bluuebunny/crossref_metadata_2025 huggingface dataset:
Harnessing tipping points in complex ecological networks
Authors: Jiang Junjie , Hastings Alan , Lai Ying-Cheng
Published: September 2019

Complex and nonlinear ecological networks can exhibit a tipping point at which a transition to a global extinction state occurs. Using real-world mutualistic networks of pollinators and plants as prototypical systems and taking into account biological constraints, we develop an ecologically feasible strategy to manage/control the tipping point by maintaining the abundance of a particular pollinator species at a constant level, which essentially removes the hysteresis associated with a tipping point. If conditions are changing so as to approach a tipping point, the management strategy we describe can prevent sudden drastic changes. Additionally, if the system has already moved past a tipping point, we show that a full recovery can occur for reasonable parameter changes only if there is active management of abundance, again due essentially to removal of the hysteresis. This recovery point in the aftermath of a tipping point can be predicted by a universal, two-dimensional reduced model.
Robust synchronization of the cell cycle and the circadian clock through bidirectional coupling
Authors: Yan Jie , Goldbeter Albert
Published: September 2019

The cell cycle and the circadian clock represent major cellular rhythms, which appear to be coupled. Thus the circadian factor BMAL1 controls the level of cell cycle proteins such as Cyclin E and WEE1, the latter of which inhibits the kinase CDK1 that governs the G2/M transition. In reverse the cell cycle impinges on the circadian clock through direct control by CDK1 of REV-ERBα, which negatively regulates BMAL1. These observations provide evidence for bidirectional coupling of the cell cycle and the circadian clock. By merging detailed models for the two networks in mammalian cells, we previously showed that unidirectional coupling to the circadian clock can entrain the cell cycle to 24 or 48 h, depending on the cell cycle autonomous period, while complex oscillations occur when entrainment fails. Here we show that the reverse unidirectional coupling via phosphorylation of REV-ERBα or via mitotic inhibition of transcription, both controlled by CDK1, can elicit entrainment of the circadian clock by the cell cycle. We then determine the effect of bidirectional coupling of the cell cycle and circadian clock as a function of their relative coupling strengths. In contrast to unidirectional coupling, bidirectional coupling markedly reduces the likelihood of complex oscillations. While the two rhythms oscillate independently as long as both couplings are weak, one rhythm entrains the other if one of the couplings dominates. If the couplings in both directions become stronger and of comparable magnitude, the two rhythms synchronize, generally at an intermediate period within the range defined by the two autonomous periods prior to coupling. More surprisingly, synchronization may also occur at a period slightly below or above this range, while in some conditions the synchronization period can even be much longer. Two or even three modes of synchronization may sometimes coexist, yielding examples of birhythmicity or trirhythmicity. Because synchronization readily occurs in the form of simple periodic oscillations over a wide range of coupling strengths and in the presence of multiple connections between the two oscillatory networks, the results indicate that bidirectional coupling favours the robust synchronization of the cell cycle and the circadian clock.
Multi-modality cerebral aneurysm haemodynamic analysis:
in vivo
4D flow MRI,
in vitro
volumetric particle velocimetry and
in silico
computational fluid dynamics
Authors: Brindise Melissa C. , Rothenberger Sean , Dickerhoff Benjamin , Schnell Susanne , Markl Michael , Saloner David , Rayz Vitaliy L. , Vlachos Pavlos P.
Published: September 2019

Typical approaches to patient-specific haemodynamic studies of cerebral aneurysms use image-based computational fluid dynamics (CFD) and seek to statistically correlate parameters such as wall shear stress (WSS) and oscillatory shear index (OSI) to risk of growth and rupture. However, such studies have reported contradictory results, emphasizing the need for in-depth multi-modality haemodynamic metric evaluation. In this work, we used
in vivo
4D flow MRI data to inform
in vitro
particle velocimetry and CFD modalities in two patient-specific cerebral aneurysm models (basilar tip and internal carotid artery). Pulsatile volumetric particle velocimetry experiments were conducted, and the particle images were processed using Shake-the-Box, a particle tracking method. Distributions of normalized WSS and relative residence time were shown to be highly yet inconsistently affected by minor flow field and spatial resolution variations across modalities, and specific relationships among these should be explored in future work. Conversely, OSI, a non-dimensional parameter, was shown to be more robust to the varying assumptions, limitations and spatial resolutions of each subject and modality. These results suggest a need for further multi-modality analysis as well as development of non-dimensional haemodynamic parameters and correlation of such metrics to aneurysm risk of growth and rupture.
Valence of social information is encoded in different subpopulations of mushroom body Kenyon cells in the honeybee brain
Authors: Traniello Ian M. , Chen Zhenqing , Bagchi Vikram A. , Robinson Gene E.
Published: September 2019

