bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of DIEP Flap and Fluorescent Angiography: A Randomized Controlled Clinical Trial
Authors: Varela Ramon , Casado-Sanchez Cesar , Zarbakhsh Shirin , Diez Jesus , Hernandez-Godoy Juan , Landin Luis
Published: October 2019

Background:

Breast reconstruction with the deep inferior epigastric perforator (DIEP) flap can be associated with complications such as fat necrosis. The authors’ objective was to assess the safety and efficacy of fluorescent angiography with indocyanine green to reduce fat necrosis.

Methods:

The authors designed a parallel, randomized, controlled clinical trial for unilateral breast reconstruction. The poorly vascularized tissues of the DIEP flap were removed based on a clinical evaluation in group 1 and based on angiographic criteria in group 2. The authors recorded the flap dimensions, perfusion in terms of fluorescence intensity, complications, reoperations, and BREAST-Q questionnaire scores for both groups.

Results:

The study included a total of 51 patients. The flaps showed no size differences after the tissue was excised. The flaps of group 2 presented higher perfusion rates (p = 0.001). The incidence of fat necrosis was 59.3 percent in group 1 and 8.3 percent in group 2 (p = 0.001). Four cases of partial necrosis were recorded in group 1 (18.2 percent) compared with none in group 2 (0 percent) (p = 0.131). Four patients underwent reoperation in group 1 (14.8 percent) compared with none in group 2 (0 percent) (p = 0.113). The patients in group 2 reported higher scores in all domains of the BREAST-Q.

Conclusions:

Fluorescent angiography with indocyanine green significantly reduced the incidence of fat necrosis without diminishing the flaps’ dimensions. The perfusion rates were significantly higher and the patients reported significantly greater satisfaction and quality of life. Fluorescent angiography with indocyanine green may be considered a safe and effective tool to enhance the outcomes of breast reconstruction with the DIEP flap.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, I.
Shorter Height Is Associated With Lower Probability of Liver Transplantation in Patients With Hepatocellular Carcinoma
Authors: Lee Eric , Sarkar Monika , Dodge Jennifer , Kohi Maureen , Mehta Neil
Published: October 2019

Background.

The effect of height and sex on liver transplantation (LT) for hepatocellular carcinoma (HCC) remains unclear.

Methods.

Using United Network for Organ Sharing (UNOS) data, 14 844 HCC patients listed for LT from 2005 to 2015 were identified. Cumulative incidence of waitlist events (LT and dropout for death or too sick) were calculated and modeled using Fine and Gray competing risk regression.

Results.

Short (SWR), mid (MWR), and long (LWR) UNOS wait regions comprised 25%, 42%, and 33% of the cohort. Three-year cumulative incidence of LT was lower in shorter height patients (≤150, 151–165, and >185 cm; 70.8%, 76.7%, and 83.5%; P < 0.001) and women (78.2% versus 79.8%; P < 0.001). On multivariable analysis, shorter height (≤150, 151–165 cm, hazard ratio [HR] versus >185 cm) was associated with lower probability of LT (0.81 and 0.89; P = 0.02) and greater dropout (HR 1.99 and 1.43; P < 0.001). Female sex was not associated with LT overall, but a significant sex and wait region interaction (P = 0.006) identified lower LT probability for women in MWR (HR versus men, 0.91; P = 0.02).

Conclusions.

Despite uniform HCC Model for End-Stage Liver Disease exception across height and sex, shorter patients and females in MWR have lower probability of LT. Consideration should be given to awarding additional Model for End-Stage Liver Disease exception points to these patients.
Randomized Sirolimus-based Early Calcineurin Inhibitor Reduction in Liver Transplantation: Impact on Renal Function
Authors: Buchholz Bettina M. , Ferguson James W. , Schnitzbauer Andreas A. , Nightingale Peter , Schlitt Hans J. , Geissler Edward K. , Mirza Darius F. ,   the International SiLVER study group
Published: October 2019

Background.

The long-term use of calcineurin inhibitors (CNIs) after liver transplantation (LT) is associated with nephrotoxicity.

Methods.

Five-year follow-up data were retrieved from the randomized controlled multicenter SiLVER trial. Standard CNI-based mammalian target of rapamycin-free immunosuppression (group A, n = 264) was compared with a 50% reduction of CNI and introduction of the mammalian target of rapamycin inhibitor Sirolimus (SIR) within 4–6 weeks after LT (group B, n = 261).

Results.

Median MELD at LT was low with 10 (7–15) (group A) and 11 (8–15) (group B) in the intention-to-treat approach. CNI dose and CNI trough were reduced by 20% and 8% (group A) versus 55% and 56% (group B) at 3 months posttransplantation. Renal function was preserved at 3 months after LT in the SIR arm (estimated glomerular filtration rate 74 [57–95] versus 67 [55–85] mL/min/1.73m2 P = 0.004) but was similarly impaired thereafter compared with group A. The per protocol analysis identified LT recipients in group B with concomitant early CNI minimization and SIR treatment ≥ year 1 with significantly superior estimated glomerular filtration rate and lowest rate of chronic kidney disease (≥stage 3) from year 1 onwards until study end. Competing risk factors for renal disease (arterial hypertension, fat metabolism disorder, and hyperglycemia) were not associated with worse kidney function.

