The photochemical reaction of peroxy radical (RO2·) and NO has been identified by field and forest studies as important source of organic nitrates (RONO2) in the atmosphere. However, this traditional ...pathway is not sufficient to explain the high concentration of RONO2. Hence, a new source of the tropospheric RONO2 from the dark reactions of nitric acid (HNO3) with aliphatic aldehydes (C1–C5) under catalysis is provided and examined for the first time by high-level quantum chemistry. The findings show that the reaction between HCHO and HNO3, which produces HOCH2ONO2, can be catalyzed by a series of metal-free catalysts (NH3, CH3NH2, CH3NHCH3, H2O, HNO3, H2SO4, HCOOH, HOOCCOOH). At 296 K, the effective rate constant for the bimolecular HNO3–HCHO reaction under the catalysis of CH3NH2 or CH3NHCH3 can be sufficiently accelerated by 5–8 order of magnitudes through this new loss pathway for HNO3 or HCHO to become competitive with the conventional loss pathway for their photochemical reactions with ·OH radical. Significantly, this new HOCH2ONO2 formation pathway from the dark reaction of HCHO with CH3NH3+NO3−/(CH3)2NH + NO3− was more favorable than the recognized source of RO2· with NO. Efficient catalysis performance of CH3NH2 and CH3NHCH3 is mainly attributed to their excellent proton receptivity capacity by activating the O–H bond of HNO3 to form stable organic nitrates (CH3NH3+NO3− and (CH3)2NH + NO3−) in the rate-determining step transition states. In the case of only considering the barrier, H2SO4 is the best catalyst among the investigated inorganic and organic acids, and dicarboxylic acid (HOOCCOOH) is stronger than monocarboxylic acid HCOOH in facilitating the RONO2 formation reaction. These new findings deepen our understanding on the unexpected source of organic nitrate and loss pathway of HNO3 or HCHO under catalysis in highly polluted regions.
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•Kinetics and mechanism for reactions of HNO3 with C1–C5 aliphatic aldehydes were studied.•Role of water, acids, and alkalies on the HNO3/HCHO reaction were analyzed.•A new loss pathway for HCHO was identified via amine-catalyzed HNO3/HCHO reaction.•An unexpected source of RONO2 with the help of catalysts was proposed and verified.•The proposed new source of RONO2 was more favorable than that of RO2·/NO reaction.
Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133(+) cells are the cause of drug ...resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133(+) cells has not been investigated methodically. In this study, we revealed that CD133(+) lung cancer cells labeled by a human CD133 promoter-driven GFP reporter exhibited drug resistance and stem cell characteristics. Treatment of H460 and H661 cell lines with low-dose cisplatin (IC(20)) was sufficient to enrich CD133(+) cells, to induce DNA damage responses, and to upregulate ABCG2 and ABCB1 expression, which therefore increased the cross-resistance to doxorubicin and paclitaxel. This cisplatin-induced enrichment of CD133(+) cells was mediated through Notch signaling as judged by increased levels of cleaved Notch1 (NICD1). Pretreatment with the γ-secretase inhibitor, N-N-(3,5-difluorophenacetyl)-1-alanyl-S-phenylglycine t-butyl ester (DAPT), or Notch1 short hairpin RNAs (shRNA) remarkably reduced the cisplatin-induced enrichment of CD133(+) cells and increased the sensitivity to doxorubicin and paclitaxel. Ectopic expression of NICD1 reversed the action of DAPT on drug sensitivity. Immunohistochemistry showed that CD133(+) cells were significantly increased in the relapsed tumors in three of six patients with lung cancer who have received cisplatin treatment. A similar effect was observed in animal experiments as cisplatin treatment increased Notch1 cleavage and the ratio of CD133(+) cells in engrafted tumors. Intratumoral injection of DAPT with cisplatin treatment significantly reduced CD133(+) cell number. Together, our results showed that cisplatin induces the enrichment of CD133(+) cells, leading to multidrug resistance by the activation of Notch signaling.
Background
Although laparoscopic sleeve gastrectomy (LSG) is an effective treatment for morbid obesity, the effects of LSG on gastroesophageal reflux disease (GERD) are controversial. This study ...evaluated the changes of GERD symptoms and erosive esophagitis (EE) in severely obese patients who underwent LSG.
