Pathogenicity and landscape of differential gene expression in mice orally infected with clinical coxsackievirus A6 (CA6).

Hand, foot, and mouth disease (HFMD) is caused by more than 20 pathogenic enteroviruses belonging to the Picornaviridae family and Enterovirus genus. Since the introduction of the enterovirus-71 (EV71) vaccine in 2016, the number of HFMD cases caused by EV71 has decreased. However, cases of infections caused by other enteroviruses, such as coxsackievirus A6 (CA6) and coxsackievirus A10, have been increasing accordingly. In this study, we used a clinical isolate of CA6 to establish an intragastric infection mouse model using 7-day-old mice to mimic the natural transmission route, by which we investigated the differential gene expression profiles associated with virus infection and pathogenicity. After intragastric infection, mice exhibited hind limb paralysis symptoms and weight loss, similar to those reported for EV71 infection in mice. The skeletal muscle was identified as the main site of virus replication, with a peak viral load reaching 2.31 × 107 copies/mg at 5 dpi and increased infiltration of inflammatory cells. RNA sequencing analysis identified differentially expressed genes (DEGs) after CA6 infection. DEGs in the blood, muscle, brain, spleen, and thymus were predominantly enriched in immune system responses, including pathways such as Toll-like receptor signaling and PI3K-Akt signaling. Our study has unveiled the genes involved in the host immune response during CA6 infection, thereby enhancing our comprehension of the pathological mechanism of HFMD.IMPORTANCEThis study holds great significance for the field of hand, foot, and mouth disease (HFMD). It not only delves into the disease's etiology, transmission pathways, and severe complications but also establishes a novel mouse model that mimics the natural coxsackievirus A6 infection process, providing a pivotal platform to delve deeper into virus replication and pathogenic mechanisms. Additionally, utilizing RNA-seq technology, it unveils the dynamic gene expression changes during infection, offering valuable leads for identifying novel therapeutic drug targets. This research has the potential to enhance our understanding of HFMD, offering fresh perspectives for disease prevention and treatment and positively impacting children's health worldwide.

Sensory-motor neuropathy in Mfn2 T105M knock-in mice and its reversal by a novel piperine-derived mitofusin activator.

Mitochondrial dysfunction is a hallmark of many genetic neurodegenerative diseases, but therapeutic options to reverse mitochondrial dysfunction are limited. While recent studies support the possibility of improving mitochondrial fusion/fission dynamics and motility to correct mitochondrial dysfunction and resulting neurodegeneration in Charcot-Marie-Tooth disease (CMT) and other neuropathies, the clinical utility of reported compounds and relevance of pre-clinical models are uncertain. Here, we describe motor and sensory neuron dysfunction characteristic of clinical CMT type 2A in a CRISPR/Casp-engineered Mfn2 Thr105Met (T105M) mutant knock-in mouse. We further demonstrate that daily oral treatment with a novel mitofusin activator derived from the natural product piperine can reverse these neurological phenotypes. Piperine derivative 8015 promoted mitochondrial fusion and motility in Mfn2-deficient cells in a mitofusin-dependent manner, and reversed mitochondrial dysfunction in cultured fibroblasts and reprogrammed motor neurons from a human CMT2A patient carrying the MFN2 T105M mutation. Like previous mitofusin activators, 8015 exhibited stereospecific functionality, but the more active stereoisomer, 8015-P2, is unique in that it has sub-nanomolar potency and undergoes entero-hepatic recirculation which extends its in vivo half-life. Daily administration of 8015-P2 to Mfn2 T105M knock-in mice for 6 weeks normalized neuromuscular and sensory dysfunction and corrected histological/ultrastructural neurodegeneration and neurogenic myoatrophy. These studies describe a more clinically relevant mouse model of CMT2A and an improved mitofusin activator derived from piperine. We posit that 8015-P2 and other piperine derivatives may benefit CMT2A or other neurodegenerative conditions wherein mitochondrial dysdynamism plays a contributory role. Significance Statement Mitochondrial dysfunction is widespread and broadly contributory in neurodegeneration, but difficult to target therapeutically. Here, we describe 8015-P2, a new small molecule mitofusin activator with ~10-fold greater potency and improved in vivo pharmacokinetics vs comparators, and demonstrate its rapid reversal of sensory and motor neuron dysfunction in an Mfn2 T105M knock-in mouse model of Charcot-Marie-Tooth disease type 2A. These findings further support the therapeutic approach of targeting mitochondrial dysdynamism in neurodegeneration.

