bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex- and caste-specific developmental responses to juvenile hormone in an ant with maternal caste determination
Authors: Brülhart J. , Süß A. , Oettler J. , Heinze J. , Schultner E. 
Published: September 2023

AbstractQueen-worker caste polyphenism in social insects is a prime example for developmental plasticity. Most of what we know about caste development comes from studies of the honeybee, in which female caste is determined during larval development and workers retain functional ovaries. The ant genusCardiocondylais one of only few genera in which complete worker sterility has evolved, so that adult workers completely lack reproductive organs. InC. obscurior, queen- and worker-destined individuals are distinct in their development by late-embryogenesis, and castes can be distinguished in a non-invasive manner from this stage onwards. This provides the opportunity to investigate the degree of flexibility in caste development in a species with early caste determination. Using topical juvenile hormone treatment, a method known to influence caste determination and differentiation in some species, we investigated whether hormone manipulation affects the development and growth of queen and worker-destined late-stage embryos and larvae, as well as of early-stage embryos which cannot yet be distinguished by caste. We found no effect of hormone treatment on female caste ratios or body sizes in any of the treated stages, even though individuals reacted to heightened hormone availability with increases in the expression ofkrüppel-homolog 1, a conserved JH first-response gene. In contrast, hormone treatment resulted in the emergence of significantly larger males. These results show that inC. obscurior, early, presumably maternal caste determination leads to irreversible and highly-canalized caste-specific development and growth.
A conserved class of viral RNA structures regulate translation reinitiation through dynamic ribosome interactions
Authors: Sherlock Madeline E. , Langeberg Conner J. , Segar Katherine E. , Kieft Jeffrey S. 
Published: September 2023

SUMMARYCertain viral RNAs encode proteins downstream of the main protein coding region, expressed through “termination-reinitiation” events, dependent on RNA structure. RNA elements located upstream of the first stop codon within these viral mRNAs bind the ribosome, preventing ribosome recycling and inducing reinitiation. We used bioinformatic methods to identify new examples of viral reinitiation-stimulating RNAs and experimentally verified their secondary structure and function. We determined the structure of a representative viral RNA-ribosome complex using cryoEM. 3D classification and variability analyses reveal that the viral RNA structure can sample a range of conformations while remaining tethered to the ribosome, which enabling the ribosome to find a reinitiation start site within a limited range of mRNA sequence. Evaluating the conserved features and constraints of this entire RNA class in the context of the cryoEM reconstruction provides insight into mechanisms enabling reinitiation, a translation regulation strategy employed by many other viral and eukaryotic systems.
Location, Location, Location: Protein kinase nanoclustering for optimized signalling output
Authors: Gormal Rachel S. , Martínez-Mármol Ramón , Brooks Andrew J. , Meunier Frédéric A. 
Published: September 2023

AbstractProtein kinases (PKs) are proteins at the core of cellular signalling and are thereby responsible for most of the cellular physiological processes and their regulations. As for all cellular proteins, they are subjected to Brownian thermal energy that tends to homogenise their distribution throughout the volume of the cell. To access their substrates and perform their critical functions, PKs localisation is therefore tightly regulated in space and time, relying upon a range of clustering mechanisms. These include post-translational modifications, protein-protein and protein-lipid interactions as well as liquid-liquid phase separation, allowing spatial restriction and ultimately regulating access to their substrates. In this review, we will mainly focus on key mechanisms mediating PK nanoclustering in physiological and pathophysiological processes. We propose that PK nanoclusters act as a cellular unit of signalling output capable of integration and regulation in space and time. We will specifically outline the various super-resolution microscopy approaches currently used to elucidate the mechanisms driving PK nanoscale clustering and explore the pathological consequences of altered kinase clustering in the context of neurodegenerative disorders, inflammation, and cancer.
Protective non-neutralizing mAbs Ab94 and Ab81 retain high-affinity and potent Fc-mediated function against SARS-CoV-2 variants from Omicron to XBB1.5
Authors: Izadi Arman , Godzwon Magdalena , Ohlin Mats , Nordenfelt Pontus 
Published: September 2023

