bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma
Authors: Lau Allison N. , Li Zhaoqi , Danai Laura V. , Westermark Anna M. , Darnell Alicia M. , Ferreira Raphael , Gocheva Vasilena , Sivanand Sharanya , Lien Evan C. , Sapp Kiera M. , Mayers Jared R. , Biffi Giulia , Chin Christopher R. , Davidson Shawn M. , Tuveson David A. , Jacks Tyler , Matheson Nicholas J. , Yilmaz Omer H. , Heiden Matthew G. Vander 
Published: March 2020

AbstractTumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between various cell types within a mixed population can be limited by the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in pancreatic cancer organoid-fibroblast co-cultures and in pancreatic tumors. In these contexts, we find pancreatic cancer cells exhibit increased pyruvate carboxylation relative to fibroblasts, and that this flux depends on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells is necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tumor tissue.
Metabolic rules of microbial community assembly
Authors: Estrela Sylvie , Vila Jean C. C. , Lu Nanxi , Bajic Djordje , Rebolleda-Gomez Maria , Chang Chang-Yu , Sanchez Alvaro 
Published: March 2020

AbstractTo develop a quantitative theory that can predict how microbiomes assemble, and how they respond to perturbations, we must identify which descriptive features of microbial communities are reproducible and predictable, which are unpredictable, and why. The emergent metagenomic structure of communities is often quantitatively convergent in similar habitats, with highly similar fractions of the metagenome being devoted to the same metabolic pathways. By contrast, the species-level taxonomic composition is often highly variable even in replicate environments. The mechanisms behind these patterns are not yet understood. By studying the self-assembly of hundreds of communities in replicate, synthetic habitats, we show that the reproducibility of microbial community assembly reflects an emergent metabolic structure, which is quantitatively predictable from first-principles, genome-scale metabolic models. Taxonomic variability within functional groups arises through multistability in population dynamics, and the species-level community composition is predictably governed by the mutual competitive exclusion of two sub-dominant strains. Our findings provide a mechanistic bridge between microbial community structure at different levels of organization, and show that the evolutionary conservation of metabolic traits, both in terms of growth responses and niches constructed, can be leveraged to quantitatively predict the taxonomic and metabolic structure of microbial communities.
Insects and recent climate change
Authors: Halsch Christopher A. , Shapiro Arthur M. , Fordyce James A. , Nice Chris C. , Thorne James H. , Waetjen David P. , Forister Matthew L. 
Published: March 2020

AbstractInsects have diversified through 400 million years of Earth’s changeable climate, yet recent and ongoing shifts in patterns of temperature and precipitation pose novel challenges as they combine with decades of other anthropogenic stressors including the conversion and degradation of land. Here we consider how insects are responding to recent climate change, while summarizing the literature on long-term monitoring of insect populations in the context of climatic fluctuations. Results to date suggest that climate change impacts on insects have the potential to be considerable, even when compared to changes in land use. The importance of climate is illustrated with a case study from the butterflies of Northern California, where we find that population declines have been severe in high-elevation areas removed from the most immediate effects of habitat loss. These results shed light on the complexity of montane-adapted insects responding to changing abiotic conditions and raise questions about the utility of temperate mountains as refugia during the Anthropocene. We consider methodological issues that would improve syntheses of results across long-term insect datasets and highlight directions for future empirical work.Significance statementAnthropogenic climate change poses multiple threats to society and biodiversity, and challenges our understanding of the resilience of the natural world. We discuss recent ideas and evidence on this issue and conclude that the impacts of climate change on insects in particular have the potential to be more severe than might have been expected a decade ago. Finally, we suggest practical measures that include the protection of diverse portfolios of species, not just those inhabiting what are currently the most pristine areas.
From taxonomic to functional dark diversity: exploring the causes of potential biodiversity and its implications for conservation
Authors: Morel Loïs , Jung Vincent , Chollet Simon , Ysnel Frédéric , Barbe Lou 
Published: March 2020

