bluuebunny/crossref_metadata_2025 huggingface dataset:
Taurine blunts doxorubicin cardiotoxicity: chronic and acute effects
Authors: Cobet V , Tacu L , Hajawi O , Rotaru V , Frasineac V , Braniste A
Published: May 2021

Funding Acknowledgements

Type of funding sources: None.

Aim. To study the functional statement of the isolated heart inherent to doxorubicin cardiotoxicity under the chronic and acute action of taurine.

Material and methods. Doxorubicin (Dx) cardiotoxicity manifested by heart failure development was reproduced classically by anthracycline i/p administration in rats in cumulative dose of 16 mg/kg (4 mg/kg four times during 2 weeks) – Dx series. Series with chronic action of taurine (Tr) included rats receiving this aminoacid daily per os during Dx administration (100 mg/kg) – Dx + Tr series. Rats of both series were sacrificed by euthanasia and the isolated heart was perfused by Krebs solution according to Langendorff (isovolumic heart) and Neely-Rovetto (working heart) methods in conditions of diverse hemodynamic and neuroendocrine efforts applying. Acute action of taurine was studied during its infusion in the perfusate of isolated hearts in final concentration of 40 µM. The hearts of intact rats constituted the control series.

Results. Chronic action of taurine has identified certain important functional benefits, the most important being underlined beneath.  The first, taurine reversed the negative inotropic effect of isolated heart on endothelin-1 (ET-1) action (10-7 M), detected in Dx series and manifested by both systolic pressure of left ventricle (LV) and cardiac output fall by about 9,1%. Taurine assured increase of these indices during ET-1 stimulation. The second, Tr notably improved both isovolumic relaxation and contraction of myocardium exhibited by significant enhancement of Veragut index (118,6 ± 9,6 vs 94,8 ± 6,5 1/sec), +dP/dPmax (8389 ± 445 vs 7216 ± 363 mm Hg/sec) and -dP/dTmax (7526 ± 378 vs 5684 ± 322 mm Hg/sec) during efforts with volume and resistance. The third, Tr significantly decreased LV end diastolic pressure (LVSDP) when coronary pressure of isovolumic heart elevated by 50% (from 80 up to 120 cm H20 column): 16,2 ± 1,2 vs 18,8 ± 1,4 mm Hg. Acute Tr action manifested by: (i) significant LVSDP diminution during 30 min of ischemia (52,4 ± 3,1 vs 63,7 ± 4,4 mm Hg) and on 45th min of reperfusion (18,3 ± 1,3 vs 22,8 ± 1,4 mm Hg), (ii) increased time of LV extrasystole appearance when the glucose content of Krebs solution was reduced by 50% (28,6 ± 2,8 vs 22,5 ± 2,4 min), and (iii) increased time of LV tachyarrhythmia appearance when the potassium content of Krebs solution raised up to 6,5 meq/L (9,2 ± 0,5 vs 6,9 ± 0,3 min).

Conclusion. Taurine, a natural calcium modulator of the heart, notably improves functional reserves of the myocardium exposed to cardiotoxic action of Dx, and could be seen as a relevant remedy of primary and secondary prophylaxis of Dx induced heart failure in oncologic patients.
Directed graph mapping is able to distinguish between the true and false rotors in a complex in-silico excitation pattern
Authors: Van Nieuwenhuyse E , Martinez-Mateu L , Saiz J , Panfilov A V , Vandersickel N
Published: May 2021

Funding Acknowledgements

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Supported in part by Dirección General de Polı́tica Cientı́fica de la Generalitat Valenciana PROMETEU 2020/043

Background

In realistic in-silico studies (Figure1, top row) it was shown that phase mapping PM (Figure 1, A) can detect the correct rotor as well as phantom rotors as an artefact of interpolation or due to the far field (Figure 1, B). After interpretation of the LAT, the far field detections could not be distinguished from the true rotor driving the excitation pattern. This can contribute to failure in Atrial Fibrillation (AF) ablation procedures.

