LATS1/2 kinases trigger self-renewal of cancer stem cells in aggressive oral cancer

Cancer stem cells (CSCs), which play important roles in tumor initiation and progression, are resistant to many types of therapies. However, the regulatory mechanisms underlying CSC-specific properties, including self-renewal, are poorly understood. Here, we found that LATS1/2, the core Hippo pathway-kinases, were highly expressed in the oral squamous cell carcinoma line SAS, which exhibits high capacity of CSCs, and that depletion of these kinases prevented SAS cells from forming spheres under serum-free conditions. Detailed examination of the expression and activation of LATS kinases and related proteins over a time course of sphere formation revealed that LATS1/2 were more highly expressed and markedly activated before initiation of self-renewal. Moreover, TAZ, SNAIL, CHK1/2, and Aurora-A were expressed in hierarchical, oscillating patterns during sphere formation, suggesting that the process consists of four sequential steps. Our results indicate that LATS1/2 trigger self-renewal of CSCs by regulating the Hippo pathway, the EMT, and cell division

CDK12 globally stimulates RNA polymerase II transcription elongation and carboxyl-terminal domain phosphorylation

Cyclin-dependent kinase 12 (CDK12) phosphorylates the carboxyl-terminal domain (CTD) of RNA polymerase II (pol II) but its roles in transcription beyond the expression of DNA damage response genes remain unclear. Here, we have used TT-seq and mNET-seq to monitor the direct effects of rapid CDK12 inhibition on transcription activity and CTD phosphorylation in human cells. CDK12 inhibition causes a genome-wide defect in transcription elongation and a global reduction of CTD Ser2 and Ser5 phosphorylation. The elongation defect is explained by the loss of the elongation factors LEO1 and CDC73, part of PAF1 complex, and SPT6 from the newly-elongating pol II. Our results indicate that CDK12 is a general activator of pol II transcription elongation and indicate that it targets both Ser2 and Ser5 residues of the pol II CTD

The zero-field superconducting phase transition obscured by finite-size effects in thick YBa2Cu3O7−δ\mathrm{\bf{YBa_{2}Cu_{3}O_{7-\delta}}} films

We report on the normal-superconducting phase transition in thick $\mathrm{YBa_{2}Cu_{3}O_{7-\delta}}$ films in zero magnetic field. We find significant finite-size effects at low currents even in our thickest films ($d = 3200$ \AA). Using data at higher currents, we can unambiguously find $T_c$ and $z$, and show $z = 2.1 \pm 0.15$, as expected for the three-dimensional XY model with diffusive dynamics. The crossover to two-dimensional behavior, seen by other researchers in thinner films ($d \leq 500$ \AA), obscures the three-dimensional transition in both zero field and the vortex-glass transition in field, leading to incorrect values of $T_c$ (or $T_g$), $\nu$, and $z$. The finite-size effects, usually ignored in thick films, are an explanation for the wide range of critical exponents found in the literature.Comment: 5 pages, 4 figure

Genopal™: A Novel Hollow Fibre Array for Focused Microarray Analysis

Expression profiling of target genes in patient blood is a powerful tool for RNA diagnosis. Here, we describe Genopal™, a novel platform ideal for efficient focused microarray analysis. Genopal™, which consists of gel-filled fibres, is advantageous for high-quality mass production via large-scale slicing of the Genopal™ block. We prepared two arrays, infectant and autoimmunity, that provided highly reliable data in terms of repetitive scanning of the same and/or distinct microarrays. Moreover, we demonstrated that Genopal™ had sensitivity sufficient to yield signals in short hybridization times (0.5 h). Application of the autoimmunity array to blood samples allowed us to identify an expression pattern specific to Takayasu arteritis based on the Spearman rank correlation by comparing the reference profile with those of several autoimmune diseases and healthy volunteers (HVs). The comparison of these data with those obtained by other methods revealed that they exhibited similar expression profiles of many target genes. Taken together, these data demonstrate that Genopal™ is an advantageous platform for focused microarrays with regard to its low cost, rapid results and reliable quality

Expression Profiling of PBMC-based Diagnostic Gene Markers Isolated from Vasculitis Patients

