Contactin-6-deficient male mice exhibit the abnormal function of the accessory olfactory system and impaired reproductive behavior.

INTRODUCTION: Contactin-6 (CNTN6), also known as NB-3, is a neural recognition molecule and a member of the contactin subgroup of the immunoglobulin superfamily. Gene encoding CNTN6 is expressed in many regions of the neural system, including the accessory olfactory bulb (AOB) in mice. We aim to determine the effect of CNTN6 deficiency on the function of the accessory olfactory system (AOS). METHODS: We examined the effect of CNTN6 deficiency on the reproductive behavior of male mice through behavioral experiments such as urine sniffing and mate preference tests. Staining and electron microscopy were used to observe the gross structure and the circuitry activity of the AOS. RESULTS: Cntn6 is highly expressed in the vomeronasal organ (VNO) and the AOB, and sparsely expressed in the medial amygdala (MeA) and the medial preoptic area (MPOA), which receive direct and/or indirect projections from the AOB. Behavioral tests to examine reproductive function in mice, which is mostly controlled by the AOS, revealed that Cntn6-/- adult male mice showed less interest and reduced mating attempts toward estrous female mice in comparison with their Cntn6+/+ littermates. Although Cntn6-/- adult male mice displayed no obvious changes in the gross structure of the VNO or AOB, we observed the increased activation of granule cells in the AOB and the lower activation of neurons in the MeA and the MPOA as compared with Cntn6+/+ adult male mice. Moreover, there were an increased number of synapses between mitral cells and granule cells in the AOB of Cntn6-/- adult male mice as compared with wild-type controls. CONCLUSION: These results indicate that CNTN6 deficiency affects the reproductive behavior of male mice, suggesting that CNTN6 participated in normal function of the AOS and its ablation was involved in synapse formation between mitral and granule cells in the AOB, rather than affecting the gross structure of the AOS.

Regulation of secondary metabolites in the endophytic fungus Penicillium sp. KMU18029 by the chemical epigenetic modifier 5-azacitidine.

The chemical epigenetic modifier 5-azacitidine (5-Aza C), a DNA methyltransferase inhibitor, was used to manipulate the endophytic fungus Penicillium sp. KMU18029. From its rice fermentation extract, a new polyketone compound (3S,4R)-3,4,8-trihydroxy-6-methyl-3,4-dihydronaphthalen-1(2H)-one (1), along with 13 known compounds, 3,4,8-trihydroxy-6-(hydroxymethyl)-3,4-dihydronaphthalen-1(2H)-one (2), decaturin B (3), 15-hydroxydecaturin A (4), oxalicine A (5), pileotin A (6), pyrandecarurin A (7), decaturenol A (8), decaturenoid (9), penisarins A (10), oxaline (11), (4E,8E)-N-D-2'-hydroxyocta-decanoyl-1-O-ß-D-glycopy-ranosyl-9-methyl-4,8-sphingadienine (12), ergosterol (13) and stigma-5-en-3-O-ß-glucoside (14), were separated. Among the known compounds, 2, 7, 12 and 14 were not found in our previous research on this strain. The structure of the new compound was identified by spectroscopic techniques such as HR-ESIMS, 1D NMR, 2D NMR and CD. Furthermore, all the isolated compounds were tested for their antimicrobial activities, and only compounds 1, 2 and 11 showed weak activities against S. aureus, with MICs of 128 µg/mL.

Combined Ultrasensitive Detection of Renal Cancer Proteins and Cells Using an Optical Microfiber Functionalized with Ti3C2 MXene and Gold Nanorod-Nanosensitized Interfaces.

The ultrasensitive and quantitative detection of renal cancer protein biomarkers present at ultralow concentrations for early-stage cancer diagnosis requires a biosensing probe possessing ultrahigh detection sensitivity and remarkable biosensing selectivity. Here, we report an optical microfiber integrated with Ti3C2-supported gold nanorod hybrid nanointerfaces for implementation in ultrasensitive sensing of the carbonic anhydrase IX (CAIX) protein and renal cancer cells. Because the evanescent field of the fiber is strongly coupled with nanointerfaces in the near-infrared region, the proposed optical microfiber biosensor achieves ultrahigh-sensitivity detection of the CAIX protein biomarker with ultralow limits of detection (LODs) of 13.8 zM in pure buffer solution and 0.19 aM in 30% serum solution. In addition, the proposed sensor also successfully and specifically recognizes living renal cancer cells in cell culture media with a LOD of 180 cells/mL. This strategy may serves as a powerful biosensing platform that combines the quantification of protein biomarkers and cancer cells, resulting in a higher accuracy of early-stage renal cancer diagnosis and screenings.

