ABSTRACT
BACKGROUND: The COVID-19 pandemic has prompted investigations into the association between this novel virus and allergic diseases, particularly asthma in children. However, the nature of this relationship remains poorly established. OBJECTIVE: This study aims to determine the clinical characteristics of children with allergic diseases who have contracted COVID-19. METHODS: A retrospective study was conducted at the Children's Hospital Affiliated to the Capital Institute of Pediatrics from January to March 2023. A total of 568 children aged 0-17 years diagnosed with asthma and COVID-19 infection were included. A comparative analysis of clinical characteristics was conducted between asthma and non-asthma groups. RESULTS: Asthmatic children with COVID-19 infection showed significantly higher frequencies of cough, wheezing, expectoration, and long-term symptoms compared to those without asthma (P < 0.05). Subgroups with poor therapy compliance exhibited elevated proportions of cough, chest tightness, and wheezing compared to good therapy compliance (P < 0.05). Multivariate logistic regression identified poor therapy compliance as a risk factor for long COVID in asthmatic children. CONCLUSION: Children with asthma secondary to COVID-19 infection were more prone to developing coughs, expectoration, and wheezing. Poor therapy compliance emerged as a significant risk factor for long COVID-19 in these individuals. IMPACT: Asthmatic children with COVID-19 infection showed significantly higher frequencies of cough, wheezing, expectoration. Poor therapy compliance was the risk factor for long COVID in asthmatic children. This article supplements the effects of different therapeutic drugs on the condition of children with asthma after infection with COVID-19 as well as the possible risk factors for the long COVID. The results of our study have important implications for public health policy makers and healthcare professionals. To understand the impact of COVID-19 on children with asthma will help guide appropriate management strategies and ensure access to necessary healthcare resources.
ABSTRACT
OBJECTIVE: This study aimed to analyze the sensitization rate of different aeroallergens in children of different age, sex, and disease groups, describe the changing trend of different aeroallergens in different ages, and analyze the sensitization risk factors for asthma. METHODS: Children (<18 years old) with suspected atopic diseases who visited the Department of Allergy of Children's Hospital Affiliated to Capital Institute of Pediatrics and underwent a skin prick test (SPT) were retrospectively enrolled from January 2019 to November 2021. RESULTS: A total of 5465 patients (3514 boys, 1951 girls; mean age, 7 ± 3 years) were enrolled. Of them, 3703 patients (67.8%) were sensitized to at least one aeroallergen. Before 4 years of age, mold was the most prevalent aeroallergen (103/380 [27.1%]), whereas after 4 years of age, weed pollen was the most prevalent aeroallergen. After 6 years of age, tree pollen became the second most prevalent aeroallergen. After 12 years of age, the sensitization rate of indoor aeroallergens was lower than that of outdoor aeroallergens. Logistic regression showed that sensitization to mold (odds ratio [OR]:1.4, 95% confidence interval (CI): 1.2-1.7, p < 0.001), animal dander (OR: 1.6, 95% CI: 1.4-1.9, p < 0.001), and polysensitization (OR: 1.4, 95% CI: 1.0-1.8, p = 0.038) were potential sensitization risk factors for asthma. CONCLUSIONS: Mold is an important allergen in early life. Different kinds of allergens affect different age groups. Patients who are sensitized to mold or animal dander or experience polysensitization should be carefully monitored for asthma risk.
