bluuebunny/crossref_metadata_2025 huggingface dataset:
Geometric deep learning framework for de novo genome assembly
Authors: Vrček Lovro , Bresson Xavier , Laurent Thomas , Schmitz Martin , Kawaguchi Kenji , Šikić Mile
Published: March 2024

The critical stage of every de novo genome assembler is identifying paths in assembly graphs that correspond to the reconstructed genomic sequences. The existing algorithmic methods struggle with this, primarily due to repetitive regions causing complex graph tangles, leading to fragmented assemblies. Here, we introduce GNNome, a framework for path identification based on geometric deep learning that enables training models on assembly graphs without relying on existing assembly strategies. By leveraging symmetries inherent to the problem, GNNome reconstructs assemblies with similar or superior contiguity compared to the state-of-the-art tools across several species, sequenced with PacBio HiFi or Oxford Nanopore. With every new genome assembled telomere-to-telomere, the amount of reliable training data at our disposal increases. Combining the straightforward generation of abundant simulated data for diverse genomic structures with the AI approach makes the proposed framework a plausible cornerstone for future work on reconstructing complex genomes with different ploidy and aneuploidy degrees. To facilitate such developments, we make the framework and the best-performing model publicly available, provided as a tool that can directly be used to assemble new haploid genomes.
NLRP3 and AIM2 inflammasomes exacerbate the pathogenic Th17 cell response to eggs of the helminthSchistosoma mansoni
Authors: Suresh Kumar Meena Kumari Madhusoodhanan , Liu Pengyu , Jump Kaile , Morales Yoelkys , Miller Emily A , Shecter Ilana , Stadecker Miguel J. , Kalantari Parisa
Published: March 2024

Infection with the helminthSchistosoma mansonican cause exacerbated morbidity and mortality via a pathogenic host CD4 T cell-mediated immune response directed against parasite egg antigens, with T helper (Th) 17 cells playing a major role in the development of severe granulomatous hepatic immunopathology. The role of inflammasomes in intensifying disease has been reported; however, neither the types of caspases and inflammasomes involved, nor their impact on the Th17 response are known. Here we show that enhanced egg-induced IL-1β secretion and pyroptotic cell death required both caspase-1 and caspase-8 as well as NLRP3 and AIM2 inflammasome activation. Schistosome genomic DNA activated AIM2, whereas reactive oxygen species, potassium efflux and cathepsin B, were the major activators of NLRP3. NLRP3 and AIM2 deficiency led to a significant reduction in pathogenic Th17 responses, suggesting their crucial and non-redundant role in promoting inflammation. Additionally, we show that NLRP3- and AIM2-induced IL-1β suppressed IL-4 and protective Type I IFN (IFN-I) production, which further enhanced inflammation. IFN-I signaling also curbed inflammasome-mediated IL-1β production suggesting that these two antagonistic pathways shape the severity of disease. Lastly, Gasdermin D (Gsdmd) deficiency resulted in a marked decrease in egg-induced granulomatous inflammation. Our findings establish NLRP3/AIM2-Gsdmd axis as a central inducer of pathogenic Th17 responses which is counteracted by IFN-I pathway in schistosomiasis.

Schistosomiasis is a major tropical parasitic disease caused by trematode worms of the genus Schistosoma. Morbidity and mortality in infection with the speciesSchistosoma mansoniare due to a pathogenic CD4 T cell-mediated immune response directed against parasite eggs, resulting in granulomatous inflammation. In severe cases of schistosomiasis, there is liver fibrosis, hepatosplenomegaly, portal hypertension, gastro-intestinal hemorrhage and death. Here we describe the role of two proteins, the NLRP3 and AIM2 inflammasomes, in intensifying disease. We found that upstream proteins which activate these inflammasomes are caspase-1 and caspase 8; these in turn lead to the activation of another protein, Gasdermin D (Gsdmd), which facilitates the release of the proinflammatory cytokine IL-1β. Importantly, we observed that mice deficient in Gsdmd exhibit diminished pathology. Finally, we discovered that the protective Type I Interferon (IFN-I) pathway counteracts the caspase/inflammasome/Gsdmd axis thereby controlling egg mediated inflammation. These results give us a deeper understanding of the functional features of the crosstalk between inflammasome and IFN-I pathway, which may lead to the identification of novel targets for therapeutic intervention.
Age-specificity in territory quality and spatial structure in a wild bird population
Authors: Woodman Joe P. , Cole Ella F. , Firth Josh A. , Sheldon Ben C.
Published: March 2024

