bluuebunny/crossref_metadata_2025 huggingface dataset:
Fracture toughness of human amniotic membranes
Authors: Koh Ching Theng , Tonsomboon Khaow , Oyen Michelle L.
Published: August 2019

Amnion is a membrane that surrounds and structurally protects the developing fetus during pregnancy. The rupture of amniotic membranes prior to both normal and preterm deliveries involves stretch forces acting on a biochemically triggered weak zone of the membranes. Fracture toughness is an important mechanical property describing how the membranes containing a defect resist fracture, but this property has never been investigated in amniotic membranes. In this work, the fracture toughness of many samples cut from four pieces of amniotic membrane from different mothers was examined by uniaxial and pure shear (mode I) fracture tests. The measurement was checked for dependence on the sample geometry and notch length. Results from the uniaxial tensile test show J-shaped stress–strain curves and confirm that the amniotic membrane is a nonlinear material. The measured fracture toughness of four amniotic membranes ranged from 0.96 ± 0.11 to 1.83 ± 0.18 kJ m
−2
. Despite considering the effect of the presence of the defect on mechanical property measurement, similar fracture behaviour was observed for pre-notched and unnotched specimens, indicating that the membranes were extremely tolerant to defects. This defect-tolerant characteristic provides insight into the understanding of fetal membrane rupture.
Quantifying the impact of tissue metabolism on solute transport in feto-placental microvascular networks
Authors: Erlich Alexander , Nye Gareth A. , Brownbill Paul , Jensen Oliver E. , Chernyavsky Igor L.
Published: August 2019

The primary exchange units in the human placenta are terminal villi, in which fetal capillary networks are surrounded by a thin layer of villous tissue, separating fetal from maternal blood. To understand how the complex spatial structure of villi influences their function, we use an image-based theoretical model to study the effect of tissue metabolism on the transport of solutes from maternal blood into the fetal circulation. For solute that is taken up under first-order kinetics, we show that the transition between flow-limited and diffusion-limited transport depends on two new dimensionless parameters defined in terms of key geometric quantities, with strong solute uptake promoting flow-limited transport conditions. We present a simple algebraic approximation for solute uptake rate as a function of flow conditions, metabolic rate and villous geometry. For oxygen, accounting for nonlinear kinetics using physiological parameter values, our model predicts that villous metabolism does not significantly impact oxygen transfer to fetal blood, although the partitioning of fluxes between the villous tissue and the capillary network depends strongly on the flow regime.
Longitudinal characterization of local perfusion of the rat placenta using contrast-enhanced ultrasound imaging
Authors: Lawrence Dylan J. , Huda Kristie , Bayer Carolyn L.
Published: August 2019

The placenta performs many physiological functions critical for development. Insufficient placental perfusion, due to improper vascular remodelling, has been linked to many pregnancy-related diseases. To study longitudinal
in vivo
placental perfusion, we have implemented a pixel-wise time–intensity curve (TIC) analysis of contrast-enhanced ultrasound (CEUS) images. CEUS images were acquired of pregnant Sprague Dawley rats after bolus injections of gas-filled microbubble contrast agents. Conventionally, perfusion can be quantified using a TIC of contrast enhancement in an averaged region of interest. However, the placenta has a complex structure and flow profile, which is insufficiently described using the conventional technique. In this work, we apply curve fitting in each pixel of the CEUS image series in order to quantify haemodynamic parameters in the placenta and surrounding tissue. The methods quantified an increase in mean placental blood volume and relative blood flow from gestational day (GD) 14 to GD18, while the mean transit time of the microbubbles decreased, demonstrating an overall rise in placental perfusion during gestation. The variance of all three parameters increased during gestation, showing that regional differences in perfusion are observable using the pixel-wise TIC approach. Additionally, the high-resolution parametric images show distinct regions of high blood flow developing during late gestation. The developed methods could be applied to assess placental vascular remodelling during the treatment of the pathologies of pregnancy.
Quantitative assessment of cervical softening during pregnancy with shear wave elasticity imaging: an
in vivo
longitudinal study
Authors: Carlson Lindsey C. , Hall Timothy J. , Rosado-Mendez Ivan M. , Mao Lu , Feltovich Helen
Published: August 2019

We report here the results of a longitudinal study of cervix stiffness during pregnancy. Thirty women, ages ranging from 19 to 37 years, were scanned with ultrasound at five time points beginning at their normal first-trimester screening (8–13 weeks) through term pregnancy (nominally 40 week) using a clinical ultrasound imaging system modified with a special ultrasound transducer and system software. The system estimated the shear wave speed (its square proportional to the shear modulus under idealized conditions) in the cervix. We found a constant fractional reduction (about 4% per week) in shear wave speed with increasing gestational age. We also demonstrated a spatial gradient in shear wave speed along the length of the cervix (softest at the distal end). Results were consistent with our previous
ex vivo
and
in vivo
work in women. Shear wave elasticity imaging may be a potentially useful clinical tool for objective assessment of cervical softening in pregnancy.
Three-dimensional camera anthropometry to assess risk of cephalopelvic disproportion-related obstructed labour in Ethiopia
Authors: Tolentino Lorenzo , Yigeremu Mahlet , Teklu Sisay , Attia Shehab , Weiler Michael , Frank Nate , Dixon J. Brandon , Gleason Rudolph L.
Published: August 2019

