Signal-induced Brd4 release from chromatin is essential for its role transition from chromatin targeting to transcriptional regulation

Bromodomain-containing protein Brd4 is shown to persistently associate with chromosomes during mitosis for transmitting epigenetic memory across cell divisions. During interphase, Brd4 also plays a key role in regulating the transcription of signal-inducible genes by recruiting positive transcription elongation factor b (P-TEFb) to promoters. How the chromatin-bound Brd4 transits into a transcriptional regulation mode in response to stimulation, however, is largely unknown. Here, by analyzing the dynamics of Brd4 during ultraviolet or hexamethylene bisacetamide treatment, we show that the signal-induced release of chromatin-bound Brd4 is essential for its functional transition. In untreated cells, almost all Brd4 is observed in association with interphase chromatin. Upon treatment, Brd4 is released from chromatin, mostly due to signal-triggered deacetylation of nucleosomal histone H4 at acetylated-lysine 5/8 (H4K5ac/K8ac). Through selective association with the transcriptional active form of P-TEFb that has been liberated from the inactive multi-subunit complex in response to treatment, the released Brd4 mediates the recruitment of this active P-TEFb to promoter, which enhances transcription at the stage of elongation. Thus, through signal-induced release from chromatin and selective association with the active form of P-TEFb, the chromatin-bound Brd4 switches its role to mediate the recruitment of P-TEFb for regulating the transcriptional elongation of signal-inducible genes.National Natural Science Foundation of China[30930046, 30670408, 81070307]; Natural Science Foundation of Fujian[C0210005, 2010J01231]; Science Planning Program of Fujian Province[2009J1010, 2010J1008]; National Foundation for fostering talents of basic science[J1030626

Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma

Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations

Author Correction: KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Vessel co-option: a unique vascular-immune niche in liver cancer

Tumor vasculature is pivotal in regulating tumor perfusion, immune cell infiltration, metastasis, and invasion. The vascular status of the tumor is intricately linked to its immune landscape and response to immunotherapy. Vessel co-option means that tumor tissue adeptly exploits pre-existing blood vessels in the para-carcinoma region to foster its growth rather than inducing angiogenesis. It emerges as a significant mechanism contributing to anti-angiogenic therapy resistance. Different from angiogenic tumors, vessel co-option presents a distinctive vascular-immune niche characterized by varying states and distribution of immune cells, including T-cells, tumor-associated macrophages, neutrophils, and hepatic stellate cells. This unique composition contributes to an immunosuppressive tumor microenvironment that is crucial in modulating the response to cancer immunotherapy. In this review, we systematically reviewed the evidence and molecular mechanisms of vessel co-option in liver cancer, while also exploring its implications for anti-angiogenic drug resistance and the immune microenvironment, to provide new ideas and clues for screening patients with liver cancer who are effective in immunotherapy

EFFECTS OF SALVIA MILTIORRHIZAE ON THE KIDNEY OF RATS WITH SEVERE ACUTE PANCREATITIS AND OBSTRUTIVE JAUNDICE

Background: Severe acute pancreatitis (SAP) and obstructive jaundice (OJ) are frequent recurring diseases that bring about huge threat to human health. Some reports have demonstrated that Salviae miltiorrhizae can protect multiple organs of SAP and OJ model animals or patients, but their related mechanisms were not clear. In this study, we observed the effects of Salvia miltiorrhizae injection on apoptosis and NF-κB expression in kidney and explored the protective effect and mechanism of Salvia miltiorrhizae on the kidney of SAP or OJ rats. The results obtained will provide a theoretical basis for clinical application of Salvia miltiorrhizae. Material and Methods: A total of 288 rats were used for SAP - and OJ-associated experiments. The mortality rates of rats, the contents of serum BUN and CREA, the expression levels of Bax, NF-κB proteins and the apoptosis index were observed, respectively. Results: The pathological changes in the kidney of SAP or OJ rats in treated group were mitigated to varying degrees. At 6 and 12 hours after operation in SAP rats or on 21 and 28 days after operation in OJ rats, the contents of serum CREA in treated group were significantly lower than those in model control group; At 3 and 6 hours after operation, the staining intensity of Bax protein of kidney in treated group was significantly lower than that in model control group; on 14 days after operation, the apoptosis index in the kidney of OJ rats in treated group was significantly lower than that in model control group. Conclusion: Salvia miltiorrhizae can exert protective effects on the kidney of SAP and OJ rats