Objective

We tested if the recently developed tool Directed Graph mapping (DGM) is less prone to far-field effects and interpolation artefacts than PM on the same in-silico data. DGM represents the excitation pattern as a directed network, from which the rotational activity is detected as cycles in that network.

Methods

Starting from the electrograms (EGMs) of the 64 electrode basket catheter, we interpolated to 957 equidistant electrodes and calculated local activation times (LATs) of the interpolated EGMs (Figure 1, C). We varied the minimal allowed conduction velocity and calculated the corresponding networks for the complete simulation time. Detections were considered as correct if they were located in the same region of the true core of the phasemaps. The false detections were classified in multiple different regions (Figure 1, D).

Results

We find that by proper choice of CVs in the graphs it is possible to achieve a 80% detection of true rotors with 26% detection of false rotors. Reducing restrictions on the CVs increased the detection rate of the false rotors. False rotors due to artifacts were not detected by DGM (Figure 1, last row).

Conclusion

DGM is able to distinguish between true and far field rotors. False detections due to interpolation artifacts as seen in the PM protocol were not observed. The velocity limits in the graph construction play a keyrole in eliminating the far field effects. Abstract Figure 1
Genotype-phenotype association in patients with arrhythmic variant of non-compaction cardiomyopathy
Authors: Rineiska N , Komissarova S , Chakova N , Dolmatovich T , Niyazova S
Published: May 2021

Funding Acknowledgements

Type of funding sources: None.

Purpose. To evaluate the genotype-phenotype association in Belarusian patients with non-compaction cardiomyopathy (NCCM) and clinically significant ventricular arrhythmias.

Methods. The study included 170 unrelated pts with NCCM prospectively observed in the RSPC "Cardiology", who underwent 24-hour Holter ECG monitoring for 12 months after entering the study. The median follow-up was 36 months [6; 152,0]. The median age of pts was 42 [18; 69] years, men – 63,2%. The arrhythmic phenotype of NCСM was diagnosed by the presence of unexplained syncope; nonsustained ventricular tachycardia, defined as ≥3 consecutive ventricular contractions lasting <30 seconds with a frequency of ≥120 bpm; the presence of ≥ 500 ventricular premature beats (VPB) per day. The diagnosis of NCCM was established on the basis of the following criteria: 1) Echocardiography of the R. Jenni criteria; 2) CMR of the S. Petersen and A. Jaquier criteria. The mutations search in the coding sequences of 174 genes was performed in 30 unrelated pts with NCCM using next generation sequencing (NGS).

Results. In 76 out of 170 (44,7%) pts, clinically significant arrhythmias were the leading manifestation of the disease. Nonsustained VT was recorded in 54 (71,1%) pts, sustained VT – in 15 (19,7%) pts, VPB more than 500 per day – in 50 (65,8%), chronic AF with episodes of nonsustained VT was noted in 34 (44,7%) pts. During the follow-up period (median follow-up of 36 months), devices (ICD/CRT-D) were implanted in 15 (19,7%) pts, appropriate shocks were observed in two of them; three pts died, among which SCD occurred in one patient with CRT-D therapy, which was ineffective in stopping sustained VT. NGS sequencing revealed 40 changes in the nucleotide sequence (5 pathogenic mutations, 30 variants with uncertain significance (VUS), 5 new substitutions) in 27 genes in 26 (86,7%) probands. The proportion of mutations in sarcomeric proteins genes was 26,9%, and in ion channel proteins genes was 23,1%. Nucleotide changes in genes encoding structural proteins accounted for 11,5%. In 38,5% of cases, not one, but two or more rare mutations were detected, and in 30,8% – amino acid replacements were found in proteins of different functional classes.

