1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10

Mycophenolic acid (MPA) is an important immunosuppressant broadly used in renal transplantation. However, the large inter-patient variability in mycophenolic acid (MPA) pharmacokinetics (PK) limits its use. We hypothesize that extrahepatic metabolism of MPA may have significant impact on MPA PK variability. Two intestinal UDP-glucuronosyltransferases 1A8 and 1A10 plays critical role in MPA metabolism. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription and on MPA glucuronidation was tested in human intestinal cell lines LS180, Caco-2 and HCT-116. The correlation between transcription levels of VD receptor (VDR) and the two UGT genes were examined in human normal colorectal tissue samples (n = 73). PK alterations of MPA following the parent drug, mycophenolate mofetil (MMF), and D3 treatment was assessed among renal transplant recipients (n = 10). Our ChIP assay validate three VDREs which were further demonstrated as transcriptional enhancers with the luciferase assays. D3 treatment significantly increased transcription of both UGT genes as well as MPA glucuronidation in cells. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12 and Cmax while over 70% elevation of total clearance of MPA. Our study suggested a significant regulatory role of VD on MPA metabolism and PK via modulating extrahepatic UGT activity

Decoding the dopamine transporter imaging for the differential diagnosis of parkinsonism using deep learning.

PURPOSE This work attempts to decode the discriminative information in dopamine transporter (DAT) imaging using deep learning for the differential diagnosis of parkinsonism. METHODS This study involved 1017 subjects who underwent DAT PET imaging ([11C]CFT) including 43 healthy subjects and 974 parkinsonian patients with idiopathic Parkinson's disease (IPD), multiple system atrophy (MSA) or progressive supranuclear palsy (PSP). We developed a 3D deep convolutional neural network to learn distinguishable DAT features for the differential diagnosis of parkinsonism. A full-gradient saliency map approach was employed to investigate the functional basis related to the decision mechanism of the network. Furthermore, deep-learning-guided radiomics features and quantitative analysis were compared with their conventional counterparts to further interpret the performance of deep learning. RESULTS The proposed network achieved area under the curve of 0.953 (sensitivity 87.7%, specificity 93.2%), 0.948 (sensitivity 93.7%, specificity 97.5%), and 0.900 (sensitivity 81.5%, specificity 93.7%) in the cross-validation, together with sensitivity of 90.7%, 84.1%, 78.6% and specificity of 88.4%, 97.5% 93.3% in the blind test for the differential diagnosis of IPD, MSA and PSP, respectively. The saliency map demonstrated the most contributed areas determining the diagnosis located at parkinsonism-related regions, e.g., putamen, caudate and midbrain. The deep-learning-guided binding ratios showed significant differences among IPD, MSA and PSP groups (P < 0.001), while the conventional putamen and caudate binding ratios had no significant difference between IPD and MSA (P = 0.24 and P = 0.30). Furthermore, compared to conventional radiomics features, there existed average above 78.1% more deep-learning-guided radiomics features that had significant differences among IPD, MSA and PSP. CONCLUSION This study suggested the developed deep neural network can decode in-depth information from DAT and showed potential to assist the differential diagnosis of parkinsonism. The functional regions supporting the diagnosis decision were generally consistent with known parkinsonian pathology but provided more specific guidance for feature selection and quantitative analysis

Streptococcal Toxic Shock Syndrome Caused by Streptococcus suis Serotype 2

BACKGROUND: Streptococcus suis serotype 2 ( S. suis 2, SS2) is a major zoonotic pathogen that causes only sporadic cases of meningitis and sepsis in humans. Most if not all cases of Streptococcal toxic shock syndrome (STSS) that have been well-documented to date were associated with the non-SS2 group A streptococcus (GAS). However, a recent large-scale outbreak of SS2 in Sichuan Province, China, appeared to be caused by more invasive deep-tissue infection with STSS, characterized by acute high fever, vascular collapse, hypotension, shock, and multiple organ failure. METHODS AND FINDINGS: We investigated this outbreak of SS2 infections in both human and pigs, which took place from July to August, 2005, through clinical observation and laboratory experiments. Clinical and pathological characterization of the human patients revealed the hallmarks of typical STSS, which to date had only been associated with GAS infection. Retrospectively, we found that this outbreak was very similar to an earlier outbreak in Jiangsu Province, China, in 1998. We isolated and analyzed 37 bacterial strains from human specimens and eight from pig specimens of the recent outbreak, as well as three human isolates and two pig isolates from the 1998 outbreak we had kept in our laboratory. The bacterial isolates were examined using light microscopy observation, pig infection experiments, multiplex-PCR assay, as well as restriction fragment length polymorphisms (RFLP) and multiple sequence alignment analyses. Multiple lines of evidence confirmed that highly virulent strains of SS2 were the causative agents of both outbreaks. CONCLUSIONS: We report, to our knowledge for the first time, two outbreaks of STSS caused by SS2, a non-GAS streptococcus. The 2005 outbreak was associated with 38 deaths out of 204 documented human cases; the 1998 outbreak with 14 deaths out of 25 reported human cases. Most of the fatal cases were characterized by STSS; some of them by meningitis or severe septicemia. The molecular mechanisms underlying these human STSS outbreaks in human beings remain unclear and an objective for further study

