HapKled: a haplotype-aware structural variant calling approach for Oxford nanopore sequencing data.

Introduction: Structural Variants (SVs) are a type of variation that can significantly influence phenotypes and cause diseases. Thus, the accurate detection of SVs is a vital part of modern genetic analysis. The advent of long-read sequencing technology ushers in a new era of more accurate and comprehensive SV calling, and many tools have been developed to call SVs using long-read data. Haplotype-tagging is a procedure that can tag haplotype information on reads and can thus potentially improve the SV detection; nevertheless, few methods make use of this information. In this article, we introduce HapKled, a new SV detection tool that can accurately detect SVs from Oxford Nanopore Technologies (ONT) long-read alignment data. Methods: HapKled utilizes haplotype information underlying alignment data by conducting haplotype-tagging using Whatshap on the reads to improve the detection performance, with three unique calling mechanics including altering clustering conditions according to haplotype information of signatures, determination of similar SVs based on haplotype information, and slack filtering conditions based on haplotype quality. Results: In our evaluations, HapKled outperformed state-of-the-art tools and can deliver better SV detection results on both simulated and real sequencing data. The code and experiments of HapKled can be obtained from https://github.com/CoREse/HapKled. Discussion: With the superb SV detection performance that HapKled can deliver, HapKled could be useful in bioinformatics research, clinical diagnosis, and medical research and development.

The Potential Role of Non-coding RNAs in Regulating Ferroptosis in Cancer: Mechanisms and Application Prospects.

Cancer is the second leading cause of death globally. Despite some successes, conventional cancer treatments are insufficient to address the growing problem of drug resistance in tumors and to achieve efficient treatment outcomes. Therefore, there is an urgent need to explore new therapeutic options. Ferroptosis, a type of iron- and reactive oxygen species-dependent regulated cell death, has been closely associated with cancer development and progression. Non-coding RNAs (ncRNAs) are a class of RNAs that do not code for proteins, and studies have demonstrated their involvement in the regulation of ferroptosis in cancer. This review aims to explore the molecular regulatory mechanisms of ncRNAs involved in ferroptosis in cancer and to emphasize the feasibility of ferroptosis and ncRNAs as novel therapeutic strategies for cancer. We conducted a systematic and extensive literature review using PubMed, Google Scholar, Web of Science, and various other sources to identify relevant studies on ferroptosis, ncRNAs, and cancer. A deeper understanding of ferroptosis and ncRNAs could facilitate the development of new cancer treatment strategies.

Fingolimod synergizes and reverses K. pneumoniae resistance to colistin.

Klebsiella pneumoniae (K. pneumoniae) infection and the rapid spread of multi-drug resistant (MDR) bacteria pose a serious threat to global healthcare. Polymyxin E (colistin), a group of cationic antimicrobial polypeptides, is currently one of the last resort treatment options against carbapenem-resistant Gram-negative pathogens. The effectiveness of colistin has been compromised due to its intensive use. This study found that fingolimod (FLD), a natural product derivative, exhibited a significant synergistic bactericidal effect on K. pneumoniae when combined with colistin, both in vitro and in vivo. The checkerboard method was employed to assess the in vitro synergistic effect of FLD with colistin. FLD enhanced the susceptibility of bacteria to colistin and lowered effectively minimum inhibitory concentrations (MIC) when compared to colistin MIC, and the fractional inhibitory concentrations (FIC) value was less than 0.3. The time-kill curve demonstrated that the combination treatment of FLD and colistin had significant bactericidal efficacy. The in vitro concurrent administration of colistin and FLD resulted in heightening membrane permeability, compromising cell integrity, diminishing membrane fluidity, and perturbing membrane homeostasis. They also induced alterations in membrane potential, levels of reactive oxygen species, and adenosine triphosphate synthesis, ultimately culminating in bacterial death. Moreover, the combination of FLD with colistin significantly influenced fatty acid metabolism. In the mouse infection model, the survival rate of mice injected with K. pneumoniae was significantly improved to 67% and pathological damage was significantly relieved with combination treatment of FLD and colistin when compared with colistin treatment. This study highlights the potential of FLD in combining with colistin for treating infections caused by MDR isolates of K. pneumoniae.

On the Crush Behavior and Energy Absorption of Sustainable Beverage Cans and Their Polyurethane Foam-Filled Structures: An Experimental Study.