Conclusions. The frequency of multiple mutations was higher (38,5%) in the group of pts with the arrhythmic NCCM phenotype. In the group of pts with implantable devices (ICD/CRT-D), mutations in the genes of sarcomeric proteins were observed more often. The genetic characteristics of pts, along with their clinical characteristics, are markers of a high risk of developing life-threatening arrhythmias and can be additionally used for predicting adverse events in pts with NCCM, as well as for early diagnosis of the disease in their relatives.
UBLED AF study for safety and efficacy between uninterrupted edoxaban, warfarin and rivaroxaban for AF/Fl ablation patients
Authors: Kumar N , Elbanhawy N , Chalil S , Abozguia K
Published: May 2021

Funding Acknowledgements

Type of funding sources: None.

Introduction

Catheter ablation in patients with atrial fibrillation (AF)/atrial flutter carries a risk of thromboembolism and major bleeding. Oral anticoagulation is advised for prevention of thromboembolic complications.

Purpose

In light of recent prospective trial data on the safety and efficacy of uninterrupted edoxaban in patients undergoing AF/flutter ablation, real-world data was aimed to compared.

Methods

A total of 228 patients who underwent AF/atrial flutter ablation over 14 months at our centre were retrospectively analyzed.  All patients received uninterrupted oral anticoagulation for at least 4 weeks prior to ablation and 3 months post-ablation. Both bleeding and thromboembolic events were assessed at 24 hours comparing patients on warfarin, rivaroxaban and edoxaban.

Results

Mean age of patients were 68.5 +/- 8 years in the warfarin group (N = 86), 63.4 +/- 10.6 years; in the edoxaban group (N = 63) and 62.3 +/- 11.6 years in the rivaroxaban group (N = 79). CHADSVASc scores were 2.43 +/- 1.34, 1.68 +/- 1.34 and 1.64 +/- 1.38 respectively. The mean left atrial sizes were 42.7 +/- 6.8 mm, 42.0 +/- 6 mm and 41.1 +/- 6.5 mm respectively. The study endpoint was death, acute thromboembolism or major bleeding. There was 1 pericardial effusion (1.2%) in the warfarin group, 1 pericardial effusion and 1 transient ischaemic attack (2.5%) in the rivaroxaban group and 1 pericardial effusion needing drainage (1.6%) in the edoxaban group. There were no significant differences in the study endpoints between groups.

Conclusion

This real-world study demonstrated no significant difference in safety and efficacy between uninterrupted edoxaban, warfarin and rivaroxaban in patients undergoing AF/flutter ablation.
Aminophylline affects the cardiac rat inward rectifier potassium current in a dual way
Authors: Ramalho NJD , Svecova O , Kula R , Simurdova M , Simurda J , Bebarova M
Published: May 2021

Funding Acknowledgements

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

Introduction

Aminophylline, a bronchodilator used in clinical practice to treat namely severe astma attacks, often induces atrial fibrillation in patients. Modifications of the inward rectifier potassium current IK1 are known to play a role in the genesis of fibrillation.

Purpose

We aimed to investigate the effect of aminophylline at clinically-relevant concentrations between 3 and 100 µM on IK1 in isolated rat ventricular myocytes.

Methods

Experiments were performed by the whole cell patch clamp technique on enzymatically isolated rat right ventricular myocytes at room temperature. IK1 was measured as the current sensitive to 100 µM Ba2+.

Results

We observed a dual steady-state effect of aminophylline at most of the applied concentrations. Either inhibition or activation was apparent in individual cells during application of aminophylline at a given concentration. The smaller was magnitude of the control IK1, the more likely was activation of the current in the presence of aminophylline and vice versa (tested at 10 and 30 µM). The effect was voltage-independent and fully reversible during the subsequent wash-out. The mean aminophylline effect was inhibitory at all concentrations (10, 15, 4, and 23%-inhibition at -50 mV at 3, 10, 30, and 100 µM, respectively). Using a modified version of the population model of IK1 channels that we published before, the dual effect can be explained by interaction of aminophylline with two channel populations in a different way, the first one being inhibited and the second one being activated by the drug. Considering various fractions of these two channel populations in individual cells, varying effects observed in the measured cells can be simulated.