Hyperkalemia burden and treatment patterns in Chinese patients on hemodialysis: final analysis of a prospective multicenter cohort study (PRECEDE-K).

OBJECTIVES: Patients with end-stage renal disease (ESRD) on hemodialysis (HD) are at risk for hyperkalemia (HK), associated with cardiac arrhythmia and sudden death. Data on the burden of HK and management techniques among HD patients in China are still scarce. This study assessed the treatment modalities, recurrence, and prevalence of HK in Chinese HD patients. METHODS: In this prospective cohort study conducted from May 2021 to July 2022, patients aged ≥18 years who had ESRD and were on HD were enrolled from 15 centers in China (up to 6 months). RESULTS: Overall, 600 patients were enrolled. At the baseline visit, mean (± standard deviation) urea reduction ratio was 68.0% ± 9.70 and Kt/V was 1.45 ± 0.496. Over 6 months, 453 (75.5%) patients experienced HK, of whom 356 (78.6%) recurred. Within 1, 2, 3, 4, 5, and 6 months, 203 (44.8%), 262 (57.8%), 300 (66.2%), 326 (72.0%), 347 (76.6%), and 356 (78.6%) patients had at least one HK recurrence event, respectively. The proportions of patients with ≥1, 2, 3, 4, 5, or 6 HK recurrence events were 356 (78.6%), 306 (67.5%), 250 (55.2%), 208 (45.9%), 161 (35.5%), and 110 (24.3%), respectively. Among the 453 patients who experienced HK, only 24 (5.3%) were treated with potassium binders: seven (1.5%) with sodium polystyrene sulfonate, 13 (2.9%) with calcium polystyrene sulfonate, and six (1.3%) with sodium zirconium cyclosilicate. CONCLUSION: Since HK is a chronic illness, long-term care is necessary. Patients on HD should have effective potassium management on non-dialysis days, yet our real-world population rarely used potassium binders. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04799067.

Mitochondrial Dysfunction and Pharmacodynamics of Mitofusin Activation in Murine Charcot-Marie-Tooth Disease Type 2A.

Mitofusin (MFN) 1 and MFN2 are dynamin GTPase family mitochondrial proteins that mediate mitochondrial fusion requiring MFN conformational shifts, formation of macromolecular complexes on and between mitochondria, and GTP hydrolysis. Damaging MFN2 mutations cause an untreatable, largely pediatric progressive peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease type 2A. We used small molecule allosteric mitofusin activators that promote MFN conformations favoring fusion to interrogate the effects of MFN2 conformation and GTPase activity on MFN2-mediated mitochondrial fusion and motility in vitro. We translated these findings in vivo by defining dose-dependent pharmacodynamic and disease-modifying effects of mitofusin activators in murine CMT2A. MFN2 catalytic GTPase activity and MFN2 conformational switching are essential for mitochondrial fusion, but the two processes are separate and dissociable. We report the first concentration-response relationships for mitofusin activators to stimulate mitochondrial transport through CMT2A neuronal axons, which is similar to their stimulation of mitochondrial fusion. In CMT2A mice, intermittent (daily short acting) and sustained (twice daily long acting) mitofusin activation were equally effective in reversing neuromuscular degeneration. Moreover, acute dose-dependent pharmacodynamic effects of mitofusin activators on mitochondrial transport through CMT2A neuronal axons anticipated those for long-term reversal of neurodegenerative phenotypes. A crossover study showed that CMT2A neuronal deficits recurred after mitofusin activators are discontinued, and revealed that CMT2A can be ameliorated by mitofusin activation even in old (>74 week) mice. These data add to our understanding of mitochondrial dysfunction induced by a CMT2A MFN2 GTPase mutation and provide additional information supporting the approach of pharmacological mitofusin activation in CMT2A. SIGNIFICANCE: This study interrogated the roles of MFN2 catalytic activity and allosteric activation on impaired mitochondrial fusion and neuronal transport as they impact an untreatable peripheral neuropathy caused by MFN2 mutations, Charcot-Marie-Tooth disease type 2A. The results mechanistically link mitochondrial fusion and motility to the relaxed MFN2 protein conformation and correction of mitochondrial abnormalities to in vivo reversal of neurodegeneration in murine CMT2A.

