bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beta-1 adrenergic receptors modulate pacemaker activity of mouse sino-atrial myocytes through L-type Cav1.3 channels
Authors: Torre E , Mesirca P , Mangoni ME 
Published: May 2021

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Doctoral program in Biology and Biotechnologies
b1- and b2- adrenergic receptors (ARs) are co-expressed in different regions of the heart. The b2/ b1 expression ratio is higher in the sino-atrial node (SAN) than in atria and ventricles, but the specific contribution of either type of receptor to modulation of pacemaker activity is still not well established. Specific stimulation of b2-ARs in rabbit SAN myocytes is associated with a positive shift of the pacemaker "funny" current (If) activation curve. However, previous studies showed that L-type Cav1.3 channels play an important role in the generation of cardiac pacemaker activity by contributing to the diastolic depolarization (DD) in SAN myocytes. Since Cav1.3 channels are positively regulated by b-ARs activation2, we investigated which is the main b-ARs isoform that modulates Cav1.3-mediated ICaL andthe pacemaker activity of SAN myocytes. To address this point, we recorded spontaneous activity and Cav1.3-mediated ICaL from mouse SAN myocytes. We found that the positive chronotropic effect of the non-selective b-AR agonist isoproterenol (ISO, 0.1mM) was decreased by the b1-ARs antagonist CGP-20712 (0.3mM) and the b2-ARs antagonist ICI-118,551 (1mM) by -18% and -9%, respectively. Perfusion of CGP-20712 strongly reduced the positive chronotropic effect induced by ISO. Finally, we recorded Cav1.3-mediated L-type currents in presence of the b1-ARs antagonist. CGP-20712 reduced the basal Cav1.3-mediated ICaL. Furthermore, the increase in Cav1.3-mediated ICaL by isoproterenol was abolished during b1-ARs inhibition by CGP-20712. In conclusion, these preliminary data show that b1- and b2-ARs differently modulate the spontaneous activity of mouse SAN myocytes. In addition, b1-ARs play a predominant role in the adrenergic regulation of L-type Cav1.3 channels to increase pacemaker activity. Future studies will be performed to clarify the role of b2-ARs antagonist on Cav1.3-mediated ICaL and the functional relationships between b-ARs and Cav1.3 channels.
Calcium/calmodulin-dependent protein kinase II stimulates the inward rectifier potassium current in beta-adrenergic adaptation of ventricular cardiomyocytes
Authors: Kiss D , Hezso T , Dienes CS , Kovacs ZS , Torok ZS , Szentandrassy N , Horvath B , Banyasz T , Nanasi PP , Magyar J 
Published: May 2021

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): NEW NATIONAL EXCELLENCE PROGRAM OF THE MINISTRY FOR INNOVATION AND TECHNOLOGY FROM THE SOURCE OF THE NATIONAL RESEARCH, DEVELOPMENT AND INNOVATION FUND.

Introduction and purpose
Acute β-adrenergic receptor (β-AR) stimulation shortens
the ventricular action potential (AP). This effect is mainly regulated by the β-
adrenergic stimulation of the cardiac potassium currents. Our aim was to investigate
the extent of calcium/calmodulin-dependent protein kinase II (CaMKII) involvement in
mediating the effect of β-AR activation on the inward rectifier potassium current – I K1 .

Methods
We carried out our experiments on isolated cardiomyocytes originating
from canine left ventricles. The inward rectifier potassium current – I K1 was measured
under a "canonical" AP under action potential voltage clamp conditions.

Data were collected in four study groups
[1] Control conditions (CTRL)
[2] Inhibition of CaMKII with 1 µM KN-93 (KN-93)
[3] Inhibition of PKA with 3 µM H-89 (H-89)
[4] Acute β-adrenergic stimulation with 10 nM isoproterenol (ISO)
[5] β-adrenergic stimulation with CaMKII inhibition (KN-93 + ISO)
[6] β-adrenergic stimulation with PKA inhibition (H-89 + ISO)
[7] β-adrenergic stimulation with inhibited PKA and CaMKII (KN-93 + H-89 + ISO)

Results
I K1 current amplitude did not differ among the studied groups, the total
carried charge however was significantly, about 30 % larger in the ISO group
compared to CTRL, and about 20 % larger compared to KN-93 + ISO. Under beta-
adrenergic stimulation, I K1 starts to activate earlier during the AP plateau. I K1 density
was about 3 times greater both at +20 mV and at 0 mV membrane potential under
the command "canonical" AP in ISO compared to CTRL. Similarly, I K1 density was
about 60 % and 90 % larger at +20 mV and at 0 mV, respectively, in KN-93 + ISO
compared to KN-93.
Similar results have been obtained by conventional voltage-clamp technique.

