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Introduction: The prevalence of heart failure with preserved ejection fraction (HFpEF) is continuously rising and predominantly affects older women often hypertensive and/or obese or diabetic. Indeed, there is evidence on sex differences in the development of HF. Hence, we studied cardiovascular performance dependent on sex and age as well as pathomechanisms on a cellular and molecular level. Methods: We studied 15-week- and 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked blood pressure and cardiac function via echocardiography. After sacrificing the 1-year survivors we studied vascular smooth muscle and endothelial function. Isolated single skinned cardiomyocytes were used to determine passive stiffness and Ca2+-dependent force. In addition, Western blots were applied to analyse the phosphorylation status of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII as well as their expression. Protein kinase activity assays were used to measure activities of CaMKII, PKG and angiotensin-converting enzyme (ACE). Results: TG male rats showed significantly higher mortality at 1 year than females or WT male rats. Left ventricular (LV) ejection fraction was specifically reduced in male, but not in female TG rats, while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte function showing different response to acetylcholine and Ca2+-sensitivity of force production, respectively cardiomyocyte functional changes were associated with altered phosphorylation states of cardiac myosin binding protein C and cardiac troponin I phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in TG animals. On a molecular level titin phosphorylation pattern was altered, though alterations were sex-specific. Thus, also the reduction of PKG expression and activity was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored by PKG and CaMKII treatments in both TG sexes. Conclusion: Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male TG rats in contrast to female TG rats was observed as well as reduced LV systolic function, whereas females mainly developed HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired titin function contributes to a sex-specific molecular mechanism. The functional derangements of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems. [ABSTRACT FROM AUTHOR]

The article focuses on understanding sex-based differences in outcomes with dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). Topics include the underrepresentation of women in clinical trials, the association between sex and adverse cardiovascular and bleeding events, and the need for a comprehensive approach considering biological, social, and environmental factors to accurately interpret these differences.

Purpose of the Review: This review aims to elucidate the transformative impact and potential of machine learning (ML) in the diagnosis, prognosis, and clinical management of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). It further aims to bridge the gap between current advances of ML and their practical application in these diseases. Recent Findings: Recent advances in ML have revolutionized prognostication, diagnosis, and treatment of MDS and AML. ML algorithms have proven effective in predicting disease progression, optimizing treatment responses, and in the stratification of patient groups. Particularly, the use of ML in genomic and epigenomic data analysis has unveiled novel insights into the molecular heterogeneity of MDS and AML, leading to better-informed therapeutic strategies. Furthermore, deep learning techniques have shown promise in analyzing complex patterns in bone marrow biopsy images, providing a potential pathway towards early and accurate diagnosis. Summary: While still in the nascent stages, ML applications in MDS and AML signify a paradigm shift towards precision medicine. The integration of ML with traditional clinical practices could potentially enhance diagnostic accuracy, refine risk stratification, and improve therapeutic approaches. However, challenges related to data privacy, standardization, and algorithm interpretability must be addressed to realize the full potential of ML in this field. Future research should focus on the development of robust, transparent ML models and their ethical implementation in clinical settings. [ABSTRACT FROM AUTHOR]

The development of cost-effective coatings with exceptional corrosion resistance is an ongoing challenge in the field of materials science. Among the promising coatings, zinc–nickel (Zn–Ni) coatings have shown great potential, especially when produced using economical electroplating technology. However, achieving optimal performance while minimizing coating thickness remains a complex task. In this study, the behavior of the responses was investigated according to the coating standards and levels, focusing on eight variables including temperature, time, cathodic current density, nickel concentration, substrate hardness, roughness, cathode–anode distance, and magnetic stirring speed. Four responses were investigated: coating thickness, roughness, microhardness, and corrosion rate with potentiodynamic polarization, using two design of experiments (DOE) methods: Plackett–Burman design (12 runs) and response surface methodology with Box–Behnken design (15 runs). The results show the degree of influence of each variable on the responses and their contribution to changing the responses. Additionally, response surfaces have been determined and it is shown that large response values can be achieved with small thicknesses. The morphological study using SEM, EDX, and XRD techniques revealed that the deposition conditions play an important role in the surface morphology. Some samples showed microcracks, while others had small grain size and were free of cracks and pores. Overall, this study provides new insights into the improvement of Zn–Ni coatings with exceptional corrosion resistance and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Extremely rare circulating tumor cell (CTC) clusters are both increasingly appreciated as highly metastatic precursors and virtually unexplored. Technologies are primarily designed to detect single CTCs and often fail to account for the fragility of clusters or to leverage cluster-specific markers for higher sensitivity. Meanwhile, the few technologies targeting CTC clusters lack scalability. Here, we introduce the Cluster-Wells, which combines the speed and practicality of membrane filtration with the sensitive and deterministic screening afforded by microfluidic chips. The >100,000 microwells in the Cluster-Wells physically arrest CTC clusters in unprocessed whole blood, gently isolating virtually all clusters at a throughput of >25 mL/h, and allow viable clusters to be retrieved from the device. Using the Cluster-Wells, we isolated CTC clusters ranging from 2 to 100+ cells from prostate and ovarian cancer patients and analyzed a subset using RNA sequencing. Routine isolation of CTC clusters will democratize research on their utility in managing cancer. Metastatic CTC clusters remain relatively unexplored due to the lack of optimized and practical technologies for their detection. Here the authors report Cluster-Wells to isolate CTC clusters in whole blood; they show this allows viable cluster retrieval for further molecular and functional analysis. [ABSTRACT FROM AUTHOR]

