bluuebunny/crossref_metadata_2025 huggingface dataset:
Compartmentalized β1-adrenergic signalling synchronizes excitation–contraction coupling without modulating individual Ca2+ sparks in healthy and hypertrophied cardiomyocytes
Authors: Yang Hua-Qian , Zhou Peng , Wang Li-Peng , Zhao Yan-Ting , Ren Yu-Jie , Guo Yun-Bo , Xu Ming , Wang Shi-Qiang
Published: January 2020

Aims

β-adrenergic receptors (βARs) play pivotal roles in regulating cardiac excitation–contraction (E-C) coupling. Global signalling of β1ARs up-regulates both the influx of Ca2+ through sarcolemmal L-type Ca2+ channels (LCCs) and the release of Ca2+ from the sarcoplasmic reticulum (SR) through the ryanodine receptors (RyRs). However, we recently found that β2AR stimulation meditates ‘offside compartmentalization’, confining β1AR signalling into subsarcolemmal nanodomains without reaching SR proteins. In the present study, we aim to investigate the new question, whether and how compartmentalized β1AR signalling regulates cardiac E-C coupling.

Methods and results

By combining confocal Ca2+ imaging and patch-clamp techniques, we investigated the effects of compartmentalized βAR signalling on E-C coupling at both cellular and molecular levels. We found that simultaneous activation of β2 and β1ARs, in contrast to global signalling of β1ARs, modulated neither the amplitude and spatiotemporal properties of Ca2+ sparks nor the kinetics of the RyR response to LCC Ca2+ sparklets. Nevertheless, by up-regulating LCC current, compartmentalized β1AR signalling synchronized RyR Ca2+ release and increased the functional reserve (stability margin) of E-C coupling. In circumstances of briefer excitation durations or lower RyR responsivity, compartmentalized βAR signalling, by increasing the intensity of Ca2+ triggers, helped stabilize the performance of E-C coupling and enhanced the Ca2+ transient amplitude in failing heart cells.

Conclusion

Given that compartmentalized βAR signalling can be induced by stress-associated levels of catecholamines, our results revealed an important, yet unappreciated, heart regulation mechanism that is autoadaptive to varied stress conditions.
Impact of intrapulmonary-artery septation to pulmonary vein obstruction for two-lung Fontan
Authors: Ishidou Motonori , Ota Keisuke , Watanebe Kentaro , Koshiyama Hiroshi , Kanno Kazuyoshi , Ito Hiroki , Murata Masaya , Hirose Keiichi , Ikai Akio , Sakamoto Kisaburo
Published: January 2020

OBJECTIVES

Patients with unbalanced pulmonary artery (PA) growth and decreased unilateral pulmonary circulation are considered unsuitable candidates for the Fontan procedure. Following our previous study on the utility of intrapulmonary-artery septation for patients with PA hypoplasia, we investigated its use in patients with pulmonary venous obstruction (PVO).

METHODS

We recruited 42 patients who underwent intrapulmonary-artery septation for unilateral PA hypoplasia and/or PVO between 1998 and 2018 and classified them into no PVO or PVO group. We analysed overall survival, success of the Fontan procedure and data from catheterization and echocardiography. In PVO, we evaluated the functional lung area before the Fontan procedure and the relevance of this parameter to operative outcomes.

RESULTS

The PVO and no-PVO group included 24 and 18 patients, respectively. One patient in the no-PVO and 6 patients in the PVO group died during follow-up; this difference was statistically significant (log-rank P = 0.040). In the no-PVO group, 15 (83%) patients achieved two-lung Fontan circulation. In the PVO group, 12 (50%) patients achieved two-lung Fontan circulation. Multivariate analysis revealed that functional lung area and shunt size [significantly larger in patients with functional lung area ≥50% in affected lung (P = 0.040)] were significant factors for successful two-lung Fontan procedure (P = 0.030).

CONCLUSIONS

Intrapulmonary-artery septation may contribute to increase functional lung area after PVO release to establish two-lung Fontan circulation in patients with PVO who have unbalanced PA growth and/or decreased unilateral pulmonary circulation.
Eight Million Years of Satellite DNA Evolution in Grasshoppers of the Genus Schistocerca Illuminate the Ins and Outs of the Library Hypothesis
Authors: Palacios-Gimenez Octavio M , Milani Diogo , Song Hojun , Marti Dardo A , López-León Maria D , Ruiz-Ruano Francisco J , Camacho Juan Pedro M , Cabral-de-Mello Diogo C
Published: January 2020

Satellite DNA (satDNA) is an abundant class of tandemly repeated noncoding sequences, showing high rate of change in sequence, abundance, and physical location. However, the mechanisms promoting these changes are still controversial. The library model was put forward to explain the conservation of some satDNAs for long periods, predicting that related species share a common collection of satDNAs, which mostly experience quantitative changes. Here, we tested the library model by analyzing three satDNAs in ten species of Schistocerca grasshoppers. This group represents a valuable material because it diversified during the last 7.9 Myr across the American continent from the African desert locust (Schistocerca gregaria), and this thus illuminates the direction of evolutionary changes. By combining bioinformatic and cytogenetic, we tested whether these three satDNA families found in S. gregaria are also present in nine American species, and whether differential gains and/or losses have occurred in the lineages. We found that the three satDNAs are present in all species but display remarkable interspecies differences in their abundance and sequences while being highly consistent with genus phylogeny. The number of chromosomal loci where satDNA is present was also consistent with phylogeny for two satDNA families but not for the other. Our results suggest eminently chance events for satDNA evolution. Several evolutionary trends clearly imply either massive amplifications or contractions, thus closely fitting the library model prediction that changes are mostly quantitative. Finally, we found that satDNA amplifications or contractions may influence the evolution of monomer consensus sequences and by chance playing a major role in driftlike dynamics.
The 2018 Mw 6.8 Zakynthos (Ionian Sea, Greece) earthquake: seismic source and local tsunami characterization
Authors: Cirella A , Romano F , Avallone A , Piatanesi A , Briole P , Ganas A , Theodoulidis N , Chousianitis K , Volpe M , Bozionellos G , Selvaggi G , Lorito S
Published: January 2020

