GPR34 senses demyelination to promote neuroinflammation and pathologies.

Sterile neuroinflammation is a major driver of multiple neurological diseases. Myelin debris can act as an inflammatory stimulus to promote inflammation and pathologies, but the mechanism is poorly understood. Here, we showed that lysophosphatidylserine (LysoPS)-GPR34 axis played a critical role in microglia-mediated myelin debris sensing and the subsequent neuroinflammation. Myelin debris-induced microglia activation and proinflammatory cytokine expression relied on its lipid component LysoPS. Both myelin debris and LysoPS promoted microglia activation and the production of proinflammatory cytokines via GPR34 and its downstream PI3K-AKT and ERK signaling. In vivo, reducing the content of LysoPS in myelin or inhibition of GPR34 with genetic or pharmacological approaches reduced neuroinflammation and pathologies in the mouse models of multiple sclerosis and stroke. Thus, our results identify GPR34 as a key receptor to sense demyelination and CNS damage and promote neuroinflammation, and suggest it as a potential therapeutic target for demyelination-associated diseases.

SVDF: enhancing structural variation detect from long-read sequencing via automatic filtering strategies.

Structural variation (SV) is an important form of genomic variation that influences gene function and expression by altering the structure of the genome. Although long-read data have been proven to better characterize SVs, SVs detected from noisy long-read data still include a considerable portion of false-positive calls. To accurately detect SVs in long-read data, we present SVDF, a method that employs a learning-based noise filtering strategy and an SV signature-adaptive clustering algorithm, for effectively reducing the likelihood of false-positive events. Benchmarking results from multiple orthogonal experiments demonstrate that, across different sequencing platforms and depths, SVDF achieves higher calling accuracy for each sample compared to several existing general SV calling tools. We believe that, with its meticulous and sensitive SV detection capability, SVDF can bring new opportunities and advancements to cutting-edge genomic research.

Peiminine triggers ferroptosis to inhibit breast cancer growth through triggering Nrf2 signaling.

BACKGROUND: Peiminine (PMI) is an active alkaloid sourced from Fritillaria thunbergii, which has been shown to suppress the development of a variety of tumors. Whereas, the roles and precise mechanism of PMI in breast cancer (BC) development remain not been clarified. METHODS: The cytotoxic effect of PMI on MCF-10A and BC cell lines (MCF-7 and BT-549) were assessed by MTT and LDH release assay. Cell proliferation was evaluated by EdU staining. Levels of Malondialdehyde (MDA), reactive oxygen species (ROS), glutathione (GSH) activity and iron assay were measured by Enzyme linked immunosorbent assay (ELISA) kits, respectively. Transmission Electron Microscope was performed to observe mitochondrial morphological structure. Immunofluorescence, immunohistochemistry, and western blot were conducted to examine protein levels, respectively. Xenograft model was used to confirm cellular findings. RESULTS: PMI treatment reduced the viability and enhanced LDH level of MCF-7 and BT-549 cells in a time- and concentration-dependent manner, and further suppressed cell proliferation in vitro and tumor growth in vivo. Subsequently, PMI administration resulted in significant increases of ROS, MDA and iron levels, reduction of GSH activity as well as mitochondrial shrinkage and GPX4 reduction, while all these phenomena could be rescued by ferrostatin-1. Mechanistically, PMI treatment led to promoted Nrf2 expression and its nuclear translocation, as well as it's downstream protein HO-1 and NQO1 expressions. Notably, ML-385, a Nrf2 specific inhibitor, greatly reversed the anti-tumor effects and pro-ferroptosis role of PMI in BC cells. CONCLUSION: Taking these finding together, PMI could stimulate ferroptosis to inhibit BC tumor growth by activating Nrf2-HO-1 signaling pathway.

Anoikis-related gene CDKN2A predicts prognosis and immune response and mediates proliferation and migration in thyroid carcinoma.

