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Background and Purpose: The P2X3 receptor, a trimeric ionotropic purinergic receptor, has emerged as a potential therapeutic target for refractory chronic cough (RCC). Nevertheless, gefapixant/AF‐219, the only marketed P2X3 receptor antagonist, might lead taste disorders by modulating the human P2X2/3 (hP2X2/3) heterotrimer. Hence, in RCC drug development, compounds exhibiting strong affinity for the hP2X3 homotrimer and a weak affinity for the hP2X2/3 heterotrimer hold promise. An example of such a molecule is sivopixant/S‐600918, a clinical Phase II RCC candidate with a reduced incidence of taste disturbance compared to gefapixant. Sivopixant and its analogue, (3‐(4‐([3‐chloro‐4‐isopropoxyphenyl]amino)‐3‐(4‐methylbenzyl)‐2,6‐dioxo‐3,6‐dihydro‐1,3,5‐triazin‐1(2H)‐yl)propanoic acid (DDTPA), exhibit both high affinity and high selectivity for hP2X3 homotrimers, compared with hP2X2/3 heterotrimers. The mechanism underlying the druggable site and its high selectivity remains unclear. Experimental Approach: To analyse mechanisms that distinguish this drug candidate from other inhibitors of the P2X3 receptors we used a combination of chimera construction, site covalent occupation, metadynamics, mutagenesis and whole‐cell recording. Key Results: The high affinity and selectivity of sivopixant/DDTPA for hP2X3 receptors was determined by the tri‐symmetric site located close to the upper vestibule. Substitution of only four amino acids inside the upper body domain of hP2X2 with those of hP2X3, enabled the hP2X2/3 heterotrimer to exhibit a similar level of apparent affinity for sivopixant/DDTPA as the hP2X3 homotrimer. Conclusion and Implications: From the receptor‐ligand recognition perspective, we have elucidated the molecular basis of novel RCC clinical candidates' cough‐suppressing properties and reduced side effects, offering a promising approach to the discovery of novel drugs that specifically target P2X3 receptors. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC) 9 is a negative regulator of adipogenic differentiation, which is required for maintenance of healthy adipose tissues. We reported that HDAC9 expression is upregulated in adipose tissues during obesity, in conjunction with impaired adipogenic differentiation, adipocyte hypertrophy, insulin resistance, and hepatic steatosis, all of which were alleviated by global genetic deletion of Hdac9. Here, we developed a novel transgenic (TG) mouse model to test whether overexpression of Hdac9 is sufficient to induce adipocyte hypertrophy, insulin resistance, and hepatic steatosis in the absence of obesity. HDAC9 TG mice gained less body weight than wild-type (WT) mice when fed a standard laboratory diet for up to 40 weeks, which was attributed to reduced fat mass (primarily inguinal adipose tissue). There was no difference in insulin sensitivity or glucose tolerance in 18-week-old WT and HDAC9 TG mice; however, at 40 weeks of age, HDAC9 TG mice exhibited impaired insulin sensitivity and glucose intolerance. Tissue histology demonstrated adipocyte hypertrophy, along with reduced numbers of mature adipocytes and stromovascular cells, in the HDAC9 TG mouse adipose tissue. Moreover, increased lipids were detected in the livers of aging HDAC9 TG mice, as evaluated by oil red O staining. In conclusion, the experimental aging HDAC9 TG mice developed adipocyte hypertrophy, insulin resistance, and hepatic steatosis, independent of obesity. This novel mouse model may be useful in the investigation of the impact of Hdac9 overexpression associated with metabolic and aging-related diseases. [ABSTRACT FROM AUTHOR]

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ZSSG (ZnSSe/rGO) composites are prepared by a hydrothermal method. The structure, morphology and material properties are investigated by various tests. Compared to ZnSe, the diffraction peaks of ZnSSe are moved to a larger angle and located between cubic phase ZnSe and cubic phase ZnS. The photocurrent density of ZSSG20 with 20 wt.% graphene is 2.17×10−5 A cm−2, which is 8.9 times higher than that of pure ZnSSe. ZSSG20 has the minimum charge transfer resistance and highest carrier density. The decreased fluorescence intensity in PL spectra indicates that graphene can effectively prevent the recombination of electron‐hole pairs. [ABSTRACT FROM AUTHOR]

Abstract Platinum-based chemotherapy is a major therapeutic regimen of lung cancer. Various single nucleotide polymorphisms (SNPs) reported were associated with platinum-based chemotherapy response and drug toxicity. However, neither of the studies explored this association from SNP-SNP interaction perspective nor taking into effects of SNP-environment consideration simultaneously. We genotyped 504 polymorphisms and explore the association of gene-gene and gene-environment interactions with platinum-based chemotherapy response and toxicity in 490 NSCLC patients. 16 SNPs were found significantly associated with platinum-based chemotherapy, and they were picked out as study object in the validation cohort. We recruited 788 patients in the validation cohort. We found that HSPD1 rs17730989-SUMF1 rs2633851 interaction was associated with platinum-based chemotherapy-induced hematologic toxicity (adjusted OR = 0.233, P = 0.018). In addition, the combined effect of ABCG2 rs2231142-CES5A rs3859104 was significantly associated with overall toxicity (adjusted OR = 8.044, P = 4.350 × 10−5). Besides, the model of ARHGAP26 rs3776332-ERCC6 rs2228528-SLC2A1 rs4658-histology was associated with platinum-based chemotherapeutic response. Gene-gene and gene-environment interactions have been identified to contribute to chemotherapy sensitivity and toxicity. They can potentially predict drug response and toxicity of platinum-based chemotherapy in NSCLC patients.

