bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Rural Residence on Kidney Transplant Rates Among Waitlisted Candidates in the VA Transplant Programs
Authors: O’Shea Amy M.J. , Franciscus Carrie L. , Kaboli Peter J. , Kalil Roberto S.
Published: July 2019

Background.

Although proportionally more veterans live in rural areas compared to nonveterans, the impact of rurality status on kidney transplantation (KTP) access among veterans is unknown. Our objective was to study KTP rates among veterans listed for KTP and to compare the impact of rurality status on KTP rates among veterans and nonveterans.

Methods.

Retrospective cohort study of adult patients waitlisted per the United Network for Organ Sharing from January 2000 to December 2014. Patient characteristics were compared using Chi-square or t tests, as appropriate, by veteran status and patient rurality. Multivariable competing-risks Cox regression was performed.

Results.

The study sample included 3281 veterans receiving care in Veteran Health Administration transplant programs and 445 177 nonveterans. Veterans, compared to nonveterans, were older (57 versus 50 y; P < 0.001), more likely to be male (96% versus 60%; P < 0.001) or diabetic at waitlisting (51% versus 41%; P < 0.001), and less likely be an urban resident (79% versus 84%; P < 0.001). Among veterans, dialysis duration prior to registration was longer among urban compared to all other rurality types (810 ± 22.1 d versus 632 to 702 ± 41.6 to 77.6 d; P = 0.02). In multivariate competing risks models, there was no evidence that the hazard of transplant among veterans differs by residential rurality.

Conclusions.

Among waitlisted veterans served by Veteran Health Administration transplant programs, residential rurality status does not portend longer waiting time for KTP.
Ultrasound Molecular Imaging of Lymphocyte-endothelium Adhesion Cascade in Acute Cellular Rejection of Cardiac Allografts
Authors: Xie Yu , Chen Yihan , Zhang Li , Wu Meiying , Deng Zhiting , Yang Yali , Wang Jing , Lv Qing , Zheng Hairong , Xie Mingxing , Yan Fei
Published: July 2019

Background.

Acute cellular rejection is one of the main reasons for graft failure after heart transplantation. A precise diagnosis at the early stage of acute cellular rejection is a big challenge for clinicians. Given the importance of the interaction between T cells and graft endothelia in initiating rejection, we developed T cell-microbubble complexes (cell-MBs) as ultrasound molecular imaging probes to monitor the lymphocyte–endothelium adhesion cascade in cardiac acute cellular rejection.

Methods.

Cell-MBs were fabricated by incubating lymphocytes with anti-CD4 antibody-conjugated MBs (MBCD4). The potential of cell-MBs as probes for detecting acute cardiac rejection was examined. Donor hearts from Brown Norway or Lewis rats were transplanted into Lewis recipients. Ultrasound molecular imaging was performed on allografts of untreated or cyclosporin A (CsA)-treated recipients, and isografts on posttransplantation day 3. Histology was used to assess rejection grades.

Results.

We detected a significantly stronger ultrasound molecular imaging signal of cell-MBs than that of MBCD4 or plain MBs in allografts of untreated and CsA-treated recipients. No signal enhancement was observed in isografts with cell-MBs. The signal of cell-MBs in allografts of the untreated group was significantly higher than that in the CsA-treated group, and the signal in the CsA-treated group was higher than that in isografts. Histology confirmed grade 3R rejection in the untreated group, grade 2R rejection in CsA-treated group, and no rejection in isografts.

Conclusions.

Our study suggests that cell-MBs can function as a promising probe to image the dynamic lymphocyte–endothelium adhesion cascade for noninvasive diagnosis of cardiac acute cellular rejection.
Improved Survival in Liver Transplant Patients Receiving Prolonged-release Tacrolimus-based Immunosuppression in the European Liver Transplant Registry (ELTR): An Extension Study
Authors: Adam René , Karam Vincent , Cailliez Valérie , Trunečka Pavel , Samuel Didier , Tisone Giuseppe , Němec Petr , Soubrane Olivier , Schneeberger Stefan , Gridelli Bruno , Bechstein Wolf O. , Risaliti Andrea , Line Pal-Dag , Vivarelli Marco , Rossi Massimo , Pirenne Jacques , Klempnauer Jurgen L. , Rummo Aleh , Di Benedetto Fabrizio , Zieniewicz Krzysztof , Troisi Roberto , Paul Andreas , Vali Toomas , Kollmar Otto , Boudjema Karim , Hoti Emir , Colledan Michele , Pratschke Johan , Lang Hauke , Popescu Irinel , Ericzon Bo-Goran , Strupas Kestutis , De Simone Paolo , Kochs Eberhard , Heyd Bruno , Gugenheim Jean , Pinna Antonio D. , Bennet William , Kazimi Mirjalal , Bachellier Philippe , Wigmore Stephen J. , Rasmussen Allan , Clavien Pierre-Alain , Hidalgo Ernest , O’Grady John G. , Zamboni Frausto , Kilic Murat , Duvoux Christophe
Published: July 2019

Background.

We compared, through the European Liver Transplant Registry, long-term liver transplantation outcomes with prolonged-release tacrolimus (PR-T) versus immediate-release tacrolimus (IR-T)–based immunosuppression. This retrospective analysis comprises up to 8-year data collected between 2008 and 2016, in an extension of our previously published study.

Methods.

