Drug-mediated shortening of action potentials in LQTS2 hiPSC-cardiomyocytes

Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) are now a well-established modality for modeling genetic disorders of the heart. This is especially so for long QT syndrome (LQTS), which is caused by perturbation of ion channel function, and can lead to fainting, malignant arrhythmias and sudden cardiac death. LQTS2 is caused by mutations in KCNH2, a gene whose protein product contributes to IKr (also known as HERG), which is the predominant repolarizing potassium current in CMs. β-blockers are the mainstay treatment for patients with LQTS, functioning by reducing heart rate and arrhythmogenesis. However, they are not effective in around a quarter of LQTS2 patients, in part, because they do not correct the defining feature of the condition, which is excessively prolonged QT interval. Since new therapeutics are needed, in this report, we biopsied skin fibroblasts from a patient who was both genetically and clinically diagnosed with LQTS2. By producing LQTS-hiPSC-CMs, we assessed the impact of different drugs on action potential duration (APD), which is used as an in vitro surrogate for QT interval. Not surprisingly, the patient's own β-blocker medication, propranolol, had a marginal effect on APD in the LQTS-hiPSC-CMs. However, APD could be significantly reduced by up to 19% with compounds that enhanced the IKr current by direct channel binding or by indirect mediation through the PPARδ/protein 14-3-3 epsilon/HERG pathway. Drug-induced enhancement of an alternative potassium current, IKATP, also reduced APD by up to 21%. This study demonstrates the utility of LQTS-hiPSC-CMs in evaluating whether drugs can shorten APD and, importantly, shows that PPARδ agonists may form a new class of therapeutics for this condition

Specific-pathogen-free pigs as an animal model for studying Chlamydia trachomatis genital infection

The purpose of the present study was to evaluate pigs as a large-animal model for female genital infection with two Chlamydia trachomatis human serovar E strains. Sixteen-week-old specific-pathogen-free female pigs (gilts) were intravaginally infected with the trachoma type E reference strain Bour or the urogenital serovar E strain 468. Several conclusions can be drawn from our findings on the pathogenicity of a primary C. trachomatis genital infection in gilts. First of all, we demonstrated that the serovar E strains Bour and 468 could ascend in the genital tract of gilts. The serovar E strains could replicate in the superficial columnar cervical epithelium and in the superficial epithelial layer of the uterus, which are known to be the specific target sites for a C. trachomatis genital infection in women. Second, inflammation and pathology occurred at the replication sites. Third, the organisms could trigger a humoral immune response, as demonstrated by the presence of immunoglobulin M (IgM), IgG, and IgA in both serum and genital secretion samples. Our findings imply that the pig model might be useful for studying the pathology, pathogenesis, and immune response to a C. trachomatis infection of the genital system

Petroleum hydrocarbon rhizoremediation and soil microbial activity improvement via cluster root formation by wild proteaceae plant species

Rhizoremediation potential of different wild plant species for total (aliphatic) petroleum hydrocarbon (TPH)-contaminated soils was investigated. Three-week-old seedlings of Acacia inaequilatera, Acacia pyrifolia, Acacia stellaticeps, Banksia seminuda, Chloris truncata, Hakea prostrata, Hardenbergia violacea, and Triodia wiseana were transplanted in a soil contaminated with diesel and engine oil as TPH at pollution levels of 4,370 (TPH1) and 7,500 (TPH2) mg kg−1, and an uncontaminated control (TPH0). After 150 days, the presence of TPH negatively affected the plant growth, but the growth inhibition effect varied between the plant species. Plant growth and associated root biomass influenced the activity of rhizo-microbiome. The presence of B. seminuda, C. truncata, and H. prostrata significantly increased the TPH removal rate (up to 30% compared to the unplanted treatment) due to the stimulation of rhizosphere microorganisms. No significant difference was observed between TPH1 and TPH2 regarding the plant tolerance and rhizoremediation potentials of the three plant species. The presence of TPH stimulated cluster root formation in B. seminuda and H. prostrata which was associated with enhanced TPH remediation of these two members of Proteaceae family. These results indicated that B. seminuda, C. truncata, and H. prostrata wild plant species could be suitable candidates for the rhizoremediation of TPH-contaminated soil

The Large Quark Mass Expansion of Gamma (Z^0 -> hadrons) and Gamma(tau^- -> nu_tau + hadrons) in the Order alpha_s^3

We present the analytical $\alpha_{s}^3$ correction to the $Z^{0}$ decay rate into hadrons. We calculate this correction up to (and including) terms of the order $(m_Z^2/m_{top}^2)^3$ in the large top quark mass expansion. We rely on the technique of the large mass expansion of individual Feynman diagrams and treat its application in detail. We convert the obtained results of six flavour QCD to the results in the effective theory with five active flavours, checking the decoupling relation of the QCD coupling constant. We also derive the large charm quark mass expansion of the semihadronic $\tau$ lepton decay rate in the $\alpha_{s}^3$ approximation.Comment: Postscript generation repaired, The complete postscript file of this article, including figures, is now available at ftp://nikhefh.nikhef.nl/pub/preprints/H94-30.ps.g

Calculations of binding energies and masses of heavy quarkonia using renormalon cancellation

