Extrachromosomal circular DNA landscape of breast cancer with lymph node metastasis.

Breast cancer (BC) is a complex disease with diverse manifestations, often resulting in lymph node metastasis (LNM) and impacting patient prognosis. Extrachromosomal circular DNA (eccDNA) has emerged as a key player in tumorigenesis, yet its contribution to BC LNM remains elusive. Here, we examined primary tumors and matched LNM tissues from 19 BC patients using the Circle-Seq method. We identified a median count of 44,682 eccDNA in primary tumor tissues and 38,057 in their paired LNM tissues. Furthermore, a ladder-like size distribution is observed in both primary tumor and LNM tissues. Meanwhile, similar repeat sequence distribution and GC content are identified from both primary tissue and LNM tissues. Finally, we found that eccDNA from both groups are flanked with palindromic trinucleotide motifs. These observations indicate that eccDNA of primary tumor and LNM tissues are from similar chromosomal origins. However, a subset of miRNA-associated eccDNA displayed selective enrichment in metastatic lesions, such as miR-6730 and miR-548AA1 genes. This observation implicates the function of miRNA-related eccDNA in the metastatic cascade. Our study uncovers the potential significance of these unique eccDNA molecules, shedding light on their role in cancer metastasis.

Value of Multimodal Ultrasound Combined with BRAF Gene in Evaluating Cervical Lymph Node Metastasis of Papillary Thyroid Microcarcinoma.

OBJECTIVE: The aim of the work described here was to explore the predictive value of multimodal ultrasound combined with the BRAF gene in cervical lymph node metastasis (CLNM) of papillary thyroid microcarcinoma (PTMC). METHODS: One hundred six patients (114 lesions) with PTMC confirmed by surgery and pathology at Yantai Yuhuangding Hospital from July 2021 to August 2022 were analyzed retrospectively. Routine ultrasound, contrast-enhanced ultrasound, shear wave elastography examination and BRAF V600E gene detection were performed before surgery. Patients were divided into two groups on the basis of post-operative pathology: non-metastasis group and metastasis group. Univariate and multivariate analyses were used to analyze the risk factors of cervical lymph node metastasis in PTMC. RESULTS: Univariate analysis revealed that there were significant differences in gender, high echo in lesions, enhancement level, peak intensity (PI) and average modulus of elasticity (Eavg) between the two groups (p < 0.05), but there was no significant difference in BRAF gene mutation (p = 0.855). Multivariate analysis revealed that male gender, microcalcification and hyper- or iso-enhancing parametric increased the risk of CLNM in PTMC (p < 0.05), and that sensitivity (92.3%) and accuracy (73.9%) were higher for combined diagnosis than for single diagnosis; the differences were statistically significant (p < 0.05). CONCLUSION: Male gender, microcalcification and hyper- or iso-enhancing parametrics of CEUS are independent risk factors for CLNM in PTMC patients. Combined diagnosis is more effective.

Evaluation of deproteinised bovine bone matrix combined with absorbable biofilm for the preservation of extraction sites of mandibular impacted wisdom teeth.

BACKGROUND: Bone defects and deep periodontal pockets often exist distal to the second molar after mandibular third molar extraction, seriously threatening the periodontal health of the second molar. OBJECTIVE: To evaluate the effect of socket preservation with bone substitute materials on alveolar bone resorption and prevention of the distal periodontal defect of the adjacent tooth after mandibular impacted third molar extraction compared with natural healing. METHODS: Ninety-nine patients with mandibular impacted teeth, treated in our hospital from January 2018 to December 2020, were randomly divided into the control and experimental groups. The experimental group underwent minimally invasive tooth extraction and socket preservation using the deproteinised bovine bone mineral, Bio-Oss and the bioabsorbable collagen membrane, Bio-Gide. The control group healed naturally after minimally invasive tooth extraction. The alveolar ridge dimension of the extraction sites, the probing depth, tooth mobility and gingival index on the distal aspect of the mandibular second molars were examined and recorded before and six months after the operations. RESULTS: There was a significant difference between the experimental group and the control group in the alveolar bone width (P< 0.05) and height (P< 0.05) before and after surgery. The probing depth of the extraction sites in both groups was reduced. CONCLUSION: Using Bio-Oss and Bio-Gide to preserve extraction sites of impacted teeth can promote recovery more effectively than natural healing on the height of the distal alveolar bone and the width of the alveolar crest of the second molar and thus improve the periodontal status of the adjacent second molar.

