SCML2 contributes to tumor cell resistance to DNA damage through regulating p53 and CHK1 stability.

SCML2 has been found to be highly expressed in various tumors. However, the extent to which SCML2 is involved in tumorigenesis and cancer therapy is yet to be fully understood. In this study, we aimed to investigate the relationship between SCML2 and DNA damage response (DDR). Firstly, DNA damage stabilizes SCML2 through CHK1-mediated phosphorylation at Ser570. Functionally, this increased stability of SCML2 enhances resistance to DNA damage agents in p53-positive, p53-mutant, and p53-negative cells. Notably, SCML2 promotes chemoresistance through distinct mechanisms in p53-positive and p53-negative cancer cells. SCML2 binds to the TRAF domain of USP7, and Ser441 is a critical residue for their interaction. In p53-positive cancer cells, SCML2 competes with p53 for USP7 binding and destabilizes p53, which prevents DNA damage-induced p53 overactivation and increases chemoresistance. In p53-mutant or p53-negative cancer cells, SCML2 promotes CHK1 and p21 stability by inhibiting their ubiquitination, thereby enhancing the resistance to DNA damage agents. Interestingly, we found that SCML2A primarily stabilizes CHK1, while SCML2B regulates the stability of p21. Therefore, we have identified SCML2 as a novel regulator of chemotherapy resistance and uncovered a positive feedback loop between SCML2 and CHK1 after DNA damage, which serves to promote the chemoresistance to DNA damage agents.

In situ polyphenol-adhesive hydrogel enhanced the noncarcinogenic repairing of KGF on the gut epithelial barrier on TNBS-induced colitis rats.

Ulcerative colitis (UC) is a chronic recurrent disease affecting the gastrointestinal tract especially colorectum. Keratinocyte growth factor (KGF) plays the vital roles in maintaining the colonic mucosal barrier. The poor stability and off-target of KGF were two hindering factors for its clinical application. Herein, in situ hydrogel (PE) with mucoadhesive ability was constructed by using temperature-sensitive poloxamer and EGCG as hydrogel-forming material and adhesive enhancer, respectively. Incorporation of EGCG led to the slight decrease of the gelled temperature and shortened the gelled time of PE hydrogel. When the concentration of EGCG is 0.1 %, PE hydrogel exhibits the suitable viscosity of 280 ± 20 Pa·s and the strong adhesive force of 725 ± 25 mN. KGF was soluble in cold PE solution to obtain KGF-loaded PE hydrogel (KGF@PE). PE hydrogel could improve the stability of KGF in vitro. KGF@PE not only could recover greatly the body weight of TNBS-induced rats but also repair their colonic morphology and goblet cell function. Moreover, the potential of repairing the epithelial barrier was indicated by upregulating tight junction proteins. Importantly, the safety of KGF@PE hydrogel for colitis was also confirmed on AOM/DSS-induced mice models. Conclusively, KGF@PE may be a promising therapeutic platform without obvious side effect for ulcerative colitis.

Self-assembled peptides-modified flexible field-effect transistors for tyrosinase detection.

Flexible biosensors have received intensive attention for real-time, non-invasive monitoring of cancer biomarkers. Highly sensitive tyrosinase biosensors, which are important for melanoma screening, remained a hurdle. Herein, high-performance tyrosinase-sensing field-effect transistor-based biosensors (bio-FETs) have been successfully achieved by self-assembling nanostructured tetrapeptide tryptophan-valine-phenylalanine-tyrosine (WVFY) on n-type metal oxide transistors. In the presence of target tyrosinase, the phenolic hydroxyl groups in WVFY are rapidly converted to benzoquinone with the consumption of protons, which could be detected potentiometrically by bio-FETs. As a result, the WVFY-modified bio-FETs exhibited an ultra-low detection limit of 1.9 fM and an optimal detection range of 10 fM to 1 nM toward tyrosinase sensing. Furthermore, flexible devices fabricated on ∼2.9-µm-thick polyimide (PI) substrates illustrated robust mechanical flexibility, which could be attached to human skin conformally. These achievements hold promise for wearable melanoma screening and provide designing guidelines for detecting other important cancer biomarkers with bio-FETs.

Recombinant invasive Lactobacillus plantarum expressing the J subgroup avian leukosis virus Gp85 protein induces protection against avian leukosis in chickens.

Avian leukosis, caused by avian leukosis virus (ALV), is an infectious tumor disease and severely hinders the development of the poultry industry. The use of Lactobacillus plantarum (L. plantarum) could effectively alleviate viremia in the early period of J subgroup ALV (ALV-J) infection. In this study, an invasive L. plantarum NC8 expressing Gp85 protein of ALV-J was constructed. After chickens were orally administered the recombinant invasive NC8, the levels of expression of CD4+ and CD8+ T lymphocytes in peripheral blood and spleen by flow cytometry and the proliferation ability of splenocytes by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were examined, and the contents of cytokines, the anti-ALV-J antibody in serum, and mucosal antibody sIgA in intestinal lavage fluid were detected by enzyme-linked immunosorbent assay (ELISA). The immunoprotective efficiency was evaluated by monitoring the infection rate, the percent of cloacal swabs and survival, body weight gain, the organ indexes, and relative virus loads after challenge with ALV-J. The results showed that the recombinant invasive strain (FnBPA-gp85) could promote the expression levels of the CD8+T cells in peripheral blood and spleen, the proliferation of splenocytes, the secretions of cytokines interleukin 2 (IL-2) and γ-interferon (IFN-γ), and the production of IgG and sIgA compared with the PBS and FnBPA control groups in chickens. The FnBPA-gp85 group was exhibited the highest immune protection against ALV-J infection. The above results indicated that the recombinant invasive NC8 could promote the cellular immunity, humoral immunity, and mucosal immunity responses in chicken and provide a new method for exploring the live vaccine against ALV-J.Key points• The FnBPA-gp85 strain could enhance cellular immunity response.• The FnBPA-gp85 strain could improve the immune protection against ALV-J infection.

A Skin-Inspired Artificial Mechanoreceptor for Tactile Enhancement and Integration.

Mechanoreceptors endow humans with the sense of touch by translating the external stimuli into coded spikes, inspiring the rise of artificial mechanoreceptor systems. However, to incorporate slow adaptive receptors-like pressure sensors with artificial neurons remains a challenge. Here we demonstrate an artificial mechanoreceptor by rationally integrating a polypyrrole-based resistive pressure sensor with a volatile NbOx memristor, to mimic the tactile sensation and perception in natural skin, respectively. The artificial mechanoreceptor enables the tactile sensory coding by converting the external mechanical stimuli into strength-modulated electrical spikes. Also, tactile sensation enhancement is achieved by processing the spike frequency characteristics with the pulse coupled neural network. Furthermore, the artificial mechanoreceptor can integrate signals from parallel sensor channels and encode them into unified electrical spikes, resembling the coding of intensity in tactile neural processing. These results provide simple and efficient strategies for constructing future bio-inspired electronic systems.