bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microglia inhibition rescues developmental hypofrontality in a mouse model of mental illness
Authors: Chini Mattia , Lindemann Christoph , Pöpplau Jastyn A. , Xu Xiaxia , Ahlbeck Joachim , Bitzenhofer Sebastian H. , Mulert Christoph , Hanganu-Opatz Ileana L. 
Published: January 2018

SUMMARYCognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal-hippocampal networks. This dysfunction emerges already during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Combining in vivo electrophysiology and optogenetics with neuroanatomy and pharmacology in neonatal mice mimicking the dual genetic - environmental etiology of psychiatric disorders, we identified pyramidal neurons in layer II/III of the prefrontal cortex as key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing result from sparser dendritic arborization and lower spine density. Pharmacological modulation of aberrantly hyper-mature microglia rescues morphological, synaptic and functional neuronal deficits and restores the early circuit function. Elucidation of the cellular substrate of developmental miswiring related to later cognitive deficits opens new perspectives for identification of neurobiological targets, amenable to therapies.HighlightsMice mimicking the etiology of mental illness have dysregulated prefrontal networkStructural and synaptic deficits cause abnormal rate and timing of pyramidal firingWeaker activation of prefrontal circuits results from deficits of pyramidal neuronsRescue of microglial function restores developing prefrontal circuits
Inter- and intra-domain functional redundancy in the rumen microbiome during plant biomass degradation
Authors: Söllinger Andrea , Tveit Alexander Tøsdal , Poulsen Morten , Noel Samantha Joan , Bengtsson Mia , Bernhardt Jörg , Frydendahl Hellwing Anne Louise , Lund Peter , Riedel Katharina , Schleper Christa , Højberg Ole , Urich Tim 
Published: January 2018

AbstractBackgroundRuminant livestock is a major source of the potent greenhouse gas methane (CH4), produced by the complex rumen microbiome. Using an integrated approach, combining quantitative metatranscriptomics with gas- and volatile fatty acid (VFA) profiling, we gained fundamental insights into temporal dynamics of the cow rumen microbiome during feed degradation.ResultsThe microbiome composition was highly individual and remarkably stable within each cow, despite similar gas emission and VFA profiles between cows. Gene expression profiles revealed a fast microbial growth response to feeding, reflected by drastic increases in microbial biomass, CH4emissions and VFA concentrations. Microbiome individuality was accompanied by high inter- and intra-domain functional redundancy among pro- and eukaryotic microbiome members in the key steps of anaerobic feed degradation. Methyl-reducing but not CO2-reducing methanogens were correlated with increased CH4emissions during plant biomass degradation.ConclusionsThe major response of the rumen microbiome to feed intake was a general growth of the whole community. The high functional redundancy of the cow-individual microbiomes was possibly linked to the robust performance of the anaerobic degradation process. Furthermore, the strong response of methylotrophic methanogens is suggesting that they might play a more important role in ruminant CH4emissions than previously assumed, making them potential targets for CH4mitigation strategies.
Engineering Plant Architecture via CRISPR/Cas9-mediated Alteration of Strigolactone Biosynthesis
Authors: Butt Haroon , Jamil Muhammad , Wang Jian You , Al-Babili Salim , Mahfouz Magdy 
Published: January 2018

AbstractPrecision plant genome engineering holds much promise for targeted improvement of crop traits via unprecedented single-base level control over the genetic material. Strigolactones (SLs) are a key determinant of plant architecture, known for their role in inhibiting shoot branching (tillering). Here, we used CRISPR/Cas9 in rice (Oryza sativa) for targeted disruption of CAROTENOID CLEAVAGE DIOXYGENASE 7 (CCD7), which controls a key step in SL biosynthesis. The ccd7 mutants exhibited a striking increase in tillering, combined with a dwarf phenotype, which could be rescued by application of the synthetic SL analog GR24. Striga germination assays and liquid chromatography–mass spectrometry analysis showed that root exudates of ccd7 mutants were also SL deficient. Taken together, our results show the power of CRISPR/Cas9 for targeted engineering of plant architecture and for elucidating the molecular underpinnings of architecture-related traits.
An Adaptive Flagellar Photoresponse Determines the Dynamics of Accurate Phototactic Steering inChlamydomonas
Authors: Leptos Kyriacos C , Chioccioli Maurizio , Furlan Silvano , Pesci Adriana I , Goldstein Raymond E 
Published: January 2018

