bluuebunny/crossref_metadata_2025 huggingface dataset:
Embryo-like features in developingBacillus subtilisbiofilms
Authors: Futo Momir , Opašić Luka , Koska Sara , Čorak Nina , Široki Tin , Ravikumar Vaishnavi , Thorsell Annika , Kifer Domagoj , Domazet-Lošo Mirjana , Vlahoviček Kristian , Mijaković Ivan , Domazet-Lošo Tomislav
Published: March 2020

Correspondence between evolution and development has been discussed for more than two centuries1. Recent work reveals that phylogeny-ontogeny correlations are indeed present in developmental transcriptomes of eukaryotic clades with complex multicellularity2–10. Nevertheless, it has been largely ignored that the pervasive presence of phylogeny-ontogeny correlations is a hallmark of development in eukaryotes6, 10–12. This perspective opens a possibility to look for similar parallelisms in biological settings where developmental logic and multicellular complexity are more obscure13–16. For instance, it has been increasingly recognized that multicellular behaviour underlies biofilm formation in bacteria13, 14, 17–19. However, it remains unclear whether bacterial biofilm growth shares some basic principles with development in complex eukaryotes14–16, 18, 20. Here we show that the ontogeny of growing Bacillus subtilis biofilms recapitulates phylogeny at the expression level. Using time-resolved transcriptome and proteome profiles, we found that biofilm ontogeny correlates with the evolutionary measures, in a way that evolutionary younger and more diverged genes were increasingly expressed towards later timepoints of biofilm growth. Molecular and morphological signatures also revealed that biofilm growth is highly regulated and organized into discrete ontogenetic stages, analogous to those of eukaryotic embryos11, 21. Together, this suggests that biofilm formation in Bacillus is a bona fide developmental process comparable to organismal development in animals, plants and fungi. Given that most cells on Earth reside in the form of biofilms22and that biofilms represent the oldest known fossils23, we anticipate that the widely-adopted vision of the first life as a single-cell and free-living organism needs rethinking.
Evidence fromAmphioxusfor acquisition of alternative mRNA splicing of NCoR corepressor after its duplication and divergence during vertebrate evolution
Authors: Privalsky Martin L.
Published: March 2020

NCoR-1 and NCoR-2 are transcriptional corepressors encoded in vertebrates by two interrelated loci and play distinct, though overlapping, roles in development, differentiation, and homeostasis. In contrast NCoR is encoded by a single locus in cephalochordates, urochordates, hemichordates, and echinoderms, with vertebrate NCoR-1 and NCoR-2 thought to be the products of a gene duplication originating near the beginning of vertebrate evolution. The structures, molecular properties, and functions of extant NCoR-1 and NCoR-2 are each substantially further diversified by alternative mRNA splicing; however it is unresolved as to whether the alternative-splicing observed in current day vertebrates reflects patterns present in the ancestral common gene or instead arose after the NCoR duplication event. This manuscript reports thatAmphioxus, a cephalochordate considered representative of the organisms that gave rise to the vertebrate lineage, lacks the alternative NCoR splicing events characteristic of vertebrates. This, together with prior taxonomic comparisons, suggests that the patterns of corepressor splicing found in existing vertebrates arose exclusively after the NCoR duplication event. Further, given that alternative-splicing of NCoR-1 and NCoR-2 appears to have arisen by a mix of convergent and divergent evolution, it is likely that both common and distinct selective pressures were operative on these corepressor paralogs after their divergence.
Rapid, direct detection of bacterial Topoisomerase 1-DNA adducts by RADAR/ELISA
Authors: Sinha Devapriya , Kiianitsa Kostantin , Sherman David R. , Maizels Nancy
Published: March 2020

