Immunisation with the BCG and DTPw vaccines induces different programs of trained immunity in mice

In addition to providing pathogen-specific immunity, vaccines can also confer nonspecific effects (NSEs) on mortality and morbidity unrelated to the targeted disease. Immunisation with live vaccines, such as the BCG vaccine, has generally been associated with significantly reduced all-cause infant mortality. In contrast, some inactivated vaccines, such as the diphtheria, tetanus, whole-cell pertussis (DTPw) vaccine, have been controversially associated with increased all-cause mortality especially in female infants in high-mortality settings. The NSEs associated with BCG have been attributed, in part, to the induction of trained immunity, an epigenetic and metabolic reprograming of innate immune cells, increasing their responsiveness to subsequent microbial encounters. Whether non-live vaccines such as DTPw induce trained immunity is currently poorly understood. Here, we report that immunisation of mice with DTPw induced a unique program of trained immunity in comparison to BCG immunised mice. Altered monocyte and DC cytokine responses were evident in DTPw immunised mice even months after vaccination. Furthermore, splenic cDCs from DTPw immunised mice had altered chromatin accessibility at loci involved in immunity and metabolism, suggesting that these changes were epigenetically mediated. Interestingly, changing the order in which the BCG and DTPw vaccines were co-administered to mice altered subsequent trained immune responses. Given these differences in trained immunity, we also assessed whether administration of these vaccines altered susceptibility to sepsis in two different mouse models. Immunisation with either BCG or a DTPw-containing vaccine prior to the induction of sepsis did not significantly alter survival. Further studies are now needed to more fully investigate the potential consequences of DTPw induced trained immunity in different contexts and to assess whether other non-live vaccines also induce similar changes.     

强心通脉灵对大鼠急性心肌梗死后心室重构的影响

目的探讨强心通脉灵对急性心肌梗死(AMI)大鼠心室重构(VR)的干预机制。方法选择Wistar大鼠85只,随机分为强心通脉灵大剂量组(QXLmax组)12只、强心通脉灵小剂量组(QXLmin组)14只、卡托普利组11只、模型组15只和假手术组13只,采取冠状动脉结扎造成AMI模型,术后均予口服给药治疗,模型组及假手术组予以相应的生理盐水。4周后处死,放射免疫法测血浆血管紧张素Ⅱ(AngⅡ)和超氧化物歧化酶(SOD)含量,计算左心室质量指数,光镜下观察心尖组织病理形态学改变,采用ABC染色测TGF-β1的表达量。结果模型组及各给药组AngⅡ水平较高,各给药组较模型组有下降趋势,其中QXLmax组较卡托普利组及QXLmin组更低。模型组及各给药组SOD水平较假手术组降低,QXLmax组及QXLmin组较模型组有升高趋势,左心室质量指数模型组较假手术组显著升高,各给药组较假手术组有升高趋势,QXLmax组较QXLmin组及卡托普利组低。卡托普利组及QXLmin组健存心肌细胞周围胶原组织明显减少,QXLmax组病理改变最轻,偶有少量胶原纤维增生。TGF-β1表达QXLmax组较QXLmin组及卡托普利组低(P<0.01)。结论强心通脉灵可降低AMI后大鼠血浆AngⅡ水平,增加SOD活性,降低左心室质量指数及心肌组织TGF-β1表达,从而平稳AMI后VR的进程。     

Unusual Cause of Methadone Poisoning

ABSTRACT. A child with respiratory distress was found to have been given an antibiotic which was reconstituted with methadone. A delay in standard emergency room management led to a delay in diagnosis and treatment.     

