bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inferring and validating mechanistic models of neural microcircuits based on spike-train data
Authors: Ladenbauer Josef , McKenzie Sam , English Daniel Fine , Hagens Olivier , Ostojic Srdjan 
Published: February 2018

AbstractThe interpretation of neuronal spike train recordings often relies on abstract statistical models that allow for principled parameter estimation and model selection but provide only limited insights into underlying microcircuits. In contrast, mechanistic models are useful to interpret microcircuit dynamics, but are rarely quantitatively matched to experimental data due to methodological challenges. Here we present analytical methods to efficiently fit spiking circuit models to single-trial spike trains. Using derived likelihood functions, we statistically infer the mean and variance of hidden inputs, neuronal adaptation properties and connectivity for coupled integrate-and-fire neurons. Comprehensive evaluations on synthetic data, validations using ground truth in-vitro and in-vivo recordings, and comparisons with existing techniques demonstrate that parameter estimation is very accurate and efficient, even for highly subsampled networks. Our methods bridge statistical, data-driven and theoretical, model-based neurosciences at the level of spiking circuits, for the purpose of a quantitative, mechanistic interpretation of recorded neuronal population activity.
Engineering Lipid Droplet Assembly Mechanisms for Improved Triacylglycerols Accumulation in S. cerevisiae
Authors: Teixeira Paulo Gonçalves , David Florian , Siewers Verena , Nielsen Jens 
Published: February 2018

AbstractProduction of triacylglycerols (TAGs) through microbial fermentation is an emerging alternative to plant and animal-derived sources. The yeast Saccharomyces cerevisiae is a preferred organism for industrial use but has natively a very poor capacity of TAG production and storage. Here, we engineered S. cerevisiae for accumulation of high TAG levels through the use of structural and physiological factors that influence assembly and biogenesis of lipid droplets. First, human and fungal perilipin genes were expressed, increasing TAG content by up to 36% when expressing the human perilipin gene PLIN3. Secondly, expression of the FIT2 homologue YFT2 resulted in a 26% increase in TAG content. Lastly, the genes ERD1 and PMR1 were deleted in order to induce an ER stress response and stimulate lipid droplet formation, increasing TAG content by 72% for Δerd1, with an additive effect for both YFT2 and PLIN3 expression. These new approaches were implemented in previously engineered strains that carry high flux of fatty acid biosynthesis and conversion of acyl-CoA into TAG, resulting in improvements of up to 138% over those high-producing strains without any substantial growth effects or abnormal cell morphology. We find that these approaches are not only a major advancement in engineering S. cerevisiae for TAG production, but also highlight the importance of lipid droplet dynamics for high lipid accumulation in yeast.
Temperature-induced changes in wheat phosphoproteome reveal temperature-regulated interconversion of phosphoforms
Authors: Vu Lam Dai , Zhu Tingting , Verstraeten Inge , van de Cotte Brigitte ,   IWGSC, Gevaert Kris , Smet Ive De 
Published: February 2018

ABSTRACTWheat (Triticum ssp.) is one of the most important human food sources. However, this crop is very sensitive to temperature changes. Specifically, processes during wheat leaf, flower and seed development and photosynthesis, which all contribute to the yield of this crop, are affected by high temperature. While this has to some extent been investigated on physiological, developmental and molecular levels, very little is known about early signalling events associated with an increase in temperature. Phosphorylation-mediated signalling mechanisms, which are quick and dynamic, are associated with plant growth and development, also under abiotic stress conditions. Therefore, we probed the impact of a short-term increase in temperature on the wheat leaf and spikelet phosphoproteome. The resulting data set provides the scientific community with a first large-scale plant phosphoproteome under the control of higher ambient temperature, which will be valuable for future studies. Our analyses also revealed a core set of common proteins between leaf and spikelet, suggesting some level of conserved regulatory mechanisms. Furthermore, we observed temperature-regulated interconversion of phosphoforms, which likely impacts protein activity.
Concentration of 2’C-methyladenosine triphosphate byLeishmania guyanensisenables specific inhibition ofLeishmaniaRNA virus 1 via its RNA polymerase
Authors: Robinson John I. , Beverley Stephen M. 
Published: February 2018