Topoisomerases are proven drug targets, but antibiotics that poison bacterial Topoisomerase 1 (Top1) have yet to be discovered. We have developed a rapid and direct assay for quantification of Top1-DNA adducts that is suitable for high throughput assays. Adducts are recovered by “RADAR fractionation”, a quick, convenient approach in which cells are lysed in chaotropic salts and detergent and nucleic acids and covalently bound adducts then precipitated with alcohol. Here we show that RADAR fractionation followed by ELISA immunodetection can quantify adducts formed by wild-type and mutant Top1 derivatives encoded by two different bacterial pathogens,Y. pestisandM. tuberculosis, expressed inE. coliorM. smegmatis, respectively. For both enzymes, quantification of adducts by RADAR/ELISA produces results comparable to the more cumbersome classical approach of CsCl density gradient fractionation. The experiments reported here establish that RADAR/ELISA assay offers a simple way to characterize Top1 mutants and analyze kinetics of adduct formation and repair. They also provide a foundation for discovery and optimization of drugs that poison bacterial Top1 using standard high-throughput approaches.
Mitochondria-mitochondria interaction networks show altered topological patterns in Parkinson’s disease
Authors: Zanin Massimiliano , Santos Bruno F. R. , Antony Paul M.A. , Berenguer-Escuder Clara , Larsen Simone B. , Hanss Zoé , Barbuti Peter , Baumuratov Aidos S. , Grossmann Dajana , Capelle Christophe , Weber Joseph , Balling Rudi , Ollert Markus , Krüger Rejko , Diederich Nico J. , He Feng Q.
Published: March 2020

Mitochondrial dysfunction is linked to pathogenesis of Parkinson’s disease (PD). However, individual-mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact with each other, we hypothesize that PD-related features might exist in topological patterns of mitochondria-mitochondria interaction networks (MINs). Here we showed that MINs form non-classical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients, however, altered topological patterns are observed in PD patients. These patterns highly correlate with PD clinical scores and a machine-learning approach based on the MIN features accurately distinguish between patients and controls with an area-under-curve value of 0.989. The MINs of midbrain dopaminergic neurons (mDANs) derived from several genetic PD patients also display specific changes. CRISPR/CAS9-based genome correction of alpha-synuclein point mutations reverses the changes in MINs of mDANs. Our MIN network analysis opens a new dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation.
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

Tumors 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

To 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

Insects 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 statement

Anthropogenic 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

Dark 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

A 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

Chronic 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.
Rapid growth and fusion of protocells in surface-adhered membrane networks
Authors: Köksal Elif S. , Liese Susanne , Xue Lin , Ryskulov Ruslan , Viitala Lauri , Carlson Andreas , Gözen Irep
Published: March 2020

Elevated temperatures might have promoted the nucleation, growth and replication of protocells on the early Earth. Recent reports have shown evidence that moderately high temperatures not only permit protocell assembly at the origin of life, but could have actively supported it. Here we show the fast nucleation and growth of vesicular compartments from autonomously formed lipid networks on solid surfaces, induced by a moderate increase in temperature. Branches of the networks, initially consisting of self-assembled interconnected nanotubes, rapidly swell into microcompartments which can spontaneously encapsulate RNA fragments. The increase in temperature further causes fusion of adjacent network-connected compartments, resulting in the redistribution of the RNA. The experimental observations and the mathematical model indicate that the presence of nanotubular interconnections between protocells facilitates the fusion process.
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

Hepatocyte-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 statement

Hepatocyte-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

TET 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

It 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

Voltage 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.

SIGNIFICANCE

KCNQ 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

Growing 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

Peroxisomes 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

Algorithms 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

The 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.
Enhanced activity of glycolytic enzymes in Drosophila and human cell models of Parkinson’s disease based on DJ-1 deficiency
Authors: Solana-Manrique Cristina , Sanz Francisco José , Ripollés Edna , Bañó M. Carmen , Torres Josema , Muñoz-Soriano Verónica , Paricio Nuria
Published: March 2020

Parkinson’s disease (PD) is a neurodenerative debilitating disorder characterized by progressive disturbances in motor, autonomic and psychiatric functions. The pathological hallmark of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta, which causes striatal dopamine deficiency. Although most PD cases are sporadic (iPD), approximately 5-10% of all patients suffer from monogenic PD forms caused by highly penetrant rare mutations segregating with the disease in families (fPD). One of the genes linked to monogenic PD is DJ-1. Mutations in DJ-1 cause autosomal recessive early-onset forms of fPD; however, it has been shown that an over-oxidized and inactive form of the DJ-1 protein is found in the brains of iPD individuals. Valuable insights into potential PD pathogenic mechanisms involving DJ-1 have been obtained from studies in cell and animal PD models based on DJ-1 deficiency such as Drosophila. Flies mutant for the DJ-1β gene, the Drosophila ortholog of human DJ-1, exhibited disease-related phenotypes such as motor defects, increased reactive oxygen species production and high levels of protein carbonylation. In the present study, we show that loss of DJ-1β function significantly increased the activities of several regulatory glycolytic enzymes. Similar results were obtained in DJ-1-deficient SH-SY5Y neuroblastoma cells, thus suggesting that loss of DJ-1 function in both PD models produces an enhancement of glycolysis. Our results also show that FDA-approved compounds such as meclizine and dimethyl fumarate, which have different clinical applications, are able to attenuate PD-related phenotypes in both models. Moreover, we found that they could exert their beneficial effect by increasing glycolysis through the activation of key glycolytic enzymes. Taken together, these results are consistent with the idea that increasing glycolysis could be a potential disease-modifying strategy for PD, as recently suggested. Besides, they also support further evaluation and potential repurposing of meclizine and dimethyl fumarate as modulators of energy metabolism for neuroprotection in PD.
Gesture’s body orientation modulates the N400 during semantic integration of gesture and visual sentence
Authors: He Yifei , Luell Svenja , Muralikrishnan R. , Straube Benjamin , Nagels Arne
Published: March 2020