In the pursuit of global energy conservation and emissions reductions, utilizing beverage cans as energy-absorbing components offers potential for a sustainable economy. This study examines the impact of foam filling on the crushing behaviors and energy absorption of various types of beverage cans. Quasi-static compression tests were conducted on five geometrically sized cans filled with three densities of polyurethane foam to study their deformation modes and calculate crashworthiness parameters within the effective stroke. Results show that empty beverage cans have lower energy absorption capacities, and deformation modes become less consistent as can size increases. Higher foam density leads to increased total energy absorption, a slight reduction in the effective compression stroke, and a tendency for specific energy absorption to initially increase and then decrease. Regarding crush behavior, smaller cans transition from a diamond mode to a concertina mode, while larger cans exhibit a columnar bending mode. Next, the coupling effect of energy absorption between foam and cans was analyzed so as to reveal the design method of energy-absorbing components. The specific energy absorption of smaller cans filled with polyurethane foam is superior to that of similar empty cans. These findings provide valuable insights for selecting next-generation sustainable energy absorption structures.

Is Prior Nonoperative or Operative Treatment of Dysplasia of the Hip Associated With Poorer Results of Periacetabular Osteotomy?

BACKGROUND: Understanding the implications of either nonoperative or operative treatment of developmental dysplasia of the hip (DDH) performed before periacetabular osteotomy (PAO) is critical to counseling patients and their families. There are limited studies, however, on PAO for the treatment of residual DDH after surgical intervention during childhood, and even less information about PAO after prior nonoperative treatment. QUESTIONS/PURPOSES: We analyzed patients who had undergone PAO for DDH and asked: Did patients with prior childhood treatment (either operative or nonoperative) (1) improve less in modified Harris hip score (mHHS), 12-item International Hip Outcome Tool (iHOT-12) score, or WOMAC score; (2) demonstrate more severe preoperative deformities; and (3) receive less complete radiographic correction and have more frequent complications than did patients whose hips had not undergone prior treatment? We also asked: (4) Were there subgroup differences among patients with DDH treated nonoperatively versus operatively before PAO in these same functional and radiographic parameters? METHODS: Between January 2011 and December 2020, a total of 90 PAOs were performed in 82 patients who had prior surgical or nonsurgical treatment. Of those, 3 patients (3 hips) with neuromuscular diseases were excluded, 4 patients (5 hips) were excluded for having received treatment after childhood, 7 hips that had undergone bilateral PAOs were excluded, and another 4 patients (4 hips) were lost to follow-up before the minimum study period of 2 years, leaving 71 patients (71 hips) for analysis (the previous treatment group). Among these, 32 patients had a history of previous surgery (the previous surgery group), and 39 patients had prior nonsurgical treatment (such as a Pavlik harness, closed reduction, spica casting) (the previous nonoperative group). During the same period, 1109 PAOs were performed in 956 patients who had no history of previous hip treatment. Following a 1:2 ratio, 142 patients (142 hips) were selected as the control group by matching for age (within 2 years difference), year of surgery (same year), and follow-up time (within 1-year difference). The patient characteristics for both the previous treatment group and the control group exhibited comparability, with mean ± SD follow-up durations of 49 ± 23 months and 48 ± 19 months, respectively. Within the previous 5 years, 3 patients (8%) in the previous nonoperative group, 4 patients (13%) in the previous surgery group, and 15 patients (11%) in the control group had not attended follow-up visits. We compared hip function and radiographic results between the two groups and performed a subgroup analysis between the previous surgery group and the previous nonoperative group. Hip function was assessed using the mHHS questionnaire, the WOMAC, and the iHOT-12 with attention to the minimum clinically important differences of these tools. The threshold values for clinically important improvement were 9.6 points, 13 points, and 16.1 points for the mHHS, iHOT-12, and WOMAC, respectively. Radiographic measurements included the lateral center-edge angle (LCEA), anterior center-edge angle (ACEA), Tönnis angle, acetabulum-head index, and acetabular wall index. We also evaluated Tönnis osteoarthritis grade and femoral head deformity. Occurrences of adverse radiographic events such as posterior column fracture, nonunion, stress fractures, insufficient coverage or overcoverage, acetabular protrusion, and progression of osteoarthritis were recorded. RESULTS: We found no clinically important differences in magnitude of improvement between the previous treatment group and the control group in terms of mHHS (mean ± SD 10 ± 12 versus 12 ± 12; p = 0.36), iHOT-12 (25 ± 18 versus 26 ± 19; p = 0.51), or WOMAC score (12 ± 12 versus 15 ± 19; p = 0.17). Preoperative deformity in the previous treatment group was more severe than in the control group (mean ± SD LCEA -1° ± 9° versus 5° ± 8°; ACEA -8° ± 18° versus 1° ± 14°; Tönnis angle 31° ± 7° versus 27° ± 7°; acetabulum-head index 56% ± 13% versus 61% ± 8%; all p < 0.001). In the previous treatment group, a higher percentage of patients exhibited flattening or irregularity of the femoral head compared with the control group (52% versus 9%; p < 0.001), and there was also a higher proportion of patients with Tönnis grade 1 or above (51% versus 42%; p < 0.001). Although there were still differences in LCEA, ACEA, and Tönnis angle between the two groups at the last follow-up, the differences were small, and the mean values were within the normal range. The previous treatment group had a higher risk of intraoperative posterior column fracture (14% and 5%; p = 0.02), insufficient acetabular coverage (20% and 8%; p = 0.01), and progression of osteoarthritis (17% and 8%; p = 0.04) compared with the control group. Subgroup analysis revealed no clinically important differences in magnitude of improvement between the previous surgery group and the previous nonoperative group in terms of mHHS (10 ± 14 versus 10 ± 11; p = 0.91), iHOT-12 (22 ± 21 versus 27 ± 14; p = 0.26), or WOMAC score (12 ± 14 versus 12 ± 11; p = 0.94). Apart from a higher proportion of patients who presented with arthritis (72% versus 34%; p = 0.01) and a smaller anterior wall index (11% ± 11% versus 20% ± 12%; p = 0.01) in the previous surgery group, all other preoperative radiographic parameters were consistent between the two groups. Additionally, the previous surgery group had a higher frequency of arthritis progression (28% versus 8%; p = 0.02), while the frequencies of other complications were similar between the two groups. Specifically, the frequencies of pubic ramus nonunion (22% versus 21%; p = 0.89), intraoperative posterior column fracture (19% versus 10%; p = 0.50), and insufficient acetabular coverage (25% versus 15%; p = 0.31) were high in both groups. CONCLUSION: We found no clinically important difference in the magnitude of improvement between patients who had childhood treatment and those who did not, but patients who had prior childhood treatment were more likely to experience serious complications, and radiographic correction in those patients was less complete. As in the case of patients who have had prior operative treatments, it is crucial not to overlook the unexpectedly severe deformity of residual DDH after previous nonoperative treatment and complications following PAO. Surgeons and patients alike should be aware of the potential for worse radiographic outcomes or an increased risk of complications when prior operative or nonoperative treatment has preceded PAO. Future studies might investigate optimal management strategies for this specific group of patients to improve outcomes and reduce complications. LEVEL OF EVIDENCE: Level III, therapeutic study.

