Alteration of RNA m6A methylation mediates aberrant RNA binding protein expression and alternative splicing in condyloma acuminatum.

Background: Condyloma acuminatum (CA) is caused by low-risk human papillomavirus, and is characterized by high recurrence after treatment. The RNA modification N6-methyladenosine (m6A) plays an important role during diverse viral infections, including high-risk HPV infection in cervical cancer. However, it is unclear whether low-risk HPV infection changes the RNA m6A methylation in CA. Methods: High-throughputm6A-sequencing was performed to profile the transcriptome-wide mRNA modifications of CA tissues infected by LR-HPVs and the paired normal tissues from CA patients. We further investigated the regulation of alternative splicing by RNA binding proteins (RBPs) with altered m6A modification and constructed a regulatory network among these RBPs, regulated alternative splicing events (RASEs) and regulated alternative splicing genes (RASGs) in CA. Results: The results show that the m6A level in CA tissues differed from that in the paired controls. Furthermore, cell cycle- and cell adhesion- associated genes with m6A modification were differentially expressed in CA tissues compared to the paired controls. In particular, seven RNA binding protein genes with specific m6A methylated sites, showed a higher or lower expression at the mRNA level in CA tissues than in the paired normal tissues. In addition, these differentially expressed RNA binding protein genes would regulate the alternative splicing pattern of apoptotic process genes in CA tissue. Conclusions: Our study reveals a sophisticated m6A modification profile in CA tissue that affects the response of host cells to HPV infection, and provides cues for the further exploration of the roles of m6A and the development of a novel treatment strategy for CA.

Insecticidal Activity of Essential Oils and Their Synergistic Effect on Improving the Efficacy of ß-Cypermethrin against Blattella germanica.

We screened the contact activity of 32 commercial essential oils (EOs) and their synergistic effect with ß-cypermethrin against Blattella germanica. Results showed that the most effective EOs against B. germanica were from Illicium verum, Syzygium aromaticum, and Cinnamomum camphora, with LD50 values of less than 500 µg/insect. The most potent synergistic effects of ß-cypermethrin on B. germanica were from Dysphania ambrosioides and Mentha canadensis. Both oils have a co-toxic factor of 133.33. The results of the major compound testing of the EOs showed that trans-anisaldehyde and thymol have the best insecticidal activity against B. germanica, with LD50 values of 141.30 and 138.61 µg/insect, respectively. The compounds with the best synergistic effect on ß-cypermethrin were γ-terpinene and linalool at a concentration of 0.5%. The co-toxic factors for γ-terpinene and linalool were 150 and 133.33, respectively, which were similar to the synergistic effect observed with 2% piperonyl butoxide.

Digital Image Analysis-Based Evaluation of Claudin-1 and Claudin-7 Delocalization in Cutaneous Squamous Cell Carcinoma and in Its Precancerous State.

Accumulating evidence has revealed that delocalization of the transmembrane proteins, Claudin-1 and Claudin-7, to the cytoplasm and/or nucleus occurs in various tumors. However, their subcellular distribution in terms of the membrane, cytoplasm, and nucleus and relationship with signaling pathways have not been elucidated during carcinogenesis. We first determined the expression of these proteins in the membrane, cytoplasm, and nucleus using ImageJ software and automatically collected the immunohistochemical quantification of dysplasia (actinic keratosis (AK)), carcinoma in situ (CIS; Bowen's disease (BD)), and invasive cutaneous squamous cell carcinoma (SCC) for digital image analysis (DIA). The activity of p-ERK, p-AKT, and p-mTOR and their correlation with subcellular Claudin-1 and Claudin-7 were also performed. Finally, we validated Claudin-1 and Claudin-7 delocalization at the cytoplasm and nucleus in cultured human normal keratinocytes and cutaneous SCC cells. Claudin-1 and Claudin-7 were delocalized as revealed by membranous, cytoplasmic, and nuclear staining in sun-exposed skin, AK, BD, and SCC. In BD, both membranous and cytoplasmic Claudin-1 (nuclear Claudin-1 decrease but no significant difference) were higher than AK, while Claudin-7 almost had the opposite situation. In SCC, cytoplasmic and nuclear Claudin-1 (membranous Claudin-1 no significant difference) was lower than in AK and sun-exposed skin, while Claudin-7 had higher membranous and cytoplasmic but lower nuclear expression. Moreover, p-AKT and p-mTOR (but not p-ERK) were downregulated in the SCC. Subcellular Claudin-1 and Claudin-7 were not only correlated with each other, but also correlated with p-ERK in BD and p-AKT and p-mTOR in SCC. Together, these results imply the delocalization of Claudin-1 and Claudin-7 and their correlation with MAPK/ERK and PI3K-AKT-mTOR signaling pathways in tumorigenesis and infiltration in cutaneous SCC.