Patients with <1 month follow-up were excluded; patients were propensity score matched for baseline characteristics. Efficacy measures included: univariate/multivariate analyses of risk factors influencing graft/patient survival up to 8 years posttransplantation, and graft/patient survival up to 4 years with PR-T versus IR-T. Overall, 13 088 patients were included from 44 European centers; propensity score–matched analyses comprised 3006 patients (PR-T: n = 1002; IR-T: n = 2004).

Results.

In multivariate analyses, IR-T-based immunosuppression was associated with reduced graft survival (risk ratio, 1.49; P = 0.0038) and patient survival (risk ratio, 1.40; P = 0.0215). There was improvement with PR-T versus IR-T in graft survival (83% versus 77% at 4 y, respectively; P = 0.005) and patient survival (85% versus 80%; P = 0.017). Patients converted from IR-T to PR-T after 1 month had a higher graft survival rate than patients receiving IR-T at last follow-up (P < 0.001), or started and maintained on PR-T (P = 0.019). One graft loss in 4 years was avoided for every 14.3 patients treated with PR-T versus IR-T.

Conclusions.

PR-T-based immunosuppression might improve long-term outcomes in liver transplant recipients than IR-T-based immunosuppression.
Charcot–Marie–Tooth disease and related disorders: an evolving landscape
Authors: Laurá Matilde , Pipis Menelaos , Rossor Alexander M. , Reilly Mary M.
Published: July 2019

Purpose of review

Charcot–Marie–Tooth (CMT) disease and related disorders are the commonest group of inherited neuromuscular diseases and represent a heterogeneous group of disorders. This review will cover recent advances in genetic diagnosis and the evolving genetic and phenotype landscape of this disease group. We will review recent evidence of the increasingly recognized phenotypic overlap with other neurodegenerative conditions including hereditary spastic paraplegia, hereditary ataxias and mitochondrial diseases and highlight the importance of deep phenotyping to inform genetic diagnosis and prognosis.

Recent findings

Through whole exome sequencing and multicentre collaboration new genes are being identified as causal for CMT expanding the genetic heterogeneity of this condition. In addition, an increasing number of variants have been identified in genes known to cause complex inherited diseases in which the peripheral neuropathy is part of the disorder and may be the presenting feature. The recent discovery of a repeat expansion in the RFC1 gene in cerebellar ataxia, neuropathy, vestibular areflexia syndrome highlights the prevalence of late-onset recessive conditions which have historically been considered to cause early-onset disease.

CMT is an evolving field with considerable phenotypic and genetic heterogeneity and deep phenotyping remains a cornerstone in contemporary CMT diagnostics.
High
p
CO
2
promotes coral primary production
Authors: Biscéré T. , Zampighi M. , Lorrain A. , Jurriaans S. , Foggo A. , Houlbrèque F. , Rodolfo-Metalpa R.
Published: July 2019

While research on ocean acidification (OA) impacts on coral reefs has focused on calcification, relatively little is known about effects on coral photosynthesis and respiration, despite these being among the most plastic metabolic processes corals may use to acclimatize to adverse conditions. Here, we present data collected between 2016 and 2018 at three natural CO
2
seeps in Papua New Guinea where we measured the metabolic flexibility (i.e.
in hospite
photosynthesis and dark respiration) of 12 coral species. Despite some species-specific variability, metabolic rates as measured by net oxygen flux tended to be higher at high
p
CO
2
(
ca
1200 µatm), with increases in photosynthesis exceeding those of respiration, suggesting greater productivity of Symbiodiniaceae photosynthesis
in hospite
, and indicating the potential for metabolic flexibility that may enable these species to thrive in environments with high
p
CO
2
. However, laboratory and field observations of coral mortality under high CO
2
conditions associated with coral bleaching suggests that this metabolic subsidy does not result in coral higher resistance to extreme thermal stress. Therefore, the combined effects of OA and global warming may lead to a strong decrease in coral diversity despite the stimulating effect on coral productivity of OA alone.
Long-term fire resilience of the Ericaceous Belt, Bale Mountains, Ethiopia
Authors: Gil-Romera Graciela , Adolf Carole , Benito Blas M. , Bittner Lucas , Johansson Maria U. , Grady David A. , Lamb Henry F. , Lemma Bruk , Fekadu Mekbib , Glaser Bruno , Mekonnen Betelhem , Sevilla-Callejo Miguel , Zech Michael , Zech Wolfgang , Miehe Georg
Published: July 2019

Fire is the most frequent disturbance in the Ericaceous Belt (ca3000–4300 m.a.s.l.), one of the most important plant communities of tropical African mountains. Through resprouting after fire,Ericaestablishes a positive fire feedback under certain burning regimes. However, present-day human activity in the Bale Mountains of Ethiopia includes fire and grazing systems that may have a negative impact on the resilience of the ericaceous ecosystem. Current knowledge ofErica–fire relationships is based on studies of modern vegetation, lacking a longer time perspective that can shed light on baseline conditions for the fire feedback. We hypothesize that fire has influencedEricacommunities in the Bale Mountains at millennial time-scales. To test this, we (1) identify the fire history of the Bale Mountains through a pollen and charcoal record from Garba Guracha, a lake at 3950 m.a.s.l., and (2) describe the long-term bidirectional feedback between wildfire andErica,which may control the ecosystem's resilience. Our results support fire occurrence in the area sinceca14 000 years ago, with particularly intense burning during the early Holocene, 10.8–6.0 cal ka BP. We show that a positive feedback betweenEricaabundance and fire occurrence was in operation throughout the Lateglacial and Holocene, and interpret the Ericaceous Belt of the Ethiopian mountains as a long-term fire resilient ecosystem. We propose that controlled burning should be an integral part of landscape management in the Bale Mountains National Park.
Dissection of Bitcoin’s multiscale bubble history from January 2012 to February 2018
Authors: Gerlach J. C. , Demos G. , Sornette D.
Published: July 2019

