Bilateral Deep Reinforcement Learning Approach for Better-than-human Car Following Model

In the coming years and decades, autonomous vehicles (AVs) will become increasingly prevalent, offering new opportunities for safer and more convenient travel and potentially smarter traffic control methods exploiting automation and connectivity. Car following is a prime function in autonomous driving. Car following based on reinforcement learning has received attention in recent years with the goal of learning and achieving performance levels comparable to humans. However, most existing RL methods model car following as a unilateral problem, sensing only the vehicle ahead. Recent literature, however, Wang and Horn [16] has shown that bilateral car following that considers the vehicle ahead and the vehicle behind exhibits better system stability. In this paper we hypothesize that this bilateral car following can be learned using RL, while learning other goals such as efficiency maximisation, jerk minimization, and safety rewards leading to a learned model that outperforms human driving. We propose and introduce a Deep Reinforcement Learning (DRL) framework for car following control by integrating bilateral information into both state and reward function based on the bilateral control model (BCM) for car following control. Furthermore, we use a decentralized multi-agent reinforcement learning framework to generate the corresponding control action for each agent. Our simulation results demonstrate that our learned policy is better than the human driving policy in terms of (a) inter-vehicle headways, (b) average speed, (c) jerk, (d) Time to Collision (TTC) and (e) string stability

Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor

After birth, cardiomyocytes (CM) acquire numerous adaptations in order to efficiently pump blood throughout an animal’s lifespan. How this maturation process is regulated and coordinated is poorly understood. Here, we perform a CRISPR/Cas9 screen in mice and identify serum response factor (SRF) as a key regulator of CM maturation. Mosaic SRF depletion in neonatal CMs disrupts many aspects of their maturation, including sarcomere expansion, mitochondrial biogenesis, transverse-tubule formation, and cellular hypertrophy. Maintenance of maturity in adult CMs is less dependent on SRF. This stage-specific activity is associated with developmentally regulated SRF chromatin occupancy and transcriptional regulation. SRF directly activates genes that regulate sarcomere assembly and mitochondrial dynamics. Perturbation of sarcomere assembly but not mitochondrial dynamics recapitulates SRF knockout phenotypes. SRF overexpression also perturbs CM maturation. Together, these data indicate that carefully balanced SRF activity is essential to promote CM maturation through a hierarchy of cellular processes orchestrated by sarcomere assembly

Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor

After birth, cardiomyocytes (CM) acquire numerous adaptations in order to efficiently pump blood throughout an animal’s lifespan. How this maturation process is regulated and coordinated is poorly understood. Here, we perform a CRISPR/Cas9 screen in mice and identify serum response factor (SRF) as a key regulator of CM maturation. Mosaic SRF depletion in neonatal CMs disrupts many aspects of their maturation, including sarcomere expansion, mitochondrial biogenesis, transverse-tubule formation, and cellular hypertrophy. Maintenance of maturity in adult CMs is less dependent on SRF. This stage-specific activity is associated with developmentally regulated SRF chromatin occupancy and transcriptional regulation. SRF directly activates genes that regulate sarcomere assembly and mitochondrial dynamics. Perturbation of sarcomere assembly but not mitochondrial dynamics recapitulates SRF knockout phenotypes. SRF overexpression also perturbs CM maturation. Together, these data indicate that carefully balanced SRF activity is essential to promote CM maturation through a hierarchy of cellular processes orchestrated by sarcomere assembly

Global burden of chronic respiratory diseases and risk factors, 1990–2019: an update from the Global Burden of Disease Study 2019

Background: Updated data on chronic respiratory diseases (CRDs) are vital in their prevention, control, and treatment in the path to achieving the third UN Sustainable Development Goals (SDGs), a one-third reduction in premature mortality from non-communicable diseases by 2030. We provided global, regional, and national estimates of the burden of CRDs and their attributable risks from 1990 to 2019. Methods: Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we estimated mortality, years lived with disability, years of life lost, disability-adjusted life years (DALYs), prevalence, and incidence of CRDs, i.e. chronic obstructive pulmonary disease (COPD), asthma, pneumoconiosis, interstitial lung disease and pulmonary sarcoidosis, and other CRDs, from 1990 to 2019 by sex, age, region, and Socio-demographic Index (SDI) in 204 countries and territories. Deaths and DALYs from CRDs attributable to each risk factor were estimated according to relative risks, risk exposure, and the theoretical minimum risk exposure level input. Findings: In 2019, CRDs were the third leading cause of death responsible for 4.0 million deaths (95% uncertainty interval 3.6–4.3) with a prevalence of 454.6 million cases (417.4–499.1) globally. While the total deaths and prevalence of CRDs have increased by 28.5% and 39.8%, the age-standardised rates have dropped by 41.7% and 16.9% from 1990 to 2019, respectively. COPD, with 212.3 million (200.4–225.1) prevalent cases, was the primary cause of deaths from CRDs, accounting for 3.3 million (2.9–3.6) deaths. With 262.4 million (224.1–309.5) prevalent cases, asthma had the highest prevalence among CRDs. The age-standardised rates of all burden measures of COPD, asthma, and pneumoconiosis have reduced globally from 1990 to 2019. Nevertheless, the age-standardised rates of incidence and prevalence of interstitial lung disease and pulmonary sarcoidosis have increased throughout this period. Low- and low-middle SDI countries had the highest age-standardised death and DALYs rates while the high SDI quintile had the highest prevalence rate of CRDs. The highest deaths and DALYs from CRDs were attributed to smoking globally, followed by air pollution and occupational risks. Non-optimal temperature and high body-mass index were additional risk factors for COPD and asthma, respectively. Interpretation: Albeit the age-standardised prevalence, death, and DALYs rates of CRDs have decreased, they still cause a substantial burden and deaths worldwide. The high death and DALYs rates in low and low-middle SDI countries highlights the urgent need for improved preventive, diagnostic, and therapeutic measures. Global strategies for tobacco control, enhancing air quality, reducing occupational hazards, and fostering clean cooking fuels are crucial steps in reducing the burden of CRDs, especially in low- and lower-middle income countries

