Relationship between metabolites of peripheral tryptophan-kynurenine metabolic pathway and clinical symptoms in patients with schizophrenia

BackgroundSchizophrenia is a common severe mental disorder with complex pathogenesis. There are few studies on the correlation between kynurenine metabolites in peripheral serum and urine in schizophrenia.ObjectiveTo investigate the concentration of tryptophan-kynurenine metabolites and interleukin-6 （IL-6） in serum and urine in patients with schizophrenia， and their correlation with clinical symptoms， so as to explore potential biological characteristics related to schizophrenia.MethodsA total of 38 patients with schizophrenia who met the criteria of the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5）， and were hospitalized or attended outpatient clinic at Hangzhou Seventh People's Hospital from December 2021 to December 2022 were included in the study. Additionally， 26 healthy individuals were concurrently recruited from the community of Hangzhou to serve as a control group. All participants were requested to complete the Positive and Negative Symptom Scale （PANSS）. The levels of tryptophan （TRP）， kynurenine （KYN）， kynurenic acid （KYNA）， quinolinic acid （QUIN）， picolinic acid （PIC）， xanthurenate and 5-hydroxytryptamine （5-HT） in both serum and urine were measured using ultra-high-performance liquid chromatography-triple quadrupole linear ion trap mass spectrometry. Serum and urine IL-6 were measured using enzyme-linked immunosorbent assay. Pearson correlation analysis was conducted to examine the correlation between serum and urinary KYN metabolites， as well as the correlation between metabolite levels and clinical symptoms in the patient group.ResultsPatients with schizophrenia had significantly higher level of IL-6 in serum （U=798.500， P<0.01） and lower level of PIC in urine （U=253.000， P=0.013） compared with the control group. Additionally， level of serum KYN was positively correlated with QUIN/KYNA ratio and QUIN/PIC ratio （r=0.562， 0.438， P<0.05） in patients with schizophrenia. 5-HT/KYN ratio in serum was positively correlated with PANSS total score and negative symptom subscale score （r=0.458， 0.455， P<0.01） in patients with schizophrenia.ConclusionSerum TRP-KYN pathway metabolite levels in patients with schizophrenia were associated with neurotoxic metabolite ratios in urine and the severity of negative symptoms. ［Funded by Zhejiang Medical and Health Science and Technology Program Exploratory （number， 2022KY990）

Seismic Behavior of Large-Span Open-Web Floors Consisting of I-Shaped Steel Chords and Steel Tube Webs

A composite large-span open-web floor (COF) system is introduced in this paper, which is composed of I-shaped steel chords, steel tube webs, and concrete slabs. One COF specimen was fabricated and tested under cyclic loadings. The failure process and hysteretic curve of the specimen were discussed in detail. Moreover, a finite element (FE) model was developed and verified by experimental results. A parametric study was performed to examine the effects of the concrete strength, steel strength, section steel thickness, and structural height. The parametric study demonstrates that the effects of the steel strength, section steel thickness, and structural height on the load-displacement hysteretic curve are proved to be significant. As for the bearing capacity and stiffness degradation of the COF system, the influence of the steel strength and section steel thickness is stronger than that of the concrete strength and structural height. Additionally, it is also found that the influence of the steel strength and section steel thickness on the energy dissipation is remarkable; the energy dissipation ability of the structure decreased with increasing the steel strength and increased with increasing the thickness of section steels

Unique Properties of the Rabbit Prion Protein Oligomer.

