Enteric-coated Mycophenolate Sodium therApy versus cyclophosphamide for induction of Remission in Microscopic PolyAngiitis (EMSAR-MPA trial): study protocol for a randomised controlled trial.

INTRODUCTION: Several studies have demonstrated that mycophenolate mofetil (MMF) may be an excellent alternative to cyclophosphamide (CYC) or rituximab for the induction of remission in non-life-threatening anti-neutrophil cytoplasmic antibodies associated vasculitis because of its strong immunosuppressive potency and low toxicity profile. Enteric-coated mycophenolate sodium (EC-MPS) was introduced to reduce gastrointestinal adverse reactions of MMF. This study will evaluate the efficacy and safety of EC-MPS combined with glucocorticoid in patients with active and non-life-threatening microscopic polyangiitis (MPA). METHODS AND ANALYSIS: This study is a multicentre, open-label, randomised controlled, non-inferiority trial. A total of 110 patients with active and non-life-threatening MPA from 11 hospitals in Shanxi Province of China will be recruited and randomised in a 1:1 ratio to receive either EC-MPS or CYC. All patients will receive the same glucocorticoid plan. We will compare oral EC-MPS (720-1440 mg/day) with intravenous pulsed CYC (7.5-15 mg/kg) administered for 3-6 months. All patients will be switched from their assigned treatment (EC-MPS or CYC) to oral azathioprine (2 mg/kg/day) after remission has been achieved, between 3 and 6 months. Azathioprine will be continued until the study ends at 18 months. The primary end point of efficacy is the remission rate at 6 months. Follow-up will continue for 18 months in order to detect an influence of induction regimen on subsequent relapse rates. ETHICS AND DISSEMINATION: This study has received approval from the Ethics Committee of the Second Hospital of Shanxi Medical University (2022YX-026). All participants are required to provide written informed consent and no study-related procedures will be performed until consent is obtained. The results of this trial will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: ChiCTR2200063823.

Direct investigations of the effects of nicardipine on calcium channels of astrocytes by Atomic Force Microscopy.

Calcium channel blockers (CCB) of astrocytes can blockade the calcium ions entry through the voltage gated calcium channels (VGCC), and is widely used in the diseases related with VGCC of astrocytes. But many aspects of the interaction mechanisms between the CCB and VGCC of astrocytes still remain unclear due to the limited resolution of the approaches. Herein the effects of the nicardipine (a type of CCB) on VGCC of astrocytes were investigated at very high spatial, force and electrical resolution by multiple modes of Atomic Force Microscopy (AFM) directly. The results reveal that after the addition of nicardipine, the recognition signals of VGCC disappeared; the specific unbinding forces vanished; the conductivity of the astrocytes decreased (the current decreased about 2.9 pA and the capacitance was doubled); the surface potential of the astrocytes reduced about 14.2 mV. The results of electrical properties investigations are consistent with the simulation experiments. The relations between these biophysical and biochemical properties of VGCC have been discussed. All these demonstrate that the interactions between nicardipine and VGCC have been studied at nanometer spatial resolution, at picoNewton force resolution and very high electrical signal resolution (pA in current, pF in capacitance and 0.1 mV in surface potential) level. The approaches are considered to be high resolution and high sensitivity, and will be helpful and useful in the further investigations of the effects of other types of CCB on ion channels, and will also be helpful in the investigations of mechanisms and therapy of ion channelopathies.

Atomic force microscopy correlates mechanical and electrical properties of HepG2 cells with curcumin concentration.

Hepatocellular carcinoma (HCC) is a highly prevalent cancer with a significant impact on human health. Curcumin, a natural compound, induces cytoskeletal changes in liver cancer cells and modifies the distribution of lipids, proteins, and polysaccharides on plasma membranes, affecting their mechanical and electrical properties. In this study, we used nanomechanical indentation techniques and Kelvin probe force microscopy (KPFM) based on atomic force microscopy (AFM) to investigate the changes in surface nanomechanical and electrical properties of nuclear and cytoplasmic regions of HepG2 cells in response to increasing curcumin concentrations. CCK-8 assays and flow cytometry results demonstrated time- and concentration-dependent inhibition of HepG2 cell proliferation by curcumin. Increasing curcumin concentration led to an initial increase and then decrease in the mechanical properties of nuclear and cytoplasmic regions of HepG2 cells, represented by the Young's modulus (E), as observed through nanoindentation. KPFM measurements indicated decreasing trends in both cell surface potential and height. Fluorescence microscopy results indicated a positive correlation between curcumin concentration and phosphatidylserine translocation from the inner to the outer membrane, which influenced the electrical properties of HepG2 cells. This study provides valuable insights into curcumin's mechanisms against cancer cells and aids nanoscale evaluation of therapeutic efficacy and drug screening.