We investigated the kinematic rupture model of the 2018 Mw 6.8 Zakynthos, Ionian Sea (Greece), earthquake by using a non-linear joint inversion of strong motion data, high-rate GPS time-series and static coseismic GPS displacements. We also tested inversion results against tide-gauge recordings of the small tsunami generated in the Ionian Sea. In order to constrain the fault geometry, we performed several preliminary kinematic inversions by assuming the parameter values resulting from different published moment tensor solutions. The lowest cost function values were obtained by using the geometry derived from the United States Geological Survey (USGS) focal solution. Between the two conjugate USGS planes, the rupture model which better fits the data is the one with the N9°E-striking 39°ESE-dipping plane. The rupture history of this model is characterized by a bilateral propagation, featuring two asperities; a main slip patch extending between 14 and 28 km in depth, 9 km northeast from the nucleation and a slightly shallower small patch located 27 km southwest from the nucleation. The maximum energy release occurs between 8 and 12 s, when both patches are breaking simultaneously. The maximum slip is 1.8 m and the total seismic moment is 2.4 × 1019 Nm, corresponding to a Mw value of 6.8. The slip angle shows a dominant right-lateral strike-slip mechanism, with a minor reverse component that increases on the deeper region of the fault. This result, in addition to the observed possibility of similar mechanisms for previous earthquakes occurred in 1959 and 1997, suggests that the tectonic deformation between the Cephalonia Transform Fault Zone and the northern tip of the Hellenic Arc Subduction zone may be accommodated by prevailing right lateral low-dipping faults, occurring on re-activated structures previously experiencing (until Pliocene) compressional regime. Comparison of predicted and observed tsunami data suggests the need of a better characterization of local harbour response for this type of relatively short-wavelength events, which is important in the context of tsunami early warning. However, the suggested dominantly strike-slip character would in turn imply a reduced tsunami hazard as compared to a dominant thrust faulting regime from this source region.
Norms, New Words, and Empirical Reality
Authors: ten Hacken Pius
Published: January 2020

The central question of this paper is how the inclusion of new words in dictionaries can be related to the empirical reality and norms of language. Because dictionaries are generally dictionaries of a language, the starting point is how this notion of named language is framed. The traditional view of a language as a system is contrasted with the corpus-based view of a language as realized in use and with the Chomskyan view based on language as a speaker’s competence. Then, the nature of words in each perspective is discussed, leading to different characterizations and different standards for the evaluation of new words. The function of new words is generally to name new concepts. In naming, word formation, sense extension, and borrowing can be used. Whereas lexicographers see their task as mainly descriptive, users often expect dictionaries to be gatekeepers. The competence-based perspective can serve as a ground where these views can be reconciled.
Integrability of Dispersionless Hirota-Type Equations and the Symplectic Monge–Ampère Property
Authors: Ferapontov E V , Kruglikov B , Novikov V
Published: January 2020

We prove that integrability of a dispersionless Hirota-type equation implies the symplectic Monge–Ampère property in any dimension $\geq 4$. In 4D, this yields a complete classification of integrable dispersionless partial differential equations (PDEs) of Hirota type through a list of heavenly type equations arising in self-dual gravity. As a by-product of our approach, we derive an involutive system of relations characterizing symplectic Monge–Ampère equations in any dimension. Moreover, we demonstrate that in 4D the requirement of integrability is equivalent to self-duality of the conformal structure defined by the characteristic variety of the equation on every solution, which is in turn equivalent to the existence of a dispersionless Lax pair. We also give a criterion of linearizability of a Hirota-type equation via flatness of the corresponding conformal structure and study symmetry properties of integrable equations.
Live-Attenuated Respiratory Syncytial Virus Vaccine With M2-2 Deletion and With Small Hydrophobic Noncoding Region Is Highly Immunogenic in Children
Authors: McFarland Elizabeth J , Karron Ruth A , Muresan Petronella , Cunningham Coleen K , Perlowski Charlotte , Libous Jennifer , Oliva Jennifer , Jean-Philippe Patrick , Moye Jack , Schappell Elizabeth , Barr Emily , Rexroad Vivian , Fearn Laura , Cielo Mikhaela , Wiznia Andrew , Deville Jaime G , Yang Lijuan , Luongo Cindy , Collins Peter L , Buchholz Ursula J
Published: January 2020

Background

Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and vaccines are needed. Live RSV vaccine D46/NS2/N/ΔM2-2-HindIII, attenuated by deletion of the RSV RNA regulatory protein M2-2, is based on previous candidate LID/ΔM2-2 but incorporates prominent differences from MEDI/ΔM2-2, which was more restricted in replication in phase 1.