Hepatic toxicity prediction of bisphenol analogs by machine learning strategy.

Toxicological studies have demonstrated the hepatic toxicity of several bisphenol analogs (BPs), a prevalent type of endocrine disruptor. The development of Adverse Outcome Pathway (AOP) has substantially contributed to the rapid risk assessment for human health. However, the lack of in vitro and in vivo data for the emerging BPs has limited the hazard assessment of these synthetic chemicals. Here, we aimed to develop a new strategy to rapidly predict BPs' hepatotoxicity using network analysis coupled with machine learning models. Considering the structural and functional similarities shared by BPs with Bisphenol A (BPA), we first integrated hepatic disease related genes from multiple databases into BPA-Gene-Phenotype-hepatic toxicity network and subjected it to the computational AOP (cAOP). Through cAOP network and conventional machine learning approaches, we scored the hepatotoxicity of 20 emerging BPs and provided new insights into how BPs' structure features contributed to biologic functions with limited experimental data. Additionally, we assessed the interactions between emerging BPs and ESR1 using molecular docking and proposed an AOP framework wherein ESR1 was a molecular initiating event. Overall, our study provides a computational approach to predict the hepatotoxicity of emerging BPs.

Prevalence, Time of Infection, and Diversity of Porcine Reproductive and Respiratory Syndrome Virus in China.