Conclusions.

Prevention of CNI nephrotoxicity by SIR-based early CNI minimization protects renal function only short-term after LT in the intention-to-treat analysis of this low MELD cohort. Yet, selected LT recipients compliant with early CNI minimization and SIR maintenance achieved better long-term renal outcomes compared with real-world practice.
Posttransplant Outcomes for cPRA-100% Recipients Under the New Kidney Allocation System
Authors: Jackson Kyle R. , Holscher Courtenay , Motter Jennifer D. , Desai Niraj , Massie Allan B. , Garonzik-Wang Jacqueline , Alachkar Nada , Segev Dorry L.
Published: October 2019

Background.

There is concern in the transplant community that outcomes for the most highly sensitized recipients might be poor under Kidney Allocation System (KAS) high prioritization.

Methods.

To study this, we compared posttransplant outcomes of 525 pre-KAS (December 4, 2009, to December 3, 2014) calculated panel-reactive antibodies (cPRA)-100% recipients to 3026 post-KAS (December 4, 2014, to December 3, 2017) cPRA-100% recipients using SRTR data. We compared mortality and death-censored graft survival using Cox regression, acute rejection, and delayed graft function (DGF) using logistic regression, and length of stay (LOS) using negative binomial regression.

Results.

Compared with pre-KAS recipients, post-KAS recipients were allocated kidneys with lower Kidney Donor Profile Index (median 30% versus 35%, P < 0.001) but longer cold ischemic time (CIT) (median 21.0 h versus 18.6 h, P < 0.001). Compared with pre-KAS cPRA-100% recipients, those post-KAS had higher 3-year patient survival (93.6% versus 91.4%, P = 0.04) and 3-year death-censored graft survival (93.7% versus 90.6%, P = 0.005). The incidence of DGF (29.3% versus 29.2%, P = 0.9), acute rejection (11.2% versus 11.7%, P = 0.8), and median LOS (5 d versus 5d, P = 0.2) were similar between pre-KAS and post-KAS recipients. After accounting for secular trends and adjusting for recipient characteristics, post-KAS recipients had no difference in mortality (adjusted hazard ratio [aHR]: 0.861.623.06, P = 0.1), death-censored graft failure (aHR: 0.521.001.91, P > 0.9), DGF (adjusted odds ratio [aOR]: 0.580.861.27, P = 0.4), acute rejection (aOR: 0.610.941.43, P = 0.8), and LOS (adjusted LOS ratio: 0.981.161.36, P = 0.08).

Conclusions.

We did not find any statistically significant worsening of outcomes for cPRA-100% recipients under KAS, although longer-term monitoring of posttransplant mortality is warranted.
Scaling in words on Twitter
Authors: Bokányi Eszter , Kondor Dániel , Vattay Gábor
Published: October 2019

Scaling properties of language are a useful tool for understanding generative processes in texts. We investigate the scaling relations in citywise Twitter corpora coming from the metropolitan and micropolitan statistical areas of the United States. We observe a slightly superlinear urban scaling with the city population for the total volume of the tweets and words created in a city. We then find that a certain core vocabulary follows the scaling relationship of that of the bulk text, but most words are sensitive to city size, exhibiting a super- or a sublinear urban scaling. For both regimes, we can offer a plausible explanation based on the meaning of the words. We also show that the parameters for Zipf’s Law and Heaps' Law differ on Twitter from that of other texts, and that the exponent of Zipf’s Law changes with city size.
Computing the exact distributions of some functions of the ordered multinomial counts: maximum, minimum, range and sums of order statistics
Authors: Bonetti Marco , Cirillo Pasquale , Ogay Anton
Published: October 2019

Starting from seminal neglected work by Rappeport (Rappeport 1968 Algorithms and computational procedures for the application of order statistics to queuing problems. PhD thesis, New York University), we revisit and expand on the exact algorithms to compute the distribution of the maximum, the minimum, the range and the sum of theJlargest order statistics of a multinomial random vector under the hypothesis of equiprobability. Our exact results can be useful in all those situations in which the multinomial distribution plays an important role, from goodness-of-fit tests to the study of Poisson processes, with applications spanning from biostatistics to finance. We describe the algorithms, motivate their use in statistical testing and illustrate two applications. We also provide the codes and ready-to-use tables of critical values.
Inferring Atlantic salmon post-smolt migration patterns using genetic assignment
Authors: Harvey A. C. , Quintela M. , Glover K. A. , Karlsen Ø. , Nilsen R. , Skaala Ø. , Sægrov H. , Kålås S. , Knutar S. , Wennevik V.
Published: October 2019

