bluuebunny/crossref_metadata_2025_split huggingface dataset:
Control of innate olfactory valence by segregated cortical amygdala circuits
Authors: Howe James R. , Chan Chung-Lung , Lee Donghyung , Blanquart Marlon , Lee James H. , Romero Haylie K. , Zadina Abigail N. , Lemieux Mackenzie E. , Mills Fergil , Desplats Paula A. , Tye Kay M. , Root Cory M. 
Published: June 2024

AbstractAnimals exhibit innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach or avoidance responses. The posterolateral cortical amygdala (plCoA) mediates innate attraction and aversion to odor. However, little is known about how this brain area gives rise to behaviors of opposing motivational valence. Here, we sought to define the circuit features of plCoA that give rise to innate attraction and aversion to odor. We characterized the physiology, gene expression, and projections of this structure, identifying a divergent, topographic organization that selectively controls innate attraction and avoidance to odor. First, we examined odor-evoked responses in these areas and found sparse encoding of odor identity, but not valence. We next considered a topographic organization and found that optogenetic stimulation of the anterior and posterior domains of plCoA elicits attraction and avoidance, respectively, suggesting a functional axis for valence. Using single cell and spatial RNA sequencing, we identified the molecular cell types in plCoA, revealing an anteroposterior gradient in cell types, whereby anterior glutamatergic neurons preferentially expressVGluT2and posterior neurons expressVGluT1. Activation of these respective cell types recapitulates appetitive and aversive behaviors, and chemogenetic inhibition reveals partial necessity for responses to innate appetitive or aversive odors. Finally, we identified topographically organized circuits defined by projections, whereby anterior neurons preferentially project to medial amygdala, and posterior neurons preferentially project to nucleus accumbens, which are respectively sufficient and necessary for innate attraction and aversion. Together, these data advance our understanding of how the olfactory system generates stereotypic, hardwired attraction and avoidance, and supports a model whereby distinct, topographically distributed plCoA populations direct innate olfactory responses by signaling to divergent valence-specific targets, linking upstream olfactory identity to downstream valence behaviors, through a population code. This suggests a novel amygdala circuit motif in which valence encoding is represented not by the firing properties of individual neurons, but by population level identity encoding that is routed through divergent targets to mediate distinct behaviors of opposing appetitive and aversive responses.
Same trait, different genes: pelvic spine loss in three brook stickleback populations in Alberta, Canada
Authors: Mee Jonathan A. , Ly Carolyn , Pigott Grace C. 
Published: June 2024

AbstractThe genetic basis of phenotypic or adaptive parallelism can reveal much about constraints on evolution. This study investigated the genetic basis of a canonically parallel trait: pelvic spine reduction in sticklebacks. Pelvic reduction has a highly parallel genetic basis in threespine stickleback in populations around the world, always involving a deletion of the pel1 enhancer ofPitx1. We conducted a genome-wide association study to investigate the genetic basis of pelvic spine reduction in three populations of brook stickleback in Alberta, Canada. Pelvic reduction did not involvePitx1in any of the three populations. Instead, pelvic reduction in one population involved a mutation in an exon ofTbx4, and it involved a mutation in an intron ofLmbr1in the other two populations. Hence, the parallel phenotypic evolution of pelvic spine reduction across stickleback genera, and among brook stickleback populations, has a non-parallel genetic basis. This suggests that there may be redundancy in the genetic basis of this adaptive polymorphism, but it is not clear whether a lack of parallelism indicates a lack of constraint on the evolution of this adaptive trait. Whether the different pleiotropic effects of different mutations have different fitness consequences, or whether certain pelvic reduction mutations confer specific benefits in certain environments, remains to be determined.Lay SummaryIn this study, we looked for the genetic basis of a well-studied trait in stickleback fish: the pelvic spines. This structure (i.e. the pelvic girdle and attached spines) has a shared developmental basis (and is homologous to) the pelvic bones and hind limbs of all tetrapods (including humans). We know from studying mice, fish, humans, and even manatees that there are several genes that could affect the development of pelvic spines and hind limbs. In one species of stickleback, the threespine stickleback, however, a single gene calledPitx1is always involved in the loss of pelvic spines in populations that have adapted to freshwater lakes. This replicated evolution of the same trait in the same environmental conditions is called parallel evolution. It’s remarkable thatPitx1is always the gene underlying this adaptive loss of spines in freshwater threespine stickleback populations. We were interested in whether this “genetic parallelism” extended to other species of stickleback that have also evolved the loss of pelvic spines. We looked at three populations of brook stickleback (which are never found in the ocean), each of which contains individuals with and without pelvic spines. We found that thePitx1genetic parallelism does not extend to brook stickleback, and, in fact, the genetic basis of pelvic spine loss differs between populations. In Muir Lake and Astotoin Lake, pelvic spine loss results from a mutation in theLmbr1gene, and in Shunda Lake, pelvic spine loss results from a mutation in theTbx4gene.
Polymerization of Tspan7 into Helical Transmembrane Skeletons for Membrane Tether Stabilization
Authors: Wang Dongju , Jia Xia , Zhang Qi , Xu Kui , Zheng Yi , Zhang Qiangfeng Cliff , Liu Nan , Wang Hong-Wei , Yu Li 
Published: June 2024

