Search

Despite advancements in assisted reproductive technology, recurrent implantation failure (RIF) remains a challenge. Endometrial factors, including ferroptosis and immunity, may contribute to this issue. This study integrated bioinformatics analysis and Mendelian randomization (MR) to investigate the expression and significance of DEFRGs in RIF. We intersected 484 ferroptosis‐associated genes with 515 differentially expressed genes (DEGs) to identify key DEFRGs. Subsequent analyses included enrichment analysis, molecular subtype identification, machine learning model development for biomarker discovery, immune cell infiltration assessment, single‐cell RNA sequencing, and MR to explore the causal relationships of selected genes with RIF. In this study, we identified 11 differentially expressed ferroptosis‐related genes (DEFRGs) between RIF and healthy individuals. Cluster analysis revealed two distinct molecular subtypes with different immune profiles and DEFRG expressions. Machine learning models highlighted MUC1, GJA1 and FANCD2 as potential diagnostic biomarkers, with high accuracy in RIF prediction. Single‐cell analysis further revealed the cellular localization and interactions of DEFRGs. MR suggested a protective effect of FANCD2 against RIF. Validation in RIF patients confirmed the differential expression of key DEFRGs, consistent with bioinformatics findings. This comprehensive study emphasize the significant role of DEFRGs in the pathogenesis of RIF, suggesting that modulating these genes could offer new avenues for treatment. The FANCD2 is a potential gene contributing to RIF pathogenesis through a non‐classical ferroptosis‐dependent pathway, providing a foundation for personalized therapeutic strategies in RIF management. [ABSTRACT FROM AUTHOR]

Background: Synonymous variants are non‐pathogenic due to non‐substitution of amino acids. However, synonymous exonic terminal nucleotide substitutions may affect splicing. Splicing variants are easily analyzed at RNA level for genes expressed in blood cells. Minigene analysis provides another method for splicing variant analysis of genes that are poorly or not expressed in peripheral blood. Methods: Whole exome sequencing was performed to screen for potential pathogenic mutations in the proband, which were validated within the family by Sanger sequencing. The pathogenicity of the synonymous mutation was analyzed using the minigene technology. Results: The proband harbored the compound heterogeneous variants c. [291G >A; 572‐50C >T] and c.681 + 1G >T in F7, of which the synonymous variant c.291G >A was located at the terminal position of exon 3. Minigene analysis revealed exon3 skipping due to this mutation, which may have subsequently affected protein sequence, structure, and function. Conclusion: Our finding confirmed the pathogenicity of c.291G >A, thus extending the pathogenic mutation spectrum of F7, and providing insights for effective reproductive counseling. [ABSTRACT FROM AUTHOR]

Aims: Itch, a common uncomfortable sensory experience, occurs frequently in inflammatory or allergic disorders. In recent years, with the discovery of itch‐specific pathways in the peripheral and central nervous system, the association between immunology and neural pathways has gradually emerged as the main mechanism of itch. Although many studies have been conducted on itch, no bibliometric analysis study focusing on this topic has been conducted. This study aimed to explore the research hotspots and trends in the itch field from a bibliometric perspective. Methods: Publications relevant to itch, published from 2003 to 2022, were retrieved from the Science Citation Index‐Expanded of Web of Science Core Collection. Publications were critically reviewed and analyzed with CiteSpace software, Vosviewer, and the bibliometric online analysis platform. Visual maps were conducted in terms of annual production, collaborating countries or institutions, productive authors, core journals, co‐cited references, and keyword bursts. Results: 2395 articles on itch that met our criteria were identified and the quantity of publications has been increasing rapidly since 2012. The USA was the most influential country. University Hospital Münster was the institution with the most publications. Gil Yosipovitch was the most prolific author. Atopic dermatitis (AD), intradermal serotonin, chronic pruritus, mechanical itch, gastrin‐releasing peptide, substance p, interleukin‐31 receptor, histamine‐induced itch, bile acid, scratching behavior, and h‐4 receptor were the top 11 clusters in co‐citation cluster analysis. Keyword burst analysis suggested that treatment, inflammation, and AD are current research hotspots. Conclusion: Global publications on itch research have increased steadily and rapidly over the past 20 years. Inflammation and AD are current research hotspots. The neuroimmunological and neuroinflammatory mechanisms of itch, as well as clinical assessment methods and therapeutic targets, will be novel research directions in the future. This study provides guidance for further itch research. [ABSTRACT FROM AUTHOR]

Aims and Objectives: The aim of this study was to assess the sleep quality in dialysis patients during the COVID‐19 epidemic and explore the association between negative psychology (including depression, anxiety, and stress) and sleep quality in this population. Design: A cross‐sectional study including three centres. Methods (Patients or Public Contribution): This cross‐sectional study included 378 dialysis patients from April to May 2022 in three dialysis centres in Shanghai. Methods. Depression, anxiety, stress, and sleep quality were measured by the Hospital Anxiety and Depression Scale (HADS), Perceived Stress Scale‐14 (PSS‐14), and Pittsburgh sleep quality index (PSQI), respectively. With a threshold of 5 to classify participants into good and poor sleep quality, with HADS/PSS‐14 scores as independent variables (per standard deviation (SD) increment), respectively and binary Logistic regression model was constructed to explore the association between the three negative psychological aspects of depression, anxiety, and stress and sleep quality. Results: The median PSQI score was 11.0 (mean ± SD: 11.8 ± 4.8). Among them, poor sleep quality (i.e., PSQI >5) was reported by 90.2% of participants. After adjusting for sociodemographic and disease‐related information, HADS‐depression was associated with a significant 49% (odds ratio (OR): 1.49; 95% CI 1.02–2.18) increase in the risk of poor sleep quality for each additional SD (2.4). Correspondingly, for each SD (7.1) increase in PSS‐14, the risk of poor sleep quality was significantly increased by 95% (OR: 1.95; 95% CI 1.35–2.82). Conclusion: During the COVID‐19 pandemic, there was a significant negative association between negative psychology, such as depression and stress, and sleep quality in dialysis patients, and this relationship was independent of the dialysis modality. Relevance to Clinical Practice: In the context of the rampant COVID‐19, the vast majority of dialysis‐dependent chronic kidney disease presents with severe sleep quality problems, and negative psychology is a potential influencing factor. [ABSTRACT FROM AUTHOR]