The mosquito Aedes aegypti is the major vector of arboviruses like dengue, Zika and chikungunya viruses. Attempts to reduce arboviruses emergence focusing on Ae. aegypti control has proven challenging due to the increase of insecticide resistances. An emerging strategy which consists of releasing Ae. aegypti artificially infected with Wolbachia in natural mosquito populations is currently being developed. The monitoring of Wolbachia-positive Ae. aegypti in the field is performed in order to ensure the program effectiveness. Here, the reliability of the Matrix‑Assisted Laser Desorption Ionization‑Time Of Flight (MALDI‑TOF) coupled with the machine learning methods like Convolutional Neural Network (CNN) to detect Wolbachia in field Ae. aegypti was assessed for the first time. For this purpose, laboratory reared and field Ae. aegypti were analyzed. The results showed that the CNN recognized Ae. aegypti spectral patterns associated with Wolbachia-infection. The MALDI-TOF coupled with the CNN (sensitivity = 93%, specificity = 99%, accuracy = 97%) was more efficient than the loop-mediated isothermal amplification (LAMP), and as efficient as qPCR for Wolbachia detection. It therefore represents an interesting method to evaluate the prevalence of Wolbachia in field Ae. aegypti mosquitoes. [ABSTRACT FROM AUTHOR]

Notably, refractory AML patients with MCL-1 dependence had a CRc rate of 52% compared with 38% in refractory AML patients without MCL-1 dependence (Supplemental Fig. A comparison of clinical outcomes among patients with MCL-1-dependent R/R AML and non-MCL-1-dependent R/R AML patients is outlined in Supplemental Tables 3-5. Eighty-two patients were enrolled onto one of the five cohorts: (1) MCL-1 <15% ( I n i = 15), (2) MCL-1: 15-<30% ( I n i = 14), (3) MCL-1: 30-<40% ( I n i = 14), (4) MCL-1: >=40% ( I n i = 25), and (5) NDHR AML with MCL-1 >=40% ( I n i = 14). [Extracted from the article]

Purpose of review: SGLT2 inhibitors (SGLT2i) are new drugs for patients with heart failure (HF) irrespective of diabetes. However, the mechanisms of SGLT2i in HF remain elusive. This article discusses the current clinical evidence for using SGLT2i in different types of heart failure and provides an overview about the possible underlying mechanisms. Recent findings: Clinical and basic data strongly support and extend the use of SGLT2i in HF. Improvement of conventional secondary risk factors is unlikely to explain the prognostic benefits of these drugs in HF. However, different multidirectional mechanisms of SGLT2i could improve HF status including volume regulation, cardiorenal mechanisms, metabolic effects, improved cardiac remodelling, direct effects on cardiac contractility and ion-homeostasis, reduction of inflammation and oxidative stress as well as an impact on autophagy and adipokines. Summary: Further translational studies are needed to determine the mechanisms of SGLT2i in HF. However, basic and clinical evidence encourage the use of SGLT2i in HFrEF and possibly HFpEF. [ABSTRACT FROM AUTHOR]

The SGLT2 inhibitor empagliflozin improved cardiovascular outcomes in patients with diabetes. As the cardiac mechanisms remain elusive, we investigated the long-term effects (up to 2 months) of empagliflozin on excitation-contraction (EC)-coupling in human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CM) in a blinded manner. IPSC from 3 donors, differentiated into pure iPSC-CM (4 differentiations), were treated with a clinically relevant concentration of empagliflozin (0.5 μmol/l) or vehicle control. Treatment, data acquisition, and analysis were conducted externally blinded. Epifluorescence microscopy measurements in iPSC-CM showed that empagliflozin has neutral effects on Ca2+ transient amplitude, diastolic Ca2+ levels, Ca2+ transient kinetics, or sarcoplasmic Ca2+ load after 2 weeks or 8 weeks of treatment. Confocal microscopy determining possible effects on proarrhythmogenic diastolic Ca2+ release events showed that in iPSC-CM, Ca2+ spark frequency and leak was not altered after chronic treatment with empagliflozin. Finally, in patch-clamp experiments, empagliflozin did not change action potential duration, amplitude, or resting membrane potential compared with vehicle control after long-term treatment. Next-generation RNA sequencing (NGS) and mapped transcriptome profiles of iPSC-CMs untreated and treated with empagliflozin for 8 weeks showed no differentially expressed EC-coupling genes. In line with NGS data, Western blots indicate that empagliflozin has negligible effects on key EC-coupling proteins. In this blinded study, direct treatment of iPSC-CM with empagliflozin for a clinically relevant duration of 2 months did not influence cardiomyocyte EC-coupling and electrophysiology. Therefore, it is likely that other mechanisms independent of cardiomyocyte EC-coupling are responsible for the beneficial treatment effect of empagliflozin. Key messages: This blinded study investigated the clinically relevant long-term effects (up to 2 months) of empagliflozin on cardiomyocyte excitation-contraction (EC)-coupling. Human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CM) were used to study a human model including a high repetition number of experiments. Empagliflozin has neutral effects on cardiomyocyte Ca2+ transients, sarcoplasmic Ca2+ load, and diastolic sarcoplasmic Ca2+ leak. In patch-clamp experiments, empagliflozin did not change the action potential. Next-generation RNA sequencing, mapped transcriptome profiles, and Western blots of iPSC-CM untreated and treated with empagliflozin showed no differentially expressed EC-coupling candidates. [ABSTRACT FROM AUTHOR]