Problems of Family Farms in China and Countermeasures

In the Communiqué of the Third Plenary Session of the 18th Central Committee of the CPC, it proposed the tasks of accelerating the building of a new type of agricultural operation system, endowing farmers with more property rights, promoting equal exchanges of factors of production and balanced allocation of public resources between urban and rural areas, and improving the institutions and mechanisms for promoting the sound development of urbanization. However, as new agricultural operating entities, family farms have problems of land circulation, lack of scientific and technological talents, and backward infrastructure. In line with these problems, this study put forward recommendations and countermeasures, in the hope of promoting increase in farmers’ income, increasing agricultural intensification and large-scale level, and realizing agricultural modernization

Simple anion receptor with imidazole and phenol groups: Forming hydrogen-bond complex with Cl⁻

748-754A simple anion receptor 2'-(2"-hydroxy-3"-methoxyphenyl)imidazo[4',5'-f]-1, 10-phenanthroline[5,6-f] (1) with imidazole and phenol groups has been synthesized and its interaction investigated with anions (F⁻, Cr⁻, Br⁻, I⁻, AcO⁻ and H₂PO₄⁻) by UV -vis and ¹H NMR titrations. Added with Cl⁻, the change of UV -vis spectra of 1 is different from that of added AcO⁻,F⁻ and H₂PO₄⁻. Also, the change of ¹H NMR titration spectra of 1 with Cl⁻ is different from that of added AcO⁻, F⁻ and H₂PO₄⁻, 1 forms supramolecular complex with Cl⁻ as a receptor and is deprotonated with AcO⁻, F⁻ and H₂PO₄⁻ as a colormetric sensor. The receptor forms H-bond complex with Cl⁻ by NH of imidazole, Hc' of phenanthroline and H₁ of phenyl. As an acid proton donor, the protons of NH of imidazole and OH of phenol are too acidic to form hydrogen-bond complex with AcO⁻, F⁻ and H₂PO₄⁻. So, the interaction of 1 with AcO⁻, H₂PO₄⁻ and F⁻ is acid-basic reaction. The affinity to anions of NH is dramatically more powerful than that of OH

Pumping up the charge density of a triboelectric nanogenerator by charge-shuttling

Conventionally, triboelectric nanogenerators are based on static charges fixed on dielectric surfaces. Here, the authors report a new mechanism using shuttling of mirror charge carriers corralled in quasi-symmetrical conduction domains, which boosts performance for blue energy harvesting

Analysis on the Dynamics of Coastline and Reclamation in Pearl River Estuary in China for Nearly Last Half Century

The Pearl River Estuary is in the geometric center of Guangdong-Hong Kong-Macao Greater Bay Area, which is one of the main battlefields to drive the high-quality development of China’s economy. This paper uses seven sets of typical satellite images in Pearl River Estuary for nearly half a century (from 1973 to 2021) to analyze the changes of coastline and sea reclamation. The results show that from 1973 to 2021, the total length of the coastline of the Pearl River Estuary increased from 240.09 km to 416.00 km, and that of the continental coastline from 186.87 km to 246.21 km (but the length of natural coastline in the continental coastline decreased from 136.91 km to 15.17 km). In the same period, the total reclamation area of the Pearl River Estuary increased by 28,256.06 ha. Before 2012, the growth rate of reclamation was generally fast. After 2012, the reclamation in China has entered a period of reflection. With reclamation was strictly controlled in the new era, only the previously approved reclamation projects and national major projects have been guaranteed, which makes the average annual growth rate of the coastline length and the reclamation area in the region show a significant downward trend. The reclamation in early days was largely for agriculture and pond culture purposes, but is shifting to transportation, industrial development, and urban construction in recent decades. This study scientifically analyzes the coastline and reclamation changes of the Pearl River Estuary in the past half century, which has a very important reference value for the next step to formulate marine ecological protection and restoration strategies, and construct a new pattern of marine space development and protection

Characterization of Biochar Derived from Pineapple Peel Waste and Its Application for Sorption of Oxytetracycline from Aqueous Solution

Physicochemical characteristics of biochar and its sorption potential for oxytetracycline (OTC) were investigated. Biochars from pineapple peel waste were produced via pyrolysis under oxygen-depleted conditions at 350 °C (BL350), 500 °C (BL500), and 650 °C (BL650), as well as the characteristics and polycyclic aromatic hydrocarbons contents of the samples were compared. The sorption kinetics of OTC onto the biochars was completed in three stages, i.e., a fast stage, a slow stage, and an equilibrium stage after 24 h. The kinetics data were perfectly fitted by the pseudo-second-order model with high correlation coefficients (R2 > 0.999). All of the sorption isotherms were nonlinear and well described by the Langmuir model. The Langmuir maximum sorption capacity (qmax) increased in the order of BL650 > BL500 > BL350. The thermodynamic parameters revealed that the sorption of OTC onto the biochars was spontaneous and endothermic. Fourier transform infrared spectroscopy (FTIR) of the biochars before and after sorption of OTC confirmed that the H-bonding interaction was the dominant sorption mechanism. The results demonstrated that biochars obtained from inexpensive and renewable materials could be utilized as a highly effective and environmentally friendly adsorbent for removing organic contaminants from wastewater