Asymmetric Synthesis of Triphenylmethanes via Organocatalytic Regio- and Enantioselective Friedel-Crafts Alkylation of Aniline Derivatives.

Herein, we described a highly regio- and enantioselective Friedel-Crafts alkylation of aniline derivatives with in situ generated ortho-quinone methides enabled by chiral phosphoric acid, furnishing a wide range of enantioenriched triarylmethanes bearing three similar benzene rings in high yields (up to 98%) with excellent stereoselectivities (up to 98% ee). Furthermore, the large-scale reactions and diversified transformations of product demonstrate the practicality of the protocol. Density functional theory calculations elucidate the origin of the enantioselectivity.

Study on stress variation of advance fiberglass anchor bolts during tunnel excavation process.

One of the main causes for excessive deformation within a tunnel is due to the instability of the soil or soft rock ahead of the excavation face. Fiberglass bolts have been shown to be a useful advance reinforcement method for the excavation face. In this paper, an improved ADECO-RS (Analysis of controlled deformation in rock and soils) method had been proposed for soft rock mountain tunnels, in terms of the partial (mainly the upper bench) excavation face reinforcement and also for the bench excavation method. Strain gauges were used to test the micro-strain in the fiberglass bolt to investigate how the axial force of the fiberglass bolt varied during the tunnel excavation. In addition, combined with the field tunnel deformation monitoring data, the relationship between the reinforcement parameters of the fiberglass bolts and the tunnel construction phase were discussed. The research results show that: (1) The stress state of the anchor rod is related to the reinforcement length of the anchor rod; (2) Excavation within the lap area of the fiberglass bolt leads to an increase in the axial force of the bolt, while excavation outside the lap area of the fiberglass bolt has no effect on the anchor; (3) Reducing the reinforcement area of rock mass will affect the stability of the excavation. To ensure the stability of the excavation face, the initial support construction loop should be completed as soon as possible; (4) In a future project with similar conditions, the recommended lap length of the fiberglass bolt could be 3 m utilizing the fiberglass bolt grouting face reinforcement method.

A CpG-Oligodeoxynucleotide Suppresses Th2/Th17 Inflammation by Inhibiting IL-33/ST2 Signaling in Mice from a Model of Adoptive Dendritic Cell Transfer of Smoke-Induced Asthma.

Tobacco smoke exposure is a major environmental risk factor that facilitates the development and progression of asthma. Our previous study showed that CpG oligodeoxynucleotide (CpG-ODN) inhibits thymic stromal lymphopoietin (TSLP)-dendritic cells (DCs) to reduce Th2/Th17-related inflammatory response in smoke-related asthma. However, the mechanism underlying CpG-ODN -downregulated TSLP remains unclear. A combined house dust mite (HDM)/cigarette smoke extract (CSE) model was used to assess the effects of CpG-ODN on airway inflammation, Th2/Th17 immune response, and amount of IL-33/ST2 and TSLP in mice with smoke-related asthma induced by adoptive transfer of bone-marrow-derived dendritic cells (BMDCs) and in the cultured human bronchial epithelium (HBE) cells administered anti-ST2, HDM, and/or CSE. In vivo, compared to the HDM alone model, the combined HDM/CSE model had aggravated inflammatory responses, while CpG-ODN attenuated airway inflammation, airway collagen deposition, and goblet cell hyperplasia and reduced the levels of IL-33/ST2, TSLP, and Th2/Th17-cytokines in the combined model. In vitro, IL-33/ST2 pathway activation promoted TSLP production in HBE cells, which could be inhibited by CpG-ODN. CpG-ODN administration alleviated Th2/Th17 inflammatory response, decreased the infiltration of inflammatory cells into the airway, and improved the remodeling of smoke-related asthma. The underlying mechanism may be that CpG-ODN inhibits the TSLP-DCs pathway by downregulating the IL-33/ST2 axis.

