bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered Affective Behaviors in Casein Kinase 1 Epsilon Mutant Mice
Authors: Zhou Lili , Fitzpatrick Karrie , Olker Christopher , Vitaterna Martha H. , Turek Fred W.
Published: June 2020

Affective behaviors and mental health are profoundly affected by disturbances in circadian rhythms. Casein kinase 1 epsilon (CSNK1E) is an essential component of the core circadian clock. Mice withtauor null mutation of this gene have shortened and lengthened circadian period respectively. Here we examined anxiety-like, fear, and depressive-like behaviors in both male and female mice of these two different mutants. Compared with wild-type mice, we found reductions in fear and anxiety-like behaviors in both mutant lines and in both sexes, with thetaumutants exhibiting the greatest phenotypic changes. However, the depressive-like behaviors had distinct phenotypic patterns, with markedly less depressive-like behaviors in female null mutants, but not intaumutants of either sex. To determine whether abnormal light entrainment oftaumutants to 24 hour light-dark cycles contributes to these phenotypic differences, we also examined these behaviors intaumutants on a 20 hour light-dark cycle close to their endogenous circadian period. The normalized entrainment restored more wild-type-like behaviors for fear and anxiety, but it induced depressive-like behavior intaumutant females. These data show that both mutations ofCsnk1ebroadly affect fear and anxiety-like behaviors, while the effects on depressive-like behavior vary with genetics, photoperiod, and sex, suggesting that the mechanisms by whichCsnk1eaffects fear and anxiety-like behaviors may be similar, but distinct from those affecting depressive-like behavior. Our study also provides experimental evidence in support of the hypothesis of beneficial outcomes from properly entrained circadian rhythms in terms of the anxiety-like and fear behaviors.
Genomic stability and adaptation of beer brewing yeasts during serial repitching in the brewery
Authors: Large Christopher R. L. , Hanson Noah , Tsouris Andreas , Saada Omar Abou , Koonthongkaew Jirasin , Toyokawa Yoichi , Schmidlin Tom , Moreno-Habel Daniela A. , McConnellogue Hal , Preiss Richard , Takagi Hiroshi , Schacherer Joseph , Dunham Maitreya J.
Published: June 2020

Ale brewing yeast are the result of admixture between diverse strains ofSaccharomyces cerevisiae, resulting in a heterozygous tetraploid that has since undergone numerous genomic rearrangements. As a result, comparisons between the genomes of modern related ale brewing strains show both extensive aneuploidy and mitotic recombination that has resulted in a loss of intragenomic diversity. Similar patterns of intraspecific admixture and subsequent selection for one haplotype have been seen in many domesticated crops, potentially reflecting a general pattern of domestication syndrome between these systems. We set out to explore the evolution of the ale brewing yeast, to understand both polyploid evolution and the process of domestication in the ecologically relevant environment of the brewery. Utilizing a common brewery practice known as ‘repitching’, in which yeasts are reused over multiple beer fermentations, we generated population time courses from multiple breweries utilizing similar strains of ale yeast. Applying whole-genome sequencing to the time courses, we have found that the same structural variations in the form of aneuploidy and mitotic recombination of particular chromosomes reproducibly rise to detectable frequency during adaptation to brewing conditions across multiple related strains in different breweries. Our results demonstrate that domestication of ale strains is an ongoing process and will likely continue to occur as modern brewing practices develop.
Study of flow effects on temperature-controlled radio-frequency ablation using phantom experiments and forward simulations
Authors: Nolte Teresa , Vaidya Nikhil , Baragona Marco , Elevelt Aaldert , Lavezzo Valentina , Maessen Ralph , Schulz Volkmar , Veroy Karen
Published: June 2020

Purpose

Blood perfusion is known to add variability to hepatic radiofrequency ablation (RFA) treatment outcomes. Simulation-assisted treatment planning taking into account blood perfusion may solve this problem in the future. Hence, this study aims to study perfusion effects on RFA in a controlled environment and to compare the outcome to a prediction made using finite volume simulations.

Methods

Ablation zones were induced in tissue-mimicking, thermochromic ablation phantoms with a single flow channel, using a RF generator with needle temperature controlled power delivery and a monopolar needle electrode. Channel radius and saline flow rate were varied and the impact of saline flow on the ablated cross-sectional area, on a potential occurrence of directional effects as well as on the delivered generator power input was studied. Finite-volume simulations reproducing the experimental geometry, flow conditions and generator power input were conducted in a second step and compared to the experimental ablation outcomes.

Results

Vessels of different radii affected the ablation result in different manners. For the channel radius of 0.275 mm both the ablated area and energy input reduced with increasing flow rate. For radius 0.9 mm the ablated area reduced with increasing flow rate but the energy input increased. An increasing area and energy input were observed towards larger flow rates for the channel radius of 2.3 mm. Directional effects, i.e., shrinking of the lesion upstream of the needle and an extension thereof downstream, were observed only for the smallest channel radius. The simulations qualitatively confirmed these observations. When using the simulations to make a prediction of ablation outcomes with flow, the mean absolute error between experimental and predicted ablation outcomes was reduced from 23% to 12% as compared to neglecting flow effects.

