Integrating porphyrin-based nanoporous organic polymers with electrochemical aptasensors for ultratrace detection of kanamycin.

The synthesis and characterization of two new porphyrin-based porous organic polymers (POPs) via Sonogashira cross-coupling reaction and leverage the two obtained POPs is reported for the fabrication of electrochemical aptasensors to detect kanamycin at an ultratrace level. The resultant electrochemical aptasensor demonstrates a high linear relationship with the logarithmic value of kanamycin concentration in the range 5 × 10-5-5 µg/L with the limit of detection of 17.6 pg/L or 36.3 fM. During the analysis of real samples from milk and river, a relative standard deviation of less than 4.39%, and good recovery values in the range 97.0-105% were obtained.

Mapping enhancer and chromatin accessibility landscapes charts the regulatory network of Alzheimer's disease.

BACKGROUND: Enhancers are regulatory elements that target and modulate gene expression and play a role in human health and disease. However, the roles of enhancer regulatory circuit abnormalities driven by epigenetic alterations in Alzheimer's disease (AD) are unclear. METHODS: In this study, a multiomic integrative analysis was performed to map enhancer and chromatin accessibility landscapes and identify regulatory network abnormalities in AD. We identified differentially methylated enhancers and constructed regulatory networks across brain regions using AD brain tissue samples. Through the integration of snATAC-seq and snRNA-seq datasets, we mapped enhancers with DNA methylation alterations (DMA) and chromatin accessibility landscapes. Core regulatory triplets that contributed to AD neuropathology in specific cell types were further prioritized. RESULTS: We revealed widespread DNA methylation alterations (DMA) in the enhancers of AD patients across different brain regions. In addition, the genome-wide transcription factor (TF) binding profiles showed that enhancers with DMA are pervasively regulated by TFs. The TF-enhancer-gene regulatory network analysis identified core regulatory triplets that are associated with brain and immune cell proportions and play important roles in AD pathogenesis. Enhancer regulatory circuits with DMA exhibited distinct chromatin accessibility patterns, which were further characterized at single-cell resolutions. CONCLUSIONS: Our study comprehensively investigated DNA methylation-mediated regulatory circuit abnormalities and provided novel insights into the potential pathogenesis of AD.

Novel Flavonoid Photoswitchable "Turn-On" Fluorescent Chemosensors: Synthesis of Bromo Flavonols for Nanomolar Aluminum Ion Detection and Cellular Imaging, among Other Applications.

Aluminum (Al), a non-essential element in living systems, can potentially cause chronic toxicity. Therefore, it is crucial to have a specific and sensitive method for detecting Al3+ in order to assess its risk to life. In this study, we designed and synthesized a novel fluorescent probe (IV) based on bromoflavonol. Upon binding to Al3+, probe IV exhibits a blue shift in emission and enhanced fluorescence, making it suitable for Al3+ detection. Our UV-Vis absorption and fluorescence emission spectra demonstrate that probe IV has high selectivity and sensitivity towards Al3+ while being immune to interference from other metal ions. Through fluorescence titration, we determined that the detection limit (LOD) of probe IV for Al3+ is 1.8 × 10-8 mol/L. Job's curve and 1 H NMR titration further confirmed a 1:1 binding stoichiometry between probe IV and Al3+. Additionally, using DFT (Density Functional Theory), we calculated the energy gap difference between IV and IV + Al3+ and found that the complex formed by probe IV and Al3+ is more stable than IV alone. We successfully detected Al3+ in tap water and river water from the middle regions of the Han River, achieving recoveries of over 96% using this probe. This demonstrates its potential for quantitative detection of Al3+ in environmental water samples. Moreover, we successfully used the probe for imaging Al3+ in MG63 cells, suggesting its potential application in biological imaging.

A simple indanone-based red emission fluorescent probe for the rapid detection of cysteine in vitro and in vivo.

Cysteine is a vital biothiols that plays an important role in numerous physiological and pathological processes. The development of simple molecule tools for detection and analysis Cys in subcellar environment is significant for further exploring their pathophysiological. In this work, a simple but activated fluorescent probe AMIA was constructed with a donor-π-accepter (D- π -A) structure, which using an indanone as the electron-withdrawing unit acting as the fluorophore, dimethylamino group attached to the position 4 of the benzene ring as the electron-donating, two double bonds as the linker group, and the acryloyl ester group as the trigger and response unit. This probe AMIA was exhibited highly selective and sensitive response to Cys over other amino acids and ions under physiological conditions. It was found that AMIA showed a red turn-on fluorescence response at 630 nm towards Cys with a large stroke shift of 170 nm and a very low detection limit of 26.3 nM. HRMS, 1H NMR and TD-DFT calculation further confirmed that the response mechanism is the Cys triggered the addition-cyclization reaction between AMIA' acryloyl group and Cys' sulfhydryl and amino unit, leading to the release of a red fluorescent dye AMIA-OH, which can be identified by naked eyes. Furthermore, AMIA was successfully applied for simultaneous determination of Cys in living cells and zebrafish with lower cytotoxicity and good cell permeability. We hope that this novel indanone-based probe AMIA will provide a new reference for visualized Cys in other complex biological system.