Methods

RSV-seronegative children aged 6–24 months received 1 intranasal dose (105 plaque-forming units [PFUs] of D46/NS2/N/ΔM2-2-HindIII [n = 21] or placebo [n = 11]) and were monitored for vaccine shedding, reactogenicity, RSV-antibody responses and RSV-associated medically attended acute respiratory illness (RSV-MAARI) and antibody responses during the following RSV season.

Results

All 21 vaccinees were infected with vaccine; 20 (95%) shed vaccine (median peak titer, 3.5 log10 PFUs/mL with immunoplaque assay and 6.1 log10 copies/mL with polymerase chain reaction). Serum RSV-neutralizing antibodies and anti-RSV fusion immunoglobulin G increased ≥4-fold in 95% and 100% of vaccines, respectively. Mild upper respiratory tract symptoms and/or fever occurred in vaccinees (76%) and placebo recipients (18%). Over the RSV season, RSV-MAARI occurred in 2 vaccinees and 4 placebo recipients. Three vaccinees had ≥4-fold increases in serum RSV-neutralizing antibody titers after the RSV season without RSV-MAARI.

Conclusions

D46/NS2/N/ΔM2-2-HindIII had excellent infectivity and immunogenicity and primed vaccine recipients for anamnestic responses, encouraging further evaluation of this attenuation strategy.

Clinical Trials Registration

NCT03102034 and NCT03099291.
Ubiquitination of IgG1 cytoplasmic tail modulates B-cell signalling and activation
Authors: Kodama Tadahiro , Hasegawa Mika , Sakamoto Yui , Haniuda Kei , Kitamura Daisuke
Published: January 2020

Upon antigen stimulation, IgG+ B cells rapidly proliferate and differentiate into plasma cells, which has been attributed to the characteristics of membrane-bound IgG (mIgG), but the underlying molecular mechanisms remain elusive. We have found that a part of mouse mIgG1 is ubiquitinated through the two responsible lysine residues (K378 and K386) in its cytoplasmic tail and this ubiquitination is augmented upon antigen stimulation. The ubiquitination of mIgG1 involves its immunoglobulin tail tyrosine (ITT) motif, Syk/Src-family kinases and Cbl proteins. Analysis of a ubiquitination-defective mutant of mIgG1 revealed that ubiquitination of mIgG1 facilitates its ligand-induced endocytosis and intracellular trafficking from early endosome to late endosome, and also prohibits the recycling pathway, thus attenuating the surface expression level of mIgG1. Accordingly, ligation-induced activation of B-cell receptor (BCR) signalling molecules is attenuated by the mIgG1 ubiquitination, except MAP kinase p38 whose activation is up-regulated due to the ubiquitination-mediated prohibition of mIgG1 recycling. Adaptive transfer experiments demonstrated that ubiquitination of mIgG1 facilitates expansion of germinal centre B cells. These results indicate that mIgG1-mediated signalling and cell activation is regulated by ubiquitination of mIgG1, and such regulation may play a role in expansion of germinal centre B cells.
Rapid identification of MDMB-CHMINACA metabolites using Zebrafish and Human Liver microsomes as the Biotransformation system by LC-QE-HF-MS
Authors: Xu Duo-qi , Dai Yong , Zhang Wen-fang , Wang Ji-fen , Wang Yan-yan , Zhang Ying , Guobin-xin  , Zhao Qiao-lin , Li Xiao
Published: January 2020

MDMB-CHMINACA is a newly synthetic cannabinoid which scoped in NMS Lab, USA. Since there are currently no published data on MDMB-CHMINACA metabolism, we aimed to identify its biotransformation pathways and major metabolites. Liquid chromatography Q-Extractive HF Hybrid Quadrupole-Orbitrap mass spectrometry (LC-QE-HF-MS) using full scan positive ion mode and targeted MS/MS (ddms2) techniques with accurate mass measurement were employed to analyze the metabolic sites and pathways. An in vivo metabolic animal model of zebrafish was established to verify the metabolic pathways of MDMB-CHMINACA obtained from human liver microsomal experiment in vitro. The results showed that 29 metabolites were generated in the zebrafish animal model and human liver microsomes model. Biotransformations mainly occurred at the cyclohexylmethyl tail of the compound, minor reactions also occurred at the tert-butyl chain, and no reaction was analysised at the indazole ring. We recommend M1 group (MDMB-CHMINACA ester hydroxylation), and M2 group (MDMB-CHMINACA monohydroxylation) as the potential poisoning markers to document MDMB-CHMINACA intake in clinical and forensic cases. Additionally, this study provides preliminary information regarding the metabolism of MDMB-CHMINACA that will guide analytical standard manufacturers to better provide suitable references for further studies on newly encountered designer drugs.
A Validated Method for the Simultaneous Determination of Quetiapine, Clozapine and Mirtazapine in Postmortem Blood and Tissue Samples
Authors: Breivik Håvard , Løkken Trine N , Slørdal Lars , Frost Joachim
Published: January 2020