We present a detailed bubble analysis of the Bitcoin to US Dollar price dynamics from January 2012 to February 2018. We introduce a robust automatic peak detection method that classifies price time series into periods of uninterrupted market growth (drawups) and regimes of uninterrupted market decrease (drawdowns). In combination with the
Lagrange Regularization Method
for detecting the beginning of a new market regime, we identify three major peaks and 10 additional smaller peaks, that have punctuated the dynamics of Bitcoin price during the analysed time period. We explain this classification of long and short bubbles by a number of quantitative metrics and graphs to understand the main socio-economic drivers behind the ascent of Bitcoin over this period. Then, a detailed analysis of the growing risks associated with the three long bubbles using the
Log-Periodic Power-Law Singularity
(LPPLS) model is based on the
LPPLS Confidence Indicators
, defined as the fraction of qualified fits of the LPPLS model over multiple time windows. Furthermore, for various fictitious ‘present’ times
t
2
before the crashes, we employ a clustering method to group the predicted critical times
t

c

of the LPPLS fits over different time scales, where
t

c

is the most probable time for the ending of the bubble. Each cluster is proposed as a plausible scenario for the subsequent Bitcoin price evolution. We present these predictions for the three long bubbles and the four short bubbles that our time scale of analysis was able to resolve. Overall, our predictive scheme provides useful information to warn of an imminent crash risk.
Bayesian tip dating reveals heterogeneous morphological clocks in Mesozoic birds
Authors: Zhang Chi , Wang Min
Published: July 2019

Recently, comprehensive morphological datasets including nearly all the well-recognized Mesozoic birds became available, making it feasible for statistically rigorous methods to unveil finer evolutionary patterns during early avian evolution. Here, we exploited the advantage of Bayesian tip dating under relaxed morphological clocks to estimate both the divergence times and evolutionary rates while accounting for their uncertainties. We further subdivided the characters into six body regions (i.e. skull, axial skeleton, pectoral girdle and sternum, forelimb, pelvic girdle and hindlimb) to assess evolutionary rate heterogeneity both along the lineages and across partitions. We observed extremely high rates of morphological character changes during early avian evolution, and the clock rates are quite heterogeneous among the six regions. The branch subtending Pygostylia shows an extremely high rate in the axial skeleton, while the branches subtending Ornithothoraces and Enantiornithes show notably high rates in the pectoral girdle and sternum and moderately high rates in the forelimb. The extensive modifications in these body regions largely correspond to refinement of the flight capability. This study reveals the power and flexibility of Bayesian tip dating implemented in MrBayes to investigate evolutionary dynamics in deep time.
Body coloration and mechanisms of colour production in Archelosauria: the case of deirocheline turtles
Authors: Brejcha Jindřich , Bataller José Vicente , Bosáková Zuzana , Geryk Jan , Havlíková Martina , Kleisner Karel , Maršík Petr , Font Enrique
Published: July 2019

Animal body coloration is a complex trait resulting from the interplay of multiple mechanisms. While many studies address the functions of animal coloration, the mechanisms of colour production still remain unknown in most taxa. Here we compare reflectance spectra, cellular, ultra- and nano-structure of colour-producing elements, and pigment types in two freshwater turtles with contrasting courtship behaviour,Trachemys scriptaandPseudemys concinna. The two species differ in the distribution of pigment cell-types and in pigment diversity. We found xanthophores, melanocytes, abundant iridophores and dermal collagen fibres in stripes of both species. The yellow chin and forelimb stripes of bothP. concinnaandT. scriptacontain xanthophores and iridophores, but the post-orbital regions of the two species differ in cell-type distribution. The yellow post-orbital region ofP. concinnacontains both xanthophores and iridophores, whileT. scriptahas only xanthophores in the yellow-red postorbital/zygomatic regions. Moreover, in both species, the xanthophores colouring the yellow-red skin contain carotenoids, pterins and riboflavin, butT. scriptahas a higher diversity of pigments thanP. concinna.Trachemys s. elegansis sexually dichromatic. Differences in the distribution of pigment cell types across body regions in the two species may be related to visual signalling but do not match predictions based on courtship position. Our results demonstrate that archelosaurs share some colour production mechanisms with amphibians and lepidosaurs (i.e. vertical layering/stacking of different pigment cell types and interplay of carotenoids and pterins), but also employ novel mechanisms (i.e. nano-organization of dermal collagen) shared with mammals.
Associations between respiratory health outcomes and coal mine fire PM2.5 smoke exposure: a cross-sectional study
Authors: Johnson Amanda L , Gao Caroline X , Dennekamp Martine , Williamson Grant J , Brown David , Carroll Matthew TC , Monaco Anthony Del , Ikin Jillian F , Abramson Michael J , Guo Yuming
Published: July 2019

Rational

In 2014, local wildfires ignited a fire in the Morwell open cut coal mine, in south-eastern Australia, which burned for six weeks. Limited research was available regarding the respiratory health effects of coal mine fire-related PM2.5 smoke exposure.

