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Abstract Hypertrophic scars arise from aberrant wound healing and can lead to functional and aesthetic impairments. One of the common interventions for treating hypertrophic scars is fractional carbon dioxide (CO2) laser, which employs narrow laser beams to stimulate dermal collagen deposition. Recent studies and reports have suggested that combining laser therapy with other interventions such as botulinum toxin type A (BTX-A) and topical growth factors may enhance treatment outcomes. Here, we examine the efficacy and safety of a sequential combination of BTX-A, fractional CO2 laser, and topical growth factors, referred to as combined therapy, for treating hypertrophic scars compared with only using fractional CO2 laser and topical growth factors, referred to as monotherapy. Our retrospective study includes 128 patients with hypertrophic scars (56 underwent monotherapy and 72 underwent combined therapy), which were followed-up for up to 15 months after the initiation of treatment to collect demographic and clinical data. Our analysis showed that the combined therapy significantly outperformed monotherapy in improving Vancouver scar scale scores (P

Abstract Background Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive ages. Our previous study has implicated a possible link between RNA editing and PCOS, yet the actual role of RNA editing, its association with clinical features, and the underlying mechanisms remain unclear. Methods Ten RNA-Seq datasets containing 269 samples of multiple tissue types, including granulosa cells, T helper cells, placenta, oocyte, endometrial stromal cells, endometrium, and adipose tissues, were retrieved from public databases. Peripheral blood samples were collected from twelve PCOS and ten controls and subjected to RNA-Seq. Transcriptome-wide RNA-Seq data analysis was conducted to identify differential RNA editing (DRE) between PCOS and controls. The functional significance of DRE was evaluated by luciferase reporter assays and overexpression in human HEK293T cells. Dehydroepiandrosterone and lipopolysaccharide were used to stimulate human KGN granulosa cells to evaluate gene expression. Results RNA editing dysregulations across multiple tissues were found to be associated with PCOS in public datasets. Peripheral blood transcriptome analysis revealed 798 DRE events associated with PCOS. Through weighted gene co-expression network analysis, our results revealed a set of hub DRE events in PCOS blood. A DRE event in the eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2:chr2:37,100,559) was associated with PCOS clinical features such as luteinizing hormone (LH) and the ratio of LH over follicle-stimulating hormone. Luciferase assays, overexpression, and knockout of RNA editing enzyme adenosine deaminase RNA specific (ADAR) showed that the ADAR-mediated editing cis-regulated EIF2AK2 expression. EIAF2AK2 showed a higher expression after dehydroepiandrosterone and lipopolysaccharide stimulation, triggering changes in the downstrean MAPK pathway. Conclusions Our study presented the first evidence of cross-tissue RNA editing dysregulation in PCOS and its clinical associations. The dysregulation of RNA editing mediated by ADAR and the disrupted target EIF2AK2 may contribute to PCOS development via the MPAK pathway, underlining such epigenetic mechanisms in the disease.

Cell counting is a common and fundamental cell measurement technique that plays a crucial role in the development and quality control of cell therapy products. However, accurate and reliable cell counting can be challenging owing to the complexity of cell preparations, diverse counting purposes, and various counting methods. This review summarizes the challenges encountered in cell counting for cell therapy products and provides strategies to improve the cell counting accuracy, thereby guiding the counting process and ensuring the quality of cell therapy products.

Abstract Brain structural changes in Parkinson’s disease (PD) are progressive throughout the disease course. Changes in surface morphology with disease progression remain unclear. This study aimed to assess the volumetric and shape changes of the subcortical nuclei during disease progression and explore their association with clinical symptoms. Thirty-four patients and 32 healthy controls were enrolled. The global volume and shape of the subcortical nuclei were compared between patients and controls at baseline. The volume and shape changes of the subcortical nuclei were also explored between baseline and 2 years of follow-up. Association analysis was performed between the volume of subcortical structures and clinical symptoms. In patients with PD, there were significantly atrophied areas in the left pallidum and left putamen, while in healthy controls, the right putamen was dilated compared to baseline. The local morphology of the left pallidum was correlated with Mini Mental State Examination scores. The left putamen shape variation was negatively correlated with changes in Unified Parkinson’s Disease Rating Scale PART III scores. Local morphological atrophy of the putamen and pallidum is an important pathophysiological change in the development of PD, and is associated with motor symptoms and cognitive status in patients with PD.

Abstract Background Spontaneous intracerebral hemorrhage (sICH) is associated with significant mortality and morbidity. Predicting the prognosis of patients with sICH remains an important issue, which significantly affects treatment decisions. Utilizing readily available clinical parameters to anticipate the unfavorable prognosis of sICH patients holds notable clinical significance. This study employs five machine learning algorithms to establish a practical platform for the prediction of short-term prognostic outcomes in individuals afflicted with sICH. Methods Within the framework of this retrospective analysis, the model underwent training utilizing data gleaned from 413 cases from the training center, with subsequent validation employing data from external validation center. Comprehensive clinical information, laboratory analysis results, and imaging features pertaining to sICH patients were harnessed as training features for machine learning. We developed and validated the model efficacy using all the selected features of the patients using five models: Support Vector Machine (SVM), Logistic Regression (LR), Random Forest (RF), XGboost and LightGBM, respectively. The process of Recursive Feature Elimination (RFE) was executed for optimal feature screening. An internal five-fold cross-validation was employed to pinpoint the most suitable hyperparameters for the model, while an external five-fold cross-validation was implemented to discern the machine learning model demonstrating the superior average performance. Finally, the machine learning model with the best average performance is selected as our final model while using it for external validation. Evaluation of the machine learning model’s performance was comprehensively conducted through the utilization of the ROC curve, accuracy, and other relevant indicators. The SHAP diagram was utilized to elucidate the variable importance within the model, culminating in the amalgamation of the above metrics to discern the most succinct features and establish a practical prognostic prediction platform. Results A total of 413 patients with sICH patients were collected in the training center, of which 180 were patients with poor prognosis. A total of 74 patients with sICH were collected in the external validation center, of which 26 were patients with poor prognosis. Within the training set, the test set AUC values for SVM, LR, RF, XGBoost, and LightGBM models were recorded as 0.87, 0.896, 0.916, 0.885, and 0.912, respectively. The best average performance of the machine learning models in the training set was the RF model (average AUC: 0.906 ± 0.029, P