Conclusions

Aminophylline at clinically-relevant concentrations affects IK1 in rat ventricular myocytes in a dual way, showing both the steady-state activation and inhibition in various cells, even at the same concentration. It may be related to a different effect of the drug on various Kir2.x subunits forming the heterotetrameric IK1 channels present at the cell membrane of a single cell.
IP3R1/GRP75/VDAC1 complex mediated endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling
Authors: Liu T , Yuan M , Gong M , He J , Zhang Z , Meng L , Tse G , Zhao Y , Bao Q , Zhang Y , Yuan M , Liu X , Wang F , Li G
Published: May 2021

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): National Natural Science Foundation of China

Background

Mitochondrial oxidative stress is an important mechanism of atrial remodeling and atrial fibrillation (AF) in the setting of diabetes. Currently, endoplasmic reticulum (ER) stress is regarded as the key link from homeostasis to dysfunction, and is a central feature of metabolic diseases such as type 2 diabetes. However, the molecular mechanisms underlying these processes have not been fully elucidated.

Objective

To explore the potential role of ER stress-mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes.

Methods

 Mouse atrial cardiomyocytes (HL-1 cells) , type 2 diabetic rats and GRP75 conditional knockout mice were used as models systems. These findings were correlated with biomarker findings in human diabetic patients with confirmed atrial fibrillation.

Results

 In the diabetic rat atria, significant ER stress was observed. Treatment with tunicamycin (TM), an ER stress agonist, mass spectrometry (MS) demonstrated many known ER stress and calmodulin proteins, including Heat shock protein family A (Hsp70) member (Hspa) 5 (GRP78) and Hspa9 (GRP75) and in situ proximity ligation assay (PLA) indicated that TM led to increased protein expression of the IP3R1 (inositol 1,4,5-trisphosphate receptors 1)/GRP75 (glucose-regulated protein 75)/VDAC1 (voltage-dependent anion channel 1) complex in HL-1 cells. Silencing of GRP75 using siRNA in HL-1 cells and GRP75 conditional knockout in our mouse model led to impaired calcium transport from the ER to mitochondria, and alleviated mitochondrial oxidative stress and calcium overload. Moreover, GRP75 deficiency attenuates atrial remodeling and AF progression in Myh6-Cre+/Hspa9flox/flox + TM mice.

Conclusions

 The IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress plays an important role in diabetic atrial remodeling. Abstract Figure
The increase of extracellular Ca2+ from physiological concentrations to hypercalcemia impairs sino-atrial automaticity
Authors: Torrente AG , Fossier L , Baudot M , Torre E , Bidaud I , Mesirca P , Mangoni ME
Published: May 2021

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): ESC FRM Lefoulon Delalande

Aims

To investigate whether extracellular hypercalcemia alters the conduction through L-type Ca2+ channels (LTCCs), impairing the pacemaker activity of the heart.

Introduction

In the sino-atrial node (SAN), membrane currents and the dynamics of intracellular Ca2+ ([Ca2+]i) generate the pacemaker activity of the heart. SAN dysfunctions (SNDs) harm heart automaticity and have been associated with abnormal dynamics of [Ca2+]i. The LTCCs, Cav1.2 and Cav1.3 carry the main Ca2+ influx of SAN cells, which is necessary to sustain [Ca2+]i dynamics. Modified extracellular Ca2+ ([Ca2+]o) could alter Ca2+ influx through these channels. For example, cancer and hyperparathyroidism can raise [Ca2+]o, causing an extracellular hypercalcemia that could alter [Ca2+]i dynamics and impair SAN activity and heart automaticity.

Methods and results

To test this hypothesis, we measured contractions, [Ca2+]i release and L-type Ca2+ current (ICa,L) in spontaneous cells of the murine SAN. Then, we recorded rate and propagation of the spontaneous action potentials (APs) generated by the SAN tissue ex-vivo.