Several studies have demonstrated that exercise preconditioning is an effective means of alleviating poststroke cognitive impairment (PSCI). Mechanisms of regulating cognitive function have not been fully elucidated. Herein, the present study is aimed at exploring the effect of the microbiota-gut-inflammasome-brain axis in the process of exercise preconditioning moderating cognitive impairment after ischemic stroke. We observed that exercise preconditioning decreased infarct size, reduced the degree of neuronal damage, and alleviated cognitive impairment in mice with ischemic stroke. In addition, exercise preconditioning also reduced the expression of inflammatory cytokines, as well as NLRP3, Caspase-1, IL-18, and IL-1β protein expressions. Ischemic stroke could downregulate the abundance of Roseburia while increasing the abundance of the Helicobacter at the level of genus. As a comparison, exercise preconditioning increased the abundance of the Lactobacillus, which was beneficial for mice at the genus level. In conclusion, exercise preconditioning can improve cognitive dysfunction after ischemic stroke through alleviating inflammation and regulating the composition and diversity of the gut microbiota, which might provide a new strategy for the prevention of PSCI. [ABSTRACT FROM AUTHOR]

Landscape morphology is a significant area of landscape architecture research. One of the scientific and technological issues in recent landscape morphology research is the use of quantitative analysis technology driven by morphology indexes and computational models to describe, compare, and analyze form features. This article focuses on the form features of the polder landscape, based on existing theoretical and practical achievements in landscape morphology. First, we choose five landscape morphology indexes based on the morphological constituent units of the landscape (elongation, rectangular compactness, concavity, ellipse compactness, and fractal dimension). Then, using the self-organizing map (SOM), we create an identification model for clustering the types of constituent units. The experimental results show that the identification model can classify polder morphology and analyze the distribution of units using typical polders in the Yangtze River's south bank as study cases. This article presents a technical approach to polder landscape morphology classification as well as a reference and developable quantitative analysis method for landscape morphology research. [ABSTRACT FROM AUTHOR]

Xq28 duplication syndrome (MIM# 300815) is a severe neurodevelopmental disorder in males due to MeCP2 overexpression. Most females with MECP2 duplication are asymptomatic carriers, but there are phenotypic heterogeneities. Skewed X‐chromosome inactivation (XCI) can protect females from exhibiting clinical phenotypes. Herein we reported two asymptomatic females (mother and grandmother) with interstitial Xq28 duplication. AR and RP2 assays showed that both had extremely skewed XCI, the Xq28 duplicated chromosome was inactivated in the mother, but was surprisingly activated in the grandmother. Interestingly, by combining RNA sequencing and whole‐exome sequencing, we confirmed that XIST only expressed in the Xq28 duplication chromosomes of the two females, indicating that the Xq28 duplication chromosomes were inactive. Meanwhile, MECP2 and most XCI genes in the duplicated X‐chromosomes were not transcriptionally expressed or upregulated, precluding major clinical phenotypes in the two females, especially the grandmother. We showed that XCI status detected using RNA sequencing was more relevant for establishing the clinical phenotype of MECP2 duplication in females. It suggested that there were other factors maintaining the XCI status in addition to DNA methylation, a possible additional inhibition mechanism occurred at the transcriptional level in the unmethylated X‐chromosome, counter balancing the MECP2 duplication's detrimental phenotype effects. [ABSTRACT FROM AUTHOR]

Magnetic resonance spectroscopy (MRS) is capable of revealing important biochemical and metabolic information of tissues noninvasively. However, the low concentrations of metabolites often lead to poor signal‐to‐noise ratio (SNR) and a long acquisition time. Therefore, the applications of MRS in detection and quantitative measurements of metabolites in vivo remain limited. Reducing or even eliminating noise can improve SNR sufficiently to obtain high quality spectra in addition to increasing the number of signal averaging (NSA) or the field strength, both of which are limited in clinical applications. We present a Spectral Wavelet‐feature ANalysis and Classification Assisted Denoising (SWANCAD) approach to differentiate signal and noise peaks in magnetic resonance spectra based on their respective wavelet features, followed by removing the identified noise components to improve SNR. The performance of this new denoising approach was evaluated by measuring and comparing SNRs and quantified metabolite levels of low NSA spectra (e.g. NSA = 8) before and after denoising using the SWANCAD approach or by conventional spectral fitting and denoising methods, such as LCModel and wavelet threshold methods, as well as the high NSA spectra (e.g. NSA = 192) recorded in the same sampling volumes. The results demonstrated that SWANCAD offers a more effective way to detect the signals and improve SNR by removing noise from the noisy spectra collected with low NSA or in the subminute scan time (e.g. NSA = 8 or 16 s). The potential applications of SWANCAD include using low NSA to accelerate MRS acquisition while maintaining adequate spectroscopic information for detection and quantification of the metabolites of interest when a limited time is available for an MRS examination in the clinical setting. [ABSTRACT FROM AUTHOR]

Metabolism reprograming is a hallmark of cancer and plays an important role in tumor progression. The aberrant metabolism in renal cell carcinoma (RCC) leads to accumulation of the oncometabolite L‐2‐hydroxyglurate (L‐2HG). L‐2HG has been reported to inhibit the activity of some α‐ketoglutarate‐dependent dioxygenases such as TET enzymes, which mediate epigenetic alteration, including DNA and histone demethylation. However, the detailed functions of L‐2HG in renal cell carcinoma have not been investigated thoroughly. In our study, we found that L‐2HG was significantly elevated in tumor tissues compared to adjacent tissues. Furthermore, we demonstrated that L‐2HG promoted vasculogenic mimicry (VM) in renal cancer cell lines through reducing the expression of PHLDB2. A mechanism study revealed that activation of the ERK1/2 pathway was involved in L‐2HG‐induced VM formation. In conclusion, these findings highlighted the pathogenic link between L‐2HG and VM and suggested a novel therapeutic target for RCC. What's new? Metabolic reprograming, a hallmark of cancer, influences tumor progression. In the case of renal cell carcinoma (RCC) specifically, progression appears to be facilitated by the oncometabolite L‐2‐hydroxyglurate (L‐2HG), though underlying mechanisms remain enigmatic. Here, the authors investigated the ability of L‐2HG in RCC to promote vasculogenic mimicry (VM), in which aggressive cancer cells form vessel‐like networks that support tumor growth. Analyses of RCC patient tissues revealed elevated L‐2HG levels, wherein tumor cells with greater L‐2HG levels exhibited more VM structures. TCGA data and high‐throughput sequencing analyses further show that L‐2HG contributes to VM formation via reduction of PHLDB2 levels. [ABSTRACT FROM AUTHOR]

