density lipoprotein cholesterol (LDL-C); thus, the level of serum uric acid (UA) is closely related to the occurrence and development of PD. Patients with low serum UA levels have a higher chance of developing PD than the ones who do not. However, the relationship between carotid plaques and PD is still unknown. METHODS: Our study was based on 68 patients with PD (known as the PD group) and 81 people without PD (known as the control group). Patients in the PD group were of the same age and gender. Both groups were recorded and analyzed for UA, LDL-C, and carotid plaques or intima-media thickness (IMT). The PD group was then divided into three subgroups: the stable plaque group, the unstable plaque group, and the non-plaque group. RESULTS: In the present study, the PD group showed a significantly lower level of UA and LDL-C than the control group (P<0.01); somehow there were no statistically significant differences in the IMT and plaque incidence between the two groups (P>0.05). There were also no significant differences (P>0.05) in both the LDL-C and UA levels in all subgroups, but there was a close relation in both age and duration of disease to IMT. According to the Hoehn and Yahr staging scale, serum levels of LDL-C were inversely correlated in PD patients, while UA was related to the duration of the disease. CONCLUSIONS: Our study suggested that there were no differences in carotid artery arteriosclerosis plaque and IMT, but the PD progress was indeed correlated with IMT. Meanwhile, LDL-C and UA had different priorities in H&Y and disease progression.

Parallel Intelligent Systems for Integrated High-Speed Railway Operation Control and Dynamic Scheduling.

The information exchange gap between current operation control and dynamic scheduling in high-speed railway systems (HRSs) still exists, and this gap has hindered the further integrative improvement of HRSs. This paper aims to explore a feasible solution to bridging the information exchange gap for further improving the efficiency of HRSs, with the parallel intelligent systems for integrated HRS operation control and dynamic scheduling first analyzed and constructed using the ACP approach, that is, "artificial systems" (A), "computational experiments," (C) and "parallel execution" (P). Then, on the basis of the constructed parallel intelligent systems, experiments on several typical scenarios in HRSs are conducted to achieve a set of control and management strategies for actual HRSs. Experimental results show that a number of powerful tools provided by the proposed parallel intelligent systems can be utilized not only to study the current HRSs, but also to further undertake research on integrated operation control and dynamic scheduling for HRSs.

Robust fault detection for the dynamics of high-speed train with multi-source finite frequency interference.

This paper proposes a composite fault detection scheme for the dynamics of high-speed train (HST), using an unknown input observer-like (UIO-like) fault detection filter, in the presence of wind gust and operating noises which are modeled as disturbance generated by exogenous system and unknown multi-source disturbance within finite frequency domain. Using system input and system output measurements, the fault detection filter is designed to generate the needed residual signals. In order to decouple disturbance from residual signals without truncating the influence of faults, this paper proposes a method to partition the disturbance into two parts. One subset of the disturbance does not appear in residual dynamics, and the influence of the other subset is constrained by H∞ performance index in a finite frequency domain. A set of detection subspaces are defined, and every different fault is assigned to its own detection subspace to guarantee the residual signals are diagonally affected promptly by the faults. Simulations are conducted to demonstrate the effectiveness and merits of the proposed method.

Robust Consensus of Nonlinear Multiagent Systems With Switching Topology and Bounded Noises.

Consensus of multiagent systems (MASs) is an intriguing topic in recent years due to its widely used application in robotics, biology, computer, and social science. In the real world, the evolution of MAS is inevitably involved in dynamical environments and the recent development of MAS calls for novel tools for the analysis of MAS with dynamic topology. In addition, the interactions between agents are generally nonlinear and environmental noises are ubiquitous in the communication channels between agents. However, the existing investigation on MAS places little attention on nonlinear models and the inner relationship between external disturbance and consensus is still unclear. Facing these problems, this paper considers an MAS in which the interactions between agents are nonlinear and the communication between agents are infected by environmental noises. By using a novel method of nonsmooth Lyapunov candidate, it has been demonstrated that such an MAS can realize robust consensus under the conditions of jointly (sequentially) connected topology and bounded noises. Finally, simulation results validate the effectiveness of these criteria.

Association of polymorphism in rs2736990 of the α-synuclein gene with Parkinson's disease in a Chinese population.

