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Objective: To explore the performance of ultrasound image-based radiomics in predicting World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading of clear-cell renal cell carcinoma (ccRCC)., Methods: A retrospective study was conducted via histopathological examination on participants with ccRCC from January 2021 to August 2023. Participants were randomly allocated to a training set and a validation set in a 3:1 ratio. The maximum cross-sectional image of the lesion on the preoperative ultrasound image was obtained, with the region of interest (ROI) delineated manually. Radiomic features were computed from the ROIs and subsequently normalized using Z-scores. Wilcoxon test and least absolute shrinkage and selection operator (LASSO) regression were applied for feature reduction and model development. The performance of the model was estimated by indicators including area under the curve (AUC), sensitivity and specificity., Results: A total of 336 participants (median age, 57 y; 106 women) with ccRCC were finally included, of whom 243 had low-grade tumors (grade 1-2) and 93 had high-grade tumors (grade 3-4). A total of 1163 radiomic features were extracted from the ROIs for model construction and 117 informative radiomics features selected by Wilcoxon test were submitted to LASSO. Our ultrasound-based radiomics model included 51 features and achieved AUCs of 0.90 and 0.79 for the training and validation sets, respectively. Within the training set, the sensitivity and specificity measured 0.75 and 0.92, respectively, whereas in the validation set, the sensitivity and specificity measured 0.65 and 0.84, respectively. In the subgroup analysis, for the training and validation sets Philips AUCs were 0.91 and 0.75, Toshiba AUCs were 0.82 and 0.90, and General Electric AUCs were 0.95 and 0.82, respectively., Conclusion: Ultrasound-based radiomics can effectively predict the WHO/ISUP grading of ccRCC., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

The brain and gut are sensory organs responsible for sensing, transmitting, integrating, and responding to signals from the internal and external environment. In-depth analysis of brain-gut axis interactions is important for human health and disease prevention. Current research on the brain-gut axis primarily relies on animal models. However, animal models make it difficult to study disease mechanisms due to inherent species differences, and the reproducibility of experiments is poor because of individual animal variations, which leads to a significant limitation of real-time sensory responses. Organ-on-a-chip platforms provide an innovative approach for disease treatment and personalized research by replicating brain and gut ecosystems in vitro. This enables a precise understanding of their biological functions and physiological responses. In this article, we examine the history and most current developments in brain, gut, and gut-brain chips. The importance of these systems for understanding pathophysiology and developing new drugs is emphasized throughout the review. This article also addresses future directions and present issues with the advancement and application of gut-brain-on-a-chip technologies., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

The circadian clock plays multiple functions in the regulation of plant growth, development and response to various abiotic stress. Here, we showed that the core oscillator component late elongated hypocotyl (LHY) was involved in rice response to salt stress. The mutations of OsLHY gene led to reduced salt tolerance in rice. Transcriptomic analyses revealed that the OsLHY gene regulates the expression of genes related to ion homeostasis and the abscisic acid (ABA) signalling pathway, including genes encoded High-affinity K + transporters (OsHKTs) and the stress-activated protein kinases (OsSAPKs). We demonstrated that OsLHY directly binds the promoters of OsHKT1;1, OsHKT1;4 and OsSAPK9 to regulate their expression. Moreover, the ossapk9 mutants exhibited salt tolerance under salt stress. Taken together, our findings revealed that OsLHY integrates ion homeostasis and the ABA pathway to regulate salt tolerance in rice, providing insights into our understanding of how the circadian clock controls rice response to salt stress., (© 2024 John Wiley & Sons Ltd.)

