Single-center retrospective study of the diagnostic value of double-balloon enteroscopy in Meckel's diverticulum with bleeding.

BACKGROUND: The study aimed to analyze the characteristic clinical manifestations of patients with intestinal disease Meckel's diverticulum (MD) complicated by digestive tract hemorrhage. Moreover, we aimed to evaluate the value of double-balloon enteroscopy (DBE) in MD diagnosis and the prognosis after laparoscopic diverticula resection. AIM: To evaluate the value of DBE in the diagnosis and the prognosis after laparoscopic diverticula resection for MD with bleeding. METHODS: The study retrospectively analyzed relevant data from 84 MD patients treated between January 2015 and March 2022 and recorded their clinical manifestations, auxiliary examination, and follow-up after laparoscopic resection of diverticula. RESULTS: (1) Among 84 MD patients complicated with hemorrhage, 77 were male, and 7 were female with an average age of 31.31 ± 10.75 years. The incidence was higher in men than in women of different ages; (2) Among the 84 MD patients, 65 (78.40%) had defecated dark red stools, and 50 (58.80%) had no accompanying symptoms during bleeding, indicating that most MD bleeding appeared a dark red stool without accompanying symptoms; (3) The shock index of 71 patients (85.20%) was < 1, suggesting that the blood loss of most MD patients was less than 20%-30%, and only a few patients had a blood loss of > 30%; (4) The DBE-positive rate was 100% (54/54), 99mTc-pertechnetate-positive scanning rate was 78% (35/45) compared with capsule endoscopy (36%) and small intestine computed tomography (19%). These results suggest that DBE and 99mTc-pertechnetate scans had significant advantages in diagnosing MD and bleeding, especially DBE was a highly precise examination method in MD diagnosis; (5) A total of 54 MD patients with hemorrhage underwent DBE examination before surgery. DBE endoscopy revealed many mucosal manifestations including normal appearance, inflammatory changes, ulcerative changes, diverticulum inversion, and nodular hyperplasia, with ulcerative changes being the most common (53.70%). This suggests that diverticular mucosal ulcer was the main cause of MD and bleeding; and (6) Laparoscopic dissection of diverticulae was performed in 76 patients, The patients who underwent postoperative follow-up did not experience any further bleeding. Additionally, follow-up examination of the 8 cases who had declined surgery revealed that 3 of them experienced a recurrence of digestive tract bleeding. These findings indicate that laparoscopic diverticula resection in MD patients complicated by bleeding had a favorable prognosis. CONCLUSION: Bleeding associated with MD was predominantly observed in male adolescents, particularly at a young age. DBE was a highly precise examination method in MD diagnosis. Laparoscopic diverticula resection effectively prevented MD bleeding and had a good prognosis.

Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy.

Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-c]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound 39, which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted cancer cell lines. Compound 39 has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, 39 demonstrates excellent brain exposure with a Kpuu of 0.64 in rats.

Spatial-temporal characteristics and driving factors of the chemical fertilizer supply/demand correlation network in China.

The rational allocation of chemical fertilizer resources is of strategic importance in mitigating agricultural source pollution and achieving agricultural green development. The spatiotemporal correlation of chemical fertilizer supply/demand and its determinants remains unclear. In this study, based on the inter-provincial chemical fertilizer supply/demand panel data of China from 1994 to 2018, an improved gravity model was employed to determine provincial chemical fertilizer supply/demand correlations. Finally, the chemical fertilizer supply/demand evolution and its driving factors were analyzed using social network analysis and a quadratic assignment procedure. The results indicated that (1) the intensity of the spatial relationship of inter-provincial chemical fertilizer supply/demand increased in a fluctuating fashion, but there was still room for improvement. The network structure presented good stability, and the spillover effect exhibited multiple superposition characteristics; (2) the spatial correlation network of inter-provincial chemical fertilizer supply/demand presented a "core-periphery" distribution pattern of the supply, demand, and balance areas. The division of blocks in the network changed in time and space, and some provinces changed their roles and positions in the network during development; (3) chemical fertilizer-related policies (e.g., Exemption Agricultural Tax, Notice on the resumption of value added tax policy on fertilizers, and Rural Revitalization Strategy) have played a positive role in the formation and development of the interprovincial spatial correlation network of chemical fertilizer supply/demand in China; (4) natural conditions and socioeconomic factors interact to promote the formation of the spatial correlation network of chemical fertilizer supply/demand. The differences in the scale of the rural labor force, the scale of agricultural mechanization, the agricultural planting structure, the populations, and urbanization levels all had a significant impact on it. The identification of the spatial characteristics of chemical fertilizer supply/demand correlation networks offers a new perspective on taking various measures to realize the cross-regional coordination of chemical fertilizer resources, strengthen the protection and utilization of agricultural resources, and promote green agricultural development.