The predictors of weaning time of renal replacement therapy (RRT) remain controversial for special patients suffering from acute kidney injury (AKI). The present work aims to perform a meta‐analysis to evaluate proper predictors of RRT weaning in AKI patients. We systematically searched EMBASE, PubMed, and Cochrane Central Register of Controlled trials for literatures between 1984 and June 2019. Studies evaluating predictors of weaning success of RRT in patients of AKI were included. Random‐effects model or fixed‐effects model meta‐analyses were performed to compute a standard mean difference (SMD). Newcastle–Ottawa Scale was employed to assess the risk of bias. We included 10 observational trials including 1453 patients. Twelve predictors including urine output, serum creatinine, serum urea, mean arterial pressure, central venous pressure, lactate, serum potassium, serum bicarbonate, pH value, SOFA score, urinary urea, and urinary creatinine were identified, showing urine output (p = 0.0000), serum creatinine (p = 0.008), serum potassium (p = 0.02), serum bicarbonate (p = 0.01), pH value (p = 0.03), urinary urea (p = 0.002), and urinary creatinine (p = 0.02) were significantly associated with weaning success. With the limited evidence, we speculate that urine output, serum creatinine, serum potassium, serum bicarbonate, pH value, urinary urea, and urinary creatinine might be associated with successful weaning. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effects of deep anterior lamellar keratoplasty (DALK) with cross‐linked acellular porcine corneal stroma (APCS) and post‐operative topical tacrolimus treatment in patients with fungal keratitis. Methods: This multicenter prospective study involved 25 cases of fungal keratitis that were treated by DALK with cross‐linked APCSs and post‐operative topical tacrolimus from December 2013 to November 2014 at the Wenzhou Eye Hospital and the Henan provincial Eye Hospital. Signs of post‐operative inflammation, corneal reepithelialization, corneal neovascularization, and graft rejection were assessed, and best corrected visual acuity (BCVA), intraocular pressure (IOP), and APCS graft transparency were monitored for the 12‐month follow‐up period. Results: All 25 patients underwent DALK without Descemet's membrane perforation. Corneal epithelium recovered completely in 17 patients in the first week, and APCS grafts maintained transparency in 18 patients at 1‐year follow‐up. The mean BCVA significantly improved from 2.16 ± 0.32 (LogMAR) at baseline to 1.56 ± 0.70 at 1‐week (P <.001), 0.95 ± 0.57 at 1‐month (P <.001), and 0.70 ± 0.51 at 3‐month follow‐ups (P <.001). The BCVA kept stable at 6‐month and 12‐month follow‐ups. Post‐operative topical tacrolimus alleviated the ciliary injection, except in one case which acute stromal rejection occurred. One patient developed fungal reinfection and underwent penetrating keratoplasty. Graft rejection occurred in three patients. No case was noted with graft splitting, elevated IOP or tacrolimus intolerance. Conclusions: DALK using cross‐linked APCS combining topical tacrolimus treatment is safe and effective in managing fungal keratitis. It may ameliorate the shortage of corneal donation globally. [ABSTRACT FROM AUTHOR]

Lymphomatoid papulosis (LyP) is a rare CD30+ lymphoproliferative primary skin disease with a benign clinical course and malignant histopathology. LyP is classified into seven subtypes based on histopathology: subtypes A through F and LyP with 6p25.3 chromosome rearrangement. We present here, a case report of a 51‐year‐old man, afflicted with multiple papules and nodules on his left arm for over 3 months and diagnosed with LyP subtype C. The patient refused treatment, and his lesions faded with no visible rash on the left arm 14 months after diagnosis. [ABSTRACT FROM AUTHOR]

Oxidative stress occurs when excess oxidative free radicals are produced in cells, which can overwhelm the normal antioxidant capacity and play an important role in many disease states. Thus, advanced functional materials which can mimic the intracellular antioxidant defense system have a huge potential to become candidates for curing oxidative stress triggered diseases. Herein, a high‐performance nanoplatform is developed with a green and mild strategy by combining mimic‐enzymatic antioxidant (Fe3O4) and nonenzymatic antioxidant (tannic acid (TA)) for constructing antioxidant defense system (Fe3O4 @ TAn nanoflowers (NFs)). Owing to the excellent peroxidase (POD)‐mimic and catalase (CAT)‐mimic capacities of Fe3O4 in various conditions, the antioxidant ability of TA and the flower‐like morphology, the Fe3O4 @ TAn NFs can effectively scavenge multiple reactive oxygen and nitrogen species. In vitro experiments verify that the Fe3O4 @ TAn NFs demonstrate synergetic antioxidative properties, which can be used to protect blood and cellular components against oxidative damage. Meanwhile, in vivo experiments demonstrate that the Fe3O4 @ TAn NFs exhibit excellent therapeutic effects for systemic inflammation on endotoxemia mice and promote wound healing owing to the excellent antioxidant and anti‐inflammatory properties. Thus, this antioxidant defense system expands the toolbox of antioxidative materials and shows potential applications in oxidative stress treatment. [ABSTRACT FROM AUTHOR]