Objective

This study examined associations between self-reported respiratory outcomes in adults and mine fire-related PM2.5 smoke exposure.

Participants

Eligible participants were adult residents of Morwell, identified using the Victorian electoral roll.

Main outcome measures

Self-reported data were collected as part of the Hazelwood Health Study Adult Survey.

Mine fire-related PM2.5 concentrations were retrospectively modelled by the Commonwealth Scientific and Industrial Research Organisation Oceans & Atmosphere Flagship. Personalised mean 24-h and peak 12-h mine fire-related PM2.5 exposures were estimated for each participant. Data were analysed by multivariate logistic regression.

Results

There was some evidence of a dose-response relationship between respiratory outcomes and mine fire PM2.5 concentrations. Chronic cough was associated with an Odds Ratio (OR) of 1.13 (95% Confidence Interval 1.03 to 1.23; p-value 0.007) per 10 μg/m3 increment in mean PM2.5 and 1.07 (1.02 to 1.12; 0.004) per 100 μg/m3 increment in peak PM2.5. Current wheeze was associated with peak PM2.5, OR=1.06 (1.02 to 1.11; 0.004) and chronic phlegm with mean PM2.5 OR=1.10 (1.00 to 1.20; 0.052). Males, participants 18-64 years and those residing in homes constructed from non-brick/concrete materials or homes with tin/metal roofs had higher estimated ORs.

Conclusions

These findings contribute to the formation of public health policy responses in the event of future major pollution episodes.

Key Messages

What is the key question?

Was there an association between mine fire-related PM2.5 smoke exposure and self-reported respiratory health outcomes for adult residents of Morwell, approximately 2.5 years after the mine fire?

What is the bottom line?

There was some evidence of a dose-response relationship between respiratory outcomes and mine fire-related PM2.5 concentrations.

Why read on?

There is limited research regarding the health effects of coal mine fire-related PM2.5 smoke exposure and to the best of our knowledge, this is the first study to examine self-reported respiratory symptoms associated with smoke exposure from a coal mine fire.
A moment of change: shifts in myeloarchitecture characterise adolescent development of cortical gradients
Authors: Paquola C , Bethlehem RAI , Seidlitz J , Wagstyl K , Romero-Garcia R , Whitaker KJ , Vos De Wael R , Williams GB ,   NSPN Consortium, Vértes PE , Margulies DS , Bernhardt BC , Bullmore ET
Published: July 2019

The biological processes underpinning adolescent brain maturation remain elusive. Expanding on previous work showing age-related changes in cortical morphology, we studied an accelerated longitudinal cohort of adolescents and young adults (n=223, two time points) to investigate dynamic reconfigurations in myeloarchitecture. Intracortical profiles were generated using magnetization transfer (MT) data, a myelin-sensitive magnetic resonance imaging contrast. Mixed-effect models of depth specific intracortical profiles demonstrated two separate processes i) related to overall increases in MT, and ii) showing a flattening of the MT profile related to enhanced signal in mid-to-deeper layers, especially in heteromodal and unimodal association cortices. This development was independent of morphological changes, and enhanced MT in mid-to-deeper layers was found to spatially co-localise specifically with gene expression markers of oligodendrocytes. Covariance analysis between all pairs of intracortical profiles revealed that these intracortical changes contributed to a gradual and dynamic differentiation from higher-order to lower-order systems. Depth-dependent trajectories of intracortical myeloarchitectural development contribute to the maturation of structural hierarchies in the human neocortex, providing a model for adolescent development that bridges microstructural and macroscopic scales of brain organization.

eLife digest

Intracortical myelin imposes a spatial structure on cortico-cortical connections, yet little is known about how myeloarchitecture develops throughout youth. We formulated a novel approach to study cortical myeloarchitecture in individual humans and leveraged an accelerated longitudinal design to track age-related changes from 14-27 years. We discovered two unique processes: one involving increasing mean myelin and another characterised by the preferential accumulation of myelin in mid-to-deeper cortical layers. Both processes contributed to an increasing segregation of lower-order from higher-order systems along the macroscale cortical hierarchy. These findings illustrate how layer specific microstructural changes contribute to the maturation of cortical organization and suggest adolescent fine tuning of hierarchical gradients of cortical networks.
Passive diffusion through nuclear pore complexes regulates levels of the yeast SAGA and SLIK coactivators complexes
Authors: Makio Tadashi , Wozniak Richard W.
Published: July 2019

Nuclear pore complexes (NPCs) control gene expression by regulating the bi-directional exchange of proteins and RNAs between nuclear and cytoplasmic compartments, including access of transcriptional regulators to the nucleoplasm. Here we show that the yeast nucleoporin Nup170, in addition to binding and silencing subtelomeric genes, supports transcription of genes regulated by the SAGA transcriptional activator. Specifically, we show that less SAGA complex is bound to target genes in the absence Nup170. Consistent with this observation, levels of the SAGA complex are decreased in cells lacking Nup170, while SAGA-related SLIK complexes are increased. This change in the ratio of SAGA to SLIK complexes is due to increased nuclear activity of Pep4, a protease responsible for production of the SLIK complex. Further analyses of various nucleoporin mutants revealed that the increased nuclear entry of Pep4 observed in thenup170Δ mutant likely occurs as consequence of an increase in the sieving limits of the NPC diffusion channel. On the basis of these results, we propose that changes in passive diffusion rates represents a mechanism for regulating SAGA/SLIK complex-mediated transcriptional events.
TNFRSF14 (HVEM) is a novel immune checkpoint for cancer immunotherapy in humanized mice
Authors: Aubert Nicolas , Brunel Simon , Olive Daniel , Marodon Gilles
Published: July 2019

Background

TNFRSF14 (herpes virus entry mediator (HVEM) delivers a negative signal to T cells through the B and T Lymphocyte Attenuator (BTLA) molecule and has been associated with a worse prognosis in numerous malignancies. A formal demonstration that the HVEM/BTLA axis can be targeted for cancer immunotherapy is however still lacking.

