Alterations of the gut microbiome are associated with epigenetic age acceleration and physical fitness

Epigenetic clocks can measure aging and predict the incidence of diseases and mortality. Higher levels of physical fitness are associated with a slower aging process and a healthier lifespan. Microbiome alterations occur in various diseases and during the aging process, yet their relation to epigenetic clocks is not explored. To fill this gap, we collected metagenomic (from stool), epigenetic (from blood), and exercise-related data from physically active individuals and, by applying epigenetic clocks, we examined the relationship between gut flora, blood-based epigenetic age acceleration, and physical fitness. We revealed that an increased entropy in the gut microbiome of physically active middle-aged/old individuals is associated with accelerated epigenetic aging, decreased fitness, or impaired health status. We also observed that a slower epigenetic aging and higher fitness level can be linked to altered abundance of some bacterial species often linked to anti-inflammatory effects. Overall our data suggest that alterations in the microbiome can be associated with epigenetic age acceleration and physical fitness.     

Deciphering the role of immune cell composition in epigenetic age acceleration: Insights from cell-type deconvolution applied to human blood epigenetic clocks

Aging is a significant risk factor for various human disorders, and DNA methylation clocks have emerged as powerful tools for estimating biological age and predicting health-related outcomes. Methylation data from blood DNA has been a focus of more recently developed DNA methylation clocks. However, the impact of immune cell composition on epigenetic age acceleration (EAA) remains unclear as only some clocks incorporate partial cell type composition information when analyzing EAA. We investigated associations of 12 immune cell types measured by cell-type deconvolution with EAA predicted by six widely-used DNA methylation clocks in data from >10,000 blood samples. We observed significant associations of immune cell composition with EAA for all six clocks tested. Across the clocks, nine or more of the 12 cell types tested exhibited significant associations with EAA. Higher memory lymphocyte subtype proportions were associated with increased EAA, and naïve lymphocyte subtypes were associated with decreased EAA. To demonstrate the potential confounding of EAA by immune cell composition, we applied EAA in rheumatoid arthritis. Our research maps immune cell type contributions to EAA in human blood and offers opportunities to adjust for immune cell composition in EAA studies to a significantly more granular level. Understanding associations of EAA with immune profiles has implications for the interpretation of epigenetic age and its relevance in aging and disease research. Our detailed map of immune cell type contributions serves as a resource for studies utilizing epigenetic clocks across diverse research fields, including aging-related diseases, precision medicine, and therapeutic interventions.     

Mitochondrial DNA somatic mutation burden and heteroplasmy are associated with chronological age,smoking, and HIV infection

The gradual accumulation of mitochondrial DNA (mtDNA) mutations is implicated in aging and may contribute to the accelerated aging phenotype seen with tobacco smoking and HIV infection. mtDNA mutations are thought to arise from oxidative damage; however, recent reports implicate polymerase γ errors during mtDNA replication. Investigations of somatic mtDNA mutations have been hampered by technical challenges in measuring low‐frequency mutations. We use primer ID‐based next‐generation sequencing to quantify both somatic and heteroplasmic blood mtDNA point mutations within the D‐loop, in 164 women and girls aged 2–72 years, of whom 35% were smokers and 56% were HIV‐positive. Somatic mutations and the occurrence of heteroplasmic mutations increased with age. While transitions are theorized to result from polymerase γ errors, transversions are believed to arise from DNA oxidative damage. In our study, both transition and transversion mutations were associated with age. However, transition somatic mutations were more prevalent than transversions, and no heteroplasmic transversions were observed. We also measured elevated somatic mutations, but not heteroplasmy, in association with high peak HIV viremia. Conversely, heteroplasmy was higher among smokers, but somatic mutations were not, suggesting that smoking promotes the expansion of preexisting mutations rather than de novo mutations. Taken together, our results are consistent with blood mtDNA mutations increasing with age, inferring a greater contribution of polymerase γ errors in mtDNA mutagenesis. We further suggest that smoking and HIV infection both contribute to the accumulation of mtDNA mutations, though in different ways.     

