bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases
Authors: Hayashi Kenshi , Teramoto Ryota , Nomura Akihiro , Asano Yoshihiro , Beerens Manu , Kurata Yasutaka , Kobayashi Isao , Fujino Noboru , Furusho Hiroshi , Sakata Kenji , Onoue Kenji , Chiang David Y , Kiviniemi Tuomas O , Buys Eva , Sips Patrick , Burch Micah L , Zhao Yanbin , Kelly Amy E , Namura Masanobu , Kita Yoshihito , Tsuchiya Taketsugu , Kaku Bunji , Oe Kotaro , Takeda Yuko , Konno Tetsuo , Inoue Masaru , Fujita Takashi , Kato Takeshi , Funada Akira , Tada Hayato , Hodatsu Akihiko , Nakanishi Chiaki , Sakamoto Yuichiro , Tsuda Toyonobu , Nagata Yoji , Tanaka Yoshihiro , Okada Hirofumi , Usuda Keisuke , Cui Shihe , Saito Yoshihiko , MacRae Calum A , Takashima Seiji , Yamagishi Masakazu , Kawashiri Masa-aki , Takamura Masayuki
Published: January 2020

Aims

The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them.

Methods and results

We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analysed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as ‘pathogenic’ by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that two variants in KCNH2 and SCN5A, four variants in SCN10A, and one variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from ‘Uncertain significance’ to ‘Likely pathogenic’ in six probands.

Conclusion

Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD.
Projecting Stand Survival and Basal Area Based on a Self-Thinning Model for Chinese Fir Plantations
Authors: Zhang Xiongqing , Cao Quang V , Wang Hanchen , Duan Aiguo , Zhang Jianguo
Published: January 2020

The self-thinning rule has played a critical role in controlling stand stocking and modeling stand development in forest stands. Chinese fir (Cunninghamia lanceolata) is a native and fast-growing tree species used for timber production and is widely grown in southern China. Effective management of this important tree species requires accurate and reasonable predictions of stand growth and survival. Remeasured data from 48 plots distributed in Fujian, Jiangxi, Guangxi, and Sichuan provinces were used to develop models to predict stand survival and basal area based on the self-thinning trajectories. These trajectories were constructed using a self-thinning slope of –1.605, as suggested by Reineke (1933) (Method 1), and the slopes estimated either from two groups of sites (Method 2) or from climate variables (Method 3). Results indicated that the stand growth and survival models using Method 3 performed best, followed by Method 2 and Method 1. In addition, stand growth and survival curves predicted from Method 3 were more similar in shape to those from the observed values, as compared with Method 1. Overall, the models based on the self-thinning lines using climate-sensitive slopes provided reasonable predictions of the stand development dynamics. Therefore, these results facilitate modeling of the relation between stand growth/survival and self-thinning under climate change.
The Genome of the Great Gerbil Reveals Species-Specific Duplication of an MHCII Gene
Authors: Nilsson Pernille , Solbakken Monica H , Schmid Boris V , Orr Russell J S , Lv Ruichen , Cui Yujun , Song Yajun , Zhang Yujiang , Baalsrud Helle T , Tørresen Ole K , Stenseth Nils Chr , Yang Ruifu , Jakobsen Kjetill S , Easterday William Ryan , Jentoft Sissel
Published: January 2020

The great gerbil (Rhombomys opimus) is a social rodent living in permanent, complex burrow systems distributed throughout Central Asia, where it serves as the main host of several important vector-borne infectious pathogens including the well-known plague bacterium (Yersinia pestis). Here, we present a continuous annotated genome assembly of the great gerbil, covering over 96% of the estimated 2.47-Gb genome. Taking advantage of the recent genome assemblies of the sand rat (Psammomys obesus) and the Mongolian gerbil (Meriones unguiculatus), comparative immunogenomic analyses reveal shared gene losses within TLR gene families (i.e., TLR8, TLR10, and the entire TLR11-subfamily) for Gerbillinae, accompanied with signs of diversifying selection of TLR7 and TLR9. Most notably, we find a great gerbil-specific duplication of the MHCII DRB locus. In silico analyses suggest that the duplicated gene provides high peptide binding affinity for Yersiniae epitopes as well as Leishmania and Leptospira epitopes, putatively leading to increased capability to withstand infections by these pathogens. Our study demonstrates the power of whole-genome sequencing combined with comparative genomic analyses to gain deeper insight into the immunogenomic landscape of the great gerbil and its close relatives.
Annual sea level variations in the Red Sea observed using GNSS
Authors: Alothman A O , Bos M , Fernandes R , Radwan Ali M , Rashwan M
Published: January 2020

