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A family of chiral nanographenes bearing [6]helicene units has been synthesized via the classical Scholl reaction. Inserting the [6]helicene unit into the parent nanographene skeleton can result in different structural topologies and optoelectric properties. Moreover, the isolated enantiomers exhibit attractive chiroptical properties.
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BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck. Zeng-Sheng-Ping, composed of Sophora tonkinensis Gagnep., Bistorta officinalis Delarbre, Sonchus arvensis L., Prunella vulgaris L., Dioscorea bulbifera L., and Dictamnus dasycarpus Turcz., was regarded as an anti-cancer drug with significant clinical efficacy, but was discontinued due to liver toxicity. Our research group developed a modified Zeng-Sheng-Ping (ZSP-M) based on original Zeng-Sheng-Ping that exhibited high efficiency and low toxicity in preliminary investigations, although its pharmacodynamic mechanism is still unclear. Here, we aimed to elucidate the pharmacodynamic material basis of ZSP-M and investigate its chemopreventive effect on OSCC by modulating tumor associated macrophages (TAMs). METHODS: Components of ZSP-M were characterized using ultra-performance liquid chromatography-mass spectrometry. Chemopreventive effect induced by ZSP-M against experimental oral cancer was investigated using the 4-nitroquinoline N-oxide precancerous lesion mouse model. RNA sequencing analysis was used to gain a global transcriptional view of the effect of ZSP-M treatment. A cell co-culture model was used to study the targeted effect of ZSP-M on TAMs and the biological properties of OSCC cells and to detect changes in TAM phenotypes. The binding of ZSP-M active compounds to TNF alpha induced protein 6 (TNFAIP6) protein was analyzed by molecular docking and dynamic simulation. RESULTS: Forty main components of ZSP-M were identified, the most abundant of which were flavonoids. ZSP-M inhibited the degree of epithelial dysplasia in precancerous lesions by inhibiting the expression of the TNFAIP6 and CD163 proteins in the precancerous lesions of the tongue. ZSP-M inhibited proliferation, colony formation, migration and invasion of SCC7 cells by targeting TAMs. ZSP-M reduced the expression of CD163+ cells, inhibited the expression of TNFAIP6 protein, Arg1 mRNA and Il10 mRNA in TAMs, and reduced IL-10 cytokine release in the co-culture environment. This effect was maintained after the addition of recombinant TNFAIP6 protein. Computer simulations showed that trifolirhizin and maackiain are well-connected to TNFAIP6. CONCLUSIONS: ZSP-M counteracts the immunosuppressive action of TAMs by specific targeting of TNFAIP6, thereby exerting chemopreventive activity of OSCC.
Subject(s)
Mouth Neoplasms , Tumor-Associated Macrophages , Animals , Mice , Mouth Neoplasms/drug therapy , Tumor-Associated Macrophages/drug effects , Carcinoma, Squamous Cell/drug therapy , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/chemistry , Humans , Cell Line, Tumor , Male , Squamous Cell Carcinoma of Head and Neck/drug therapyABSTRACT
In this research, four water-insoluble flavonoid compounds were utilized and reacted with arginine to prepare four carbonized polymer dots with good water-solubility in a hydrothermal reactor. Structural characterization demonstrated that the prepared carbonized polymer dots were classic core-shell structure. Effect of the prepared carbonized polymer dots on protein amyloid aggregation was further investigated using hen egg white lysozyme and human lysozyme as model protein in aqueous solution. All of the prepared carbonized polymer dots could retard the amyloid aggregation of hen egg white lysozyme and human lysozyme in a dose-depended manner. All measurements displayed that the inhibition ratio of luteolin-derived carbonized polymer dots (CPDs-1) was higher than that of the other three carbonized polymer dots under the same dosage. This result may be interpreted by the highest content of phenolic hydroxyl groups on the periphery. The inhibition ratio of CPDs-1 on hen egg white lysozyme and human lysozyme reached 88â¯% and 83â¯% at the concentration of 0.5â¯mg/mL, respectively. CPDs-1 also could disaggregate the formed mature amyloid fibrils into short aggregates.