AbstractOur understanding of phototaxis of biflagellates stems almost exclusively from the model algaChlamydomonas reinhardtii, via studies of its flagella, light-sensor and steering. However, no comprehensive model linking all these aspects of its physiology and behavior has been constructed and tested experimentally. Here, we develop such a mathematical model by coupling an adaptive flagellar photoresponse to rigid-body dynamics tailored to details of flagellar beating, and corroborate it with experimental data – at the flagellar and tactic levels – to explain the accurate phototactic steering of this alga. We experimentally validate the hypothesized adaptive flagellar photoresponse using high spatio-temporal resolution methodology on immobilized cells, and corroborate the predicted reorientation dynamics of phototactic swimmers using 3D-tracking of free-swimming cells. Finally, we reconfirm, both theoretically and experimentally, that the adaptive nature of the response has peak fidelity at a frequency of about 1.6 Hz, corresponding to the rotation frequency of the cell body.
Truncation and Motif Based Pan-Cancer Analysis Highlights Novel Tumor Suppressing Kinases
Authors: Hudson Andrew M. , Stephenson Natalie L. , Li Cynthia , Trotter Eleanor , Fletcher Adam J. , Katona Gitta , Bieniasz-Krzywiec Patrycja , Howell Matthew , Wirth Chris , Furney Simon , Miller Crispin J. , Brognard John 
Published: January 2018

AbstractA major challenge in cancer genomics is identifying driver mutations from the large number of neutral passenger mutations within a given tumor. Here, we utilize motifs critical for kinase activity to functionally filter genomic data to identify driver mutations that would otherwise be lost within mutational noise. In the first step of our screen, we define a putative tumor suppressing kinome by identifying kinases with truncation mutations occurring within or before the kinase domain. We aligned these kinase sequences and, utilizing data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas databases, identified amino acids that represent predicted hotspots for loss-of-function mutations. The functional consequences of new LOF mutations were validated and the top 15 hotspot LOF residues were used in a pan-cancer analysis to define the tumor-suppressing kinome. A ranked list revealed MAP2K7 as a candidate tumor suppressor in gastric cancer, despite the mutational frequency of MAP2K7 falling within the mutational noise for this cancer type. The majority of mutations in MAP2K7 abolished catalytic activity compared to the wild type kinase, consistent with a tumor suppressive role for MAP2K7 in gastric cancer. Furthermore, reactivation of the JNK pathway in gastric cancer cells harboring LOF mutations in MAP2K7 or JNK1 suppresses clonogenicity and growth in soft agar, demonstrating the functional importance of inactivating the JNK pathway in gastric cancer. In summary, our data highlights a broadly applicable strategy to identify functional cancer driver mutations leading us to define the JNK pathway as tumor suppressive in gastric cancer.SummaryA unique computational pan-cancer analysis pinpoints novel tumor suppressing kinases, and highlights the power of functional genomics by defining the JNK pathway as tumor suppressive in gastric cancer.
Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors
Authors: Ayeni Deborah , Miller Braden , Kuhlman Alexandra , Ho Ping-Chih , Robles-Oteiza Camila , Gaefele Mmaserame , Levy Stellar , de Miguel Fernando J. , Perry Curtis , Guan Tianxia , Zelterman Daniel , Homer Robert , Liu Zongzhi , Kaech Susan , Politi Katerina 
Published: January 2018

AbstractEpidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells. Using mouse models, we studied the immunological profile of mutantEGFR-driven lung tumors before and after erlotinib treatment. We found that erlotinib triggered the recruitment of inflammatory T cells into the lungs. Interestingly, this phenotype could be recapitulated by tumor regression mediated by deprivation of the EGFR oncogene indicating that tumor regression alone was sufficient for these immunostimulatory effects. Erlotinib treatment also led to increased maturation of myeloid cells and an increase in CD40+ dendritic cells. Our findings lay the foundation for understanding the effects of TKIs on the tumor microenvironment and highlights potential avenues for investigation of targeted and immuno-therapy combination strategies to treat EGFR mutant lung cancer.
Global analysis of gene expression dynamics identifies factors required for accelerated mRNA degradation
Authors: Miller Darach , Brandt Nathan , Gresham David 
Published: January 2018

AbstractCellular responses to changing environments frequently involve rapid reprogramming of the transcriptome. Regulated changes in mRNA degradation rates can accelerate reprogramming by clearing or stabilizing extant transcripts. Here, we measured mRNA stability using 4-thiouracil labeling in the budding yeastSaccharomyces cerevisiaeduring a nitrogen upshift and found that 78 mRNAs are subject to destabilization. These transcripts include Nitrogen Catabolite Repression (NCR) and carbon metabolism mRNAs, suggesting that mRNA destabilization is a mechanism for targeted reprogramming. To explore the molecular basis of destabilization we implemented a SortSeq approach to screen using the pooled deletion collection library fortransfactors that mediate rapidGAP1mRNA repression. We combined low-input multiplexed Barcode sequencing with branched-DNA single-molecule mRNA FISH and Fluorescence-activated cell sorting (BFF) to identify that the Lsm1-7p/Pat1p complex and general mRNA decay machinery are important forGAP1mRNA clearance. We also find that the decapping modulatorSCD6,translation factor eIF4G2, and the 5’ UTR ofGAP1are important for this repression, suggesting that translational control may impact the post-transcriptional fate of mRNAs in response to environmental changes.
Spindle assembly in egg extracts of the Marsabit clawed frog, Xenopus borealis
Authors: Kitaoka Maiko , Heald Rebecca , Gibeaux Romain 
Published: January 2018

ABSTRACTEgg extracts of the African clawed frog Xenopus laevis have provided a cell-free system instrumental in elucidating events of the cell cycle, including mechanisms of spindle assembly. Comparison with extracts from the diploid Western clawed frog, Xenopus tropicalis, which is smaller at the organism, cellular and subcellular levels, has enabled the identification of spindle size scaling factors. We set out to characterize the Marsabit clawed frog, Xenopus borealis, which is intermediate in size between the two species, but more recently diverged in evolution from X. laevis than X. tropicalis. X. borealis eggs were slightly smaller than those of X. laevis, and slightly smaller spindles were assembled in egg extracts. Interestingly, microtubule distribution across the length of the X. borealis spindles differed from both X. laevis and X. tropicalis. Extract mixing experiments revealed common scaling phenomena among Xenopus species, while characterization of spindle factors katanin, TPX2, and Ran indicate that X. borealis spindles possess both X. laevis and X. tropicalis features. Thus, X. borealis egg extract provides a third in vitro system to investigate interspecies scaling and spindle morphometric variation.
Rehydration rates and the prevalence of xylem-hydration of flowers
Authors: Roddy Adam B. , Brodersen Craig R. 
Published: January 2018

AbstractAngiosperm flowers are remarkably diverse anatomically and morphologically, yet they all must satisfy the physiological constraints of supplying sufficient amounts of water and carbon effectively promote pollination. Flowers often occur in the hottest, driest parts of the plant canopy and can face harsh abiotic conditions. Prior evidence suggests that extant species vary dramatically in how water is delivered to flowers, with some evidence that water may be imported into flowers by the phloem. Here we measured midday water potential gradients between flowers, leaves, and stems often phylogenetically diverse species. We further tested the likelihood of xylem-hydration by measuring rates of rehydration after experimentally induced desiccation. There was no significant difference in rehydration rates between leaves and flowers. These results are consistent with xylem-hydration of flowers and suggest that there has been little modification to the mechanisms of water transport despite the diversity of floral form.
Genetically increased serum calcium levels reduce Alzheimer’s disease risk
Authors: Jiang Qinghua , Hu Yang , Jin Shuilin , Liu Guiyou 
Published: January 2018