Methods

We used immunodeficient NOD.SCID.gc-null mice reconstituted with human PBMC and grafted with human tumor cell lines subcutaneously. Tumor growth was compared using linear and non linear regression statistical modeling. The phenotype of tumor-infiltrating leukocytes was determined by flow cytometry. Statistical testing between groups was performed by a non-parametric t test. Quantification of mRNA in the tumor was performed using NanoString pre-designed panels. Bioinformatics analyses were performed using Metascape, Gene Set Enrichment Analysis and Ingenuity Pathways Analysis with embedded statistical testing.

Results

We showed that a murine monoclonal antibody to human HVEM significantly impacted the growth of various HVEM-positive cancer cell lines in humanized NSG mice. Using CRISPR/cas9 mediated deletion of HVEM, we showed that HVEM expression by the tumor was necessary and sufficient to observe the therapeutic effect. Tumor cell killing by the mAb was dependent on innate immune cells still present in NSG mice, as indicated byin vivoandin vitroassays. Mechanistically, tumor control by human T cells by the mAb was dependent on CD8 T cells and was associated with an increase in the proliferation and number of tumor-infiltrating leukocytes. Accordingly, the expression of genes belonging to T cell activation pathways, such as JAK/STAT and NFKB were enriched in anti-HVEM-treated mice, whereas genes associated with immuno-suppressive pathways were decreased. Finally, we developed a simplein vivoassay to directly demonstrate that HVEM/BTLA is an immune checkpoint for T-cell mediated tumor control.

Conclusions

Our results show that targeting HVEM is a promising strategy for cancer immunotherapy.
Exploring the infection dynamics of a bacterial pathogen on a remote oceanic island reveals annual epizootics impacting an albatross population
Authors: Jaeger Audrey , Gamble Amandine , Lagadec Erwan , Lebarbenchon Camille , Bourret Vincent , Tornos Jérémy , Barbraud Christophe , Lemberger Karin , Delord Karine , Weimerskirch Henri , Thiebot Jean-Baptiste , Boulinier Thierry , Tortosa Pablo
Published: July 2019

Oceanic islands with reduced species richness provide an opportunity to investigate the emergence, maintenance and transmission of infectious diseases threatening wildlife. On Amsterdam Island, in the southern Indian Ocean, massive and recurrent mortality of the nestlings of Indian yellow-nosed albatross (Thalassarche carteri) has been attributed to avian cholera caused byPasteurella multocida, a bacterial pathogen of likely human introduction. To understand the annual dynamics of pathogen prevalence, we measured the shedding of bacterial DNA by the albatrosses during four successive breeding seasons. The screening of 583 bird swabs by Real-Time PCR revealed an intense circulation ofP. multocidaduring each study year, with a steady increase of infection prevalence across the breeding season. In the three years of highest pathogen prevalence, the epizootics were associated with massive die-offs of nestlings, inducing low annual fledging success (< 20%). These findings and developed PCR protocol have crucial applications for refining wildlife conservation plans aiming at controlling this disease.
The wild species genome ancestry of domestic chickens
Authors: Lawal Raman Akinyanju , Martin Simon H. , Vanmechelen Koen , Vereijken Addie , Silva Pradeepa , Al-Atiyat Raed Mahmoud , Aljumaah Riyadh Salah , Mwacharo Joram M. , Wu Dong-Dong , Zhang Ya-Ping , Hocking Paul M. , Smith Jacqueline , Wragg David , Hanotte Olivier
Published: July 2019

Hybridization and/or introgression play a key role in the evolutionary history of animal species. It is commonly observed in several orders in wild birds. The domestic chickenGallus gallus domesticusis the commonest livestock species exploited for the benefit of mankind. The origin of its diversity remains unsettled. Here, we report a genome-wide analyses for signatures of introgression within domestic village chicken. We first established the genome-wide phylogeny and divergence time across the genusGallus, showing the sister relationships between Grey junglefowlG. sonneratiiand Ceylon junglefowlG. lafayettiiand that the Green junglefowl is the first diverging lineage within the genusGallus. Then, by analysing the whole-genome sequences of geographically diverse chicken populations, we reveal extensive bidirectional introgression between Grey junglefowl and domestic chicken and to a much less extent with Ceylon junglefowl. A single case of Green junglefowlG. variusintrogression was identified. These introgressed regions include biological functions related to the control of gene expression. Our results show that while the Red junglefowl is the main ancestral species, introgressive hybridization episodes have impacted the genome and contributed to the diversity of domestic chicken, although likely at different level across its geographic range.
Vaccine-induced ICOS+CD38+ cTfh are sensitive biosensors of age-related changes in inflammatory pathways
Authors: Herati Ramin Sedaghat , Silva Luisa Victoria , Vella Laura A. , Muselman Alexander , Alanio Cecile , Bengsch Bertram , Kurupati Raj K. , Kannan Senthil , Manne Sasikanth , Kossenkov Andrew V. , Canaday David H. , Doyle Susan A. , Ertl Hildegund C.J. , Schmader Kenneth E. , Wherry E. John
Published: July 2019

