bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glutamate and Dysconnection in the Salience Network: Neurochemical, Effective-connectivity, and Computational Evidence in Schizophrenia
Authors: Limongi Roberto , Jeon Peter , Mackinley Michael , Das Tushar , Dempster Kara , Théberge Jean , Bartha Robert , Wong Dickson , Palaniyappan Lena 
Published: November 2019

AbstractIn the dysconnection hypothesis, psychosis is caused by NMDA hypofunction resulting in aberrant network connectivity. Combining a cognitive-control task, functional magnetic resonance spectroscopy, and functional magnetic resonance imaging, we tested this hypothesis in the salience network of 20 first-episode psychosis (FEP) and 20 healthy control (HC) subjects. Across groups, glutamate concentration in the dorsal anterior cingulate cortex (dACC) was associated with higher and lower inhibitory connectivity in the dACC and in the anterior insula (AI) respectively. Crucially, glutamate concentration correlated negatively with the inhibitory influence on the excitatory neuronal population in the dACC of FEP subjects. Furthermore, aberrant computational parameters of the cognitive-control task performance were associated with aberrant inhibitory connections. Finally, the strength of connections from the dACC to the AI correlated negatively with severity of social withdrawal. These findings support a link between glutamate-mediated cortical disinhibition, deficits in effective connectivity, and computational performance in psychosis.
Local Glutamate-Mediated Dendritic Plateau Potentials Change the State of the Cortical Pyramidal Neuron
Authors: Gao Peng P. , Graham Joseph. W. , Zhou Wen-Liang , Jang Jinyoung , Angulo Sergio , Dura-Bernal Salvador , Hines Michael , Lytton William W. , Antic Srdjan D. 
Published: November 2019

AbstractDendritic spikes in thin dendritic branches (basal and oblique dendrites) of pyramidal neurons are traditionally inferred from spikelets measured in the cell body. Here, we used laser-spot voltage-sensitive dye imaging in cortical pyramidal neurons (rat brain slices) to investigate the voltage waveforms of dendritic potentials occurring in response to spatially-restricted glutamatergic inputs. Local dendritic potentials lasted 200–500 ms and propagated to the cell body where they caused sustained 10-20 mV depolarizations. Plateau potentials propagating from dendrite to soma, and action potentials propagating from soma to dendrite, created complex voltage waveforms in the middle of the thin basal dendrite, comprised of local sodium spikelets, local plateau potentials, and back-propagating action potentials, superimposed on each other. Our model replicated these experimental observations and made predictions, which were tested in experiments. Dendritic plateau potentials occurring in basal and oblique branches put pyramidal neurons into an activated neuronal state (“prepared state”), characterized by depolarized membrane potential and faster membrane responses. The prepared state provides a time window of 200-500 ms during which cortical neurons are particularly excitable and capable of following afferent inputs. At the network level, this predicts that sets of cells with simultaneous plateaus would provide cellular substrate for the formation of functional neuronal ensembles.New & NoteworthyIn cortical pyramidal neurons, we recorded glutamate-mediated dendritic plateau potentials using voltage imaging, and created a computer model that recreated experimental measures from dendrite and cell body. Our model made new predictions, which were then tested in experiments. Plateau potentials profoundly change neuronal state -- a plateau potential triggered in one basal dendrite depolarizes the soma and shortens membrane time constant, making the cell more susceptible to firing triggered by other afferent inputs.
Concepts for structured illumination microscopy with extended axial resolution through mirrored illumination
Authors: Manton James D. , Ströhl Florian , Fiolka Reto , Kaminski Clemens F. , Rees Eric J. 
Published: November 2019

AbstractWide-field fluorescence microscopy, while much faster than confocal microscopy, suffers from a lack of optical sectioning and poor axial resolution. 3D structured illumination microscopy (SIM) has been demonstrated to provide optical sectioning and to double the resolution limit both laterally and axially, but even with this the axial resolution is still worse than the lateral resolution of unmodified wide-field microscopy. Interferometric schemes using two high numerical aperture objectives, such as 4Pi confocal and I5M microscopy, have improved the axial resolution beyond that of the lateral, but at the cost of a significantly more complex optical setup. Here, we investigate a simpler dual-objective scheme which we propose can be easily added to an existing 3D-SIM microscope, providing lateral and axial resolutions in excess of 125 nm with conventional fluorophores and without the need for interferometric detection.
Predicting glaucoma prior to its onset using deep learning
Authors: Thakur Anshul , Goldbaum Michael , Yousefi Siamak 
Published: November 2019