AbstractIMPORTANCE Alzheimer’s disease (AD) is the leading cause of disability in the elderly. It has been a long time about the calcium hypothesis of AD on the basis of emerging evidence since 1994. However, most studies focused on the association between calcium homeostasis and AD, and concerned the intracellular calcium concentration. Only few studies reported reduced serum calcium levels in AD. Until now, it remains unclear whether serum calcium levels are genetically associated with AD risk.OBJECTIVE To evaluate the genetic association between increased serum calcium levels and AD riskDESIGN, SETTING, AND PARTICIPANTS We performed a Mendelian randomization study to investigate the association of increased serum calcium with AD risk using the genetic variants from the large-scale serum calcium genome-wide association study (GWAS) dataset (N=61,079 individuals of European descent) and the large-scale AD GWAS dataset (N=54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Inverse-variance weighted meta-analysis (IVW) was used to provide a combined estimate of the genetic association. Meanwhile, we selected the weighted median regression and MR-Egger regression as the complementary analysis methods to examine the robustness of the IVW estimate.EXPOSURES Genetic predisposition to increased serum calcium levelsMAIN OUTCOMES AND MEASURES The risk of AD.RESULTS We selected 6 independent genetic variants influencing serum calcium levels as the instrumental variables. IVW analysis showed that a genetically increased serum calcium level (per 1 standard deviation (SD) increase 0.5-mg/dL) was significantly associated with a reduced AD risk (OR=0.56, 95% CI: 0.34-0.94, P=5.00E-03). Meanwhile, both the weighted median estimate (OR=0.60, 95% CI: 0.34-1.06, P=0.08) and MR-Egger estimate (OR=0.66, 95% CI: 0.26-1.67, P=0.381) were consistent with the IVW estimate in terms of direction and magnitude.CONCLUSIONS AND RELEVANCE We provided evidence that genetically increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be further conducted to assess the effect of serum calcium levels on AD risk, and further clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.Key PointsQuestion Is there a genetic relationship between elevated serum calcium levels and the risk of Alzheimer’s disease?Findings This Mendelian randomization study showed that the genetically increased serum calcium levels were associated with the reduced risk of Alzheimer’s disease.Meaning These findings provide evidence that genetically increased serum calcium levels could reduce the risk of Alzheimer’s disease.
Schistosomiasis Induces Persistent DNA Methylation and Tuberculosis-specific Immune Changes
Authors: DiNardo Andrew R. , Nishiguchi Tomoki , Mace Emily M. , Rajapakshe Kimal , Mtetwa Godwin , Kay Alexander , Maphalala Gugu , Secor W. Evan , Mejia Rojelio , Orange Jordan S. , Coarfa Cristian , Bhalla Kapil N. , Graviss Edward A , Mandalakas Anna M. , Makedonas George 
Published: January 2018