The rapid development and advances in nanomaterials and nanotechnology in the past two decades have made profound impact in our approaches to individualized disease diagnosis and treatment. Nanomaterials, mostly in the range of 10–200 nm, developed for biomedical applications provide a wide range of platforms for building and engineering functionalized structures, devices, or systems to fulfill the specific diagnostic and therapeutic needs. Driven by achieving the ultimate goal of clinical translation, sub‐5 nm nano‐constructs, in particular inorganic nanoparticles such as gold, silver, silica, and iron oxide nanoparticles, have been developed in recent years to improve the biocompatibility, delivery and pharmacokinetics of imaging probes and drug delivery systems, as well as in vivo theranostic applications. The emerging studies have provided new findings that demonstrated the unique size‐dependent physical properties, physiological behaviors and biological functions of the nanomaterials in the range of the sub‐5 nm scale, including renal clearance, novel imaging contrast, and tissue distribution. This advanced review attempts to introduce the new strategies of rational design for engineering nanoparticles with the core sizes under 5 nm in consideration of the clinical and translational requirements. We will provide readers the update on recent discoveries of chemical, physical, and biological properties of some biocompatible sub‐5 nm nanomaterials as well as their demonstrated imaging and theranostic applications, followed by sharing our perspectives on the future development of this class of nanomaterials. This article is categorized under:Diagnostic Tools > in vivo Nanodiagnostics and ImagingImplantable Materials and Surgical Technologies > Nanomaterials and Implants [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the impact of cardiac structure and function at baseline on the outcomes associated with arteriovenous fistula (AVF) in patients on hemodialysis (HD). Patients who initiated HD aged ≥70 years and received a mature AVF creation were included retrospectively. Echocardiographic parameters measured within 1 week before AVF creation were acquired. The observational period for each patient was from the point of AVF creation to the last time of follow-up unless AVF abandonment or death occurred. Kaplan-Meier and Cox proportional hazard regression analyses were conducted. A total of 82 elderly Chinese HD patients with mature radiocephalic AVF (RCAVF) and EF ≥50% were analyzed. During the median study period of 26.8 (12-40) months, 42 (51.2%) experienced RCAVF dysfunction and 34 (41.5%) progressed to abandonment. Primary and cumulative patencies at 6, 12, 24, and 36 months were 81%, 73%, 48%, 38%, and 84%, 81%, 68%, 55%, respectively. Left ventricle end-diastolic volume (LVEDV) ≤103.5 mL (HR = 2.5, P = .019) and the right side of RCAVF (HR = 3.59, P = .003) significantly predicted RCAVF dysfunction. The main pulmonary artery internal diameter (MPAID) ≤21.5 mm (HR = 4.3, P = .001) as well as the right side (HR = 2.95, P = .047) were the independent predictors for RCAVF abandonment. In conclusion, LVEDV, MPAID assessed by echocardiography and the right side of RCAVF, showed significant predictive implications for the outcomes of RCAVF. Disparities among nationalities in the areas of utilization and patency of AVFs necessitate additional studies. [ABSTRACT FROM AUTHOR]

Aim: Vascular calcification (VC) is a common complication in chronic kidney disease (CKD) and has been shown to be associated with increased cardiovascular events and mortality. This study was to explore the role of Wnt‐signaling pathway in CKD VC, and the association between VC and blood pressure variability (BPV) which is a risk factor of cardiovascular events. Methods: Adult male Sprague‐Dawley rats were divided into adenine‐induced CKD group (n = 5), 5/6 nephrectomy CKD group (n = 5), sham group (n = 5) and control group (n = 5). Low‐calcium‐high‐phosphate diets were introduced to induce vascular calcification. Both daytime (hour‐to‐hour during the day) and mid‐term (day‐to‐day for 9 days) blood pressure (BP) were collected and analyzed for BPV metrics. At sacrifice, kidney, heart and aorta samples were taken for histological analyses. Calcium deposition in aorta was identified with Alizarin Red stain and graded. Immunohistochemistry stain and western blot were performed for Wnt3a, Wnt5a, β‐catenin, sclerostin, osteopontin, and α‐SMA. Results: Compared with control rats, CKD rats suffered from markedly severer VC (Grade 2.6 ± 0.2 and 1.8 ± 0.8 vs 0.0 ± 0.0 and 0.2 ± 0.4, P =.0010). VC was positively correlated with vascular Wnt3a and β‐catenin expression (P =.0032 and.0000), but not significantly associated with Wnta5a or sclerostin. Besides, CKD rats showed increased BPV (P <.001), which was also positively correlated with VC. Conclusion: We confirmed that CKD rats had enhanced Wnt‐signaling in vascular tissue and severer aorta calcification together with increased BPV. Wnt pathway may be a potential target in future VC and BPV management in CKD. SUMMARY AT A GLANCE: Vascular calcification was positively correlated with Wnt‐signaling and blood pressure variability (BPV) based on two experimental CKD models. These findings provide a new potential target for BPV management. [ABSTRACT FROM AUTHOR]

Dried fruits of black goji were investigated for their fatty acid, mineral contents, and antioxidant activity against isoproterenol‐induced acute myocardial ischemia in mice was revealed. It was observed that the key fatty acids from Lycium ruthenicum Murr. (LRM) oil studied included linoleic (59.38%), oleic (20.85%), palmitic (7.07%), linolenic (2.98%), and stearic acids (5.31%), which together comprised 95.59% of the total fatty acids. The key mineral nutrients studied were potassium (17,631.15 mg/kg), calcium (2004.4 mg/kg), and magnesium (1,274.6 mg/kg), while copper, iron, manganese, and zinc were found in trace. Moreover, oral administration of water extraction of LRM exhibited significant reduction of enzyme activities, and MDA level triggered by ISO to be near normal level, while exhibited a significant increase of SOD and GSH activities. Our results provide deep insight on LRM as a potential source of high‐value phytochemicals for the development of new functional food and beverage products. [ABSTRACT FROM AUTHOR]