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative disorders infecting both humans and animals. Recent works have demonstrated that the soluble prion protein oligomer (PrPO), the intermediate of the conformational transformation from the host-derived cellular form (PrPC) to the disease-associated Scrapie form (PrPSc), exerts the major neurotoxicity in vitro and in vivo. Rabbits show strong resistance to TSEs, the underlying mechanism is unclear to date. It is expected that the relative TSEs-resistance of rabbits is closely associated with the unique properties of rabbit prion protein oligomer which remain to be addressed in detail. In the present work, we prepared rabbit prion protein oligomer (recRaPrPO) and human prion protein oligomer (recHuPrPO) under varied conditions, analyzed the effects of pH, NaCl concentration and incubation temperature on the oligomerization, and compared the properties of recRaPrPO and recHuPrPO. We found that several factors facilitated the formation of prion protein oligomers, including low pH, high NaCl concentration, high incubation temperature and low conformational stability of monomeric prion protein. RecRaPrPO was formed more slowly than recHuPrPO at physiological-like conditions (< 57°C, < 150 mM NaCl). Furthermore, recRaPrPO possessed higher susceptibility to proteinase K and lower cytotoxicity in vitro than recHuPrPO. These unique properties of recRaPrPO might substantially contribute to the TSEs-resistance of rabbits. Our work sheds light on the oligomerization of prion proteins and is of benefit to mechanistic understanding of TSEs-resistance of rabbits

Structural and Functional Insights into the Stealth Protein CpsY of <i>Mycobacterium tuberculosis</i>

Mycobacterium tuberculosis (Mtb) is an important and harmful intracellular pathogen that is responsible for the cause of tuberculosis (TB). Mtb capsular polysaccharides can misdirect the host’s immune response pathways, resulting in additional challenges in TB treatment. These capsule polysaccharides are biosynthesized by stealth proteins, including CpsY. The structure and functional mechanism of Mtb CpsY are not completely delineated. Here, we reported the crystal structure of CpsY201−520 at 1.64 Å. CpsY201−520 comprises three β-sheets with five α-helices on one side and three on the other. Four conserved regions (CR1–CR4) are located near and at the base of its catalytic cavity, and three spacer segments (S1–S3) surround the catalytic cavity. Site-directed mutagenesis demonstrated the strict conservation of R419 at CR3 and S1–S3 in regulating the phosphotransferase activity of CpsY201−520. In addition, deletion of S2 or S3 (∆S2 or ∆S3) dramatically increased the activity compared to the wild-type (WT) CpsY201−520. Results from molecular dynamics (MD) simulations showed that S2 and S3 are highly flexible. Our study provides new insights for the development of new vaccines and targeted immunotherapy against Mtb.</i

Design of the Depth Controller for a Floating Ocean Seismograph

Floating ocean seismograph (FOS) is a vertical underwater vehicle used to detect ocean earthquakes by observing P waves at teleseismic distances in the oceans. With the requirements of rising to the surface and transmitting data to the satellite in real time and diving to the desired depth and recording signals, the depth control of FOS needs to be zero overshoot and accurate with fast response. So far, it remains challenging to implement such depth control due to the variation of buoyancy caused by the seawater density varying with the depth. The deeper the water is, the greater the impacts on buoyancy are. To tackle it, a fuzzy sliding mode controller considering the influence of seawater density change is proposed and simulated in MATLAB/SIMULINK based on the variable buoyancy system and state space function of FOS. Compared with proportional-integral-derivative (PID) controller, fuzzy PID controller and sliding mode controller, the simulation results indicate that the proposed controller shows its superiority regardless of the disturbing force. Its advantages include smaller steady-state error, faster response time, smaller system chatter, and well robustness. This proves that the designed fuzzy sliding mode controller is able to meet the working requirements and thus, lays a foundation for FOS application

Crown Structure Metrics to Generalize Aboveground Biomass Estimation Model Using Airborne Laser Scanning Data in National Park of Hainan Tropical Rainforest, China