AbstractPurposeTo assess the accuracy of deep learning models to predict glaucoma development from fundus photographs several years prior to disease onset.DesignA deep learning model for prediction of glaucomatous optic neuropathy or visual field abnormality from color fundus photographs.ParticipantsWe retrospectively included 66,721 fundus photographs from 3,272 eyes of 1,636 subjects to develop deep leaning models.MethodFundus photographs and visual fields were carefully examined by two independent readers from the optic disc and visual field reading centers of the ocular hypertension treatment study (OHTS). When an abnormality was detected by the readers, subject was recalled for re-testing to confirm the abnormality and further confirmation by an endpoint committee. Using OHTS data, deep learning models were trained and tested using 85% of the fundus photographs and further validated (re-tested) on the remaining (held-out) 15% of the fundus photographs.Main Outcome MeasuresAccuracy and area under the receiver-operating characteristic curve (AUC).ResultsThe AUC of the deep learning model in predicting glaucoma development 4-7 years prior to disease onset was 0.77 (95% confidence interval 0.75, 0.79). The accuracy of the model in predicting glaucoma development about 1-3 years prior to disease onset was 0.88 (0.86, 0.91). The accuracy of the model in detecting glaucoma after onset was 0.95 (0.94, 0.96).ConclusionsDeep learning models can predict glaucoma development prior to disease onset with reasonable accuracy. Eyes with visual field abnormality but not glaucomatous optic neuropathy had a higher tendency to be missed by deep learning algorithms.
Androgen Receptor Signaling Regulates the Transcriptome of Prostate Cancer Cells by Modulating Global Alternative Splicing
Authors: Shah Kalpit , Gagliano Teresa , Garland Lisa , O’Hanlon Timothy , Bortolotti Daria , Gentili Valentina , Rizzo Roberta , Giamas Georgios , Dean Michael 
Published: November 2019

AbstractAndrogen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen-deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line anti-androgen therapies, including bicalutamide (CASODEX®) and enzalutamide (XTANDI®). However, the progression-free survival rate for the CRPC patients on anti-androgen therapies is only 8 to 19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR-signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation- and inhibition-of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes. Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist mediated switch inIDH1andPL2G2Aisoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many AR-regulated alternatively spliced exons. And, using 2D-invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist driven tumor invasion. In conclusion, until now, AR signaling has been primarily thought to modulate transcriptome of prostate epithelial cells by inducing or suppressing gene expression. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide.
Microbial ecology of Atlantic salmon, Salmo salar, hatcheries: impacts of the built environment on fish mucosal microbiota
Authors: Minich Jeremiah J , Jantawongsri Khattapan , Johnston Colin , Bowie Kate , Bowman John , Knight Rob , Nowak Barbara , Allen Eric 
Published: November 2019

ABSTRACTSuccessful rearing of fish in hatcheries is critical for conservation, recreational fishing, and commercial fishing through wild stock enhancements, and aquaculture production. Flow through (FT) hatcheries require more water than Recirculating-Aquaculture-Systems (RAS) which enable up to 99% of water to be recycled thus significantly reducing environmental impacts. Here, we evaluated the biological and physical microbiome interactions of the built environment of a hatchery from three Atl salmon hatcheries (RAS n=2, FT n=1). Six juvenile fish were sampled from tanks in each of the hatcheries for a total of 60 fish across 10 tanks. Water and tank side biofilm samples were collected from each of the tanks along with three salmon body sites (gill, skin, and digesta) to assess mucosal microbiota using 16S rRNA sequencing. The water and tank biofilm had more microbial richness than fish mucus while skin and digesta from RAS fish had 2× the richness of FT fish. Body sites each had unique microbial communities (P<0.001) and were influenced by the various hatchery systems (P<0.001) with RAS systems more similar. Water and especially tank biofilm richness was positively correlated with skin and digesta richness. Strikingly, the gill, skin and digesta communities were more similar to the origin tank biofilm vs. all other experimental tanks suggesting that the tank biofilm has a direct influence on fish-associated microbial communities. The results from this study provide evidence for a link between the tank microbiome and the fish microbiome with the skin microbiome as an important intermediate.IMPORTANCEAtlantic salmon, Salmo salar, is the most farmed marine fish worldwide with an annual production of 2,248 million metric tonnes in 2016. Salmon hatcheries are increasingly changing from flow through towards RAS design to accommodate more control over production along with improved environmental sustainability due to lower impacts on water consumption. To date, microbiome studies on hatcheries have focused either on the fish mucosal microbiota or the built environment microbiota, but have not combined the two to understand interactions. Our study evaluates how water and tank biofilm microbiota influences fish microbiota across three mucosal environments (gill, skin, and digesta). Results from this study highlight how the built environment is a unique source of microbes to colonize fish mucus and furthermore how this can influence the fish health. Further studies can use this knowledge to engineer built environments to modulate fish microbiota for a beneficial phenotype.
The relationship between microbial population size and disease in the Arabidopsis thaliana phyllosphere
Authors: Karasov Talia L. , Neumann Manuela , Duque-Jaramillo Alejandra , Kersten Sonja , Bezrukov Ilja , Schröppel Birgit , Symeonidi Efthymia , Lundberg Derek S. , Regalado Julian , Shirsekar Gautam , Bergelson Joy , Weigel Detlef 
Published: November 2019