Coated cysteamine, a potential feed additive for ruminants - An updated review.

For sustainable development, better performance, and less gas pollution during rumen fermentation, there is a need to find a green and safe feed additive for ruminants. Cysteamine (CS) is a biological compound naturally produced in mammalian cells. It is widely used as a growth promoter in ruminants because of its ability to control hormone secretions. It mainly controls the circulating concentration of somatostatin and enhances growth hormone production, leading to improved growth performance. CS modulates the rumen fermentation process in a way beneficial for the animals and environment, leading to less methane production and nutrients loss. Another beneficial effect of using CS is that it improves the availability of nutrients to the animals and enhances their absorption. CS also works as an antioxidant and protects the cells from oxidative damage. In addition, CS has no adverse effects on bacterial and fungal alpha diversity in ruminants. Dietary supplementation of CS enhances the population of beneficial microorganisms. Still, no data is available on the use of CS on reproductive performance in ruminants, so there is a need to evaluate the effects of using CS in breeding animals for an extended period. In this review, the action mode of CS was updated according to recently published data to highlight the beneficial effects of using CS in ruminants.

Involvement of Glutamate Cysteine Ligase Genes in Tolerance to Emamectin Benzoate in Spodoptera frugiperda and Their Putative Regulatory Mechanisms.

As the rate-limiting enzyme in de novo Glutathione (GSH) biosynthesis, the mammalian glutamate cysteine ligase (Gcl) catalytic (Gclc) and modifier (Gclm) subunits are regulated at multiple levels, whereas the function and regulatory mechanism of insect Gcl remain to be explored. In this study, we identified and characterized SfGclc and SfGclm in Spodoptera frugiperda. SfGclc and SfGclm were highly expressed in the hindgut and relatively less expressed in other tissues. The exposure of the third instar larvae to LC30 of emamectin benzoate (EMB) significantly reduced the GSH content with a concomitant upregulation of SfGclc and SfGclm. Further in vivo pretreatment with L-BSO, the Gcl inhibitor, increased the susceptibility of S. frugiperda to EMB. Consistently, overexpression of SfGclc and SfGclm increased the Sf9 cell viability under EMB treatment. Finally, both RNAi and the dual-luciferase reporter assay in Sf9 cells revealed that SfGclc is regulated by transcription factor CncC. These data provide insights into the function and regulatory mechanism of insect Gcl, and they imply that disruption of the redox homeostasis might be a practical strategy to enhance the insecticidal activity of EMB and other insecticides.

GC­MSC­derived circ_0024107 promotes gastric cancer cell lymphatic metastasis via fatty acid oxidation metabolic reprogramming mediated by the miR­5572/6855­5p/CPT1A axis.

Gastric cancer tissue­derived mesenchymal stem cells (GC­MSCs) play a critical role in facilitating gastric cancer metastasis. Recently, circular RNAs (circRNAs) and metabolic reprogramming have been found to be extensively involved in the malignant progression of tumors, including gastric cancer. However, the biological role and potential mechanisms of GC­MSC­derived circRNAs in metabolic reprogramming remain elusive. Herein, the expression profiles of circRNAs and mRNAs were compared between GC­MSCs and bone marrow­derived MSCs (BM­MSCs) using microarray analysis. circ_0024107 was identified to mediate GC­MSCs to promote gastric cancer lymphatic metastasis by inducing fatty acid oxidation (FAO) metabolic reprogramming. Mechanistically, circ_0024107 served as a sponge of miR­5572 and miR­6855­5p to elicit the FAO metabolic reprograming of GC­MSCs by upregulating carnitine palmitoyltransferase 1A (CPT1A). In addition, GC­MSCs promoted metastasis which was dependent on the induction of FAO in gastric cancer cells mediated by circ_0024107. The circ_0024107/miR­5572/6855­5p/CPT1A axis was deregulated in gastric cancer tissues and GC­MSCs, and was associated with lymph node metastasis and the prognosis of patients with gastric cancer. Taken together, the findings of the present study suggest the crucial role of FAO metabolic reprogramming mediated by GC­MSC­derived circ_0024107 in synergistically promoting gastric cancer lymphatic metastasis via miR­5572/6855­5p­CPT1A signaling; this suggests that circ_0024107 may be an attractive target for gastric cancer intervention.

