Insulin resistance (IR) plays a critical role in cardiovascular diseases and metabolic diseases. In this study, we identified the downregulation of DMRT2 in adipose tissues from insulin-resistant ...subjects through bioinformatics analysis and in an insulin-resistant mouse model through experimental analysis. DMRT2 overexpression significantly attenuated HDF-induced insulin resistance and inflammation in mice. Moreover, in control and insulin-resistant differentiated mouse 3T3-L1 adipocytes, DMRT2 overexpression attenuated but DMRT2 knockdown enhanced the insulin resistance of 3T3-L1 adipocytes. DMRT2 interacted with FXR and positively regulated FXR level and transcription activity. In both control and insulin-resistant differentiated mouse 3T3-L1 adipocytes, FXR knockdown enhanced the insulin resistance and attenuated the effects of DMRT2 overexpression upon 3T3-L1 adipocyte insulin resistance. In conclusion, we identify the downregulation of DMRT2 in the insulin-resistant mouse model and cell model. DMRT2 interacts with FXR and improves insulin resistance in adipocytes.
•Average breast cancer awareness level is still low in developing countries.•Women should be educated to prevent breast cancer effectively.•This is the largest-scale systematic analysis on breast ...cancer awareness.•Cumulative and subgroup analysis were first used in this type of review.
To summarize the awareness levels of breast cancer (BC) worldwide and investigate factors associated with BC awareness to determine differences in awareness between China and other countries.
This systematic review followed the PRISMA guidelines and included 92 articles up to July, 2021. We calculated percentages for BC awareness levels and conducted subgroup analysis and cumulative meta-analysis.
A total 84% (95% confidence interval 95%CI: 78–90%) of women knew about BC; however, only 51% (95%CI: 37–66%) and 40% (95%CI: 24–56%) of women were aware of BC symptoms and BC risk factors, respectively. The most commonly known BC symptom was breast lump (71%, 95%CI: 62–80%), and BC family history was the most well-known BC risk factor (61%, 95%CI: 54–69%). Subgroup analysis showed lower awareness levels among Chinese and Asian women than women from other countries. Cumulative meta-analysis showed no obvious progress in BC awareness levels over time. We investigated 15 awareness-related factors, the most frequent of which were education level (61.8%), occupation (29.4%), and age (26.5%).
BC awareness levels remain low. Improving BC awareness is critical, especially in developing countries.
Effective education programs are urgently needed to improve women’s BC awareness.
Two new cobalt-diphosphonates templated by protonated 1,2-bis(3-aminopropylamino)ethane (BAPEN), (C8N4H26)0.5·Co(HEDP)·H2O (1) and (C8N4H26)·Co2(HEDP)2(H2O)2·5H2O (2), were hydrothermally prepared ...(HEDP = CH3C(OH)(PO3)2, 1-hydroxyethylidenediphosphonate). Compounds 1 and 2 exhibit anionic 1D Co-HEDP chain and 2D Co-HEDP layer structure, respectively. The structure diversities from 1D chain to 2D layer was realized by adjusting the synthetic parameters. Their magnetism and proton conduction have been studied. Magnetic measurements indicated that the title compounds exhibit weak magnetic interactions. Compounds 1 and 2 feature a proton conductivity of 3.57 × 10–4 and 9.43 × 10–5 S cm–1 at 100% relative humidity and 65 °C, respectively.
To evaluate the effect of acupuncture on anisometropic amblyopia (AA) and explore its potential mechanism for children with AA.
Seventy-six children with monocular AA were randomized into a ...conventional treatment group and a combined treatment group of acupuncture and conventional treatment, with 38 patients in each group. In the conventional treatment group, on the base of patching regimen, the red flashing, grating and visual stimulation were delivered. Each approach lasted for 5 min per session and was given once every two days, three times a week, for 4 consecutive weeks. In the acupuncture-combined treatment group, on the base of the regimen of conventional treatment group, acupuncture was applied to Jingming (BL1), Cuanzhu (BL2), Fengchi (GB20) and Guangming (GB37), with needles retained for 20 min per session, once every two days, three times of intervention a week and for 4 consecutive weeks. Before and after treatment, the best corrected vision acuity (BCVA) was observed to evaluate the clinical effect in the two groups. Before treatment started, 15 patients with AA on left side were randomized selected from each group and the resting-state functional magnetic resonance imaging (rs-fMRI) was operated before and after treatment. Simultaneously, eight healthy children with normal visual acuity were recruited to be the normal control group and received one-time rs-fMRI scanning. Based on the activation likelihood estimation (ALE), the visual “what” pathway network was constructed. By analyzing the amplitude of low frequency fluctuation (ALFF) and the regional homogeneity (ReHo), the differences in the regional autonomous function activities in the key brain areas of the “what” pathway were compared among the three groups.