Conclusion

Simulations can improve the prediction of RFA ablation regions in the presence of various blood flow effects. Our findings therefore underline the potential of simulation-assisted, patient-individual RFA treatment planning and guidance for the prediction of RFA outcomes in the presence of blood flow.

Additional comments

-Teresa Nolte and Nikhil Vaidya contributed equally to this work.

-Volkmar Schulz and Karen Veroy contributed equally to this work.

-A single reference experiment, i.e., not using a flow channel, and the image in the upper left corner of Figure 4 were included into a publication submitted to Int. J. Hyperthermia for model validation purposes.
Multitrait genetic-phenotype associations to connect disease variants and biological mechanisms
Authors: Julienne Hanna , Laville Vincent , McCaw Zachary R. , He Zihuai , Guillemot Vincent , Lasry Carla , Ziyatdinov Andrey , Vaysse Amaury , Lechat Pierre , Ménager Hervé , Goff Wilfried Le , Dube Marie-Pierre , Kraft Peter , Ionita-Laza Iuliana , Vilhjálmsson Bjarni J. , Aschard Hugues
Published: June 2020

Background

Genome-wide association studies (GWAS) uncovered a wealth of associations between common variants and human phenotypes. These results, widely shared across the scientific community as summary statistics, fostered a flurry of secondary analysis: heritability and genetic correlation assessment, pleiotropy characterization and multitrait association test. Amongst these secondary analyses, a rising new field is the decomposition of multitrait genetic effects into distinct profiles of pleiotropy.

Results

We conducted an integrative analysis of GWAS summary statistics from 36 phenotypes to decipher multitrait genetic architecture and its link to biological mechanisms. We started by benchmarking multitrait association tests on a large panel of phenotype sets and established theOmnibustest as the most powerful in practice. We detected 322 new associations that were not previously reported by univariate screening. Using independent significant associations, we investigated the breakdown of genetic association into clusters of variants harboring similar multitrait association profile. Focusing on two subsets of immunity and metabolism phenotypes, we then demonstrate how SNPs within clusters can be mapped to biological pathways and disease mechanisms, providing a putative insight for numerous SNPs with unknown biological function. Finally, for the metabolism set, we investigate the link between gene cluster assignment and success of drug targets in random control trials. We report additional uninvestigated drug targets classified by clusters.

Conclusions

Multitrait genetic signals can be decomposed into distinct pleiotropy profiles that reveal consistent with pathways databases and random control trials. We propose this method for the mapping of unannotated SNPs to putative pathways.
Calculating metalation in cells reveals CobW acquires CoIIfor vitamin B12biosynthesis upon binding nucleotide
Authors: Young Tessa R. , Martini Maria Alessandra , Osman Deenah , Morton Richard J. , Deery Evelyne , Warren Martin J. , Robinson Nigel J.
Published: June 2020

Protein metal-occupancy (metalation)in vivohas been elusive. Here we develop a metalation-calculator which accounts for inter-metal competition and changing metal-availabilities inside cells. The calculations are based on available free-energies of metals determined from the responses of metal sensors. We use the calculator to understand the function and mechanism of CobW, a predicted CoII-chaperone for vitamin B12. CobW is calculated to acquire negligible metal alone: But, upon binding nucleotide (GTP) and MgII, CobW assembles a high-affinity site that can obtain CoIIor ZnIIfrom the intracellular milieu. In idealised cells with sensors at the mid-points of their responses, competition within the cytosol enables CoIIto outcompete ZnIIfor binding CobW. Thus, CoIIis the cognate metal. However, after growth in different [CoII], CoII-occupancy ranges from 10 to 97% which matches CobW-dependent B12synthesis. The calculator reveals how CobW acquires its metal and is made available for use with other proteins.
Thyroid Hormones-Thyrotropin Interrelationships in Thyroid Dysfunction States
Authors: Lamichhane Tika Ram , Pant Sandeep Prashad , Lamichhane Binod , Paudel Sharma , Yadav Binod Kumar , Lamichhane Hari Prasad
Published: June 2020

Objective of this research is to explore the complex correlations among FT3, FT4 and TSH in thyroid dysfunction states. A total of 3425 outpatients were included to analyze their thyroid function tests measured at the university teaching hospital. The subjects under study were categorized as euthyroid (70.45%), subclinical hypothyroid (18.95%), overt hypothyroid (3.30%), subclinical hyperthyroid (5.11%) and overt hyperthyroid (2.19%) patients. The linear and non-linear relations among FT3, FT4 and TSH were modeled statistically to understand their role in thyroid functions. The prevalence of hypothyroidism is higher than hyperthyroidism in which females are more vulnerable than males. The correlation between FT3 and FT4 increases from euthyroidism (r = 0.1, P <0.001) to overt thyroid dysfunctions (r = 0.91, P <0.001). The non-linear complex correlations between FT4 and TSH are significantly explained by well fitted sigmoid curves of four-parameter logistic (4PL) model (R2= 0.97 and P <0.001) in both hypothyroidism and hyperthyroidism interfaced with euthyroidism. The 4PL curves are response trajectories of pituitary TSH which exhibit the turning points of thyroid dysfunction states by the deviation in serum FT4. The negative slopes and correlations observed in the linear fits in TSHvsFT3 or FT4 are the indicators of negative feedback mechanism in the thyroid cycle.
Coupling between fast and slow oscillator circuits inCancer borealisis temperature compensated
Authors: Powell D.J. , Haddad S.A. , Gorur-Shandilya S. , Marder E.
Published: June 2020

