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BackgroundCreatinine-cystatin C ratio (CCR) has been demonstrated as an objective marker of sarcopenia in clinical conditions but has not been evaluated as an osteoporosis marker in individuals with normal renal function.MethodsWe selected 271,831 participants with normal renal function from UK Biobank cohort. Multivariable linear/logistic regression and Cox proportional hazards model were used to investigate the phenotypic relationship between CCR and osteoporosis in total subjects and gender-stratified subjects. Based on the genome-wide association study (GWAS) data, linkage disequilibrium regression (LDSC) and Mendelian randomization (MR) analysis were performed to reveal the shared genetic correlations and infer the causal effects, respectively.ResultsAmongst total subjects and gender-stratified subjects, serum CCR was positively associated with eBMD after adjusting for potential risk factors (all P

BackgroundTranscutaneous auricular vagus nerve stimulation (taVNS) has emerged as a potentially effective neuromodulation technique for addressing neurological disorders, including disorders of consciousness. Expanding upon our prior clinical study, which demonstrated the superior effectiveness of a 4-week taVNS treatment in patients with minimally conscious state (MCS) compared to those in a vegetative state/unresponsive wakefulness state, the aim of this investigation was to evaluate the safety and therapeutic efficacy of taVNS in individuals with MCS through a sham-controlled randomized double-blind clinical trial.MethodsA cohort of 50 adult patients (male = 33, female = 17) diagnosed with a MCS were randomly assigned to either the active taVNS (N = 25) or sham taVNS (N = 25) groups. The treatment period lasted for 4 weeks, followed by an 8-week follow-up period. The Coma Recovery Scale-Revised (CRS-R) and Glasgow Coma Scale (GCS) were administered at baseline and weekly during the initial 4 weeks. Additionally, the Disability Rating Scale (DRS) was used to assess the patients’ functional abilities via telephone at week 12. Furthermore, various neurophysiological measures, including electroencephalogram (EEG), upper-limb somatosensory evoked potentials (USEP), brainstem auditory evoked potentials (BAEP), and P300 event-related potentials (P300), were employed to monitor changes in brain activity and neural conduction pathways.ResultsThe scores for the active taVNS group in the CRS-R and GCS showed greater improvement over time compared to the sham taVNS group (CRS-R: 1-week, Z = −1.248, p = 0.212; 2-week, Z = −1.090, p = 0.276; 3-week, Z = −2.017, p = 0.044; 4-week, Z = −2.267, p = 0.023. GCS: 1-week, Z = −1.325, p = 0.185; 2-week, Z = −1.245, p = 0.213; 3-week, Z = −1.848, p = 0.065; 4-week, Z = −1.990, p = 0.047). Additionally, the EEG, USEP, BAEP, and P300 also demonstrated significant improvement in the active taVNS group compared to the sham taVNS group at week 4 (EEG, Z = −2.086, p = 0.037; USEP, Z = −2.014, p = 0.044; BAEP, Z = −2.298, p = 0.022; P300 amplitude, Z = −1.974, p = 0.049; P300 latency, t = 2.275, p = 0.027). Subgroup analysis revealed that patients with MCS derived greater benefits from receiving taVNS treatment earlier (CRS-R, Disease duration ≤ 1-month, mean difference = 8.50, 95% CI = [2.22, 14.78], p = 0.027; GCS, Disease duration ≤ 1-month, mean difference = 3.58, 95% CI = [0.14, 7.03], p = 0.044). By week 12, the active taVNS group exhibited lower Disability Rating Scale (DRS) scores compared to the sham taVNS group (Z = −2.105, p = 0.035), indicating a more favorable prognosis for MCS patients who underwent taVNS. Furthermore, no significant adverse events related to taVNS were observed during treatment.ConclusionThe findings of this study suggest that taVNS may serve as a potentially effective and safe intervention for facilitating the restoration of consciousness in individuals diagnosed with MCS. This therapeutic approach appears to enhance cerebral functioning and optimize neural conduction pathways.Clinical trial registrationhttp://www.chictr.org.cn, Identifier ChiCTR2200066629.

