Discovery of novel diaryl substituted isoquinolin-1(2H)-one derivatives as hypoxia-inducible factor-1 signaling inhibitors for the treatment of rheumatoid arthritis.

Since synovial hypoxic microenvironment significantly promotes the pathological progress of rheumatoid arthritis (RA), hypoxia-inducible factor 1 (HIF-1) has been emerged as a promising target for the development of novel therapeutic agents for RA treatment. In this study, we designed and synthesized a series of diaryl substituted isoquinolin-1(2H)-one derivatives as HIF-1 signaling inhibitors using scaffold-hopping strategy. By modifying the substituents on N-atom and 6-position of isoquinolin-1-one, we discovered compound 17q with the most potent activities against HIF-1 (IC50 = 0.55 µM) in a hypoxia-reactive element (HRE) luciferase reporter assay. Further pharmacological studies revealed that 17q concentration-dependently blocked hypoxia-induced HIF-1α protein accumulation, reduced inflammation response, inhibited cellular invasiveness and promoted VHL-dependent HIF-1α degradation in human RA synovial cell line. Moreover, 17q improved the pathological injury of ankle joints, decreased angiogenesis and attenuated inflammation response in the adjuvant-induced arthritis (AIA) rat model, indicating the promising therapeutic potential of compound 17q as an effective HIF-1 inhibitor for RA therapy.

Detection of Helicobacter pylori Infection in Human Gastric Fluid Through Surface-Enhanced Raman Spectroscopy Coupled With Machine Learning Algorithms.

Diagnostic methods for Helicobacter pylori infection include, but are not limited to, urea breath test, serum antibody test, fecal antigen test, and rapid urease test. However, these methods suffer drawbacks such as low accuracy, high false-positive rate, complex operations, invasiveness, etc. Therefore, there is a need to develop simple, rapid, and noninvasive detection methods for H. pylori diagnosis. In this study, we propose a novel technique for accurately detecting H. pylori infection through machine learning analysis of surface-enhanced Raman scattering (SERS) spectra of gastric fluid samples that were noninvasively collected from human stomachs via the string test. One hundred participants were recruited to collect gastric fluid samples noninvasively. Therefore, 12,000 SERS spectra (n = 120 spectra/participant) were generated for building machine learning models evaluated by standard metrics in model performance assessment. According to the results, the Light Gradient Boosting Machine algorithm exhibited the best prediction capacity and time efficiency (accuracy = 99.54% and time = 2.61 seconds). Moreover, the Light Gradient Boosting Machine model was blindly tested on 2,000 SERS spectra collected from 100 participants with unknown H. pylori infection status, achieving a prediction accuracy of 82.15% compared with qPCR results. This novel technique is simple and rapid in diagnosing H. pylori infection, potentially complementing current H. pylori diagnostic methods.

Deterministic full-scenario analysis for maximum credible earthquake hazards.

Great earthquakes are one of the major threats to modern society due to their great destructive power and unpredictability. The maximum credible earthquake (MCE) for a specific fault, i.e., the largest magnitude earthquake that may occur there, has numerous potential scenarios with different source processes, making the future seismic hazard highly uncertain. We propose a full-scenario analysis method to evaluate the MCE hazards with deterministic broadband simulations of numerous scenarios. The full-scenario analysis is achieved by considering all uncertainties of potential future earthquakes with sufficient scenarios. Here we show an application of this method in the seismic hazard analysis for the Xiluodu dam in China by simulating 22,000,000 MCE scenarios in 0-10 Hz. The proposed method can provide arbitrary intensity measures, ground-motion time series, and spatial ground-motion fields for all hazard levels, which enables more realistic and accurate MCE hazard evaluations, and thus has great application potential in earthquake engineering.

Changes in Bacterial and Fungal Microbiomes Associated with Tomatoes of Healthy and Infected by Fusarium oxysporum f. sp. lycopersici.

