bluuebunny/crossref_metadata_2025_split huggingface dataset:
eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer
Authors: Boyer Jacob A. , Sharma Malvika , Dorso Madeline A. , Mai Nicholas , Amor Corina , Reiter Jason M. , Kannan Ram , Gadal Sunyana , Xu Jianing , Miele Matthew , Li Zhuoning , Chen Xiaoping , Chang Qing , Pareja Fresia , Worland Stephan , Warner Douglas , Sperry Sam , Chiang Gary G. , Thompson Peggy A. , Yang Guangli , Ouerfelli Ouathek , de Stanchina Elisa , Wendel Hans-Guido , Rosen Ezra Y. , Chandarlapaty Sarat , Rosen Neal 
Published: May 2024

AbstractThe majority of human breast cancers are dependent on hormone-stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap-independent and mTOR inhibitor insensitive, but dependent on 5’ UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short-lived targets of ER such as cyclin D1 and other components of the cyclin D-CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand-independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant—an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial (NCT04092673) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer.
Identifying Candidate Genes for Sugar Accumulation in Sugarcane Cultivars: From a Syntenic Genomic Region to a Gene Coexpression Network
Authors: Martins Mônica Letícia Turibio , Sforça Danilo Augusto , dos Santos Luís Paulo , Pimenta Ricardo José Gonzaga , Mancini Melina Cristina , Aono Alexandre Hild , da Silva Cláudio Benício Cardoso , Vautrin Sonia , Bellec Arnaud , Vicentini Renato , Bérgès Helene , da Silva Carla Cristina , de Souza Anete Pereira 
Published: May 2024

AbstractElucidating the intricacies of the sugarcane genome is essential for breeding superior cultivars. This economically important crop originates from hybridizations of highly polyploidSaccharumspecies. However, the large size (10 Gb), high polyploidy, and aneuploidy of the sugarcane genome pose significant challenges to complete genome sequencing, assembly, and annotation. One successful strategy for identifying candidate genes linked to agronomic traits, particularly those associated with sugar accumulation, leverages synteny and potential collinearity with related species. In this study, we explored synteny between sorghum and sugarcane. Genes from a sorghum Brix QTL were used to screen bacterial artificial chromosome (BAC) libraries from two Brazilian sugarcane varieties (IACSP93-3046 and SP80-3280). The entire region was successfully recovered, confirming synteny and collinearity between the species. Manual annotation identified 51 genes in the hybrid varieties that were subsequently confirmed to be present inSaccharum spontaneum. To identify candidate genes for sugar accumulation, this study employed a multifaceted approach, including retrieving the genomic region of interest, performing gene-by-gene analysis, analyzing RNA-seq data of internodes fromSaccharum officinarumandS. spontaneumaccessions, constructing a coexpression network to examine the expression patterns of genes within the studied region and their neighbors, and finally identifying differentially expressed genes (DEGs). This comprehensive approach led to the discovery of three candidate genes potentially involved in sugar accumulation: an ethylene-responsive transcription factor (ERF), an ABA 8’-hydroxylase, and a prolyl oligopeptidase (POP). These findings could be valuable for identifying additional candidate genes for other important agricultural traits and directly targeting candidate genes for further work in molecular breeding.
Gradual labeling with fluorogenic probes for MINFLUX nanoscopy of densely packed structures
Authors: Yao Longfang , Si Dongjuan , Chen Liwen , Li Shu , Guan Jiaxin , Ma Jiong , Zhang Qiming , Wang Jing , Wang Lu , Gu Min 
Published: May 2024

