Single-cell and transcriptome analysis reveals TAL cells in diabetic nephropathy.

Diabetic nephropathy is a global public health concern with multifaceted pathogenesis, primarily involving hypertension. Excessive activation of AT1R has been strongly associated with hypertension onset and progression in diabetic nephropathy. This study aimed to conduct thick ascending limb cell single-cell and transcriptomic analysis in diabetic nephropathy, including screening for biological markers, cellular communication, and immune infiltration, to identify potential biomarkers and effective means for prevention and treatment. By using high-dimensional weighted gene co-expression network analysis, least absolute shrinkage and selection operator, machine learning, neural deconvolution, quasi-chronological analysis, non-negative matrix factorization clustering, and monocyte chemotactic protein-induced counter, we identified 7 potential thick ascending limb cell biomarkers for diabetic nephropathy and elucidated the bone morphogenetic protein pathway's regulation of thick ascending limb cells through podocyte epithelial cells and podocyte cells. The study also highlighted the role of COBL, PPARGC1A, and THSD7A in non-negative matrix factorization clustering and their relationship with thick ascending limb cell immunity in diabetic nephropathy. Our findings provide new insights and avenues for managing diabetic nephropathy, ultimately alleviating the burden on patients and society.

Neuropsychiatric features of Parkinson's disease in the era prior to the use of dopaminergic therapies.

BACKGROUND: Psychosis in Parkinson's disease includes hallucinations and delusions. Other non-psychotic neuropsychiatric features include depression, anxiety and apathy. There is currently controversy over whether psychosis in Parkinson's is an intrinsic part of the disorder or the result of dopaminergic medications. This study aimed to examine a historical cohort of individuals with Parkinson's prior to the use of dopaminergic therapy to assess the prevalence of psychotic and other neuropsychiatric features. METHODS: The case notes of patients with Parkinson's disease admitted to the National Hospital for Neurology and Neurosurgery, London between 1924 and 1946 were examined. Demographic and clinical variables were extracted along with any neuropsychiatric features. Cases meeting criteria for encephalitis lethargica were excluded. RESULTS: 115 cases of individuals with Parkinson's disease were identified. 58 (41.7%) were female. Mean age was 54.0 (SD 9.6) years and mean time since Parkinson's diagnosis was 5.3 (SD 5.7) years. No individuals met criteria for encephalitis lethargica. No cases of hallucinations or delusions were reported. There was one case of an illusion in a patient who was using anticholinergic medication. Other neuropsychiatric features reported were sleep disorder (present in 10, 8.7%), depression (8, 7.0%), memory impairment (5, 4.3%), impulsivity (4, 3.5%), bradyphrenia (4, 3.5%), impaired attention (3, 2.6%), anxiety (1, 0.9%), fatigue (1, 0.9%) and apathy (1, 0.9%). CONCLUSIONS: Prior to the use of dopaminergic therapies, patients with Parkinson's disease admitted to hospital rarely, if ever, reported psychotic symptoms, although other neuropsychiatric symptoms were more prevalent. The main limitation is that a lack of systematic enquiry about psychotic symptoms may have resulted in underreporting.

Ultrahigh-Strength Porous Ceramic Composites via a Simple Directional Solidification Process.

Porous ceramics possess great application potential in various fields. However, the contradiction between their pores and their strength have significantly hampered their applications. In this study, we present a simple directional solidification process that relies on its in situ pore forming mechanism to fabricate Al2O3/Y3Al5O12/ZrO2 porous eutectic ceramic composites with a highly dense and nanostructured eutectic skeleton matrix and a lotus-type porous structure. The flexural strength of this porous ceramic composite with a porosity of 34% is 497 MPa at ambient temperature, which is a new record of the strength of all current porous ceramics. This strength can remain at 324 MPa when the temperature increases up to 1773 K because of its refined lamellar structure and strong bonding interface. We demonstrate an interesting application of the directional solidification in efficiently preparing the ultrahigh-strength porous ceramic with high purity. The findings will open a window to the strength of porous ceramics.

Characterization and Biological Activities of Four Biotransformation Products of Diosgenin from Rhodococcus erythropolis.