Understanding migratory patterns is important for predicting and mitigating unwanted consequences of environmental change or anthropogenic challenges on vulnerable species. Wild Atlantic salmon undergo challenging migrations between freshwater and marine environments, and the numbers of salmon returning to their natal rivers to reproduce have declined over several decades. Mortality from sea lice linked to fish farms within their seaward migration routes is proposed as a contributing factor to these declines. Here, we used 31 microsatellite markers to establish a genetic baseline for the main rivers in the Hardangerfjord, western Norway. Mixed stock analysis was used to assign Atlantic salmon post-smolts caught in trawls in 2013–2017 back to regional reporting units. Analyses demonstrated that individuals originating from rivers located in the inner region of the fjord arrived at the outer fjord later than individuals from middle and outer fjord rivers. Therefore, as post-smolts originating from inner rivers also have to migrate longer distances to exit the fjord, these data suggest that inner fjord populations are more likely to be at risk of mortality through aquaculture-produced sea lice, and other natural factors such as predation, than middle or outer fjord populations with earlier exit times and shorter journeys. These results will be used to calibrate models estimating mortality from sea lice on wild salmon for the regulation of the Norwegian aquaculture industry.
Brightly coloured tissues in limid bivalves chemically deter predators
Authors: Dougherty Lindsey F. , Niebergall Alexandria K. , Broeckling Corey D. , Schauer Kevin L. , Li Jingchun
Published: October 2019

Members of the marine bivalve family Limidae are known for their bright appearance. In this study, their colourful tissues were examined as a defence mechanism towards predators. We showed that when attacked by the peacock mantis shrimp (
Odontodactylus scyllarus
), the ‘disco’ clam,
Ctenoides ales
, opened wide to expose brightly coloured tissues to the predator. The predator also significantly preferred to consume the internal, non-colourful clam tissues than the external, colourful tissues. Mass spectrometry-based metabolomic analysis confirmed that colourful tissues had significantly different chemical compositions than the non-colourful ones. The internal, non-colourful tissues had metabolite profiles more similar to an outgroup bivalve than to the species' own colourful external tissues. A number of the compounds that differentiated the colourful tissues from the non-colourful tissues appeared to be peptide-like, which potentially serve as the underlying defensive compounds. This is the first study demonstrating that colourful bivalve tissues are used for chemical defence.
Enhancing synchrony in multiplex network due to rewiring frequency
Authors: Rakshit Sarbendu , Bera Bidesh K. , Kurths Jürgen , Ghosh Dibakar
Published: October 2019

Most of the previous studies on synchrony in multiplex networks have been investigated using different types of intralayer network architectures which are either static or temporal. Effect of a temporal layer on intralayer synchrony in a multilayered network still remains elusive. In this paper, we discuss intralayer synchrony in a multiplex network consisting of static and temporal layers and how a temporal layer influences other static layers to enhance synchrony simultaneously. We analytically derive local stability conditions for intralayer synchrony based on the master stability function approach. The analytically derived results are illustrated by numerical simulations on up to five-layers multiplex networks with the paradigmatic Lorenz system as the node dynamics in each individual layer.
Assessing the effects of quantitative host resistance on the life-history traits of sporulating parasites with growing lesions
Authors: Leclerc Melen , Clément Julie A. J. , Andrivon Didier , Hamelin Frédéric M.
Published: October 2019

Assessing life-history traits of parasites on resistant hosts is crucial in evolutionary ecology. In the particular case of sporulating pathogens with growing lesions, phenotyping is difficult because one needs to disentangle properly pathogen spread from sporulation. By considering
Phytophthora infestans
on potato, we use mathematical modelling to tackle this issue and refine the assessment of pathogen response to quantitative host resistance. We elaborate a parsimonious leaf-scale model by convolving a lesion growth model and a sporulation function, after a latency period. This model is fitted to data obtained on two isolates inoculated on three cultivars with contrasted resistance level. Our results confirm a significant host–pathogen interaction on the various estimated traits, and a reduction of both pathogen spread and spore production, induced by host resistance. Most interestingly, we highlight that quantitative resistance also changes the sporulation function, the mode of which is significantly time-lagged. This alteration of the infectious period distribution on resistant hosts may have strong impacts on the dynamics of parasite populations, and should be considered when assessing the durability of disease control tactics based on plant resistance management. This inter-disciplinary work also supports the relevance of mechanistic models for analysing phenotypic data of plant–pathogen interactions.
Early evolution of the ossicular chain in Cetacea: into the middle ear gears of a semi-aquatic protocetid whale
Authors: Mourlam Mickaël J. , Orliac Maeva J.
Published: October 2019

Modifications of the morphology and acoustic properties of the ossicular chain are among the major changes that accompanied the adaptation of Cetacea to the aquatic environment. Thus, data on the middle ear ossicles of early whales are crucial clues to understand the first steps of the emblematic terrestrial/aquatic transition that occurred in that group. Yet, the delicate nature and very small size of these bones make their preservation in the fossil record extremely rare. Due to the scarcity of available data, major questions remain concerning the sound transmission pathways in early non-fully aquatic whales. Virtual reconstruction of a partially complete ossicular chain of an Eocene protocetid whale documents for the first time the three ossicles of a semi-aquatic archaeocete. Contrary to previous hypotheses, these ossicles present different evolutionary patterns, showing that the ossicular chain does not act as a single morphological module. Functional analyses of the different middle ear units highlight a mosaic pattern of terrestrial and aquatic signatures. This integrative anatomical and functional study brings strong evidence that protocetids were adapted to their dual acoustic environment with efficient hearing in both air and water.
Long-term persistence of structured habitats: seagrass meadows as enduring hotspots of biodiversity and faunal stability
Authors: Hyman A. Challen , Frazer Thomas K. , Jacoby Charles A. , Frost Jessica R. , Kowalewski Michał
Published: October 2019

