From musk to body odor: Decoding olfaction through genetic variation.

The olfactory system combines input from multiple receptor types to represent odor information, but there are few explicit examples relating olfactory receptor (OR) activity patterns to odor perception. To uncover these relationships, we performed genome-wide scans on odor-perception phenotypes for ten odors in 1000 Han Chinese and validated results for six of these odors in an ethnically diverse population (n = 364). In both populations, consistent with previous studies, we replicated three previously reported associations (ß-ionone/OR5A1, androstenone/OR7D4, cis-3-hexen-1-ol/OR2J3 LD-band), but not for odors containing aldehydes, suggesting that olfactory phenotype/genotype studies are robust across populations. Two novel associations between an OR and odor perception contribute to our understanding of olfactory coding. First, we found a SNP in OR51B2 that associated with trans-3-methyl-2-hexenoic acid, a key component of human underarm odor. Second, we found two linked SNPs associated with the musk Galaxolide in a novel musk receptor, OR4D6, which is also the first human OR shown to drive specific anosmia to a musk compound. We noticed that SNPs detected for odor intensity were enriched with amino acid substitutions, implying functional changes of odor receptors. Furthermore, we also found that the derived alleles of the SNPs tend to be associated with reduced odor intensity, supporting the hypothesis that the primate olfactory gene repertoire has degenerated over time. This study provides information about coding for human body odor, and gives us insight into broader mechanisms of olfactory coding, such as how differential OR activation can converge on a similar percept.

A Minimalist Iron Oxide Nanoprobe for the High-Resolution Depiction of Stroke by Susceptibility-Weighted Imaging.

The precise mapping of collateral circulation and ischemic penumbra is crucial for diagnosing and treating acute ischemic stroke (AIS). Unfortunately, there exists a significant shortage of high-sensitivity and high-resolution in vivo imaging techniques to fulfill this requirement. Herein, a contrast enhanced susceptibility-weighted imaging (CE-SWI) using the minimalist dextran-modified Fe3O4 nanoparticles (Fe3O4@Dextran NPs) are introduced for the highly sensitive and high-resolution AIS depiction under 9.4 T for the first time. The Fe3O4@Dextran NPs are synthesized via a simple one-pot coprecipitation method using commercial reagents under room temperature. It shows merits of small size (hydrodynamic size 25.8 nm), good solubility, high transverse relaxivity (r2) of 51.3 mM-1s-1 at 9.4 T, and superior biocompatibility. The Fe3O4@Dextran NPs-enhanced SWI can highlight the cerebral vessels readily with significantly improved contrast and ultrahigh resolution of 0.1 mm under 9.4 T MR scanner, enabling the clear spatial identification of collateral circulation in the middle cerebral artery occlusion (MCAO) rat model. Furthermore, Fe3O4@Dextran NPs-enhanced SWI facilitates the precise depiction of ischemia core, collaterals, and ischemic penumbra post AIS through matching analysis with other multimodal MR sequences. The proposed Fe3O4@Dextran NPs-enhanced SWI offers a high-sensitivity and high-resolution imaging tool for individualized characterization and personally precise theranostics of stroke patients.

A new approach towards highly sensitive detection of endogenous N-acetylaspartic acid, N-acetylglutamic acid, and N-acetylaspartylglutamic acid in brain tissues based on strong anion exchange monolith microextraction coupled with UHPLC-MS/MS.

A novel in-tube solid-phase microextraction coupled with an ultra-high performance liquid chromatography-mass spectrometry method has been established for simultaneous quantification of three crucial brain biomarkers N-acetylaspartic acid (NAA), N-acetylglutamic acid (NAG), and N-acetylaspartylglutamic acid (NAAG). A polymer monolith with quaternary ammonium as the functional group was designed and exhibited efficient enrichment of target analytes through strong anion exchange interaction. Under the optimized conditions, the proposed method displayed wide linear ranges (0.1-80 nM for NAA and NAG, 0.2-160 nM for NAAG) with good precision (RSDs were lower than 15%) and low limits of detection (0.019-0.052 nM), which is by far the most sensitive approach for NAA, NAG, and NAAG determination. Furthermore, this approach has been applied to measure the target analytes in mouse brain samples, and endogenous NAA, NAG, and NAAG were successfully detected and quantified from only around 5 mg of cerebral cortex, cerebellum, and hippocampus. Compared with existing methods, the newly developed method in the current study provides highest sensitivity and lowest sample consumption for NAA, NAG, and NAAG measurements, which would potentially be utilized in determining and tracking these meaningful brain biomarkers in diseases or treatment processes, benefiting the investigations of pathophysiology and treatment of brain disorders.