Marek's disease virus US3 protein kinase phosphorylates chicken HDAC 1 and 2 and regulates viral replication and pathogenesis.

Marek's disease virus (MDV) is a potent oncogenic alphaherpesvirus that elicits a rapid onset of malignant T-cell lymphomas in chickens. Three MDV types, including GaHV-2 (MDV-1), GaHV-3 (MDV-2) and MeHV-1 (HVT), have been identified and all encode a US3 protein kinase. MDV-1 US3 is important for efficient virus growth in vitro. To study the role of US3 in MDV replication and pathogenicity, we generated an MDV-1 US3-null virus and chimeric viruses by replacing MDV-1 US3 with MDV-2 or HVT US3. Using MD as a natural virus-host model, we showed that both MDV-2 and HVT US3 partially rescued the growth deficiency of MDV-1 US3-null virus. In addition, deletion of MDV-1 US3 attenuated the virus resulting in higher survival rate and lower MDV specific tumor incidence, which could be partially compensated by MDV-2 and HVT US3. We also identified chicken histone deacetylase 1 (chHDAC1) as a common US3 substrate for all three MDV types while only US3 of MDV-1 and MDV-2 phosphorylate chHDAC2. We further determined that US3 of MDV-1 and HVT phosphorylate chHDAC1 at serine 406 (S406), while MDV-2 US3 phosphorylates S406, S410, and S415. In addition, MDV-1 US3 phosphorylates chHDAC2 at S407, while MDV-2 US3 targets S407 and S411. Furthermore, biochemical studies show that MDV US3 mediated phosphorylation of chHDAC1 and 2 affect their stability, transcriptional regulation activity, and interaction network. Using a class I HDAC specific inhibitor, we showed that MDV US3 mediated phosphorylation of chHDAC1 and 2 is involved in regulation of virus replication. Overall, we identified novel substrates for MDV US3 and characterized the role of MDV US3 in MDV pathogenesis

US3 Serine/Threonine Protein Kinase from MDV-1, MDV-2, and HVT Differentially Regulate Viral Gene Expression and Replication

Gallid alphaherpesvirus 2 (GaHV-2), commonly known as Marek’s disease virus type 1 (MDV-1), is an oncogenic avian alphaherpesvirus, and along with its close relatives—Gallid alphaherpesvirus 3 (GaHV-3) or MDV-2 and Meleagrid alphaherpesvirus 1 (MeHV-1) or turkey herpesvirus (HVT)—belongs to the Mardivirus genus. We and others previously showed that MDV-1 US3 protein kinase plays an important role in viral replication and pathogenesis, which could be partially compensated by MDV-2 and HVT US3. In this study, we further studied the differential roles of MDV-1, MDV-2 and HVT US3 in regulating viral gene expression and replication. Our results showed that MDV-2 and HVT US3 could differentially compensate MDV-1 US3 regulation of viral gene expression in vitro. MDV-2 and HVT US3 could also partially rescue the replication deficiency of MDV-1 US3 null virus in the spleen and thymus, as determined by immunohistochemistry analysis of MDV-1 pp38 protein. Importantly, using immunohistochemistry and dual immunofluorescence assays, we found that MDV-2 US3, but not HVT US3, fully compensated MDV-1 US3 regulation of MDV-1 replication in bursal B lymphocytes. In conclusion, our study provides the first comparative analysis of US3 from MDV-1, MDV-2 and HVT in regulating viral gene expression in cell culture and MDV-1 replication in lymphocytes

Comparative analysis of the chrysanthemum transcriptome with DNA methylation inhibitors treatment and silencing MET1 lines

