A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 Protein.

Melanoma is a highly aggressive tumor with a poor prognosis, and half of all melanoma patients harbor BRAF mutations. A BRAF inhibitor, vemurafenib (PLX4032), has been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to treat advanced melanoma patients with BRAFV600E mutation. However, the efficacy of vemurafenib is impeded by adaptive resistance in almost all patients. In this study, using a cell-based SELEX (systematic evolution of ligands by exponential enrichment) strategy, we obtained a DNA aptamer (named LL4) with high affinity and specificity against vemurafenib-resistant melanoma cells. Optimized truncated form (LL4A) specifically binds to vemurafenib-resistant melanoma cells with dissociation constants in the nanomolar range and with excellent stability and low toxicity. Meanwhile, fluorescence imaging confirmed that LL4A significantly accumulated in tumors formed by vemurafenib-resistant melanoma cells, but not in control tumors formed by their corresponding parental cells in vivo. Further, a transmembrane protein CD63 was identified as the binding target of aptamer LL4A using a pull-down assay combined with the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. CD63 formed a supramolecular complex with TIMP1 and β1-integrin, activated the nuclear factor кB (NF-кB) and mitogen-activated protein kinase (MAPK) signaling pathways, and contributed to vemurafenib resistance. Potentially, the aptamer LL4A may be used diagnostically and therapeutically in humans to treat targeted vemurafenib-resistant melanoma

A rolling bearing fault diagnosis method based on VMD – multiscale fractal dimension/energy and optimized support vector machine

To achieve the goal of automated rolling bearing fault diagnosis, a variational mode decomposition (VMD) based diagnosis scheme was proposed. VMD was firstly used to decompose the vibration signals into a series of band-limited intrinsic mode functions (BLIMFs). Subsequently, the multiscale fractal dimension (MSFD) and multiscale energy (MSEN) of each BLIMF were calculated and combined together as features of the original vibration signals. In an attempt to accelerate the classification speed, one-way analysis of variance (ANOVA) test was adopted to extract significant features from the redundant features. Finally, those significant features were fed into the optimized support vector machine (SVM), which was optimized by the genetic algorithm (GA), for classification. Experimental results on the international public Case Western Reserve University bearing data indicate the effectiveness of the proposed method with a classification accuracy of 99.75 % for seven classes. Moreover, our approach also shows good anti-noise performance in different signal-to-noise ratios (SNRs)

Robust memristors based on layered two-dimensional materials

Van der Waals heterostructures are formed by stacking layers of different two-dimensional materials and offer the possibility to design new materials with atomic-level precision. By combining the valuable properties of different 2D systems, such heterostructures could potentially be used to address existing challenges in the development of electronic devices, particularly those that require vertical multi-layered structures. Here we show that robust memristors with good thermal stability, which is lacking in traditional memristors, can be created from a van der Waals heterostructure composed of graphene/MoS2–xO x/graphene. The devices exhibit excellent switching performance with an endurance of up to 107 and a high operating temperature of up to 340 °C. With the help of in situ electron microscopy, we show that the thermal stability is due to the MoS2–xO x switching layer, as well as the graphene electrodes and the atomically sharp interface between the electrodes and the switching layer. We also show that the devices have a well-defined conduction channel and a switching mechanism that is based on the migration of oxygen ions. Finally, we demonstrate that the memristor devices can be fabricated on a polyimide substrate and exhibit good endurance against over 1,000 bending cycles, illustrating their potential for flexible electronic applications

Preparation, structure and antimicrobial properties of modified gelatin composite hydrogel from chicken, bovine and porcine lung

In this paper, the reaction process parameters of the hydrogel produced by the modified gelatin from chicken, bovine and porcine lungs with carboxymethyl chitosan (CMCS) and oxidized glucomannan (OKGM) were optimized to produce Schiff base reaction. The results showed the properties of the three composite hydrogels are improved when the value of gelatin/CMCS/OKGM reached 1:2:2. The best modified gelatin/CMCS/OKGM of bovine lung composite hydrogel (COBH) had a gelatin strength of 8.14 N, a swelling rate of 257%, a water evaporation rate of 66.86%, and an antibacterial property of 38.02%. The properties of modified gelatin/CMCS/OKGM of chicken lung composite hydrogel (COCH) were similar to those of COBH. However, the water holding capacity of COCH was higher than that of COBH. The properties of the modified gelatin/CMCS/OKGM for porcine lung composite hydrogel (COPH) were significantly decreased over those of the other two. Therefore, COCH has potential applications in food coating and preservation

