bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Circadian Phase Response Curve to Light: Conservation across Seasons and Anchorage to Sunset
Authors: Dollish Hannah K. , Kaladchibachi Sevag , Negelspach David C. , Fernandez Fabian-Xosé 
Published: April 2021

AbstractPhototherapy outcomes are dependent on the precision by which the magnitude and direction of light’s circadian phase-shifting effects can be predicted. Such predictions are largely based on photic phase-response curves (PRCs) generated from animals housed under seasonally agnostic equatorial photoperiods with alternating 12-hour segments of light and darkness. Most of the human population, however, lives at northerly latitudes (20-50° N of the Equator) where seasonal variations in the light-dark schedule are pronounced. Here, we address this disconnect by constructing the first high-resolution seasonal atlas for light-induced circadian phase-resetting. Testing the light responses of nearly 4,000Drosophilaat 120 timepoints across 5 seasonally relevant photoperiods (i.e., LD 8:16, 10:14, 12:12, 14:10, and 16:8; 24 hourly intervals surveyed in each), we determined that many aspects of the circadian PRC waveform are conserved with increasing daylength. Surprisingly though, irrespective of LD schedule, the start of the PRCs always remained anchored to the timing of subjective sunset, creating a differential overlap of the advance zone with the morning hours after subjective sunrise that was maximized under summer photoperiods and minimized under winter photoperiods. These data suggest that circadian photosensitivity is effectively extinguished by the early winter morning and out of optimal phase alignment with the wake schedules of many individuals (which revolve around the timing of sunrise regardless of season). They raise the possibility that phototherapy protocols for conditions such as seasonal depression might be improved with programmed light exposure during the final hours of sleep.
Oncogenic BRAF Induces Whole-Genome Doubling Through Suppression of Cytokinesis
Authors: Darp Revati , Vittoria Marc A. , Ganem Neil J. , Ceol Craig J. 
Published: April 2021

AbstractMelanomas and other solid tumors commonly have increased ploidy, with near-tetraploid karyotypes being most frequently observed. Such karyotypes have been shown to arise through whole-genome doubling events that occur during early stages of tumor progression. The generation of tetraploid cells via whole-genome doubling is proposed to allow nascent tumor cells the ability to sample various pro-tumorigenic genomic configurations while avoiding the negative consequences that chromosomal gains or losses have in diploid cells. Whereas a high prevalence of whole-genome doubling events has been established, the means by which whole-genome doubling arises is unclear. Here, we find that BRAFV600E, the most common mutation in melanomas, can induce whole-genome doubling via cytokinesis failurein vitroand in a zebrafish melanoma model. Mechanistically, BRAFV600Ecauses decreased activation and localization of RhoA, a critical cytokinesis regulator. BRAFV600Eactivity during G1/S phases of the cell cycle is required to suppress cytokinesis. During G1/S, BRAFV600Eactivity causes inappropriate centriole amplification, which is linked in part to inhibition of RhoA and suppression of cytokinesis. Together these data suggest that common abnormalities of melanomas linked to tumorigenesis – amplified centrosomes and whole-genome doubling events – can be induced by oncogenic BRAF and other mutations that increase RAS/MAPK pathway activity.Statement of SignificanceWhole-genome doubling is prevalent in many types of solid tumors and important in shaping tumor genomes, yet the causes of whole-genome doubling are not well understood. Here, we discover that oncogenic BRAFV600Ecan induce whole-genome doubling through suppression of cytokinesis, and BRAFV600E-induced whole-genome doubling can occur in melanocytes and be present in nascent melanoma cells upon tumorigenesis.
Chitinase 3-like-1 Contributes to Acetaminophen-induced Liver Injury by Promoting Hepatic Platelet Recruitment
Authors: Shan Zhao , Li Leike , Atkins Constance Lynn , Wang Meng , Wen Yankai , Jeong Jongmin , Moreno Nicolas F. , Feng Dechun , Gui Xun , Zhang Ningyan , Lee Chun Geun , Elias Jack Angel , Lee William , Gao Bin , Lam Fong Wilson , An Zhiqiang , Ju Cynthia 
Published: April 2021