Objective: The effects of mesenchymal stem cells (MSCs) and MSC-derived exosomes (MSC-exos) on serum metabolites and intestinal microbiota in rats after liver trauma were discussed. Methods: Adult Wistar Albino rats were assigned into control, model (liver trauma), MSCs, and MSC-exos groups (n = 6). The study examined changes in the inflammatory environment in liver tissues were analyzed by histological examination and analysis of macrophage phenotypes. Alterations in serum metabolites were determined by untargeted metabonomics, and gut microbiota composition was characterized by 16S rDNA sequencing. Correlations between specific gut microbiota, metabolites, and inflammatory response were calculated using Spearman correlation analysis. Results: Rats with liver trauma after MSCs and MSC-exos treatment exhibited attenuated inflammatory infiltration and necrosis in liver tissues. MSCs and MSC-exos treatment reduced the proportion of M1 macrophages, accompanied by a decrease in inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α) levels. Furthermore, MSCs and MSC-exos treatment expanded the proportion of M2 macrophages, accompanied by an increase in arginase-1 (Arg-1) and interleukin-10 (IL-10) levels. The beneficial effects of MSC-exo treatment on rats with liver trauma were superior to those of MSC treatment. The composition and abundance of the gut microbiota and metabolites were altered in pathological rats, whereas MSC and MSC-exo intervention partially restored specific gut microbiota and metabolite alterations. At the phylum level, alterations in Bacteroidota, Proteobacteria, and Verrucomicrobiota were observed after MSC and MSC-exo intervention. At the genus level, Intestinimonas, Alistipes, Aerococcus, Faecalibaculum, and Lachnospiraceae_ND3007_group were the main differential microbiota. 6-Methylnicotinamide, N-Methylnicotinamide, Glutathione, oxidized, ISOBUTYRATE, ASCORBATE, EICOSAPENTAENOATE, GLYCEROL 3-PHOSPHATE, and Ascorbate radical were selected as important differential metabolites. There was a clear correlation between Ascorbate, Intestinimonas/Faecalibaculum and inflammatory cytokines. Conclusion: MSC-exos promoted the repair of tissue damage in rats with liver trauma by regulating serum metabolites and intestinal microbiota, providing new insights into how MSC-exos reduced inflammation in rats with liver trauma.

Abstract Purpose There is no report about the direct relationship between m6A modification and androgen receptor (AR)-related genes in prostate cancer (PC). We aimed to study the mechanisms of m6A methylation in regulating the pathogenesis of PC from the perspective of AR-related genes. Methods qRT-PCR was applied to detect the expression of m6A-related genes in PC cell with or without AR inhibitor. The effects of YTHDF1 knockdown on PC cell viability, apoptosis, migration and invasion were investigated using flow cytometry, wound healing and transwell assays, respectively. The mechanism of YTHDF1 action was investigated using m6A RNA immunoprecipitation (MeRIP) sequencing. The biological functions of YTHDF1 were also explored through in vivo experiments. Results YTHDF1 was significantly down-regulated in AR inhibitor group. YTHDF1 knockdown significantly decreased AR level, viability and m6A methylation level of PC cells. TRIM68 was identified as a direct target of YTHDF1. Both YTHDF1 and TRIM68 knockdown increased apoptosis, and decreased cell viability, migration, and invasion of PC cells, while TRIM68 overexpression reversed the effects of YTHDF1 knockdown on PC cells. In addition, knockdown of YTHDF1 or TRIM68 significantly decreased the m6A methylation level, and mRNA and protein levels of YTHDF1, TRIM68 and AR in PC cells, while TRIM68 overexpression increased the expression levels above. Furthermore, subcutaneous xenografts of nude mice also revealed that TRIM68 could reverse the effects of YTHDF1 knockdown in PC in vivo. Conclusion This study suggested the key role of YTHDF1-mediated m6A modification in PC progression by regulating androgen function-related gene TRIM68 in PC.