AbstractLeishmaniais a widespread trypanosomatid protozoan parasite causing significant morbidity and mortality in humans. The endobiont dsRNA virusLeishmaniaRNA virus 1 (LRV1) chronically infects some strains, where it increases parasite numbers and virulence in murine leishmaniasis models, and correlates with increased treatment failure in human disease. Previously, we reported that 2’-C-methyladenosine (2CMA) potently inhibited LRV1 inLeishmania guyanensis(Lgy) andL. braziliensis, leading to viral eradication at concentrations above 10 µM. Here we probed the cellular mechanisms of 2CMA inhibition, involving metabolism, accumulation and inhibition of the viral RNA dependent RNA polymerase (RDRP). Activation to 2CMA triphosphate (2CMATP) was required, as 2CMA showed no inhibition of RDRP activity from virions purified on cesium chloride gradients. In contrast, 2CMA-TP showed IC50s ranging from 150 to 910 µM, depending on the CsCl density of the virion (empty, ssRNA- and dsRNA-containing).Lgyparasites incubatedin vitrowith 10 µM 2CMA accumulated 2CMA-TP to 410 µM, greater than the most sensitive RDRP IC50 measured. Quantitative modeling showed good agreement between the degree of LRV1 RDRP inhibition and LRV1 levels. These results establish that 2CMA activity is due to its conversion to 2CMA-TP, which accumulates to levels that inhibit RDRP and cause LRV1 loss. This attests to the impact of the Leishmania purine uptake and metabolism pathways, which allow even a weak RDRP inhibitor to effectively eradicate LRV1 at micromolar concentrations. Future RDRP inhibitors with increased potency may have potential therapeutic applications for ameliorating the increased Leishmania pathogenicity conferred by LRV1.
DROSHA associates to DNA damage sites and is required for DNA repair
Authors: Cabrini Matteo , Roncador Marco , Galbiati Alessandro , Cipolla Lina , Iannelli Fabio , Sabbioneda Simone , Fagagna Fabrizio d’Adda di , Francia Sofia 
Published: February 2018

AbstractThe DNA damage response (DDR) is the signaling cascade through which a cell recognizes DNA lesions, and promotes their resolution via the repair pathways of Non-Homologous End Joining (NHEJ), or Homologous Recombination (HR). We recently demonstrated that DROSHA boosts DDR signaling by processing damage-induced long non-coding RNAs into smaller DNA damage response RNAs (DDRNAs). However, the location at which DROSHA exerts its DDR functions, relative to sites of DNA damage, remains unknown.To investigate DROSHA’s localization during DDR activation, we used the DiVA cellular system, which allows the controlled induction of several DNA double strand breaks (DSBs) in the human genome. Indeed, by genome wide chromatin immunoprecipitation followed by next generation sequencing, we demonstrate that DROSHA associates with DSBs. In support of this, DSB-recruitment of DROSHA is detectable at the single-cell level by Proximity Ligation Assay between DROSHA and known DDR markers, and by DNA damage in situ ligation followed by Proximity Ligation Assay (DI-PLA), which demonstrates proximity of DROSHA to DNA ends. DROSHA recruitment occurs at both genic and inter-genic DSBs, suggesting that its recruitment is independent from ongoing transcription preceding damage generation. DROSHA’s recruitment to DNA lesions occurs throughout the cell cycle, and with a preference for NHEJ-prone DSBs. Consistently, inhibition of the HR pathway increases DROSHA recruitment, and DROSHA knock down strongly impairs NHEJ efficiency in a GFP-reporter cellular system for monitoring NHEJ DNA repair. Overall, these results demonstrate that DROSHA acts locally at sites of DNA damage to promote NHEJ DNA repair.
Multiplexed enrichment and genomic profiling of peripheral immune cell subsets on a microfluidic chip
Authors: Reyes Miguel , Vickers Dwayne , Billman Kianna , Eisenhaure Thomas , Hoover Paul , Browne Edward , Rao Deepak A. , Hacohen Nir , Blainey Paul C. 
Published: February 2018