AbstractEpigenetic mechanisms, like DNA methylation, determine immune cell phenotype. To understand the epigenetic alterations induced by helminth co-infections, we evaluated the longitudinal effect of ascariasis and schistosomiasis infection on CD4+ T cell DNA methylation and the downstream tuberculosis (TB)-specific and BCG-induced immune phenotype. All experiments were performed on human primary immune cells from a longitudinal cohort of recently TB-exposed children. Compared to age-matched uninfected controls, children with active Schistosoma haematobium and Ascaris lumbricoides infection had 751 differentially DNA methylated genes with 72% hyper-methylated. Gene ontology pathway analysis identified inhibition of IFN-γ signaling, cellular proliferation, and the Th1 pathway. Targeted RT-PCR after methyl-specific endonuclease digestion confirmed DNA hyper-methylation of the transcription factors BATF3, ID2, STAT5A, IRF5, PPARg, RUNX2, IRF4 and NFATC1 and cytokines or cytokine receptors IFNGR1, TNFS11, RELT (TNF receptor), IL12RB2 and IL12B (p< 0.001; Sidak-Bonferroni). Functional blockage of the IFN-γ signaling pathway was confirmed with helminth-infected individuals having decreased up-regulation of IFN-γ-inducible genes (Mann-Whitney p < 0.05). Hypo-methylation of the IL-4 pathway and DNA hyper-methylation of the Th1 pathway was confirmed by antigen-specific multidimensional flow cytometry demonstrating decreased TB-specific IFN-γ and TNF and increased IL-4 production by CD4+ T cells (Wilcoxon signed rank P <0.05). In S.haematobium infected individuals, these DNA methylation and immune phenotypic changes persisted at least six months after successful deworming. This work demonstrates that helminth infection induces DNA methylation and immune perturbations that inhibit TB-specific immune control and that the duration of these changes are helminth-specific.
Distinct contributions of tensile and shear stress on E-cadherin levels during morphogenesis
Authors: Kale Girish R. , Yang Xingbo , Philippe Jean-Marc , Mani Madhav , Lenne Pierre-François , Lecuit Thomas 
Published: January 2018

AbstractDuring epithelial morphogenesis, cell contacts (junctions) are constantly remodeled by mechanical forces that work against adhesive forces. E-cadherin complexes play a pivotal role in this process by providing persistent cell adhesion and by transmitting mechanical tension. In this context, it is unclear how mechanical forces affect E-cadherin adhesion and junction dynamics.DuringDrosophilaembryo axis elongation, Myosin-II activity in the apico-medial and junctional cortex generates mechanical forces to drive junction remodeling. Here we report that the ratio between Vinculin and E-cadherin intensities acts as a ratiometric readout for these mechanical forces (load) at E-cadherin complexes. Medial Myosin-II loads E-cadherin complexes on all junctions, exerts tensile forces, and increases levels of E-cadherin. Junctional Myosin-II, on the other hand, biases the distribution of load between junctions of the same cell, exerts shear forces, and decreases the levels of E-cadherin. This work suggests distinct effects of tensile versus shear stresses on E-cadherin adhesion.
The Eighty Five Percent Rule for Optimal Learning
Authors: Wilson Robert C. , Shenhav Amitai , Straccia Mark , Cohen Jonathan D. 
Published: January 2018

AbstractResearchers and educators have long wrestled with the question of how best to teach their clients be they human, animal or machine. Here we focus on the role of a single variable, the difficulty of training, and examine its effect on the rate of learning. In many situations we find that there is a sweet spot in which training is neither too easy nor too hard, and where learning progresses most quickly. We derive conditions for this sweet spot for a broad class of learning algorithms in the context of binary classification tasks, in which ambiguous stimuli must be sorted into one of two classes. For all of these gradient-descent based learning algorithms we find that the optimal error rate for training is around 15.87% or, conversely, that the optimal training accuracy is about 85%. We demonstrate the efficacy of this ‘Eighty Five Percent Rule’ for artificial neural networks used in AI and biologically plausible neural networks thought to describe human and animal learning.
Identifying Antimicrobial Peptides using Word Embedding with Deep Recurrent Neural Networks
Authors: Hamid Md-Nafiz , Friedberg Iddo 
Published: January 2018

AbstractAntibiotic resistance constitutes a major public health crisis, and finding new sources of antimicrobial drugs is crucial to solving it. Bacteriocins, which are bacterially-produced antimicrobial peptide products, are candidates for broadening the available choices of an-timicrobials. However, the discovery of new bacteriocins by genomic mining is hampered by their sequences’ low complexity and high variance, which frustrates sequence similarity-based searches. Here we use word embeddings of protein sequences to represent bacteriocins, and apply a word embedding method that accounts for amino acid order in protein sequences,to predict novel bacteriocins from protein sequences without using sequence similarity. Our method predicts, with a high probability, six yet unknown putative bacteriocins in Lactobacil-lus. Generalized, the representation of sequences with word embeddings preserving sequence order information can be applied to protein classification problems for which sequence simi-larity cannot be used.