Psychotropic drugs are regularly present in cases of sudden, unexpected death. Such drugs also tend to express significant postmortem redistribution. To facilitate further investigation of this phenomenon, reliable quantitative methods applicable to multiple biological matrices are needed. We present a validated ultra-performance liquid chromatography–tandem mass spectrometry method for the simultaneous quantification of quetiapine, clozapine and mirtazapine in postmortem whole blood, skeletal muscle, brain tissue and liver tissue using high-performance liquid chromatography–tandem mass spectrometry. Sample preparation was performed using liquid–liquid extraction. The validated ranges were 3.8–1534, 16–1960 and 13–1060 μg/L for quetiapine, clozapine and mirtazapine, respectively. Within-run and between-run accuracy (87.4–122%) and precision (CV 1.5–8.9%), matrix effects (95–101%) and recovery (35.7–92%) were validated at two concentration levels; 5.8 and 1227 μg/L for quetiapine, 25 and 1568 μg/L for clozapine and 20 and 849 μg/L for mirtazapine. Stability in a 10°C environment was assessed for treated samples of brain, liver and muscle tissue, showing deviations in analyte concentrations ranging from −8% to 9% after 3 days. The analyte concentrations in treated samples of whole blood stored at 4°C deviated by <5% after 5 days. The method was applied in three forensic autopsy cases implicating quetiapine, clozapine and mirtazapine, respectively, in supratherapeutic concentrations.
The Wound Microbiology and the Outcomes of the Systemic Antibiotic Prophylaxis in a Mass Burn Casualty Incident
Authors: Yeong Eng-Kean , Sheng Wang-Huei , Hsueh Po-Ren , Hsieh Szu-Min , Huang Hui-Fu , Ko An-Ta , Tai Hao-Chih , Lai Hong-Shiee , Chang Shan-Chwen
Published: January 2020

This paper describes the wound microbiology and outcome of using systemic antibiotic prophylaxis (SAP) in mass burn casualties (MBC). The charts of 31 patients (mean age: 21 years, mean burn area: 42% of the total body surface area) injured in a dust explosion were reviewed for 1 month after the burn. Polymicrobial and rare pathogen wound infections (Acinetobacter junii, Aeromonas sobri, et al) were common in MBC due to sterility breech. Following the use of SAP for 2 to 14 days after admission, there was a reduction in wound infection rate from 45% at week 1 postburn to 10% at week 4. In addition, no blood stream infection occurred in the first week after the burns. Multidrug-resistant Acinetobacter baumannii, Klebsiella pneumoniae, and Candida albicans were the top three wound pathogens cultured. Multidrug-resistant microorganism infections were found in 39% of the patients, and the odds ratios for the these infections in burn patients with more than ≥40% total body surface area and in patients receiving two or more classes of antibiotics were 41.7 (95% confidence interval [CI] = 2.1–810.7, P = .01) and 9.9 (95% CI= 1.0–92.7, P = .04), respectively. Although SAP did not prevent wound or blood stream infections, no mortality occurred in our patients. A randomized controlled study is needed to investigate the impact of SAP on burn mortality in MBC.
3D printed compact heat exchangers with mathematically defined core structures
Authors: Kim Jiho , Yoo Dong-Jin
Published: January 2020

This paper describes a new design method for generating a compact heat exchanger (CHX) computational model consisting of triply periodic minimal surface (TPMS) core structures. These TPMS-based core structures are not easy to design using existing CAD systems, especially in the case of CHXs with complex 3D geometries. In this paper, we introduce a novel CHXs design strategy based on the calculation of volumetric distance fields (VDFs). All geometric components, including TPMS-based core structure, heat exchanger exterior shape, and a set of parts for inlet and outlet, are expressed as VDFs in a given design domain. This VDF-based geometric components description allows for the computationally efficient design of a complex-shaped CHX computational model with high levels of geometric complexity. In conjunction with several TPMS-based CHX prototypes built with additive manufacturing (AM) technologies, we describe and discuss the design and manufacturing results for a wide range of CHXs with various geometries to validate the effectiveness of the newly proposed design method. Besides, by examining the heat transfer performance experimental data, we show that the innovative CHX production method using the combination of VDF-based Boolean operations, TPMS-based core structures, and AM technologies proposed in this paper can create an ultra-efficient CHX while maintaining an allowable pressure drop.
An introduction to feedback Turing computability
Authors: Ackerman Nathanael L , Freer Cameron E , Lubarsky Robert S
Published: January 2020

Feedback computability is computation with an oracle that contains the correct convergence/divergence information for all computations calling that same oracle. Here we study feedback Turing computability, as well as feedback for some smaller classes of computation. We also examine some versions of parallelization of these notions.
Statistical Evidence, Normalcy, and the Gatecrasher Paradox
Authors: Blome-Tillmann Michael
Published: January 2020

Martin Smith has recently proposed, in this journal, a novel and intriguing approach to puzzles and paradoxes in evidence law arising from the evidential standard of the Preponderance of the Evidence. According to Smith, the relation of normic support provides us with an elegant solution to those puzzles. In this paper I develop a counterexample to Smith’s approach and argue that normic support can neither account for our reluctance to base affirmative verdicts on bare statistical evidence nor resolve the pertinent paradoxes. Normic support is, as a consequence, not a successful epistemic anti-luck condition.
seestar: Selection functions for spectroscopic surveys of the Milky Way
Authors: Everall Andrew , Das Payel
Published: January 2020

Selection functions are vital for understanding the observational biases of spectroscopic surveys. With the wide variety of multiobject spectrographs currently in operation and becoming available soon, we require easily generalizable methods for determining the selection functions of these surveys. Previous work, however, has largely been focused on generating individual, tailored selection functions for every data release of each survey. Moreover, no methods for combining these selection functions to be used for joint catalogues have been developed.

