bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational Modeling of the Gut Microbiota Predicts Metabolic Mechanisms of RecurrentClostridioides difficileInfection
Authors: Henson Michael A. 
Published: April 2020

AbstractApproximately 30% of patients who have aClostridioides difficileinfection (CDI) will suffer at least one incident of reinfection. While the underlying causes of CDI recurrence are poorly understood, interactions betweenC. difficileand other commensal gut bacteria are thought to play an important role. In this study, anin silicometagenomics pipeline was used to process taxa abundance data from 225 CDI patient stool samples into sample-specific models of bacterial community metabolism. The predicted metabolite production capabilities of each community were shown to provide improved recurrence prediction compared to direct use of taxa abundance data. More specifically, clustered metabolite synthesis rates generated from post-diagnosis samples produced a highEnterobacteriaceaecluster with disproportionate numbers of recurrent samples and patients. This cluster was predicted to have significantly reduced capabilities for secondary bile acid synthesis but elevated capabilities for aromatic amino acid catabolism. When applied to 40 samples from fecal microbiota transplantation (FMT) patients and their donors, community modeling generated a highEnterobacteriaceaecluster with a disproportionate number of pre-FMT samples. This cluster also was predicted to exhibit reduced secondary bile acid synthesis and elevated aromatic amino acid catabolism. Because clustering of CDI and FMT samples did not identify statistical differences inC. difficileabundances, these model predictions support the hypothesis thatEnterobacteriaceaemay create a gut environment favorable forC. difficilespore germination and toxin synthesis.ImportanceClostridioides difficileis an opportunistic human pathogen responsible for acute and sometimes chronic infections of the colon. Elderly individuals who are immunocompromised, frequently hospitalized and recipients of antibiotics are particular susceptible to infection. Approximately 30% of treated patients will suffer at least one episode of reinfection, commonly termed recurrence. The objective of the current study was to utilize computational metabolic modeling to investigate the hypothesis that recurrent infections are related to the composition of the gut bacterial community within each patient. Our model predictions suggest that patients who have high compositions of the bacterial familyEnterobacteriaceaeduring antibiotic treatment are more likely to develop recurrent infections due to a metabolically-disrupted gut environment. Successful treatment of recurrent patients with transplanted fecal matter is predicted to correct this metabolic disruption, suggesting that interactions betweenC. difficileandEnterobacteriaceaeare worthy of additional study.
Predicting unrecognized enhancer-mediated genome topology by an ensemble machine learning model
Authors: Tang Li , Hill Matthew C. , Wang Jun , Wang Jianxin , Martin James F. , Li Min 
Published: April 2020

AbstractTranscriptional enhancers commonly work over long genomic distances to precisely regulate spatiotemporal gene expression patterns. Dissecting the promoters physically contacted by these distal regulatory elements is essential for understanding developmental processes as well as the role of disease-associated risk variants. Modern proximity-ligation assays, like HiChIP and ChIA-PET, facilitate the accurate identification of long-range contacts between enhancers and promoters. However, these assays are technically challenging, expensive, and time-consuming, making it difficult to investigate enhancer topologies, especially in uncharacterized cell types. To overcome these shortcomings, we therefore designed LoopPredictor, an ensemble machine learning model, to predict genome topology for cell types which lack long-range contact maps. To enrich for functional enhancer-promoter loops over common structural genomic contacts, we trained LoopPredictor with both H3K27ac and YY1 HiChIP data. What’s more, the integration of several related multi-omics features facilitated identifying and annotating the predicted loops. LoopPredictor is able to efficiently identify cell type-specific enhancer mediated loops, and promoter-promoter interactions, with a modest feature input requirement. Comparable to experimentally generated H3K27ac HiChIP data, we found that LoopPredictor was able to identify functional enhancer loops. Furthermore, to explore the cross-species prediction capability of LoopPredictor, we fed mouse multi-omics features into a model trained on human data and found that the predicted enhancer loops outputs were highly conserved. LoopPredictor enables the dissection of cell type-specific long-range gene regulation, and can accelerate the identification of distal disease-associated risk variants.
Independent apical and basal mechanical systems determine cell and tissue shape in theDrosophilawing disc
Authors: Badugu Amarendra , Käch Andres 
Published: April 2020

