bluuebunny/crossref_metadata_2025_split huggingface dataset:
A biosynthetic platform for antimalarial drug discovery
Authors: Wilkinson Mark D. , Lai Hung-En , Freemont Paul S. , Baum Jake 
Published: October 2019

ABSTRACTAdvances in synthetic biology have enabled production of a variety of compounds using bacteria as a vehicle for complex compound biosynthesis. Violacein, a naturally occurring indole pigment with antibiotic properties, can be biosynthetically engineered in Escherichia coli expressing its non-native synthesis pathway. To explore whether this synthetic biosynthesis platform could be used for drug discovery, here we have screened bacterially-derived violacein against the main causative agent of human malaria, Plasmodium falciparum. We show the antiparasitic activity of bacterially-derived violacein against the P. falciparum 3D7 laboratory reference strain as well as drug-sensitive and resistant patient isolates, confirming the potential utility of this drug as an antimalarial. We then screen a biosynthetic series of violacein derivatives against P. falciparum growth. The demonstrated varied activity of each derivative against asexual parasite growth points to potential for further development of violacein as an antimalarial. Towards defining its mode of action, we show that biosynthetic violacein affects the parasite actin cytoskeleton, resulting in an accumulation of actin signal that is independent of actin polymerization. This activity points to a target that modulates actin behaviour in the cell either in terms of its regulation or its folding. More broadly, our data show that bacterial synthetic biosynthesis is a suitable platform for antimalarial drug discovery with potential applications in high-throughput and cost-effective drug screening with otherwise chemically-intractable natural products.
Bayesian statistics show a lack of change in excitability following bihemispheric HD-TDCS over the primary somatosensory cortices
Authors: Selene Gallo , Baaijen Thijs J. , Judith Suttrup , Carolina Fernandes-Henriques , Christian Keysers , Valeria Gazzola 
Published: October 2019

ABSTRACTBackgroundHigh Definition transcranial Direct Current Stimulation (HD-tDCS) is a method meant to explore the causal structure-function relationship of brain areas, developed to improve the spatial resolution of tDCS, but the validity of tDCS results is currently under intense debateObjectiveThe goal of this study is to validate a new HD-tDCS protocol for bilateral modulation of the Somatosensory Cortex (SI). The new montage is meant to increase the focus of the stimulation while limiting the area of the scalp covered by electrodes. We aim to characterize the effect of the stimulation in terms of directionality, consistency and reproducibility.MethodsWe aim to leverage a 1 × 1 montage to most focally stimulate the primary somatosensory cortex (SI) and measure modulation via Somatosensory Evoked Potentials (SEP) triggered by median nerve stimulation.ResultsThe results of Experiment1 suggest that our montage increases the amplitude of the SEP component N30. In Experiment2, we aim to replicate our finding and to assess the duration of the modulatory effect on N30 over time. Data from Experiment2 fails to replicate N30 modulation. A sequential Bayesian analysis performed on N30 data from both experiments indicates that the effect fluctuates across participants, without a clear homogenous directionality.ConclusionThis study sets boundaries on the effect size that can be expected for this montage and illustrates the need to include replication samples or larger sample sizes to avoid overestimating effect sizes. We conclude that our montage has insufficient effect size for use in moderately sample-sized experimental studies and clinical applications.
Hox genes are essential for the development of novel serial homologous eyespots on the wings of Bicyclus anynana butterflies
Authors: Matsuoka Yuji , Monteiro Antónia 
Published: October 2019