In spontaneously beating SAN cells, we observed that the modification of [Ca2+]o affected [Ca2+]i and cell contractility through changes of ICa,L. In particular, the increase of [Ca2+]o dysregulated pacemaker activity, likely through excessive Ca2+ influx mediated by Cav1.2.

[Ca2+]o increase to hypercalcemia induced arrhythmia also in the intact SAN tissues, activating ectopic leading regions of pacemaking and impairing conduction towards the atria.

Conclusions

Hypercalcemia causes excessive Cav1.2-mediated Ca2+ influx, which alters [Ca2+]I leading to pacemaker impairment. Modulation of LTCC may reduce pacemaker dysfunctions, preventing SND progression.
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

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

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

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

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

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

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

We 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

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

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

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

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

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

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.
Potential and sky coverage for off-axis fringe tracking in optical long baseline interferometry
Authors: Boskri Abdelkarim , Petrov Romain G , El Halkouj Thami , Hadjara Massinissa , Leftley James , Benkhaldoun Zouhair , Cruzalèbes Pierre , Ziad Aziz , Carbillet Marcel
Published: May 2021

The spectacular results provided by the second-generationVLTI instruments GRAVITY and MATISSE on active galactic nuclei (AGN) trigger and justify a strong increase in the sensitivity limit of optical interferometers. A key component of such an upgrade is off-axis fringe tracking. To evaluate its potential and limitations, we describe and analyse its error budget including fringe sensing precision and temporal, angular and chromatic perturbations of the piston. The global tracking error is computed using standard seeing parameters for different sites, seeing conditions and telescope sizes for the current GRAVITY Fringe Tracker (GFT) and a new concept of Hierarchical Fringe Tracker. Then, it is combined with a large catalogue of guide star candidates from Gaia to produce sky coverage maps that give the probability to find a usable off-axis guide star in any part of the observable sky. These maps can be used to set the specifications of the system, check its sensitivity to seeing conditions, and evaluate the feasibility of science programs. We check the availability of guide stars and the tracking accuracy for a large set of 15 799 Quasars to confirm the feasibility of a large program on Broad Line Regions in the K band with the GFT and show how it can be extended to the L, M, and N bands. Another set of 331 well-characterized nearby AGNs shows the high potential of MATISSE for imaging and characterization of the dust torus in the N band under off-axis tracking on both Unit Telescopes and Auxiliary Telescopes.
Broad Concordance in the Spatial Distribution of Adaptive and Neutral Genetic Variation across an Elevational Gradient in Deer Mice
Authors: Schweizer Rena M , Jones Matthew R , Bradburd Gideon S , Storz Jay F , Senner Nathan R , Wolf Cole , Cheviron Zachary A
Published: May 2021

When species are continuously distributed across environmental gradients, the relative strength of selection and gene flow shape spatial patterns of genetic variation, potentially leading to variable levels of differentiation across loci. Determining whether adaptive genetic variation tends to be structured differently than neutral variation along environmental gradients is an open and important question in evolutionary genetics. We performed exome-wide population genomic analysis on deer mice sampled along an elevational gradient of nearly 4,000 m of vertical relief. Using a combination of selection scans, genotype−environment associations, and geographic cline analyses, we found that a large proportion of the exome has experienced a history of altitude-related selection. Elevational clines for nearly 30% of these putatively adaptive loci were shifted significantly up- or downslope of clines for loci that did not bear similar signatures of selection. Many of these selection targets can be plausibly linked to known phenotypic differences between highland and lowland deer mice, although the vast majority of these candidates have not been reported in other studies of highland taxa. Together, these results suggest new hypotheses about the genetic basis of physiological adaptation to high altitude, and the spatial distribution of adaptive genetic variation along environmental gradients.
Microfluidics-Based Bioassays and Imaging of Plant Cells
Authors: Yanagisawa Naoki , Kozgunova Elena , Grossmann Guido , Geitmann Anja , Higashiyama Tetsuya
Published: May 2021