Efficacy and Safety of Paclitaxel-Coated Balloon Angioplasty for Dysfunctional Arteriovenous Fistulas: A Multicenter Randomized Controlled Trial.

RATIONALE & OBJECTIVE: Previous studies have illustrated the potential superiority of drug-coated balloons (DCBs) in maintaining patency after initial angioplasty for arteriovenous fistula (AVF) dysfunction due to stenosis. Our trial evaluated the efficacy and safety of DCBs for preventing fistula restenosis in Chinese hemodialysis patients. STUDY DESIGN: Multicenter, prospective, randomized, open-label, blinded end point, controlled trial. SETTINGS & PARTICIPANTS: A total of 161 hemodialysis patients with fistula dysfunction from 10 centers in China. INTERVENTION: Participants were randomized 1:1 to treatment with initial dilation followed by DCB angioplasty or conventional high-pressure balloon (HPB) angioplasty. OUTCOMES: The primary end point was target lesion primary patency defined as the target lesion intervention-free survival in conjunction with an ultrasonography-measured peak systolic velocity ratio (PSVR) ≤2.0 at 6 months. The secondary end points included 1) device, technical, clinical, and procedural success; 2) major adverse events; 3) degree of target lesion stenosis at 6 months; and 4) clinically driven target lesion and target shunt revascularization within 12 months. RESULTS: The percentage with target lesion primary patency as defined by a PSVR ≤2.0 was higher in the DCB group than in the control group (65% vs 37%, respectively; rate difference, 28% [95% CI, 13%-43%]; P <0.001) at 6 months. The target lesion and target shunt intervention-free survival of the DCB group were not superior to those of the control group at 6 months (P = 0.3 and P = 0.2, respectively) but were superior at 12 months (target lesion intervention-free survival: 73% for DCB vs 58% for control [P = 0.04]; target shunt intervention-free survival: 73% for DCB vs 57% for control [P = 0.04]). The average degree of target lesion stenoses at 6 months was not significantly different between the 2 groups (44% ± 16% for DCB vs 49% ± 18% for control; P = 0.09). There were no significant differences in major adverse events or in device, technical, clinical, or procedural success rates between the groups. LIMITATIONS: Small sample size; short follow-up period; procedural differences between the 2 groups such as unequal inflation times and balloon lengths. CONCLUSIONS: Compared to conventional HPB angioplasty, DCB treatment achieved superior primary patency defined using PSVR measured at 6 months and superior intervention-free survival of both the target lesion and the target shunt at 12 months without evidence of greater adverse events. FUNDING: Funded by ZhuHai Cardionovum Medical Device Co., Ltd. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02962141.

Incidence of interstitial pneumonitis in non-Hodgkin's lymphoma patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximab.