Ecological studies indicate that structurally complex habitats support elevated biodiversity, stability and resilience. The long-term persistence of structured habitats and their importance in maintaining biodiverse hotspots remain underexplored. We combined geohistorical data (dead mollusc assemblages, ‘DA’) and contemporary surveys (live mollusc assemblages, ‘LA’) to assess the persistence of local seagrass habitats over multi-centennial timescales and to evaluate whether they acted as long-term drivers of biodiversity, stability and resilience of associated fauna. We sampled structured seagrass meadows and open sandy bottoms along Florida's Gulf Coast. Results indicated that: (i) LA composition differed significantly between the two habitat types, (ii) LA from seagrass sites were characterized by significantly elevated local biodiversity and significantly higher spatial stability, (iii) DA composition differed significantly between the two habitat types, and (iv) fidelity between LA and DA was significantly greater for seagrass habitats. Contemporary results support the hypotheses that local biodiversity and spatial stability of marine benthos are both elevated in structured seagrass habitats. Geohistorical results suggest that structured habitats persist as local hotspots of elevated biodiversity and faunal stability over centennial-to-millennial timescales; indicating that habitat degradation and concomitant loss within structurally complex marine systems is a key driver of declining biodiversity and resilience.
Treatment advantage in HBV/HIV coinfection compared to HBV monoinfection in a South African cohort
Authors: Maponga Tongai G , McNaughton Anna L , Van Schalkwyk Marije , Hugo Susan , Nwankwo Chikezie , Taljaard Jantjie , Mokaya Jolynne , Smith David A , van Vuuren Cloete , Goedhals Dominique , Gabriel Shiraaz , Andersson Monique I , Preiser Wolfgang , van Rensburg Christo , Matthews Philippa C
Published: October 2019

Objective

Prompted by international targets for elimination of hepatitis B virus (HBV) infection, we performed a cross-sectional observational study of adults with chronic HBV (CHB) infection in South Africa, characterising individuals with HBV monoinfection vs. those coinfected with HBV/HIV, to evaluate the impact of therapy and to guide improvements in clinical care as guidelines for antiviral therapy change over time.

Design

We prospectively recruited 115 adults with CHB, over a period of one year at a university hospital in Cape Town, South Africa. HIV coinfection was present in 39 (34%) subjects. We recorded cross-sectional demographic, clinical and laboratory data.

Results

Adults with HBV monoinfection were comparable to those with HBV/HIV coinfection in terms of age, sex and body mass. HBeAg-positive status was more common among those with HIV coinfection (p=0.01). However, compared to HBV/HIV coinfection, HBV monoinfected patients were less likely to have had assessment with elastography (p<0.0001) and less likely to be on antiviral treatment (p<0.0001). The HBV monoinfected group was more likely to have detectable HBV viraemia (p=0.04), and features suggesting underlying liver disease including moderate/severe thrombocytopaenia (p=0.007), elevated bilirubin (p=0.004), and APRI score >2 (p=0.02). Three cases of hepatocellular carcinoma were documented, all in patients with HBV monoinfection.

Conclusion

In this setting, individuals with HBV monoinfection are disadvantaged in terms of clinical assessment and appropriate antiviral therapy compared to those with HIV coinfection, associated with relatively worse liver health. Enhanced advocacy, education, resources and infrastructure are required to optimise interventions for CHB.
Primary motor cortex has independent representations for ipsilateral and contralateral arm movements but correlated representations for grasping
Authors: Downey John E , Quick Kristin M , Schwed Nathaniel , Weiss Jeffrey M , Wittenberg George F , Boninger Michael L , Collinger Jennifer L
Published: October 2019

Motor commands for the arms and hands generally originate in contralateral motor cortex anatomically. However, ipsilateral primary motor cortex shows activity related to arm movement despite the lack of direct connections. The extent to which the activity related to ipsilateral movement is independent from that related to contralateral movement is unclear based on conflicting conclusions in prior work. Here we present the results of bilateral arm and hand movement tasks completed by two human subjects with intracortical microelectrode arrays implanted in left primary motor cortex for a clinical brain-computer interface study. Neural activity was recorded while they attempted to perform arm and hand movements in a virtual environment. This enabled us to quantify the strength and independence of motor cortical activity related to continuous movements of each arm. We also investigated the subjects’ ability to control both arms through a brain-computer interface system. Through a number of experiments, we found that ipsilateral arm movement was represented independently of, but more weakly than, contralateral arm movement. However, the representation of grasping was correlated between the two hands. This difference between hand and arm representation was unexpected, and poses new questions about the different ways primary motor cortex controls hands and arms.
Structure-Based Discovery of a Novel Small-Molecule Inhibitor of Methicillin-Resistant S. aureus
Authors: Liu Jie , Kozhaya Lina , Torres Victor J. , Unutmaz Derya , Lu Min
Published: October 2019