Methods
Forty-seven severely obese women and 19 severely obese men (mean age of 37.2 ± 12.7 years) who underwent LSG between August 2007 and November 2009 were enrolled. All patients completed the Reflux Disease Questionnaire and underwent esophagogastroduodenoscopy preoperatively and at least 1 year after LSG.
Results
The median follow-up period was 12 months (range, 12–21). After surgery, significant decreases were reported in mean body mass index (36.3 ± 4.1 vs. 25.8 ± 2.9 kg/m
2
), mean waist circumference (109.5 ± 12.8 vs. 85.7 ± 9.5 cm), and prevalence of metabolic syndrome (54.5 vs. 7.6 %;
P
< 0.001 for both). Conversely, a significant increase was observed in the prevalence of GERD symptoms (12.1 vs. 47 %) and EE (16.7 vs. 66.7 %) after LSG (
P
< 0.001 for both). The prevalence of hiatal hernias also increased significantly (6.1 vs. 27.3 %;
P
< 0.001) after LSG, and it was significantly higher in patients with than those without EE after LSG (9.1 vs. 36.4 %, respectively;
P
= 0.02).
Conclusions
Although LSG can achieve significant weight loss and improvement of comorbidities in severely obese patients, the prevalence and severity of GERD symptoms and EE increase after the operation. The occurrence of EE after LSG is related to the presence of a hiatal hernia after the operation.
The homology‐independent targeted integration (HITI) strategy enables effective CRISPR/Cas9‐mediated knockin of therapeutic genes in nondividing cells in vivo, promising general therapeutic solutions ...for treating genetic diseases like X‐linked juvenile retinoschisis. Herein, supramolecular nanoparticle (SMNP) vectors are used for codelivery of two DNA plasmids—CRISPR‐Cas9 genome‐editing system and a therapeutic gene, Retinoschisin 1 (RS1)—enabling clustered regularly interspaced short palindromic repeats (CRISPR)‐associated protein 9 (CRISPR/Cas9) knockin of the RS1 gene with HITI. Through small‐scale combinatorial screenings, two SMNP vectors, with Cas9 and single guide RNA (sgRNA)‐plasmid in one and Donor‐RS1 and green fluorescent protein (GFP)‐plasmid in the other, with optimal delivery performances are identified. These SMNP vectors are then employed for CRISPR/Cas9 knockin of RS1/GFP genes into the mouse Rosa26 safe‐harbor site in vitro and in vivo. The in vivo study involves intravitreally injecting the two SMNP vectors into the mouse eyes, followed by repeated ocular imaging by fundus camera and optical coherence tomography, and pathological and molecular analyses of the harvested retina tissues. Mice ocular organs retain their anatomical integrity, a single‐copy 3.0‐kb RS1/GFP gene is precisely integrated into the Rosa26 site in the retinas, and the integrated RS1/GFP gene is expressed in the retinas, demonstrating CRISPR/Cas9 knockin of RS1/GFP gene.
Two supramolecular nanoparticle (SMNP) vectors codeliver two DNA plasmids—a CRISPR‐Cas9 construct and a therapeutic gene, RS1. Both SMNP vectors are intravitreally injected into the eyes of mice to enable CRISPR/Cas9 knockin of the RS1 gene using the homology‐independent targeted integration (HITI) strategy, to test a potential nonviral therapeutic solution for X‐linked juvenile retinoschisis (XLRS).
Background
Obesity is a risk factor for nonalcoholic fatty liver disease (NAFLD), which appears to improve after weight loss induced by bariatric surgery in Western countries. The present study aims ...to determine the alterations of clinical measurements and liver histology of NAFLD after bariatric surgery in morbidly obese Chinese patients.
Methods
Between November 2006 and December 2007, 21 morbidly obese patients receiving intra-operative liver biopsy and follow-up liver biopsy 1 year after laparoscopic Roux-en-Y gastric bypass were enrolled. NAFLD activity score (NAS) and fibrosis stage were histologically evaluated.