Abstract Background Primary liver cancer has significant intratumor genetic heterogeneity (IGH), which drives cancer evolution and prevents effective cancer treatment. CRISPR/Cas9-induced mouse liver cancer models can be used to elucidate how IGH is developed. However, as CRISPR/Cas9 could induce chromothripsis and extrachromosomal DNA in cells in addition to targeted mutations, we wondered whether this effect contributes to the development of IGH in CRISPR/Cas9-induced mouse liver cancer. Methods CRISPR/Cas9-based targeted somatic multiplex-mutagenesis was used to target 34 tumor suppressor genes (TSGs) for induction of primary liver tumors in mice. Target site mutations in tumor cells were analyzed and compared between single-cell clones and their subclones, between different time points of cell proliferation, and between parental clones and single-cell clones derived from mouse subcutaneous allografts. Genomic instability and generation of extrachromosomal circular DNA (eccDNA) was explored as a potential mechanism underlying the oscillation of target site mutations in these liver tumor cells. Results After efficiently inducing autochthonous liver tumors in mice within 30–60 days, analyses of CRISPR/Cas9-induced tumors and single-cell clones derived from tumor nodules revealed multiplexed and heterogeneous mutations at target sites. Many target sites frequently displayed more than two types of allelic variations with varying frequencies in single-cell clones, indicating increased copy number of these target sites. The types and frequencies of targeted TSG mutations continued to change at some target sites between single-cell clones and their subclones. Even the proliferation of a subclone in cell culture and in mouse subcutaneous graft altered the types and frequencies of targeted TSG mutations in the absence of continuing CRISPR/Cas9 genome editing, indicating a new source outside primary chromosomes for the development of IGH in these liver tumors. Karyotyping of tumor cells revealed genomic instability in these cells manifested by high levels of micronuclei and chromosomal aberrations including chromosomal fragments and chromosomal breaks. Sequencing analysis further demonstrated the generation of eccDNA harboring targeted TSG mutations in these tumor cells. Conclusions Small eccDNAs carrying TSG mutations may serve as an important source supporting intratumor heterogeneity and tumor evolution in mouse liver cancer induced by multiplexed CRISPR/Cas9.

Abstract Background Coffee is the most widely consumed psychostimulant worldwide. Emerging evidence indicates that coffee consumption habit significantly reduces the risk of developing Parkinson’s disease (PD). However, the effect of coffee consumption on nigrostriatal dopaminergic neurodegeneration is still largely unknown. We therefore aim to investigate the role of coffee consumption in nigrostriatal dopaminergic neurodegeneration using dopamine transporter (DAT) imaging in PD and healthy controls (HC). Methods A total of 138 PD patients and 75 HC with questionnaires about coffee consumption, and DAT scans were recruited from the Parkinson’s Progression Markers Initiative cohort. Demographic, clinical, and striatal DAT characteristics were compared across subgroups of current, former, and never coffee consumers in PD and HC, respectively. Furthermore, partial correlation analyses were performed to determine whether there was a relationship between coffee cups consumed per day and striatal DAT characteristics in each striatal region. In addition, the factors that may have influenced the loss of nigrostriatal dopaminergic neurons were included in multiple linear regression analyses to identify significant contributing factors to DAT availability in each striatal region. Results PD patients had lower DAT availability in each striatal region than HC (p

Abstract Background Voiding trials are used to identify women at risk for postoperative urinary retention while performing optimal voiding trial management with minimal burden to the patient and medical service team. We performed a systematic review and meta-analysis of postoperative void trials following urogynecologic surgery to investigate (1) the optimal postoperative void trial methodology and (2) the optimal criteria for assessing void trial. Method We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and relevant reference lists of eligible articles from inception to April 2022. We identified any randomized controlled trials (RCTs) in English that studied void trials in patients undergoing urogynecologic surgery. Study selection (title/abstract and full text), data extraction, and risk of bias assessment were conducted by two independent reviewers. Extracted study outcomes included the following: the correct passing rate, time to discharge, discharge rate without a catheter after the initial void trial, postoperative urinary tract infection, and patient satisfaction. Results Void trial methodology included backfill-assisted and autofill studies (2 RCTs, n = 95). Backfill assistance was more likely to be successful than autofill (RR 2.12, 95% CI 1.29, 3.47, P = 0.00); however, no significant difference was found in the time to discharge (WMDs = − 29.11 min, 95% CI − 57.45, 1.23, P = 0.06). The criteria for passing void trial included subjective assessment of the urinary force of stream and objective assessment of the standard voiding trial (3 RCTs, n = 377). No significant differences were found in the correct passing rate (RR 0.97, 95% CI 0.93, 1.01, P = 0.14) or void trial failure rate (RR 0.78, 95% CI 0.52, 1.18, P = 0.24). Moreover, no significant differences were found in the complication rates or patient satisfaction between the two criteria. Conclusion Bladder backfilling was associated with a lower rate of catheter discharge after urogynecologic surgery. The subjective assessment of FOS is a reliable and safe method for assessing postoperative voiding because it is less invasive. Systematic review registration PROSPERO CRD42022313397

There are currently no studies exploring omicron infection and male sexual function and semen quality. Our aim was to estimate changes in sexual function and semen quality in men recovering from infection since the COVID-19 Omicron pandemic started in China in late 2022. We collected 1540 questionnaires and assessed male function before infection and acute phase after infection by using International Index of Erectile Function-5, Premature Ejaculation Diagnostic Tool, and Arizona Sexual Experience Scale. We also collected the before and after semen analysis results of 247 male patients. During the acute phase after infection, the proportion of erectile dysfunction was significantly higher than before infection, but ejaculatory function was not significantly altered; In addition, semen analysis showed significant difference in semen concentration, semen activity and PR a+b sperm forward movement after infection compared to pre-infection.: COVID-19 Omicron can affect erectile function as well as sexual experience in male patients in the acute phase. Decreased sexual function due to COVID-19 Omicron may be related to body temperature and anxiety during infection.

[This corrects the article DOI: 10.1371/journal.pone.0060860.].