BACKGROUND AND OBJECTIVE: Previous genetic studies in Parkinson's disease (PD) have provided conclusive evidence for association of genes with strong biological rationale for PD. Recently several studies in different populations have found a strong association between idiopathic PD and the single-nucleotide polymorphism (SNP) rs2736990, located within an intron of the α-synuclein (SNCA) gene. In this study, we aimed to verify these findings and to explore the characteristic of the association in a subset of Chinese Han PD patients. MATERIALS AND METHODS: A total of 515 unrelated patients with sporadic PD and 450 healthy ethnically matched control subjects were recruited consecutively for the study. Patients and healthy controls were genotyped for SNCA rs2736990 variant by polymerase chain reaction - ligase detection reaction. RESULTS: Our data showed a significant association between the rs2736990 polymorphism and PD, the frequency of the allele C in PD patients was significantly higher than that in controls (P = 0.017, OR = 1.26, 95% confident intervals (CI) =1.04-1.51). The distribution of C > T genotypes was different between patients and controls (P = 0.027). Furthermore, allele C of SNP rs2736990 in early-onset PD was significantly more frequent than that in healthy controls (P = 0.007, odds ratio = 1.60, 95% CI = 1.13-2.26). CONCLUSIONS: Our study demonstrated that SNCA rs2736990 C > T polymorphism was associated with susceptibility to PD in Chinese Han population. Further studies are needed to replicate the association we found.

Advanced intimal hyperplasia without luminal narrowing of leptomeningeal arteries in CADASIL.

BACKGROUND AND PURPOSE: Leptomeningeal artery abnormalities in Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) have not been extensively characterized. We quantified substructure and diameter of leptomeningeal arteries in CADASIL compared with age-matched controls and the very old; in addition, we characterized intimal thickening in CADASIL using immunohistochemistry. METHODS: Frontal and temporal cortex of 6 genetically proven CADASIL brains (average age, 66 years), 6 controls without symptoms of cerebrovascular disease, and 6 very old brains (average age, 89 years) were examined for leptomeningeal artery intimal, medial, and adventitial thickness; inner diameter; and sclerotic index and for smooth muscle markers. RESULTS: The intima of CADASIL arteries was thickened 5-fold compared with controls and the very aged (P<0.0001). Medial thickness was lower in CADASIL compared with controls and the very old (P<0.01). The adventitia was not significantly increased in CADASIL compared with age-matched controls. Arterial diameters were not smaller in CADASIL compared with controls. Sclerotic index was significantly increased in CADASIL compared with other groups (P<0.00001). Intimal cells in CADASIL expressed smooth muscle actin, S100A4, and vimentin but not desmin. CONCLUSIONS: Principle changes of leptomeningeal arteries in CADASIL include intimal thickening and medial thinning, but not luminal narrowing. Smooth muscle-like cells participate in neointimal thickening of CADASIL arteries.

Bidirectional encroachment of collagen into the tunica media in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Arteries in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are susceptible to smooth muscle loss and fibrosis, but the molecular components underlying these dramatic vascular changes are not well characterized. The purpose of this study was to investigate the distribution of collagen isoforms in the cerebral vessels of North American CADASIL patients with classical NOTCH3 mutations. Expression of types I-VI collagen in brains obtained at autopsy from six CADASIL patients with cysteine-altering mutations in NOTCH3 was compared to control brain expression. We identified a consistent increase of types I, III, IV, and VI collagen in CADASIL brains. Strong accumulation of types I, III, IV and VI collagen was noted in all calibers of vessels, including small and medium-sized leptomeningeal arteries, small penetrating white matter arteries, and capillaries. Within leptomeningeal arteries, where we could define the three tunicae of each vessel, we found distinct collagen subtype distribution patterns in CADASIL. Types I and III collagen were largely found in either adventitial/medial or transmural locations. Type IV collagen was strictly intimal/medial. Type VI collagen was adventitial or adventitial/medial. Within the thickened penetrating arteries of CADASIL patients, all four collagens extended through most of the arterial wall. We observed increased staining of capillaries in CADASIL for types I, IV, and VI collagen. In conclusion, brain vascular collagen subtypes are increased in CADASIL in multiple layers of all sizes of arteries, with disease-specific changes most prominent in the tunica media and thickened small penetrating vessels. In diseased arteries, types I, III, and VI collagen spreads from an external location (adventitia) into the vascular media, while type IV collagen accumulates in an internal pattern (intima and media). These observations are consistent with a pathological role for collagen accumulation in the vascular media in CADASIL.

SNP rs356219 of the α-synuclein (SNCA) gene is associated with Parkinson's disease in a Chinese Han population.