Body orientation of gesture entails social-communicative intention, and may thus influence how gestures are perceived and comprehended together with auditory speech during face-to-face communication. To date, despite the emergence of neuroscientific literature on the role of body orientation on hand action perception, limited studies have directly investigated the role of body orientation in the interaction between gesture and language. To address this research question, we carried out an EEG experiment presenting to participants (n=21) videos of frontal and lateral hand gestures of five-seconds (e.g., raising a hand), followed by visually presented sentences that are either congruent or incongruent with the hand gesture (e.g., ‘the mountain ishigh/low…’). All participants underwent a semantic-probe task, judging whether a target word is related or unrelated to the gesture-speech event. EEG results suggest that, during the perception phase of hand-gestures, while both frontal and lateral gestures elicited power decrease in both the alpha (8-12Hz) and the beta (16-24Hz) bands, lateral gestures elicited reduced power decrease in the beta band when compared with frontal gestures. For sentence comprehension, at the critical word whose meaning is congruent/incongruent with the gesture, frontal gestures elicited an N400 effect for gesture-sentence incongruency. More importantly, this incongruency effect was significantly reduced for lateral gestures. The findings suggest that body orientation plays a crucial role in gesture perception, and that its inferred social-communicative intention influences gesture-sentence semantic integration in an interactive manner.
Dynamical phase diagram of an auto-regulating gene in fast switching conditions
Authors: Jia Chen , Grima Ramon
Published: March 2020

While the steady-state behavior of stochastic gene expression with auto-regulation has been extensively studied, its time-dependent behavior has received much less attention. Here, under the assumption of fast promoter switching, we derive and solve a reduced chemical master equation for an auto-regulatory gene circuit with translational bursting and cooperative protein-gene interactions. The analytical expression for the time-dependent probability distribution of protein numbers enables a fast exploration of large swaths of parameter space. For a unimodal initial distribution, we identify three distinct types of stochastic dynamics: (i) the protein distribution remains unimodal at all times; (ii) the protein distribution becomes bimodal at intermediate times and then reverts back to being unimodal at long times (transient bimodality) and (iii) the protein distribution switches to being bimodal at long times. For each of these, the deterministic model predicts either monostable or bistable behaviour and hence there exist six dynamical phases in total. We investigate the relationship of the six phases to the transcription rates, the protein binding and unbinding rates, the mean protein burst size, the degree of cooperativity, the relaxation time to the steady state, the protein mean and the type of feedback loop (positive or negative). We show that transient bimodality is a noise-induced phenomenon that occurs when protein expression is sufficiently bursty and we use theory to estimate the observation time window when it is manifest.
Contributions of the four essential entry glycoproteins to HSV-1 tropism and the selection of entry routes
Authors: Hilterbrand Adam T. , Daly Raecliffe E. , Heldwein Ekaterina E.
Published: March 2020

Herpes Simplex viruses (HSV-1 and HSV-2) encode up to 16 envelope proteins, four of which are essential for entry. However, whether these four proteins alone are sufficient to dictate the broad cellular tropism of HSV-1 and the selection of different cell-type dependent entry routes is unknown. To begin addressing this, we previously pseudotyped VSV, lacking its native glycoprotein G, with only the four essential entry glycoproteins of HSV-1: gB, gH, gL, and gD. This novel VSVΔG-BHLD pseudotype recapitulated several important features of HSV-1 entry: the requirement for gB, gH, gL, gD, a cellular receptor, and sensitivity to anti-gB and anti-gH/gL neutralizing antibodies. However, due to the use of a single cell type in that study, the tropism of the VSVΔG-BHLD pseudotype was not investigated. Here, we show that the cellular tropism of the pseudotype is severely limited compared to wild-type HSV-1 and that its entry pathways differ from the native HSV-1 entry pathways. To test the hypothesis that other HSV-1 envelope proteins may contribute to HSV-1 tropism, we generated a derivative pseudotype containing the HSV-1 glycoprotein gC (VSVΔG-BHLD-gC) and observed a gC-dependent increase in entry efficiency in two cell types. We propose that the pseudotyping platform developed here has the potential to uncover functional contributions of HSV-1 envelope proteins to entry in a gain-of-function manner.

