Cell-specific models of hiPSC-CMs developed by the gradient-based parameter optimization method fitting two different action potential waveforms.

Parameter optimization (PO) methods to determine the ionic current composition of experimental cardiac action potential (AP) waveform have been developed using a computer model of cardiac membrane excitation. However, it was suggested that fitting a single AP record in the PO method was not always successful in providing a unique answer because of a shortage of information. We found that the PO method worked perfectly if the PO method was applied to a pair of a control AP and a model output AP in which a single ionic current out of six current species, such as I, I, I, I, I or I was partially blocked in silico.

Ionic Mechanisms of Propagated Repolarization in a One-Dimensional Strand of Human Ventricular Myocyte Model.

Although repolarization has been suggested to propagate in cardiac tissue both theoretically and experimentally, it has been challenging to estimate how and to what extent the propagation of repolarization contributes to relaxation because repolarization only occurs in the course of membrane excitation in normal hearts. We established a mathematical model of a 1D strand of 600 myocytes stabilized at an equilibrium potential near the plateau potential level by introducing a sustained component of the late sodium current (). By applying a hyperpolarizing stimulus to a small part of the strand, we succeeded in inducing repolarization which propagated along the strand at a velocity of 1~2 cm/s.

Efficacy of antimicrobial therapy in patients with uncomplicated acute colonic diverticulitis: an updated systematic review and meta-analysis.

The need for antimicrobial therapy for uncomplicated acute diverticulitis of the colon remains controversial. We conducted a systematic review of the efficacy of antimicrobial agents against this disease, including new randomized controlled trials (RCTs) reported in recent years, and evaluated their efficacy using a meta-analytic approach. RCTs were searched using PubMed, EMBASE, Google Scholar, Cochrane Library, Ichushi-Web, and eight registries.

Gradient-based parameter optimization method to determine membrane ionic current composition in human induced pluripotent stem cell-derived cardiomyocytes.

Premature cardiac myocytes derived from human induced pluripotent stem cells (hiPSC-CMs) show heterogeneous action potentials (APs), probably due to different expression patterns of membrane ionic currents. We developed a method for determining expression patterns of functional channels in terms of whole-cell ionic conductance (G) using individual spontaneous AP configurations. It has been suggested that apparently identical AP configurations can be obtained using different sets of ionic currents in mathematical models of cardiac membrane excitation.

Improved CRISPR genome editing using small highly active and specific engineered RNA-guided nucleases.

Streptococcus pyogenes (Spy) Cas9 has potential as a component of gene therapeutics for incurable diseases. One of its limitations is its large size, which impedes its formulation and delivery in therapeutic applications. Smaller Cas9s are an alternative, but lack robust activity or specificity and frequently recognize longer PAMs.

Evaluating the impact of biannual school-based and community-wide treatment on urogenital schistosomiasis in Niger.

Background: The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) coordinated a five-year study implemented in several countries, including Niger, to provide an evidence-base for programmatic decisions regarding cost-effective approaches to preventive chemotherapy for schistosomiasis control.

Methods: This was a cluster-randomised trial investigating six possible combinations of annual or biannual community-wide treatment (CWT), school-based treatment (SBT), and holidays from mass treatment over four years. The most intense arm involved two years of annual CWT followed by 2 years of biannual CWT, while the least intensive arm involved one year of annual SBT followed by a year without treatment and two more years of annual SBT.

The exercise intensity of square-stepping exercise in community-dwelling late elderly females.

[Purpose] Square-stepping exercise is recommended for elderly people, as it has a positive effect on cognitive and physical functions; however, few studies have examined the exercise intensity of square-stepping exercise. Therefore, we aimed to examine the exercise intensity of square-stepping exercise in community-dwelling late elderly females. [Participants and Methods] Study 1: The participants, constituting 12 community-dwelling late elderly females (age: 78.

Publisher Correction: The immune cell landscape in kidneys of patients with lupus nephritis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mechanisms Underlying Spontaneous Action Potential Generation Induced by Catecholamine in Pulmonary Vein Cardiomyocytes: A Simulation Study.

Cardiomyocytes and myocardial sleeves dissociated from pulmonary veins (PVs) potentially generate ectopic automaticity in response to noradrenaline (NA), and thereby trigger atrial fibrillation. We developed a mathematical model of rat PV cardiomyocytes (PVC) based on experimental data that incorporates the microscopic framework of the local control theory of Ca release from the sarcoplasmic reticulum (SR), which can generate rhythmic Ca release (limit cycle revealed by the bifurcation analysis) when total Ca within the cell increased. Ca overload in SR increased resting Ca efflux through the type II inositol 1,4,5-trisphosphate (IP) receptors (InsPR) as well as ryanodine receptors (RyRs), which finally triggered massive Ca release through activation of RyRs via local Ca accumulation in the vicinity of RyRs.

Advanced 3D Analysis and Optimization of Single-Molecule FISH in Muscle.

Single-molecule fluorescence in situ hybridization (smFISH) provides direct access to the spatial relationship between nucleic acids and specific subcellular locations. The ability to precisely localize a messenger RNA can reveal key information about its regulation. Although smFISH is well established in cell culture or thin sections, the utility of smFISH is hindered in thick tissue sections due to the poor probe penetration of fixed tissue, the inaccessibility of target mRNAs for probe hybridization, high background fluorescence, spherical aberration along the optical axis, and the lack of methods for image segmentation of organelles.

Methods for high-dimensional analysis of cells dissociated from cryopreserved synovial tissue.

Background: Detailed molecular analyses of cells from rheumatoid arthritis (RA) synovium hold promise in identifying cellular phenotypes that drive tissue pathology and joint damage. The Accelerating Medicines Partnership RA/SLE Network aims to deconstruct autoimmune pathology by examining cells within target tissues through multiple high-dimensional assays. Robust standardized protocols need to be developed before cellular phenotypes at a single cell level can be effectively compared across patient samples.