We have developed a Poisson likelihood estimation method for calculating selection functions in a Bayesian framework, which can be generalized to any multiobject spectrograph. We include a robust treatment of overlapping fields within a survey as well as selection functions for combined samples with overlapping footprints. We also provide a method for transforming the selection function that depends on the sky positions, colour, and apparent magnitude of a star to one that depends on the galactic location, metallicity, mass, and age of a star. This ‘intrinsic’ selection function is invaluable for chemodynamical models of the Milky Way. We demonstrate that our method is successful at recreating synthetic spectroscopic samples selected from a mock galaxy catalogue.
The impact of isomers on a kilonova associated with neutron star mergers
Authors: Fujimoto Shin-ichiro , Hashimoto Masa-aki
Published: January 2020

We investigate the significance of isomers on a kilonova associated with neutron star mergers (NSMs) for the first time. We calculate the evolution of abundances and energy generation rates ($\dot{\epsilon }_{\rm nuc}$) of ejecta from NSMs, taking into account β− decay through isomers. We find that for ejecta with electron fraction (Ye) of 0.2–0.3, $\dot{\epsilon }_{\rm nuc}$ is appreciably changed from those without isomers, due to the large change in timing of β− decay through the isomeric states (ISs) of ${}^{123,125,127} \rm Sn$ and ${}^{128} \rm Sb$. In particular, the effects of the isomers on $\dot{\epsilon }_{\rm nuc}$ are prominent for ejecta of Ye ∼ 0.25, which could emit a fraction of an early, blue component of a kilonova observed in GW170817. When the excitation from a ground state to its IS is important, the isomers of ${}^{129} \rm Sb$ and ${}^{129, 131} \rm Te$ also cause additional and appreciable change in $\dot{\epsilon }_{\rm nuc}$. Furthermore, we demonstrate that larger amounts of lanthanide-free ejecta result in a better fit of an observed light curve of the kilonova in GW170817 if the isomers are taken into account.
Out of Tibet: Genomic Perspectives on the Evolutionary History of Extant Pikas
Authors: Wang XiaoYun , Liang Dan , Jin Wei , Tang MingKun , Shalayiwu  , Liu ShaoYing , Zhang Peng
Published: January 2020

Pikas are widely distributed in the Northern Hemisphere and are highly adapted to cold and alpine environments. They are one of the most complex and problematic groups in mammalian systematics, and the origin and evolutionary history of extant pikas remain controversial. In this study, we sequenced the whole coding sequences of 105 pika samples (29 named species and 1 putative new species) and obtained DNA data for more than 10,000 genes. Our phylogenomic analyses recognized four subgenera of extant pikas: Alienauroa, Conothoa, Ochotona, and Pika. The interrelationships between the four subgenera were strongly resolved as (Conothoa, (Alienauroa, (Ochotona, Pika))), with the mountain group Conothoa being the sister group of all other pikas. Our divergence time and phylogeographic analyses indicated that the last common ancestor of extant pikas first occurred on in the middle Miocene, ∼14 Ma. The emergence of opportunities related to the climate, food supply, and spreading paths in concert promoted the dispersal of pikas from the Qinghai-Tibetan Plateau (QTP) to other parts of Eurasia and North America. We found that the genes that were positively selected in the early evolution of pikas were most concentrated in functional categories related to cold tolerance. These results suggest that the QTP may have served as a training ground for cold tolerance in early pikas, which gives pikas a great advantage when the climate continued to cool after the middle Miocene. Our study highlights the importance of the QTP as a center of origin for many cold-adapted animals.
Phenotypic Convergence Is Not Mirrored at the Protein Level in a Lizard Adaptive Radiation
Authors: Corbett-Detig Russell B , Russell Shelbi L , Nielsen Rasmus , Losos Jonathan
Published: January 2020

There are many compelling examples of molecular convergence at individual genes. However, the prevalence and the relative importance of adaptive genome-wide convergence remain largely unknown. Many recent works have reported striking examples of excess genome-wide convergence, but some of these studies have been called into question because of the use of inappropriate null models. Here, we sequenced and compared the genomes of 12 species of anole lizards that have independently converged on suites of adaptive behavioral and morphological traits. Despite extensive searches for a genome-wide signature of molecular convergence, we found no evidence supporting molecular convergence at specific amino acids either at individual genes or at genome-wide comparisons; we also uncovered no evidence supporting an excess of adaptive convergence in the rates of amino acid substitutions within genes. Our findings indicate that comprehensive phenotypic convergence is not mirrored at genome-wide protein-coding levels in anoles, and therefore, that adaptive phenotypic convergence is likely not constrained by the evolution of many specific protein sequences or structures.
Differential tissue-specific damage caused by bacterial epididymo-orchitis in the mouse
Authors: Klein Britta , Bhushan Sudhanshu , Günther Stefan , Middendorff Ralf , Loveland Kate L , Hedger Mark P , Meinhardt Andreas
Published: January 2020