Importance

Herpes simplex viruses (HSV-1 and HSV-2) contain up to 16 different proteins in their envelopes. Four of these, glycoproteins gB, gD, gH, and gL, are termed essential with regard to entry whereas the rest are typically referred to as non-essential based on the entry phenotypes of the respective single genetic deletions. However, the single-gene deletion approach, which relies on robust loss-of-function phenotypes, may be confounded by functional redundancies among the many HSV-1 envelope proteins. We have developed a pseudotyping platform, in which the essential four entry glycoproteins are isolated from the rest, which can be added back individually for systematic gain-of-function entry experiments. Here, we show the utility of this platform for dissecting the contributions of HSV envelope proteins, both the essential four and the remaining dozen (using gC as an example), to HSV entry.
Assortative mate choice and epistatic mating-trait architecture induce complex movement of the crow hybrid zone
Authors: Metzler Dirk , Knief Ulrich , Peñalba Joshua V. , Wolf Jochen B. W.
Published: March 2020

Hybrid zones provide a window into the evolutionary processes governing species divergence. While the role of postzygotic isolation has been extensively characterized in the context of hybrid zones, the contribution of prezygotic isolation is less well explored. Here, we investigate the effects of assortative mate choice, the underlying preference function and mating-trait architecture, and the strength of sexual selection on hybrid zone dynamics. We explore this question by means of a mathematical model parameterized with phenotype and genotype data from the hybrid zone between all-black carrion and grey-coated hooded crows. The best-fit model resulted in narrow clines for two mating-trait loci coding for colour phenotype maintained by a moderate degree of assortative mating. Epistasis between the two loci induced hybrid-zone movement in favor of alleles conveying dark plumage followed by a shift in the opposite direction favouring grey-coated phenotypes ∼1,200 generations after secondary contact. Unlinked neutral loci diffused near-unimpeded across the zone. These results were generally robust to the choice of matching rule (self-referencing or parental imprinting) and effects of genetic drift. Overall, this study illustrates under which conditions assortative mating can maintain steep clines in mating-trait loci without generalizing to genome-wide reproductive isolation. It further emphasizes the importance of mating-trait architecture for spatio–temporal hybrid-zone dynamics.
Identification of Interleukin1β as an Amplifier of Interferon alpha-induced Antiviral Responses
Authors: Robichon Katharina , Maiwald Tim , Schilling Marcel , Schneider Annette , Willemsen Joschka , Salopiata Florian , Teusel Melissa , Salopiata  , Kreutz Clemens , Ehlting Christian , Huang Jun , Chakraborty Sajib , Huang Xiaoyun , Damm Georg , Seehofer Daniel , Lang Philipp A. , Bode Johannes G. , Binder Marco , Bartenschlager Ralf , Timmer Jens , Klingmüller Ursula
Published: March 2020

The induction of an interferon-mediated response is the first line of defense against pathogens such as viruses. Yet, the dynamics and extent of interferon alpha (IFNα)-induced antiviral genes vary remarkably and comprise three expression clusters: early, intermediate and late. By mathematical modeling based on time-resolved quantitative data, we identified mRNA stability as well as a negative regulatory loop as key mechanisms endogenously controlling the expression dynamics of IFNα-induced antiviral genes in hepatocytes. Guided by the mathematical model, we uncovered that this regulatory loop is mediated by the transcription factor IRF2 and showed that knock-down of IRF2 results in enhanced expression of early, intermediate and late IFNα-induced antiviral genes. Co-stimulation experiments with different pro-inflammatory cytokines revealed that this amplified expression dynamics of the early, intermediate and late IFNα-induced antiviral genes can be mimicked by co-application of IFNα and interleukin1 beta (IL1β). Consistently, we found that IL1β enhances IFNα-mediated repression of viral replication. Conversely, we observed that in IL1β receptor knock-out mice replication of viruses sensitive to IFN is increased. Thus, IL1β is capable to potentiate IFNα-induced antiviral responses and could be exploited to improve antiviral therapies.