Mycobacteriophage Derived Lipoarabinomannan Binding Protein for Recognizing Non-Tuberculosis Mycobacteria.

Non-tuberculosis mycobacteria (NTM) is one family of pathogens usually leading to nosocomial infections. Exploration of high-performance biological recognition agent plays a pivotal role for the development of point-of-care testing device and kit for detecting NTM. Mycobacterium smegmatis (M. smegmatis) is a NTM which has been frequently applied as an alternative model for highly pathogenic mycobacteria. Herein, a recombinant tail protein derived from mycobacteriophage SWU1 infecting M. smegmatis was expressed with Escherichia coli system and noted as GP89. It shows a fist-like structure according to the results of homology modeling and ab initio modeling. It is confirmed as a lipoarabinomannan (LAM) binding protein, which can recognize studied NTM genus since abundant LAM constructed with d-mannan and d-arabinan is distributed over the mycobacterial surface. Meanwhile an enhanced green fluorescent protein (eGFP)-fused GP89 protein was acquired with a fusion expression technique. Then GP89 and eGFP-fused GP89 were applied to establish a sensitive and rapid method for fluorescent detection of M. smegmatis with a broad linear range of 1.0 × 102 to 1.0 × 106 CFU mL-1 and a low detection limit of 69 CFU mL-1. Rapid and reliable testing of antimicrobial susceptibility was achieved by the GP89-based fluorescent method. The present work provides a promising recognition agent for studied NTM and opens an avenue for clinical diagnosis of NTM-induced infections.

Bioactive sorbicillinoids from a rhizospheric soil-derived Paecilomyces sp. KMU21009.

A new hybrid sorbicillinoid named paeciureallin (1) and a new monomeric sorbicillinoid named paecillyketide (2), along with six known analogues (3-8), were isolated from the rhizospheric soil-derived fungus Paecilomyces sp. KMU21009 associated with Delphinium yunnanense. Their structures were elucidated by extensive spectroscopic analysis and comparison with literature values. Paeciureallin (1) is the first example of hybrid sorbicillinoids possessing a rare sorbicillinoid urea unit and containing a ß-D-ribofuranose functionality. In pharmacological studies, compounds 1 and 2 were evaluated for in vitro anti-inflammatory and cytotoxic activities. Paeciureallin (1) exhibited moderate cytotoxicity against SW480 and A549 cell lines, and the IC50 values were 32.0 ± 0.1 and 34.4 ± 2.0 µM, respectively.

The mechanisms and functions of TNF-α in intervertebral disc degeneration.

Low back pain (LBP) is one of the most common health problems in people's lives, which brings a massive burden to clinicians, and the leading cause of LBP is intervertebral disc degeneration (IDD). IDD is mainly caused by factors such as aging, mechanical stress, and lack of nutrition. The pathological mechanism of IDD is very complex, involving inflammatory response, cell metabolism disorder, and so on. Unfortunately, in the current treatment of IDD, only relieving symptoms as the primary means of relieving a patient's pain cannot effectively inhibit or reverse the progression of IDD. Tumor necrosis factor-α (TNF-α) is a multifunctional pro-inflammatory factor involved in many diseases' pathological processes. With the in-depth study of the pathological mechanism of IDD, more and more evidence has shown that TNF-α is an essential activator of IDD, which is related to the metabolic disorder, inflammatory responses, apoptosis, and other pathological processes of extracellular dissociation in the intervertebral disc. Therefore, anti-TNF-α therapy is an effective therapeutic target for alleviating IDD, especially in inhibiting extracellular matrix degradation and reducing inflammatory responses. This article reviews the pathological role of TNF-α in IDD and the latest research progress of TNF-α inhibitors in treating IDD.

Application of serum SERS technology based on thermally annealed silver nanoparticle composite substrate in breast cancer.

