Cell death in the central nervous system causes neurologic diseases, in which reactive oxygen species (ROS) play a critical role by either inducing cellular oxidative stress or by increasing the cell tolerance against insult. Neurologic diseases may potentially be treated by regulating ROS levels in a certain range with small molecules. We studied preconditioning with two polynitrogen manganese complexes (1 and 2) to regulate intracellular ROS levels in the protection of both the differentiated rat pheochromocytoma cell line (PC12 cells) and neurons against H2O2-induced apoptosis. Pre-treatment with the two complexes attenuated the cell apoptosis caused by H2O2. And the ROS-related neuroprotective mechanisms were explored. Both complexes activate the hypoxia inducible factor-related pathways and increase the cell adaptation to oxidative stress. Pre-treatment with complex 1 eliminated intracellular ROS, which also activated antioxidase system, while short-term incubation of complex 2, generated low levels of ROS leading to cell survival.

Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator in cancer cell survival, epithelial-mesenchymal transition, and tumorigenesis. Inhibition of EZH2 has become a promising therapeutic option for various human malignancies. Previously, we demonstrated that the EZH2/miR-30d/karyopherin (importin) beta 1 (KPNB1) signaling pathway is critical for malignant peripheral nerve sheath tumor (MPNST) cell survival in vitro and for tumorigenesis in vivo. Here, we sought to determine the antitumor effects of pharmacological inhibition of EZH2 on MPNST in vitro and in vivo.

Scoring DNA sequences against Position Weight Matrices (PWMs) is a widely adopted method to identify putative transcription factor binding sites. While common bioinformatics tools produce scores that can reflect the binding strength between a specific transcription factor and the DNA, these scores are not directly comparable between different transcription factors. Other methods, including p-value associated approaches (Touzet H, Varré J-S. Efficient and accurate p-value computation for position weight matrices. Algorithms Mol Biol. 2007;2(1510.1186):1748-7188), provide more rigorous ways to identify potential binding sites, but their results are difficult to interpret in terms of binding energy, which is essential for the modeling of transcription factor binding dynamics and enhancer activities.

To evaluate the identification method using the microRNA markers miR10b and miR135b to distinguish semen stains from menstrual blood, peripheral blood, vaginal fluid and so on body fluid stains. The expression levels of miR10b and miR35b in semen stains and menstrual blood and so on were detected utilizing a real-time quantitative PCR technique with a specific fluorescence-labeled TaqMan probe. RNU6b was used as the internal reference gene; the difference in their expression was analyzed, and the specificity, sensitivity, and detection capability of the techniques were evaluated. The expression of miR10b and miR135b in semen stains was significantly higher than that of other body fluid stains, with a mean value of ΔCт from-6 to-7. However, it ranged from-2 to-4 for other body fluid stains. The initial criteria for judging which semen stains can be identified were determined by analyzing the research results. When the threshold value was set to 0.04, the CT value could be detected in the target genes miR10b, miR135b and in the internal reference gene RNU6b, and CT values are<40, ΔCT[10b-U6]<-5.5, and ΔCT[135b-U6]<-6, respectively, and the semen stain could be identified. The expression levels of miR10b and miR135b are higher in semen with strong tissue specificity; thus, they can be used to differentiate semen stains from other body fluid stains in forensic science.

The ability to selectively destroy cancer cells while sparing normal tissue is highly desirable during the cancer therapy. Here, magnetic targeted photothermal therapy was demonstrated by the integration of MoS2 (MS) flakes and Fe3O4 (IO) nanoparticles (NPs), where MoS2 converted near-infrared (NIR) light into heat and Fe3O4 NPs served as target moiety directed by external magnetic field to tumor site. The MoS2/Fe3O4 composite (MSIOs) functionalized by biocompatible polyethylene glycol (PEG) were prepared by a simple two-step hydrothermal method. And the as-obtained MSIOs exhibit high stability in bio-fluids and low toxicity in vitro and in vivo. Specifically, the MSIOs can be applied as a dual-modal probe for T2-weighted magnetic resonance (MR) and photoacoustic tomography (PAT) imaging due to their superparamagnetic property and strong NIR absorption. Furthermore, we demonstrate an effective result for magnetically targeted photothermal ablation of cancer. All these results show a great potential for localized photothermal ablation of cancer spatially/timely guided by the magnetic field and indicated the promise of the multifunctional MSIOs for applications in cancer theranostics.