Iodine deficiency during pregnancy can cause iodine deficiency disorders (IDD). However, it is unclear about iodine and thyroid status of Chinese pregnant women and neonates after the implementation of the revised universal salt iodisation (USI) level in 2012. Therefore, the aim of the cross-sectional study was to determine iodine nutrition and thyroid status among pregnant women and their neonates in China after the implementation of USI. Medical records of pregnant women and neonates in Northern Jiangsu People's Hospital between January 2016 and December 2017 were reviewed and included. We included 3060 mother-and-newborn pairs in the study. Mean age of participants was 28.2 ± 4.1 years. TSH, FT3, and FT4 of participants were within normal reference range. The overall mean neonatal TSH, birth weight, and prevalence of low birth weight (LBW) were 4.86 ± 2.06 mIU/L, 3358 ± 455 g, and 3.2%, respectively. The prevalence of neonatal TSH values >5 mIU/L was 29.3%, suggesting iodine deficiency in the region. In conclusion, our results indicated iodine deficiency in the region, according to the neonatal TSH cutoff recommended by WHO/UNICEF/IGD. More efforts are urgently required to improve iodine status of pregnant women in the region in order to prevent a re-emergence of iodine deficiency. [ABSTRACT FROM AUTHOR]

Coronary artery calcifications (CACs) are common among maintenance hemodialysis (MHD) patients and associated with increased morbidity and mortality due to cardiovascular events. The insight into chronic kidney disease‐mineral and bone disorder (CKD‐MBD) established a correlation between dysregulated mineral metabolism and CACs. This study aimed to identify the association of mineral content outside of bone (MCOB) with CACs and cardiovascular events in MHD patients. In the pilot prospective study with no intervention, patients underwent body composition assessment by body composition monitor after hemodialysis and computed tomography examination using the Agatston scoring method simultaneously within a week. The primary end point included cardiovascular events and cardiovascular death. Correlations and receiver operating characteristic analysis elucidated the associations of MCOB with CACs; multivariate analysis assessed the cardiovascular risk for groups with different MCOB. One hundred three eligible patients with an average age of 48 (35‐63) years old were enrolled and followed up to 12 (11‐12.5) months, among which 52.4% had detectable CACs at baseline. MCOB showed an inverse correlation with Agatston score and significantly discriminated the patients with Agatston score > 0 (AUC = 0.737; P < 0.001) and 400 (AUC = 0.733; P < 0.001). MCOB ≤ 9.2657 mg/kg was an independent risk factor for CACs (OR = 4.853; P = 0.044) and strong predictor for cardiovascular morbidity and mortality (HR = 10.108; P = 0.042), as well as rehospitalization (HR = 2.689; P = 0.004). MCOB inversely correlated with the presence and extent of CACs, and could discriminate Agatston score > 0 and 400, which also presented as an independent indicator for CKD‐MBD and 1‐year cardiovascular prognosis in adult MHD patients. Additional studies are required for identifying this issue. [ABSTRACT FROM AUTHOR]

Lycium fruits (Lycium barbarum, Lycium chinense) are mainly cultivated and distributed in Northwest China. The fruits and root bark have been used in Chinese traditional medicine for centuries. In this study, Lycium dry fruit extracts from the main cultivation areas in China together with a sample from Nepal were subjected to a comparative metabolic profiling, including total carbohydrate content, total phenolic content, vitamin C content, carotenoid content, and mineral contents. Results showed that there was a slight difference in contents of nutrients and phytochemicals among samples from different areas. The total carbohydrate content was higher in the sample from Guazhou, Gansu province (69.47%), with an average value of total carbohydrate content of 61.59%, while the highest total phenolic content value was 14.13 mgGAE/g from Nepal. Data concerning vitamin C content ranged between 33.15 and 113.8 mg/100 g, with an average value of 55.29 mg/100 g. Zeaxanthin dipalmitate content in Lycium dry fruits ranged from 419.34 to 1008.90 μg/g among the different samples, with the highest content (1008.90 μg/g) observed in Tianjing. It appeared that we could not clearly differentiate Lycium samples in terms of their metabolic and mineral profile. The quantitative difference observed among samples might be linked to soil composition and environmental aspect of the harvest place. Our results were somehow in the same range as those reported in the literature. Therefore, Lycium fruits could be used as a dietary source of natural function foods and be worthy of development and utilization. [ABSTRACT FROM AUTHOR]

Copyright of Veterinary Dermatology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

With rapid advances in nanomedicine, magnetic nanoparticles (MNPs) have emerged as a promising theranostic tool in biomedical applications, including diagnostic imaging, drug delivery and novel therapeutics. Significant preclinical and clinical research has explored their functionalization, targeted delivery, controllable drug release and image-guided capabilities. To further develop MNPs for theranostic applications and clinical translation in the future, we attempt to provide an overview of the recent advances in the development and application of MNPs for drug delivery, specifically focusing on the topics concerning the importance of biomarker targeting for personalized therapy and the unique magnetic and contrast-enhancing properties of theranostic MNPs that enable image-guided delivery. The common strategies and considerations to produce theranostic MNPs and incorporate payload drugs into MNP carriers are described. The notable examples are presented to demonstrate the advantages of MNPs in specific targeting and delivering under image guidance. Furthermore, current understanding of delivery mechanisms and challenges to achieve efficient therapeutic efficacy or diagnostic capability using MNP-based nanomedicine are discussed. [ABSTRACT FROM AUTHOR]