A case report of diagnosis of liver metastasis of medullary thyroid carcinoma by multimodal ultrasound.

Medullary thyroid carcinoma is a rare malignant neuroendocrine tumor. Distant metastasis is difficult to detect early. It is most common in lung, liver, bone and brain. This case was reported as liver metastasis of medullary thyroid carcinoma in an elderly woman, but routine ultrasound findings were atypical. After a series of relevant imaging examinations, contrast-enhanced ultrasound and ultrasound-guided puncture biopsy were used to confirm the nature of the intrahepatic lesions. Therefore, we believe that multimodal ultrasound is of great value in the diagnosis of liver metastasis of medullary thyroid carcinoma.

Gastric cancer cell-originated small extracellular vesicle induces metabolic reprogramming of BM-MSCs through ERK-PPARγ-CPT1A signaling to potentiate lymphatic metastasis.

Tumor microenvironment and metabolic reprogramming are critical for tumor metastasis. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are widely involved in the formation of tumor microenvironment and present oncogenic phenotypes to facilitate lymph node metastasis (LNM) in response to small extracellular vesicles (sEV) released by gastric cancer (GC) cells. However, whether metabolic reprograming mediates transformation of BM-MSCs remains elusive. Herein, we revealed that the capacity of LNM-GC-sEV educating BM-MSCs was positively correlated with the LNM capacity of GC cells themselves. Fatty acid oxidation (FAO) metabolic reprogramming was indispensable for this process. Mechanistically, CD44 was identified as a critical cargo for LNM-GC-sEV enhancing FAO via ERK/PPARγ/CPT1A signaling. ATP was shown to activate STAT3 and NF-κB signaling to induce IL-8 and STC1 secretion by BM-MSCs, thereby in turn facilitating GC cells metastasis and increasing CD44 levels in GC cells and sEV to form a persistent positive feedback loop between GC cells and BM-MSCs. The critical molecules were abnormally expressed in GC tissues, sera and stroma, and correlated with the prognosis and LNM of GC patients. Together, our findings uncover the role of metabolic reprogramming mediated BM-MSCs education by LNM-GC-sEV, which presents a novel insight into the mechanism underlying LNM and provides candidate targets for GC detection and therapy.

Recent advances in fluorescent probes of peroxynitrite: Structural, strategies and biological applications.

Peroxynitrite (ONOO-), owing to its high oxidative and nitrating stress, is associated with several physiological processes in addition to various pathological processes, including those related to neurodegenerative diseases and cancer. Detection of ONOO- at the cellular level is of great significance to understand its pathogenesis. To this end, a variety of fluorescent probes based on small molecules and nanoparticles (NPs) have been engineered and applied as excellent tools for imaging of ONOO- in cells as well as in their diverse biological applications. In this review, we highlight representative cases of fluorescent probes based on recognition mechanism and emphasize their response type (ratiometric, two-photon, long-wavelength/near-infrared, and targeting) in ONOO- detection in the last five years. We further discuss their design strategy, sensing mechanism, and application in bio-imaging and describe NP-based probes according to diverse nanoplatforms.

Value of clinical features combined with multimodal ultrasound in predicting lymph node metastasis in cervical central area of papillary thyroid carcinoma.