The translation of rare codons relies on their corresponding rare tRNAs, which could not be fully charged under amino acid starvation. Theoretically, disrupted or retarded translation caused by the lack of charged rare tRNAs can be partially restored by feeding or intracellular synthesis of the corresponding amino acids. Inspired by this assumption, we develop a screening or selection system for obtaining overproducers of a target amino acid by replacing its common codons with the corresponding synonymous rare alternative in the coding sequence of selected reporter proteins or antibiotic-resistant markers. Results show that integration of rare codons can inhibit gene translations in a frequency-dependent manner. As a proof-of-concept, Escherichia coli strains overproducing L-leucine, L-arginine or L-serine are successfully selected from random mutation libraries. The system is also applied to Corynebacterium glutamicum to screen out L-arginine overproducers. This strategy sheds new light on obtaining and understanding amino acid overproduction strains.

Oral squamous cell carcinoma (OSCC) is usually preceded by the oral premalignant lesions, mainly oral leukoplakia (OLK) after repeated insults of carcinogens, tobacco. B(a)P and DMBA are key carcinogens in tobacco smoke. In the present study, for the first time we established the cancerous cell line OSCC-BD induced by B(a)P/DMBA mixture and transformed from dysplastic oral leukoplakia cell line DOK. Cell morphology, proliferation ability, migration ability, colony formation, and tumorigenicity were studied and confirmed the malignant characteristics of OSCC-BD cells. We further identified the differential proteins between DOK and OSCC-BD cells by stable isotope dimethyl labeling based quantitative proteomic method, which showed 18 proteins up-regulated and 16 proteins down-regulated with RSD < 8%. Differential proteins are mainly related to cell cycle, cell proliferation, DNA replication, RNA splicing and apoptosis. Abberant binding function, catalysis activity and transportor activity of differential proteins might contribute to the malignant transformation of OLK. Of the 34 identified differential proteins with RSD < 8%, 13 novel cancer-related proteins were reported in the present study. This study might provide a new insight into the mechanism of OLK malignant transformation and the potent biomarkers for early diagnosis, meanwhile further facilitate the application of the quantification proteomics to carcinogenesis research.

The outbreak of coronavirus disease 2019 (COVID-19) is a global health emergency. Various omics results have been reported for COVID-19, but the molecular hallmarks of COVID-19, especially in those patients without comorbidities, have not been fully investigated. Here we collect blood samples from 231 COVID-19 patients, prefiltered to exclude those with selected comorbidities, yet with symptoms ranging from asymptomatic to critically ill. Using integrative analysis of genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles, we report a trans-omics landscape for COVID-19. Our analyses find neutrophils heterogeneity between asymptomatic and critically ill patients. Meanwhile, neutrophils over-activation, arginine depletion and tryptophan metabolites accumulation correlate with T cell dysfunction in critical patients. Our multi-omics data and characterization of peripheral blood from COVID-19 patients may thus help provide clues regarding pathophysiology of and potential therapeutic strategies for COVID-19.

Oral squamous cell carcinoma (OSCC) is one of the common cancers worldwide. The lack of specific biomarkers and therapeutic targets leads to delayed diagnosis and hence the poor prognosis of OSCC patients. Thus, it is urgent to identify effective biomarkers and therapeutic targets for OSCC.