(1) Clinical effect: After treatment, BCVA was (0.6 0.5, 0.6), higher than that (0.4 0.3, 0.5) before treatment, presenting the statistical difference (P < 0.05) in the conventional treatment group. BCVA was (0.6 0.6, 0.8), higher than that (0.4 0.4, 0.5) before treatment, presenting the statistical difference (P < 0.05) in the acupuncture-combined treatment group. BCVA in the acupuncture-combined treatment group was higher than that of the conventional treatment group (P < 0.05) after treatment. The total effective rate was 86.1% in the acupuncture-combined treatment group, higher than that (65.8%) of the conventional treatment group (P < 0.05). (2) Mechanism: ① ALFF: In comparison with the healthy control group, the ALFF in the primary visual cortex of the “what” pathway for AA children was reduced significantly (P < 0.05), and ALFF in the right fusiform gyrus and the right inferior temporal gyrus increased significantly when compared with the healthy children (P < 0.05). Compared with that before treatment, there was no significant difference in the brain areas of the “what” pathway after treatment in the conventional treatment group (P > 0.05). In the acupuncture-combined treatment group, ALFF in the right inferior occipital gyrus and the right fusiform gyrus of the “what” pathway increased after treatment when compared with that before treatment (P < 0.05). After treatment, in comparison with the conventional treatment group, there was no significant difference in the brain areas of “what” pathway in the acupuncture-combined treatment group (P > 0.05). ② ReHo: ReHo in the right inferior occipital gyrus, the right fusiform gyrus and the right inferior temporal gyrus in the “what” pathway was elevated significantly in AA children when compared with that in the healthy control group (P < 0.05). ReHo of the left inferior occipital gyrus and the left fusiform gyrus increased significantly after treatment when compared with that before treatment in the conventional treatment group (P<0.05). ReHo of the right inferior occipital gyrus, the left and the right fusiform gyrus increased significantly after treatment when compared with that before treatment in the acupuncture-combined treatment group (P < 0.05). After treatment, ReHo of the right inferior temporal gyrus in the “what” pathway in the acupuncture-combined treatment group was significantly higher than that of the conventional treatment group (P < 0.05).
The acupuncture combined with conventional treatment improves BCVA and the total effective rate of AA children. The changes in the regional function activity of the brain areas within the “what” pathway were dominated by the compensatory increase of the autonomous activity in the occipital lobe (inferior occipital gyrus) and the temporal lobe (inferior temporal gyrus) in AA children. Both conventional treatment and acupuncture can enhance the intensity of autonomous function activities in the occipital lobe (inferior occipital gyrus) and the temporal lobe (fusiform gyrus / inferior temporal gyrus) in the “what” pathway so as to relieve visual impairment. ReHo in the inferior temporal gyrus in the acupuncture-combined treatment group was higher than that of the conventional treatment group and it suggests that the inferior temporal gyrus may be the key brain area to the improvement of visual function in the “what” pathway.
Catalase (CAT) is an important antioxidant enzyme that protects aerobic organisms against oxidative damage by degrading hydrogen peroxide to oxygen and water. CAT mRNAs have been cloned from many ...species and employed as useful biomarkers of oxidative stress. In the present study, we cloned the cDNA sequence of CAT gene from freshwater planarian Dugesia japonica (designated as DjCAT) by means of RACE method. Sequence analysis and multiple alignment jointly showed that the full-length cDNA sequence consists of 1734 nucleotides, encoding 506 amino acids. Three catalytic amino acid residues of His71, Asn144 and Tyr354, two CAT family signature sequences of a proximal active site signature (60FDRERIPERVVHAKGGGA77) and a heme-ligand signature motif (350RLFSYRDTQ358) are highly conserved, suggesting that the DjCAT belongs to the NADPH and heme-binding CAT family and has similar functions. In addition, the transcriptional level of CAT gene and activity of CAT enzyme upon acute exposure of environmental pollutants glyphosate and 1-decyl-3-methylimidazolium bromide (C10mimBr) were investigated systematically. The variation of CAT mRNA expression in D. japonica was quantified by real-time PCR and the results indicated that it was up-regulated after exposure to glyphosate or C10mimBr with a dose-dependent manner but not linearly. Even though the variation trend of CAT activity upon glyphosate stress was not monotonously increased and inconsistent with that after C10mimBr exposure on day 1 and 3 sampling time, with the duration prolonged to day 5 they both presented a dose-dependent increase and the differences achieved extreme significance in all treated groups compared to the control. These findings suggested that DjCAT plays an important role in antioxidant defense in D. japonica, and the mRNA expression of CAT would also be used as an effective biomarker to monitor the pollution in aquatic environment just like its corresponding enzyme.