Liquid biopsy is currently a non-destructive and convenient method of cancer screening, due to human blood containing a variety of cancer-related biomolecules. Therefore, the development of an accurate and rapid breast cancer screening technique combined with breast cancer serum is crucial for the treatment and prognosis of breast cancer patients. In this study, the surface enhanced Raman spectroscopy (SERS) technique is used to enhance the Raman spectroscopy (RS) signal of serum based on a high sensitivity thermally annealed silver nanoparticle/porous silicon bragg mirror (AgNPs/PSB) composite substrate. Compared with RS, SERS reflects more and stronger spectral peak information, which is beneficial to discover new biomarkers of breast cancer. At the same time, to further explore the diagnostic ability of SERS technology for breast cancer. In this study, the raw spectral data are processed by baseline correction, polynomial smoothing, and normalization. Then, the relevant feature information of SERS and RS is extracted by principal component analysis (PCA), and five classification models are established to compare the diagnostic performance of SERS and RS models respectively. The experimental results show that the breast cancer diagnosis model based on the improved SERS substrate combined with the machine learning algorithm can be used to distinguish breast cancer patients from controls. The accuracy, sensitivity, specificity and AUC values of the SVM model are 100%, 100%, 100% and 100%, respectively, as well as the training time of 4ms. The above experimental results show that the SERS technology based on AgNPs/PSB composite substrate, combined with machine learning methods, has great potential in the rapid and accurate identification of breast cancer patients.

Mir155 regulates osteogenesis and bone mass phenotype via targeting S1pr1 gene.

MicroRNA-155 (miR155) is overexpressed in various inflammatory diseases and cancer, in which bone resorption and osteolysis are frequently observed. However, the role of miR155 on osteogenesis and bone mass phenotype is still unknown. Here, we report a low bone mass phenotype in the long bone of Mir155-Tg mice compared with wild-type mice. In contrast, Mir155-KO mice showed a high bone mass phenotype and protective effect against inflammation-induced bone loss. Mir155-KO mice showed robust bone regeneration in the ectopic and orthotopic model, but Mir155-Tg mice showed compromised bone regeneration compared with the wild-type mice. Similarly, the osteogenic differentiation potential of bone marrow stromal stem cells (BMSCs) from Mir155-KO mice was robust and Mir155-Tg was compromised compared with that of wild-type mice. Moreover, Mir155 knockdown in BMSCs from wild-type mice showed higher osteogenic differentiation potential, supporting the results from Mir155-KO mice. TargetScan analysis predicted sphingosine 1-phosphate receptor-1 (S1pr1) as a target gene of Mir155, which was further confirmed by luciferase assay and Mir155 knockdown. S1pr1 overexpression in BMSCs robustly promoted osteogenic differentiation without affecting cell viability and proliferation. Furthermore, osteoclastogenic differentiation of Mir155-Tg bone marrow-derived macrophages was inhibited compared with that of wild-type mice. Thus, Mir155 showed a catabolic effect on osteogenesis and bone mass phenotype via interaction with the S1pr1 gene, suggesting inhibition of Mir155 as a potential strategy for bone regeneration and bone defect healing.

C/EBPß expression decreases in cervical cancer and leads to tumorigenesis.