Subject(s)
Allergens , Asthma , Skin Tests , Humans , Child , Male , Female , Allergens/immunology , China/epidemiology , Child, Preschool , Prevalence , Asthma/epidemiology , Asthma/immunology , Retrospective Studies , Adolescent , Risk Factors , Infant , Pollen/immunology , Fungi/immunology , Age FactorsABSTRACT
BACKGROUND: With the intensification of China's aging population, the demand for elderly care services has become increasingly prominent. At the same time, rapid development of internet technology provides more convenience and possibilities for the elderly. However, the coordinated development between the internet and elderly care services still faces challenges. This study aims to measure the level of coupling and coordinated development between the internet and elderly care services in China, and analyze the influencing factors, in order to provide reference for promoting elderly care services. METHODS: In this paper, the entropy method and coupling coordination degree model were used to measure the coupling coordination development index of the internet and elderly care services in China from 2012 to 2021. In addition, considering that the coordinated development between the two is affected by many factors, the Tobit model was used to analyze the main factors affecting the integration of the internet and elderly care services. RESULTS: (1) The coupling and coordination of the Internet and senior care services is in its infancy, but the coupling and coordination of the two is on the rise, and there is still a lot of room for development in the future. (2) In terms of time scale, the coupling coordination development level between the internet and elderly care services in China has gone through three stages of "disorder recession-transition coordination-coordinated development". (3) In terms of influencing factors, government management ability has a more positive impact on the development of the integration of the Internet and senior care services, financial support, scientific and technological investment and the level of innovation play a mild pulling role, while the level of informatization to a certain extent restricts the level of integration of the Internet and senior care services. CONCLUSION: In order to promote the coordinated development of China's Internet and senior care services, it is necessary to comprehensively understand the current situation and development space of China's Internet and senior care services coupling coordination degree, accurately grasp the dynamic trend of China's Internet and senior care services coupling and coordinated development, promote the stage of leapfrogging, and fully consider the influencing factors, so as to realize the optimal allocation of policies and resources. These measures will help to promote a more coordinated and sustainable development of the internet and elderly care services in China.
Subject(s)
Aging , Financial Support , Humans , Aged , China , Government , Internet , Economic DevelopmentABSTRACT
BACKGROUND: Cow's milk allergy (CMA) is one of the most common food allergies in young children. As improved diagnostic tools, allergic tests are inconsistent and limited in predicting anaphylaxis. OBJECTIVE: To explore risk factors for anaphylaxis and to determine practical cut-offs for allergic tests in predicting anaphylaxis. METHODS: This is a prospective cohort study. Children with IgE-mediated CMA were enrolled and divided into three groups (Group 1: non-anaphylaxis; Group 2: GRADE I anaphylaxis; Group 3: GRADE II-IV anaphylaxis that warranted epinephrine). Prick-to-prick tests (PTPs) using fresh cow's milk (CM) were performed. Serum specific IgE (sIgE) against CM and its components, including casein, alpha-lactalbumin, beta-lactoglobulin, and bovine serum albumin were measured. The 90% and 95% positive predictive value (PPV) decision points for predicting anaphylaxis were determined. Potential predictors of anaphylaxis were evaluated in logistic regression models. RESULTS: This study included 134 CMA patients with a median age of 14.4 months. The sensitization rate to any CM component was 89%. Group 3 was more likely to be sensitized to multiple CM components and have higher sIgE levels. The 95% PPV diagnostic decision points of casein-sIgE in predicting anaphylaxis was 13.0 kUA/L. For GRADE II-IV anaphylaxis, casein-sIgE ≥ 54.9 kUA/L could provide a PPV of 88.9%. The elevated casein-sIgE level (OR 14.0, P=0.025) and complicating respiratory allergic diseases (OR 4.8, P=0.022) were independent risk factors for GRADE II-IV anaphylaxis. CONCLUSION: High casein-sIgE levels are strongly associated with CM anaphylaxis. Detection of casein-sIgE may offer an additional value for the prediction of CM anaphylaxis.
ABSTRACT
Herein, we report a photoredox-catalyzed decarboxylative addition of N-substituted acetic acids to aldehydes to generate secondary alcohols under mild reaction conditions. Protic solvents were found to be critical to the successful implementation of this methodology. This strategy enables the formation of a novel C-C bond between aldehydes and N-substituted acetic acid derivatives of weakly nucleophilic and medicinally relevant heteroaryls such as indoles, pyrroles, indazoles, and azaindoles.
ABSTRACT
Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.