AbstractDark diversity is an emerging and promising concept proposed to estimate the recruitment potential of natural communities and guide conservation and restoration policies. It represents all the species that could be present in a community due to favourable environmental conditions, but are currently lacking. To date, experimental approaches only measured taxonomic dark diversity, mainly based on species coexistence, which relies partly on neutral processes. Thus, these approaches may fail to identify the biodiversity which is lacking for deterministic reasons, and can hence hardly bring out suitable restoration methods.Here, we propose a novel method to estimate dark diversity, which is based on more deterministic coexistence: the coexistence of species’ functional features. We adapted the Beals’ co-occurrence index using functional groups, and we estimated functional dark diversity based on coexistence of functional groups. We then made use of functional dark diversity to address a persistent issue of restoration ecology: how does passive rewilding impact the ecological integrity of recovered communities? We compared spontaneous, secondary woodlands with ancient forests, in terms of taxonomic and functional dark diversity of vascular plants and spiders.Our results indicated that functional dark diversity does not equate to taxonomic dark diversity. Considering plants, recent woodlands surprisingly harboured less functional dark diversity than ancient forests, while they had a very similar amount of taxonomic dark diversity. Concerning spiders, recent woodlands harboured a similar amount of functional dark diversity as ancient forests, but more taxonomic dark diversity. Also, the composition of functional dark diversity differed between forest types, shedding light on their past assembly processes and unveiling their potential for conservation and effective restoration.Synthesis and applications. Functional dark diversity brings novel perspectives for ecological diagnostic and restoration. Combined to taxonomic dark diversity, it enables to identify easily the deterministic constrains which limit the re-assembly of ecological communities after land-use changes and to predict the realistic, possible establishments of functional features. Here, we showed that spontaneous woodlands can have very similar, sometimes even higher, ecological integrity than that of ancient forests, and hence may be valuable habitats to be conserved from an ecological perspective.
Object representations in the human brain reflect the co-occurrence statistics of vision and language
Authors: Bonner Michael F. , Epstein Russell A. 
Published: March 2020

ABSTRACTA central regularity of visual perception is the co-occurrence of objects in the natural environment. Here we use machine learning and fMRI to test the hypothesis that object co-occurrence statistics are encoded in the human visual system and elicited by the perception of individual objects. We identified low-dimensional representations that capture the latent statistical structure of object co-occurrence in real-world scenes, and we mapped these statistical representations onto voxelwise fMRI responses during object viewing. We found that cortical responses to single objects were predicted by the statistical ensembles in which they typically occur, and that this link between objects and their visual contexts was made most strongly in the anterior portion of the scene-selective parahippocampal place area. In contrast, a language-based statistical model of the co-occurrence of object names in written text predicted responses in neighboring regions of object-selective visual cortex. Together, these findings show that the sensory coding of objects in the human brain reflects the latent statistics of object context in visual and linguistic experience.
The effect of acute sleep deprivation on skeletal muscle protein synthesis and the hormonal environment
Authors: Lamon Séverine , Morabito Aimee , Arentson-Lantz Emily , Knowles Olivia , Vincent Grace Elizabeth , Condo Dominique , Alexander Sarah , Garnham Andrew , Paddon-Jones Douglas , Aisbett Brad 
Published: March 2020