ABSTRACTThe human immune system consists of many specialized cell subsets that simultaneously carry out a diverse range of functions using overlapping pathways and signals. Subset-specific immune profiling can resolve immune activity in autoimmune disease, cancer immunity, and infectious disease that may not be discoverable or detectable in analyses of crude blood samples. The activity of specific subsets may help predict the course of disease and response to therapy in certain patient populations. Here, we present a low-input microfluidic system for sorting immune cells into subsets and profiling their cellular states by gene expression analysis using full-length RNA-seq. Our system is robust and has the potential to make multiplexed subset-specific analysis routine in many research laboratories and clinical settings. We validate the device’s technical performance by benchmarking its subset enrichment and genomic profiling performance against standard protocols. We make the added value of subset-resolved profiling over crude samples clear throughex vivoexperiments that show subset-specific stimulated responses. Finally, we demonstrate the scalability of our device by profiling four immune cell subsets in blood from systemic lupus erythematosus (SLE) patients and matched controls enrolled in a clinical study. The results from our initial cohort confirm the role of type I interferons in lupus pathogenesis and further show that the canonical interferon signature for SLE is prominent in B cells, demonstrating the ability of our integrated analytical platform to identify cell-specific disease signatures.
Emergence of Human Amygdala Functional Networks: 3 Months to 5 Years of Age
Authors: Gabard-Durnam L.J. , O’Muircheartaigh J. , Dirks H. , Dean D.C. , Tottenham N. , Deoni S. 
Published: February 2018

AbstractAlthough the amygdala’s role in shaping social behavior is especially important during early post-natal development, very little is known of human amygdala functional development before childhood. To address this important gap, this study used resting-state fMRI to examine early functional network development of the amygdala and its subregions in 80 participants from 3-months to 5-years of age. Whole brain functional connectivity with the whole amygdala and its laterobasal and superficial nuclear groups were largely similar to those seen in older children and adults, and functional distinctions between subregion networks exist already. These patterns suggest many amygdala functional circuits are intact from infancy, especially those that are part of larger motor, visual, auditory and subcortical (basal ganglia especially) networks. Notably, these observed robust amygdala functional networks in infancy precede reports to date of elicited amygdala reactivity in development. Developmental changes in connectivity were observed between the laterobasal nucleus and bilateral ventral temporal and motor cortex as well as between the superficial nuclei and medial thalamus, occipital cortex and a different region of motor cortex. These results show amygdala-subcortical and sensory-cortex connectivity begins refinement prior to childhood, though connectivity changes with associative and frontal cortical areas, seen after early childhood, were not evident in this age range. These findings represent early steps in understanding amygdala network dynamics across infancy through early childhood, an important period of emotional and cognitive development.
NeoDTI: Neural integration of neighbor information from a heterogeneous network for discovering new drug-target interactions
Authors: Wan Fangping , Hong Lixiang , Xiao An , Jiang Tao , Zeng Jianyang 
Published: February 2018

AbstractMotivationAccurately predicting drug-target interactions (DTIs) in silico can guide the drug discovery process and thus facilitate drug development. Computational approaches for DTI prediction that adopt the systems biology perspective generally exploit the rationale that the properties of drugs and targets can be characterized by their functional roles in biological networks.ResultsInspired by recent advance of information passing and aggregation techniques that generalize the convolution neural networks (CNNs) to mine large-scale graph data and greatly improve the performance of many network-related prediction tasks, we develop a new nonlinear end-to-end learning model, called NeoDTI, that integrates diverse information from heterogeneous network data and automatically learns topology-preserving representations of drugs and targets to facilitate DTI prediction. The substantial prediction performance improvement over other state-of-the-art DTI prediction methods as well as several novel predicted DTIs with evidence supports from previous studies have demonstrated the superior predictive power of NeoDTI. In addition, NeoDTI is robust against a wide range of choices of hyperparameters and is ready to integrate more drug and target related information (e.g., compound-protein binding affinity data). All these results suggest that NeoDTI can offer a powerful and robust tool for drug development and drug repositioning.Availability and implementationThe source code and data used in NeoDTI are available at: https://github.com/FangpingWan/NeoDTI.Contactzengjy321@tsinghua.edu.cnSupplementary informationSupplementary data are available at Bioinformatics online.
Reversing Glial Scar Back To Neural Tissue Through NeuroD1-Mediated Astrocyte-To-Neuron Conversion
Authors: Zhang Lei , Lei Zhuofan , Guo Ziyuan , Pei Zifei , Chen Yuchen , Zhang Fengyu , Cai Alice , Mok Yung Kin , Lee Grace , Swaminnathan Vishal , Wang Fan , Bai Yuting , Chen Gong 
Published: February 2018