We aimed to identify miRNAs that were closely related to breast cancer (BRCA). By integrating several methods including significance analysis of microarrays, fold change, Pearson's correlation analysis, t test, and receiver operating characteristic analysis, we developed a decision-tree-based scoring algorithm, called Optimized Scoring Mechanism for Primary Synergy MicroRNAs (O-PSM). Five synergy miRNAs (hsa-miR-139-5p, hsa-miR-331-3p, hsa-miR-342-5p, hsa-miR-486-5p, and hsa-miR-654-3p) were identified using O-PSM, which were used to distinguish normal samples from pathological ones, and showed good results in blood data and in multiple sets of tissue data. These five miRNAs showed accurate categorization efficiency in BRCA typing and staging and had better categorization efficiency than experimentally verified miRNAs. In the Protein-Protein Interaction (PPI) network, the target genes of hsa-miR-342-5p have the most regulatory relationships, which regulate carcinogenesis proliferation and metastasis by regulating Glycosaminoglycan biosynthesis and the Rap1 signaling pathway. Moreover, hsa-miR-342-5p showed potential clinical application in survival analysis. We also used O-PSM to generate an R package uploaded on github (SuFei-lab/OPSM accessed on 22 October 2021). We believe that miRNAs included in O-PSM could have clinical implications for diagnosis, prognostic stratification and treatment of BRCA, proposing potential significant biomarkers that could be utilized to design personalized treatment plans in BRCA patients in the future.

Goosegrass (Eleusine indica) is one of the worst agricultural weeds in China. Molecular markers were developed for genetic diversity and population structure analyses. In this study, we identified 8391 expressed sequence tag-simple sequence repeat (EST-SSR) markers from the de novo assembled unigenes of E. indica. Mononucleotides were the most abundant type of repeats (3591, 42.79%), followed by trinucleotides (3162, 37.68%). The most dominant mononucleotide and trinucleotide repeat motifs were A/T (3406, 40.59%) and AAT/ATT (103, 1.5%), respectively. Fourteen pairs of EST-SSR primers were verified and used to analyze the genetic diversity and population structure of 59 goosegrass populations. A total of 49 alleles were amplified, with the number of alleles (Na) ranging from two to eleven per locus, and the effective number of alleles (Ne) ranged from 1.07 to 4.53. The average polymorphic information content (PIC) was 0.36. Genetic structure analysis (K = 2) and principal coordinate analysis divided 59 E. indica populations into two groups in a manner similar to the unweighted pair-group method (Dice genetic similarity coefficient = 0.700). This study developed a set of EST-SSR markers in E. indica and successfully analyzed the diversity and population genetic structures of 59 E. indica populations in China.

Liver transplantation is the only treatment available for pediatrics with end-stage liver disease. However, neurological damage is prone to occur after liver transplantation, especially in children. Accumulating evidence has shown that sevoflurane is closely linked to brain injury induced by liver transplantation. However, the study on the role of sevoflurane in brain injury induced by liver transplantation is rare and needs to be further investigated. The study is aiming to investigate the effects of sevoflurane on brain injury induced by liver transplantation and its underlying mechanisms. The brain injury rat model was built through 70% hepatic ischemia-reperfusion (HIR) of young rats. We detected the ferroptosis and brain injury after HIR by histological, transmission electron microscope analyses, western blot, and Enzyme-linked immunosorbent assays. And we detected the level of ferroptosis in brain by using sevoflurane during HIR compared with HIR without using sevoflurane. At the same time, we use iron inhibitor deferoxamine (DFO) to verify that the brain injury was caused by ferrotosis of brain. The results indicated that the pathological injury, ferroptosis indicators, and brain injury indicators were aggravated in the sevoflurane group compared with the HIR group, the decrease in the degree of brain injury and ferroptosis was observed in the group using DFO. Collectively, the results suggest that ferroptosis may mediate sevoflurane-aggravated young rats' brain injury induced by liver transplantation. Our findings provide a potential therapeutic target for brain injury after pediatric liver transplantation.