AbstractHepatic platelet accumulation contributes to acetaminophen (APAP)-induced liver injury (AILI). However, little is known about the molecular pathways involved in platelet recruitment to the liver and whether targeting such pathways could attenuate AILI. The present study unveiled a critical role of chitinase 3-like-1 (Chi3l1) in hepatic platelet recruitment during AILI. Increased Chi3l1 and platelets in the liver were observed in patients and mice overdosed with APAP. Compared to wild-type (WT) mice, Chi3l1-/-mice developed attenuated AILI with markedly reduced hepatic platelet accumulation. Mechanistic studies revealed that Chi3l1 signaled through CD44 on macrophages to induce podoplanin expression, which mediated platelet recruitment through C-type lectin-like receptor 2. Moreover, APAP treatment of CD44-/-mice resulted in much lower numbers of hepatic platelets and liver injury than WT mice, a phenotype similar to that in Chi3l1-/-mice. Recombinant Chi3l1 could restore hepatic platelet accumulation and AILI in Chi3l1-/-mice, but not in CD44-/-mice. Importantly, we generated anti-Chi3l1 monoclonal antibodies and demonstrated that they could effectively inhibit hepatic platelet accumulation and AILI. Overall, we uncovered the Chi3l1/CD44 axis as a critical pathway mediating APAP-induced hepatic platelet recruitment and tissue injury. We demonstrated the feasibility and potential of targeting Chi3l1 to treat AILI.
Complex effects of kinase localization revealed by compartment-specific regulation of protein kinase A activity
Authors: LaCroix Rebecca , Lin Benjamin , Levchenko Andre 
Published: April 2021

SummaryKinase activity in signaling networks frequently depends on regulatory subunits that can both inhibit activity by interacting with the catalytic subunits and target the kinase to distinct molecular partners and subcellular compartments. Here, using a new synthetic molecular interaction system, we show that translocation of a regulatory subunit of the protein kinase A (PKA-R) to the plasma membrane has a paradoxical effect on the membrane kinase activity. It can both enhance it at lower translocation levels, even in the absence of signaling inputs, and inhibit it at higher translocation levels, suggesting its role as a linker that can both couple and decouple signaling processes in a concentration-dependent manner. We further demonstrate that superposition of gradients of PKA-R abundance across single cells can control the directionality of cell migration, reversing it at high enough input levels. Thus complexin vivopatterns of PKA-R localization can drive complex phenotypes, including cell migration.
Sumoylation of the human histone H4 tail inhibits p300-mediated transcription by RNA polymerase II in cellular extracts
Authors: Leonen Calvin J. A. , Shimada Miho , Weller Caroline E. , Nakadai Tomoyoshi , Hsu Peter , Shelton Patrick M. M. , Sadilek Martin , Zheng Ning , Roeder Robert G. , Chatterjee Champak 
Published: April 2021

AbstractPost-translational modification of histone H4 by the small ubiquitin-like modifier (SUMO) protein was associated with gene repression. However, this could not be proven due to the challenge of site-specifically sumoylating H4 in cells. Biochemical crosstalk between SUMO and other histone modifications, such as H4 acetylation and H3 methylation, that are associated with active genes also remains unclear. We addressed these challenges in mechanistic studies using H4 chemically modified at Lys12 by SUMO-3 (H4K12su) that was incorporated into mononucleosomes and chromatinized plasmids. Mononucleosome-based assays revealed that H4K12su inhibits transcription-activating H4 tail acetylation by the histone acetyltransferase p300, and transcription-associated H3K4 methylation by the extended catalytic module of the Set1/COMPASS histone methyltransferase complex. Activator- and p300-dependent in vitro transcription assays with chromatinized plasmids revealed H4K12su inhibits RNA polymerase II-mediated transcription and H4 tail acetylation. Thus, we have uncovered negative biochemical crosstalk with acetylation/methylation and the direct inhibition of RNAPII-mediated transcription by H4K12su.
A neural circuit linking two sugar sensors regulates satiety-dependent fructose drive inDrosophila
Authors: Musso Pierre-Yves , Junca Pierre , Gordon Michael D 
Published: April 2021

