The histone demethylase JMJD1C regulates CPS1 expression and promotes the proliferation of paroxysmal nocturnal haemoglobinuria clones through cell metabolic reprogramming.

Paroxysmal nocturnal haemoglobinuria (PNH) is a disorder resulting from erythrocyte membrane deficiencies caused by PIG-A gene mutations. While current treatments alleviate symptoms, they fail to address the underlying cause of the disease-the pathogenic PNH clones. In this study, we found that the expression of carbamoyl phosphate synthetase 1 (CPS1) was downregulated in PNH clones, and the level of CPS1 was negatively correlated with the proportion of PNH clones. Using PIG-A knockout K562 (K562 KO) cells, we demonstrated that CPS1 knockdown increased cell proliferation and altered cell metabolism, suggesting that CPS1 participates in PNH clonal proliferation through metabolic reprogramming. Furthermore, we observed an increase in the expression levels of the histone demethylase JMJD1C in PNH clones, and JMJD1C expression was negatively correlated with CPS1 expression. Knocking down JMJD1C in K562 KO cells upregulated CPS1 and H3K36me3 expression, decreased cell proliferation and increased cell apoptosis. Chromatin immunoprecipitation analysis further demonstrated that H3K36me3 regulated CPS1 expression. Finally, we demonstrated that histone demethylase inhibitor JIB-04 can suppressed K562 KO cell proliferation and reduced the proportion of PNH clones in PNH mice. In conclusion, aberrant regulation of the JMJD1C-H3K36me3-CPS1 axis contributes to PNH clonal proliferation. Targeting JMJD1C with a specific inhibitor unveils a potential strategy for treating PNH patients.

Maize requires arogenate dehydratase 2 for resistance to Ustilago maydis and plant development.

Maize (Zea mays) smut is a common biotrophic fungal disease caused by Ustilago maydis and leads to low maize yield. Maize resistance to U. maydis is a quantitative trait. However, the molecular mechanism underlying the resistance of maize to U. maydis is poorly understood. Here, we reported that a maize mutant caused by a single gene mutation exhibited defects in both fungal resistance and plant development. maize mutant highly susceptible to U. maydis (mmsu) with a dwarf phenotype forms tumors in the ear. A map-based cloning and allelism test demonstrated that 1 gene encoding a putative arogenate dehydratase/prephenate dehydratase (ADT/PDT) is responsible for the phenotypes of the mmsu and was designated as ZmADT2. Combined transcriptomic and metabolomic analyses revealed that mmsu had substantial differences in multiple metabolic pathways in response to U. maydis infection compared with the wild type. Disruption of ZmADT2 caused damage to the chloroplast ultrastructure and function, metabolic flux redirection, and reduced the amounts of salicylic acid (SA) and lignin, leading to susceptibility to U. maydis and dwarf phenotype. These results suggested that ZmADT2 is required for maintaining metabolic flux, as well as resistance to U. maydis and plant development in maize. Meanwhile, our findings provided insights into the maize response mechanism to U. maydis infection.

PMI-controlled mannose metabolism and glycosylation determines tissue tolerance and virus fitness.

Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered immunometabolic response cascade and reduces tissue damage. Safe and inexpensive D-mannose can compete with glucose for the same transporter and hexokinase. Such competitions suppress glycolysis, reduce mitochondrial reactive-oxygen-species and succinate-mediated hypoxia-inducible factor-1α, and thus reduce virus-induced proinflammatory cytokine production. The combinatorial treatment by D-mannose and antiviral monotherapy exhibits in vivo synergy despite delayed antiviral treatment in mouse model of virus infections. Phosphomannose isomerase (PMI) knockout cells are viable, whereas addition of D-mannose to the PMI knockout cells blocks cell proliferation, indicating that PMI activity determines the beneficial effect of D-mannose. PMI inhibition suppress a panel of virus replication via affecting host and viral surface protein glycosylation. However, D-mannose does not suppress PMI activity or virus fitness. Taken together, PMI-centered therapeutic strategy clears virus infection while D-mannose treatment reprograms glycolysis for control of collateral damage.

An engineered Sox17 induces somatic to neural stem cell fate transitions independently from pluripotency reprogramming.

