Graphene film has been demonstrated as promising active materials for electric double layer capacitors (EDLCs), mainly due to its excellent mechanical flexibility and freestanding morphology. In this work, the distribution and variation pattern of electrolyte ions in graphene-film based EDLC electrodes are investigated with a 11B magic-angle spinning nuclear magnetic resonance (MAS-NMR) spectroscopy. For neutral graphene films soaked with different amounts of electrolytes (1 M TEABF4/ACN), weakly and strongly adsorbed anions are identified based on the resonances at different 11B chemical shifts. Unlike other porous carbonaceous materials, the strongly adsorbed anions are found as the major electrolyte anions components in graphene films. Further measurements on the ion population upon charging are carried out with applying different charging voltages on the graphene films. Results indicate that the charging process of graphene-film based EDLCs can be divided into two distinct charge storage stages (i.e., ejection of co-ions and adsorption of counter-ions) for different voltages. The as-obtained results will be useful for the design and fabrication of high performance graphene-film based EDLCs.

Aim. To study the efficacy and safety of subantimicrobial dose (SD) doxycycline(50 mg/d) in patients with active and moderate-to-severe Graves' orbitopathy (GO). Methods. Thirteen patients with active and moderate-to-severe GO received once daily oral doxycycline (50 mg/d) for 12 wk. Treatment response at 24 wk was used as the primary outcome, measured by a composite of improvement in Clinical Activity Score (CAS), diplopia, motility, soft tissue swelling, proptosis, and eyelid aperture. Secondary outcome was the change of quality of life score (QoL, including visual functioning subscale and appearance subscale). Adverse events were also recorded. Results. Overall improvement was noted in eight out of 13 patients (61.5%, 95% CI 31.6%-86.1%). Both CAS and soft tissue swelling significantly ameliorated in eight patients at 24 wk. Five patients (38.5%) had improvement in ocular motility of ≥8 degrees. Eyelid aperture (46.2%) also decreased remarkably. For QoL, a significant improvement in appearance subscale (P = 0.008) was noted during the study, whereas no difference was observed in visual functioning subscale (P = 0.21). Two patients reported mild stomachache at 12 wk. Conclusions. SD doxycycline appears to be effective and safe for the treatment of active and moderate-to-severe GO. It might serve as a new promising therapeutic strategy for GO. This trial is registered with NCT01727973.

The pentatricopeptide repeat (PPR) proteins characterized by tandem repeats of a degenerate 35-amino-acid motif function in all aspects of organellar RNA metabolism, many of which are essential for organellar gene expression. In this study, we report the characterization of a fission yeast Schizosaccharomyces pombe PPR protein, Ppr10 and a novel Ppr10-associated protein, designated Mpa1. The ppr10 deletion mutant exhibits growth defects in respiratory media, and is dramatically impaired for viability during the late-stationary phase. Deletion of ppr10 affects the accumulation of specific mitochondrial mRNAs. Furthermore, deletion of ppr10 severely impairs mitochondrial protein synthesis, suggesting that Ppr10 plays a general role in mitochondrial protein synthesis. Ppr10 interacts with Mpa1 in vivo and in vitro and the two proteins colocalize in the mitochondrial matrix. The ppr10 and mpa1 deletion mutants exhibit very similar phenotypes. One of Mpa1's functions is to maintain the normal protein level of Ppr10 protein by protecting it from degradation by the mitochondrial matrix protease Lon1. Our findings suggest that Ppr10 functions as a general mitochondrial translational activator, likely through interaction with mitochondrial mRNAs and mitochondrial translation initiation factor Mti2, and that Ppr10 requires Mpa1 association for stability and function.

