bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical, genetic and functional analysis of R562S-Kv7.1 mutation associated with long QT syndrome type 1
Authors: Svecova O , Kula R , Chmelikova L , Hosek J , Synkova I , Novotny T , Bebarova M 
Published: May 2021

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): Ministry of Education, Youth and Sports of the Czech Republic

Introduction
Loss-of-function variants of the KCNQ1 gene are associated with life-threatening arrhythmogenic long QT syndrome type 1 (LQT1). This gene encodes structure of the slow delayed rectifier potassium channel (IKs). Some functional characteristics of the C-terminal KCNQ1 variant c.1686G &gt; C (p.R562S) have been recently described [1]. However, accumulation of the current under beta-adrenergic stimulation, essential for shortening the action potential duration during exercise, have not been tested.

Purpose
The aim of this study was to analyse clinical and genetic characteristics of the R562S variant in our patients and to investigate impact of the variant on IKs channel function with a special focus on reactivity of the channels on beta-adrenergic stimulation.

Methods
The clinical diagnosis was established according to ESC Guidelines including QTc analysis at rest and after exercise. The molecular genetics diagnostics followed according to current practices (the massive parallel sequencing since 2016). The biophysical analysis was performed on Chinese hamster ovary cells (CHO) by the whole cell patch clamp technique at 37 °C. CHO cells were transiently transfected with wild type (WT) and/or R562S human IKs channels (KCNQ1/KCNE1/Yotiao, 1:2:4). Cyclic adenosine monophosphate (cAMP, 200 µM) and okadaic acid (OA, 0.2 µM) in the pipette solution were used to simulate the beta-adrenergic stimulation. In the confocal microscopy experiments, expression of Yotiao was omitted and GFP-tagged KCNQ1 was used.

Results
The variant R562S-Kv7.1 has been identified in 7 heterozygous carriers from 3 putatively unrelated families in the Czech Republic. The genotype was associated with long QT syndrome phenotype (prolonged QTc, symptoms including syncopes and aborted cardiac arrest) in some of the carriers. The basic functional analysis proved that both homozygous and heterozygous R562S channels are expressed on the cell membrane (confocal microscopy) and carry IKs (whole cell patch clamp) which agrees with the recently published data on this variant. Importantly, reactivity on beta-adrenergic stimulation was absent in both homozygous and heterozygous R562S channels (n = 14 and 8, respectively), but present in the wild-type channels (increase by 51.4 ± 11.1 % at 120-s cAMP/OA diffusion; n = 12).

Conclusions
The R562S-Kv7.1 variant may be a founder LQT1 variant in our region which will be further investigated in the future. This variant impairs response of IKs channel to beta-adrenergic stimulation. Absence of this essential regulation may considerably aggravate the channel dysfunction and, thus, may result in life-threatening arrhythmias in R562S carriers during exercise.
Culture conditions effect properties of the Na+/K+-ATPase pump current in hiPSC cardiomyocytes
Authors: Ismaili D , Gurr K , Horvath A , Hansen A , Eschenhagen T , Christ T 
Published: May 2021

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): BMBF

Background
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) provide an opportunity to study human cardiac physiology and pathophysiology or to use for cardiac repair as well as for cardiovascular drug testing. Suitability for these purposes requires generating hiPSC cardiomyocytes that share typical electrophysiological properties of adult human cardiomyocytes. In the human heart the Na+/K+-ATPase pump current plays a major role in the regulation of contractile force and electrical stability. So far there are no data about Na+/K+-ATPase pump current function in hiPSC cardiomyocytes available.

Purpose
We compared the properties of Na+/K+-ATPase pump current in hiPSC cardiomyocytes from conventional monolayers (ML) culture to three-dimensional engineered heart tissue (EHT).

Methods
HiPSC cardiomyocytes differentiated from in-house control hiPSC cell line C25 were dissociated from ML and EHT culture. Na+/K+-ATPase pump current was recorded by whole-cell patch clamp technique at 37°C. The holding potential was -40 mV to inactivate sodium current. Current was measured in the absence of K+ and after adding 5.4 mM potassium chloride (KCL). Na+/K+-ATPase pump current was defined as the ouabain (10 µM) sensitive current. Voltage-dependency of Na+/K+-ATPase pump was determined using rectangular voltage pulses (increasing from -120 mV to +60 mV).