Porcine reproductive and respiratory syndrome virus (PRRVS) is a major swine viral pathogen that affects the pig industry worldwide. Control of early PRRSV infection is essential, and different types of PRRSV-positive samples can reflect the time point of PRRSV infection. This study aims to investigate the epidemiological characteristics of PRRSV in China from Q4 2021 to Q4 2022, which will be beneficial for porcine reproductive and respiratory syndrome virus (PRRSV)control in the swine production industry in the future. A total of 7518 samples (of processing fluid, weaning serum, and oral fluid) were collected from 100 intensive pig farms in 21 provinces, which covered all five pig production regions in China, on a quarterly basis starting from the fourth quarter of 2021 and ending on the fourth quarter of 2022. Independent of sample type, 32.1% (2416/7518) of the total samples were PCR-positive for PRRSV, including 73.6% (1780/2416) samples that were positive for wild PRRSV, and the remaining were positive for PRRSV vaccine strains. On the basis of the time of infection, 58.9% suckling piglets (processing fluid) and 30.8% weaning piglets (weaning serum) showed PRRSV infection at an early stage (approximately 90% of the farms). The sequencing analysis results indicate a wide range of diverse PRRSV wild strains in China, with lineage 1 as the dominant strain. Our study clearly demonstrates the prevalence, infection stage, and diversity of PRRSV in China. This study provides useful data for the epidemiological understanding of PRRSV, which can contribute to the strategic and systematic prevention and control of PRRSV in China.

Characterization and correlation analysis of microbial flora and flavor profile of stinky acid, a Chinese traditional fermented condiment.

To explore the microbial diversity and flavor profiles of stinky acid, we utilized high-throughput sequencing, culture-based techniques, and bionic E-sensory technologies. The results revealed a significant correlation between the acidity levels of stinky acid and the richness of its microbial community. Ten core bacterial genera and three core fungal genera exhibited ubiquity across all stinky acid samples. Through E-nose analysis, it was found that sulfides constituted the principal odor compounds responsible for stinky acid's distinct aroma. Further insights arose from the correlation analysis, indicating the potential contribution of Debaryomyces yeast to the sour taste profile. Meanwhile, three genera-Rhizopus and Thermoascus and Companilactobacillus-were identified as contributors to aromatic constituents. Interestingly, the findings indicated that Rhizopus and Thermoascus could reduce the intensity of the pungent odor of stinky acid. In summary, this investigation's outcomes offer new insights into the complex bacterial diversity of stinky acid.

All-dielectric geometric metasurfaces for the generation and manipulation of perfect high-order Poincaré sphere beams.

A high-order Poincaré sphere (HOPS) can be used to describe high-order modes of waveguides and vector beams, since it generalizes the feature of spin and the orbital angular momentum of light. HOPS beams are such beams with polarization states on the HOPS, which have potential applications in optical manipulation and optical communication. In general, the intensity distribution of this kind of beam changes with the topological charge, which limits their practical applications. Based on the concept of perfect vortex beams (PVBs), perfect HOPS beams have been proposed to solve this problem. Here, a flexible and compact scheme based on all-dielectric metasurfaces for realizing and manipulating perfect HOPS beams at near-infrared wavelength was demonstrated. Geometric-phase-only manipulation was employed for simultaneously controlling the phase and polarization of the incident light. By varying the incident polarization, several selected polarization states on the HOPS could be realized by the proposed metasurface. Further, the single ultra-thin metasurface can also realize high quality multiplexing perfect HOPS beams that carry different topological charges. Finally, a cascaded metasurface system has been proposed for generating and manipulating multiple HOPS beams. This compact flat-optics-based scheme for perfect HOPS beam generation and manipulation demonstrated here can be used for on-chip optical manipulation and integrated optical communication in the future.

A comprehensive lung CT landmark pair dataset for evaluating deformable image registration algorithms.