Evaluation of Serum Proinflammatory Cytokine IL-17A and Tight Junction Protein Claudin-1 in Psoriasis.

Objective: This study aimed to estimate serum IL-17A and Claudin-1 levels, investigate their correlation, and evaluate their diagnostic significance as potential blood-based biomarkers in psoriasis. Methods: Serum IL-17A and Claudin-1 concentrations were determined using enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed to determine differences in serum levels of IL-17A and Claudin-1, their bivariable correlation with psoriasis severity, as Psoriasis Area Severity Index (PASI), and their predictive abilities using receiver operating characteristic (ROC) curves. Results: Significantly higher IL-17A and lower Claudin-1 levels were found in psoriasis (p < 0.05). PASI did not correlate significantly with either IL-17A or Claudin-1 in psoriasis and their subtypes. The only significant correlation between serum IL-17A and Claudin-1 was shown in late-onset psoriasis (r = 0.630, p = 0.028). ROC curve analysis indicated the serum IL-17A, serum Claudin-1, and combination of IL-17A and serum Claudin-1 for predicting psoriasis with the areas under the curve (AUC) of 0.951 (p < 0.0001), 0.709 (p = 0.0119), and 0.949 (p < 0.0001), respectively. Moreover, the potential role in distinguishing between early-onset and late-onset psoriasis: we obtained serum IL-17A, serum Claudin-1, and their combination AUC of 0.590 (p = 0.3126), 0.741 (p = 0.0045), and 0.741 (p = 0.0067), respectively. However, none of the serum IL-17A, serum Claudin-1, and their combination was well-performed discriminating mild psoriasis from moderate-to-severe psoriasis with AUC of 0.553 (p = 0.5596), 0.518 (p = 0.8539), and 0.559 (p = 0.5225), respectively. Conclusion: These preliminary results suggest that the serum Claudin-1 as a potential biomarker and the relationship and possible regulatory interactions between IL-17A and Claudin-1 in psoriasis are distinguishable by age of onset.

Optimal optical path difference of an asymmetric common-path coherent-dispersion spectrometer.

Optical path difference (OPD) is a very significant parameter in the asymmetric common-path coherent-dispersion spectrometer (CODES), which directly determines the performance of the CODES. In order to improve the performance of the instrument as much as possible, a temperature-compensated optimal optical path difference (TOOPD) method is proposed. The method does not only consider the influence of temperature change on the OPD but also effectively solves the problem that the optimal OPD cannot be obtained simultaneously at different wavelengths. Taking the spectral line with a Gaussian-type power spectral density distribution as a representative, the relational expression between the OPD and the visibility of interference fringes formed by the CODES is derived for the stellar absorption/emission line. Further, the optimal OPD is deduced according to the efficiency function, and the relationship between the optimal OPD and wavelength is analyzed. Then, based on the materials' dispersion characteristics, different optical materials are combined and added to the interferometer's reflected and transmitted optical path to implement the optimal OPD at different wavelengths, thereby improving the detection precision. Meanwhile, the materials whose refractive index negatively changes with temperature are selected to reduce or even offset the temperature impact on OPD, and hence the system's stability is improved and further improves the detection precision. Under certain input conditions, the material combination that approximates the optimal OPD is performed within the range of 0.66-0.9 µm. The simulation results show that the maximal difference between the optimal OPD obtained by the efficiency function and the OPD produced by the material combination is 0.733 mm for the absorption line and 1.122 mm for the emission line, which is reduced by 1 time compared with only one material. The influence of temperature on the OPD can be reduced by 2-3 orders of magnitude by material combination, which greatly ameliorates the stability of the whole spectrometer. Hence, the TOOPD method provides a new idea for further improving the high-precision radial velocity detection of the asymmetric common-path CODES.

Microbiome in Healthy Women Between Two Districts With Different Air Quality Index.

Although the diversity and abundance of skin microbiome are mainly determined by intrinsic factors, including gender, age, anatomical site, and ethnicity, we question whether facial microbiome could be affected by long-term exposure to airborne pollution. Using 16S ribosomal RNA (rRNA) gene amplicon sequencing, we analyzed the facial bacterial microbiome of healthy and young Chinese women (25-35 years old) between two districts with different air quality indices (AQIs) in Zhejiang Province. The overall microbiome structure was obviously different between these two districts. It revealed an increase in both the abundance and diversity of facial bacterial microbiome in Hangzhou (HZ) with higher AQI compared with those in Yunhe (YH) with lower AQI. Linear discriminant analysis (LDA) and Lefse analysis identified a total of 45 genera showing significant overrepresentation in the HZ group. Furthermore, PICRUSt analysis showed that functional pathways associated with metabolism of saturated fatty acid were relatively more predominant in the HZ group, whereas those with DNA repair or mitochondrial DNA replication were more predominant in the YH group. Our present data can provide useful information for further researches on the composition and function of the skin microbiome related to air pollution factors as well as for the development of therapeutic agents targeting the microbes and their metabolites to resist damages of airborne pollutants.