Pharmacokinetics, mass balance, and metabolism of [14C]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension.

TPN171 is a novel phosphodiesterase-5 (PDE5) inhibitor used to treat pulmonary arterial hypertension (PAH) and erectile dysfunction (ED), which currently is undergoing phase II clinical trials in China. In this single-center, single-dose, nonrandomized, and open design study, radiolabeled [14C]TPN171 was used to investigate the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of TPN171 in 6 healthy Chinese male volunteers. Each volunteer was administered a single oral suspension of 10 mg (100 µCi) of [14C]TPN171. We found that TPN171 was absorbed rapidly in humans with a peak time (Tmax) of 0.667 h and a half-life (t1/2) of approximately 9.89 h in plasma. Excretion of radiopharmaceutical-related components was collected 216 h after administration, accounting for 95.21% of the dose (46.61% in urine and 48.60% in feces). TPN171 underwent extensive metabolism in humans. Twenty-two metabolites were detected in human plasma, urine, and feces using a radioactive detector combined with a high-resolution mass spectrometer. According to radiochromatograms, a glucuronide metabolite of O-dealkylated TPN171 exceeded 10% of the total drug-related components in human plasma. However, according to the Food and Drug Administration (FDA) guidelines, no further tests are needed to evaluate the safety of this metabolite because it is a phase II metabolite, but the compound is still worthy of attention. The main metabolic biotransformation of TPN171 was mono-oxidation (hydroxylation and N-oxidation), dehydrogenation, N-dealkylation, O-dealkylation, amide hydrolysis, glucuronidation, and acetylation. Cytochrome P450 3A4 (CYP3A4) mainly catalyzed the formation of metabolites, and CYP2E1 and CYP2D6 were involved in the oxidative metabolism of TPN171 to a lesser extent. According to the incubation data, M1 was mainly metabolized to M1G by UDP-glucuronosyltransferase 1A9 (UGT1A9), followed by UGT1A7 and UGT1A10.

Recent Advances in Metal-Organic-Framework-Based Nanocarriers for Controllable Drug Delivery and Release.

Metal-organic frameworks (MOFs) have a good designability, a well-defined pore, stimulus responsiveness, a high surface area, and a controllable morphology. Up to now, various MOFs have been widely used as nanocarriers and have attracted lots of attention in the field of drug delivery and release because of their good biocompatibility and high-drug-loading capacity. Herein, we provide a comprehensive summary of MOF-based nanocarriers for drug delivery and release over the last five years. Meanwhile, some representative examples are highlighted in detail according to four categories, including the University of Oslo MOFs, Fe-MOFs, cyclodextrin MOFs, and other MOFs. Moreover, the opportunities and challenges of MOF-based smart delivery vehicles are discussed. We hope that this review will be helpful for researchers to understand the recent developments and challenges of MOF-based drug-delivery systems.

Study on time effect of residual pressure and bearing characteristics of jacked pile in saturated silt foundation.

The history of stress in soil mass and pile surface roughness significantly impacts the time effect of residual pressure at the pile end and bearing characteristics of the jacked pile. In this study, the impacts of soil over-consolidation ratio and pile surface roughness on the time effect of residual pressure and bearing characteristics of jacked pile end in saturated silt foundation are explored. Through the independently developed model test device for the vertical bearing characteristics of jacked pile, the driving of jacked pile with different pile surface roughness and static load tests at different resting phases are carried out on saturated silt foundations with different over-consolidation ratios. The model box is cylindrical in shape with a size of 40 cm × 48 cm (inner diameter × height) and is made of transparent tempered glass. The results show that: the increase in surface roughness of jacked pile in saturated silt foundation causes not only the increase in the pile side friction but also the increase in the pile end resistance during the static pressure sinking pile; the change laws on the residual pressure of pile end and limit friction resistance of pile side for jacked pile in saturated silt foundation vary with over-consolidation ratio of soil mass and the pile surface roughness.

Interplay of Environmental Regulation and Local Protectionism in China.

