bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational Modeling of the Gut Microbiota Predicts Metabolic Mechanisms of RecurrentClostridioides difficileInfection
Authors: Henson Michael A.
Published: April 2020

Approximately 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.

Importance

Clostridioides 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

Transcriptional 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

How 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

Introduction

Cross-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.

Methods

The 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.

Results

Higher 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.

Conclusion

These 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

During 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

A 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

Navigating 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

Enhancer 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

HemiparasiticStriga(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

The 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

Chromatin 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 Summary

Chromatin 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.
Turning old foes into new allies – harnessing drainage canals for biodiversity conservation in desiccated novel ecosystems
Authors: Tölgyesi Csaba , Torma Attila , Bátori Zoltán , Šeat Jelena , Popović Miloš , Gallé Róbert , Gallé-Szpisjak Nikolett , Erdős László , Vinkó Tamás , Kelemen András , Török Péter
Published: April 2020

Drainage canals are ubiquitous components of agricultural landscapes worldwide. Although canals have greatly contributed to biodiversity loss by desiccating wetlands, they have recently attracted conservation attention due to their potential to function as refugia for native wetland-dependent species in intensively managed landscapes. However, their conservation role in complex landscapes comprising a mosaic of agricultural and desiccated semi-natural habitats, on which canals still pose a heavy burden, is unknown. Improved understanding of drainage canals and related biodiversity in these landscapes could help unlock their potential and support synergistic land management for nature conservation and water management.

We applied a multitaxon approach, including plants, butterflies, true bugs, spiders and birds, to (1) assess the conservation value of drainage canals in a heavily drained European lowland region, (2) to test landscape-level and local canal parameters for aiding prioritization among canal types, and (3) to propose a reconciliation-based management framework that suits the interest of all stakeholders.

We found that drainage canals concentrate more species across most taxa than adjacent semi-natural habitats, owing to the micro-environmental heterogeneity and the comparatively low management intensity in the canals. The species-concentrating capacity is particularly high in canals that traverse semi-natural habitats, although agricultural canals also support remarkable species diversity. However, agricultural canals are important dispersal corridors for invasive plants, which may negatively affect native species. Canal size has little effect on biodiversity but habitat stress is an important determinant. The higher the stress (due to sandiness and salinity), the higher is the added value of canals to landscape-wide biodiversity.

Synthesis and applications

We provide evidence that drainage canals can harbour surprisingly high levels of biodiversity and should therefore be recognized as important novel ecosystems with high conservation value, even within semi-natural habitats. Canals have previously been considered detrimental to nature conservation due to their association with loss of wetlands. However, by reducing water loss with reversible obstructions, controlling invasive species and applying specific conservation measures, they may be turned into conservation allies without compromising long-term interests of water management and agricultural land use.
Disentangling the Independent Contributions of Visual and Conceptual Features to the Spatiotemporal Dynamics of Scene Categorization
Authors: Greene Michelle R. , Hansen Bruce C.
Published: April 2020

Human scene categorization is characterized by its remarkable speed. While many visual and conceptual features have been linked to this ability, significant correlations exist between feature spaces, impeding our ability to determine their relative contributions to scene categorization. Here, we employed a whitening transformation to decorrelate a variety of visual and conceptual features and assess the time course of their unique contributions to scene categorization. Participants (both sexes) viewed 2,250 full-color scene images drawn from 30 different scene categories while having their brain activity measured through 256-channel EEG. We examined the variance explained at each electrode and time point of visual event-related potential (vERP) data from nine different whitened encoding models. These ranged from low-level features obtained from filter outputs to high-level conceptual features requiring human annotation. The amount of category information in the vERPs was assessed through multivariate decoding methods. Behavioral similarity measures were obtained in separate crowdsourced experiments. We found that all nine models together contributed 78% of the variance of human scene similarity assessments and was within the noise ceiling of the vERP data. Low-level models explained earlier vERP variability (88 ms post-image onset), while high-level models explained later variance (169 ms). Critically, only high-level models shared vERP variability with behavior. Taken together, these results suggest that scene categorization is primarily a high-level process, but reliant on previously extracted low-level features.