SummaryMembrane tethers, thin tubular extensions of the plasma membrane, form during cell migration, adhesion, and signaling. Various types exist, though their maintenance mechanisms are not fully understood. This study employs live cell imaging,in vitroreconstitution, andin situcryo-EM analysis to show that Tspan7, typically a freely diffusing transmembrane protein, forms long cylindrical polymers in right-handed helical formations on retraction fibers. These polymers assemble into spiral tubule structures, acting as a “transmembrane skeleton”, enriching Tspan7 on retraction fibers and promoting their formation. Our findings reveal a novel assembly strategy for transmembrane proteins and a mechanism for maintaining membrane tethers.
The Ptch methylase installs an m3U modification on 28S rRNA for efficient protein synthesis in flies and men
Authors: Chen Jie , Bai Yaofu , Huang Yuantai , Cui Min , Wang Yiqing , Gu Zhenqi , Wu Xiaolong , Li Yubin , Rong Yikang S. 
Published: June 2024

AbstractThe ribosomal RNA (rRNA) is one of the most heavily modified RNA species in nature. Although we have advanced knowledge of the sites, functions and the enzymology of many of the rRNA modifications from all kingdoms, we lack basic understanding on many of those that are not universally present. A single N3modified Uridine base (m3U) was identified on the 28S rRNA from human and frog over thirty years ago, which is absent in bacteria or yeast. Here we show that the equivalent m3U is present in Drosophila, and that the Ptch enzyme and its human homolog are both necessary and sufficient for carrying out the modification. The Ptch-modified U is at a functional center of the large ribosome, and consistentlyptch-mutant cells suffer loss of ribosomal functions. Ptch, proposed to be the most druggable RNA methyltransferases in human, represents a unique target where ribosomal functions could be specifically compromised in cancer cells.
MORC2 phosphorylation fine tunes its DNA compaction activity
Authors: Tan Winnie , Park Jeong Veen , Venugopal Hariprasad , Lou Jie Qiong , Dias Prabavi Shayana , Baldoni Pedro L. , Dite Toby , Moon Kyoung-Wook , Keenan Christine R. , Gurzau Alexandra D. , Leis Andrew , Yousef Jumana , Vaibhav Vineet , Dagley Laura F. , Ang Ching-Seng , Corso Laura , Davidovich Chen , Vervoort Stephin J. , Smyth Gordon K. , Blewitt Marnie E. , Allan Rhys S. , Hinde Elizabeth , D’Arcy Sheena , Ryu Je-Kyung , Shakeel Shabih 
Published: June 2024