The objectives of this study were to isolate lactic acid bacteria (LAB) from a raw Moroccan camel milk collected after the incorporation of a specific Argane by-products diet, and to investigate their technological properties as well as their probiotic features. The molecular identification of the isolates indicated that they belong to Weissella confusa, Weissella cibaria or Enterococcus durans species. Our results revealed that the tested isolates have a fast acidifying ability (values ranging between 0.045 ± 0.01 to 0.93 ± 0.01 after only 4 h incubation), important proteolysis, autolysis, lipolytic activities and an important diacetyl and exopolysaccharides production. All these isolates demonstrated a high tolerance to gastrointestinal conditions, namely to gastric simulated juice (survival rate ranged between 75.05 ± 7.88 and 85.55 ± 1.77%) and to bile salts (survival rate between 42.79 ± 1.11 and 82.75 ± 1.01%). The autoaggregation, hydrophobicity and antioxidant activity mean values of the isolates were 13.26–41.16%, 13.23–54.47% and 47.57–63.31%, respectively. Importantly, LAB cultures exhibited antibacterial activity against Gram-negative and Gram-positive pathogenic bacteria and none of the tested isolates presented antibiotic resistance, haemolytic or DNase activities. This study revealed interesting properties for LAB isolated and supported their utilization as autochthone starters for camel milk fermentation that represent a challenge process. These results presented as well the probiotic potential for a possible human consumption. [ABSTRACT FROM AUTHOR]

Directed acyclic graphs (DAGs) are used in many domains ranging from computer science to bioinformatics, including industry and geoscience. They enable to model complex evolutions where spatial objects (e.g., soil erosion) may move, (dis)appear, merge or split. We study a new graph-based representation, called attributed DAG (a-DAG). It enables to capture interactions between objects as well as information on objects (e.g., characteristics or events). In this paper, we focus on pattern mining in such data. Our patterns, called weighted paths, offer a good trade-off between expressiveness and complexity. Frequency and compactness constraints are used to filter out uninteresting patterns. These constraints lead to an exact condensed representation (without loss of information) in the single-graph setting. A depth-first search strategy and an optimized data structure are proposed to achieve the efficiency of weighted path discovery. It does a progressive extension of patterns based on database projections. Relevance, scalability and genericity are illustrated by means of qualitative and quantitative results when mining various real and synthetic datasets. In particular, we show how such an approach can be used to monitor soil erosion using remote sensing and geographical information system (GIS) data. [ABSTRACT FROM AUTHOR]

The complex physiological signal transduction networks that respond to the dual challenges of inflammatory and oxidative stress are major factors that promote the development of cardiovascular pathologies. These signaling networks contribute to the development of age-related diseases, suggesting crosstalk between the development of aging and cardiovascular disease. Inhibition and/or attenuation of these signaling networks also delays the onset of disease. Therefore, a concept of targeting the signaling networks that are involved in inflammation and oxidative stress may represent a novel treatment paradigm for many types of heart disease. In this review, we discuss the molecular mechanisms associated with the physiological responses to inflammation and oxidative stress especially in heart failure with preserved ejection fraction and emphasize the nature of the crosstalk of these signaling processes as well as possible therapeutic implications for cardiovascular medicine. [ABSTRACT FROM AUTHOR]

Purpose of Review: Artificial intelligence (AI), and in particular its subcategory machine learning, is finding an increasing number of applications in medicine, driven in large part by an abundance of data and powerful, accessible tools that have made AI accessible to a larger circle of investigators. Recent Findings: AI has been employed in the analysis of hematopathological, radiographic, laboratory, genomic, pharmacological, and chemical data to better inform diagnosis, prognosis, treatment planning, and foundational knowledge related to benign and malignant hematology. As more widespread implementation of clinical AI nears, attention has also turned to the effects this will have on other areas in medicine. Summary: AI offers many promising tools to clinicians broadly, and specifically in the practice of hematology. Ongoing research into its various applications will likely result in an increasing utilization of AI by a broader swath of clinicians. [ABSTRACT FROM AUTHOR]

Hospital systems, payers, and regulators have focused on reducing length of stay (LOS) and early readmission, with uncertain benefit. Interpretable machine learning (ML) may assist in transparently identifying the risk of important outcomes. We conducted a retrospective cohort study of hospitalizations at a tertiary academic medical center and its branches from January 2011 to May 2018. A consecutive sample of all hospitalizations in the study period were included. Algorithms were trained on medical, sociodemographic, and institutional variables to predict readmission, length of stay (LOS), and death within 48–72 h. Prediction performance was measured by area under the receiver operator characteristic curve (AUC), Brier score loss (BSL), which measures how well predicted probability matches observed probability, and other metrics. Interpretations were generated using multiple feature extraction algorithms. The study cohort included 1,485,880 hospitalizations for 708,089 unique patients (median age of 59 years, first and third quartiles (QI) [39, 73]; 55.6% female; 71% white). There were 211,022 30-day readmissions for an overall readmission rate of 14% (for patients ≥65 years: 16%). Median LOS, including observation and labor and delivery patients, was 2.94 days (QI [1.67, 5.34]), or, if these patients are excluded, 3.71 days (QI [2.15, 6.51]). Predictive performance was as follows: 30-day readmission (AUC 0.76/BSL 0.11); LOS > 5 days (AUC 0.84/BSL 0.15); death within 48–72 h (AUC 0.91/BSL 0.001). Explanatory diagrams showed factors that impacted each prediction. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) arise in older adults through stepwise acquisitions of multiple somatic mutations. Here, analyzing 1809 MDS patients, we infer clonal architecture by using a stringent, the single-cell sequencing validated PyClone bioanalytic pipeline, and assess the position of the mutations within the clonal architecture. All 3,971 mutations are grouped based on their rank in the deduced clonal hierarchy (dominant and secondary). We evaluated how they affect the resultant morphology, progression, survival and response to therapies. Mutations of SF3B1, U2AF1, and TP53 are more likely to be dominant, those of ASXL1, CBL, and KRAS are secondary. Among distinct combinations of dominant/secondary mutations we identified 37 significant relationships, of which 12 affect clinical phenotypes, 5 cooperatively associate with poor prognosis. They also predict response to hypomethylating therapies. The clonal hierarchy has distinct ranking and the resultant invariant combinations of dominant/secondary mutations yield novel insights into the specific clinical phenotype of MDS. [ABSTRACT FROM AUTHOR]

The objective of this work was to study the effect of the incorporation of argane by-products (meal and pulp) in ewe's diet on the production and quality of milk and the performance of lambs in the lactation phase. Twenty ewes were divided into two equal groups. The first one has been fed with argane by-product diet (AD), and the second with a control diet (CD). The results showed an improvement in milk production with an average of 26.3% for AD compared with the CD group. AD group lambs showed a significant difference (p < 0.05) compared with the CD group during lactation phase. The ash and protein levels were not affected by treatments; however, fat, lactose, density, and fusion point content show more fluctuations for both treatments (p < 0.05). The physicochemical parameters of sheep milk showed high (p < 0.01) to very high (p < 0.001) significant change, along the lactation weeks. Except the Zn which showed no significant difference (p > 0.05), the mineral composition of both milks (Na, K, Ca, Mg, P, and Fe) was significant (p < 0.05). It is concluded that, in terms of performances, argane by-products could replace the conventional diet for ewes without substantial detrimental effects. Therefore, argane by-product could be used as a cost-effective feed for sheep in dry areas. [ABSTRACT FROM AUTHOR]

Background and Objective: The development of new targeted therapies in kidney cancer has shaped disease management in the metastatic phase. Our study aims to conduct a cost-utility analysis of sunitinib versus pazopanib in first-line setting in Canada for metastatic renal cell carcinoma (mRCC) patients using real-world data.Methods: A Markov model with Monte-Carlo microsimulations was developed to estimate the clinical and economic outcomes of patients treated in first-line with sunitinib versus pazopanib. Transition probabilities were estimated using observational data from a Canadian database where real-life clinical practice was captured. The costs of therapies, disease progression, and management of adverse events were included in the model in Canadian dollars ($Can). Utility and disutility values were included for each health state. Incremental cost-utility ratio (ICUR) and incremental cost-effectiveness ratios (ICER) were calculated for a time horizon of 5 years, from the Canadian Healthcare System perspective.Results: The cost difference was $36,303 and the difference in quality-adjusted life year (QALY) was 0.54 in favour of sunitinib with an ICUR of $67,227/QALY for sunitinib versus pazopanib. The major cost component (56%) is related to best supportive care (BSC) where patients tend to stay for a longer period of time compared to other states. The difference in life years gained (LYG) between sunitinib and pazopanib was 1.21 LYG (33.51 vs 19.03 months) and the ICER was $30,002/LYG. Sensitivity analysis demonstrated the robustness of the model with a high probability of sunitinib being a cost-effective option when compared to pazopanib.Conclusion: When using real-world evidence, sunitinib is found to be a cost-effective treatment compared to pazopanib in mRCC patients in Canada. [ABSTRACT FROM AUTHOR]