PURPOSE: Deformable image registration (DIR) is a key enabling technology in many diagnostic and therapeutic tasks, but often does not meet the required robustness and accuracy for supporting clinical tasks. This is in large part due to a lack of high-quality benchmark datasets by which new DIR algorithms can be evaluated. Our team was supported by the National Institute of Biomedical Imaging and Bioengineering to develop DIR benchmark dataset libraries for multiple anatomical sites, comprising of large numbers of highly accurate landmark pairs on matching blood vessel bifurcations. Here we introduce our lung CT DIR benchmark dataset library, which was developed to improve upon the number and distribution of landmark pairs in current public lung CT benchmark datasets. ACQUISITION AND VALIDATION METHODS: Thirty CT image pairs were acquired from several publicly available repositories as well as authors' institution with IRB approval. The data processing workflow included multiple steps: (1) The images were denoised. (2) Lungs, airways, and blood vessels were automatically segmented. (3) Bifurcations were directly detected on the skeleton of the segmented vessel tree. (4) Falsely identified bifurcations were filtered out using manually defined rules. (5) A DIR was used to project landmarks detected on the first image onto the second image of the image pair to form landmark pairs. (6) Landmark pairs were manually verified. This workflow resulted in an average of 1262 landmark pairs per image pair. Estimates of the landmark pair target registration error (TRE) using digital phantoms were 0.4 mm ± 0.3 mm. DATA FORMAT AND USAGE NOTES: The data is published in Zenodo at https://doi.org/10.5281/zenodo.8200423. Instructions for use can be found at https://github.com/deshanyang/Lung-DIR-QA. POTENTIAL APPLICATIONS: The dataset library generated in this work is the largest of its kind to date and will provide researchers with a new and improved set of ground truth benchmarks for quantitatively validating DIR algorithms within the lung.

Salidroside inhibited the proliferation of gastric cancer cells through up-regulating tumor suppressor miR-1343-3p and down-regulating MAP3K6/MMP24 signal molecules.

Salidroside inhibited the proliferation of cancer cell. Nevertheless, the mechanism has not been completely clarified. The purpose of the study is to explore the mechanisms of salidroside against gastric cancer. To analyze the changes of microRNA (miRNA) in gastric cancer cells under the treatment of salidroside, the miRNA expression was analyzed by using RNA-seq in cancer cells for 24 h after salidroside treatment. The differentially expressed miRNAs were clustered and their target genes were analyzed. Selected miRNA and target mRNA genes were further verified by q-PCR. The expressions of target genes in cancer cells were detected by immunohistochemistry. Cancer cell apoptotic index was significantly increased after salidroside treatment. The proliferation of gastric cancer cells were blocked at S-phase cell cycle. The expression of 44 miRNAs changed differentially after salidroside treatment in cancer cells. Bioinformatic analysis showed that there were 1384 target mRNAs corresponding to the differentially expressed miRNAs. Surprisingly, salidroside significantly up-regulated the expression of tumor suppressor miR-1343-3p, and down-regulated the expression of MAP3K6, STAT3 and MMP24-related genes. Salidroside suppressed the growth of gastric cancer by inducing the cancer cell apoptosis, arresting the cancer cell cycle and down-regulating the related signal transduction pathways. miRNAs are expressed differentially in gastric cancer cells after salidroside treatment, playing important roles in regulating proliferation and metastasis. Salidroside may suppress the growth of gastric cancer by up-regulating the expression of the tumor suppressor miR-1343-3p and down-regulating the expression of MAP3K6 and MMP24 signal molecules.

Hepatocellular carcinoma cells downregulate NADH:Ubiquinone Oxidoreductase Subunit B3 to maintain reactive oxygen species homeostasis.

BACKGROUND: HCC is a leading cause of cancer-related death. The role of reactive oxygen species (ROS) in HCC remains elusive. Since a primary ROS source is the mitochondrial electron transport chain complex Ι and the NADH:ubiquinone Oxidoreductase Subunit B3 (NDUFB3), a complex I subunit, is critical for complex I assembly and regulates the associated ROS production, we hypothesize that some HCCs progress by hijacking NDUFB3 to maintain ROS homeostasis. METHODS: NDUFB3 in human HCC lines was either knocked down or overexpressed. The cells were then analyzed in vitro for proliferation, migration, invasiveness, colony formation, complex I activity, ROS production, oxygen consumption, apoptosis, and cell cycle. In addition, the in vivo growth of the cells was evaluated in nude mice. Moreover, the role of ROS in the NDUFB3-mediated changes in the HCC lines was determined using cellular and mitochondrion-targeted ROS scavengers. RESULTS: HCC tissues showed reduced NDUFB3 protein expression compared to adjacent healthy tissues. In addition, NDUFB3 knockdown promoted, while its overexpression suppressed, HCC cells' growth, migration, and invasiveness. Moreover, NDUFB3 knockdown significantly decreased, whereas its overexpression increased complex I activity. Further studies revealed that NDUFB3 overexpression elevated mitochondrial ROS production, causing cell apoptosis, as manifested by the enhanced expressions of proapoptotic molecules and the suppressed expression of the antiapoptotic molecule B cell lymphoma 2. Finally, our data demonstrated that the apoptosis was due to the activation of the c-Jun N-terminal kinase (JNK) signaling pathway and cell cycle arrest at G0/G1 phase. CONCLUSIONS: Because ROS plays essential roles in many biological processes, such as aging and cancers, our findings suggest that NDFUB3 can be targeted for treating HCC and other human diseases.