Hyperspectral deep convolution anomaly detection based on weight adjustment strategy.

Hyperspectral anomaly detection has garnered much research in recent years due to the excellent detection ability of hyperspectral remote sensing in agriculture, forestry, geological surveys, environmental monitoring, and battlefield target detection. The traditional anomaly detection method ignores the non-linearity and complexity of the hyperspectral image (HSI), while making use of the effectiveness of spatial information rarely. Besides, the anomalous pixels and the background are mixed, which causes a higher false alarm rate in the detection result. In this paper, a hyperspectral deep net-based anomaly detector using weight adjustment strategy (WAHyperDNet) is proposed to circumvent the above issues. We leverage three-dimensional convolution instead of the two-dimensional convolution to get a better way of handling high-dimensional data. In this study, the determinative spectrum-spatial features are extracted across the correlation between HSI pixels. Moreover, feature weights in the method are automatically generated based on absolute distance and the spectral similarity angle to describe the differences between the background pixels and the pixels to be tested. Experimental results on five public datasets show that the proposed approach outperforms the state-of-the-art baselines in both effectiveness and efficiency.

EGFR inhibitor gefitinib regulates barrier function in human epidermal keratinocytes via the modulation of the expression of claudins.

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been frequently used in targeted therapy for lung cancer. However, the widespread use of gefitinib in targeted therapy for patients with lung cancer is hampered by its common skin toxicities. The present study aimed to investigate the mechanisms underlying the skin toxicities of gefitinib. Normal human epidermal keratinocytes (NHEKs) treated with gefitinib were used for a series of in vitro assays, including MTT, reverse transcription­quantitative polymerase chain reaction, western blot analysis, immunohistochemistry and transepithelial electrical resistance and paracellular permeability detection. In the present study, it was determined that the skin toxicities of gefitinib may be due to claudin (CLDN)1 and CLDN4 downregulation and CLDN2 upregulation in NHEKs. Additionally, Src and signal transducer and activator of transcription 3 pathways were involved in gefitinib­induced barrier function disruption in NHEKs. In conclusion, the present study may provide novel insights for improving skin toxicity of gefitinib in patients with lung cancer.

Histopathological diagnosis of persistent pruritic eruptions associated with adult-onset Still's disease.

AIMS: Persistent pruritic eruptions (PPEs), presenting with dyskeratotic keratinocytes histologically, are characteristic skin rash in patients with adult-onset Still's disease (AOSD). The lesions may be histologically similar to other entities that present with dyskeratosis. In the present study, we compared the histopathological features between PPEs and other entities presenting with dyskeratosis. METHODS AND RESULTS: To investigate whether histopathological findings can be used to discriminate among PPEs and other entities presenting with dyskeratotic keratinocytes, cutaneous histopathological changes of PPEs associated with AOSD (n = 26) were compared with those of systemic lupus erythematosus (SLE) (n = 16), dermatomyositis (n = 19), and drug eruption (n = 16). Dyskeratosis was observed in the upper one-third of the epidermal layer in all 26 PPEs. The rate of dyskeratosis for PPEs was higher than that for SLE (18.8%) and dermatomyositis (15.8%). In drug eruptions, the dyskeratotic cells were distributed in all levels of the epidermis. Variable densities of neutrophils were found in the dermis in all PPEs. CONCLUSIONS: Although this was a retrospective study conducted at a single centre, presentation of dyskeratotic keratinocytes in the upper one-third of the epidermal layer is a distinctive histopathological reactive pattern of PPEs. This pattern may be a useful histopathological marker for early diagnosis of AOSD.

Ultrasensitive amperometric aptasensor for the epithelial cell adhesion molecule by using target-driven toehold-mediated DNA recycling amplification.

An amperometric aptasensor is reported for the electrochemical determination of the epithelial cell adhesion molecule (EpCAM). It is based on a combination of EpCAM-driven toehold-mediated DNA recycling amplification, the specific recognition of EpCAM aptamer, and its binding to EpCAM. Hairpin probe 1 (Hp1) with a toehold region was modified with a 5'-thiol group (5'-SH) and self-assembled onto the surface of a gold electrode. Upon addition of EpCAM, the probe A (a 15-mer) is liberated from the aptamer/probe A complex and then hybridizes with the toehold domain of Hp1. This results in the exposure of another toehold for further hybridizing with hairpin probe 2 (Hp2) to displace probe A in the presence of Hp2 that was labeled with the electrochemical probe Methylene Blue (MB). Subsequently, liberated probe A is hybridized again with another Hp1 to start the next round of DNA recycling amplification by reusing probe A. This leads to the formation of plenty of MB-labeled DNA strands on the electrode surface and generates an amplified current. This 1:N probe-response amplification results in ultrasensitive and specific detection of EpCAM, with a 20 pg·mL-1 detection limit. The electrode is highly stable and regenerable. It was successfully applied to the determination of EpCAM in spiked human serum, urine and saliva, and thus provides a promising tool for early clinical diagnosis. Graphical abstract Schematic illustration of the electrochemical detection for EpCAM. The method is based on aptamer-based recognition and EpCAM-driven toehold-mediated DNA recycling amplification. Hp1: Hairpin probe 1; Hp2: Hairpin probe 2; MB: Methylene blue; MCH: 6-Mercapto-1-hexanol; EpCAM: Epithelial cell adhesion molecule.