Humoral immune responses are dysregulated with aging but details remain incompletely understood. In particular, little is known about the effects of aging on T follicular helper (Tfh) CD4 cells, the subset that provides critical help to B cells for effective humoral immunity. We previously demonstrated that influenza vaccination increases a circulating Tfh (cTfh) subset that expresses ICOS and CD38, contains influenza-specific memory cells, and is correlated with antibody responses. To directly study the effects of aging on the cTfh response, we performed transcriptional profiling and cellular analysis before and after influenza vaccination in young and elderly adults. Several key differences in cTfh responses were revealed in the elderly. First, whole blood transcriptional profiling defined cross-validated genesets of youth versus aging and these genesets were, compared to other T cells, preferentially enriched in ICOS+CD38+ cTfh from young and elderly subjects, respectively, following vaccination. Second, vaccine-induced ICOS+CD38+ cTfh from the elderly were enriched for transcriptional signatures of inflammation including TNF-NFkB pathway activation. Indeed, we reveal a paradoxical positive effect of TNF signaling on Tfh providing help to B cells linked to survival circuits that may explain detrimental effects of TNF blockade on vaccine responses. Finally, vaccine-induced ICOS+CD38+ cTfh displayed strong enrichment for signatures of underlying age-associated biological changes. Thus, these data reveal key biological changes in cTfh during aging and also demonstrate the sensitivity of vaccine-induced cTfh to underlying changes in host physiology. This latter observation suggests that vaccine-induced cTfh could function as sensitive biosensors of underlying inflammatory and/or overall immune health.

One sentence summary

Transcriptional profiling of vaccine-induced circulating T follicular helper cell responding to influenza vaccination reveals age-associated effects on Tfh such as alterations in TNF-NFkB signaling.
How range residency and long-range perception change encounter rates
Authors: Martinez-Garcia Ricardo , Fleming Christen H. , Seppelt Ralf , Fagan William F. , Calabrese Justin M.
Published: July 2019

Encounter rates link movement strategies to intra- and inter-specific interactions, and therefore translate individual movement behavior into higher-level ecological processes. Indeed, a large body of interacting population theory rests on the law of mass action, which can be derived from assumptions of Brownian motion in an enclosed container with exclusively local perception. These assumptions imply completely uniform space use, individual home ranges equivalent to the population range, and encounter dependent on movement paths actually crossing. Mounting empirical evidence, however, suggests that animals use space non-uniformly, occupy home ranges substantially smaller than the population range, and are often capable of nonlocal perception. Here, we explore how these empirically supported behaviors change pairwise encounter rates. Specifically, we derive novel analytical expressions for encounter rates under Ornstein-Uhlenbeck motion, which features non-uniform space use and allows individual home ranges to differ from the population range. We compare OU-based encounter predictions to those of Reflected Brownian Motion, from which the law of mass action can be derived. For both models, we further explore how the interplay between the scale of perception and home range size affects encounter rates. We find that neglecting realistic movement and perceptual behaviors can systematically bias encounter rate predictions.
HdaB: a novel and conserved DnaA-related protein that targets the RIDA process to stimulate replication initiation
Authors: Frandi Antonio , Collier Justine
Published: July 2019

Exquisite control of the DnaA initiator is critical to ensure that bacteria initiate chromosome replication in a cell cycle-coordinated manner. In many bacteria, the DnaA-related and replisome-associated Hda/HdaA protein interacts with DnaA to trigger the regulatory inactivation of DnaA (RIDA) and prevent over-initiation events. In theC. crescentus Alphaproteobacterium, the RIDA process also targets DnaA for its rapid proteolysis by Lon. The impact of the RIDA process on adaptation of bacteria to changing environments remains unexplored. Here, we identify a novel and conserved DnaA-related protein, named HdaB, and show that homologs from three differentAlphaproteobacteriacan inhibit the RIDA process, leading to over-initiation and cell death when expressed in actively growingC. crescentuscells. We further show that HdaB interacts with HdaAin vivo, most likely titrating HdaA away from DnaA. Strikingly, we find that HdaB accumulates mainly during stationary phase and that it shortens the lag phase upon exit from stationary phase. Altogether, these findings suggest that expression ofhdaBduring stationary phase prepares cells to restart the replication of their chromosome as soon as conditions improve, a situation often met by free-living or facultative intracellularAlphaproteobacteria.
Genetic algorithm-based personalized models of human cardiac action potential
Authors: Smirnov D.N. , Syunyaev R.A. , Deviatiiarov R.M. , Gusev O.A. , Aras K.K. , Koppel A.C. , Efimov I.R.
Published: July 2019