Subject(s)
Amyloid , Flavonoids , Muramidase , Polymers , Protein Aggregates , Muramidase/chemistry , Muramidase/metabolism , Humans , Polymers/chemistry , Polymers/pharmacology , Amyloid/chemistry , Amyloid/antagonists & inhibitors , Flavonoids/chemistry , Flavonoids/pharmacology , Protein Aggregates/drug effects , Animals , Chickens , Carbon/chemistryABSTRACT
OBJECTIVES: Compromised hepatic fatty acid oxidation (FAO) has been observed in human MASH patients and animal models of MASLD/MASH. It remains poorly understood how and when the hepatic FAO pathway is suppressed during the progression of MASLD towards MASH. Hepatic ChREBP⺠is a classical lipogenic transcription factor that responds to the intake of dietary sugars. METHODS: We examined its role in regulating hepatocyte fatty acid oxidation (FAO) and the impact of hepatic Chrebpa deficiency on sensitivity to diet-induced MASLD/MASH in mice. RESULTS: We discovered that hepatocyte ChREBP⺠is both necessary and sufficient to maintain FAO in a cell-autonomous manner independently of its DNA-binding activity. Supplementation of synthetic PPARâº/δ agonist is sufficient to restore FAO in Chrebp-/- primary mouse hepatocytes. Hepatic ChREBP⺠was decreased in mouse models of diet-induced MAFSLD/MASH and in patients with MASH. Hepatocyte-specific Chrebp⺠knockout impaired FAO, aggravated liver steatosis and inflammation, leading to early-onset fibrosis in response to diet-induced MASH. Conversely, liver overexpression of ChREBPâº-WT or its non-lipogenic mutant enhanced FAO, reduced lipid deposition, and alleviated liver injury, inflammation, and fibrosis. RNA-seq analysis identified the CYP450 epoxygenase (CYP2C50) pathway of arachidonic acid metabolism as a novel target of ChREBPâº. Over-expression of CYP2C50 partially restores hepatic FAO in primary hepatocytes with Chrebp⺠deficiency and attenuates preexisting MASH in the livers of hepatocyte-specific Chrebpâº-deleted mice. CONCLUSIONS: Our findings support the protective role of hepatocyte ChREBPa against diet-induced MASLD/MASH in mouse models in part via promoting CYP2C50-driven FAO.
Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Fatty Acids , Hepatocytes , Liver , Mice, Inbred C57BL , Oxidation-Reduction , Animals , Female , Humans , Male , Mice , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Cytochrome P-450 Enzyme System , Cytochrome P450 Family 2/metabolism , Cytochrome P450 Family 2/genetics , Diet/adverse effects , Disease Models, Animal , Fatty Acids/metabolism , Hepatocytes/metabolism , Lipid Metabolism , Liver/metabolism , Mice, KnockoutABSTRACT
Many proteins could aggregate into amyloid fibrils under certain conditions. However, the aggregation process and morphology of the fibrils may be significantly different because of the distinct protein structure. In this article, the hydrophilic carbon dots (Lys-CA-CDs) were prepared using lysine (Lys) and citric acid (CA) as reactant under the assistance of a microwave. The dissimilar modulation effect of Lys-CA-CDs on the aggregation process of distinct structure protein was further investigated, where bovine serum albumin (BSA) and hen egg white lysozyme (HEWL) were chosen as model proteins. All results showed that Lys-CA-CDs displayed the contrary influence on the aggregation process of BSA and HEWL. Lys-CA-CDs could induce BSA to aggregate into more wormlike fibrils and inhibit the aggregation of HEWL into hair-like fibrils. The influence on the aggregation process of BSA may be assigned to the increased concentration of BSA around the Lys-CA-CDs caused by their interaction. However, inserting of Lys-CA-CDs into the inner structure of HEWL led to the change of protein secondary structure. The change of secondary structure further made it difficult for HEWL to aggregate into fibrils and Lys-CA-CDs showed the inhibition effect on HEWL aggregation.