Results
Outwardly directed Na+/K+-ATPase pump could be recorded at -40 mV when KCL was added to the bath solution (5.4 mM). Currents were larger in EHT than in ML (0.8 ± 0.08 pA/pF n = 16 ML vs. 1.29 ± 0.13 pA/pF n = 28 EHT; p &lt; 0.05). The K+-induced outward current was abolished by ouabain. The K+- and ouabain-sensitive current densities were similar in size (0.84 ± 0.11 pA/pF n = 16 ML vs. 1.12 ± 0.11 pA/pF n = 28 EHT for ouabain), indicating the measured K+-induced current was Na+/K+-ATPase pump current. Increasing extracellular K+-concentration in a stepwise manner (0,25 mM, 0,5 mM, 1 mM, 2 mM, 5,4 mM and 10 mM) showed a concentration-dependent relationship to Na+/K+-ATPase pump current with throughout higher current densities in EHT compared to ML (sensitivity to K+ not different). Na+/K+-ATPase pump current showed expected voltage-dependency with +0.23 ± 0.13 pA/pF at -120 mV and +0.89 ± 0.16 pA/pF at +60 mV (n= 18) in ML and with +0.71 ± 0.17 pA/pF at -120 mV and +1.2 ± 0.2 pA/pF at +60 mV (n= 24) in EHT.

Conclusion
HiPSC cardiomyocytes possess Na+/K+-ATPase pump current. Current density is in the range of human cardiomyocytes in EHT but substantially smaller in ML. 3D culturing may be needed to develop the physiological properties of Na+/K+-ATPase pump current.
Electro-mechanical and mechano-electrical interactions in healthy and drug-induced LQTS rabbit hearts
Authors: Lewetag R , Hornyik T , Jacobi S , Moss R , Pilia N , Menza M , Perez-Feliz S , Bode C , Seemann G , Odening KE 
Published: May 2021

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): German Research Foundation

Background
Electrical and mechanical heterogeneities and their interactions (electro-mechanical and mechano-electrical coupling; EMC / MEC) are essential for normal cardiac function. Alterations in these can result in increased arrhythmia formation.

Purpose
With this study, we aim to investigate EMC and MEC under physiological and pathological conditions to better understand their roles in arrhythmia development.

Methods
Multi-channel ECG and TPM-MRI were used to measure regional differences in EMC in healthy ("control") and IKr-blocker E-4031 induced acute LQTS ("E-4031") rabbit hearts in vivo. MEC was studied in both groups by acutely changing mechanical function (increased preload by 6 ml/kg BW bolus of NaCl).

Results
In acute LQTS hearts (E-4031 10µg/kg bolus + 1µg/(kg*min) iv), cardiac repolarization was markedly prolonged compared to healthy controls, (p &lt; 0.0001; n = 13), with increased QT-dispersion (Max-Min), a marker for regional heterogeneity of repolarization (p &lt; 0.01; n = 13).
Changing electrical function by E-4031 resulted in changes of mechanical features (EMC): in acute LQTS hearts, diastolic longitudinal velocity (Vz) was reduced in all basal (p = 0.003; n = 19) and 4/6 mid segments (p = 0.006; n = 19). Longitudinal diastolic TTP was prolonged significantly in 5/6 basal and 4/6 mid segments by E-4031. These alterations led to an increased apicobasal heterogeneity of longitudinal contraction duration (basal-apical Vz_dia_TTP [ms] 2.9 ± 10.6 vs. 21.1 ± 21.3; p = 0.01; n = 9).
Increased preload acutely prolonged QTc in both "control" and "E-4031" hearts (‘control’ 156.6 ± 11.6 to 198.3 ± 20.3; p &lt; 0.0001 vs. ‘E-4031’ 193.9 ± 19.6 to 256.0 ± 37.5; p &lt; 0.0001; n = 13) (MEC). This effect was more pronounced in "E-4031" acute LQTS hearts than in healthy hearts (Figure 1; delta QTc [ms] ‘control’ 41.6 ± 14.9 vs. ‘E4031’ 62.1 ± 32.1; p &lt; 0.006, n = 13). QT-dispersion (Max-Min) was increased significantly upon mechanical change only in "E-4031" (‘E-4031’ 25.8 ± 5.5 to 32.7 ± 12.3; p &lt; 0.03, n = 13).

