scCAD: Cluster decomposition-based anomaly detection for rare cell identification in single-cell expression data.

Single-cell RNA sequencing (scRNA-seq) technologies have become essential tools for characterizing cellular landscapes within complex tissues. Large-scale single-cell transcriptomics holds great potential for identifying rare cell types critical to the pathogenesis of diseases and biological processes. Existing methods for identifying rare cell types often rely on one-time clustering using partial or global gene expression. However, these rare cell types may be overlooked during the clustering phase, posing challenges for their accurate identification. In this paper, we propose a Cluster decomposition-based Anomaly Detection method (scCAD), which iteratively decomposes clusters based on the most differential signals in each cluster to effectively separate rare cell types and achieve accurate identification. We benchmark scCAD on 25 real-world scRNA-seq datasets, demonstrating its superior performance compared to 10 state-of-the-art methods. In-depth case studies across diverse datasets, including mouse airway, brain, intestine, human pancreas, immunology data, and clear cell renal cell carcinoma, showcase scCAD's efficiency in identifying rare cell types in complex biological scenarios. Furthermore, scCAD can correct the annotation of rare cell types and identify immune cell subtypes associated with disease, thereby offering valuable insights into disease progression.

Incorporation of Decidual Stromal Cells Derived Exosomes in Sodium Alginate Hydrogel as an Innovative Therapeutic Strategy for Advancing Endometrial Regeneration and Reinstating Fertility.

Intrauterine adhesion (IUA) stands as a prevalent medical condition characterized by endometrial fibrosis and scar tissue formation within the uterine cavity, resulting in infertility and, in severe cases, recurrent miscarriages. Cell therapy, especially with stem cells, offers an alternative to surgery, but concerns about uncontrolled differentiation and tumorigenicity limit its use. Exosomes, more stable and immunogenicity-reduced than parent cells, have emerged as a promising avenue for IUA treatment. In this study, a novel approach has been proposed wherein exosomes originating from decidual stromal cells (DSCs) are encapsulated within sodium alginate hydrogel (SAH) scaffolds to repair endometrial damage and restore fertility in a mouse IUA model. Current results demonstrate that in situ injection of DSC-derived exosomes (DSC-exos)/SAH into the uterine cavity has the capability to induce uterine angiogenesis, initiate mesenchymal-to-epithelial transformation (MET), facilitate collagen fiber remodeling and dissolution, promote endometrial regeneration, enhance endometrial receptivity, and contribute to the recovery of fertility. RNA sequencing and advanced bioinformatics analysis reveal miRNA enrichment in exosomes, potentially supporting endometrial repair. This finding elucidates how DSC-exos/SAH mechanistically fosters collagen ablation, endometrium regeneration, and fertility recovery, holding the potential to introduce a novel IUA treatment and offering invaluable insights into the realm of regenerative medicine.

Unsupervised clustering analysis of comprehensive health status and its influencing factors on women of childbearing age: a cross-sectional study from a province in central China.

BACKGROUND: Most previous studies on women of childbearing age have focused on reproductive health and fertility intentions, and evidence regarding the comprehensive health status of women of childbearing age is limited. This study aimed to comprehensively examine the health status of women of childbearing age through a multi-method and multi-indicator evaluation, analyze the factors that influence their overall health, and provide sound recommendations for the improvement and promotion of healthy behaviors. METHODS: Data on women of childbearing age living in Shanxi Province were collected between September 2021 and January 2022 through online and offline surveys. The k-means algorithm was used to assess health-related patterns in women, and multivariate nonconditional logistic regression was used to assess the influencing factors of women's overall health. RESULTS: In total, 1,258 of 2,925 (43%) participants were classified as having a good health status in all five domains of the three health dimensions: quality of life, mental health, and illness. Multivariate logistic regression showed that education level, gynecological examination status, health status of family members, access to medical treatment, age, cooking preferences, diet, social support, hand washing habits, attitude toward breast cancer prevention, and awareness of reproductive health were significantly associated with different health patterns. CONCLUSIONS: The comprehensive health status of women of childbearing age in Shanxi Province is generally good; however, a large proportion of women with deficiencies in some dimensions remains. Since lifestyle greatly impacts women's health, health education on lifestyle and health-related issues should be strengthened.