AbstractChronic sleep loss is a potent catabolic stressor, increasing the risk of metabolic dysfunction and loss of muscle mass and function. To provide mechanistic insight into these clinical outcomes, we sought to determine if acute sleep deprivation blunts skeletal muscle protein synthesis and promotes a catabolic environment. Healthy young adults (N=13; 7 male, 6 female) were subjected to one night of total sleep deprivation (DEP) and normal sleep (CON) in a randomized cross-over design. Anabolic and catabolic hormonal profiles, skeletal muscle fractional synthesis rate and markers of muscle protein degradation were assessed across the following day. Acute sleep deprivation reduced muscle protein synthesis by 18% (CON: 0.072 ± 0.015 vs. DEP: 0.059 ± 0.014 %•h-1, p=0.040). In addition, it increased plasma cortisol by 21% (p=0.030) and decreased plasma testosterone, but not IGF-1, by 22% (p=0.029). A single night of total sleep deprivation is sufficient to induce anabolic resistance and a pro-catabolic environment. These acute changes may represent mechanistic precursors driving the metabolic dysfunction and body composition changes associated with chronic sleep deprivation.
Heat treatment functionalizes hepatocyte-like cells derived from human embryonic stem cells
Authors: Imamura Satoshi , Yoshimoto Koki , Terada Shiho , Kamei Ken-ichiro 
Published: March 2020

AbstractHepatocyte-like cells derived from human pluripotent stem cells (hPSC-HLCs) offer an alternative to primary hepatocytes commonly used for drug screenings and toxicological tests. Although tremendous efforts have been made to facilitate hepatic functions of hPSC-HLCs using growth factors and chemicals, these cells have not yet reached hepatic functions comparable to hepatocytes in vivo. Therefore, there exists a critical need to use an alternative trigger to facilitate hepatic functions in hPSC-HLCs. We noted that human liver temperature (around 39°C) is higher than normal human body temperature (around 36.5°C), yet hepatocytes are generally cultured at 37°C in-vitro. Here we showed that hepatic functions of hPSC-HLCs would be facilitated under physiological liver temperatures. We identified the optimal temperature by treating HLCs derived from H9 human embryonic stem cells (hESC-HLCs) at 39°C and 42°C. 42°C-treatment caused significantly greater cell death compared to 39°C. We also confirmed the increases of hepatic functions, such as secretion of albumin, cytochrome P450 3A4 (CYP3A4) activities, and collagen productions, without severe cell damages. To elucidate the underlying mechanisms of heat-induced hepatic functions, RNA-seq was to identify gene expression signatures due to 39°C-treated hESC-HLCs. This study also showed the possible mechanisms of heat-induced hepatic function via glucocorticoid receptor pathway and molecular chaperons. In combination with existing hepatic differentiation protocols, the method proposed here may further improve hepatic functions for hPSCs, and lead to the realization of drug discovery efforts and drug toxicological tests.Significance statementHepatocyte-like cells derived from human pluripotent stem cells (hPSC-HLCs) offer an alternative to primary hepatocytes commonly used for drug screenings and toxicological tests. We noted that human liver temperature (around 39°C) is higher than normal human body temperature (around 36.5°C), affecting the in-vitro hepatic functions of hPSC-HLCs, such as metabolic activities. Here we showed that hepatic functions of hPSC-HLCs, albumin secretion, CYP3A4 activities, and collagen production would be facilitated under physiological liver temperatures at 39°C, without severe cell damages. RNA-seq was used to elucidate the underlying mechanisms of heat-induced hepatic functions. This study also showed the possible mechanisms of heat-induced hepatic function via glucocorticoid receptor pathway and molecular chaperons.
The chromatin remodeler LSH controls genome-wide cytosine hydroxymethylation
Authors: de Dieuleveult Maud , Bizet Martin , Colin Laurence , Calonne Emilie , Bachman Martin , Li Chao , Stancheva Irina , Fuks François , Deplus Rachel 
Published: March 2020