Subject(s)
Protein-Tyrosine Kinases , Signal Transduction , Syk Kinase , Protein Kinase Inhibitors/pharmacologyABSTRACT
Objective: This study aimed at comparing sacrospinous ligament fixation (SSLF) with uterosacral and cardinal ligament fixation (USCLF) concerning complications and outcomes in patients with pelvic organ prolapse (POP). Methods: A retrospective analysis was performed on the clinical data of patients with POP stage III or above uterine prolapse treated at Wenzhou People's Hospital from January 2013 to December 2019. Patients were divided into two groups: USCLF group and SSLF group. The perioperative indicators, postoperative complications, pelvic organ prolapse quantification (POP-Q), Pelvic Floor Distress Inventory-20 (PFDI-20), and POP/Urinary Incontinence Sexual Questionnaire-12 (PISQ-12) scores of the groups were analyzed and compared. Results: (1) The operative time and intraoperative blood loss in the USCLF group were lower than those in the SSLF group, with statistical significance (p < 0.05). (2) The incidence of postoperative buttock pain in the SSLF group was 10.7% (6/56), higher than that in the USCLF group (0/56) (Fisher's exact test, p = 0.027). (3) At one year of follow-up, significant improvement in Aa, Ba, C, Ap, and Bp values was observed in both groups (p < 0.05). The values of the Aa and Ba sites in the USCLF group were lower than those in the SSLF group one year after surgery (p < 0.05). (4) The PFDI-20 and PISQ-12 scores of the groups one year after surgery were lower than those before surgery (p < 0.05). Conclusion: Uterosacral and cardinal ligament suture fixation leads to less bleeding and better postoperative quality of life than preoperative and may be better than SSLF at preventing the recurrence of anterior wall prolapse after surgery.
Subject(s)
Pelvic Organ Prolapse , Quality of Life , Female , Humans , Retrospective Studies , Pelvic Organ Prolapse/surgery , Pain, Postoperative , Ligaments/surgeryABSTRACT
BACKGROUND: Elymus breviaristatus and Elymus sinosubmuticus are perennial herbs, not only morphologically similar but also sympatric distribution. The genome composition of E. sinosubmuticus has not been reported, and the relationship between E. sinosubmuticus and E. breviaristatus is still controversial. We performed artificial hybridization, genomic in situ hybridization, and phylogenetic analyses to clarify whether the two taxa were the same species. RESULTS: The high frequency bivalent (with an average of 20.62 bivalents per cell) at metaphase I of pollen mother cells of the artificial hybrids of E. breviaristatus (StYH) × E. sinosubmuticus was observed. It illustrated that E. sinosubmuticus was closely related to E. breviaristatus. Based on genomic in situ hybridization results, we confirmed that E. sinosubmuticus was an allohexaploid, and the genomic constitution was StYH. Phylogenetic analysis results also supported that this species contained St, Y, and H genomes. In their F1 hybrids, pollen activity was 53.90%, and the seed setting rate was 22.46%. Those indicated that the relationship between E. sinosubmuticus and E. breviaristatus is intersubspecific rather than interspecific, and it is reasonable to treated E. sinosubmuticus as the subspecies of E. breviaristatus. CONCLUSIONS: In all, the genomic constitutions of E. sinosubmuticus and E. breviaristatus were StYH, and they are species in the genus Campeiostachys. Because E. breviaristatus was treated as Campeistachys breviaristata, Elymus sinosubmuticus should be renamed Campeiostachys breviaristata (Keng) Y. H. Zhou, H. Q. Zhang et C. R. Yang subsp. sinosubmuticus (S. L. Chen) Y. H. Zhou, H. Q. Zhang et L. Tan.