The prevalence and burden of four major chronic diseases in the Shanxi Province of Northern China.

Background: Chronic non-communicable diseases constitute an important public health problem that is closely related to behavioral risk factors. The study examined the prevalence, burden, and behavioral risk factors relevant to four major chronic diseases in Shanxi Province, China. The results obtained could provide a basis for the formulation of chronic disease prevention and control strategies in north China. Methods: A multi-stage random sampling method was used to select 14,137 residents aged ≥15 years who completed a questionnaire survey and physical examination. The disease burden was evaluated using the disability-adjusted life years (DALY) index. The extent of disease burden attributable to smoking and drinking behavior was analyzed using counterfactual analysis. Results: The total DALYs due to the four major chronic diseases was 938,100. The years of life lost due to stroke accounted for 74.86%; the years of life lived with disabilities accounted for 54.0 and 68.1% of the total disease burden of coronary heart disease and diabetes. Coronary heart disease attributed to smoking (105,600) was the highest, followed by stroke (77,200), hypertension (6,000), and diabetes mellitus (5,900). Stroke attributed to drinking (30,700) was the highest followed by coronary heart disease (16,700) and diabetes (1,100). The disease burden caused by smoking and drinking was higher in men (164,000 and 40,700, respectively) than in women (30,700 and 7,300, respectively). Conclusion: There is a high prevalence and significant burden associated with major chronic diseases in Shanxi Province. Therefore, the need for the application of various interventions to control smoking and drinking (the major predisposing factors) should be applied to reduce this burden.

Machine learning techniques for CT imaging diagnosis of novel coronavirus pneumonia: a review.

Since 2020, novel coronavirus pneumonia has been spreading rapidly around the world, bringing tremendous pressure on medical diagnosis and treatment for hospitals. Medical imaging methods, such as computed tomography (CT), play a crucial role in diagnosing and treating COVID-19. A large number of CT images (with large volume) are produced during the CT-based medical diagnosis. In such a situation, the diagnostic judgement by human eyes on the thousands of CT images is inefficient and time-consuming. Recently, in order to improve diagnostic efficiency, the machine learning technology is being widely used in computer-aided diagnosis and treatment systems (i.e., CT Imaging) to help doctors perform accurate analysis and provide them with effective diagnostic decision support. In this paper, we comprehensively review these frequently used machine learning methods applied in the CT Imaging Diagnosis for the COVID-19, discuss the machine learning-based applications from the various kinds of aspects including the image acquisition and pre-processing, image segmentation, quantitative analysis and diagnosis, and disease follow-up and prognosis. Moreover, we also discuss the limitations of the up-to-date machine learning technology in the context of CT imaging computer-aided diagnosis.

Identifying Excessive Intake of Oil and Salt to Prevent and Control Hypertension: A Latent Class Analysis.

Introduction: To identify health hazard behaviors and provide a basis for targeted management and intervention for patients with hypertension, we classified their health-related behaviors. Methods: A multi-stage random sampling method was used to conduct an on-site questionnaire survey among residents aged ≥15 years in a certain urban area of Taiyuan City, Shanxi Province, China. A latent class analysis was used to classify the lifestyle behaviors of patients with hypertension. The lifestyle behavior characteristics of different types of patients with hypertension and their awareness of hypertension were assessed. Results: The prevalence of hypertension in Taiyuan City was 19.5%. Patients with hypertension were classified into three clusters according to their lifestyle patterns: smoking and drinking (13.35%), excessive edible oil and salt intake (68.27%), and healthy behavior (18.38%). Comparing the three latent classes of lifestyle, the distribution of age, sex, marital status, and education level was different (P < 0.05). The awareness of hypertension and the rate of control among the three classes were also different (P < 0.05). Conclusion: The lifestyle behaviors of patients with hypertension have evident classification characteristics. Approximately two-thirds of the patients with hypertension have an excessive intake of oil and salt. Therefore, targeted and precise intervention measures should be taken to control the intake of oil and salt in this cohort.