Over 600 Myr of evolutionary divergence between vertebrates and invertebrates is associated with considerable neuroanatomical variation both across and within these lineages. By contrast, valence encoding is an important behavioural trait that is evolutionarily conserved across vertebrates and invertebrates, and enables individuals to distinguish between positive (potentially beneficial) and negative (potentially harmful) situations. We tested the hypothesis that social interactions of positive and negative valence are modularly encoded in the honeybee brain (i.e. encoded in different cellular subpopulations) as in vertebrate brains. In vertebrates, neural activation patterns are distributed across distinct parts of the brain, suggesting that discrete circuits encode positive or negative stimuli. Evidence for this hypothesis would suggest a deep homology of neural organization between insects and vertebrates for valence encoding, despite vastly different brain sizes. Alternatively, overlapping localization of valenced social information in the brain would imply a ‘re-use' of circuitry in response to positive and negative social contexts, potentially to overcome the energetic constraints of a tiny brain. We used immediate early gene expression to map positively and negatively valenced social interactions in the brain of the western honeybeeApis mellifera. We found that the valence of a social signal is represented by distinct anatomical subregions of the mushroom bodies, an invertebrate sensory neuropil associated with social behaviour, multimodal sensory integration, learning and memory. Our results suggest that the modularization of valenced social information in the brain is a fundamental property of neuroanatomical organization.
Toxicants Associated with Spontaneous Abortion in the Comparative Toxicogenomics Database (CTD)
Authors: Harris Sean M. , Jin Yuan , Loch-Caruso Rita , Padilla Ingrid Y. , Meeker John , Bakulski Kelly M.
Published: September 2019

Background

Up to 70% of all pregnancies result in either implantation failure or spontaneous abortion (SA). Many events occur before women are aware of their pregnancy and we lack a comprehensive understanding of high-risk SA chemicals. In epidemiologic research, failure to account for a toxicant’s impact on SA can also bias toxicant-birth outcome associations. Our goal was to identify chemicals with a high number of interactions with SA genes, based on known toxicogenomic responses.

Methods

We used reference SA (MeSH: D000022) and chemical gene lists from the Comparative Toxicogenomics Database in three species (human, mouse, and rat). We prioritized chemicals (n=25) found in maternal blood/urine samples or in groundwater, tap water, or Superfund sites. For chemical-disease gene sets of sufficient size (n=13 chemicals, n=20 comparisons), chi-squared enrichment tests and proportional reporting ratios (PRR) were calculated. We then cross-validated enrichment results. Finally, among the SA genes, we assessed enrichment for gene ontology biological processes and for chemicals associated with SA in humans, we visualized specific gene-chemical interactions.

Results

The number of unique genes annotated to a chemical ranged from 2 (bromacil) to 5,607 (atrazine), and 121 genes were annotated to SA. In humans, all chemicals tested were highly enriched for SA gene overlap (all p<0.001; parathion PRR=7, cadmium PRR=6.5, lead PRR=3.9, arsenic PRR=3.5, atrazine PRR=2.8). In mice, highest enrichment (p<0.001) was observed for naphthalene (PRR=16.1), cadmium (PRR=12.8), arsenic (PRR=11.6), and carbon tetrachloride (PRR=7.7). In rats, we observed highest enrichment (p<0.001) for cadmium (PRR=8.7), carbon tetrachloride (PRR=8.3), and dieldrin (PRR=5.3). Our findings were robust to 1,000 permutations each of gene sets ranging in size from 100 to 10,000. SA genes were overrepresented in biological processes: inflammatory response (q=0.001), collagen metabolic process (q=1×10−13), cell death (q=0.02), and vascular development (q=0.005).

Conclusion

We observed chemical gene sets (parathion, cadmium, naphthalene, carbon tetrachloride, arsenic, lead, dieldrin, and atrazine) were highly enriched for SA genes. Exposures to chemicals linked to SA, thus linked to probability of live birth, may deplete fetuses susceptible to adverse birth outcomes. Our findings have critical public health implications for successful pregnancies as well as the interpretation of environmental pregnancy cohort analyses.
Comprehensive characterisation of cell-free tumour DNA in plasma and urine of patients with renal tumours
Authors: Smith Christopher G , Moser Tina , Burge Johanna , Eldridge Matthew , Riediger Anja L , Mouliere Florent , Chandrananda Dineika , Heider Katrin , Wan Jonathan CM , Warren Anne Y , Morris James , Hudecova Irena , Cooper Wendy N , Mitchell Thomas J , Gale Davina , Ruiz-Valdepenas Andrea , Klatte Tobias , Ursprung Stephan , Sala Evis , Riddick Antony CP , Aho Tevita F , Armitage James N , Perakis Samantha , Pichler Martin , Seles Maximilian , Wcislo Gabriel , Welsh Sarah J , Matakidou Athena , Eisen Tim , Massie Charles E , Rosenfeld Nitzan , Heitzer Ellen , Stewart Grant D
Published: September 2019

Cell-free tumour-derived DNA (ctDNA) allows non-invasive monitoring of cancers but its utility in renal cell cancer (RCC) has not been established. Here, untargeted and targeted sequencing methods, applied to two independent cohorts of renal tumour patients (n=90), were used to determine ctDNA content in plasma and urine. Our data revealed lower plasma ctDNA levels in RCC relative to other cancers, with untargeted detection of ∼33%. A sensitive personalised approach, applied to plasma and urine from select patients improved detection to ∼50%, including in patients with early-stage and even benign lesions.