High temperature (HT) can affect the accumulation of seed storage materials and cause adverse effects on the yield and quality of rice. DNA methylation plays an important role in plant growth and development. Here, we identified a new demethylase gene OsDML4 and discovered its function in cytosine demethylation to affect endosperm formation. Loss of function of OsDML4 induced chalky endosperm only under HT and dramatically reduced the transcription and accumulation of glutelins and 16 kDa prolamin. The expression of two transcription factor genes RISBZ1 and RPBF was significantly decreased in the osdml4 mutants, which caused adverse effects on the formation of protein bodies (PBs) with greatly decreased PB-II number, and incomplete and abnormally shaped PB-IIs. Whole-genome bisulfite sequencing analysis of seeds at 15 d after pollination revealed much higher global methylation levels of CG, CHG, and CHH contexts in the osdml4 mutants compared with the wild type. Moreover, the RISBZ1 promoter was hypermethylated but the RPBF promoter was almost unchanged under HT. No significant difference was detected between the wild type and osdml4 mutants under normal temperature. Our study demonstrated a novel OsDML4-mediated DNA methylation involved in the formation of chalky endosperm only under HT and provided a new perspective in regulating endosperm development and the accumulation of seed storage proteins in rice., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Transcription factors (TFs) specifically bind to DNA, recruit cofactor proteins and modulate target gene expression, rendering them essential roles in the regulation of numerous biological processes. Meanwhile, mutated or dysregulated TFs are involved in a variety of human diseases. As multiple signaling pathways ultimately converge at TFs, targeting these TFs directly may prove to be more specific and cause fewer side effects, than targeting the upfront conventional targets in these pathways. All these features together endue TFs with great potential and high selectivity as therapeutic drug targets. However, TFs have been historically considered "undruggable", mainly due to their lack of structural information, especially about the appropriate ligand-binding sites and protein-protein interactions, leading to relatively limited choices in the TF-targeting drug design. In this review, we summarize the recent progress of TF-targeting drugs and highlight certain strategies used for targeting TFs, with a number of representative drugs that have been approved or in the clinical trials as examples. Various approaches in targeting TFs directly or indirectly have been developed. Common direct strategies include aiming at defined binding pockets, proteolysis-targeting chimaera (PROTAC), and mutant protein reactivation. In contrast, the indirect ones comprise inhibition of protein-protein interactions between TF and other proteins, blockade of TF expression, targeting the post-translational modifications, and targeting the TF-DNA interactions. With more comprehensive structural information about TFs revealed by the powerful cryo-electron microscopy technology and predicted by machine-learning algorithms, plus more efficient compound screening platforms and a deeper understanding of TF-disease relationships, the development of TF-targeting drugs will certainly be accelerated in the near future., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Galectin-3, a microglia/macrophage-derived inflammatory mediator, plays a role in the stroke progression. In this single-center prospective study, we included 288 consecutive patients with a first-ever acute ischemic stroke to assess the association between galectin-3 serum level and clinical severity at admission and outcome at discharge by univariate and multivariate logistic regression. The results were presented as odds ratios (OR) and 95% confidence intervals (CI). Patients with high severity and poor outcomes had higher serum levels of galectin-3 (P<0.001 and P<0.001). Multivariate analysis suggested that a galectin-3 serum level in the highest quartile (The lowest three quartiles[Q1-3] as the reference) was associated with poor functional outcome (OR, 3.15; 95% CI, 2.44-3.87). The AUC (standard error) for the NIHSS and the combined model were 0.764 (0.031) and 0.823 (0.027), corresponding to a difference of 0.059 (0.004). This study shows that higher serum levels of galectin-3 are associated with stroke severity at admission and stroke prognosis at discharge in ischemic stroke.

3β-Angeloyloxy-8β,10β-dihydroxyeremophila-7(11)-en-12,8α-lactone (FJ1) inhibited effectively paraquat (PQ)-induced injury in SH-SY5Y cells. In this way, FJ1 was shown to reverse the PQ-induced activation of caspase-9 and caspase-3, the increase in Bax/Bcl-2 ratio, and the release of cytochrome c. The mechanism was associated with a reduction of oxidative stress, including the decrease in the levels of ROS and MDA and maintaining the activity of SOD and GSH. Taken together, findings revealed that FJ1 had protective effects against PQ-induced injury via attenuating the oxidative stress in SH-SY5Y cells, which suggested that FJ1 might be a candidate for further evaluation against neurodegeneration in Parkinson's disease.

Six analogous dumbbell-shaped 3d-4f complexes MLn were obtained by the reaction of Ln(NO 3 ) 3 (Ln = Eu, Gd, Dy) and M(OAc) 2 (M = Co, Ni) without any other organic ligands, and M 5 Gd 4 exhibited a large magnetocaloric effect (-ΔS m = 31.0, 37.3 J kg -1 K -1 for Co 5 Gd 4 and Ni 5 Gd 4 respectively), while M 5 Dy 4 and Co 5 Eu 4 showed single molecule magnet behaviour. To the best of our knowledge, Co 5 Eu 4 is the first Eu-based cluster to display single molecule magnet behaviour (U eff = 16.4 K).

Objective: High expression levels of lncRNA associated with microvascular invasion in HCC (lncRNA MVIH) were found to correlate with several solid tumors. However, little is known concerning the function of MVIH in glioma. The purpose of our study is to explore the role of lncRNA MVIH in clinical glioma samples and cell lines., Patients and Methods: The expression levels of MVIH were analyzed in glioma surgical resection tissues and cells by RT-PCR. Additionally, the associations of MVIH expression with clinicopathological features were analyzed. Survival and Cox proportional-hazards regression analyses were performed to determine the correlation between MVIH expression levels and prognosis in the patients. The cell proliferation, migration ability, invasion ability were measured successively by CKK-8 assay, transwell and wound healing assay., Results: We found that MVIH was significantly upregulated in glioma cell lines and tissues. Furthermore, MVIH expression was positively correlated with KPS and WHO grade. Patients with MVIH high expression tumors had a worse overall survival compared to patients with MVIH high expression tumors. Moreover, Univariate and multivariate Cox regression analysis confirmed that MVIH was an independent risk factor for glioma. Finally, in vitro, we showed that up-regulation of MVIH expression promoted human glioma cells proliferation, invasion and migration, while down-regulation of MVIH expression suppressed human glioma cells proliferation, invasion and migration., Conclusions: Our findings indicated that MVIH expression may serve not only as a prognostic marker but also as a potential therapeutic target in glioma.