Translocated microbiome composition determines immunological outcome in treated HIV infection

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SARS-CoV-2 prolonged infection during advanced HIV disease evolves extensive immune escape

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Impulsive SUI epidemic model for HIV/AIDS with chronological age and infection age

This paper develops an impulsive SUI model of human immunodeficiency virus/acquired immunodeficiency syndrome(HIV/AIDS) epidemic for the first time to study the dynamic behavior of this model. The SUI model is described by impulsive partial differential equations. First, the well-posedness of the model is attained by the method of characteristic lines and iterative method. Secondly, the basic reproduction number R₀(q,T) of the epidemic which depends on the impulsive HIV-finding period T and the HIV-finding proportion q is obtained by mathematical analysis. Our result shows that HIV/AIDS epidemic can be theoretically eradicated if we can have the suitable HIV-finding proportion q and the impulsive HIV-finding period T such that R₀(q,T)<1. We also conjecture that the infection-free periodic solution of the SUI model is unstable when R₀(q,T)>1.     

Impact of gene-modified T cells on HIV infection dynamics

Previous clinical trials in HIV-infected patients involving infusion of T cells protected by an antiviral gene have failed to show any therapeutic benefit. The value of such a treatment approach is thus still highly controversial. In this study, the anticipated effects of gene-modified cells on virus and T-cell kinetics are analysed by mathematical modeling. Because technically only a small fraction of all T cells in a patient can be manipulated ex vivo, therapeutic success will depend on the accumulation of gene-modified cells after infusion into the patient by in vivo selection. Our simulations predict that a significant therapeutic benefit is conferred only by antiviral genes that inhibit HIV replication before virus integration (class I genes). Genes that inhibit viral protein expression (class II, used in previous clinical trials), require a much higher inhibitory activity than class I genes to promote the regeneration of T cells and reduce the viral load. Inhibition of virus assembly and release alone (class III) confers no selective advantage to the T cell and is therefore ineffective unless combined with class I (or, possibly, class II) genes. Also crucial in determining the clinical outcome are the regenerative capacity of the gene-modified cells and the level of HIV replication in the patient. These results can be important for guiding future strategies in the field of gene therapy for HIV infection.     

Therapeutic potential of RNA interference against cellular targets of HIV infection

RNA interference is not only very promising in identifying new targets for drug development, siRNA/shRNA themselves may be directly used as therapeutic agents. In inhibiting viral infections by RNA interference, both viral targets and cellular proteins have been evaluated. Most of the early studies in this field had chosen viral targets for RNA interference. However, recent efforts are mainly focusing on cellular proteins for RNA silencing due to the realization that a variety of viral responses substantially minimize siRNA effects. With the application of siRNA approaching, many new cellular targets relevant to HIV infection have been identified. The value of siRNA/shRNA in the treatment of AIDS is largely dependent on better understanding of the biology of HIV replication. Efforts in the identification of cellular processes with the employment of siRNA/shRNA have shed some new lights on our understanding of how HIV infection occurs. Furthermore, the relative specific effects and simplicity of design makes siRNA/shRNA themselves to be favorable drug leads. J. Zhang and Y. O. Wu contributed equally to this article.     

The probability of HIV infection in a new host and its reduction with microbicides

We use a simple mathematical model to estimate the probability and its time dependence that one or more HIV virions successfully infect target cells. For the transfer of a given number of virions to target cells we derive expressions for the probability P(inf), of infection. Thus, in the case of needlestick transfer we determine P(inf) and an approximate time window for post-exposure prophylaxis (PEP). For heterosexual transmission, where the transfer process is more complicated, a parameter gamma is employed which measures the strength of the infection process. For the smaller value of gamma, P(inf) is from 6x10(-5) to 0.93 or from 7.82x10(-6) to 0.29, where the lower figures are for the transfer of 100 virions and the upper figures are for the transfer of 4.4 million virions. We estimate the reductions in P(inf) which occur with a microbicide of a given efficacy. It is found that reductions may be approximately as stated when the number of virions transferred is less than about 10(5), but declines to zero for viral loads above that number. It is concluded that PEP should always be applied immediately after a needlestick incident. Further, manufacturers of microbicides should be encouraged to investigate and report their effectiveness at various transferred viral burdens.     