Vasculitis (angiitis) is a systemic autoimmune disease that often causes fatal symptoms. We aimed to isolate cDNA markers that would be useful for diagnosing not only vasculitis but also other autoimmune diseases. For this purpose, we used stepwise subtractive hybridization and cDNA microarray analyses to comprehensively isolate the genes whose expressions are augmented in peripheral blood mononuclear cells (PBMCs) pooled from vasculitis patients. Subsequently, we used quantitative real-time polymerase chain reaction (qRT–PCR) to examine the mRNA levels of each candidate gene in individual patients. These analyses indicated that seven genes exhibit remarkably augmented expression in many vasculitis patients. Of these genes, we analyzed G0/G1 switch gene 2 (G0S2) further because G0S2 expression is also enhanced in the PBMCs of patients with systemic lupus erythematodes (SLE). We generated G0S2 transgenic mice that ubiquitously overexpress human G0S2. Although we did not observe any obvious vasculitis-related histopathologic findings in these mice, these mice are unhealthy as they produce only few offspring and showed elevated serum levels of two autoimmunity-related antibodies, anti-nuclear antibody, and anti-double strand DNA antibody. Thus, our large-scale gene profiling study may help finding sensitive and specific DNA markers for diagnosing autoimmune diseases including vasculitis and SLE

Simultaneous disruption of two DNA polymerases, Polη and Polζ, in Avian DT40 cells unmasks the role of Polη in cellular response to various DNA lesions

Replicative DNA polymerases are frequently stalled by DNA lesions. The resulting replication blockage is released by homologous recombination (HR) and translesion DNA synthesis (TLS). TLS employs specialized TLS polymerases to bypass DNA lesions. We provide striking in vivo evidence of the cooperation between DNA polymerase η, which is mutated in the variant form of the cancer predisposition disorder xeroderma pigmentosum (XP-V), and DNA polymerase ζ by generating POLη−/−/POLζ−/− cells from the chicken DT40 cell line. POLζ−/− cells are hypersensitive to a very wide range of DNA damaging agents, whereas XP-V cells exhibit moderate sensitivity to ultraviolet light (UV) only in the presence of caffeine treatment and exhibit no significant sensitivity to any other damaging agents. It is therefore widely believed that Polη plays a very specific role in cellular tolerance to UV-induced DNA damage. The evidence we present challenges this assumption. The phenotypic analysis of POLη−/−/POLζ−/− cells shows that, unexpectedly, the loss of Polη significantly rescued all mutant phenotypes of POLζ−/− cells and results in the restoration of the DNA damage tolerance by a backup pathway including HR. Taken together, Polη contributes to a much wide range of TLS events than had been predicted by the phenotype of XP-V cells

An IND-CCA-Secure Code-Based EncryptionScheme Using Rank Metric

The use of rank instead of Hamming metric has been proposed to address the main drawback of code-based cryptography: large key sizes. There exist several Key Encapsulation Mechanisms (KEM) and Public Key Encryption (PKE) schemes using rank metric including some submissions to the NIST call for standardization of Post-Quantum Cryptography. In this work, we present an IND-CCA PKE scheme based on the McEliece adaptation to rank metric proposed by Loidreau at PQC 2017. This IND-CCA PKE scheme based on rank metric does not use a hybrid construction KEM + symmetric encryption. Instead, we take advantage of the bigger message space obtained by the different parameters chosen in rank metric, being able to exchange multiple keys in one ciphertext. Our proposal is designed considering some specific properties of the random error generated during the encryption. We prove our proposal IND-CCA-secure in the QROM by using a security notion called disjoint simulatability introduced by Saito et al. in Eurocrypt 2018. Moreover, we provide security bounds by using the semi-oracles introduced by Ambainis et al

Secure Key Encapsulation Mechanism with Compact Ciphertext and Public Key from Generalized Srivastava code

Code-based public key cryptosystems have been found to be an interesting option in the area of Post-Quantum Cryptography. In this work, we present a key encapsulation mechanism (KEM) using a parity check matrix of the Generalized Srivastava code as the public key matrix. Generalized Srivastava codes are privileged with the decoding technique of Alternant codes as they belong to the family of Alternant codes. We exploit the dyadic structure of the parity check matrix to reduce the storage of the public key. Our encapsulation leads to a shorter ciphertext as compared to DAGS proposed by Banegas et al. in Journal of Mathematical Cryptology which also uses Generalized Srivastava code. Our KEM provides IND-CCA security in the random oracle model. Also, our scheme can be shown to achieve post-quantum security in the quantum random oracle model