Cisplatin chemoresistance is a clinical obstacle in the treatment of gastric cancer (GC). Enhanced DNA repair capacity may lead to cisplatin resistance. However, the detailed molecular mechanism of GC cisplatin resistance specifically involving nucleotide excision repair (NER) is not clear. However, the mechanism through which the NER pathway contributes to cisplatin resistance in GC is still unclear. In light of the crucial role of microRNAs (miRNAs) in regulating protein expression and biological behavior, we aimed to analyze the expression and function of miR-192-5p in the NER pathway and its role in cisplatin resistance in GC. Comet assays were performed to measure the amount of DNA damage and repair in the SGC7901 and SGC7901/DDP GC cell lines by observing the tail length. MiRNA expression levels in SGC7901/DDP and SGC7901 cells were detected by microarray. Quantitative real-time PCR (qRT-PCR) was carried out to confirm the expression level of miR-192-5p. Lentiviral vector transfection modifies miR-192-5p levels in SGC7901/DDP and SGC7901 cells. The IC50 values of cisplatin-treated cells were assessed by MTT assays. The protein level was determined by Western blot and immunohistochemistry. With enhanced DNA repair, the expression levels of ERCC3 and ERCC4 in SGC 7901DDP cells increased, while miR-192-5p was significantly downregulated in SGC7901/DDP compared with SGC7901 cells. ERCC3 and ERCC4 were identified as the main targets of miR-192-5p. Forced expression of miR-192-5p in SGC7901/DDP cells significantly inhibited the expression of ERCC3 and ERCC4, making GC cells more sensitive to cisplatin in vitro and in vivo. In contrast, knockdown of miR-192-5p expression in SGC7901 cells increased the expression of ERCC3 and ERCC4, resulting in cisplatin resistance in vitro and in vivo. MiR-192-5p partially reversed GC cisplatin resistance by targeting ERCC3 and ERCC4, which participate in the NER pathway, suggesting that miR-192-5p may be a potential biomarker and therapeutic target for GC cisplatin resistance.

Retinoblastoma (RB) is a common intraocular malignancy in children. Due to the poor prognosis of RB, it is crucial to search for efficient diagnostic and therapeutic strategies. Studies have shown that methyltransferase-like 3 (METTL3), a major RNA N (6)-adenosine methyltransferase, is closely related to the initiation and development of cancers. Nevertheless, whether METTL3 is associated with RB remains unexplored. Therefore, we investigated the function and mechanisms of METTL3 in the regulation of RB progression. We manipulated METTL3 expression in RB cells. Then, cell proliferation, apoptosis, migration and invasion were analysed. We also analysed the expression of PI3K/AKT/mTOR pathway members. Finally, we incorporated subcutaneous xenograft mouse models into our studies. The results showed that METTL3 is highly expressed in RB patients and RB cells. We found that METTL3 knockdown decreases cell proliferation, migration and invasion of RB cells, while METTL3 overexpression promotes RB progression in vitro and in vivo. Moreover, two downstream members of the PI3K/AKT/mTOR pathway, P70S6K and 4EBP1, were affected by METTL3. Our study revealed that METTL3 promotes the progression of RB through PI3K/AKT/mTOR pathways in vitro and in vivo. Targeting the METTL3/PI3K/AKT/mTOR signalling axis could be a promising therapeutic strategy for the treatment of RB.

N6-methyladenosine (m6A) modification of mRNA is emerging as a vital mechanism regulating RNA function. Here, we show that fragile X mental retardation protein (FMRP) reads m6A to promote nuclear export of methylated mRNA targets during neural differentiation. Fmr1 knockout (KO) mice show delayed neural progenitor cell cycle progression and extended maintenance of proliferating neural progenitors into postnatal stages, phenocopying methyltransferase Mettl14 conditional KO (cKO) mice that have no m6A modification. RNA-seq and m6A-seq reveal that both Mettl14cKO and Fmr1KO lead to the nuclear retention of m6A-modified FMRP target mRNAs regulating neural differentiation, indicating that both m6A and FMRP are required for the nuclear export of methylated target mRNAs. FMRP preferentially binds m6A-modified RNAs to facilitate their nuclear export through CRM1. The nuclear retention defect can be mitigated by wild-type but not nuclear export-deficient FMRP, establishing a critical role for FMRP in mediating m6A-dependent mRNA nuclear export during neural differentiation.

Retinal ischemia-reperfusion (I/R) often results in intractable visual impairments, where blood retinal barrier (BRB) homeostasis mediated by retinal pigment epithelium (RPE) and retinal microvascular endothelium (RME) is crucial. However, strategies targeting the BRB are limited. Thus, we investigated the inconclusive effect of lycopene (LYC) in retinal protection under I/R. LYC elevated cellular viability and reversed oxidative stress in aRPE-19 cells/hRME cells under I/R conditions based on oxygen-glucose deprivation (OGD) in vitro. Molecular analysis showed that LYC promoted NRF2 expression and enhanced the downstream factors of the KEAP1/NRF2/ARE pathway: LYC increased the activities of antioxidants, including SOD and CAT, whereas it enhanced the mRNA expression of HO-1 (ho-1) and NQO-1 (nqo-1). The activation resulted in restrained ROS and MDA. On the other hand, LYC ameliorated the damage to retinal function and morphology in a mouse I/R model, which was established by unilateral ligation of the left pterygopalatine artery/external carotid artery and reperfusion. LYC promoted the expression of NRF2 in both the neural retina and the RPE choroid in vivo. This evidence revealed the potential of LYC in retinal protection under I/R, uncovering the pharmacological effect of the KEAP1/NRF2/ARE pathway in BRB targeting. The study generates new insights into scientific practices in retinal research.