Forest aboveground biomass (AGB) is an important indicator for characterizing forest ecosystem structures and functions. Therefore, how to effectively investigate forest AGB is a vital mission. Airborne laser scanning (ALS) has been demonstrated as an effective way to support investigation and operational applications among a wide range of applications in the forest inventory. Moreover, three-dimensional structure information relating to AGB can be acquired by airborne laser scanning. Many studies estimated AGB from variables that were extracted from point cloud data, but few of them took full advantage of variables related to tree crowns to estimate the AGB. In this study, the main objective was to evaluate and compare the capabilities of different metrics derived from point clouds obtained from ALS. Particularly, individual tree-based alpha-shape, along with other traditional and commonly used plot-level height and intensity metrics, have been used from airborne laser scanning data. We took the random forest and multiple stepwise linear regression to estimate the AGB. By comparing AGB estimates with field measurements, our results showed that the best approach is mixed metrics, and the best estimation model is random forest (R2 = 0.713, RMSE = 21.064 t/ha, MAE = 15.445 t/ha), which indicates that alpha-shape may be a good alternative method to improve AGB estimation accuracy. This method provides an effective solution for estimating aboveground biomass from airborne laser scanning

Simplified Optimal Estimation of Time-Varying Electromyogram Standard Deviation (EMGσ): Evaluation on Two Datasets

To facilitate the broader use of EMG signal whitening, we studied four whitening procedures of various complexities, as well as the roles of sampling rate and noise correction. We separately analyzed force-varying and constant-force contractions from 64 subjects who completed constant-posture tasks about the elbow over a range of forces from 0% to 50% maximum voluntary contraction (MVC). From the constant-force tasks, we found that noise correction via the root difference of squares (RDS) method consistently reduced EMG recording noise, often by a factor of 5–10. All other primary results were from the force-varying contractions. Sampling at 4096 Hz provided small and statistically significant improvements over sampling at 2048 Hz (~3%), which, in turn, provided small improvements over sampling at 1024 Hz (~4%). In comparing equivalent processing variants at a sampling rate of 4096 Hz, whitening filters calibrated to the EMG spectrum of each subject generally performed best (4.74% MVC EMG-force error), followed by one universal whitening filter for all subjects (4.83% MVC error), followed by a high-pass filter whitening method (4.89% MVC error) and then a first difference whitening filter (4.91% MVC error)—but none of these statistically differed. Each did significantly improve from EMG-force error without whitening (5.55% MVC). The first difference is an excellent whitening option over this range of contraction forces since no calibration or algorithm decisions are required

Prion protein oligomer and its neurotoxicity

National Natural Science Foundation of China [31170717, 91129713, 30900233]The prion diseases, also known as transmissible spongiform encephalopathies, are fatal neurodegenerative disorders. According to the protein only hypothesis, the key molecular event in the pathogenesis of prion disease is the conformational conversion of the host-derived cellular prion protein (PrPC) into a misfolded form (scrapie PrP, PrPSc). Increasing evidence has shown that the most infectious factor is the smaller subfibrillar oligomers formed by prion proteins. Both the prion oligomer and PrPSc are rich in -sheet structure and resistant to the proteolysis of proteinase K. The prion oligomer is soluble in physiologic environments whereas PrPSc is insoluble. Various prion oligomers are formed in different conditions. Prion oligomers exhibited more neurotoxicity both in vitro and in vivo than the fibrillar forms of PrPSc, implying that prion oligomers could be potential drug targets for attacking prion diseases. In this article, we describe recent experimental evidence regarding prion oligomers, with a special focus on prion oligomer formation and its neurotoxicity

Comparison of recHuPrP^O-induced and recRaPrP^O-induced toxicities on human glioblastoma cell lines U87.

<p>Cells were incubated with oligomeric PrP^O proteins at different concentrations for 48 h (37°C). Cytotoxicity was quanitified as a function of cell viability by the MTS assay (n = 3, mean±SD; *, <i>p</i><0.01; ***, <i>p</i><0.001; by Multiple Comparison Test).</p

Thermal-induced unfolding transitions of recRaPrP^C and recHuPrP^C proteins analyzed by Far-UV CD spectroscopy.

<p>The buffer contained 20 mM NaOAc, 0–200 mM NaCl, pH 5.5. The unfolded fraction calculated from Δε at 222 nm is plotted as a function of temperature.</p