The Inferential Binding Sites of GCGR for Small Molecules Using Protein Dynamic Conformations and Crystal Structures.

Glucagon receptor (GCGR) is a class B1 G-protein-coupled receptor that plays a crucial role in maintaining human blood glucose homeostasis and is a significant target for the treatment of type 2 diabetes mellitus (T2DM). Currently, six small molecules (Bay 27-9955, MK-0893, MK-3577, LY2409021, PF-06291874, and LGD-6972) have been tested or are undergoing clinical trials, but only the binding site of MK-0893 has been resolved. To predict binding sites for other small molecules, we utilized both the crystal structure of the GCGR and MK-0893 complex and dynamic conformations. We docked five small molecules and selected the best conformation based on binding mode, docking score, and binding free energy. We performed MD simulations to verify the binding mode of the selected small molecules. Moreover, when selecting conformations, results of competitive binding were referred to. MD simulation indicated that Bay 27-9955 exhibits moderate binding stability in Pocket 3. MK-3577, LY2409021, and PF-06291874 exhibited highly stable binding to Pocket 2, consistent with experimental results. However, LY2409021 may also bind to Pocket 5. Additionally, LGD-6972 exhibited relatively stable binding in Pocket 5. We also conducted structural modifications of LGD-6972 based on the results of MD simulations and predicted its analogues' bioavailability, providing a reference for the study of GCGR small molecules.

Temporal and spatial differences in the vaginal microbiome of Chinese healthy women.

Background: Up the reproductive tract, there are large differences in the composition of vaginal microbes. Throughout the menstrual cycle, the structure of the vaginal microbiome shifts. Few studies have examined both in combination. Our study was designed to explore trends in the microbiome of different parts of the vagina in healthy women over the menstrual cycle. Methods: We performed metagenomic sequencing to characterize the microbiome differences between the cervical orifice and mid-vagina throughout the menstrual cycle. Results: Our results showed the vaginal microbiome of healthy women in the cervical orifice and the mid-vagina was similar during the periovulatory and luteal phases, with Lactobacillus being the dominant bacteria. In the follicular phase, Acinetobacter was detected in the cervical orifice. From the follicular phase to the luteal phase, the community state types (all five community status types were defined as CSTs) in samples No. 10 and No. 11 changed from CST III to CST I. In addition, the composition of the vaginal microbiome in healthy women from different regions of China was significantly different. We also detected viruses including Human alphaherpesvirus 1 (HSV-1) during periovulatory phase. Conclusion: This study is valuable for understanding whether the microbial composition of the vagina is consistent in different parts of the menstrual cycle.

Wage Penalties or Wage Premiums? A Socioeconomic Analysis of Gender Disparity in Obesity in Urban China.

Global obesity as a major public health problem has increased at pandemic rate, with men often outpacing women. Survey data show that the overall prevalence of obesity is higher among women than men, yet in high-income developed countries, the prevalence of overweight is higher among men than women. The differential impact of different economic stages has prompted research in transition economies such as China. Using an instrumental variable approach based on a sample of 13,574 individuals from nine provinces in the Chinese Household Income Project (CHIP), we find a 7% excess-weight premium in wages for overweight men and a 4.6% penalty for overweight women, compared to their healthy-weight peers. We also find an inverse u-shaped association between the body mass index (BMI) and logarithm of monthly income for men, with an implied optimum above the threshold of obesity, while women are better off the slimmer they are. The excess-weight premium in wages for Chinese urban men might be associated with entrenched business practices of excessive dining and drinking associated with senior positions. Policies aimed at reducing obesity in China must be adapted to its unique sociocultural context in order to have gender-differentiated effects.

Functional Prediction of Chronic Kidney Disease Susceptibility Gene PRKAG2 by Comprehensively Bioinformatics Analysis.

The genetic predisposition to chronic kidney disease (CKD) has been widely evaluated especially using the genome-wide association studies, which highlighted some novel genetic susceptibility variants in many genes, and estimated glomerular filtration rate to diagnose and stage CKD. Of these variants, rs7805747 in PRKAG2 was identified to be significantly associated with both serum creatinine and CKD with genome wide significance level. Until now, the potential mechanism by which rs7805747 affects CKD risk is still unclear. Here, we performed a functional analysis of rs7805747 variant using multiple bioinformatics software and databases. Using RegulomeDB and HaploReg (version 4.1), rs7805747 was predicated to locate in enhancer histone marks (Liver, Duodenum Mucosa, Fetal Intestine Large, Fetal Intestine Small, and Right Ventricle tissues). Using GWAS analysis in PhenoScanner, we showed that rs7805747 is not only associated with CKD, but also is significantly associated with other diseases or phenotypes. Using metabolite analysis in PhenoScanner, rs7805747 is identified to be significantly associated with not only the serum creatinine, but also with other 16 metabolites. Using eQTL analysis in PhenoScanner, rs7805747 is identified to be significantly associated with gene expression in multiple human tissues and multiple genes including PRKAG2. The gene expression analysis of PRKAG2 using 53 tissues from GTEx RNA-Seq of 8555 samples (570 donors) in GTEx showed that PRKAG2 had the highest median expression in Heart-Atrial Appendage. Using the gene expression profiles in human CKD, we further identified different expression of PRKAG2 gene in CKD cases compared with control samples. In summary, our findings provide new insight into the underlying susceptibility of PRKAG2 gene to CKD.

[Compression of interference hyperspectral image based on FHALS-NTD].

A hyperspectral interference image compression algorithm based on fast hierarchical alternating least squares nonnegative tensor Tucker decomposition (FHALS-NTD) is proposed. Firstly, the interference hyperspectral image is decomposed by 3-D OPD lifting-based discrete wavelet transform (3D OPT-LDWT) in the OPD direction. Then, the 3D DWT sub-bands decomposed are used as a three order nonnegative tensor, which is decomposed by the proposed FHALS-NTD algorithm to obtain 8 core tensors and 24 unknown component matrices. Finally, to obtain the final compressed bit-stream, each unknown component matrices element is quantized, and each core tensor is encoded by the proposed bit-plane coding of significant coefficients. The experimental results showed that the proposed compression algorithm could be used for reliable and stable work and has good compressive property. In the compression ratio range from 32 : 1 to 4 : 1, the average peak signal to noise ratio of proposed compression algorithm is higher than 40 dB. Compared with traditional approaches, the proposed method could improve the average PSNR by 1.23 dB. This effectively improves the compression performance of hyperspectral interference image.