Coupled oscillatory circuits are ubiquitous in nervous systems. Given that most biological processes are temperature sensitive, it is remarkable that the neuronal circuits of poikilothermic animals can maintain coupling across a wide range of temperatures. Within the stomatogastric ganglion (STG) of the crab,Cancer borealis, the fast pyloric rhythm (~1Hz) and the slow gastric mill rhythm (~0.1Hz) are precisely coordinated at ~11°C such that there is an integer number of pyloric cycles per gastric mill cycle (integer coupling). Upon increasing temperature from 7-23°C, both oscillators showed similar temperature-dependent increases in cycle frequency, and integer coupling between the circuits was conserved. Thus, although both rhythms show temperature dependent changes in rhythm frequency, the processes that couple these circuits maintain their coordination over a wide range of temperature. Such robustness to temperature changes could be part of a toolbox of processes that enables neural circuits to maintain function despite global perturbations.
Inhibition of Mitochondrial Fission and iNOS in the Dorsal Vagal Complex Protects from Overeating and Weight Gain
Authors: Patel Bianca , New Lauryn , Griffiths Joanne C. , Deuchars Jim , Filippi Beatrice M.
Published: June 2020

The dorsal vagal complex (DVC) senses changes in insulin levels and controls glucose homeostasis, feeding behaviour and body weight. Three days of high-fat diet (HFD) in rats is sufficient to induce insulin resistance in the DVC and impair its ability to regulate feeding behaviour. HFD-feeding is associated with increased mitochondrial fission in the DVC and fission is regulated by dynamin-related protein 1 (Drp1). Higher Drp1 activity can inhibit insulin signalling, although the exact mechanisms controlling body weight remain elusive. Here we show that Drp1 activation in DVC leads to higher body weight in rats and Drp1 inhibition in HFD-fed rats reduced body weight gain, cumulative food intake and adipose tissue, and prevented insulin resistance. Rats expressing active Drp1 in the DVC had higher levels of inducible nitric oxide synthase (iNOS) and knockdown of iNOS in the DVC of HFD-fed rats led to a reduction in body weight gain, cumulative food intake and adipose tissue, and prevented insulin resistance. In obese insulin-resistant animals, inhibition of mitochondrial fission or DVC iNOS knockdown restored insulin sensitivity and decreased food intake, body weight and fat deposition. Finally, we show that inhibiting mitochondrial fission in DVC astrocytes is sufficient to protect rats from developing HFD-dependent insulin resistance, hyperphagia, body weight gain and fat deposition. Our study uncovers new molecular and cellular targets for brain regulation of whole-body metabolism, which could inform new strategies to combat obesity and diabetes.
MAGIC: Mosaic Analysis by gRNA-Induced Crossing-over
Authors: Allen Sarah E. , Koreman Gabriel T. , Sarkar Ankita , Wang Bei , Wolfner Mariana F. , Han Chun
Published: June 2020

Mosaic animals have provided the platform for many fundamental discoveries in developmental biology, cell biology, and other fields. Techniques to produce mosaic animals by mitotic recombination have been extensively developed inDrosophila melanogasterbut are less common for other laboratory organisms. Here, we reportmosaicanalysis bygRNA-inducedcrossing-over (MAGIC), a new technique for generating mosaic animals based on DNA double-strand breaks produced by CRISPR/Cas9. MAGIC efficiently produces mosaic clones in both somatic tissues and the germline ofDrosophila. Further, by developing a MAGIC toolkit for one chromosome arm, we demonstrate the method’s application in characterizing gene function in neural development and in generating fluorescently marked clones in wild-derivedDrosophilastrains. Eliminating the need to introduce recombinase-recognition sites in the genome, this simple and versatile system simplifies mosaic analysis inDrosophilaand can be applied in any organism that is compatible with CRISPR/Cas9.
LINE-1 expression in cancer correlates with DNA damage response, copy number variation, and cell cycle progression
Authors: McKerrow Wilson , Wang Xuya , Mita Paolo , Cao Song , Grivainis Mark , Ding Li , LaCava John , Boeke Jef , Fenyö David
Published: June 2020

Retrotransposons are genomic DNA sequences that are capable of copying themselves to new genomic locations via RNA intermediates; LINE-1 is the only retrotransposon that remains autonomous and active in the human genome. The mobility of LINE-1 is largely repressed in somatic tissues, but LINE-1 is active in many cancers. Recent studies using LINE-1 constructs indicate that host cells activate a DNA damage response (DDR) to repair retrotransposition intermediates and resolve conflicts between LINE-1 and DNA replication. Using multi-omic data from the CPTAC project, we found correlations between LINE-1 expression and ATM-MRN-SMC DDR signalling in endometrial cancer and between LINE-1 and the ATR-CHEK1 pathway in p53 wild type breast cancer. This provides evidence that conflicts between LINE-1 and DNA replication occur in at least some human cancers. Furthermore, LINE-1 expression in these cancers is correlated with the total amount of copy number variation genome wide, indicating that, when active in cancer, pointing to a direct impact of LINE-1 associated DNA damage on genome structure. We also find that, in endometrial and ovarian cancer, LINE-1 expression is correlated with the expression of genes that drive cycle progression including E2F3, PLK1 and Aurora kinase B. This study provides evidence, supporting recent work in model cell lines, of a LINE-1/DDR connection in human tumors and raises the possibility of additional interactions between LINE-1 and the cell cycle.
Ceramic Packaging in Neural Implants
Authors: Shen Konlin , Maharbiz Michel M.
Published: June 2020