Biological therapy of traditional therapy-resistant adult-onset Still's disease: an evidence-based review.

BACKGROUND: Biotherapy is becoming increasingly important in the treatment of adult-onset Still's disease (AOSD). The aim of our study was to evaluate the efficacy and safety of biological therapy for AOSD resistant to traditional therapy. PATIENTS AND METHODS: Database of Library of Congress, the PubMed, and Web of Science Core Collection were used to retrieve relevant articles published in English language until March 2017. Only studies published in English language were included, and the additional references quoted in these articles were also checked. Articles concerning the efficacy and safety of all the biotherapies in refractory AOSD were evaluated. RESULTS: There were 112 articles available in total; 422 AOSD patients were given at least one biologic. We found that 293 patients (69.43%) had received TNF-α blocking agents (infiliximab, etanercept, and adalimumab), 194 patients (45.97%) were treated with IL-1 receptor antagonists (anakinra, rilonacept, and canakinumab), 163 patients (38.63%) were given IL-6 inhibitor (tocilizumab), and 24 patients (5.69%) received rituximab and abatacept. The efficacy of biological therapy and overall tolerance of biological therapy for refractory AOSD were good. Thirty two of 271 patients given anti-TNF-α therapies (11.81%), 116 patients receiving IL-1 inhibitors (65.54%), 124 patients receiving tocilizumab (76.07%), and 13 patients given other biological therapies (36.11%) achieved remission. Side effects of biologic therapy were infections such as urinary tract infections and soft tissue abscess. CONCLUSION: Our findings suggest that anakinra and tocilizumab may be good choices for the treatment of refractory AOSD considering the effectiveness and safety.

Concurrence of Sweet's syndrome, pathergy phenomenon and erythema nodosum-like lesions.

We report the case of a 54-year-old woman with concurrent Sweet's syndrome, pathergy phenomenon and eythema nodosum-like lesions associated with suppurative tonsillitis. Tender, violaceous and highly edematous papules and plaques were detected on the forearms and legs, some of which were pseudovesicular. Similar edematous papules were detected on the dorsum of the hands at the sites of intravenous injection. Biopsies of a plaque on the forearm and a papule at the site of intravenous injection confirmed the presence of Sweet's syndrome. Multiple, tender, violet-red, subcutaneous erythematous nodules were revealed on the legs. A biopsy taken from a nodule on the leg revealed septal panniculitis. To our knowledge, no patient with concurrent Sweet's syndrome, pathergy phenomenon, and erythema nodosum-lesions had been reported yet in previous literature.

Concurrence of Sweet's Syndrome, Pathergy Phenomenon and Erythema Nodosum-like Lesions

We report the case of a 54-year-old woman with concurrent Sweet's syndrome, pathergy phenomenon and eythema nodosum-like lesions associated with suppurative tonsillitis. Tender, violaceous and highly edematous papules and plaques were detected on the forearms and legs, some of which were pseudovesicular. Similar edematous papules were detected on the dorsum of the hands at the sites of intravenous injection. Biopsies of a plaque on the forearm and a papule at the site of intravenous injection confirmed the presence of Sweet's syndrome. Multiple, tender, violet-red, subcutaneous erythematous nodules were revealed on the legs. A biopsy taken from a nodule on the leg revealed septal panniculitis. To our knowledge, no patient with concurrent Sweet's syndrome, pathergy phenomenon, and erythema nodosum-lesions had been reported yet in previous literature.

Syndrome in question.

Vulvovaginal-gingival syndrome is characterized by erosions and desquamation of the vulva, vagina, and gingiva. We reported a case of a 32-year-old woman presenting with an 8-year history of damage to the vulval and perianal anatomy and limitation of mouth opening. The patient's symptoms were relieved after treatment with topical tacrolimus cream.

Syndrome in question

Vulvovaginal-gingival syndrome is characterized by erosions and desquamation of the vulva, vagina, and gingiva. We reported a case of a 32-year-old woman presenting with an 8-year history of damage to the vulval and perianal anatomy and limitation of mouth opening. The patient's symptoms were relieved after treatment with topical tacrolimus cream.