AbstractThe eyespot patterns found on the wings of nymphalid butterflies are novel serial homologous traits that originated first in hindwings and subsequently in forewings, suggesting that eyespot development might be dependent on Hox genes. Hindwings differ from forewings in the expression of Ultrabithorax (Ubx), but the function of this Hox gene in eyespot development as well as that of another Hox gene Antennapedia (Antp), expressed specifically in eyespots centers on both wings, are still unclear. We used CRISPR-Cas9 to target both genes in Bicyclus anynana butterflies. We show that Antp is essential for eyespot development on the forewings and for the differentiation of white centers and larger eyespots on hindwings, whereas Ubx is essential for the development of at least some hindwing eyespots but also for repressing the size of other eyespots. Additionally, Antp is essential for the development of silver scales in male wings. In summary, Antp and Ubx, in addition to their conserved roles in modifying serial homologous traits along the anterior-posterior axis of animals, have acquired a novel role in promoting the development of a new set of serial homologs, the eyespot patterns, in both forewings (Antp) and hindwings (Antp and Ubx) of B. anynana butterflies. We propose that the peculiar pattern of eyespot origins on hindwings first, followed by forewings, could be due to an initial co-option of Ubx into eyespot development, followed by a later, partially redundant co-option of Antp into the same network.
In vivo and in vitro human gene essentiality estimations capture contrasting functional constraints
Authors: Caldu-Primo JL , Verduzco-Martínez JA , Alvarez-Buylla ER , Davila-Velderrain J 
Published: October 2019

AbstractGene essentiality estimation is a popular empirical approach to link genotypes to phenotypes. In humans, essentiality is estimated based on loss-of-function (LoF) mutation intolerance, either from population exome sequencing (in vivo) data or CRISPR-based in vitro perturbation experiments. Both approaches identify genes presumed to have strong detrimental consequences on the organism upon mutation. Are these genes functionally distinct and constrained by having key roles? Do in vivo and in vitro estimations equally recover these constraints? To address these questions, here we integrated disparate genome-scale datasets and compared structural, functional, and evolutionary features of essential genes versus genes with extremely high mutational tolerance and proteome expectation. We found that essentiality estimates do recover functional constraints. However, the organismal or cellular context of estimation leads to functionally contrasting properties underlying the constraint. Our results suggest that depletion of LoF mutations in human populations effectively captures developmental, organismal-level functional constraints not experimentally accessible through CRISPR-based screens. Finally, we identify a new set of genes (OrgEssential), which are intolerant of LoF mutation in vivo but highly tolerant in vitro. These genes drive observed functional constraint differences and have an unexpected preference for nervous system expression.
EEG correlates of perceived food product similarity in a cross-modal taste-visual task
Authors: Domracheva M. , Kulikova S. 
Published: October 2019

AbstractThe most common tools to understand perception of food products are hall-tests, surveys, observations, etc. However to get reliable results these approaches require large samples, making them costly and time-consuming. Furthermore, they are also highly expert-dependent and rely on the assumption that study participants can express their preferences consciously and explicitly. Here we suggested an EEG-based approach to evaluate perceived product similarity in a cross-modal taste-visual task. Two candidate neurometrics measured from Fz electrode were tested: the amplitude of N430-620 from evoked response potentials (ERP) and the power of induced gamma oscillations during 400-600 ms period after visual stimulus presentation. Both suggested metrics showed a strong correlation with the perceived similarity scores at both individual and group levels, however N430-630 had greater inter-subject variability making it less suitable for practical applications. The results based on the power of induced gamma oscillations (N=18) not only reflected the results from traditional hall-tests (N=200) but also allowed better discrimination between different food products.
Variation in host home range decreases rabies vaccination effectiveness by increasing the spatial spread of rabies
Authors: McClure Katherine M. , Gilbert Amy T. , Chipman Richard B. , Rees Erin , Pepin Kim M. 
Published: October 2019