The lifetime of neural implants is strongly dependent on packaging due to the aqueous and biochemically aggressive nature of the body. Over the last decade, there has been a drive towards neuromodulatory implants which are wireless and approaching millimeter-scales with increasing electrode count. A so-far unrealized goal for these new types of devices is an in-vivo lifetime comparable to a sizable fraction of a healthy patient’s lifetime (>10-20 years). Existing, approved medical implants commonly encapsulate components in metal enclosures (e.g. titanium) with brazed ceramic inserts for electrode feedthrough. It is unclear how amenable the traditional approach is to the simultaneous goals of miniaturization, increased channel count, and wireless communication. Ceramic materials have also played a significant role in traditional medical implants due to their dielectric properties, corrosion resistance, biocompatibility, and high strength, but are not as commonly used for housing materials due to their brittleness and the difficulty they present in creating complex housing geometries. However, thin film technology has opened new opportunities for ceramics processing. Thin films derived largely from the semiconductor industry can be deposited and patterned in new ways, have conductivities which can be altered during manufacturing to provide conductors as well as insulators, and can be used to fabricate flexible substrates. In this review, we give an overview of packaging for neural implants, with an emphasis on how ceramic materials have been utilized in medical device packaging, as well as how ceramic thin film micromachining and processing may be further developed to create truly reliable, miniaturized, neural implants
Multispecies integrated population model reveals bottom-up dynamics in a seabird predator-prey system
Authors: Quéroué Maud , Barbraud Christophe , Barraquand Frédéric , Turek Daniel , Delord Karine , Pacoureau Nathan , Gimenez Olivier
Published: June 2020

Assessing the effects of climate and interspecific relationships on communities is challenging because of the complex interplay between species population dynamics, their interactions, and the need to integrate information across several biological levels (individuals – populations – communities). Usually used to quantify species interactions, integrated population models (IPMs) have recently been extended to communities. These models allow fitting multispecies matrix models to data from multiple sources while simultaneously accounting for various sources of uncertainty in each data source. We used multispecies IPMs accommodating climate conditions to quantify the relative contribution of climate vs. interspecific interactions on demographic parameters, such as survival and breeding success, in the dynamics of a predator-prey system. We considered a stage-structured predator–prey system combining 22 years of capture–recapture data and population counts of two seabirds, the Brown Skua (Catharacta lönnbergi) and its main prey the Blue Petrel (Halobaena caerulea) both breeding on the Kerguelen Islands in the Southern Ocean. Our results showed that climate and predator-prey interactions drive the demography of skuas and petrels in different ways. The breeding success of skuas appeared to be largely driven by the number of petrels and to a lesser extent by intraspecific density-dependence. In contrast, there was no evidence of predation effects on the demographic parameters of petrels, which were affected by oceanographic factors (chlorophyll a and sea surface temperature anomalies). We conclude that bottom-up mechanisms are the main drivers of this skua-petrel system. We discuss the mechanisms by which climate variability and predator-prey relationships may affect the demographic parameters of these seabirds. Taking into account both species interactions and environmental covariates in the same analysis improved our understanding of species dynamics.
Estimating intracranial pressure via low-dimensional models: toward a practical tool for clinical decision support at multi-hour timescales
Authors: Stroh J.N. , Bennett T. , Kheyfets V. , Albers D.
Published: June 2020

Abstract

Broad clinical application of non-invasive intracranial pressure (ICP) monitoring using computational models requires a method of modeling ICP on the basis of easily measured patient data such as radial or brachial arterial blood pressure (ABP). These models may be highly complex, rendering them too slow for clinical and operational use, or may rely on data that is not consistently available. Coupling these models to an upstream vasculature component model decreases data requirements. For the purposes of clinical decision support at multi-hour timescales, two natural choices for model development are to increase intracranial model complexity or to include feedback mechanisms between ICP and vascular model components. We compare the performance of these two approaches by evaluating model estimates against observed ICP in the case of a slow hypertensive event from a publically available dataset. The simpler model with bi-directional feedback requires minimal identifiability and is sufficiently accurate over these timescales, while a more complex is difficult and expensive to identify well enough to be accurate. Furthermore, the bi-directional simple model operates orders of magnitude faster than the more anatomically accurate model when driven by high-resolution ABP. It may also be configured to use lower resolution ABP summary data that is consistently clinically available. The simpler models are fast enough to support future developments such as patient-specific parametrization and assimilation of other clinical data streams which are illustrated during the case of a complex ICP regime for a different patient. We present model comparisons to highlight the advantages of the incorporated simple model and its possible predictive power with further optimization.
Impact of the accuracy of case-based surveillance data on the estimation of time-varying reproduction numbers
Authors: Starnini Michele , Aleta Alberto , Tizzoni Michele , Moreno Yamir
Published: June 2020