Diosgenin (DSG), a steroidal sapogenin derived from the tuberous roots of yam, possesses multiple biological properties. DSG has been widely used as a starting material for the industrial production of steroid drugs. Despite its significant pharmacological activities, moderate potency and low solubility hinder the medicinal application of DSG. Biotransformation is an efficient method to produce valuable derivatives of natural products. In this work, we performed the biotransformation of DSG using five Rhodococcus strains. Compounds 1-4 were isolated and identified from Rhodococcus erythropolis. Compounds 1 and 2 showed potent cytotoxicity against the A549, MCF-7, and HepG2 cell lines. Compounds 3 and 4 are novel entities, and each possesses a terminal carboxyl group attached to the spiroacetal ring. Remarkably, 4 exhibited significant cell protective effects for kidney, liver, and vascular endothelial cells, suggesting the therapeutic potential of this compound in chronic renal diseases, atherosclerosis, and hypertension. We further optimized the fermentation conditions aiming to increase the titer of compound 4. Finally, the yield of compound 4 was improved by 2.9-fold and reached 32.4 mg/L in the optimized conditions. Our study lays the foundation for further developing compound 4 as a cell protective agent.

Simultaneous Determination of Xanthine and Hypoxanthine Using Polyglycine/rGO-Modified Glassy Carbon Electrode.

A novel electrochemical sensor was developed for selective and sensitive determination of xanthine (XT) and hypoxanthine (HX) based on polyglycine (p-Gly) and reduced graphene oxide (rGO) modified glassy carbon electrode (GCE). A mixed dispersion of 7 µL of 5 mM glycine and 1 mg/mL GO was dropped on GCE for the fabrication of p-Gly/rGO/GCE, followed by cyclic voltammetric sweeping in 0.1 M phosphate buffer solution within -0.45~1.85 V at a scanning rate of 100 mV·s-1. The morphological and electrochemical features of p-Gly/rGO/GCE were investigated by scanning electron microscopy and cyclic voltammetry. Under optimal conditions, the linear relationship was acquired for the simultaneous determination of XT and HX in 1-100 µM. The preparation of the electrode was simple and efficient. Additionally, the sensor combined the excellent conductivity of rGO and the polymerization of Gly, demonstrating satisfying simultaneous sensing performance to both XT and HX.

2D/3D-Shaped Fe0.8Ni0.2S2/ZIF-67 as a Nanozyme for Rapid Measurement of H2O2 and Ascorbic Acid with a Low Limit of Detection.

Metal-organic frameworks (MOFs) can be used as ideal artificial nanozymes for an open structure to transfer substances and products. The nanozymic mechanism of MOFs needs further investigation for wide application. In this manuscript, no peroxidase-like activity was found for ZIF-67 (a kind of MOF), however, it enhanced the peroxidase-like activity of the Fe0.8Ni0.2S2/ZIF-67 composite, in which Fe0.8Ni0.2S2 was the active composition. The catalytic constant (Kcat) is higher at 1.98 (for TMB) and 2.08 (for H2O2) times and the catalytic efficiency (Kcat/Km) is higher at 3.13 (for TMB) and 2.67 (for H2O2) times, than those of Fe0.8Ni0.2S2. The Km value decreased about 85 times (for H2O2) for Fe0.8Ni0.2S2/ZIF-67 than that of horseradish peroxidase (natural enzyme). The mechanism was proposed. The limit of detection of H2O2 for Fe0.8Ni0.2S2/ZIF-67 is 0.039 µM, which is lower by about 18.2 times than that of Fe0.8Ni0.2S2. Simultaneously, Fe0.8Ni0.2S2/ZIF-67 was used to rapidly detect ascorbic acid for only 1.0 min in food monitoring. This study may be important to design a new kind of nanozyme.

Origin of proton induced fluorescence quenching of colloidal carbon dots: reshaping of Schrödinger wavefunctions and huge red shift of transition energy.