Subject(s)
Chimera/genetics , Classification , Elymus/classification , Elymus/genetics , Genome, Plant , Hybridization, Genetic , Phylogeny , China , Genetic Variation , Species SpecificityABSTRACT
Natural hybridization has been frequently observed in Triticeae; however, few studies have investigated the origin of natural intergeneric Triticeae hybrids. In the present study, we discovered three putative hybrid Triticeae plants in the Western Sichuan Plateau of China. Morphologically, the putative hybrids were intermediate between Kengyilia melanthera (2n = 6x = 42; StStYYPP) and Campeiostachys dahurica var. tangutorum (2n = 6x = 42; StStYYHH) with greater plant height and tiller number. Cytological analyses demonstrated that the hybrids were hexaploid with 42 chromosomes (2n = 6x = 42). At metaphase I, 12.10-12.58 bivalents and 13.81-14.18 univalents per cell were observed in the hybrid plants. Genomic in situ hybridization demonstrated that the hybrids had StStYYHP genomes. Phylogenetic analysis of Acc1 sequences indicated that the hybrids were closely related to K. melanthera and C. dahurica var. tangutorum. Our morphological, cytological, and molecular analyses indicate that these hexaploid natural hybrid plants may be hybrids of K. melanthera and C. dahurica var. tangutorum.
Subject(s)
Elymus , Poaceae , Poaceae/genetics , Phylogeny , Genome, Plant , Cytogenetic Analysis , Hybridization, Genetic , In Situ Hybridization , Elymus/geneticsABSTRACT
Tracing evolutionary history proves challenging for polyploid groups that have evolved rapidly, especially if an ancestor of a polyploid is extinct. The Ns-containing polyploids are recognized as the NsXm and StHNsXm genomic constitutions in Triticeae. The Ns originated from Psathyrostachys, while the Xm represented a genome of unknown origin. Here, we use genetic information in plastome to trace the complex lineage history of the Ns-containing polyploid species by sampling 26 polyploids and 90 diploid taxa representing 23 basic genomes in Triticeae. Phylogenetic reconstruction, cluster plot of genetic distance matrix, and migration event demonstrated that (1) the Ns plastome originated from different Psathyrostachys species, and the Xm plastome may originate from an ancestral lineage of Henrardia, Agropyron, and Eremopyrum; (2) the Ns, Xm, and St genome donors separately served as the maternal parents during the speciation of the Ns-containing polyploid species, resulting in a maternal haplotype polymorphism; (3) North AmericanLeymusspecies might originate from colonization during late Miocene via the Bering land bridge and were the paternal donor of the StHNsXm genome Pascopyrum species. Our results shed new light on our understanding of the rich diversity and ecological adaptation of the Ns-containing polyploid species.
Subject(s)
Poaceae , Polyploidy , Biological Evolution , Genome, Plant , Phylogeny , Poaceae/genetics , Sequence Analysis, DNAABSTRACT
ObjectiveAsthmatic children presenting with chest tightness as the only symptom have not been widely recognized. This study attempted to find risk factors, summarize clinical features and offer some suggestions for the diagnosis of this atypical asthma.Methods: We studied 94 children, aged 6 to 14 years, who complained only of chest tightness. Data from clinical manifestations and laboratory tests were analyzed. The atypical asthma group (n = 58) showed positive bronchial challenge tests, and symptoms either improved or resolved in response to the bronchodilator. The control group (n = 36) had negative results on the bronchial challenge, diurnal PEF, and BDR tests, and no response to asthma treatment with bronchodilator.Results: Pollution, weather, recent house renovation, and air-conditioning use may be risk factors for children with atypical asthma. These children had more accompanying symptoms of rhinitis and rhinitis family history (P < 0.05), and a higher positive detection rate of inhaled allergens and multiple sensitizations. Parameters of the pulmonary function test were lower in the atypical asthma group than in the control group, and they also had higher FeNO values. If a cutoff value of improvement in FEV1 of BDR were set at 8.9%, sensitivity would be 48.2%, which is higher than a 12% cutoff.Conclusions: Environmental factors appeared to cause development of the isolated chest tightness symptom. Clinical history and laboratory tests could provide partial values for this diagnosis. In the absence of a bronchial challenge test, a margin of improvement in FEV1 of BDR set at 8.9% may be helpful.
