bluuebunny/crossref_metadata_2025_split huggingface dataset:
The evolution of extreme fertility defied ancestral gonadotropin mediated brain-reproduction tradeoff
Authors: Shpigler Hagai Y , Herb Brian , Drnevich Jenny , Band Mark , Robinson Gene E , Bloch Guy 
Published: May 2020

AbstractGonadotropic hormones coordinate processes in diverse tissues regulating animal reproductive physiology and behavior. Juvenile hormone (JH) is the ancient and most common gonadotropin in insects, but not in advanced eusocial honey bees and ants. To probe the evolutionary basis of this change, we combined endocrine manipulations, transcriptomics, and behavioral analyses to study JH regulated processes in a bumble bee showing an intermediate level of sociliality. We found that in the fat body, more JH-regulated genes were upregulated and enriched for metabolic and biosynthetic pathways. This transcriptomic pattern is consistent with earlier evidence that JH is the major gonadotropin in the bumble bee. In the brain, most JH-regulated genes were downregulated and enriched for protein turnover pathways. Brain ribosomal protein gene expression was similarly downregulated in dominant workers, which naturally have high JH titers. In other species, similar downregulation of protein turnover is found in aging brains or under stress, and is associated with compromised long-term memory and health. These findings suggest a previously unknown gonadotropin-mediated tradeoff. We did not find a similar downregulation of protein turnover pathways in the brain of honey bees in which JH is not a gonadotropin but rather regulates division of labor. These differences between JH effets in the bumble bee and in the advanced eusocial honey bee suggest that the evolution of advanced eusociality was associated with modifications in hormonal signaling supporting extended and extremely high fertility while reducing the ancient costs of high gonadotropin titers to the brain.
The Role of Conjunctive Representations in Regulating Actions
Authors: Kikumoto Atsushi , Mayr Ulrich 
Published: May 2020

AbstractAction selection appears to rely on conjunctive representations that nonlinearly integrate task-relevant features (Kikumoto & Mayr, 2020). We test here the corollary hypothesis that such representations are also intricately involved during attempts to stop an action—a key aspect of action regulation. We tracked both conjunctive representations and those of constituent rule, stimulus, or response features through trial-by-trial representational similarity analysis of the EEG signal in a combined, rule-selection and stop-signal paradigm. Across two experiments with student participants (N= 57), we found (a) that the strength of decoded conjunctive representations prior to the stop signal uniquely predicted trial-by-trial stopping success (Exp. 1) and (b) that these representations were selectively suppressed following the onset of the stop signal (Exp. 1 and 2). We conclude that conjunctive representations are key to successful action execution and therefore need to be suppressed when an intended action is no longer appropriate.Statement of RelevanceSome theorists have posited that as a necessary step during action selection, action-relevant features need to be combined within a conjunctive representation that is more than the sum if its basic features. Consequently, such representations should also play a critical role when trying to stop an intended action—a key aspect of self-regulation. However direct evidence of conjunctive representations has been elusive. Using a method for tracking both conjunctive and basic-feature representations on a trial-by-trial basis in the EEG signal, we show that the stronger the conjunctive representations, the harder it was to stop the intended action. Furthermore, the stopping process also selectively reduced the strength of conjunctive representations. These results further our knowledge about action regulation by showing that conjunctive representations are a necessary precursor for carrying out actions successfully and for that reason also need to be the target of self-regulatory stopping attempts.
A functional screening platform for engineering chimeric antigen receptors with reduced on-target, off-tumour activation
Authors: Di Roberto Raphaël B. , Rueda Rocío Castellanos , Frey Samara , Egli David , Vazquez-Lombardi Rodrigo , Reddy Sai T. 
Published: May 2020

ABSTRACTChimeric antigen receptor (CAR) T cell therapies have advanced substantially in the clinic for cancer immunotherapy. However, challenges related to safety persist; one major concern is when CARs respond to antigen present on healthy cells (on-target, off-tumour response). A strategy to ameliorate this consists in engineering the affinity of CARs such that they are only activated by tumor cells expressing high antigen levels. Here, we developed a CAR T cell display platform for functional screening based on cell signaling. Starting with a CAR with high affinity towards its target antigen, we used CRISPR-Cas9 genome editing to generate a library of antigen-binding domain variants. Following multiple rounds of functional screening and deep sequencing-guided selection, CAR variants were identified that were discriminatively activated by tumor cells based on antigen expression levels. Our platform demonstrates how directed evolution based on functional screening can be used to enhance the selectivity and safety of CARs.
Determination of primary microRNA processing in clinical samples by targeted pri-miR-sequencing
Authors: Conrad Thomas , Ntini Evgenia , Lang Benjamin , Cozzuto Luca , Andersen Jesper B , Marquardt Jens U , Ponomarenko Julia , Tartaglia Gian Gaetano , Ørom Ulf A V 
Published: May 2020