AbstractVariants in the poorly characterised oncoprotein, MORC2, a chromatin remodelling ATPase, lead to defects in epigenetic regulation and DNA damage response. The C-terminal domain (CTD) of MORC2, frequently phosphorylated in DNA damage, promotes cancer progression, but its role in chromatin remodelling remains unclear. Here, we report a molecular characterisation of full-length, phosphorylated MORC2, demonstrating its preference for binding open chromatin and functioning as a DNA sliding clamp. We identified a phosphate interacting motif within the CTD that dictates ATP hydrolysis rate and cooperative DNA binding. The DNA binding impacts several structural domains within the ATPase region. We provide the first visual proof that MORC2 induces chromatin remodelling through ATP hydrolysis-dependent DNA compaction, regulated by its phosphorylation state. These findings highlight phosphorylation of MORC2 CTD as a key modulator of chromatin remodelling, presenting it as a potential therapeutic target.
Non-canonical altPIDD1 protein: unveiling the true major translational output of thePIDD1gene
Authors: Comtois Frédérick , Jacques Jean-François , Métayer Lenna , Ouedraogo Wend Yam DD , Ouangraoua Aïda , Denault Jean-Bernard , Roucou Xavier 
Published: June 2024

AbstractProteogenomics has enabled the detection of novel proteins encoded in non-canonical or alternative open reading frames (altORFs) in genes already coding a reference protein. Reanalysis of proteomic and ribo-seq data revealed that the p53-induced death domain-containing protein (orPIDD1) gene encodes a second 171 amino acid protein, altPIDD1, in addition to the known 910 amino acid-long PIDD1 protein. The two ORFs overlap almost completely, and the translation initiation site of altPIDD1 is located upstream of PIDD1. AltPIDD1 has more translational and protein level evidence than PIDD1 across various cell lines and tissues. In HEK293 cells, the altPIDD1 to PIDD1 ratio is 40 to 1, as measured with isotope-labeled (heavy) peptides and targeted proteomics. AltPIDD1 localizes to cytoskeletal structures labeled with phalloidin, including stress fibres, lamellipodia and filopodia, interacts with cytoskeletal proteins and is cleaved during apoptosis. Unlike most non-canonical proteins, altPIDD1 is not evolutionarily young but emerged in placental mammals. Overall, we identifyPIDD1as a dual-coding gene, with altPIDD1, not the annotated protein, being the primary product of translation.Summary blurbThis research uncoversPIDD1as a dual-coding gene, revealing a previously unknown protein, altPIDD1, as the primary product with higher expression and cytoskeletal interactions.
LasR regulates protease IV expression at suboptimal growth temperatures inPseudomonas aeruginosa
Authors: Done Rachel E. , Robertson Joshua K. , Prezioso Samantha M. , Goldberg Joanna B. 
Published: June 2024

ABSTRACTThe opportunistic pathogenPseudomonas aeruginosacauses debilitating lung infections in people with cystic fibrosis, as well as eye, burn, and wound infections in otherwise immunocompetent individuals. Many ofP. aeruginosa’s virulence factors are regulated by environmental changes associated with human infection, such as a change in temperature from ambient to human body temperature. One such virulence factor is protease IV (PIV). Interestingly,pivexpression is higher at ambient temperatures (22-28°C) compared to human body temperature (37°C). We found thatpivexpression was thermoregulated at stationary phase, but not exponential phase, and thatpivis thermoregulated at the level of transcription. Protein levels of known transcriptional regulators ofpiv, the quorum sensing regulator LasR and the gene-silencing histone nucleoid silencing proteins MvaT/MvaU, were not thermoregulated. Using a transcriptional reporter forpiv, we show that LasR activatespivexpression at stationary phase at 25°C but not 37°C, while MvaT/MvaU are not required forpivthermoregulation. We also identified alasbox in thepivpromoter, which is important forpivthermoregulation. We propose that LasR directly regulatespivat stationary phase at 25°C but has a negligible impact at 37°C. Here, we show thatpivis uniquely regulated by LasR in a temperature-dependent manner. Our findings suggest that the LasRI quorum sensing regulon ofP. aeruginosamay not be fully characterized and that growth at non-standard laboratory conditions such as lower temperatures could reveal previously unrecognized quorum sensing regulated genes.IMPORTANCEPseudomonas aeruginosais a versatile opportunistic pathogen capable of causing many different types of infections that are often difficult to treat, such as lung infections in people with cystic fibrosis. Temperature regulates the expression of many virulence factors that contribute toP. aeruginosa’s ability to cause infection, yet our mechanistic understanding of virulence factor thermoregulation is poor. In this study, we show that the virulence factor protease IV is thermoregulated at the level of transcription via temperature-dependent upregulation by the quorum sensing regulator, LasR. Mechanistic studies of virulence factor thermoregulation will expand our understanding of howP. aeruginosaexperiences different environments, including the mammalian host. Our work also highlights the importance of growth conditions in studying gene regulation, as it elucidates the regulation of protease IV by LasR, which was previously not well understood.
The effect of long-range linkage disequilibrium on allele-frequency dynamics under stabilizing selection
Authors: Negm Sherif , Veller Carl 
Published: June 2024