AbstractHow cell shape and mechanics are organized in three dimensions during tissue morphogenesis is poorly understood. In theDrosophilawing imaginal disc, we examined the mechanical processes that determine the shape of epithelial cells. Since it has been known that basement membrane influences the mechanics intracellularly, we reexamined the material properties of the basement membrane with fluorescence and transmission electron microscopy in its native environment. Further, we investigated the effect on cell shape and tissue mechanics when disruptions were instigated at three different time scales: (1) short (seconds with laser cutting), (2) medium (minutes with drug treatments), and (3) long (days with RNAi interference). We found regions in which the basement membrane is much thicker and heterogeneous than previously reported. Disrupting the actin cytoskeleton through drug treatment affects cell shape only at the apical surface, while the shapes in the medial and basal surfaces were not altered. In contrast, when integrin function was inhibited via RNAi or basement membrane integrity was disrupted by drug treatment, the medial and basal cell shapes were affected. We propose that basement membrane thickness patterns determine the height and basal surface area of cells and the curvature of folds in the wing disc. Based on these findings and previous studies, we propose a model of how cell shapes and tissue properties were determined by highly local, modular apical and basal mechanics.Graphical abstract
Vascular burden is associated with a decline in default-mode and global resting-state functional connectivity in individuals at risk for Alzheimer’s disease
Authors: Köbe Theresa , Binette Alexa Pichet , Vogel Jacob W. , Meyer Pierre-François , Breitner John C. S. , Poirier Judes , Villeneuve Sylvia ,   for the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) Research Group
Published: April 2020

AbstractIntroductionCross-sectional studies suggest that cardiovascular risk factors and Alzheimer’s disease (AD) biomarkers are associated with abnormal brain resting-state functional connectivity in aging and AD; however, evidence is missing regarding longitudinal changes in functional connectivity. In this study, we investigate whether cholesterol levels and blood pressure are associated with changes in functional connectivity over time in asymptomatic individuals at risk for AD. The analyses were repeated with cerebral β-amyloid (Aβ) andtaudeposition in a subset of the participants.MethodsThe study sample included 247 cognitively unimpaired individuals (185 women/ 62 men; mean [SD] age of 63 [5.3] years) of the PREVENT-AD cohort with a parental or multiple-sibling history of sporadic AD. Plasma total-, HDL-, and LDL-cholesterol and systolic and diastolic blood pressure were measured at baseline. Global brain functional connectivity, and connectivity from canonical functional networks, were computed from resting-state functional MRI obtained at baseline and up to four years of annual follow-ups, using a predefined functional parcellation. A subset of participants underwenttau-PET ([18F]Flortaucipir) and Aβ-PET ([18F]NAV4694). Vascular and AD measures were examined as predictors of brain functional connectivity changes in linear mixed-effects models.ResultsHigher total-cholesterol and LDL-cholesterol levels were associated with greater reduction of functional connectivity in the default-mode network over time. In addition, while overall whole-brain functional connectivity showed an increase over time across the entire sample higher diastolic blood pressure was associated with reduction in whole-brain functional connectivity. The associations were similar when the analyses were repeated using two other functional brain parcellations. The findings with total-cholesterol and diastolic blood pressure were also similar but attenuated when performed in a subsample of participants with PET (n=91), whereas AD biomarkers were not associated with changes in functional connectivity over time in this subsample.ConclusionThese findings provide evidence that vascular burden is associated with a decrease in brain functional connectivity over time in older adults with elevated risk for AD. The impact of vascular risk factors on functional brain changes might precede AD pathology-related changes.
Visualizing Rev1 Catalyze Protein-template DNA Synthesis
Authors: Weaver Tyler M. , Cortez Luis M. , Khoang Thu H. , Washington M. Todd , Agarwal Pratul , Freudenthal Bret D. 
Published: April 2020