Annual sea level variations in the Red Sea have amplitudes of 15–20 cm as observed using various techniques such as tide gauges, satellite altimetry and recently Gravity Recovery and Climate Experiment (GRACE) satellite data. In this study, we demonstrate that Global Navigation Satellite System (GNSS) observations can also be used to measure the effect of these sea level variations. The extra water mass presses on the seafloor, which causes horizontal and vertical deformations. Using time-series from 10 coastal GNSS stations, we observe annual horizontal and vertical loading displacements with amplitudes of 2–5 mm. When correcting for atmospheric, hydrological and surface water loading and a residual geocentre motion, significant annual signals of approximately 0.5 and 2 mm are still observed for the horizontal and vertical components, respectively. In the northern Red Sea, the observed annual signals and predicted annual sea level loading show good agreement. This confirms that the signal is mostly a result of the variations in water mass and thermal expansion. Furthermore, we conclude that the uncertainties in the hydrological model over Ethiopia and Eritrea influence the loading over the southern Red Sea, which was underestimated in previous studies using GRACE data.
Sequential modelling of the 2016 Central Italy earthquake cluster using multisource satellite observations and quantitative assessment of Coulomb stress change
Authors: Xu Qian , Chen Qiang , Zhao Jingjing , Liu Xianwen , Yang Yinghui , Zhang Yijun , Liu Guoxiang
Published: January 2020

A sequence of earthquake events consisting of three large shocks occurred in Central Italy from August to October in 2016 with the duration of almost 2 months. The preliminary study on the seismic mechanism suggests that the sequence of events is the result from the activity of the SW dipping Mt Bove–Mt Vettore–Mt Gorzano normal fault system. For investigation and understanding of the coseismic faulting of the seismogenic fault alignment, we collect a set of comprehensive satellite observations including the Sentinel-1A, ALOS-2/PALSAR-2 and GPS data to map the coseismic surface deformation and estimate the source models in this study. The derived faulting model for the first Amatrice event is characterized by two distinct slip asperities suggesting that it is a predominantly normal dip-slip motion with slight strike-slip component. The second event, Visso earthquake is almost a purely normal rupture. The third Norcia event is dominated by the normal dip-slip rupture of the seismogenic fault, and has propagated up to the ground with significant slip. The three faulting models are then utilized to quantify the Coulomb failure stress (CFS) change over the seismic zone. First, the CFS change on the subsequent two seismogenic faults of the earthquake sequence is estimated, and the derived positive CFS change induced by the preceding earthquakes suggests that the early events have positive effects on triggering the subsequent seismicity. We then explore the response relation of the aftershocks including 961 events with magnitudes larger than M 3.0 to the CFS change over the seismic zone. It suggests that the rupture pattern of the aftershocks is similar to the major shocks with predominantly normal dip-slip. To assess the risk of the future seismic hazard, we analyse quantitatively the spatial distribution of aftershock occurrence and CFS transfer at the seismogenic depth, indicating that the ruptures of the three major shocks do partly release the accumulated strain on the associated fault alignment as well as the dense aftershock, but the CFS increase zone with few aftershocks in the southwest of the eastern Quaternary fault alignment of Central Italy poses the potential of further rupture. In particular, the distribution of aftershock migration also suggests that the north extension of the Mt Bove fault is the potential zone with rupture risk.
Collective Management of Copyright in Greece After the Implementation of Directive 2014/26/EU
Authors: Stavridou Sylvia
Published: January 2020

The Collective Management Law (L. 4481/17) transposed Directive 2014/26/EU into national law, and also set a voluminous legal framework on collective management with intensive state intervention. This placed Greece’s collective management organisations (CMOs) in a less favourable operating condition compared with those in other Member States. The implementation procedure in Greece plunged the music market into crisis, and showed that many national CMOs were unprepared to adapt to the new burdensome administrative measures and overloaded the existing competent authority with a variety of monitoring and supervisory tasks. The challenge for legislative initiatives and supervisory mechanisms remains to strike a balance between the quest for transparency and accountability and the viability of smaller and weaker CMOs. This article aims to give a short survey of the new legal framework on collective management in relation to the current day-to-day situation and the case law.
Participatory constitution-making: Introduction
Authors: Choudhry Sujit , Tushnet Mark
Published: January 2020

At least since the late eighteenth century, constitutions have been understood as emanations of the will of “the People,” as the ultimate expression of an inherent popular sovereignty. In the form of theories of constituent power, accounts of constitutional foundations blended notional or conceptual “descriptions” of the People, which anchored the political legitimacy of constitutional orders in the idea of hypothetical consent, with empirical claims that the nation’s actual people were represented in constitution-making processes through elected delegates and thereby were the authors of and gave consent to its fundamental law. As part of the third wave of democratization, there was an important shift in what popular participation consisted of—from indirect participation by elected representatives to direct, popular participation in the constitution-making process. As a matter of constitutional process, this led to the growing practice, and expectation, that major constitutional changes should be ratified through referenda.
Circulating Forms of B-Type Natriuretic Peptide in Very Preterm Infants
Authors: Harris Sarah L , Troughton Richard , Lewis Lynley , Austin Nicola , Pemberton Chris
Published: January 2020

Background

B-type natriuretic peptide (BNP) is a cardiac hormone released with an N-terminal fragment (NTproBNP) under conditions of ventricular pressure or volume overload. BNP has been proposed for use as a biomarker of cardiac dysfunction in premature infants in the setting of hemodynamically significant patent ductus arteriosus (HsPDA) and bronchopulmonary dysplasia (BPD). In adult settings the presence of proBNP and glycosylated isoforms may affect assay interpretation. However, there are limited data on how immature preterm physiology may affect BNP or NTproBNP levels and no published data on post-translational BNP processing in premature infants.