Pneumonitis is a rare but severe and potentially fatal adverse effect in chemotherapy of lymphoma. This study is aimed to investigate the incidence of interstitial pneumonitis in non-Hodgkin's lymphoma (NHL) patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximab. Lymphoma patients were retrospectively reviewed, and eligible patients were included in this study. According to the chemotherapy regimens, patients were classified in four groups: combination of vincristine, cyclophosphamide, doxorubicin, and prednisone (CHOP group) with rituximab (RCHOP group) and combination of vincristine, cyclophosphamide, pegylated liposomal doxorubicin and prednisone (CDOP group) with rituximab (RCDOP group). Incidence and severity of interstitial pneumonitis were compared among the four groups. Among 757 patients reviewed, 207 patients were included in final analysis. Thirteen patients developed chemotherapy-induced interstitial pneumonitis, and the mean cycle of chemotherapy before the onset of pneumonitis was 4. Incidence rates of pneumonitis were 0, 1.8, 17.4, and 21.1% in CHOP, RCHOP, CDOP, and RCDOP groups, respectively (p < 0.001). The mean grades of pneumonitis were 0, 2, 2.5, and 3 in four groups, respectively (p < 0.001). After adjustment of confounders, chemotherapy regimens (OR 3.491, 95% CI 1.527-7.981, p = 0.003) and neutropenia in previous cycles (OR 2.186, 95% CI 1.281-3.731, p = 0.004) were independently associated with the incidence of pneumonitis. Interstitial pneumonitis should be highlighted in NHL patients who received more than 4 cycles of RCDOP chemotherapy regimen, especially in those who had grade 4 neutropenia in the previous cycles of chemotherapy.

The Milk of Cows Immunized with Trivalent Inactivated Vaccines Provides Broad-Spectrum Passive Protection against Hand, Foot, and Mouth Disease in Neonatal Mice.

Hand, foot, and mouth disease (HFMD) is a contagious viral infection predominantly affecting infants and young children, caused by multiple enteroviruses, including Enterovirus 71 (EV71), Coxsackievirus A16 (CA16), Coxsackievirus A10 (CA10), and Coxsackievirus A6 (CA6). The high pathogenicity of HFMD has garnered significant attention. Currently, there is no specific treatment or broad-spectrum preventive measure available for HFMD, and existing monovalent vaccines have limited impact on the overall incidence or prevalence of the disease. Consequently, with the emergence of new viral strains driven by vaccine pressure, there is an urgent need to develop strategies for the rapid response and control of new outbreaks. In this study, we demonstrated the broad protective effect of maternal antibodies against three types of HFMD by immunizing mother mice with a trivalent inactivated vaccine targeting EV71, CA16, and CA10, using a neonatal mouse challenge model. Based on the feasibility of maternal antibodies as a form of passive immunization to prevent HFMD, we prepared a multivalent antiviral milk by immunizing dairy cows with the trivalent inactivated vaccine to target multiple HFMD viruses. In the neonatal mouse challenge model, this immunized milk exhibited extensive passive protection against oral infections caused by the three HFMD viruses. Compared to vaccines, this strategy may offer a rapid and broadly applicable approach to providing passive immunity for the prevention of HFMD, particularly in response to the swift emergence and spread of new variants.

Pathogenicity and transcriptomic profiling reveals immunology molecular hallmarks after CA10 virus infection.

BACKGROUND: Hand, foot and mouth disease (HFMD) is a common infectious disease caused by viral infection by a variety of enteroviruses, with coxsackievirus A 10 (CA10) having become more prevalent in recent years. METHODS: In this study, models of CA10 infection were established in 7-day-old Institute of Cancer Research (ICR) mice by intraperitoneal injection to analyze the pathogenicity of the virus. RNA sequencing analysis was used to screen the differentially expressed genes (DEGs) after CA10 infection. Coxsackievirus A 16 (CA16) and enterovirus 71 (EV71) infections were also compared with CA10. RESULTS: After CA10 virus infection, the mice showed paralysis of the hind limbs at 3 days post infection and weight loss at 5 days post infection. We observed viral replication in various tissues and severe inflammatory cell infiltration in skeletal muscle. The RNA-sequencing analysis showed that the DEGs in blood, muscle, thymus and spleen showed heterogeneity after CA10 infection and the most up-regulated DEGs in muscle were enriched in immune-related pathways. Compared with CA16 and EV71 infection, CA10 may have an inhibitory effect on T helper (Th) cell differentiation and cell growth. Additionally, the common DEGs in the three viruses were most enriched in the immune system response, including the Toll-like receptor pathway and the nucleotide-binding and oligomerization domain (NOD)-like pathway. CONCLUSIONS: Our findings revealed a group of genes that coordinate in response to CA10 infection, which increases our understanding of the pathological mechanism of HFMD.