Ascending bacterial urinary tract infections can cause epididymo-orchitis. In the cauda epididymidis, this frequently leads to persistent tissue damage. Less coherent data is available concerning the functional consequences of epididymo-orchitis on testis and caput epididymidis. This in vivo study addresses the functional and spatial differences in responsiveness of murine epididymis and testis to infection with uropathogenic Escherichia coli (UPEC). Whole transcriptome analysis (WTA) was performed on testis, caput, corpus and cauda epididymidis of adult C57BL/6 J wildtype mice. Following UPEC-induced epididymo-orchitis in these mice, epididymal and testicular tissue damage was evaluated histologically and semi-quantitatively at 10 days and 31 days post-inoculation. Expression of inflammatory markers and candidate antimicrobial genes were analysed by RT-qPCR. WTA revealed distinct differences in gene signatures between caput and cauda epididymidis, particularly amonst immunity-related genes. Cellular and molecular signs of testicular inflammation and disruption of spermatogenesis were noticed at day 10, but recovery was observed by day 31. In contrast to the cauda, the caput epididymidis did not reveal any signs of gross morphological damage or presence of pro-inflammatory processes despite confirmed infection. In contrast to beta-defensins, known UPEC-associated antimicrobial peptides (AMP), like Lcn2, Camp and Lypd8, were inherently highly expressed or upregulated in the caput following infection, potentially allowing an early luminal protection from UPEC. At the time points investigated, the caput epididymidis was protected from any obvious infection/inflammation-derived tissue damage. Studies addressing earlier time-points will conclude whether in the caput epididymidis a pro-inflammatory response is indeed not essential for effective protection from UPEC.
Effects of chain length and geometry on the activation of DNA damage bypass by polyubiquitylated PCNA
Authors: Takahashi Diane T , Wollscheid Hans-Peter , Lowther Jonathan , Ulrich Helle D
Published: January 2020

Ubiquitylation of the eukaryotic sliding clamp, PCNA, activates a pathway of DNA damage bypass that facilitates the replication of damaged DNA. In its monoubiquitylated form, PCNA recruits a set of damage-tolerant DNA polymerases for translesion synthesis. Alternatively, modification by K63-linked polyubiquitylation triggers a recombinogenic process involving template switching. Despite the identification of proteins interacting preferentially with polyubiquitylated PCNA, the molecular function of the chain and the relevance of its K63-linkage are poorly understood. Using genetically engineered mimics of polyubiquitylated PCNA, we have now examined the properties of the ubiquitin chain required for damage bypass in budding yeast. By varying key parameters such as the geometry of the junction, cleavability and capacity for branching, we demonstrate that either the structure of the ubiquitin-ubiquitin junction or its dynamic assembly or disassembly at the site of action exert a critical impact on damage bypass, even though known effectors of polyubiquitylated PCNA are not strictly linkage-selective. Moreover, we found that a single K63-junction supports substantial template switching activity, irrespective of its attachment site on PCNA. Our findings provide insight into the interrelationship between the two branches of damage bypass and suggest the existence of a yet unidentified, highly linkage-selective receptor of polyubiquitylated PCNA.
The Drosophila MLR COMPASS complex is essential for programming cis-regulatory information and maintaining epigenetic memory during development
Authors: Zraly Claudia B , Zakkar Abdul , Perez John Hertenstein , Ng Jeffrey , White Kevin P , Slattery Matthew , Dingwall Andrew K
Published: January 2020

The MLR COMPASS complex monomethylates H3K4 that serves to epigenetically mark transcriptional enhancers to drive proper gene expression during animal development. Chromatin enrichment analyses of the Drosophila MLR complex reveals dynamic association with promoters and enhancers in embryos with late stage enrichments biased toward both active and poised enhancers. RNAi depletion of the Cmi (also known as Lpt) subunit that contains the chromatin binding PHD finger domains attenuates enhancer functions, but unexpectedly results in inappropriate enhancer activation during stages when hormone responsive enhancers are poised, revealing critical epigenetic roles involved in both the activation and repression of enhancers depending on developmental context. Cmi is necessary for robust H3K4 monomethylation and H3K27 acetylation that mark active enhancers, but not for the chromatin binding of Trr, the MLR methyltransferase. Our data reveal two likely major regulatory modes of MLR function, contributions to enhancer commissioning in early embryogenesis and bookmarking enhancers to enable rapid transcriptional re-activation at subsequent developmental stages.
Supraorbital Keyhole Approach for Resection of Prechiasmatic Craniopharyngioma: 2-Dimensional Operative Video
Authors: May Adrien T , Guatta Ramona , Meling Torstein R
Published: January 2020

Craniopharyngioma are benign extra-axial tumors occurring classically in the vicinity of the sella. Because of the complex anatomy surrounding the sella turcica comprising, among others, the vessels of the circle of Willis, the optic nerves, chiasma and optic pathway, the hypothalamus, the third ventricle, and the pituitary gland, a large variety of technical approaches have been described. We illustrate, in this video, a unilateral supraorbital keyhole approach to access and entirely extirpate a prechiasmatic craniopharyngioma.