Cigars are developing rapidly around the world, but the content characteristics of aroma precursors and their contribution to sensory perception have not been fully elucidated. In this study, 69 aroma precursors from 61 tobaccos of different parts and origins were systematically determined, and the sensory characteristics of middle leaves from different origins and their correlation with aroma precursors were evaluated. The results showed that tobacco parts mainly affected amino acid content, and contents of nicotine, oxalic acid, malic acid, isovaleric acid, cystine, glutarnine, glycine, isoleucine, glutamicacid, asparticacid, and fructose-proline were significantly changed. Tobacco origins mainly influenced the contents of amino acids, polyacids and high fatty acids, and sugar alcohols, and significantly affected the contents of myosmine, anabasine, nonanoic acid, propanetriol, mannitol, mannose, glucose, alanine, arginine, glutarnine, glutamicacid, histidine, serine, threonine, tryptophan, fructose-alanine, and fructose-asparagine. The flavor characteristics were prominent by wood aroma, and the style and quality characteristics varied greatly among different origins of middle leaves. There were 34, 21, and 22 aroma precursors with high correlations with flavor, style, and quality characteristics. This study provides support for regulating the content and coordination of aroma precursors in different tobacco parts and origins to improve sensory characteristics.

IntroductionMonkeypox is a zoonotic disease caused by brick-shaped enveloped monkeypox (Mpox) virus that belongs to the family of ancient viruses known as Poxviridae. Subsequently, the viruses have been reported in various countries. The virus is transmitted by respiratory droplets, skin lesions, and infected body fluids. The infected patients experience fluid-filled blisters, maculopapular rash, myalgia, and fever. Due to the lack of effective drugs or vaccines, there is a need to identify the most potent and effective drugs to reduce the spread of monkeypox. The current study aimed to use computational methods to quickly identify potentially effective drugs against the Mpox virus.MethodsIn our study, the Mpox protein thymidylate kinase (A48R) was targeted because it is a unique drug target. We screened a library of 9000 FDA-approved compounds of the DrugBank database by using various in silico approaches, such as molecular docking and molecular dynamic (MD) simulation.ResultsBased on docking score and interaction analysis, compounds DB12380, DB13276, DB13276, DB11740, DB14675, DB11978, DB08526, DB06573, DB15796, DB08223, DB11736, DB16250, and DB16335 were predicted as the most potent. To examine the dynamic behavior and stability of the docked complexes, three compounds—DB16335, DB15796, and DB16250 —along with the Apo state were simulated for 300ns. The results revealed that compound DB16335 revealed the best docking score (-9.57 kcal/mol) against the Mpox protein thymidylate kinase.DiscussionAdditionally, during the 300 ns MD simulation period, thymidylate kinase DB16335 showed great stability. Further, in vitro and in vivo study is recommended for the final predicted compounds.

BackgroundWhile osteoimmunology interactions between the immune and skeletal systems are known to play an important role in osteoblast development, differentiation and bone metabolism related disease like osteoporosis, such interactions in either bone microenvironment or peripheral circulation in vivo at the single-cell resolution have not yet been characterized.MethodsWe explored the osteoimmunology communications between immune cells and osteoblastic lineage cells (OBCs) by performing CellphoneDB and CellChat analyses with single-cell RNA sequencing (scRNA-seq) data from human femoral head. We also explored the osteoimmunology effects of immune cells in peripheral circulation on skeletal phenotypes. We used a scRNA-seq dataset of peripheral blood monocytes (PBMs) to perform deconvolution analysis. Then weighted gene co-expression network analysis (WGCNA) was used to identify monocyte subtype-specific subnetworks. We next used cell-specific network (CSN) and the least absolute shrinkage and selection operator (LASSO) to analyze the correlation of a gene subnetwork identified by WGCNA with bone mineral density (BMD).ResultsWe constructed immune cell and OBC communication networks and further identified L-R genes, such as JAG1 and NOTCH1/2, with ossification related functions. We also found a Mono4 related subnetwork that may relate to BMD variation in both older males and postmenopausal female subjects.ConclusionsThis is the first study to identify numerous ligand-receptor pairs that likely mediate signals between immune cells and osteoblastic lineage cells. This establishes a foundation to reveal advanced and in-depth osteoimmunology interactions to better understand the relationship between local bone microenvironment and immune cells in peripheral blood and the impact on bone phenotypes.