ABSTRACTNerve injury often causes neuronal loss and glial proliferation, disrupting the delicate balance between neurons and glial cells in the brain. Recently, we have developed an innovative technology to convert internal reactive glial cells into functional neurons inside the mouse brain. Here, we further demonstrate that such glia-to-neuron conversion can rebalance neuron-glia ratio and reverse glial scar back to neural tissue. Specifically, using a severe stab injury model in the mouse cortex, we demonstrated that ectopic expression of NeuroD1 in reactive astrocytes significantly reduced glial reactivity and transformed toxic A1 astrocytes into less harmful astrocytes before neuronal conversion. Importantly, astrocytes were not depleted after neuronal conversion but rather repopulated due to its intrinsic proliferation capability. Remarkably, converting reactive astrocytes into neurons also significantly reduced microglia-mediated neuroinflammation. Moreover, accompanying regeneration of new neurons together with repopulation of new astrocytes, blood-brain-barrier was restored and synaptic density was rescued in the injury sites. Together, these results demonstrate that glial scar can be reversed back to neural tissue through rebalancing neuron:glia ratio after glia-to-neuron conversion.
Extinction recall of fear memories formed before stress is not affected despite amygdalar hyperactivity
Authors: Rahman Mohammed Mostafizur , Shukla Ashutosh , Chattarji Sumantra 
Published: February 2018

AbstractStress is known to exert its detrimental effects not only by enhancing fear, but also by impairing its extinction. However, in earlier studies stress exposure invariably preceded both processes. Thus, compared to unstressed animals, stressed animals had to extinguish fear memories from higher levels of freezing caused by prior exposure to stress. Here we decouple the two processes to examine if stress specifically impairs fear extinction. Strikingly, when fear memories were formed before stress exposure, thereby allowing animals to initiate extinction from comparable levels of fear, recall of fear extinction was unaffected. Despite this we observed a persistent increase in theta activity in the BLA. Theta activity in the mPFC, by contrast, was normal. Stress also disrupted mPFC-BLA theta-frequency synchrony and directional coupling. Thus, in the absence of the fear-enhancing effects of stress, the expression of fear reflects normal regulation of mPFC activity, not stress-induced hyperactivity in the amygdala.
High-quality ultrastructural preservation using cryofixation for 3D electron microscopy of genetically labeled tissues
Authors: Tsang Tin Ki , Bushong Eric A. , Boassa Daniela , Hu Junru , Romoli Benedetto , Phan Sebastien , Dulcis Davide , Su Chih-Ying , Ellisman Mark H. 
Published: February 2018

ABSTRACTElectron microscopy (EM) offers unparalleled power to study cell substructures at the nanoscale. Cryofixation by high-pressure freezing offers optimal morphological preservation, as it captures cellular structures instantaneously in their near-native states. However, the applicability of cryofixation is limited by its incompatibilities with diaminobenzidine labeling using genetic EM tags and the high-contrast en bloc staining required for serial block-face scanning electron microscopy (SBEM). In addition, it is challenging to perform correlated light and electron microscopy (CLEM) with cryofixed samples. Consequently, these powerful methods cannot be applied to address questions requiring optimal morphological preservation and high temporal resolution. Here we developed an approach that overcomes these limitations; it enables genetically labeled, cryofixed samples to be characterized with SBEM and 3D CLEM. Our approach is broadly applicable, as demonstrated in cultured cells, Drosophila olfactory organ and mouse brain. This optimization exploits the potential of cryofixation, allowing quality ultrastructural preservation for diverse EM applications.
Influenza A Virus Negative Strand RNA is Translated for CD8+ T Cell Immunosurveillance
Authors: Hickman Heather D. , Mays Jacqueline W. , Gibbs James , Kosik Ivan , Magadan Javier , Takeda Kazuyo , Das Suman , Reynoso Glennys V. , Ngudiankama Barbara F. , Wei JiaJie , Shannon John P. , McManus Daniel , Yewdell Jonathan W. 
Published: February 2018