NIR-II Upconversion Photoluminescence of Er3+ Doped LiYF4 and NaY(Gd)F4 Core-Shell Nanoparticles.

The availability of colloidal nano-materials with high efficiency, stability, and non-toxicity in the near infrared-II range is beneficial for biological diagnosis and therapy. Rare earth doped nanoparticles are ideal luminescent agents for bio-applications in the near infrared-II range due to the abundant energy level distribution. Among them, both excitation and emission range of Er3+ ions can be tuned into second biological window range. Herein, we report the synthesis of ∼15 nm LiYF4, NaYF4, and NaGdF4 nanoparticles doped with Er3+ ions and their core-shell structures. The luminescent properties are compared, showing that Er3+ ions with single-doped LiYF4 and NaYF4 nanoparticles generate stronger luminescence than Er3+ ions with doped NaGdF4, despite the difference in relative intensity at different regions. By epitaxial growth an inert homogeneous protective layer, the surface luminescence of the core-shell structure is further enhanced by about 5.1 times, 6.5 times, and 167.7 times for LiYF4, NaYF4, and NaGdF4, respectively. The excellent luminescence in both visible and NIR range of these core-shell nanoparticles makes them potential candidate for bio-applications.

MiRNA-26a inhibits myocardial infarction-induced apoptosis by targeting PTEN via JAK/STAT pathways.

INTRODUCTION: Acute myocardial infarction (MI) is a common cause of the morbidity and mortality of cardiovascular diseases in the world. Acute MI lead to cardiovascular output after formation of myocardial ischemia and circulatory arrest in coronary heart diseases. However, the mechanisms underlying MI injury are poorly understood. We explored the part played by miR-26a in myocardial infarction (MI). MATERIAL AND METHODS: Decreased miR-26a expression in H2O2-treated newborn murine ventricular cardiomyocytes (NMVCs) was observed, as well as in the infarcted heart of MI mouse model, compared to untreated NMVCs and healthy mouse heart tissue, respectively. Conversely, the upregulation of phosphatase and tensin homolog (PTEN) was observed in H2O2-treated NMVCs, and in infarcted hearts. An MTT assay and BrdU staining showed that H2O2 treatment attenuated cell viability in NMVCs, whereas miR-26a overexpression increased cell viability. Both TUNEL assay and flow cytometry (FC) displayed that miR-26a expression suppressed H2O2-induced cell apoptosis. Besides, miR-26a overexpression suppressed the upregulation of PTEN expression in H2O2-treated NMVCs by directly binding to PTEN 3'-UTR. RESULTS: PI3K/Akt and JAK/STAT signal transduction pathways were found to be regulated through cross-talk between miR-26a and PTEN. Furthermore, agomiR-26a treatment in MI mouse model considerably suppressed the size of the infarcted regions, and improved cardiac activity. CONCLUSIONS: MiR-26a expression in MI cardiac tissues was downregulated in response to H2O2 stress, whereas it could still protect against cell death by modulation of the PI3K/Akt and JAK/STAT signal transduction pathways by directly targeting PTEN.

Activating Sphingosine-1-phospahte signaling in endothelial cells increases myosin light chain phosphorylation to decrease endothelial permeability thereby inhibiting cancer metastasis.

Targeting the metastatic process to prevent disease dissemination in cancer remains challenging. One step in the metastatic cascade involves cancer cells transiting through the vascular endothelium after inflammation has increased the permeability of this cellular layer. Reducing inflammation-mediated gaps in the vascular endothelium could potentially be used to retard metastasis. This study describes the development of a novel ASR396-containing nanoparticle designed to activate the Sphingosine-1-Phosphate Receptor 1 (S1PR1) in order to tighten the junctions between the endothelial cells lining the vascular endothelium thereby inhibiting metastasis. ASR396 was derived from the S1PR1 agonist SEW2871 through chemical modification enabling the new compound to be loaded into a nanoliposome. ASR396 retained S1PR1 binding activity and the nanoliposomal formulation (nanoASR396) made it systemically bioavailable upon intravenous injection. Studies conducted in microvessels demonstrated that nanoASR396 significantly attenuated inflammatory mediator-induced permeability increase through the S1PR1 activation. Similarly, nanoASR396 inhibited gap formation mediated by inflammatory agents on an endothelial cell monolayer by decreasing levels of phosphorylated myosin light chain protein thereby inhibiting cellular contractility. In animal models, nanoASR396 inhibited lung metastasis by up to 80%, indicating its potential for retarding melanoma metastasis. Thus, a novel bioavailable nanoparticle-based S1PR1 agonist has been developed to negate the effects of inflammatory mediators on the vascular endothelium in order to reduce the metastatic dissemination of cancer cells.