The fluorescence quenching by protons is a universal phenomenon but the mechanism remains unclear. Here, we take the fluorescent amide-terminated carbon dots as a prototype to study the proton fluorescence quenching mechanism by using both experiments and time-dependent density functional theory calculations. The study reveals that when an approached proton is captured by the weakly negatively charged fluorophore group of the colloidal carbon dot, it will substantially change the electron wavefunctions owing to the strong proton-electron interaction, and this leads to highly diminished energy gap and resultant fluorescence quenching in the visible spectral region. The protons generated by hydrolysis of various types of metal ions also exhibit fruitful fluorescence quenching and the quenching efficiency is roughly proportional to the hydrolysis constant of the metal ion. This fluorescence quenching mechanism is quite distinct from the conventional ones involving electron or energy transfer.

Stormwater retention performance of green roofs with various configurations in different climatic zones.

Green roof stormwater retention performance is fundamentally related to design configurations and climates. Efficient tools for assessing stormwater retention performance of green roofs with various configurations in different climates are highly desirable for practical applications. In this study, a hydrological model which can be used to simulate dynamic changes in moisture content and evapotranspiration of green roofs is developed and tested (with average Nash-Sutcliffe Efficiency of 0.8197 for calibration and 0.8252 for verification) using monitoring data (2018-2019) of four green roofs with various configurations. The model is applied to simulate long-term (1970-2018) moisture content, actual evapotranspiration, and retention performance of green roofs in eight cities across different climates of China. Green roofs built with engineered soil and Portulaca grandiflora show the largest evapotranspiration and thus provide the largest stormwater retention rates (Rr), while green roofs with light growing medium and Sedum lineare show the lowest evapotranspiration and Rr. Rr of green roofs increases as climate changes from humid to arid. Green roofs at Guangzhou (humid climate) provide the lowest Rr (28% ± 3%) caused by plenty of rainfall (1827 mm), while green roofs at Urumqi (desert climate) show the lowest mean annual actual evapotranspiration (167-269 mm) but provide the largest Rr (84% ± 5%) as a result of the lowest annual rainfall (282 mm). The results highlight that stormwater retention performance of green roofs could be enhanced through configuration optimization. However, a limiting factor in improving green roofs water retention rates may be the peculiarity of local climatic conditions.

An effective enzymatic assay for pH selectively measuring direct and total bilirubin concentration by using of CotA.

In this study, we aimed to develop B. subtilis spore coat protein A (CotA) for the enzymatic determination of bilirubin. Firstly, molecular docking and oxidation kinetic analysis confirmed the feasibility of CotA for oxidizing bilirubin. Secondly, CotA showed pH-preferable oxidization performance to direct bilirubin (DB) in acidic conditions and an alkaline-catalytic oxidation capacity to total bilirubin (TB). Mechanism analysis results confirm that the conformational changes of CotA, DB and UB caused by pH changes are responsible for the selective oxidation of DB and TB by CotA. Then, CotA exhibits better structural characteristics and enzymatic performance than M. verrucaria-derived bilirubin oxidase (Mv-BOD). Besides, the strong anti-interference ability helps CotA adapt to complex catalytic environment in the detection of DB and TB. Our results prove that CotA can be used as a promising candidate bio-enzymatic detection reagent for DB and TB.

Modulating the plasmon-mediated silver oxidation using thiophenol molecules as monitored by in situ SERS spectroscopy.

Effective charge separation is essential in plasmon-mediated photochemistry and is usually achieved by constructing plasmon-semiconductor interfaces, which is usually challenging. In this work, by monitoring the plasmon-mediated silver oxidation with in situ Raman spectroscopy, we demonstrate that the adsorbed thiophenol molecules could modulate the rate of photochemical reactions by tuning the charge separation at the plasmon-molecule interfaces. It is found that the thiophenol molecules with strong electron-withdrawing or donating functional groups could accelerate or decelerate the rate of plasmon-mediated silver oxidation, respectively. Owing to the easy tuning of the electronic structures of organic molecules via substitution, our method provides a versatile and convenient approach for the fine modulation of plasmon-mediated photochemical reactions.

Consistency evaluation between dispensing granule and traditional decoction from Coptidis Rhizoma by using an integrated quality-based strategy.