Advanced strategies to interconvert cell types provide promising avenues to model cellular pathologies and to develop therapies for neurological disorders. Yet, methods to directly transdifferentiate somatic cells into multipotent induced neural stem cells (iNSCs) are slow and inefficient, and it is unclear whether cells pass through a pluripotent state with full epigenetic reset. We report iNSC reprogramming from embryonic and aged mouse fibroblasts as well as from human blood using an engineered Sox17 (eSox17FNV). eSox17FNV efficiently drives iNSC reprogramming while Sox2 or Sox17 fail. eSox17FNV acquires the capacity to bind different protein partners on regulatory DNA to scan the genome more efficiently and has a more potent transactivation domain than Sox2. Lineage tracing and time-resolved transcriptomics show that emerging iNSCs do not transit through a pluripotent state. Our work distinguishes lineage from pluripotency reprogramming with the potential to generate more authentic cell models for aging-associated neurodegenerative diseases.

GCSTI: A Single-Cell Pseudotemporal Trajectory Inference Method Based on Graph Compression.

The single-cell pseudotemporal trajectory inference is an important way to explore the process of developmental changes within a cell. Due to the uneven rate of cell growth, changes in gene expression depend less on the time of data collection and more on a cell's "internal clock". To overcome the challenges of gene analysis, and replicate biological developmental processes, several strategies have been put forth. However, due to the size of single-cell datasets, locating relevant signposts usually necessitate clustering analysis or a sizable amount of priori information. To this end, we propose a novel single-cell pseudotemporal trajectory inference technique: GCSTI method, which is based on graph compression and doesn't rely on a priori knowledge or clustering procedures, can handle the trajectory inference problem for a large network in a stable and efficient manner. Additionally, we simultaneously improve the pseudotime defining method currently employed in this study in order to obtain more trustworthy and beneficial outcomes for trajectory inference. Finally, we validate the efficacy and stability of the GCSTI method using datasets from human skeletal muscle myogenic cells and four simulated datasets.

FSG-based divinable time-varying formation tracking of multiple Lagrangian agents with unknown disturbances and directed graphs.

In this paper, a flexible shape generator (FSG) is designed to achieve the divinable transformation process of the time-varying formation, and consider the FSG-based time-varying formation tracking (TVFT) problem of multiple Lagrangian agents with unknown disturbances and directed graphs. A hierarchical control algorithm is newly designed to achieve the control goal without using the prior information of the system model and bounded disturbances, and the specific implementation of the proposed hierarchical algorithms is also provided. By using the Hurwitz criterion and adaptive system theory, the sufficient conditions are derived and the stability analysis show that the formation tracking errors of the considered system are uniform ultimate bounded. Several simulation examples are performed on five two-degree-of-freedom mechanical arms to show the effectiveness of theoretical results.

Chronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8+ T cell exhaustion and curtails anti-PD-1 efficacy.

Identifying signals that govern the differentiation of tumor-infiltrating CD8+ T cells (CD8+ TILs) toward exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues, enhancing terminal CD8+ T cell exhaustion in tumors. We find enrichment of IFN-I-stimulated genes (ISGs) within exhausted CD8+ T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8+ TILs devoid of IFN-I signaling develop less exhaustion features, provide better tumor control, and show greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-I stimulation perturbs lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promote lipid peroxidation, which potentiates metabolic and functional exhaustion of Tex cells. Thus, cell-intrinsic IFN-I signaling regulates the extent of CD8+ TIL exhaustion and has important implications for immunotherapy.

Comparing the B and T cell-mediated immune responses in patients with type 2 diabetes receiving mRNA or inactivated COVID-19 vaccines.