Methods

Pooled serial plasma samples from preterm infants born at less than 30 weeks gestation were analyzed for BNP congeners using Luminex® assay and high performance liquid chromatography. Samples were grouped according to clinical status: Group 1, no HsPDA and no BPD, Group 2 HsPDA and no/mild BPD, Group 3 HsPDA and moderate/severe BPD.

Results

Plasma from 15 infants was analyzed, and across all three groups NTproBNP predominated with minimal amounts of other isoforms; no glycosylation was detected.

Conclusions

NTproBNP appears to be the predominant isoform across each of our clinical groups in our pooled sample analysis with no evidence of significant glycosylation. This suggests NTproBNP is likely to be a robust marker in this clinical setting.
Leveraging the health information technology infrastructure to advance federal research priorities
Authors: Zayas-Cabán Teresa , Abernethy Amy P , Brennan Patricia Flatley , Devaney Stephanie , Kerlavage Anthony R , Ramoni Rachel , White P Jon
Published: January 2020

Ensuring that federally funded health research keeps pace with the explosion of health data depends on better information technology (IT), access to high-quality electronic health data, and supportive policies. Because it prominently funds and conducts health research, the U.S. federal government needs health IT to rapidly evolve and has the ability to drive that evolution. The Office of the National Coordinator for Health Information Technology developed the National Health IT Priorities for Research: A Policy and Development Agenda (the Agenda) that identifies health IT priorities for research in consultation with relevant federal agencies. This article describes support for the Agenda from the Food and Drug Administration, the National Institutes of Health, and the Veterans Health Administration. Advancing the Agenda will benefit these agencies and support their missions as well as the entire ecosystem leveraging the health IT infrastructure or using data from health IT systems for research.
An investigation on the factors affecting machine learning classifications in gamma-ray astronomy
Authors: Luo Shengda , Leung Alex P , Hui C Y , Li K L
Published: January 2020

We have investigated a number of factors that can have significant impacts on the classification performance of gamma-ray sources detected by Fermi Large Area Telescope (LAT) with machine learning techniques. We show that a framework of automatic feature selection can construct a simple model with a small set of features that yields better performance over previous results. Secondly, because of the small sample size of the training/test sets of certain classes in gamma-ray, nested re-sampling and cross-validations are suggested for quantifying the statistical fluctuations of the quoted accuracy. We have also constructed a test set by cross-matching the identified active galactic nuclei (AGNs) and the pulsars (PSRs) in the Fermi-LAT 8-yr point source catalogue (4FGL) with those unidentified sources in the previous 3rd Fermi-LAT Source Catalog (3FGL). Using this cross-matched set, we show that some features used for building classification model with the identified source can suffer from the problem of covariate shift, which can be a result of various observational effects. This can possibly hamper the actual performance when one applies such model in classifying unidentified sources. Using our framework, both AGN/PSR and young pulsar (YNG)/millisecond pulsar (MSP) classifiers are automatically updated with the new features and the enlarged training samples in 4FGL catalogue incorporated. Using a two-layer model with these updated classifiers, we have selected 20 promising MSP candidates with confidence scores $\gt 98{{\ \rm per\ cent}}$ from the unidentified sources in 4FGL catalogue that can provide inputs for a multiwavelength identification campaign.
MAGMO: polarimetry of 1720-MHz OH masers towards southern star-forming regions
Authors: Ogbodo C S , Green J A , Dawson J R , Breen S L , Mao S A , McClure-Griffiths N M , Robishaw T , Harvey-Smith L
Published: January 2020

From targeted observations of ground-state hydroxyl (OH) masers towards 702 Methanol Multibeam survey 6.7-GHz methanol masers, in the Galactic longitude range from 186° through the Galactic Centre to 20°, made as part of the ‘MAGMO’ (Mapping the Galactic Magnetic field through OH masers) project, we present the physical and polarization properties of the 1720-MHz OH maser transition, including the identification of Zeeman pairs. We present 10 new and 23 previously catalogued 1720-MHz OH maser sources detected towards star-forming regions (SFRs). In addition, we also detected 16 1720-MHz OH masers associated with supernova remnants and two sites of diffuse OH emission. Towards the 33 star formation masers, we identify 44 Zeeman pairs, implying magnetic field strengths ranging from −11.4 to +13.2 mG, and a median magnetic field strength of |BLOS| ∼ 6 mG. With limited statistics, we present the in situ magnetic field orientation of the masers and the Galactic magnetic field distribution revealed by the 1720-MHz transition. We also examine the association statistics of 1720-MHz OH SFR masers with other ground-state OH masers, excited-state OH masers, class I and class II methanol masers, and water masers, and compare maser positions with mid-infrared images of the parent SFRs. Of the 33 1720-MHz star formation masers, 10 are offset from their central exciting sources, and appear to be associated with outflow activity.
The contribution of nearby supernova remnants on the cosmic ray flux at Earth
Authors: A L-Zetoun A , Achterberg A
Published: January 2020