Thyroid carcinoma (THCA) is a tumor commonly occurring in the endocrine system, and its incidence rate is increasing yearly. Anoikis is a type of cell death involved in the carcinogenesis process. This study aimed to investigate the prognosis and immune correlations of anoikis in THCA. Our study used several bioinformatics algorithms (co-expression analysis, univariate and multivariate Cox analysis) to screen anoikis-related genes (ARGs) to construct risk models. Through receiver operating characteristic (ROC) curve, nomogram, and independent prognostic analysis found that the constructed model had ideal predictive value for THCA. The consensus clustering method was used to divide ARG patterns into three subgroups, and there were significant differences in survival among the three subgroups. The CIBERSORT algorithm demonstrated strong correlations among immune infiltrating cells, prognostic genes, and risk scores. Univariate and multivariate Cox analysis showed that CDKN2A is an independent prognostic gene. Basic experiments (immunohistochemistry, qRT-PCR, etc.) showed that the expression levels of CDKN2A mRNA and protein were highly expressed in THCA, which was consistent with the results of bioinformatics analysis. In vitro, the knockdown of CDKN2A significantly inhibited the proliferation and migration of THCA cells. In summary, our study utilized eight ARGs to construct an accurate risk model. ARGs, especially CDKN2A, play a crucial role in the occurrence and development of THCA and can become potential targets for treating THCA patients.

Plasmonic direct-writing lithography via high numerical aperture objectives.

The exploration of light-matter interactions at the sub-wavelength scale requires advanced nano-patterning tools with low cost and high flexibility. Plasmonic lithography as a promising candidate receives much attention owing to its ability to confine ultraviolet light sources into an extremely tiny volume. To date, most plasmonic patterning schemes utilize metallic nano-structures to achieve tight focusing. The drawback is that the plasmonic structures need, however, to be pre-defined, usually accompanied with the expense of complex fabrication processes. Here we numerically and experimentally report an antenna-free plasmonic lithography technique using high numerical aperture (NA) objectives as the scanning head. Minimum feature sizes of 0.36λ/NA and 0.46λ/NA are numerically and experimentally demonstrated, respectively, under the linearly polarized continuous-wave illumination at 457 nm with no involvement of nonlinear effects. Back-focal-plane imaging is used to visualize surface-plasmon excitations, acting as a viable way of adjusting focus precisely. Our method can serve as a candidate for laser processing at the sub-wavelength scale, and offers a truly convenient and economical way of nano-patterning.

Binning Metagenomic Contigs Using Unsupervised Clustering and Reference Databases.

Metagenomics can directly extract the genetic material of all microorganisms from the environment, and obtain metagenomic samples with a large number of unknown DNA sequences. Binning of metagenomic contigs is a hot topic in metagenomics research. There are two key challenges for the current unsupervised metagenomic clustering algorithms. First, unsupervised metagenomic clustering methods rarely use reference databases, causing a certain waste of resources. Second, unsupervised metagenomic clustering methods are restricted by the characteristics of the sequences and the clustering algorithms, and the binning effect is limited. Therefore, a new binning method for metagenomic contigs using unsupervised clustering methods and reference databases is proposed to address these challenges, to make full use of the advantages of unsupervised clustering methods and reference databases constructed by scientists to improve the overall binning effect. This method uses the integrated SVM classification model to further bin the unsupervised clustering parts that do not perform well. Our proposed method was tested on simulated datasets and a real dataset and compared with other state-of-the-art metagenomic clustering methods including CONCOCT, Metabin2.0, Autometa, and MetaBAT. The results show that our method can achieve higher precision rate and improve the binning effect.

MetaCRS: unsupervised clustering of contigs with the recursive strategy of reducing metagenomic dataset's complexity.