AbstractAntibodies play a central role in the immune defense against SARS-CoV-2. There is substantial evidence supporting that Fc-mediated effector functions of anti-spike antibodies contribute to anti-SARS-Cov-2 immunity. We have previously shown that two non-neutralizing but opsonic mAbs, Ab81 and Ab94, are protective against lethal Wuhan SARS-CoV-2 infection in mice. The protective effect was comparable to a potent neutralizing antibody, Ab59. Here, we hypothesized that, unlike the neutralizing antibodies, non-neutralizing opsonic antibodies would have a higher likelihood of retaining their function to the mutated variants, potentially functioning as broadly protective mAbs. Most of the mutations on the SARS-CoV-2 variants cluster on neutralizing epitopes, leaving other epitopes unaltered. We observed that neutralizing antibodies lost binding to Omicron. In contrast, seven non-neutralizing opsonic antibodies retained nanomolar affinity towards Omicron, BA.2, BA.4, and BA.5. Focusing on the two protective non-neutralizing antibodies Ab81 and Ab94, we showed that they maintain their strong reactivity even to XBB, XBB1.5, and BQ1.1. In the case of Ab94, interestingly, it even has increased affinity towards all variants except for XBB, which is comparable to WT. Finally, we show that Ab94 and Ab81 have potent Fc-mediated functions in vitro against the XBB and BQ1.1 and that combining the mAbs in a cocktail further enhances the effect. These results show that protective non-neutralizing mAbs such as Ab94 and Ab81 can be a viable strategy for anti-SARS-CoV-2 mAb therapies against current and possibly future SARS-CoV-2 variants and that opsonic epitopes could have implications for vaccine design.
Evolutionary Adaptation of an HP1-protein Chromodomain Integrates Chromatin and DNA Sequence Signals
Authors: Baumgartner Lisa , Ipsaro Jonathan J. , Hohmann Ulrich , Handler Dominik , Schleiffer Alexander , Duchek Peter , Brennecke Julius 
Published: September 2023

ABSTRACTMembers of the diverse heterochromatin protein 1 (HP1) family play crucial roles in heterochromatin formation and maintenance. Despite the similar affinities of their chromodomains for di- and tri-methylated histone H3 lysine 9 (H3K9me2/3), different HP1 proteins exhibit distinct chromatin binding patterns, likely due to interactions with various specificity factors. Here, we elucidate the molecular basis of the interaction between the HP1 protein Rhino, a crucial factor of theDrosophilapiRNA pathway, and Kipferl, a DNA sequence-specific C2H2zinc finger protein and Rhino guidance factor. Through phylogenetic analyses, structure prediction, andin vivogenetics, we identify a single amino acid change within Rhino’s chromodomain, G31D, that does not affect H3K9me2/3 binding but disrupts the interaction between Rhino and Kipferl. Flies carrying therhinoG31Dmutation phenocopykipferlmutant flies, with Rhino redistributing from piRNA clusters to satellite repeats, causing pronounced changes in the ovarian piRNA profile ofrhinoG31Dflies. Thus, Rhino’s chromodomain functions as a dual-specificity module, facilitating interactions with both a histone mark and a DNA-binding protein.
Functional opsin patterning forDrosophilacolor vision is established through signaling pathways in adjacent object-detection neurons
Authors: Kitamata Manabu , Otake Yoshiaki , Kitagori Hideaki , Zhang Xuanshuo , Maki Yusuke , Boku Rika , Takeuchi Masato , Nakagoshi Hideki 
Published: September 2023

AbstractVision is mainly based on two different tasks, object detection and color discrimination through activities of photoreceptor (PR) cells.Drosophilacompound eye consists of ∼800 ommatidia. Every ommatidium contains eight PR cells; six outer cells (R1-R6) and two inner cells (R7 and R8) by which object detection and color vision are achieved, respectively. Expression of opsin genes in R7 and R8 is highly coordinated through the instructive signal from R7 to R8, and two major ommatidial subtypes are distributed stochastically; pale type expresses Rh3/Rh5, while yellow type expresses Rh4/Rh6 in R7/R8. The homeodomain protein Defective proventriculus (Dve) is expressed in yellow-type R7 and in six outer PRs, and it is involved in Rh3 repression to specify the yellow-type R7.dvemutant eyes exhibited atypical coupling, Rh3/Rh6 and Rh4/Rh5, indicating that the Dve activity is required for proper opsin coupling. Surprisingly, Dve activity in R1 is required for instructive signal, whereas those in R6 and R7 block the signal. Our results indicate that functional coupling of two different neurons is established through signaling pathways from adjacent neurons that are functionally different.Summary StatementDve activity is required for proper opsin coupling of two neurons that is established through signaling pathways from adjacent neurons that are functionally different.
Genome-wide CRISPR activation screen identifies JADE3 as an antiviral activator of NF-kB
Authors: Munir Moiz , Embry Aaron , Doench John G. , Heaton Nicholas S. , Wilen Craig B. , Orchard Robert C. 
Published: September 2023