Age influences behaviour, survival, and reproduction; hence variation in population age structure can affect population-level processes. The extent of spatial age structure may be important in driving spatially-variable demography, particularly when space-use is linked to reproduction, yet it is not well understood. We use long-term data from a wild bird population to examine spatial age structure and quantify covariance between territory quality and age. We find associations between age and aspects of territory quality, but little evidence for spatial age structure compared to territory quality and reproductive structure. We also report little between-year repeatability of spatial age structure compared to structure in reproductive output. We suggest that high breeding site fidelity and frequent territory turnover by younger breeders, driven by high mortality and immigration rates, limits the association between age and territory quality and weakens overall spatial age structure. Greater spatial structure and repeatability in reproductive output compared to age suggests that habitat quality may be more important in driving spatially-variable demography than age in this system. We suggest that the framework developed here can be used in other taxa to assess spatial age structure, particularly in longer-lived species where we predict from our findings there may be greater structure.
The genomic trajectory of ovarian high grade serous carcinoma is determined in STIC lesions
Authors: Cheng Z. , Ennis D.P. , Lu B. , Mirza H.B. , Sokota C. , Kaur B. , Singh N. , Le Saux O. , Russo G. , Giannone G. , Tookman L.A. , Krell J. , Barnes C. , McDermott J. , McNeish I.A.
Published: March 2024

Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying aTP53mutation, known as ‘p53 signatures’, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinomas (STIC) lesions, which, in turn, progress into invasive HGSC that readily spread to the ovary and disseminate around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole genome duplication observed in late-stage disease are determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded samples (FFPE) from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of whole genome duplication, arises early in HGSC, and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development.
Analysis of higher order interactions quantifies co-ordination in the epigenome and reveals novel biological relationships in Kabuki syndrome
Authors: Cuvertino Sara , Garner Terence , Martirosian Evgenii , Walusimbi Bridgious , Kimber Susan J. , Banka Siddharth , Stevens Adam
Published: March 2024

Complex direct and indirect relationships between multiple variables are a characteristic of all natural systems and are defined as higher order interactions (HOIs). Traditional differential and network analyses fail to account for the richness of omic datasets and miss HOIs. We investigated genome-wide peripheral blood DNA methylation data from Kabuki syndrome type 1 (KS1) and control individuals, identified 2,002 differentially methylated points (DMPs), and inferred 17 differentially methylated regions, which represent only 189 DMPs. We followed these results with quantification of HOIs by applying hypergraph network models on all the CpGs in the two datasets and revealed differences in co-ordination of the DMPs along with lower entropy and higher co-ordination of the peripheral epigenome in KS1 implying reduced network complexity. We demonstrate that the hypergraph approach captures substantially more information, enables factoring trans-relationships, and identifies biologically relevant pathways that escape the standard analyses. These findings construct the basis of a suitable model that is not computationally intensive for the analysis of the organisation of the epigenome in rare diseases. This approach can be applied to other types of omic datasets, and to other fields of science and medicine to investigate mechanism in big data.
Use of Mucosally Administered Outer Membrane Vesicles Derived fromBordetella pertussisto Diminish Nasal Bacterial Colonization
Authors: Rudi E. , Gaillard E. , Bottero D , Hozbor D
Published: March 2024

Background

We previously identifiedBordetella pertussis-derived outer membrane vesicles (OMVs) as a promising immunogen for improving pertussis vaccines. In this study, we evaluated the efficacy of our vaccine prototype in immunization strategies aimed at reducing disease transmission by targeting colonization in the upper airways while maintaining protection against severe disease by reducing colonization in the lower respiratory tract.