Subject(s)
Amyloid , Carbon , Hydrophobic and Hydrophilic Interactions , Muramidase , Protein Aggregates , Serum Albumin, Bovine , Muramidase/chemistry , Muramidase/metabolism , Carbon/chemistry , Serum Albumin, Bovine/chemistry , Amyloid/chemistry , Animals , Protein Aggregates/drug effects , Cattle , Lysine/chemistry , Protein Structure, Secondary , Quantum Dots/chemistry , Chickens , Citric Acid/chemistryABSTRACT
Six previously unreported solanidane steroidal alkaloids, namely lyrasolanosides A-F, were isolated from Solanum lyratum. In addition, five known steroidal alkaloids were also identified. The structures of these compounds were determined through the use of NMR, HRESIMS,UV, IR and ECD analysis. To assess their bioactivities, the cytotoxic effects of the six previously unreported compounds were evaluated on A549 cells. The results revealed that lyrasolanoside B (2) exhibited the highest potency among them. Lyrasolanoside B (2) exhibited significant inhibition of cell migration, invasion, and adhesion dramatically. Mechanistically, it was found to suppress the activity of JAK2/STAT3 signaling pathway by downregulating the expression of phosphorylated JAK2/STAT3 in an exosome-dependent manner. In addition, lyrasolanoside B (2) was found to significantly upregulate the expression of E-cadherin and downregulate the expression of N-cadherin and vimentin. These findings indicate that lyrasolanoside B (2) inhibits the metastasis of A549 cells by suppressing exosome-mediated EMT. These findings suggest that lyrasolanoside B (2) may inhibit the metastasis of lung cancer by regulating A549-derived exosomes.
Subject(s)
Solanum , Humans , A549 Cells , Molecular Structure , Solanum/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/isolation & purification , Cell Movement/drug effects , Phytochemicals/pharmacology , Phytochemicals/isolation & purification , Solanaceous Alkaloids/pharmacology , Solanaceous Alkaloids/isolation & purification , Signal Transduction/drug effects , Alkaloids/pharmacology , Alkaloids/isolation & purification , ChinaABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Perioperative or postoperative adjuvant chemotherapy based on 5-fluorouracil (5-FU) is a common first-line adjuvant therapy for gastric cancer (GC). However, drug resistance and the side effects of 5-FU have reduced its efficacy. Among these side effects, gastrointestinal (GI) toxicity is one of the most common. Xianglian Pill (XLP) is a Chinese patent medicine that is commonly used for the treatment of diarrhoea. It can reduce inflammation and has a protective effect on the intestinal mucosa. Recent studies have shown that many components of XLP can inhibite tumor cell growth. However, the therapeutic effect of XLP in combination with 5-FU on GC is unclear. AIM OF THE STUDY: To investigate whether the combination of XLP and 5-FU can enhance anti-GC activity while reducing GI toxicity. MATERIALS AND METHODS: XLP was administered orally during intraperitoneal injection of 5-FU in GC mice model. Mice were continuously monitored for diarrhea and xenograft tumor growth. After 2 weeks, the mice were sacrificed and serum was collected to determine interleukin-6 levels. Pathological changes, the expression of pro-inflammatory factors and p38 mitogen-activated protein kinase (MAPK) in GI tissue were determined by Western blot analysis. Pathological changes, apoptosis levels and p38 MAPK expression levels in xenograft tissues were also determined. RESULTS: The results showed that XLP could alleviate GI mucosal injury caused by 5-FU, alleviated diarrhea, and inhibited the expression of nuclear factor (NF)-κB and myeloid differentiation primary response-88. Besides, XLP could promote the 5-FU-induced apoptosis of GC cells and enhance the inhibitory effect of 5-FU on tumor xenografts. Further study showed that XLP administration could regulate the expression of p38 MAPK. CONCLUSIONS: XLP in combination with 5-FU could alleviate its GI side effects and enhance its inhibitory effect on xenograft tumor. Moreover, these effects were found to be related to the regulation of the p38 MAPK/NF-κB pathway.
Subject(s)
Drugs, Chinese Herbal , Fluorouracil , Stomach Neoplasms , Humans , Mice , Animals , Fluorouracil/toxicity , Stomach Neoplasms/drug therapy , NF-kappa B/metabolism , MAP Kinase Signaling System , Diarrhea/chemically induced , Diarrhea/drug therapy , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities (NEDASB) is a rare autosomal dominant disorder caused by a heterozygous mutation in the NOVA2 gene on chromosome 19q13. Here, we describe the generation and characterization of an iPSC line derived from the peripheral blood of a 7-year-old patient carrying a novel heterozygous mutation in NOVA2 (c.625 del). The iPSCs with the confirmed patient-specific mutation were demonstrated by pluripotency markers, a normal karyotype, and the ability to differentiate into three germ layers. This NOVA2-mutant iPSC line could facilitate disease modeling and therapy development studies for NEDASB.