Conclusion
E-4031-induced changes in electrical function resulted in marked alterations in mechanical features via EMC. Similarly, acute changes in mechanical function (increased preload) resulted in electrical changes via MEC. Importantly, QT-prolonging effects of acutely increased preload, as well as its effects on regional heterogeneity of repolarization, were more pronounced in E-4031-induced acute LQTS hearts, indicating that cardiac repolarization in LQTS may be more susceptible to acute MEC effects than in healthy hearts. Acute MEC effects may thus play an additional role in LQT-related arrhythmogenesis. Abstract Figure.
MFAP4 deletion attenuates the progression of angiotensin II-induced atrial fibrosis and atrial fibrillation
Authors: Wang Huibo , Liu Mingxin , Wang Xixing , Shuai Wei , Fu Hui 
Published: May 2021

Abstract

Aims
Microfibrillar-associated protein 4 (MFAP4) is associated with atrial fibrillation (AF). Nevertheless, the specific role and underlying mechanism of MFAP4 in atrial fibrosis, the hallmark of AF, remain undefined. This study aims to elucidate the role of MFAP4 in the regulation of atrial fibrosis and to explore the underlying mechanism.

Methods and results
This study used MFAP4 knockout (MFAP4-KO) mice and their wild-type (WT) littermates to investigate the effect of angiotensin II (Ang II) (2000 ng/kg/min for 3 weeks) on atrial fibrosis and susceptibility to AF in terms of morphology, histology, electrophysiology, and molecular biology. MFAP4 deletion in mice did not alter cardiac structure and function at baseline. After treatment with Ang II, the MFAP4-KO mice showed a decreased left atrial enlargement and fibrosis, slowed atrial conduction, and reduced susceptibility to AF compared with the WT mice. Regarding the mechanism, we found that MFAP4 deletion markedly inhibited activated focal adhesion kinase (FAK)-mediated PI3K-AKT signalling and MEK1/2-ERK1/2 signalling after Ang II treatment.

Conclusions
Overall, our study showed that loss of MFAP4 attenuates Ang II-mediated left atrial fibrosis and dilation and decreases susceptibility to AF by decreasing the phosphorylation of FAK and inhibiting the activation of the PI3K-AKT and MEK1/2-ERK1/2 signalling pathways. These findings further indicate that targeting MFAP4 may be a potential upstream therapeutic option for atrial fibrosis and AF.
Effect of seasonality on physico-chemical and microbiological properties of nicastrese milk and artisanal cheese
Authors: Pino Alessandra , Liotta Luigi , Caggia Cinzia , Chiofalo Vincenzo , De Nardo Floro , Zumbo Alessandro , Todaro Aldo , Randazzo Cinzia Lucia 
Published: May 2021

ABSTRACT
Nicastrese is an indigenous Italian goat breed reared in the Calabria region under semi-extensive practices. From January to June, the milk yield of 400 multiparous Nicastrese goats was evaluated. In addition, tank milk and ripened cheese samples were subjected to physico-chemical and microbiological analyses with the aim to assess the effect of the seasonality on quality parameters. The volatile organic compounds profile of the ripened Nicastrese cheese samples was evaluated. Results showed that the seasonality had a significant effect on milk fat, lactose, urea, citric acid contents and acidity. Microbiological analysis of tank milk samples revealed variability among the different microbial groups investigated except for Escherichia coli. In addition, faecal coliforms and Listeria spp. were never detected. Regarding 60 days ripened cheese samples, almost all microbial groups showed a significant decrease during the analysed period, with the exception of Enterobacteria. It is interesting to note that Escherichia coli and Listeria spp. were not detected in any cheese sample investigated, confirming the cheese safety. Overall, volatile organic compounds, detected on cheese samples, decreased trough the investigated period and this behavior could be related to the feeding quality and to the milk's goat nutritional components.
Elastoplastic source model for microseismicity and acoustic emission
Authors: Minakov Alexander , Yarushina Viktoriya 
Published: May 2021

SUMMARYThe microseismic events can often be characterized by a complex non-double couple source mechanism. Recent laboratory studies recording the acoustic emission during rock deformation help connecting the components of the seismic moment tensor with the failure process. In this complementary contribution, we offer a mathematical model which can further clarify these connections. We derive the seismic moment tensor based on classical continuum mechanics and plasticity theory. The moment tensor density can be represented by the product of elastic stiffness tensor and the plastic strain tensor. This representation of seismic sources has several useful properties: (i) it accounts for incipient faulting as a microseismicity source mechanism, (ii) it does not require a pre-defined fracture geometry, (iii) it accounts for both shear and volumetric source mechanisms, (iv) it is valid for general heterogeneous and anisotropic rocks and (v) it is consistent with elasto-plastic geomechanical simulators. We illustrate the new approach using 2-D numerical examples of seismicity associated with cylindrical openings, analogous to wellbore, tunnel or fluid-rich conduit and provide a simple analytic expression of the moment density tensor. We compare our simulation results with previously published data from laboratory and field experiments. We consider four special cases corresponding to ‘dry’ elastically homogeneous and elastically heterogeneous isotropic rocks, ‘dry’ transversely isotropic rocks and ‘wet’ isotropic rocks. The model highlights theoretical links between stress state, geomechanical parameters and conventional representations of the moment tensor such as Hudson source type parameters.
Surgical management of an aortic root dilatation in a patient suffering from Hunter syndrome
Authors: Poitier Bastien , Amrane Mourad , Bruneval Patrick , Achouh Paul 
Published: May 2021