The miR166 targets CsHDZ3 genes to negatively regulate drought tolerance in tea plant (Camellia sinensis).

Drought is the stressor with a significant adverse impact on the yield stability of tea plants. HD-ZIP III transcription factors (TFs) play important regulatory roles in plant growth, development, and stress responses. However, whether and how HD-ZIP III TFs are involved in drought response and tolerance in tea plants remains unclear. Here, we identified seven HD-ZIP III genes (CsHDZ3-1 to CsHDZ3-7) in tea plant genome. The evolutionary analysis demonstrated that CsHDZ3 members were subjected to purify selection. Subcellular localization analysis revealed that all seven CsHDZ3s located in the nucleus. Yeast self-activation and dual-luciferase reporter assays demonstrated that CsHDZ3-1 to CsHDZ3-4 have trans-activation ability whereas CsHDZ3-5 to CsHDZ3-7 served as transcriptional inhibitors. The qRT-PCR assay showed that all seven CsHDZ3 genes could respond to simulated natural drought stress and polyethylene glycol treatment. Further assays verified that all CsHDZ3 genes can be cleaved by csn-miR166. Overexpression of csn-miR166 inhibited the expression of seven CsHDZ3 genes and weakened drought tolerance of tea leaves. In contrast, suppression of csn-miR166 promoted the expression of seven CsHDZ3 genes and enhanced drought tolerance of tea leaves. These findings established the foundation for further understanding the mechanism of CsHDZ3-miR166 modules' participation in drought responses and tolerance.

Distribution of hepatitis C virus in eastern China from 2011 to 2020: a Bayesian spatiotemporal analysis.

Objective: This study aimed to evaluate the spatiotemporal distribution of patients with hepatitis C virus (HCV) and the factors influencing this distribution in Jiangsu Province, China, from 2011 to 2020. Methods: The incidence of reported HCV in Jiangsu Province from 2011 to 2020 was obtained from the Chinese Information System for Disease Control and Prevention (CISDCP). R and GeoDa software were used to visualize the spatiotemporal distribution and the spatial autocorrelation of HCV. A Bayesian spatiotemporal model was constructed to explore the spatiotemporal distribution of HCV in Jiangsu Province and to further analyze the factors related to HCV. Results: A total of 31,778 HCV patients were registered in Jiangsu Province. The registered incidence rate of HCV increased from 2.60/100,000 people in 2011 to 4.96/100,000 people in 2020, an increase of 190.77%. Moran's I ranged from 0.099 to 0.354 (P < 0.05) from 2011 to 2019, indicating a positive spatial correlation overall. The relative risk (RR) of the urbanization rate, the most important factor affecting the spread of HCV in Jiangsu Province, was 1.254 (95% confidence interval: 1.141-1.376), while other factors had no significance. Conclusion: The reported HCV incidence rate integrally increased in the whole Jiangsu Province, whereas the spatial aggregation of HCV incidence was gradually weakening. Our study highlighted the importance of health education for the floating population and reasonable allocation of medical resources in the future health work.

Evaluating the Metabolic Basis of α-Gal A mRNA Therapy for Fabry Disease.

mRNA injection-based protein supplementation has emerged as a feasible treatment for Fabry disease. However, whether the introduction of LNP-encapsulated mRNA results in the alteration of metabolomics in an in vivo system remains largely unknown. In the present study, α-galactosidase A (α-Gal A) mRNA was generated and injected into the Fabry disease mouse model. The α-Gal A protein was successfully expressed. The level of globotriaosylsphingosine (Lyso-Gb3), a biomarker for Fabry disease, as well as pro-inflammatory cytokines such as nuclear factor kappa-B (NF-κB), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α), were greatly decreased compared to the untreated control, indicating the therapeutic outcome of the mRNA drug. Metabolomics analysis found that the level of 20 metabolites was significantly altered in the plasma of mRNA-injected mice. These compounds are primarily enriched in the arachidonic acid metabolism, alanine, aspartate and glutamate metabolism, and glycolysis/gluconeogenesis pathways. Arachidonic acid and 5-hydroxyeicosatetraenoic acid (5-HETE), both of which are important components in the eicosanoid pathway and related to inflammation response, were significantly increased in the injected mice, possibly due to the presence of lipid nanoparticles. Moreover, mRNA can effectively alter the level of metabolites in the amino acid and energy metabolic pathways that are commonly found to be suppressed in Fabry disease. Taken together, the present study demonstrated that in addition to supplementing the deficient α-Gal A protein, the mRNA-based therapeutic agent can also affect levels of metabolites that may help in the recovery of metabolic homeostasis in the full body system.