We demonstrate a flexible genome-wide association study platform built upon the iPlant Collaborative Cyber-infrastructure. The platform supports big data management, sharing, and large-scale study of both genotype and phenotype data on clusters. End users can add their own analysis tools and create customized analysis workflows through the graphical user interfaces in both iPlant Discovery Environment and BioExtract server. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A key advancement target for oxygen reduction reaction catalysts is to simultaneously improve both the electrochemical activity and durability. To this end, the efficacy of a new highly conductive support that comprises of a 0.5 nm titanium oxynitride film coated by atomic layer deposition onto an array of carbon nanotubes has been investigated. Support effects for pure platinum and for a platinum (50 at %)/nickel alloy have been considered. Oxynitride induces a downshift in the d-band center for pure platinum and fundamentally changes the platinum particle size and spatial distribution. This results in major enhancements in activity and corrosion stability relative to an identically synthesized catalyst without the interlayer. Conversely, oxynitride has a minimal effect on the electronic structure and microstructure, and therefore, on the catalytic performance of platinum-nickel. Calculations based on density functional theory add insight with regard to compositional segregation that occurs at the alloy catalyst-support interface. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate an ultrashort echo time (UTE) imaging approach for improving the detection of receptor targeted magnetic nanoparticles in cancer xenograft models using positive contrast. Materials and Methods: Iron oxide nanoparticle (IONP) conjugated with tumor targeting ligands were prepared. A 3D UTE gradient echo sequence with the shortest TE of 0.07 msec was evaluated on a 3T magnetic resonance imaging (MRI) scanner using IONP solution, cancer cells bound with targeted IONPs and orthotopic human pancreatic, and breast cancer mouse models administered tumor targeting IONPs. A simulation was performed to analyze contrast-to-noise ratios (CNR) of UTE images and subtraction of the images obtained UTE and longer TE (SubUTE). T2-weighted imaging and T2 relaxometry mapping were applied for comparison and validation. Results: UTE and SubUTE images showed positive contrast in pancreatic tumors accumulated with EGFR targeted ScFvEGFR-IONPs and mammary tumors accumulated with uPAR targeted ATF-IONPs. The positive contrast observed in UTE images was consistent with the negative contrast observed in the T2-weighted images. A flip angle of 10° and a maximal possible TE for the second echo are suitable for SubUTE imaging. [ABSTRACT FROM AUTHOR]

Purpose: To obtain positive contrast based on T₁ weighting from magnetic iron oxide nanoparticle (IONP) using ultrashort echo time (UTE) imaging and investigate quantitative relationship between positive contrast and the core size and concentration of IONPs.Materials and Methods: Solutions of IONPs with different core sizes and concentrations were prepared. T₁ and T₂ relaxation times of IONPs were measured using the inversion recovery turbo spin echo (TSE) and multi-echo spin echo sequences at 3 Tesla. T₁ -weighted UTE gradient echo and T₂-weighted TSE sequences were used to image IONP samples. U87MG glioblastoma cells bound with arginine-glycine-aspartic acid (RGD) peptide and IONP conjugates were scanned using UTE, T₁ and T₂-weighted sequences.Results: Positive contrast was obtained by UTE imaging from IONPs with different core sizes and concentrations. The relative-contrast-to-water ratio of UTE images was three to four times higher than those of T₂-weighted TSE images. The signal intensity increases as the function of the core size and concentration. Positive contrast was also evident in cell samples bound with RGD-IONPs.Conclusion: UTE imaging allows for imaging of IONPs and IONP bound tumor cells with positive contrast and provides contrast enhancement and potential quantification of IONPs in molecular imaging applications. [ABSTRACT FROM AUTHOR]

Purpose To obtain positive contrast based on T1 weighting from magnetic iron oxide nanoparticle (IONP) using ultrashort echo time (UTE) imaging and investigate quantitative relationship between positive contrast and the core size and concentration of IONPs. Materials and Methods Solutions of IONPs with different core sizes and concentrations were prepared. T1 and T2 relaxation times of IONPs were measured using the inversion recovery turbo spin echo (TSE) and multi-echo spin echo sequences at 3 Tesla. T1-weighted UTE gradient echo and T2-weighted TSE sequences were used to image IONP samples. U87MG glioblastoma cells bound with arginine-glycine-aspartic acid (RGD) peptide and IONP conjugates were scanned using UTE, T1 and T2-weighted sequences. Results Positive contrast was obtained by UTE imaging from IONPs with different core sizes and concentrations. The relative-contrast-to-water ratio of UTE images was three to four times higher than those of T2-weighted TSE images. The signal intensity increases as the function of the core size and concentration. Positive contrast was also evident in cell samples bound with RGD-IONPs. Conclusion UTE imaging allows for imaging of IONPs and IONP bound tumor cells with positive contrast and provides contrast enhancement and potential quantification of IONPs in molecular imaging applications. J. Magn. Reson. Imaging 2011;33:194-202. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Human hypoxanthine-guanine phosphoribosyltransferase (HPRT) (EC 2.4.2.8) catalyzes the conversion of hypoxanthine and guanine to their respective nucleoside monophosphates. Human HPRT deficiency as a result of genetic mutations is linked to both Lesch-Nyhan disease and gout. In the present study, we have characterized phosphoribosyltransferase domain containing protein 1 (PRTFDC1), a human HPRT homolog of unknown function. The PRTFDC1 structure has been determined at 1.7 Å resolution with bound GMP. The overall structure and GMP binding mode are very similar to that observed for HPRT. Using a thermal-melt assay, a nucleotide metabolome library was screened against PRTFDC1 and revealed that hypoxanthine and guanine specifically interacted with the enzyme. It was subsequently confirmed that PRTFDC1 could convert these two bases into their corresponding nucleoside monophosphate. However, the catalytic efficiency ( k/ K) of PRTFDC1 towards hypoxanthine and guanine was only 0.26% and 0.09%, respectively, of that of HPRT. This low activity could be explained by the fact that PRTFDC1 has a Gly in the position of the proposed catalytic Asp of HPRT. In PRTFDC1, a water molecule at the position of the aspartic acid side chain position in HPRT might be responsible for the low activity observed by acting as a weak base. The data obtained in the present study indicate that PRTFDC1 does not have a direct catalytic role in the nucleotide salvage pathway. [ABSTRACT FROM AUTHOR]