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains represents a major threat to public health. MRSA elaborates an arsenal of secreted host-damaging virulence factors to mediate pathogenicity and blunt immune defense. Panton-Valentine leukocidin (PVL) and α-toxin are pore-forming cytotoxins of recognized importance in the development of invasive MRSA infection and are thus potential targets for antivirulence therapy. We report the X-ray crystal structures of PVL and α-toxin in their soluble, monomeric and oligomeric, membrane-inserted pore states, in complex with n-tetradecylphosphocholine (C14PC). The structures reveal two evolutionarily conserved phosphatidylcholine binding mechanisms and their roles in modulating host cell attachment, oligomer assembly and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of novel antivirulence agents to combat MRSA.
Impact of early childhood malnutrition on the adult brain function: an ERP study
Authors: Roger Kassandra , Vannasing Phetsamone , Tremblay Julie , Bringas Vega Maria L. , Bryce Cyralene P. , Rabinowitz Arielle G. , Valdés-Sosa Pedro A. , Galler Janina R. , Gallagher Anne
Published: October 2019

According to the World Health Organization, 45% of deaths among children under five years of age are caused by malnutrition, which impacts more than 224 million children globally. The Barbados Nutrition Study (BNS) is a 50+ year longitudinal study on a Barbadian cohort with histories of moderate to severe protein-energy malnutrition (PEM) limited to the first year of life and a healthy comparison group. We have previously used quantitative electroencephalography (EEG) to highlight differences in brain function duringchildhood(lower alpha1 activity and higher theta, alpha2 and beta activity) between participants who suffered from early PEM and controls. In order to determine whether similar differences between the PEM and control groups persisted intoadulthood, our current study used recordings obtained during a Go-No-Go task in a subsample of the original BNS cohort (N=53) at ages 45-51 years. We found that previously malnourished adults (n=24) had a higher rate of omission errors on the task relative to controls (n=29). Evoked-Related Potentials (ERP) were significantly different in participants with histories of early PEM, who presented with lower N2 amplitudes (p<0.05). These findings are typically associated with impaired conflict monitoring and/or attention deficits and may therefore be linked to the attentional and executive function deficits that have been previously reported in this cohort in childhood and again in middle-adulthood.

Highlights

Childhood malnutrition increases risk of brain function alterations.

There is a need to investigate the evolution of those outcomes later in life.

Adults who suffered childhood malnutrition undertook a Go-No-Go task during EEG.

Task performance and N2 amplitude were reduced in malnutrition group (vs control).

First evidence of adult brain function alteration following childhood malnutrition.
Comparative genomics of globaloptrA-carryingEnterococcus faecalisuncovers common genetic features and a chromosomal hotspot foroptrAacquisition
Authors: Freitas Ana R. , Tedim Ana P. , Novais Carla , Peixe Luísa
Published: October 2019

Linezolid-resistantEnterococcus faecalis(LREfs) carryingoptrAare increasingly reported globally from multiple sources, but we still lack a comprehensive analysis of human and animaloptrA-LREfs strains. We investigated the phylogenetic structure, genetic content [antimicrobial resistance (AMR), virulence, prophages, plasmidome] andoptrA-containing platforms of 28 publicly availableoptrA-positiveE. faecalisgenomes from different hosts in 7 countries. In the genome-level analysis,in housedatabases with 57 virulence and 391 plasmid replication genes were tested for the first time. Our analysis showed a diversity of clones and adaptive gene sequences related to a wide range of genera, mainly but not exclusive fromFirmicutes. The content in AMR and virulence genes was highly identical in contrast to the diversity of phages and plasmids observed. Epidemiologically unrelated clones (ST476-like and ST21-like) obtained from human clinical and animal hosts in different continents over 5 years (2012-2017) were phylogenetically related (3-122 SNPs difference). They also exhibited identical AMR and virulence profiles, highlighting a global spread ofoptrA-positive strains with relevant adaptive traits in livestock and that they might originate from an animal reservoir.optrAwas located on the chromosome within a Tn6674-like element (n=9) or on medium-size plasmids (30-60 kb; n=14) belonging to main plasmid families (RepA_N/Inc18/Rep_3). In most cases, the immediate gene vicinity ofoptrAwas identical in chromosomal (Tn6674) and plasmid (impB-fexA-optrA) backbones. Tn6674was always inserted in the same ΔradCintegration site and embedded in a 32 kb chromosomal platform common to diverse strains from different origins (patients, healthy humans, and animals) in Europe, Africa, and Asia during 2012-2018. This platform is conserved among hundreds ofE. faecalisgenomes and we here propose a conserved chromosomal hotspot foroptrAintegration. The finding ofoptrAin strains sharing identical adaptive features and genetic backgrounds across different hosts and countries suggest the occurrence of common and independent genetic events occurring in distant regions, and might explain the easyde novogeneration ofoptrA-positive strains. It also anticipates a dramatic increase ofoptrAcarriage and spread with a serious impact in the efficacy of linezolid for the treatment of Gram-positive infections.
Vestigial Auriculomotor Activity Indicates the Direction of Auditory Attention in Humans
Authors: Strauss Daniel J. , Corona-Strauss Farah I. , Schroeer Andreas , Flotho Philipp , Hannemann Ronny , Hackley Steven A.
Published: October 2019

It is commonly assumed that, unlike dogs and cats, we humans do not make ear movements when focusing our attention reflexively toward novel sounds or voluntarily toward those that are goal–relevant. In fact, it has been suggested that we do have a pinna–orienting system. Although this system became vestigial about 25 million years ago, it still exists as a “neural fossil” within the brain. Consistent with this hypothesis, we demonstrate for the first time that the direction of auditory attention is reflected in the sustained electrical activity of muscles within the vestigial auriculomotor system.