Zacopride Exerts an Antiarrhythmic Effect by Specifically Stimulating the Cardiac Inward Rectifier Potassium Current in Rabbits: Exploration of a New Antiarrhythmic Strategy.

BACKGROUND: Zacopride, a potent antagonist of 5-HT3 receptors and an agonist of 5-HT4 receptors, is a gastrointestinal prokinetic agent. In a previous study, we discovered that zacopride selectively stimulated the inward rectifier potassium current (IK1) in the rat and that agonizing IK1 prevented or eliminated aconitine-induced arrhythmias in rats. OBJECTIVE: Our aims were to confirm that the antiarrhythmic effects of zacopride are mediated by selectively enhancing IK1 in rabbits. METHODS: The effects of zacopride on the function of the main ion channels were investigated using a whole-cell patch-clamp technique in rabbits. Effects of zacopride on cardiac arrhythmias were also explored experimentally both in vivo and in vitro. RESULTS: Zacopride moderately enhanced cardiac IK1 but had no apparent action on voltage-gated sodium current (INa), L- type calcium current (ICa-L), sodium-calcium exchange current (INa/Ca), transient outward potassium current (Ito), or delayed rectifier potassium current (IK) in rabbits. Zacopride also had a marked antiarrhythmic effect in vivo and in vitro. We proved that the resting membrane potential (RMP) was hyperpolarized in the presence of 1 µmol/L zacopride, and the action potential duration (APD) at 90% repolarization (APD90) was shortened by zacopride (0.1-10 µmol/L) in a concentration- dependent manner. Furthermore, zacopride at 1 µmol/L significantly decreased the incidence of drug-induced early afterdepolarization (EAD) in rabbit ventricular myocytes. CONCLUSION: Zacopride is a selective agonist of rabbit cardiac IK1 and that IK1 enhancement exerts potential antiarrhythmic effects.

IK1 channel agonist zacopride suppresses ventricular arrhythmias in conscious rats with healing myocardial infarction.

AIMS: Arrhythmogenesis of chronic myocardial infarction (MI) is associated with the prolongation of action potential, reduction of inward rectifier potassium (IK1, Kir) channels and hyper-activity of Calcium/calmodulin-dependent kinase II (CaMKII) in cardiomyocytes. Zacopride, a selective IK1 agonist, was applied to clarify the cardioprotection of IK1 agonism via a CaMKII signaling on arrhythmias post-MI. METHODS: Male SD rats were implanted wireless transmitter in the abdominal cavity and subjected to left main coronary artery ligation or sham operation. The telemetric ECGs were monitored per day throughout 4 weeks. At the endpoint, isoproterenol (1.28 mg/kg, i.v.) was administered for provocation test. The expressions of Kir2.1 (dominant subunit of IK1 in ventricle) and CaMKII were detected by Western-blotting. KEY FINDINGS: In the telemetric rats post-MI, zacopride significantly reduced the episodes of atrioventricular conduction block (AVB), premature ventricular contraction (PVC), ventricular tachycardia (VT) and ventricular fibrillation (VF), without significant effect on superventricular premature contraction (SPVC). In provocation test, zacopride suppressed the onset of ventricular arrhythmias in conscious PMI or sham rats. The expression of Kir2.1 was significantly downregulated and p-CaMKII was upregulated post-MI, whereas both were restored by zacopride treatment. SIGNIFICANCE: IK1/Kir2.1 might be an attractive target for pharmacological controlling of lethal arrhythmias post MI.