Overexpression of Corin Ameliorates Kidney Fibrosis through Inhibition of Wnt/ß-Catenin Signaling in Mice.

The Wnt/ß-catenin pathway represents a promising therapeutic target for mitigating kidney fibrosis. Corin possesses the homologous ligand binding site [Frizzled-cysteine-rich domain (Fz-CRD)] similar to Frizzled proteins, which act as receptors for Wnt. The Fz-CRD has been found in eight different proteins, all of which, except for corin, are known to bind Wnt and regulate its signal transmission. We hypothesized that corin may inhibit the Wnt/ß-catenin signaling pathway and thereby reduce fibrogenesis. Reduced expression of corin along with the increased activity of Wnt/ß-catenin signaling was found in unilateral ureteral obstruction (UUO) and ureteral ischemia/reperfusion injury (UIRI) models. In vitro, corin bound to the Wnt1 through its Fz-CRDs and inhibit the Wnt1 function responsible for activating ß-catenin. Transforming growth factor-ß1 inhibited corin expression, accompanied by activation of ß-catenin; conversely, overexpression of corin attenuated the fibrotic effects of transforming growth factor-ß1. In vivo, adenovirus-mediated overexpression of corin attenuated the progression of fibrosis, which was potentially associated with the inhibition of Wnt/ß-catenin signaling and the down-regulation of its target genes after UUO and UIRI. These results suggest that corin acts as an antagonist that protects the kidney from pathogenic Wnt/ß-catenin signaling and from fibrosis following UUO and UIRI.

Effects of surface properties of GaN semiconductors on cell behavior.

In recent years, semiconductors have aroused great interest in connecting, observing and influencing the behavior of biological elements, and it is possible to use semiconductor-cell compound interfaces to discover new signal transduction in the biological field. Among them, III-V nitride semiconductors, represented by gallium nitride (GaN), are used as substrates to form semiconductor-biology interfaces with cells, providing a platform for studying the effects of semiconductors on cell behavior. The interfaces between GaN substrate and cells play an important role in detecting and manipulating cell behaviors and provide a new opportunity for studying cell behavior and developing diagnostic systems. Hence, it is necessary to understand how the properties of the GaN substrate directly influence the behavior of biological tissues, and to create editable biological interfaces according to the needs. This paper reviews the synergism between GaN semiconductors and biological cells. The electrical properties, persistent photoconductivity (PPC), nanostructures, and chemical functionalization of GaN on the promotion of cell behaviors, such as growth, adhesion, differentiation, and signal transduction, are emphatically introduced. The purpose of this study is to provide guidance to explore the detection and regulation methods of cell behavior based on semiconductors and promote the application of them in the field of bioelectronics, such as biochips, biosensors, and implantable systems.

Single molecule localizations of voltage-gated sodium channel NaV1.5 on the surfaces of normal and cancer breast cells.

Voltage-gated sodium channels (VGSCs) are widely expressed in various types of tumor and cancer cells, and NaV1.5 is overexpressed in highly metastatic breast cancer cells. There may be positive relations between the expression levels of NaV1.5 and breast cancer recurrence and metastasis. Herein, NaV1.5 was detected and localized on the surfaces of normal and cancer breast cells by the single molecule recognition imaging (SMRI) mode of atomic force microscopy (AFM). The results reveal that NaV1.5 was irregularly distributed on the surfaces of normal and cancer breast cells. The NaV1.5 has an area percentage of 0.6% and 7.2% on normal and cancer breast cells, respectively, which indicates that there is more NaV1.5 on cancer cells than on normal cells. The specific interaction forces and binding kinetics in the NaV1.5-antibody complex system were investigated with the single molecule force spectroscopy (SMFS) mode of AFM, indicating that the stability of the NaV1.5-antibody on normal breast cells is higher than that on cancer breast cells. All these results will be useful to study the interactions of other ion channel-antibody systems, and will also be useful to understand the role of sodium channels in tumor metastasis and invasion.

Temporal and spatial differentiation characteristics of ecosystem service values based on the ecogeographical division of China: a case study in the Yellow River Basin, China.