Surface electromyograms (EMGs) were taken from muscles that either move the pinna or alter its shape. To assess reflexive, stimulus-driven attention we presented novel sounds from speakers at four different lateral locations while the participants silently read a boring text in front of them. To test voluntary, goal-directed attention we instructed participants to listen to a short story coming from one of these speakers, while ignoring a competing story from the corresponding speaker on the opposite side.

In both experiments, EMG recordings showed larger activity at the ear on the side of the attended stimulus, but with slightly different patterns. Upward movement (perking) differed according to the lateral focus of attention only during voluntary orienting; rearward folding of the pinna’s upper-lateral edge exhibited such differences only during reflexive orienting. The existence of a pinna-orienting system in humans, one that is experimentally accessible, offers opportunities for basic as well as applied science. It could lead to a better understanding of the evolution of auditory attention and support the near real–time decoding of auditory attention in technical applications, for example, for attentionally controlled hearing aids that preferentially amplify sounds the user is attempting to listen to.
Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory
Authors: Levitan David , Liu Chenghao , Yang Tracy , Shima Yasuyuki , Lin Jian-You , Wachutka Joseph , Marrero Yasmin , Ghoddousi Ramin Ali Marandi , Beltrame Eduardo da Veiga , Katz Donald B. , Nelson Sacha B.
Published: October 2019

Conditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms are poorly understood, however. We used RNAseq from BLApn to identify learning-related changes in Stk11, a kinase with well-studied roles in growth, metabolism and development, but not previously implicated in learning. Deletion of Stk11 restricted to BLApn completely blocks memory when occurring prior to training, but not following it, despite altering neither BLApn-dependent encoding of taste palatability in gustatory cortex, nor transcriptional activation of BLApn during training. Deletion of Stk11 in BLApn also increases their intrinsic excitability. Conversely, BLApn activated by CTA to express the immediate early gene Fos had reduced excitability. BLApn knockout of Fos also increased excitability and impaired learning. These data suggest that Stk11 and Fos expression play key roles in CTA long-term memory formation, perhaps by modulating the intrinsic excitability of BLApn.
Improved computational identification of drug response using optical measurements of human stem cell derived cardiomyocytes in microphysiological systems
Authors: Jæger Karoline Horgmo , Charwat Verena , Charrez Bérénice , Finsberg Henrik , Maleckar Mary M. , Wall Samuel , Healy Kevin E. , Tveito Aslak
Published: October 2019

Cardiomyocytes derived from human induced pluripotent stem cells hold great potential for drug screening applications. However, their usefulness is limited by the relative immaturity of cells’ electro-physiological properties as compared to native cardiomyocytes in the adult human heart. In this work, we extend and improve on methodology to address this limitation, building on previously introduced computational procedures which predict drug effects for mature cells based on changes in optical measurements of action potentials and Ca2+transients made in stem cell derived cardiac microtissues. This methodology quantifies ion channel changes through the inversion of data into a mathematical model, and maps this response to a mature phenotype through the assumption of functional invariance of fundamental intracellular and membrane channels during maturation.

Here we utilize an updated action potential model to represent both immature and mature cells, apply an IC50-based model of dose-dependent drug effects, and introduce a continuation-based optimization algorithm for analysis of dose escalation measurements using five drugs with known effects. The improved methodology can identify drug induced changes more efficiently, and quantitate important metrics such as IC50 in line with published values. Consequently, the updated methodology is a step towards employing computational procedures to elucidate drug effects in mature cardiomyocytes for new drugs using stem cell-derived experimental tissues.
Gut microbiota differently contributes to intestinal immune phenotype and systemic autoimmune progression in female and male lupus-prone mice
Authors: Johnson Benjamin M. , Gaudreau Marie-Claude , Gudi Radhika , Brown Robert , Gilkeson Gary , Vasu Chenthamarakshan
Published: October 2019

1.