Cephalopelvic disproportion (CPD)-related obstructed labour requires delivery via Caesarean section (C/S); however, in low-resource settings around the world, facilities with C/S capabilities are often far away. This paper reports three low-cost tools to assess the risk of CPD, well before labour, to provide adequate time for referral and planning for delivery. We performed tape measurement- and three-dimensional (3D) camera-based anthropometry, using two 3D cameras (Kinect and Structure) on primigravida, gestational age ≥ 36 weeks, from Addis Ababa, Ethiopia. Novel risk scores were developed and tested to identify models with the highest predicted area under the receiver-operator characteristic curve (AUC), detection rate (true positive rate at a 5% false-positive rate, FPR) and triage rate (true negative rate at a 0% false-negative rate). For tape measure, Kinect and Structure, the detection rates were 53%, 61% and 64% (at 5% FPR), the triage rates were 30%, 56% and 63%, and the AUCs were 0.871, 0.908 and 0.918, respectively. Detection rates were 77%, 80% and 84% at the maximum
J
-statistic, which corresponded to FPRs of 10%, 15% and 11%, respectively, for tape measure, Kinect and Structure. Thus, tape measurement anthropometry was a very good predictor and Kinect and Structure anthropometry were excellent predictors of CPD risk.
Three-dimensional morphological analysis of placental terminal villi
Authors: Plitman Mayo Romina , Abbas Yassen , Charnock-Jones D. Stephen , Burton Graham J. , Marom Gil
Published: August 2019

Transport of nutrients and waste between the maternal and fetal circulations during pregnancy takes place at the final branches of the placental villous trees. Therefore, and unsurprisingly, pregnancy complications have been related to the maldevelopment of terminal villi. However, a deep analysis of placental villous morphology has been limited by tissue processing and imaging techniques. In this proof-of-principle study, placental lobules were fixed by perfusion and small clumps of villi were stained, sectioned optically and reconstructed. Morphological and network analyses were suggested and demonstrated on samples of normal placentas. The results show that most parameters are almost constant within a placenta but that there exists an inter-individual variation. Network analysis suggests that the feto-placental capillary network has several paths within an individual villus, serving as an efficient transport system. Three-dimensional reconstruction from confocal laser scanning microscopy images is a potent technique able to quantify placental architecture and capture the significant irregularities in vessel diameter and membrane thickness. This approach has the potential to become a powerful tool to further our understanding of the differences in placental structure which may underlie pregnancy complications.
Redefining the Bladder Cancer Phenotype using Patterns of Familial Risk
Authors: Hanson Heidi A. , Leiser Claire L. , Martin Christopher , Gupta Sumati , Smith Ken R. , Dechet Christopher , Lowrance William , O’Neil Brock , Camp Nicola J.
Published: August 2019

Relatives of bladder cancer (BCa) patients have been shown to be at increased risk for kidney, lung, thyroid, and cervical cancer after correcting for smoking related behaviors that may concentrate in some families. We demonstrate a new method to simultaneously assess risks for multiple cancers to identify distinct multi-cancer configurations (multiple different cancer types that cluster in relatives) surrounding BCa patients. We identified 6,416 individuals with urothelial carcinoma and familial information using the Utah Cancer Registry and Utah Population Database (UPDB). First-degree relatives, second-degree relatives, and first cousins were used to construct a familial enrichment matrix for cancer-types previously shown to be individually associated with BCa. K-medioids clustering were used to identify Familial Multi-Cancer Configurations (FMC). A case-control design and Cox regression with a 1:5 ratio of BCa cases to cancer-free controls was used to quantify the risk in specific relative-types and spouses in each FMC. Clustering analysis revealed 12 distinct FMCs, each exhibiting a different pattern of cancer co-aggregation. Of the 12 FMCs, four exhibited strong familial risk of bladder cancer along with specific patterns of increased risk of cancers in other sites (BCa FMCs), and were the focus of further investigation. Cancers at increased risk in these four BCa FMCs most commonly included melanoma, prostate and breast cancer and less commonly included leukemia, lung, pancreas and kidney cancer. A network-based approach can be used with familial data to discover new phenotype clusters for BCa, providing new directions for discovering patterns of cancer clustering.
Flow-induced symmetry breaking in growing bacterial biofilms
Authors: Pearce Philip , Song Boya , Skinner Dominic J. , Mok Rachel , Hartmann Raimo , Singh Praveen K. , Jeckel Hannah , Oishi Jeffrey S. , Drescher Knut , Dunkel Jörn
Published: August 2019

Bacterial biofilms represent a major form of microbial life on Earth and serve as a model active nematic system, in which activity results from growth of the rod-shaped bacterial cells. In their natural environments, ranging from human organs to industrial pipelines, biofilms have evolved to grow robustly under significant fluid shear. Despite intense practical and theoretical interest, it is unclear how strong fluid flow alters the local and global architectures of biofilms. Here, we combine highly time-resolved single-cell live imaging with 3D multi-scale modeling to investigate the mechanisms by which flow affects the dynamics of all individual cells in growing biofilms. Our experiments and cell-based simulations reveal three quantitatively different growth phases in strong external flow, and the transitions between them. In the initial stages of biofilm development, flow induces a downstream gradient in cell orientation, causing asymmetrical droplet-like biofilm shapes. In the later developmental stages, when the majority of cells are sheltered from the flow by the surrounding extracellular matrix, buckling-induced cell verticalization in the biofilm core restores radially symmetric biofilm growth, in agreement with predictions of a 3D continuum model.
The Safety and Efficacy of Transdermal Auricular Vagal Nerve Stimulation Earbud Electrodes for Modulating Autonomic Arousal, Attention, Sensory Gating, and Cortical Brain Plasticity in Humans
Authors: Tyler William J. , Wyckoff Sarah , Hearn Taylor , Hool Nicholas
Published: August 2019