Subject(s)
Asthma , Rhinitis , Asthma/diagnosis , Asthma/drug therapy , Asthma/epidemiology , Bronchial Provocation Tests , Bronchodilator Agents/therapeutic use , Child , Humans , Rhinitis/drug therapy , Risk FactorsABSTRACT
The applications of alginate lyase are diverse, but efficient commercial enzymes are still unavailable. In this study, a novel alginate lyase with high activity was obtained from the marine bacteria Vibrio sp. Ni1. The ORF of the algB gene has 1824 bp, encoding 607 amino acids. Homology analysis shows that AlgB belongs to the PL7 family. There are two catalytic domains with the typical region of QIH found in AlgB. The purified recombinant enzyme of AlgB shows highest activity at 35 °C, pH 8.0, and 50 mmol/L Tris-HCl without any metal ions. Only K+ slightly enhances the activity, while Fe2+ and Cu2+ strongly inhibit the activity. The AlgB preferred polyM as substrate. The end products of enzymatic mixture are DP2 and DP3, without any metal ion to assist them. This enzyme has good industrial application prospects.
Subject(s)
Polysaccharide-Lyases , Vibrio , Alginates/metabolism , Bacterial Proteins/metabolism , Cloning, Molecular , Hydrogen-Ion Concentration , Ions , Metals/pharmacology , Polysaccharide-Lyases/metabolism , Substrate Specificity , Vibrio/metabolismABSTRACT
Plant functional traits and strategies hold the promise to explain species distribution, but few studies have linked multiple traits to multiple niche dimensions (i.e., light, water, and nutrients). Here, we analyzed for 29 liana species in a Chinese tropical seasonal rainforest how: (1) trait associations and trade-offs lead to different plant strategies; and (2) how these traits shape species' niche dimensions. Eighteen functional traits related to light, water, and nutrient use were measured and species niche dimensions were quantified using species distribution in a 20-ha plot combined with data on canopy gaps, topographic water availability, and soil nutrients. We found a tissue toughness spectrum ranging from soft to hard tissues along which species also varied from acquisitive to conservative water use, and a resource acquisition spectrum ranging from low to high light capture and nutrient use. Intriguingly, each spectrum partly reflected the conservative-acquisitive paradigm, but at the same time, the tissue toughness and the resource acquisition spectrum were uncoupled. Resource niche dimensions were better predicted by individual traits than by multivariate plant strategies. This suggests that trait components that underlie multivariate strategy axes, rather than the plant strategies themselves determine species distributions. Different traits were important for different niche dimensions. In conclusion, plant functional traits and strategies can indeed explain species distributions, but not in a simple and straight forward way. Although the identification of global plant strategies has significantly advanced the field, this research shows that global, multivariate generalizations are difficult to translate to local conditions, as different components of these strategies are important under different local conditions.
Subject(s)
Rainforest , Trees , Phenotype , Plant Leaves , Seasons , Tropical Climate , WaterABSTRACT
The high energy consumption of high apparent electrical resistivity (AER) in sludge during the later stages of the electro-dewatering (EDW) process is a difficult problem; however, analysis of sludge AER may contribute to a reduction in energy consumption. In this study, the variations in the AER of activated sludge and potential mechanisms related to sludge properties were systematically examined. First, a sludge cake was divided into four horizontal layers, in order to investigate the sludge AER in each layer. Then, the effects of variations in water distribution, oxidation-reduction potential (ORP), pH, metal ions, sludge conductivity, zeta potential, temperature, and sludge microstructure on the AER in each layer were explored. The results showed that the sludge AER began to increase from the bottom layers to the top layers when the moisture content (MC) was decreased to 60%. The formation of nonionic chemical systems and the gas barrier layer could increase the AER in the top layers, and the increase in sludge AER in the bottom layers was due to the decrease in MC and sludge conductivity. In addition, electrolyte release and electromigration had a significant effect on the sludge AER. This work identifies potential causes for the increase in AER, and provides a reference for solving problems related to high AER in sludge during the later stages of the EDW process.