The new coronavirus SARS-COV-2, which emerged in late 2019 from Wuhan city of China was regarded as causing agent of the COVID-19 pandemic. The primary protease which is also known by various synonymous i.e., main protease, 3-Chymotrypsin-like protease (3CLPRO) has a vital role in the replication of the virus, which can be used as a potential drug target. The current study aimed to identify novel phytochemical therapeutics for 3CLPRO by machine learning-based virtual screening. A total of 4,000 phytochemicals were collected from deep literature surveys and various other sources. The 2D structures of these phytochemicals were retrieved from the PubChem database, and with the use of a molecular operating environment, 2D descriptors were calculated. Machine learning-based virtual screening was performed to predict the active phytochemicals against the SARS-CoV-2 3CLPRO. Random forest achieved 98% accuracy on the train and test set among the different machine learning algorithms. Random forest model was used to screen 4,000 phytochemicals which leads to the identification of 26 inhibitors against the 3CLPRO. These hits were then docked into the active site of 3CLPRO. Based on docking scores and protein-ligand interactions, MD simulations have been performed using 100 ns for the top 5 novel inhibitors, ivermectin, and the APO state of 3CLPRO. The post-dynamic analysis i.e,. Root means square deviation (RMSD), Root mean square fluctuation analysis (RMSF), and MM-GBSA analysis reveal that our newly identified phytochemicals form significant interactions in the binding pocket of 3CLPRO and form stable complexes, indicating that these phytochemicals could be used as potential antagonists for SARS-COV-2.

Chemical analysis of atmospheric aerosols by conventional analytical methods is usually required to perform complicated and time-consuming sample preparation processes. In recent decades, ambient ionization mass spectrometry (AI-MS) methods have been proven to be simple, rapid, and effective analytical tools for direct analysis of various complex samples. In this work, we applied porous paper filters for direct adsorptive sampling of tobacco smoke, and then the sampled paper filters were performed the emitters of the paper spray ionization (PSI) device. An auto-sampling device was made to control the generation and collection of tobacco smoke. Nicotine, the typical compound of tobacco smoke, was used to optimize the key conditions of auto-sampling. Moreover, different types of tobacco smoke were also compared with multivariate variable analysis, and the makers of tobacco smoke from different sources of tobacco smoke were investigated. By using this method, direct sampling and analysis of a single tobacco sample can be completed within minutes. Overall, our results show that PSI-MS is a powerful tool that integrates collection, extraction, ionization, and identification analytes in smoke.