The risk of developing systemic lupus erythematosus (SLE) is about 9 times higher among women compared to men. Our recent report, which used (SWRxNZB) F1 (SNF1) mouse model of spontaneous lupus, showed a potential link between immune response initiated in the gut mucosa at juvenile age (sex hormone independent) and SLE susceptibility. Here, this mouse model, we show that gut microbiota contributes to a pro-inflammatory immune response in the intestine and autoimmune progression, primarily in females, leading to an associated gender bias. We found that gut microbiota composition in male and female littermates are significantly different only at adult age and depletion of gut microbes causes suppression of autoimmune progression only in females. In agreement, microbiota depletion suppressed the pro-inflammatory cytokine response of gut mucosa in both juvenile and adult females. In male SNF1 mice, on the other hand, orchidectomy (castration) caused changes in the composition of gut microbiota and a modest acceleration of autoimmune progression. However, cecum microbiota transplantation studies failed to show superior protection of females from autoimmunity by androgen-influenced gut microbiota. Overall, our work shows that microbiota-dependent pro-inflammatory immune response in the gut mucosa of females initiated at juvenile ages and androgen-dependent protection of males contributes to gender differences in the intestinal immune phenotype and systemic autoimmune progression.
The seagrass methylome memorizes heat stress and is associated with variation in stress performance among clonal shoots
Authors: Jueterbock A , Boström C , Coyer James A , Olsen JL , Kopp M , Dhanasiri AKS , Smolina I , Arnaud-Haond S , Van de Peer Y , Hoarau G
Published: October 2019

Evolutionary theory predicts that clonal organisms are more susceptible to extinction than sexually reproducing organisms, due to low genetic variation and slow rates of evolution. In agreement, conservation management considers genetic variation as the ultimate measure of a population’s ability to survive over time. However, clonal plants are among the oldest living organisms on our planet. Here, we test the hypothesis that clonal seagrass meadows display epigenetic variation that complements genetic variation as a source of phenotypic variation. In a clonal meadow of the seagrass Zostera marina we characterized DNA methylation among 42 shoots. We also sequenced the whole genome of 10 shoots to correlate methylation patterns with photosynthetic performance under exposure to, and recovery from 27°C, while controlling for somatic mutations. Here, we show for the first time that clonal seagrass shoots display DNA methylation variation that is associated with variation in fitness-related traits: photosynthetic performance and heat stress resilience. The co-variation in DNA methylation and phenotype may be linked via gene expression because methylation patterns varied in functionally relevant genes involved in photosynthesis, and in the repair and prevention of heat-induced protein damage. A >five week epigenetic heat stress memory may heat-harden previously heat-exposed shoots. While genotypic diversity has been shown to enhance stress resilience in seagrass meadows, we suggest that epigenetic variation plays a similar role in meadows dominated by a single genotype. Consequently, conservation management of clonal plants should consider epigenetic variation as indicator of resilience and stability, and restoration efforts may benefit from stress-priming transplanted seeds or shoots.
No statistical evidence for an effect of CCR5-∆32 on lifespan in the UK Biobank cohort
Authors: Maier Robert , Akbari Ali , Wei Xinzhu , Patterson Nick , Nielsen Rasmus , Reich David
Published: October 2019

A recent study reported that a 32-base-pair deletion in the CCR5 gene (CCR5-∆32) is deleterious in the homozygous state in humans. Evidence for this came from a survival analysis in the UK Biobank cohort, and from deviations from Hardy-Weinberg equilibrium at a polymorphism tagging the deletion (rs62625034). Here, we carry out a joint analysis of whole-genome genotyping data and whole-exome sequencing data from the UK Biobank, which reveals that technical artifacts are a more plausible cause for deviations from Hardy-Weinberg equilibrium at this polymorphism. Specifically, we find that individuals homozygous for the deletion in the sequencing data are underrepresented in the genotyping data due to an elevated rate of missing data at rs62625034, possibly because the probe for this SNP overlaps with the ∆32 deletion. Another variant which has a higher concordance with the deletion in the sequencing data shows no associations with mortality. A phenome-wide scan for effects of variants tagging this deletion shows an overall inflation of association p-values, but identifies only one trait at p < 5×10−8, and no mediators for an effect on mortality. These analyses show that the original reports of a recessive deleterious effect of CCR5-∆32 are affected by a technical artifact, and that a closer investigation of the same data provides no positive evidence for an effect on lifespan.
Phylogeographic and phylodynamic approaches to epidemiological hypothesis testing
Authors: Dellicour Simon , Lequime Sebastian , Vrancken Bram , Gill Mandev S. , Bastide Paul , Gangavarapu Karthik , Matteson Nathaniel L. , Tan Yi , du Plessis Louis , Fisher Alexander A. , Nelson Martha I. , Gilbert Marius , Suchard Marc A. , Andersen Kristian G. , Grubaugh Nathan D. , Pybus Oliver G. , Lemey Philippe
Published: October 2019

Computational analyses of pathogen genomes are increasingly used to unravel the dispersal history and transmission dynamics of epidemics. Here, we show how to go beyond historical reconstructions and use spatially-explicit phylogeographic and phylodynamic approaches to formally test epidemiological hypotheses. We illustrate our approach by focusing on the West Nile virus (WNV) spread in North America that has been responsible for substantial impacts on public, veterinary, and wildlife health. WNV isolates have been sampled at various times and locations across North America since its introduction to New York twenty years ago. We exploit this genetic data repository to demonstrate that factors hypothesised to affect viral dispersal and demography can be formally tested. Specifically, we detail and apply an analytical workflow consisting of state-of-the art methods that we further improve to test the impact of environmental factors on the dispersal locations, velocity, and frequency of viral lineages, as well as on the genetic diversity of the viral population through time. We find that WNV lineages tend to disperse faster in areas with higher temperatures and we identify temporal variation in temperature as a main predictor of viral genetic diversity through time. Using a simulation procedure, we find no evidence that viral lineages preferentially circulate within the same migratory bird flyway, suggesting a substantial role for non-migratory birds or mosquito dispersal along the longitudinal gradient. Finally, we also separately apply our testing approaches on the three WNV genotypes that circulated in North America in order to understand and compare their dispersal ability. Our study demonstrates that the development and application of statistical approaches, coupled with comprehensive pathogen genomic data, can address epidemiological questions that might otherwise be difficult or impractically expensive to answer.
CCR5-del32 is not deleterious in the homozygous state in humans
Authors: Gudbjartsson Daniel , Sulem Patric , Stefansson Kári , Mars Nina , Karjalainen Juha , Ripatti Samuli , Palotie Aarno , Daly Mark
Published: October 2019