BACKGROUND: Over the last decades, increasing knowledge about the genetic architecture of Parkinson's disease(PD) has provided novel insights into the pathogenesis of the disorder. Recently, several studies in different populations have found a strong association between idiopathic PD and the single-nucleotide polymorphism (SNP) rs356219, which is located in the 3'UTR of the SNCA gene. In this study, we aimed to verify these findings and to explore further the nature of the association in a subset of Chinese Han PD patients. METHODS: Four hundred and three unrelated patients with sporadic PD and 315 healthy ethnically matched control subjects were recruited consecutively for the study. Patients and normal controls were genotyped for SNCA rs356219 variant by ligase detection reaction (LDR). RESULTS: A statistically significant difference was found in the frequencies of the single alleles of rs356219 (χ(2) = 12.986,P = 0.002) between PD patients and normal subjects. The distribution of A > G genotypes was different between patients and controls (χ(2) = 13.243, P < 0.001). The OR for subjects with the variant genotypes (AG and GG) was 1.88 (95%CI = 1.27-2.78, P = 0.001). The frequencies of the homozygous genotype for this variant was 42.2% (170 patients), which was significantly higher than that in controls (32.4%, P < 0.001). CONCLUSION: The results suggested that SNCA rs356219 variant might have an increased risk of susceptibility to PD in a Chinese Han population. Further studies are needed to replicate the association that we found.

RAD51 135G>C polymorphism contributes to breast cancer susceptibility: a meta-analysis involving 26,444 subjects.

RAD51 plays a key role in homologous recombination repair of double-stranded DNA breaks which may cause chromosomal breaks and genomic instability. We performed a meta-analysis of 9 epidemiological studies involving 13,241 cases and 13,203 controls that examined the association between RAD51 135G>C polymorphism and breast cancer. No significant association of RAD51 135G>C polymorphism with breast cancer was found in overall and European populations. However, after the studies which did not fulfill Hardy-Weinberg equilibrium were excluded, we observed an overall significant increased breast cancer risk (for the recessive model CC vs. GG/CG: OR = 1.35, 95% CI = 1.05-1.74, P (heterogeneity) = 0.06). In summary, our meta-analysis suggested the RAD51 135G > C polymorphism may contribute to breast cancer susceptibility.

[Correlation study of semaphorin 5a with risk of Parkinson's disease in a Chinese Han population].

OBJECTIVE: To investigate the relationship of Semaphorin 5A (SEMA5A) and risk of Parkinson's disease (PD). METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to check two single nucleotide polymorphisms (SNPs) within SEMA5A in 244 PD patients and 174 healthy control subjects of Chinese Han ancestry. And the results were verified by gene sequencing. RESULTS: The SEMA5A variant genotype (allele) of rs7702187 and rs3798097 had no correlation with the risk of PD in the samples (rs7702187: OR(genotype AT) 0.95, 95% CI 0.61-1.48, OR (genotype AA) = 1.84, 95% CI 0.85-3.99, OR(genotype AT + AA) = 1.21, 95% CI 0.82-1.77, P > 0.05; rs3798097: OR(genotype CT) = 1.06, 95% CI 0.62-1.79, OR(genotype TT) = 0.72, 95% CI 0.10-5.18, OR(genotype CT + T) = 1.01, 95% CI 0.62-1.67, P > 0.05). Comparing with the most common haplotype TC, neither AC haplotype nor TT haplotype showed any correlation with risk of PD (OR = 1.19, 95% CI 0.84-1.69 for AC haplotype P > 0.05; OR = 0.99, 95% CI 0.59-1.70 for TT haplotype, P > 0.05). CONCLUSION: SEMA5A is not implicated in PD risk in a Chinese Han population.

A novel P755L mutation in LRRK2 gene associated with Parkinson's disease.

Parkinson's disease is a common neurodegenerative disorder. The identification of leucine-rich repeat kinase 2 (LRRK2) gene mutations as a cause of Parkinson's disease has greatly expanded our knowledge of the genetic and molecular pathogenesis of this disorder. By denaturing high-performance liquid chromatography and gene sequencing in patients and controls, we identified a novel frequent heterozygous 2264C-->T substitution, which causes a proline-to-leucine mutation (P755L) in LRRK2 gene. In our sample of 598 patients of Chinese Han ancestry, 12 cases carried the same LRRK2 mutation. Our results indicated that this single mutation was implicated in 2% of sporadic patients. We suggest that testing for this mutation will be important in the management and genetic counseling of patients with Parkinson's disease.