空间转录物组学技术进展及其在神经科学领域中的应用

空间转录物组学是在单细胞RNA测序技术基础上实现细胞空间位置信息测定的组学技术。该技术克服了单细胞转录物组学在单细胞分离建库过程中丢失细胞在组织中空间信息的问题,可同时提供研究对象的转录物组数据信息和在组织中的空间位置信息。空间转录物组学技术对研究细胞谱系的发生过程、细胞间的调控机制和相互作用等具有重要作用,是组学技术研究的重要发展方向和热点。近年来,空间转录物组学技术发展迅速,新的检测方法不断产生,检测灵敏度、分辨率和检测通量等技术指标不断提升。本文根据获取空间信息的原理不同,将较为常用的空间转录物组学技术进行了分类,总结了各类方法的检测原理、代表性技术手段及其相应的技术指标。随后,从脑细胞类型区分与细胞层图谱构建、神经系统相关疾病特征分析与标志物研究两个方面举例论述了空间转录物组学技术在神经科学中的应用。最后,对空间转录物组学技术目前存在的问题进行了总结,并对其未来的发展方向进行了展望。     

Paradoxical suppression of poly-specific broadly neutralizing antibodies in the presence of strain-specific neutralizing antibodies following HIV infection

One of the first immunologic responses against HIV infection is the presence of neutralizing antibodies that seem able to inactivate several HIV strains. Moreover, in vitro studies have shown the existence of monoclonal antibodies that exhibit broad crossclade neutralizing potential. Yet their number is low and slow to develop in vivo. In this paper, we investigate the potential benefits of inducing poly-specific neutralizing antibodies in vivo throughout immunization. We develop a mathematical model that considers the activation of families of B lymphocytes producing poly-specific and strain-specific antibodies and use it to demonstrate that, even if such families are successful in producing neutralizing antibodies, the competition between them may limit the poly-specific response allowing the virus to escape. We modify this model to account for viral evolution under the pressure of antibody responses in natural HIV infection. The model can reproduce viral escape under certain conditions of B lymphocyte competition. Using these models we provide explanations for the observed antibody failure in controlling natural infection and predict quantitative measures that need to be satisfied for long-term control of HIV infection.     

Advanced age promotes colonic dysfunction and gut‐derived lung infection after stroke

Bacterial infection a leading cause of death among patients with stroke, with elderly patients often presenting with more debilitating outcomes. The findings from our retrospective study, supported by previous clinical reports, showed that increasing age is an early predictor for developing fatal infectious complications after stroke. However, exactly how and why older individuals are more susceptible to infection after stroke remains unclear. Using a mouse model of transient ischaemic stroke, we demonstrate that older mice (>12 months) present with greater spontaneous bacterial lung infections compared to their younger counterparts (7–10 weeks) after stroke. Importantly, we provide evidence that older poststroke mice exhibited elevated intestinal inflammation and disruption in gut barriers critical in maintaining colonic integrity following stroke, including reduced expression of mucin and tight junction proteins. In addition, our data support the notion that the localized pro‐inflammatory microenvironment driven by increased tumour necrosis factor‐α production in the colon of older mice facilitates the translocation and dissemination of orally inoculated bacteria to the lung following stroke onset. Therefore, findings of this study demonstrate that exacerbated dysfunction of the intestinal barrier in advanced age promotes translocation of gut‐derived bacteria and contributes to the increased risk to poststroke bacterial infection.     

Monte Carlo estimates of natural variation in HIV infection

We describe a Monte Carlo simulation of the within-host dynamics of human immunodeficiency virus 1 (HIV-1). The simulation proceeds at the level of individual T-cells and virions in a small volume of plasma, thus capturing the inherent stochasticity in viral replication, mutation and T-cell infection. When cell lifetimes are distributed exponentially in the Monte Carlo approach, our simulation results are in perfect agreement with the predictions of the corresponding systems of differential equations from the literature. The Monte Carlo model, however, uniquely allows us to estimate the natural variability in important parameters such as the T-cell count, viral load, and the basic reproductive ratio, in both the presence and absence of drug therapy. The simulation also yields the probability that an infection will not become established after exposure to a viral inoculum of a given size. Finally, we extend the Monte Carlo approach to include distributions of cell lifetimes that are less-dispersed than exponential.     

鼻咽癌转录组学研究的现状与进展

转录组学是一门在整体水平上研究某一时刻某一细胞中基因全部转录本种类、结构和功能及转录调控规律的学科,它为研究鼻咽癌不同发病阶段的分子机理和调控网络提供全新的手段.现简要介绍鼻咽癌不同发病阶段相关易感/抑瘤基因的分离鉴定及其功能研究,各阶段基因转录谱和转录调控网络的构建等方面的研究现状和进展.