Studies aimed at characterizing the evolution of COVID-19 disease often rely on case-based surveillance data publicly released by health authorities, that can be incomplete and prone to errors. Here, we quantify the biases caused by the use of inaccurate data in the estimation of the Time-Varying Reproduction Number R(t). By focusing on Italy and Spain, two of the hardest-hit countries in Europe and worldwide, we show that if the symptoms’ onset time-series is inferred from the notification date series, the R(t) curve cannot capture nor describe accurately the early dynamics of the epidemic. Furthermore, the effectiveness of the containment measures that were implemented, such as national lockdowns, can be properly evaluated only when R(t) is estimated using the real time-series of dates of symptoms’ onset. Our findings show that extreme care should be taken when a pivotal quantity like R(t) is used to make decisions and to evaluate different alternatives.
Short Communication: Vitamin D and COVID-19 infection and mortality in UK Biobank
Authors: Hastie Claire E , Pell Jill P , Sattar Naveed
Published: June 2020

Purpose

Vitamin D has been proposed as a potential causal factor in COVID-19 risk. We aimed to establish whether blood 25-hydroxyvitamin D (25(OH)D) concentration was associated with COVID-19 mortality, and inpatient confirmed COVID-19 infection, in UK Biobank participants.

Methods

UK Biobank recruited 502,624 participants aged 37-73 years between 2006 and 2010. Baseline exposure data, including 25(OH)D concentration, were linked to COVID-19 mortality. Univariable and multivariable Cox proportional hazards regression analyses were performed for the association between 25(OH)D and COVID-19 death, and poisson regression analyses for the association between 25(OH)D and severe COVID-19 infection.

Results

Complete data were available for 341,484 UK Biobank participants, of which 656 had inpatient confirmed COVID-19 infection and 203 died of COVID-19 infection. Vitamin D was associated with severe COVID-19 infection and mortality univariably (mortality HR=0.99; 95% CI 0.98-0.998; p=0.016), but not after adjustment for confounders (mortality HR=0.998; 95% CI=0.99-1.01; p=0.696).

Conclusions

Our findings do not support a potential link between vitamin D concentrations and risk of severe COVID-19 infection and mortality. Recommendations for vitamin D supplementation to lessen COVID-19 risks may provide false reassurance.
Identification of SARS-CoV-2 RNA in Healthcare Heating, Ventilation, and Air Conditioning Units
Authors: Horve Patrick F. , Dietz Leslie , Fretz Mark , Constant David A. , Wilkes Andrew , Townes John M. , Martindale Robert G. , Messer William B. , Van Den Wymelenberg Kevin G.
Published: June 2020

Available information on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission by small particle aerosols continues to evolve rapidly. To assess the potential role of heating, ventilation, and air conditioning (HVAC) systems in airborne viral transmission, this study sought to determine the viral presence, if any, on air handling units in a healthcare setting where Coronavirus Disease 2019 (COVID-19) patients were being treated. The presence of SARS-CoV-2 RNA was detected in approximately 25% of samples taken from nine different locations in multiple air handlers. While samples were not evaluated for viral infectivity, the presence of viral RNA in air handlers raises the possibility that viral particles can enter and travel within the air handling system of a hospital, from room return air through high efficiency MERV-15 filters and into supply air ducts. Although no known transmission events were determined to be associated with these specimens, the findings suggest the potential for HVAC systems to facilitate transmission by environmental contamination via shared air volumes with locations remote from areas where infected persons reside. More work is needed to further evaluate the risk of SARS-CoV-2 transmission via HVAC systems and to verify effectiveness of building operations mitigation strategies for the protection of building occupants. These results are important within and outside of healthcare settings and may present a matter of some urgency for building operators of facilities that are not equipped with high-efficiency filtration.
Fast Variational Alignment of non-flat 1D Displacements for Applications in Neuroimaging
Authors: Flotho Philipp , Thinnes David , Kuhn Bernd , Roome Christopher J. , Vibell Jonas F. , Strauss Daniel J.
Published: June 2020

Background

In the context of signal analysis and pattern matching, alignment of 1D signals for the comparison of signal morphologies is an important problem. For image processing and computer vision, 2Doptical flow(OF) methods find wide application for motion analysis and image registration and variational OF methods have been continuously improved over the past decades.

New Method

We propose a variational method for the alignment and displacement estimation of 1D signals. We pose the estimation of non-flat displacements as an optimization problem with a similarity and smoothness term similar to variational OF estimation. To this end, we can make use of efficient optimization strategies that allow real-time applications on consumer grade hardware.

Results

We apply our method to two applications from functional neuroimaging: The alignment of 2-photon imaging line scan recordings and the denoising of evoked and event-related potentials in single trial matrices. We can report state of the art results in terms of alignment quality and computing speeds.

Existing Methods

Existing methods for 1D alignment target mostly constant displacements, do not allow native subsample precision or precise control over regularization or are slower than the proposed method.