AbstractA central goal in microbiome research is to learn what distinguishes a healthy from a dysbiotic microbial community. Shifts in diversity and taxonomic composition are important indicators of dysbiosis, but a full understanding also requires knowledge of absolute microbial population sizes. In addition to the number of microbial cells, information on taxonomic composition can provide important insight into microbiome function and disease state. Here we use shotgun metagenomics to simultaneously assess microbiome composition and microbial load in the phyllosphere of wild populations of the plant Arabidopsis thaliana. We find that wild plants vary substantially in the load of colonizing microbes, and that high loads are typically associated with the proliferation of single taxa, with only a few putatively pathogenic taxa achieving high abundances in the field. Our results suggest (i) that the inside of a plant leaf is on average sparsely colonized with an estimated two bacterial genomes per plant genome and an order of magnitude fewer eukaryotic microbial genomes, and (ii) that higher levels of microbial cells often indicate successful colonization by pathogens. Lastly, our results show that load is a significant explanatory variable for loss of estimated Shannon diversity in phyllosphere microbiomes, implying that reduced diversity may be a significant predictor of microbial dysbiosis in a plant leaf.
Batch cultivation of non-transgenic males suitable for SIT programs
Authors: Das Siba , Maselko Maciej , Upadhyay Ambuj , Smanski Michael J. 
Published: November 2019

AbstractThe field performance of Sterile Insect Technique (SIT) is improved by sex-sorting and releasing only the sterile males. This can be accomplished by resource-intensive separation of males from females by morphology. Alternatively, sex-ratio biasing genetic constructs can be used to selectively kill one sex without the need for manual or automated sorting, but the resulting genetically engineered (GE) control agents would be subject to additional governmental regulation. Here we describe and demonstrate a method for the batch production of non-GE males that is applicable for sex-selective production of males suitable for genetic biocontrol programs. This method could be applied to generate the heterogametic sex (XY, or WZ) in any organism with chromosomal sex determination. We observed up to 100% sex-selection with batch cultures of more than 103individuals. Using a stringent transgene detection assay, we demonstrate the potential of mass rearing of transgene free males.
Detection of a novel African-lineage-like Zika virus naturally infecting free-living neotropical primates in Southern Brazil
Authors: de Almeida Paula Rodrigues , Ehlers Luiza Presser , Demoliner Meriane , Eisen Ana Karolina Antunes , Girardi Viviane , De Lorenzo Cíntia , Bianchi Matheus Viezzer , Mello Lauren , Pavarini Saulo Pettinati , Driemeier David , Sonne Luciana , Spilki Fernando Rosado 
Published: November 2019

SummaryMosquito borne flaviviruses cause a series of important diseases in humans and animals. These viruses are maintained in cycles involving replication in mosquito and in vertebrate hosts. Most natural hosts are vertebrate animals living in sylvatic or peridomestic environments. Human contact with these environments may result in host shifts that lead to the establishment of urban transmission cycles. Zika virus is aFlavivirusthat persists in nature in a transmission cycle involving non-human primates (NHP). Its recent emergence in Brazil has shed light upon the importance of surveying this agent in Brazilian sylvatic environments. Here we present histopathological and molecular evidence that free ranging howler monkeys (Alouatta guariba) in Southern Brazil are infected by ZIKV closely related to African lineage MR766. Nine NHP were nested RT-PCR positive for ZIKV RNA. Sequence analysis revealed 96 to 98% identity to ZIKV MR766 and 85% identity to ZIKV P6-740, the current epidemic strain. The affected howler monkeys presented discrete inflammatory infiltrates in several tissues and immunohistochemichal (IHC) labeling of viral antigen was observed in placenta. These findings point to the circulation of African lineage Zika virus in the Americas in non-human primates. And raises the possibility that ZIKV was introduced into the Americas on more than one occasion.
Dynamic macromolecular composition and high exudation rates inProchlorococcus
Authors: Roth-Rosenberg Dalit , Aharonovich Dikla , Omta Anne-Willem , Follows Michael J. , Sher Daniel 
Published: November 2019