Subject(s)
Induced Pluripotent Stem Cells , Humans , Child , Induced Pluripotent Stem Cells/metabolism , Cell Differentiation/genetics , Karyotype , Mutation , Germ Layers , Leukocytes, Mononuclear/metabolism , Neuro-Oncological Ventral AntigenABSTRACT
Five undescribed eudesmane methyl esters (1-5), three undescribed eudesmane-12,6-olides (6-8), and 21 known analogues (9-29) were isolated from the aerial part of Artemisia princeps Pamp. Their structures were established by detailed analysis of the NMR and HRESIMS data. The absolute configurations of 1-8 were determined based on single-crystal X-ray diffraction analysis and ECD calculations. Moreover, the inhibitory effects on LPS-induced NO production in BV-2 microglial cells of all the isolated compounds were assessed. Except for compounds 2, 4, 10, and 11, the others showed significant inhibitory activities, with IC50 values of 0.73-18.66 µM, wherein the potential structure-activity relationship was also discussed.
Subject(s)
Artemisia , Sesquiterpenes, Eudesmane , Sesquiterpenes , Artemisia/chemistry , Molecular Structure , Sesquiterpenes/chemistry , Structure-Activity Relationship , Sesquiterpenes, Eudesmane/pharmacology , Sesquiterpenes, Eudesmane/chemistryABSTRACT
HBV-miR-3 is encoded by HBV and takes part in pathogenesis of HBV-related liver disease. Whether HBV-miR-3 has a relationship with HBV replication and is predictive of PegIFN-α treatment response is still unknown. HBV-miR-3 quantification is based on qRT-PCR. The relationship of HBV-miR-3 and HBV replication, and predictive value of HBV-miR-3 were evaluated in a cohort of 650 HBeAg positive patients from a multi-center, randomized phase III clinical trial for the study of PegIFN-a2b. HBV-miR-3 is significantly positively related to HBVDNA, HBVpgRNA, HBeAg and HBsAg at baseline and at all the different time points during PegIFN-α treatment. Both univariate regression analyses and multivariate logistic regression analyses showed HBV-miR-3 is a predictor of HBeAg seroconversion in the patients treated with PegIFN-α at weeks of 0, 12, and 24. 70.0% of patients with HBV-miR-3 < 3log at week 12 achieved HBeAg seroconversion, otherwise, with HBV-miR-3 > 6log at week 12 no patient obtained HBeAg seroconversion. Conbination of HBV-miR-3 and HBeAg is more strongly predictive of HBeAg seroconversion (83.64%) at week 12. HBV-miR-3 is new biomarker for HBV replication and positively correlated to HBV replication. HBV-miR-3 is also an early predictor of HBeAg seroconversion in the patients treated with PegIFN-α.
Subject(s)
Antiviral Agents , MicroRNAs , Humans , Antiviral Agents/therapeutic use , Hepatitis B virus/genetics , Interferon-alpha/therapeutic use , Hepatitis B e Antigens , Seroconversion , Polyethylene Glycols/therapeutic use , Treatment Outcome , DNA, Viral , Recombinant Proteins/therapeutic useABSTRACT
A pair of novel chiral 1-phenylethylamine-modified twistarenes (4 and 11; compound 4 = 9,14-di-tert-butyl-7,16-diphenyl-2-(1-phenylethyl)-1H-benzo[8',9']triphenyleno[2',3':6,7]fluoreno[2,1,9-def]isoquinoline-1,3(2H)-dione) have been synthesized and characterized, and how the solvent component affects the chirality transfer of their self-assembled processes is investigated in mixtures with THF and H2O. The ordered assembly of 11 exhibits circular dichroism response. In addition, both 11a and 11b display positive photoconducting behavior.