IK1 Channel Agonist Zacopride Alleviates Cardiac Hypertrophy and Failure via Alterations in Calcium Dyshomeostasis and Electrical Remodeling in Rats.

Intracellular Ca2+ overload, prolongation of the action potential duration (APD), and downregulation of inward rectifier potassium (IK1) channel are hallmarks of electrical remodeling in cardiac hypertrophy and heart failure (HF). We hypothesized that enhancement of IK1 currents is a compensation for IK1 deficit and a novel modulation for cardiac Ca2+ homeostasis and pathological remodeling. In adult Sprague-Dawley (SD) rats in vivo, cardiac hypertrophy was induced by isoproterenol (Iso) injection (i.p., 3 mg/kg/d) for 3, 10, and 30 days. Neonatal rat ventricular myocytes (NRVMs) were isolated from 1 to 3 days SD rat pups and treated with 1 µmol/L Iso for 24 h in vitro. The effects of zacopride, a selective IK1/Kir2.1 channel agonist, on cardiac remodeling/hypertrophy were observed in the settings of 15 µg/kg in vivo and 1 µmol/L in vitro. After exposing to Iso for 3 days and 10 days, rat hearts showed distinct concentric hypertrophy and fibrosis and enhanced pumping function (P < 0.01 or P < 0.05), then progressed to dilatation and dysfunction post 30 days. Compared with the age-matched control, cardiomyocytes exhibited higher cytosolic Ca2+ (P < 0.01 or P < 0.05) and lower SR Ca2+ content (P < 0.01 or P < 0.05) all through 3, 10, and 30 days of Iso infusion. The expressions of Kir2.1 and SERCA2 were downregulated, while p-CaMKII, p-RyR2, and cleaved caspase-3 were upregulated. Iso-induced electrophysiological abnormalities were also manifested with resting potential (RP) depolarization (P < 0.01), APD prolongation (P < 0.01) in adult cardiomyocytes, and calcium overload in cultured NRVMs (P < 0.01). Zacopride treatment effectively retarded myocardial hypertrophy and fibrosis, preserved the expression of Kir2.1 and some key players in Ca2+ homeostasis, normalized the RP (P < 0.05), and abbreviated APD (P < 0.01), thus lowered cytosolic [Ca2 +]i (P < 0.01 or P < 0.05). IK1channel blocker BaCl2 or chloroquine largely reversed the cardioprotection of zacopride. We conclude that cardiac electrical remodeling is concurrent with structural remodeling. By enhancing cardiac IK1, zacopride prevents Iso-induced electrical remodeling around intracellular Ca2+ overload, thereby attenuates cardiac structural disorder and dysfunction. Early electrical interventions may provide protection on cardiac remodeling.

H2 O2 -induced microvessel barrier dysfunction: the interplay between reactive oxygen species, nitric oxide, and peroxynitrite.

Elevated H2 O2 is implicated in many cardiovascular diseases. We previously demonstrated that H2 O2 -induced endothelial nitric oxide synthase (eNOS) activation and excessive NO production contribute to vascular cell injury and increases in microvessel permeability. However, the mechanisms of excessive NO-mediated vascular injury and hyperpermeability remain unknown. This study aims to examine the functional role of NO-derived peroxynitrite (ONOO- ) in H2 O2 -induced vascular barrier dysfunction by elucidating the interrelationships between H2 O2 -induced NO, superoxide, ONOO- , and changes in endothelial [Ca2+ ]i and microvessel permeability. Experiments were conducted on intact rat mesenteric venules. Microvessel permeability was determined by measuring hydraulic conductivity (Lp). Endothelial [Ca2+ ]i , NO, and O2- were assessed with fluorescence imaging. Perfusion of vessels with H2 O2 (10 µmol/L) induced marked productions of NO and O2- , resulting in extensive protein tyrosine nitration, a biomarker of ONOO- . The formation of ONOO- was abolished by inhibition of NOS with NG -Methyl-L-arginine. Blocking NO production or scavenging ONOO- by uric acid prevented H2 O2 -induced increases in endothelial [Ca2+ ]i and Lp. Additionally, the application of exogenous ONOO- to microvessels induced delayed and progressive increases in endothelial [Ca2+ ]i and microvessel Lp, a pattern similar to that observed in H2 O2 -perfused vessels. Importantly, ONOO- caused further activation of eNOS with amplified NO production. We conclude that the augmentation of NO-derived ONOO- is essential for H2 O2 -induced endothelial Ca2+ overload and progressively increased microvessel permeability, which is achieved by self-promoted amplifications of NO-dependent signaling cascades. This novel mechanism provides new insight into the reactive oxygen and/or reactive nitrogen species-mediated vascular dysfunction in cardiovascular diseases.