Many surgical interventions for cardiovascular disease are limited by the availability of autologous vessels or suboptimal performance of prosthetic materials. Tissue engineered vascular grafts show significant promise, but have yet to achieve clinical efficacy in small caliber (<5 mm) arterial applications. We previously designed cell-free elastomeric grafts containing solvent casted, particulate leached poly(glycerol sebacate) (PGS) that degraded rapidly and promoted neoartery development in a rat model over 3 months. Building on this success but motivated by the need to improve fabrication scale-up potential, we developed a novel method for electrospinning smaller grafts composed of a PGS microfibrous core enveloped by a thin poly(ε-caprolactone) (PCL) outer sheath. Electrospun PGS-PCL composites were implanted as infrarenal aortic interposition grafts in mice and remained patent up to the 12 month endpoint without thrombosis or stenosis. Many grafts experienced a progressive luminal enlargement up to 6 months, however, due largely to degradation of PGS without interstitial replacement by neotissue. Lack of rupture over 12 months confirmed sufficient long-term strength, due primarily to the persistent PCL sheath. Immunohistochemistry further revealed organized contractile smooth muscle cells and neotissue in the inner region of the graft, but a macrophage-driven inflammatory response to the residual polymer in the outer region of the graft that persisted up to 12 months. Overall, the improved surgical handling, long-term functional efficacy, and strength of this new graft strategy are promising, and straightforward modifications of the PGS core should hasten cellular infiltration and associated neotissue development and thereby lead to improved small vessel replacements.

Objective: Our objective is to determine the value of enhanced substantia nigra echo in the diagnosis of Parkinson's disease by analyzing the intensity and area of substantia nigra echo by transcranial Doppler sonography (TCS)., Patients and Methods: 36 patients diagnosed as ultra early stage Parkinson's disease between 2013 November and 2014 August were selected as the disease group, and 32 healthy people with the similar representation of age and gender were selected as the control group. TCS was used to detect the echo intensity and the echo intensity of the same location of bilateral hemicerebrum was used to evaluate the bilateral substantia nigra echo. The age and gender were also used for correlation analysis with the results of substantia nigra echo., Results: In the control group, there were 17 patients of substantia nigra echo grade I (53.1%), 13 cases of substantia nigra echo grade II (40.6%), 2 cases of substantia nigra echo grade III (6.3%). While in the disease group, there were 4 cases of substantia nigra echo grade II (11.1%), 13 cases of substantia nigra echo grade III (36.1%), 12 cases of substantia nigra echo grade IV (33.3%) and 7 cases of substantia nigra echo grade V (19.4%). The ratio of enhanced substantia nigra echo in Parkinson's disease patients was significantly higher than the control group. The analysis of the factors related to motor symptoms in Parkinson's disease patients revealed that the area of bilateral substantia nigra echo was negatively correlated with gender, but positively correlated with age, S/M ratio and UPDRS II score. However, there was no correlation with H-Y stage. The sensitivity of substantia nigra echo in diagnosing Parkinson's disease was 32/36=88.89% and the specificity was 30/32 = 93.75%., Conclusions: Analysis of substantia nigra echo is practically useful for the diagnosis of the ultra early stage Parkinson's disease, which can potentially improve the accuracy of clinical diagnosis to significantly enhance the early clinical prevention and reduce later disability.

A new tetra-α-substituted zinc(II) phthalocyanine containing dodeca-amino groups (compound 4) and its quaternized analogue (compound 5) have been prepared and evaluated for their photoactivities against Candida albicans. Compared with the dodeca-amino phthalocyanine 4, the dodeca-cationic phthalocyanine 5 exhibits a higher photodynamic inactivation against C. albicans with an IC90 value down to 1.46 μM, which can be attributed to its non-aggregated nature in aqueous environments and more efficient cellular uptake. More interestingly, 5 shows a higher photodynamic inactivation on C. albicans due to its stronger affinity to C. albicans cells than mammalian cells. These results suggest that the highly positive-charged phthalocyanine 5 is a potential non-aggregated antifungal photosensitizer, which shows some selectivity toward the fungus., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In Part II, I present a legal challenge to the Prescription Drug User Fee Act (PDUFA) from an administrative law perspective. While I share sympathies with those who believe PDUFA represents an unacceptable conflict of interest for the FDA, I posit arguments purely from the framework of permissible administrative agency discretion so as to avoid ambivalent analytical and empirical arguments. My argument is that given the statutory and case law determinations of permissible federal agency discretion, the FDA cannot assess a flat user fee for widely variable types of services it renders during the drug approval process. Thus, the current implementation of PDUFA is legally impermissible. Subsequently, in Part III, I compare PDUFA to three other agency user-fee mechanisms and propose specific improvements to PDFUA to minimize its conflict of interest while maintaining its revenue efficiency., (Copyright by Cleveland State University.)