OBJECTIVE: To explore the clinical features, multimodal ultrasound features and multimodal ultrasound imaging features in predicting lymph node metastasis in the central cervical region of papillary thyroid carcinoma. METHODS: A total of 129 patients with papillary thyroid carcinoma (PTC) confirmed by pathology were selected from our hospital from September 2020 to December 2022. According to the pathological results of cervical central lymph nodes, these patients were divided into metastatic group and non-metastatic group. Patients were randomly sampled and divided into training group (n = 90) and verification group (n = 39) according to the ratio of 7:3. The independent risk factors for central lymph node metastasis (CLNM) were determined by least absolute shrinkage and selection operator and multivariate logistic regression. Based on independent risk factors to build a prediction model, select the best diagnostic effectiveness of the prediction model sketch line chart, and finally, the line chart calibration and clinical benefits were evaluated. RESULTS: A total of 8, 11 and 17 features were selected from conventional ultrasound images, shear wave elastography (SWE) images and contrast-enhanced ultrasound (CEUS) images to construct the Radscore of conventional ultrasound, SWE and CEUS, respectively. After univariate and multivariate logistic regression analysis, male, multifocal, encapsulation, iso-high enhancement and multimodal ultrasound imaging score were independent risk factors for cervical CLNM in PTC patients (p < 0.05). Based on independent risk factors, a clinical combined with multimodal ultrasound feature model was constructed, and multimodal ultrasound Radscore were added to the clinical combined with multimodal ultrasound feature model to form a joint prediction model. In the training group, the diagnostic efficacy of combined model (AUC = 0.934) was better than that of clinical combined with multimodal ultrasound feature model (AUC = 0.841) and multimodal ultrasound radiomics model (AUC = 0.829). In training group and validation group, calibration curves show that the joint model has good predictive ability for cervical CLNM of PTC patients; The decision curve shows that most of the net benefits of the nematic chart are higher than those of clinical + multimodal ultrasound feature model and multimodal ultrasound radiomics model within a reasonable risk threshold range. CONCLUSION: Male, multifocal, capsular invasion and iso-high enhancement are independent risk factors of CLNM in PTC patients, and the clinical plus multimodal ultrasound model based on these four factors has good diagnostic efficiency. The joint prediction model after adding multimodal ultrasound Radscore to clinical and multimodal ultrasound features has the best diagnostic efficiency, high sensitivity and specificity, which is expected to provide objective basis for accurately formulating individualized treatment plans and evaluating prognosis.

Hsa_circ_0073453 modulates IL-8 secretion by GC-MSCs to promote gastric cancer progression by sponging miR-146a-5p.

Gastric cancer associated mesenchymal stem cells (GC-MSCs) have been demonstrated to promote gastric cancer progression in a paracrine manner. IL-8 is highly secreted by GC-MSCs and is crucial for their oncogenic function. However, the mechanism underlying the modulation of IL-8 secretion by GC-MSCs has not been well elucidated. In this study, Shbio-human ceRNA array was used to identify dysregulated mRNAs and circRNAs between GC-MSCs and bone marrow derived mesenchymal stem cells (BM-MSCs). IL-8 was validated to be a critical paracrine cytokine for GC-MSCs promoting migration and invasion of gastric cancer cells. circ_0073453 was identified as a novel GC-MSC-derived circRNA which acted as a sponge of miR-146a-5p, thus increasing IL-8 expression and secretion to promote gastric cancer cell metastasis. Furthermore, circ_0073453 modulated IL-8 secretion by GC-MSCs to enhance gastric cancer cells PD-L1 expression to resist cytotoxic CD8+ T cell-killing. circ_0073453/miR-146a-5p/IL-8 axis was deregulated in gastric cancer tissues and associated with prognosis depending on MSC abundance in cancer tissues. Taken together, our findings suggest that circ_0073453/miR-146a-5p/IL-8 axis is critical for GC-MSCs promoting gastric cancer progression. Hence, hsa_circ_0073453 may be a potential therapeutic target for gastric cancer.

Integrated bioinformatics analysis for the identification of hub genes and signaling pathways related to circANRIL.