Conclusion
Based on the results of our researches the CaMKII activation plays an
important role in β -adrenergic stimulation the I K1 potassium current.
Mexiletine rescues the mixed phenotype in SCN5A-1795insD hiPSC-CMs
Authors: Nasilli G , Yiangou L , Palandri C , Verkerk AO , Davis RP , Casini S , Remme CA 
Published: May 2021

Abstract

Funding Acknowledgements
Type of funding sources: None.

Background
The sodium channel blocker mexiletine can reduce late sodium current (INa) in patients with LQT3 syndrome, and additionally restore the decreased peak INa associated with SCN5A loss of function mutations.

Purpose
To investigate whether mexiletinecan rescue the mixed phenotype associated with the SCN5A-1795insD mutation in human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs).

Methods and Results
HEK293 cells transfected with SCN5A-1795insD and SCN5A-WT and hiPSC-CMs from a patient carrying the SCN5A-1795insD mutation were incubated with a therapeutic dose of mexiletine (10 µM) or vehicle (H2O) for 48h. Peak INa, late INa and action potential (AP) properties were assessed by patch-clamp analysis. In HEK-293 cells transfected with SCN5A-1795insD or SCN5A-WT, exposure to mexiletine caused a significant increase in peak INa, in addition to a small increase in late INa in HEK-293 cells transfected with SCN5A-1795insD. In 1795insD hiPSC-CMs, peak INa was significantly increased whereas late INa was unchanged after mexiletine treatment. Accordingly, mexiletine increased AP upstroke velocity in SCN5A-1795insD hiPSC-CMs (indicating a rescue of INa availability), while AP amplitude, resting membrane potential and AP duration were unaffected.

Conclusions
Chronic treatment with a therapeutic concentration of mexiletine is capable of rescuing the mixed phenotype in SCN5A-1795insD hiPSC-CMs.
Genome comparison of three lager yeasts reveals key genes affecting yeast flocculation during beer fermentation
Authors: Zhou Xuefei , Suo Jingyi , Liu Chunfeng , Niu Chengtuo , Zheng Feiyun , Li Qi , Wang Jinjing 
Published: May 2021

ABSTRACT
Yeast flocculation plays an essential role in industrial application. Appropriate flocculation of yeast cells at the end of fermentation benefits the cell separation in production, which is an important characteristic of lager yeast for beer production. Due to the complex fermentation environment and diverse genetic background of yeast strains, it is difficult to explain the flocculation mechanism and find key genes that affect yeast flocculation during beer brewing. By analyzing the genomic mutation of two natural mutant yeasts with stronger flocculation ability compared to the parental strain, it was found that the mutated genes common in both mutants were enriched in protein processing in endoplasmic reticulum, membrane lipid metabolism and other pathways or biological processes involved in stress responses. Further functional verification of genes revealed that regulation of RIM101 and VPS36 played a role in lager yeast flocculation under the brewing condition. This work provided new clues for improving yeast flocculation in beer brewing.
Nuku, a family of primate retrocopies derived from KU70
Authors: Rowley Paul A , Ellahi Aisha , Han Kyudong , Patel Jagdish Suresh , Van Leuven James T , Sawyer Sara L 
Published: May 2021