The identification of spatiotemporal changes in ecosystem service values (ESVs) and their drivers is the basis for ecosystem service administration and decision-making. This research focuses on the Yellow River Basin (YRB). With a multitemporal land use and land cover (LULC) dataset (1995-2018), the equivalence coefficient method with spatiotemporal dynamic correction and exploratory spatial data analysis methods were used to evaluate ESV changes due to LULC changes and their spatial characteristics. The contributions of the ESV driving factors and their mutual effects were also investigated via geographic detectors. The results revealed that (1) the land use structure of the YRB, mainly grassland and cultivated land, was stable from 1995 to 2018. However, the transition between land use types was dramatic, including urban expansion accompanied by losses of farmland, grassland, and unused land; increased forestland; and significant increases in water bodies and wetland areas. (2) During the study period, the overall ESV of the YRB increased, and hydrological regulation and climate regulation services dominated the change in the ESVs in the study area. The ESV exhibited obvious ecogeographical pattern differentiation and evident positive spatial autocorrelation. High values were concentrated in the southern part of the study area, including the southeastern part of the Qinghai-Tibet Plateau region and the central part of the East Asian monsoon region. Low values were concentrated in the northwestern arid zone, dominated by desert and grassland ecosystems. (3) Because of the fragility of the regional ecological background, the spatial differentiation of the ESVs in the YRB is dependent on natural factors; however, anthropogenic factors such as the degree of land use and the human activity intensity also lead to ESV differentiation. The synergistic effects of human activities, landscape pattern changes, and natural factors result in the spatial differentiation of the ESVs in the research region. Therefore, human activities affecting the ecological environment should be controlled, nature-based solutions should be advocated, patch diversity should be increased, landscape fragmentation should be reduced, LULC ecosystem service functions should be improved, and the relationship among economic, social, and ecological landscape resources should be coordinated.

Exploring the Driving Factors of Remote Sensing Ecological Index Changes from the Perspective of Geospatial Differentiation: A Case Study of the Weihe River Basin, China.

Using the Google Earth Engine (GEE) platform, Moderate-resolution image spectroradiometer (MODIS) data of the Weihe River Basin from 2001 to 2021 were acquired, four ecological indicators, namely, greenness, wetness, heat, and dryness, were extracted, and the remote sensing ecological index (RSEI) was constructed through principal component analysis. In addition, the geographic detectors and a multi-scale geographic weighted regression model (MGWR) were used to identify the main driving factors of RSEI changes and capture the differences in spatial changes from different perspectives using multiple indicators. The results show that (1) the quality of the eco-environment in the Weihe River basin improved as a whole from 2001 to 2021, and the RSEI increased from 0.376 to 0.414. In terms of the RSEI grade, the medium RSEI and high RSEI areas increased significantly and the growth rate increased significantly, reaching 26.42% and 27.70%, respectively. (2) Spatially, the quality of the eco-environment in the Weihe River Basin exhibited a spatial distribution pattern that was high in the south and low in the north, among which the quality of the eco-environment in the Weihe River Basin in northern Shaanxi and northwestern Ningxia and Gansu was relatively low. In addition, during the study period, the RSEI of the Qinling Mountains in the southern part of the Weihe River Basin and the Jinghe River and Luohe River areas improved significantly. The urban area on the Guanzhong Plain in the Weihe River Basin experienced rapid economic growth, and urban expansion led to a significant decrease in the quality of the eco-environment. (3) The eco-environment quality in the Weihe River Basin is the result of the interaction of natural, anthropogenic, and landscape pattern factors. All of the interactions between the influencing factors had a stronger influence than those of the individual factors. There were significant differences between the individual drivers and the spatial variation in RSEI, suggesting that different factors dominate the variation in RSEI in different regions, and zonal management is crucial to achieving sustainable management of RSEI. The study shows that to improve the eco-environment quality of the Weihe River Basin, it is necessary to further strengthen ecological protection projects, reasonably allocate landscape elements, and strengthen the resistance and resilience of the ecosystem.

[Responses of radial growth of Pinus tabuliformis to climate change at the northern slopes of Qinling Mountains, China]. / 秦岭北麓油松径向生长对气候变化的响应.

A standard chronology (STD) was established with Pinus tabuliformis samples collected from Nanwutai at the northern slopes of the Qinling Mountains. The correlations between radial growth of P. tabuliformis and climatic factors were explored. The results showed that radial growth was positively correlated with moisture factors in previous September and current May. The radial growth was positively correlated with temperature factors in pre-vious November and negatively with that in previous October and current May. There was significant lag effect of climatic factors on the radial growth. The radial growth of P. tabuliformis was well correlated with the PDSI drought severity index, with positive correlations being identified from September to December of the previous year and in May of the current year. The regression model was able to simulate the relationship between STD and PDSI. The formations of extremely wide and narrow tree-ring were mainly a result of drought condition. Combined with climatic factors, PDSI could better reflect the radial growth characteristics of P. tabuliformis.