A machine-learning based model predicted detection, potentially offering a means of triaging samples for personalised analysis. In addition, with limited data we observed that plasma, and for the first time, urine ctDNA may better represent tumour heterogeneity than tissue biopsy. Furthermore, longitudinal sampling of >200 plasma samples revealed that ctDNA can track disease course. Additional datasets will be required to validate these findings.

Overall, our data highlight RCC as a ctDNA-low malignancy, but indicate potential clinical utility provided improvement in detection approaches.

One sentence summary

Complementary sequencing methods show that cell-free tumour DNA levels are low in renal cancer though, via various strategies, may still be informative.
Parietal Cortex Integrates Object Orientation and Saccade Signals to Update Grasp Plans
Authors: Baltaretu Bianca R. , Monaco Simona , Velji-Ibrahim Jena , Luabeya Gaelle N. , Douglas Crawford J.
Published: September 2019

Coordinated reach-to-grasp movements are often accompanied by rapid eye movements (saccades) that displace the desired object image relative to the retina. Parietal cortex compensates for this by updating reach goals relative to current gaze direction, but its role in the integration of oculomotor and visual orientation signals for updating grasp plans is unknown. Based on a recent perceptual experiment, we hypothesized that inferior parietal cortex (specifically supramarginal gyrus; SMG) integrates saccade and visual signals to update grasp plans in more superior parietal areas. To test this hypothesis, we employed a functional magnetic resonance adaptation paradigm, where saccades sometimes interrupted grasp preparation toward a briefly presented object that later reappeared (with the same/different orientation) just before movement. Right SMG and several parietal grasp areas, namely left anterior intraparietal sulcus (aIPS) and bilateral superior parietal lobe (SPL), met our criteria for transsaccadic orientation integration: during movement preparation, they showed task-dependent saccade modulations and, during grasp execution, they were specifically sensitive to changes in object orientation that followed saccades. Finally, SMG showed enhanced functional connectivity with both prefrontal saccade areas (consistent with oculomotor input) and aIPS / SPL (consistent with sensorimotor output). These results support the general role of parietal cortex for the integration of visuospatial perturbations, and provide specific cortical modules for the integration of oculomotor and visual signals for grasp updating.

Significance Statement

The cortical mechanisms that update reach goals during eye movements are well documented, but it is not known how object features are linked to oculomotor signals when updating grasp plans. Here, we employed functional magnetic resonance imaging adaptation (fMRIa) and functional connectivity analysis to identify a cluster of inferior parietal (supramarginal gyrus) and superior parietal (intraparietal and superior parietal) regions that show functional connectivity with frontal cortex saccade centers, and also show saccade-specific modulations during unexpected changes in object / grasp orientation. This provides a network - complementary to the goal updater network - that integrates visuospatial updating into grasp plans, and may help explain some of the more complex symptoms associated with parietal damage such as constructional ataxia.
An updated genotype classification system for Zika viruses
Authors: Nebenzahl-Guimaraes Hanna , Libin Pieter , Pimentel Victor , Pingarilho Marta , Theys Kristof , Abecasis Ana B.
Published: September 2019

Despite the Zika virus’ rapid spread throughout the Americas in 2015, its phylogenetic classification is limited to either an ‘African’ or ‘Asian’ genotype. This classification no longer reflects the present genetic diversity of circulating strains and their geographic reach. Using 414 publicly available Zika virus genomes from 40 different countries, we created alignments of different genomic fragments with high phylogenetic signal and used these to construct multiple maximum likelihood trees (IQTree). We observed groups of strains from three major geographic regions that consistently cluster into monophyletic clades: African (AF), Asian (AS) and American (AM), the latter of which cluster into four further sub-clades: Caribbean (C), South American (SA1 and SA2) and Central American (CA). The inter-genetic distances of these clades are all significantly greater than their intra-genetic distances (p=0.05). A decision demonstrates that only five nucleotide positions are needed to correctly classify 90% of our dataset into the newly described genotypes.
Improving the diagnosis and classification of Ph-negative myeloproliferative neoplasms through deep phenotyping
Authors: Sirinukunwattana Korsuk , Aberdeen Alan , Theissen Helen , Sousos Nikolaos , Psaila Bethan , Mead Adam J. , Turner Gareth D.H. , Rees Gabrielle , Rittscher Jens , Royston Daniel
Published: September 2019

Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by excessive proliferation of myeloid lineages. Accurate classification and appropriate management of MPNs requires integration of clinical, morphological and genetic findings. Despite major advances in understanding the molecular and genetic basis, morphological assessment of the bone marrow trephine (BMT) remains paramount in differentiating between MPN subtypes and reactive conditions. However, morphological assessment is heavily constrained by a reliance on subjective, qualitative and poorly reproducible criteria. To address this, we have developed a machine-learning strategy for the automated identification and quantitative analysis of megakaryocyte morphology using clinical BMT samples. Using a sample cohort of recently diagnosed or established ET (n = 48) and reactive control cases (n = 42) we demonstrated a high predictive accuracy (AUC = 0.95) of automated tissue ET diagnosis based upon these specific megakaryocyte phenotypes. These separate morphological phenotypes showed evidence of specific genotype associations, which offers promise that an automated cell phenotyping approach may be of clinical diagnostic utility as an adjunct to standard genetic and molecular tests. This has great potential to assist in the routine assessment of newly diagnosed or suspected MPN patients and those undergoing treatment / clinical follow-up. The extraction of quantitative morphological data from BMT sections will also have value in the assessment of new therapeutic strategies directed towards the bone marrow microenvironment and can provide clinicians and researchers with objective, quantitative data without significant demands upon current routine specimen workflows.
Transcriptomic Stratification of Late-Onset Alzheimer’s Cases Reveals Novel Genetic Modifiers of Disease Pathology
Authors: Milind Nikhil , Preuss Christoph , Haber Annat , Ananda Guru , Mukherjee Shubhabrata , John Cai , Shapley Sarah , Tyler Anna L. , Logsdon Benjamin A. , Crane Paul K. , Carter Gregory W.
Published: September 2019

Late-Onset Alzheimer’s disease (LOAD) is a common, complex genetic disorder well-known for its heterogeneous pathology. The genetic heterogeneity underlying common complex diseases poses a major challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) analysis to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5×10−8, rs1990620G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.
Phenotypic Switching of Naïve T cells to Immune-suppressive Treg-like Cells by Mutant KRAS
Authors: Kalvala Arjun , Wallet Pierre , Yang Lu , Wang Chongkai , Li Haiqing , Nam Arin , Nathan Anusha , Mambetsariev Isa , Poroyko Valeriy , Gao Hanlin , Chu Peiguo , Sattler Martin , Bild Andrea , Manuel Edwin R. , Lee Peter P. , Jolly Mohit Kumar , Kulkarni Prakash , Salgia Ravi
Published: September 2019

Oncogenic (mutant) Ras protein Kirsten rat sarcoma viral oncogene homolog (KRAS) promotes uncontrolled proliferation, altered metabolism, and loss of genome integrity in a cell-intrinsic manner. Here, we demonstrate that CD4+T cells when incubated with tumor-derived exosomes from mutant (MT) KRAS non-small cell lung cancer (NSCLC) cells, patient sera, or a mouse xenograft model, induce phenotypic conversion to FOXP3+Treg-like cells that are immune-suppressive. Furthermore, transfecting T cells with MT KRAS cDNA alone induced phenotypic switching and mathematical modeling supported this conclusion. Single-cell sequencing identified the interferon pathway as the mechanism underlying the phenotypic switch. These observations highlight a novel cytokine-independent, cell-extrinsic role for KRAS in T cell phenotypic switching. Thus, targeting this new class of Tregs represents a unique therapeutic approach for NSCLC. Since KRAS is the most frequently mutated oncogene in a wide variety of cancers, the findings of this investigation are likely to be of broad interest and have a large scientific impact.
Impact of suboptimal APOBEC3G neutralization on the emergence of HIV drug resistance in humanized mice
Authors: Hernandez Matthew M. , Fahrny Audrey , Jayaprakash Anitha , Gers-Huber Gustavo , Dillon-White Marsha , Audigé Annette , Mulder Lubbertus C.F. , Sachidanandam Ravi , Speck Roberto F. , Simon Viviana
Published: September 2019

HIV diversification facilitates immune escape and complicates antiretroviral therapy. In this study, we take advantage of a humanized mouse model to probe the contribution of APOBEC3 mutagenesis to viral evolution. Humanized mice were infected with isogenic HIV molecular clones (HIV-WT, HIV-45G, HIV-ΔSLQ) that differ only in their ability to counteract APOBEC3G (A3G). Infected mice remained naïve or were treated with the RT inhibitor lamivudine (3TC). Viremia, emergence of drug resistant variants and quasispecies diversification in the plasma compartment were determined throughout infection. While both HIV-WT and HIV-45G achieved robust infection, over time HIV-45G replication was significantly reduced compared to HIV-WT in the absence of 3TC treatment. In contrast, treatment response differed significantly between HIV-45G and HIV-WT infected mice. Antiretroviral treatment failed in 91% of HIV-45G infected mice while only 36% of HIV-WT infected mice displayed a similar negative outcome. Emergence of 3TC resistant variants and nucleotide diversity were determined by analyzing 155,462 single HIV reverse transcriptase (RT) and 6,985vifsequences from 33 mice. Prior to treatment, variants with genotypic 3TC resistance (RT-M184I/V) were detected at low levels in over a third of all animals. Upon treatment, the composition of the plasma quasispecies rapidly changed leading to a majority of circulating viral variants encoding RT-184I. Interestingly, increased viral diversity prior to treatment initiation correlated with higher plasma viremia in HIV-45G but not in HIV-WT infected animals. Taken together, HIV variants with suboptimal anti-A3G activity were attenuated in the absence of selection but display a fitness advantage in the presence of antiretroviral treatment.