AbstractEvery living cell is composed of macromolecules such as proteins, DNA, RNA and pigments. The ratio between these macromolecular pools depends on the allocation of resources within the organism to different physiological requirements, and in turn affects biogeochemical cycles of elements such as carbon, nitrogen and phosphorus. Here, we present detailed measurements of the macromolecular composition ofProchlorococcusMIT9312, a representative strain of a globally abundant marine primary producer, as it grows and declines due to nitrogen starvation in laboratory batch cultures. As cells reached stationary stage and declined, protein per cell decreased by ∼30% whereas RNA per cell and pigments per cell decreased by ∼75%. The decline stage was associated with the appearance of chlorotic cells which had higher forward scatter (a proxy for cell size) but lower chlorophyll autofluorescence, as well as with changes in photosynthetic pigment composition. Specifically, during culture decline divinyl-chlorophyll-like pigments emerged, which were not observed during exponential growth. These divinyl-chlorophyll-like pigments were also observed in natural samples from the Eastern Mediterranean. Around >80% of the carbon fixed byProchlorococcusMIT9312 (but not of a different strain, NATL2A) was released into the growth media as dissolved organic carbon under these laboratory conditions. Variations in RNA/protein indicate that, broadly defined, the macromolecular composition ofProchlorococcusMIT9312 is more similar to eukaryotic phytoplankton than to marine heterotrophic bacteria, possibly due to the significant investment in photosynthetic machinery of phototrophs.
Lymphatic metastases have more diverse roots than distant metastases
Authors: Reiter Johannes G. , Nagpal Shriya , Naxerova Kamila 
Published: November 2019

AbstractBoth lymphatic and distant metastases arise through cancer cell migration and colonization of ectopic sites. Nonetheless, the two metastasis types are associated with significantly different clinical outcomes, suggesting that distinct biological mechanisms may drive their formation. Here we show fundamental differences in the seeding patterns of lymphatic and distant metastases. Analyzing the reconstructed phylogenies of human colorectal cancers, we find that distant metastases typically are monophyletic, originating from one common ancestor. Lymphatic metastases, in contrast, are almost exclusively polyphyletic and can be seeded from many primary tumor regions. We develop a rigorous mathematical framework for quantifying the phylogenetic diversity of metastases while accounting for differential lesion sampling among patients. Our results indicate that a smaller fraction of primary tumor cells gives rise to distant metastases than lymphatic metastases. Thus, the two metastasis types exhibit profoundly distinct phylogenetic traits, indicating that different evolutionary mechanisms may drive their formation and influence their clinical behavior.
Selective protein O-GlcNAcylation in cells by a proximity-directed O-GlcNAc transferase
Authors: Ramirez Daniel H. , Aonbangkhen Chanat , Wu Hung-Yi , Naftaly Jeffrey A. , Tang Stephanie , O’Meara Timothy R. , Woo Christina M. 
Published: November 2019

AbstractO-LinkedN-acetylglucosamine (O-GlcNAc) is a monosaccharide that plays an essential role in cellular signaling throughout the nucleocytoplasmic proteome of eukaryotic cells. Yet, the study of post-translational modifications like O-GlcNAc has been limited by the lack of strategies to induce O-GlcNAcylation on a target protein in cells. Here, we report a generalizable genetic strategy to induce O-GlcNAc to specific target proteins in cells using a nanobody as a proximity-directing agent fused to O-GlcNAc transferase (OGT). Fusion of a nanobody that recognizes GFP (nGFP) or a nanobody that recognizes the four-amino acid sequence EPEA (nEPEA) to OGT(4), a truncated form of OGT, yielded a nanobody-OGT(4) construct that selectively delivered O-GlcNAc to the target protein (e.g., JunB, cJun, Nup62) and reduced alteration of global O-GlcNAc levels in the cell. Quantitative chemical proteomics confirmed the selective increase in O-GlcNAc to the target protein by nanobody-OGT(4). Glycoproteomics revealed that nanobody-OGT(4) or full-length OGT produced a similar glycosite profile on the target protein. Finally, we demonstrate the ability to selectively target endogenous α-synuclein for glycosylation in HEK293T cells. Thus, the use of nanobodies to redirect OGT substrate selection is a versatile strategy to induce glycosylation of desired target proteins in cells that will facilitate discovery of O-GlcNAc functions and provide a mechanism to engineer O-GlcNAc signaling. The proximity-directed OGT approach for protein-selective O-GlcNAcylation is readily translated to additional protein targets and nanobodies that may constitute a generalizable strategy to control post-translational modifications in cells.Significance StatementNature uses post-translational modifications (PTMs) like glycosylation as a mechanism to alter protein signaling and function. However, the study of these modified proteins in cells is confined to loss-of-function strategies, such as mutagenic elimination of the modification site. Here, we report a generalizable strategy for induction of O-GlcNAc to a protein target in cells. The O-GlcNAc modification is installed by O-GlcNAc transferase (OGT) to thousands of nucleocytoplasmic proteins. Fusion of a nanobody to OGT enables the selective increase of O-GlcNAc levels on a series of target proteins. The described approach will facilitate direct studies of O-GlcNAc and its regulatory enzymes and drive new approaches to engineer protein signaling via a strategy that may be conceptually translatable to additional PTMs.