Abstract
The gene encoding the ubiquitous DNA repair protein, Ku70p, has undergone extensive copy number expansion during primate evolution. Gene duplications of KU70 have the hallmark of long interspersed element-1 mediated retrotransposition with evidence of target-site duplications, the poly-A tails, and the absence of introns. Evolutionary analysis of this expanded family of KU70-derived “NUKU” retrocopies reveals that these genes are both ancient and also actively being created in extant primate species. NUKU retrocopies show evidence of functional divergence away from KU70, as evinced by their altered pattern of tissue expression and possible tissue-specific translation. Molecular modeling predicted that amino acid changes in Nuku2p at the interaction interface with Ku80p would prevent the assembly of the Ku heterodimer. The lack of Nuku2p-Ku80p interaction was confirmed by yeast two-hybrid assay, which contrasts the robust interaction of Ku70p-Ku80p. While several NUKU retrocopies appear to have been degraded by mutation, NUKU2 shows evidence of positive natural selection, suggesting that this retrocopy is undergoing neofunctionalization. Although Nuku proteins do not appear to antagonize retrovirus transduction in cell culture, the observed expansion and rapid evolution of NUKUs could be being driven by alternative selective pressures related to infectious disease or an undefined role in primate physiology.
Analysis of Caenorhabditis elegans acetylcholine synthesis mutants reveals a temperature-sensitive requirement for cholinergic neuromuscular function
Authors: Duerr Janet S , McManus John R , Crowell John A , Rand James B 
Published: May 2021

Abstract
In Caenorhabditis elegans, the cha-1 gene encodes choline acetyltransferase (ChAT), the enzyme that synthesizes the neurotransmitter acetylcholine. We have analyzed a large number of cha-1 hypomorphic mutants, most of which are missense alleles. Some homozygous cha-1 mutants have approximately normal ChAT immunoreactivity; many other alleles lead to consistent reductions in synaptic immunostaining, although the residual protein appears to be stable. Regardless of protein levels, neuromuscular function of almost all mutants is temperature-sensitive, i.e., neuromuscular function is worse at 25° than at 14°. We show that the temperature effects are not related to acetylcholine release, but specifically to alterations in acetylcholine synthesis. This is not a temperature-dependent developmental phenotype, because animals raised at 20° to young adulthood and then shifted for 2 h to either 14° or 25° had swimming and pharyngeal pumping rates similar to animals grown and assayed at either 14° or 25°, respectively. We also show that the temperature-sensitive phenotypes are not limited to missense alleles; rather, they are a property of most or all severe cha-1 hypomorphs. We suggest that our data are consistent with a model of ChAT protein physically, but not covalently, associated with synaptic vesicles; and there is a temperature-dependent equilibrium between vesicle-associated and cytoplasmic (i.e., soluble) ChAT. Presumably, in severe cha-1 hypomorphs, increasing the temperature would promote dissociation of some of the mutant ChAT protein from synaptic vesicles, thus removing the site of acetylcholine synthesis (ChAT) from the site of vesicular acetylcholine transport. This, in turn, would decrease the rate and extent of vesicle-filling, thus increasing the severity of the behavioral deficits.
Estimation of the spawning stock and recruitment relationship ofOctopus vulgarisin Asturias (Bay of Biscay) with generalized depletion models: implications for the applicability of MSY
Authors: Roa-Ureta Rubén H , Fernández-Rueda M del Pino , Acuña José Luis , Rivera Antonella , González-Gil Ricardo , García-Flórez Lucía 
Published: May 2021

AbstractWe developed a new type of generalized depletion model adapted to the rapid life cycle of Octopus vulgaris and the data collection framework put in place in its co-managed small-scale fishery (SSF) in Asturias, northwest Spain. The model uses weekly data from 19 seasons to estimate annual recruitment and female spawners emigration out of the vulnerable stock to attend to their broods. The matched annual spawners-recruitment (SR) magnitudes are then used as observations in a non-Bayesian hierarchical inference framework. The Shepherd SR model was selected among three alternatives. The stock has a high degree of density-dependence, leading to overcompensation. The estimated SR model has an unstable equilibrium point, driving the stock to deterministic cyclic fluctuations under small disturbances. Under those conditions the maximum sustainable yield (MSY) is not applicable, lending further credence to Sidney Holt’s opposition to the MSY as a basis for the elaboration of fishery management objectives, with potentially wide relevance to the management of SSF and cephalopod fisheries. We argue that harvest rates based on mean latent productivity, a concept that includes the MSY as a special case, are more adequate and sustainable for fluctuating stocks.
Simple Modules for Affine Vertex Algebras in the Minimal Nilpotent Orbit
Authors: Futorny Vyacheslav , Hernández Morales Oscar Armando , Ramirez Luis Enrique 
Published: May 2021