INTRODUCTION: Dispensing granule, an innovative product of traditional Chinese medicine decoction, is widely practiced in clinic. As a prerequisite to support the clinical medication, quality consistency between dispensing granule and traditional decoction need to be evaluated. Furthermore, a generally applicable strategy for consistency evaluation of dispensing granule is needed. OBJECTIVE: In this study, we aimed to propose an integrated quality-based strategy to assess consistency between dispensing granule and traditional decoction taking Coptidis Rhizoma (CR) as a case study. METHODOLOGY: For chemical consistency evaluation, efficacy-related Coptis alkaloids were quantified with high-performance liquid chromatography (HPLC). The "Mean ± 3SD" of analyte contents in traditional decoction was considered as the criterion of consistency. And, as auxiliary analysis, principal component analysis (PCA) was employed for data visualisation. For biological consistency evaluation, two one-side t-tests and 90% confidence intervals of the geometric mean ratio of antibacterial zone diameter and 50% inhibitory concentration (IC50 ) of α-glucosidase inhibition were calculated. The scope of 80.00% to 125.00% was taken as in vitro bioequivalence interval. It was considered internally consistent with traditional decoction when the chemical and biological indices of dispensing granule fulfilled the preset criteria simultaneously. RESULTS: Eight out of 20 batches of CR dispensing granule were demonstrated consistent with traditional decoction in chemistry and biological activities. CONCLUSIONS: A generally applicable strategy was recommended that integrates chemical and biological characteristics for consistency evaluation of dispensing granule.

Viperin inhibits classical swine fever virus replication by interacting with viral nonstructural 5A protein.

Classical swine fever virus (CSFV) is a single-stranded RNA flavivirus that can cause serious diseases in porcine species, including symptoms of infarction, systemic hemorrhage, high fever, or depression. Viperin is an important interferon-inducible antiviral gene that has been shown to inhibit CSFV, but the exact mechanisms by which it is able to do so remain poorly characterized. In the present study, we determined that CSFV infection led to viperin upregulation in PK-15 cells (porcine kidney cell). When viperin was overexpressed in these cells, this markedly attenuated CSFV replication, with clear reductions in viral copy number after 12 to 48 hours postinfection. Immunofluorescence microscopy revealed that the viral NS5A protein colocalized with viperin in infected cells, and this was confirmed via confocal laser scanning microscopy using labeled versions of these proteins, and by co-immunoprecipitation which confirmed that NS5A directly interacts with viperin. When NS5A was overexpressed, this inhibited the replication of CSFV, and we determined that the radical SAM domain and N-terminal domain of viperin was critical for its ability to bind to NS5A, with the latter being most important for this interaction. Together, our in vitro results highlight a potential mechanism whereby viperin is able to inhibit CSFV replication. These results have the potential to assist future efforts to prevent or treat systemic CSFV-induced disease, and may also offer more general insights into the antiviral role of viperin in innate immunity.

Prediction of the Au4S crystal via a superatom network model: from clusters to solids.

Owing to their unique properties, thiolate-protected gold clusters (denoted as Aun(SR)m) have attracted intense research interest both experimentally and theoretically. The superatom complex (SAC) and superatom network (SAN) models are significantly well-known concepts to explain the electronic stability of Aun(SR)m. Based on the structural characters of Aun(SR)m, the tetrahedral Au4 unit was found to be an elementary building block and used to design a series of tetrahedron-network clusters. In this work, we first build a Au22(µ4-S)(SH)12 cluster consisting of a network of four non-conjugated tetrahedral Au4 units and confirm that it is a local minimum on the potential energy surface by density functional theory calculations. Chemical bonding analysis by the AdNDP method reveals that the electronic structure of Au22(µ4-S)(SH)12 follows the SAN (4 × 2e) model. Based on the structural character of the Au22(µ4-S)(SH)12 cluster, we utilize the diamond lattice as a template to construct a stable Au4S crystal in which each S atom binds to four Au4 superatoms. The computational results demonstrate that the structure has rather good dynamic and thermal stabilities, and it is an indirect semiconductor with a band gap of 2.68 eV at the HSE06 level. Chemical bonding analysis performed by the SSAdNDP method reveals that the Au4S can be seen as a SAN crystal. These bonding patterns and properties of the solid provide references for further investigation of cluster-assembled materials.