ABSTRACTTET proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), leading to a dynamic epigenetic state of DNA that can influence transcription. While TET proteins have been associated with either epigenetic repression or activation complexes, the overall understanding of the molecular mechanisms involved in TET-mediated regulation of gene transcription still remains limited. Here, we show that TET proteins interact with lymphoid-specific helicase (LSH), a chromatin remodeling factor belonging to the SNF2 super family. Lsh knock-out leads to a significant reduction of 5-hydroxymethylation global level in mouse embryonic fibroblasts (MEFs) and in embryonic stem cells (ESC). Whole genome sequencing of 5hmC in wild-type versus Lsh knock-out MEFs and ESCs showed that in absence of Lsh, some regions of the genome gain 5hmC while others lose it, with not much effect on gene expression. We further show that 5hmC modifications upon Lsh loss is not a direct consequence of 5mC decrease, as differentially hydroxymethylated regions (DhMR) did not overlap with DMR (differentially methylated regions), underlying that these modifications occurred at different genomic loci. Altogether, our results suggest that LSH is a key regulator of 5hmC in both MEFs and ESC and that TET proteins rely on specific factors to establish genome-wide 5hmC patterns.
Values Encoded in Orbitofrontal Cortex Are Causally Related to Economic Choices
Authors: Ballesta Sébastien , Shi Weikang , Conen Katherine E. , Padoa-Schioppa Camillo 
Published: March 2020

AbstractIt has long been hypothesized that economic choices rely on the assignment and comparison of subjective values. Indeed, when agents make decisions, neurons in orbitofrontal cortex encode the values of offered and chosen goods. Moreover, neuronal activity in this area suggests the formation of a decision. However, it is unclear whether these neural processes are causally related to choices. More generally, the evidence linking economic choices to value signals in the brain remains correlational. We address this fundamental issue using electrical stimulation in rhesus monkeys. We show that suitable currents bias choices by increasing the value of individual offers. Furthermore, high-current stimulation disrupts both the computation and the comparison of subjective values. These results demonstrate that values encoded in orbitofrontal cortex are causal to economic choices.
THE ROLE OF POTASSIUM CHANNELS IN THE PATHOGENESIS OF GASTROINTESTINAL CANCERS AND THERAPEUTIC POTENTIAL
Authors: Shorthouse David , Zhuang John L , Rahrmann Eric P , Kosmidou Cassandra , Rahrmann Katherine Wickham , Hall Michael , Greenwood Benedict , Devonshire Ginny , Gilbertson Richard J , Fitzgerald Rebecca C. , Hall Benjamin A 
Published: March 2020

ABSTRACTVoltage sensitive potassium channels play an important role in controlling membrane potential and ionic homeostasis in the gut and have been implicated in gastrointestinal (GI) cancers. Through large scale analysis of 1594 patients with GI cancers coupled within vitromodels we find KCNQ family genes are mutated in ~30% of patients, and play therapeutically targetable roles in GI cancer growth. KCNQ1 and KCNQ3 mediate the WNT pathway and MYC to increase proliferation, and its resultant effects on cadherins junctions. This also highlights novel roles for KCNQ3 in non-excitable tissues. We additionally discover that activity of KCNQ3 sensitises cancer cells to existing potassium channel inhibitors, and that inhibition of KCNQ activity reduces proliferation of GI cancer. These findings reveal a novel and exploitable role for potassium channels in the advancement of human cancer, and highlight that supplemental treatments for GI cancers may exist through KCNQ inhibitors.SIGNIFICANCEKCNQ channels modulate the WNT pathway and MYC signalling, and drive growth of gastrointestinal cancers. Available drugs modulate these pathways and offer therapeutic potential in gastrointestinal cancer.
A quasi-paired cohort strategy reveals the impaired detoxifying function of microbes in the gut of autistic children
Authors: Zhang Mengxiang , Chu Yanan , Meng Qingren , Ding Rui , Shi Xing , Wang Zuqun , He Yi , Zhang Juan , Liu Jing , Zhang Jie , Yu Jun , Kang Yu , Wang Juan 
Published: March 2020