ABSTRACTAnimal movement influences the spatial spread of wildlife infectious diseases through host-host contact structure and hence pathogen transmission. Wildlife disease hosts vary in characteristics related to pathogen transmission, which can increase the spread and intensity of disease outbreaks. The consequences of home range size variation on wildlife disease dynamics are poorly understood, but could help to predict disease spread and determine more effective disease management strategies.We developed a spatially-explicit individual-based model to examine the effect of variation in host home range size on the spatial spread rate, persistence, and incidence of rabies virus (RABV) in raccoons (Procyon lotor). We tested the hypothesis that host home range area variation decreases vaccination effectiveness in wildlife host populations following pathogen invasion into a vaccination zone.We simulated raccoon demography and RABV dynamics across a range of magnitudes and variances in weekly home range radius distributions for raccoons, and compared results to conditions that assumed a fixed host home range area. We examined how variable host home range radius distributions influenced the relative effectiveness of three components of orally-baited raccoon RABV vaccination (ORV) programs—timing and frequency of bait delivery, width of the zone where ORV baits were delivered, and proportion of hosts immunized.Variability in home range radius distributions increased RABV spread rates by 1.2 - 5.2-fold compared to simulations with fixed radii. More variable host home range radius distributions decreased relative vaccination effectiveness by 71% compared to less variable host home range radius distributions under conventional vaccination conditions. We found that vaccination timing was more influential for vaccination effectiveness than vaccination frequency or vaccination zone width.Our results suggest that variation in wildlife home range exploration increases the spatial spread and incidence of wildlife disease. Our vaccination results underscore the importance of prioritizing individual-level space use data collection to understand the dynamics of wildlife diseases and plan their effective control and elimination.
Spontaneous mutations that confer resistance to 2-deoxyglucose act through Hxk2 and Snf1 pathways to regulate gene expression and HXT endocytosis
Authors: Soncini Samantha R. , Chandrashekarappa Dakshayini G. , Augustine David A. , Callahan Kenny P. , O’Donnell Allyson F. , Schmidt Martin C. 
Published: October 2019

AbstractYeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the glucose analog 2-deoxyglucose. Spontaneous mutations inS. cerevisiaethat conferred resistance to 2-deoxyglucose were identified by whole genome sequencing. In addition to three aneuploid strains, we detected missense alleles of theHXK2, REG1, GLC7andSNF1genes that were shown to confer significant resistance to 2-deoxyglucose. All three missense alleles inHXK2resulted in significantly reduced catalytic activity. Missense alleles affecting the Snf1 kinase pathway (REG1,GLC7andSNF1)exhibited different capacities to affect the regulation of invertase expression. Of the seven missense alleles identified in this study, all but one affected hexose transporter endocytosis by increasing plasma membrane occupancy of the Hxt3 protein. Increased expression of the DOG (deoxyglucose) phosphatases has been associated with resistance to 2-deoxyglucose. Expression of both theDOG1andDOG2mRNA was elevated after treatment with 2-deoxyglucose. Deletion of theHXK2andREG1genes confers resistance to 2-deoxyglucose and causes increased expression of theDOG2mRNA. We conclude that Snf1 kinase-mediated regulation of the endocytosis of the hexose transporters and regulation ofDOG2expression are important mechanisms for resistance to 2-deoxyglucose. However, the dominantSNF1-G53Rallele can confer additional 2-deoxyglucose resistance in cells that are genetically compromised in both the endocytosis andDOGpathways. Thus at least one more mechanism for conferring resistance to this glucose analog remains to be discovered.Author SummaryYeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the glucose analog 2-deoxyglucose. Another similarity between yeast cells and human tumor cells is that both cells can acquire resistance to 2-deoxyglucose, an outcome that can limit the usefulness of some cancer therapeutics. In this study, we used bakers’ yeast as a model organism to better understand the mechanism of toxicity and acquisition of resistance to 2-deoxyglucose. Spontaneous mutations in S. cerevisiae that conferred resistance to 2-deoxyglucose were isolated and identified by whole genome sequencing, a technology that was not available until recently. Our studies indicate that 2-deoxyglucose becomes toxic after it is phosphorylated by an enzyme called hexokinase. One important route to resistance is to reduce hexokinase activity. Other parallel pathways to resistance include increased expression of a hydrolase that degrades the toxic metabolite, altered localization of glucose transporters and altered glucose signal transduction pathways.
Correlation between increased atrial expression of genes related to fatty acid metabolism and autophagy in patients with chronic atrial fibrillation
Authors: Shingu Yasushige , Takada Shingo , Yokota Takashi , Shirakawa Ryosuke , Yamada Akira , Ooka Tomonori , Katoh Hiroki , Kubota Suguru , Matsui Yoshiro 
Published: October 2019