Significance Statement

In a single fixation, we glean enough information to describe a general scene category. Many types of features are associated with scene categories, ranging from low-level properties such as colors and contours, to high-level properties such as objects and attributes. Because these properties are correlated, it is difficult to understand each property’s unique contributions to scene categorization. This work uses a whitening transformation to remove the correlations between features and examines the extent to which each feature contributes to visual event-related potentials (vERPs) over time. We found that low-level visual features contributed first, but were not correlated with categorization behavior. High-level features followed 80 ms later, providing key insights into how the brain makes sense of a complex visual world.
Parallel visual pathways with topographic versus non-topographic organization connect theDrosophilaeyes to the central brain
Authors: Timaeus Lorin , Geid Laura , Sancer Gizem , Wernet Mathias F. , Hummel Thomas
Published: April 2020

One hallmark of the visual system is the strict retinotopic organization from the periphery towards the central brain, spanning multiple layers of synaptic integration. RecentDrosophilastudies on the computation of distinct visual features have shown that retinotopic representation is often lost beyond the optic lobes, due to convergence of columnar neuron types onto optic glomeruli. Nevertheless, functional imaging revealed a spatially accurate representation of visual cues in the central complex (CX), raising the question how this is implemented on a circuit level. By characterizing the afferents to a specific visual glomerulus, the anterior optic tubercle (AOTU), we discovered a spatial segregation of topographic versus non-topographic projections from molecularly distinct classes of medulla projection neurons (medullo-tubercular, or MeTu neurons). Distinct classes of topographic versus non-topographic MeTus form parallel channels, terminating in separate AOTU domains. Both types then synapse onto separate matching topographic fields of tubercular-bulbar (TuBu) neurons which relay visual information towards the dendritic fields of central complex ring neurons in the bulb neuropil, where distinct bulb sectors correspond to a distinct ring domain in the ellipsoid body. Hence, peripheral topography is maintained due to stereotypic circuitry within each TuBu class, providing the structural basis for spatial representation of visual information in the central complex. Together with previous data showing rough topography of lobula projections to a different AOTU subunit, our results further highlight the AOTUs role as a prominent relay station for spatial information from the retina to the central brain.
Role of Differential Expression of miRNAs miR-125a, miR-200a and miR-199a in Metastatic Property of Ovarian Cancer Cell lines and Relationship between miR-199a and its Predicted Target Protein GSK3β
Authors: Rana Divya RSJB , Xu Lin , Zhang Jie
Published: April 2020

Ovarian cancer is a gynecological cancer of high mortality rate. Most of the ovarian cancer origin from the surface epithelium of the ovaries. Ovarian cancers gain metastatic and invasive properties from various biochemical events taking place during tumorogenesis. MicroRNAs (miRNA) are non-coding RNAs and they have an important function of inhibiting translation of specific mRNAs in the cytoplasm. Present study uses two ovarian cancer cell lines as model to study the differential expression of miR-125a, miR-200a, and miR-199a, and provides indirect proof for possible relationship between miR-199a and its predicted target gene Glycogen Synthase Kinase 3 β (GSK3β). As expected the expression of these three microRNAs are decreased in metastatic ovarian cancer cell line A2780 compared to epithelial ovarian cancer OVCAR3. Reciprocal expression pattern of miR-199a and its predicted target GSK3β was found in two different cell lines providing information on possible inhibitory role of miR-199a against GSK3β.
Potentials of Aqueous Extract ofBambusa vulgaristo Reactivate β-Cells of Pancreas in Alloxan-Induced Diabetic Wistar Rats
Authors: Akiibinu MO. , Folawuyo OS. , Oyekan IO. , Ibikunle I. , Kolawole OT. , Adesiyan A. , Anetor J. , Akiibinu SO. , Tayo F.
Published: April 2020