Single-centre empirical analysis of double-balloon enteroscopy in the diagnosis and treatment of small bowel diseases: A retrospective study of 466 cases.

BACKGROUND AND OBJECTIVE: The diagnosis and treatment of small bowel diseases (SBDs) has always been a challenge. The purpose of this study was to evaluate the value of double-balloon enteroscopy (DBE) in the diagnosis and treatment of small bowel diseases. METHOD: The clinical data of 466 patients who underwent double-balloon enteroscopy (DBE) in the Endoscope Center of Gastroenterology Department of the First People's Hospital of Yunnan Province from Jan. 2015 to Dec. 2020 were analysed retrospectively. The factors included age, sex, indications, endoscopic treatment results, pathological results, discharge diagnosis and so on. RESULTS: A total of 370 patients underwent 466 double-balloon enteroscopies, among whom 274 underwent one examination and 96 received two-way examinations (oral and transanal approaches). Abnormalities were detected in 299 cases, with a detection rate of 80.81% (299/370). The common indications were occult gastrointestinal bleeding (OGIB) (30.8%, 114/370) and abdominal pain (28.3%, 105/370). The diagnosis rates were 64.9% and 77.1%, respectively. The common positive findings included nonspecific inflammation/erosion (60 cases), ulcers (34 cases), diverticulum (32 cases), polyps (26 cases) and Crohn's disease (CD) (24 cases). The common tumours were lymphoma(12 cases), adenocarcinoma(11 cases) and stromal tumour(8 cases). Lymphoma was mostly located in the ileum, while stromal tumours and adenocarcinoma were mostly located in the duodenum and jejunum. The main endoscopic intervention measures were haemostasis and polypectomy, including haemostatic clip, argon plasma coagulation (APC), endoscopic mucosal resection (EMR), endoscopic trap resection, endoscopic foreign body extraction and other operations, without serious complications. CONCLUSION: DBE has a high success rate in the diagnosis and treatment of some SBDs, and it is a safe and effective management method.

Experimental Evolution of Multidrug Resistance in Neurospora crassa under Antifungal Azole Stress.

Multidrug resistance, defined as the resistance to multiple drugs in different categories, has been an increasing serious problem. Limited antifungal drugs and the rapid emergence of antifungal resistance prompt a thorough understanding of how the occurrence of multidrug resistance develops and which mechanisms are involved. In this study, experimental evolution was performed under single-azole-drug stress with the model filamentous fungus Neurospora crassa. By about 30 weeks of continuous growth on agar plates containing ketoconazole or voriconazole with weekly transfer, four evolved multidrug-resistant strains 30thK1, 30thK2, 26thV1, and 24thV2 were obtained. Compared to the ancestral strain, all four strains increased resistance not only to commonly used azoles, including ketoconazole, voriconazole, itraconazole, fluconazole, and triadimefon, but also to antifungal drugs in other categories, including terbinafine (allylamine), amorolfine (morpholine), amphotericin B (polyene), polyoxin B (chitin synthesis inhibitor), and carbendazim (ß-tubulin inhibitor). After 8 weeks of growth on agar plates without antifungal drugs with weekly transfer, these evolved strains still displayed multidrug-resistant phenotype, suggesting the multidrug resistance could be stably inherited. Transcriptional measurement of drug target genes and drug transporter genes and deletion analysis of the efflux pump gene cdr4 in the evolved strains suggest that overexpression of cdr4 played a major role in the resistance mechanisms for azoles and terbinafine in the evolved strains, particularly for 30thK2 and 26thV1, and evolved drug-resistant strains had less intracellular ketoconazole accumulation and less disruption of ergosterol accumulations under ketoconazole stress compared to wild type. Mutations specifically present in evolved drug-resistant strains were identified by genome re-sequencing, and drug susceptibility test of knockout mutants for most of mutated genes suggests that mutations in 16 genes, functionally novel in drug resistance, potentially contribute to multidrug resistance in evolved strains.