Increased circulating microparticles in streptozotocin-induced diabetes propagate inflammation contributing to microvascular dysfunction.

KEY POINTS: Circulating microparticles (MPs) are elevated in many cardiovascular diseases and have been considered as biomarkers of disease prognosis; however, current knowledge of MP functions has been mainly derived from in vitro studies and their precise impact on vascular inflammation and disease progression remains obscure. Using a diabetic rat model, we identified a >130-fold increase in MPs in plasma of diabetic rats compared to normal rats, the majority of which circulated as aggregates, expressing multiple cell markers and largely externalized phosphatidylserine; vascular images illustrate MP biogenesis and their manifestations in microvessels of diabetic rats. Using combined single microvessel perfusion and systemic cross-transfusion approaches, we delineated how diabetic MPs propagate inflammation in the vasculature and transform normal microvessels into an inflammatory phenotype observed in the microvessels of diabetic rats. Our observations derived from animal studies resembling conditions in diabetic patients, providing a mechanistic insight into MP-mediated pathogenesis of diabetes-associated multi-organ microvascular dysfunction. ABSTRACT: In various cardiovascular diseases, microparticles (MPs), the membrane-derived vesicles released during cell activation, are markedly increased in the circulation. These MPs have been recognized to play diverse roles in the regulation of cellular functions. However, current knowledge of MP function has been largely derived from in vitro studies. The precise impact of disease-induced MPs on vascular inflammation and disease progression remains obscure. In this study we investigated the biogenesis, profile and functional roles of circulating MPs using a streptozotocin-induced diabetic rat model with well-characterized microvascular functions. Our study revealed a >130-fold increase in MPs in the plasma of diabetic rats compared to normal rats. The majority of these MPs originate from platelets, leukocytes and endothelial cells (ECs), and circulate as aggregates. Diabetic MPs show greater externalized phosphatidylserine (PS) than normal MPs. When diabetic plasma or isolated diabetic MPs were perfused into normal microvessels or systemically transfused into normal rats, MPs immediately adhered to endothelium and subsequently mediated leukocyte adhesion. These microvessels then exhibited augmented permeability responses to inflammatory mediators, replicating the microvascular manifestations observed in diabetic rats. These effects were abrogated when MPs were removed from diabetic plasma or when diabetic MPs were pre-coated with a lipid-binding protein, annexin V, suggesting externalized PS to be key in mediating MP interactions with endothelium and leukocytes. Our study demonstrated that the elevated MPs in diabetic plasma are actively involved in the propagation of vascular inflammation through their adhesive surfaces, providing mechanistic insight into the pathogenesis of multi-organ vascular dysfunction that commonly occurs in diabetic patients.

Study of main and cross-over effects on pressure relief among body mass index (BMI), body position and supporting material properties.

Pressure ulcers influence people with limited mobility who must spend a long time lying or sitting because these positions create high interfacial pressure between the body and supporting materials. Supporting materials, such as mattresses and cushions, are designed to prevent pressure ulcers by increasing the contact area, reducing the interfacial pressure or reducing the contact time. Foam is the most common supporting material for relieving pressure because it is cheap and easy to change its shape to fit the contour of the body. Past studies showed that BMI, body position and supporting material properties have an impact on relieving pressure; however, there is no study of the main and cross-over effects among these parameters. This study aims to investigate the main and cross-over effects among BMI, body position and supporting material properties on pressure relieving performance using univariate ANOVA and correlation analysis. It was found that body position and foam density were the main effect and BMI and body position, and body position and foam density were the cross-over effects on pressure relief. It was also found that low density Polyurethane (PU) foam of less than 4 cm in thickness as well as the appropriate K2 and K3 moduli are best suited for pressure relief. The actual value of foam thickness and the appropriate K2 and K3 moduli are subject to BMI values and body position. The significance of the outcomes from this study is that it will aid in optimizing the design of supporting materials with varied BMI values and body positions to greatly reduce pressure ulcers for ailing patients.