We present a novel genetic algorithm-based solution to determine the set of cardiomyocyte model parameters based on experimental human action potential (AP) recordings. The novel approach is based on AP waveform dependence on the heart rate. In order to find the steady-state solution, optimized parameters include conductivities of ionic channels and exchangers augmented by slow variables, intracellular sodium concentration and sarcoplasmic reticulum calcium load. The algorithm is enhanced by a novel mutation operator, based on Cauchy distribution along a random direction in parameter space. We also demonstrate that increasing the number of elite organisms up to 7% results in faster convergence. Test runs indicate that algorithm error is below 5% for IKr, 7% for IK1and INaand 13% for ICaL. Experimental signal-to-noise ratio above 28 dB was sufficient for high quality algorithm performance. The algorithm validation using optical mapping recordings of human ventricular AP demonstrated low error that was below 6 mV for AP waveform and less than 16 ms for AP duration. Further validation of the personalized models was done using mRNA expression profile of two donor hearts. The mRNA-based model reproduced AP waveform dependence on cycle length with 13 mV accuracy and AP duration with 20 ms accuracy.
Rapid dissolution of dioecy by experimental evolution
Authors: Cossard G. G. , Gerchen J. F. , Li X. , Cuenot Y. , Pannell J. R.
Published: July 2019

Evolutionary transitions from hermaphroditism to dioecy have been frequent in flowering plants, but recent analysis indicates that reversions from dioecy to hermaphroditism have also been common. Here, we use experimental evolution to expose a mechanism for such reversions. We removed males from dioecious populations of the wind-pollinated plant Mercurialis annua and allowed natural selection to act on the remaining females that varied in their propensity for the occasional production of male flowers; such ‘leaky’ sex expression is common in both males and females of dioecious plants. Over only four generations, females evolved a 23-fold increase in average male-flower production. The phenotypic masculinization of females was also sufficient to render them effective at siring progeny in the presence of males. Our study illustrates the rapid dissolution of dioecy and the evolution of functional hermaphroditism under conditions that may frequently occur during periods of low population density, repeated colonization, or range expansion. It thereby experimentally validates a mechanism for a major transition in plant sexual systems..
Cortical selectivity driven by connectivity: Innate connectivity patterns of the visual word form area
Authors: Li Jin , Osher David E. , Hansen Heather A. , Saygin Zeynep M.
Published: July 2019

What determines the functional organization of cortex? One hypothesis is that innate connectivity patterns set up a scaffold upon which functional specialization can later take place. We tested this hypothesis by asking whether the visual word form area (VWFA), an experience-driven region, was already connected to proto language networks in neonates scanned within one week of birth. With resting-state fMRI, we found that neonates showed adult-like functional connectivity, and observed that i) language regions connected more strongly with the putative VWFA than other adjacent ventral visual regions that also show foveal bias, and ii) the VWFA connected more strongly with frontotemporal language regions than with regions adjacent to these language regions. These data suggest that the location of the VWFA is earmarked at birth due to its connectivity with the language network, providing evidence that innate connectivity instructs the later refinement of cortex.
The Genetic History of France
Authors: Pierre Aude Saint , Giemza Joanna , Karakachoff Matilde , Alves Isabel , Amouyel Philippe , Dartigues Jean-François , Tzourio Christophe , Monteil Martial , Galan Pilar , Hercberg Serge , Redon Richard , Génin Emmanuelle , Dina Christian
Published: July 2019

The study of the genetic structure of different countries within Europe has provided significant insights into their demographic history and their actual stratification. Although France occupies a particular location at the end of the European peninsula and at the crossroads of migration routes, few population genetic studies have been conducted so far with genome-wide data. In this study, we analyzed SNP-chip genetic data from 2 184 individuals born in France who were enrolled in two independent population cohorts. Using FineStructure, six different genetic clusters of individuals were found that were very consistent between the two cohorts. These clusters match extremely well the geography and overlap with historical and linguistic divisions of France. By modeling the relationship between genetics and geography using EEMS software, we were able to detect gene flow barriers that are similar in the two cohorts and corresponds to major French rivers or mountains. Estimations of effective population sizes using IBDNe program also revealed very similar patterns in both cohorts with a rapid increase of effective population sizes over the last 150 generations similar to what was observed in other European countries. A marked bottleneck is also consistently seen in the two datasets starting in the fourteenth century when the Black Death raged in Europe. In conclusion, by performing the first exhaustive study of the genetic structure of France, we fill a gap in the genetic studies in Europe that would be useful to medical geneticists but also historians and archeologists.
Template Switching Mediates Contractions of a Repetitive Coding Region inS. cerevisiae
Authors: Stewart Taylor , Exner Alexandra E. , Patnaik Paras , Fuchs Stephen M.
Published: July 2019

The C-terminal domain (CTD) is an essential domain of the largest subunit of RNA polymerase II, Rpb1p, and is composed of 26 tandem repeats of a seven-amino acid sequence, YSPTSPS. Despite being an essential domain within an essential gene, we have previously demonstrated that the CTD coding region is genetically unstable. Furthermore, yeast with a truncated or mutated CTD sequence are capable of promoting spontaneous genetic expansion or contraction of this coding region to improve fitness. We investigated the mechanism by which the CTD contracts using a tet-off reporter system forRPB1to monitor genetic instability within the CTD coding region. We report that contractions require the post-replication repair factor Rad5p but, unlike expansions, not the homologous recombination factors Rad51p and Rad52p. Sequence analysis of contraction events reveals that deleted regions are flanked by microhomologies. We also find that G-quadruplex forming sequences predicted by the QGRS Mapper are enriched on the noncoding strand of the CTD compared to the body ofRPB1. Formation of G-quadruplexes in the CTD coding region could block the replication fork, necessitating post-replication repair by template switching. We propose that contractions of the CTD result when microhomologies misalign during Rad5p-dependent template switching via fork reversal.
Broadband slow-wave modulation in posterior and anterior cortex tracks distinct states of propofol-induced unconsciousness
Authors: Stephen Emily P. , Hotan Gladia C. , Pierce Eric T. , Harrell P. Grace , Walsh John L. , Brown Emery N. , Purdon Patrick L.
Published: July 2019