Conclusions

Our method is implemented as a MATLAB toolbox and is online available. It is suitable for 1D alignment problems, where high accuracy and high speed is needed and non-constant displacements occur.
Dynamic population stage-structure stabilizes complex ecological communities
Authors: de Roos André M.
Published: June 2020

Natural ecological communities are diverse, complex and often surprisingly stable, but the mechanisms underlying their stability remain a theoretical enigma1-5. Interactions such as competition and predation presumably structure communities6, yet theory predicts that complex communities are only stable when species growth rates are mostly limited by intraspecific self-regulation rather than by interactions with resources, competitors and predators3,5,7. Current theory, however, only considers the network topology of population-level interactions between species and neglects within-population differences among juvenile and adult individuals. Here, using model simulations, I show that including commonly observed differences in vulnerability to predation and foraging efficiency between juvenile and adult individuals results in up to ten times larger, more complex communities than in simulations without population stage-structure. These diverse communities are stable or fluctuate with limited amplitude, even though in the model only a single basal species is self-regulated and the population-level interaction network is highly connected. Analysis of the species interaction matrix predicts the simulated communities to be unstable but extending the matrix with a population structure subsystem reveals that dynamic changes in population stage-structure completely cancel out this instability. Common differences between juveniles and adults and fluctuations in their relative abundance hence have a decisive influence on the stability of complex natural communities and their vulnerability when environmental conditions change. Thus, community persistence can not be explained by the network of interactions between the constituting species alone.
Application of Airy beam Light sheet microscopy to examine early neurodevelopmental structures in 3D hiPSC-derived human cortical spheroids
Authors: Adhya Dwaipayan , Chennell George , Crowe James , Valencia-Alarcón Eva P. , Seyforth James , Honsy Neveen , Yasvoina Marina V. , Forster Robert , Baron-Cohen Simon , Vernon Anthony C. , Sriavstava Deepak. P.
Published: June 2020

Background

The inability to observe relevant biological processesin vivosignificantly restricts human neurodevelopmental research. Advances in appropriatein vitromodel systems, including patient-specific human brain organoids and human Cortical Spheroids (hCSs) offer a pragmatic solution to this issue. In particular, hCSs are an accessible method of generating homogenous organoids of dorsal telencephalic fate, which recapitulate key aspects of human corticogenesis, including the formation of neural rosettes. These neurogeneic niches give rise to neural progenitors that subsequently differentiate into neurons. Atypical formation of these structures has been associated with neurodevelopmental disorders such as autism spectrum conditions, from studies of patient-specific human induced pluripotent stem cells grown as 2D cultures. Thus far however, conventional methods of tissue preparation in this field limit the ability to image these structures in three-dimensions within intact hSC or other 3D preparations. To overcome this limitation, we have sought to optimise a methodological approach to process hCSs to maximise the utility of a novel Airy-beam light sheet microscope (ALSM) to acquire high resolution volumetric images of internal structures within hCS representative of early developmental time points.

Results

Conventional approaches to imaging hCS by confocal microscopy were limited in their ability to image effectively into intact spheroids. Conversely, volumetric acquisition by ALSM offered superior imaging through intact, non-clarified,in vitrotissues, in both speed and resolution as compared to conventional confocal imaging systems. Furthermore, optimised immunohistochemistry and optical clearing of hCSs afforded improved imaging at depth. This permitted visualization of the morphology of the inner lumen of neural rosettes.

Conclusion

We present an optimized methodology that takes advantage of an ALSM system that can rapidly image intact 3D brain organoids at high resolution while retaining a large field of view. This imaging modality can be applied to both non-cleared and clearedin vitrohuman brain spheroids derived from hiPSCs for precise examination of their internal 3D structures. Furthermore, this process represents a rapid, highly efficient method to examine and quantify in 3D the formation of key structures required for the coordination of neurodevelopmental processes in both health and disease states. We posit that this approach would facilitate investigation of human neurodevelopmental processes.
Repeated stimulation or tonic-signaling chimeric antigen receptors drive regulatory T cell exhaustion
Authors: Lamarche Caroline , Novakovsky German E. , Qi Christopher N. , Weber Evan W. , Mackall Crystal L. , Levings Megan K
Published: June 2020

Regulatory T cell (Treg) therapy is a promising approach to improve outcomes in transplantation and autoimmunity. In conventional T cell therapy, chronic stimulation can result in poorin vivofunction, a phenomenon termed exhaustion. Whether or not Tregs are also susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how two methods which induce conventional T cell exhaustion – repetitive stimulation or expression of a tonic-signaling chimeric antigen receptor (CAR) – affect human Tregs. With each repetitive polyclonal stimulation Tregs progressively acquired an exhausted phenotype, and became less suppressivein vitro. Tregs expressing a tonic-signaling CAR rapidly acquired an exhausted phenotype and had major changes in their transcriptome and metabolism. Although tonic-signaling CAR-Tregs remained stable and suppressivein vitro, they lostin vivofunction, as tested in a model of xenogeneic graft-versus-host disease. The finding that human Tregs are susceptible to exhaustion has important implications for the design of Treg adoptive immunotherapy strategies.
Stabilizing selection of seasonal influenza receptor binding in populations with partial immunity
Authors: Hay James A. , Junus Alvin , Riley Steven , Yuan Hsiang-Yu
Published: June 2020