Ability of the damaged pancreas to generate new β-cells when activated with external stimuli has been documented. This study assessed the potentials of aqueous extract ofbambusa vulgarisleaf to reactivate damaged β-cells in insulin dependent diabetes mellitus (IDDM). Eighteen healthy male Wistar rats (12 weeks old; weight= between 150 and 200g) were used for this study. The rats were randomly divided into three groups (six per group); group A (un-induced); group B (untreated alloxan-induced diabetics); group C (alloxan-induced diabetics treated with 200mg/kg body weight of freshly prepared extract ofbambusa vulgarisleaf). Fasting blood sugar (FBS) and plasma insulin levels were determined in all animals using glucometer and enzyme linked immunosorbent assay methods respectively. Sections of pancreas tissues were prepared for histology. IDDM was confirmed in groups B and C (FBS increased significantly=p<0.05) after 2 days of alloxan administration). The FBS remained significantly (p>0.05) higher in group B, compared to group A, but reduced significantly (p<0.05) in group C after 7 days of treatment withbambusa vulgarisleaf extract. On the 7th day, plasma insulin level decreased significantly (p<0.05) in group B, but no significant difference observed in group C compared with group A. Histology reports showed damaged pancreas in group B, while Group C showed normal islet cells after 7 days of oral administration ofbambusa vulgarisextract. In conclusion, aqueous extract ofBambusa vulgariscould restore the activities of alloxan-damaged pancreas. The extract could be a reliable alternative to synthetic pharmaceuticals in the treatment IDDM.
An analytical framework for interpretable and generalizable ‘quasilinear’ single-cell data analysis
Authors: Zhou Jian , Troyanskaya Olga G.
Published: April 2020

Scaling single-cell data exploratory analysis with the rapidly growing diversity and quantity of single-cell omics datasets demands more interpretable and robust data representation that is generalizable across datasets. To address this challenge, here we developed a novel ‘quasilinear’ framework that combines the interpretability and transferability of linear methods with the representational power of nonlinear methods. Within this framework, we introduce a data representation and visualization method, GraphDR, and a structure discovery method, StructDR, that unifies cluster, trajectory, and surface estimation and allows their confidence set inference. We applied both methods to diverse single-cell RNA-seq datasets from whole embryos and tissues. Unlike PCA and t-SNE, GraphDR and StructDR generated representations that both distinguished highly specific cell types and were comparable across datasets. In addition, GraphDR is at least an order of magnitude faster than commonly used nonlinear methods. Our visualizations of scRNA-seq data from developing zebrafish and Xenopus embryos revealed extruding branches of lineages from a continuum of cell states, suggesting that the current branch view of cell specification may be oversimplified. Moreover, StructDR identified a novel neuronal population using scRNA-seq data from mouse hippocampus. An open-source python library and a user-friendly graphical interface for 3D data visualization and analysis with these methods are available athttps://github.com/jzthree/quasildr.
Differential localization patterns of pyruvate kinase isoforms in murine naïve, formative and primed pluripotent states
Authors: Dierolf Joshua G. , Watson Andrew J. , Betts Dean H.
Published: April 2020