AbstractGrowing evidence suggests that autism spectrum disorder (ASD) is highly associated with dysbiosis in the gut microbiome. However, results of metagenome-based microbiome studies are not always consistent due to great individual diversity that overwhelms disease-associated alterations. Here, we proposed a novel analysis strategy—quasi-paired cohort and applied it to a metagenomic study of ASD microbiomes. By comparing the paired samples of ASD and neurotypical subjects, we identified significant deficiencies in ASD children in detoxifying enzymes and pathways, which showed strong correlations to mitochondrial damage. Diagnostic models with these detoxifying enzymes accurately discriminated ASD individuals from controls, and the dysfunction score inferred from the model increased with the clinical rating scores of ASD. Conclusively, our findings suggest a previously undiscovered mechanism in which impaired microbial detoxification leads to toxicant accumulation and mitochondrion damage contributes to the pathogenesis of ASD. This novel mechanism points to future therapeutic strategies of rebuilding microbial detoxification for ASD.
A PEROXO-Tag enables rapid isolation of peroxisomes from human cells
Authors: Ray G. Jordan , Boydston Elizabeth A. , Shortt Emily , Wyant Gregory A. , Lourido Sebastian , Chen Walter W. , Sabatini David M. 
Published: March 2020

ABSTRACTPeroxisomes are metabolic organelles that perform a diverse array of critical functions in human physiology. Traditional isolation methods for peroxisomes can take more than one hour to complete and can be laborious to implement. To address this, we have now extended our prior work on rapid organellar isolation to peroxisomes via the development of a peroxisomally-localized 3XHA epitope tag (“PEROXO-Tag”) and associated immunoprecipitation (“PEROXO-IP”) workflow. Our PEROXO-IP workflow has excellent reproducibility, is easy to implement, and achieves highly rapid (~10 minutes post-homogenization) and specific isolation of human peroxisomes, which we characterize here via proteomic profiling. By offering speed, specificity, reproducibility, and ease of use, the PEROXO-IP workflow should facilitate studies on the biology of peroxisomes.
DOMINO: a novel algorithm for network-based identification of active modules with reduced rate of false calls
Authors: Levi Hagai , Elkon Ran , Shamir Ron 
Published: March 2020

AbstractAlgorithms for active module identification (AMI) are central to analysis of omics data. Such algorithms receive a gene network and nodes’ activity scores as input and report sub-networks that show significant over-representation of accrued activity signal (‘active modules’), thus representing biological processes that presumably play key roles in the analyzed biological conditions. Although such methods exist for almost two decades, only a handful of studies attempted to compare the biological signals captured by different methods. Here, we systematically evaluated six popular AMI methods on gene expression (GE) and GWAS data. Notably, we observed that GO terms enriched in modules detected by these methods on the real data were often also enriched on modules found on randomly permuted input data. This indicated that AMI methods frequently report modules that are not specific to the biological context measured by the analyzed omics dataset. To tackle this bias, we designed a permutation-based method that evaluates the empirical significance of GO terms reported as enriched in modules. We used the method to fashion five novel performance criteria for evaluating AMI methods. Last, we developed DOMINO, a novel AMI algorithm, that outperformed the other six algorithms in extensive testing on GE and GWAS data. Software is available athttps://github.com/Shamir-Lab.
CA1 20-40 Hz oscillatory dynamics reflect trial-specific information processing supporting nonspatial sequence memory
Authors: Gattas Sandra , Elias Gabriel A. , Yassa Michael A. , Fortin Norbert J. 
Published: March 2020

AbstractThe hippocampus is known to play a critical role in processing information about temporal context. However, it remains unclear how hippocampal oscillations are involved, and how their functional organization is influenced by connectivity gradients. We examined local field potential activity in CA1 as rats performed a complex odor sequence memory task. We find that odor sequence processing epochs were characterized by increased power in the 4-8 Hz and 20-40 Hz range, with 20-40 Hz oscillations showing a power gradient increasing toward proximal CA1. Running epochs were characterized by increased power in the 8-12 Hz range and across higher frequency ranges (>24 Hz), with power gradients increasing toward proximal and distal CA1, respectively. Importantly, 20-40 Hz power increased with knowledge of the sequence and carried trial-type-specific information. These results suggest that 20-40 Hz oscillations are associated with trial-specific processing of nonspatial information critical for order memory judgments.