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PURPOSE: To investigate in-hospital mortality and hospital length of stay (LOS) in infants requiring tracheostomy with bronchopulmonary dysplasia (BPD). METHODS: We explored the correlation between tracheostomy with in-hospital mortality and LOS in infant patients hospitalized with BPD, using the data from Nationwide Inpatient Sample between 2008 and 2017 in the United States. In-hospital mortality and LOS was compared in patients who underwent tracheostomy with those patients who did not after propensity-score matching. RESULTS: A total of 10,262 children ≤2 years old hospitalized with BPD, 847 (8%) underwent tracheostomy, and 821 patients underwent tracheostomy were matched with 1602 patients without tracheostomy. Tracheostomy group was correlated with higher in-hospital mortality(OR(95%CI):2.98(2.25-3.95)) and prolonged LOS(absolute difference(95%CI):97.0(85.6-108.4)). CONCLUSIONS: Tracheostomy was correlated with increased in-hospital mortality and prolonged LOS. Such information may contribute to better decision-making process between clinicians and parents regarding tracheostomy to manage parent expectations, as well as better interdisciplinary teamwork.
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Background: Penthorum chinense Pursh (PCP) is widely utilized in China to treat a variety of liver diseases. It has been shown that flavonoids inhibit inflammation and have the potential to attenuate tissue damage and fibrosis. However, the mechanisms underlying how total flavonoids isolated from PCP (TFPCP) exert their anti-fibrotic effects remain unclear. Methods: The chemical composition of TFPCP was determined using UHPLC-Q-Orbitrap HRMS. Subsequently, rats were randomly assigned to a control group (Control), a carbon tetrachloride (CCl4)-induced hepatic fibrosis model group (Model), a positive control group [0.2 mg/(kgâday)] of Colchicine), and three TFPCP treatment groups [50, 100, and 150 mg/(kgâday)]. All substances were administered by gavage and treatments lasted for 9 weeks. Simultaneously, rats were intraperitoneally injected with 10%-20% CCl4 for 9 weeks to induce liver fibrosis. At the end of the experiment, the liver ultrasound, liver histomorphological, biochemical indicators, and inflammatory cytokine levels were tested respectively. The underlying mechanisms were assessed using Western blot, immunohistochemistry, immunofluorescence, RT-qPCR, and metabolomics. Results: Fourteen flavonoids were identified in TFPCP. Compared with control animals, CCl4-treated rats demonstrated obvious liver injury and fibrosis, manifested as increases in gray values, distal diameter of portal vein (DDPV) and a decrease in blood flow velocity (VPV) in the ultrasound analysis; increased biochemical index values (serum levels of ALT, AST, TBIL, and ALP); marked increases in the contents of fibrotic markers (PC III, COL4, LN, HA) and inflammatory factors (serum TNF-α, IL-6, and IL-1ß); and significant pathological changes. However, compared with the Model group, the ultrasound parameters were significantly improved and the serum levels of inflammatory cytokines were reduced in the TFPCP group. In contrast, the expression of TGF-ß1, TLR4, and MyD88, as well as the p-P65/P65 and p-IκBα/IκBα ratios, were considerably reduced following TFPCP treatment. In addition, we identified 32 metabolites exhibiting differential abundance in the Model group. Interestingly, TFPCP treatment resulted in the restoration of the levels of 20 of these metabolites. Conclusion: Our findings indicated that TFPCP can ameliorate hepatic fibrosis by improving liver function and morphology via the inactivation of the TLR4/MyD88-mediated NF-κB pathway and the regulation of liver metabolism.
