The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation

The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G₂/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1–3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle.     

ADRB2, brain white matter integrity and cognitive ageing in the Lothian Birth Cohort 1936

The non-synonymous mutations arg16gly (rs1042713) and gln27glu (rs1042714) in the adrenergic β-2 receptor gene (ADRB2) have been associated with cognitive function and brain white matter integrity. The current study aimed to replicate these findings and expand them to a broader range of cognitive and brain phenotypes. The sample used is a community-dwelling group of older people, the Lothian Birth Cohort 1936. They had been assessed cognitively at age 11 years, and undertook further cognitive assessments and brain diffusion MRI tractography in older age. The sample size range for cognitive function variables was N = 686–765, and for neuroimaging variables was N = 488–587. Previously-reported findings with these genetic variants did not replicate in this cohort. Novel, nominally significant associations were observed; notably, the integrity of the left arcuate fasciculus mediated the association between rs1042714 and the Digit Symbol Coding test of information processing speed. No significant associations of cognitive and brain phenotypes with ADRB2 variants survived correction for false discovery rate. Previous findings may therefore have been subject to type 1 error. Further study into links between ADRB2, cognitive function and brain white matter integrity is required.     

Three-dimensional image-guided combined intracavitary and interstitial high-dose-rate brachytherapy in cervical cancer: A systematic review

PurposeTo evaluate the local control and toxicities of three-dimensional image-guided combined intracavitary and interstitial (IC/IS) high-dose-rate brachytherapy (BT) in cervical cancer through a systematic review.Methods and MaterialsA systematic review of relevant studies was performed through the PubMed, Web of Science, and Cochrane Library databases through May 10, 2020. Articles reporting on IC/IS technology, volumetric doses to high-risk clinical target volume (HR-CTV) and organs at risk (OARs), tumor control and/or treatment-related side effects were identified. The key information, including the type of applicator, implantation technology, characteristics of implantation, volumetric doses, tumor control, and/or treatment-related side effects, was extracted. A probit model analysis between HR-CTV D90 and tumor local control was performed.ResultsTwelve studies encompassing 520 patients were included in the probit model between HR-CTV D90 and the local control rate. The probit model showed a significant relationship between the HR-CTV D90 value and the local control probability, p = 0.003. The prescribed dose of 85 Gy_EQD2,10 would in theory warrant an 87.4% (95% confidence interval 82.5%–90.5%) local control rate.ConclusionIC/IS BT is an appropriate method to achieve a high therapeutic ratio for tumors with large volumes or poor responses after external irradiation in cervical cancer. The probit model showed that the dose escalation of HR-CTV D90 was helpful to improve the local tumor control rate.     

Lymphoma outbreak in a GASH:Sal hamster colony

We have detected a high incidence of lymphomas in a colony of GASH:Sal Syrian golden hamsters (Mesocricetus auratus). This strain is characterised by its ability to present convulsive crises of audiogenic origin. Almost 16 % (90 males and 60 females) of the 975 animals were affected during a 5-year period by the development of a progressing lymphoid tumour and exhibited similar clinical profiles characterised by lethargy, anorexia, evident abdominal distension, and a rapid disease progression resulting in mortality within 1 to 2 weeks. A TaqMan® probe-based real-time PCR analysis of genomic DNA from different tissue samples of the affected animals revealed the presence of a DNA sequence encoding the hamster polyomavirus (HaPyV) VP1 capsid protein. Additionally, immunohistochemical analysis using HaPyV-VP1-specific monoclonal antibodies confirmed the presence of viral proteins in all hamster tumour tissues analysed within the colony. An indirect ELISA and western blot analysis confirmed the presence of antibodies against the VP1 capsid protein in sera, not only from affected and non-affected GASH:Sal hamsters but also from control hamsters from the same breeding area. The HaPyV genome that accumulated in tumour tissues typically contained deletions affecting the noncoding regulatory region and adjacent sequences coding for the N-terminal part of the capsid protein VP2.     

Thalamic atrophy in patients with pure hereditary spastic paraplegia type 4

Journal of Neurology - SPG4 is an autosomal dominant pure form of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. HSP is considered an upper motor neuron disorder...     

成年大鼠最后区神经干细胞的检测及鉴定

目的 观察性别决定基因高迁移率组蛋白( SOX2)和巢蛋白(Nestin)阳性表达细胞及溴脱氧尿密啶核苷（BrdU）阳性标记细胞在最后区的分布。方法 成年雄性SD大鼠12只,6~8周龄,随机分为两组,每组6只。一组大鼠按照50mg/kg（0.3ml）腹腔注射BrdU,连续3d给药,每天2次;另一组注射等量生理盐水。4d后灌注大鼠,行免疫组织化学及免疫荧光检测。 结果 免疫组织化学染色显示,SOX2阳性表达细胞在最后区的腹侧部呈明显的V字形分布,背侧部呈带状分布,中央部散在分布。Nestin阳性表达细胞在最后区的腹侧部呈明显的V字形强阳性分布,中央部呈弱阳性表达。在最后区可见少量阳性BrdU标记细胞。SOX2/BrdU荧光双标染色显示,SOX2阳性表达细胞较密集分布,可见少量SOX2/BrdU双阳性细胞。SOX2/Nestin荧光双标染色显示,SOX2阳性表达细胞较密集分布,可见少量SOX2/Nestin双阳性表达细胞。结论 最后区SOX2及Nestin阳性细胞密集表达,呈明显的区域分布;在最后区内存在少量BrdU阳性标记细胞及SOX2/BrdU和SOX2/Nestin双阳性细胞;最后区可能存在神经干细胞/祖细胞。     

A new mutation in the human cytomegalovirus UL97 gene may confer ganciclovir resistance in Chinese kidney transplant recipients

Mutations in the UL97 gene are the most common mechanism of human cytomegalovirus resistance to ganciclovir in transplant recipients. In this study, UL97 fragments were amplified and sequenced in 70 Chinese kidney transplant recipients who were diagnosed as having an active cytomegalovirus infection. A new mutation, C518Y, was identified in two kidney recipients, and this strain showed high-grade ganciclovir resistance by plaque reduction assay. The known mutations L595 W and C607F were detected in one recipient, but the D605E mutation was found in 42.9 % (30/70) of kidney recipients. The prevalence of this mutation was higher than that in Europe and may be associated with different regions or races.     

Sevoflurane Combined with ATP Activates Caspase-1 and Triggers Caspase-1-Dependent Pyroptosis in Murine J774 Macrophages

Sevoflurane is one of the most commonly used volatile anesthetics. Recent studies have shown that sevoflurane plays an important role in modulation of inflammation and immunity. However, little is known about the related molecular mechanisms. This study was designed to investigate the effects and mechanisms of sevoflurane on inflammatory cell death pyroptosis in the murine macrophage cell line J774 cells. Sevoflurane combined with ATP could increase the level of activated caspase-1, pyroptosis, and reactive oxygen species (ROS). Furthermore, treatment of cells with the caspase-1 inhibitor Ac-YVAD-CMK dramatically decreased the percentage of pyroptosis. In addition, inhibition of ROS with N-acetyl-l-cysteine or diphenyleneiodonium significantly reduced the activated levels of caspase-1. These results demonstrated that sevoflurane combined with ATP could activate caspase-1 and trigger caspase-1-dependent pyroptosis through the modulation of ROS production.