ABSTRACTIngestion of certain sugars leads to activation of fructose sensors within the brain of flies, which then sustain or terminate feeding behavior depending on internal state. Here, we describe a three-part neural circuit that links satiety with fructose sensing. We show that AB-FBl8 neurons of the Fan-shaped body display oscillatory calcium activity when hemolymph glycemia is high, and that these oscillations require synaptic input from SLP-AB neurons projecting from the protocerebrum to the asymmetric body. Suppression of activity in this circuit, either by starvation or genetic silencing, promotes specific drive for fructose ingestion. Moreover, neuropeptidergic signaling by tachykinin bridges fan-shaped body activity and Gr43a-mediated fructose sensing. Together, our results demonstrate how a three-layer neural circuit links the detection of two sugars to impart precise satiety-dependent control over feeding behavior.
Ubiquitin specific protease 1 expression and function in T cell immunity
Authors: Omilusik Kyla D , Nadjsombati Marija S , Yoshida Tomomi M , Shaw Laura A , Goulding John , Goldrath Ananda W 
Published: April 2021

AbstractT cells are essential mediators of the immune responses against infectious diseases and provide long-lived protection from reinfection. The differentiation of naive T cells to effector T cells and subsequent differentiation and persistence of memory T cell populations in response to infection is a highly regulated process. E protein transcription factors and their inhibitors, Id proteins, are important regulators of both CD4+and CD8+T cell responses; however, their regulation at the protein level has not been explored. Recently, the deubiquitinase USP1 was shown to stabilize Id2 and modulate cellular differentiation in osteosarcomas. Here, we investigated a role for Usp1 in posttranslational control of Id2 and Id3 in T cells. We show that Usp1 was upregulated in T cells following activationin vitroor following infectionin vivo, and the extent of Usp1 expression correlated with the degree of T cell expansion. Usp1 directly interacted with Id2 and Id3 following T cell activation. However, Usp1-deficiency did not impact Id protein abundance in effector T cells or alter effector CD8+T cell expansion or differentiation following a primary infection. Usp1 deficiency did result in a gradual loss of memory cells over time and impaired accumulation and altered differentiation following a secondary infection. Together, these results identify Usp1 as a player in modulating recall responses at the protein level and highlight differences in regulation of T cell responses between primary and subsequent infection encounters. Finally, our observations reveal that differential regulation of Id2/3 proteins between immune vs non-immune cell types.
Immunogenicity of a public neoantigen derived from mutatedPIK3CA
Authors: Chandran Smita S. , Ma Jiaqi , Klatt Martin G. , Dundar Friederike , Bandlamudi Chaitanya , Razavi Pedram , Wen Hannah Y. , Weigelt Britta , Zumbo Paul , Fu Si Ning , Banks Lauren B. , Bestman Watchain D. , Drilon Alexander , Betel Doron , Scheinberg David A. , Baker Brian M. , Klebanoff Christopher A. 
Published: April 2021

ABSTRACTPublic neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrent mutations in driver genes that are restricted by prevalent HLA alleles. Here, we report on a high-throughput platform combining single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant (Mut)PIK3CA, among the most common genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this method, we developed a library of TCRs that recognize an endogenously processed neoepitope containing a commonPIK3CAhotspot mutation that is restricted by HLA-A*03:01. Mechanistically, immunogenicity to this public NeoAg arises primarily from enhanced stability of the neopeptide/HLA complex caused by a preferred HLA anchor substitution. Structural studies indicated that the HLA-bound neopeptide presents a relatively “featureless” surface dominated by the peptide’s backbone. To overcome the challenge of binding such an epitope with high specificity and affinity, we discovered that a lead TCR clinical candidate engages the neopeptide through an extended interface aided by an unusually long β-chain complementarity-determining region 3 (CDR3β) loop. In a pan-cancer cohort of patients with diverse malignancies that express thePIK3CApublic NeoAg, we observed spontaneous immunogenicity, NeoAg clonal conservation, and in a limited number of cases, evidence of targeted immune escape. Together, these results establish the immunogenic potential of MutPIK3CA, creating a framework for off-the-shelf immunotherapies targeting this public NeoAg.
Class II LBD genesZmLBD5andZmLBD33regulate gibberellin and abscisic acid biosynthesis
Authors: Xiong Jing , Feng Xuanjun , Zhang Weixiao , Wang Xianqiu , Hu Yue , Zhang Xuemei , Wu Fengkai , Guo Wei , Xie Wubing , Wang Qingjun , Xu Jie , Lu Yanli 
Published: April 2021