AbstractThe innate immune system features a web of interacting pathways that require exquisite regulation. To identify novel nodes in this immune landscape we conducted a gain of function, genome-wide CRISPR activation screen with influenza A virus. We identified both appreciated and novel antiviral genes, including JADE3 a protein involved in directing the histone acetyltransferase HBO1 complex to modify chromatin and regulate transcription. JADE3 is both necessary and sufficient to restrict influenza A virus infection. Interestingly, expression of the closely related paralogues JADE1 and JADE2 are unable to restrict influenza A virus infection, suggesting a distinct function of JADE3. We identify both shared and unique transcriptional signatures between uninfected cells expressing JADE3 and JADE2. These data provide a framework for understanding the overlapping and distinct functions of the JADE family of paralogues. Specifically, we find that JADE3 expression activates the NF-kB signaling pathway, consistent with an antiviral function. Therefore, we propose JADE3, but not JADE1 or JADE2, activates an antiviral genetic program involving the NF-kB pathway to restrict influenza A virus infection.
Upc2-mediated mechanisms of azole resistance inCandida auris
Authors: Li Jizhou , Aubry Lola , Brandalise Danielle , Coste Alix T. , Sanglard Dominique , Lamoth Frederic 
Published: September 2023

ABSTRACTCandida aurisis an emerging yeast pathogen of major concern because of its ability to cause hospital outbreaks of invasive candidiasis and to develop resistance to antifungal drugs. A majority ofC. aurisisolates are resistant to fluconazole, a first-line treatment of invasive candidiasis. Mechanisms of azole resistance are multiple, including mutations in the target geneERG11and activation of the transcription factors Tac1b and Mrr1, which control the drug transporters Cdr1 and Mdr1, respectively. In this study, we investigated the role the transcription factor Upc2, which is known to regulate the ergosterol biosynthesis pathway and azole resistance in otherCandidaspp.Genetic deletion and hyperactivation of Upc2 by epitope tagging inC. aurisresulted in drastic increased and decreased susceptibility to azoles, respectively. This effect was conserved in strains with genetic hyperactivation of Tac1b or Mrr1. Reverse transcription PCR analyses showed that Upc2 regulatesERG11expression and also activates the Mrr1/Mdr1 pathway. We showed that upregulation ofMDR1by Upc2 could occur independently from Mrr1. The impact ofUPC2deletion onMDR1expression and azole susceptibility in a hyperactive Mrr1 background was stronger than that ofMRR1deletion in a hyperactive Upc2 background. While Upc2 hyperactivation resulted in a significant increase of expression ofTAC1b,CDR1expression remained unchanged.Taken together, our results showed that Upc2 is crucial for azole resistance inC. auris, via regulation of the ergosterol biosynthesis pathway and activation of the Mrr1/Mdr1 pathway. Notably, Upc2 is a very potent and direct activator of Mdr1.
Emergence of bluetongue virus serotype 3 in the Netherlands in September 2023
Authors: Holwerda Melle , Santman-Berends Inge M.G.A. , Harders Frank , Engelsma Marc , Vloet Rianka P.M. , Dijkstra Eveline , van Gennip Rene G.P. , Mars Maria H. , Spierenburg Marcel , Roos Lotte , van den Brom René , van Rijn Piet A. 
Published: September 2023