Bacillus anthracis is well known in connection with biological warfare. The search for new drug targets and antibiotics is highly motivated because of upcoming multiresistant strains. Thymidylate kinase is an ideal target since this enzyme is at the junction of the de novo and salvage synthesis of dTTP, an essential precursor for DNA synthesis. Here the expression and characterization of thymidylate kinase from B. anthracis ( Ba-TMPK) is presented. The enzyme phosphorylated deoxythymidine-5′-monophosphate (dTMP) efficiently with K m and V max values of 33 μM and 48 μmol mg−1 min−1, respectively. The efficiency of deoxyuridine-5′-monophosphate phosphorylation was ∼10% of that of dTMP. Several dTMP analogs were tested, and D-FMAUMP (2′-fluoroarabinosyl-5-methyldeoxyuridine-5′-monophosphate) was selectively phosphorylated with an efficiency of 172% of that of D-dTMP, but l-FMAUMP was a poor substrate as were 5-fluorodeoxyuridine-5′-monophosphate (5FdUMP) and 2′,3′-dideoxy-2′,3′-didehydrothymidine-5′-monophosphate (d4TMP). No activity could be detected with 3′-azidothymidine-5′-monophosphate (AZTMP). The corresponding nucleosides known as efficient anticancer and antiviral compounds were also tested, and d-FMAU was a strong inhibitor with an IC50 value of 10 μM, while other nucleosides- l-FMAU, dThd, 5-FdUrd, d4T, and AZT, and 2′-arabinosylthymidine-were poor inhibitors. A structure model was built for Ba-TMPK based on the Staphylococcus aureus TMPK structure. Docking with various substrates suggested mechanisms explaining the differences in substrate selectivity of the human and the bacterial TMPKs. These results may serve as a start point for development of new antibacterial agents. [ABSTRACT FROM AUTHOR]

The crystal structure of uridine monophosphate kinase (UMP kinase, UMPK) from the opportunistic pathogen Ureaplasma parvum was determined and showed similar three-dimensional fold as other bacterial and archaeal UMPKs that all belong to the amino acid kinase family. Recombinant UpUMPK exhibited Michaelis–Menten kinetics with UMP, with Km and Vmax values of 214 ± 4 µm and 262 ± 24 µmol·min−1·mg−1, respectively, but with ATP as variable substrate the kinetic analysis showed positive cooperativity, with an n value of 1.5 ± 0.1. The end-product UTP was a competitive inhibitor against UMP and a noncompetitive inhibitor towards ATP. Unlike UMPKs from other bacteria, which are activated by GTP, GTP had no detectable effect on UpUMPK activity. An attempt to create a GTP-activated enzyme was made using site-directed mutagenesis. The mutant enzyme F133N (F133 corresponds to the residue in Escherichia coli that is involved in GTP activation), with F133A as a control, were expressed, purified and characterized. Both enzymes exhibited negative cooperativity with UMP, and GTP had no effect on enzyme activity, demonstrating that F133 is involved in subunit interactions but apparently not in GTP activation. The physiological role of UpUMPK in bacterial nucleic acid synthesis and its potential as target for development of antimicrobial agents are discussed. [ABSTRACT FROM AUTHOR]

Mollicutes are wall-less bacteria and cause various diseases in humans, animals and plants. They have the smallest genomes with low G + C content and lack many genes of DNA, RNA and protein precursor biosynthesis. Nucleoside diphosphate kinase (NDK), a house-keeping enzyme that plays a critical role in the synthesis of nucleic acids precursors, i.e. NTPs and dNTPs, is absent in all the Mollicutes genomes sequenced to date. Therefore, it would be of interest to know how Mollicutes synthesize dNTPs/NTPs without NDK. To answer this question, nucleoside monophosphate kinases (NMPKs) from Ureaplasma were studied regarding their role in the synthesis of NTPs/dNTPs. In this work, Ureaplasma adenylate kinase, cytidylate kinase, uridylate kinase and thymidylate kinase were cloned and expressed in Escherichia coli. The recombinant enzymes were purified and characterized. These NMPKs are base specific, as indicated by their names, and capable of converting (d)NMPs directly to (d)NTPs. The catalytic rates of (d)NTPs and (d)NDP synthesis by these NMPKs were determined using tritium-labelled (d)NMPs, and the rates for (d)NDP synthesis, in general, were much higher (up to 100-fold) than that of (d)NTP. Equilibrium studies with adenylate kinase suggested that the rates of NTPs/dNTPs synthesis by NMPKs in vivo are probably regulated by the levels of (d)NMPs. These results strongly indicate that NMPKs could substitute the NDK function in vivo. [ABSTRACT FROM AUTHOR]

Thymidine kinase (TK) is the key enzyme in salvaging thymidine to produce thymidine monophosphate. Owing to its ability to phosphorylate nucleoside analogue prodrugs, TK has gained attention as a rate-limiting drug activator. We describe the structures of two bacterial TKs, one from the pathogen Bacillus anthracis in complex with the substrate dT, and the second from the food-poison-associated Bacillus cereus in complex with the feedback inhibitor dTTP. Interestingly, in contrast with previous structures of TK in complex with dTTP, in this study dTTP occupies the phosphate donor site and not the phosphate acceptor site. This results in several conformational changes compared with TK structures described previously. One of the differences is the way tetramers are formed. Unlike B. anthracis TK, B. cereus TK shows a loose tetramer. Moreover, the lasso-domain is in open conformation in B. cereus TK without any substrate in the active site, whereas in B. anthracis TK the loop conformation is closed and thymidine occupies the active site. Another conformational difference lies within a region of 20 residues that we refer to as phosphate-binding β-hairpin. The phosphate-binding β-hairpin seems to be a flexible region of the enzyme which becomes ordered upon formation of hydrogen bonds to the α-phosphate of the phosphate donor, dTTP. In addition to descriptions of the different conformations that TK may adopt during the course of reaction, the oligomeric state of the enzyme is investigated. [ABSTRACT FROM AUTHOR]

Thymidine kinases have been found in most organisms, from viruses and bacteria to mammals. Ureaplasma urealyticum ( parvum), which belongs to the class of cell-wall-lacking Mollicutes, has no de novo synthesis of DNA precursors and therefore has to rely on the salvage pathway. Thus, thymidine kinase ( Uu-TK) is the key enzyme in dTTP synthesis. Recently the 3D structure of Uu-TK was determined in a feedback inhibitor complex, demonstrating that a lasso-like loop binds the thymidine moiety of the feedback inhibitor by hydrogen bonding to main-chain atoms. Here the structure with the substrate deoxythymidine is presented. The substrate binds similarly to the deoxythymidine part of the feedback inhibitor, and the lasso-like loop binds the base and deoxyribose moieties as in the complex determined previously. The catalytic base, Glu97, has a different position in the substrate complex from that in the complex with the feedback inhibitor, having moved in closer to the 5′-OH of the substrate to form a hydrogen bond. The phosphorylation of and inhibition by several nucleoside analogues were investigated and are discussed in the light of the substrate binding pocket, in comparison with human TK1. Kinetic differences between Uu-TK and human TK1 were observed that may be explained by structural differences. The tight interaction with the substrate allows minor substitutions at the 3 and 5 positions of the base, only fluorine substitutions at the 2′-Ara position, but larger substitutions at the 3′ position of the deoxyribose. [ABSTRACT FROM AUTHOR]