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BACKGROUND: Progressive reduction of sodium intake is an attractive approach for addressing excessive salt intake, but evidence for this strategy in real practice is limited. We aimed to determine the feasibility, effectiveness, and safety of a progressive sodium intake reduction intervention in real-world setting. METHODS: We randomized 48 residential elderly care facilities in China, with 1612 participants aged 55 years and older, to either progressive reduction (PR, 24 facilities) or no reduction (NR, 24 facilities) of the supply of study salt to the kitchens of these facilities for 2 years. The primary efficacy outcome was systolic blood pressure (SBP) at any scheduled follow-up visit. Secondary efficacy outcomes included diastolic blood pressure (DBP) at any scheduled follow-up visit, and major adverse cardiovascular events (comprising non-fatal stroke, non-fatal myocardial infarction, hospitalized non-fatal heart failure, or vascular death) and total mortality. The perception of food saltiness, the addition of out-of-study salt in meals, and 24-h urinary sodium excretion were used as process indicators. RESULTS: Pre-specified analysis per randomization found no effect of the intervention on the 2-year overall mean systolic and diastolic blood pressure (SBP, DBP) and any other outcomes. However, post hoc analysis showed that the intervention effect on blood pressure varied over multiple follow-up visits (p for interaction < 0.046) and presented favorable differences at the 24-month visit (SBP = - 3.0 mmHg, 95%CI = - 5.6, - 0.5; p = 0.020; DBP = - 2.0 mmHg, 95%CI - 3.4, - 0.63; p = 0.004). The effect on 24-h sodium was non-significant (- 8.4 mmol, 95%CI = - 21.8 to 4.9, p = 0.216), though fewer participants with NR than with PR reported food tasting bland (odds ratio 0.46; 95%CI 0.29 to 0.73; p = 0.001). Reporting of bland food taste and other process measures indicated that intervention delivery and adherence were not fully achieved as designed. CONCLUSIONS: The experience of this real-world study demonstrated that achieving acceptability and sustainability of the progressive sodium intake reduction strategy among older adults was challenging, but it has shown potential for effectiveness in these and potentially other residential settings if the lessons of DECIDE-Salt are applied in further studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03290716).
Subject(s)
Hypertension , Sodium Chloride, Dietary , Aged , Humans , Middle Aged , Blood Pressure/physiology , Sodium Chloride, Dietary/adverse effectsABSTRACT
Polarization-sensitive detectors have significant applications in modern communication and information processing. In this study. We present a polarization-sensitive detector based on a MoTe2/WTe2 heterojunction, where WTe2 forms a favorable bandgap structure with MoTe2 after forming the heterojunction. This enhances the carrier separation efficiency and photoelectric response. We successfully achieved wide spectral detection ranging from visible to near-infrared light. Specifically, under zero bias, our photodetector exhibits a responsivity (R) of 0.6 A/W and a detectivity (D*) of 3.6 × 1013 Jones for 635 nm laser illumination. Moreover, the photoswitching ratio can approach approximately 6.3 × 105. Importantly, the polarization sensitivity can reach 3.5 (5.2) at 635 (1310) nm polarized light at zero bias. This study both unveils potential for utilizing MoTe2/WTe2 heterojunctions as polarization-sensitive detectors and provides novel insights for developing high-performance optoelectronic devices.
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Background: Cerebral palsy (CP) is a neurodevelopmental disorder characterized by motor impairment. In this study, we aimed to describe the characteristics of amino acids (AA) in the plasma of children with CP and identify AA that could play a potential role in the auxiliary diagnosis and treatment of CP. Methods: Using high performance liquid chromatography, we performed metabolomics analysis of AA in plasma from 62 CP children and 60 healthy controls. Univariate and multivariate analyses were then applied to characterize different AA. AA markers associated with CP were then identified by machine learning based on the Lasso regression model for the validation of intra-sample interactions. Next, we calculated a discriminant formula and generated a receiver operating characteristic (ROC) curve based on the marker combination in the discriminant diagnostic model. Results: A total of 33 AA were detected in the plasma of CP children and controls. Compared with controls, 5, 7, and 10 different AA were identified in total participants, premature infants, and full-term infants, respectively. Of these, ß-amino-isobutyric acid [p = 2.9*10(-4), Fold change (FC) = 0.76, Variable importance of protection (VIP) = 1.75], tryptophan [p = 5.4*10(-4), FC = 0.87, VIP = 2.22], and asparagine [p = 3.6*10(-3), FC = 0.82, VIP = 1.64], were significantly lower in the three groups of CP patients than that in controls. The combination of ß-amino-isobutyric acid, tryptophan, and taurine, provided high levels of diagnostic classification and risk prediction efficacy for preterm children with an area under the curve (AUC) value of 0.8741 [95% confidence interval (CI): 0.7322-1.000]. The discriminant diagnostic formula for preterm infant with CP based on the potential marker combination was defined by p = 1/(1 + e-(8.295-0.3848* BAIBA-0.1120*Trp + 0.0108*Tau)). Conclusion: Full-spectrum analysis of amino acid metabolomics revealed a distinct profile in CP, including reductions in the levels of ß-amino-isobutyric acid, tryptophan, and taurine. Our findings shed new light on the pathogenesis and diagnosis of premature infants with CP.