Application of BP Artificial Neural Network in Preparation of Ni-W Graded Coatings.

The internal stress difference between soft-ductile aluminum alloy substrate and hard-brittle Ni-W alloy coating will cause stress concentration, thus leading to the problem of poor bonding force. Herein, this work prepared the Ni-W graded coating on aluminum alloy matrix by the pulse electrodeposition method in order to solve the mechanical mismatch problem between substrate and coatings. More importantly, a backward propagation (BP) neural network was applied to efficiently optimize the pulse electrodeposition process of Ni-W graded coating. The SEM, EDS, XRD, Vickers hardness tester and Weighing scales are used to analyze the micromorphology, chemical element, phase composition, and micro hardness as well as oxidation weight increase, respectively. The results show that the optimal process conditions with BP neural network are as follows: the bath temperature is 30 °C, current density is 15 mA/cm2 and duty cycle is 0.3. The predicted value of the model agrees well with the experimental value curve, the relative error is minor. The maximum error is less than 3%, and the correlation coefficient is 0.9996. The Ni-W graded coating prepared by BP neural network shows good bonding with the substrate which has flat and smooth interface. The thickness of the coating is about 136 µm, which slows down the oxidation of the substrate and plays an effective role in protecting the substrate.

Coupling Coordination Relationship and Driving Mechanism between Urbanization and Ecosystem Service Value in Large Regions: A Case Study of Urban Agglomeration in Yellow River Basin, China.

Mastering the coupling and coordination relationship and driving mechanism of urbanization and ecosystem service value (ESV) is of great significance to ecological protection and regional sustainable development. In this paper, the coupling coordination model, geographic detector and GWR model are used to analyze the spatio-temporal coupling interaction between urbanization and ESV and the spatial differentiation characteristics of influencing factors from 1995 to 2018. The results of the study are as follows: (1) During the study period, cities in the Yellow River Basin experienced accelerated urban expansion, and the ESV of forests, water and wetlands increased, which offset the reduction in ESV due to the expansion of construction land and farmland and grassland. (2) The degree of coupling and coordination between the two gradually improved, but the overall situation showed a low-level coupling and coordination process. Mild coupling coordination gradually increased, reaching an increase of 38.10%; severe imbalance types tended to disappear, decreasing by 52.38%, and coupling subtypes developed from lagging urbanization to ESV backward types. The high-value areas of the coupling coordination degree are distributed in the high-value areas of ESV in the north of the upper reaches, and the low-value areas are distributed in the cities of Henan and Shandong with high urbanization levels in the downstream and most resource-based cities in the middle reaches. (3) In addition, the spatial intensity of the effect of each dominant factor on the degree of coupling coordination is different. Economic growth, technological development, environmental regulations and the proportion of forest land have positive and belt-shaped alienation characteristics for the coupling and coordination of the two, and infrastructure and temperature show negative driving characteristics. Therefore, the coupling and coordination relationship between ESV and urbanization should be clarified to help future urban planning. On the basis of determining the regional environmental carrying capacity and the adjustment direction of the rational planning of land resources, the impact of urban barriers formed by administrative boundaries and natural geographical conditions on the development of urban agglomerations should be broken to achieve the overall high-quality and coordinated development of the basin.

Research on the application of compound microorganism preparation in reusing urban reclaimed water in circulating cooling water system.

A biological method was developed for reusing urban reclaimed water in circulating cooling water systems (CCWS), in which the compound microorganism preparation (CMP) mainly included nitrobacteria, Bacillus subtilis, photosynthetic bacteria and Thiobacillus denitrificans, was used to control the scaling, corrosion and biofouling of CCWS. The abundant carbon, nitrogen and phosphorus in urban reclaimed water met the needs of microbial growth. Compared with chemical agents, CMP had the advantages of high efficiency, no additional chemicals and being more economical. The research results showed that CMP improved water quality and decreased ammonia nitrogen (NH3-N) and chemical oxygen demand (COD). The concentration ratio of CCWS reached 3.87 using CMP. The corrosion inhibition rate of CMP and the removal rate on biofouling achieved 99.69% and 22.21%, respectively. The mechanisms of CMP to control scaling, corrosion and biofouling were discussed, and the surface characteristics and chemical compositions of corrosion products and biofouling were analyzed.

Improvement of pristinamycin I (PI) production in Streptomyces pristinaespiralis by metabolic engineering approaches.