Acquiring protective immunity through vaccination is essential, especially for patients with type 2 diabetes who are vulnerable for adverse clinical outcomes during coronavirus disease 2019 (COVID-19) infection. Type 2 diabetes (T2D) is associated with immune dysfunction. Here, we evaluated the impact of T2D on the immunological responses induced by mRNA (BNT162b2) and inactivated (CoronaVac) vaccines, the two most commonly used COVID-19 vaccines. The study consisted of two parts. In Part 1, the sera titres of IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) alpha receptor binding domain (RBD), their neutralizing capacity, and antigen-specific CD4+T and CD8+T cell responses at 3-6 months after vaccination were compared between BNT162b2 (n=60) and CoronaVac (n=50) vaccinees with or without T2D. Part 2 was a time-course study investigating the initial B and T cell responses induced by BNT162b2 among vaccinees (n=16) with or without T2D. Our data showed that T2D impaired both cellular and humoral immune responses induced by CoronaVac. For BNT162b2, T2D patients displayed a reduction in CD4+T-helper 1 (Th1) differentiation following their first dose. However, this initial defect was rectified by the second dose of BNT162b2, resulting in comparable levels of memory CD4+ and CD8+T cells, anti-RBD IgG, and neutralizing antibodies with healthy individuals at 3-6 months after vaccination. Hence, T2D influences the effectiveness of COVID-19 vaccines depending on their platform. Our findings provide a potential mechanism for the susceptibility of developing adverse outcomes observed in COVID-19 patients with T2D and received either CoronaVac or just one dose of BNT162b2.

Autoantibodies in systemic lupus erythematosus: From immunopathology to therapeutic target.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ inflammatory damage and wide spectrum of autoantibodies. The autoantibodies, especially anti-dsDNA and anti-Sm autoantibodies are highly specific to SLE, and participate in the immune complex formation and inflammatory damage on multiple end-organs such as kidney, skin, and central nervous system (CNS). However, the underlying mechanisms of autoantibody-induced tissue damage and systemic inflammation are still not fully understood. Single cell analysis of autoreactive B cells and monoclonal antibody screening from patients with active SLE has improved our understanding on the origin of autoreactive B cells and the antigen targets of the pathogenic autoantibodies. B cell depletion therapies have been widely studied in the clinics, but the development of more specific therapies against the pathogenic B cell subset and autoantibodies with improved efficacy and safety still remain a big challenge. A more comprehensive autoantibody profiling combined with functional characterization of autoantibodies in diseases development will shed new insights on the etiology and pathogenesis of SLE and guide a specific treatment to individual SLE patients.

Bacillus Calmette-Guérin-induced trained immunity protects against SARS-CoV-2 challenge in K18-hACE2 mice.

SARS-CoV-2 has been confirmed in over 450 million confirmed cases since 2019. Although several vaccines have been certified by the WHO and people are being vaccinated on a global scale, it has been reported that multiple SARS-CoV-2 variants can escape neutralization by antibodies, resulting in vaccine breakthrough infections. Bacillus Calmette-Guérin (BCG) is known to induce heterologous protection based on trained immune responses. Here, we investigated whether BCG-induced trained immunity protected against SARS-CoV-2 in the K18-hACE2 mouse model. Our data demonstrate that i.v. BCG (BCG-i.v.) vaccination induces robust trained innate immune responses and provides protection against WT SARS-CoV-2, as well as the B.1.617.1 and B.1.617.2 variants. Further studies suggest that myeloid cell differentiation and activation of the glycolysis pathway are associated with BCG-induced training immunity in K18-hACE2 mice. Overall, our study provides the experimental evidence that establishes a causal relationship between BCG-i.v. vaccination and protection against SARS-CoV-2 challenge.

Intranasal administration of a single dose of a candidate live attenuated vaccine derived from an NSP16-deficient SARS-CoV-2 strain confers sterilizing immunity in animals.

Live attenuated vaccines might elicit mucosal and sterilizing immunity against SARS-CoV-2 that the existing mRNA, adenoviral vector and inactivated vaccines fail to induce. Here, we describe a candidate live attenuated vaccine strain of SARS-CoV-2 in which the NSP16 gene, which encodes 2'-O-methyltransferase, is catalytically disrupted by a point mutation. This virus, designated d16, was severely attenuated in hamsters and transgenic mice, causing only asymptomatic and nonpathogenic infection. A single dose of d16 administered intranasally resulted in sterilizing immunity in both the upper and lower respiratory tracts of hamsters, thus preventing viral spread in a contact-based transmission model. It also robustly stimulated humoral and cell-mediated immune responses, thus conferring full protection against lethal challenge with SARS-CoV-2 in a transgenic mouse model. The neutralizing antibodies elicited by d16 effectively cross-reacted with several SARS-CoV-2 variants. Secretory immunoglobulin A was detected in the blood and nasal wash of vaccinated mice. Our work provides proof-of-principle evidence for harnessing NSP16-deficient SARS-CoV-2 for the development of live attenuated vaccines and paves the way for further preclinical studies of d16 as a prototypic vaccine strain, to which new features might be introduced to improve safety, transmissibility, immunogenicity and efficacy.

Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus.

The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these 'SLE-like' conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

Stochastic quasi-synchronization of heterogeneous delayed impulsive dynamical networks via single impulsive control.

This paper investigates the quasi-synchronization problem of the stochastic heterogeneous complex dynamical networks with impulsive couplings and multiple time-varying delays. It is shown that this kind of dynamical networks can achieve exponential quasi-synchronization by exerting impulsive control added on only one chosen pinning node. By employing the Lyapunov stability theory, some sufficient criteria on quasi-synchronization for this dynamical network are established, revealing the relationship between the quasi-synchronization performance and the stochastic perturbations as well as the frequency and strength of impulsive coupling. Finally, some numerical examples are used to illustrate the effectiveness of the main results.

Evaluation on radiation shielding of the Halcyon linear accelerator room in a hospital / 中国职业医学

OBJECTIVE: To explore the radiation shielding problem of Halcyon linear accelerator room. METHODS: According to the dose estimation method recommended by GBZ/T 201.2—2011 Radiation Shielding Requirements for Radiotherapy room--Part 2: Radiotherapy Room of Electron Linear Accelerators(hereinafter referred to as GBZ/T 201.2—2011) and NCRP report No.151 Structural Shielding Design and Evaluation for Megavoltage X-and Gamma-Ray Radiotherapy Facilities the required shielding thickness of 6.0 MeV Halcyon linear machine room is evaluated and compared with the existing machine room. After the equipment was put into use, we measured and verified the dose equivalent rate around each point. RESULTS: ⅰ) The transmittance of the main beam passing through the self-shielding system was 0.06%. The theoretical shielding thickness of the main beam path sites A, C and L of the accelerator(two main shielding walls and room top sites respectively) was 136.00, 130.00 and 136.00 cm, which was lower than the required shielding thickness of the main shielding area specified in GBZ/T 201.2—2011 for 6.0 MeV accelerator. ⅱ) Compared with the existing equipment rooms in the hospital, except that the thickness of the top secondary shield(80.00 cm) and the thickness of the west section of the outer wall of the labyrinth(100.00 cm) are smaller, the rest meets the shielding requirements. ⅲ) After the transformation of the computer room and the installation of Halcyon linear accelerator, the surrounding dose equivalent rate was lower than the control level required by GBZ/T 201.2—2011. CONCLUSION: The self-shielding design of Halcyon linear accelerator can effectively protect 6.0 MeV rays used for treatment, reduce the shielding thickness required for the main shielding area, reduce the shielding construction cost of the equipment room and increase the usable area of the equipment room.

Identification of Diagnostic Biomarkers and Subtypes of Liver Hepatocellular Carcinoma by Multi-Omics Data Analysis.

As liver hepatocellular carcinoma (LIHC) has high morbidity and mortality rates, improving the clinical diagnosis and treatment of LIHC is an important issue. The advent of the era of precision medicine provides us with new opportunities to cure cancers, including the accumulation of multi-omics data of cancers. Here, we proposed an integration method that involved the Fisher ratio, Spearman correlation coefficient, classified information index, and an ensemble of decision trees (DTs) for biomarker identification based on an unbalanced dataset of LIHC. Then, we obtained 34 differentially expressed genes (DEGs). The ability of the 34 DEGs to discriminate tumor samples from normal samples was evaluated by classification, and a high area under the curve (AUC) was achieved in our studied dataset and in two external validation datasets (AUC = 0.997, 0.973, and 0.949, respectively). Additionally, we also found three subtypes of LIHC, and revealed different biological mechanisms behind the three subtypes. Mutation enrichment analysis showed that subtype 3 had many enriched mutations, including tumor protein p53 (TP53) mutations. Overall, our study suggested that the 34 DEGs could serve as diagnostic biomarkers, and the three subtypes could help with precise treatment for LIHC.

Anti-cyclic citrullinated peptide antibody predicts the development of rheumatoid arthritis in patients with undifferentiated arthritis.