Aim: Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan found in traditional Chinese herbs, has been determined to exhibit a variety of pharmacological activities, including anti-tumor, anti-inflammation, neuroprotection, and endurance enhancement. In the present study, we investigated the antioxidation and anti-fatigue effects of arctigenin in rats., Methods: Rat L6 skeletal muscle cell line was exposed to H2O2 (700 μmol/L), and ROS level was assayed using DCFH-DA as a probe. Male SD rats were injected with arctigenin (15 mg·kg(-1)·d(-1), ip) for 6 weeks, and then the weight-loaded forced swimming test (WFST) was performed to evaluate their endurance. The levels of antioxidant-related genes in L6 cells and the skeletal muscles of rats were analyzed using real-time RT-PCR and Western blotting., Results: Incubation of L6 cells with arctigenin (1, 5, 20 μmol/L) dose-dependently decreased the H2O2-induced ROS production. WFST results demonstrated that chronic administration of arctigenin significantly enhanced the endurance of rats. Furthermore, molecular biology studies on L6 cells and skeletal muscles of the rats showed that arctigenin effectively increased the expression of the antioxidant-related genes, including superoxide dismutase (SOD), glutathione reductase (Gsr), glutathione peroxidase (GPX1), thioredoxin (Txn) and uncoupling protein 2 (UCP2), through regulation of two potential antioxidant pathways: AMPK/PGC-1α/PPARα in mitochondria and AMPK/p53/Nrf2 in the cell nucleus., Conclusion: Arctigenin efficiently enhances rat swimming endurance by elevation of the antioxidant capacity of the skeletal muscles, which has thereby highlighted the potential of this natural product as an antioxidant in the treatment of fatigue and related diseases.

Objective: To investigate the incidence, pathogens, and clinical features of infection in consecutive cases from 2010 to 2012 in Peking Union Medical College Hospital., Method: The incidence, pathogen, treatment, and outcomes of patients with hematological diseases who had positive findings of bacterium in their samples from 2010 to 2012 were retrospectively analyzed., Results: There were 449 positive samples (5.8%) from 4 890 patients during this period, among which 388 were proved to be with pathogenic bacteria. Samples separated from patients with community-aquired infections accounted for 8.4% of all positive samples. Most community-aquired infections were caused by Gram-negative bacteria (75%), although no multidrug-resistant bacteria was observed. Samples separated from patients with nosocomial infections accounted for 91.6% of all positive samples. Respiratory tract (49.4%) and peripheral blood (32.6%) were the most common samples with positive results. Skin soft tissues (10.4%), and urine (3.7%) were less common samples. Most of the pathogenic bacteria of the nosocomial infections were Gram-negative (66.9%). The most common Gram-negative bacteria included Escherichia coli (13.8%), Pseudomonas aeruginosa (12.1%), and Klebsiella pneumonia (12.1%), while Staphylococcus aureus (10.4%), Enterococcus faecium (7.0%), and Staphylococcus epidermidis (5.1%) were the most common Gram-positive bacteria. Gram-negative bacteria consisted of most of sputum samples and peripheral blood samples. Samples from the surface of skin wound and anal swab were composed largely by Gram-positive bacteria (63.8%). The detection rates of extended-spectrum beta-lactamase-producing Klebsiella pneumonia/Klebsiella oxytoca, Escherichia coli, and Proteus mirabilis were 24.0%, 87.9% and 38.4%, respectively. The resistance to Acinetobacter baumannii was serious. Multidrug-resistant, extensive drug resistant and pan drug resistant A. baumannii acountted for 74% of all A. Baumannii infections. Stenotrophomonas maltophilia showed low resistance to sulfamethoxazole/trimethoprim, levofloxacin and minocycline. Also, 22 methicillin-resistant Staphylococcus aureus and 9 methicillin-resistant Staphylococcus Epidermidis were detected, which were only sensitive to vancomycin, teicoplanin, and linezolid. All patients were treated in the haematology wards and most of them were under agranulocytosis or immunosuppression. Finally, 22 patients reached clinical recovery through anti-infective therapy, whereas 49 patients died. Among those deaths, 42 patients attributed to severe infections and infection-associated complications. Fourteen of all the deaths might be infected with drug-resistance bacteria. There were 61 samples proved to be bacteria colonization. Nonfermenters such as Acinetobacter baumannii and Stenotrophomonas maltophilia made up for a large amount of bacteria colonization., Conclusions: The pathogens of nosocomial infections in the hematology ward are mainly Gram-negative bacteria. The incidences and pathogens vary from different infection sites. Nosocomial infection still has a higher mortality rate. Once nonfermenters are detected positive, the pathogenic or colonial bacteria should be distinguished.

Ever since the discovery of the first microRNAs in C. elegans, increasing numbers of endogenous small RNAs have been discovered. Endogenous siRNAs (endo-siRNAs) have emerged in the last few years as a largely independent class of small RNAs that regulate endogenous gene expression, with mechanisms distinct from those of piRNAs and miRNAs. Quantification of these small RNAs and their effect on target RNAs is a powerful tool for the analysis of RNAi; however, detection of small RNAs can be difficult due to their small size and relatively low abundance. Here, we describe the novel FirePlex assay for directly detecting endo-siRNA levels in bulk, as well as an optimized qPCR method for detecting the effect of endo-siRNAs on gene targets. Intriguingly, the loss of endo-siRNAs frequently results in enhanced experimental RNAi. Thus, we also present an optimized method to assess the indirect impact of endo-siRNAs on experimental RNAi efficiency.

