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The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology.

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2-hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D-2HG, we generated transgenic mice with conditionally activated IDH2(R140Q) and IDH2(R172K) alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span, recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant up-regulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2(R140Q)-expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2(R140Q) in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition.

Inhibition of the functional activity of Filamenting temperature-sensitive mutant Z (FtsZ) protein, an essential and highly conserved bacterial cytokinesis protein, is a promising approach for the development of a new class of antibacterial agents. Berberine, a benzylisoquinoline alkaloid widely used in traditional Chinese and native American medicines for its antimicrobial properties, has been recently reported to inhibit FtsZ. Using a combination of in silico structure-based design and in vitro biological assays, 9-phenoxyalkyl berberine derivatives were identified as potent FtsZ inhibitors. Compared to the parent compound berberine, the derivatives showed a significant enhancement of antibacterial activity against clinically relevant bacteria, and an improved potency against the GTPase activity and polymerization of FtsZ. The most potent compound 2 strongly inhibited the proliferation of Gram-positive bacteria, including methicillin-resistant S. aureus and vancomycin-resistant E. faecium, with MIC values between 2 and 4 µg/mL, and was active against the Gram-negative E. coli and K. pneumoniae, with MIC values of 32 and 64 µg/mL respectively. The compound perturbed the formation of cytokinetic Z-ring in E. coli. Also, the compound interfered with in vitro polymerization of S. aureus FtsZ. Taken together, the chemical modification of berberine with 9-phenoxyalkyl substituent groups greatly improved the antibacterial activity via targeting FtsZ.

The dominance of Asian communities in international league tables such as those produced by The Program for International Student Assessment, which monitors competence in literacy and numeracy, has resulted in a policy discourse from the English government of failing schools, deficit curricular and ineffective teachers. This in turn has led to a re-defining of the National Curriculum framework for pupils educated in England with greater focus given in the Early Years curriculum to Mathematical functions particularly those associated with skills in counting; understanding and using number; calculating simple addition and subtraction problems and the understanding of shape, space and measure. Drawing on research carried out in Hong Kong and England this article offers a cross-cultural comparison of the expectations of Early Years Teachers in terms of the capabilities of early learners in achieving elements of number competency. The study of teachers' expectation is a neglected field in research when applied to compare intercultural achievement. In identifying divergent national expectations, the current panic over what constitutes an appropriate maths curriculum is critiqued and recommendations made for further exploration into teachers' expectations as to the age and stage at which elements of the maths curriculum are introduced in English schools.

In the present study, the mediating roles of syllable awareness, orthographic knowledge, and vocabulary skills and the moderating role of morpheme family size in the association between morphological awareness and Chinese character reading were investigated with 176 second-grade Hong Kong Chinese children. In the path analyses, the results indicated significant partial mediating effects of semantic radical function knowledge and vocabulary skills but not of syllable awareness and pseudocharacter identification. A significant moderating effect of morpheme family size was also observed. Children with relatively poor compounding structure awareness performed much more poorly in reading Chinese characters that had a small family size. The mediating and moderating effects documented in the present study can help us understand the mechanism involved in the relationship between morphological awareness and Chinese character reading and provide evidence as a basis for modifying current instruction strategies for improving Chinese children's reading performance.

Metastasis is the dominant cause of patient death in small-cell lung cancer (SCLC), and a better understanding of the molecular mechanisms underlying SCLC metastasis may potentially improve clinical treatment. Through genome-scale screening for key regulators of mouse [Rb1.sup.-/-] [Trp53.sup.-/-] SCLC metastasis using the pooled CRISPR/Cas9 library, we identified Cullin5 (CUL5) and suppressor of cytokine signaling 3 (SOCS3), two components of the Cullin-RING E3 ubiquitin ligase complex, as top candidates. Mechanistically, the deficiency of CUL5 or SOCS3 disrupted the functional formation of the E3 ligase complex and prevented the degradation of integrin [beta]1, which stabilized integrin [beta]1 and activated downstream focal adhesion kinase/SRC (FAK/SRC) signaling and eventually drove SCLC metastasis. Low expression levels of CUL5 and SOCS3 were significantly associated with high integrin [beta]1 levels and poor prognosis in a large cohort of 128 clinical patients with SCLC. Moreover, the CUL5-deficient SCLCs were vulnerable to the treatment of the FDA-approved SRC inhibitor dasatinib. Collectively, this work identifies the essential role of CUL5- and SOCS3- mediated integrin [beta]1 turnover in controlling SCLC metastasis, which might have therapeutic implications., Introduction Small-cell lung cancer (SCLC) is the most aggressive and highly metastatic subtype of lung cancer and accounts for approximately 15% of all lung cancer cases (1). The 5-year survival [...]

Introduction: Total knee arthroplasty has been adopted to be the most successful treatment for advanced knee osteoarthritis. The adoption of multimodal periarticular analgesic (MPI) has been shown to have satisfactory pain control after surgery. However, there is relatively lack of data investigating whether this mode of pain control is effective in enhancing rehabilitation. Method: This is a prospective randomized control trial from July 2017 to June 2018, including 82 patients, in which 43 of them had MPI injection and 39 of them had no MPI injection. Primary outcome measures included the number of days required to perform straight leg raise, length of hospital stay, and Insall knee score upon discharge. Secondary outcome measures included total dose of patient-controlled analgesia (PCA) consumption postoperatively and visual analog scale (VAS) at rest and on motion during postoperative days 1–4. Result: The MPI group performed significantly better than the femoral nerve block (FNB) group in terms of early functional outcome, namely the number of days required to perform straight leg raising and length of hospital stay. The total postoperative PCA consumption and VAS score on motion during postoperative day 1 were also significantly better for MPI group. There was no difference in Insall knee score upon discharge between these two groups. Conclusion: Compared to FNB, MPI depicts a faster inpatient rehabilitation, accounted by its quadriceps-sparing, and better pain relief especially in the early postoperative period.