AbstractSingle-molecule localization in densely packed structures represents a formidable challenge in nanoscopy. Here we develop a gradual labeling method with fluorogenic probes for MINFLUX nanoscopy (GLF-MINFLUX), with which individual proteins in packed structures can be sequential illuminated and quantitatively localized at the nanoscale solely by adjusting probe concentration. With a 1.7-fold localization precision improvement and 2.2-fold faster acquisition, GLF-MINFLUX enables dual-channel nanoscale imaging of densely neuronal microtubules and microfilaments, and three-dimensional quantitative mapping of individual TOM20 proteins in mitochondrial clusters.
Modeling Riboswitches: The impact of SAM concentration on the folding of the SAM-II riboswitch
Authors: Alaidi Osama 
Published: May 2024

ABSTRACTSeveral mechanistic (thermodynamic) models have been developed for the folding of SAM-II riboswitch as a function of SAM and magnesium concentrations. For each model, the model parameters (equilibrium constants) have been determined from experimental (apparent) binding data, based on the underlying assumptions of the model. The predicted titration curves computed from the different models were calculated and compared with actual experimental observation of the fraction of the RNA forming a pseudoknot at specific concentration of the ligands. Strikingly, only one of the six models correctly predicts the experimental findings, confirming the dominant mechanism of the riboswitch function. More interestingly, the latter mechanism is found to be the most efficient compared to the other possible mechanisms. The study sheds light on the cognate ligand conformational capture mechanism of the SAM-II riboswitch in the presence of specific concentrations of magnesium ions. The presented mathematical and thermodynamic framework, as well as the inferred equilibrium constants, provide foundations for making accurate quantitative prediction of the SAM-II riboswitch ensemble populations as a function of SAM and magnesium concentrations. The mechanistic linked equilibria model can be generalized to describe other thermodynamically driven riboswitches and hence facilitate identifying RNA intermediates that can be leveraged for small molecule drug design.
In vitro spatiotemporal reconstruction of human skeletal muscle organogenesis
Authors: Mavrommatis Lampros , Daya Nassam , Volke Leon , Lu I-Na , Zhuge Heidi , Stehling Martin , Zeuschner Dagmar , Jeong Hyun-Woo , Yang Ji-Hun , Meyer zu Hörste Gerd , Brand-Saberi Beate , Schöler Hans R. , Vorgerd Matthias , Zaehres Holm 
Published: May 2024

SummarySpatiotemporal recapitulation of long-range trajectories for lineages that influence body patterning along the medio-lateral and proximal-distal axes during embryogenesis in anin vitrosystem remains elusive. Here we introduce a three-dimensional organoid approach, termed Gastruloids-Lateraloid-Musculoids (GLMs), to model human neural crest, lateral plate mesoderm and skeletal muscle lineage development at the forelimb level following gastrulation and during limb patterning. GLMs harvest neuro-mesodermal progenitors with the potential to establish neural and paraxial mesodermal populations, while single cell analyses and spatial transcriptomics demonstrate promotion of mesodermal lineage segregation during gastrulation and spatial recapitulation of migration events along the medio-lateral axis for vagal neural crest, hypaxial myogenesis and lateral plate mesodermal lineages. Comparative analyses to developmental atlases and adult muscle stem cell data confirm a pool of hypaxial migrating myogenic progenitors that in a niche dependent manner change their embryonic anatomical developmental program to a fetal myogenic program, thus enabling them to resist specification in a cell autonomous manner and facilitate long termin vitroexpansion. GLMs model human myogenesis at the forelimb level, establish fetal muscle stem cells equivalent to those that sustain the growth phase of the embryo and provide a 3Din vitrosystem for investigating neural crest, early fore-gut and lateral plate mesoderm development.
An MST-based assay reveals new binding preferences of IFIT1 for canonically and non-canonically capped RNAs
Authors: Spiewla Tomasz , Grab Katarzyna , Depaix Anais , Ziemkiewicz Kamil , Warminski Marcin , Jemielity Jacek , Kowalska Joanna 
Published: May 2024