Fungal Zn(II)2Cys6 Transcription Factor ADS-1 Regulates Drug Efflux and Ergosterol Metabolism under Antifungal Azole Stress.

Antifungal azoles are the most widely used antifungal drugs in clinical and agricultural practice. Fungi can mount adaptive responses to azole stress by modifying the transcript levels of many genes, and the responsive mechanisms to azoles are the basis for fungi to develop azole resistance. In this study, we identified a new Zn(II)2Cys6 transcription factor, ADS-1, with a positive regulatory function in transcriptional responses to azole stress in the model filamentous fungal species Neurospora crassa Under ketoconazole (KTC) stress, the ads-1 transcript level was significantly increased in N. crassa Deletion of ads-1 increased susceptibility to different azoles, while its overexpression increased resistance to these azoles. The cdr4 gene, which encodes the key azole efflux pump, was positively regulated by ADS-1. Deletion of ads-1 reduced the transcriptional response by cdr4 to KTC stress and increased cellular KTC accumulation under KTC stress, while ads-1 overexpression had the opposite effect. ADS-1 also positively regulated the transcriptional response by erg11, which encodes the azole target lanosterol 14α-demethylase for ergosterol biosynthesis, to KTC stress. After KTC treatment, the ads-1 deletion mutant had less ergosterol but accumulated more lanosterol than the wild type, while ads-1 overexpression had the opposite effect. Homologs of ADS-1 are widely present in filamentous fungal species of Ascomycota but not in yeasts. Deletion of the gene encoding an ADS-1 homolog in Aspergillus flavus also increased susceptibility to KTC and itraconazole (ITZ). Besides, deletion of A. flavusads-1 (Afads-1) significantly reduced the transcriptional responses by genes encoding homologs of CDR4 and ERG11 in A. flavus to KTC stress, and the deletion mutant accumulated more KTC but less ergosterol. Taken together, these findings demonstrate that the function and regulatory mechanism of ADS-1 homologs among different fungal species in azole responses and the basal resistance of azoles are highly conserved.

miR-129-5p inhibits proliferation, migration, and invasion in rectal adenocarcinoma cells through targeting E2F7.

microRNAs (miRNAs), a kind of small noncoding RNAs, are considered able to regulate expression of genes and mediate RNA silencing. miR-129-5p was shown to be a cancer-related miRNA. However, the influence of miR-129-5p in rectal adenocarcinoma (READ) development remains to be determined. Based on the TCGA data, downregulation of miR-129-5p in READ samples was observed. Manual restoration of the miR-129-5p in SW1463 and SW480 cell lines significantly inhibited invasion, migration, and proliferation of READ cell lines, while the apoptosis ability was enhanced. Meanwhile, we found E2F7 acted as a potential target of miR-129-5p and was upregulated in READ samples. E2F7 upregulation reversed the repression of miR-129-5p on READ development. Finally, in vivo experiments showed that inhibition of tumor growth in nude mice was achieved through upregulating miR-129-5p. Overall, our findings suggest increasing of miR-129-5p leads to the suppression of READ progression through regulating the expression of E2F7, which may provide novel insights into the treatment of READ.

Transcription factor CCG-8 plays a pivotal role in azole adaptive responses of Neurospora crassa by regulating intracellular azole accumulation.

Azoles are the most widely used antifungals for controlling fungal infections in clinic and agriculture. Fungi can adapt to azole stress by rapidly activating the transcription of a number of genes, and some of these genes can elevate resistance to azoles. We had reported the transcription factor CCG-8 as a new regulator in the adaptation to antifungal azole stress in Neurospora crassa and Fusarium verticillioides. In this study, we further investigate the mechanisms by which CCG-8 promotes fungal adaptation to azole stress using N. crassa as a model. While deletion of ccg-8 made N. crassa hypersensitive to azoles, ccg-8 overexpression strain was more resistant to azoles than wild type, which further confirmed the positive role of ccg-8 in the adaptation to antifungal azoles. Liquid chromatography-mass spectrometry analysis showed that deletion of ccg-8 resulted in decrease of ergosterol biosynthesis, and high accumulation of toxic sterol 14α-methyl-3,6-diol and ketoconazole (KTC) in the cells, whereas intracellular accumulation of ketoconazole was decreased in the ccg-8 overexpression strain as compared to wild type. For analyzing the effect of CCG-8 on azole export, we tested the contribution of predicted multidrug transporters to azole resistance and found that CDR4 is the major contributor for azole efflux in N. crassa. Interestingly, overexpression of cdr4 or erg11 in the ccg-8 deletion mutant restored its hypersensitive phenotype and overexpression of cdr4 can reduce the level of intracellular KTC. However, the double mutant of ccg-8 and cdr4 was more sensitive than each single mutant, suggesting that drug efflux pump CDR4 plays less contribution for intracellular azole accumulation in the ccg-8 deletion mutant, and CCG-8 may regulate drug uptake. Together, our results revealed that CCG-8 plays a pivotal role in azole adaptive responses of N. crassa by regulating the drug accumulation in the cells.

The Hsp90 Co-chaperones Sti1, Aha1, and P23 Regulate Adaptive Responses to Antifungal Azoles.

Heat Shock Protein 90 (Hsp90) is essential for tumor progression in humans and drug resistance in fungi. However, the roles of its many co-chaperones in antifungal resistance are unknown. In this study, by susceptibility test of Neurospora crassa mutants lacking each of 18 Hsp90/Calcineurin system member genes (including 8 Hsp90 co-chaperone genes) to antifungal drugs and other stresses, we demonstrate that the Hsp90 co-chaperones Sti1 (Hop1 in yeast), Aha1, and P23 (Sba1 in yeast) were required for the basal resistance to antifungal azoles and heat stress. Deletion of any of them resulted in hypersensitivity to azoles and heat. Liquid chromatography-mass spectrometry (LC-MS) analysis showed that the toxic sterols eburicol and 14α-methyl-3,6-diol were significantly accumulated in the sti1 and p23 deletion mutants after ketoconazole treatment, which has been shown before to led to cell membrane stress. At the transcriptional level, Aha1, Sti1, and P23 positively regulate responses to ketoconazole stress by erg11 and erg6, key genes in the ergosterol biosynthetic pathway. Aha1, Sti1, and P23 are highly conserved in fungi, and sti1 and p23 deletion also increased the susceptibility to azoles in Fusarium verticillioides. These results indicate that Hsp90-cochaperones Aha1, Sti1, and P23 are critical for the basal azole resistance and could be potential targets for developing new antifungal agents.

Nitrogen/carbon atomic ratio-dependent performances of nitrogen-doped carbon-coated metal oxide nanocrystals for anodes in lithium-ion batteries.

We report the hydrothermal synthesis of the N-doped carbon-coated NiO nanocrystals (N-C-NiO NCs) with tunable N/C atomic ratios using the nitrogen-containing ionic liquids (ILs) as new carbon precursor, and the N-doped carbon layer composition-dependent performances of N-C-NiO NCs anode for lithium-ion batteries (LIBs). The results indicate that the N-doped carbon coating can significantly enhance the electronic conductivity, effectively avoid the problems of cracking or pulverization of the NiO, and prevent the aggregation of the active materials upon cycling. These properties make the synthesized material a promising anode material for LIBs. The N-C-NiO NCs with the N/C atomic ratio of 21.2% in the N-doped carbon layer show a high specific capacity of ∼710 mAh g(-1) at a current rate of 0.3 C (very closed to the theoretical capacity of 718 mAh g(-1) for NiO), a high rate capability (still able to deliver a discharge capacity of ∼430 mAh g(-1) at a current density of 10 C), and good capacity retention upon cycling (maintains at 710 mAh g(-1) at least up to the 50th cycle) compared with those of pristine NiO nanoparticles. Moreover, the electrochemical performances of the N-C-NiO NCs depend on the composition (N/C atomic ratios) in the N-doped carbon layer and are enhanced with increasing of the N/C ratios. Our approach offers an effective and convenient technique to improve the specific capacities and rate capabilities of highly insulating electrode materials for batteries and may also provide general and effective approach toward the synthesis of other metal oxides coated with N-doped carbon layer.

Aptamer-functionalized graphene oxide for highly efficient loading and cancer cell-specific delivery of antitumor drug.