MicroRNA in the Exosomes Mediated by Resveratrol to Activate Neuronal Cells.

Resveratrol (RSV), a polyphenol, is known to have a wide range of pharmacological properties in vitro. RSV may have therapeutic value for various neurodegenerative diseases via neuroprotective effects. However, it is not yet clear whether RSV can induce intestinal-brain interactions. It is assumed that the intestinal cells may secrete some factors after being stimulated by other substances. These secreted factors may activate nerve cells through gut-brain interaction, such as exosomes. In this study, it was discovered that Caco-2 cells treated with RSV secrete exosomes to activate SH-SY5Y neuronal cells. The results showed that secreted factors from RSV-treated Caco-2 cells activated SH-SY5Y. The exosomes of RSV-treated Caco-2 cells activated SH-SY5Y cells, which was manifested in the lengthening of the nerve filaments of SH-SY5Y cells. The exosomes were characterized using transmission electron microscopy and sequenced using the Illumina NovaSeq 6000 sequencer. The results showed that the miRNA expression profile of exosomes after RSV treatment changed, and twenty-six kinds of miRNAs were identified which expressed differentially between the control group and the RSV-treated group. Among them, three miRNAs were selected as candidate genes for inducing SH-SY5Y neural cell activation. Three miRNA mimics could activate SH-SY5Y neurons. These results suggested that the miRNA in intestinal exocrine cells treated with RSV may play an important role in the activation of SH-SY5Y neurons.

AKR1C3 silencing inhibits autophagy-dependent glycolysis in thyroid cancer cells by inactivating ERK signaling.

Thyroid cancer is a highly differentiated and poorly malignant tumor. Interfering with glycolysis has become an effective means of controlling cancer progression and autophagy is negatively correlated with glycolysis. Aldo-keto reductase family 1 member C3 (AKR1C3) has been demonstrated to be highly expressed in thyroid cancer tissue and the higher AKR1C3 expression predicted the worse prognosis. We aimed to explore whether AKR1C3 could affect thyroid cancer progression by regulating autophagy-dependent glycolysis. AKR1C3 expression in thyroid cancer cells was detected by western blot. Then, AKR1C3 was knocked down by transfection with short hairpin RNA specific to AKR1C3 in the absence or presence of 3-methyladenine (3-MA) or PMA treatment. Cell cycle and apoptosis was detected by flow cytometry. Immunofluorescence staining was used to analyze LC3B expression. Extracellular acidification, glucose uptake and lactic acid secretion were detected. To evaluate the tumorigenicity of AKR1C3 insufficiency on thyroid cancer in vivo, TPC-1 cells with AKR1C3 knockdown were injected subcutaneously into nude mice. Then, cyclinD1 and Ki67 expression in tumorous tissues was measured by immunohistochemical analysis. Apoptosis was assessed by terminal-deoxynucleoitidyl transferase mediated nick end labeling staining. Additionally, the expression of proteins related to cell cycle, apoptosis, glycolysis, autophagy, and extracellular signal-regulated kinase (ERK) signaling in cells and tumor tissues was assessed by western blot. Highly expressed AKR1C3 was observed in thyroid cancer cells. AKR1C3 knockdown induced cell cycle arrest and apoptosis of TPC-1 cells. Besides, autophagy was activated and glycolysis was inhibited following AKR1C3 silencing, and 3-MA treatment restored the impacts of AKR1C3 silencing on glycolysis. The further experiments revealed that AKR1C3 insufficiency inhibited ERK signaling and PMA application reversed AKR1C3 silencing-induced autophagy in TPC-1 cells. The in vivo results suggested that AKR1C3 knockdown inhibited the development of subcutaneous TPC-1 tumors in nude mice and inactivated the ERK signaling. Collectively, AKR1C3 silencing inhibited autophagy-dependent glycolysis in thyroid cancer by inactivating ERK signaling.

Comparison of Anterior Center-Edge Angle Measured From the Acetabular Sourcil Versus the Anterior Bone-Edge of the Acetabulum: A Descriptive Laboratory Study.