ABSTRACTIFIT proteins (interferon-induced proteins with tetratricopeptide repeats) are key components of the innate immune response that bind to viral and cellular RNA targets to inhibit viral translation and replication. The RNA target recognition is guided by molecular patterns, particularly at the RNA 5’ ends. IFIT1 preferably binds RNAs modified with the 7-methylguanosine (m7G) cap-0 structure, while RNAs with cap-1 structure are recognized with lower affinity. Less is known about the propensity of IFIT1 to recognize non-canonical RNA 5’ ends, including hypermethylated and non-canonical RNA caps. Deciphering the structure-function relationship for IFIT1-RNA interaction may improve understanding of cellular selection of IFIT targets and guide the design of exogenously delivered therapeutic RNAs, but requires high-throughput and robust analytical methods. Here, we report a biophysical assay for quick, direct, in-solution affinity assessment of differently capped RNAs with IFIT1. The procedure, which relies on measuring microscale thermophoresis (MST) of fluorescently labelled protein as a function of increasing ligand concentration, is applicable to various RNA lengths and sequences without the need for labelling or affinity tagging. Using the assay, we examined thirteen canonically and non-canonically 5’-capped RNAs, revealing new binding preferences of IFIT1. The 5’ terminal m6A mark in the m7G cap had a protective function against IFIT1, which was additive with the effect observed for the 2’-O position (m6Amcap-1). In contrast, an increased affinity for IFIT1 was observed for several non-canonical caps, including trimethylguanosine (TMG), unmethylated (G), and flavin-adenine dinucleotide (FAD) caps. The results suggest new potential cellular targets of IFIT1 and may contribute to broadening the knowledge on the mechanisms of the innate immune response as well as the more effective design of chemically modified mRNAs.
Oncogenic signaling in the adultDrosophilaprostate-like accessory gland leads to activation of a conserved pro-tumorigenic program, in the absence of proliferation
Authors: Church S. Jaimian , Pulianmackal Ajai J. , Dixon Joseph A. , Loftus Luke V. , Amend Sarah R. , Pienta Kenneth , Cackowski Frank C. , Buttitta Laura A. 
Published: May 2024

AbstractDrosophilamodels for tumorigenesis and metastasis have revealed conserved mechanisms of signaling that are also involved in mammalian cancer. Many of these models use the proliferating tissues of the larval stages ofDrosophiladevelopment, when tissues are highly mitotically active, or stem cells are abundant. FewerDrosophilatumorigenesis models use adult animals to initiate tumor formation when many tissues are largely terminally differentiated and postmitotic. TheDrosophilaaccessory glands are prostate-like tissues and a model for some aspects of prostate tumorigenesis using this tissue has been explored. In this model, oncogenic signaling was induced during the proliferative stage of accessory gland development, raising the question of how oncogenic activity would impact the terminally differentiated and postmitotic adult tissue. Here, we show that oncogenic signaling in the adultDrosophilaaccessory gland leads to activation of a conserved pro-tumorigenic program, similar to that observed in mitotic larval tissues, but in the absence of proliferation. Oncogenic signaling in the adult postmitotic gland leads to tissue hyperplasia with nuclear anaplasia and aneuploidy through endoreduplication, which increases polyploidy and occasionally results in non-mitotic neoplastic-like extrusions. We compare gene expression changes in ourDrosophilamodel with that of endocycling prostate cancer cells induced by chemotherapy, which potentially mediate tumor recurrence after treatment. Similar signaling pathways are activated in theDrosophilagland and endocycling cancer cells, suggesting the adult accessory glands provide a useful model for aspects of prostate cancer progression that do not involve cellular proliferation.
Associations Between Prenatal Vitamin D and Placental Gene Expression
Authors: Parenti Mariana , Melough Melissa M. , Lapehn Samantha , MacDonald James , Bammler Theo , Firsick Evan J. , Choi Hyo Young , Derefinko Karen J. , Enquobahrie Daniel A. , Carroll Kecia N. , LeWinn Kaja Z. , Bush Nicole R. , Zhao Qi , Sathyanarayana Sheela , Paquette Alison G. 
Published: May 2024