Mitochondrial deoxyguanosine kinase (dGK) catalyzes the initial phosphorylation of purine deoxynucleosides. Mutations in the dGK gene leading to deficiency in dGK activity is one of the causes of severe mitochondrial DNA depletion diseases. We used site-directed mutagenesis to introduce the clinically observed genetic alterations in the dGK gene and characterized the recombinant enzymes. The R142K enzyme had very low activity with deoxyguanosine and no activity with deoxyadenosine. The E227K mutant enzyme had unchanged Km values for all its substrates but very low Vmax values. C-terminal truncated dGK proteins were inactive. These results may help to define the role of dGK in mitochondrial DNA (mtDNA) precursor synthesis. [Copyright &y& Elsevier]

Ureaplasma urealyticum ( U. urealyticum), belonging to the class Mollicutes, is a human pathogen colonizing the urogenital tract and causes among other things respiratory diseases in premature infants. We have studied the salvage of pyrimidine deoxynucleosides in U. urealyticum and cloned a key salvage enzyme, thymidine kinase (TK) from U. urealyticum. Recombinant Uu-TK was expressed in E. coli, purified and characterized with regards to substrate specificity and feedback inhibition. Uu-TK efficiently phosphorylated thymidine (dThd) and deoxyuridine (dUrd) as well as a number of pyrimidine nucleoside analogues. All natural ribonucleoside/deoxyribonucleoside triphosphates, except dTTP, served as phosphate donors, while dTTP was a feedback inhibitor. The level of Uu-TK activity in U. urealyticum extracts increased upon addition of dUrd to the growth medium. Fluoropyrimidine nucleosides inhibited U. urealyticum and M. pneumoniae growth and this inhibitory effect could be reversed by addition of dThd, dUrd or deoxytetrahydrouridine to the growth medium. Thus, the mechanism of inhibition was most likely the depletion of dTTP, either via a blocked thymidine kinase reaction and/or thymidylate synthesis step and these metabolic reactions should be suitable targets for antimycoplasma chemotherapy. [ABSTRACT FROM AUTHOR]

Summary Bacterial endotoxin (lipopolysaccharide; LPS) and platelet-activating factor (PAF) are important triggers of bowel inflammation and injury. We have previously shown that LPS activates the transcription factor nuclear factor (NF)-κB in the intestine, which up-regulates many pro-inflammatory genes. This effect partly depends on neutrophils and endogenous PAF. However, whether LPS and PAF directly activate NF-κB in enterocytes remains controversial. In this study, we first investigated the effect of LPS and PAF on NF-κB activation in IEC-6 (a non-transformed rat small intestinal crypt cell line) cells, by electrophoresis mobility shift assay and supershift, and found that LPS, but not PAF, activates NF-κB mostly as p50–p65 heterodimers. The effect was slower than tumour necrosis factor (TNF). Both LPS and TNF induce the expression of the NF-κB-dependent gene inducible nitric oxide synthase (iNOS), which occurs subsequent to NF-κB activation. We then examined the effect of LPS and TNF on the inhibitory molecules IκBα and IκBβ. We found that TNF causes rapid degradation of IκBα and IκBβ. In contrast, LPS did not change the levels of IκBα and IκBβ up to 4 hr (by Western blot). However, in the presence of cycloheximide, there was a slow reduction of IκBα and IκBβ, which disappeared almost completely at 4 hr. These observations suggest that LPS causes slow degradation and synthesis of IκBα and IκBβ and therefore activates NF-κΒ via at least two mechanisms: initially, through an IκB-independent mechanism, and later, via an increased turnover of the inhibitor IκB. NF-κΒ activation precedes the gene expression of iNOS (assayed by reverse transcription–polymerase chain reaction), suggesting that LPS up-regulates iNOS via this transcription factor. [ABSTRACT FROM AUTHOR]

Mycoplasmas are unable to synthesize purine and pyrimidine bases de novo. Therefore, salvage of existing nucleosides and bases is essential for their survival. Four mycoplasma species were studied with regard to their ability to phosphorylate deoxynucleosides. High levels of thymidine kinase (TK), deoxycytidine kinase (dCK), deoxyguanosine kinase (dGK) and deoxyadenosine kinase (dAK) activities were detected in extracts from Mycoplasma pneumoniae, Mycoplasma mycoides subsp. mycoides SC (M. mymySC), Acholeplasma laidlawii (A. laidlawii) and Mycoplasma arginini (M. arginini). Nucleoside phosphotransferase activities were found at high levels in A. laidlawii and low levels in M. arginini. Pyrophosphate-dependent deoxynucleoside kinase activities were detected mainly in A. laidlawii and M. mymySC extracts. Two open reading frames were identified in the M. mymySC genome; one showed 25% sequence identity to human dGK and the other one had about 26% sequence identity to human TK1. The M. mymySC dGK-like enzyme was cloned, expressed in Escherichia coli and affinity-purified. This enzyme phosphorylated dAdo, dGuo and dCyd, and the highest catalytic rate was with dAdo as substrate. Therefore, we suggest that this enzyme should be named deoxyadenosine kinase. The physiological role of mycoplasma dAK and TK may be to support the unusually large dATP and dTTP pools required for replication of mycoplasma genomes. [ABSTRACT FROM AUTHOR]

The co-crystallized compound (III), based on mixed valence polyoxovanadate [VIV12VV6O42] 6- and compound (IV) are solvothermally synthesized and characterized by single crystal XRD, IR, XPS, and magnetic and luminescence measurements. [ABSTRACT FROM AUTHOR]