AbstractSince 1998, WOAH-notifiable bluetongue virus (BTV) serotype 1, 2, 3, 4, 6, 8, 9, 11, and 16 have been reported in Europe. In mid-August, 2006, a BTV-8 outbreak started in Northwestern Europe. The Netherlands was declared BT-free again in February 2012 and annual monitoring demonstrated BT-freedom up to 2023. On September 3rd2023, clinical manifestations in sheep typical for BT were notified to the Dutch Food and Product Safety Consumer Authority. Laboratory diagnosis confirmed BTV-infection on September 6 and the first notifications of clinical signs in cattle were also reported. Two days later, the virus was identified as serotype 3 by whole genome sequencing. Clinical signs were like these of BTV-8 outbreak and were most serious in sheep. Retrospective analysis revealed no earlier circulation of BTV. It was concluded that the BTV-3 outbreak was detected shortly after introduction, while the virus source and route of introduction remains unknown.Article summary lineDuring September 2023, a novel serotype 3 Bluetongue virus (BTV) emerged in the Netherlands which affected sheep and cattle.
Non-coding 886 (nc886/vtRNA2-1), the epigenetic odd duck – implications for future studies
Authors: Raitoharju Emma , Rajić Sonja , Marttila Saara 
Published: September 2023

AbstractNon-coding 886 (nc886,VTRNA2-1) is the only human polymorphically imprinted gene, in which the methylation status is not determined by genetics. Existing literature regarding the establishment, stability, and consequences of the methylation pattern, as well as the nature and function of the nc886 RNAs transcribed from the locus, are contradictory. For example, the methylation status of the locus has been reported to be stable through life and across somatic tissues, but also susceptible to environmental effects. The nature of the produced nc886 RNAs has been redefined multiple times and are still under debate and in carcinogenesis, these RNAs have been reported to have conflicting roles. In addition, due to the bimodal methylation pattern of thenc886locus, traditional genome-wide methylation analyses can lead to false-positive results, especially in smaller datasets.Here, we aim to summarise the existing literature regardingnc886, discuss how the characteristics ofnc886give rise to contradictory results, and reinterpret, reanalyse and, where possible, replicate the results presented in the current literature. We also introduce novel findings on how thenc886methylation pattern distribution is associated with the geographical origins of the population and describe the methylation changes in a large variety of human tumours. Through the example of this one peculiar genetic locus and RNA, we aim to highlight issues in the analysis of DNA methylation and non-coding RNAs in general and offer our suggestions for what should be taken into consideration in future analyses.
Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation
Authors: Feng Lijuan , Barrows Douglas , Zhong Liangwen , Mätlik Kärt , Porter Elizabeth G. , Djomo Annaelle M. , Yau Iris , Soshnev Alexey A. , Carroll Thomas S. , Wen Duancheng , Hatten Mary E. , Garcia Benjamin A. , Allis C. David 
Published: September 2023

SummaryChromatin is a crucial regulator of gene expression and tightly controls development across species. Mutations in only one copy of multiple histone genes were identified in children with developmental disorders characterized by microcephaly, but their mechanistic roles in development remain unclear. Here we focus on dominant mutations affecting histone H4 lysine 91. These H4K91 mutants form aberrant nuclear puncta at specific heterochromatin regions. Mechanistically, H4K91 mutants demonstrate enhanced binding to the histone variant H3.3, and ablation of H3.3 or the H3.3-specific chaperone DAXX diminishes the mutant localization to chromatin. Our functional studies demonstrate that H4K91 mutant expression increases chromatin accessibility, alters developmental gene expression through accelerating pro-neural differentiation, and causes reduced mouse brain sizein vivo, reminiscent of the microcephaly phenotypes of patients. Together, our studies unveil a distinct molecular pathogenic mechanism from other known histone mutants, where H4K91 mutants misregulate cell fate during development through abnormal genomic localization.
Investigating the effects of contextual information, visual working memory, and inhibitory control in hybrid visual search
Authors: Barbosa Alessandra , Ries Anthony J. , Kamienkowski Juan E. , Ison Matias J. 
Published: September 2023