BACKGROUND: Metagenomics technology can directly extract microbial genetic material from the environmental samples to obtain their sequencing reads, which can be further assembled into contigs through assembly tools. Clustering methods of contigs are subsequently applied to recover complete genomes from environmental samples. The main problems with current clustering methods are that they cannot recover more high-quality genes from complex environments. Firstly, there are multiple strains under the same species, resulting in assembly of chimeras. Secondly, different strains under the same species are difficult to be classified. Thirdly, it is difficult to determine the number of strains during the clustering process. RESULTS: In view of the shortcomings of current clustering methods, we propose an unsupervised clustering method which can improve the ability to recover genes from complex environments and a new method for selecting the number of sample's strains in clustering process. The sequence composition characteristics (tetranucleotide frequency) and co-abundance are combined to train the probability model for clustering. A new recursive method that can continuously reduce the complexity of the samples is proposed to improve the ability to recover genes from complex environments. The new clustering method was tested on both simulated and real metagenomic datasets, and compared with five state-of-the-art methods including CONCOCT, Maxbin2.0, MetaBAT, MyCC and COCACOLA. In terms of the number and quality of recovered genes from metagenomic datasets, the results show that our proposed method is more effective. CONCLUSIONS: A new contigs clustering method is proposed, which can recover more high-quality genes from complex environmental samples.

Association Between Serum Human Epididymis Protein 4 Levels and Cardiovascular Events in Obese Patients with Breast Cancer.

BACKGROUND: Patients with cancer have a higher incidence of cardiovascular diseases (CVDs). We aimed to evaluate the relationship between serum human epididymal protein 4 (HE4) levels and cardiovascular events in obese patients with breast cancer. METHODS: Serum HE4 levels in 316 obese patients with breast cancer were measured at baseline and then prospectively followed up for approximately 36 months. The prognostic value of serum HE4 for predicting cardiovascular events was analyzed by the Cox proportional hazard model. RESULTS: Serum HE4 was significantly associated with CVD history after adjustment for confounding factors (OR= 1.50; 95% CI 1.23-3.43; P=0.038) using multivariable logistic regression analysis. The multivariable Cox proportional hazard analysis suggested that serum HE4 had an independent prognostic value for predicting cardiovascular events in patients with breast cancer (HR=2.21, 95% CI 1.60-5.13, P<0.001). Additionally, sensitivity analysis showed that the independent association still existed. Stratified analysis showed that this relationship was not affected by chemoradiotherapy. CONCLUSION: Serum HE4 is significantly related to cardiovascular events and poses good prognostic value for predicting cardiovascular events in obese patients with breast cancer. Serum HE4 may be a valuable indicator for the early detection of cardiovascular complications in obese patients with breast cancer.

Safety and efficacy of preoperative mFOLFOX6 regimen chemotherapy for locally resectable advanced rectal cancer. / 术前采用mFOLFOX6æ–¹æ¡ˆåŒ–å­¦æ²»ç–—å¯åˆ‡é™¤çš„å±€éƒ¨è¿›å±•æœŸç›´è‚ ç™Œçš„å®‰å ¨æ€§å’Œæœ‰æ•ˆæ€§.