Mutations that alter cellular receptor binding of influenza hemagglutinin (HA) have profound effects on immune escape. Despite its high mutation rate, it is not fully understood why human influenza HA displays limited antigenic diversity across circulating viruses. We applied phylogenetic analysis and phylodynamic modeling to understand the evolutionary and epidemiological effects of binding avidity adaptation in humans using net charge as a marker for receptor binding avidity. Using 686 human influenza A/H3N2 HA sequences, we found that HA net charge followed an age-specific pattern. Phylogenetic analysis suggested that many binding variants have reduced fitness. Next, we developed an individual-based disease dynamic model embedded with within-host receptor binding adaptation and immune escape in a population with varied partial immunity. The model showed that mean binding avidity was unable to adapt to values that maximized transmissibility due to competing selective forces between within- and between-host levels. Overall, we demonstrated stabilizing selection of virus binding in a population with increasing partial immunity. These findings have potential implications in understanding the evolutionary mechanisms that determine the intensity of seasonal influenza epidemics.
Elevated Neurokinin 1-Receptor Expression in uterine products of conception is associated with first trimester Miscarriages
Authors: Mehboob Riffat , Gilani Syed Amir , Hassan Amber , Tirmazi Adeel Haider , Ahmad Fridoon Jawad , Akram Javed
Published: June 2020

Background

Miscarriage is a common complication of early pregnancy, mostly occurring in first trimester. However, the etiological factors, prognostic and diagnostic biomarkers are not well known. Neurokinin-1 Receptor (NK-1R) is a receptor of tachykinin peptide, Substance P (SP) and has a role in various pathological conditions, cancers but it’s association with miscarriages and significance as a clinicopathological parameter is not studied. Accordingly, the present study aimed to clarify the localization and expression for NK-1R in human retained products of conception. Role of NK-1R is not known in miscarriages.

Materials and Methods

NK-1R expression was assessed in products of conception by immunohistochemistry. Protein expression was evaluated using the nuclear labelling index (%).

Results

Ten human products of conception tissues were studied by immunohistochemistry to demonstrate the localization of NK-1R. The expression of NK-1R protein was high in all the cases of POCs. NK-1R expression showed no notable differences among different cases of miscarriages irrespective of the mother’s age and gestational age at which the event occurred.

Conclusions

Expression of NK-1R was similar in all the cases and it was intense. It shows that dysregulation of NK-1R along with its ligand Substance P might be involved in miscarriages. Our results provide fundamental data regarding this anti-NK-1R strategy. Thus, the present study recommends that SP/NK1R system might, therefore, be considered as an emerging and promising diagnostic and therapeutic strategy against miscarriages. Hence, we report for the first time, the expression and localization of NK-1R in products of conception. We suggest NK-1R antagonist in addition to the Immunoglobulins and Human chorionic gonadotropin, to diagnose and treat spontaneous miscarriages.
Novel mode of filament formation in UPA-promoted CARD8 and NLRP1 Inflammasomes
Authors: Hollingsworth L. Robert , David Liron , Li Yang , Griswold Andrew R. , Sharif Humayun , Fontana Pietro , Fu Tian-Min , Ruan Jianbin , Bachovchin Daniel A. , Wu Hao
Published: June 2020

NLRP1 and CARD8 are related cytosolic sensors that upon activation form supramolecular signalling complexes known as canonical inflammasomes, resulting in caspase-1 activation, cytokine maturation and/or pyroptotic cell death. NLRP1 and CARD8 use their C-terminal (CT) fragments containing a caspase recruitment domain (CARD) and the UPA subdomain of a function-to-find domain (FIIND) for self-oligomerization and recruitment of the inflammasome adaptor ASC and/or caspase-1. Here, we report cryo-EM structures of NLRP1-CT and CARD8-CT assemblies, in which the respective CARDs form central helical filaments that are promoted by oligomerized, but flexibly linked UPAs surrounding the filaments. We discover that subunits in the central NLRP1CARDfilament dimerize with additional exterior CARDs, which roughly doubles its thickness and is unique among all known CARD filaments. The thick NLRP1 filament only forms with the presence of UPA, which we hypothesize drives the intrinsic propensity for NLRP1CARDdimerization. Structural analyses provide insights on the requirement of ASC for NLRP1-CT signalling and the contrasting direct recruitment of caspase-1 by CARD8-CT. Additionally, we present a low-resolution 4 ASCCARD–4 caspase-1CARDoctamer structure, illustrating that ASC uses opposing surfaces for NLRP1, versus caspase-1, recruitment. These structures capture the architecture and specificity of CARD inflammasome polymerization in NLRP1 and CARD8.
The evolution of seasonal migration and the slow-fast continuum of life history in birds
Authors: Winger Benjamin M. , Pegan Teresa M.
Published: June 2020