BackgroundEffective identification of high-risk rheumatoid arthritis (RA) individuals is still a challenge. Whether the combined effects of multiple previously reported genetic loci together with lifestyle factors can improve the prediction of RA risk remains unclear.MethodsBased on previously reported results and a large-scale Biobank dataset, we constructed a polygenic risk score (PRS) for RA to evaluate the combined effects of the previously identified genetic loci in both case-control and prospective cohorts. We then evaluated the relationships between several lifestyles and RA risk and determined healthy lifestyles. Then, the joint effects of healthy lifestyles and genetic risk on RA risk were evaluated.ResultsWe found a positive association between PRS and RA risk (OR = 1.407, 95% confidence interval (CI) = 1.354~1.463; HR = 1.316, 95% CI = 1.257~1.377). Compared with the low genetic risk group, the group with intermediate or high genetic risk had a higher risk (OR = 1.347, 95% CI = 1.213~1.496; HR = 1.246, 95% CI = 1.108~1.400) (OR = 2.169, 95% CI = 1.946~2.417; HR = 1.762, 95% CI = 1.557~1.995). After adjusting for covariates, we found protective effects of three lifestyles (no current smoking, regular physical activity, and moderate body mass index) on RA risk and defined them as healthy lifestyles. Compared with the individuals with low genetic risks and favorable lifestyles, those with high genetic risks and unfavorable lifestyles had as high as OR of 4.637 (95%CI = 3.767~5.708) and HR of 3.532 (95%CI = 2.799~4.458).ConclusionsIn conclusion, the integration of PRS and lifestyles can improve the prediction of RA risk. High RA risk can be alleviated by adopting healthy lifestyles but aggravated by adopting unfavorable lifestyles.

Gonadotropins play vital roles in the regulation of female reproductive ability and fertility. Our study aimed to determine the effects of superovulation induced by increasing doses of equine chorionic gonadotropin [eCG; also referred to as pregnant mare serum gonadotropin (PMSG)] on the developmental competence of mouse embryos and on aneuploidy formation during in vitro fertilization (IVF). eCG dose-dependently enhanced the oocyte yield from each mouse. Administration of 15 IU eCG significantly reduced the fertilization rate and the formation of four-cell embryos and blastocysts and increased the risk of chromosome aneuploidy. The IVF-derived blastocysts in the 15 IU eCG treatment group had the fewest total cells, inner cell mass (ICM) cells and trophectoderm (TE) cells. Moreover, more blastocysts and fewer apoptotic cells were observed in the 0, 5, and 10 IU eCG treatment groups than in the 15 IU eCG treatment group. We also investigated reactive oxygen species (ROS) levels and variations in several variables: mitochondrial membrane potential (MMP); active mitochondria; mitochondrial superoxide production; adenosine triphosphate (ATP) content; spindle structures; chromosome karyotypes; microfilament distribution; and the expression of Aurora B [an important component of the chromosomal passenger complex (CPC)], the spindle assembly checkpoint (SAC) protein mitotic arrest deficient 2 like 1 (MAD2L1), and the DNA damage response (DDR) protein γH2AX. Injection of 15 IU eCG increased ROS levels, rapidly reduced MMP, increased active mitochondria numbers and mitochondrial superoxide production, reduced ATP content, increased abnormal spindle formation rates, and induced abnormalities in chromosome number and microfilament distribution, suggesting that a high dose of eCG might alter developmental competence and exert negative effects on IVF-obtained mouse embryos. Additionally, the appearance of γH2AX and the significantly increased expression of Aurora B and MAD2L1 suggested that administration of relatively high doses of eCG caused Aurora B-mediated SAC activation triggered by ROS-induced DNA damage in early mouse IVF-derived embryos for self-correction of aneuploidy formation. These findings improve our understanding of the application of gonadotropins and provide a theoretical basis for gonadotropin treatment.