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

Abstract Mutation breeding is a significant means of increasing breeding efficiency and accelerating breeding process. In present study, we explored a new method for mutations inducing in rice (Oryza sativa L.) by using direct current electrophoresis bath (DCEB). The results showed that 20 mM NaCl solution is the optimal buffer, and the mortality of rice seeds followed an upward trend with increasing voltage and processing time of DCEB. By exploring the mutagenic effects of γ-irradiation and DCEB on seed vigor and physiological damages, we found that the physiological damages induced by DCEB on seed vigor were significant compared with that by γ-irradiation. We screened two mutants with low filled grain percentage and one mutant with abnormal hull from the M2 generations. These three mutants were confirmed to be authentic mutants based on 48 SSR markers followed by the protocol NY/T 1433–2014. Whole-genome resequencing detected a total of 503 and 537 polymorphisms in the two mutants, respectively, and the DCEB mutagenesis induced mainly InDel variants, while the exon region of mutant genes occupied a large proportion, especially the SNP variants, which occupied about 20% of the mutation sites in the exon region.

Abstract. Background:. Extracellular matrix (ECM) remodeling is the most important pathomechanism of pelvic organ prolapse (POP). Fibroblasts are the key to ECM regulation. The passaging capacity of human vaginal wall fibroblasts (hVWFs) is limited in vitro. Here, we aimed to immortalize hVWFs through the introduction of human telomerase reverse transcriptase (hTERT). Methods:. Primary cells were derived from the vaginal wall tissue of patients with POP. Cellular senescence was detected via senescence-associated β-galactosidase staining. We employed a lentiviral transfection vector to stably express hTERT in hVWFs at passage 3, generating immortalized hVWFs (i-hVWFs). We then assessed cellular proliferation via the CCK-8 and EdU assays as well as cellular migration via wound healing assays. G-banded chromosome karyotypic analysis was performed to evaluate chromosomal karyotype stability. Finally, cellular tumorigenesis capacity was assessed in nude mice. A two-tailed Student's t test was used to compare differences between the two groups. Results:. Our results showed that senescence of primary hVWFs significantly increased from passage seven. From passage 11, hVWFs showed a significantly higher senescence percentage than i-hVWFs. During the continuous passage, i-hVWFs presented stability in proliferation, migration capacity, expression of ECM regulation-related genes, and chromosome karyotype. In vivo tumorigenesis was absent in i-hVWFs. Conclusions:. The senescence of hVWFs significantly increased from the seventh passage, and we successfully used hTERT to immortalize hVWFs derived from patients with POP. Studies on POP that require a long-lived hVWF line will benefit from our technique.

Abstract Prior studies have focused on the overall behavior of randomly moving particle swarms. However, the characteristics of the stochastic-constrained particles that form ubiquitously within these swarms remain oblivious. This study demonstrates a generalized diffusion equation for stochastic-constrained particles that considers the velocity and location aggregation effects observed from their parent particle swarm (i.e., a completely random particle swarm). This equation can be approximated as the form of Schrödinger equation in the microcosmic case (low relative density) and describe the dynamics of the total mass distribution in the macrocosmic case (high relative density). The predicted density distribution of the particle swarm in the stable aggregation state is consistent with the total mass distribution of massive, relaxed galaxy clusters (at least in the range of $$r

Abstract We present a novel surface coating to resolve the stability of α-AlH3. Inspired by the strong chemical adhesion of mussels, the polymerization of dopamine was first introduced to coat α-AlH3 through simple situ polymerization. The α-AlH3 was used as a substrate. In-depth characterizations confirmed the formation of polydopamine (PDA) on the α-AlH3 surface. The coated α-AlH3 sample was characterized by X-ray diffraction X-ray photoelectron spectrometry and Scanning Electron Microscope. The results show that a strong PDA film is formed on the surface of α-AlH3, and PDA@α-AlH3 retains its primary morphology. The crystal form of α-AlH3 does not change after coating with PDA. The XPS analysis results show that N1 s appears on the material after coating with PDA, indicating that polydopamine is formed on the surface of α-AlH3. The moisture absorption tests show that the moisture absorption rate of α-AlH3 is greatly reduced after being coated with PDA. The excellent intact ability of PDA prevents α-AlH3 from reacting with water in air. The thermal stability of α-AlH3 before and after coating was analyzed by DSC. This work demonstrates the successful applications of dopamine chemistry to α-AlH3, thereby providing a potential method for metastable materials.

Abstract Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression, yet how this process is regulated by oncogenic signal remains largely unknown. Here, we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m6A reader YTHDC1 in lung cancer. Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing, specifically triggering RBM4 splicing from the full isoform (RBM4-FL) to the short isoform (RBM4-S) in a kinase-independent manner. RBM4-S functions as a tumor promoter by abolishing RBM4-FL-mediated inhibition of the activity of the SRSF1-mTORC1 signaling pathway. Mechanistically, AURKA disrupts the binding of SRSF3 to YTHDC1, resulting in the inhibition of RBM4-FL production induced by the m6A-YTHDC1-SRSF3 complex. In turn, AURKA recruits hnRNP K to YTHDC1, leading to an m6A-YTHDC1-hnRNP K-dependent exon skipping to produce RBM4-S. Importantly, the small molecules that block AURKA nuclear translocation, reverse the oncogenic splicing of RBM4 and significantly suppress lung tumor progression. Together, our study unveils a previously unappreciated role of nuclear AURKA in m6A reader YTHDC1-dependent oncogenic RNA splicing switch, providing a novel therapeutic route to target nuclear oncogenic events.