We consider anisotropic diffusion of Galactic cosmic rays in the Galactic magnetic field, using the Jansson–Farrar model for the field. In this paper, we investigate the influence of source position on the cosmic ray flux at the Earth in two ways: (1) by considering the contribution from cosmic ray sources located in different intervals in Galactocentric radius, and (2) by considering the contribution from a number of specific and individual close-by supernova remnants. Our calculation is performed by using a fully three-dimensional stochastic method. This method is based on the numerical solution of a set of stochastic differential equations, equivalent to Itô formulation, that describes the propagation of the Galactic cosmic rays.
Mirror principle and the red-giant bump: the battle of entropy in low-mass stars
Authors: Hekker S , Angelou G C , Elsworth Y , Basu S
Published: January 2020

The evolution of low-mass stars into red giants is still poorly understood. During this evolution the core of the star contracts and, simultaneously, the envelope expands – a process known as the ‘mirror’. Additionally, there is a short phase where the trend for increasing luminosity is reversed. This is known as the red giant branch bump. We explore the underlying physical reasons for these two phenomena by considering the specific entropy distribution in the star and its temporal changes. We find that between the luminosity maximum and luminosity minimum of the bump there is no mirror present and the star is fully contracting. The contraction is halted and the star regains its mirror when the hydrogen-burning shell reaches the mean molecular weight discontinuity. This marks the luminosity minimum of the bump.
Principles of RNA and nucleotide discrimination by the RNA processing enzyme RppH
Authors: Gao Ang , Vasilyev Nikita , Kaushik Abhishek , Duan Wenqian , Serganov Alexander
Published: January 2020

All enzymes face a challenge of discriminating cognate substrates from similar cellular compounds. Finding a correct substrate is especially difficult for the Escherichia coli Nudix hydrolase RppH, which triggers 5′-end-dependent RNA degradation by removing orthophosphate from the 5′-diphosphorylated transcripts. Here we show that RppH binds and slowly hydrolyzes NTPs, NDPs and (p)ppGpp, which each resemble the 5′-end of RNA. A series of X-ray crystal structures of RppH-nucleotide complexes, trapped in conformations either compatible or incompatible with hydrolysis, explain the low reaction rates of mononucleotides and suggest two distinct mechanisms for their hydrolysis. While RppH adopts the same catalytic arrangement with 5′-diphosphorylated nucleotides as with RNA, the enzyme hydrolyzes 5′-triphosphorylated nucleotides by extending the active site with an additional Mg2+ cation, which coordinates another reactive nucleophile. Although the average intracellular pH minimizes the hydrolysis of nucleotides by slowing their reaction with RppH, they nevertheless compete with RNA for binding and differentially inhibit the reactivity of RppH with triphosphorylated and diphosphorylated RNAs. Thus, E. coli RppH integrates various signals, such as competing non-cognate substrates and a stimulatory protein factor DapF, to achieve the differential degradation of transcripts involved in cellular processes important for the adaptation of bacteria to different growth conditions.
A crucial RNA-binding lysine residue in the Nab3 RRM domain undergoes SET1 and SET3-responsive methylation
Authors: Lee Kwan Yin , Chopra Anand , Burke Giovanni L , Chen Ziyan , Greenblatt Jack F , Biggar Kyle K , Meneghini Marc D
Published: January 2020

The Nrd1–Nab3–Sen1 (NNS) complex integrates molecular cues to direct termination of noncoding transcription in budding yeast. NNS is positively regulated by histone methylation as well as through Nrd1 binding to the initiating form of RNA PolII. These cues collaborate with Nrd1 and Nab3 binding to target RNA sequences in nascent transcripts through their RRM RNA recognition motifs. In this study, we identify nine lysine residues distributed amongst Nrd1, Nab3 and Sen1 that are methylated, suggesting novel molecular inputs for NNS regulation. We identify mono-methylation of one these residues (Nab3-K363me1) as being partly dependent on the H3K4 methyltransferase, Set1, a known regulator of NNS function. Moreover, the accumulation of Nab3-K363me1 is essentially abolished in strains lacking SET3, a SET domain containing protein that is positively regulated by H3K4 methylation. Nab3-K363 resides within its RRM and physically contacts target RNA. Mutation of Nab3-K363 to arginine (Nab3-K363R) decreases RNA binding of the Nab3 RRM in vitro and causes transcription termination defects and slow growth. These findings identify SET3 as a potential contextual regulator of Nab3 function through its role in methylation of Nab3-K363. Consistent with this hypothesis, we report that SET3 exhibits genetic activation of NAB3 that is observed in a sensitized context.
The molecular aetiology of tRNA synthetase depletion: induction of a GCN4 amino acid starvation response despite homeostatic maintenance of charged tRNA levels
Authors: McFarland Matthew R , Keller Corina D , Childers Brandon M , Adeniyi Stephen A , Corrigall Holly , Raguin Adélaïde , Romano M Carmen , Stansfield Ian
Published: January 2020