Role of H+ ions in volume and voltage of epithelial cell nuclei

Condensation of chromatin depends upon the ion composition in the cell nucleus. We tested in isolated nuclei of Madin-Darby canine kidney cells the influence of various ions on nuclear volume (i. e. DNA packing) and intranuclear voltage. After isolation, nuclei were superfused with cytosolic solutions in which Na⁺, K⁺, Ca²⁺ and H⁺ ions were varied. With video-imaging and microelectrode techniques nuclear volume and intranuclear potential were measured in response to the various ions. In control cytosolic solution, isolated nuclei exhibited an intranuclear electrical potential of –6.5±0.5 mV (relative to a reference electrode in the cytosolic solution) corresponding to a nuclear volume of 250±10 fl (n=104). Changing the Na⁺, K⁺ or free Ca²⁺ concentration in the superfusate in the physiological range resulted in minor changes of volume and intranuclear potential whereas pH altered both parameters dramatically. Nuclear swelling and intranuclear negative voltage increased with alkalinization and decreased when pH was reduced. An intact nuclear envelope was found to be no prerequisite for maintaining intranuclear negativity, indicating that the composition and functional state of nuclear chromatin rather than specific ion permeabilities of the nuclear envelope determine nuclear electrical potential. We present a model that explains nuclear volume and voltage on the basis of interaction between negatively charged DNA and positively charged histones of the nuclear chromatin.     

The kinase haspin is required for mitotic histone H3 Thr 3 phosphorylation and normal metaphase chromosome alignment

Post-translational modifications of conserved N-terminal tail residues in histones regulate many aspects of chromosome activity. Thr 3 of histone H3 is highly conserved, but the significance of its phosphorylation is unclear, and the identity of the corresponding kinase unknown. Immunostaining with phospho-specific antibodies in mammalian cells reveals mitotic phosphorylation of H3 Thr 3 in prophase and its dephosphorylation during anaphase. Furthermore we find that haspin, a member of a distinctive group of protein kinases present in diverse eukaryotes, phosphorylates H3 at Thr 3 in vitro. Importantly, depletion of haspin by RNA interference reveals that this kinase is required for H3 Thr 3 phosphorylation in mitotic cells. In addition to its chromosomal association, haspin is found at the centrosomes and spindle during mitosis. Haspin RNA interference causes misalignment of metaphase chromosomes, and overexpression delays progression through early mitosis. This work reveals a new kinase involved in composing the histone code and adds haspin to the select group of kinases that integrate regulation of chromosome and spindle function during mitosis and meiosis.     

STAT3 couples with 14-3-3σ to regulate BCR signaling,B-cell differentiation,and IgE production

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Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia

Mixed-lineage leukemia (MLL) fusion proteins are potent inducers of leukemia, but how these proteins generate aberrant gene expression programs is poorly understood. Here we show that the MLL-AF4 fusion protein occupies developmental regulatory genes important for hematopoietic stem cell identity and self-renewal in human leukemia cells. These MLL-AF4-bound regions have grossly altered chromatin structure, with histone modifications catalyzed by trithorax group proteins and DOT1 extending across large domains. Our results define direct targets of the MLL fusion protein, reveal the global role of epigenetic misregulation in leukemia, and identify new targets for therapeutic intervention in cancer.     

pH modulates conducting and gating behaviour of single calcium release channels

Intracellular pH changes affect excitation-contraction coupling in skeletal, and cardiac muscles. However the proton implication in modulating the sarcoplasmic reticulum Ca²⁺ release channel activity has never been visualized at single channel level. A large conducting Ca²⁺ release pathway has previously been characterized after incorporation of skeletal and cardiac sarcoplasmic reticulum vesicles into planar lipid bilayers. This channel has been activated by micromolar and millimolar concentrations of Ca²⁺ and ATP, respectively. The pH was independently varied on each side of the channels. Acidification of the cis-chamber (7.4 to 6.6) induced a modification of the gating behaviour, resulting in a decrease of the open probability. This effect was completely reversible. On the other hand, acidification of the trans-chamber (7.4 to 6.8) induced a reduction of the unitary conductance of the sarcoplasmic reticulum Ca²⁺ release channel.