Long noncoding RNAs (lncRNAs) are untranslated transcripts greater than 200 nucleotides in length. Despite not being translated, they play a role in the regulation of transcription, translation, and other cellular processes and have been identified as key regulator in the progression of atherosclerosis. This study focused on the lncRNA X-inactive specific transcript (XIST), which participates in the regulation of X chromosome inactivation. XIST is produced by the XIST gene and is located on human chromosome Xql3.2. We also focused on discovering the possible role and mechanism of lncRNA XIST in oxidized low-density lipoprotein- (ox-LDL-) stimulated vascular smooth muscle cells (VSMCs), which could further help evalute its possible a role in the progression of atherosclerosis. XIST was overexpressed in ox-LDL-stimulated VSMCs, while the expression of miR-539-5p was decreased. XIST knockdown hindered the proliferation and migration of ox-LDL-treated VSMCs. XIST inhibits the miR-539-5p expression through direct interaction. Besides, miR-539-5p inhibitors can partially reverse the effect of XIST depletion on the proliferation and migration of VSMCs induced by ox-LDL stimulation. Further mechanistic analysis showed that secreted phosphoprotein 1 (SPP1) is the target of miR-539-5p, and XIST acts as a competing endogenous RNA for miR-539-5p to enhance the expression of SPP1. In addition, miR-539-5p inhibitor exerts its proliferation and migration effects by activating the miR-539-5p/SPP1 axis in VSMCs stimulated by ox-LDL. In conclusion, our study findings show that XIST inhibition can inhibit the proliferation and migration of atherosclerosis vascular smooth muscle cells, which provides a new theoretical basis for atherosclerosis treatment.

DNA aneuploidy has attracted growing interest in clinical practice. Nevertheless, its prognostic value in gastric cancer patients remains controversial. This meta-analysis aims to explore the impact of DNA ploidy status on the survival of gastric cancer patients.

Selective covalent CDK7 inhibitor THZ1 is a promising potential anti-tumor drug in many kinds of cancers. Epithelial-mesenchymal Transition (EMT) is highly related to cancer initiation, development, invasion and metastasis and other pathogenesis processes. We treated cancer cell line Hela229 and three retinoblastoma cell lines so-RB50, WERI-Rb-1, Y79 with gradient concentration of THZ1, and found that THZ1 could inhibit cell viability and EMT, suggesting that THZ1 may be a promising drug for human cervical cancer and retinoblastoma treatment. Our results verified the role of THZ1 in EMT for the first time, however, the mechanism needs further study. Here we report that THZ1 suppresses the TGFβ2 induced EMT in human SRA01/04 lens epithelial cells (LECs), rabbit primary lens epithelial cells, and whole rat lens culture semi-in vivo model. RNA-sequencing and KEGG analysis revealed that the THZ1 inhibits EMT by down-regulating phosphorylate Smad2 and Notch signaling pathway. On the other hand, we found that THZ1 could strongly inhibit LECs proliferation through G2/M phase arrest as well as attenuating of MAPK, PI3K/AKT signaling pathway. Our results uncovered the function and underlying mechanism of THZ1 in regulation of EMT, which provides a new perspective of the anti-tumor effect by THZ1 and may offer a novel treatment for PCO.