BACKGROUND: Cervical cancer is currently estimated to be the fourth most common cancer among women worldwide and the leading cause of cancer-related deaths in some of the world's poorest countries. C/EBPß has tumor suppressor effects because it is necessary for oncogene-induced senescence. However, C/EBPß also has an oncogenic role. The specific role of C/EBPß in cervical cancer as a tumor suppressor or oncoprotein is unclear. OBJECTIVE: To explore the role of the C/EBPß protein in cervical tumorigenesis and progression. METHODS: Quantitative RT-PCR was used to analyze C/EBPß (15 cervical cancer tissue samples and 15 corresponding normal cervical tissue samples), miR-661, and MTA1 mRNA expression in clinical samples (10 cervical cancer tissue samples and 10 corresponding normal cervical tissue samples). Immunohistochemistry was used to analyze C/EBPß (381 clinical samples), Ki67 (80 clinical samples) and PCNA ( 60 clinical samples) protein expression. MALDI-TOF MassARRAY was used to analyze C/EBPß gene methylation (13 cervical cancer tissues and 13 corresponding normal cervical tissues). Cell proliferation was analyzed by CCK-8 in cervical cancer cell lines. Western blotting and immunohistochemistry were performed to detect C/EBPß protein expression levels, and mRNA expression was analyzed by quantitative RT-PCR analysis. Flow cytometry was performed to measure cell cycle distribution and cell apoptosis. Colony formation, Transwell, cell invasion, and wound healing assays were performed to detect cell migration and invasion. RESULTS: C/EBPß protein expression was significantly reduced in cervical cancer tissues compared with cervicitis tissues (P < 0.01). Ki67 protein and PCNA protein expression levels were significantly higher in cervical cancer tissues compared with cervicitis tissues. The rate of C/EBPß gene promoter methylation of CpG12, 13, 14 and CpG19 in cervical cancer tissues was significantly increased compared with normal cervical tissue (P < 0.05). In addition, C/EBPß was overexpressed in cervical cancer cells and this overexpression inhibited cell proliferation, migration, invasion, arrested cells in S phase, and promoted apoptosis. CONCLUSIONS: We have demonstrated that C/EBPß decreased in cervical cancer tissues and overexpression of the C/EBPß gene in cervical cancer cells could inhibit proliferation, invasion and migration.

Transcriptome analysis of barley (Hordeum vulgare L.) under waterlogging stress, and overexpression of the HvADH4 gene confers waterlogging tolerance in transgenic Arabidopsis.

BACKGROUND: Waterlogging is one of the major abiotic stresses in barley and greatly reduces grain yield and quality. To explore the mechanism controlling waterlogging tolerance in barley, physiological, anatomical and transcriptional analyses were performed in two contrasting barley varieties, viz. Franklin (susceptible) and TX9425 (tolerant). RESULTS: Compared to Franklin, TX9425 had more adventitious roots and aerenchymas and higher antioxidant enzyme activities. A total of 3064 and 5693 differentially expressed genes (DEGs) were identified in TX9425 after 24 h and 72 h of waterlogging treatment, respectively, while 2297 and 8462 DEGs were identified in Franklin. The results suggested that TX9425 was less affected by waterlogging stress after 72 h of treatment. The DEGs were enriched mainly in energy metabolism, hormone regulation, reactive oxygen species (ROS) scavenging, and cell wall-modifying enzymes. Alcohol dehydrogenase (ADH) plays an important role in response to waterlogging stress. We found that HvADH4 was significantly upregulated under waterlogging stress in TX9425. Transgenic Arabidopsis overexpressing HvADH4 displayed higher activity of antioxidant enzymes and was more tolerant to waterlogging than the wild type (WT). CONCLUSIONS: The current results provide valuable information that will be of great value for the exploration of new candidate genes for molecular breeding of waterlogging tolerance in barley.

RNA mis-splicing drives viral mimicry response after DNMTi therapy in SETD2-mutant kidney cancer.

Tumors with mutations in chromatin regulators present attractive targets for DNA hypomethylating agent 5-aza-2'-deoxycytidine (DAC) therapy, which further disrupts cancer cells' epigenomic fidelity and reactivates transposable element (TE) expression to drive viral mimicry responses. SETD2 encodes a histone methyltransferase (H3K36me3) and is prevalently mutated in advanced kidney cancers. Here, we show that SETD2-mutant kidney cancer cells are especially sensitive in vitro and in vivo to DAC treatment. We find that the viral mimicry response are direct consequences of mis-splicing events, such as exon inclusions or extensions, triggered by DAC treatment in an SETD2-loss context. Comprehensive epigenomic analysis reveals H3K9me3 deposition, rather than DNA methylation dynamics, across intronic TEs might contribute to elevated mis-splicing rates. Through epigenomic and transcriptomic analyses, we show that SETD2-deficient kidney cancers are prone to mis-splicing, which can be therapeutically exacerbated with DAC treatment to increase viral mimicry activation and provide synergy with combinatorial immunotherapy approaches.

Leptin-deficient ob/ob mice exhibit periodontitis phenotype and altered oral microbiome.

