CKS Proteins Promote Checkpoint Recovery by Stimulating Phosphorylation of Treslin

CKS proteins are small (9-kDa) polypeptides that bind to a subset of the cyclin-dependent kinases. The two paralogs expressed in mammals, Cks1 and Cks2, share an overlapping function that is essential for early development. However, both proteins are frequently overexpressed in human malignancy. It has been shown that CKS protein overexpression overrides the replication stress checkpoint, promoting continued origin firing. This finding has led to the proposal that CKS protein-dependent checkpoint override allows premalignant cells to evade oncogene stress barriers, providing a causal link to oncogenesis. Here, we provide mechanistic insight into how overexpression of CKS proteins promotes override of the replication stress checkpoint. We show that CKS proteins greatly enhance the ability of Cdk2 to phosphorylate the key replication initiation protein treslin in vitro. Furthermore, stimulation of treslin phosphorylation does not occur by the canonical adapter mechanism demonstrated for other substrates, as cyclin-dependent kinase (CDK) binding-defective mutants are capable of stimulating treslin phosphorylation. This effect is recapitulated in vivo, where silencing of Cks1 and Cks2 decreases treslin phosphorylation, and overexpression of wild-type or CDK binding-defective Cks2 prevents checkpoint-dependent dephosphorylation of treslin. Finally, we provide evidence that the role of CKS protein-dependent checkpoint override involves recovery from checkpoint-mediated arrest of DNA replication

Achieving Peace on the Korean Peninsula

The possibility of peace seems closer than ever before, but caution is necessary

Tunable Magnetic Resonance in Microwave Spintronics Devices

Magnetic resonance is one of the key properties of magnetic materials for the application of microwave spintronics devices. The conventional method for tuning magnetic resonance is to use an electromagnet, which provides very limited tuning range. Hence, the quest for enhancing the magnetic resonance tuning range without using an electromagnet has attracted tremendous attention. In this paper, we exploit the huge exchange coupling field between magnetic interlayers, which is on the order of 4000 Oe and also the high frequency modes of coupled oscillators to enhance the tuning range. Furthermore, we demonstrate a new scheme to control the magnetic resonance frequency. Moreover, we report a shift in the magnetic resonance frequency as high as 20 GHz in CoFe-based tunable microwave spintronics devices, which is 10X higher than conventional methods

Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study

Objective: Serum α-fetoprotein (AFP) is the most commonly used biomarker for screening hepatocellular carcinoma (HCC) but fails to detect about half of the patients. Thus, we investigated if circulating microRNAs (miRNAs) could outperform AFP for HCC detection. Design: A retrospective cohort study. Setting: Two clinical centres in China. Participants: The exploration phase included 96 patients with HCC who received primary curative hepatectomy, and the validation phase included 29 hepatitis B carriers, 57 patients with HCC and 30 healthy controls. Main outcome measures: Expression of miRNAs was measured by real-time quantitative reverse transcription-PCR. Areas under receiver operating characteristic curves were used to determine the feasibility of using serum miRNA concentration as a diagnostic marker for defining HCC. A multivariate logistic regression analysis was used to evaluate performances of combined serum miRNAs. Results: In the exploration phase, miRNA profiling on resected tumour/adjacent non-tumour tissues identified miR-15b, miR-21, miR-130b and miR-183 highly expressed in tumours. These miRNAs were also detectable in culture supernatants of HCC cell lines and in serum samples of patients. Remarkably, these serum miRNAs were markedly reduced after surgery, indicating the tumour-derived source of these circulating miRNAs. In a cross-centre validation study, combined miR-15b and miR-130b demonstrated as a classifier for HCC detection, yielding a receiver operating characteristic curve area of 0.98 (98.2% sensitivity and 91.5% specificity). The detection sensitivity of the classifier in a subgroup of HCCs with low AFP (<20 ng/ml) was 96.7%. The classifier also identified early-stage HCC cases that could not be detected by AFP. Conclusion: The combined miR-15b and miR-130b classifier is a serum biomarker with clinical value for HCC screening.published_or_final_versio

Molecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote

The box jellyfish Chironex fleckeri is extremely venomous, and envenoming causes tissue necrosis, extreme pain and death within minutes after severe exposure. Despite rapid and potent venom action, basic mechanistic insight is lacking. Here we perform molecular dissection of a jellyfish venom-induced cell death pathway by screening for host components required for venom exposure-induced cell death using genome-scale lenti-CRISPR mutagenesis. We identify the peripheral membrane protein ATP2B1, a calcium transporting ATPase, as one host factor required for venom cytotoxicity. Targeting ATP2B1 prevents venom action and confers long lasting protection. Informatics analysis of host genes required for venom cytotoxicity reveal pathways not previously implicated in cell death. We also discover a venom antidote that functions up to 15 minutes after exposure and suppresses tissue necrosis and pain in mice. These results highlight the power of whole genome CRISPR screening to investigate venom mechanisms of action and to rapidly identify new medicines

Compression Fractures in the Setting of Diffuse Idiopathic Skeletal Hyperostosis

Compression fractures are the most common vertebral fractures. They involve the anterior column of the spine, and are considered stable fractures due to the presence of intact posterior ligaments that aid in resisting further collapse and deformity. They are thus often managed conservatively. We describe a series of 3 cases that were initially diagnosed as compression fractures and managed conservatively. With the abundance of compression fractures and increase in preference for conservative management of compression fractures, it is of utmost importance to recognize the possibility of other spinal co-pathologies, especially that of hyperostosis of the spine, both by clinical judgment as well as radiological analysis before embarking on conservative management, should there be under-treatment and development of complications that could have otherwise been avoided, as in the cases presented in this series

Software Architecture and System Design of Rubin Observatory

Starting from a description of the Rubin Observatory Data Management System Architecture, and drawing on our experience with and involvement in a range of other projects including Gaia, SDSS, UKIRT, and JCMT, we derive a series of generic design patterns and lessons learned.Comment: 10 pages ADASS XXXII submissio