Seasonal migration is a widespread adaptation in environments with predictable periods of resource abundance and scarcity. Migration is frequently associated with high mortality, suggesting that migratory species live on the “fast” end of the slow-fast continuum of life history. However, few interspecific comparative studies have tested this assumption and prior assessments have been complicated by environmental variation among breeding locations. We evaluate how migration distance influences the tradeoff between reproduction and survival in 45 species of mostly passerine birds that breed sympatrically in North American boreal forests but migrate to a diversity of environments and latitudes for the northern winter. We find, after accounting for mass and phylogeny, that longer distance migrations to increasingly amenable winter environments are correlated with reduced annual reproductive output, but also result in increased adult survival compared to shorter-distance migrations. Non-migratory boreal species have life history parameters more similar to long-distance migrants than to shorter-distance migrants. These results suggest that long-distance migration and other highly specialized strategies for survival in seasonal environments impose selection pressures that both confer and demand high adult survival rates. That is, owing to the reproductive cost of long-distance migration, this strategy can only persist if balanced by high adult survival. Our results reveal migratory distance as a fundamental life history parameter that predicts, and is inextricable from, the balance of survival and reproduction. Our study further provides evolutionary context for understanding the annual cycle demography of migratory species and the strategies long-distance migrants use to maximize survival on their journeys.
Estimating the state of the Covid-19 epidemic in France using a non-Markovian model
Authors: Forien Raphaël , Pang Guodong , Pardoux Étienne
Published: June 2020

In this paper, we use a deterministic non-Markovian epidemic model to estimate the state of the Covid-19 epidemic in France. This model allows us to consider realistic distributions for the exposed and infectious periods in a SEIR model, contrary to standard ODE models which only consider exponentially distributed exposed and infectious periods. We present theoretical results linking the (unobserved) parameters of the model to various quantities which are more easily measured during the early stages of an epidemic. We also stress the main quantitative differences between the non-Markovian and the Markovian (ODE) model. We then apply these results to estimate the state of the Covid-19 epidemic in France by analyzing three regions: the Paris region, the northeast regions and the rest of the country, based on current knowledge on the infection fatality ratio and the exposed and infectious periods distributions for Covid-19. Our analysis is based on the hospital data published daily by Santé Publique France (daily hospital admissions, intensive care unit admissions and hospital deaths).
Facilitation of neural responses to targets moving against optic flow
Authors: Nicholas Sarah , Nordström Karin
Published: June 2020

For the human observer, it can be difficult to follow the motion of small objects, especially when they move against background clutter. In contrast, insects efficiently do this, as evidenced by their ability to capture prey, pursue conspecifics, or defend territories, even in highly textured surrounds. We here recorded from target selective descending neurons (TSDNs) which likely subserve these impressive behaviors. To simulate the type of background optic flow that would be generated by the pursuer’s own movements through the world, we used the coherent motion of a perspective distorted sparse dot field. We show that hoverfly TSDN responses to target motion are suppressed when such background optic flow moves in the same direction as the target. Indeed, the neural responses are strongly attenuated against both translational sideslip as well as rotational yaw. More strikingly, we show that TSDNs are facilitated by background optic flow in the opposite direction to the target, if the target moves horizontally. Furthermore, we show that a small, frontal spatial window of background optic flow is enough to fully facilitate or attenuate TSDN responses to target motion. We argue that the TSDN response facilitation could be beneficial in modulating corrective turns during target pursuit.

Significance statement

Target detection in visual clutter is a difficult computational task that insects, with their poor resolution compound eyes and small brains, do successfully and with extremely short behavioral delays. We here show that the responses of target selective descending neurons are attenuated by background motion in the same direction as target motion, but facilitated by opposite direction background motion. This finding is important for understanding conspecific pursuit behavior, since these descending neurons likely control behavioral output. The facilitation that we describe would come into effect if the hoverfly is subjected to background motion in one direction, but the target it is pursuing moves in the opposite direction, and could therefore be used to modulate gaze stabilizing corrective turns.
Amplitude of high frequency oscillations as a biomarker of the seizure onset zone
Authors: Charupanit Krit , Sen-Gupta Indranil , Lin Jack J , Lopour Beth A
Published: June 2020

Objective

Studies of high frequency oscillations (HFOs) in epilepsy have primarily tested the HFO rate as a biomarker of the seizure onset zone (SOZ), but the rate varies over time and is not robust for all individual subjects. As an alternative, we tested the performance of HFO amplitude as a potential SOZ biomarker using two automated detection algorithms.

Method

HFOs were detected in intracranial electroencephalogram (iEEG) from 11 patients using a machine learning algorithm and a standard amplitude-based algorithm. For each detector, SOZ and non-SOZ channels were classified using the rate and amplitude of high frequency events, and performance was compared using receiver operating characteristic curves.

Results

The amplitude of detected events was significantly higher in SOZ. Across subjects, amplitude more accurately classified SOZ/non-SOZ than rate (higher values of area under the ROC curve and sensitivity, and lower false positive rates). Moreover, amplitude was more consistent across segments of data, indicated by lower coefficient of variation.

Conclusion

As an SOZ biomarker, HFO amplitude offers advantages over HFO rate: it exhibits higher classification accuracy, more consistency over time, and robustness to parameter changes.

Significance

This biomarker has the potential to increase the generalizability of HFOs and facilitate clinical implementation as a tool for SOZ localization.