OBJECTIVES: Neoadjuvant chemotherapy combined with radical surgery has become the treatment model for locally advanced rectal cancer. The purpose of this study was to evaluate the safety and efficacy of postoperative mFOLFOX6 regimen chemotherapy for locally resectable advanced rectal cancer. METHODS: This was a prospective study. A total of 82 patients with locally advanced rectal cancer admitted to Affiliated Nanhua Hospital, University of South China from February 2015 to December 2017 were selected as the subjects. The patients received 4 courses of mFOLFOX6 chemotherapy and underwent surgery within 4-6 weeks after chemotherapy. The incidences of chemotherapy-related adverse reactions, postoperative complications, and clinical pathological reactions were analyzed. RESULTS: In the period from mFOLFOX6 chemotherapy to preoperative, 82 patients with locally advanced rectal cancer was reported chemotherapy-related adverse reactions, including Grade 4 neutropenia (2.4%), catheter related infection (2.4%), and anorexia (2.4%), Grade 3 nausea (2.4%) and anorexia (2.4%), Grade 2 neutropenia (14.6%) and peripheral neuropathy (7.3%). Finally, 76 patients with locally advanced rectal cancer completed surgery, including 56 (73.7%) with anterior rectum resection, 16 (21.1%) with abdominal perineal resection, and 72 (94.7%) with pelvic nerve preservation. A total of 22 (28.9%) patients had surgical complications, including 8 (10.5%) with complications of Grade 3 or above. The complications with high incidence were intestinal obstruction, anastomotic leakage, and sepsis. Among the 76 patients who completed chemotherapy and surgery, T stage was decreased in 28 (36.8%) and N stage was decreased in 44 (57.9%); forty-two (55.3%) were in pathological Stage I, 20 (26.3%) in Stage IIA, 12 (15.8%) in Stage IIB, and 2 (2.6%) in Stage IIIA. Ten patients were suspected of tumor invasion of surrounding organs before chemotherapy, of which 4 patients did not need to extend the resection of surrounding organs after chemotherapy and achieved R0 resection of tumor; 2 in T4b stage before chemotherapy received extended resection of surrounding organs, and the postoperative pathological result was T3, and achieved R0 resection; 1 diagnosed as poorly differentiated adenocarcinoma with seminal vesicle invasion in the evaluation before chemotherapy had T-stage progression after operation. There were 66 (86.8%) patients of partial response (PR), 9 (11.8%) of stable disease (SD) and 1 (1.3%) of progressive disease (PD). There was no complete response (CR) and no new lesion. CONCLUSIONS: Preoperative mFOLFOX6 regimen chemotherapy for locally resectable advanced rectal cancer is a safe and feasible treatment strategy, and it is worthy of clinical application.

Localized surface plasmon mode-enhanced spectrum-tunable radiation in electrically driven plasmonic antennas.

A spectrum-tunable source with ultra-small volume is highly desired by on-chip information processing technologies. As a promising candidate, light emission from electrically driven tunnel junctions has gained much interest. In this Letter, using a gap bowtie antenna-based metal-insulator-metal junction as the source, multiple peaks are found in the electroluminescence spectrum of the antenna system. We attribute the peaks observed in the experimental emission spectrum to resonant plasmon modes that are supported by the antennas. This explanation is confirmed numerically by finite difference time domain calculations and analytically by using a theory imitated from scanning tunneling microscopy. Our results show that the localized surface plasmon modes can be finely tuned by varying the gap distances and the geometries of the antennas, which eventually contribute to a spectrum-tunable light source. This Letter may provide a path for spectrum-tunable electrically driven light sources on photonic devices.

Unidirectional propagation of electrically driven surface plasmon polaritons: a numerical study.

Electrically excited surface plasmon polaritons (SPPs) created, for instance, through the energy loss from inelastic electron tunneling, have received great interest recently because of their potential for facilitating the integration of on-chip information processing elements. Consequently, finding a convenient method of realizing the propagation control of such a kind of SPPs becomes a valuable research topic. Optical antennas array, with a relatively large footprint, are commonly used for steering SPPs. In this paper, with the aid of two plasmonic strip-type antennas that are placed next to each other, we present a feasible method of propagation control of electrically driven SPPs in a scanning tunneling microscope (STM) system. Results show that STM-induced SPPs propagate along a preferred direction due to the in-plane SPP interference effects, which can be easily engineered by the widths of the antennas. This result is very useful for compact plasmonic circuits design.

[Clinical and imaging features of 36 odontogenic keratocysts associated with an impacted tooth].