AbstractAtrial metabolic disturbance contributes to the onset and development of atrial fibrillation (AF). Autophagy plays a role in maintaining the cellular energy balance. We examined whether the altered atrial expression of genes related to fatty acid metabolism is linked to that related to autophagy in chronic AF. Right atrial tissue was obtained during heart surgery from 51 patients with sinus rhythm (SR, n=38) or chronic AF (n=13). Preoperative fasting serum free-fatty-acid levels were significantly higher in the AF patients. The atrial gene expression of fatty acid binding protein 3 (FABP3), which is involved in the cells’ fatty acid uptake and intracellular fatty acid transport, was significantly increased in AF patients compared to SR patients; in the SR patients it was positively correlated with the right atrial diameter and intra-atrial EMD, parameters of structural and electrical atrial remodeling that was evaluated by an echocardiography. In contrast, the two groups’ atrial contents of diacylglycerol (DAG), a toxic fatty acid metabolite, were comparable. Importantly, the atrial gene expression of microtubule-associated protein light chain 3 (LC3) was significantly increased in the AF patients, and autophagy-related genes including LC3 were positively correlated with the atrial expression of FABP3. In conclusion, in chronic AF patients, the atrial expression of FABP3 was upregulated in association with autophagy-related genes without altered atrial DAG content. Our findings may support the hypothesis that dysregulated cardiac fatty acid metabolism contributes to the progression of AF and induction of autophagy has a cardioprotective effect against cardiac lipotoxicity in chronic AF.
Ovine fetuses from slaughterhouses: a useful source for neural cell primary cultures
Authors: Farina Vittorio , Gadau Sergio Domenico , Lepore Gianluca , Carcupino Marcella , Zedda Marco 
Published: October 2019

AbstractA lot of evidence demonstrates that sheep could represent an experimental model to set up medical procedures in a view of their application on humans. Sheep are chosen as model for human biomechanical studies because their skeleton has some similarities with humans. Sheep are gyrencephalic so the cerebral cortex can show valuable signposts to identify particular cortical regions, unlike rats that are lissencephalic animals. The aim of this work was to set up sheep primary cultures from ovine fetuses at different ages, from pregnant uteri retrieved at local abattoirs. Cell characterization demonstrated that one cell population was immunopositive to GFAP and identifiable as astrocytes, whereas a second cell type was III β-tubulin-positive, and hence classified as neurons. A 60 day old fetus is suitable to obtain neurons, whereas in a 90 day old fetus the cell culture is predominantly characterized by glial cells. The procedure here proposed is inexpensive. Indeed, the fetuses casually found during sheep slaughtering have no cost, unlike the classical experimental animals, such as mice, rats, rabbits, that require very high economical efforts. Finally, our protocol fully eliminates the need of animal killing, being living animals replaced by a validated in vitro model in agreement with the 3Rs statement.
How to better conserve with genetic data: origin and population structure of Brazilian locally adapted hair sheep (Ovis aries) breeds
Authors: Paim Tiago do Prado , Paiva Samuel Rezende , Martins de Toledo Natália , Yamaghishi Michel Beleza , Carneiro Paulo Luiz Souza , Facó Olivardo , Mello de Araújo Adriana , Azevedo Hymerson Costa , Caetano Alexandre Rodrigues , McManus Concepta 
Published: October 2019