The Caenorhabditis elegans nuclear RNA interference defective (Nrde) mutants were identified by their inability to silence polycistronic transcripts in enhanced RNAi (Eri) mutant backgrounds. Here, we report additional nrde-3-dependent RNAi phenomena that extend the mechanisms, roles, and functions of nuclear RNAi. We show that nrde-3 mutants are broadly RNAi deficient and that overexpressing NRDE-3 enhances RNAi. Consistent with NRDE-3 being a dose-dependent limiting resource for effective RNAi, we find that NRDE-3 is required for eri-dependent enhanced RNAi phenotypes, although only for a subset of target genes. We then identify pgl-1 as an additional limiting RNAi resource important for eri-dependent silencing of a nonoverlapping subset of target genes, so that an nrde-3; pgl-1; eri-1 triple mutant fails to show enhanced RNAi for any tested gene. These results suggest that nrde-3 and pgl-1 define separate and independent limiting RNAi resource pathways. Limiting RNAi resources are proposed to primarily act via endogenous RNA silencing pathways. Consistent with this, we find that nrde-3 mutants misexpress genes regulated by endogenous siRNAs and incompletely silence repetitive transgene arrays. Finally, we find that nrde-3 contributes to transitive RNAi, whereby amplified silencing triggers act in trans to silence sequence-similar genes. Because nrde-dependent silencing is thought to act in cis to limit the production of primary transcripts, this result reveals an unexpected role for nuclear processes in RNAi silencing.

Liver kinase B1 (LKB1) has important roles in governing energy homeostasis by regulating the activity of the energy sensor kinase AMP-activated protein kinase (AMPK). The regulation of LKB1 function, however, is still poorly understood. Here we demonstrate that the orphan nuclear receptor Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. This Nur77 function is antagonized by the chemical compound ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), which interacts with Nur77 with high affinity and at specific sites. TMPA binding of Nur77 results in the release and shuttling of LKB1 to the cytoplasm to phosphorylate AMPKα. Moreover, TMPA effectively reduces blood glucose and alleviates insulin resistance in type II db/db and high-fat diet- and streptozotocin-induced diabetic mice but not in diabetic littermates with the Nur77 gene knocked out. This study attains a mechanistic understanding of the regulation of LKB1-AMPK axis and implicates Nur77 as a new and amenable target for the design and development of therapeutics to treat metabolic diseases.

Small RNAs play a variety of regulatory roles, including highly conserved developmental functions. Caenorhabditis elegans not only possesses most known small RNA pathways, it is also an easy system to study their roles and interactions during development. It has been proposed that in C. elegans , some small RNA pathways compete for access to common limiting resources. The strongest evidence supporting this model is that disrupting the production or stability of endogenous short interfering RNAs (endo-siRNAs) enhances sensitivity to experimentally induced exogenous RNA interference (exo-RNAi). Here, we examine the relationship between the endo-siRNA and microRNA (miRNA) pathways, and find that, consistent with competition among these endogenous small RNA pathways, endo-siRNA pathway mutants may enhance miRNA efficacy. Furthermore, we show that exo-RNAi may also compete with both endo-siRNAs and miRNAs. Our data thus provide support that all known Dicer-dependent small RNA pathways may compete for limiting common resources. Finally, we observed that both endo-siRNA mutants and animals experiencing exo-RNAi have increased expression of miRNA-regulated stage-specific developmental genes. These observations suggest that perturbing the small RNA flux and/or the induction of exo-RNAi, even in wild-type animals, may impact development via effects on the endo-RNAi and microRNA pathways.

RNA interference (RNAi) is a powerful research tool that has enabled molecular insights into gene activity, pathway analysis, partial loss-of-function phenotypes, and large-scale genomic discovery of gene function. While RNAi works extremely well in the non-parasitic nematode C. elegans, it is also especially useful in organisms that lack facile genetic analysis. Extensive genetic analysis of the mechanisms, delivery and regulation of RNAi in C. elegans has provided mechanistic and phenomenological insights into why RNAi is so effective in this species. These insights are useful for the testing and development of RNAi in other nematodes, including parasitic nematodes where more effective RNAi would be extremely useful. Here, we review the current advances in C. elegans for RNA delivery methods, regulation of cell autonomous and systemic RNAi phenomena, and implications of enhanced RNAi mutants. These discussions, with a focus on mechanism and cross-species application, provide new perspectives for optimizing RNAi in other species.