Subject(s)
Sewage , Waste Disposal, Fluid , Electricity , Wastewater , WaterABSTRACT
Both cadmium (Cd) contamination and boron (B) deficiency in farmland soils pose a threat to the yield and quality of crops in Southern China. The present study investigated the mechanisms by which B reduces Cd accumulation in rice (Oryza sativa) seedlings. Boron supplementation partially restored the decline in shoot and root biomass caused by Cd treatment (26% and 33%, respectively), with no significant difference between the B+Cd and control groups. We also found that B significantly reduced shoot and root Cd concentrations (by 64% and 25%, respectively) but increased Cd concentration (by 43%) and proportion (from 38% to 55%) in root cell walls. Transcriptome analysis and biochemical tests suggested that B supplementation enhanced lignin and pectin biosynthesis, pectin demethylation, and sulfur and glutathione metabolism. Moreover, B decreased the expression of some Cd-induced transporter-related genes (i.e., HMA2, Nramp1, and several ABC genes). These results indicate that B relieved Cd toxicity and reduced Cd accumulation in rice seedlings by restraining Cd uptake and translocation from root to shoot by improving Cd tolerance and chelation ability. These novel findings would benefit further investigations into how B influences Cd uptake, translocation, detoxification, and accumulation in crops.
Subject(s)
Oryza , Seedlings , Boron/toxicity , Cadmium/toxicity , Crops, Agricultural , Oryza/geneticsABSTRACT
The increase of electrical resistance (ER) and energy consumption (EC) during the later stage of dewatering is a major problem hindering the development of electro-dewatering (EDW) technology. As the variations of sludge characteristics are significant during the EDW process, the relationships between sludge characteristics and ER and EC during EDW remain unclear. In this study, the effects of moisture content (MC), thickness, pH, conductivity, zeta potential, temperature, and gas volume on the ER and EC during the EDW process were statistically investigated using correlation and multiple linear regression analyses. Herein, the results showed that the ER of the sludge near the anode was primarily affected by pH, whereas the sludge near the cathode was primarily affected by the MC and conductivity. Further, sludge temperature and conductivity were the most reliable indicators to predict the EC near the anode and cathode, respectively. The results of this study provide theoretical guidance useful for solving the increase of ER and EC during the later stage of the EDW process.
Subject(s)
Sewage , Waste Disposal, Fluid , Electric Conductivity , Electric Impedance , Electrodes , WaterABSTRACT
To investigate the diploid-polyploid relationships and the role of maternal progenitors in establishment of polyploid richness in Triticeae, 35 polyploids representing almost all genomic constitutions together with 48 diploid taxa representing 20 basic genomes in the tribe were analyzed. Phylogenomic reconstruction, genetic distance matrix, and nucleotide diversity patterns of plastome sequences indicated that (1) The maternal donor of the annual polyploid species with the U- and D-genome are related to extant Ae. umbellulata and Ae. tauschii, respectively. The maternal donor to the annual polyploid species with the S-, G-, and B-genome originated from the species of Sitopsis section of the genus Aegilops. The annual species with the Xe-containing polyploids were donated by Eremopyrum as the female parent; (2) Pseudoroegneria and Psathyrostachys were the maternal donor of perennial species with the St- and Ns-containing polyploids, respectively; (3) The Lophopyrum, Thinopyrum and Dasypyrum genomes contributed cytoplasm genome to Pseudoroegneria species as a result of incomplete lineage sorting and/or chloroplast captures, and these lineages were genetically transmitted to the St-containing polyploid species via polyploidization; (4) There is a reticulate relationship among the St-containing polyploid species. It can be suggested that genetic heterogeneity might associate with the richness of the polyploids in Triticeae.
Subject(s)
Diploidy , Evolution, Molecular , Genome, Plastid , Poaceae/genetics , Polyploidy , Base Sequence , Genes, Plant , Genetic Variation , Likelihood Functions , Nucleotides/genetics , PhylogenyABSTRACT
Acute lung injury (ALI) caused by sepsis occurs early and the condition is severe, and is also an important reason for accelerating the death of patients. Increasing evidence has identified long non-coding RNA (lncRNA) metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) as a regulator of ALI. However, the potential mechanism underlying MALAT1 on ALI still needs further identification. To explore the mechanisms of gene regulation expression mediated by MALAT1 through miR-149/MyD88 in lung injury inflammation, we constructed a lung injury inflammatory model using the lipopolysaccharides (LPS)-induced method and quantificated the cytokines and signaling cascade molecules as well as miR-149. The MALAT1, myeloid differentiation factor 88 (MyD88), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 levels were significantly increased, and the nuclear factor-κB (NF-κB) pathway was activated, but the miR-149 level was decreased in the LPS-induced ALI model. miR-149 directly targeted both lncRNA MALAT1 and the MyD88 gene. Knockdown of MALAT1 down-regulated the levels of MyD88, TNF-α, IL-1ß, and IL-6, and inhibited the NF-κB pathway. However, MALAT1 knockdown up-regulated the expression of miR-149. Overexpression of miR-149 down-regulated MyD88, TNF-α, IL-1ß, and IL-6 levels, and inhibited the NF-κB pathway. MALAT1 acts as a pro-inflammatory factor in ALI via the miR-149/MyD88/NF-κB axis and is therefore a potential novel therapeutic target for ALI treatment.
ABSTRACT
Spleen tyrosine kinase (SYK) is a non-receptor cytosolic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signaling, inhibition of SYK has been targeted in a variety of disease areas. Herein, we report the optimization of a series of potent and selective SYK inhibitors, focusing on improving metabolic stability, pharmacokinetics and hERG inhibition. As a result, we identified 30, which exhibited no hERG activity but unfortunately was poorly absorbed in rats and mice. We also identified a SYK chemical probe, 17, which exhibits excellent potency at SYK, and an adequate rodent PK profile to support in vivo efficacy/PD studies.
Subject(s)
Indazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Syk Kinase/antagonists & inhibitors , Animals , Binding Sites , Caco-2 Cells , Crystallography, X-Ray , ERG1 Potassium Channel/antagonists & inhibitors , Humans , Indazoles/chemical synthesis , Indazoles/metabolism , Indazoles/pharmacokinetics , Mice , Microsomes, Liver/metabolism , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Rats, Wistar , Structure-Activity Relationship , Syk Kinase/chemistry , Syk Kinase/metabolismABSTRACT
Since the effect of electro-dewatering (EDW) on sludge water holding capacity was unknown, tests were conducted in this study to investigate the water holding capacity of EDW sludge and the potential mechanism related to the sludge physicochemical characteristics, EPS properties and sludge structure. Sludge was dewatered to the average moisture content (AMC) of 80%, 70% and 60% with different applied voltages at 20, 30 and 40V in EDW, respectively. Then the dewatered sludge near the anode and cathode were rewatered. The variation of sludge water holding capacity in EDW process was evaluated in terms of filterability and saturated moisture content (SMC), and the filterability was assessed by the specific resistance to filtration (SRF) of rewatered sludge. The results indicated that SRF of rewatered sludge near the cathode increased greatly. The proteins/polysaccharides (PN/PS) of loosely bound extracellular polymeric substances (LB-EPS) was significantly positively correlated with SRF (r = 0.891, p < 0.01). Moreover, the exposure of hydrophobic sites or groups in PN near the cathode improved the surface hydrophobicity of sludge, which reduced the filterability. In addition, higher voltage could destroy the sludge structure near the anode at the later stage of EDW process, leading to the decrease of SRF and SMC. These results expanded the knowledge about changes in sludge properties and water holding capacity during EDW process.