ABSTRACTBackgroundVitamin D is a hormone regulating gene transcription. Prenatal vitamin D has been linked to immune and vascular function in the placenta, a key organ of pregnancy. To date, studies of vitamin D and placental gene expression have focused on a limited number of candidate genes. Transcriptome-wide RNA sequencing can provide a more complete representation of the placental effects of vitamin D.ObjectiveWe investigated the association between prenatal vitamin D levels and placental gene expression in a large, prospective pregnancy cohort.MethodsParticipants were recruited in Shelby County, Tennessee in the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study. Vitamin D level (plasma total 25-hydroxyvitatmin D, [25(OH)D]) was measured at mid-pregnancy (16-28 weeks’ gestation) and delivery. Placenta samples were collected at birth. RNA was isolated and sequenced. We identified differentially expressed genes (DEGs) using adjusted linear regression models. We also conducted weighted gene co-expression network analysis (WGCNA).ResultsThe median 25(OH)D of participants was 21.8 ng/mL at mid-pregnancy (N=774, IQR: 15.4-26.5 ng/mL) and 23.6 ng/mL at delivery (N=753, IQR: 16.8-29.1 ng/mL). Placental expression of 25 DEGs was associated with 25(OH)D at mid-pregnancy, but no DEG was associated with 25(OH)D at delivery. DEGs were related to energy metabolism, cytoskeletal function, and RNA transcription. Using WGCNA, we identified 2 gene modules whose expression was associated with 25(OH)D at mid-pregnancy and 1 module associated with 25(OH)D at delivery. These modules were enriched for genes related to mitochondrial and cytoskeletal function, and were regulated by transcription factors includingARNT2,BHLHE40,FOSL2,JUND, andNFKB1.ConclusionsOur results indicate that 25(OH)D during mid-pregnancy, but not at delivery, is associated with placental gene expression at birth. Future research is needed to investigate a potential role of vitamin D in programming placental mitochondrial metabolism, intracellular transport, and transcriptional regulation during pregnancy.
A phosphorylation code coordinating transcription condensate dynamics with DNA replication
Authors: Marmolejo Carlos Origel , Sanchez Celina , Lee Juyoung , Werner Marcel , Roberts Paige , Hamperl Stephan , Saldivar Joshua C. 
Published: May 2024

SUMMARYChromatin is organized into compartments enriched with functionally-related proteins driving non-linear biochemical activities. Some compartments,e.g.transcription foci, behave as liquid condensates. While the principles governing the enrichment of proteins within condensates are being elucidated, mechanisms that coordinate condensate dynamics with other nuclear processes like DNA replication have not been identified. We show that at the G1/S cell cycle transition, large transcription condensates form at histone locus bodies (HLBs) in a cyclin-dependent kinase 1 and 2 (CDK1/2)-dependent manner. As cells progress through S phase, ataxia-telangiectasia and Rad3-related (ATR) accumulates within HLBs and dissolves the associated transcription condensates. Integration of CDK1/2 and ATR signaling creates a phosphorylation code within the intrinsically-disordered region of mediator subunit 1 (MED1) coordinating condensate dynamics with DNA replication. Disruption of this code results in imbalanced histone biosynthesis, and consequently, global DNA damage. We propose the spatiotemporal dynamics of transcription condensates are actively controlled via phosphorylation and essential for viability of proliferating cells.
Asesino: a nucleus-forming phage that lacks PhuZ
Authors: Prichard Amy , Sy Annika , Meyer Justin , Villa Elizabeth , Pogliano Joe 
Published: May 2024