Recently, Wei and Nielsen1 reported an analysis of UK Biobank data which suggested that the well-known HIV-protective variant CCR5-del32 is associated with a 21% increase in all-cause mortality. We demonstrate, using two well-powered population samples in Iceland and Finland with extensive health data and death information, neither an effect on mortality nor increase in risk of any disease. Further reexamination of the UK Biobank (UKBB) data suggests that the very modest association was with a SNP of poor genotyping quality – at a nearby proxy SNP, no statistically significant impact on mortality nor deviation from Hardy-Weinberg equilibrium exists in the UKBB sample. We thus find no evidence of any meaningful risk of increased mortality from homozygosity of CCR5-del32.
Headwaters fed by subterranean ice: potential climate refugia for mountain stream communities?
Authors: Tronstad Lusha M. , Hotaling Scott , Giersch J. Joseph , Wilmot Oliver J. , Finn Debra S.
Published: October 2019

Near-term extirpations of macroinvertebrates are predicted for mountain streams worldwide as a warming climate drives the recession of high-elevation ice and snow. However, hydrological sources likely vary in their resistance to climate change and thus streams fed by more resistant sources could persist as climate refugia for imperiled biota. In 2015-2016, we measured habitat characteristics and quantified macroinvertebrate community structure along six alpine streams in the Teton Range, Wyoming, USA. Strong differences in habitat characteristics (e.g., temperature, bed stability, conductivity) confirmed three major stream sources: surface glaciers, perennial snowfields, and subterranean ice. Subterranean ice-fed streams – termed “icy seeps” – appear common in the Teton Range and elsewhere yet are globally understudied. Midges in the family Chironomidae dominated our study sites, representing 78.6% of all specimens sampled, with nematodes, caddisflies (Neothremma), and mayflies (Epeorus) also common. At the community-scale, glacier-and snowmelt-fed streams differed significantly in multivariate space, with icy-seep communities intermediate between them, incorporating components of both assemblages. Because the thermal environment of subterranean ice, including rock glaciers, is decoupled from large-scale climatic conditions, we predict that icy seeps will remain intact longer than streams fed by surface ice and snow. Furthermore, our results suggest that icy seeps are suitable habitat for many macroinvertebrates occupying streams fed by vulnerable hydrological sources. Thus, icy seeps may act as key climate refugia for mountain stream biodiversity, an idea in need of further investigation.
Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease
Authors: Wang Minghui , Li Aiqun , Sekiya Michiko , Beckmann Noam D. , Quan Xiuming , Schrode Nadine , Fernando Michael B. , Yu Alex , Zhu Li , Cao Jiqing , Lyu Liwei , Horgusluoglu Emrin , Wang Qian , Guo Lei , Wang Yuan-shuo , Neff Ryan , Song Won-min , Wang Erming , Shen Qi , Zhou Xianxiao , Ming Chen , Ho Seok-Man , Vatansever Sezen , Kaniskan H. Umit , Jin Jian , Zhou Ming-Ming , Ando Kanae , Ho Lap , Slesinger Paul A. , Yue Zhenyu , Zhu Jun , Gandy Sam , Ehrlich Michelle E. , Cai Dongming , Haroutunian Vahram , Iijima Koichi M. , Schadt Eric , Brennand Kristen J. , Zhang Bin
Published: October 2019

To study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimer’s Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A, a critical subunit of vacuolar-type H+-ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.
Suprathreshold contrast response in normal and anomalous trichromats
Authors: Knoblauch Kenneth , Marsh-Armstrong Brennan , Werner John S.
Published: October 2019

Maximum Likelihood Difference Scaling was used to measure suprathreshold contrast response difference scales for low-frequency Gabor patterns modulated along luminance and L-M color directions in normal, protanomalous, and deuteranomalous observers. Based on a signal-detection model, perceptual scale values, parameterized as d′, were estimated by maximum likelihood. The difference scales were well fit by a Michaelis-Menten model, permitting estimates of response and contrast gain parameters for each subject. Anomalous observers showed no significant differences in response or contrast gain from normal observers for luminance contrast. For chromatic modulations, however, anomalous observers displayed higher contrast and lower response gain compared to normal observers. These effects cannot be explained by simple pigment shift models and support a compensation mechanism to optimize the mapping of the input contrast range to the neural response range. A linear relation between response and contrast gain suggests a neural trade-off between them.