Synthetic promoters are considered ideal candidates in driving robust gene expression. Most of the available synthetic promoters are minimal promoters, for which the upstream sequence of the 5' end of the core region is usually excluded. Although the upstream sequence has been shown to mediate transcription of natural promoters, its impact on synthetic promoters has not been widely studied. Here, a library of chromosomal DNA fragments is randomly fused with the 5' end of the J23119 synthetic promoter, and the transcriptional performance of the promoter is evaluated through β-galactosidase assay, fluorescence intensity and chemical biosynthesis. Results show that changes in the upstream sequence can induce significant variation in the promoter strength of up to 5.8-fold. The effect is independent of the length of the insertions and the number of potential transcription factor binding sites. Several DNA fragments that are able to enhance the transcription of both the natural and the synthetic promoters are identified. This study indicates that the synthetic minimal promoters are susceptible to the surrounding sequence context. Therefore, the upstream sequence should be treated as an indispensable component in the design and application of synthetic promoters, or as an independent genetic part for the fine-tuning of gene expression.

It is still challenging to make accurate diagnosis of biliary atresia (BA) with sonographic gallbladder images particularly in rural area without relevant expertise. To help diagnose BA based on sonographic gallbladder images, an ensembled deep learning model is developed. The model yields a patient-level sensitivity 93.1% and specificity 93.9% [with areas under the receiver operating characteristic curve of 0.956 (95% confidence interval: 0.928-0.977)] on the multi-center external validation dataset, superior to that of human experts. With the help of the model, the performances of human experts with various levels are improved. Moreover, the diagnosis based on smartphone photos of sonographic gallbladder images through a smartphone app and based on video sequences by the model still yields expert-level performances. The ensembled deep learning model in this study provides a solution to help radiologists improve the diagnosis of BA in various clinical application scenarios, particularly in rural and undeveloped regions with limited expertise.

Schizophrenia patients often experience auditory hallucinations (AHs) and visual hallucinations (VHs). However, the degree and type of brain and retinal alterations associated with combined AHs and VHs in schizophrenia patients remain unknown. There is an urgent need for a study that investigates the trajectory of brain and retinal alterations in patients with first-episode untreated schizophrenia accompanied by combined AHs and VHs (FUSCHAV).

Prostate cancer (PCa) is one of the most common malignant tumours in the world and seriously affects health of men. Studies have shown that microRNA (miR)-29b-3p and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE) play important roles in influencing the proliferation and apoptosis of PCa cells. However, the molecular mechanism of miR-29b-3p and YWHAE in the proliferation and apoptosis of PCa cells remains unclear. In the present study, bioinformatics as well as in vivo and in vitro experiments were used to predict and verify the targeting relationship between YWHAE and mir-29B-3p and investigate the potential roles of YWHAE and mir-29b-3p in the proliferation and apoptosis of 22RV1 cells. Using bioinformatics and a double luciferase system assay, it was confirmed that miR-29b-3p can target YWHAE 3'untranslated region and affect the expression of YWHAE, suggesting that miR-29b-3p may be a potential miRNA of YWHAE. Reverse transcription-quantitative PCR, Cell Counting Kit-8, Transwell and cell scratch assays showed that miR-29b-3p significantly inhibited the proliferation, invasion and migration of 22Rv1 cells (P<0.01). Rescue experiments demonstrated that YWHAE gene introduction reversed the inhibitory effect of miR-29b-3p on 22Rv1 cells. Western blotting revealed that the upregulation of miR-29b-3p inhibited YWHAE expression, resulting in a very significant decrease in the ratio of p-BAD/BAD and full-length caspase 3/cleaved caspase 3 (P<0.01) and an extremely significant increase in the ratio of BAX/BCL-2 (P<0.01). A tumourigenesis test in nude mice in vivo confirmed that the upregulation of miR-29b-3p inhibited tumour growth by targeting YWHAE. The present experiments confirmed that miR-29b-3p plays a tumour suppressor role in 22Rv1 PCa cells, and the YWHAE/BCL-2 regulatory axis plays a vital role in miR-29b-3p regulating the proliferation and apoptosis of 22Rv1 cells. These results may provide a theoretical basis for the diagnosis and targeted treatment of PCa.