Environmental regulation (ER) and local protectionism (LP) are important policy tools for Chinese local governments to improve the environment and promote growth, respectively, but we know little about their interplay in dealing with pollution-intensive industries and enterprises. Using spatial correlation analysis and spatial panel simultaneous equations models, we investigated the spatial characteristics and interactions of the ER and LP in China's 285 prefectural cities. We found that the high-ER-intensity areas were spreading from the eastern to the central and western regions, and the patterns of LP transited from high in the north and low in the south to high in the west and low in the east. There was a negative correlation spatially between ER and LP. LP could inhibit the increase in ER intensity, while the continuously increasing ER intensity could restrict LP through the competitive behavior from the "race to the bottom" to the "race to the top" among local governments. The effect of ER restricting LP was significant from 2008 to 2013 and prominent in the east, which was dominated by "race to the top" competition, while LP had a greater inhibitory effect on ER in the central and western regions, which preferred to obtain tax revenues from pollution-intensive industries. The results imply that removing the roots of local protectionism, improving the environmental governance system, and formulating differentiated regional environmental regulatory measures will help local governments balance economic growth and environmental protection.

Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects.

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25-800 mg. T1/2 was within 4.80-6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.

CdS and Ag synergistically improved the performance of g-C3N4 on visible-light photocatalytic degradation of pollution.

CdS-AgO@g-C3N4 nanocomposites were successfully synthesized and characterized by XRD, N2 physical adsorption, XPS, SEM, TEM, EDX, and UV-Vis DRS (various technical means). The adsorption light range of as-prepared materials could extend to the whole visible light region with the addition of Ag. Silver can act as a bridge to facilitate the separation of electrons and holes, thereby greatly enhancing the photocatalytic activity of CdS-AgO@g-C3N4, enabling the maximum degradation efficiency of salicylic acid in water to reach 92.8% under visible light. Peroxy radical is the most important radical in the photocatalytic reaction process, followed by electron and hole, while hydroxyl radical has almost no effect. In addition, the mechanism of photocatalytic process was also explored.

A Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TPN171H, a Novel Phosphodiesterase Type 5 Inhibitor, in Healthy Subjects.

PURPOSE: TPN171H is a novel, potent and selective phosphodiesterase type 5 (PDE5) inhibitor for the treatment of pulmonary arterial hypertension (PAH). The objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of TPN171H in healthy subjects after single and multiple dosing, in addition, to investigate the food effect on pharmacokinetics and safety of TPN171H. METHODS: The entire study was comprised of three parts: Part I (single ascending-dose study), Part II (food effect study), and Part III (multiple ascending-dose study). A total of 63 healthy subjects were enrolled in the study. TPN171H tablet or placebo was administered per protocol requirements. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events. RESULTS: In Part I, AUC and Cmax were proved to be linear within the 5-30 mg dose range. T1/2 of TPN171H was 8.02-10.88 h. In Part II, we figured out that TPN171H administration under fed condition could decrease Cmax, prolong Tmax, but had no effect on AUC. In Part III, the accumulation ratio at steady-state for AUC and Cmax indicated that TPN171H has a slight accumulation upon repeated dosing. Subjects were generally tolerable after TPN171H administration. Compared with other PDE5 inhibitors, TPN171H was found to have no impact on blood pressure and color discrimination. CONCLUSION: TPN171H was safe and generally tolerated in healthy subjects. Based on the half-life, food effect, and safety profile of TPN171H, we recommend a once-daily, post-meal administration of TPN171H in subsequent clinical studies in healthy subjects and patients with PAH.

Weinreb Amide Approach to the Practical Synthesis of a Key Remdesivir Intermediate.

Currently, remdesivir is the first and only FDA-approved antiviral drug for COVID-19 treatment. Adequate supplies of remdesivir are highly warranted to cope with this global public health crisis. Herein, we report a Weinreb amide approach for preparing the key intermediate of remdesivir in the glycosylation step where overaddition side reactions are eliminated. Starting from 2,3,5-tri-O-benzyl-d-ribonolactone, the preferred route consisting of three sequential steps (Weinreb amidation, O-TMS protection, and Grignard addition) enables a high-yield (65%) synthesis of this intermediate at a kilogram scale. In particular, the undesirable PhMgCl used in previous methods was successfully replaced by MeMgBr. This approach proved to be suitable for the scalable production of the key remdesivir intermediate.

Mesoporous magnetic g-C3N4 nanocomposites for photocatalytic environmental remediation under visible light.