Our work was motivated by the goal of developing a Targeted Neuroplasticity Training (TNT) method for enhancing foreign language learning. To this end, our primary effort was to evaluate new and optimized approaches to noninvasive vagal nerve stimulation (VNS). We considered several Human Factors Dimensions to develop methods that would be amenable to comfortable, everyday use in common training environments or contexts. Several approaches to noninvasive or external vagal nerve stimulation have been described. Transcutaneous modulation of the left cervical branch of the vagus nerve can be uncomfortable for users resulting in a distracting experience, which may not be ideal for augmenting plasticity during training. Transdermal auricular vagal nerve stimulation (taVNS) offers another approach by targeting nerve fibers innervating the external ear. Prior methods have described many different approached using electrode clips on the ear or stainless-steel ball electrodes, which can respectively result in mechanical discomfort and electrical stimulus discomfort due to high current densities. Other approaches use carbon-doped or conductive rubbers, which require wetting. This is problematic since small degrees of dehydration cause significant changes in the electrical impedance of the skin-electrode interface. Detailed human cadaveric studies have shown the external auditory meatus or ear canal is highly innervated by branches of the auricular vagus nerve. Therefore, we designed taVNS electrodes that were fabricated as a biocompatible, hydrogel earbud electrodes for unilateral or bilateral use. We then evaluated the safety and efficacy of these approaches across a range of stimulus frequencies and intensities. We further evaluated the influence of this approach on autonomic physiology by recording heart rate, heart rate variability, skin conductance, skin temperature, and respiration rate. We investigated attention using simultaneous EEG and pupillometry during auditory stimulation tasks. We further studied the effects on sensory gating and plasticity by examining EEG brain activity patterns obtained during auditory mismatch negativity tasks. Finally, we investigated the basic safety and tolerability of the methods and approaches. We found that a simple, dry (hydrogel), earbud electrode design is a safe and effective method for achieving taVNS. Given the safety, preliminary efficacy, and comfort outcomes observed, we conclude taVNS approaches using earbud electrodes warrant further development and investigation as a TNT tool, to mediate human-computer interactions, for brain-computer interfaces, and as medical devices for the treatment of pervasive health disorders.
Uncovering a hidden diversity: optimized protocols for the extraction of bacteriophages from soil
Authors: Göller Pauline C. , Haro-Moreno Jose M. , Rodriguez-Valera Francisco , Loessner Martin J. , Gómez-Sanz Elena
Published: August 2019

Background

Bacteriophages are the most numerous biological entities on earth and play a crucial role in shaping microbial communities. Investigating the bacteriophage community from soil samples will shed light not only on the yet largely unknown phage diversity, but also may result in novel insights into phage biology and functioning. Unfortunately, the study of soil viromes lags far behind any other ecological model system, due to the heterogeneous soil matrix that rises major technical difficulties in the extraction process. Resolving these technical challenges and establishing a standardized extraction protocol is therefore a fundamental prerequisite for replicable results and comparative virome studies.

Results

We here report the optimization of protocols for extraction of bacteriophage DNA from soil preceding metagenomic analysis such that the protocol can equally be harnessed for phage isolation. As an optimization strategy, soil samples were spiked with a viral community consisting of phages from different families (106 PFU/g soil): Listeria phage ΦA511 (Myovirus), Staphylococcus phage Φ2638AΔLCR (Siphovirus), and Escherichia phage ΦT7 (Podovirus). The efficacy of bacteriophage (i) elution, (ii) filtration, (iii) concentration, and (iv) DNA extraction methods was tested. Successful extraction routes were selected based on spiked phage recovery and low bacterial 16S rRNA gene contaminants. Natural agricultural soil viromes were then extracted with the optimized methods and shotgun sequenced. Our approach yielded sufficient amounts of inhibitor-free viral DNA for non-amplification dependent sequencing and low 16S rRNA gene contamination levels (≤ 0.2 ‰). Compared to previously published protocols, the number of bacterial read contamination was decreased by 65 %. In addition, 468 novel circularized soil phage genomes in size up to 235 kb were obtained from over 29,000 manually identified viral contigs, promising the discovery of a large, previously inaccessible viral diversity.