AbstractMicroRNA expression is important for gene regulation and deregulated microRNA expression is often observed in disease such as cancer. The processing of primary microRNA transcripts is an important regulatory step in microRNA biogenesis. Due to low expression level and association with chromatin primary microRNAs are challenging to study in clinical samples where input material is limited.Here, we present a high-sensitivity targeted method to determine processing efficiency of several hundred primary microRNAs from total RNA using as little as 500 thousand Illumina HiSeq sequencing reads. We validate the method using RNA from HeLa cells and show the applicability to clinical samples by analyzing RNA from normal liver and hepatocellular carcinoma.We identify 24 primary microRNAs with significant changes in processing efficiency from normal liver to hepatocellular carcinoma, among those the highly expressed miRNA-122 and miRNA-21, demonstrating that differential processing of primary microRNAs is occurring and could be involved in disease. With our method presented here we provide means to study pri-miRNA processing in disease from clinical samples.
Conservative and liberal attitudes drive polarized neural responses to political content
Authors: Leong Yuan Chang , Chen Janice , Willer Robb , Zaki Jamil 
Published: May 2020

AbstractPeople tend to interpret political information in a manner that confirms their prior beliefs, a cognitive bias that contributes to rising political polarization. In this study, we combined functional magnetic resonance imaging with semantic content analyses to investigate the neural mechanisms that underlie the biased processing of real-world political content. We scanned American participants with conservative-leaning or liberal-leaning immigration attitudes while they watched news clips, campaign ads, and public speeches related to immigration policy. We searched for evidence of “neural polarization”: activity in the brain that diverges between people who hold liberal versus conservative political attitudes. Neural polarization was observed in the dorsomedial prefrontal cortex (DMPFC), a brain region associated with the interpretation of narrative content. Neural polarization in the DMPFC intensified during moments in the videos that included risk-related and moral-emotional language, highlighting content features most likely to drive divergent interpretations between conservatives and liberals. Finally, participants whose DMPFC activity closely matched that of the average conservative or the average liberal participant were more likely to change their attitudes in the direction of that group’s position. Our work introduces a novel multi-method approach to study the neural basis of political cognition in naturalistic settings. Using this approach, we characterize how political attitudes biased information processing in the brain, the language most likely to drive polarized neural responses, and the consequences of biased processing for attitude change. Together, these results shed light on the psychological and neural underpinnings of how identical information is interpreted differently by conservatives and liberals.Significance StatementPartisan biases in processing political information contribute to rising divisions in society. How do such biases arise in the brain? We measured the neural activity of participants watching videos related to immigration policy. Despite watching the same videos, conservative and liberal participants exhibited divergent neural responses. This “neural polarization” between groups occurred in a brain area associated with the interpretation of narrative content, and intensified in response to language associated with risk, emotion, and morality. Furthermore, polarized neural responses predicted attitude change in response to the videos. These findings suggest that biased processing in the brain drives divergent interpretations of political information and subsequent attitude polarization.
Computational Electrostatics Predict Variations in SARS-CoV-2 Spike and Human ACE2 Interactions
Authors: Morton Scott P. , Phillips Joshua L. 
Published: May 2020

ABSTRACTSARS-CoV-2 is a novel virus that is presumed to have emerged from bats to crossover into humans in late 2019. As the global pandemic ensues, scientist are working to evaluate the virus and develop a vaccine to counteract the deadly disease that has impacted lives across the entire globe. We perform computational electrostatic simulations on multiple variants of SARS-CoV-2 spike protein s1 in complex with human angiotensin-converting enzyme 2 (ACE2) variants to examine differences in electrostatic interactions across the various complexes. Calculations are performed across the physiological pH range to also examine the impact of pH on these interactions. Two of six spike protein s1 variations having greater electric forces at pH levels consistent with nasal secretions and significant variations in force across all five variants of ACE2. Five out of six spike protein s1 variations have relatively consistent forces at pH levels of the lung, and one spike protein s1 variant that has low potential across a wide range of pH. These predictions indicate that variants of SARS-CoV-2 spike proteins and human ACE2 in certain combinations could potentially play a role in increased binding efficacy of SARS-CoV-2 in vivo.
Developmental co-emergence of cardiac and gut tissues modeled by human iPSC-derived organoids
Authors: Silva A.C. , Matthys O.B. , Joy D.A. , Kauss M.A. , Natarajan V. , Lai M.H. , Turaga D. , Blair A.P. , Alexanian M. , Bruneau B.G. , McDevitt T.C. 
Published: May 2020