Drug-Coated Balloon Angioplasty for Dysfunctional Arteriovenous Hemodialysis Fistulae: A Randomized Controlled Trial.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of paclitaxel-coated balloons (AcoArt Orchid) in treating dysfunctional arteriovenous fistulae. METHODS: The drug-eluting balloon for arteriovenous (AV) fistula in China trial was a prospective, multicenter, randomized controlled study. Patients who had ≥50% venous stenosis of the AV fistula and symptoms indicating significant hemodynamic changes were included. After successful predilation with a high-pressure balloon (residual stenosis ≤30%), patients were randomized 1:1 to either a paclitaxel-coated balloon or an uncoated control balloon. The primary efficacy outcome was assessed at 6 months, and safety assessment was conducted within 30 days of the procedure. The 12-month results were also analyzed. RESULTS: The study included 244 patients, equally distributed between the two groups. The primary target lesion patency was 91% (106/116) for the drug-coated balloon (DCB) group and 67% (79/118) for the plain balloon catheter group, representing a difference of 24.63% (95% confidence interval, 14.68 to 34.58; P < 0.001). The secondary efficacy end point was primary target lesion patency at 12 months, which was 66% (74/112) for the DCB group and 46% (52/112) for the plain balloon catheter group (95% confidence interval, 6.57 to 32.08; P = 0.004). The mean number of reinterventions per patient to maintain target lesion patency during the 12 months after the index procedure was 0.39 (48/122) in the DCB group and 0.77 (94/122) in the plain balloon catheter group ( P = 0.001). The primary safety end point did not differ between groups ( P = 0.25). CONCLUSIONS: AcoArt Orchid DCB showed better primary patency rates compared with plain balloon angioplasty for treating stenotic lesions in dysfunctional hemodialysis AV fistulae at 6 and 12 months. It required fewer repeated interventions and had comparable safety in 1 year. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: AcoArt III/Arterio-venous Fistula in China, NCT03366727 .

Zr(H2O)2EDTA modulated luminescent carbon dots as fluorescent probes for fluoride detection.

A novel fluorescent probe (Zr(CDs-COO)(2)EDTA) has been designed for fluoride ion (F(-)) content detection based on the competitive ligand reactions carried out between the carboxylate groups (-COOH) on the surface of the luminescent carbon dots (CDs) and F(-) coordinated to Zr(H(2)O)(2)EDTA. The strong and stable fluorescence signal of this probe was quenched upon the addition of F(-) as a result of the formation of the non-fluorescent complex Zr(F)(2)EDTA, due to the stronger affinity of F(-) than the -COOH in the CDs to Zr(IV). The fluorescence change (ΔF) in this process was linear with respect to the content of F(-), ranging from 0.10 µM to 10 µM. The probe has been applied to F(-) detection in toothpaste and water samples with satisfactory results. Moreover, the mechanism of this Zr(H(2)O)(2)EDTA modulated fluorescent probe for the detection of F(-) was also discussed.

Chitosan-based hydrogel wound dressing: From mechanism to applications, a review.

As promising biomaterials, hydrogels are widely used in the medical engineering field, especially in wound repairing. Compared with traditional wound dressings, such as gauze and bandage, hydrogel could absorb and retain more water without dissolving or losing its three-dimensional structure, thus avoiding secondary injury and promoting wound healing. Chitosan and its derivatives have become hot research topics for hydrogel wound dressing production due to their unique molecular structure and diverse biological activities. In this review, the mechanism of wound healing was introduced systematically. The mechanism of action of chitosan in the first three stages of wound repair (hemostasis, antimicrobial properties and progranulation), the effect of chitosan deacetylation and the molecular weight on its performance are analyzed. Additionally, the recent progress in intelligent and drug-loaded chitosan-based hydrogels and the features and advantages of chitosan were discussed. Finally, the challenges and prospects for the future development of chitosan-based hydrogels were discussed.