Algorithms for Pedigree Comparison.

Reconstruction of ancestral relationships among genera, species, and populations is a core task in evolutionary biology. At the population level, pedigrees have been commonly used. Reconstruction of pedigree is required in practice due to legal or medical reasons. Pedigrees are very important to geneticists for inferring haplotype segments, recombination, and allele sharing status with which disease loci can be identified. Evaluating reconstruction methods requires comparing the inferred pedigree and the known pedigrees. Moreover, comparison of pedigrees is required in studying relationships among crops such as maize, wheat and barley, etc. In this paper, we discuss three models for comparison of pedigrees, the maximum pedigree isomorphism problem, the maximum paternal-path-preserved mapping problem, and the minimum edge-cutting mapping problem. For the maximum pedigree isomorphism problem, we prove that the problem is NP-hard and give a fixed-parameter algorithm for the problem. For the maximum paternal-path-preserved mapping problem, we give a dynamic-programming algorithm to find the mapping that preserves the maximum number of paternal paths between the two input pedigrees. For the minimum edge-cutting mapping problem, we prove that the problem is NP-hard and give a fixed-parameter algorithm with running time , where is the number of vertices in the two input pedigrees and is the number of edges to be cut. This algorithm is useful in practice when comparing two similar pedigrees.

Transendothelial movement of adiponectin is restricted by glucocorticoids.

Altered permeability of the endothelial barrier in a variety of tissues has implications both in disease pathogenesis and treatment. Glucocorticoids are potent mediators of endothelial permeability, and this forms the basis for their heavily prescribed use as medications to treat ocular disease. However, the effect of glucocorticoids on endothelial barriers elsewhere in the body is less well studied. Here, we investigated glucocorticoid-mediated changes in endothelial flux of Adiponectin (Ad), a hormone with a critical role in diabetes. First, we used monolayers of endothelial cells in vitro and found that the glucocorticoid dexamethasone increased transendothelial electrical resistance and reduced permeability of polyethylene glycol (PEG, molecular weight 4000 Da). Dexamethasone reduced flux of Ad from the apical to basolateral side, measured both by ELISA and Western blotting. We then examined a diabetic rat model induced by treatment with exogenous corticosterone, which was characterized by glucose intolerance and hyperinsulinemia. There was no change in circulating Ad but less Ad protein in skeletal muscle homogenates, despite slightly higher mRNA levels, in diabetic vs control muscles. Dexamethasone-induced changes in Ad flux across endothelial monolayers were associated with alterations in the abundance of select claudin tight junction (TJ) proteins. shRNA-mediated knockdown of one such gene, claudin-7, in HUVEC resulted in decreased TEER and increased adiponectin flux, confirming the functional significance of Dex-induced changes in its expression. In conclusion, our study identifies glucocorticoid-mediated reductions in flux of Ad across endothelial monolayers in vivo and in vitro This suggests that impaired Ad action in target tissues, as a consequence of reduced transendothelial flux, may contribute to the glucocorticoid-induced diabetic phenotype.

The IK1/Kir2.1 channel agonist zacopride prevents and cures acute ischemic arrhythmias in the rat.