ABSTRACTAs nucleus-forming phages become better characterized, understanding their unifying similarities and unique differences will help us understand how they occupy varied niches and infect diverse hosts. All identified nucleus-forming phages fall within the proposed Chimalliviridae family and share a core genome of 68 unique genes including chimallin, the major nuclear shell protein. A well-studied but non-essential protein encoded by many nucleus-forming phages is PhuZ, a tubulin homolog which aids in capsid migration, nucleus rotation, and nucleus positioning. One clade that represents 24% of all currently known chimalliviruses lacks a PhuZ homolog. Here we show thatErwiniaphage Asesino, one member of this PhuZ-less clade, shares a common overall replication mechanism with other characterized nucleus-forming phages despite lacking PhuZ. We show that Asesino replicates via a phage nucleus that encloses phage DNA and partitions proteins in the nuclear compartment and cytoplasm in a manner similar to previously characterized nucleus-forming phages. Consistent with a lack of PhuZ, however, we did not observe active positioning or rotation of the phage nucleus within infected cells. These data show that some nucleus-forming phages have evolved to replicate efficiently without PhuZ, providing an example of a unique variation in the nucleus-based replication pathway.
L-Dopa induced dyskinesias require Cholinergic Interneuron expression of Dopamine 2 receptor
Authors: Uribe-Cano Santiago , Malave Lauren , Kottmann Andreas H. 
Published: May 2024

ABSTRACTBackgroundStriatal Cholinergic Interneurons (CIN) are drivers of L-Dopa induced Dyskinesias (LID). However, what signaling pathways elicit aberrant CIN activity remains unclear. CIN express D2 and D5 receptors suggesting repeated activation of these receptors in response to L-Dopa could promote LID. While the role of D5 in this process has recently been probed, little is known about the role of D2.MethodMice with CIN-specific D2 ablation (D2CINKO) underwent unilateral 6-OHDA lesion and chronic L-Dopa dosing, throughout which LID severity was quantified. The effect of D2CINKO on histological markers of LID severity and CIN activity were also quantified postmortem.ResultsD2CINKO attenuated LID across L-Dopa doses, reduced expression of histological LID marker p-ERK, and prevented L-Dopa-induced increases in CIN activity marker p-rpS6 in the dorsolateral striatum.ConclusionThe activation of D2 specifically on CIN is a key driver of LID.
Regulation of brain development by the Minibrain/Rala signaling network
Authors: Brown Melissa , Sciascia Erika , Ning Ken , Adam Wesam , Veraksa Alexey 
Published: May 2024

AbstractThe human dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) is implicated in the pathology of Down syndrome, microcephaly, and cancer, however the exact mechanism through which it functions is unknown. Here, we have studied the role of theDrosophilaortholog of DYRK1A, Minibrain (Mnb), in brain development. The neuroblasts (neural stem cells) that eventually give rise to differentiated neurons in the adult brain are formed from a specialized tissue in the larval optic lobe called the neuroepithelium, in a tightly regulated process. Molecular marker analysis ofmnbmutants revealed alterations in the neuroepithelium and neuroblast regions of developing larval brains. Using affinity purification-mass spectrometry (AP-MS), we identified the novel Mnb binding partners Ral interacting protein (Rlip) and RALBP1 associated Eps domain containing (Reps). Rlip and Reps physically and genetically interact with Mnb, and the three proteins may form a ternary complex. Mnb phosphorylates Reps, and human DYRK1A binds to the Reps orthologs REPS1 and REPS2. Furthermore, Mnb engages the small GTPase Ras-like protein A (Rala) to regulate brain and wing development. This work uncovers a previously unrecognized early role of Mnb in the neuroepithelium and defines the functions of the Mnb/Reps/Rlip/Rala signaling network in brain development.Significance statementThe kinase Minibrain(Mnb)/DYRK1A regulates the development of the brain and other tissues across many organisms. Here we show the critical importance of Mnb within the developing neuroepithelium. Advancing our understanding of Mnb function, we identified novel protein interactors of Mnb, Reps and Rlip, which function together with Mnb to regulate growth inDrosophila melanogaster. We also identify and characterize a role for the small GTPase Rala in Mnb-regulated growth and nervous system development. This work reveals an early role of Mnb in brain development and identifies a new Mnb/Reps/Rlip/Rala signaling axis.