Conclusion

We have shown a dramatically enhanced extraction of the soil phage community by protocol optimization that has proven robustness in both a culture-depended as well as through metaviromic analysis. Our huge data set of manually curated soil viral contigs roughly doubles the amount of currently available soil virome data, and provide insights into the yet largely undescribed soil viral sequence space.
Asymmetrical diversification of the receptor-ligand interaction controlling self-incompatibility in Arabidopsis
Authors: Maxime Chantreau , Poux Céline , Lensink Marc F. , Brysbaert Guillaume , Vekemans Xavier , Castric Vincent
Published: August 2019

How two-components genetic systems accumulate evolutionary novelty and become diversified in the course of evolution is a fundamental problem in evolutionary systems biology. In the Brassicaceae, self-incompatibility (SI) is a spectacular example of a diversified allelic series in which numerous highly diverged receptor-ligand combinations are segregating in natural populations. However, the evolutionary mechanisms by which new SI specificities arise in the first place have remained elusive. Usingin plantaancestral protein resurrection, we demonstrate that two allelic variants currently segregating as distinct receptor-ligand combinations diverged through an asymmetrical process whereby one variant has retained the same recognition specificity as the (now extinct) ancestor, while the other has functionally diverged and now represents a novel specificity no longer recognized by the ancestor. Examination of the structural determinants of the shift in binding specificity suggests that allosteric changes may be an important source of evolutionary novelty in this highly diversified receptor-ligand system.
Including variability in air temperature warming scenarios in a lake simulation model highlights uncertainty in predictions of cyanobacteria
Authors: Krinos Arianna I. , Farrell Kaitlin J. , Daneshmand Vahid , Subratie Kensworth C. , Figueiredo Renato J. , Carey Cayelan C.
Published: August 2019

Despite growing evidence that climate change will increase temperature variability and the frequency of temperature extremes, many modeling studies that analyze the effects of warming scenarios on cyanobacteria in lakes examine uniform warming temperature scenarios without including any variability. Here, we used the one-dimensional hydrodynamic General Lake Model coupled to Aquatic EcoDynamics modules (GLM-AED) to simulate 11 years of nitrogen-fixing and non-nitrogen-fixing cyanobacterial biomass in Lake Mendota (Madison, WI, USA). We developed climate scenarios with either uniform (constant) warming or variable warming based on random sampling of daily air temperatures from either a normal or Poisson probability distribution. We found that while the median cyanobacterial biomass among repeated simulations for each of the years was similar regardless of whether or not air temperature variability was included in the climate scenarios, the randomly-sampled air temperature distribution scenarios exhibited much greater variability in the year-to-year cyanobacterial biomass estimates. Our results suggest that including temperature variability in climate scenarios may substantially change our understanding of how climate warming may alter cyanobacterial blooms over yearly to decadal time scales. To more effectively predict the range of possible future cyanobacterial dynamics, both the magnitude and variability of warming must be considered when developing climate scenarios for lake modeling studies.
An integrated population model for estimating the relative effects of natural and anthropogenic factors on a threatened population of Pacific trout
Authors: Scheuerell Mark D. , Ruff Casey P. , Anderson Joseph H. , Beamer Eric M.
Published: August 2019

Assessing the degree to which at-risk species are regulated by density dependent versus density independent factors is often complicated by incomplete or biased information. If not addressed in an appropriate manner, errors in the data can affect estimates of population demographics, which may obfuscate the anticipated response of the population to a specific action.

We developed a Bayesian integrated population model that accounts explicitly for interannual variability in the number of reproducing adults and their age structure, harvest, and environmental conditions. We apply the model to 41 years of data for a population of threatened steelhead troutOncorhynchus mykissusing freshwater flows, ocean indices, and releases of hatchery-born conspecifics as covariates.

We found compelling evidence that the population is under strong density dependence, despite being well below its historical population size. In the freshwater portion of the lifecycle, we found a negative relationship between productivity (offspring per parent) and peak winter flows, and a positive relationship with summer flows. We also found a negative relationship between productivity and releases of hatchery conspecifics. In the marine portion of the lifecycle, we found a positive correlation between productivity and the North Pacific Gyre Oscillation. Furthermore, harvest rates on wild fish have been sufficiently low to ensure very little risk of overfishing.

Synthesis and applications.The evidence for density dependent population regulation, combined with the substantial loss of juvenile rearing habitat in this river basin, suggests that habitat restoration could benefit this population of at-risk steelhead. Our results also imply that hatchery programs for steelhead need to be considered carefully with respect to habitat availability and recovery goals for wild steelhead. If releases of hatchery steelhead have indeed limited the production potential of wild steelhead, there are likely significant tradeoffs between providing harvest opportunities via hatchery steelhead production, and achieving wild steelhead recovery goals.
Multipotent radial glia progenitors and fate-restricted intermediate progenitors sequentially generate diverse cortical interneuron types
Authors: Kelly Sean M. , Raudales Ricardo , Moissidis Monika , Kim Gukham , Huang Z. Josh
Published: August 2019

GABAergic interneurons deploy numerous inhibitory mechanisms that regulate cortical circuit operation, but the developmental programs that generate diverse interneuron types remain not well understood. We carried out a comprehensive genetic fate mapping of the radial glial progenitors (RGs) and intermediate progenitors (IP) in the medial ganglionic eminence (MGE). We reveal thatNkx2.1+RGs are multipotent and mediate two consecutive waves of neurogenesis, each sequentially generating different sets of interneuron types that laminate the neocortex in an inside-out-inside order. The first wave is restricted to the caudal MGE, has limited neurogenic capacity, and involves mostly apical IPs. The second wave initiates throughout the MGE and features a large set of fate-restricted basal IPs that amplify and diversify interneurons. Chandelier cells are generated toward the end of each wave and laminate in an outside-in order. Therefore, separate pools of multipotent RGs deploy temporal cohorts of IPs to sequentially generate diverse interneuron types.
Selection on mutators is not frequency-dependent
Authors: Raynes Yevgeniy , Weinreich Daniel M.
Published: August 2019