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Based on the charge-polarity control, a novel anti-ambipolar heterotransistor is proposed based on a special In2Se3&WSe2 van der Waals heterostructure. Unlike traditional logic transistors, our anti-ambipolar heterotransistor can treat an optical signal as an input to change its operating state, that is, with the switching of the optical signal, it shows a reversible polarity change between anti-ambipolar and P-type. Moreover, with the increase of laser power density from 0 to 4.4 mW cm-2, the current value corresponding to the anti-ambipolar peak of the device (Ipeak) shifts from 0 to 4.3 nA, and the voltage value corresponding to the anti-ambipolar peak of the device (Vpeak) can shift from -7 to -5.67 V. These phenomena demonstrate that the charge neutrality point of the anti-ambipolar heterotransistor can be selectively varied with the change of laser power density. In addition, the aforementioned device possesses a high Ion/Ioff ratio of about 104 (405 nm, 4.4 mW cm-2) at 0 V. These properties indicate that our unique anti-ambipolar In2Se3&WSe2 heterotransistor can be employed in photo-triggered inverters for future optoelectronic circuits, and it has great potential to improve the integration of overall chip circuits by implementing optoelectronic logic functions in a unit.
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There is a paucity of high-quality evidence on the effectiveness and safety of salt reduction strategies, particularly for older people, who have the most to benefit but are at higher risk of adverse effects. Here, we conducted a clinical trial in which 48 residential elderly care facilities in China (1,612 participants including 1,230 men and 382 women, 55 years or older) were cluster-randomized using a 2 × 2 factorial design to provision of salt substitute (62.5% NaCl and 25% KCl) versus usual salt and to a progressively restricted versus usual supply of salt or salt substitute for 2 years. Salt substitute compared with usual salt lowered systolic blood pressure (-7.1 mmHg, 95% confidence interval (CI) -10.5 to -3.8), meeting the primary outcome of the trial, whereas restricted supply compared with usual supply of salt or salt substitute had no effect on systolic blood pressure. Salt substitute also lowered diastolic blood pressure (-1.9 mmHg, 95% CI -3.6 to -0.2) and resulted in fewer cardiovascular events (hazard ratio (HR) 0.60, 95% CI 0.38-0.96), but had no effect on total mortality (HR 0.84, 95% CI 0.63-1.13). From a safety standpoint, salt substitute increased mean serum potassium and led to more frequent biochemical hyperkalemia, but was not associated with adverse clinical outcomes. In contrast, salt restriction had no effect on any study outcome. The results of this trial indicate that use of salt substitute, but not efforts to restrict salt supply, may achieve blood pressure lowering and deliver health benefits to residents of elderly care facilities in China. Clinicaltrials.gov registration: NCT03290716.
Subject(s)
Hypertension , Male , Humans , Female , Aged , Blood Pressure , Hypertension/complications , Sodium Chloride/pharmacology , Sodium Chloride, Dietary/adverse effects , China/epidemiologyABSTRACT
Neurodevelopmental disorders (NDDs) have heterogeneity in both clinical characteristics and genetic factors. EBF3 is a recently discovered gene associated with a syndromic form of NDDs characterized by hypotonia, ataxia and facial features. In this study, we report twelve unrelated individuals with EBF3 variants using next-generation sequencing. Five missense variants (four novel variants and one known variant) and seven copy number variations (CNVs) of EBF3 gene were identified. All of these patients exhibited developmental delay/intellectual disability. Ataxia was observed in 33% (6/9) of the patients, and abnormal muscle tone was observed in 55% (6/11) of the patients. Aberrant MRI reports were noted in 64% (7/11) of the patients. Four novel missense variants were all located in the DNA-binding domain. The pathogenicity of these variants was validated by in vitro experiments. We found that the subcellular protein localization of the R152C and F211L mutants was changed, and the distribution pattern of the R163G mutant was changed from even to granular. Luciferase assay results showed that the four EBF3 mutants' transcriptional activities were all significantly decreased (p < 0.01). Our study further expanded the gene mutation spectrum of EBF3-related NDD.