AbstractStabilizing selection on a polygenic trait reduces the trait’s genetic variance by (i) generating correlations (linkage disequilibria) between opposite-effect alleles throughout the genome and (ii) selecting against rare alleles at polymorphic loci that affect the trait, eroding heterozygosity at these loci. Here, we characterize the impact of the linkage disequilibria, which stabilizing selection generates on a rapid timescale, on the subsequent allele-frequency dynamics at individual loci, which proceed on a slower timescale. We obtain expressions for the expected per-generation change in minor-allele frequency at individual loci, as functions of the effect sizes at these loci, the strength of selection on the trait, its variance and heritability, and the linkage relations among loci. Using whole-genome simulations, we show that our expressions predict allele-frequency dynamics under stabilizing selection more accurately than the expressions that have previously been used for this purpose. Our results have implications for understanding the genetic architecture of complex traits.
Antibiotic resistant bacteria survive treatment by doubling while shrinking
Authors: Campey Adrian , Chait Remy , Tsaneva-Atanasova Krasimira , Pagliara Stefano 
Published: June 2024

AbstractMany antibiotics that are used in healthcare, farming and aquaculture end up in environments with different spatial structures that might promote heterogeneity in the emergence of antibiotic resistance. However, experimental evolution of microbes at sub-inhibitory concentrations of antibiotics has been mainly carried out at the population level which does not allow capturing heterogeneity within bacterial populations. Here we investigate and compare the emergence of resistance to ciprofloxacin inEscherichia coliin well mixed and structured environments using experimental evolution, genomics and microfluidics-based time-lapse microscopy. We discover that resistance to ciprofloxacin and cross-resistance to other antibiotics is stronger in the well-mixed environment due to the emergence of target mutations, whereas efflux regulator mutations emerge in the structured environment. The latter mutants also harbour sub-populations of persisters that survive high concentrations of ciprofloxacin that inhibit bacterial growth at the population level. In contrast, genetically resistant bacteria that display target mutations also survive high concentrations of ciprofloxacin that inhibit their growth via population-level antibiotic tolerance. These resistant and tolerant bacteria keep doubling while shrinking in size in the presence of ciprofloxacin and regain their original size after antibiotic removal, which constitutes a newly discovered phenotypic response. This new knowledge sheds light on the diversity of strategies employed by bacteria to survive antibiotics and poses a stepping stone for understanding the link between mutations at the population level and phenotypic single-cell responses.
Tricellular junction recruitment of the Wave regulatory complex by Sidekick and Lar induces protrusive activity resolving cell intercalation
Authors: Calvary Lisa , Alégot Hervé , Pouchin Pierre , Richard Graziella , Vachias Caroline , Mirouse Vincent 
Published: June 2024