AbstractDuring embryogenesis, paracrine signaling between tissues in close proximity contributes to the determination of their respective cell fate(s) and development into functional organs. Organoids arein vitromodels that mimic organ formation and cellular heterogeneity, but lack the paracrine input of surrounding tissues. Here, we describe a human multilineage iPSC-derived organoid that recapitulates cooperative cardiac and gut development and displays extensive cellular and structural complexity of both tissues. We demonstrate that the presence of endoderm tissue (gut/intestine) in multilineage organoids contributed to the development of the cardiac tissue, specifically cardiomyocyte expansion, compartmentalization, enrichment of atrial/nodal cells, myocardial compaction and functional fetal-like maturation. Overall, this study demonstrates the ability to generate specific cooperative tissues originating from different germ lineages within a single organoid model, an advance that will further the examination of multi-tissue interactions during development and disease.
Pazopanib induces dramatic but transient contraction of myeloid suppression compartment in favor of adaptive immunity
Authors: Rinchai Darawan , Verzoni Elena , Huber Veronica , Cova Agata , Squarcina Paola , De Cecco Loris , de Braud Filippo , Ratta Raffaele , Dugo Matteo , Lalli Luca , Vallacchi Viviana , Rodolfo Monica , Roelands Jessica , Castelli Chiara , Chaussabel Damien , Procopio Giuseppe , Bedognetti Davide , Rivoltini Licia 
Published: May 2020

AbstractAnti-angiogenic tyrosine-kinase inhibitors (TKIs) and immune checkpoint blockade (ICB) constitute the backbone of metastatic renal cell carcinoma (mRCC) treatment. The development of the optimal combinatorial or sequential approach is hindered by the lack of comprehensive data regarding TKI-induced immunomodulation and its kinetics. Through the use of orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines, we demonstrated that the anti-angiogenic TKI pazopanib induces a dramatic and coherent reshaping of systemic immunity in mRCC patients, downsizing the myeloid-derived suppressor cell (MDSC) compartment in favor of a strong enhancement of cytotoxic T and Natural Killer (NK) cell effector functions. The intratumoral expression level of a MDSC signature here generated was strongly associated with poor prognosis in mRCC patients. The marked but transient nature of this immunomodulation, peaking at the 3rdmonth of treatment, provides the rationale for the use of TKIs as a preconditioning strategy to improve the efficacy of ICB.
Signal-to-Signal Neural Networks for Improved Spike Estimation from Calcium Imaging Data
Authors: Sebastian Jilt , Sur Mriganka , Murthy Hema A. , Magimai.-Doss Mathew 
Published: May 2020

AbstractSpiking information of individual neurons is essential for functional and behavioral analysis in neuroscience research. Calcium imaging techniques are generally employed to obtain activities of neuronal populations. However, these techniques result in slowly-varying fluorescence signals with low temporal resolution. Estimating the temporal positions of the neuronal action potentials from these signals is a challenging problem. In the literature, several generative model-based and data-driven algorithms have been studied with varied levels of success. This article proposes a neural network-based signal-to-signal conversion approach, where it takes as input raw-fluorescence signal and learns to estimate the spike information in an end-to-end fashion. Theoretically, the proposed approach formulates the spike estimation as a single channel source separation problem with unknown mixing conditions. The source corresponding to the action potentials at a lower resolution is estimated at the output. Experimental studies on the spikefinder challenge dataset show that the proposed signal-to-signal conversion approach significantly outperforms state-of-the-art-methods in terms of Pearson’s correlation coefficient and Spearman’s rank correlation coefficient and yields comparable performance for the area under the receiver operating characteristics measure. We also show that the resulting system: (a) has low complexity with respect to existing supervised approaches and is reproducible; (b) is layer-wise interpretable; and (c) has the capability to generalize across different calcium indicators.Author summaryInformation processing by a population of neurons is studied using two-photon calcium imaging techniques. A neuronal spike results in an increased intracellular calcium concentration. Fluorescent calcium indicators change their brightness upon a change in the calcium concentration, and this change is captured in the imaging technique. The task of estimating the actual spike positions from the brightness variations is formally referred to as spike estimation. Several signal processing and machine learning-based algorithms have been proposed in the past to solve this problem. However, the task is still far from being solved. Here we present a novel neural network-based data-driven algorithm for spike estimation. Our method takes the fluorescence recording as the input and synthesizes the spike information signal, which is well-correlated with the actual spike positions. Our method outperforms state-of-the-art methods on standard evaluation framework. We further analyze different components of the model and discuss its benefits.
DAnkrd49 and Bdbt act via Casein Kinase Iε to regulate planar polarity inDrosophila
Authors: Strutt Helen , Strutt David 
Published: May 2020