The intercalated layer of coal seam plays an important role in the propagation of hydraulic fracturing. To understand the role of the intercalated layer, a composite coal seam model considering the thickness of the intercalated layer was established. Based on the block distinct element method, the effects of rock structure (thickness of the coal seam and intercalated layer), rock properties (elastic modulus), and construction parameters (injection rate and fluid viscosity) on the penetration behavior of hydraulic fractures were analyzed. The results show that the intercalated layers influence the fracture deflection and have a hindering effect on fracture propagation. The thickness of the intercalated layer affects the stress on the bedding plane and the front edge of the fractures. On the contrary, the thickness of the coal seam mainly affects the penetration ability of hydraulic fractures and the extent of hydraulic fracture propagation. In addition, the elastic modulus of the intercalated layers and coal seams affects the hindering effect of the intercalated layer. The high injection rates reduce the hindering effect of the intercalated layer. When fracturing with a high-viscosity fluid, fractures are more likely to enter the intercalated layer. However, excessively high viscosity can make it difficult for fractures to penetrate the intercalated layer. This study can provide theoretical guidance for the fracturing of composite coal seams. [ABSTRACT FROM AUTHOR]

Melanoma is a melanocyte‐derived malignant cancer and is known for its early metastasis and high mortality rates. It is a highly cutaneous tumour disease that could be related to the abnormal immune microenvironment, and the identification of reliable diagnostic and prognostic markers is crucial for improving patient outcomes. In the search for biomarkers, various types of RNAs have been discovered and recognized as reliable prognostic markers. Among these, small nucleolar RNAs (snoRNAs) have emerged as a promising avenue for studying early diagnosis and prognostic markers in tumours due to their widespread presence in tissues, tumour specificity and stability. In our study, we analysed snoRNAs data from melanoma samples in the TCGA‐SKCM cohort and developed a prognostic model comprising 12 snoRNAs (SNORD9, SNORA31, SNORD14E, SNORA14A, SNORA5A, SNORD83A, SNORA75, AL096855, AC007684, SNORD14A, SNORA65 and AC004839). This model exhibited unique prognostic accuracy and demonstrated a significant correlation with the immune infiltration tumour microenvironment. Additionally, analysis of the GSE213145 dataset, which explored the sensitivity and resistance of immune checkpoint inhibitors, further supported the potential of snoRNAs as prognostic markers for immunotherapy. Overall, our study contributes reliable prognostic and immune‐related biomarkers for melanoma patients. These findings can offer valuable insights for the future discovery of novel melanoma treatment strategies and hold promise for improving clinical outcomes in melanoma patients. [ABSTRACT FROM AUTHOR]

Objective: Impaired adipogenic differentiation exacerbates metabolic disease in obesity. This study reported that high‐fat diet (HFD)‐fed mice housed at thermoneutrality exhibited impaired adipogenic differentiation, attributed to increased expression of histone deacetylase 9 (HDAC9). However, the impact of HFD on adipogenic differentiation is reportedly variable, possibly reflecting divergent environmental conditions such as housing temperature. Methods: C57BL/6J (wild‐type [WT]) mice were housed at either thermoneutral (28–30°C) or ambient (20–22°C) temperature and fed HFD or chow diet (CD) for 12 weeks. For acute exposure experiments, WT or transient receptor potential cation channel subfamily M member 8 (TRPM8) knockout mice housed under thermoneutrality were acutely exposed to ambient temperature for 6 to 24 h. Results: WT mice fed HFD and housed at thermoneutrality, compared with ambient temperature, gained more weight despite reduced food intake. They likewise exhibited increased inguinal adipose tissue HDAC9 expression and reduced adipogenic differentiation in vitro and in vivo compared with CD‐fed mice. Conversely, HFD‐fed mice housed at ambient temperature exhibited minimal change in adipose HDAC9 expression or adipogenic differentiation. Acute exposure of WT mice to ambient temperature reduced adipose HDAC9 expression independent of sympathetic β‐adrenergic signaling via a TRPM8‐dependent mechanism. Conclusions: Adipose HDAC9 expression is temperature sensitive, regulating adipogenic differentiation in HFD‐fed mice housed under thermoneutrality. [ABSTRACT FROM AUTHOR]