Mesoporous magnetic Fe3O4/g-C3N4 nanocomposites were synthesized by a facile precipitation method using deionized water as solution. And the prepared magnetic materials were characterized by mean of various detection methods. At the same time, the photocatalytic activity of the synthetic material as photocatalyst under visible light was tested by taking the degradation of rhodamine B in water as a mark. Results show that as-synthesized Fe3O4/g-C3N4 nanocomposites have high specific surface areas of about 5-10.5 times that of pure g-C3N4 and high saturation magnetizations, which can ensure the smooth recovery of used nanomaterials under the action of external magnetic field. The addition of Fe3O4 greatly extents the response range of g-C3N4 nanomaterials to visible light and reduces the recombination rate of photoinduced electron-hole pairs. Meanwhile, the photocatalytic activity of the synthetic materials increases so that the degradation ratio of rhodamine B in water reached 97.6% after 4 h visible light irradiation. Furthermore, prepared magnetic Fe3O4/g-C3N4 nanocomposites have also excellent stability so that the degradation ratio of rhodamine B was almost not reduce after 5 times of continuous reuse of photocatalyst. Free radical scavenging experiments shows that hydroxyl groups are the main free radicals of photocatalytic reaction, peroxyradicals and holes play the secondary role. Therefore, it can be predicted that the synthesized mesoporous magnetic Fe3O4/g-C3N4 nanomaterials will have a broad application prospect in environmental remediation.

Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir.

The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here we report the cryo-electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resolution and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.

Fabrication of CdS-SBA-15 nanomaterials and their photocatalytic activity for degradation of salicylic acid under visible light.

CdS-SBA-15 nanomaterials were synthesized by solvothermal method using cadmium nitrate as cadmium source and thiourea as sulfur source. The properties of as-prepared materials were characterized by means of XRD, FTIR, TEM, XPS, N2 physisorption, UV-Vis DRS and PL spectra, etc. The results show as-synthesized materials have partially ordered mesoporous structure, larger specific surface area, and higher content of CdS and good crystallinity. The combination of SBA-15 and CdS did almost no reduction in the absorption light range of CdS, but greatly increased the photocapacity of the composite. The synergistic effect of CdS and SBA-15 leads to improving the photocatalytic degradation activity of salicylic acid under visible light. When the photocatalyst was 30 mg (0.75 g/L) and the concentration of salicylic acid was 10 mg/L, the maximum degradation efficiency of salicylic acid was 84.93% after 6 h of light. Photocatalytic reaction has a lower activation energy (2.90 kJ/mol), activation enthalpy (3.13 kJ/mol) and activation entropy (-281.00 J/(mol K)). The photocatalytic mechanism study demonstrates that superoxide radicals (O2•-) are the most key active species, e- and h+ have something to do with the photocatalytic reaction, while ·OH has little to do with the photocatalytic reaction. In sum, the protection effect of SBA-15 on CdS nanomaterials makes the composite have a higher photolumination intensity and a higher photocatalytic activity.

Pharmacokinetics-Driven Optimization of 4(3 H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension.

Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.

Continuation of structure-activity relationship study of novel benzamide derivatives as potential antipsychotics.

A series of benzamide derivatives possessing potent dopamine D2 , serotonin 5-HT1A , and 5-HT2A receptor properties were synthesized and evaluated as potential antipsychotics. Among them, 5-(4-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)butoxy)-N-cyclopropyl-2-fluorobenzamide (4k) held the best pharmacological profile. It not only exhibited potent and balanced activities for the D2 , 5-HT1A , and 5-HT2A receptors, but was also endowed with low to moderate activities for the 5-HT2C , H1 , and M3 receptors, suggesting a low propensity for inducing weight gain or diabetes. In animal models, compound 4k reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy or muscle relaxation induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, 4k was selected as a candidate for further development.

A novel thermometer-type hydrogel senor for glutathione detection.

A thermometer-type visual sensor for glutathione (GSH) sensing was developed with stimulus-responsive fluorescent hydrogel which was obtained by using 5, 6-bicarboxylic fluorescein crossli`nked partly ammoniated polyacrylamide. Various experimental parameters such as the particle size of hydrogel, buffer solution and swelling time were optimized. It is accessible to measure the volume change of hydrogel with the sensor by reading the graduation on a pipette like thermometer with naked eye. The concentration of the GSH depended on the volume in a certain range as the signal. Satisfactory agreements between the sensor and HPLC results for atuomolan tablet assays indicated the capability of the thermometer-type sensors for the analysis of real samples. These findings proved the utility of stimulus-responsive, intelligent hydrogel and the suitability of thermometer-style visual sensor design for quantitative assays.

Characterization of the complete mitochondrial genome of Onychostoma macrolepis (Teleostei: Cyprinidae).

In this study, the entire mitogenome sequence of the O. macrolepis has been sequenced. However, its systematic classification is still undetermined. The complete mitochondrial genome is 16,621bp, which includes 37 genes (13 protein-coding genes, 2 rRNA genes and 22 tRNA genes) and 1 control region.The overall base composition is 34.52% A, 19.01% T, 25.58% C, 20.89% G, showing AT rich feature (55.76%). Its structure type is similar to the mitogenome of Cyprinidae. Phylogenetic tree showed that O. macrolepis belong to Barbinae.