Heat Shock Factor A1s are required for phytochrome-interacting factor 4-mediated thermomorphogenesis in Arabidopsis.

Thermomorphogenesis and the heat shock (HS) response are distinct thermal responses in plants that are regulated by PHYTOCHROME-INTERACTING FACTOR 4 (PIF4) and HEAT SHOCK FACTOR A1s (HSFA1s), respectively. Little is known about whether these responses are interconnected and whether they are activated by similar mechanisms. An analysis of transcriptome dynamics in response to warm temperature (28°C) treatment revealed that 30 min of exposure activated the expression of a subset of HSFA1 target genes in Arabidopsis thaliana. Meanwhile, a loss-of-function HSFA1 quadruple mutant (hsfa1-cq) was insensitive to warm temperature-induced hypocotyl growth. In hsfa1-cq plants grown at 28°C, the protein and transcript levels of PIF4 were greatly reduced, and the circadian rhythm of many thermomorphogenesis-related genes (including PIF4) was disturbed. Additionally, the nuclear localization of HSFA1s and the binding of HSFA1d to the PIF4 promoter increased following warm temperature exposure, whereas PIF4 overexpression in hsfa1-cq partially rescued the altered warm temperature-induced hypocotyl growth of the mutant. Taken together, these results suggest that HSFA1s are required for PIF4 accumulation at a warm temperature, and they establish a central role for HSFA1s in regulating both thermomorphogenesis and HS responses in Arabidopsis.

Comparative transcriptome analysis to unveil genes affecting the host cuticle destruction in Metarhizium rileyi.

Insect pathogenic fungi, also known as entomopathogenic fungi, are one of the largest insect pathogenic microorganism communities, represented by Beauveria spp. and Metarhizium spp. Entomopathogenic fungi have been proved to be a great substitute for chemical pesticide in agriculture. In fact, a lot of functional genes were also already characterized in entomopathogenic fungi, but more depth of exploration is still needed to reveal their complicated pathogenic mechanism to insects. Metarhizium rileyi (Nomuraea rileyi) is a great potential biocontrol fungus that can parasitize more than 40 distinct species (mainly Lepidoptera: Noctuidae) to cause large-scale infectious diseases within insect population. In this study, a comparative analysis of transcriptome profile was performed with topical inoculation and hemolymph injection to character the infectious pattern of M. rileyi. Appressorium and multiple hydrolases are indispensable constituents to break the insect host primary cuticle defense in entomopathogenic fungi. Within our transcriptome data, numerous transcripts related to destruction of insect cuticle rather growth regulations were obtained. Most importantly, some unreported ribosomal protein genes and novel unannotated protein (hypothetical protein) genes were proved to participate in the course of pathogenic regulation. Our current data provide a higher efficiency gene library for virulence factors screen in M. rileyi, and this library may be also useful for furnishing valuable information on entomopathogenic fungal pathogenic mechanisms to host.

Comprehensive analyses of 723 transcriptomes enhance genetic and biological interpretations for complex traits in cattle.

By uniformly analyzing 723 RNA-seq data from 91 tissues and cell types, we built a comprehensive gene atlas and studied tissue specificity of genes in cattle. We demonstrated that tissue-specific genes significantly reflected the tissue-relevant biology, showing distinct promoter methylation and evolution patterns (e.g., brain-specific genes evolve slowest, whereas testis-specific genes evolve fastest). Through integrative analyses of those tissue-specific genes with large-scale genome-wide association studies, we detected relevant tissues/cell types and candidate genes for 45 economically important traits in cattle, including blood/immune system (e.g., CCDC88C) for male fertility, brain (e.g., TRIM46 and RAB6A) for milk production, and multiple growth-related tissues (e.g., FGF6 and CCND2) for body conformation. We validated these findings by using epigenomic data across major somatic tissues and sperm. Collectively, our findings provided novel insights into the genetic and biological mechanisms underlying complex traits in cattle, and our transcriptome atlas can serve as a primary source for biological interpretation, functional validation, studies of adaptive evolution, and genomic improvement in livestock.