Background: Antisense noncoding RNA in the INK4 locus (ANRIL) is located on human chromosome 9p21, and modulation of ANRIL expression mediates susceptibility to some important human disease, including atherosclerosis (AS) and tumors, by affecting the cell cycle circANRIL and linear ANRIL are isoforms of ANRIL. However, it remains unclear whether these isoforms have distinct functions. In our research, we constructed a circANRIL overexpression plasmid, transfected it into HEK-293T cell line, and explored potential core genes and signaling pathways related to the important differential mechanisms between the circANRIL-overexpressing cell line and control cells through bioinformatics analysis. Methods: Stable circANRIL-overexpressing (circANRIL-OE) HEK-293T cells and control cells were generated by infection with the circANRIL-OE lentiviral vector or a negative control vector, and successful transfection was confirmed by conventional flurescence microscopy and quantitative real-time PCR (qRT-PCR). Next, differentially expressed genes (DEGs) between circANRIL-OE cells and control cells were detected. Subsequently, Gene Ontology (GO) biological process (BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to explore the principal functions of the significant DEGs. A protein-protein interaction (PPI) network and competing endogenous RNA (ceRNA) network were constructed in Cytoscape to determine circularRNA (circRNA)- microRNA(miRNA)-messenger RNA (mRNA) interactions and hub genes, and qRT-PCR was used to verify changes in the expression of these identified target genes. Results: The successful construction of circANRIL-OE cells was confirmed by plasmid sequencing, visualization with fluorescence microscopy and qRT-PCR. A total of 1745 DEGs between the circANRIL-OE group and control were identified, GO BP analysis showed that these genes were mostly related to RNA biosynthesis and processing, regulation of transcription and signal transduction. The KEGG pathway analysis showed that the up regulated DEGs were mainly enriched in the MAPK signaling pathway. Five associated target genes were identified in the ceRNA network and biological function analyses. The mRNA levels of these five genes and ANRIL were detected by qRT-PCR, but only COL5A2 and WDR3 showed significantly different expression in circANRIL-OE cells.

Exosomal CD44 Transmits Lymph Node Metastatic Capacity Between Gastric Cancer Cells via YAP-CPT1A-Mediated FAO Reprogramming.

Background: Lymph node metastasis (LNM) commonly occurs in gastric cancer (GC) and is tightly associated with poor prognosis. Exosome-mediated lymphangiogenesis has been considered an important driver of LNM. Whether exosomes directly transmit the LNM phenotype between GC cells and its mechanisms remain elusive. Methods: A highly lymphatic metastatic GC cell line (HGC-27-L) was established by serial passage of parental HGC-27 cells in BALB/c nude mice. The capacities of migration, invasion and LNM; fatty acid oxidation (FAO) levels; and the role of exosome-transferred LNM phenotype were compared among HGC-27-L, HGC-27 and primary GC cell line AGS. Exosomes derived from GC cells and sera were separately isolated using ultracentrifugation and ExoQuick exosome precipitation solution, and were characterized by transmission electron microscopy, Nanosight and western blotting. Transwell assay and LNM models were conducted to evaluate the capacities of migration, invasion and LNM of GC cells in vitro and in vivo. ß-oxidation rate and CPT1 activity were measured to assess FAO. CPT1A inhibitor etomoxir was used to determine the role of FAO. Label-free LC-MS/MS proteome analysis screened the differential protein profiling between HGC-27-exosomes and AGS-exosomes. Small interference RNAs and YAP inhibitor verteporfin were used to elucidate the role and mechanism of exosomal CD44. TCGA data analysis, immunochemistry staining and ELISA were performed to analyze the expression correlation and clinical significance of CD44/YAP/CPT1A. Results: FAO was increased in lymphatic metastatic GC cells and indispensable for sustaining LNM capacity. Lymphatic metastatic GC cell-exosomes conferred LNM capacity on primary GC cells in an FAO-dependent way. Mechanistically, CD44 was identified to be enriched in HGC-27-exosomes and was a critical cargo protein regulating exosome-mediated transmission, possibly by modulating the RhoA/YAP/Prox1/CPT1A signaling axis. Abnormal expression of CD44/YAP/CPT1A in GC tissues was correlated with each other and associated with LNM status, stages, invasion and poor survival. Serum exosomal CD44 concentration was positively correlated with tumor burden in lymph nodes. Conclusions: We uncovered a novel mechanism: exosomal CD44 transmits LNM capacity between GC cells via YAP-CPT1A-mediated FAO reprogramming from the perspective of exosomes-transferred LNM phenotype. This provides potential therapeutic targets and a non-invasive biomarker for GC patients with LNM.