AbstractThe core planar polarity proteins are essential mediators of tissue morphogenesis, controlling both the polarised production of cellular structures and polarised tissue movements. During development the core proteins promote planar polarisation by becoming asymmetrically localised to opposite cell edges within epithelial tissues, forming intercellular protein complexes that coordinate polarity between adjacent cells. Here we describe a novel protein complex that regulates the asymmetric localisation of the core proteins in theDrosophilapupal wing. DAnkrd49 (an ankyrin repeat protein) and Bride of Doubletime (Bdbt, a non-canonical FK506 binding protein family member) physically interact, and regulate each other’s levelsin vivo. Loss of either protein results in a reduction in core protein asymmetry and disruption of the placement of trichomes at the distal edge of pupal wing cells. Post-translational modifications are thought to be important for the regulation of core protein behaviour and their sorting to opposite cell edges. Consistent with this, we find that loss of DAnkrd49 or Bdbt leads to reduced phosphorylation of the core protein Dishevelled and to decreased Dishevelled levels both at cell junctions and in the cytoplasm. Bdbt has previously been shown to regulate activity of the kinase Discs Overgrown (Dco, also known as Doubletime or Casein Kinase Iε), and Dco itself has been implicated in regulating planar polarity by phosphorylating Dsh as well as the core protein Strabismus. We demonstrate that DAnkrd49 and Bdbt act as dominant suppressors of Dco activity. These findings support a model whereby Bdbt and DAnkrd49 act together to modulate the activity of Dco during planar polarity establishment.Author summaryIn many animal tissues, sheets of cells are polarised in the plane of the tissue, which is evident by the production of polarised structures, such as hairs on the fly wing that point in the same direction or cilia that beat in the same direction. One group of proteins controlling this coordinated polarity are the core planar polarity proteins, which localise asymmetrically within cells such that some core proteins localise to one cell end and others to the opposite cell end. It is thought that modifications such as phosphorylation may locally regulate core protein stability, and this promotes sorting of proteins to different cell ends. We identify two proteins, DAnkrd49 and Bdbt, that form a complex and regulate core protein asymmetry. Loss of either protein causes a reduction in overall levels of the core protein Dishevelled (Dsh), and a reduction in its phosphorylation. We provide evidence that the effect on core protein asymmetry is mediated via regulation of the kinase activity of Discs overgrown (Dco, also known as Doubletime/Casein Kinase Iε) by DAnkrd49 and Bdbt. We propose that modulation of Dco activity by DAnkrd49 and Bdbt is a key step in the sorting of core proteins to opposite cell ends.
TheO-GlcNAc transferase OGT is a conserved and essential regulator of the cellular and organismal response to hypertonic stress
Authors: Urso Sarel J. , Comly Marcella , Hanover John A. , Lamitina Todd 
Published: May 2020

AbstractThe conservedO-GlcNAc transferase OGTO-GlcNAcylates serine and threonine residues of intracellular proteins to regulate their function. OGT is required for viability in mammalian cells, but its specific roles in cellular physiology are poorly understood. Here we describe a conserved requirement for OGT in an essential aspect of cell physiology: the hypertonic stress response. Through a forward genetic screen inCaenorhabditis elegans, we discovered OGT is acutely required for osmoprotective protein expression and adaptation to hypertonic stress. Gene expression analysis shows thatogt-1functions through a post-transcriptional mechanism. Human OGT partially rescues theC. elegansphenotypes, suggesting that the osmoregulatory functions of OGT are ancient. Intriguingly, mutations that ablateO-GlcNAcylation activity in either human orC. elegansOGT rescue the hypertonic stress response phenotype. Our findings are among the first to demonstrate a specific physiological role for OGT at the organismal level and demonstrate that OGT engages in important molecular functions outside of its well described roles in post-translational O-GlcNAcylation of intracellular proteins.Author SummaryThe ability to sense and adapt to changes in the environment is an essential feature of cellular life. Changes in environmental salt and water concentrations can rapidly cause cell volume swelling or shrinkage and, if left unchecked, will lead to cell and organismal death. All organisms have developed similar physiological strategies for maintaining cell volume. However, the molecular mechanisms that control these physiological outputs are not well understood in animals. Using unbiased genetic screening inC. elegans, we discovered that a highly conserved enzyme called O-GlcNAc transferase (OGT) is essential for regulating physiological responses to increased environmental solute levels. A human form of OGT can functionally substitute for worm OGT, showing that this role is conserved across evolution. Surprisingly, the only known enzymatic activity of OGT was not required for this role, suggesting this enzyme has important undescribed molecular functions. Our studies reveal a new animal-specific role for OGT in the response to osmotic stress and show thatC. elegansis an important model for defining the conserved molecular mechanisms that respond to alterations in cell volume.