Author Summary

Innate immune responses contribute to the control of viral infections and the induction of interferon alpha (IFNα)-mediated antiviral responses is an important component. However, IFNα induces a multitude of antiviral response genes and the expression dynamics of these genes can be classified as early, intermediate and late. Here we show, based on a mathematical modeling approach, that mRNA stability as well as the negative regulator IRF2 control the expression dynamics of IFNα-induced antiviral genes. Knock-down of IRF2 resulted in the amplified IFNα-mediated induction of the antiviral genes and this amplified expression of antiviral genes could be mimicked by co-stimulation with IFNα and IL1β. We observed that co-stimulation with IFNα and IL1β enhanced the repression of virus replication and that knock-out of the IL1 receptor in mice resulted in increased replication of a virus sensitive to IFNα. In sum, our studies identified IL1β as an important amplifier of IFNα-induced antiviral responses.
Genetic connectivity and diversity of endangered species the scalloped hammerhead sharkSphyrna lewini(Griffith & Smith 1834) population in Indonesia and Western Indian Ocean
Authors: Hadi Sutanto , Andayani Noviar , Muttaqin Effin , Simeon Benaya M , Ichsan Muhammad , Subhan Beginer , Madduppa Hawis
Published: March 2020

The scalloped hammerhead sharkSphyrna lewiniis an endangered species which expected to population declined worldwide including in Indonesia due to overexploited. However, there is a lack of information regarding recent population structure to promote proper management and conservation status in Indonesia. This study aimed to investigate the genetic diversity, population structure and connectivity ofS. lewinipopulation in Indonesia from three major sharks landing sites in Aceh (n= 41), Balikpapan (n= 30), Lombok (n= 29), and additional sequences retrieved from West Papua (n= 14) and Western Indian Ocean population (n= 65). Analyses of mitochondrial CO1 gene successfully identified a total of 179 sequences ofS. lewiniwith an average 594 bp nucleotide with 40 polymorphic loci in 4 haplotypes for Indonesian population and 8 haplotypes for Western Indian Ocean. The overall values of genetic diversity in Indonesia was high (Hd= 0.7171; π= 0.0126), with the highest was in Aceh (Hd= 0.6683; π= 0.0198), and the lowest was in Papua (Hd= 0.1429; π= 0.0005), while in Western Indian Ocean the overall value was fairly low (Hd= 0.2322; π= 0.0010). The AMOVA andFSTrevealed three significant population subdivisions in Indonesia (FST= 0.4415;p< 0.001) with separated population for Aceh and West Papua, and a mixing population between Balikpapan and Lombok (FST= 0.044;p= 0.089), whereas relatively no significant differentiation within population in Western Indian Ocean (FST= −0.0131;p= 0.6011), and significant different level showed by Indonesian population compared with Western Indian Ocean population (FST= 0.7403;p< 0.001). The construction of haplotype network exhibited evidence of gene flow and haplotype sharing between populations. This result indicated a complex and limited connectivity population ofS. lewiniin Indonesia, and between Western Indian Ocean in regional scale which need co-management action across region.
Specialization of mid-tier stages of dorsal and ventral pathways in stereoscopic processing
Authors: Yoshioka Toshihide W. , Doi Takahiro , Abdolrahmani Mohammad , Fujita Ichiro
Published: March 2020

The division of labor between the dorsal and ventral visual pathways is an influential model of parallel information processing in the cerebral cortex. However, direct comparison of the two pathways at the single-neuron resolution has been scarce. Here we compare how MT and V4, mid-tier areas of the two pathways in the monkey, process binocular disparity, a powerful cue for depth perception and visually guided actions. We report a novel tradeoff where MT neurons transmit disparity signals quickly and robustly, whereas V4 neurons markedly transform the nature of the signals with extra time to solve the stereo correspondence problem. Therefore, signaling speed and robustness are traded for computational complexity. The key factor in this tradeoff was the shape of disparity tuning: V4 neurons had more even-symmetric tuning than MT neurons. Moreover, this correlation between tuning shape and signal transformation was present across individual neurons within both MT and V4. Overall, our results reveal both distinct signaling advantages and common tuning-curve features of the dorsal and ventral pathways in stereoscopic processing.