Abstract Large eyelid defect after excision of malignancies or trauma is difficult to reconstruct due to special structure and function of the eyelid. In this study, we aimed to present the outcomes of subcutaneous pedicled propeller flap for reconstructing the large eyelid defect after excision of malignancies or trauma. A retrospective review of patients diagnosed with eyelid defect due to excision of malignancies or trauma, and undergoing subcutaneous pedicled propeller flap for reconstructing the large eyelid defect, was conducted at our hospital. The clinical data were collected and analyzed. A total of 15 patients were included in the cases series. Nine patients were diagnosed with basal cell carcinoma, 3 patients with epidermoid carcinoma, and 3 patients with trauma. All the defects were successfully covered with this designed flap. There was no flap necrosis in all the cases. No functional problems were observed in all of the cases. At long-term postoperative follow-up, the average score of patients’ satisfaction was good. This subcutaneous pedicled propeller flap is a feasible alternative technique for reconstructing the large eyelid defect after excision of malignancies or trauma. This flap option could avoid the use of free flaps for large defect.

Abstract. Background:. Endoscopic biopsy can underestimate gastric malignancies as low-grade intraepithelial neoplasia (LGIN). Definitively diagnosed LGIN would progress. This study aimed to evaluate predictive factors to identify malignancies misdiagnosed as LGIN by biopsy and LGIN at high risk of progression. Methods:. The clinical records of patients diagnosed with gastric LGIN by endoscopic biopsy who underwent at least two endoscopies during the first year of follow-up between 2007 and 2017 were retrospectively collected. Three endoscopists reviewed photographs of the initial endoscopy, described lesion characteristics, and made endoscopic diagnoses. Logistic regression was used to analyze predictors to identify malignancies underestimated as LGIN. A receiver operating characteristic curve was used to evaluate the diagnostic accuracy of these predictors. Patient clinical outcomes of follow-up >1 year were collected. Kaplan–Meier estimates with log-rank tests and Cox proportional hazards regression were used to analyze predictors of progression. Results:. Overall, 48 of 182 (26.4%) patients were proven to have malignancies. A single lesion, a large lesion size, and marked intestinal metaplasia (IM) were independent predictors of initially misdiagnosed malignancies. The area under the curve of these predictors was 0.871, with a sensitivity of 68.7% and specificity of 92.5%. Twelve of 98 patients (12.2%) progressed during the 33-month median follow-up period. A whitish appearance, irregular margins, marked IM, and histological diagnosis of LGIN more than twice within the first year were predictors for progression. Conclusions:. Lesions diagnosed as LGIN by biopsy with marked IM and other predictors above should be prudently treated for high potential to be malignancies or progress. Endoscopic follow-up with repeated biopsies within the first year is recommended.

Abstract It has been more than 100 years since the advent of special relativity, but the reasons behind the related phenomena are still unknown. This article aims to inspire people to think about such problems. With the help of Mathematica software, I have proven the following problem by means of statistics: In 3-dimensional Euclidean space, for point particles whose speeds are c and whose directions are uniformly distributed in space (assuming these particles’ reference system is $$\mathcal {R}_{0}$$ R 0 , if their average velocity is 0), when some particles (assuming their reference system is $$\mathcal {R}_{u}$$ R u ), as a particle swarm, move in a certain direction with a group speed u (i.e., the norm of the average velocity) relative to $$\mathcal {R}_{0}$$ R 0 , their (or the sub-particle swarm’s) average speed relative to $$\mathcal {R}_{u}$$ R u is slower than that of particles (or the same scale sub-particle swarm) in $$\mathcal {R}_{0}$$ R 0 relative to $$\mathcal {R}_{0}$$ R 0 . The degree of slowing depends on the speed u of $$\mathcal {R}_{u}$$ R u and accords with the quantitative relationship described by the Lorentz factor $$\frac{c}{\sqrt{c^2-u^2}}$$ c c 2 - u 2 . Base on this conclusion, I have deduced the speed distribution of particles in $$\mathcal {R}_{u}$$ R u when observing from $$\mathcal {R}_{0}$$ R 0 .

Toads release toxic dry secretions from glands in their skin. Toxin possesses a wide range of biological effects, but little is known about its specific gene expression pattern and regulatory mechanisms. The Asiatic toad (Bufo gargarizans) is widely used to produce toxin. Here, we explored the gene expression of 30 tissue samples from three different skin sites (parotoid gland, dorsal skin, and abdomen skin) of B. gargarizans. After de novo assembly, 783,130 unigenes with an average length of 489 bp (N50 = 556 bp) were obtained. A total of 9,248 significant differentially expressed genes (DEGs) were detected. There were 8,819 DEGs between the parotoid gland and abdomen skin and 1,299 DEGs between the dorsal skin and abdomen skin, while only 1,283 DEGs were obtained between the parotoid gland and dorsal skin. Through enrichment analysis, it was found that the detected differential gene expressions corresponded to the different functions of different skin sites. Our key findings were the genetic expression of toxin secretion, the protection function of skin, and the related genes such as HSD3B, Cyp2c, and CAT, LGALS9. In conclusion, we provide useful transcript resources to study the gene expression and gene function of B. gargarizans and other amphibians. The detected DEGs between different sites of the skin provided better insights into the genetic mechanisms of toxin secretion and the protection function of skin for amphibians.

