The balance of Polo-like kinase 1 in tumorigenesis

Polo-like kinase 1 (Plk1) belongs to a family of conserved serine/threonine kinases with a polo-box domain, which have similar but non-overlapping functions in the cell cycle progression. Plk1 plays a key role to ensure the normal mitosis. Interestingly, overexpression of Plk1 is associated with tumor development and could serve as a prognostic marker for many cancers. Due to Plk1 overexpression, several Plk1 inhibitors have been developed and tested for the cancer treatment. However, in a recent study, it has been suggested that down-regulation of Plk1 could also induce aneuploidy and tumor formation in vivo. Therefore, a normal level of Plk1 is important for mitosis. And caution should be taken when Plk1 inhibitors are used in the clinical trial and their side effects including tumorigenesis should be carefully evaluated

Existence of periodic solutions for a 2nth-order nonlinear difference equation

AbstractThe authors consider the 2nth-order difference equationΔn(rt−nΔnxt−n)+f(t,xt)=0,n∈Z(3),t∈Z, where f:Z×R→R is a continuous function in the second variable, f(t+T,z)=f(t,z) for all (t,z)∈Z×R, rt+T=rt for all t∈Z, and T a given positive integer. By the Linking Theorem, some new criteria are obtained for the existence and multiplicity of periodic solutions of the above equation

TYK2 promotes malignant peripheral nerve sheath tumor progression through inhibition of cell death

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise most commonly in the setting of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome. Despite aggressive multimodality therapy, outcomes are dismal and most patients die within 5 years of diagnosis. Prior genomic studies in our laboratory identified tyrosine kinase 2 (TYK2) as a frequently mutated gene in MPNST. Herein, we explored the function of TYK2 in MPNST pathogenesis. METHODS: Immunohistochemistry was utilized to examine expression of TYK2 in MPNSTs and other sarcomas. To establish a role for TYK2 in MPNST pathogenesis, murine and human TYK2 knockdown and knockout cells were established using shRNA and CRISPR/Cas9 systems, respectively. RESULTS: We have demonstrated that TYK2 was highly expressed in the majority of human MPNSTs examined. Additionally, we demonstrated that knockdown of Tyk2/TYK2 in murine and human MPNST cells significantly increased cell death in vitro. These effects were accompanied by a decrease in the levels of activated Stats and Bcl-2 as well as an increase in the levels of Cleaved Caspase-3. In addition, Tyk2-KD cells demonstrated impaired growth in subcutaneous and metastasis models in vivo. CONCLUSION: Taken together, these data illustrate the importance of TYK2 in MPNST pathogenesis and suggest that the TYK2 pathway may be a potential therapeutic target for these deadly cancers

Superhydrophobic Substrates from Off-The-Shelf Laboratory Filter Paper: Simplified Preparation, Patterning, and Assay Application

Off-the-shelf laboratory filter paper of different pore-sizes and thicknesses can be modified with fluorine-free organosilanes to be superhydrophobic, patternable, and ready for quantitative assay applications. In particular, we have demonstrated that cellulose filter paper treated with a binary hexane solution of short (methyltrichlorosilane, MTS) and long (octadecyltrichlorosilane, OTS) organosilanes, exhibits remarkably high water contact angles (> 150 °) and low wetting hysteresis (~10 °). Beyond the optimized ratio between the two organosilanes, we have discovered that the thickness rather than the pore size dictates the resulting superhydrophobicity. Scanning electron microscope (SEM) images showed that silianization does not damage the cellulose microfibers; instead they are coated with uniform, particulate nanostructures, which should contribute to the observed surface properties. The modified filter paper is chemically stable and mechanically durable; it can be readily patterned with UV/ozone treatment to create hydrophilic regions to prepare chemical assays for colorimetric pH and nitrite detections

Integrated Smartphone-App-Chip System for On-Site Ppb-Level Colorimetric Quantitation of Aflatoxins

We demonstrate herein an integrated, smartphone-app-chip (SPAC) system for on-site quantitation of food toxins, as demonstrated with aflatoxin B1 (AFB1), at parts-per-billion (ppb) level in food products. The detection is based on an indirect competitive immunoassay fabricated on a transparent plastic chip with the assistance of a microfluidic channel plate. A 3D-printed optical accessory attached to a smartphone is adapted to align the assay chip and to provide uniform illumination for imaging, with which high-quality images of the assay chip are captured by the smartphone camera and directly processed using a custom-developed Android app. The performance of this smartphone-based detection system was tested using both spiked and moldy corn samples; consistent results with conventional ELISA kits were obtained. The achieved detection limit (3±1 μg/kg, equivalent to ppb) and dynamic response range (0.5−250 μg/kg) meet the requested testing standards set by authorities worldwide. We envision that the integrated SPAC system promises to be a simple and accurate method of food toxin quantitation, bringing much benefit for rapid on-site screening

CHFR is important for the first wave of ubiquitination at DNA damage sites

Protein ubiquitination plays an important role in activating the DNA damage response and maintain-ing genomic stability. In response to DNA double-strand breaks (DSBs), a ubiquitination cascade occurs at DNA lesions. Here, we show that checkpoint with Forkhead-associated (FHA) and RING finger domain protein (CHFR), an E3 ubi-quitin ligase, is recruited to DSBs by poly(ADP-ribose) (PAR). At DSBs, CHFR regulates the first wave of protein ubiquitination. Moreover, CHFR ubiquitinates PAR polymerase 1 (PARP1) and regulates chromatin-associated PARP1 in vivo. Thus, these results demonstrate that CHFR is an important E3 ligase in the early stage of the DNA damage response, which mediates the crosstalk between ubiquitination and poly-ADP-ribosylation

A New Adjuvant MTOM Mediates Mycobacterium tuberculosis Subunit Vaccine to Enhance Th1-Type T Cell Immune Responses and IL-2+ T Cells

The only licensed vaccine Mycobacterium bovis Bacillus Calmette–Guérin (BCG) cannot prevent the prevalence of tuberculosis (TB), which remains a major public health problem worldwide. A more effective TB vaccine than BCG is urgently needed. Subunit vaccine is a promising strategy, and suitable adjuvants will benefit the development of effective TB subunit vaccines. MTO, consisting of monophosphoryl lipid A (MPLA), trehalose-6,6′-dibehenate (TDB), and MF59, was developed as an adjuvant of TB vaccine because of its ability to evoke the Th1-type T cell responses, while it is insufficient to induce single and multifunctional IL-2+ T cells and has a limited ability to confer protection against Mycobacterium tuberculosis infection. Heat-killed Mycobacterium vaccae (Mv), which can evoke cytotoxic CD8+ and CD4+ T cell responses and has adjuvanticity, was, in this study, combined with MTO to produce a new adjuvant, called MTOM. The TB fusion protein Rv3407-PhoY2-Ag85A-Rv2626c-RpfB (WH121) was mixed with MTO, Mv, and MTOM to produce three subunit vaccines, and the protective efficacy and immune responses were compared in C57BL/6 mice. WH121/MTOM provided better protection against TB than the other two vaccines, matching the performance of BCG vaccine. MTOM showed stronger ability to increase single and multifunctional IL-2+ T cells and induce Th1-type responses than MTO or Mv. Therefore, MTOM might be a promising adjuvant that could contribute to the development of TB subunit vaccines