IMPORTANCE

Both viral (e.g., reverse transcriptase,RT) and host factors (e.g., APOBEC3G (A3G)) can contribute to HIV sequence diversity. This study shows that suboptimal anti-A3G activity shapes viral fitness and drives viral evolution in the plasma compartment of humanized mice.
Offspring production of ovarian organoids derived from spermatogonial stem cells by chromatin reorganization
Authors: Luo Huacheng , Li Xiaoyong , Tian Geng G. , Li Dali , Hou Changliang , Ding Xinbao , Hou Lin , Lyu Qifeng , Yang Yunze , Cooney Austin J. , Xie Wenhai , Xiong Ji , Wang Hu , Zhao Xiaodong , Wu Ji
Published: September 2019

Fate determination of germline stem cells remains poorly understood at the chromatin structure level1,2. Here, we demonstrate successful production of offspring from oocytes transdifferentiated from mouse spermatogonial stem cells (SSCs) with tracking of transplanted SSCs in vivo, single cell whole exome sequencing, and in 3D cell culture reconstitution of the process of oogenesis derived from SSCs. Furthermore, we demonstrate direct induction of germline stem cells (iGSCs) differentiated into functional oocytes by transduction of H19, Stella, and Zfp57 and inactivation of Plzf in SSCs after screening with ovarian organoids. Using high throughput chromosome conformation, we uncovered extensive chromatin reorganization during SSC conversion into iGSCs, which was highly similar to female germline stem cells. We observed that although topologically associating domains were stable during SSC conversion, chromatin interactions changed in a striking manner, altering 35% of inactive and active chromosomal compartments throughout the genome. These findings have important implications in various areas including mammalian gametogenesis, genetic and epigenetic reprogramming, biotechnology, and medicine.
Test-retest reliability and long-term stability of 3-tissue constrained spherical deconvolution methods for analyzing diffusion MRI data
Authors: Newman Benjamin T. , Dhollander Thijs , Reynier Kristen A. , Panzer Matthew B. , Druzgal T. Jason
Published: September 2019

Purpose

Several recent studies have utilized a 3-tissue constrained spherical deconvolution pipeline to obtain quantitative metrics of brain tissue microstructure from diffusion-weighted MRI data. The three tissue compartments, comprising white matter-, grey matter-, and CSF-like (free water) signals, are potentially useful in the evaluation of brain microstructure in a range of pathologies. However, the reliability and long-term stability of these metrics has not yet been evaluated.

Methods

This study examined estimates of whole brain microstructure for the three tissue compartments, in three separate test-retest cohorts. Each cohort has different lengths of time between baseline and retest, ranging from within the same scanning session in the shortest interval to three months in the longest interval. Each cohort was also collected with different acquisition parameters.

Results

The CSF-like compartment displayed the greatest reliability across all cohorts, with intraclass correlation coefficient (ICC) values being above 0.95 in each cohort. White matter-like and grey matter-like compartments both demonstrated very high reliability in the immediate cohort (both ICC>0.90), however this declined in the 3 month interval cohort to both compartments having ICC>0.80. Regional CSF-like signal fraction was examined in bilateral hippocampus and had an ICC>0.80 in each cohort.

Conclusion

The 3-tissue CSD techniques provide reliable and stable estimates of tissue microstructure composition, up to 3 months longitudinally in a control population. This forms an important basis for further investigations utilizing 3-tissue CSD techniques to track changes in microstructure across a variety of brain pathologies.
Variability in Locomotor Dynamics Reveals the Critical Role of Feedback in Task Control
Authors: Uyanik Ismail , Sefati Shahin , Stamper Sarah A. , Cho Kyoung-A , Ankarali M. Mert , Fortune Eric S. , Cowan Noah J.
Published: September 2019

Animals vary considerably in size, shape, and physiological features across individuals, but yet achieve behavioral performances that are virtually indistinguishable between conspecifics. We examined how animals compensate for morphophysiological variation by measuring the system dynamics of individual knifefish (Eigenmannia virescens) in a refuge tracking task. Kinematic measurements ofEigenmanniawere used to generate individualized estimates of each fish’s locomotor plant and controller revealing substantial variability between fish. To test the impact of this variability on behavioral performance, these models were used to perform simulated ‘brain transplants’—computationally swapping controllers and plants between individuals. We found that simulated closed-loop performance was robust to mismatch between plant and controller. This suggests that animals rely on feedback rather than precisely tuned neural controllers to compensate for morphophysiological variability.
Range of motion and between-measurement variation of spinal kinematics in sound horses at trot on the straight line and on the lunge
Authors: Hardeman A. , Byström A. , Roepstorff L. , Swagemakers J.H. , van Weeren P.R. , Bragança F.M. Serra
Published: September 2019