Results
The mean body mass index fell from 43.8 ± 7.5 to 28.3 ± 4.6 kg/m
2
(
P
< 0.01). Biochemical improvement was found in serum levels of alanine aminotransferase (
P
< 0.01) and γ-glutamyltransferase (
P <
0.01), but not aspartate aminotransferase (
P =
0.66). Histological improvement was noted in NAS (
P
< 0.01) and individual components, including steatosis (
P
< 0.01), ballooning degeneration (
P
< 0.01), and lobular inflammation (
P
= 0.02). Pre-operatively, 4 (19.0%), 11 (52.4%), and 6 (28.6%) patients were found to have NAS ≧5, 3 or 4, and ≦2, respectively. All patients had NAS ≦2 after surgery. Fibrosis stage also showed significant improvement (
P
< 0.01).
Conclusions
Bariatric surgery can achieve a dramatic improvement of NAFLD both biochemically and histologically in morbidly obese Chinese patients.
Inherited Retinal Diseases (IRDs) are considered one of the leading causes of blindness worldwide. However, the majority of them still lack a safe and effective treatment due to their complexity and ...genetic heterogeneity. Recently, gene therapy is gaining importance as an efficient strategy to address IRDs which were previously considered incurable. The development of the clustered regularly-interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system has strongly empowered the field of gene therapy. However, successful gene modifications rely on the efficient delivery of CRISPR-Cas9 components into the complex three-dimensional (3D) architecture of the human retinal tissue. Intriguing findings in the field of nanoparticles (NPs) meet all the criteria required for CRISPR-Cas9 delivery and have made a great contribution toward its therapeutic applications. In addition, exploiting induced pluripotent stem cell (iPSC) technology and in vitro 3D retinal organoids paved the way for prospective clinical trials of the CRISPR-Cas9 system in treating IRDs. This review highlights important advances in NP-based gene therapy, the CRISPR-Cas9 system, and iPSC-derived retinal organoids with a focus on IRDs. Collectively, these studies establish a multidisciplinary approach by integrating nanomedicine and stem cell technologies and demonstrate the utility of retina organoids in developing effective therapies for IRDs.
In this study, we combine graphene with gold oxide (AuO x ), a transparent and high-work-function electrode material, to achieve a high-efficient, low-bias, large-area, flexible, transparent, ...broadband, and bifacial-operable photodetector. The photodetector operates through hot electrons being generated in the graphene and charge separation occurring at the AuO x –graphene heterojunction. The large-area graphene covering the AuO x electrode efficiently prevented reduction of its surface; it also acted as a square-centimeter-scale active area for light harvesting and photodetection. Our graphene/AuO x photodetector displays high responsivity under low-intensity light illumination, demonstrating picowatt sensitivity in the ultraviolet regime and nanowatt sensitivity in the infrared regime for optical telecommunication. In addition, this photodetector not only exhibited broadband (from UV to IR) high responsivity3300 A W–1 at 310 nm (UV), 58 A W–1 at 500 nm (visible), and 9 A W–1 at 1550 nm (IR)but also required only a low applied bias (0.1 V). The hot-carrier-assisted photoresponse was excellent, especially in the short-wavelength regime. In addition, the graphene/AuO x photodetector exhibited great flexibility and stability. Moreover, such vertical heterojunction-based graphene/AuO x photodetectors should be compatible with other transparent optoelectronic devices, suggesting applications in flexible and wearable optoelectronic technologies.
PurposeRetinal detachment (RD) is a sight-threatening ocular disease caused by separation of the neurosensory retina from the underlying retinal pigment epithelium layer. Its genetic basis is unclear ...because of a limited amount of data. In this study, we aimed to identify genetic risk loci associated with RD in participants without diabetes mellitus and to construct a polygenic risk score (PRS) to predict the risk of RD. MethodsA genome-wide association study was conducted using data from the Taiwan Biobank to identify RD risk loci. A total of 1533 RD cases and 106,270 controls were recruited, all of whom were Han Chinese. Replication studies were performed using data from the UK Biobank and Biobank Japan. To construct the PRS, a traditional clumping and thresholding method was performed and validated by fivefold cross-validation. ResultsTwo novel loci with significant associations were identified. These two genes were TMEM132D (lead single nucleotide polymorphism SNP: rs264498, adjusted-P = 7.18 × 10-9) and VIPR2 (lead SNP: rs3812305, adjusted-P = 8.38 × 10-9). The developed PRS was effective in discriminating individuals at high risk of RD with a dose-response relationship. The quartile with the highest risk had an odds ratio of 1244.748 compared to the lowest risk group (95% confidence interval, 175.174-8844.892). ConclusionsTMEM132D and VIPR2 polymorphisms are genetic candidates linked to RD in Han Chinese populations. Our proposed PRS was effective at discriminating high-risk from low-risk individuals.