Serum CCAT2 as a biomarker for adjuvant diagnosis and prognostic prediction of cervical cancer.

Growing evidence indicates that lncRNA colon cancer-associated transcript 2 (CCAT2) is associated with cancers. However, the clinical value of CCAT2 in cervical cancer (CC) remains unclear. In this study, serum CCAT2 level was detected by real-time quantitative PCR (RT-qPCR). Carbohydrate antigen 125 (CA125) and squamous-cell carcinoma antigen (SCC) were detected by electrochemiluminescence. A receiver operating characteristic (ROC) curve was utilized to estimate the diagnostic efficiency of CCAT2. Kaplan-Meier survival analysis and univariable and multivariable analyses were performed to assess the prognostic value of CCAT2. The relative expression level of CCAT2 in primary CC patients was significantly higher than that in cervical intraepithelial neoplasias (CIN) patients and healthy controls (both P < 0.001). CCAT2 relative expression was positively correlated with tumor Federation of Gynecology and Obstetrics (FIGO) stage, SCC-Ag and lymph node metastasis (LNM) (all P < 0.05). CCAT2 expression in recurrent/metastatic CC was significantly higher compared with primary CC (P < 0.0001) or operated CC (P < 0.0001) and during follow-up, CCAT2 expression was increased before surgery and decreased significantly after surgery (P < 0.0001). Furthermore, the overall survival rate of CC patients with high CCAT2 expression group markedly decreased as compared with that of low CCAT2 expression group (P = 0.026). Univariate analyses indicated that CCAT2 was a poor prognostic factor associated with overall survival (OS). Our study indicates that CCAT2 may be valuable in complementary diagnosis and monitoring of progression and prognosis of CC patients. Combined detection of CCAT2, CA125 and SCC can greatly improve the diagnostic efficiency of primary CC.

A patient with granulomatous amoebic encephalitis caused by Balamuthia mandrillaris survived with two excisions and medication.

BACKGROUND: Granulomatous amoebic encephalitis (GAE) is a rare central nervous system infection caused by the Balamuthia mandrillaris or Acanthamoeba species. Diagnosis is challenging because of the non-specific clinical presentation, cerebrospinal fluid analysis, and radiological features. There is no effective treatment for GAE to date. CASE PRESENTATION: A 54-year-old male was admitted to hospital after experiencing acute onset of numbness and weakness on his left limb. Due to the initial consideration of intracranial tumor, surgical removal of the right parietal lesion was performed. However, the patient had a headache accompanied by diplopia, difficulty walking and a new lesion was found in the left occipital-parietal lobe two weeks after the first operation. High-throughput next-generation sequencing (NGS) detected the presence of high copy reads of the B. mandrillaris genome sequence in the patient's blood, cerebral spinal fluid (CSF), and brain tissue. Pathological investigation of the brain tissue showed granulomatous changes and amoebic trophozoite scattered around blood vessels under high magnification. The patient was re-operated due to developing progressive confusion caused by subfalcine herniation of the left cerebral hemisphere. The lesions of the right parietal lobe were obviously decreasing in size after the first surgery, and the lesions of the left occipital lobe and the sunfalcine herniation didn't ameliorate two months after the second surgery. The patient was transferred to local hospital for continuous treatment with sulfamethoxazole and azithromycin. After five months of the second surgery, the patient showed good recovery with mild headache. CONCLUSIONS: This is the first report of a patient with B. mandrillaris encephalitis initially confirmed by NGS and have experienced two excisions, responding favorably to the combination of surgeries and medications. Early surgical resection of intracranial lesions combined with drug treatment may offer the chance of a cure.

DGAT2-MOGAT2 SNPs and Gene-Environment Interactions on Serum Lipid Profiles and the Risk of Ischemic Stroke.