Methods

We assessed different mucosal administration strategies in a murine model, including homologous 2-dose schedules and heterologous prime-boost strategies combining intramuscular (IM) systemic immunization with mucosal routes (intranasal (IN) or sublingual (SL)). We utilized mucosal c-di-AMP and/or systemic alum adjuvants to formulate the OMV vaccine prototype. A homologous IM immunization schedule and commercial vaccines were used for comparison.

Results

All tested heterologous schemes induced higher levels of specific IgG with significant avidity, as well as high levels of IgG1 and IgG2 compared, to corresponding homologous 2-dose schemes via mucosal routes (OMVIN-INor OMVSL-SL). High IgA levels were observed post-B. pertussischallenge following OMVIN-INtreatments and heterologous treatments where the second dose was administered via a mucosal route. Furthermore, schemes involving the intranasal route, whether in a homologous or heterologous scheme, induced the highest levels of IL-17 and IFN-γ. Accordingly, these schemes showed superior efficacy against nasal colonization than the commercial vaccines. Specifically, homologous intranasal immunization exhibited the highest protective capacity against nasal colonization while maintaining an excellent level of protection in the lower respiratory tract. To enhance the protective capacity against nasal colonization further, we conducted a comparative analysis of formulations containing different adjuvants (c-di-AMP, alum, or a combination of both) administered via homologous intranasal routes. These assays revealed that the use of alum, either alone or in combination with c-di-AMP, did not enhance the immune protective capacity.

Conclusions

All the experiments presented here highlight that the use of OMVs, regardless of the scheme utilized, with the exception of OMVSL-SL, outperformed acellular pertussis (aP) vaccines, achieving a greater reduction in bacterial colonization in the upper respiratory tract (p<0.001).
Sequence composition and conservation predict the phenotypic relevance of transposable elements
Authors: Cerruti Yari , Fusco Daniela , Jahanbin Mahdis , Marnetto Davide , Provero Paolo
Published: March 2024

Transposable elements (TEs) are powerful drivers of genome evolution, in part through their ability to rapidly rewire the host regulatory network by creating transcription factor binding sites that can potentially be turned to the host’s advantage in a process called exaptation. However, the effects on the host phenotype vary widely among different TEs. Here, we classify TEs based on their contribution to the human host phenotypes at both molecular and macroscopic scales. TE contributions to chromatin accessibility, gene expression, and the heritability of complex traits are strongly correlated to each other, confirming that the main mechanism through which TEs affect the host phenotype is through the rewiring of the regulatory network. TE sequence and evolutionary features are able to explain a large fraction of the variance in phenotypic relevance, and in particular more than 50% of the variance of their contribution to the heritability of complex traits. A conspicuous exception to this pattern is represented by TEs of the ERV1 family, whose phenotypic impact cannot be explained by our model: In particular, this family includes a set of relatively young TEs whose phenotypic relevance is much larger than would be expected based on their sequence and evolutionary parameters. These TEs are involved in fast-evolving biological processes related to the interaction of the organism with its environment. In conclusion, our results confirm quantitatively that TE insertions affect the host phenotype mostly through the rewiring of its regulatory network; identify a signature of phenotypic relevance based on sequence and conservation properties; and highlight several TEs as promising candidates for functional studies.
miRNA circuit modules for precise, tunable control of gene expression
Authors: Du Rongrong , Flynn Michael J. , Honsa Monique , Jungmann Ralf , Elowitz Michael B.
Published: March 2024