Diffuse large B cell lymphoma (DLBCL) is a common and fatal hematological malignancy. Long noncoding RNAs (lncRNAs) have emerged as crucial biomarkers and regulators in many cancers. Novel lncRNA biomarker in DLBCL needs to be investigated badly, as well as its function and molecular mechanism. To further explore, microarray analysis was performed to identify the differentially expressed lncRNAs in DLBCL tissues. To investigate the biological functions of SMAD5-AS1, we performed gain- and loss-of-function experiments in vitro and in vivo. Furthermore, bioinformatics analysis, dual-luciferase reporter assays, Argonaute 2-RNA immunoprecipitation (AGO2-RIP), RNA pull-down assay, quantitative PCR arrays, western blot assay, TOPFlash/FOPFlash reporter assay, and rescue experiments were conducted to explore the underlying mechanisms of competitive endogenous RNAs (ceRNAs). We found that SMAD5-AS1 was down-regulated in DLBCL tissues and cell lines. Functionally, SMAD5-AS1 downregulation promoted cell proliferation in vitro and in vivo, whereas SMAD5-AS1 overexpression could lead to the opposite effects in vitro and in vivo. Bioinformatics analysis and luciferase assays revealed that miR-135b-5p was a direct target of SMAD5-AS1, which was validated by dual-luciferase reporter assays, AGO2-RIP, RNA pull-down assay, and rescue experiments. Also, dual-luciferase reporter assays and rescue experiments demonstrated that miR-135b-5p targeted the adenomatous polyposis coli (APC) gene directly. SMAD5-AS1/miR-135b-5p inhibits the cell proliferation via inactivating the classic Wnt/β-catenin pathway in the form of APC dependency. Our results indicated that SMAD5-AS1 inhibits DLBCL proliferation by sponging miR-135b-5p to up-regulate APC expression and inactivate classic Wnt/β-catenin pathway, suggesting that SMAD5-AS1 may act as a potential biomarker and therapeutic target for DLBCL.

Complex insertions and deletions (indels) are formed by simultaneously deleting and inserting DNA fragments of different sizes at a common genomic location. Here we present a systematic analysis of somatic complex indels in the coding sequences of samples from over 8,000 cancer cases using Pindel-C. We discovered 285 complex indels in cancer-associated genes (such as PIK3R1, TP53, ARID1A, GATA3 and KMT2D) in approximately 3.5% of cases analyzed; nearly all instances of complex indels were overlooked (81.1%) or misannotated (17.6%) in previous reports of 2,199 samples. In-frame complex indels are enriched in PIK3R1 and EGFR, whereas frameshifts are prevalent in VHL, GATA3, TP53, ARID1A, PTEN and ATRX. Furthermore, complex indels display strong tissue specificity (such as VHL in kidney cancer samples and GATA3 in breast cancer samples). Finally, structural analyses support findings of previously missed, but potentially druggable, mutations in the EGFR, MET and KIT oncogenes. This study indicates the critical importance of improving complex indel discovery and interpretation in medical research.

The microbiota from different body sites are dominated by different major groups of microbes, but the variations within a body site such as the mouth can be more subtle. Accurate predictive models can serve as useful tools for distinguishing sub-sites and understanding key organisms and their roles and can highlight deviations from expected distributions of microbes. Good classification depends on choosing the right combination of classifier, feature representation, and learning model. Machine-learning procedures have been used in the past for supervised classification, but increased attention to feature representation and selection may produce better models and predictions.

Background: Several studies have revealed the effect of probiotic supplementation in patients with type 2 diabetes (T2DM) on the amelioration of low-grade inflammation, which plays an important role in the pathogenesis of T2DM. However, the effects of the clinical application of probiotics on inflammation in individuals with T2DM remain inconsistent. This study aims to investigate the comprehensive effects of probiotics on inflammatory markers in adults with T2DM. Methods: PubMed, Embase, Cochrane Library, and the Web of Science were searched to identify randomized controlled trials (RCTs) exploring the effect of probiotic supplementation on inflammatory markers in individuals with T2DM through March 11, 2021. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. We used a random-effects model to calculate the standardized mean difference (SMD) between the probiotic supplementation and control groups. Results: Seventeen eligible studies were selected with a total of 836 participants, including 423 participants in probiotic supplementation groups and 413 participants in control groups. Our study demonstrated that compared with the control condition, probiotic intake produced a beneficial effect in reducing the levels of plasma inflammation markers, including tumour necrosis factor-α (TNF-α) (SMD [95% CI]; -0.37 [-0.56, -0.19], p < 0.0001) and C-reactive protein (CRP) (SMD [95% CI]; -0.21 [-0.42, -0.01], p = 0.040), while it had no effect on the plasma interleukin-6 (IL-6) level (SMD [95% CI]; -0.07 [-0.27, 0.13], p = 0.520). In addition, our results support the notion that probiotic supplementation improves glycaemic control, as evidenced by a significant reduction in fasting blood glucose (FPG), HbA1c and HOMA-IR (SMD [95% CI]: -0.24 [-0.42, -0.05], p = 0.010; -0.19 [-0.37, -0.00], p = 0.040; -0.36 [-0.62, -0.10], p = 0.006, respectively). Conclusion: Our study revealed some beneficial effects of probiotic supplementation on improving inflammatory markers and glucose homeostasis in individuals with T2DM. Probiotics might be a potential adjuvant therapeutic approach for T2DM.