During protein synthesis, charged tRNAs deliver amino acids to translating ribosomes, and are then re-charged by tRNA synthetases (aaRS). In humans, mutant aaRS cause a diversity of neurological disorders, but their molecular aetiologies are incompletely characterised. To understand system responses to aaRS depletion, the yeast glutamine aaRS gene (GLN4) was transcriptionally regulated using doxycycline by tet-off control. Depletion of Gln4p inhibited growth, and induced a GCN4 amino acid starvation response, indicative of uncharged tRNA accumulation and Gcn2 kinase activation. Using a global model of translation that included aaRS recharging, Gln4p depletion was simulated, confirming slowed translation. Modelling also revealed that Gln4p depletion causes negative feedback that matches translational demand for Gln-tRNAGln to aaRS recharging capacity. This maintains normal charged tRNAGln levels despite Gln4p depletion, confirmed experimentally using tRNA Northern blotting. Model analysis resolves the paradox that Gln4p depletion triggers a GCN4 response, despite maintenance of tRNAGln charging levels, revealing that normally, the aaRS population can sequester free, uncharged tRNAs during aminoacylation. Gln4p depletion reduces this sequestration capacity, allowing uncharged tRNAGln to interact with Gcn2 kinase. The study sheds new light on mutant aaRS disease aetiologies, and explains how aaRS sequestration of uncharged tRNAs can prevent GCN4 activation under non-starvation conditions.
Higher mortality risk among kidney transplant recipients than among estimated glomerular filtration rate–matched patients with CKD—preliminary results
Authors: Cheddani Lynda , Liabeuf Sophie , Essig Marie , Snanoudj Renaud , Jacquelinet Christian , Kerleau Clarisse , Metzger Marie , Balkau Beverley , Drüeke Tilman B , Hourmant Maryvonne , Massy Ziad A ,   Nantes Kidney and Pancreas Transplantation Group and the Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) Study Group, Hourmant Maryvonne , Blancho Gilles , Diego Cantarovich , Jacques Dantal , Garandeau Claire , Giral Magali , Meurette Aurélie , Chapelet Agnès , Deltombe Clément , Gourraud-Vercel Caroline , Figueres Lucile , Ville Simon , Jacquemont Lola , Branchereau Julien , Karam Georges , Kandell Christine , Moreau Anne , Renaudin Karine , Cesbron Anne , Delbos Florent , Walencik Alexandre , Devis Anne , Ayav Carole , Besson-Dubourg Vanessa , Briançon Serge , Cannet Dorothée , Combe Christian , Fouque Denis , Frimat Luc , Herpe Yves-Edouard , Laville Maurice , Pascal Christophe , Robinson Bruce M , Stengel Bénédicte , Lange Céline , Legrand Karine , Speyer Elodie
Published: January 2020

Background

Although kidney transplantation prolongs survival relative to dialysis, it is associated with a higher death rate than in the general population. The objective of the present study was to assess and compare the risk of mortality and frequency of non-lethal cardiovascular (CV) events in kidney transplant recipients (KTRs) beyond 1 year after successful transplantation versus patients with chronic kidney disease (CKD) using propensity score–matched analysis of estimated glomerular filtration rate (eGFR) and other parameters.

Methods

After propensity score matching, we studied 340 KTRs from the French Données Informatisées et Validées en Transplantation cohort and 605 non-transplant patients with CKD (CKDps) from the French Chronic Kidney Disease–Renal Epidemiology and Information Network cohort. The mean ± standard deviation eGFR was 42 ± 13 and 41 ± 12 mL/min/  1.73 m2, respectively (P = 0.649). Descriptive data were completed by a survival analysis with Cox regression models.

Results

After a median follow-up period of 2.8 years (KTRs 2.0 years, CKDp 2.9 years), 71 deaths were recorded (31 and 40 in the KTR and CKD groups, respectively). Univariate analysis showed that KTRs had a significantly greater risk of mortality than CKDps. In multivariable analysis, KTRs were found to have a 2.7-fold greater risk of mortality [hazard ratio 2.7 (95% confidence interval 1.6–4.7); P = 0.005]. There was no between-group difference concerning the risk of CV events (P = 0.448). CV death rates in KTRs (29.0%) approximated those of CKDps (22.5%), whereas death rates due to infections were higher in KTRs (19.4% versus 10.0%).

Conclusion

Beyond 1 year after transplantation, KTRs, who possibly had a longer CKD history, had a significantly greater mortality risk than eGFR-matched CKDps. The excess risk was not associated with CV events.
Internal Auditory Canal Variability: Anatomic Variation Affects Cisternal Facial Nerve Visualization
Authors: Cohen Michael A , Abou-Al-Shaar Hussam , Gozal Yair M , Karsy Michael , Alzhrani Gmaan , Shelton Clough , Couldwell William T
Published: January 2020

BACKGROUND

The internal auditory canal (IAC) is an important landmark during surgery for lesions of the cerebellopontine angle. There is significant variability in the position and orientation of the IAC radiographically, and the authors have noted differences in surgical exposure depending on the individual anatomy of the IAC.

OBJECTIVE

To test the hypothesis that IAC position and orientation affects the surgical exposure of the IAC and facial nerve, especially when performing the translabyrinthine approach.