Purpose of Review: The number of online resources for patients with MDS is exponentially increasing; this is in large part due to the advent of social media which has introduced multiple avenues for information exchange and communication. Whether this information is targeted towards the patient population or not, the wealth of information online represents a new era of patient engagement in their health care. This review aims to highlight the different online resources being used in the field of MDS.Recent Findings: Patients with MDS have access to the opinions of thought leaders in the field, advances in research and clinical trials, and the latest updates at national conferences and leading journals through social media.Summary: Social media is a powerful educational resource for patients with MDS when used conscientiously. [ABSTRACT FROM AUTHOR]

Purpose of Review: To evaluate established prognostic models in chronic myelomonocytic leukemia (CMML) and describe the challenges associated with their application in clinical practice.Recent Findings: CMML is a clonal hematopoietic stem cell disorder with heterogeneous clinical and molecular features. Outcomes of CMML patients can vary from indolent disease with expected survival measured in years versus proliferative subtypes with rapid progression to acute myeloid leukemia and survival measured in months. Several prognostic scoring systems have been developed to risk stratify CMML patients. While all these models are valid, they demonstrate significant predictive heterogeneity.Summary: Significant intra-patient (applying different models in the same patient giving rise to different prognostic results) and intra-model (patients in a similar prognostic group by a given model can be reclassified to different risk groups by other models) heterogeneities exist when applying current CMML prognostic models in the clinic. A personalized prediction approach may open new opportunities in risk stratifying patients with CMML and other myeloid malignancies. [ABSTRACT FROM AUTHOR]

Serine/threonine protein phosphatase 5 (PP5) is ubiquitously expressed in eukaryotic cells; however, its function in cardiomyocytes is unknown. Under basal conditions, PP5 is autoinhibited, but enzymatic activity rises upon binding of specific factors, such as the chaperone Hsp90. Here we show that PP5 binds and dephosphorylates the elastic N2B-unique sequence (N2Bus) of titin in cardiomyocytes. Using various binding and phosphorylation tests, cellculture manipulation, and transgenic mouse hearts, we demonstrate that PP5 associates with N2Bus in vitro and in sarcomeres and is antagonistic to several protein kinases, which phosphorylate N2Bus and lower titin-based passive tension. PP5 is pathologically elevated and likely contributes to hypo-phosphorylation of N2Bus in failing human hearts. Furthermore, Hsp90-activated PP5 interacts with components of a sarcomeric, N2Bus-associated, mechanosensor complex, and blocks mitogen-activated protein-kinase signaling in this complex. Our work establishes PP5 as a compartmentalized, well-controlled phosphatase in cardiomyocytes, which regulates titin properties and kinase signaling at the myofilaments. [ABSTRACT FROM AUTHOR]

Purpose of Review: The purpose of this study is to review established prognostic models in myelodysplastic syndromes (MDS) and describe how molecular data can be used to improve patient risk stratification. Recent Findings: Somatic mutations are common in MDS and are associated with disease features including outcomes. Several recurrently mutated genes have prognostic significance independent of risk stratification tools used in practice. However, this prognostic impact can depend on the clinicogenetic context in which mutations occur. Qualitatively, SF3B1 mutations appear favorable only in patients with < 5% bone marrow blasts while mutations of several genes, including ASXL1, SRSF2, U2AF1, NRAS, and IDH2, appear adverse in this context. Mutations of TP53, RUNX1, and EZH2 appear adverse regardless of blast percentage. Consensus on how to best incorporate mutations into risk assessment is still being developed. Summary: Somatic mutations can refine risk stratification and improve the accuracy of existing prognostic models, often upstaging or downstaging patients across the boundary of higher- and lower-risk MDS. [ABSTRACT FROM AUTHOR]

Reversible post-translational modifications of various cardiac proteins regulate the mechanical properties of the cardiomyocytes and thus modulate the contractile performance of the heart. The giant protein titin forms a continuous filament network in the sarcomeres of striated muscle cells, where it determines passive tension development and modulates active contraction. These mechanical properties of titin are altered through post-translational modifications, particularly phosphorylation. Titin contains hundreds of potential phosphorylation sites, the functional relevance of which is only beginning to emerge. Here, we provide a state-of-the-art summary of the phosphorylation sites in titin, with a particular focus on the elastic titin spring segment. We discuss how phosphorylation at specific amino acids can reduce or increase the stretch-induced spring force of titin, depending on where the spring region is phosphorylated. We also review which protein kinases phosphorylate titin and how this phosphorylation affects titin-based passive tension in cardiomyocytes. A comprehensive overview is provided of studies that have measured altered titin phosphorylation and titin-based passive tension in myocardial samples from human heart failure patients and animal models of heart disease. As our understanding of the broader implications of phosphorylation in titin progresses, this knowledge could be used to design targeted interventions aimed at reducing pathologically increased titin stiffness in patients with stiff hearts. [ABSTRACT FROM AUTHOR]