The ability to express transgenes at specified levels is critical for understanding cellular behaviors, and for applications in gene and cell therapy. Transfection, viral vectors, and other gene delivery methods produce varying protein expression levels, with limited quantitative control, while targeted knock-in and stable selection are inefficient and slow. Active compensation mechanisms can improve precision, but the need for additional proteins or lack of tunability have prevented their widespread use. Here, we introduce a toolkit of compact, synthetic miRNA-based circuit modules that provide precise, tunable control of transgenes across diverse cell types. These circuits, termed DIMMERs (Dosage-Invariant miRNA-Mediated Expression Regulators) use multivalent miRNA regulatory interactions within an incoherent feed-forward loop architecture to achieve nearly uniform protein expression over more than two orders of magnitude variation in underlying gene dosages or transcription rates. They also allow coarse and fine control of expression, and are portable, functioning across diverse cell types. In addition, a heuristic miRNA design algorithm enables the creation of orthogonal circuit variants that independently control multiple genes in the same cell. These circuits allowed dramatically improved CRISPR imaging, and super-resolution imaging of EGFR receptors with transient transfections. The toolbox provided here should allow precise, tunable, dosage-invariant expression for research, gene therapy, and other biotechnology applications.

One sentence description

Compact synthetic miRNA-based regulatory circuits enable tunable, orthogonal, and generalizable dosage-invariant gene expression control for research and biotechnology.
In sickness and in health: RNA-Seq finds viruses associated with mutualist quality in the Amazonian plant-antAllomerus octoarticulatus
Authors: Tocora María C , Reid Christopher , Huisken Jesse , Xue Haoran , Frederickson Megan E
Published: March 2024

Ant-plant symbioses are classic examples of mutualism in which ant "bodyguards" defend myrmecophytic plants against enemies in exchange for nest sites and often food. We used RNA-Seq to profile the transcriptomes ofAllomerus octoarticulatusant workers, which aggressively defend the Amazonian plantCordia nodosaagainst herbivores, but to varying degrees. Field behavioral assays with herbivores in the Peruvian Amazon showed striking variation among colonies in the relative zeal with whichA. octoarticulatusworkers defend their host plant. Highly effective and ineffective bodyguards differed in their gene expression profiles, which revealed viral infections significantly associated with ant bodyguarding behavior. Transcripts from eight new positive-sense single-stranded RNA viruses were differentially expressed between colonies with high- or low-quality bodyguards. Colonies of high- and low-quality bodyguards were infected by distinct viruses, including viruses clustering phylogenetically with viruses known to cause aggression or reduced locomotion, respectively, in bees. Gene expression, including of immunity-related genes, also differed between broodcare workers and bodyguard ants, suggesting bodyguarding is a distinct worker task. Ant colony health and viral infections may influence ant cooperation with plants in ant-plant mutualisms.
HemaCisDB: An Interactive Database for Analyzing Cis-Regulatory Elements Across Hematopoietic Malignancies
Authors: Cai Xinping , Zhang Qianru , Liu Bolin , Sun Lu , Liu Yuxuan
Published: March 2024

Noncoding cis-regulatory elements (CREs), such as transcriptional enhancers, are key regulators of gene expression programs. Accessible chromatin and H3K27ac are well-recognized markers for CREs associated with their biological function. Deregulation of CREs is commonly found in hematopoietic malignancies yet the extent to which CRE dysfunction contributes to pathophysiology remains incompletely understood. Here, we developed HemaCisDB, an interactive, comprehensive, and centralized online resource for CRE characterization across hematopoietic malignancies, serving as a useful resource for investigating the pathological roles of CREs in blood disorders. Currently, we collected 922 ATAC-seq, 190 DNase-seq, and 531 H3K27ac ChIP-seq datasets from patient samples and cell lines across different myeloid and lymphoid neoplasms. HemaCisDB provides comprehensive quality control metrics to assess ATAC-seq, DNase-seq, and H3K27ac ChIP-seq data quality. The analytic modules in HemaCisDB include transcription factor (TF) footprinting inference, super-enhancer identification, and core transcriptional regulatory circuitry analysis. Moreover, HemaCisDB also enables the study of TF binding dynamics by comparing TF footprints across different disease types or conditions via web-based interactive analysis. Together, HemaCisDB provides an interactive platform for CRE characterization to facilitate mechanistic studies of transcriptional regulation in hematopoietic malignancies. HemaCisDB is available athttps://hemacisdb.chinablood.com.cn/.
Katanin, kinesin-13 and ataxin-2 inhibit premature interaction between maternal and paternal genomes inC. eleganszygotes
Authors: Beath Elizabeth A. , Bailey Cynthia , Magadum Meghana Mahantesh , Qiu Shuyan , McNally Karen L. , McNally Francis J.
Published: March 2024