METHODS

The authors retrospectively reviewed magnetic resonance imaging studies of 50 randomly selected patients with pathologically confirmed vestibular schwannomas. Measurements, including the anterior (APD) and posterior (PPD) petrous distances, the anterior (APA) and posterior (PPA) petro-auditory angles, and the internal auditory angle (IAA), were obtained to quantify the position and orientation of the IAC within the petrous temporal bone.

RESULTS

The results quantitatively demonstrate tremendous variability of the position and orientation of the IAC in the petrous temporal bone. The measurement ranges were APD 10.2 to 26.1 mm, PPD 15.1 to 37.2 mm, APA 104 to 157°, PPA 30 to 96°, and IAA –5 to 40°.

CONCLUSION

IAC variability can have a substantial effect on the surgical exposure of the IAC and facial and vestibulocochlear nerves. Specifically, a horizontally oriented IAC with a small IAA may have significant impact on visualization of the facial nerve within its cisternal segment with the translabyrinthine approach. The retrosigmoid approach is less affected with IAC variability in position and angle.
Art as an Asset: Evidence from Keynes the Collector
Authors: Chambers David , Dimson Elroy , Spaenjers Christophe
Published: January 2020

The risk-return characteristics of art as an asset have been previously studied through aggregate price indexes. By contrast, we examine the long-run buy-and-hold performance of an actual portfolio, namely, the collection of John Maynard Keynes. We find that its performance has substantially exceeded existing estimates of art market returns. Our analysis of the collection identifies general attributes of art portfolios crucial in explaining why investor returns can substantially diverge from market returns: transaction-specific risk, buyer heterogeneity, return skewness, and portfolio concentration. Furthermore, our findings highlight the limitations of art price indexes as a guide to asset allocation or performance benchmarking. (JEL B26, C43, G11, G12, G14, Z11) Received: September 7, 2018: Editorial decision: November 24, 2019 by Editor: Nikolai Roussanov
Methods for analysing lineage tracing datasets
Authors: Kostiou Vasiliki , Zhang Huairen , Hall Michael WJ , Jones Philip H , Hall Benjamin A
Published: January 2020

A single population of stem cells maintains many epithelial tissues. Transgenic mouse cell tracking has frequently been used to study the growth dynamics of competing clones in these tissues. A mathematical model (the ‘single progenitor model’) has been argued to reproduce the observed stem cell dynamics accurately. This requires three parameters to describe the growth dynamics observed in transgenic mouse cell tracking- a division rate, a stratification rate, and the probability of dividing symmetrically. Deriving these parameters is time intensive and complex process. We compare the alternative strategies for analysing this source of experimental data, identifying an approximate Bayesian computation-based approach as the best in terms of efficiency and appropriate error estimation. We support our findings by explicitly modelling biological variation and consider the impact of different sampling regimes. All tested solutions are made available to allow new datasets to be analysed following our workflows. Based on our findings we make recommendations for future experimental design.
Shift of maternal gut microbiome of Tibetan antelope (Pantholops hodgsonii) during the perinatal period
Authors: Shi Yue , Miao Ziyan , Su Jianping , Wasser Samuel K.
Published: January 2020

The maternal gut microbiome can influence and be affected by the substantial physiological changes taking place during the perinatal period. However, little information is known about the changes in the maternal gut microbiome during this period. Tibetan antelope (Pantholops hodgsonii) provide a unique system to address this issue because their summer migration cycle is synchronized with the perinatal period. We used 16S rRNA gene sequencing to generate gut microbiome profiles using fecal samples collected from female migratory Tibetan antelope. We then correlated microbiome diversity with fecal hormone metabolite concentrations of glucocorticoids (GCs) and triiodothyronine (T3) extracted from the same fecal samples. The maternal gut microbiome of Tibetan antelope was dominated by Firmicutes and Bacteroidetes. There was a clear separation in gut microbial composition by female reproductive states based on both hierarchical clustering and PCoA analyses. The shift in the maternal gut microbiome likely reflects the metabolic and immune system dynamics during the perinatal period. Overall, the microbiome diversity was higher in the late pregnancy compared to the postpartum period. The negative association between T3 and microbiome diversity may be moderated by the shift of reproductive states since the correlations disappeared when considering each reproductive state separately. Integrating the microbiome dimension, migration pattern and reproduction may have direct conservation implications as by establishing a baseline of the physiological changes during the migration/perinatal period, we can have a better understanding of the impacts of increasing human activities on the Tibetan Plateau on the reproductive health of Tibetan antelope.
Complex multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidal behaviors
Authors: Polimanti Renato , Levey Daniel F. , Pathak Gita A. , Wendt Frank R. , Nunez Yaira Z. , Ursano Robert J. , Kessler Ronald C. , Kranzler Henry R. , Stein Murray B. , Gelernter Joel
Published: January 2020

Background and Aims

Substance dependence diagnoses (SDs) are important risk factors for suicidal behaviors. We investigated the associations of multiple SDs with different suicidal behaviors and tested how genetic background moderates these associations.

Design

Multivariate logistic regression to investigate the associations of SDs with suicidal behaviors; structured linear mixed model to study multivariate gene– environment interactions.

Setting

The Yale-Penn cohort was recruited to investigate the genetics of SDs. The Army STARRS (Study to Assess Risk and Resilience in Servicemembers) cohort was recruited to evaluate mental health risk and resilience for suicidal behaviors among Army personnel.