PURPOSE: To analyse the imaging features of odontogenic keratocysts (OKCs) associated with an impacted tooth. METHODS: Clinical and radiological data of 235 cases with OKCs were respectively investigated, with emphasis on imaging features of 36 OKCs, which were associated with an unerupted tooth. RESULTS: In 36 cases of OKCs associated with an impacted tooth, the ratio of male to female was 1.77:1, and molar-ramus was involved in 26 cases (72.22％). OKCs in association with an unerupted tooth occurred mostly in patients ranging from 20 to 30 years (19 cases, 52.8％). There were 27 cases (75％) of unilocular and 9 cases (25％) multilocualr radiolucency. Thirteen cases (36.11%) were related to the crown of the impacted teeth, and the unerupted teeth also were impacted as a result of malposition in which the entire teeth appeared to be enveloped by cysts (15 cases, 41.67%), or adjacent to cyst wall (8 cases, 22.22%). CONCLUSIONS: Radiographically, one of the most imaging features of OKCs in association with an unerupted tooth is that its entire tooth appears to be enveloped by cyst or adjacent to cyst, while pericoronal radiolucencies surrounding an impacted tooth are rarely seen.

40 nm thick photoresist-compatible plasmonic nanolithography using a bowtie aperture combined with a metal-insulator-metal structure.

In this Letter, 40 nm thick photoresist (PR)-compatible plasmonic nanolithography using a bowtie aperture incorporated with a metal-insulator-metal (MIM) structure is studied numerically and experimentally. The simulation results show that with a 20 nm index-matching layer, the light field that exits from the bowtie aperture penetrates into a 40 nm thick PR by using a MIM configuration. Imaging contrast calculations indicate that sub-45 nm resolution with an exposure depth in the order of tens of nanometers is achievable, which is confirmed by the experimental results. In addition, the ability to generate high-resolution, complex patterns using this technique via scanning is demonstrated. This brings plasmonic nanolithography using a bowtie aperture one step closer to practical applications.

Non-near-field sub-diffraction focusing in the visible wavelength range by a Fibonacci subwavelength circular grating.

This study proposes a Fibonacci subwavelength circular grating (FiSCG) arranged with Au concentric annuli. The numerical results show that, when illuminated by radially polarized light with a wavelength of 632.8 nm, four foci can be observed in the non-near-field with full width at half-maximum (FWHM) of 0.378λ, 0.421λ, 0.520λ, and 0.496λ, respectively. These possess low sidelobe intensity. Moreover, FiSCG achieves non-near-field sub-diffraction focusing in the visible wavelength range by varying the widths of the air slit and the Au ring. The ratio of the widths and the incident wavelength is about 0.4. This finding provides a wider applied range for FiSCG and a reference for the research on Fibonacci-arranged structures.

Octreotide stimulates somatostatin receptor-induced apoptosis of SW480 colon cancer cells by activation of glycogen synthase kinase-3ß, A Wnt/ß-catenin pathway modulator.

BACKGROUND/AIMS: Peptide hormone somatostatin and its receptors (SSTRs) have a wide range of physiological functions and play a role in the treatment of numerous human diseases, including colorectal cancer. Octreotide, a somatostatin-analog peptide, inhibits growth of colonic cancer SW480 cells through Wnt/ß-catenin pathway modulation. However, the specific octreotide-stimulating SSTR subtypes and the signal-transduction mechanism responsible for the negative regulation of Wnt/ß-catenin pathway by octreotide have not been fully elucidated. METHODOLOGY: Octreotide-induced apoptosis in SW480 colon cancer cells mediated by SSTR2,SSTR5-dependent regulation of the Wnt/ß-catenin pathway components GSK-3ß and ß-catenin was investigated. Cell apoptosis of SW480 cells was measured by apoptosis-DNA ladder assay. SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 mRNA expression levels were confirmed by RT-PCR; ß-catenin, TCF-4, cyclin D1, c-Myc, and GSK-3ß protein levels were examined by Western blot. The distribution of ß-catenin in the cell was analyzed with immunocytochemistry. RESULTS: Octreotide treatment increased SSTR2,SSTR5-induced apoptosis of SW480 colon cancer cells, promoted the plasma membrane accumulation of ß-catenin, inactivated T-cell factor-dependent transcription, and downregulated Wnt target genes cyclin D1 and c-Myc. Further, octreotide treatment mediated the activation of GSK-3. CONCLUSIONS: These preliminary findings showed the negative regulation of the Wnt/ß-catenin pathway by peptide hormone G protein-coupled receptors SSTRs.