Nucleolar protein interacting with the FHA domain of pKi-67 (NIFK) is a Ki-67-interacting protein. However, its precise function in cancer remains largely uninvestigated. Here we show the clinical ...significance and metastatic mechanism of NIFK in lung cancer. NIFK expression is clinically associated with poor prognosis and metastasis. Furthermore, NIFK enhances Ki-67-dependent proliferation, and promotes migration, invasion in vitro and metastasis in vivo via downregulation of casein kinase 1α (CK1α), a suppressor of pro-metastatic TCF4/β-catenin signaling. Inversely, CK1α is upregulated upon NIFK knockdown. The silencing of CK1α expression in NIFK-silenced cells restores TCF4/β-catenin transcriptional activity, cell migration, and metastasis. Furthermore, RUNX1 is identified as a transcription factor of CSNK1A1 (CK1α) that is negatively regulated by NIFK. Our results demonstrate the prognostic value of NIFK, and suggest that NIFK is required for lung cancer progression via the RUNX1-dependent CK1α repression, which activates TCF4/β-catenin signaling in metastasis and the Ki-67-dependent regulation in cell proliferation.
Oral squamous cell carcinoma (OSCC) is a prevalent type of oral cancer. While therapeutic innovations have made strides, radioresistance persists as a significant hindrance in OSCC treatment. Despite ...identifying numerous targets that could potentially suppress the oncogenic attributes of OSCC, the exploration of oncogenic protein kinases for cancer therapy remains limited. Consequently, the functions of many kinase proteins in OSCC continue to be largely undetermined. In this research, we aim to disclose protein kinases that target OSCC and elaborate their roles and molecular mechanisms. Through the examination of the kinome library of radiotherapy-resistant/sensitive OSCC cell lines (HN12 and SAS), we identified a key gene, the tyrosine phosphorylation-regulated kinase 3 (DYRK3), a member of the DYRK family. We developed an in vitro cell model, composed of radiation-resistant OSCC, to scrutinize the clinical implications and contributions of DYRK3 and phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase (PAICS) signaling in OSCC. This investigation involves bioinformatics and human tissue arrays. We seek to comprehend the role of DYRK3 and PAICS signaling in the development of OSCC and its resistance to radiotherapy. Various in vitro assays are utilized to reveal the essential molecular mechanism behind radiotherapy resistance in connection with the DYRK3 and PAICS interaction. In our study, we quantified the concentrations of DYRK3 and PAICS proteins and tracked the expression levels of key pluripotency markers, particularly PPAT. Furthermore, we extended our investigation to include an analysis of Glut-1, a gene recognized for its linkage to radioresistance in oral squamous cell carcinoma (OSCC). Furthermore, we conducted an in vivo study to affirm the impact of DYRK3 and PAICS on tumor growth and radiotherapy resistance, focusing particularly on the role of DYRK3 in the radiotherapy resistance pathway. This focus leads us to identify new therapeutic agents that can combat radiotherapy resistance by inhibiting DYRK3 (GSK-626616). Our in vitro models showed that inhibiting PAICS disrupts purinosome formation and influences the survival rate of radiation-resistant OSCC cell lines. These outcomes underscore the pivotal role of the DYRK3/PAICS axis in directing OSCC radiotherapy resistance pathways and, as a result, influencing OSCC progression or therapy resistance. Our findings also reveal a significant correlation between DYRK3 expression and the PAICS enzyme in OSCC radiotherapy resistance.
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