H2S mediates apoptosis in response to inflammation through PI3K/Akt/NFκB signaling pathway.

OBJECTIVES: Hydrogen sulfide (H2S) is involved in regulating cell apoptosis and proliferation. However, The effects and mechanism of H2S on the apoptosis of mammary epithelial cells that suffer from an inflammatory response remain unknown. RESULTS: An inflammatory cell model was used to explore whether exogenous H2S regulates lipopolysaccharides (LPS)-induced cell proliferation and apoptosis. We found that H2S affected cell viability, the inflammatory response and apoptosis in LPS-treated cells in a concentration-dependent manner. Moreover, exogenous H2S rescued LPS-induced cystathionine γ-lyase (CSE) inhibition and cystathionine ß-synthase (CBS) synthesis. Interestingly, in cells undergoing inflammation-induced apoptosis, H2S activated the PI3K/Akt and NFκB signal pathways both tested concentrations. Akt appeared to be a key crosstalk molecule that played a "bridge" role. CONCLUSIONS: H2S regulates LPS-induced inflammation and apoptosis by activating the PI3K/Akt/NFκB signaling pathway. Hence, NaHS may be clinically useful for preventing or treating mastitis.

Silver Nanowire-Templated Molecular Nanopatterning and Nanoparticle Assembly for Surface-Enhanced Raman Scattering.

Developing simple and cost-efficient methods for fabricating molecular patterns is of great importance in the field of nanoscience and nanotechnology. Here, a simple and convenient method was developed for fabricating nanopatterns composed of positively charged silane molecules by using silver nanowires as templates. The as-obtained silane pattern copies the shape of the silver nanowires and is only 0.7 nm thick, which can later be used for templated assembly of small molecules and nanoparticles of opposite charges. As a proof of concept, the resultant assembly could be further used for surface-enhanced Raman scattering.

Preparation of graphene oxide-montmorillonite nanocomposite and its application in multiple-pollutants removal from aqueous solutions.

It is of interest to develop a novel fabrication method of a mineral adsorbent for wastewater treatment to remove the combination of heavy metal ions and refractory organic contaminants. The crosslinking agent stearyl trimethyl ammonium chloride was added into a suspension of montmorillonite and graphene oxide to implement their recombination to fabricated graphene oxide-montmorillonite nanocomposite (GMN). The fabricated nanocomposite was characterized by X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, Brunauer-Emmett-Teller analysis and zeta potential. Results indicated that GMN exhibited a honeycomb texture, providing the chemical reaction site for the simultaneous adsorption of Pb2+ and p-nitrophenol (PNP). Factors including pH value, contact time, contact temperature and GMN dosage in the adsorption process were crucial for both Pb2+ adsorption and PNP adsorption. The optimum adsorption capacities of Pb2+ and PNP onto GMN were 19.39 mg·g-1 and 14.90 mg·g-1 under the condition of pH = 6, contact temperature 55 °C, contact time 60 min and GMN dosage 0.10 g, respectively. Data from experimental studies on simultaneous adsorption was well described by the pseudo-second-order model. The implementation of this work shows that GMN is a promising material for application in the simultaneous removal of heavy metal ions and refractory organic contaminants.

S100 calcium-binding protein A12 as a diagnostic index for subclinical mastitis in cows.

Diagnosis of subclinical mastitis is very important in management of the dairy industry and improvement of dairy cow productivity. S100A12, that is found in related tissues of mammals, is considered as an index for diagnosing inflammatory reaction. To evaluate whether S100A12 is involved in subclinical mastitis, milk somatic cell mRNA from 276 dairy cows was used to detect the transcriptional level of S100A12 by real-time quantitative polymerase chain reaction. A predictive analysis for mastitis was performed, and the correlation between S100A12 and other subclinical mastitis indicators was also assessed. The transcriptional levels of S100A12 in the milk of cows with mastitis were significantly higher than those in the milk of healthy cows (p < 0.05). The correlation analysis showed that S100A12 was positively associated with the somatic cell count and the sodium and chloride concentrations of milk. In contrast, a negative correlation was found between S100A12 and the potassium concentration and pH of milk. However, no significant correlation was detected between S100A12 and the other parameters, such as protein, lactose, ash, fat, density, Ca2+ and SNF. These results suggested that the S100A12 level in milk may serve as a diagnostic tool for subclinical mastitis in cows without obvious clinical signs.