A controversy 5 has developed in recent years over the role that frontal and posterior cortices play in mediating consciousness and unconsciousness. One hypothesis proposes that posterior sensory and association cortices are the principal mediators of consciousness, citing evidence that strong slow-wave activity over posterior cortex during sleep disrupts the contents of dreaming. A competing hypothesis proposes that frontal-posterior interactions are critical to ignite a conscious percept, since activation of frontal cortex appears necessary for perception and can reverse unconsciousness under anesthesia. In both cases, EEG slow-waves (< 1 Hz) are considered evidence that up- and down-states are disrupting cortical activity necessary for consciousness. Here, we used anesthesia to study the interaction between the slow-wave and higher frequency activity in humans. If slow-waves are derived from underlying up and down-states, then they should modulate activity across a broad range of frequencies. We found that this broadband slow-wave modulation does occur: broadband slow-wave modulation occurs over posterior cortex when subjects initially become unconscious, but later encompasses both frontal and posterior cortex when subjects are more deeply anesthetized and likely unarousable. Based on these results, we argue that unconsciousness under anesthesia comprises several shifts in brain state that disrupt the sensory contents of consciousness distinct from arousal and awareness of those contents.

Significance Statement

The roles of frontal and posterior cortices in mediating consciousness and unconsciousness are controversial. Disruption of posterior cortex during sleep appears to suppress the contents of dreaming, yet activation of frontal cortex appears necessary for perception and can reverse unconsciousness under anesthesia. We studied the time course of regional cortical disruption, as mediated by slow-wave modulation of broadband activity, during anesthesia-induced unconsciousness in humans. We found that broadband slow-wave modulation covered posterior cortex when subjects initially became unconscious, but later encompassed both frontal and posterior cortex when subjects were deeply anesthetized and likely unarousable. This suggests that unconsciousness under anesthesia comprises several shifts in brain state that disrupt the contents of consciousness distinct from arousal and awareness of those contents.
A Halo of Reduced Dinoflagellate Abundances In and Around Eelgrass Beds
Authors: Jacobs-Palmer Emily , Gallego Ramón , Ramón-Laca Ana , Kunselman Emily , Cribari Kelly , Horwith Micah , Kelly Ryan P.
Published: July 2019

Seagrass beds provide a variety of ecosystem services, both within and outside the bounds of the habitat itself. Here we use environmental DNA (eDNA) amplicons to analyze a broad cross-section of taxa from ecological communities in and immediately surrounding eelgrass (Zostera marina). Sampling seawater along transects extending alongshore outward from eelgrass beds, we demonstrate that eDNA provides meter-scale resolution of communities in the field. We evaluate eDNA abundance indices for thirteen major phylogenetic groups of marine and estuarine taxa along these transects, finding highly local changes linked with proximity to Z. marina for a diverse group of dinoflagellates, and for no other group of taxa. Eelgrass habitat is consistently associated with dramatic reductions in dinoflagellate abundance both within the contiguous beds and for at least fifteen meters outside, relative to nearby sites without eelgrass. These results are consistent with the hypothesis that eelgrass-associated communities have allelopathic effects on dinoflagellates, and that these effects can extend in a halo beyond the bounds of the contiguous beds. Because many dinoflagellates are capable of forming Harmful Algal Blooms (HABs) toxic to humans and other animal species, the apparent salutary effect of eelgrass habitat on neighboring waters has important implications for public health as well as shellfish aquaculture and harvesting.
Urbilaterian origin and evolution of sNPF-type neuropeptide signalling
Authors: Yañez-Guerra Luis Alfonso , Zhong Xingxing , Moghul Ismail , Butts Thomas , Zampronio Cleidiane G. , Jones Alexandra M. , Mirabeau Olivier , Elphick Maurice R.
Published: July 2019

Physiology and behaviour are controlled by neuropeptide signalling systems comprising peptide ligands and cognate receptors. Molecular phylogenetics combined with experimental identification of neuropeptide-receptor pairs has revealed that many neuropeptide signalling systems originated in the urbilaterian common ancestor of protostomes and deuterostomes. Neuropeptide-Y/neuropeptide-F (NPY/NPF)-type signalling is one such example, whereas NPY/NPF-related short-NPF (sNPF)-type signalling has hitherto only been identified in protostomes. Here we report the discovery of a neuropeptide (pQDRSKAMQAERTGQLRRLNPRF-NH2) that is the ligand for an sNPF-type receptor in a deuterostome, the starfish Asterias rubens (Phylum Echinodermata). Informed by phylogenetic analysis of sequence data, we conclude that the paralogous NPY/NPF-type and sNPF-type signalling systems originated in Urbilateria but NPY/NPF-type signalling was lost in echinoderms. Furthermore, we present evidence that sNPF-type peptides are orthologs of vertebrate prolactin-releasing peptides. Our findings demonstrate the importance of experimental studies on echinoderms for reconstructing the evolutionary history of neuropeptide signalling systems.