Background: Measuring anterior hip coverage on false-profile (FP) radiographs is important for judging anterior hip coverage. Conventionally, the anterior center-edge angle (ACEA) is measured from the anterior edge of the acetabular sourcil (sourcil ACEA); however, the anterior bone edge is also used as the anterior landmark. Purpose: To determine whether the sourcil ACEA or the bone-edge ACEA better represents the anterior coverage of the hip joint. Study Design: Descriptive laboratory study. Methods: We retrospectively observed 49 hips in 49 patients who underwent isolated periacetabular osteotomy. The sourcil ACEA was measured according to the standard procedure. Then, 3-dimensional (3D) volumetric models were made from computed tomographic data. The acetabular surface of the 3D model was labeled and projected onto a simulated FP radiograph, enabling the edge of the acetabulum to be identified. This simulated FP radiograph was used to measure the "true ACEA," as well as the sourcil ACEA and the bone-edge ACEA, and the 3 measurements were compared. Statistical analysis was performed-including testing for normal distribution, measuring interobserver agreement, evaluating differences between measurements, and validating correlation. Results: The mean sourcil ACEA was 8.6° (range, -3.9° to 31.7°) smaller than that of the true ACEA (P < .001); there was a strong correlation (r = 0.81; P < .001) between the 2. The mean bone-edge ACEA was 16.8° (range, -1.7° to 45.4°) greater than that of the true ACEA (P < .001); there was a moderate correlation (r = 0.57; P < 0.001) between the 2. Conclusion: Both the sourcil ACEA and bone-edge ACEA differed from the true ACEA. However, compared with the bone-edge ACEA, the sourcil ACEA was numerically closer to the true ACEA and had a stronger correlation with it . Clinical Relevance: While the exact edge of the true bearing surface of the articular cartilage may not be visible on the FP radiograph, the sourcil ACEA can be effectively utilized as a reliable surrogate when evaluating the anterior acetabular coverage in hip preservation surgery.

Kled: an ultra-fast and sensitive structural variant detection tool for long-read sequencing data.

Structural Variants (SVs) are a crucial type of genetic variant that can significantly impact phenotypes. Therefore, the identification of SVs is an essential part of modern genomic analysis. In this article, we present kled, an ultra-fast and sensitive SV caller for long-read sequencing data given the specially designed approach with a novel signature-merging algorithm, custom refinement strategies and a high-performance program structure. The evaluation results demonstrate that kled can achieve optimal SV calling compared to several state-of-the-art methods on simulated and real long-read data for different platforms and sequencing depths. Furthermore, kled excels at rapid SV calling and can efficiently utilize multiple Central Processing Unit (CPU) cores while maintaining low memory usage. The source code for kled can be obtained from https://github.com/CoREse/kled.

Research on the Relations Among Personality Traits, Sports Commitment, and Exercise Behavior - A Case Study of Chinese College Students.

Purpose: To explore the relations among personality traits, sports commitment, and exercise behavior of Chinese college students. To test whether sports commitment plays an intermediary role in the process of personality traits affecting exercise behavior. To explore the factors that affect Chinese college students' exercise behavior from the psychological level, to promote college students to actively participate in physical exercise. Methods: A questionnaire survey was conducted on 1200 students from 6 universities using the "Personality Trait Scale", "Sports Commitment Scale" and "Exercise Behavior Scale". SPSS was used to analyze the differences between genders and urban and rural areas; and correlation analysis was conducted on the personality traits, sports commitment, and exercise behaviors of college students. Finally, AMOS was used to establish a structural equation model to test the mediating role of sports commitment. Results: There are significant differences between different genders in each factor of personality traits (P<0.05); there is no significant difference between different genders in the participation opportunities of sports commitment (P=0.734), and there are significant differences in other factors. There were significant differences in each factor of exercise behavior (P<0.05). There were no significant differences in personality traits, sports commitment, and exercise behavior between urban and rural students (P> 0.05). There was a significant correlation among personality traits, sports commitment, and exercise behavior (P < 0.01). The direct effect of personality traits on exercise behavior was not significant (P > 0.05), but there was only the mediating effect of sports commitment. Conclusion: There is a significant correlation among Chinese college students' personality traits, sports commitment, and exercise behavior. Sports commitment plays an intermediary role between personality traits and sports commitment. Improving the level of sports commitment can encourage Chinese college students to participate in physical exercise.