A Novel Partial Agonist of Peroxisome Proliferator-Activated Receptor γ with Excellent Effect on Insulin Resistance and Type 2 Diabetes.

Partial agonists of peroxisome proliferator-activated receptor γ (PPARγ) reportedly reverse insulin resistance in patients with type 2 diabetes mellitus. In this work, a novel non-thiazolidinedione-partial PPARγ ligand, MDCCCL1636 [N-(4-hydroxyphenethyl)-3-mercapto-2-methylpropanamide], was investigated. The compound displayed partial agonist activity in biochemical and cell-based transactivation assays and reversed insulin resistance. MDCCCL1636 showed a potential antidiabetic effect on an insulin-resistance model of human hepatocarcinoma cells (HepG2). High-fat diet-fed streptozotocin-induced diabetic rats treated with MDCCCL1636 for 56 days displayed reduced fasting serum glucose and reversed dyslipidemia and pancreatic damage without significant weight gain. Furthermore, MDCCCL1636 had lower toxicity in vivo and in vitro than pioglitazone. MDCCCL1636 also potentiated glucose consumption and inhibited the impairment in insulin signaling targets, such as AKT, glycogen synthase kinase 3ß, and glycogen synthase, in HepG2 human hepatoma cells. Overall, our results suggest that MDCCCL1636 is a promising candidate for the prevention and treatment of type 2 diabetes mellitus.

Structure and percolation of one-patch spherocylinders.

When the volume fraction exceeds the threshold, the colloidal particles would form a spanning cluster to realize percolation, which is affected by the shape of the particles, interaction between particles, etc. In this paper, we use the Monte Carlo method to study the structure and percolation of a system of one-patch spherocylinders which have been fabricated recently [Chaudhary et al., J. Am. Chem. Soc., 2012, 134, 12901]. With strong adsorption, one-patch spherocylinders self-assemble into multipods which further make contact with each other to form a percolation network at a high volume fraction, while the percolation network is inhibited by the local structures in a system of one-patch spheres. The main multipods are dipods when the patch angle equals π/3, while they are tetrapods and pentapods when the patch angle equals 2π/3. With enhancing the adsorption, the bigger the patch angle, the more the percolation threshold drops. The orientational order parameter, the distribution of the relative orientation between the nearest neighbors and the probabilities of a spherocylinder owning n adsorbing neighbors have been calculated to analyze the formation and transition of the structures.

Transforming growth factor-ß1 (TGF-ß1) induces mouse precartilaginous stem cell proliferation through TGF-ß receptor II (TGFRII)-Akt-ß-catenin signaling.

Precartilaginous stem cells (PSCs) could self-renew or differentiate into chondrocytes to promote bone growth. In the current study, we aim to understand the role of transforming growth factor-ß1 (TGF-ß1) in precartilaginous stem cell (PSC) proliferation, and to study the underlying mechanisms. We successfully purified and primary-cultured PSCs from the neonate mice' perichondrial mesenchyme, and their phenotype was confirmed by the PSC marker fibroblast growth factor receptor-3 (FGFR-3) overexpression. We found that TGF-ß1 induced Akt-glycogen synthase kinase-3ß (GSK3ß) phosphorylation and ß-catenin nuclear translocation in the mouse PSCs, which was almost blocked by TGF-ß receptor-II (TGFRII) shRNA knockdown. Further, perifosine and MK-2206, two Akt-specific inhibitors, suppressed TGF-ß1-induced GSK3ß phosphorylation and ß-catenin nuclear translocation. Akt inhibitors, as well as ß-catenin shRNA knockdown largely inhibited TGF-ß1-stimulated cyclin D1/c-myc gene transcription and mouse PSC proliferation. Based on these results, we suggest that TGF-ß1 induces Akt activation to promote ß-catenin nuclear accumulation, which then regulates cyclin D1/c-myc gene transcription to eventually promote mouse PSC proliferation.