This work reports a novel anticancer drug loading and cell-specific delivery system based on cell type-specific aptamer-functionalized graphene oxide (GO) using decitabine (DAC) and A549 cells as anticancer drug and target cell model, respectively. We conjugated GO with aptamer A1 (a 45-base oligonucleotide that binds to A549 cells with high specificity and affinity) and then loaded DAC onto the surface of GO (A1-GO/DAC complex). The loading capacity of DAC on the GO surface is dependent on pH and initial DAC concentration; the saturated loading capacity, as high as ∼3.0 mg DAC per mg GO (corresponding to the loading efficiency of ∼64%), is attained at physiological pH (7.4) and initial DAC concentration of higher than 0.7 mg mL-1. The release of DAC from the complex is also pH dependent, and DAC is released at a quicker rate at acidic pH conditions (pH 5.5) than at the physiological pH. The complexes can specifically recognize A549 cells from other types of cancer cells and subtypes of lung cancer cells due to the specific binding of the aptamer with the cells. Importantly, cell viability assay results reveal that the complex displays a much higher therapeutic efficacy in inhibiting the growth of the cancer cells by inducing cell membrane damage compared to the DAC-free drug. The high DAC payload and antitumor efficacy render our developed system promising for different biomedical applications.

A graphene-amorphous FePO4 hollow nanosphere hybrid as a cathode material for lithium ion batteries.

Amorphous FePO(4) hollow nanospheres were directly grown on graphene for use as a cathode material in lithium ion batteries. This hybrid exhibits high rate capability and good cycle stability because of efficient Li(+) ion diffusion through the thin wall of the hollow nanospheres and fast electron transport through the graphene.

Indirect electrocatalytic determination of choline by monitoring hydrogen peroxide at the choline oxidase-prussian blue modified iron phosphate nanostructures.

Choline, as a marker of cholinergic activity in brain tissue, is very important in biological and clinical analysis, especially in the clinical detection of the neurodegenerative disorders disease. This work presents an electrochemical approach for the detection of choline based on prussian blue modified iron phosphate nanostructures (PB-FePO(4)). The obtained nanostructures showed a good catalysis toward the electroreduction of H(2)O(2), and an amperometric choline biosensor was developed by immobilizing choline oxidase on the PB-FePO(4) nanostructures. The biosensor exhibited a rapid response (ca. 2s), low detection limit (0.4±0.05 µM), wide linear range (2 µM to 3.2 mM), high sensitivity (~75.2 µAm M(-1) cm(-2)), as well as good stability and repeatability. In addition, the common interfering species, such as ascorbic acid, uric acid and 4-acetamidophenol did not cause obvious interference due to the low detection potential (-0.05 V versus saturated calomel electrode). This nanostructure could be used as a promise platform for the construction of other oxidase-based biosensors.

Iron phosphate nanostructures synthesized by microwave method and their applications in biosensing.

A fast, simple microwave heating method has been developed for synthesizing iron phosphate (FePO(4)) nanostructures. The nanostructures were characterized and confirmed by transmission electronic microscopy (TEM), scanning electronic microscopy (SEM), energy-dispersive x-ray spectroscopy (EDS), x-ray photoelectron spectroscopy (XPS), x-ray powder diffraction (XRD), Fourier transform infrared (FT-IR), and UV-vis spectroscopy. The morphology and the size of the nanomaterials are significantly influenced by the concentration of the precursors and the kinds of surfactants. The nanostructures have been employed as an electrode substrate to immobilize myoglobin (Mb) and to facilitate the direct electron transfer (DET) reaction of the protein. After being immobilized on the nanomaterials, Mb can keep its natural structure and undergo effective DET reaction with a pair of well-defined redox peaks at - (330 ± 3.0) mV (pH 6.8) and an apparent electron transfer rate constant of 5.54 s(-1). The Mb-FePO(4)/GC electrode displays good features in the electrocatalytic reduction of H(2)O(2), and thus can be used as a biosensor for detecting substrates with a low detection limit (5 ± 1 µM), a wide linear range (0.01-2.5 mM), a high sensitivity (ca. 85 ± 3 µA mM(-1) cm(-2)), as well as good stability and reproducibility. Therefore, FePO(4) nanomaterials can become a simple and effective biosensing platform for the integration of proteins/enzymes and electrodes, which can provide analytical access to a large group of enzymes for a wide range of bioelectrochemical applications.