Background: Recently, it has been proposed that epigenetic variation may contribute to the risk of complex genetic diseases like cancer. We aimed to demonstrate that epigenetic changes in normal cells, collected years in advance of the first signs of morphological transformation, can predict the risk of such transformation., Methods: We analyzed DNA methylation (DNAm) profiles of over 27,000 CpGs in cytologically normal cells of the uterine cervix from 152 women in a prospective nested case-control study. We used statistics based on differential variability to identify CpGs associated with the risk of transformation and a novel statistical algorithm called EVORA (Epigenetic Variable Outliers for Risk prediction Analysis) to make predictions., Results: We observed many CpGs that were differentially variable between women who developed a non-invasive cervical neoplasia within 3 years of sample collection and those that remained disease-free. These CpGs exhibited heterogeneous outlier methylation profiles and overlapped strongly with CpGs undergoing age-associated DNA methylation changes in normal tissue. Using EVORA, we demonstrate that the risk of cervical neoplasia can be predicted in blind test sets (AUC = 0.66 (0.58 to 0.75)), and that assessment of DNAm variability allows more reliable identification of risk-associated CpGs than statistics based on differences in mean methylation levels. In independent data, EVORA showed high sensitivity and specificity to detect pre-invasive neoplasia and cervical cancer (AUC = 0.93 (0.86 to 1) and AUC = 1, respectively)., Conclusions: We demonstrate that the risk of neoplastic transformation can be predicted from DNA methylation profiles in the morphologically normal cell of origin of an epithelial cancer. Having profiled only 0.1% of CpGs in the human genome, studies of wider coverage are likely to yield improved predictive and diagnostic models with the accuracy needed for clinical application., Trial Registration: The ARTISTIC trial is registered with the International Standard Randomised Controlled Trial Number ISRCTN25417821.

AMP-activated kinase (AMPK) as a key controller in the regulation of whole-body energy homeostasis, plays an important role in protecting the body from metabolic diseases. Recently, improved glucose, lipid utility and increased insulin sensitivity were observed on several diabetic rodent models treated with crude mogrosides isolated from the fruit of Siraitia grosvenorii Swingle, but the precise active compounds responsible for the anti-diabetic activity of this plant have not been clearly identified. In our current work, acid hydrolysis of crude mogrosides provided five new cucurbitane triterpenoids (1-4, 8), along with three known ones (5-7). The main aglycone mogrol (7) and compounds 4 and 8 were found to be potent AMPK activators in the HepG2 cell line. This result suggested AMPK activation by the mogroside aglycones 7 and 8 was proved to contribute at least partially to the anti-hyperglycemic and anti-lipidemic properties in vivo of S. grosvenorii., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Time irreversibility is a subject of increasing interest in biomedicine. However, measurements of this property have been limited to a two-dimensional state space and few effective methods for high-dimensional time irreversibility testing have been reported. Using a strategy based on multiple bidimensional tests, we propose an extension of the traditional low-dimensional method for the estimation of time irreversibility in a high-dimensional state space. The method is applied to both physiological and synthetic interbeat (RR) intervals and the results indicate that time irreversibility should be an intrinsic characteristic of human RR intervals and is complementary to the conventional properties that can be measured in the time and frequency domain. Furthermore, a loss of time irreversibility is detected when the method is applied to patients with congestive heart failure (CHF). Compared with the traditional time irreversibility test, the proposed method is not only capable of quantifying time irreversibility in a more reliable manner, but is also effective for analysis of short records of only a few minutes' length, which would be more useful clinically., (Copyright © 2011 IPEM. Published by Elsevier Ltd. All rights reserved.)

Gene knockdown by RNA interference (RNAi) in Caenorhabditis elegans is readily achieved by feeding bacteria expressing double-stranded RNA (dsRNA). Enhanced RNAi (Eri) mutants facilitate RNAi due to their hypersensitivity to dsRNA. Here, we compare eight Eri mutants for sensitivity to ingested dsRNA, targeting a variety of tissue-specific genes.

Genome-wide association (GWA) studies have proved extremely successful in identifying novel genetic loci contributing effects to complex human diseases. In doing so, they have highlighted the fact that many potential loci of modest effect remain undetected, partly due to the need for samples consisting of many thousands of individuals. Large-scale international initiatives, such as the Wellcome Trust Case Control Consortium, the Genetic Association Information Network, and the database of genetic and phenotypic information, aim to facilitate discovery of modest-effect genes by making genome-wide data publicly available, allowing information to be combined for the purpose of pooled analysis. In principle, disease or control samples from these studies could be used to increase the power of any GWA study via judicious use as "genetically matched controls" for other traits. Here, we present the biological motivation for the problem and the theoretical potential for expanding the control group with publicly available disease or reference samples. We demonstrate that a naïve application of this strategy can greatly inflate the false-positive error rate in the presence of population structure. As a remedy, we make use of genome-wide data and model selection techniques to identify "axes" of genetic variation which are associated with disease. These axes are then included as covariates in association analysis to correct for population structure, which can result in increases in power over standard analysis of genetic information from the samples in the original GWA study., ((c) 2010 Wiley-Liss, Inc.)

Rheumatoid arthritis (RA) is three times more common in females than in males, suggesting that sex may play a role in modifying genetic associations with disease. We have addressed this hypothesis by performing sex-differentiated and sex-interaction analyses of a genome-wide association study of RA in a North American population. Our results identify a number of novel associations that demonstrate strong evidence of association in both sexes combined, with no evidence of heterogeneity in risk between males and females. However, our analyses also highlight a number of associations with RA in males or females only. These signals may represent true sex-specific effects, or may reflect a lack of power to detect association in the smaller sample of males, and thus warrant further investigation.