Evolutionary dynamics and adaptive analysis of Seneca Valley virus.

Over the past 20 years, the Seneca Valley virus (SVV) has emerged in various countries and regions around the world. Infected pigs display symptoms similar to foot-and-mouth disease and other vesicular diseases, causing severe economic losses to affected countries. In recent years, the number of SVV infections has been increasing in Brazil, China, and the United States. In this study, we comprehensively analyzed SVV genomic sequence data from the perspectives of evolutionary dynamics, phylogeography, and codon usage bias. We aimed to gain further insights into SVV's genetic diversity, spatiotemporal distribution patterns, and evolutionary adaptations. Phylogenetic analysis revealed that SVV has evolved into eight distinct lineages. Based on the results of phylogeographic analysis, it is speculated that the United States might have been the source of SVV, from where it subsequently spread to different countries and regions. Moreover, our analysis of positive selection sites in SVV capsid proteins suggests their potential importance in the process of receptor recognition. Finally, codon preference analysis indicates that natural selection has been a primary evolutionary driver influencing SVV codon usage bias. In conclusion, our in-depth investigation into SVV's origin, dissemination, evolution, and adaptation emphasizes the significance of SVV surveillance and control measures.

Determination of trace human chorionic gonadotropin by using multiwall carbon nanotubes as phosphorescence labeling reagent.

Taking advantage of the cutting effect of the strong oxidation of benzoyl peroxide [(C(6)H(5)CO)(2)O(2)] on the end of multiwall carbon nanotubes (MWNTs) to obtain water-soluble multiwall nanotubes (MWNTs') and the spiking effect of polyacrylamide (PA) on the room temperature phosphorescence (RTP) of MWNTs', a new phosphorescent labeling reagent, MWNTs'-PA, has been developed in this study. The product ß-Ab(HCG)-MWNTs'-PA obtained by MWNTs'-PA labeling human chorionic gonadotropin-ß-subunit three-dimensional core monoclonal antibody (ß-Ab(HCG)) not only could maintain good RTP characteristics of MWNTs' but also could take specific immunoreaction with ß-HCG to form ß-HCG- ß-Ab(HCG)-MWNTs'-PA, resulting in the increase of MWNTs' RTP signal. Thus, a new solid substrate room temperature phosphorescence immunoassay (SSRTPIA) for the determination of ß-HCG has been established. The limits of detection (LODs) of the new method were 0.021pgspot(-1) for the direct way at 447/615nm (λ(ex)(max)/λ(em)(max)) and 0.016pgspot(-1) for the sandwich way at 447/614nm (λ(ex)(max)/λ(em)(max)). This sensitive, accurate, and precise method was used to determine ß-HCG and diagnose human diseases by the direct way or the sandwich way, with the results coinciding with those obtained by chemiluminescence immunoassay. Meanwhile, the mechanisms of MWNTs' labeling ß-Ab(HCG) and determining ß-HCG are also discussed.

Phosphole modified pentathienoacene: synthesis, electronic properties and self-assembly.

A series of new ladder π-conjugated materials, phosphole modified pentathienoacene (PO-PTA), are synthesized and characterized. Single-crystal X-ray results demonstrate that methyl-disubstituted PO-PTA forms a face-to-face dimer structure driven by π-π interactions. The investigations of optical properties showed that the oxidized phosphole moiety in this ladder system can effectively narrow the band gap. PO-PTA is a promising building block in π-conjugated polymers and oligomers for optoelectronic applications. The derivative of PO-PTA, obtained by introducing four long alkyl chains, can self-assemble into one-dimensional (1D) fibers based on intermolecular π-π interactions, dipole-dipole interactions and van der Waals interactions. Interestingly, the uniform and well-ordered monolayers were also obtained for PO-PTA derivative on a HOPG (highly oriented pyrolytic graphite) surface.

A promising CdSe@CdS-quantum dots-cysteine for the determination of trace IgE by solid substrate room temperature phosphorescence immunoassay.