AbstractIn real-life scenarios, individuals frequently engage in tasks that involve searching for one of various items stored in memory. This combined process of visual search and memory search is known as hybrid search. To date, most hybrid search studies have been restricted to average observers looking for previously well-memorized targets in blank backgrounds. Here we investigated the effects of context and the role of memory in hybrid search by modifying the task’s memorization phase to occur in all-new single trials. Additionally, we aimed to assess how individual differences in visual working memory capacity and inhibitory control influence performance during hybrid search. In an online experiment, 110 participants searched for potential targets in images with and without context. A change detection and go/no-go task were also performed to measure working memory capacity and inhibitory control, respectively. We show that, in target present trials, the main hallmarks of hybrid search remain present, with a linear relationship between reaction time and visual set size, and a logarithmic relationship between reaction time and memory set size. Context affected search efficiency in different ways. In target-absent trials we found large differences between context-present and absent conditions, suggesting participants’ adoption of adaptive strategies. Finally, working memory capacity did not predict most search performance measures. Inhibitory control, when relationships were significant, could account for only a small portion of the variability in the data. This study provides insights into the effects of context and individual differences on search efficiency and termination.
A genome-wide CRISPR/Cas9 screen identifies genes that regulate the cellular uptake of α-synuclein fibrils by modulating heparan sulfate proteoglycans
Authors: Vanderperre B. , Muraleedharan A. , Dorion M.-F. , Larroquette F. , Del Cid Pellitero E. , Rajakulendran N. , Chen C. X.-Q. , Larivière R. , Michaud-Tardif C. , Chidiac R. , Lipuma D. , MacLeod G. , Thomas R. , Wang Z. , Reintsch W.E. , Luo W. , Shlaifer I. , Fuming Z. , Xia K. , Yan L. , Steinhart Z. , Linhardt R.J. , Trempe J.-F. , Liu J. , Durcan T.M. , Angers S. , Fon E.A. 
Published: September 2023

ABSTRACTSynucleinopathies are characterized by the accumulation and propagation of α-synuclein (α-syn) aggregates throughout the brain, leading to neuronal dysfunction and death. Understanding how these aggregates propagate from cell to cell in a prion-like fashion thus holds great therapeutic promises. Here, we focused on understanding the cellular processes involved in the entry and accumulation of pathological α-syn aggregates. We used an unbiased FACS-based genome-wide CRISPR/Cas9 knockout (KO) screening to identify genes that regulate the accumulation of α-syn preformed fibrils (PFFs) in cells. We identified key genes and pathways specifically implicated in α-syn PFFs intracellular accumulation, including heparan sulfate proteoglycans (HSPG) biosynthesis and Golgi trafficking. We show that all confirmed hits affect heparan sulfate (HS), a post-translational modification known to act as a receptor for proteinaceous aggregates including of α-syn and tau. Intriguingly, KO ofSLC39A9andC3orf58genes, encoding respectively a Golgi-localized exporter of Zn2+, and the Golgi-localized putative kinase DIPK2A, specifically impaired the uptake of α-syn PFFs uptake but not of tau oligomers, by preventing the binding of PFFs to the cell surface. Mass spectrometry-based analysis of HS chains indicated major defects in HS maturation inSLC39A9andC3orf58KO cells, explaining the cell surface binding deficit. Our findings now clearly establish these two genes as HSPG-modulating factors. Interestingly,C3orf58KO human iPSC-derived microglia exhibited a strong reduction in their ability to internalize α-syn PFFs. Altogether, our data establish HSPGs as major receptors for α-syn PFFs binding on the cell surface and identifies new players in α-syn PFFs cell surface binding and uptake.
Deep learning reveals the role of copy number variation in the genetic architecture of a highly polymorphic sexual trait
Authors: van der Bijl Wouter , Shu Jacelyn J. , Goberdhan Versara S. , Sherin Linley M. , Cortázar-Chinarro María , Corral-López Alberto , Mank Judith E. 
Published: September 2023

AbstractThe extraordinary variation in male guppy coloration has proven a powerful model for studying the interplay of natural and sexual selection. Many guppy populations exhibit substantial Y-linkage of color traits, and this has hampered the identification of the genetic architecture underlying male guppy color, as well as clouded our understanding of how this exceptional level of diversity is maintained. Here we identify the heritability and genetic basis of male color variation using convolutional neural networks for high-resolution phenotyping coupled with selection experiments, controlled pedigrees and whole-genome resequencing for a Genome Wide Association Study (GWAS) of color. Our phenotypic and genomic results converge to show that color patterning in guppies is a combination of many heritable features, each with a partially overlapping genetic architecture spanning the entire genome. Unusually, our GWAS results suggest that copy number variation, particularly copies shared between the Y chromosome and the remainder of the genome, is responsible for much of the variation in color in guppies, providing a potential mechanism for the maintenance of variation of this classic model trait.