Abstract
Hunter syndrome is a rare disease leading to glycosaminoglycan accumulation in tissues. Multiple organs are involved, but prognosis is mainly conditioned by cardiac and respiratory failures. Cardiac valvular impairment is quite common but aortic root dilatation is rarely described. This article covers a case of surgical root replacement due to aortic valve insufficiency and aortic root dilatation documented with magnetic resonance and computed tomography angiographies. Anatomic pathology reported both aortic valve and aorta with mucoid overload and elastic fibre depletion. These patients do have a risk of aortic root dilatation, which justifies periodic monitoring. Diagnosis must be made using indexed measures.
Constructing Non-Semisimple Modular Categories With Relative Monoidal Centers
Authors: Laugwitz Robert , Walton Chelsea 
Published: May 2021

Abstract
This paper is a contribution to the construction of non-semisimple modular categories. We establish when Müger centralizers inside non-semisimple modular categories are also modular. As a consequence, we obtain conditions under which relative monoidal centers give (non-semisimple) modular categories, and we also show that examples include representation categories of small quantum groups. We further derive conditions under which representations of more general quantum groups, braided Drinfeld doubles of Nichols algebras of diagonal type, give (non-semisimple) modular categories.
The Case of (Digital) Wagner
Authors: Kivy Peter 
Published: May 2021

Abstract
The article argues that the proposal to produce a digital Ring cycle was not just ethically and economically misguided, but aesthetically misguided as well. Orchestras produces performances, and the proposed digital Ring would not have produced genuine performances of the Ring operas. Nevertheless, a digital musical work might allow us to reconstruct, and in that way recover and gain access to, a full-fledged musical work.
Investigation of the introduction and dissemination of vanB Enterococcus faecium in the Capital Region of Denmark and development of a rapid and accurate clone-specific vanB E. faecium PCR
Authors: Pinholt Mette , Mollerup Sarah , Boye Kit , Worning Peder , Holzknecht Barbara Juliane , Nygaard Sanne , Nielsen Karen Leth , Hasman Henrik , Roer Louise , Hammerum Anette M. , Westh Henrik , Schønning Kristian 
Published: May 2021

Abstract

Background
During 2018–19, an increase of vanB vancomycin-resistant Enterococcus faecium (VREfm) was observed in the Capital Region of Denmark. vanA/vanB PCR performed directly on rectal swabs is accurate in detection of vanA; however, the positive predictive value for vanB-positive samples is low because of the presence of vanB in non-enterococcal gut commensals.

Objectives
We investigated the epidemiology and clonal relatedness of vanB VREfm from the period 2015–19 and describe the application of a clone-specific vanB VREfm PCR assay for rapid and accurate detection of vanB VREfm in rectal screening samples.

Methods
vanB VREfm were investigated using epidemiological data and WGS data. The SeqSphere+ software was used to analyse MLST and cgMLST, and de novo assemblies were annotated to determine insertion sites for the vanB transposon (Tn1549). A clone-specific vanB VREfm PCR assay was designed to detect the sequence bridging Tn1549 and the E. faecium chromosome (araA2) in the dominant cluster.

Results
Two hundred and seventy-five vanB VREfm isolates were identified, of which 76% were identified in 2019. A dominant cluster (Cluster 1, n = 204, 74%), six minor clusters and 15 singletons were identified. All Cluster 1 isolates and six non-Cluster 1 isolates had Tn1549 integrated into araA2. In 2019, the PCR assay would have detected 92% of all rectal screening samples containing vanB VREfm.