The labelling reagent CdSe@CdS-QDs-Cys (QDs-Cys) with the grain diameter of 4.5 nm was synthesized by modifying CdSe@CdS quantum dots (QDs) with cysteine (Cys). At the same time, QDs-Cys-Ab(IgE), a phosphorescent quantum dot probe, was developed based on the labelling reaction between -COOH of QDs-Cys and -NH(2) of goat anti human IgE antibody (Ab(IgE)). This probe with excellent biocompatibility and high specificity could not only emit strong and stable room temperature phosphorescence (RTP), but also could carry out specific immunoassay (IA) with immunoglobulin E (IgE), causing the RTP of the system to sharply enhance. Thus, a new solid substrate room temperature phosphorescence immunoassay (SSRTPIA) for the determination of IgE was established. The limit of quantification (LOQ) of the method was 0.12 fg spot(-1), corresponding concentration was 3.0 × 10(-13) g mL(-1) and sampling quantity was 0.40 µL spot(-1). This highly selective, sensitive and accurate SSRTPIA has been applied to determine IgE in biological samples and diagnose diseases, and the results agreed well with those obtained by enzyme-link immunoassay (ELISA). Meanwhile, the mechanisms of QDs-Cys labelling Ab(IgE) and the determination of IgE by SSRTPIA were also discussed.

Construction of hydrophilic hypercrosslinked polymer based on natural kaempferol for highly effective extraction of 5-nitroimidazoles in environmental water, honey and fish samples.

A series of novel hydroxyl-functional hypercrosslinked polymers (named as HCPs-Kae) were fabricated using natural and environmentally benign kaempferol as monomer via one-step Friedel-Crafts reaction. The prepared HCP-Kae1-24 h exhibited large surface area, good hydrophilicity and excellent adsorption performance to 5-nitroimidazoles (5-NDZs). Thus, by applying HCP-Kae1-24 h as a solid-phase extraction adsorbent, a sensitive method was developed for enrichment of 5-NDZs including metronidazole, ronidazole, secnidazole, dimetridazole and ornidazole prior to high performance liquid chromatography analysis. Under the optimum conditions, good linearities were achieved in the range of 0.10-100.0 ng mL-1 for water, 1.3-500.0 ng g-1 for honey, and 1.7-100.0 ng g-1 for fish meat. The detection limits of the method were 0.03-0.05 ng mL-1, 0.4-1.0 ng g-1, 0.5-1.0 ng g-1 for water, honey and fish meat, respectively. High method recovery was obtained in the range of 84-118% with relative standard deviations lower than 8.9%. The established method was successfully applied to the detection of 5-NDZs in environmental water, honey and fish samples. This work provides a new strategy for constructing hydroxyl-functional HCPs by using natural resource as robust adsorbent for adsorption/extraction applications.

Plastic responses of fine root morphology and architecture traits to nitrogen addition in ectomycorrhizal and arbuscular mycorrhizal tree species in an evergreen broadleaved forest.

We measured the morphology traits (specific root length, specific root surface area, root tissue density, average root diameter) and architecture traits (root fork, root fork ratio, increase rate of root length, root tip density, root fork density) of fine roots in two mycorrhiza tree species, Castanopsis faberi (ectomycorrhizal) and Schima superba (arbuscular mycorrhizal), in an evergreen broadleaved forest in the middle subtropical zone. Root bags method was used in an in situ nitrogen deposition experiment. The aim of this study was to reveal the differences in the plastic responses of fine root morphology and architecture traits to nitrogen deposition between the different mycorrhizal trees. The plastic responses of specific root length, specific root surface area and root fork to nitrogen addition decreased from the first-order root to the fourth-order root, while root tissue density showed an opposite pattern. Such a result indicated a trade-off between nutrient acquisition and resource maintenance of different fine root orders. Different mycorrhizal tree species adopted diffe-rent adaptation strategies to the variations of soil nitrogen availability. C. faberi adopted an opportuni-stic strategy, which relied on fine root to improve nutrient absorption efficiency, enhanced the capacity of space expansion and in-situ nutrient absorption to focus on rapid nutrient absorption strategy. S. superba did not change fine root morphological traits through the trade-off between nutrient absorption efficiency and root construction cost, but relied more on the complementarity between mycorrhizal fungi and fine root architecture traits for nutrient acquisition. The differences in the cost of maintaining and constructing fine root C between different mycorrhizal trees led to fine root adopting the most suitable nutrient capture strategy.

PEGylated PAMAM dendrimer-doxorubicin conjugates: in vitro evaluation and in vivo tumor accumulation.

PURPOSE: To investigate the effects of PEGylation degree and drug conjugation style on the in vitro and in vivo behavior of PEGylated polyamidoamine (PAMAM) dendrimers-based drug delivery system. METHODS: Doxorubicin (DOX) was conjugated to differently PEGylated PAMAM dendrimers by acid-sensitive cis-aconityl linkage and acid-insensitive succinic linkage to produce the products of PPCD and PPSD conjugates, respectively. In vitro evaluations including pH-dependent DOX release, cytotoxicity, cellular uptake, cell internalization mechanism, and intracellular localization were performed. Tumor accumulation was also visualized by in vivo fluorescence imaging. RESULTS: DOX release from PPCD conjugates followed an acid-triggered manner and increased with increasing PEGylation degree. In vitro cytotoxicity of PPCD conjugates against ovarian cancer (SKOV-3) cells increased, while cellular uptake decreased with increasing PEGylation degree. PPSD conjugates released negligible drug at any tested pH condition and were less cytotoxic. The conjugates were internalized by SKOV-3 cells via clathrin-mediated and adsorptive endocytosis, and were delivered to acidic lysosomes where DOX was released from PPCD conjugates and diffused into the nuclei. PPCD conjugates with highest PEGylation degree showed the highest tumor accumulation in mice inoculated with SKOV-3 cells. CONCLUSION: The obtained results suggested that PPCD conjugates with highest PEGylation degree would be a potential candidate for solid tumor treatment.

Electrical-Driven Release and Migration of Herbicide Using a Gel-Based Nanocomposite.

In this work, an electrical-driven release and migration glyphosate (EDRMG) was fabricated using a nanocomposite made up of attapulgite (ATP), glyphosate (Gly), and calcium alginate (CA). Therein, ATP-CA acted as a nanonetwork-structured carrier to efficiently load plenty of Gly to form porous ATP-Gly-CA hydrogel spheres (actually EDRMG-0.5) via a cross-linking reaction. The pores in EDRMG-0.5 hydrogel spheres were enlarged under an electric field because of the Coulomb force of the anionic CA polymer, and the release of negatively charged Gly from the spheres could be driven by the electric field force. Thus, EDRMG-0.5 exhibited a great electroresponsively controlled-release property, which was confirmed by a pot experiment. Importantly, the EDRMG-0.5 hydrogel spheres had fine biocompatibility on fish and mice, displaying good biosafety. This work provides a low cost and promising approach to control Gly release, deliver Gly precisely, and improve utilization efficiency, which might have a high application value.

Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases.

Mutations in the mitochondrial fusion protein mitofusin (MFN) 2 cause the chronic neurodegenerative condition Charcot-Marie-Tooth disease type 2A (CMT2A), for which there is currently no treatment. Small-molecule activators of MFN1 and MFN2 enhance mitochondrial fusion and offer promise as therapy for this condition, but prototype compounds have poor pharmacokinetic properties. Herein, we describe a rational design of a series of 6-phenylhexanamide derivatives whose pharmacokinetic optimization yielded a 4-hydroxycyclohexyl analogue, 13, with the potency, selectivity, and oral bioavailability of a preclinical candidate. Studies of 13 cis- and trans-4-hydroxycyclohexyl isostereomers unexpectedly revealed functionality and protein engagement exclusively for the trans form, 13B. Preclinical absorption, distribution, metabolism, and excretion (ADME) and in vivo target engagement studies of 13B support further development of 6-phenylhexanamide derivatives as therapeutic agents for human CMT2A.