The evolutionary fate of mutator mutations – i.e., genetic variants that raise the genome-wide mutation rate – in asexual populations is often described as being frequency (or number) dependent. This common intuition suggests that mutators can invade a population by hitchhiking with a sweeping beneficial mutation, but only when sufficiently frequent to produce such a mutation before non-mutators do. Here, we use stochastic, agent-based simulations to show that neither the strength nor the sign of selection on mutators depend on their initial frequency, and while the overall probability of hitchhiking increases predictably with frequency, the per-capita probability of fixation remains unchanged.
Polygenic Hyperlipidemias and Coronary Artery Disease Risk
Authors: Ripatti Pietari , Rämö Joel T , Mars Nina J , Söderlund Sanni , Benner Christian , Surakka Ida , Kiiskinen Tuomo , Havulinna Aki S , Palta Priit , Freimer Nelson B , Salomaa Veikko , Pirinen Matti , Palotie FinnGen Aarno , Taskinen Marja-Riitta , Ripatti Samuli
Published: August 2019

Background

Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). Monogenic familial hypercholesterolemia associates with higher increase in CAD risk than expected from a single LDL-C measurement, likely due to lifelong cumulative exposure to high LDL-C. It remains unclear to what extent a high polygenic load of LDL-C or TG-increasing variants associates with increased CAD risk.

Methods and Results

We derived polygenic risk scores (PRS) with ∼6M variants for LDL-C and TG with weights from a UK biobank-based genome-wide association study with ∼500K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the FINRISK cohort, and to CAD risk in 135 300 individuals (13 695 CAD cases) from the FinnGen project.

In FINRISK, LDL-C ranged from 2.83 (95% CI 2.79-2.89) to 3.80 (3.72-3.88) and TG from 0.99 (0.95-1.01) to 1.52 (1.48-1.58) mmol/l between the lowest and highest 5% of the respective PRS distributions. The corresponding CAD prevalences ranged from 8.2% to 12.7% for the LDL-C PRS and from 8.2% to 12.1% for the TG PRS in FinnGen. Furthermore, CAD risk was 1.36-fold higher (OR, 95% CI 1.24-1.49) for the LDL-C PRS and 1.31-fold higher (1.20-1.44) for the TG PRS for those with the PRS >95thpercentile vs those without. These estimates were only slightly attenuated when adjusting for a CAD PRS (OR 1.26 [95% CI 1.15-1.39] for LDL-C and 1.21 [1.10-1.32] for TG PRS).

Conclusions

The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and mostly independent of a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing more direct guidance for clinical translation.
Enduring consequences of perinatal fentanyl exposure in mice
Authors: Alipio Jason B. , Brockett Adam T. , Fox Megan E. , Tennyson Stephen S. , deBettencourt Coreylyn A. , El-Metwally Dina , Francis Nikolas A. , Kanold Patrick O. , Lobo Mary Kay , Roesch Matthew R. , Keller Asaf
Published: August 2019

Opioid use by pregnant women is an understudied consequence associated with the opioid epidemic, resulting in a rise in the incidence of neonatal opioid withdrawal syndrome (NOWS), and lifelong neurobehavioral deficits that result from perinatal opioid exposure. There are few preclinical models that accurately recapitulate human perinatal drug exposure, and few focus on fentanyl, a potent synthetic opioid that is a leading driver of the opioid epidemic. To investigate the consequences of perinatal opioid exposure, we administered fentanyl to mouse dams in their drinking water throughout gestation and until litters were weaned at postnatal day (PD) 21. Fentanyl-exposed dams delivered smaller litters, and had higher litter mortality rates compared to controls. Metrics of maternal care behavior were not affected by the treatment, nor were there differences in dams’ weight or liquid consumption throughout gestation and 21 days postpartum. Twenty-four hours after weaning and drug cessation, perinatal fentanyl-exposed mice exhibited signs of spontaneous somatic withdrawal behavior, and sex-specific weight fluctuations that normalized in adulthood. At adolescence (PD 35) they displayed elevated anxiety-like behaviors and decreased grooming, assayed in the elevated plus maze and sucrose splash tests. Finally, by adulthood (PD 55) they displayed impaired performance in a two-tone auditory discrimination task. Collectively, our findings suggest that perinatal fentanyl exposed mice exhibit somatic withdrawal behavior and changes across the lifespan reminiscent of humans born with NOWS.
Population-Level Disease Dynamics Reflect Individual Heterogeneities in Transmission
Authors: Siva-Jothy Jonathon A. , White Lauren A. , Craft Meggan E. , Vale Pedro F.
Published: August 2019