Clinical assessment of spinal motion in horses is part of many routine clinical exams but remains highly subjective. A prerequisite for the quantification is the assessment of the expected normal range of motion and variability of back kinematics. The aim of this study was to objectively quantify spinal kinematics and between-measurement, -surface and -day variation in owner-sound horses. In an observational study, twelve owner-sound horses were trotted 12 times on four different paths (hard/soft straight line, soft lunge left and right). Measurements were divided over three days, with five repetitions on day one and two, and two repetitions on day three (recheck) which occurred 28-55 days later. Optical motion capture was used to collect kinematic data. Elements of the outcome were: 1) Ranges of Motion (ROM) with confidence intervals per path and surface, 2) a variability model to calculate between-measurement variation and test the effect of time, surface and path, 3) intraclass correlation coefficients (ICC) to determine repeatability. ROM was lowest on the hard straight line. Cervical lateral bending was doubled on the left compared to the right lunge. Mean variation for the flexion-extension and lateral bending of the whole back were 0.8 and 1 degrees. Pelvic motion showed a variation of 1.0 (pitch), 0.7 (yaw) and 1.3 (roll) degrees. For these five parameters, a tendency for more variation on the hard surface and reduced variation with increased repetitions was observed. More variation was seen on the recheck (p<0.001). ICC values for the pelvis were between 0.76 and 0.93, for the whole back flexion-extension and lateral bending between 0.51 and 0.91. Between-horse variation was substantially higher than within-horse variation. Concluding, ROM and variation in spinal biomechanics are horse-specific and small, necessitating individual analysis and making subjective clinical assessment of spinal kinematics challenging.
Gradients in the cerebellar cortex enable Fourier-like transformation and improve storing capacity
Authors: Straub Isabelle , Witter Laurens , Eshra Abdelmoneim , Hoidis Miriam , Byczkowicz Niklas , Maaß Sebastian , Delvendahl Igor , Dorgans Kevin , Savier Elise , Bechmann Ingo , Eilers Jens , Krüger Martin , Isope Philippe , Hallermann Stefan
Published: September 2019

Cerebellar granule cells (GCs) making up majority of all the neurons in the vertebrate brain, but heterogeneities among GCs and potential functional consequences are poorly understood. Here, we identified unexpected gradients in the biophysical properties of GCs. GCs closer to the white matter (inner-zone GCs) had higher firing thresholds and could sustain firing with larger current inputs. Dynamic clamp experiments showed that inner- and outer-zone GCs preferentially respond to high- and low-frequency mossy fiber inputs, respectively, enabling to disperse the mossy fiber input into its frequency components as performed by a Fourier transformation. Furthermore, inner-zone GCs have faster axonal conduction velocity and elicit faster synaptic potentials in Purkinje cells. Neuronal network modeling revealed that these gradients improve spike-timing precision of Purkinje cells and decrease the number of GCs required to learn spike-sequences. Thus, our study uncovers biophysical gradients in the cerebellar cortex enabling a Fourier-like transformation of mossy fiber inputs.
Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation
Authors: Vilarrasa-Blasi Roser , Soler-Vila Paula , Verdaguer-Dot Núria , Russiñol Núria , Di Stefano Marco , Chapaprieta Vicente , Clot Guillem , Farabella Irene , Cuscó Pol , Agirre Xabier , Prosper Felipe , Beekman Renée , Beà Silvia , Colomer Dolors , Stunnenberg Henk , Gut Ivo , Campo Elias , Marti-Renom Marc A. , Martin-Subero José Ignacio
Published: September 2019

Despite recent advances, the dynamics of genome architecture and chromatin function during human cell differentiation and its potential reorganization upon neoplastic transformation remains poorly characterized. Here, we integrate in situ Hi-C and nine additional omic layers to define and biologically characterize the dynamic changes in three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) patients. Beyond conventional active (A) and inactive (B) compartments, an integrative analysis of Hi-C data reveals the presence of a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, we detect that 28% of the compartments change at defined maturation stages and mostly involve the intermediate compartment. The transition from naive to germinal center B cells is associated with widespread chromatin activation, which mostly reverts into the naive state upon further maturation of germinal center cells into memory B cells. The analysis of CLL and MCL neoplastic cells points both to entity and subtype-specific alterations in chromosome organization. Remarkably, we observe that large chromatin blocks containing key disease-specific genes alter their 3D genome organization. These include the inactivation of a 2Mb region containing the EBF1 gene in CLL and the activation of a 6.1Mb region containing the SOX11 gene in clinically aggressive MCL. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.
SIRT6 is a DNA Double-Strand Break Sensor
Authors: Onn Lior , Portillo Miguel , Ilic Stefan , Cleitman Gal , Stein Daniel , Kaluski Shai , Shirat Ido , Slobodnik Zeev , Einav Monica , Erdel Fabian , Akabayov Barak , Toiber Debra
Published: September 2019

DNA double strand breaks are the most deleterious type of DNA damage. In this work, we show that SIRT6 directly recognizes DNA damage through a tunnel-like structure, with high affinity for double strand breaks. It relocates to sites of damage independently of signalling and known sensors and activates downstream signalling cascades for double strand break repair by triggering ATM recruitment, H2AX phosphorylation and the recruitment of proteins of the Homologous Recombination and Non-Homologous End Joining pathways. Our findings indicate that SIRT6 plays a previously uncharacterized role as DNA damage sensor, which is critical for initiating the DNA damage response (DDR). Moreover, other Sirtuins share some DSB binding capacity and DDR activation. SIRT6 activates the DDR, before the repair pathway is chosen, and prevents genomic instability. Our findings place SIRT6 at the top of the DDR and pave the road to dissect the contributions of distinct double strand break sensors in downstream signalling.
Artifact-free whole-slide imaging with structured illumination microscopy and Bayesian image reconstruction
Authors: Johnson Karl , Hagen Guy M.
Published: September 2019

Background

Structured illumination microscopy (SIM) is a method which can be used to image biological samples and can achieve both optical sectioning and super-resolution effects. Optimization of the imaging setup and data processing methods results in high quality images without artifacts due to mosaicking or due to the use of SIM methods. Reconstruction methods based on Bayesian estimation can be used to produce images with a resolution beyond that dictated by the optical system.