Arrhythmogenesis in acute myocardial infarction (MI) is associated with depolarization of resting membraine potential (RMP) and decrease of inward rectifier potassium current (IK1) in cardiomyocytes. However, clinical anti-arrhythmic agents that primarily act on RMP by enhancing the IK1 channel are not currently available. We hypothesized that zacopride, a selective and moderate agonist of the IK1/Kir2.1 channels, prevents and cures acute ischemic arrhythmias. To test this viewpoint, adult Sprague-Dawley (SD) rats were subjected to MI by ligating the left main coronary artery. The antiarrhythmic effects of zacopride (i.v. infusion) were observed in the settings of pre-treatment (zacopride given 3 min prior to coronary occlusion), post-treatment (zacopride given 3 min after coronary occlusion) and therapeutic treatment (zacopride given 30 s after the onset of the first sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) post MI). In all the three treatment modes, zacopride (15 µg/kg) inhibited MI-induced ventricular tachyarrhythmias, as shown by significant decreases in the premature ventricular contraction (PVC) and the duration and incidence of VT or VF. In Langendorff perfused rat hearts, the antiarrhythmic effect of 1 µmol/L zacopride were reversed by 1 µmol/L BaCl2, a blocker of IK1 channel. Patch clamp results in freshly isolated rat ventricular myocytes indicated that zacopride activated the IK1 channel and thereby reversed hypoxia-induced RMP depolarization and action potential duration (APD) prolongation. In addition, zacopride (1 µmol/L) suppressed hypoxia- or isoproterenol- induced delayed afterdepolarizations (DADs). In Kir2.x transfected Chinese hamster ovary (CHO) cells, zacopride activated the Kir2.1 homomeric channel but not the Kir2.2 or Kir2.3 channels. These results support our hypothesis that moderately enhancing IK1/Kir2.1 currents as by zacopride rescues ischemia- and hypoxia- induced RMP depolarization, and thereby prevents and cures acute ischemic arrhythmias. This study brings a new viewpoint to antiarrhythmic theories and provides a promising target for the treatment of acute ischemic arrhythmias.

Heterogeneous network model to infer human disease-long intergenic non-coding RNA associations.

With the knowledge of molecular biology it is highlighting that long non-coding RNAs (lncRNAs) play a critical role in many important biological processes, such as imprinting control, cell differentiation, immune responses, human diseases, tumorigenesis and other biological processes. This study proposes a novel computational method, named KRWRH, to infer disease-lincRNA associations with the influence of phenotype information and tissue expression details of lincRNA. Gaussian interaction profile kernel is calculated for diseases and lincRNAs and random walk with restart method is used for final prediction. The proposed method KRWRH is compared with four existing methods: LRLSLDA, TslncRNA, NRWRH, and RWRH. The experimental results based on the leave-one-out cross validation, ROC curves, and mean enrichment show that the proposed method KRWRH is able to predict known and unknown disease-lincRNA associations more effectively.

Activation of IK1 channel by zacopride attenuates left ventricular remodeling in rats with myocardial infarction.

Activating IK1 channels is considered to be a promising antiarrhythmic strategy. Zacopride has been identified as a selective IK1 channel agonist and can suppress triggered arrhythmias. Whether this drug also exerts a beneficial effect on cardiac remodeling is unknown, and the present study sought to address this question. Cardiac remodeling was induced through coronary ligation-induced myocardial infarction (MI) in male Sprague-Dawley rats. Zacopride (15 µg/kg) was administered (intraperitoneally) daily for 28 days after MI to determine whether it could attenuate MI-induced cardiac remodeling. A 4-week treatment with zacopride attenuated post-MI cardiac remodeling, as shown by the reduced left ventricular end-diastolic dimension and left ventricular end-systolic dimension and the increased ejection fraction and fractional shortening in zacopride-treated animals compared with animals treated with vehicle (all P < 0.05). Furthermore, zacopride significantly decreased myocardial collagen deposition, cardiomyocyte hypertrophy, the plasma level of brain natriuretic peptide, and cardiomyocyte ultrastructural injury. Zacopride also upregulated the expression of the IK1 channel protein and downregulated the expression of phosphorylated p70S6 kinase (p-p70S6K) and mTOR. These beneficial effects of zacopride were partially abolished by the IK1 channel blocker chloroquine. We conclude that the activation of IK1 channel by zacopride attenuates post-MI cardiac remodeling by suppressing mTOR-p70S6 kinase signaling.