Fertilization occurs before completion of oocyte meiosis in the majority of animal species and sperm contents move long distances within zygotes of mouse andC. elegans. If incorporated into the meiotic spindle, paternal chromosomes could be expelled into a polar body resulting in lethal monosomy. Through live imaging of fertilization inC. elegans, we found that the microtubule disassembling enzymes, katanin and kinesin-13 limit long range movement of sperm contents and that maternal ataxin-2 maintains paternal DNA and paternal mitochondria as a cohesive unit that moves together. Depletion of katanin or double depletion of kinesin-13 and ataxin-2 resulted in capture of the sperm contents by the meiotic spindle. Thus limiting movement of sperm contents and maintaining cohesion of sperm contents within the zygote both contribute to preventing premature interaction between maternal and paternal genomes.
Phosphoproteomic analysis reveals the diversity of signaling behind ErbB inhibitor-induced phenotypes
Authors: Vaparanta Katri , Jokilammi Anne , Merilahti Johannes , Örling Johanna , Virtanen Noora , Sahlgren Cecilia , Elenius Klaus , Paatero Ilkka
Published: March 2024

The impact of kinase inhibitors on the phosphoproteome has been rarely investigated at a whole organism level. Here we performed a phosphoproteomic analysis in embryonic zebrafish to identify the signaling pathways perturbed by ErbB receptor tyrosine kinase inhibitors at the organism level. The phosphorylation of proteins associated with the PI3K/Akt, p38 MAPK, Notch, Hippo/Yap and β-catenin signaling pathways were differentially regulated by the ErbB inhibitors. Gene set enrichment analyses indicated differential neurological and myocardial phenotypes of different ErbB inhibitors. To assess the neurological and myocardial effects, motility and ventricle growth assays were performed on zebrafish embryos treated with the ErbB and downstream signaling pathway inhibitors. The treatment with the inhibitors targeting the PI3K/Akt, p38 MAPK, and Notch signaling pathways along with the ErbB inhibitors AG1478 and Lapatinib perturbed the overall movement and ventricle wall growth of zebrafish embryos. Taken together, these results indicate that inhibitors with the same primary targets can affect different signaling pathways while eliciting similar physiological phenotypes.
Initial Learning in the Brain: From Rules to Action
Authors: Fregni Sofia , Wolfensteller Uta , Ruge Hannes
Published: March 2024

We used fMRI to investigate the neural changes and representational dynamics associated with different learning modes during initial learning and subsequent implementation of previously acquired stimulus-response (S-R) associations. We compared instruction-based learning (INS) and trial-and-error learning (TE) via a third observation-based learning (OBS) condition. This was yoked to the TE condition and shared features with both, the INS and TE conditions. During learning, neural changes were observed in the Frontoparietal and Default Mode Networks across learning modes, consistent with a general decrease in cognitive control demand as learning progresses. INS and TE exhibited condition-specific signal changes, which we interpreted in the context of covert motor preparation during INS, and intentional action and increased cognitive control demand during early TE trials, respectively. Multivariate pattern analysis revealed individual rule information in bilateral prefrontal, premotor, and parietal cortices across learning modes. Most regions revealed consistent representations of individual S-R rules between the learning stage and subsequent implementation stage, regardless of the learning mode. This suggests that initially formed S-R rule representations guide task performance during S-R rule implementation, irrespective of how they are acquired. Finally, within the primary motor cortex, individual S-R rules were decodable during the learning stage not only when motor responses were overtly executed, as in TE, but also in the absence of overt motor execution, as in INS. This finding substantiates previous claims of covert motor preparatory mechanisms during INS.
Cdonis required for organ Left-Right patterning via regulating DFCs migration and the sequential ciliogenesis
Authors: Deng Zhilin , Chang Wenqi , Li Chengni , Li Botong , Huang Shuying , Huang Jingtong , Zhang Ke , Li Yuanyuan , Liu Xingdong , Ran Qin , Guo Zhenhua , Huang Sizhou
Published: March 2024