Fusarium wilt of tomato caused by the pathogen Fusarium oxysporum f. sp. lycopersici (Fol) is one of the most devastating soilborne diseases of tomato. To evaluate whether microbial community composition associated with Fol-infected tomato is different from healthy tomato, we analyzed the tomato-associated microbes in both healthy and Fol-infected tomato plants at both the taxonomic and functional levels; both bacterial and fungal communities have been characterized from bulk soil, rhizosphere, rhizoplane, and endosphere of tomatoes using metabarcoding and metagenomics approaches. The microbial community (bacteria and fungi) composition of healthy tomato was significantly different from that of diseased tomato, despite similar soil physicochemical characteristics. Both fungal and bacterial diversities were significantly higher in the tomato plants that remained healthy than in those that became diseased; microbial diversities were also negatively correlated with the concentration of Fol pathogen. Network analysis revealed the microbial community of healthy tomato formed a larger and more complex network than that of diseased tomato, probably providing a more stable community beneficial to plant health. Our findings also suggested that healthy tomato contained significantly greater microbial consortia, including some well-known biocontrol agents (BCAs), and enriched more functional genes than diseased tomato. The microbial taxa enriched in healthy tomato plants are recognized as potential suppressors of Fol pathogen invasion.

Antimicrobial crinane-type alkaloids from the bulbs of Crinum latifolium.

A phytochemical investigation on the 90% ethanol aqueous extract of the bulbs of Crinum latifolium led to the isolation of three new crinane-type alkaloids, designated as crinumlatines A-C (1-3). The structures of the new compounds were elucidated by spectroscopic analysis (NMR, IR, UV, and MS). The isolated alkaloids were tested in vitro for antimicrobial potentials against 5 pathogenic microorganisms. As a result, compounds 1-3 exhibited some antimicrobial activity against the tested Gram negative bacteria with minimum inhibitory concentration values less than 50 µg/ml.

Microbiota in the Rhizosphere and Seed of Rice From China, With Reference to Their Transmission and Biogeography.

Seeds play key roles in the acquisition of plant pioneer microbiota, including the transmission of microbes from parent plants to offspring. However, the issues about seed microbial communities are mostly unknown, especially for their potential origins and the factors influencing the structure and composition. In this study, samples of rice seed and rhizosphere were collected from northeast and central-south China in two harvest years and analyzed using a metabarcoding approach targeting 16S rRNA gene region. A higher level of vertical transmission (from parent seed microbiota to offspring) was revealed, as compared to the acquisition from the rhizosphere (25.5 vs 10.7%). The core microbiota of the rice seeds consisted of a smaller proportion of OTUs (3.59%) than that of the rice rhizosphere (7.54%). Among the core microbiota, species in Arthrobacter, Bacillus, Blastococcus, Curtobacterium, Pseudomonas, and Ramlibacter have been reported as potential pathogens and/or beneficial bacteria for plants. Both the seed and the rhizosphere of rice showed distance-decay of similarity in microbial communities. Seed moisture and winter mean annual temperature (WMAT) had significant impacts on seed microbiota, while WMAT, total carbon, available potassium, available phosphorus, aluminum, pH, and total nitrogen significantly determined the rhizosphere microbiota. Multiple functional pathways were found to be enriched in the seed or the rhizosphere microbiota, which, to some extent, explained the potential adaptation of bacterial communities to respective living habitats. The results presented here elucidate the composition and possible sources of rice seed microbiota, which is crucial for the health and productivity management in sustainable agriculture.

Mechanism for large-scale canyon deformations due to filling of large reservoir of hydropower project.

Large storage dam projects may modify geo-environmental conditions in many ways. The reservoir impoundment of the 285.5 m high Xiluodu arch dam located on the Jinsha River (China) caused large-scale canyon deformations, including significant canyon contraction and uplift movements from reservoir to downstream valley. The dam experienced subsequent tilting towards upstream and raised a safety concern of the project. A Thermo-Hydro-Mechanical (THM) mechanism is proposed for this extraordinary behavior. Due to reservoir impounding and seepage, significant temperature drops and fluid pressure increase within the underlying geothermal limestone aquifer in a synclinal basin are primary root causes. Finite element THM simulations successfully reproduce these unique deformations. Recent observations of large quantities of thermalized discharge water downstream and high pore pressure in the limestone layer provide further support for the proposed mechanism. Furthermore, refined numerical modeling is adopted to evaluate the safety of Xiluodu dam subjected to potential larger canyon contractions. We conclude that these unprecedented phenomena are dominantly the consequence of THM response to regional hydrogeological evolution following the build-up of a large reservoir. The accumulated canyon contractions at the current stage would not pose a direct threat to the dam safety, but a tripled situation may cause severe safety issues.