SummaryCell intercalation, a fundamental morphogenetic process characterized by the exchange of neighboring cells, plays a pivotal role in epithelial tissue development. While the initiation of new junctions remains poorly understood, recent research indicates the involvement of tricellular junction actors. In this study, we explore the contribution of the WAVE regulatory complex (WRC), a critical regulator of branched F-Actin generation, in tissue elongation and cell intercalation within the Drosophila ovarian follicular epithelium. WRC localizes at tricellular junctions, where it orchestrates the generation of highly dynamic protrusions emanating from one cell and extending between the bicellular junctions of neighboring cells. This protrusive activity is essential for the initiation of new junctions in cells located at the extremities of these junctions. Furthermore, our findings indicate that WRC recruitment at tricellular junctions is a redundant process, involving the cooperative action of the two transmembrane proteins Sidekick and Lar. Disruption of this recruitment impairs protrusive activity, cell intercalation resolution, and tissue elongation, thereby mechanistically bridging molecular, cellular and tissular scales. Consequently, this elucidates a critical mechanism underlying epithelial morphogenesis through actin polymerization at tricellular junctions.
Chromosomal fusions and large-scale inversions are key features for adaptation in Arctic codfish species
Authors: Hoff Siv N.K , Maurstad Marius , Tørresen Ole K. , Berg Paul R. , Præbel Kim , Jakobsen Kjetill S. , Jentoft Sissel 
Published: June 2024

AbstractThe evolutionary impact of structural variants, such as chromosomal inversions, is well documented, especially for their role in local adaptation in high gene flow systems. However, the role of other genomic rearrangements like chromosomal fusions, fissions, and translocations is still relatively unexplored. Here we present six chromosome-level Gadid reference genomes for the non-migratory Atlantic cod (Gadus morhua) i.e., Norwegian coastal cod (NCC), Atlantic haddock(Melanogrammus aeglefinus),burbot (Lota lota), European hake (Merluccius merluccius) as well as two keystone Arctic codfishes: the polar cod (Boreogadus saida) and Arctic cod (Arctogadus glacialis). Within a comparative genomics framework, we uncovered several lineage-specific chromosomal fusions, resulting in a reduced number of chromosomes compared to the ancestral state in the two cold-water adapted codfishes. The identified fusions were not homologous, i.e., indicating that they originate from independent evolutionary events. Additionally, a high number of partly overlapping chromosomal inversions between the two species were detected. Using a smaller population dataset, we uncovered a high degree of conservation for some of the overlapping inversions (including some breakpoint regions), suggesting that these regions are under selection, and potentially of evolutionary importance. With the use of chromosome-level genome assemblies, we demonstrate how large genomic reorganizations are likely to play important roles in speciation processes and thus, in particular to adaptation to freezing environmental conditions. Moreover, we observe that such massive rearrangement events can take place across relatively short evolutionary time scales.
Nutrient Signaling-Dependent Quaternary Structure Remodeling Drives the Catalytic Activation of metazoan PASK
Authors: Dhungel Sajina , Xiao Michael , Rajesh Rajaian Pushpabai , Kikani Chintan 
Published: June 2024

AbstractThe Per-Arnt-Sim (PAS) domains are characterized by diverse sequences and feature tandemly arranged PAS and PAS-associated C-terminal (PAC) motifs that fold seamlessly to generate the metabolite-sensing PAS domain. Here, using evolutionary scale sequence, domain mapping, and deep learning-based protein structure analysis, we deconstructed the sequence-structure relationship to unearth a novel example of signal-regulated assembly of PAS and PAC subdomains in metazoan PAS domain-regulated kinase (PASK). By comparing protein sequence, domain architecture, and computational protein models between fish, bird, and mammalian PASK orthologs, we propose the existence of previously unrecognized third PAS domain of PASK (PAS-C) formed through long-range intramolecular interactions between the N-terminal PAS fold and the C-terminal PAC fold. We experimentally validated this novel structural design using residue-level cross-linking assays and showed that the PAS-C domain assembly is nutrient-responsive. Furthermore, by combining structural phylogeny approaches with residue-level cross-linking, we revealed that the PAS-C domain assembly links nutrient sensing with quaternary structure reorganization in PASK, stabilizing the kinase catalytic core of PASK. Thus, PAS-C domain assembly likely integrates environmental signals, thereby relaying sensory information for catalytic control of the PASK kinase domain. In conclusion, we theorize that during their horizontal transfer from bacteria to multicellular organisms, PAS domains gained the capacity to integrate environmental signals through dynamic modulation of PAS and PAC motif interaction, adding a new regulatory layer suited for multicellular systems. We propose that metazoan PAS domains are likely to be more dynamic in integrating sensory information than previously considered, and their structural assembly could be targeted by regulatory signals and exploited to develop therapeutic strategies.