BACKGROUND: Clinical outcomes of undifferentiated arthritis (UA) are diverse, and only 40% of patients with UA develop rheumatoid arthritis (RA) after 3 years. Discovering predictive markers at disease onset for further intervention is critical. Therefore, our objective was to analyze the clinical outcomes of UA and ascertain the predictors for RA development. METHODS: We performed a prospective, multi-center study from January 2013 to October 2016 among Chinese patients diagnosed with UA in 22 tertiary-care hospitals. Clinical and serological parameters were obtained at recruitment. Follow-up was undertaken in all patients every 12 weeks for 2 years. Predictive factors of disease progression were identified using multivariate Cox proportional hazards regression. RESULTS: A total of 234 patients were recruited in this study, and 17 (7.3%) patients failed to follow up during the study. Among the 217 patients who completed the study, 83 (38.2%) patients went into remission. UA patients who developed RA had a higher rheumatoid factor (RF)-positivity (42.9% vs. 16.8%, χ = 8.228, P = 0.008), anti-cyclic citrullinated peptide (CCP) antibody-positivity (66.7% vs. 10.7%, χ = 43.897, P < 0.001), and double-positivity rate of RF and anti-CCP antibody (38.1% vs. 4.1%, χ = 32.131, P < 0.001) than those who did not. Anti-CCP antibody but not RF was an independent predictor for RA development (hazard ratio 18.017, 95% confidence interval: 5.803-55.938; P < 0.001). CONCLUSION: As an independent predictor of RA, anti-CCP antibody should be tested at disease onset in all patients with UA.

C1q restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism.

Deficiency of C1q, the initiator of the complement classical pathway, is associated with the development of systemic lupus erythematosus (SLE). Explaining this association in terms of abnormalities in the classical pathway alone remains problematic because C3 deficiency does not predispose to SLE. Here, using a mouse model of SLE, we demonstrate that C1q, but not C3, restrains the response to self-antigens by modulating the mitochondrial metabolism of CD8+ T cells, which can themselves propagate autoimmunity. C1q deficiency also triggers an exuberant effector CD8+ T cell response to chronic viral infection leading to lethal immunopathology. These data establish a link between C1q and CD8+ T cell metabolism and may explain how C1q protects against lupus, with implications for the role of viral infections in the perpetuation of autoimmunity.

Multisynchronization of Coupled Heterogeneous Genetic Oscillator Networks via Partial Impulsive Control.

This paper focuses on the collective dynamics of multisynchronization among heterogeneous genetic oscillators under a partial impulsive control strategy. The coupled nonidentical genetic oscillators are modeled by differential equations with uncertainties. The definition of multisynchronization is proposed to describe some more general synchronization behaviors in the real. Considering that each genetic oscillator consists of a large number of biochemical molecules, we design a more manageable impulsive strategy for dynamic networks to achieve multisynchronization. Not all the molecules but only a small fraction of them in each genetic oscillator are controlled at each impulsive instant. Theoretical analysis of multisynchronization is carried out by the control theory approach, and a sufficient condition of partial impulsive controller for multisynchronization with given error bounds is established. At last, numerical simulations are exploited to demonstrate the effectiveness of our results.

Multistability and Bifurcation Analysis of Inhibitory Coupled Cyclic Genetic Regulatory Networks With Delays.

Many biological systems have the conspicuous property to present more than one stable state and diverse rhythmic behaviors. A closed relationship between these complex dynamic behaviors and cyclic genetic structures has been witnessed by pioneering works. In this paper, a typical structure of inhibitory coupled cyclic genetic networks is introduced to further enlighten this mechanism of stability and biological rhythms of living cells. The coupled networks consist of two identical cyclic genetic subnetworks, which inhibit each other directly. Each subnetwork can be regarded as a genetic unit at the cellular level. Multiple time delays, including both internal and coupling delays, are considered. The existence of positive equilibriums for this kind of coupled systems is proved, and the stability for each equilibrium is analyzed without or with delays. It is shown that the coupled networks with positive cyclic genetic units have an ability to show multistability, while the coupled networks with negative units may present a series of Hopf bifurcations with the variation of time delays. Several numerical simulations are made to prove our results.