NADH protect against radiation enteritis by enhancing autophagy and inhibiting inflammation through PI3K/AKT pathway.

Radiotherapy is an important method for cancer treatment but it has serious side-effects at high doses. One of the greatest challenges in radiotherapy is that radiation affects both healthy tissue and cancer tissues. For abdominal or pelvic lesions, the bowel is the most easily injured by irradiation. Radiation may cause radiation enteritis, intestinal inflammatory infiltration, or intestinal perforation. Coenzyme NADH involves in energy metabolism and transportation of nucleic acid, proteins and carbohydrates. In our study, NADH was used to protect the intestinal wall from irradiation injury in IEC-6 normal intestinal epithelial cells. By flow cytometry, we found that NADH can inhibit the cell death and the producing of reactive oxygen species (ROS). The immunofluorescence assay showed that cell autophagy was increased in the NADH group. Western blot data indicated that NADH promoted the microtubule associated protein 1A/1B-light chain 3(LC3)-I to LC3II and the expression of IL-1ß and TNFα decreased in a dose dependent manner. Interestingly, a specific PI3K/AKT inhibitor (3MA) decreased the expression of inflammatory factors. In the animal experiment, after 12 Gy radiation, there were less TNFα and more LC3II in the RT+NADH group than that of RT group. Compared with the mock, there was no significant damage in the NADH group. Thus, our study provides the evidence that NADH may protect against radiation enteritis by suppressing inflammation and enhancing autophagy through PI3K/AKT pathway in normal intestinal cells.

Long-Term Feeding of Elemental Sulfur Alters Microbial Community Structure and Eliminates Mercury Methylation Potential in Sulfate-Reducing Bacteria Abundant Activated Sludge.

This study reported a novel observation that the long-term cultivation of sulfur-reducing bacteria (S0RB) from a sulfate-reducing bacteria (SRB)-abundant seeding sludge with elemental sulfur feeding significantly shaped the microbial community structure and eliminated the mercury methylation potential in the S0RB-enriched sludge. In this study, the enrichments of SRB and S0RB from activated sludge were obtained through long-term cultivations. Subsequently, the batch tests showed that approximately 5000 µg/L Hg (II) was completely removed from the solution by both the SRB-enriched and S0RB-enriched sludge. Extremely low or no MeHg production was observed in the S0RB-enriched sludge (less than the limit of detection, 0.01 µg/L), while 1.49 µg/L MeHg accumulated in the SRB-enriched sludge. Other batch tests using the sludge samples from a replication of the cultivation showed that the methylation capability of the S0RB-enriching sludge gradually diminished to a negligible level over a 6 month cultivation time. However, some mercury-methylation-related bacteria were present in the enrichment of S0RB such as Geobacter. The absence of MeHg in the S0RB-enriched sludge may be attributed to the dissolved organic matter (DOM) instead of the sulfur- and sulfate-reduction pathway or MeHg demethylation when exposed to Hg (II). The cultivated S0RB could be used for mercury-contaminated wastewater treatment without MeHg concern.

[Studies on photoinduced electron and proton transfer reactions of nucleic acid and aromatic ketone].

The transient absorption spectra of two aromatic ketones (benzophenone (BP), xanthone (XT)) and four nucleic acids (guanosine 5'-monophosphate (GMP), adenosine 5'-monophosphate (AMP), cytidine 5'-monophosphate (CMP), thymidine 5'-monophosphate (TMP)) were obtained in 1 : 1 CH3CN/H2O solution by using time-resolved laser flash photolysis at 355 nm. From the changes of the transient absorption spectra the authors can conclude that photoinduced proton transfer following electron transfer from GMP and AMP to excited BP and XT occurs, which is in accordance with free energy change of the reactions. For CMP and TMP, electron transfer and proton transfer do not appear because no ketyl and anion radical are generated. In addition, the rate constants for electron transfer from GMP, AMP, CMP, and TMP to the excited BP and XT were determined. As can be seen, there is a good correlation between kq and the free energy changes (deltaG) of the electron transfer reaction.