 A 40-yr-old healthy male presented to the emergency department with a history of rapid visual deterioration in the left eye in the last 10 d. A brain computed tomography scan showed a circumscribed prechiasmatic cystic lesion partially calcified that was radiologically compatible with a craniopharyngioma on the magnetic resonance imaging. We decided to access the lesion by a right-sided subfrontal corridor using a frontal wrinkle for the skin incision. This technique allows rapid and safe access to the central prechiasmatic region. By choosing a contralateral approach, we aim at optimizing the control on the opposite optic nerve with a perpendicular view. Total removal of the craniopharyngioma was accomplished without causing neurological deterioration. In fact, left eye visual disturbances were immediately retrieved after the surgery. No endocrinological issue or postoperative complication was reported. Minimal cosmetic disturbances are achieved with a meticulous skin incision and bone flap reconstruction.
Shareholder rights
Authors: Armour John
Published: January 2020

‘Shareholder rights’ are the legal entitlements of shareholders vis-à-vis companies in which they invest. A large body of research has sought to investigate how shareholder rights foster accountability of controllers. The concern has been that without accountability, managers and dominant shareholders will use their power to further their own interests at the expense of outside investors. A contrasting concern is that strengthening shareholder rights may come at the expense of other parties, which may also lead to misallocation of corporate resources. A recently-emerging body of research suggests that the relationship between shareholder rights and social welfare is not monotonic, but rather inverse-U-shaped. We argue that the calibration and impact of shareholder rights depends crucially on the institutional channel(s) through which they are implemented—voting, litigation, and/or market pricing. In particular, the market pricing channel intensifies the effects of shareholder rights in ways that can be excessive. This can harm not only other constituencies but also shareholders, as it can promote short-termism and systemic externalities. These problems are less pronounced for shareholder rights implemented through the voting channel.
The Relationship Between Body Mass Index and Pain Intensity Among Veterans with Musculoskeletal Disorders: Findings from the MSD Cohort Study
Authors: Higgins Diana M , Buta Eugenia , Heapy Alicia A , Driscoll Mary A , Kerns Robert D , Masheb Robin , Becker William C , Hausmann Leslie R M , Bair Matthew J , Wandner Laura , Janke E Amy , Brandt Cynthia A , Goulet Joseph L
Published: January 2020

Objective

To examine the relationship between body mass index (BMI) and pain intensity among veterans with musculoskeletal disorder diagnoses (MSDs; nontraumatic joint disorder; osteoarthritis; low back, back, and neck pain).

Setting

Administrative and electronic health record data from the Veterans Health Administration (VHA).

Subjects

A national cohort of US military veterans with MSDs in VHA care during 2001–2012 (N = 1,759,338).

Methods

These cross-sectional data were analyzed using hurdle negative binomial models of pain intensity as a function of BMI, adjusted for comorbidities and demographics.

Results

The sample had a mean age of 59.4, 95% were male, 77% were white/Non-Hispanic, 79% were overweight or obese, and 42% reported no pain at index MSD diagnosis. Overall, there was a J-shaped relationship between BMI and pain (nadir = 27 kg/m2), with the severely obese (BMI ≥ 40 kg/m2) being most likely to report any pain (OR vs normal weight = 1.23, 95% confidence interval = 1.21–1.26). The association between BMI and pain varied by MSD, with a stronger relationship in the osteoarthritis group and a less pronounced relationship in the back and low back pain groups.

Conclusions

There was a high prevalence of overweight/obesity among veterans with MSD. High levels of BMI (>27 kg/m2) were associated with increased odds of pain, most markedly among veterans with osteoarthritis.
Inpatient epidemiology and economic burden of granulomatosis with polyangiitis: a 10-year study of the national inpatient sample
Authors: Ungprasert Patompong , Koster Matthew J , Cheungpasitporn Wisit , Wijarnpreecha Karn , Thongprayoon Charat , Kroner Paul T
Published: January 2020

Objective

To characterize inpatient epidemiology and economic burden of granulomatosis with polyangiitis (GPA).

Methods

Patients with GPA were identified from the Nationwide Inpatient Sample (NIS), the largest inpatient database in the USA consisting of over 4000 non-federal acute care hospitals, using the ICD-9 CM code. A cohort of comparators without GPA was also constructed from the same database. Data on demographics, procedures, length of stay, mortality, morbidity and total hospitalization charges were extracted. All analysed data were extracted from the database for the years 2005–2014.

Results

The inpatient prevalence of GPA was 32.6 cases per 100 000 admissions. GPA itself (38.3%), pneumonia (13.7%) and sepsis (8.4%) were the most common reasons for admission. After adjusting for potential confounders, the all-cause mortality adjusted odds ratio (aOR) of patients with GPA was significantly higher than that of patients without GPA (aOR 1.20; 95% CI: 1.41, 1.61). This was also true for several morbidities, including acute kidney injury, multi-organ failure, shock and need for intensive care unit admission. Hospitalizations of patients with GPA were associated with higher cost as demonstrated by an adjusted additional mean of $5125 (95% CI: $4719, $5531) for total hospital cost and an adjusted additional mean of $16 841 (95% CI: $15 280, $18 403) for total hospitalization charges when compared with patients without GPA.

