A CRISPR/Cas9 gene editing strategy has been remarkable in excising segments of integrated HIV-1 DNA sequences from the genome of latently infected human cell lines and by introducing InDel ...mutations, suppressing HIV-1 replication in patient-derived CD4+ T-cells, ex vivo. Here, we employed a short version of the Cas9 endonuclease, saCas9, together with a multiplex of guide RNAs (gRNAs) for targeting the viral DNA sequences within the 5'-LTR and the Gag gene for removing critically important segments of the viral DNA in transgenic mice and rats encompassing the HIV-1 genome. Tail-vein injection of transgenic mice with a recombinant Adeno-associated virus 9 (rAAV9) vector expressing saCas9 and the gRNAs, rAAV:saCas9/gRNA, resulted in the cleavage of integrated HIV-1 DNA and excision of a 978 bp DNA fragment spanning between the LTR and Gag gene in the spleen, liver, heart, lung and kidney as well as in the circulating lymphocytes. Retro-orbital inoculation of rAAV9:saCas9/gRNA in transgenic rats eliminated a targeted segment of viral DNA and substantially decreased the level of viral gene expression in circulating blood lymphocytes. The results from the proof-of-concept studies, for the first time, demonstrate the in vivo eradication of HIV-1 DNA by CRISPR/Cas9 on delivery by an rAAV9 vector in a range of cells and tissues that harbor integrated copies of viral DNA.
Summary
To identify the critical genes and pathways that related to OP development in male AS patients, bioinformatic gene analysis and qRT-PCR validation were performed. SBNO2 and VPS13B were ...identified as the potential target for OP development, which may be valuable for the prevention of OP in male AS patients.
Introduction
Osteoporosis (OP) is common in men with ankylosing spondylitis (AS). The specific pathogenesis of OP in AS, however, is still unclear. The present study attempted to identify potential genes associated with the development of OP in males with AS.
Methods
Gene expression profiles were downloaded from the GSE73754 and GSE35959 datasets from the Gene Expression Omnibus (GEO). Data from OsteoporosAtlas were downloaded as a supplement. Differentially expressed genes (DEGs) were determined with the
limma
package. The overlapping DEGs between male AS-related genes and OP-related genes were determined. The DEGs were validated by qRT-PCR in the blood samples of males with AS. Weighted gene co-expression network analysis (WGCNA) was utilized to establish a co-expression network to identify the hub genes.
Results
A total of 17 overlapping DEGs were identified; 6 genes in 17 overlapping DEGs were verified as the essential genes in the pathogenesis of OP in male AS by qRT-PCR analysis. After WGCNA, the modules of MEblue (> 0.6) and MEred (> 0.8) were screened out by the correlation analysis and were determined to function mainly in MAPK signaling pathway and osteoclast differentiation. Analysis of the two modules revealed VPS13B and SBNO2 as key genes due to the high degree of correlation. Both genes play an important role in bone metabolism regulation in male AS. Two hub genes MYD88 in MEblue and NCK1 in MEred with high degree of connectivity were selected.
Conclusions
Gender-specific SBNO2 and VPS13B may be key genes involved in OP in male AS.
The p53 pathway is composed of hundreds of genes and their products that respond to a wide variety of stress signals. These responses to stress include apoptosis, cellular senescence or cell cycle ...arrest. In addition the p53-regulated genes produce proteins that communicate these stress signals to adjacent cells, prevent and repair damaged DNA and create feedback loops that enhance or attenuate p53 activity and communicate with other signal transduction pathways. Many questions remain to be explored in our understanding of how this network of genes plays a role in protection from cancers, therapy and integrating the homeostatic mechanisms of stress management and fidelity in a cell and organism. The goal of this chapter is to elucidate some of those questions and suggest new directions for this area of research.
Background
Liver resection is effective for hepatocellular carcinoma (HCC) exceeding the Milan criteria in selected patients. However, the benefit of anatomical resection (AR) versus non‐anatomical ...resection (NAR) has not been clarified in this patient subgroup. This study aimed to compare outcomes between AR and NAR for HCC exceeding the Milan criteria.
Methods
Data on consecutive patients with HCC exceeding the Milan criteria who underwent liver resection with curative intent over a recent 6‐year interval were extracted from a prospective single‐centre HCC database and examined retrospectively. The postoperative outcomes of patients were compared before and after propensity score matching.
Results
Some 546 patients were included: 264 in the AR and 282 in the NAR group. In the original cohort, the AR group contained more patients with larger tumours, multiple tumours, macroscopic portal vein tumour thrombi, incomplete tumour capsules and microscopic vascular invasion. After propensity score matching, 177 pairs of patients were selected. The baseline data, including liver function and tumour burden, were similar in the matched groups. The 3‐year recurrence‐free survival rate was comparable between the matched NAR and AR groups (36·5 versus 28·5 per cent; P = 0·448). Similar results were observed for 3‐year overall survival (57·5 versus 50·3 per cent; P = 0·385), recurrence patterns and early recurrence rates (57·6 per cent versus 59·9 per cent; P = 0·712).
Conclusion
AR and NAR achieved favourable and similar outcomes for HCC exceeding the Milan criteria in selected patients.
No difference
Toll-like receptors (TLRs) are a family of pattern recognition receptors involved in cardiovascular diseases. Notably, numerous studies have demonstrated that TLR4 activates the expression of several ...of pro-inflammatory cytokine genes that play pivotal roles in myocardial inflammation, particularly myocarditis, myocardial infarction, ischemia-reperfusion injury, and heart failure. In addition, TLR4 is an emerging target for anti-inflammatory therapies. Given the significance of TLR4, it would be useful to summarize the current literature on the molecular mechanisms and roles of TLR4 in myocardial inflammation. Thus, in this review, we first introduce the basic knowledge of the TLR4 gene and describe the activation and signaling pathways of TLR4 in myocardial inflammation. Moreover, we highlight the recent progress of research on the involvement of TLR4 in myocardial inflammation. The information reviewed here may be useful to further experimental research and to increase the potential of TLR4 as a therapeutic target.
We present measurements of the number density of voids in the dark matter distribution from a series of N-body simulations of a Λ cold dark matter cosmology. We define voids as spherical regions of ...ρv = 0.2ρm around density minima in order to relate our results to the predicted abundances using the excursion set formalism. Using a linear underdensity of δv = −2.7, from a spherical evolution model, we find that a volume-conserving model, which does not conserve number density in the mapping from the linear to non-linear regime, matches the measured abundance to within 16 per cent for a range of void radii 1 < r(h
−1 Mpc) < 15. This model fixes the volume fraction of the universe which is in voids and assumes that voids of a similar size merge as they expand by a factor of 1.7 to achieve a non-linear density of ρv = 0.2ρm today. We find that the model of Sheth and van de Weygaert for the number density of voids greatly overpredicts the abundances over the same range of scales. We find that the volume-conserving model works well at matching the number density of voids measured from the simulations at higher redshifts, z = 0.5 and 1, as well as correctly predicting the abundances to within 25 per cent in a simulation of a matter dominated Ωm = 1 universe. We examine the abundance of voids in the halo distribution and find fewer small, r < 10 h
−1 Mpc, voids and many more large, r > 10 h
−1 Mpc, voids compared to the dark matter. These results indicate that voids identified in the halo or galaxy distribution are related to the underlying void distribution in the dark matter in a complicated way which merits further study if voids are to be used as a precision probe of cosmology.
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