Protein Kinase D3 Is Essential for Prostratin-Activated Transcription of Integrated HIV-1 Provirus Promoter via NF-<i>κ</i>B Signaling Pathway

Prostratin has been proposed as a promising reagent for eradicating the latent HIV-1 provirus by inducing HIV-1 transcription activation. The molecular mechanism of this activation, however, is far from clear. Here, we show that the protein kinase D3 (PKD3) is essential for prostratin-induced transcription activation of latent HIV-1 provirus. First, silencing PKD3, but not the other members of PKD family, blocked prostratin-induced transcription of HIV-1. Second, overexpressing the constitutively active form of PKD3, but not the wild-type or kinase-dead form of PKD3, augmented the expression of HIV-1. Consistent with this observation, we found that prostratin could trigger PKD3 activation by inducing the phosphorylation of its activation loop. In addition, we identified PKCεof the novel PKC subfamily as the upstream kinase for this phosphorylation. Finally, the activation effect of PKD3 on HIV-1 transcription was shown to depend on the presence ofκB element and the prostratin-induced activation of NF-κB, as indicated by the fact that silencing PKD3 blocked prostratin-induced NF-κB activation and NF-κB-dependent HIV-1 transcription. Therefore, for the first time, PKD3 is implicated in the transcription activation of latent HIV-1 provirus, and our results revealed a molecular mechanism of prostratin-induced HIV-1 transcription via PKCε/PKD3/NF-κB signaling pathway.</jats:p

Experimental study of equal biaxial-to-uniaxial compressive strength ratio of concrete at early ages

The ratio of equal biaxial to uniaxial compressive strength of concrete, denoted as β, is an important parameter in the determination of failure criterion for concrete, which has been widely adopted in finite element codes in simulation of fracture and failure of concrete. However, there is no experimental study on β conducted for concretes at early ages. In this study, an experimental study on the uniaxial and equal biaxial compressive strengths of concretes at early ages up to 28 days was carried out using an in-house electro-hydraulic servo-controlled triaxial test machine. Concrete specimens with different coarse aggregate sizes (10 mm, 20 mm, 30 mm) and strength grades (C30, C40, C50) were tested at various ages (6 h, 12 h, 1 d, 3 d, 7 d, 14 d, 28 d). The results showed that β decreases with the increase of concrete age. In comparison, there are less significant effects of concrete strength and maximum coarse aggregate size on β. By regression analyses of experimental results, an empirical equation was proposed for β by considering the effects of age on β for concrete at early ages.The financial support of the National Natural Science Foundation of China under the grants of NSFC 51478084, 51421064, and 51478083, partial finance support from the UK Royal Academy of Engineering through the Distinguished Visiting Fellow scheme under the grant DVF1617_5_21 is gratefully acknowledged

Influence of paste thickness on the coated aggregates on properties of high-density sulphoaluminate cement concrete

An improved method for the densified mixture design algorithm and Fuller curve were used to design high-density sulphoaluminate cement concrete (HDSC). The performance of HDSC is significantly influenced by the paste thickness on the coated aggregates. Sulphoaluminate cement concrete mixtures containing aggregates coated with 3 different paste thickness of t=10μm, 20μm, and 30μm and water-binder ratios (W/B) of 0.25, 0.30 and 0.35 were prepared. The results of experiments show that paste thickness on the coated aggregates significantly influences the mechanical properties and durability of HDSC. With the increase of paste thickness, the compressive strength is increased, but the electrical resistivity is decreased, particularly at the early ages of 1 and 3 days. The sulfate corrosion resistance coefficients of HDSC are larger than 1.0, the total porosity can be less than 7%, and the micropore (i.e. with pore size less than 20nm) can be larger than 70%