Mouse embryonic stem cells (mESCs) and mouse epiblast stem cells (mEpiSCs) represent opposite ends of a pluripotency continuum, referred to as naïve and primed pluripotent states, respectively. These divergent pluripotent states differ in several ways including growth factor requirements, transcription factor expression, DNA methylation patterns, and metabolic profiles. Naïve cells employ both glycolysis and oxidative phosphorylation (OXPHOS), whereas primed cells preferentially utilize aerobic glycolysis, a trait shared with cancer cells referred to as the Warburg effect. Until recently, metabolism has been regarded as a by-product of cell fate; however, evidence now supports metabolism as being a driver of stem cell state and fate decisions. Pyruvate kinase muscle isoforms (PKM1 and PKM2) are important for generating and maintaining pluripotent stem cells (PSCs) and mediating the Warburg effect. Both isoforms catalyze the last step of glycolysis generating adenosine triphosphate and pyruvate, however, the precise role(s) of PKM1/2 in naïve and primed pluripotency is not well understood. The primary objective was to characterize the cellular expression and localization patterns of PKM1 and PKM2 in mESCs, chemically transitioned epiblast-like cells (mEpiLCs) representing formative pluripotency, and mEpiSCs using immunoblotting, flow cytometry and confocal microscopy. The results indicate that PKM1 and PKM2 are not only localized to the cytoplasm but also accumulate in differential subnuclear regions of mESC, mEpiLCs and mEpiSCs as determined by a quantitative, confocal microscopy colocalization employing orthogonal projections and airyscan processing. Importantly, we discovered that the subnuclear localization of PKM1/2 shifts during the transition from mESCs, mEpiLCs and mEpiSCs. We have also authenticated a new method of selecting formative pluripotency cells from naïve and primed populations using the cell surface markers SSEA1 and CD24. Finally, we have comprehensively validated the appropriateness and power of the Pearson’s correlation coefficient and Manders’ overlap coefficient for assessing nuclear and cytoplasmic protein colocalization in PSCs by immunofluorescence confocal microscopy. We propose that nuclear PKM1/2 assists with distinct pluripotency state maintenance and lineage priming by non-canonical mechanisms. These results advance our understanding of the overall mechanisms controlling naïve, formative and primed pluripotency.
Microvascular Injury in Mild Traumatic Brain Injury Accelerates Alzheimer-like Pathogenesis in Mice
Authors: Wu Yingxi , Zeng Jianxiong , Pluimer Brock , Dong Shirley , Xie Xiaochun , Guo Xinying , Liang Xinyan , Feng Sudi , Wu Haijian , Yan Youzhen , Chen Jian-Fu , Maria Naomi Sta , Ma Qingyi , Gomez-Pinilla Fernando , Zhao Zhen
Published: April 2020

Introduction

Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer’s disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored.

Methods

We established a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, and examined the time courses of microvascular injury, blood-brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also determined the brain clearance of β-amyloid, as well as amyloid pathology and cognitive functions after mTBI in the 5xFAD mouse model of AD.

Results

mTBI induced microvascular injury with BBB breakdown, pericyte loss and cerebral blood flow reduction in mice, which preceded gliosis. mTBI also impaired brain amyloid clearance via the vascular pathways. More importantly, mTBI accelerated amyloid pathology and cognitive impairment in the 5xFAD mice.

Discussion

Our data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD.
Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity that may underly population disparities in this disease
Authors: Wang Yong-Fei , Zhang Yan , Lin Zhiming , Zhang Huoru , Wang Ting-You , Cao Yujie , Morris David L. , Sheng Yujun , Yin Xianyong , Zhong Shi-Long , Gu Xiaoqiong , Lei Yao , He Jing , Wu Qi , Shen Jiangshan Jane , Yang Jing , Lam Tai-Hing , Lin Jia-Huang , Mai Zhi-Ming , Guo Mengbiao , Tang Yuanjia , Chen Yanhui , Song Qin , Ban Bo , Chiu Mok Chi , Cui Yong , Lu Liangjing , Shen Nan , Sham Pak C. , Lau Chak Sing , Smith David K. , Vyse Timothy J. , Zhang Xuejun , Lau Yu Lung , Yang Wanling
Published: April 2020

Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underly the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertook a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture were identified. Nine disease loci showed clear ancestral group heterogeneity and implicated antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores performed significantly better when trained on matched ancestral data sets. These analyses help to reveal the genetic bases for disparities in SLE among ancestral groups.
DNA Sequence Preference forDe NovoCentromere Formation on aCaenorhabditis elegansArtificial Chromosome
Authors: Lin Zhongyang , Yuen Karen Wing Yee
Published: April 2020