Cdonandbocare members of the cell adhesion molecule subfamily III Ig/fibronectin. Although they were reported to be involved in muscle and neural development at late developmental stage, while their early roles in embryonic development are unknown. Here we discovered that zebrafishcdonbut notbocwas expressed in dorsal forerunner cells (DFCs) and epitheliums of Kupffer’s vesicle (KV), implying the possible role ofcdonin organ LR patterning. Further data showed that the liver and heart LR patterning was disturbed incdonmorphants andcdonmutants. Mechanically, we found thatcdonloss of function led to dispersed DFCs migration, smaller KV and defective ciliogenesis, which resulting in randomizedNodal/spawsignaling and the sequential organ LR patterning defect. Finally, predominant distribution of acdonMO in DFCs led to defects in DFCs migration, KV morphogenesis/ciliogenesis,Nodal/spawsignaling and organ LR asymmetry, being similar to those incdonmorphants andcdon-/-embryos, indicating a cell-autonomous role ofcdonin regulating KV formation and ciliogenesis during LR patterning. In conclusion, our data demonstrated that, during gastrulation stage and early somitogenesis stage,cdonis required for proper DFCs migration, KV formation and ciliogenesis, thus playing an important role in setting up organ LR asymmetry.
Long-term evolution reveals the role of the circadian cycle in the environmental adaptation of cyanobacteria
Authors: Mendaña Alfonso , Santos-Merino María , Gutiérrez-Lanza Raquel , Domínguez-Quintero Marina , Medina Juan Manuel , González-Guerra Ana , Campa Víctor , Ducos-Galand Magaly , López-Igual Rocío , Volke Daniel C. , Gugger Muriel , Nikel Pablo I. , Mazel Didier , de la Cruz Fernando , Fernández-López Raúl
Published: March 2024

Circadian clocks synchronize internal cellular states with diurnal rhythms. Widespread in bacteria and eukaryotes, they regulate a variety of physiological processes, from hormone secretion in animals to carbon fixation in photosynthetic organisms. The adaptive role of circadian clocks is assumed to stem from their ability to anticipate environmental change, yet their impact on ecological adaptation remains unclear. Here, we use experimental evolution to study the interplay between fitness and circadian regulation in the model cyanobacteriumSynechococcus elongatusPCC 7942. After 1,200 generations under continuous, high-intensity illumination, we obtained a strain that grew six times faster than its ancestral counterpart. Genome sequencing revealed three mutations fixed in the population, two of which replicated the fast-growing phenotype in the wild-type. A deletion in SasA, a key circadian regulator, was essential for fast growth. Transcriptomic and metabolomic analyses revealed that this mutation perturbed the rhythmicity of the cycle, while simultaneously locking the cell in a transcriptomic response to high intensity illumination. A comparison with another fast- growing isolate, UTEX 2973, showed convergent transcriptomic states despite different driving mutations. Our results indicate that the clock acts not only as a timekeeping device, but also as an adaptive mechanism to optimize growth across diverse ecological conditions.
Spacer acquisition in type VI CRISPR-Cas systems associated with reverse transcriptase-Cas1 fusion proteins
Authors: Molina-Sanchez Maria Dolores , Martinez-Abarca Francisco , Millan Vicenta , Mestre Mario Rodriguez , Toro Nicolas
Published: March 2024