L-2-hydroxyglutarate (L-2HG) is an oncometabolite found elevated in renal tumors. However, this molecule might have physiological roles that extend beyond its association with cancer, as L-2HG levels are elevated in response to hypoxia and during Drosophila larval development. L-2HG is known to be metabolized by L-2HG dehydrogenase (L2HGDH), and loss of L2HGDH leads to elevated L-2HG levels. Despite L2HGDH being highly expressed in the kidney, its role in renal metabolism has not been explored. Here, we report our findings utilizing a novel CRISPR/Cas9 murine knockout model, with a specific focus on the role of L2HGDH in the kidney. Histologically, L2hgdh knockout kidneys have no demonstrable histologic abnormalities. However, GC-MS metabolomics demonstrates significantly reduced levels of the TCA cycle intermediate succinate in multiple tissues. Isotope labeling studies with [U-13C] glucose demonstrate that restoration of L2HGDH in renal cancer cells (which lowers L-2HG) leads to enhanced incorporation of label into TCA cycle intermediates. Subsequent biochemical studies demonstrate that L-2HG can inhibit the TCA cycle enzyme α-ketoglutarate dehydrogenase. Bioinformatic analysis of mRNA expression data from renal tumors demonstrates that L2HGDH is co-expressed with genes encoding TCA cycle enzymes as well as the gene encoding the transcription factor PGC-1α, which is known to regulate mitochondrial metabolism. Restoration of PGC-1α in renal tumor cells results in increased L2HGDH expression with a concomitant reduction in L-2HG levels. Collectively, our analyses provide new insight into the physiological role of L2HGDH as well as mechanisms that promote L-2HG accumulation in disease states.

Leaf senescence is a complex organized developmental stage limiting the yield of crop plants, and alfalfa is an important forage crop worldwide. However, our understanding of the molecular mechanism of leaf senescence and its influence on biomass in alfalfa is still limited. In this study, RNA sequencing was utilized to identify differentially expressed genes (DEGs) in young, mature, and senescent leaves, and the functions of key genes related to leaf senescence. A total of 163,511 transcripts and 77,901 unigenes were identified from the transcriptome, and 5,133 unigenes were differentially expressed. KEGG enrichment analyses revealed that ribosome and phenylpropanoid biosynthesis pathways, and starch and sucrose metabolism pathways are involved in leaf development and senescence in alfalfa. GO enrichment analyses exhibited that six clusters of DEGs are involved in leaf morphogenesis, leaf development, leaf formation, regulation of leaf development, leaf senescence and negative regulation of the leaf senescence biological process. The WRKY and NAC families of genes mainly consist of transcription factors that are involved in the leaf senescence process. Our results offer a novel interpretation of the molecular mechanisms of leaf senescence in alfalfa.

Abstract Zirconium phosphide (ZrP) powders were synthesized by elemental combination method via the direct reaction of zirconium powders with red phosphorus, and characterized by XRD, SEM, XPS, XRF, SAED and TEM measurements. The obtained ZrP powders were found to exhibit apparent activity in the ready eliminateion of nitric oxide (NO) via facile redox reactions, and the elimination dynamics was evaluated within the context of various important experimental parameters, such as reaction temperature and gas concentration. At a fixed amount of ZrP powders, an increasing amount of NO would be eliminated with increasing reaction temperature, and complete conversion of NO to N2 could be reached in the range of 700 to 800 °C. The addition of NH3 also facilitated NO elimination at a fixed reaction temperature. Furthermore, of the products of the elimination process, zirconia (ZrO2) powder is a kind of biocompatible material, red phosphorus can be used to produce safety matches, organophosphorous pesticide and phosphor bronze, and the produced N2 might be collected and used as a protective gas or be converted into liquid nitrogen for other purposes.

Background: High cost of imported pacemakers is a main obstacle for Chinese patients suffering from bradyarrhythmia, and a domestically developed pacemaker will help lower the burden. This study aimed to evaluate the safety and efficacy of Qinming8631 DR (Qinming Medical, Baoji, China), the first domestically developed dual-chamber pacemaker of China, compared with a commercially available pacemaker Talos DR (Biotronik, Berlin, Germany) in Chinese patients. Methods: A prospective randomized trial was conducted at 14 centers in China. Participants were randomized into trial (Qinming8631 DR) and control (Talos DR) groups. Parameters of the pacing systems were collected immediately after device implantation and during follow-ups. The effective pacing rate at 6-month follow-up was recorded as the primary end point. Electrical properties, magnet response, single- and double-pole polarity conversion, rate response function, and adverse events of the pacing system were analyzed. The Cochran-Mantel-Haenszel Chi-square test, paired t-test, and Wilcoxon signed-rank test were used for measuring primary qualitative outcomes and comparing normally and abnormally distributed measurement data. Results: A total of 225 patients with a diagnosis of bradyarrhythmia and eligible for this study were randomly enrolled into the trial (n = 113) and control (n = 112) groups. They underwent successful pacemaker implantation with acceptable postoperative pacing threshold and sensitivity. Effective pacing rates of trial and control groups were comparable both in the full analysis set and the per protocol set (81.4% vs. 79.5%, P = 0.712 and 95.4% vs. 89.5%, P = 0.143, respectively). In both data sets, noninferiority of the trial group was above the predefined noninferiority limit(−9.5%). Conclusions: This study established the noninferiority of Qinming8631 DR to Talos DR. The safety and efficacy of Qinming8631 DR pacemaker were comparable to those of Talos DR in treating patients with cardiac bradyarrhythmia.

The analysis of traffic collisions is essential for urban safety and the sustainable development of the urban environment. Reducing the road traffic injuries and the financial losses caused by collisions is the most important goal of traffic management. In addition, traffic collisions are a major cause of traffic congestion, which is a serious issue that affects everyone in the society. Therefore, traffic collision analysis is essential for all parties, including drivers, pedestrians, and traffic officers, to understand the road risks at a finer spatio-temporal scale. However, traffic collisions in the urban context are dynamic and complex. Thus, it is important to detect how the collision hotspots evolve over time through spatio-temporal clustering analysis. In addition, traffic collisions are not isolated events in space. The characteristics of the traffic collisions and their surrounding locations also present an influence of the clusters. This work tries to explore the spatio-temporal clustering patterns of traffic collisions by combining a set of network-constrained methods. These methods were tested using the traffic collision data in Jianghan District of Wuhan, China. The results demonstrated that these methods offer different perspectives of the spatio-temporal clustering patterns. The weighted network kernel density estimation provides an intuitive way to incorporate attribute information. The network cross K-function shows that there are varying clustering tendencies between traffic collisions and different types of POIs. The proposed network differential Local Moran's I and network local indicators of mobility association provide straightforward and quantitative measures of the hotspot changes. This case study shows that these methods could help researchers, practitioners, and policy-makers to better understand the spatio-temporal clustering patterns of traffic collisions.