Attributed directed graphs are directed graphs in which nodes are associated with sets of attributes. Many data from the real world can be naturally represented by this type of structure, but few algorithms are able to directly handle these complex graphs. Mining attributed graphs is a difficult task because it requires combining the exploration of the graph structure with the identification of frequent itemsets. In addition, due to the combinatorics on itemsets, subgraph isomorphisms (which have a significant impact on performances) are much more numerous than in labeled graphs. In this paper, we present a new data mining method that can extract frequent patterns from one or more directed attributed graphs. We show how to reduce the combinatorial explosion induced by subgraph isomorphisms thanks to an appropriate processing of automorphic patterns. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDSs) are a heterogeneous group of disorders characterized by the accumulation of complex genetic alterations that drive disease pathogenesis and outcome. Several prognostic models have been developed over the last two decades to risk stratify patients with MDS. These models mainly used clinical variables including blast percentage, cytopenias, cytogenetics, transfusion dependency, and age. Recently, somatic mutations in specific genes have been shown to impact overall survival in MDS and can be incorporated into established prognostic models to improve their predictive abilities. Here, we review the advantages and disadvantages of established prognostic models in MDS and the impact of emerging data regarding the incorporation of somatic mutations in risk stratification. [ABSTRACT FROM AUTHOR]

In this paper, we evaluate the throughput of cooperative ARQ and HARQ I protocols in underlay cognitive radio networks using semi blind relays. Semi Blind Relays do not require to estimate the channel of the first hop, they use only some channel statistics. Relays help the secondary source to deliver its packet. Only relays that generate an interference to primary receiver lower than a predefined threshold will be activated. Three relay selection techniques are considered: opportunistic relaying, partial and reactive relay selection. Opportunistic relaying consists in selecting the relay that offers the highest end-to-end SNR. Partial relay selection consists in selecting the relay that offers the highest SNR of the first hop. Reactive relay selection consists in selecting the relay that offers the highest SNR of the second hop. This relay is selected among the active ones that generate an interference to primary receiver lower than a predefined threshold. To the best of our knowledge, there are no studies dealing with throughput evaluation of HARQ protocols for cognitive radio networks using opportunistic relaying, partial and reactive relay selection. Besides, this is the first paper to deal with HARQ protocols using semi blind relays. Previous studies dealt with outage, bit and symbol error probabilities evaluation for cognitive radio networks. [ABSTRACT FROM AUTHOR]

Frequent pattern mining is an important data mining task with a broad range of applications. Initially focused on the discovery of frequent itemsets, studies were extended to mine structural forms like sequences, trees or graphs. In this paper, we introduce a new domain of patterns, attributed trees (atrees), and a method to extract these patterns in a forest of atrees. Attributed trees are trees in which vertices are associated with itemsets. Mining this type of patterns (called asubtrees), which combines tree mining and itemset mining, requires the exploration of a huge search space. To make our approach scalable, we investigate the mining of condensed representations. For attributed trees, the classical concept of closure involves both itemset closure and structural closure. We present three algorithms for mining all patterns, closed patterns w.r.t. itemsets (content) and/or structure in attributed trees. We show that, for low support values, mining content-closed attributed trees is a good compromise between non-redundancy of solutions and execution time. [ABSTRACT FROM AUTHOR]

Redox/cysteine modification of proteins that regulate calcium cycling can affect contraction in striated muscles. Understanding the nature of these modifications would present the possibility of enhancing cardiac function through reversible cysteine modification of proteins, with potential therapeutic value in heart failure with diastolic dysfunction. Both heart failure and muscular dystrophy are characterized by abnormal redox balance and nitrosative stress. Recent evidence supports the synergistic role of oxidative stress and inflammation in the progression of heart failure with preserved ejection fraction, in concert with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signalling via modification of the giant protein titin. Although antioxidant therapeutics in heart failure with diastolic dysfunction have no marked beneficial effects on the outcome of patients, it, however, remains critical to the understanding of the complex interactions of oxidative/nitrosative stress with pro-inflammatory mechanisms, metabolic dysfunction, and the redox modification of proteins characteristic of heart failure. These may highlight novel approaches to therapeutic strategies for heart failure with diastolic dysfunction. In this review, we provide an overview of oxidative stress and its effects on pathophysiological pathways. We describe the molecular mechanisms driving oxidative modification of proteins and subsequent effects on contractile function, and, finally, we discuss potential therapeutic opportunities for heart failure with diastolic dysfunction. [ABSTRACT FROM AUTHOR]