In zygotes, the capacity of G2/M checkpoint and DNA repair mechanisms to respond to DNA damage varies depending on different external stressors. In our previous studies, we found that mild oxidative stress induced a G2/M phase delay in mouse zygotes fertilized in vitro, due to the activation of the spindle assembly checkpoint. However, it is unclear whether the G2/M phase delay involves G2 arrest, triggered by activation of the G2/M checkpoint, and whether AMPK, a highly conserved cellular energy sensor, is involved in G2 arrest and DNA damage repair in mouse zygotes. Here, we found that mouse zygotes treated with 0.03 mM H2O2 at 7 h post-insemination (G1 phase), went into G2 arrest in the first cleavage. Furthermore, phosphorylated H2AX, a specific DNA damage and repair marker, can be detected since the early S phase. We also observed that oxidative stress induced phosphorylation and activation of AMPK. Oxidative stress-activated AMPK first localized in the cytoplasm of the mouse zygotes in the late G1 phase and then translocated to the nucleus from the early S phase. Overall, most of the activated AMPK accumulated in the nuclei of mouse zygotes arrested in the G2 phase. Inhibition of AMPK activity with Compound C and SBI-0206965 abolished oxidative stress-induced G2 arrest, increased the activity of CDK1, and decreased the induction of cell cycle regulatory proteins p53 and p21. Moreover, bypassing G2 arrest after AMPK inhibition aggravated oxidative stress-induced DNA damage at M phase, increased the apoptotic rate of blastocysts, and reduced the formation rate of 4-cell embryos and blastocysts. Our results suggest the G2/M checkpoint and DNA repair mechanisms are operative in coping with mild oxidative stress-induced DNA damage. Further, AMPK activation plays a vital role in the regulation of the oxidative stress-induced G2 arrest through the inhibition of CDK1 activity via p53/p21 pathways, thereby facilitating the repair of DNA damage and the development and survival of oxidative stress-damaged embryos. Our study provides insights into the molecular mechanisms underlying oxidative-stress induced embryonic developmental arrest, which is crucial for the development of novel strategies to ensure viable embryo generation.

BackgroundGenome-wide association studies (GWASs) routinely identify loci associated with risk factors for osteoporosis. However, GWASs with relatively small sample sizes still lack sufficient power to ascertain the majority of genetic variants with small to modest effect size, which may together truly influence the phenotype. The loci identified only account for a small percentage of the heritability of osteoporosis. This study aims to identify novel genetic loci associated with DXA-derived femoral neck (FNK) bone mineral density (BMD) and quantitative ultrasound of the heel calcaneus estimated BMD (eBMD), and to detect shared/causal variants for the two traits, to assess whether the SNPs or putative causal SNPs associated with eBMD were also associated with FNK-BMD.MethodsNovel loci associated with eBMD and FNK-BMD were identified by the genetic pleiotropic conditional false discovery rate (cFDR) method. Shared putative causal variants between eBMD and FNK-BMD and putative causal SNPs for each trait were identified by the colocalization method. Mendelian randomization analysis addresses the causal relationship between eBMD/FNK-BMD and fracture.ResultsWe identified 9,500 (cFDR < 9.8E-6), 137 (cFDR < 8.9E-4) and 124 SNPs associated with eBMD, FNK-BMD, and both eBMD and FNK-BMD, respectively, with 37 genomic regions where there was a SNP that influences both eBMD and FNK-BMD. Most genomic regions only contained putative causal SNPs associated with eBMD and 3 regions contained two distinct putative causal SNPs influenced both traits, respectively. We demonstrated a causal effect of FNK-BMD/eBMD on fracture.ConclusionMost of SNPs or putative causal SNPs associated with FNK-BMD were also associated with eBMD. However, most of SNPs or putative causal SNPs associated with eBMD were not associated with FNK-BMD. The novel variants we identified may help to account for the additional proportion of variance of each trait and advance our understanding of the genetic mechanisms underlying osteoporotic fracture.

Canine piroplasmosis is a significant disease in dogs caused by Babesia and Theileria parasites. The clinical manifestations range from mild illness to serious disease depending on the parasite species and the physical condition of the infected dog. Canine piroplasmosis has been reported to be prevalent in China. However, no molecular evidence of the disease has been reported in pet dogs from Wuhan. In this study, 118 blood samples were randomly collected from pet dogs in veterinary clinics. The blood samples were subjected to both microscopic examination and reverse line blot (RLB) hybridization assays to detect piroplasm infection. Parasites were observed in 10 blood samples via microscopic examination, whereas there were 14 Babesia gibsoni-positive RLB tests. Phylogenetic analysis was performed after the 18S rRNA and ITS gene sequences from the 14 positive samples were cloned and sequenced. The results confirmed the existence of B. gibsoni in this area. This is the first molecular report of canine babesiosis in pet dogs from Wuhan, China. Pet dogs are companion animals, and the prevalence of babesiosis will be of concern in daily life. This study will help veterinarians better understand the prevalence of canine babesiosis and provide a guide for disease control in pet dogs.