To test the hypothesis that exogenous purified angiotensin II (ANG) might cause apoptosis of alveolar epithelial cells (AECs) and acute lung injury, male Wistar rats were intratracheally instilled with purified ANG (10 mumol/L), ANG plus the caspase inhibitor ZVAD-fmk (60 mumol/L), ANG plus the ANG receptor AT1 antagonist losartan (LOS, 100 mumol/L) or sterile phosphate-buffered saline (PBS) vehicle alone. Six or 20 h later, the lungs were lavaged in situ for determination of bronchoalveolar lavage (BAL) fluid content of hemoglobin (Hb) and fluorescent (BODIPY)-albumin, a bolus of which was injected intravenously 15 min prior to BAL. Terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) revealed that instillation of ANG, but not PBS alone, increased labeling of fragmented DNA in bronchiolar epithelial cells and in AECs (P<0.05) at 6 h post-ANG. Increased TUNEL was abrogated by concurrent instillation of ZVAD-fmk or LOS. Significant increased numbers of caspase-positive cells were observed by anti-caspase 3 immunolabeling after instillation of ANG (P<0.01); the same doses of LOS or ZVAD-fmk that blocked TUNEL also blocked the activation of caspase 3 (P<0.01). Intratracheal instillation of ANG also remarkably increased BAL BODIPY-albumin (P< 0.01) and Hb (P<0.05), both of which were eliminated by ZVAD-fmk or LOS. These data indicate that exposure of AECs to ANG in vivo is sufficient to induce apoptosis and alveolar epithelial barrier injury mediated by ANG receptor AT1.

This paper presents a novel monitor which uses ARM controller AT91SAM7S64 as its main processor, LCM (Liquid Crystal Display Module) for displaying ECG waves, SD (Secure Digital memory) card for data storage and RF module PTR8000 for radio data transmission. This portable monitor boasts alarm function for abnormality and can provide dynamic ECG monitoring for patients.

Genotype imputation is potentially a zero-cost method for bridging gaps in coverage and power between genotyping platforms. Here, we quantify these gains in power and coverage by using 1,376 population controls that are from the 1958 British Birth Cohort and were genotyped by the Wellcome Trust Case-Control Consortium with the Illumina HumanHap 550 and Affymetrix SNP Array 5.0 platforms. Approximately 50% of genotypes at single-nucleotide polymorphisms (SNPs) exclusively on the HumanHap 550 can be accurately imputed from direct genotypes on the SNP Array 5.0 or Illumina HumanHap 300. This roughly halves differences in coverage and power between the platforms. When the relative cost of currently available genome-wide SNP platforms is accounted for, and finances are limited but sample size is not, the highest-powered strategy in European populations is to genotype a larger number of individuals with the HumanHap 300 platform and carry out imputation. Platforms consisting of around 1 million SNPs offer poor cost efficiency for SNP association in European populations.

Objective: To study the clinical and molecular genetic characteristics of spinal bulbar muscular atrophy (SBMA)., Methods: The clinical data, including case history, physical examination, biochemical analyses of blood, EMG, and muscle biopsy, of 5 Chinese patients with SBMA, all males, aged 29 - 58, with the onset age of 36 (17 - 49), were collected the information of in 5 cases. Four patients underwent PCR to examine the number of copies of CAG repeat region in androgen receptor (AR) gene., Results: The clinical characteristics of the 5 patients included atrophy of lingualis, dysarthria, weakness and waste of the limbs, especially in the hands, and elevated creatine kinase (CK), fasting glucose, testosterone, and progesterone in the blood. EMG showed denervation motor potentials in all cases. The muscle biopsy in one case showed neurogenic atrophy. The number of (CAG) n repeat in AR gene was 50 - 62 in the, remarkably from that of 13 normal controls (19 - 20) without overlapping., Conclusion: SBMA affects the middle age males, shows a slowly progressing muscular atrophy in spinal and bulbar muscles. The different number of (CAG) n repeat of AR gene between the SBMA patients and the normal controls may be an important identification to differentiate SBMA from other motor neuron diseases.