In a previous transcriptome analysis of early response genes in rice during Magnaporthe oryzae infection, we identified a CONSTANS-like (COL) gene OsCOL9. In the present study, we investigated the functional roles of OsCOL9 in blast resistance. OsCOL9 belonged to group II of the COL protein family, and it contained a BB-box and a C-terminal CCT (CONSTANS, COL and TOC1) domain. OsCOL9 was found in the nucleus of rice cells, and it exerted transcriptional activation activities through its middle region (MR). Magnaporthe oryzae infection induced OsCOL9 expression, and transgenic OsCOL9 knock-out rice plants showed increased pathogen susceptibility. OsCOL9 was a critical regulator of pathogen-related genes, especially PR1b, which were also activated by exogenous salicylic acid (SA) and 1-aminocyclopropane-1-carboxylicacid (ACC), the precursor of ethylene (ET). Further analysis indicated that OsCOL9 over-expression increased the expressions of phytohormone biosynthetic genes, NPR1, WRKY45, OsACO1 and OsACS1, which were related to SA and ET biosynthesis. Interestingly, we found that OsCOL9 physically interacted with the scaffold protein OsRACK1 through its CCT domain, and the OsRACK1 expression was induced in response to exogenous SA and ACC as well as M. oryzae infection. Taken together, these results indicated that the COL protein OsCOL9 interacted with OsRACK1, and it enhanced the rice blast resistance through SA and ET signaling pathways.

ObjectivesTo retrospectively validate the new Chinese DIC scoring system (CDSS).MethodsThis study retrospectively collected the information of 619 patients (371 cases with non-hematologic malignancies, 248 cases with hematologic malignancies) who suspected of DIC in Wuhan Union Hospital during 2013-4 to 2014-6. We validated CDSS by comparing it with three leading scoring systems, from International Society on Thrombosis and Haemostasis (ISTH), Japanese Association for Acute Medicine (JAAM) and Japanese Ministry of Health and Welfare (JMHW), and evaluated its prognostic value by 28 days mortality, APACHE II and SOFA score.ResultsIn non-hematologic malignancies, CDSS was more specific than JAAM (72.55% vs. 50.49%, pConclusionsWe are the first group to propose CDSS. It emphasized the values of the clinical manifestations, the rapidly declining platelet count, APTT in the diagnosis of DIC and used D-dimer as the fibrin-related maker. DIC with hematological malignancies was treated as a special part. In this study we can see that CDSS displayed an acceptable property for the diagnosis of DIC with appropriate sensitivity and specificity, and also had a good prognostic value for DIC patients.

It has been well established that S-adenosyl-L-methionine (SAMe) is the principal methyl donor in methyltransferase reactions and that SAMe supplementation restores hepatic glutathione (GSH) deposits and attenuates liver injury. However, the effectiveness of SAMe therapy in chronic liver disease has not been adequately addressed. We searched globally recognized electronic databases, including PubMed, the Cochrane Database and EMBASE, to retrieve relevant randomized controlled trials (RCTs) of chronic liver disease published in the past 20 years. We then performed a systematic review and meta-analysis of the enrolled trials that met the inclusion criteria.The results showed that twelve RCTs from 11 studies, which examined 705 patients, were included in this research. For liver function, certain results obtained from data synthesis and independent comparisons demonstrated significant differences between the levels of total bilirubin (TBIL) and aspartate transaminase (AST). However, no studies identified significant differences regarding alanine transaminase (ALT) levels. An analysis of the adverse events and long-term prognosis also indicated no significant differences between the SAMe and the placebo groups. In a subgroup analysis of gravidas and children, several of the included data indicated that there was a significant difference in the pruritus score. Furthermore, the results regarding ursodeoxycholic acid (UDCA) and stronger neo-minophagen C (SNMC) indicated that both treatments were more effective than SAMe was in certain chronic liver diseases. These findings suggest that SAMe could be used as the basis of a medication regimen for liver function improvement because of its safety. However, SAMe also demonstrated limited clinical value in the treatment of certain chronic liver diseases.

Scutellarin (SCU), a flavonoid glycoside compound, has been successfully used in clinic for treatment of ischemic diseases in China. In this report, we checked the effects of SCU on endothelium dysfunction (ED) of coronary artery (CA) against myocardial ischemia reperfusion (MIR) injury in vivo. The involvement of PKG-Iα was further studied using cultured endothelial cells subjected to hypoxia reoxygenation (HR) injury in vitro. In rat MIR model, SCU (45 and 90 mg/kg, iv) significantly reduced ischemic size and restored the endothelium-dependent vasodilation of isolated CA rings. PKG inhibitor Rp-8-Br-cGMP (50 μg/kg, iv) could ameliorate the protective effects of SCU. Increase in phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a main substrate of PKG, at Ser 239 was observed in both heart tissue and serum of SCU-treated animals. In cultured human cardiac microvascular endothelial cells (HCMECs), SCU (1 and 10 μM) dose-dependently protected cell viability and increased the mRNA and protein level of PKG-Iα against HR injury. The activity of PKG was also increased by SCU treatment. The activation of PKG-1α was then studied using targeted proteomic analysis (MRM-MS) checking the phosphorylation state of the autophosphorylation domain (aa42-94). Significant decrease in phosphorylation of PKG-Iα at Ser50, Ser72, Ser89 was induced by HR injury while SCU treatment significantly increased the phosphorylation of PKG-Iα, not only at Ser50, Ser72 and Ser89, but also at Ser44 and Thr58 (two novel phosphorylation domains). Our results demonstrate PKG-Iα might play an important role in the protective effects of SCU on ED against MIR injury.