Findings

Five complete datasets are presented including large panoramic SIM images of human tissues in pathophysiological conditions. Cancers of the prostate, skin, ovary, and breast, as well as tuberculosis of the lung, were imaged using SIM. The samples are available commercially and are standard histological preparations stained with hematoxylin and eosin.

Conclusion

The use of fluorescence microscopy is increasing in histopathology. There is a need for methods which reduce artifacts when employing image stitching methods or optical sectioning methods such as SIM. Stitched SIM images produce results which may be useful for intraoperative histology. Releasing high quality, full slide images and related data will aid researchers in furthering the field of fluorescent histopathology.
An Open Source Mesh Generation Platform for Biophysical Modeling Using Realistic Cellular Geometries
Authors: Lee Christopher T. , Laughlin Justin G. , Moody John B. , Amaro Rommie E. , McCammon J. Andrew , Holst Michael J. , Rangamani Padmini
Published: September 2019

Advances in imaging methods such as electron microscopy, tomography, and other modalities are enabling high-resolution reconstructions of cellular and organelle geometries. Such advances pave the way for using these geometries for biophysical and mathematical modeling once these data can be represented as a geometric mesh, which, when carefully conditioned, enables the discretization and solution of partial differential equations. In this study, we outline the steps for a naïve user to approachGAMer 2, a mesh generation code written in C++ designed to convert structural datasets to realistic geometric meshes, while preserving the underlying shapes. We present two example cases, 1) mesh generation at the subcellular scale as informed by electron tomography, and 2) meshing a protein with structure from x-ray crystallography. We further demonstrate that the meshes generated byGAMerare suitable for use with numerical methods. Together, this collection of libraries and tools simplifies the process of constructing realistic geometric meshes from structural biology data.

SIGNIFICANCE

As biophysical structure determination methods improve, the rate of new structural data is increasing. New methods that allow the interpretation, analysis, and reuse of such structural information will thus take on commensurate importance. In particular, geometric meshes, such as those commonly used in graphics and mathematics, can enable a myriad of mathematical analysis. In this work, we describeGAMer 2, a mesh generation library designed for biological datasets. UsingGAMer 2and associated toolsPyGAMerandBlendGAMer, biologists can robustly generate computer and algorithm friendly geometric mesh representations informed by structural biology data. We expect thatGAMer 2will be a valuable tool to bring realistic geometries to biophysical models.
Hormonal and neural correlates of care in active versus observing poison frog parents
Authors: Fischer Eva K , O'Connell Lauren A
Published: September 2019

The occasional reversal of sex-typical behavior suggests that many of the neural circuits underlying behavior are conserved between males and females and can be activated in response to the appropriate social condition or stimulus. Most poison frog species (Family Dendrobatidae) exhibit male uniparental care, but flexible compensation has been observed in some species, where females will take over parental care duties when males disappear. We investigated hormonal and neural correlates of sex-typical and sex-reversed parental care in a typically male uniparental species, the Dyeing Poison Frog (Dendrobates tinctorius). We first characterized hormone levels and whole brain gene expression across parental care stages during sex-typical care. Surprisingly, hormonal changes and brain gene expression differences associated with active parental behavior in males were mirrored in their non-caregiving female partners. To further explore the disconnect between neuroendocrine patterns and behavior, we characterized hormone levels and neural activity patterns in females performing sex-reversed parental care. In contrast to hormone and gene expression patterns, we found that patterns of neural activity were linked to the active performance of parental behavior, with sex-reversed tadpole transporting females exhibiting neural activity patterns more similar to those of transporting males than non-caregiving females. We suggest that parallels in hormones and brain gene expression in active and observing parents are related to females ability to flexibly take over parental care in the absence of their male partners.
Why does a flying fish taxi on sea surface before take-off? A hydrodynamic interpretation
Authors: Deng Jian , Wang Shuhong , Zhang Lingxin , Mao Xuerui
Published: September 2019