Uncovering lupus nephritis-specific genes and the potential of TNFRSF17-targeted immunotherapy: a high-throughput sequencing study

IntroductionLupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). This study aimed to identify LN specific-genes and potential therapeutic targets.MethodsWe performed high-throughput transcriptome sequencing on peripheral blood mononuclear cells (PBMCs) from LN patients. Healthy individuals and SLE patients without LN were used as controls. To validate the sequencing results, qRT-PCR was performed for 5 upregulated and 5 downregulated genes. Furthermore, the effect of the TNFRSF17-targeting drug IBI379 on patient plasma cells and B cells was evaluated by flow cytometry.ResultsOur analysis identified 1493 and 205 differential genes in the LN group compared to the control and SLE without LN groups respectively, with 70 genes common to both sets, marking them as LN-specific. These LN-specific genes were significantly enriched in the ‘regulation of biological quality’ GO term and the cell cycle pathway. Notably, several genes including TNFRSF17 were significantly overexpressed in the kidneys of both LN patients and NZB/W mice. TNFRSF17 levels correlated positively with urinary protein levels, and negatively with complement C3 and C4 levels in LN patients. The TNFRSF17-targeting drug IBI379 effectively induced apoptosis in patient plasma cells without significantly affecting B cells.DiscussionOur findings suggest that TNFRSF17 could serve as a potential therapeutic target for LN. Moreover, IBI379 is presented as a promising treatment option for LN

A potential relationship between MMP-9 rs2250889 and ischemic stroke susceptibility

PurposeIschemic stroke (IS), a serious cerebrovascular disease, greatly affects people's health and life. Genetic factors are indispensable for the occurrence of IS. As a biomarker for IS, the MMP-9 gene is widely involved in the pathophysiological process of IS. This study attempts to find out the relationship between MMP-9 polymorphisms and IS susceptibility.MethodsA total of 700 IS patients and 700 healthy controls were recruited. The single nucleotide polymorphism (SNP) markers of the MMP-9 gene were genotyped by the MassARRAY analyzer. Multifactor dimensionality reduction (MDR) was applied to generate SNP–SNP interaction. Furthermore, the relationship between genetic variations (allele and genotype) of the MMP-9 gene and IS susceptibility was analyzed by calculating odds ratios (ORs) and 95% confidence intervals (CIs).ResultsOur results demonstrated that rs2250889 could significantly increase the susceptibility to IS in the codominant, dominant, overdominant, and log-additive models (p < 0.05). Further stratification analysis showed that compared with the control group, rs2250889 was associated with IS risk in different case groups (age, female, smoking, and non-drinking) (p < 0.05). Based on MDR analysis, rs2250889 was the best model for predicting IS risk (cross-validation consistency: 10/10, OR = 1.56 (1.26–1.94), p < 0.001).ConclusionOur study preliminarily confirmed that SNP rs2250889 was significantly associated with susceptibility to IS

Functional Divergence among Silkworm Antimicrobial Peptide Paralogs by the Activities of Recombinant Proteins and the Induced Expression Profiles

Antimicrobial peptides are small-molecule proteins that are usually encoded by multiple-gene families. They play crucial roles in the innate immune response, but reports on the functional divergence of antimicrobial peptide gene families are rare. In this study, 14 paralogs of antimicrobial peptides belonging to cecropin, moricin and gloverin families were recombinantly expressed in pET expression systems. By antimicrobial activity tests, peptides representing paralogs in the same family of cecropin and moricin families, displayed remarkable differences against 10 tested bacteria. The evolutionary rates were relatively fast in the two families, which presented obvious functional divergence among paralogs of each family. Four peptides of gloverin family had similar antimicrobial spectrum and activity against tested bacteria. The gloverin family showed similar antimicrobial function and slow evolutionary rates. By induced transcriptional activity, genes encoding active antimicrobial peptides were upregulated at obviously different levels when silkworm pupae were infected by three types of microbes. Association analysis of antimicrobial activities and induced transcriptional activities indicated that the antimicrobial activities might be positively correlated with induced transcriptional activities in the cecropin and moricin families. These results suggest that representative BmcecB6, BmcecD and Bmmor as the major effector genes have broad antimicrobial spectrum, strong antimicrobial activity and high microbe-induced expression among each family and maybe play crucial roles in eliminating microbial infection