BACKGROUND AND OBJECTIVE: Leptin-deficient obesity is associated with various systemic diseases including diabetes and low bone mass phenotype. However, the periodontal status of leptin-deficient obese individuals is still unclear. In this study, we aimed to analyze the periodontal status, alveolar bone phenotype, and oral microbiome status in leptin-deficient obese mice (ob/ob mice). METHODS: This study used 12-week-old wild-type and ob/ob male mice. The alveolar bone phenotype and periodontal status in the maxilla were analyzed by micro-CT and histological analysis. Osteoclasts in alveolar bone were visualized by TRAP staining. Expressions of inflammatory markers (MMP-9, IL-1ß, and TGF-ß1) and osteoclastogenic markers (RANKL and OPG) in periodontium were analyzed by immunohistochemistry and RT-qPCR. The oral microbiome was analyzed by 16 S rDNA sequencing. RESULTS: CEJ-ABC distance in maxillary molars (M1-M3) of ob/ob mice was significantly higher compared with that of wild-type. The alveolar bone BV/TV ratio was reduced in ob/ob mice compared with wild-type. Higher numbers of osteoclasts were observed in ob/ob mice alveolar bone adjacent to the molar root. Epithelial hyperplasia in gingiva and disordered periodontal ligaments was observed in ob/ob mice. RANKL/OPG expression ratio was increased in ob/ob mice compared with wild-type. Expressions of inflammatory markers MMP-9, IL-1ß, and TGF-ß1 were increased in ob/ob mice compared with wild-type. Oral microbiome analysis showed that beneficial bacteria Akkermansia and Ruminococcaceae_UCG_014 were more abundant in the wild-type mice while the inflammation-related Flavobacterium was more abundant in ob/ob mice. CONCLUSION: In conclusion, ob/ob mice showed higher expressions of inflammatory factors, increased alveolar bone loss, lower abundance of the beneficial bacteria, and higher abundance of inflammatory bacteria in the oral cavity, suggesting leptin-deficient obesity as a risk factor for periodontitis development in ob/ob mice.

The regulatory approvals of immune checkpoint inhibitors in China and the United States: A cross-national comparison study.

Immune checkpoint inhibitors (ICIs) are currently one of the most popular treatment methods for cancers. Several ICIs have been approved in China and the United States. We created a database of approved ICIs by extracting the information of interest from the drug labels and reviewing documents disclosed on the official websites of the US Food and Drug Administration (FDA) and the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) and compared the difference between the marketed ICIs in China and the United States regarding the number of indications, tumor types, review time, treatment setting, and so forth. Until June 30, 2022, 9 and 15 ICIs had been approved for 86 and 58 indications in the United States and China, involving 20 and 14 types of tumors, respectively. The correlation between indications and disease incidence was higher in China (r = 0.64) than in the United States (r = 0.45). About half of the indications were approved as first-line therapies in combination with chemotherapy, target therapy, or immunotherapy. Over 30% of indications were approved under accelerated or conditional approval in the two countries. A shorter regulatory review time was required by the FDA (median:181 days) compared to the NMPA (median: 279 days) for the new indication approval. Five ICIs marketed in China were approved by the FDA before the NMPA, with the median launch delay for the same indication of 344 days in China. A differentiated clinical development program that focuses on meeting unmet needs may bring new success for subsequent ICI products.

Heteroatom Coordination Regulates Iron Single-Atom-Catalyst with Superior Oxygen Reduction Reaction Performance for Aqueous Zn-Air Battery.

Platinum group metal (PGM)-free M-N-C catalysts have exhibited dramatic electrocatalytic performance and are considered the most promising candidate of the Pt catalysts in oxygen reduction reaction (ORR). However, the electrocatalytic performance of the M-N-C catalysts is still limited by their inferior intrinsic activity and finite active site density. Regulating the coordination environment and increasing the pore structure of the catalyst is an effective strategy to enhance the electrocatalytic performance of the M-N-C catalysts. In this work, the coordination environment and pore structure exquisitely regulated Fe-N-C catalyst exhibit excellent ORR activity and durability. With the enhanced intrinsic activity and increased active site density, the optimized Fe-N/S-C catalyst shows impressive ORR activity (E1/2  = 0.904 V vs reversible hydrogen electrode (RHE)) and superior long-term durability in an alkaline medium. As the advanced physical characterization and theoretical chemistry methods illustrate, the S-modified Fe-Nx (Fe-N3 /S-C) moiety is confirmed as the improved active center for ORR, and the increased active site density further improved ORR efficiency. Based on the Fe-N/S-C cathode, a Zn-air battery is fabricated and shows superior power density (315.4 mW cm-2 ) and long-term discharge stability at 20 mA cm-2 . This work would open a new perspective to design atomically dispersed iron-metal site catalysts for advanced electro-catalysis.