•The cDNA of CAT was firstly cloned and characterized from planarian Dugesia japonica.•mRNA expression of CAT and enzyme activity of CAT in response to pollutants were explored.•CAT plays an important role in antioxidant defense in Dugesia japonica.•CAT mRNA expression would be used as an effective biomarker in pollution monitoring.
Abstract
The histone chaperone FACT (FAcilitates Chromatin Transcription) plays an essential role in transcription and DNA replication by its dual functions on nucleosome assembly to maintain ...chromatin integrity and nucleosome disassembly to destabilize nucleosome and facilitate its accessibility simultaneously. Mono-ubiquitination at Lysine 119 of H2A (ubH2A) has been suggested to repress transcription by preventing the recruitment of FACT at early elongation process. However, up to date, how ubH2A directly affects FACT on nucleosome assembly and disassembly remains elusive. In this study, we demonstrated that the dual functions of FACT are differently regulated by ubH2A. The H2A ubiquitination does not affect FACT’s chaperone function in nucleosome assembly and FACT can deposit ubH2A–H2B dimer on tetrasome to form intact nucleosome. However, ubH2A greatly restricts FACT binding on nucleosome and inhibits its activity of nucleosome disassembly. Interestingly, deubiquitination of ubH2A rescues the nucleosome disassembly function of FACT to activate gene transcription. Our findings provide mechanistic insights of how H2A ubiquitination affects FACT in breaking nucleosome and maintaining its integrity, which sheds light on the biological function of ubH2A and various FACT’s activity under different chromatin states.
Graphical Abstract
Graphical Abstract
ubH2A restricts FACT binding on nucleosome, but maintains FACT's chaperone function.
Due to the blood-brain barrier, plasma is not an ideal source to evaluate the genetic characteristics of central nervous system tumors. Thus, cerebrospinal fluid (CSF) is becoming an alternative ...biopsy type to evaluate the genetic landscape of intracranial tumors. We aimed to explore the genetic profiles of CSF-derived circulating tumor DNA (ctDNA) to predict intracranial tumor responses and monitor mutational evolution during the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases.
We conducted a prospective study of 92 newly diagnosed NSCLC patients with brain metastases. Paired CSF and plasma samples were collected at baseline, 8 weeks after treatment initiation, and disease progression. All samples underwent next-generation sequencing of 425 cancer-related genes.
At baseline, the positive detection rates of ctDNA in CSF, plasma, and extracranial tumors were 63.7% (58/91), 91.1% (82/90), and 100% (58/58), respectively. A high level of genetic heterogeneity was observed between paired CSF and plasma, while concordance in driver mutations was also observed. A higher number of unique copy number variations was detected in CSF-ctDNA than in plasma. ctDNA positivity of CSF samples at baseline was associated with poor outcomes (HR=2.565, P=0.003). Moreover, patients with ≥ 50% reductions in the concentrations of CSF ctDNA after 8 weeks of treatment had significantly longer intracranial progression-free survivals (PFS) than patients with < 50% reductions in CSF ctDNA concentrations (13.27 months vs 6.13 months, HR=0.308, P=0.017). A ≥ 50% reduction in CSF ctDNA concentrations had better concordance with radiographic intracranial tumor responses than plasma. A ≥ 50% reduction in plasma ctDNA concentrations was also associated with longer extracranial PFS (11.57 months vs 6.20 months, HR=0.406, P=0.033). Based on clonal evolution analyses, the accumulation of subclonal mutations in CSF ctDNA was observed after 8 weeks of treatment. The clonal mutations that remained in more than 80% in CSF after 8 weeks also predicted shorter intracranial PFS (HR=3.785, P=0.039).
CSF ctDNA exhibited unique genetic profiles of brain metastases, and dynamic changes in CSF ctDNA could better predict intracranial tumor responses and track clonal evolution during treatment in NSCLC patients with brain metastases.
ClinicalTrials.gov identifier: NCT03257735.