Abstract
We explicitly construct, in terms of Gelfand–Tsetlin tableaux, a new family of simple positive energy representations for the simple affine vertex algebra $V_k(\mathfrak{s}\mathfrak{l}_{n+1})$ in the minimal nilpotent orbit of $\mathfrak{s}\mathfrak{l}_{n+1}$. These representations are quotients of induced modules over the affine Kac–Moody algebra $\widehat{\mathfrak{s}\mathfrak{l}}_{n+1} $ and include in particular all admissible simple highest weight modules and all simple modules induced from $\mathfrak{s}\mathfrak{l}_2$. Any such simple module in the minimal nilpotent orbit has bounded weight multiplicities.
Pyrethroid Resistance and Fitness Cost Conferred by the super-kdr Mutation M918L in Rhopalosiphum padi (Hemiptera: Aphididae)
Authors: Wang Kang , Zhao Jun Ning , Bai Jiao Yang , Shang Yun Zhu , Zhang Si Qian , Hou Yi Fan , Chen Mao Hua , Han Zhao Jun 
Published: May 2021

Abstract
Pyrethroid insecticides have been widely utilized for insect pest control. Target-site resistance is one of the major mechanisms explaining pest resistance to pyrethroids. This study quantified pyrethroid resistance and fitness cost conferred by the voltage-gated sodium channel (VGSC) M918L mutation in Rhopalosiphum padi. Six s-kdr-SS and six s-kdr-RS parthenogenetic lineages were established from the same field population and were reared in the laboratory without exposure to pesticides for more than one year. Enzyme activity analysis demonstrated that metabolic resistance had no impact on these lineages. Bioassays showed that the M918L mutation strongly affected pyrethroid efficiency, conferring moderate resistance to bifenthrin (type I) (39.0-fold) and high resistance to lambda-cyhalothrin (type II) (194.7-fold). Compared with the life table of s-kdr-SS lineages, s-kdr-RS lineages exhibited a relative fitness cost with significant decreases in longevity and fecundity. Meanwhile, competitive fitness was measured by blending various ratios of s-kdr-SS and s-kdr-SS aphids. The results indicated that M918L-mediated resistance showed a significant fitness cost in the presence of wild aphids without insecticide pressure. The fitness cost strongly correlated with the initial resistance allele frequency. This work characterized the novel s-kdr M918L mutation in R. padi, defined its function in resistance to different types of pyrethroids, and documented that the M918L-mediated resistance has a significant fitness cost.
Trends and Opportunities in Tick-Borne Disease Geography
Authors: Lippi Catherine A , Ryan Sadie J , White Alexis L , Gaff Holly D , Carlson Colin J 
Published: May 2021

Abstract
Tick-borne diseases are a growing problem in many parts of the world, and their surveillance and control touch on challenging issues in medical entomology, agricultural health, veterinary medicine, and biosecurity. Spatial approaches can be used to synthesize the data generated by integrative One Health surveillance systems, and help stakeholders, managers, and medical geographers understand the current and future distribution of risk. Here, we performed a systematic review of over 8,000 studies and identified a total of 303 scientific publications that map tick-borne diseases using data on vectors, pathogens, and hosts (including wildlife, livestock, and human cases). We find that the field is growing rapidly, with the major Ixodes-borne diseases (Lyme disease and tick-borne encephalitis in particular) giving way to monitoring efforts that encompass a broader range of threats. We find a tremendous diversity of methods used to map tick-borne disease, but also find major gaps: data on the enzootic cycle of tick-borne pathogens is severely underutilized, and mapping efforts are mostly limited to Europe and North America. We suggest that future work can readily apply available methods to track the distributions of tick-borne diseases in Africa and Asia, following a One Health approach that combines medical and veterinary surveillance for maximum impact.
Dosimetric impact of rotational setup errors in volumetric modulated arc therapy for postoperative cervical cancer
Authors: Tsujii Katsutomo , Ueda Yoshihiro , Isono Masaru , Miyazaki Masayoshi , Teshima Teruki , Koizumi Masahiko 
Published: May 2021