Decrease of bioaerosols in westerlies from Chinese coast to the northwestern Pacific: Case data comparisons.

The dissemination of bioaerosols in the westerly wind from the Asian continent to the northwestern Pacific constantly links the land and marine ecosystems. Several observation campaigns targeting bioaerosols were conducted in the coastal city Qingdao of China (QD), at a coast site of Kumamoto in southwestern Japan (KM), and in the northwestern Pacific (NP) between 2014 and 2016. We compared the concentration of bioaerosols in the range of 1.1-7.0 µm obtained in those campaigns to investigate their variation in the westerly wind. The substantial influence of westerlies on bioaerosol concentration was confirmed in the three areas. In the case of non-dust air, the arrival of the continental air led to a 29 % decrease of bioaerosols at KM while a 57 % increase at NP, indicating that the concentration in non-dust air was lower than the local level in the island air while higher than that in the remote marine air. In case of dust occurrence, bioaerosols in the air decreased with the distance from the Asian continent at KM and NP consecutively, and the arrival of the air caused a 2-fold increase at KM and a 1.7-fold increase at NP. The relative concentration increase rate of bioaerosols (IRRC), defined as the ratio of the increment of bioaerosols caused by long-distance transported air to the local level in each area, decreased rapidly after the air left the continent in the dust cases, which is similar to the decrease of the dry deposition flux of dust reported in the literature. This result indicates that the reduction of bioaerosols in the dusty air was likely dominated by the removal of bioaerosols attached to dust particles.

Mass balance, metabolic disposition, and pharmacokinetics of a novel selective inhibitor of PI3Kδ [14C] SHC014748M in healthy Chinese subjects following oral administration.

PURPOSE: SHC014748M is a potent, novel selective PI3Kδ isoform inhibitor and is proposed for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. This study investigated the pharmacokinetics, mass balance, metabolism and excretion of SHC014748M in Chinese male subjects following a single oral dose of 150 mg (100 µCi) [14C] SHC014748M. METHODS: Six healthy Chinese male subjects administrated an oral suspension of 150 mg (100 µCi) [14C] SHC014748M and the samples of blood, urine and feces were collected for measuring. Liquid chromatography-tandem mass spectrometry and liquid scintillation counter were utilized to obtain mass balance and the pharmacokinetic data. RESULTS: The median Tmax for [14C]-radioactivity was 1.6 ± 0.5 h after the oral administration of [14C] SHC014748M and the mean Cmax was 3863 ± 354 ng Eq./mL in plasma, while the mean Cmax, t1/2 values and AUC0-∞ values for total radioactivity in whole blood were 2466 ± 518 ng Eq./mL, 32.2 ± 30.5 h and 66,236 ± 44,232 h * ng Eq./mL, respectively. Fecal excretion was proposed as the predominant elimination route, accounting for a mean of 90.68 ± 11.38% of the administered dose, whereas the mean urine excretion was 6.00 ± 1.48% within 336 h post-dose. The proposed major metabolic pathway of [14C] SHC014748M in the human body were as follows: (I) monooxidation, (II) glucuronide acid conjugation, and (III) monoxide-hydrogenation. CONCLUSIONS: SHC014748M was absorbed, metabolized and excreted with unchanged SHC014748M as its main circulating component in plasma following oral administration. In addition, it was speculated that fecal excretion was the principal excretion pathway; meanwhile, monohydroxy, glucuronide conjugation, oxygen, and hydrogenation were the major clearance pathways of SHC014748M through urine and/or feces. TRIAL REGISTRATION: The trial registration number: CTR20202505.