This study aimed to investigate the independent clinical, pathological, and radiological factors associated with extracapsular extension in radical prostatectomy specimens and to improve the accuracy of predicting extracapsular extension of prostate cancer before surgery. Methods: From August 2018 to June 2023, the clinical and pathological data of 229 patients with confirmed prostate cancer underwent radical prostatectomy from The Second Hospital of Yinzhou. The patients' multiparametric magnetic resonance imaging data were graded using the Likert scale. The chi-square or independent-sample T-test was used to analyze the related factors for an extracapsular extension. Multivariate analysis was used to identify independent factors associated with extracapsular extension in prostate cancer. Additionally, receiver operating characteristic curve analysis was used to calculate the area under the curve and assess the diagnostic performance of our model. The clinical decision curve was used to analyze the clinical net income of Likert scale, biopsy positive rate, biopsy GG, and combined mode. Results: Of the 229 patients, 52 had an extracapsular extension, and 177 did not. Multivariate analysis showed that the Likert scale score, biopsy grade group and biopsy positive rate were independent risk factors for extracapsular extension in prostate cancer. The area under the curves for the Likert scale score, biopsy grade group, and biopsy positive rate were 0.802, 0.762, and 0.796, respectively. Furthermore, there was no significant difference in the diagnostic efficiency for extracapsular extension (P>0.05). However, when these three factors were combined, the diagnostic efficiency was significantly improved, and the area under the curve increased to 0.905 (P<0.05). In the analysis of the decision curve, The clinical net income of the combined model is obviously higher than that of Likert scale, biopsy positive rate, and biopsy GG. Conclusion: The Likert scale, biopsy grade group and biopsy positive rate are independent risk factors for extracapsular extension in prostate cancer, and their combination can significantly improve the diagnostic efficiency for an extracapsular extension. [ABSTRACT FROM AUTHOR]

Introduction: Monkeypox is a zoonotic disease caused by brick-shaped enveloped monkeypox (Mpox) virus that belongs to the family of ancient viruses known as Poxviridae. Subsequently, the viruses have been reported in various countries. The virus is transmitted by respiratory droplets, skin lesions, and infected body fluids. The infected patients experience fluid-filled blisters, maculopapular rash, myalgia, and fever. Due to the lack of effective drugs or vaccines, there is a need to identify the most potent and effective drugs to reduce the spread of monkeypox. The current study aimed to use computational methods to quickly identify potentially effective drugs against the Mpox virus. Methods: In our study, the Mpox protein thymidylate kinase (A48R) was targeted because it is a unique drug target. We screened a library of 9000 FDA-approved compounds of the DrugBank database by using various in silico approaches, such as molecular docking and molecular dynamic (MD) simulation. Results: Based on docking score and interaction analysis, compounds DB12380, DB13276, DB13276, DB11740, DB14675, DB11978, DB08526, DB06573, DB15796, DB08223, DB11736, DB16250, and DB16335 were predicted as the most potent. To examine the dynamic behavior and stability of the docked complexes, three compounds--DB16335, DB15796, and DB16250--along with the Apo state were simulated for 300ns. The results revealed that compound DB16335 revealed the best docking score (-9.57 kcal/mol) against the Mpox protein thymidylate kinase. Discussion: Additionally, during the 300 ns MD simulation period, thymidylate kinase DB16335 showed great stability. Further, in vitro and in vivo study is recommended for the final predicted compounds. [ABSTRACT FROM AUTHOR]