Host heterogeneity in disease transmission is widespread and presents a major hurdle to predicting and minimizing pathogen spread. Using theDrosophila melanogastermodel system infected withDrosophilaC virus, we integrate experimental measurements of individual host heterogeneity in social aggregation, virus shedding, and disease-induced mortality into an epidemiological framework that simulates outbreaks of infectious disease. We use these simulations to calculate individual variation in disease transmission and apportion this variation to specific components of transmission: social network degree distribution, infectiousness, and infection duration. The experimentally-observed variation produces substantial differences in individual transmission potential, providing evidence for genetic and sex-specific effects on disease dynamics at a population level. Manipulating variation in social network connectivity, infectiousness, and infection duration in simulated populations reveals that these components affect disease transmission in clear and distinct ways. We consider the implications of this genetic and sex-specific variation in disease transmission and discuss implications for appropriate control methods given the relative contributions made by social aggregation, virus shedding, and infection duration to transmission in other host-pathogen systems.
Resting-state and task-based centrality of dorsolateral prefrontal cortex predict resilience to inhibitory repetitive transcranial magnetic stimulation
Authors: Fitzsimmons Sophie M.D.D. , Douw Linda , van den Heuvel Odile A. , van der Werf Ysbrand D. , Vriend Chris
Published: August 2019

Background

Repetitive transcranial magnetic stimulation (rTMS) is used to investigate normal brain function in healthy participants and as a treatment for brain disorders. Various subject factors can influence individual response to rTMS, including brain network properties.

Objective/Hypothesis

A previous study by our group showed that ‘virtually lesioning’ the left dorsolateral prefrontal cortex (dlPFC; important for cognitive flexibility) using inhibitory rTMS reduced performance on a set-shifting task. We aimed to determine whether this behavioural response was related to topological features of pre-TMS resting-state and task-based functional networks.

Methods

Inhibitory (1Hz) rTMS was applied to the left dlPFC in 16 healthy participants, and to the vertex in 17 participants as a control condition. Participants performed a set-shifting task during fMRI at baseline and directly after a single rTMS session 1-2 weeks later. Functional network topology measures were calculated from resting-state and task-based fMRI scans using graph theoretical analysis.

Results

The dlPFC-stimulated group, but not the vertex group, showed reduced set shifting performance after rTMS associated with lower task-based betweenness centrality of the dlPFC at baseline (p=.030) and a smaller reduction in task-based betweenness centrality after rTMS (p=.024). Reduced repeat trial accuracy after rTMS was associated with higher baseline resting state node strength of the dlPFC (p=.017).

Conclusions

Our results suggest that behavioural response to inhibitory rTMS to the dlPFC is dependent on baseline functional network features. Individuals with more globally integrated stimulated regions show greater resilience to inhibitory rTMS, while individuals with more locally well-connected regions show greater vulnerability.

Highlights

Functional brain network properties predict behavioural response to 1Hz DLPFC rTMS

Globally integrated stimulated regions are resilient to effects of inhibitory rTMS

Segregated, locally well-connected regions are vulnerable to inhibitory rTMS

Change in performance after rTMS correlates with change in network properties
The abundance and diversity of West Nile virus mosquito vectors in two Regional Units of Greece during the onset of the 2018 transmission season
Authors: Bisia Marina , Jeffries Claire L , Lytra Ioanna , Michaelakis Antonios , Walker Thomas
Published: August 2019

Background

West Nile virus (WNV) is a zoonotic arbovirus of great medical and veterinary importance, threatening the health of humans and equines worldwide. Mosquitoes belonging to the Culex (Cx.) pipiens complex are major vectors but numerous other mosquito species have also been implicated as vectors of WNV. Due to variations in blood-feeding behaviour, the different biotypes and hybrids of Cx. pipiens influence the transmission of WNV, from enzootic cycles (between mosquitoes and birds), to spill-over transmission to humans and equines.

Methods

In this study, mosquitoes were collected and analysed from two regional units (RUs) of Greece with reported cases of WNV within the past 4 years; Palaio Flairo and Argolida (in Attica and Peloponnese regions, respectively). Collections using different types of mosquito surveillance traps were undertaken in May-June 2018 during the early period of the WNV transmission season.

Results

A total of 1062 mosquitoes were collected, with Biogents Sentinel traps (BG traps) collecting both a greater number of mosquitoes across all species and Cx. pipiens complex individuals than Centres for Disease Control miniature light traps (CDC traps) or Heavy Duty Encephalitis Vector Survey traps (EVS traps). Identification of collected mosquitoes (using both morphological keys and molecular barcoding) confirmed the presence of additional species including Aedes (Ae.) albopictus, Ae. caspius and Culiseta (Cs.) longiareolata. The prevalence of Cx. pipiens biotypes in the RU of Palaio Faliro was 54.5% pipiens type, 20.0% molestus type and 25.5% hybrids. In the RU of Argolida, the collection comprised 68.1% pipiens type, 8.3% molestus type and 23.6% hybrids. Screening individual unfed female mosquitoes for WNV (molecular xenomonitoring) resulted in detection in three females of the pipiens type and in one hybrid; all collected from the RU of Argolida.