AbstractTo probe the limits of CD8+ T cell immunosurveillance, we inserted the model peptide SIINFEKL into influenza A virus (IAV) negative strand gene segments. Although IAV genomic RNA is widely considered as non-coding, there is a conserved, relatively long open reading frame present in the genomic strand of segment eight, encoding a potential protein termed NEG8. The biosynthesis of NEG8 from IAV has yet to be demonstrated. While we failed to detect NEG8 protein expression in IAV infected cells, cell surface Kb-SIINFEKL complexes are generated when SIINFEKL is genetically appended to the predicted COOH-terminus of NEG8, as shown by activation of OT-I T cellsin vitroandin vivo. Moreover, recombinant IAV encoding SIINFEKL embedded in the negative strand of the NA-stalk coding sequence also activates OT-I T cellsin vivo. Together, our findings demonstrate both the translation of sequences on the negative strand of a single stranded RNA virus and its relevance anti-viral immunosurveillance.SignificanceEvery gene encodes complementary information on the opposite strand that can potentially be used for immunosurveillance. In this study, we show that the influenza A virus “non-coding” strand translated into polypeptides during a viral infection of either cultured cells or mice that can be recognized by CD8+ T cells. Our findings raise the possibility that influenza virus uses its negative strand to generate proteins useful to the virus. More generally, it adds to a growing literature showing that immunosurveillance extends to gene sequences generally thought not to be converted into proteins. The relevance of translating this “dark” information extends from viral immunity to cancer immunotherapy and autoimmunity.
Financial stress and farm bankruptcies in US agriculture
Authors: Dinterman Robert , Katchova Ani L. , Harris James Michael 
Published: February 2018

Purpose
The purpose of this paper is to evaluate farm financial stress within the USA over the past 20 years and the agricultural and economic factors which have impacted farm businesses. The effect of the 2005 Bankruptcy Abuse Prevention and Consumer Protection Act (BAPCPA) on farm financial stress is further evaluated. In particular, Chapter 12 bankruptcies – which can only be filed by farmers – were only a temporary measure until BAPCPA made Chapter 12 a permanent fixture in bankruptcy law.

Design/methodology/approach
Chapter 12 bankruptcy filings from 1997 until 2016 are used as a proxy for farm financial stress. Panel fixed effects models are used to determine relevant factors affecting financial stress for farmers from agricultural and macroeconomic perspectives. Further, models incorporating pre- and post-BAPCPA regimes are utilized.

Findings
The results show that macroeconomic factors (interest and unemployment rates) are strong predictors of farm bankruptcies for farms while agricultural land values are the only consistent strong predictor among the agricultural factors. When evaluating the post-BAPCPA regime, only agricultural land values continue to be a significant predictor of farm bankruptcies. The findings also indicate a dynamic relationship with agricultural land values, where current year values are negatively related but previous year land values are positively related to bankruptcies.

Originality/value
The authors provide an analysis of the post-BAPCPA regime on farm bankruptcies that has not been evaluated within the literature yet. Further, the findings illuminate discussion on a potentially dynamic relationship with financial stress and agricultural land values.
Researching drinking “with” young people: a palette of methods
Authors: Wilkinson Samantha , Wilkinson Catherine 
Published: February 2018

Purpose
The purpose of this paper is to outline a study characterised by “pockets” of co-production and argue for the benefits of offering young people a palette of interdisciplinary methods to “opt into”, giving participants the opportunity to discuss their drinking practices and experiences “on their own terms”.

Design/methodology/approach
In total, 40 young people, aged 15-24 years, from the suburban case study locations of Chorlton and Wythenshawe, Manchester, UK, were recruited for multi-stage qualitative research. The participants were presented with a suite of both long-standing and innovative methods that they could “opt into”, including: interviews, peer interviews, diaries, mobile phone interviews, text messaging and participant observation.

Findings
This paper shows that both long-standing and innovative methods have their own individual strengths for researching into young people’s alcohol consumption practices and experiences. Yet, each of the methods utilised in this study also had specific drawbacks for researching substance use. Offering a palette of methods for participants to “opt into” was thus beneficial in: offsetting the weaknesses of other methods; triangulating the study findings; and enabling participants to communicate with the researcher in culturally credible ways.

Originality/value
By offering an honest account about the successes and failures of deploying a range of methods when exploring young people’s drinking practices and experiences, this paper is valuable for researchers in, and beyond, the field of substance use, seeking to broaden their methodological toolkit.