Abstract Background As one of the ten most famous flowers in China, the chrysanthemum has rich germplasm with a variety of flowering induction pathways, most of which are photoperiod-induced. After treatment with DNA methylation inhibitors, it was found that DNA methylation plays an important role in flowering regulation, but the mechanism of action remains unclear. Therefore, in this study, curcumin, 5-azaC, their mixed treatment, and MET1-RNAi lines were used for transcriptome sequencing to find out how different treatments affected gene expression in chrysanthemums at different stages of flowering. Results Genomic DNA methylation levels were measured using HPLC technology. The methylation level of the whole genome in the vegetative growth stage was higher than that in the flowering stage. The methylation level of DNA in the vegetative growth stage was the lowest in the curcumin and mixed treatment, and the methylation level of DNA in the transgenic line, mixed treatment, and curcumin treatment was the lowest in the flowering stage. The flowering rate of mixed treatment and curcumin treatment was the lowest. Analysis of differentially expressed genes in transcriptomes showed that 5-azaC treatment had the most differentially expressed genes, followed by curcumin and transgenic lines, and mixed treatment had the fewest. In addition, 5-azaC treatment resulted in the differential expression of multiple DNA methylation transferases, which led to the differential expression of many genes. Analysis of differentially expressed genes in different treatments revealed that different treatments had gene specificity. However, the down-regulated GO pathway in all 4 treatments was involved in the negative regulation of the reproductive process, and post-embryonic development, and regulation of flower development. Several genes associated with DNA methylation and flowering regulation showed differential expression in response to various treatments. Conclusions Both DNA methylase reagent treatment and targeted silencing of the MET1 gene can cause differential expression of the genes. The operation of the exogenous application is simple, but the affected genes are exceedingly diverse and untargeted. Therefore, it is possible to construct populations with DNA methylation phenotypic diversity and to screen genes for DNA methylation regulation

Intratumoural microbiome can predict the prognosis of hepatocellular carcinoma after surgery

Abstract Background The dismal prognosis of hepatocellular carcinoma (HCC) is closely associated with characteristics of the tumour microenvironment (TME). Recent studies have confirmed the presence and potential influence of the microbiome in TME on cancer progression. Elucidating the relationship between microbes in the TME and cancer could provide valuable insights into novel diagnostic markers and therapeutic strategies for HCC and thus warrants a closer investigation of the role of intratumoural microbiome in the HCC TME. Methods We determined the presence of intratumoural microbiome using fluorescence in situ hybridisation, and explored the microbial community profiles in the HCC TME in paired tumour and adjacent normal tissues using 16S rDNA sequencing. Microbial signatures were characterised in the paired group, and their correlation with clinical characteristics was further investigated. We clustered the microbial signatures of tumour tissues by hepatotypes, and further analysis was performed to elucidate the independent prognostic value of the hepatotypes. Results This study revealed that microbial profiles and community networks differed notably between tumours and adjacent normal tissues. Proteobacteria and Actinobacteria were the most abundant phyla in the HCC TME. The TME microbial profiles also revealed heterogeneities between individuals and between multiple tumour lesions. Clustering of the microbial profiles into two hepatotypes revealed different microbial network patterns. Additionally, the hepatotypes were revealed to be independent prognostic factors in patients with resected HCC. Conclusions Our study illuminates the microbial profiles in the TME of HCC and presents the hepatotype as a potential independent biomarker for the prognostic prediction of HCC after surgery

Data_Sheet_1_Interaction between intratumoral microbiota and tumor mediates the response of neoadjuvant therapy for rectal cancer.docx

BackgroundPrevious observations have demonstrated that the response to neoadjuvant chemoradiotherapy (nCRT) is highly variable in patients with locally advanced rectal cancer (LARC). Recent studies focusing on the intratumoral microbiota of colorectal cancer have revealed its role in oncogenesis and tumor progression. However, limited research has focused on the influence of intratumoral microbiota on the nCRT of LARC.MethodsWe explored the microbial profiles in the tumor microenvironment of LARC using RNA-seq data from a published European cohort. Microbial signatures were characterized in pathological complete response (pCR) and non-pCR groups. Multi-omics analysis was performed between intratumor microbiomes and transcriptomes.ResultsMicrobial α and β diversity were significantly different in pCR and non-pCR groups. Twelve differential microbes were discovered between the pCR and non-pCR groups, six of which were related to subclusters of cancer-associated fibroblasts (CAFs) associated with extracellular matrix formation. A microbial risk score based on the relative abundance of seven differential microbes had predictive value for the nCRT response (AUC = 0.820, p ConclusionOur study presents intratumoral microbes as potential independent predictive markers for the response of nCRT to LARC and demonstrates the underlying mechanism by which the interaction between intratumoral microbes and CAFs mediates the response to nCRT.</p