Two series of lanthanide phosphonates, H4BAPEN1.5·Ln2(HEDP)3·5H2O Ln = Gd3+ (1-Gd), Tb3+ (1-Tb), Dy3+ (1-Dy) and H4BAPEN0.5·LnLi(HHEDP)2(H2O)2·2H2O Ln = Gd3+ (2-Gd), Tb3+ (2-Tb), Dy3+ (2-Dy) (HEDP = ...1-hydroxyethylidenediphosphonate) displaying diverse structures have been successfully constructed templated by a protonated aliphatic organic amine 1,2-bis(3-aminopropylamino)ethane (BAPEN). The connection of Ln(III) ions and the diphosphonate ligand generates the one-dimensional (1D) chains for both series 1 and 2. Interestingly, 2D layered heterometallic diphosphonate networks were fabricated in series 2 wherein the adjacent Ln–HHEDP chains are joined together through the linkage of Li+. Notably, the compounds feature interesting proton conduction behavior. The conductivity increases smoothly with rising temperature, indicating that these compounds could act as promising candidates for temperature sensing. Moreover, the magnetic properties of them have been investigated.
Photochromic materials have application in various areas such as anti-counterfeiting, display, switches, etc. Most of reported photochromic materials are supported by photoactive moieties such as ...diarylethenes, pyridinium, azo compounds. Compared with the broadly investigated photochromic materials driven by photoactive units, the generation of new photochromic materials based on nonphotoactive units is of paramount significance from the perspective of basic research and practical application. Based on the proton coupled electron transfer (PCET) mechanism, the introduction of conjugated triangular tripyridine-derivative unit TPT (2,4,6-tri(4-pyridyl)-1,3,5-triazine) and linear dipyridine-derivative unit BPYB (1,4-di(pyridine-4-yl)benzene) into the zincochloride system generates two hybrid halometallates with photochromic performance, H2BPYBZnCl4·H2O (1) and H3TPT2Zn3Cl12·4H2O (2). Both 1 and 2 feature isolated inorganic ZnCl42− tetrahedra (as electron donors and H-bond acceptors) and protonated organic polypyridine derivatives units H2BPYB2+ and H3TPT3+ (as electron acceptors and H-bond donors). Experimental characterization, together with the structure-property relationship analysis, indicates that the resulting photocoloration and related photoresponsive properties of 1 and 2 is ascribable to the PCET mechanism.
The introduction of protonated conjugated polypyridine derivative units to the zincochloride system yields two hybrid halometallates with photochromic performance driven by the proton coupled electron transfer mechanism. Display omitted
•Two hybrid halometallates based on nonphotoactive polypyridine-derivative moieties were solvothermally synthesized.•They feature isolated inorganic ZnCl42− tetrahedra and protonated organic polypyridine units.•The photocoloration and related photoresponsive properties is ascribable to the proton coupled electron transfer mechanism.
The substituted quinoline compound MT-5 was identified as a novel mTOR inhibitor via a rationally virtual screening strategy. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 μM) and ...antiproliferative effect against HCT-116 cells (IC50: 4.61 μM). MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, SD rat plasma, and liver microsomes. Computational studies of the MT-5 binding to mTOR protein have also been performed, which would provide a theoretical reference for further structural modification.
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•A rationally virtual screening strategy has been established for mTOR inhibitors.•MT-5 was obtained from ChemDiv database, and it showed potent kinase inhibitory activity (IC50: 8.90 μM) and antiproliferative effect on HCT-116 cells (IC50: 4.61 μM).•The potential antitumor mechanism of MT-5 has been investigated.•MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, SD rat plasma and liver microsomes.•Computational studies of MT-5 binding to mTOR protein have also been performed.
The abnormal activation of the mTOR pathway is closely related to the occurrence and progression of cancer, especially colorectal cancer. In this study, a rational virtual screening strategy has been established and MT-5, a novel mTOR inhibitor with a quinoline scaffold, was obtained from the ChemDiv database. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 μM) and antiproliferative effects against various cancer cell lines, especially HCT-116 cells (IC50: 4.61 μM), and this was 2.2-fold more potent than that of the cisplatin control (IC50: 9.99 μM). Western blot, cell migration, cycle arrest, and apoptosis assays were performed with HCT-116 cells to investigate the potential anticancer mechanism of MT-5. Metabolic stability results in vitro indicated that MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, rat plasma, and liver microsomes. In addition, the key contribution of the residues around the binding pocket of MT-5 in binding to the mTOR protein was also investigated from a computational perspective.
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