Conclusions
vanB VREfm increased due to the introduction and nosocomial transmission of the successful Cluster 1. The clone-specific PCR assay detected vanB VREfm outbreak isolates in rectal screening samples rapidly and accurately.
Automatic design system for generating routing layout of tubes, hoses, and cable harnesses in a commercial truck
Authors: Kim Saekyeol , Kim Shinyu , Choi Taeheok , Kwon Taejoon , Lee Tae Hee , Lee Kwangrae 
Published: May 2021

Abstract
Although many routing algorithms have been developed, it is difficult for designers in the automotive industry to adopt them because of the complicated preliminary steps that are required. This study presents a systematic framework for generating the routing layout of the tubes, hoses, and cable harnesses in a commercial truck. The routing layout design problem in a commercial truck is analysed and defined. For routing operations, a sequential graph-based routing algorithm is employed to rapidly provide a routing solution. Because a reference routing layout design does not exist in most engineering problems, a cell-based genetic algorithm combined with a modified maze algorithm is employed to generate a reference design. To consider the clamping condition of the routing components, a new fitness function in the genetic algorithm is implemented. The numerical study shows that the proposed routing algorithm provides a better reference routing layout design than the conventional algorithm. The proposed automatic design system was applied to the routing layout design problem of a commercial truck. It was demonstrated that the proposed framework satisfies all industrial practitioners’ functional requirements and provides a systematic method of solving the routing layout design problem, considering all its characteristics.
Current status of medical treatment for gastroenteropancreatic neuroendocrine neoplasms and future perspectives
Authors: Hijioka Susumu , Morizane Chigusa , Ikeda Masafumi , Ishii Hiroshi , Okusaka Takuji , Furuse Junji 
Published: May 2021

Abstract
Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumors. In this review, we summarize the results of various clinical trials that have been conducted to investigate the efficacy and safety of various therapeutic options for NENs. Based on the encouraging results obtained from these trials, various therapeutic options have been established for the treatment of NENs, including somatostatin analogs (SSAs), molecularly targeted drugs and cytotoxic agents. In addition, peptide receptor radionucleotide therapy has recently been evaluated for the treatment of various NENs. We also discuss the approach for selecting the appropriate drugs and sequence of treatment with the various drug classes, as recommended by different treatment guidelines. Finally, we discuss the scope for future research in this field, especially into the merits of combination therapy with molecularly targeted drugs plus SSAs, along with ongoing studies.
Cost-effectiveness of trifluridine/tipiracil against nivolumab for heavily pretreated metastatic gastric cancer in Japan
Authors: Takushima Yusuke , Igarashi Ataru , Yoshihara Hiroshi , Shitara Kohei , Doi Toshihiko 
Published: May 2021

Abstract

Objective
Nivolumab and trifluridine/tipiracil have significantly improved the overall survival of patients with heavily pretreated metastatic gastric cancer in different placebo-controlled phase III trials. Accordingly, nivolumab and trifluridine/tipiracil have been approved and recommended for patients with heavily pretreated metastatic gastric cancer in Japan. The aim of this study was to assess the cost-effectiveness of trifluridine/tipiracil against nivolumab.

Methods
A partitioned survival model, which consisted of three health states, namely, ‘pre-progression,’ ‘post-progression,’ and ‘death,’ was constructed. Efficacy and safety data were derived from the TAGS and ATTRACTION-2 trials. Costs were estimated based on the standard clinical pathway and national insurance fee schedules. One-way and probabilistic sensitivity analyses were performed. The threshold value was set to JPY 7 500 000 (USD 68 182) for each quality-adjusted life-year.

Results
The expected median overall survival and progression-free survival were 5.59 and 1.99 months for trifluridine/tipiracil and 5.26 and 1.55 months for nivolumab, respectively. The quality-adjusted life-year and expected costs per patient were 0.4379 and JPY 2 054 625 (USD 18 678) for trifluridine/tipiracil and 0.5295 and JPY 5 018 148 (USD 45 620) for nivolumab, respectively. The expected median progression-free survival and overall survival were equivalent with trifluridine/tipiracil and nivolumab, whereas the expected quality-adjusted life-year with trifluridine/tipiracil was slightly lower than that with nivolumab. However, trifluridine/tipiracil reduced the total treatment cost by JPY 2 963 523 (USD 26 996) compared with that of nivolumab. The incremental cost-effectiveness ratio of nivolumab versus trifluridine/tipiracil was JPY 32 352 489 (USD 294 113) per quality-adjusted life-year gained.

Conclusions
Trifluridine/tipiracil was more cost-effective than nivolumab for patients with heavily pretreated metastatic gastric cancer.