Single-step genome-wide association analyses of claw horn lesions in Holstein cattle using linear and threshold models.

BACKGROUND: Lameness in dairy cattle is primarily caused by foot lesions including the claw horn lesions (CHL) of sole haemorrhage (SH), sole ulcers (SU), and white line disease (WL). This study investigated the genetic architecture of the three CHL based on detailed animal phenotypes of CHL susceptibility and severity. Estimation of genetic parameters and breeding values, single-step genome-wide association analyses, and functional enrichment analyses were performed. RESULTS: The studied traits were under genetic control with a low to moderate heritability. Heritability estimates of SH and SU susceptibility on the liability scale were 0.29 and 0.35, respectively. Heritability of SH and SU severity were 0.12 and 0.07, respectively. Heritability of WL was relatively lower, indicating stronger environmental influence on the presence and development of WL than the other two CHL. Genetic correlations between SH and SU were high (0.98 for lesion susceptibility and 0.59 for lesion severity), whereas genetic correlations of SH and SU with WL also tended to be positive. Candidate quantitative trait loci (QTL) were identified for all CHL, including some on Bos taurus chromosome (BTA) 3 and 18 with potential pleiotropic effects associated with multiple foot lesion traits. A genomic window of 0.65 Mb on BTA3 explained 0.41, 0.50, 0.38, and 0.49% of the genetic variance for SH susceptibility, SH severity, WL susceptibility, and WL severity, respectively. Another window on BTA18 explained 0.66, 0.41, and 0.70% of the genetic variance for SH susceptibility, SU susceptibility, and SU severity, respectively. The candidate genomic regions associated with CHL harbour annotated genes that are linked to immune system function and inflammation responses, lipid metabolism, calcium ion activities, and neuronal excitability. CONCLUSIONS: The studied CHL are complex traits with a polygenic mode of inheritance. Most traits exhibited genetic variation suggesting that animal resistance to CHL can be improved with breeding. The CHL traits were positively correlated, which will facilitate genetic improvement for resistance to CHL as a whole. Candidate genomic regions associated with lesion susceptibility and severity of SH, SU, and WL provide insights into a global profile of the genetic background underlying CHL and inform genetic improvement programmes aiming at enhancing foot health in dairy cattle.

Multifunctional regulation of NADPH oxidase in growth, microsclerotia formation and virulence in Metarhizium rileyi.

OBJECTIVES: Microsclerotia (MS), anti-stress structures produced by many filamentous fungi, have been proven to be a great substitute for conidia in the production of insecticides within entomogenous fungi. NADPH oxidase (Nox) is a highly conserved ROS-response protein family that is widespread in eukaryotes and plays distinct roles in environmental fitness among various filamentous fungi. However, it is not clear whether the formation of MS and pathogenicity in entomogenous fungi is regulated by the Nox inside. In this study, we reported the presence of NADPH oxidase homologs in a great potential biocontrol fungus, Metarhizium rileyi, and further showed multiple biological functions. RESULTS: Three Nox homologous genes in M. rileyi showed high expression throughout the entire process of MS formation. Targeted deletion of MrNoxA, MrNoxB and MrNoxR all led to a decrease in MS yield and impaired morphology. Moreover, the anti-adversity assay showed that they are indispensable for growth, osmotic pressure and oxidative stress regulation in Metarhizium rileyi. Most importantly, △MrNoxR and △MrNoxA but not △MrNoxB showed a dramatic reduction in virulence via inoculation. The normality of appressoria might be unaffected in mutants since there are no striking differences in virulence compared with WT by topical injections. CONCLUSION: Our results revealed that NADPH oxidase plays important roles in growth regulation, MS formation and pathogenicity in M. rileyi, perhaps in the ROS response and hyphal polarity.