Participants

Yale-Penn participants (N=15,557) were assessed via the Semi-Structured Assessment for Drug Dependence and Alcoholism. Army STARRS participants (N=11,236) were evaluated using the self-administered Composite International Diagnostic Interview Screening Scales.

Measurement

Lifetime self-reported suicidal behaviors (ideation, SI; planning; attempt, SA); Lifetime DSM-IV diagnoses and criteria for dependence on alcohol, cannabis, cocaine (CoD), opioid (OD), and nicotine (ND) (Yale-Penn); substance use disorder (SUD) (Army STARRS).

Findings

In Yale-Penn, lifetime polysubstance dependence was strongly associated with lifetime suicidal behaviors: individuals with five SDs showed increased odds ranging from OR=6.77 (95%CI=5.74-7.99) for SI to OR=3.61 (95%CI=2.7-4.86) for SA. In Army STARRS, SUD was associated with increased odds ranging from OR=2.88 (95%CI=2.6-3.19) for SI to OR=3.92 (95%CI=3.19-4.81) for SA. In Yale-Penn, we identified multivariate gene–environment interactions (Bayes factors, BF > 0) of SI with respect to a gene cluster on chromosome 16 (LCAT, p=1.82×10−7; TSNAXIP1, p=2.13×10−7; CENPT, p=2.32×10−7; PARD6A, p=5.57×10−7) for OD (BF=12.2), CoD (BF=12.1), ND (BF=9.2), and polysubstance dependence (BF=2.1).

Conclusions

Comorbidity of multiple SDs is a significant suicide risk factor and heritability of suicidal behaviors is partially moderated by multivariate gene interactions.
Network-based Translation of GWAS Findings to Pathobiology and Drug Repurposing for Alzheimer’s Disease
Authors: Fang Jiansong , Zhang Pengyue , Wang Quan , Zhou Yadi , Chiang Chien-Wei , Chen Rui , Zhang Bin , Li Bingshan , Lewis Stephen J. , Pieper Andrew A. , Li Lang , Cummings Jeffrey , Cheng Feixiong
Published: January 2020

Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer’s disease (AD). However, utilizing GWAS to identify high-confidence AD risk genes (ARGs) that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful. To address this critical problem in the field, we have developed a genotype-informed, network-based methodology that interrogates pathogenesis to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and preclinical AD models, drug-target networks, and the human protein-protein interactome, along with large-scale patient database validation andin vitromechanistic observations in human microglia cells. Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.895, 95% confidence interval [CI] 0.841-0.951, P = 3.97 × 10−4) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR =0.921, 95% CI 0.861-0.983,P= 0.0146), an insulin secretagogue that is also used to treat type 2 diabetes.In vitroexperiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD. In summary, we present an integrated, network-based methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD.
The Concurrent Initiation of Medications Is Associated with Discontinuation of Buprenorphine Treatment for Opioid Use Disorder
Authors: Zhang Pengyue , Chiang Chien-Wei , Quinney Sara , Donneyong Macarius , Lu Bo , Huang Lei Frank , Cheng Feixiong
Published: January 2020

Introduction

Retention in buprenorphine treatment for opioid use disorder (OUD) yields better opioid abstinence and reduces all-cause mortality for patients with OUD. Despite significant efforts have been made to expand the availability and use of buprenorphine in the United States, its retention rates remain on a low level. The current study examines discontinuation of buprenorphine with respect to concurrent initiation of other medications using real-world evidence.

Methods

Case-crossover study was conducted to examine discontinuation of buprenorphine using a large-scale longitudinal health dataset including 148,306 commercially-insured individuals initiated on medications for opioid use disorder (MOUD). Odds ratios and Bonferroni adjusted p-values were calculated for medications and therapeutic classes of medications.

Results

Clonidine was associated with increased discontinuation risk of buprenorphine both using the buprenorphine dataset alone (OR = 1.583 and adjusted p-value = 1.22 × 10−6) and using naltrexone as a comparison drug (OR = 2.706 and adjusted p-value = 4.11 × 10−5). Opioid medications (oxycodone, morphine and fentanyl) and methocarbamol were associated with increased discontinuation risk of buprenorphine using the buprenorphine dataset alone (adjusted p-value < 0.05), but not significant using naltrexone as a comparison drug. 6 drug therapeutic classes were associated with increased discontinuation risk of buprenorphine both using the buprenorphine dataset alone and using naltrexone as a comparison drug (adjusted p-value < 0.05).