Many plant processes occur in the context of and in interaction with a surrounding matrix such as soil (e.g. root growth and root–microbe interactions) or surrounding tissues (e.g. pollen tube growth through the pistil), making it difficult to study them with high-resolution optical microscopy. Over the past decade, microfabrication techniques have been developed to produce experimental systems that allow researchers to examine cell behavior in microstructured environments that mimic geometrical, physical and/or chemical aspects of the natural growth matrices and that cannot be generated using traditional agar plate assays. These microfabricated environments offer considerable design flexibility as well as the transparency required for high-resolution, light-based microscopy. In addition, microfluidic platforms have been used for various types of bioassays, including cellular force assays, chemoattraction assays and electrotropism assays. Here, we review the recent use of microfluidic devices to study plant cells and organs, including plant roots, root hairs, moss protonemata and pollen tubes. The increasing adoption of microfabrication techniques by the plant science community may transform our approaches to investigating how individual plant cells sense and respond to changes in the physical and chemical environment.
The Holstein–Lewis humerus shaft fracture in children: are they different from adults?
Authors: Singh Vivek , Hayes Hannah V. , Kazemi Namdar , Dey Sukalyan , Parikh Shital N.
Published: May 2021

Spiral fractures in the distal third humerus shaft (Holstein–Lewis fracture pattern) have been associated with high risk of radial nerve palsy in adults and surgical treatment is recommended as the treatment of choice to remove the entrapped nerve from the fracture site. But this association and treatment approach has not been evaluated in pediatric humerus shaft fractures. In a retrospective study, 38 pediatric patients with Holstein–Lewis fracture configuration were identified after a review of radiographs of 1609 patients with humerus shaft fracture. Age at initial presentation, sex, mechanism of injury, side involved, presence of any associated injuries, neurovascular status, radial nerve status, fracture management, and any complications were noted. Thiry-three (86.8%) patients with mean age 10.1 ± 3.7 years were successfully treated by closed methods. Five patients (13.2%) with mean age 15.2 ± 2.6 years underwent surgical treatment. Contrary to adults, no children/adolescents had radial nerve palsy at presentation. Radiographic healing was acceptable in all cases at latest follow-up. Holstein–Lewis fracture behaves differently in children with no increased risk of radial nerve palsy. Majority can be treated conservatively. The thick periosteum in children may offer protection to the radial nerve and may be responsible for the success of closed treatment.
A Anchoring Technique Using Long Bent Rods for Open Reduction of Thoracolumbar Dislocation
Authors: Guo Xiaohui , Wang Baocang , An Yi , Jin Xin , Guo Zhiliang , Han Shuo , Huo Yongxin , Liu Lanze
Published: May 2021

Objective:

The purpose of this study was to evaluate the effectiveness of a novel surgical open reduction method for thoracolumbar dislocation.

Materials and Methods:

This study included a total of 15 patients of thoracolumbar dislocation. All patients underwent posterior thoracolumbar open reduction and fixation using this technique. Preoperative x-ray, computed tomography (CT), and magnetic resonance imaging were used to evaluate the dislocation. The American Spinal Injury Association grade of spinal cord injury before and afer the operation were record. All patients were followed up for 2 years, and x-ray, CT were used to observe postoperative reduction and fusion.

Results:

Postoperative x-ray and CT images of all patients indicated good recovery of the spinal sequence, and no neurological deterioration or surgically related complications occurred. All patients were followed up for 2 years, no patients were lost to follow-up. During the follow-up period, x-ray and CT images showed no complications related to internal fixation such as fracture and loosening of screws and rods were found.

Conclusion:

A anchoring technique using long bent rods is a safe, simple, accurate, and easy to replicate and implement method, which can be applied in the surgical treatment for thoracolumbar dislocation.