In this paper, we propose a static hybrid multihop relaying protocol where some relays amplify the received signal whereas the remaining ones use decode and forward (DF) relaying. The relaying mode in each relay is set using the distance between the different nodes and the average SNR. The exact and asymptotic bit error probabilities, the block error probability and the throughput of hybrid automatic repeat request (HARQ) protocols are derived. Simulation results are provided in different contexts to compare the performance of hybrid relaying to conventional AF and DF relaying. In the second part of the paper, we propose a static hybrid amplify and forward (AF) and DF relaying using distributed space-time coding (DSTC). Relays close to the source amplify the received signal, and the remaining relays transmit only if they correctly decoded. All AF relays and DF relays that have correctly decoded transmit using DSTC in order to benefit from spatial diversity. The proposed protocol offers better performance than AF relaying using DSTC and similar performance to DF relaying using DSTC. However, the complexity and transmission delays of the proposed static hybrid AF-DF relaying is lower than that of DF relaying since decoding is not performed at AF relays. [ABSTRACT FROM AUTHOR]

Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signalling is often depressed by heart disease. PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7, 8) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

Co-location mining is a classical problem in spatial pattern mining. Considering a set of boolean spatial features, the goal is to find subsets of features frequently located together. It has wide applications in environmental management, public safety, transportation or tourism. These last years, many algorithms have been proposed to extract frequent co-locations. However, most solutions do a 'data-centered knowledge discovery' instead of a 'expert-centered knowledge discovery'. Successfully providing useful and interpretable patterns to experts is still an open problem. In this setting, we propose a domain-driven co-location mining approach that combines constraint-based mining and cartographic visualization. Experts can push new domain constraints into the mining algorithm, resulting in more relevant patterns and more efficient extraction. Then, they can visualize solutions using a new concise and intuitive cartographic visualization of co-locations. Using this original visualization approach, they identify new interesting patterns, and use uninteresting ones to define new constraints and refine their analysis. These proposals have been integrated into a prototype based on PostGIS geographic information system. Experiments have been done using a real geological datasets studying soil erosion, and results have been validated by a domain expert. [ABSTRACT FROM AUTHOR]

Increased levels of interleukin-6 (IL-6) have been observed in patients with acute myocarditis and are associated with poor prognosis. This study was designed to examine whether treatment with anti-IL-6 receptor antibody improves cardiac dysfunction and left ventricular (LV) remodeling in experimental Coxsackie virus B3 (CVB3)-induced myocarditis. C57BL6/J mice were subjected to acute CVB3 infection. One day after viral infection mice were treated with a single injection of an anti-IL-6 receptor antibody (MR16-1, tocilizumab) or control IgG. Seven days after viral infection, LV function was examined by conductance catheter technique, cardiac remodeling assessed by estimation of titin phosphorylation, cardiac fibrosis, and inflammatory and antiviral response by immunohistochemistry, RT-PCR and cell culture experiments. Compared to controls, infected mice displayed an impaired systolic and diastolic LV function associated with an increase in cardiac inflammation, fibrosis and impaired titin phosphorylation. IL-6 receptor blockade led to a shift of the immune response to a Th1 direction and significant reduction of viral load. In addition, cardiac immune response, extracellular matrix regulation and titin function improved, resulting in a preserved LV function. IL-6 receptor blockade exerts cardiac beneficial effects by antiviral and immunomodulatory actions after induction of an acute murine CVB3 virus myocarditis. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and is frequently associated with metabolic risk factors. Patients with HFpEF have only a slightly lower mortality than patients with HF and reduced EF. The pathophysiology of HFpEF is currently incompletely understood, which precludes specific therapy. Both HF phenotypes demonstrate distinct cardiac remodeling processes at the macroscopic, microscopic, and ultrastructural levels. Increased diastolic left-ventricular (LV) stiffness and impaired LV relaxation are important features of HFpEF, which can be explained by changes in the extracellular matrix and the cardiomyocytes. In HFpEF, elevated intrinsic cardiomyocyte stiffness contributes to high diastolic LV stiffness. Posttranslational changes in the sarcomeric protein titin, affecting titin isoform expression and phosphorylation, contribute to elevated cardiomyocyte stiffness. Increased nitrosative/oxidative stress, impaired nitric oxide bioavailability, and down-regulation of myocardial cyclic guanosine monophosphate and protein kinase G signaling could trigger posttranslational modifications of titin, thereby augmenting cardiomyocyte and LV diastolic stiffness. [ABSTRACT FROM AUTHOR]