AbstractDuring DNA replication, replicative DNA polymerases may encounter DNA lesions, which can stall replication forks. One way to prevent replication fork stalling is through the recruitment of specialized translesion synthesis (TLS) polymerases that have evolved to incorporate nucleotides opposite DNA lesions. Rev1 is a specialized TLS polymerase that bypasses abasic sites as well as minor-groove and exocyclic guanine adducts. It does this by using a unique protein-template mechanism in which the template base is flipped out of the DNA helix and the incoming dCTP hydrogen bonds with an arginine side chain. To observe Rev1 catalysis at the atomic level, we employed time-lapse X-ray crystallography. We found that Rev1 flips out the template base prior to binding the incoming nucleotide. Binding the incoming nucleotide changes the conformation of the DNA substrate to orient it for nucleotidyl transfer, and this is not coupled to large structural changes in the protein like those observed with other DNA polymerases. Moreover, we found that following nucleotide incorporation, Rev1 converts the pyrophosphate product to two mono-phosphates, which drives the reaction in the forward direction. Following nucleotide incorporation, the hydrogen bonds between the incorporated nucleotide and the arginine side chain are broken, but the templating base remains extrahelical. These post-catalytic changes prevent potentially mutagenic processive synthesis by Rev1 and facilitate dissociation of the DNA product from the enzyme.
Accurate inference in parametric models reshapes neuroscientific interpretation and improves data-driven discovery
Authors: Sachdeva Pratik S. , Livezey Jesse A. , Dougherty Maximilian E. , Gu Bon-Mi , Berke Joshua D. , Bouchard Kristofer E. 
Published: April 2020

AbstractA central goal of systems neuroscience is to understand the relationships amongst constituent units in neural populations and their modulation by external factors using high-dimensional and stochastic neural recordings. Statistical models, particularly parametric models, play an instrumental role in accomplishing this goal, because their fitted parameters can provide insight into the underlying biological processes that generated the data. However, extracting conclusions from a parametric model requires that it is fit using an inference procedure capable of selecting the correct parameters and properly estimating their values. Traditional approaches to parameter inference have been shown to suffer from failures in both selection and estimation. Recent development of algorithms that ameliorate these deficiencies raises the question of whether past work relying on such inference procedures have produced inaccurate systems neuroscience models, thereby impairing their interpretation. Here, we used the Union of Intersections, a statistical inference framework capable of state-of-the-art selection and estimation performance, to fit functional coupling, encoding, and decoding models across a battery of neural datasets. We found that, compared to baseline procedures, UoI inferred models with increased sparsity, improved stability, and qualitatively different parameter distributions, while maintaining predictive performance across recording modality, brain region, and task. Specifically, we obtained highly sparse functional coupling networks with substantially different community structure, more parsimonious encoding models, and decoding models that rely on fewer single-units. Together, these results demonstrate that accurate parameter inference reshapes interpretation in diverse neuroscience contexts. The ubiquity of model-based data-driven discovery in biology suggests that analogous results would be seen in other fields.
Ecological and social drivers of neighbor recognition and the dear enemy effect in a poison frog
Authors: Tumulty James P. , Bee Mark A. 
Published: April 2020

ABSTRACTNavigating social relationships frequently rests on the ability to recognize familiar individuals using phenotypic characteristics. Across diverse taxa, animals vary in their capacities for social recognition but the ecological and social sources of selection for recognition are often unclear. In a comparative study of two closely related species of poison frogs, we identified a species difference in social recognition of territory neighbors and investigated potential sources of selection underlying this difference. In response to acoustic playbacks, male golden rocket frogs (Anomaloglossus beebei) recognized the calls of neighbors and displayed a “dear enemy effect” by responding less aggressively to neighbors’ calls than strangers’ calls. In contrast, male Kai rocket frogs (Anomaloglossus kaiei) were equally aggressive to the calls of neighbors and strangers. This species difference in behavior was associated with key differences in reproductive ecology and characteristics of territories. Golden rocket frogs defended reproductive resources in the form of bromeliads, which is expected to create a threat asymmetry between neighbors and strangers favoring decreased aggression to neighbors. In contrast, Kai rocket frogs did not defend reproductive resources. Further, compared with Kai rocket frog territories, golden rocket frog territories occurred at higher densities and were defended for longer periods of time, creating a more complex social environment with more opportunities for repeated but unnecessary aggression between neighbors, which should favor the ability to recognize and exhibit less aggression towards neighbors. These results suggest that differences in reproductive ecology can drive changes in social structure that select for social recognition.
Structural dynamics of non-synonymous SNPs of histone methyltransferase EZH2 involved in Weaver Syndrome
Authors: Chandra Babu Tirumalasetty Muni , Keshri Vivek , Yu Cuicui , Qin Danian , Huang Chengyang 
Published: April 2020