Conclusion

Inpatient prevalence of GPA was higher than what would be expected from prevalence in the general population. Hospitalizations of patients with GPA were associated with higher morbidity, mortality and cost.
Self–other overlap and interpersonal neural synchronization serially mediate the effect of behavioral synchronization on prosociality
Authors: Feng Xiaodan , Sun Binghai , Chen Chuansheng , Li Weijian , Wang Ying , Zhang Wenhai , Xiao Weilong , Shao Yuting
Published: January 2020

Behavioral synchronization has been found to facilitate social bonding and prosociality but the neural mechanisms underlying such effects are not well understood. In the current study, 60 dyads were hyperscanned using functional near-infrared spectroscopy while they performed either a synchronous key-pressing task or a control task. After the task, they were asked to perform the dictator game to assess their prosocial behavior. We also measured three potential mediating variables: self–other overlap, perceived similarity and interpersonal neural synchronization. Results showed that dyads in the synchronization group were higher in behavioral synchronization, interpersonal neural synchronization (INS) at the right dorsolateral prefrontal cortex, self–other overlap, perceived similarity and prosociality than those in the control group. INS was significantly associated with prosocial behaviors and self–other overlap. After testing four meditation models, we found that self–other overlap and INS played a serial mediation role in the effect of behavioral synchronization on prosociality. These results contribute to our understanding of the neural and cognitive mechanisms underlying the effect of behavioral synchronization on prosocial behavior.
Focused attention meditation training modifies neural activity and attention: longitudinal EEG data in non-meditators
Authors: Yoshida Kazuki , Takeda Kenta , Kasai Tetsuko , Makinae Shiika , Murakami Yui , Hasegawa Ai , Sakai Shinya
Published: January 2020

Focused attention meditation (FAM) is a basic meditation practice that cultivates attentional control and monitoring skills. Cross-sectional studies have highlighted high cognitive performance and discriminative neural activity in experienced meditators. However, a direct relationship between neural activity changes and improvement of attention caused by meditation training remains to be elucidated. To investigate this, we conducted a longitudinal study, which evaluated the results of electroencephalography (EEG) during three-stimulus oddball task, resting state and FAM before and after 8 weeks of FAM training in non-meditators. The FAM training group (n = 17) showed significantly higher P3 amplitude during the oddball task and shorter reaction time (RT) for target stimuli compared to that of the control group (n = 20). Furthermore, a significant negative correlation between F4-Oz theta band phase synchrony index (PSI) during FAM and P3 amplitude during the oddball task and a significant positive correlation between F4-Pz theta band PSI during FAM and P3 amplitude during the oddball task were observed. In contrast, these correlations were not observed in the control group. These findings provide direct evidence of the effectiveness of FAM training and contribute to our understanding of the mechanisms underpinning the effects of meditation on brain activity and cognitive performance.
Morphometric Variation at Different Spatial Scales: Coordination and Compensation in the Emergence of Organismal Form
Authors: Mitteroecker Philipp , Bartsch Silvester , Erkinger Corinna , Grunstra Nicole D S , Le Maître Anne , Bookstein Fred L
Published: January 2020

It is a classic aim of quantitative and evolutionary biology to infer genetic architecture and potential evolutionary responses to selection from the variance–covariance structure of measured traits. But a meaningful genetic or developmental interpretation of raw covariances is difficult, and classic concepts of morphological integration do not directly apply to modern morphometric data. Here, we present a new morphometric strategy based on the comparison of morphological variation across different spatial scales. If anatomical elements vary completely independently, then their variance accumulates at larger scales or for structures composed of multiple elements: morphological variance would be a power function of spatial scale. Deviations from this pattern of “variational self-similarity” (serving as a null model of completely uncoordinated growth) indicate genetic or developmental coregulation of anatomical components. We present biometric strategies and R scripts for identifying patterns of coordination and compensation in the size and shape of composite anatomical structures. In an application to human cranial variation, we found that coordinated variation and positive correlations are prevalent for the size of cranial components, whereas their shape was dominated by compensatory variation, leading to strong canalization of cranial shape at larger scales. We propose that mechanically induced bone formation and remodeling are key mechanisms underlying compensatory variation in cranial shape. Such epigenetic coordination and compensation of growth are indispensable for stable, canalized development and may also foster the evolvability of complex anatomical structures by preserving spatial and functional integrity during genetic responses to selection.[Cranial shape; developmental canalization; evolvability; morphological integration; morphometrics; phenotypic variation; self-similarity.]
Benzothiadiazole Conditions the Bean Proteome for Immunity to Bean Rust
Authors: Cooper Bret , Beard Hunter S. , Garrett Wesley M. , Campbell Kimberly B.
Published: January 2020

The common bean rust fungus reduces harvests of the dry, edible common bean. Natural resistance genes in the plant can provide protection until a fungal strain that breaks resistance emerges. In this study, we demonstrate that benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester (BTH) sprayed on susceptible beans induces resistance to common bean rust. Protection occurred as soon as 72 h after treatment and resulted in no signs of disease 10 days after inoculation with rust spores. By contrast, the susceptible control plants sustained heavy infections and died. To understand the effect BTH has on the bean proteome, we measured the changes of accumulation for 3,973 proteins using mass spectrometry. The set of 409 proteins with significantly increased accumulation in BTH-treated leaves included receptor-like kinases SOBIR1, CERK1, and LYK5, which perceive pathogens, and EDS1, a regulator of the salicylic acid defense pathway. Other proteins that likely contributed to resistance included pathogenesis-related proteins, a full complement of enzymes that catalyze phenylpropanoid biosynthesis, and protein receptors, transporters, and enzymes that modulate other defense responses controlled by jasmonic acid, ethylene, brassinosteroid, abscisic acid, and auxin. Increases in the accumulation of proteins required for vesicle-mediated protein secretion and RNA splicing occurred as well. By contrast, more than half of the 168 decreases belonged to chloroplast proteins and proteins involved in cell expansion. These results reveal a set of proteins needed for rust resistance and reaffirm the utility of BTH to control disease by amplifying the natural immune system of the bean plant.