A new myofilament contraction model with ATP consumption for ventricular cell model.

A new contraction model of cardiac muscle was developed by combining previously described biochemical and biophysical models. The biochemical component of the new contraction model represents events in the presence of Ca-crossbridge attachment and power stroke following inorganic phosphate release, detachment evoked by the replacement of ADP by ATP, ATP hydrolysis, and recovery stroke. The biophysical component focuses on Ca activation and force (F ) development assuming an equivalent crossbridge.

Regulation of the glucose supply from capillary to tissue examined by developing a capillary model.

A new glucose transport model relying upon diffusion and convection across the capillary membrane was developed, and supplemented with tissue space and lymph flow. The rate of glucose utilization (J ) in the tissue space was described as a saturation function of glucose concentration in the interstitial fluid (C ), and was varied by applying a scaling factor f to J . With f = 0, the glucose diffusion ceased within ~20 min.

Short- and long-term outcomes after pancreaticoduodenectomy following total gastorectomy: Report of case series and literature review.

Purpose: Pancreaticoduodenectomy (PD) following gastrectomy (TG) should be considered challenging even currently although its procedure and clinical value have been being standardized. Short- and long-term outcomes as well as standard reconstruction method following these procedures remain unclear. In order to clarify these issues, we reviewed worldwide English literature and 4 of our own cases of PD for patients with previous TG.

Mechanisms underlying the volume regulation of interstitial fluid by capillaries: a simulation study.

Background: Control of the extracellular fluid volume is one of the most indispensable issues for homeostasis of the internal milieu. However, complex interdependence of the pressures involved in determination of fluid exchange makes it difficult to predict a steady-state tissue volume under various physiological conditions without mathematical approaches.

Methods: Here, we developed a capillary model based on the Starling's principle, which allowed us to clarify the mechanisms of the interstitial-fluid volume regulation.

Modeling analysis of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ mobilization under the control of glucagon-like peptide-1 in mouse pancreatic β-cells.

Glucagon-like peptide-1 (GLP-1) is an intestinally derived blood glucose-lowering hormone that potentiates glucose-stimulated insulin secretion from pancreatic β-cells. The secretagogue action of GLP-1 is explained, at least in part, by its ability to stimulate cAMP production so that cAMP may facilitate the release of Ca(2+) from inositol trisphosphate receptor (IP3R)-regulated Ca(2+) stores. However, a quantitative model has yet to be provided that explains the molecular mechanisms and dynamic processes linking GLP-1-stimulated cAMP production to Ca(2+) mobilization.

A human ventricular myocyte model with a refined representation of excitation-contraction coupling.

Cardiac Ca(2+)-induced Ca(2+) release (CICR) occurs by a regenerative activation of ryanodine receptors (RyRs) within each Ca(2+)-releasing unit, triggered by the activation of L-type Ca(2+) channels (LCCs). CICR is then terminated, most probably by depletion of Ca(2+) in the junctional sarcoplasmic reticulum (SR). Hinch et al.

Location of α-tocopherol and α-tocotrienol to heterogeneous cell membranes and inhibition of production of peroxidized cholesterol in mouse fibroblasts.

Background: α-Tocopherol (α-T) and α-tocotrienol (α-T3) are well recognized as lipophilic antioxidants. Nevertheless, there is limited knowledge on their location in heterogeneous cell membranes. We first investigated the distribution of α-T and α-T3 to the cholesterol-rich microdomains (lipid rafts and caveolae) of heterogeneous cell membranes by incubating these antioxidants with cultured mouse fibroblasts.

EAD and DAD mechanisms analyzed by developing a new human ventricular cell model.

It has long been suggested that the Ca(2+)-mechanisms are largely involved in generating the early afterdepolarization (EAD) as well as the delayed afterdepolarization (DAD). This view was examined in a quantitative manner by applying the lead potential analysis to a new human ventricular cell model. In this ventricular cell model, the tight coupled LCC-RyR model (CaRU) based on local control theory (Hinch et al.

A single acetylation of 18 S rRNA is essential for biogenesis of the small ribosomal subunit in Saccharomyces cerevisiae.

Biogenesis of eukaryotic ribosome is a complex event involving a number of non-ribosomal factors. During assembly of the ribosome, rRNAs are post-transcriptionally modified by 2'-O-methylation, pseudouridylation, and several base-specific modifications, which are collectively involved in fine-tuning translational fidelity and/or modulating ribosome assembly. By mass-spectrometric analysis, we demonstrated that N(4)-acetylcytidine (ac(4)C) is present at position 1773 in the 18 S rRNA of Saccharomyces cerevisiae.

Non-selective distribution of isomeric cholesterol hydroperoxides to microdomains in cell membranes and activation of matrix metalloproteinase activity in a model of dermal cells.

Cholesterol hydroperoxides (ChOOHs) are included as lipid peroxidation products in the skin exposed to ultraviolet (UV) light irradiation. They may exert physicochemical actions affecting biomembrane rigidity because cholesterol is one of the major components of cell membranes. We investigated the distribution of isomeric ChOOHs in heterogeneous cell membranes with different lipid profiles using mouse fibroblast NIH-3T3 cells as a model of the dermis.

Torsin mediates primary envelopment of large ribonucleoprotein granules at the nuclear envelope.

A previously unrecognized mechanism through which large ribonucleoprotein (megaRNP) granules exit the nucleus is by budding through the nuclear envelope (NE). This mechanism is akin to the nuclear egress of herpes-type viruses and is essential for proper synapse development. However, the molecular machinery required to remodel the NE during this process is unknown.