Genetic parameters of sole lesion recovery in Holstein cows.

Sole hemorrhage and sole ulcers, referred to as sole lesions, are important causes of lameness in dairy cattle. The objective of this study was to estimate the genetic parameters of a novel trait reflecting how well cows recovered from sole lesions and the genetic correlation of this trait with overall susceptibility to sole lesions. A cohort of Holstein dairy cows was prospectively enrolled on 4 farms and assessed at 4 timepoints: before calving, immediately after calving, in early lactation, and in late lactation. At each timepoint, sole lesions were recorded at the claw level by veterinary surgeons and used to define 2 binary traits: (1) susceptibility to sole lesions-whether animals were affected with sole lesions at least once during the study or were unaffected at every assessment, and (2) sole lesion recovery-whether sole lesions healed between early and late lactation. Animals were genotyped and pedigree details extracted from the national database. Analyses were conducted with BLUPF90 software in a single-step framework; genetic parameters were estimated from animal threshold models using Gibbs sampling. The genetic correlation between both traits was approximated as the correlation between genomic estimated breeding values, adjusting for their reliabilities. A total of 2,025 animals were used to estimate the genetic parameters of sole lesion susceptibility; 44% of animals recorded a sole lesion at least once during the study period. The heritability of sole lesion susceptibility, on the liability scale, was 0.25 (95% highest density interval = 0.16-0.34). A total of 498 animals were used to estimate the genetic parameters of sole lesion recovery; 71% of animals had recovered between the early and late lactation assessments. The heritability of sole lesion recovery, on the liability scale, was 0.27 (95% highest density interval = 0.02-0.52). The approximate genetic correlation between each trait was -0.11 (95% confidence interval = -0.20 to -0.02). Our results indicate that recovery from sole lesions is heritable. If this finding is corroborated in further studies, it may be possible to use selective breeding to reduce the frequency of chronically lame cows. As sole lesion recovery appears to be weakly genetically related to sole lesion susceptibility, successful genetic improvement of sole lesion recovery would benefit from selection on this trait directly.

NVTrans-UNet: Neighborhood vision transformer based U-Net for multi-modal cardiac MR image segmentation.

With the rapid development of artificial intelligence and image processing technology, medical imaging technology has turned into a critical tool for clinical diagnosis and disease treatment. The extraction and segmentation of the regions of interest in cardiac images are crucial to the diagnosis of cardiovascular diseases. Due to the erratically diastolic and systolic cardiac, the boundaries of Magnetic Resonance (MR) images are quite fuzzy. Moreover, it is hard to provide complete information using a single modality due to the complex structure of the cardiac image. Furthermore, conventional CNN-based segmentation methods are weak in feature extraction. To overcome these challenges, we propose a multi-modal method for cardiac image segmentation, called NVTrans-UNet. Firstly, we employ the Neighborhood Vision Transformer (NVT) module, which takes advantage of Neighborhood Attention (NA) and inductive biases. It can better extract the local information of the cardiac image as well as reduce the computational cost. Secondly, we introduce a Multi-modal Gated Fusion (MGF) network, which can automatically adjust the contributions of different modal feature maps and make full use of multi-modal information. Thirdly, the bottleneck layer with Atrous Spatial Pyramid Pooling (ASPP) is proposed to expand the feature receptive field. Finally, the mixed loss is added to the cardiac image to focus the fuzzy boundary and realize accurate segmentation. We evaluated our model on MyoPS 2020 dataset. The Dice score of myocardial infarction (MI) was 0.642 ± 0.171, and the Dice score of myocardial infarction + edema (MI + ME) was 0.574 ± 0.110. Compared with the baseline, the MI increases by 11.2%, and the MI + ME increases by 12.5%. The results show the effectiveness of the proposed NVTrans-UNet in the segmentation of MI and ME.

Response of the runoff process to meteorological drought: Baseflow index as an important indicator.

Runoff and baseflow are two hydrological elements most closely involved in water-resource management. Defining the response of runoff/baseflow to meteorological drought (MD) is helpful for designing precise drought resisting measures. Thus, Pearson correlation coefficients and mutual information scores between runoff/baseflow and MD in five sub-basins of the Weihe River Basin (WRB) were estimated on a weekly scale, and the best response times of runoff/baseflow to MD on annual and calendar months were determined according to the maximum degree of response. Furthermore, the spatial and seasonal differences in response characteristics in the WRB were discussed and the baseflow index (BFI) was introduced to further explain the propagation process of MD to runoff/baseflow. The results showed that (1) in addition to the response time, the transition sequences of MD propagating to runoff and baseflow varied across basins due to the specific basin properties; (2) Response time of runoff to MD was related to BFI value and showed significant seasonality and hydrological periodicity. In summer and autumn (wet season), the response was faster and stronger, whereas the opposite occurred in winter and spring (normal/dry season); (3) BFI values indicated the main path of drought propagation, explaining the variation in response time between basins and seasons; hence, it can be used to simply and effectively determine the propagation speed of MD to runoff. This study clarified the response characteristics of the runoff process to MD and enhanced our understanding of the drought propagation process, which is crucial for mitigating and managing drought-related hazards.

Analysis and simulation of the driving mechanism and ecological effects of land cover change in the Weihe River basin, China.

Land cover change (LCC) is both a consequence and a cause of global environmental change. This paper attempts to construct a framework to reveal the driving mechanism and ecological effects of different ecological factors under LCC and to explore the ecological characteristics of future LCC. A rule-mining framework based on a land expansion analysis strategy (LEAS) in the patch-generating land use simulation (PLUS) model was used to analyze the drivers of LCC. Neighborhood analysis and ecological effect index were used to investigate multiple ecological effects of LCC. Remote sensing-based ecological indices (RSEI) and the PLUS and stepwise regression model were introduced to explore and predict the integrated ecological effect of LCC. Focusing on the Weihe River basin, study's main drivers of LCC were precipitation, temperature, elevation, population, water table depth, proximity to governments and motorways, GDP, and topsoil organic carbon were the main drivers of LCC. Change directionality were similar for the effects of greenness and biomass formation but opposite for summertime and wintertime temperature. In addition, the conversion of land cover types to cropland had the most significant integrated ecological effect, followed by forest, grassland-shrubland, and other types. The RSEI is predicted to rise to 0.77 in 2030, and the areas where the ecological quality grade will improve and decrease are concentrated on the east and west sides of Ziwuling Mountain, respectively. The findings of this study have practical significance for land management and ecological protection.

The global prevalence of oral leukoplakia: a systematic review and meta-analysis from 1996 to 2022.

BACKGROUND: Oral leukoplakia(OLK) is a common oral potentially malignant disorder. The global prevalence of solely OLK was published in 2003, while the prevalence varied among different studies. In recent years, large-scale summary and definition-related analyses obtain insufficient attention. This study aimed to perform a systematic review of prevalence studies of oral leukoplakia and assess predisposing factors of its occurrence. METHODS: The search terms ("Oral leukoplakia" OR OLK OR leukoplakia) AND (prevalence OR incidence OR epidemiology) were searched in databases (Pubmed, Embase, Scopus, and Web of Science) for OLK studies published from January 1996 until December 2022. The estimated prevalence calculation and risk of bias analysis used STATA 16.0. RESULTS: We obtained 69 studies, including 1,263,028 participants, from 28 countries, and 6 continents. The prevalence was 1.39%, varying from 0.12 to 33.33%. The overall pooled estimated prevalence of OLK was 2.23% for population-based studies, 1.36% for clinic-based population studies, and 9.10% for specific populations. The pooled prevalence in different continents ranged from 0.33 to 11.74% with a statistical difference in the population-based calculation. The estimated prevalence of OLK was higher in males than in females. Those who smoked and consumed alcohol had a higher prevalence than those who did not. CONCLUSION: Combining data from 69 published studies, the prevalence of OLK was determined as 1.39% and the pooling estimated global prevalence was 3.41%. The prevalence was relatively consistent and stable across different continents and different definitions. A higher pooled estimated prevalence was found among males, those aged over 60 years old, smokers, and alcohol consumers. The results from the included studies in this systematic review revealed that the prevalence was relatively consistent and stable across various definitions and continents, which may help in developing global treatment and prevention strategies for oral leukoplakia.

[Pharmacokinetics and tissue distribution of four alkaloids in Ermiao Pills and Sanmiao Pills in normal and arthritic model rats].

This work aimed to investigate the differences of pharmacokinetics and tissue distribution of four alkaloids in Ermiao Pills and Sanmiao Pills in normal and arthritic model rats. The rat model of arthritis was established by injecting Freund's complete adjuvant, and ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) in the positive ion multiple reaction monitoring(MRM) mode was used for the determination of four alkaloids in plasma and tissues of normal and arthritic rats after administration of Ermiao Pills and Sanmiao Pills, respectively. The differences in pharmacokinetics and tissue distribution of the four active components were compared, and the effect of Achyranthis Bidentatae Radix on the major components of Sanmiao Pills was explored. This study established an UPLC-MS/MS for simultaneous determination of four alkaloids, and the specificity, linearity, accuracy, precision, and stability of this method all met the requirements. Pharmacokinetics study found that as compared with normal rats, the AUC and C_(max) of phellodendrine, magnoflorine, berberine and palmatine in model rats were significantly decreased after administration of Ermiao Pills, the clearance rate CL/F was significantly increased, and the distribution and tissue/plasma concentration ratio of the four alkaloids in the liver, kidney, and joint were significantly reduced. Achyranthis Bidentatae Radix increased the AUC of phellodendrine, berberine, and palmatine, reduced the clearance rate, and significantly increased the distribution of the four alkaloids in the liver, kidney, and joints in arthritic rats. However, it had no significant effect on the pharmacokinetics and tissue distribution of the four alkaloids in normal rats. These results suggest that Achyranthis Bidentatae Radix may play a guiding role in meridian through increasing the tissue distribution of effective components in Sanmiao Pills under arthritis states.

Transcriptional Profiling Reveals a Time-of-Day-Specific Role of REVEILLE 4/8 in Regulating the First Wave of Heat Shock-Induced Gene Expression in Arabidopsis.

Although much is known about plant responses to heat shock (HS), how plants sense high temperature and the primary HS signal transduction pathway leading to HS-regulated gene expression are still poorly understood. To identify primary transcription factors that mediate HS-regulated gene expression and their target genes, RNA sequencing was performed to detect genes whose expression is rapidly altered by HS in Arabidopsis (Arabidopsis thaliana). The results showed several genes were induced after only 5 min of HS treatment, suggesting that HS signaling occurs very rapidly. Analysis of the cis-elements in the promoters of genes upregulated by 10 min of HS treatment identified HEAT SHOCK FACTOR A1s (HSFA1s) and circadian clock proteins REVEILLE4 (RVE4) and RVE8 as essential transcription factors that independently mediate early HS-induced gene expression. Using hsfa1a/b/d/e and rve4/8 mutants, we identified subsets of HSFA1s- or RVE4/8-dependent early HS-induced genes and showed RVE4/8 regulate plant thermotolerance partially by regulating the expression of downstream transcription factors ETHYLENE RESPONSIVE FACTOR53 (ERF53) and ERF54, specifically around noon. These findings reveal a potential transcriptional regulatory hierarchy governing the first wave of HS-induced gene expression. They also provided important insight into the mechanism by which the circadian clock gates thermotolerance and prepares plants for exposure to high temperatures during the day.

Construction of a novel necroptosis-related lncRNA signature for prognosis prediction in esophageal cancer.

BACKGROUND: Esophageal cancer (EC), one highly malignant gastrointestinal cancer, is the 6th leading cause of cancer-related deaths worldwide. Necroptosis and long non-coding RNA (lncRNA) play important roles in the occurrence and development of EC, but the research on the role of necroptosis-related lncRNA in EC is not conclusive. This study aims to use bioinformatics to investigate the prognostic value of necroptosis-related lncRNA in EC. METHODS: Transcriptome data containing EC and normal samples, and clinical information were obtained from the Cancer Genome Atlas database. 102 necroptosis-related genes were obtained from Kanehisa Laboratories. Necroptosis-related lncRNAs were screened out via univariate, multivariate Cox and the least absolute shrinkage and selection operator regression analyses to construct the risk predictive model. The reliability of the risk model was evaluated mainly through quantitative real-time PCR (qRT-PCR), the receiver operating characteristic (ROC) curves and the constructed nomogram. KEGG pathways were explored in the high- and low-risk groups of EC patients via gene set enrichment analyses (GSEA) software. Immune microenvironment and potential therapeutic agents in risk groups were also analyzed. RESULTS: A 6 necroptosis-related lncRNAs risk model composed of AC022211.2, Z94721.1, AC007991.2, SAMD12-AS1, AL035461.2 and AC051619.4 was established to predict the prognosis level of EC patients. qRT-PCR analysis showed upregulated Z94721.1 and AL035461.2 mRNA levels and downregulated AC051619.4 mRNA level in EC tissues compared with normal tissues. According to clinical characteristics, the patients in the high-risk group had a shorter overall survival than the low-risk group. The ROC curve and nomogram confirmed this model as one independent and predominant predictor. GSEA analysis showed metabolic and immune-related pathways enriched in the risk model. Most of the immune cells and immune checkpoints were positively correlated with the risk model, mainly active in the high-risk group. For the prediction of potential therapeutic drugs, 16 compounds in the high-risk group and 2 compounds in the low-risk group exhibited higher sensitivity. CONCLUSIONS: Our results supported the necroptosis-related lncRNA signature could independently predict prognosis of EC patients, and provided theoretical basis for improving the clinical treatment of EC.

Atom-precise fluorescent copper cluster for tumor microenvironment targeting and transient chemodynamic cancer therapy.

BACKGROUND: Reactive oxygen species (ROS) have been widely studied for cancer therapy. Nevertheless, instability and aspecific damages to cellular biomolecules limit the application effect. Recently, significant research efforts have been witnessed in the flourishing area of metal nanoclusters (NCs) with atomically precise structures for targeted release of ROS but few achieved success towards targeting tumor microenvironment. RESULTS: In this work, we reported an atomically precise nanocluster Cu6(C4H3N2S)6 (Cu6NC), which could slowly break and generate ROS once encountered with acidic. The as-prepared Cu6NC demonstrated high biological safety and efficient chemodynamic anti-tumor properties. Moreover, Cu6NC enabled transient release of ROS and contained targeting behavior led by the tumor microenvironment. Both in vitro and in vivo experiments confirmed that Cu6NC demonstrated a low cytotoxicity for normal cells, while presented high cytotoxicity for tumor cells with a concentration-dependent manner. CONCLUSIONS: This work not only reported a promising candidate for chemodynamic cancer therapy, but also paved the route to address clinical issues at the atomic level.

Skimmianine as a novel therapeutic agent suppresses proliferation and migration of human esophageal squamous cell carcinoma via blocking the activation of ERK1/2.

Esophageal squamous cell carcinoma (ESCC), one of the main histopathological subtypes of esophageal cancer (EC), is characterized by high morbidity and mortality. Clinical treatment for ESCC lacks specific molecular targets and effective therapeutic drugs. Skimmianine (SK), one of the natural fluroquinolone alkaloids, is widely present in Rutaceae family plants. Here, we mainly used CCK-8 assay, clone formation, flow cytometry analysis, wound-healing assay, Transwell assay, western blot, quantitative real-time PCR (qRT-PCR), molecular docking analysis, tumor xenograft assay, and immunohistochemistry (IHC) staining to investigate the potential anti-tumor effect of SK on ESCC. We demonstrated that SK inhibited the proliferation of TE-1 and Eca109 cells via inducing the G0/G1 phase cell cycle arrest, prevented the migration and invasion of tumor cells via regulating epithelial-mesenchymal transition (EMT) in vitro. In addition, SK obviously suppressed the growth of xenografted Eca109 tumors in nude mice. The anti-tumor mechanism of SK could be blocking the activation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the mitogen-activated protein kinase (MAPK)/ERK signaling pathway. Our basic research suggests that SK can be a potential therapeutic agent for ESCC.

Genetic parameters and genome-wide association study of digital cushion thickness in Holstein cows.

The digital cushion is linked to the development of claw horn lesions (CHL) in dairy cattle. The objectives of this study were to (1) estimate genetic parameters for digital cushion thickness (DCT), (2) estimate the genetic correlation between DCT and CHL, and (3) identify candidate genes associated with DCT. A cohort of 2,352 Holstein dairy cows were prospectively enrolled on 4 farms and assessed at 4 time points: before calving, immediately after calving, in early lactation, and in late lactation. At each time point, CHL was recorded by veterinary surgeons, and ultrasonographic images of the digital cushion were stored and retrospectively measured at 2 anatomical locations. Animals were genotyped and pedigree details extracted from the national database. Genetic parameters were estimated following a single-step approach implemented in AIREMLF90. Four traits were analyzed: the 2 DCT measurements, sole lesions (sole hemorrhage and sole ulcers), and white line lesions. All traits were analyzed with univariate linear mixed models; bivariate models were fit to estimate the genetic correlation between traits within and between time points. Single-marker and window-based genome-wide association analyses of DCT traits were conducted at each time point; candidate genes were mapped near (<0.2 Mb) or within the genomic markers or windows with the largest effects. Heritability estimates of DCT ranged from 0.14 to 0.44 depending on the location of DCT measurement and assessment time point. The genetic correlation between DCT and sole lesions was generally negative, notably between DCT immediately after calving and sole lesions in early or late lactation, and between DCT in early or late lactation and sole lesion severity in early or late lactation. Digital cushion thickness was not genetically correlated with white line lesions. A polygenic background to DCT was found; genes associated with inflammation, fat metabolism, and bone development were mapped near or within the top markers and windows. The moderate heritability of DCT provides an opportunity to use selective breeding to change DCT in a population. The negative genetic correlation between DCT and sole lesions at different stages of production lends support to current hypotheses of sole lesion pathogenesis. Highlighted candidate genes provide information regarding the complex genetic background of DCT in Holstein cows, but further studies are needed to explore and corroborate these findings.

Evodiamine decreased the systemic exposure of pravastatin in non-alcoholic steatohepatitis rats due to the up-regulation of hepatic OATPs.

CONTEXT: Patients with non-alcoholic steatohepatitis (NASH) may have a simultaneous intake of pravastatin and evodiamine-containing herbs. OBJECTIVE: The effect of evodiamine on the pharmacokinetics of pravastatin and its potential mechanisms were investigated in NASH rats. MATERIALS AND METHODS: The NASH model was conducted with feeding a methionine choline-deficient (MCD) diet for 8 weeks. Sprague-Dawley rats were randomised equally (n = 6) into NASH group, evodiamine group (10 mg/kg), pravastatin group (10 mg/kg), and evodiamine (10 mg/kg) + pravastatin (10 mg/kg) group. Normal control rats were fed a standard diet. Effects of evodiamine on the pharmacokinetics, distribution, and uptake of pravastatin were investigated. RESULTS: Evodiamine decreased Cmax (159.43 ± 26.63 vs. 125.61 ± 22.17 µg/L), AUC0-t (18.17 ± 2.52 vs. 14.91 ± 2.03 mg/min/L) and AUC0-∞ (22.99 ± 2.62 vs. 19.50 ± 2.31 mg/min/L) of orally administered pravastatin in NASH rats, but had no significant effect in normal rats. Evodiamine enhanced the uptake (from 154.85 ± 23.17 to 198.48 ± 26.31 pmol/mg protein) and distribution (from 736.61 ± 108.07 to 911.89 ± 124.64 ng/g tissue) of pravastatin in NASH rat liver. The expression of Oatp1a1, Oatp1a4, and Oatp1b2 was up-regulated 1.48-, 1.38-, and 1.51-fold by evodiamine. Evodiamine decreased the levels of IL-1ß, IL-6, and TNF-α by 27.82%, 24.76%, and 29.72% in NASH rats, respectively. DISCUSSION AND CONCLUSIONS: Evodiamine decreased the systemic exposure of pravastatin by up-regulating the expression of OATPs. These results provide a reference for further validation of this interaction in humans.