Centromeric DNA sequences vary in different species, but share common characteristics, like high AT-content, repetitiveness, and low, but not no, transcriptional activity. Yet, neocentromeres can be found on non-centromeric, ectopic sequences, suggesting that centromeres can be established and maintained epigenetically. In contrast, canonical centromeric DNA sequences are more competent inde novocentromere formation on artificial chromosomes (ACs). To determine if specific DNA sequence features are preferred for new centromere formation, we injected different DNA sequences into the gonad of a holocentric model organism,Caenorhabditis elegans, to form ACs in embryos, and monitored mitotic AC segregation. We demonstrated that AT-rich sequences, but not repetitive sequences, acceleratedde novocentromere formation on ACs. We also injected fragmentedSaccharomyces cerevisiaegenomic DNA to construct a less repetitive, more complex AC that can propagate through generations. By whole-genome sequencing andde novoassembly of AC sequences, we deduced that this AC was formed through non-homologous end joining. By CENP-AHCP-3chromatin immunoprecipitation followed by sequencing (ChIP-seq), we found that CENP-AHCP-3domain width on both the AC and endogenous chromosomes is positively correlated with AT-content. Besides, CENP-AHCP-3binds to unexpressed gene loci or non-genic regions on the AC, consistent with the organization of endogenous holocentromeres.
Single-cell copy number lineage tracing enabling gene discovery
Authors: Wang Fang , Wang Qihan , Mohanty Vakul , Liang Shaoheng , Dou Jinzhuang , Han Jincheng , Minussi Darlan Conterno , Gao Ruli , Ding Li , Navin Nicholas , Chen Ken
Published: April 2020

Aneuploidy plays critical roles in genome evolution.

Alleles, whose dosages affect the fitness of an ancestor, will have altered frequencies in the descendant populations upon perturbation.

Single-cell sequencing enables comprehensive genome-wide copy number profiling of thousands of cells at various evolutionary stage and lineage. That makes it possible to discover dosage effects invisible at tissue level, provided that the cell lineages can be accurately reconstructed.

Here, we present a Minimal Event Distance Aneuploidy Lineage Tree (MEDALT) algorithm that infers the evolution history of a cell population based on single-cell copy number (SCCN) profiles. We also present a statistical routine named lineage speciation analysis (LSA), which facilitates discovery of fitness-associated alterations and genes from SCCN lineage trees.

We assessed our approaches using a variety of single-cell datasets. Overall, MEDALT appeared more accurate than phylogenetics approaches in reconstructing copy number lineage. From the single-cell DNA-sequencing data of 20 triple-negative breast cancer patients, our approaches effectively prioritized genes that are essential for breast cancer cell fitness and are predictive of patient survival, including those implicating convergent evolution. Similar benefits were observed when applying our approaches on single-cell RNA sequencing data obtained from cancer patients.

The source code of our study is available athttps://github.com/KChen-lab/MEDALT.
Resistance, resilience, and functional redundancy of freshwater bacterioplankton communities facing a gradient of agricultural stressors in a mesocosm experiment
Authors: Barbosa da Costa Naíla , Fugère Vincent , Hébert Marie-Pier , Xu Charles C.Y. , Barrett Rowan D.H. , Beisner Beatrix E. , Bell Graham , Yargeau Viviane , Fussmann Gregor F. , Gonzalez Andrew , Shapiro B. Jesse
Published: April 2020

Agricultural pollution with fertilizers and pesticides is a common disturbance to freshwater biodiversity. Bacterioplankton communities are at the base of aquatic food webs, but their responses to these potentially interacting stressors are rarely explored. To test the extent of resistance and resilience in bacterioplankton communities faced with agricultural stressors, we exposed freshwater mesocosms to single and combined gradients of two commonly used pesticides: the herbicide glyphosate (0-15 mg/L) and the neonicotinoid insecticide imidacloprid (0-60 μg/L), in high or low nutrient backgrounds. Over the 43-day experiment, we tracked variation in bacterial density with flow cytometry, carbon substrate use with Biolog EcoPlates, and taxonomic diversity and composition with environmental 16S rRNA gene amplicon sequencing. We show that only glyphosate (at the highest dose, 15 mg/L), but not imidacloprid, nutrients, or their interactions measurably changed community structure, favoring members of the Proteobacteria including the genus Agrobacterium. However, no change in carbon substrate use was detected throughout, suggesting functional redundancy despite taxonomic changes. We further show that communities are resilient at broad, but not fine taxonomic levels: 24 days after glyphosate application the precise amplicon sequence variants do not return, and tend to be replaced by phylogenetically close taxa. We conclude that high doses of glyphosate – but still within commonly acceptable regulatory guidelines – alter freshwater bacterioplankton by favoring a subset of higher taxonomic units (i.e. genus to phylum) that transiently thrive in the presence of glyphosate. Longer-term impacts of glyphosate at finer taxonomic resolution merit further investigation.