Objective: To elucidate the roles of Bcl-2 and Bax in experimental immunological liver injury in rat and the effect of lowering serum levels on the expression and the injury., Methods: 48 male Wistar rats were divided into six groups randomly. The animal model of iron low-load was created by intravenation of deferoxamine (DFO) or phlebotomy respectively, and immunological liver damage model was reproduced by injection of BCG (Bacilli Calmette Guein) and lipopolysaccharide (LPS). Then the following parameters were determined such as serum iron (SI) concentration, transferrin (TRF) concentration, total proteins (TP) volume, the serum activity of aspartate aminotransferase (AST), malondialdehyde (MDA) content, iron content (HIC), the expression of Bcl-2 and Bax proteins in liver tissue were assayed; the ratio of Bax to Bcl-2, apoptotic index (AI), and proliferative index (PI) were also calculated., Results: (1) The amount of Bax expression in liver injury group was significantly higher than that of control one, but no change in Bcl-2 expression. The ratio of Bax to Bcl-2 and AI augmented significantly, along with increased serum activities of AST and level of MDA, reduced volume of TP in liver injury animals. (2) The serum activity of AST and TP volume in both of the control groups with DFO and phlebotomy pretreatment remained at control level. Although the expression of Bax and Bcl-2, Bax/Bcl-2 ratio and AI were all higher than those of blank controls, the increased magnitudes of Bax/Bcl-2 ratio and Al were significantly lower than those of the liver injury animals. (3) The expression amounts of Bcl-2 and Bax increased in the injury animals induced after injecting DFO or phlebotomy, thus Bax/Bcl-2 ratio and Al increased. However, Bax/Bcl-2 ratio and AI of them were less than those of the injuries without lowered SI, and the magnitude of increased serum activity of AST was lower than that of the injuries, but no change in TP volume in the rats with lowered SI. The MDA levels in the injuries with lower value of serum iron were lower than those of the animals without lower SI., Conclusion: The results show that the apoptotic process of hepatocyte accelerates in immunological liver injury, apoptosis may facilitate hepatocyte damage. Effect of iron on the expression of apoptosis regulating proteins have played an important role in apoptosis of immunological hepatic injury.

During 1998 the primary focus of the Genome Sequence DataBase (GSDB; http://www.ncgr.org/gsdb ) located at the National Center for Genome Resources (NCGR) has been to improve data quality, improve data collections, and provide new methods and tools to access and analyze data. Data quality has been improved by extensive curation of certain data fields necessary for maintaining data collections and for using certain tools. Data quality has also been increased by improvements to the suite of programs that import data from the International Nucleotide Sequence Database Collaboration (IC). The Sequence Tag Alignment and Consensus Knowledgebase (STACK), a database of human expressed gene sequences developed by the South African National Bioinformatics Institute (SANBI), became available within the last year, allowing public access to this valuable resource of expressed sequences. Data access was improved by the addition of the Sequence Viewer, a platform-independent graphical viewer for GSDB sequence data. This tool has also been integrated with other searching and data retrieval tools. A BLAST homology search service was also made available, allowing researchers to search all of the data, including the unique data, that are available from GSDB. These improvements are designed to make GSDB more accessible to users, extend the rich searching capability already present in GSDB, and to facilitate the transition to an integrated system containing many different types of biological data.

In 1997 the primary focus of the Genome Sequence DataBase (GSDB; www. ncgr.org/gsdb ) located at the National Center for Genome Resources was to improve data quality and accessibility. Efforts to increase the quality of data within the database included two major projects; one to identify and remove all vector contamination from sequences in the database and one to create premier sequence sets (including both alignments and discontiguous sequences). Data accessibility was improved during the course of the last year in several ways. First, a graphical database sequence viewer was made available to researchers. Second, an update process was implemented for the web-based query tool, Maestro. Third, a web-based tool, Excerpt, was developed to retrieve selected regions of any sequence in the database. And lastly, a GSDB flatfile that contains annotation unique to GSDB (e.g., sequence analysis and alignment data) was developed. Additionally, the GSDB web site provides a tool for the detection of matrix attachment regions (MARs), which can be used to identify regions of high coding potential. The ultimate goal of this work is to make GSDB a more useful resource for genomic comparison studies and gene level studies by improving data quality and by providing data access capabilities that are consistent with the needs of both types of studies.

The unit discharges of carotid chemosensory afferent fibers were recorded in the in vitro carotid body (CB)--sinus nerve preparations (n = 55) from 29 rabbits. The results were as follows: (1) The discharge of all the units increased from 0.86 +/- 0.21 to 1.75 +/- 0.40 imp/s (P < 0.001) upon lowering the pH of modified Locke solution. (2) Addition of nicotine at doses of 1, 3, 6, 10 and 15 micrograms/ml to the solution led to a dose-dependent increase in the discharge from 0.60 +/- 0.21 to 0.96 +/- 0.21, 1.19 +/- 0.30. 1.24 +/- 0.29, 1.48 +/- 0.41 and 1.82 +/- 0.39 imp/s, respectively (r = 0.94, P < 0.001, n = 10). Nicotinic stimulation was antagonized by D-tubocurarine but the basal discharge was not significantly affected. (3) Superfusion of the CB with acid solution increased the discharge from 0.95 +/- 0.34 to 1.84 +/- 0.55 imp/s (P < 0.01, n = 19); After injections of nicotine 1-5 micrograms/ml to acid perfusate the unit discharge showed an increase from 0.96 +/- 0.25 to 1.53 +/- 0.24 imp/s. The degree of increase was less as compared with that due to mere acidification (P < 0.05). (4) D-tubocurarine did not alter the action of acid solution on chemosensory discharge (P > 0.05, n = 17). The present results suggest that ACh might act only as a modulator on carotid chemosensory activity without involving N-cholinergic receptor directly as did by low pH perfusion of CB.