Flying fish have been observed jumping out of warm ocean waters worldwide. Before take-off, the flying fish are seen to taxi on the water surface by rapidly beating their semi-submerged tail fins, which process may help them airborne with enough speed to glide over a long distance. To understand the underlying physical mechanisms, here, we study a flying fish, 0.25 m in length and 0.191 kg in weight, considering both its underwater swimming and surface taxiing locomotion. Its hydrodynamic characteristics are numerically studied by computational fluid dynamics (CFD). Underwater, the fish is assumed to swim at a constant speed of 10 m s−1. Different critical frequencies are identified for various maximum deflected angles, ranging from θ0 = 10° to 30°, at which the fish reaches cruising states, when the horizontal forces are balanced. The corresponding minimum power required for cruising swimming is 350 W, obtained at a deflected angle of 10° and a critical frequency of 145 Hz. In contrast, in the taxiing stage, the minimum power required for a stead-state locomotion at 10 m s−1 is 36 W, occurring at a deflected angle of 15° and a frequency of 50 Hz. We note that the power is significantly smaller than the swimming locomotion. Further, by increasing the flapping power, we find that larger speeds can be achieved. In specific, when the power is brought up to 350 W, it can reach a speed of 16.5 m s−1. Clearly, from the direct comparison between the two locomotive modes, it is apparently evidenced that the flying fish can be further accelerated by taxiing along the water surface.
Using synthetic datasets to better understand and explain health outcomes associated with common single nucleotide polymorphisms
Authors: Wood Thomas R. , Owens Nathan
Published: September 2019

Due to decreasing costs and a move towards “personalised medicine”, the use of direct-to-consumer genetic analyses is increasing. Both consumers and healthcare practitioners must therefore be able to understand the true disease risks associated with common genetic single nucleotide polymorphisms (SNPs). However, most population studies of common SNPs only provide average (+/−error) phenotypic or risk descriptions for a given genotype, which hides the true heterogeneity of the population and reduces the ability of an individual to determine how they themselves might truly be effected. Here, we describe the use of synthetic datasets generated from descriptive phenotypic data published on common SNPs associated with obesity, elevated fasting blood glucose, and methylation status. Using both simple statistical theory and full graphical representation of the generated data, we show that single common SNPs are associated with a less than 10% likelihood of effecting final phenotype, even in homozygotes. The significant heterogeneity in the data, as well as the baseline disease risk of Western populations suggests that most disease risk is dominated by the effect of the modern environment.
FAP overexpression induce Epithelial-Mesenchymal Transition (EMT) in oral squamous cell carcinoma by down-regulating DPP9 gene
Authors: Wu Qing-qing , Zhao Meng , Huang Guang-zhao , Zheng Ze-nan , Zeng Wei-sen , Lv Xiao-zhi
Published: September 2019

FAP acts as a tumor promoter via epithelial-mesenchymal transition (EMT) in human oral squamous cell carcinoma (OSCC). The present study was designed to investigate the interaction proteins with FAP and explore the precise mechanism of FAP promoting EMT in OSCC. IP-MS analysis confirmed that DPP9 was an interacting protein of FAP. DPP9 was down-regulated in OSCC tissue samples compared with MNT using immunohistochemistry and quantitative-PCR detection. Lower DPP9 was correlated with unfavorable overall survival of patients with OSCC. Repressing DPP9 accelerates the proliferation of OSCC cells in vitro and in vivo. Mechanistically, overexpression of FAP downregulate the expression of the DPP9 and the effect of FAP on OSCC proliferation, migration, invasion and EMT could be reversed by up-regulated DPP9. Our study suggests that FAP could induce EMT and promote carcinogenesis in oral squamous cell carcinoma by down-regulating DPP9 gene. That will hint different dimension on therapy for patients with OSCC.
Optimization of a phase-space beam position and size monitor for low-emittance light sources
Authors: Samadi Nazanin , Shi Xianbo , Chapman Dean
Published: September 2019

The recently developed vertical phase-space beam position and size monitor (ps-BPM) system has proven to be able to measure the electron-source position, angle, size and divergence simultaneously in the vertical plane at a single location of a beamline. The optimization of the ps-BPM system is performed by ray-tracing simulation to maximize the instrument sensitivity and resolution. The contribution of each element is studied, including the monochromator, the K-edge filter, the detector and the source-to-detector distance. An optimized system is proposed for diffraction-limited storage rings, such as the Advanced Photon Source Upgrade project. The simulation results show that the ps-BPM system can precisely monitor the source position and angle at high speed. Precise measurements of the source size and divergence will require adequate resolution with relatively longer integration time.
Early career academics’ understanding of library language
Authors: Yesmin Shamima , Ahmed S.M. Zabed
Published: September 2019

Purpose

The purpose of this paper is to empirically examine the understanding of library terminologies by early career faculty members in a newly established rural university setting at the south coast of Bangladesh.

Design/methodology/approach

A campus-wide survey was conducted using a structured questionnaire consisted of demographic questions and 35 multiple-choice questions on library terminologies. The multiple-choice questions asked faculty members to select the correct answer from a set of five answers.

Findings

The findings indicate that early career university teachers lack adequate understanding of library terms; in fact, many of them either gave incorrect answers or was unsure about the term. It was found that faculty members had relatively better understandings of commonly used library terminologies, but they had real difficulties comprehending computer and technology-related terms. Significant differences were observed for some of the terms in case of their age, designation and teaching experience.

Originality/value

This current study is unique in two ways: first, this is the first time an effort has been made to empirically examine the understanding of library terminologies by early career faculty members; and second, this study was conducted at a university in Bangladesh where the first language is not English.