AbstractEnhancer of zeste homolog 2 (EZH2) is a histone H3 lysine 27 methyltransferases. Non-synonymous SNPs (nsSNPs) in the ezh2 gene may cause Weaver Syndrome that is a prominent and rare congenital disorder. Several EZH2 genetic variants have been characterized and reported, but there is no information available on their structural dynamics. Our study employs an in silico approach for structural and functional characterization of EZH2 nsSNPs. We identified 19 EZH2 nsSNPs majorly associated with Weaver Syndrome, among which four SET-domain nsSNPs including V621M, A677T, R679C, and H689Y significantly affected EZH2 structure. We conducted the triplicate of 100 ns of molecular dynamics simulations (MDS) to compare the dynamic interaction behaviors between wild-type and mutants of EZH2 with their substrate, H3K27me0 peptide. The simulation results revealed that the mutants had higher levels of structural variations as evidenced by secondary structure, density, distance plots, and principal component analysis. Compared to EZH2-WT, the mutants A677T and H689Y have shown lower binding energy with H3K27me0 peptide due to the denaturing of 310 helixes as exemplified by MM/PBSA calculations and secondary structure analysis. Our analysis shed light on mechanisms of structural variations of EZH2 nsSNPs and lay a stone to develop mutant-based therapeutic strategies for the design of target-specific scaffolds against Weaver Syndrome.
Distributional Range, Population Variability and Ecology ofStriga aspera inKogi State, Nigeria
Authors: Izaka Aigbokhan Emmanuel , Enemadukwu Ohiaba Emmanuel 
Published: April 2020

ABSTRACTHemiparasiticStriga(Orobanchaceae) commonly called witchweed is native to tropical Africa.Striga asperaparasitizes wild grasses and its distribution range in Nigeria extends from the Sudan savanna to Guinea Savanna to the southern limit of the Derived savanna just before the forest belt is reached. This study aims to identify and delineate the incidence and distribution range and infestation patterns ofStriga asperawithin the different floristic areas within in Kogi State (Southern Guinea Savanna) and to establish if vegetation type and edaphic have potential influences onStrigapresence. To determine the distribution range and potential hosts ofStriga aspera, several opportunistic road reconnaissance surveys were conducted traversing six major towns in Kogi State (Kabba, Okene, Lokoja, Idah, Ayingba and Igala-mela) from July to September, 2015. IdentifiedStrigainfested sites were georeferenced and subjected to further vegetation analysis obtained from randomly placed 0.5 m x 0.5 m quadrats in triplicates and compared with adjoining uninfected control sites. Data for the following attributes were collected: density, relative frequency, relative density and summed dominance ratio. To isolate and determine potential Striga host, an inventory of common companion plants at infested sites were taken and screened for presence of haustorium. Edaphic soils properties were determined using standard laboratory protocols. Degree of phenotypic variability within and among the differentStrigapopulations were determine using 14 morphological characters obtained from 10 randomly selected witchweed plants at each infested sites and evaluated using Principal Component Analysis and hierarchical cluster analysis. Nine sites: Idaku, Alokoina (1 and 2), Ala, Adogo (1 and 2), Ichekene, Indori and Old-Egume Road) were found to be Striga infested and all were confined to the low open woodland Southern Guinea savanna (SGS) vegetation dominated byDaniellia/Prosopiscomplex. The commonS. asperahost was found to beDigitaria sp.Other companion species common at infested sites were:Sida acuta, Centrosema pubesence, Mariscus flabelliformis, Chloris pilosa, Pennisetum pedicellatumandSynderella nodiflora.Soil chemical profile reveals thatS. asperainfestation as commonly occurs in areas acidic soils of pH ranging from 5.3 to 5.7. The Cluster analysis clearly show the similarity amongS. asperaidentified while the PCA clearly segregated the different locations whereS. asperawas found. Findings in this study suggest that not all areas in the Derived savanna in Kogi State despite similar climatic and edaphic conditions supportStrigainfestation which showed a clustered distribution pattern. This strongly support the hypothesis that vegetation types operating at the microenvironment level may exert influences in witchweed infestation patterns.
Structural analysis of the PTEN:P-Rex2 signalling node reveals how cancer-associated mutations coordinate to hyperactivate Rac1
Authors: D’Andrea Laura , Lucato Christina M. , Marquez Elsa A. , Chang Yong-Gang , Civciristov Srgjan , Huang Cheng , Elmlund Hans , Schittenhelm Ralf B. , Mitchell Christina A. , Whisstock James C. , Halls Michelle L. , Ellisdon Andrew M. 
Published: April 2020