Feature construction has been studied extensively, including for 0/1 data samples. Given the recent breakthroughs in closedness-related constraint-based mining, we are considering its impact on feature construction for classification tasks. We investigate the use of condensed representations of frequent itemsets based on closedness properties as new features. These itemset types have been proposed to avoid set counting in difficult association rule mining tasks, i.e. when data are noisy and/or highly correlated. However, our guess is that their intrinsic properties (say the maximality for the closed itemsets and the minimality for the δ-free itemsets) should have an impact on feature quality. Understanding this remains fairly open, and we discuss these issues thanks to itemset properties on the one hand and an experimental validation on various data sets (possibly noisy) on the other hand. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a major cause of mortality and morbidity and one of the most frequent reasons for hospital admission in the United States and Europe. Currently, more than 50% of HF patients have a normal (N) left ventricular (LV) ejection fraction (EF) (LVEF >50%). The main pathophysiologic processes involved in HFNEF are increased LV stiffness and abnormal relaxation, resulting in impaired LV filling. Hypertension and myocardial ischemia are the most common causes of HFNEF. Precipitating factors include volume overload, tachycardia, physical exercise, systemic stressors (such as fever and infection), arrhythmia, increased salt intake, and use of nonsteroidal anti-inflammatory drugs. There is little evidence to guide treatment, as previously HFNEF patients have been excluded from clinical trials on the basis of a normal LVEF. Survival improved over time in patients with reduced (R) EF (HFREF) (LVEF <40%), reflecting the beneficial effects of treatment in this phenotype. However, survival did not improve for HFNEF patients. The approach to the treatment of HFNEF patients should focus on reducing LV filling pressure, controlling hypertension, modifying ischemia, and improving LV relaxation. Therefore, diuretics are suitable for HFNEF patients to reduce ventricular filling pressure. Hypertension can be treated by using multiple agents if necessary. Drugs of particular interest and recommended to treat hypertension are calcium channel blockers (CCBs) and antagonists of the renin-angiotensin-aldosterone system, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone antagonists. Ischemic heart disease can be treated with antiplatelet therapy, anticoagulants, and β-blockers. Heart rate control in atrial fibrillation can be achieved with β-blockers and digoxin. Finally, ACE inhibitors and ARBs could potentially decrease LV hypertrophy in hypertensive patients with HFNEF. [ABSTRACT FROM AUTHOR]

Lenalidomide is an active treatment for multiple myeloma (MM) and is increasingly used as part of the initial treatment of this disease. Recent reports have suggested decreases in the number of CD34+ cells collected and increases in the failure rate among patients whose initial therapy contained lenalidomide when mobilized with G-CSF alone. A retrospective data analysis of 364 patients with MM who underwent stem cell mobilization and attempted harvest at the Hospital of the University of Pennsylvania between January 2002 and December 2007 was performed. Forty-three of the patients received lenalidomide in their induction regimen, and were mobilized with either CY and G-CSF or G-CSF alone. The number of apheresis cycles and the failure rate were lower, whereas the mean number of collected stem cells was higher in patients who were mobilized with CY and G-CSF in comparison with G-CSF alone. This suggests that lenalidomide does not prevent the harvest of adequate numbers of CD34 cells for autologous stem cell transplant, but mobilization with G-CSF and CY may be required to obtain adequate numbers of stem cells. Finally, in our study, the number of lenalidomide cycles did not correlate with stem cell yield. [ABSTRACT FROM AUTHOR]

ivation of the β-adrenergic receptor (βAR) pathway is the main mechanism of the heart to increase cardiac output via protein kinase A (PKA)-mediated phosphorylation of cellular target proteins, and perturbations therein may contribute to cardiac dysfunction in heart failure. In the present study a comprehensive analysis was made of mediators of the βAR pathway, myofilament properties and cardiac structure in patients with idiopathic (IDCM; n = 13) and ischemic (ISHD; n = 10) cardiomyopathy in comparison to non-failing hearts (donor; n = 10) for the following parameters: βAR density, G-coupled receptor kinases 2 and 5, stimulatory and inhibitory G-proteins, phosphorylation of myofilament targets of PKA, protein phosphatase 1, phospholamban, SERCA2a and single myocyte contractility. All parameters exhibited the expected alterations of heart failure, but for most of them the extent of alteration was greater in IDCM than in ISHD. Histological analysis also revealed higher collagen in IDCM compared to ISHD. Alterations in the βAR pathway are more pronounced in IDCM than in ISHD and may reflect sequential changes in cellular protein composition and function. Our data indicate that cellular dysfunction is more severe in IDCM than in ISHD. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate if antibodies against β-adrenergic receptors (βARs) can be used to determine expression of βAR in human myocardium. Western blotting was performed to investigate the specificity of antibodies directed against β1AR and β2AR in human left ventricular tissue. A comparison was made between cardiac tissue from patients with idiopathic dilated cardiomyopathy and ischemic heart disease and nonfailing donors. The antibodies directed against β1AR and β2AR recognized several protein bands at different molecular weights. Moreover, both antibodies also recognized multiple proteins in Chinese hamster ovary cells expressing β1AR, β2AR, and even β3AR. βAR antibodies are not specific and are not suited to study expression of βAR in human myocardium. [ABSTRACT FROM AUTHOR]