Individual randomized trials are not powered to assess the relationship between use of sodium-glucose transporter 2 inhibitors and risk of stroke. We sought to explore this issue by a meta-analysis incorporating relevant trials including several latest trials.

Metabolic profiling in COVID-19 patients has been associated with disease severity, but there is no report on sex-specific metabolic changes in discharged survivors. Herein we used an integrated approach of LC-MS-and GC-MS-based untargeted metabolomics to analyze plasma metabolic characteristics in men and women with non-severe COVID-19 at both acute period and 30 days after discharge. The results demonstrate that metabolic alterations in plasma of COVID-19 patients during the recovery and rehabilitation process were presented in a sex specific manner. Overall, the levels of most metabolites were increased in COVID-19 patients after the cure relative to acute period. The major plasma metabolic changes were identified including fatty acids in men and glycerophosphocholines and carbohydrates in women. In addition, we found that women had shorter length of hospitalization than men and metabolic characteristics may contribute to predict the duration from positive to negative in non-severe COVID-19 patients. Collectively, this study shed light on sex-specific metabolic shifts in non-severe COVID-19 patients during the recovery process, suggesting a sex bias in prognostic and therapeutic evaluations based on metabolic profiling.

In chimeric antigen receptor (CAR)-T cell therapy, the role and mechanism of indoleamine 2, 3 dioxygenase 1 (IDO1) in enhancing antitumor immunity require further study. IDO1 is one of the most important immunosuppressive proteins in esophageal squamous cell carcinoma (ESCC). However, the IDO1 inhibitor, epacadostat, has failed in phase III clinical trials; its limited capacity to inhibit IDO1 expression at tumor sites was regarded as a key reason for clinical failure. In this study, we innovatively loaded the IDO1 inhibitor into hyaluronic acid-modified nanomaterial graphene oxide (HA-GO) and explored its potential efficacy in combination with CAR-T cell therapy. We found that inhibition of the antitumor effect of CAR-T cells in ESCC was dependent on the IDO1 metabolite kynurenine. Kynurenine could suppress CAR-T cell cytokine secretion and cytotoxic activity. Inhibiting IDO1 activity significantly enhanced the antitumor effect of CAR-T cells in vitro and in vivo. Our findings suggested that IDO1 inhibitor-loaded nanosheets could enhance the antitumor effect of CAR-T cells compared with free IDO1 inhibitor. Nanosheet-loading therefore provides a promising approach for improving CAR-T cell therapeutic efficacy in solid tumors.

Background and objectives: Supernumerary extraocular muscle (SEOM) is extremely rare. The purpose of this paper was to review the clinical characteristics and surgical outcomes of SEOM patients with atypical restrictive strabismus. Materials and Methods: A retrospective review was conducted on the data from 12 SEOM cases. Pre- and post-operative measurements consisted of visual acuity, cycloplegic refraction, ocular alignment, ocular motility, binocular vision, and imaging. Management strategies included either conservative or surgical treatments. Results: Of the 12 cases reviewed (seven females, five males), the mean ± SD age was 14.3 ± 10.6 years (range: 4-38 years). The right eye was affected in six cases, the left in five, and both eyes in one case. The major clinical manifestations included restrictive ocular motility (12 cases), with seven cases in no less than three directions; varying degrees of horizontal or vertical strabismus; ipsilateral amblyopia (10 cases); and unequal palpebral aperture (10 cases). Imaging results revealed muscular bands originating from the annulus of Zinn and insertion into the globe or other recti, as well as anomalous muscular bands connecting two or more recti, sometimes with optic nerve involvement. Three patients received conservative treatment, while rectus recession with or without resection (seven patients) or rectus disinsertion plus globe fixation (two patients) were performed in those receiving surgical treatments. A surgical success was achieved in four cases. Conclusions: For restrictive strabismus, imaging plays an important role in the diagnosis of SEOM. When the SEOM is difficult to resect, a personalized surgical strategy may be required to achieve a good ocular alignment.

Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine.

Helicobacter pylori can cause many kinds of gastric disorders, ranging from gastritis to gastric cancer. Cytotoxin-associated gene A (CagA)+ H. pylori is more likely to cause gastric histopathologic damage than CagA- H. pylori. However, the underlying mechanism needs to be further investigated.