Background: The genetic susceptibility to ischemic stroke (IS) is still not well-understood. Recent genome-wide association studies (GWASes) found that several single nucleotide polymorphisms (SNPs) in the Diacylglycerol acyltransferase 2 gene (DGAT2) and monoacylglycerol O-acyltransferase 2 (MOGAT2) cluster were associated with serum lipid levels. However, the association between the DGAT2-MOGAT2 SNPs and serum lipid phenotypes has not yet been verified in the Chinese people. Therefore, the present study was to determine the DGAT2-MOGAT2 SNPs and gene-environment interactions on serum lipid profiles and the risk of IS. Methods: Genotyping of 5 SNPs (DGAT2 rs11236530, DGAT2 rs3060, MOGAT2 rs600626, MOGAT2 rs609379, and MOGAT2 rs10899104) in 544 IS patients and 561 healthy controls was performed by the next-generation sequencing technologies. The association between genotypes and serum lipid data was determined by analysis of covariance, and a corrected P-value was adopted after Bonferroni correction. Unconditional logistic regression analysis was performed to assess the association between genotypes and the risk of IS after adjustment of potential confounders. Results: The rs11236530A allele was associated with increased risk of IS (CA/AA vs. CC, OR = 1.45, 95%CI = 1.12-1.88, P = 0.0044), whereas the rs600626G-rs609379A-rs10899104G haplotype was associated with decreased risk of IS (adjusted OR = 0.67, 95% CI = 0.48-0.93, P = 0.018). The rs11236530A allele carriers had lower high-density lipoprotein cholesterol (HDL-C) concentrations than the rs11236530A allele non-carriers (P < 0.001). The interactions of rs11236530-smoking, rs3060-smoking and rs10899104-smoking influenced serum apolipoprotein B levels, whereas the interactions of rs11236530- and rs3060-alcohol affected serum HDL-C levels (P I < 0.004-0.001). The interaction of rs600626G-rs609379A-rs10899104G-alcohol (OR = 0.41, 95% CI = 0.22-0.76) and rs600626G-rs609379C-rs10899104T-alcohol (OR = 0.12, 95% CI = 0.04-0.36) decreased the risk of IS (P I < 0.0001). Conclusions: The rs11236530A allele was associated with decreased serum HDL-C levels in controls and increased risk of IS in patient group. The rs600626G-rs609379A-rs10899104G haplotype, the rs600626G-rs 609379A-rs10899104G-alcohol and rs600626G-rs609379C-rs10899104T-alcohol interactions were associated with decreased risk of IS. The rs11236530 SNP may be a genetic marker for IS in our study populations.

Effect of SYTL3-SLC22A3 Variants, Their Haplotypes, and G × E Interactions on Serum Lipid Levels and the Risk of Coronary Artery Disease and Ischaemic Stroke.

Background: The current study aimed to investigate the effects of synaptotagmin-like 3 (SYTL3) and solute carrier family 22 member 3 (SLC22A3) single nucleotide polymorphisms (SNPs) and gene-environment (G × E) interactions on blood lipid levels as well as the risk of coronary artery disease (CAD) and ischaemic stroke (IS) in the Southern Chinese Han population. Methods: The genetic makeup of 6 SYTL3-SLC22A3 SNPs in 2269 unrelated participants (controls, 755; CAD, 758 and IS, 756) of Chinese Han ethnicity was detected by the next-generation sequencing techniques. Results: The allele and genotype frequencies of the SYTL3 rs2129209 and SLC22A3 rs539298 SNPs were significantly different between the case and control groups. The SLC22A3 rs539298 SNP was correlated with total cholesterol (TC) levels in controls, the rs539298G allele carriers maintained lower TC levels than the rs539298G allele non-carriers. At the same time, the SLC22A3 rs539298 SNP interacted with alcohol consumption reduced the risk of CAD and IS. The SYTL3-SLC22A3 A-C-A-A-A-A, G-T-C-G-C-A and A-T-A-A-C-A haplotypes increased and the A-C-A-A-C-G haplotype reduced the risk of CAD, whereas the SYTL3-SLC22A3 A-C-A-A-A-A, G-T-C-G-A-G and A-T-A-A-C-A haplotypes increased and the A-C-A-A-A-G and A-C-A-A-C-G haplotypes reduced the risk of IS. In addition, several SNPs interacted with alcohol consumption, body mass index ≥ 24 kg/m2 and cigarette smoking to affect serum lipid parameters such as triglyceride, high-density lipoprotein cholesterol, TC, and apolipoprotein A1 levels. Conclusions: Several SYTL3-SLC22A3 variants, especially the rs539298 SNP, several haplotypes, and G × E interactions, were related to blood lipid parameters and the risk of CAD and IS in the Southern Chinese Han population.