Pristinamycin, produced by Streptomyces pristinaespiralis, which is a streptogramin-like antibiotic consisting of two chemically unrelated components: pristinamycin I (PI) and pristinamycin II (PII), shows potent activity against many antibiotic-resistant pathogens. However, so far pristinamycin production titers are still quite low, particularly those of PI. In this study, we constructed a PI single component producing strain by deleting the PII biosynthetic genes (snaE1 and snaE2). Then, two metabolic engineering approaches, including deletion of the repressor gene papR3 and chromosomal integration of an extra copy of the PI biosynthetic gene cluster (BGC), were employed to improve PI production. The final engineered strain ΔPIIΔpapR3/PI produced a maximum PI level of 132 mg/L, with an approximately 2.4-fold higher than that of the parental strain S. pristinaespiralis HCCB10218. Considering that the PI biosynthetic genes are clustered in two main regions in the 210 kb "supercluster" containing the PI and PII biosynthetic genes as well as a cryptic polyketide BGC, these two regions were cloned separately and then were successfully assembled into the PI BGC by the transformation-associated recombination (TAR) system. Collectively, the metabolic engineering approaches employed is very efficient for strain improvement in order to enhance PI titer.

Involvement of the TetR-Type Regulator PaaR in the Regulation of Pristinamycin I Biosynthesis through an Effect on Precursor Supply in Streptomyces pristinaespiralis.

UNLABELLED: Pristinamycin I (PI), produced by Streptomyces pristinaespiralis, is a streptogramin type B antibiotic, which contains two proteinogenic and five aproteinogenic amino acid precursors. PI is coproduced with pristinamycin II (PII), a member of streptogramin type A antibiotics. The PI biosynthetic gene cluster has been cloned and characterized. However, thus far little is understood about the regulation of PI biosynthesis. In this study, a TetR family regulator (encoded by SSDG_03033) was identified as playing a positive role in PI biosynthesis. Its homologue, PaaR, from Corynebacterium glutamicum serves as a transcriptional repressor of the paa genes involved in phenylacetic acid (PAA) catabolism. Herein, we also designated the identified regulator as PaaR. Deletion of paaR led to an approximately 70% decrease in PI production but had little effect on PII biosynthesis. Identical to the function of its homologue from C. glutamicum, PaaR is also involved in the suppression of paa expression. Given that phenylacetyl coenzyme A (PA-CoA) is the common intermediate of the PAA catabolic pathway and the biosynthetic pathway of L-phenylglycine (L-Phg), the last amino acid precursor for PI biosynthesis, we proposed that derepression of the transcription of paa genes in a ΔpaaR mutant possibly diverts more PA-CoA to the PAA catabolic pathway, thereby with less PA-CoA metabolic flux toward L-Phg formation, thus resulting in lower PI titers. This hypothesis was verified by the observations that PI production of a ΔpaaR mutant was restored by L-Phg supplementation as well as by deletion of the paaABCDE operon in the ΔpaaR mutant. Altogether, this study provides new insights into the regulation of PI biosynthesis by S. pristinaespiralis. IMPORTANCE: A better understanding of the regulation mechanisms for antibiotic biosynthesis will provide valuable clues for Streptomyces strain improvement. Herein, a TetR family regulator PaaR, which serves as the repressor of the transcription of paa genes involved in phenylacetic acid (PAA) catabolism, was identified as playing a positive role in the regulation of pristinamycin I (PI) by affecting the supply of one of seven amino acid precursors, L-phenylglycine, in Streptomyces pristinaespiralis. To our knowledge, this is the first report describing the interplay between PAA catabolism and antibiotic biosynthesis in Streptomyces strains. Considering that the PAA catabolic pathway and its regulation by PaaR are widespread in antibiotic-producing actinomycetes, it could be suggested that PaaR-dependent regulation of antibiotic biosynthesis might commonly exist.

Regulation of the expression of histone H3.3 by differential polyadenylation.

Previously we have shown that the 3' untranslated regions (UTRs) of the replacement histone genes H3.3.A and H3.3B of Drosophila melanogaster differ in their nucleotide sequences and have different polyadenylation sites. To understand their functional relevance, which might explain the presence and evolutionary conservation of 2 different H3.3 genes, green fluorescent protein (GFP) constructs with different 3' UTR sections were studied by the expression of GFP as a marker protein. Here we show that the polyadenylation signals modify the cell-specific translation of the histone replacement variants in testes and ovaries. The H3.3A gene may be required to provide postmeiotic histone H3.3 in the male germ line in transition to chromatin packaging in sperm.