ABSTRACTLateral organ boundaries domain (LBD) proteins are plant-specific transcription factors. Class ILBDmembers are widely reported to be pivotal for organ development, however, the role of class II members is unknown in cereal crops. Class II LBD proteins are distinguished from class I by the lack of a Gly-Ala-Ser (GAS) peptide and leucine-zipper-like coiled-coil domain, which is thought to be essential for protein dimerization. In this study, ZmLBD5 and ZmLBD33 form homo- and hetero-dimers, like class I members. At seedling stage,ZmLBD5promoted biomass accumulation (shoot dry weight and root dry weight), root development (root length, root number, and root volume), and organ expansion (leaf area), whileZmLBD33repressed these processes and display a dwarf phenotype. BothZmLBD5andZmLBD33displayed negative roles in drought tolerance mainly by increasing stomatal density and stomatal aperture. RNA sequencing, gene ontology enrichment analysis, and transient luciferase expression assays indicated thatZmLBD5andZmLBD33are mainly involved in the regulation of theTPS-KS-GA2oxgene module, which comprises key enzymatic genes upstream of GA and ABA biosynthesis. GA1content increased inZmLBD5-overexpressing seedlings, while GA3and abscisic acid content decreased in both transgenic seedlings. Consequently, exogenous GA1or GA3undoubtedly rescued the dwarf phenotype ofZmLBD33-overexpressing plants, with GA1performing better. The study ofZmLBD5andZmLBD33sheds light on the function of the class IILBDgene family in maize.
Discovery and characterization of Hv1-type proton channels in reef-building corals
Authors: Rangel-Yescas Gisela E. , Cervantes Cecilia , Cervantes-Rocha Miguel A. , Suarez-Delgado Esteban , Banaszak Anastazia T. , Maldonado Ernesto , Ramsey Ian. S. , Rosenbaum Tamara , Islas León D. 
Published: April 2021

AbstractVoltage-dependent proton-permeable channels are membrane proteins mediating a number of important physiological functions. Here we report the presence of a gene encoding for Hv1 voltage-dependent, proton-permeable channels in two species of reef-building corals. We performed a characterization of their biophysical properties and found that these channels are fast-activating and modulated by the pH gradient in a distinct manner. The biophysical properties of these novel channels make them interesting model systems. We have also developed an allosteric gating model that provides mechanistic insight into the modulation of voltage-dependence by protons. This work also represents the first functional characterization of any ion channel in scleractinian corals. We discuss the implications of the presence of these channels in the membranes of coral cells in the calcification and pH regulation processes and possible consequences of ocean acidification related to the function of these channels.
ModernAcinetobacter baumanniiclinical isolates replicate inside spacious vacuoles and egress from macrophages
Authors: Sycz Gabriela , Di Venanzio Gisela , Sartorio Mariana G. , Nguyen-Hung Le , Scott Nichollas E. , Beatty Wandy L. , Feldman Mario F. 
Published: April 2021

AbstractMultidrug-resistantAcinetobacter baumanniiinfections are increasing at alarming rates. Therefore, novel antibiotic-sparing treatments to combat theseA. baumanniiinfections are urgently needed. The development of these interventions would benefit from a better understanding of this bacterium’s pathobiology, which remains poorly understood.A. baumanniiis regarded as an extracellular opportunistic pathogen. However, research onAcinetobacterhas largely focused on common lab strains, such as ATCC 19606, that have been isolated several decades ago. These strains exhibit reduced virulence when compared to recently isolated clinical strains. In this work, we demonstrate that, unlike ATCC 19606, several modernA. baumanniiclinical isolates, including the recent clinical urinary isolate UPAB1, persist and replicate inside macrophages within spacious vacuoles. We show that intracellular replication of UPAB1 is dependent on a functional type I secretion system (T1SS) and pAB5, a large conjugative plasmid that controls the expression of several chromosomally-encoded genes. Finally, we show that UPAB1 escapes from the infected macrophages by a lytic process. To our knowledge, this is the first report of intracellular growth and replication ofA. baumannii. We suggest that intracellular replication within macrophages may contribute to evasion of the immune response, dissemination, and antibiotic tolerance ofA. baumannii.
Temperature-induced reorganisation of Schistocephalus solidus (Cestoda) proteome during the transition to the warm-blooded host
Authors: Borvinskaya Ekaterina V. , Kochneva Albina A. , Drozdova Polina B. , Balan Olga V. , Zgoda Victor G. 
Published: April 2021