ABSTRACTThe PTEN:P-Rex2 complex is one of the most commonly mutated signaling nodes in metastatic cancer. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cell proliferation. Here, using extensive crosslinking mass spectrometry and functional studies, we provide crucial mechanistic insights into PTEN:P-Rex2 complex assembly and co-inhibition. PTEN is anchored to P-Rex2 by interactions between the PTEN PDZ-BM tail and the second PDZ domain of P-Rex2. This interaction bridges PTEN across the P-Rex2 surface, occluding PTEN membrane-binding and PI(3,4,5)P3hydrolysis. Conversely, PTEN both allosterically promotes an autoinhibited P-Rex2 conformation and occludes Gβγ binding and GPCR activation. These insights allow us to define a new gain-of-function class of cancer mutations within the PTEN:P-Rex2 interface that uncouples PTEN inhibition of Rac1 signaling. These findings provide a mechanistic framework to understand the dysregulation of the PTEN:P-Rex2 signaling node in metastatic cancer.
PBAP chromatin remodeler mediates enhancer-driven transcription inDrosophila
Authors: Shidlovskii Y.V. , Shaposhnikov A.V. , Bylino O.V. , Amendola D. , De Simone G. , Afeltra N. , Schedl P. , Digilio F.A. , Giordano E. 
Published: April 2020

AbstractChromatin remodeler SWI/SNF is an important participant of gene activation acting predominantly by opening chromatin structure on promoters and enhancers. Here we describe its novel mode of action by mediating targeted action of enhancer. We studied functions of two signature subunits of PBAP subfamily, BAP170 and SAYP, inDrosophila. These subunits were stably tethered onto transgene reporter carryinghsp70core promoter. Tethered subunits mediate transcription of reporter in a pattern prescribed by nearby enhancer in multiple loci throughout the genome, where the reporter construct was located. Both tethered SAYP and BAP170 recruit the whole PBAP complex onto reporter promoter. Studying difference between these subunits, we found that BAP170-dependent transcription is more resistant to depletion of other PBAP subunits, what may imply the principal role of BAP170 in establishing enhancer-dependent transcription.Author SummaryChromatin remodelers are key molecular machines that are responsible for local changes in chromatin structure in the nucleus. However, their functions in gene expression regulation seem to be broader. We describe the involvement of the SWI/SNF family of remodelers in establishing enhancer-promoter communication, which is apparently independent of its local remodeling activity.Using an artificial tethering of a remodeler on a promoter, we demonstrated that promoters of a certain type become responsive to activation by a nearby enhancer only in the presence of the remodeler, while a remodeler tethering itself is insufficient for gene activation. Thus, our approach helps to uncover novel aspects of molecular interplay on regulatory elements during the gene activation process.