We use various methods of Borel integration to calculate the binding ground energies and masses of b-bbar and t-tbar quarkonia. The methods take into account the leading infrared renormalon structure of the hard+soft part of the binding energies E(s), and of the corresponding quark pole masses m_q, where the contributions of these singularities in M(s) = 2 m_q + E(s) cancel. Beforehand, we carry out the separation of the binding energy into its hard+soft and ultrasoft parts. The resummation formalisms are applied to expansions of m_q and E(s) in terms of quantities which do not involve renormalon ambiguity, such as MSbar quark mass, and alpha_s. The renormalization scales are different in calculations of m_q, E(s) and E(us). The MSbar mass of b quark is extracted, and the binding energies of t-tbar and the peak (resonance) energies for (t+tbar) production are obtained.Comment: 23 pages, 8 double figures, revtex4; the version to appear in Phys.Rev.D; extended discussion between Eqs.(25) and (26); the paragraph between Eqs.(32) and (33) is new and explains the numerical dependence of the residue parameter on the factorization scale; several new references were added; acknowledgments were modified; the numerical results are unchange

Ground-state properties of tubelike flexible polymers

In this work we investigate structural properties of native states of a simple model for short flexible homopolymers, where the steric influence of monomeric side chains is effectively introduced by a thickness constraint. This geometric constraint is implemented through the concept of the global radius of curvature and affects the conformational topology of ground-state structures. A systematic analysis allows for a thickness-dependent classification of the dominant ground-state topologies. It turns out that helical structures, strands, rings, and coils are natural, intrinsic geometries of such tubelike objects

Mitigation of petroleum-hydrocarbon-contaminated hazardous soils using organic amendments:A review

The term “Total petroleum hydrocarbons” (TPH) is used to describe a complex mixture of petroleum-based hydrocarbons primarily derived from crude oil. Those compounds are considered as persistent organic pollutants in the terrestrial environment. A wide array of organic amendments is increasingly used for the remediation of TPH-contaminated soils. Organic amendments not only supply a source of carbon and nutrients but also add exogenous beneficial microorganisms to enhance the TPH degradation rate, thereby improving the soil health. Two fundamental approaches can be contemplated within the context of remediation of TPH-contaminated soils using organic amendments: (i) enhanced TPH sorption to the exogenous organic matter (immobilization) as it reduces the bioavailability of the contaminants, and (ii) increasing the solubility of the contaminants by supplying desorbing agents (mobilization) for enhancing the subsequent biodegradation. Net immobilization and mobilization of TPH have both been observed following the application of organic amendments to contaminated soils. This review examines the mechanisms for the enhanced remediation of TPH-contaminated soils by organic amendments and discusses the influencing factors in relation to sequestration, bioavailability, and subsequent biodegradation of TPH in soils. The uncertainty of mechanisms for various organic amendments in TPH remediation processes remains a critical area of future research. © 2021 Elsevier B.V

Magnetic Field Amplification in Galaxy Clusters and its Simulation

We review the present theoretical and numerical understanding of magnetic field amplification in cosmic large-scale structure, on length scales of galaxy clusters and beyond. Structure formation drives compression and turbulence, which amplify tiny magnetic seed fields to the microGauss values that are observed in the intracluster medium. This process is intimately connected to the properties of turbulence and the microphysics of the intra-cluster medium. Additional roles are played by merger induced shocks that sweep through the intra-cluster medium and motions induced by sloshing cool cores. The accurate simulation of magnetic field amplification in clusters still poses a serious challenge for simulations of cosmological structure formation. We review the current literature on cosmological simulations that include magnetic fields and outline theoretical as well as numerical challenges.Comment: 60 pages, 19 Figure

Heavy baryon properties with NLO accuracy in perturbative QCD

We present an analysis of the static properties of heavy baryons at next-to-leading order in the perurbative expansion of QCD. We obtain analytical next-to-leading order three-loop results for the two-point correlators of baryonic currents with one finite mass quark field for a variety of quantum numbers of the baryonic currents. We consider both the massless limit and the HQET limit of the correlator as special cases of the general finite mass formula and find agreement with previous results. We present closed form expressions for the moments of the spectral density. We determine the residues of physical baryon states using sum rule techniques.Comment: 43 pages in LaTeX, including 3 figure

Cardiomyocytes from human pluripotent stem cells: from laboratory curiosity to industrial biomedical platform

Cardiomyocytes from human pluripotent stem cells (hPSCs-CMs) could revolutionise biomedicine. Global burden of heart failure will soon reach USD $90bn, while unexpected cardiotoxicity underlies 28% of drug withdrawals. Advances in hPSC isolation, Cas9/CRISPR genome engineering and hPSC-CM differentiation have improved patient care, progressed drugs to clinic and opened a new era in safety pharmacology. Nevertheless, predictive cardiotoxicity using hPSC-CMs contrasts from failure to almost total success. Since this likely relates to cell immaturity, efforts are underway to use biochemical and biophysical cues to improve many of the ~ 30 structural and functional properties of hPSC-CMs towards those seen in adult CMs. Other developments needed for widespread hPSC-CM utility include subtype specification, cost reduction of large scale differentiation and elimination of the phenotyping bottleneck. This review will consider these factors in the evolution of hPSC-CM technologies, as well as their integration into high content industrial platforms that assess structure, mitochondrial function, electrophysiology, calcium transients and contractility. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel