bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pupil Size Reflects Exploration and Exploitation in Visual Search (and It’s Like Object-Based Attention)
Authors: Regnath Franziska , Mathôt Sebastiaan 
Published: February 2021

AbstractThe adaptive gain theory (AGT) posits that activity in the locus coeruleus (LC) is linked to two behavioral modes: exploitation, characterized by focused attention on a single task; and exploration, characterized by a lack of focused attention and frequent switching between tasks. Furthermore, pupil size correlates with LC activity, such that large pupils indicate increased LC firing, and by extension also exploration behavior. Most evidence for this correlation in humans comes from complex behavior in game-like tasks. However, predictions of the AGT naturally extend to a very basic form of behavior: eye movements. To test this, we used a visual-search task. Participants searched for a target among many distractors, while we measured their pupil diameter and eye movements. The display was divided into four randomly generated regions of different colors. Although these regions were irrelevant to the task, participants were sensitive to their boundaries, and dwelled within regions for longer than expected by chance. Crucially, pupil size increased before eye movements that carried gaze from one region to another. We propose that eye movements that stay within regions (or objects) correspond to exploitation behavior, whereas eye movements that switch between regions (or objects) correspond to exploration behavior.Public Significance StatementWhen people experience increased arousal, their pupils dilate. The adaptive-gain theory proposes that pupil size reflects neural activity in the locus coeruleus (LC), which in turn is associated with two behavioral modes: a vigilant, distractible mode (“exploration”), and a calm, focused mode (“exploitation”). During exploration, pupils are larger and LC activity is higher than during exploitation. Here we show that the predictions of this theory generalize to eye movements: smaller pupils coincide with eye movements indicative of exploitation, while pupils slightly dilate just before make eye movements that are indicative of exploration.
Comparing Methods for Species Tree Estimation With Gene Duplication and Loss
Authors: Willson James , Roddur Mrinmoy Saha , Warnow Tandy 
Published: February 2021

AbstractSpecies tree inference from gene trees is an important part of biological research. One confounding factor in estimating species trees is gene duplication and loss which can lead to gene trees with multiple copies of the same gene. In recent years there have been several new methods developed to address this problem that have substantially improved on earlier methods; however, the best performing methods (ASTRAL-Pro, ASTRID-multi, and FastMulRFS) have not yet been directly compared. In this study, we compare ASTRAL-Pro, ASTRID-multi, and FastMulRFS under a wide variety of conditions. Our study shows that while all three have very good accuracy, nearly the same under many conditions, ASTRAL-Pro and ASTRID-multi are more reliably accurate than FastMuLRFS, and that ASTRID-multi is often faster than ASTRAL-Pro. The datasets generated for this study are freely available in the Illinois Data Bank athttps://databank.illinois.edu/datasets/IDB-2418574
Single-cell RNA-sequencing reveals pre-meiotic X-chromosome dosage compensation inDrosophila testis
Authors: Witt Evan , Shao Zhantao , Hu Chun , Krause Henry M. , Zhao Li 
Published: February 2021

AbstractDosage compensation (DC) is a mechanism by which X chromosome transcription is equalized in the somatic cells of both males and females. In male fruit flies, expression levels of the X-chromosome are increased two-fold to compensate for their single X chromosome. In testis, dosage compensation is thought to cease during meiosis, however, the timing and degree of the resulting transcriptional suppression is difficult to separate from global meiotic downregulation of each chromosome. To address this, we analyzed testis single-cell RNA-sequencing (scRNA-seq) data from twoDrosophila melanogasterstrains. We found evidence that the X chromosome is equally transcriptionally active as autosomes in somatic and pre-meiotic cells, and less transcriptionally active than autosomes in meiotic and post-meiotic cells. In cells experiencing dosage compensation, close proximity to MSL (male-specific lethal) chromatin entry sites (CES) correlates with increased X chromosome transcription. We found low or undetectable level of germline expression of mostmslgenes,mle, roX1androX2via sequencing or RNA-FISH, and no evidence of germline nuclearroX1/2localization. Our results suggest that, although DC occurs in somatic and premeiotic germ cells inDrosophilatestis, there might be non-canonical factors involved in the dosage compensation. The single-cell expression patterns and enrichment statistics of detected genes can be explored interactively in our database:https://zhao.labapps.rockefeller.edu/gene-expr/.
Drug Conjugates of Antagonistic RSPO4 Mutant For Simultaneous Targeting of LGR4/5/6 for Cancer Treatment
Authors: Cui Jie , Park Soohyun , Yu Wangsheng , Carmon Kendra , Liu Qingyun J. 
Published: February 2021

AbstractLGR4-6 (Leucine-rich repeating containing, G-protein-coupled receptors 4, 5, and 6) are three related receptors with distinct roles in organ development and stem cell survival. All three receptors are upregulated in gastrointestinal cancers to different levels, and LGR5 has been shown to be enriched in cancer stem cells. Antibody-drug conjugates (ADCs) targeting LGR5 showed robust antitumor effect in vivo but could not eradicate tumors due to plasticity of LGR5-positive cancer cells. As LGR5-negative cells often express LGR4 or LGR6 or both, we reasoned that simultaneous targeting of all three LGRs may provide a more effective approach. R-spondins (RSPOs) bind to LGR4-6 with high affinity and potentiate Wnt signaling. We identified an RSPO4 mutant (Q65R) that retains potent LGR binding but no longer potentiates Wnt signaling. The RSPO4 mutant was fused to the N-terminus of human IgG1-Fc to create a peptibody which was then conjugated with cytotoxins monomethyl auristatin or duocarmycin by site-specific conjugation. The resulting peptibody drug conjugates (PDCs) showed potent cytotoxic effects on cancer cell lines expressing any LGR in vitro and suppressed tumor growth in vivo without inducing intestinal enlargement or other adverse effects. These results suggest that RSPO-derived PDCs may provide a novel approach to the treatment of cancers with high LGR expression.
Objective pupillometry shows that perceptual styles covary with autistic-like personality traits
Authors: Tortelli Chiara , Turi Marco , Burr David C. , Binda Paola 
Published: February 2021

AbstractWe measured the modulation of pupil-size (in constant lighting) elicited by observing transparent surfaces of black and white moving dots, perceived as a cylinder rotating about its vertical axis. The direction of rotation was swapped periodically by flipping stereo-depth of the two surfaces. Pupil size modulated in synchrony with the changes in front-surface color (dilating when black). The magnitude of pupillary modulation was larger for participants with higher Autism-Spectrum Quotient (AQ), consistent with a local style of perception, with attention focused on the front surface. The modulation with surface color, and its correlation with AQ, was equally strong when participants passively viewed the stimulus. No other indicator, including involuntary pursuit eye-movements, covaried with AQ. These results reinforce our previous report with a similar bistable stimulus (Turi, Burr, & Binda, 2018), and go on to show that bistable illusory motion is not necessary for the effect, or its dependence on AQ.
Targeting interleukin-1 for reversing fat browning and muscle wasting in infantile nephropathic cystinosis
Authors: Cheung Wai W , Hao Sheng , Zheng Ronghao , Wang Zhen , Gonzalez Alex , Zhou Ping , Hoffman Hal M , Mak Robert H 
Published: February 2021

ABSTRACTBackgroundCtns−/−mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Inflammatory cytokines such as IL-1 trigger inflammatory cascades and play an important role in the pathogenesis of cachexia. Anakinra is an FDA-approved IL-1 receptor antagonist that blocks IL-1 signaling and may provide targeted novel therapy.MethodsCtns−/−mice were bred toIl6−/−andIl1β−/−mice.Ctns−/−mice and wild type control were treated with anakinra (2.5 mg.kg.day, IP) or saline as vehicle for 6 weeks. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning. We measured gastrocnemius weight, total lean mass content, muscle function (grip strength and rotarod activity), muscle fiber size, muscle fatty infiltration and expression of molecules regulating muscle metabolism. We also evaluated the effects of anakinra on the muscle transcriptome.ResultsIl-1β deficiency or treatment with anakinra normalized food intake and weight gain, fat and lean mass content, metabolic rate and muscle function inCtns−/−mice. Anakinra also diminished molecular perturbations of energy homeostasis in adipose tissue and muscle, specifically, aberrant expression of beige adipose cell biomarkers (UCP-1, CD137, Tmem26 and Tbx1) and molecules implicated in adipocyte tissue browning (Cox2/Pgf2α, Tlr2, Myd88 and Traf6) in inguinal white adipose tissue inCtns−/−mice. Moreover, anakinra normalized gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration inCtns−/−mice. This was accompanied by correction of the increased muscle wasting signaling pathways (increased protein content of ERK1/2, JNK, p38 MAPK and NF-κB p65 and gene expression of Atrogin-1 and Myostatin) and the decreased myogenesis process (decreased gene expression of MyoD and Myogenin) in gastrocnemius ofCtns−/−mice. Finally, anakinra normalized or attenuated 12 of those top 20 differentially expressed muscle genes inCtns−/−mice.ConclusionsAnakinra attenuates adipose tissue browning and muscle wasting inCtns−/−mice. IL-1 receptor blockade may represent a novel targeted treatment for cachexia in patients with infantile nephropathic cystinosis.
Elephant seal muscle cells adapt to sustained glucocorticoid exposure by shifting their metabolic phenotype
Authors: Torres-Velarde Julia Maria , Kolora Sree Rohit Raj , Khudyakov Jane I. , Crocker Daniel E. , Sudmant Peter H. , Vázquez-Medina José Pablo 
Published: February 2021

AbstractElephant seals experience natural periods of prolonged food deprivation while breeding, molting, and undergoing postnatal development. Prolonged food deprivation in elephant seals increases circulating glucocorticoids without inducing muscle atrophy, but the cellular mechanisms that allow elephant seals to cope with such conditions remain elusive. We generated a cellular model and conducted transcriptomic, metabolic, and morphological analyses to study how seal cells adapt to sustained glucocorticoid exposure. Seal muscle progenitor cells differentiate into contractile myotubes with a distinctive morphology, gene expression profile, and metabolic phenotype. Exposure to dexamethasone at three ascending concentrations for 48h modulated the expression of 6 clusters of genes related to structural constituents of muscle and pathways associated with energy metabolism and cell survival. Knockdown of the glucocorticoid receptor (GR) and downstream expression analyses corroborated that GR mediates the observed effects. Dexamethasone also decreased cellular respiration, shifted the metabolic phenotype towards glycolysis, and induced mitochondrial fission and dissociation of mitochondria-ER interactions without decreasing cell viability. Knockdown of DDIT4, a GR target involved in the dissociation of mitochondria-ER membranes, recovered respiration and modulated antioxidant gene expression. These results show that adaptation to sustained glucocorticoid exposure in elephant seal myotubes involves a metabolic shift toward glycolysis, which is supported by alterations in mitochondrial morphology and a reduction in mitochondria-ER interactions, resulting in decreased respiration without compromising cell survival.
Optical regulation of endogenous RhoA reveals selection of cellular responses by signal amplitude
Authors: Ju Jeongmin , Lee Hae Nim , Ning Lin , Ryu Hyunjoo , Zhou Xin X. , Chun Hyeyeon , Lee Yong Woo , Lee-Richerson Austin I. , Jeong Cherlhyun , Lin Michael Z. , Seong Jihye 
Published: February 2021

ABSTRACTHow protein signaling networks respond to different input strengths is an important but poorly understood problem in cell biology. For example, the small GTPase RhoA regulates both focal adhesion (FA) growth or disassembly, but whether RhoA serves as a switch selecting between cellular outcomes, or if outcomes are simply modulated by additional factors in the cell, is not clear. Here, we develop a photoswitchable RhoA guanine exchange factor, psRhoGEF, to precisely control endogenous RhoA activity. We also develop a FRET-based biosensor to allow visualization of RhoA activity together with psRhoGEF control. Using these new optical tools, we discover that low levels of RhoA activation preferentially induce FA disassembly in a Src-dependent manner, while high levels induce both FA growth and disassembly in a ROCK-dependent manner. Thus, rheostatic control of RhoA activation with photoswitchable RhoGEF reveals that cells can use signal amplitude to produce multiple responses to a single biochemical signal.
Rational Design of Programmable Monodisperse Semi-Synthetic Protein Nanomaterials Containing Engineered Disulfide Functionality
Authors: Bhandari Pavankumar Janardhan , Sandanaraj Britto S 
Published: February 2021

AbstractThe reversible nature of disulfide functionality has been exploited to design intelligent materials such as nanocapsules, micelles, vesicles, inorganic nanoparticles, peptide and nucleic acid nanodevices. However, to our knowledge, there are no reports on design of semi-synthetic protein assemblies containing an engineered disulfide bond. Towards that end, herein, we disclose a new chemical methodology for the construction redox-sensitive protein assemblies using monodisperse facially amphiphilic protein-dendron bioconjugates. The disulfide functionality is strategically placed between the dendron and protein domains. The custom designed bioconjugates self-assembled into nanoscopic objects of a defined size dictated by the nature of dendron domain. The stimuli-responsive behavior of the protein assemblies is demonstrated using a suitable redox trigger.
Impact of cobas PCR Media Freezing on SARS-CoV-2 Viral RNA Integrity and Whole Genome Sequencing Analyses
Authors: Benoit Patrick , Point Floriane , Gagnon Simon , Kaufmann Daniel E. , Tremblay Cécile , Harrigan Richard Paul , Hardy Isabelle , Coutlée François , Lapierre Simon Grandjean 
Published: February 2021

ABSTRACTSARS-CoV-2 whole genome sequencing is an important molecular biology tool performed to support many aspects of the response to the pandemic. Freezing of primary clinical nasopharyngeal swab samples and shipment to reference laboratories is usually required since RNA sequencing is rarely available in routine clinical microbiology laboratories where initial diagnosis and support to outbreak investigations occur. The cobas PCR Media transport medium developed by Roche facilitates high throughput analyses on cobas multianalyzer PCR platforms. There is no data on the stability of SARS-CoV-2 RNA after freezing and thawing of clinical samples in this transport medium, but potential denaturing of the molecular template could impair test results. Our objective was to compare the quality and results of SARS-CoV-2 genomic sequencing when performed on fresh or frozen samples in cobas PCR Media. Viral whole genome sequencing was performed using Oxford Nanopore Technologies MinION platform. Genomic coverage and sequencing depth did not significantly differ between fresh and frozen samples (n=10). For samples with lower viral inoculum and PCR cycle threshold above 30, sequencing quality scores and detection of single nucleotide polymorphisms did not differ either. Freezing of cobas PCR Media does not negatively affect the quality of SARS-CoV-2 RNA sequencing results and it is therefore a suitable transport medium for outsourcing sequencing analyses to reference laboratories. Those results support secondary use of diagnostic nasopharyngeal swab material for viral sequencing without requirement for additional clinical samples.
COVIDHunter: An Accurate, Flexible, and Environment-Aware Open-Source COVID-19 Outbreak Simulation Model
Authors: Alser Mohammed , Kim Jeremie S. , Alserr Nour Almadhoun , Tell Stefan W. , Mutlu Onur 
Published: February 2021

AbstractMotivationEarly detection and isolation of COVID-19 patients are essential for successful implementation of mitigation strategies and eventually curbing the disease spread. With a limited number of daily COVID-19 tests performed in every country, simulating the COVID-19 spread along with the potential effect of each mitigation strategy currently remains one of the most effective ways in managing the healthcare system and guiding policy-makers. We introduceCOVIDHunter, a flexible and accurate COVID-19 outbreak simulation model that evaluates the current mitigation measures that are applied to a region and provides suggestions on what strength the upcoming mitigation measure should be. The key idea of COVIDHunter is to quantify the spread of COVID-19 in a geographical region by simulating the average number of new infections caused by an infected person considering the effect of external factors, such as environmental conditions (e.g., climate, temperature, humidity) and mitigation measures.ResultsUsing Switzerland as a case study, COVIDHunter estimates that the policy-makers need to keep the current mitigation measures for at least 30 days to prevent demand from quickly exceeding existing hospital capacity. Relaxing the mitigation measures by 50% for 30 days increases both thedailycapacity need for hospital beds anddailynumber of deaths exponentially by an average of 23.8 ×, who may occupy ICU beds and ventilators for a period of time. Unlike existing models, the COVIDHunter model accurately monitors and predicts the daily number of cases, hospitalizations, and deaths due to COVID-19. Our model is flexible to configure and simple to modify for modeling different scenarios under different environmental conditions and mitigation measures.Availabilityhttps://github.com/CMU-SAFARI/COVIDHunterContactalserm@ethz.ch,omutlu@ethz.chSupplementary informationSupplementary data is available atBioinformaticsonline.
Hepatocyte nuclear factor 4a and glucocorticoid receptor coordinately regulate lipid metabolism in mice fed a high-fat-high-sugar diet
Authors: Lu Hong , Lei Xiaohong , Guo Shangdong , Winkler Rebecca , John Savio , Kumar Devendra , Li Wenkuan , Alnouti Yazen 
Published: February 2021

ABSTRACTHepatocyte nuclear factor 4α (HNF4α) and glucocorticoid receptor (GR), master regulators of liver metabolism, are down-regulated in fatty liver diseases. The present study was aimed to elucidate the role of down-regulation of HNF4α and GR in fatty liver and hyperlipidemia. Adult mice with liver-specific heterozygote and knockout (knockout) of HNF4α were fed a low-fat diet (LFD) or a high-fat-high-sugar diet (HFHS) for 15 days. Compared to LFD-fed mice, HFHS-fed wildtype mice had hepatic induction of lipid catabolic genes and down-regulation of lipogenic genes. Compared to HFHS-fed wildtype mice, HNF4α heterozygote mice had down-regulation of lipid catabolic genes, induction of lipogenic genes, and increased hepatic and blood levels of lipids, whereas HNF4α knockout mice had mild hypolipidemia, down-regulation of lipid-efflux genes, but induction of genes for uptake/storage of lipids. Sterol-regulatory-element-binding protein-1c (SREBP-1C), a master lipogenic regulator, was induced in HFHS-fed HNF4α heterozygote mice. In reporter assays, HNF4α potently inhibited the transactivation of mouse and human SREBP-1C promoter by liver X receptor. Surprisingly, nuclear GR proteins were gene-dosage-dependently decreased in HNF4α heterozygote and knockout mice. HFHS-fed mice with liver-specific knockout of GR had increased hepatic lipids and induction of SREBP-1C and PPARγ. In reporter assays, GR and HNF4α synergistically/additively induced lipid catabolic genes. Phosphorylation of AMP-activated protein kinase (AMPK), a key GR modulator, was dramatically decreased in HNF4α knockout mice. Thus, cooperative induction of lipid catabolic genes and suppression of lipogenic genes by HNF4α and GR, modulated by AMPK, may mediate the early resistance to HFHS-induced fatty liver and hyperlipidemia.
Integrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2)
Authors: Karmakar Shilpita , Ramirez Oscar , Paul Kiran V. , Gupta Abhishek K. , Botti Valentina , de los Mozos Igor Ruiz , Neuenkirchen Nils , Ross Robert J. , Neugebauer Karla M. , Pillai Manoj M. 
Published: February 2021

ABSTRACTMusashi 2 (MSI2) is an RNA binding protein (RBP) that regulates asymmetric cell division and cell fate decisions in normal and cancer stem cells. MSI2 appears to repress translation by binding to 3’ untranslated regions (3’UTRs) of mRNA, but the identity of functional targets remains unknown. Here we used iCLIP to identify direct RNA binding partners of MSI2 and integrated these data with polysome profiling to obtain insights into MSI2 function. iCLIP revealed specific MSI2 binding to thousands of target mRNAs largely in 3’UTRs, but translational differences were restricted to a small fraction of these transcripts, indicating that MSI2 regulation is not triggered by simple binding. Instead, the functional targets identified here were bound at higher density and contain more “U/TAG” motifs compared to targets bound non-productively. To further distinguish direct and indirect targets, MSI2 was acutely depleted. Surprisingly, only 50 transcripts were found to undergo translational induction on acute MSI2 loss. Eukaryotic elongation factor 3A (EIF3A) was determined to be an immediate, direct target. We propose that MSI2 down-regulation of EIF3A amplifies these effects on the proteome. Our results also underscore the challenges in defining functional targets of RBP since mere binding does not imply a discernible functional interaction.
Tn7-CRISPR-Cas12K elements manage pathway choice using truncated repeat-spacer units to target tRNA attachment sites
Authors: Hsieh Shan-Chi , Peters Joseph E. 
Published: February 2021

AbstractCRISPR-Cas systems provide a defense against mobile elements. These defense systems have been naturally coopted multiple times for guide RNA-directed transposition by Tn7-like transposons. Elements associated with a type I-F CRISPR-Cas system categorize guide RNAs, maintaining a standard CRISPR array capable of acquiring new spacers targeting other mobile elements while maintaining a special guide RNA allowing integration into a conserved site in the chromosome called an attachment site. We show here that Tn7-like elements associated with a type V-K (Cas12K-based) system use a similar strategy to target diverse tRNA genes as attachment sites. These guides are encoded as truncated minimal repeat-spacer units and are found in distinct locations. Multiple pieces of information support that V-K guide RNAs are acquired using a type I-D adaptation system, but remain private to the V-K transposition process. This catalog of Cas12K elements and naturally occurring insertions will help future work engineering precision integration systems.