AbstractThe protein composition (proteome) of cestode Schistocephalus solidus was measured in an experiment simulating the transition of the parasite from a cold-blooded to a warm-blooded host. Infective S. solidus plerocercoids obtained from the three-spined stickleback Gasterosteus aculeatus were heated at 40 °C for 1 hour or cultured in vitro at 40 °C and 22 °C for 48 hours. In the short-term experiment, the content of only one tegument protein decreased after heating. After long-term heating, which triggered parasite sexual maturation, an increase in the content of ribosomal proteins, translation initiation factors and enzymes of the amino acid biosynthesis pathway was observed. The synthesis of certain gene products for carbohydrate metabolism, including glycolysis/gluconeogenesis, was found to be regulated in the parasite by temperature.Summary statementThe study focuses on the processes that determine the survival of parasites in warm-blooded animals, and thus demonstrates the potential for the application of proteomics in veterinary medicine.
TheORGAN SIZE(ORG) locus contributes to isometric gigantism in domesticated tomato
Authors: Vicente Mateus Henrique , MacLeod Kyle , Fernandes Figueiredo Cassia Regina , de Oliveira Figueira Antonio Vargas , Mohareb Fady , Kevei Zoltán , Thompson Andrew J. , Zsögön Agustin , Pereira Peres Lázaro Eustáquio 
Published: April 2021

AbstractGigantism is a key component of the domestication syndrome, a suite of traits that differentiates crops from their wild relatives. Allometric gigantism is strongly marked in horticultural crops, causing disproportionate increases in the size of edible parts such as stems, leaves or fruits. Tomato (Solanum lycopersicum) has attracted attention as a model for fruit gigantism, and many genes have been described controlling this trait. However, the genetic basis of a corresponding increase in size of vegetative organs contributing to isometric gigantism, has remained relatively unexplored. Here, we identified a 0.4 Mbp region on chromosome 7 in introgression lines (ILs) from the wild speciesSolanum pennelliiin two different tomato genetic backgrounds (cv. M82 and cv. Micro-Tom) that controls vegetative and reproductive organ size in tomato. The locus, namedORGAN SIZE(ORG), was fine-mapped using genotype-by-sequencing. A survey of literature revealed thatORGoverlaps with previously mapped QTLs controlling tomato fruit weight during domestication. Alleles from the wild species led to reduced cell number in different organs, which was partially compensated by greater cell expansion in leaves but not in fruits. The result was a proportional reduction in leaf, flower and fruit size in the ILs harbouring the wild alleles. These findings suggest that selection for large fruit during domestication also tends to select for increases in leaf size by influencing cell division. Since leaf size is relevant for both source-sink balance and crop adaptation to different environments, the discovery ofORGcould allow fine-tuning of these parameters.One sentence summaryA locus that controls isometric size increase in vegetative and reproductive organs of tomato through changes in cell division
FRAME-tags: genetically encoded fluorescent markers for multiplexed barcoding and time-resolved tracking of live cells
Authors: Anzalone Andrew V. , Jimenez Miguel , Cornish Virginia W. 
Published: April 2021

ABSTRACTCellular barcodes offer critical tools for tracking cellular identity in biological systems. Although genetically encoded fluorescent barcodes are ideal for real-time tracking, their scalability is constrained by the broad, overlapping emission spectra characteristic of fluorescent proteins (FPs). Here, we describe a palette of genetically encoded fluorescent barcodes called FRAME-tags, which break this scalability barrier by encoding barcode identity as unique FP expression ratios. FRAME-tags use −1 programmed ribosomal frameshifting RNA motifs to precisely control the translational output of multiple FPs from a single mRNA, leading to extremely narrow and resolvable ratios of the corresponding cellular fluorescence distributions. With this platform, we constructed 20 resolvable FRAME-tags in yeast using just two FPs, and further demonstrated that 100 or more distinguishable FRAME-tags could be made by the addition of a third FP. We used FRAME-tags to map the dynamic fitness landscape of yeast co-cultures, and to characterize the expression pattern of 20 yeast promoters in multiplex across diverse conditions. FRAME-tags offer a valuable new tool for cellular barcoding that enables time-resolved characterization of complex biological systems using widely available fluorescence detection techniques and a minimal number of spectral channels.