OBJECTIVES: We investigated the association of serum magnesium (Mg) levels and major adverse cardiac events (MACEs) after drug-eluting stent (DES) implantation. BACKGROUND: Mg depletion plays a key role in the pathphysiologic features of diabetes mellitus, hypertension, thrombosis, arrhythmias and coronary artery disease. Whether the depletion is related to the long-term prognosis of DES implantation is not known. METHODS: From 2008 to 2011, we enrolled 414 consecutive patients

Injured endothelium is an important target for drug and/or gene therapy because brain microvascular endothelial cells (BMECs) play critical roles in various pathophysiological conditions. RNA-mediated gene silencing presents a new therapeutic approach for treating such diseases, but major challenge is to ensure minimal toxicity and target delivery of siRNA to injured BMECs. Injured BMECs overexpress tissue factor (TF), which the fusion protein EGFP-EGF1 could be targeted to. In this study, TNF alpha (TNF-α) was chosen as a stimulus for primary BMECs to produce injured endothelium in vitro. The EGFP-EGF1-PLGA nanoparticles (ENPs) with loaded TF-siRNA were used as a new carrier for targeted delivery to the injured BMECs. The nanoparticles then produced intracellular RNA interference against TF. We compared ENP-based transfections with NP-mediated transfections, and our studies show that the ENP-based transfections result in a more efficient downregulation of TF. Our findings also show that the TF siRNA-loaded ENPs had minimal toxicity, with almost 96% of the cells viable 24 h after transfection while Lipofectamine-based transfections resulted in only 75% of the cells. Therefore, ENP-based transfection could be used for efficient siRNA transfection to injured BMECs and for efficient RNA interference (RNAi). This transfection could serve as a potential treatment for diseases, such as stroke, atherosclerosis and cancer.

Brain-derived neurotrophic factor (BDNF) was recently identified as a factor produced by multiple myeloma (MM) cells, which may contribute to bone resorption and disease progression in MM, though the molecular mechanism of this process is not well understood. The purpose of this study was to test the effect of BDNF on bone disease and growth of MM cells both in vitro and in vivo. Co- and triple-culture systems were implemented. The in vitro results demonstrate that BDNF augmented receptor activator of nuclear factor kappa B ligand (RANKL) expression in human bone marrow stromal cells, thus contributing to osteoclast formation. To further clarify the effect of BDNF on myeloma bone disease in vivo, ARH-77 cells were stably transfected with an antisense construct to BDNF (AS-ARH) or empty vector (EV-ARH) to test their capacity to induce MM bone disease in SCID-rab mice. Mice treated with AS-ARH cells were preserved, exhibited no radiologically identifiable lytic lesions and, unlike the controls treated with EV-ARH cells, lived longer and showed reduced tumor burden. Consistently, bones harboring AS-ARH cells showed marked reductions of RANKL expression and osteoclast density compared to the controls harboring EV-ARH cells. These results provide further support for the potential osteoclastogenic effects of BDNF, which may mediate stromal-MM cell interactions to upregulate RANKL secretion, in myeloma bone diseases.

BACKGROUND: Protein C (PC) is one of the most important physiological inhibitors of coagulation proteases. Hereditary PC deficiency causes a predisposition to venous thrombosis (VT). The genetic characteristics of PC deficiency in the Chinese population remain unknown. METHODS: Thirty-four unrelated probands diagnosed with hereditary PC deficiency were investigated. PC activity and antigen levels were measured. Mutation analysis was performed by sequencing the PROC gene. In silico analyses, including PolyPhen-2, SIFT, multiple sequence alignment, splicing prediction, and protein molecular modeling were performed to predict the consequences of each variant identified. One recurrent mutation and its relative risk for thrombosis in relatives were analyzed in 11 families. The recurrent mutation was subsequently detected in a case (VT patients)-control study, and the adjusted odds ratio (OR) for VT risk was calculated by logistic regression analysis. RESULTS: A total of 18 different mutations, including 12 novel variants, were identified. One common mutation, PROC c.565C>T (rs146922325:C>T), was found in 17 of the 34 probands. The family study showed that first-degree relatives bearing this variant had an 8.8-fold (95%CI = 1.1-71.6) increased risk of venous thrombosis. The case-control (1003 vs. 1031) study identified this mutation in 5.88% patients and in 0.87% controls, respectively. The mutant allele conferred a high predisposition to venous thrombosis (adjusted OR = 7.34, 95%CI = 3.61-14.94). The plasma PC activity and antigen levels in heterozygotes were 51.73±6.92 U/dl and 75.17±4.84 U/dl, respectively. CONCLUSIONS: This is the first study on the genetic background of PC deficiency in the Chinese population. The PROC c.565C>T mutation is the most frequent cause of PC deficiency as well as a prevalent risk factor for VT in Chinese individuals. The inclusion of this variant in routine thrombophilic detection may improve the diagnosis and prevention of venous thrombosis.