Conclusion

Concurrent initiation of medications is associated with increased discontinuation risk of buprenorphine. Opioid medications are prescribed among patients on MOUD and associated with increased discontinuation risk of buprenorphine. Analgesics is associated with increased discontinuation risk of buprenorphine for patients without previous exposure of pain medications.
Development of Gene Editing Strategies for Humanβ-Globin (HBB) Gene Mutations
Authors: Kalkan Batuhan Mert , Kala Ezgi Yagmur , Yuce Melek , Alpaslan Medine Karadag , Kocabas Fatih
Published: January 2020

Recent developments in gene editing technology have enabled scientists to modify DNA sequence by using engineered endonucleases. These gene editing tools are promising candidates for clinical applications, especially for treatment of inherited disorders like sickle cell disease (SCD). SCD is caused by a point mutation in human β-globin gene (HBB). Clinical strategies have demonstrated substantial success, however there is not any permanent cure for SCD available. CRISPR/Cas9 platform uses a single endonuclease and a single guide RNA (gRNA) to induce sequence-specific DNA double strand break (DSB). When this accompanies a repair template, it allows repairing the mutated gene. In this study, it was aimed to target HBB gene via CRISPR/Cas9 genome editing tool to introduce nucleotide alterations for efficient genome editing and correction of point mutations causing SCD in human cell line, by Homology Directed Repair (HDR). We have achieved to induce target specific nucleotide changes on HBB gene in the locus of mutation causing SCD. The effect of on-target activity of bone fide standard gRNA and newly developed longer gRNA were examined. It is observed that longer gRNA has higher affinity to target DNA while having the same performance for targeting and Cas9 induced DSBs. HDR mechanism was triggered by co-delivery of donor DNA repair templates in circular plasmid form. In conclusion, we have suggested methodological pipeline for efficient targeting with higher affinity to target DNA and generating desired modifications on HBB gene.

Graphical abstract

Highlights

HBB gene were targeted by spCas9 in close proximity to the SCD mutation

Long gRNA, which is designed to target SCD mutation, is sickle cell disease specific and exhibits indistinguishable level of cleavage activity on target locus.

Functional HBB HDR repair templates with 1 Kb and 2 Kb size were generated to cover all known mutations in the HBB gene.

Replacement of PAM sequence in HDR template with HindIII recognition sequence allowed a quick assessment of the HDR efficiency.

HDR template: Cas9-GFP vector 2:1 ratio yielded the highest HDR events/GFP+ cells.
A gradient from long-term memory to novel cognition: transitions through default mode and executive cortex
Authors: Wang Xiuyi , Margulies Daniel S. , Smallwood Jonathan , Jefferies Elizabeth
Published: January 2020

Human cognition flexibly guides decision-making in familiar and novel situations. Although these decisions are often treated as dichotomous, in reality, situations are neither completely familiar, nor entirely new. Contemporary accounts of brain organization suggest that neural function is organized along a gradient from unimodal regions of sensorimotor cortex, through executive regions to transmodal default network. We examined whether this graded view of neural organization helps to explain how decision-making changes across situations that vary in their alignment with long-term knowledge. Functional magnetic resonance imaging found that as decisions are made in an increasingly familiar context, the BOLD signal follows this neural gradient, with stronger responses in default regions when items are linked in long-term memory. In this way, neural organization is optimized to support decision-making in both highly familiar and less familiar situations.
Flight demand and environmental niche are associated with molecular evolutionary rates in a large avian radiation
Authors: Duchene David A. , Montoya Paola , Claramunt Santiago , Cadena Daniel A.
Published: January 2020

Among the macroevolutionary drivers of molecular evolutionary rates, metabolic demands and environmental energy have been a central topic of discussion. The large number of studies examining these associations have found mixed results, and have rarely explored the interactions among various factors impacting molecular evolutionary rates. Taking the diverse avian family Furnariidae as a case study, we examined the association between several estimates of molecular evolutionary rates with proxies of metabolic demands imposed by flight (wing loading and the hand-wing index) and proxies of environmental energy across the geographic ranges of species (temperature and UV radiation). We found evidence that species that fly less have greater wing loading and this is associated with accelerated rates of mutation. An elongated wing morphology is associated with greater flight activity and with molecular signatures of positive selection or reduced population sizes. Meanwhile, environmental temperature and UV radiation interact to explain molecular rates at sites affected by selection and population size, contrary to the expectation of their impact on mutation rates. Our results suggest that the demands of flight and environmental energy pose multiple evolutionary pressures on the genome either by driving mutation rates or via their association with natural selection or population size.
Mental compression of spatial sequences in human working memory using numerical and geometrical primitives
Authors: Al Roumi Fosca , Marti Sébastien , Wang Liping , Amalric Marie , Dehaene Stanislas
Published: January 2020

How does the human brain store sequences of spatial locations? The standard view is that each consecutive item occupies a distinct slot in working memory. Here, we formulate and test the alternative hypothesis that the human brain compresses the whole sequence using an abstract, language-like code that captures the numerical and geometrical regularities of the sequence at multiple nested levels. We exposed participants to spatial sequences of fixed length but variable regularity, and asked them to remember the sequence in order to detect deviants, while their brain activity was recorded using magneto-encephalography. Using multivariate decoders, each successive location could be decoded from brain signals, and upcoming locations were anticipated prior to their actual onset. Crucially, sequences with lower complexity, defined as the minimal description length provided by the formal language, and whose memory representation was therefore predicted to be more compressed, led to lower error rates and to increased anticipations. Furthermore, neural codes specific to the numerical and geometrical primitives of the postulated language could be detected, both in isolation and within the sequences. These results suggest that the human brain detects sequence regularities at multiple nested levels and uses them to compress long sequences in working memory.