Arabidopsis cryptochrome 1 controls photomorphogenesis through regulation of H2A.Z deposition.

Light is a key environmental cue that fundamentally regulates plant growth and development, which is mediated by the multiple photoreceptors including the blue light (BL) photoreceptor cryptochrome 1 (CRY1). The signaling mechanism of Arabidopsis thaliana CRY1 involves direct interactions with CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1)/SUPPRESSOR OF PHYA-105 1 and stabilization of COP1 substrate ELONGATED HYPOCOTYL 5 (HY5). H2A.Z is an evolutionarily conserved histone variant, which plays a critical role in transcriptional regulation through its deposition in chromatin catalyzed by SWR1 complex. Here we show that CRY1 physically interacts with SWC6 and ARP6, the SWR1 complex core subunits that are essential for mediating H2A.Z deposition, in a BL-dependent manner, and that BL-activated CRY1 enhances the interaction of SWC6 with ARP6. Moreover, HY5 physically interacts with SWC6 and ARP6 to direct the recruitment of SWR1 complex to HY5 target loci. Based on previous studies and our findings, we propose that CRY1 promotes H2A.Z deposition to regulate HY5 target gene expression and photomorphogenesis in BL through the enhancement of both SWR1 complex activity and HY5 recruitment of SWR1 complex to HY5 target loci, which is likely mediated by interactions of CRY1 with SWC6 and ARP6, and CRY1 stabilization of HY5, respectively.

The Clinical Features and Prognosis of Anti-NMDAR Encephalitis Depends on Blood Brain Barrier Integrity.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune nervous system disease that has become increasingly recognized. This retrospective study is aimed to analyze the relations between clinical manifestations and blood brain barrier (BBB) integrity in anti-NMDAR encephalitis patients. METHODS: Anti-NMDAR encephalitis patients were admitted to the First Affiliated Hospital of Guangxi Medical University from April 2014 to April 2020. Patients were grouped by the normal BBB and damaged BBB groups according to the cerebrospinal fluid (CSF) albumin/serum albumin (QAlb). Neutrophil-to-lymphocyte ratio (NLR) in peripheral blood was used for estimating the inflammatory status. The modified Rankin Scale (mRS) was used to assess prognosis. RESULTS: Seventy-three anti-NMDAR encephalitis patients were diagnosed based on the autoimmune encephalitis diagnosis criteria of 2016. Fifty-three (72.6%) patients were in the normal BBB group and twenty (27.4%) were in the BBB damaged group. There were no significant differences in gender, age, psychiatric disturbances, epilepsy, speech disorder, motor dysfunction, memory dysfunction, and autonomic dysfunction between the two groups (p>0.05). Nevertheless, the proportions of decreased consciousness, ICU admission, NLR, CSF protein and intrathecal IgG synthesis (IgGIF, IgGLoc) in the damaged BBB group were higher than that in the normal BBB group (p<0.05). Patients (79.2%) with normal BBB had good prognosis compared to patients with damaged BBB (50%) after 2 months follow-up. The median mRS before and after immunotherapy in the damaged BBB group were significantly higher than that in the normal BBB group (p<0.01, p<0.05, respectively). Additionally, QAlb increased was positively correlated with the quantitative intrathecal IgG synthesis (IgGLoc: r=0.66; IgGIF: r=0.433, all p<0.001). CONCLUSION: The dysfunction of BBB can be helpful in evaluating its prognosis since QAlb showed associations with ICU admission, NLR, a higher CSF protein, intrathecal IgG synthesis (IgGLoc, IgGIF) and mRS score after 2 months follow-up.