Abstract
We aimed to evaluate the impact of rotational setup errors on the doses received during postoperative volumetric-modulated arc therapy (VMAT) for cervical cancer. Overall, 121 cone-beam computed tomography (CBCT) sets from 20 patients were rigidly registered to reference computed tomography (CT) sets based on bony landmarks. The rotational setup errors (pitch, yaw and roll) were calculated. Then, 121 CT sets involving rotational setup errors were created, and the dose distribution in these CT sets were recalculated. The recalculated dosimetric parameters for the clinical target volume (CTV) and organs at risk (OAR) were compared to the reference values, and the correlation coefficients between the dosimetric parameter differences and rotational setup errors were calculated. Only the pitch setup error was moderately correlated with CTV coverage (r ≥ 0.40) and strongly correlated with V45 for the bladder (r ≥ 0.91) and V40 for the rectum, small bowel and bone marrow (r ≥ 0.91). The maximum dosimetric difference in a single fraction and overall fractions was −1.59% and −0.69% in D98 for the CTV, 11.72% and 5.17% in V45 for the bladder and −8.03% and −4.68% in V40 for the rectum, respectively. In conclusion, rotational setup errors only slightly impact dose coverage during postoperative cervical cancer VMAT. However, the pitch setup error occasionally affected the doses received by the bladder or the rectum in the overall fraction when the error was systematic. Thus, rotational setup errors should be corrected by adjusting six-degree-of-freedom (DOF) couches to reduce dosimetric differences in the OARs.
The time delay of CLASS B1600+434 from VLA multi-frequency and polarization monitoring
Authors: Biggs A D 
Published: May 2021

ABSTRACT
We present an analysis of archival multi-frequency Very Large Array monitoring data of the two-image gravitational lens system CLASS B1600+434, including the polarization properties at 8.5 GHz. From simulating radio light curves incorporating realistic external variability in image A, we find time delays consistent at 1σ for all frequencies and in total flux density and polarization. The delay with the smallest uncertainty (total flux density at 8.5 GHz) is $42.3^{+2.0}_{-1.8}$ (random) ±0.5 (systematic) d (equivalent to 42.3 ± 2.1 d) whereas combining all delay estimates gives a slightly higher value of 43.6 ± 1.2 d. Both values are lower than the previously published radio result and inconsistent with that found in the optical. H0 determination is difficult due to the complicated lensing mass and the lack of constraints provided by only two images. However, analysis of archival Very Long Baseline Interferometry data reveals jets in this system for the first time, the orientations of which provide model constraints. In addition, extremely sensitive maps made from combining all the monitoring data reveal faint emission on one side of the lensing galaxy that we speculate might be the result of a naked-cusp lensing configuration. Finally, we find clear evidence for external variability in image A on time-scales of days to years, the frequency dependence of which supports the previous conclusion that this is predominantly due to microlensing. External variability seems to be completely absent in image B and this does not appear to be a consequence of scatter-broadening in the interstellar medium of the lensing galaxy.
Ionized gas properties of the extreme starburst galaxy Haro 11 – temperature and metal abundance discrepancies
Authors: Menacho V , Östlin G , Bik A , Adamo A , Bergvall N , Della Bruna L , Hayes M , Melinder J , Rivera-Thorsen T E 
Published: May 2021

ABSTRACT
We use high quality VLT/MUSE data to study the kinematics and the ionized gas properties of Haro 11, a well-known starburst merger system and the closest confirmed Lyman continuum leaking galaxy. We present results from integrated line maps, and from maps in three velocity bins comprising the blueshifted, systemic, and redshifted emission. The kinematic analysis reveals complex velocities resulting from the interplay of virial motions and momentum feedback. Star formation happens intensively in three compact knots (knots A, B, and C), but one, knot C, dominates the energy released in supernovae. The halo is characterized by low gas density and extinction, but with large temperature variations, coincident with fast shock regions. Moreover, we find large temperature discrepancies in knot C, when using different temperature-sensitive lines. The relative impact of the knots in the metal enrichment differs. While knot B is strongly enriching its closest surrounding, knot C is likely the main distributor of metals in the halo. In knot A, part of the metal enriched gas seems to escape through low density channels towards the south. We compare the metallicities from two methods and find large discrepancies in knot C, a shocked area, and the highly ionized zones, that we partially attribute to the effect of shocks. This work shows, that traditional relations developed from averaged measurements or simplified methods, fail to probe the diverse conditions of the gas in extreme environments. We need robust relations that include realistic models where several physical processes are simultaneously at work.