Conclusions

As hybrids play an important role in spill-over transmission of WNV to humans and equines, these findings highlight the importance of undertaking entomological surveillance programs incorporating molecular xenomonitoring at the onset of the transmission season to provide an early warning system for health authorities aiming to prevent WNV outbreaks in Greece.
Agency and responsibility over virtual movements controlled through different paradigms of brain–computer interface
Authors: Nierula Birgit , Spanlang Bernhard , Martini Matteo , Borrell Mireia , Nikulin Vadim V. , Sanchez-Vives Maria V.
Published: August 2019

Agency is the attribution of an action to the self and is a prerequisite for experiencing responsibility over its consequences. Here we investigated agency and responsibility by studying the control of movements of an embodied avatar, via brain computer interface (BCI) technology, in immersive virtual reality. After induction of virtual body ownership by visuomotor correlations, healthy participants performed a motor task with their virtual body. We compared the passive observation of the subject’s ‘own’ virtual arm performing the task with (1) the control of the movement through activation of sensorimotor areas (motor imagery) and (2) the control of the movement through activation of visual areas (steady-state visually evoked potentials). The latter two conditions were carried out using a brain–computer interface (BCI) and both shared the intention and the resulting action. We found that BCI-control of movements engenders the sense of agency, which is strongest for sensorimotor areas activation. Furthermore, increased activity of sensorimotor areas, as measured using EEG, correlates with levels of agency and responsibility. We discuss the implications of these results for the neural bases of agency, but also in the context of novel therapies involving BCI and the ethics of neurotechnology.

Key points summary

We induced embodiment of a virtual body and its movements were controlled by two different BCI paradigms – one based on signals from sensorimotor versus one from visual cortical areas.

BCI-control of movements engenders agency, but not equally for all paradigms.

Cortical sensorimotor activation correlates with agency and responsibility.

This has significant implications for neurological rehabilitation and neuroethics.
Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration
Authors: Cauquil Marie , Mias Céline , Guilbeau-Frugier Céline , Karsenty Clément , Seguelas Marie-Hélène , Genet Gaël , Renaud-Gabardos Edith , Prats Anne-Catherine , Pons Véronique , Branchereau Maxime , Heymes Christophe , Calise Denis , Lairez Olivier , Daviaud Danièle , Honton Benjamin , Frongia Céline , Ducommun Bernard , Delisle Marie-Bernadette , Arvanitis Dina N. , Pathak Atul , Sénard Jean-Michel , Galés Céline
Published: August 2019

Aims

Deciphering the innate mechanisms governing the blockade of proliferation in adult cardiomyocytes (CMs) is challenging for mammalian heart regeneration. Despite the exit of CMs from the cell cycle during the postnatal maturation period coincides with their morphological switch to a typical adult rod-shape, whether these two processes are connected is unknown. Here, we examined the role of ephrin-B1, a CM rod-shape stabilizer, in adult CM proliferation and cardiac regeneration.

Methods and results

Transgenic- or AAV9-based ephrin-B1 repression in adult mouse heart led to substantial proliferation of resident CMs and tissue regeneration to compensate for apex resection, myocardial infarction (MI) and senescence. Interestingly, in the resting state, CMs lacking ephrin-B1 did not constitutively proliferate, indicative of no major cardiac defects. However, they exhibited proliferation-competent signature, as indicated by higher mononucleated state and a dramatic decrease of miR-195 mitotic blocker, which can be mobilized under neuregulin-1 stimulation in vitro and in vivo. Mechanistically, the post-mitotic state of the adult CM relies on ephrin-B1 sequestering of inactive phospho-Yap1, the effector of the Hippo-pathway, at the lateral membrane. Hence, ephrin-B1 repression leads to phospho-Yap1 release in the cytosol but CM quiescence at resting state. Upon cardiac stresses (apectomy, MI, senescence), Yap1 could be activated and translocated to the nucleus to induce proliferation-gene expression and consequent CM proliferation

Conclusions

Our results identified ephrin-B1 as a new natural locker of adult CM proliferation and emphasize that targeting ephrin-B1 may prove a future promising approach in cardiac regenerative medicine for HF treatment.

Significance

The mammalian adult heart is unable to regenerate due to the inability of cardiomyocytes (CMs) to proliferate and replace cardiac tissue lost. Exploiting CM-specific transgenic mice or AAV9-based gene therapy, this works identifies ephrin-B1, a specific rod-shape stabilizer of the adult CM, as a natural padlock of adult CM proliferation for compensatory adaptation to different cardiac stresses (apectomy, MI, senescence), thus emphasizing a new link between the adult CM morphology and their proliferation potential. Moreover, the study demonstrates proof-of-concept that targeting ephrin-B1 may be an innovative therapeutic approach for ischemic heart failure.
Disentangling the impact of environmental and phylogenetic constraints on prokaryotic strain diversity
Authors: Maistrenko Oleksandr M. , Mende Daniel R. , Luetge Mechthild , Hildebrand Falk , Schmidt Thomas S. B. , Li Simone S. , Coelho Luis Pedro , Huerta-Cepas Jaime , Sunagawa Shinichi , Bork Peer
Published: August 2019

Microbial organisms inhabit virtually all environments and encompass a vast biological diversity. The pan-genome concept aims to facilitate an understanding of diversity within defined phylogenetic groups. Hence, pan-genomes are increasingly used to characterize the strain diversity of prokaryotic species. To understand the interdependency of pan-genome features (such as numbers of core and accessory genes) and to study the impact of environmental and phylogenetic constraints on the evolution of conspecific strains, we computed pan-genomes for 155 phylogenetically diverse species using 7000 high-quality genomes. We show that many pan-genome features such as functional diversity and core genome nucleotide diversity are correlated to each other. Further, habitat flexibility as approximated by species ubiquity is associated with several pan-genome features, particularly core genome size. In general, environment had a stronger impact on pan-genome features than phylogenetic signal. Similar environmental preferences led to convergent evolution of pan-genomic features in distant phylogenetic clades. For example, the soil environment promotes expansion of pan-genome size, while host-associated habitats lead to its reduction.
Response-related signals increase confidence but not metacognitive performance
Authors: Filevich Elisa , Koß Christina , Faivre Nathan
Published: August 2019