Lithium (Li) is a well-established mood disorder treatment and may be neuroprotective. Bi-directional regulation (i.e. affecting manic symptoms and depressive symptoms) by Li has not been demonstrated. This study explored: (1) bidirectional regulation by Li in murine models of depression, mania, and bipolar disorder (BP); and (2) potential Li synergism with antidepressant/anti-mania agents. The chronic unpredictable mild stress (CUMS) and ketamine-induced mania (KM) models were used. These methods were used in series to produce a BP model. In vivo two-photon imaging was used to visualize Ca2+ activity in the dorsolateral prefrontal cortex. Depressiveness, mania, and cognitive function were assessed with the forced swim task (FST), open field activity (OFA) task, and novel object recognition task, respectively. In CUMS mice, Ca2+ activity was increased strongly by Li and weakly by lamotrigine (LTG) or valproate (VPA), and LTG co-administration reduced Li and VPA monotherapy effects; depressive immobility in the FST was attenuated by Li or LTG, and attenuated more strongly by LTG-VPA or LTG-Li; novel object exploration was increased strongly by Li and weakly by LTG-Li, and reduced by LTG, VPA, or LTG-VPA. In KM mice, Li or VPA attenuated OFA mania symptoms and normalized Ca2+ activity partially; Li improved cognitive function while VPA exacerbated the KM alteration. These patterns were replicated in the respective BP model phases. Lithium had bi-directional, albeit weak, mood regulation effects and a cognitive supporting effect. Li co-administration with antidepressant/-manic agents enhanced mood-regulatory efficacy while attenuating their cognitive-impairing effects.

Increasing evidences have revealed that solasodine, isolated from Solanum sisymbriifolium fruits, has multiple functions such as anti-oxidant, anti-tumor and anti-infection. However, its role in pancreatic cancer has not been well studied.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase that is extensively involved in the autophagy process by interacting with diverse autophagy initiation and autophagosome maturation molecules. However, whether TRAF6 interacts with lysosomal proteins to regulate Mycobacterium-induced autophagy has not been completely characterized. Herein, the present study showed that TRAF6 interacted with lysosomal key proteins Rab7 through RING domain which caused Rab7 ubiquitination and subsequently ubiquitinated Rab7 binds to STX17 (syntaxin 17, a SNARE protein that is essential for mature autophagosome), and thus promoted the fusion of autophagosomes and lysosomes. Furthermore, TRAF6 enhanced the initiation and formation of autophagosomes in Mycobacterium-induced autophagy in both BMDMs and RAW264.7 cells, as evidenced by autophagic flux, colocalization of LC3 and BCG, autophagy rates, and autophagy-associated protein expression. Noteworthy to mention, TRAF6 deficiency exacerbated lung injury and promoted BCG survival. Taken together, these results identify novel molecular and cellular mechanisms by which TRAF6 positively regulates Mycobacterium-induced autophagy.

The impaired differentiation ability of resident cells and disordered immune microenvironment in periodontitis pose a huge challenge for bone regeneration. Herein, we construct a piezoelectric hydrogel to rescue the impaired osteogenic capability and rebuild the regenerative immune microenvironment through bioenergetic activation. Under local mechanical stress, the piezoelectric hydrogel generated piezopotential that initiates osteogenic differentiation of inflammatory periodontal ligament stem cells (PDLSCs) via modulating energy metabolism and promoting adenosine triphosphate (ATP) synthesis. Moreover, it also reshapes an anti-inflammatory and pro-regenerative niche through switching M1 macrophages to the M2 phenotype. The synergy of tilapia gelatin and piezoelectric stimulation enhances in situ regeneration in periodontal inflammatory defects of rats. These findings pave a new pathway for treating periodontitis and other immune-related bone defects through piezoelectric stimulation-enabled energy metabolism modulation and immunomodulation.