AbstractBrazilian hair sheep constitute a genetic diversity hotspot of sheep breeds. These locally adapted genetic resources developed in harsh environments of the Brazilian Northwest (semi-arid) and maintained important traits for this region, such as parasite resistance, heat tolerance and high pelt quality. Genotypes (50K SNP chip) from seven Brazilian sheep breeds (5 hair and 2 coarse wool types) and 87 worldwide breeds were used to verify population structure, admixture and genetic diversity, using PCA and ADMIXTURE analyses. We constructed a phylogenetic tree and evaluated migration events between genetic groups using TREEMIX software. Brazilian Somali, a fat-tailed breed, was the unique breed with high relationship with East African breeds and formed a distinct cluster from other Brazilian breeds. This breed seems to contribute to formation of Santa Inês, Morada Nova and Brazilian Fat-tail breeds. Brazilian Blackbelly had a clear relationship with Barbados Blackbelly, which appeared as another group. Other Brazilian breeds seem to form a further genetic group with some recent admixtures. Morada Nova remained as a separate group, not showing a strong relationship with European or African breeds, only revealing a migration event from Sidaoun, an Algerian hair breed. Brazilian Fat-tail and Morada Nova share a common ancestor, but the first received introgressions from Brazilian Somali and Afrikaner breeds, explaining the fat-tail phenotype. Santa Inês received strong contribution from Bergamasca and had an admixed origin with recent introgressions from other breeds, mainly from Suffolk animals. In conclusion, Brazilian Somali and Brazilian Fat-tail are the most endangered sheep genetic resources in Brazil.
Learning Your Heart Actions From Pulse: ECG Waveform Reconstruction From PPG
Authors: Zhu Qiang , Tian Xin , Wong Chau-Wai , Wu Min 
Published: October 2019

AbstractThis paper studies the relation between electrocardiogram (ECG) and photoplethysmogram (PPG) and infers the waveform of ECG via the PPG signals that can be obtained from affordable wearable Internet-of-Things (IoT) devices for mobile health. In order to address this inverse problem, a transform is proposed to map the discrete cosine transform (DCT) coefficients of each PPG cycle to those of the corresponding ECG cycle based on our proposed cardiovascular signal model. The proposed method is evaluated with different morphologies of the PPG and ECG signals on three benchmark datasets with a variety of combinations of age, weight, and health conditions using different training setups. Experimental results show that the proposed method can achieve a high prediction accuracy greater than 0.92 in averaged correlation for each dataset when the model is trained subject-wise. With a signal processing and learning system that is designed synergistically, we are able to reconstruct ECG signals by exploiting the relation of these two types of cardiovascular measurement. The reconstruction capability of the proposed method can enable low-cost ECG screening from affordable wearable IoT devices for continuous and long-term monitoring. This work may open up a new research direction to transfer the understanding of the clinical ECG knowledge base to build a knowledge base for PPG and data from wearable devices.
Information Enhanced Model Selection for Gaussian Graphical Model with Application to Metabolomic Data
Authors: Zhou Jie , Hoen Anne G. , McRitchie Susan , Pathmasiri Wimal , Viles Weston D. , Nguyen Quang P. , Madan Juliette C. , Dade Erika , Karagas Margaret R. , Gui Jiang 
Published: October 2019

AbstractIn light of the low signal-to-noise nature of many large biological data sets, we propose a novel method to learn the structure of association networks using Gaussian graphical models combined with prior knowledge. Our strategy includes two parts. In the first part, we propose a model selection criterion called structural Bayesian information criterion (SBIC), in which the prior structure is modeled and incorporated into Bayesian information criterion (BIC). It is shown that the popular extended BIC (EBIC) is a special case of SBIC. In the second part, we propose a two-step algorithm to construct the candidate model pool. The algorithm is data-driven and the prior structure is embedded into the candidate model automatically. Theoretical investigation shows that under some mild conditions SBIC is a consistent model selection criterion for high-dimensional Gaussian graphical model. Simulation studies validate the superiority of the proposed algorithm over the existing ones and show the robustness to the model misspecification. Application to relative concentration data from infant feces collected from subjects enrolled in a large molecular epidemiological cohort study validates that metabolic pathway involvement is a statistically significant factor for the conditional dependence between metabolites. Furthermore, new relationships among metabolites are discovered which can not be identified by the conventional methods of pathway analysis. Some of them have been widely recognized in biological literature.