Confidence judgements are a central tool for research in metacognition. In a typical task, participants first perform perceptual (first-order) decisions and then rate their confidence in these decisions. The relationship between confidence and first-order accuracy is taken as measure of metacognitive performance. Confidence is often assumed to stem from decision-monitoring processes alone, but processes that co-occur with the first-order decision may also play a role in confidence formation. In fact, across a broad range of tasks, trials with quick reaction times to the first-order task are often judged with relatively higher confidence than those with slow responses. This robust finding suggests that confidence could be informed by a readout of reaction times in addition to decision-monitoring processes. To test this possibility, we assessed the contribution of response-related signals to confidence and, in particular, to metacognitive performance (i.e., a measure of the adequacy of these confidence judgements). In a factorial design, we measured the effect of making an overt (vs. covert) decision, as well as the effect of pairing a motor action to the stimulus about which the first-order decision is made. Against our expectations, we found no differences in overall confidence or metacognitive performance when first-order responses were covert as opposed to overt. Further, actions paired to visual stimuli presented led to higher confidence ratings, but did not affect metacognitive performance. These results suggest that some of the relationships between first-order decisional signals and confidence might indeed be correlational, and attributable to an upstream cognitive process, common to the two of them.
Pan-active imidazolopiperazine antimalarials target thePlasmodium falciparumintracellular secretory pathway
Authors: LaMonte Gregory M. , Marapana Danushka S. , Gnadig Nina , Ottilie Sabine , Luth Madeline R. , Worgall Tilla S. , Rocamora Frances , Goldgof Gregory M. , Mohunlal Roxanne , Kumar T.R Santha , Thompson Jenny K. , Vigil Edgar , Yang Jennifer , Hutson Dylan , Johnson Trevor , Huang Jianbo , Williams Roy M. , Zou Bing Yu , Cheung Andrea L. , Kumar Prianka , Egan Timothy J. , Lee Marcus C.S. , Siegel Dionicio , Cowman Alan F. , Fidock David A. , Winzeler Elizabeth A.
Published: August 2019

Abstract

One of the most promising new compound classes in clinical development for the treatment of malaria is the imidazolopiperazines (IZPs) class. Human trials have demonstrated that members of the IZP series, which includes KAF156 (Ganaplacide) and GNF179, are potent and effective againstPlasmodiumsymptomatic asexual blood-stage infections. Unlike other commonly used antimalarials, they also prevent transmission and block future infection in animal models. Despite the identification of severalPlasmodium falciparumresistance mechanisms including mutations in ER-localized PfCARL (PfEMP65), Acetyl-coA transporter, and PfUGT transporter, IZP’s mechanism of action remains unknown.

To investigate, we combinedin vitroevolution and whole-genome analysis in the model organismSaccharomyces cerevisiaewith molecular, metabolomic, and chemogenomic methods, inP. falciparum.S. cerevisiaeclones that resist IZP activity carry multiple mutations in genes that encode endoplasmic reticulum(ER)-based lipid homeostasis and autophagy includingelo2,elo3,sur2,atg15andlcb4, as well as ER-basedsec66.InPlasmodium, IZPs cause inhibition of protein trafficking, block the establishment of new permeation pathways and result in ER expansion. We also observe sensitization with other secretion inhibitors such as brefeldin A and golgicidin as well as synthetic lethality with PfSEC62. Our data show that IZPs target the secretory pathway and highlight a novel mechanism for blocking parasite growth and development that is distinct from those of standard compounds used to treat malaria. In addition, we provide physiological signatures and hallmarks for inhibitors that work through this mechanism of action and show that IZPs are tool compounds for studying ER-dependent protein processing in different species.
The transcription factor E2A drives neural differentiation in pluripotent cells
Authors: Rao Chandrika , Malaguti Mattias , Mason John O. , Lowell Sally
Published: August 2019

The intrinsic mechanisms that link extracellular signalling to the onset of neural differentiation are not well understood. In pluripotent mouse cells, BMP blocks entry into the neural lineage via transcriptional upregulation of Inhibitor of Differentiation (Id) factors. We have previously identified that the major binding partner of Id proteins in pluripotent cells is the basic helix-loop-helix (bHLH) transcription factor (TF), E2A. Id1 can prevent E2A from forming heterodimers with bHLH TFs or from forming homodimers. Here, we show that overexpression of a forced E2A homodimer is sufficient to drive robust neural commitment in pluripotent cells, even under non-permissive conditions. Conversely, we find that E2A null cells display a defect in their neural differentiation capacity. E2A acts as an upstream activator of neural lineage genes, includingSox1andFoxd4, and as a repressor of Nodal signalling. Our results suggest a crucial role for E2A in establishing neural lineage commitment in pluripotent cells.