In prokaryotes, CRISPR-Cas systems store memories of past infections in the form of spacers integrated into CRISPR arrays. When associated with type III CRISPR-Cas systems, Reverse transcriptase-Cas1 fusion proteins (RT-Cas1) enable these defense systems to acquire spacers from RNA sources. However, despite the specific targeting of RNA by the Cas13-containing type VI CRISPR-Cas systems, there is no evidence of RNA-origin spacer acquisition. Using computational analyses, we recently reported the association of RT-Cas1 fusion proteins with type VI-A systems. In this study, we found that RT-Cas1 fusion proteins were also associated with complete type VI-B systems in bacteria from gut metagenomes, constituting a variant system that harbors a linked CorA-encoding locus in addition to the CRISPR array and adaptation RT-Cas1/Cas2 module. By combining in vitro and in vivo experiments, we demonstrated that type VI RT-CRISPR systems are functional for spacer acquisition and CRISPR array processing, and that the associated RT enables spacer acquisition from RNA molecules, thus demonstrating that the system is capable of functioning independently of other in-trans systems. These findings highlight the importance of RTs in RNA-targeting CRISPR-Cas systems, suggesting a potential defense mechanism against RNA-based invaders in specific environments.
The conserved membrane-proximal domain of Sbh1/ Sec61β guides signal peptides into the Sec61 channel
Authors: Yadhanapudi Lalitha , Bhadra Pratiti , Barbieri Guido , Jung Martin , Lommel Mark , Helms Volkhard , Römisch Karin
Published: March 2024

Protein secretion begins with protein translocation through the universally conserved Sec61 channel in the endoplasmic reticulum (ER) membrane. The function of its β-subunit, called Sbh1 in yeast, remains poorly understood. Sbh1/Sec61β has a cytosolic domain consisting of two parts: the N-terminal approximately 40 amino acids are intrinsically unstructured, followed by a conserved membrane proximal (CMP) domain. Sbh1 is anchored to the Sec61 channel by a single C-terminal transmembrane domain. Phosphorylation of the Sbh1/Sec61β intrinsically unstructured domain allows regulated import of specific proteins into the ER. We show here that S3/T5 phosphorylation of Sbh1 results in a conformational change in the Sbh1 intrinsically unstructured N-terminus. We also address the function of the Sbh1/Sec61β CMP domain. We identify a potential interaction site in the Sbh1 CMP domain with the Sec61 N-terminal amphipathic helix using molecular dynamics (MD) modelling. Peptide panning revealed that the Sbh1 CMP domain contains a binding site for Sbh1-dependent signal peptides. Using site-directed mutagenesis, we show that the CMP region controls import of Sbh1-dependent translocation substrates into the ER. We conclude that the Sbh1 CMP domain functions as a gatekeeper that recognizes and guides specific substrates towards the Sec61 channel for insertion.
Cortico-striatal action control inherent of opponent cognitive-motivational styles
Authors: Avila Cassandra , Sarter Martin
Published: March 2024

Turning on cue or stopping at a red light requires attending to such cues to select action sequences, or suppress action, in accordance with learned cue-associated action rules. Cortico-striatal projections are an essential part of the brain’s attention-motor interface. Glutamate-sensing microelectrode arrays were used to measure glutamate transients in the dorsomedial striatum (DMS) of male and female rats walking a treadmill and executing cued turns and stops. Prelimbic-DMS projections were chemogenetically inhibited to determine their behavioral necessity and the cortico-striatal origin of cue-evoked glutamate transients. Furthermore, we investigated rats exhibiting preferably goal-directed (goal trackers, GTs) versus cue-driven attention (sign trackers, STs), to determine the impact of such cognitive-motivational biases on cortico-striatal control. GTs executed more cued turns and initiated such turns more slowly than STs. During turns, but not missed turns or cued stops, cue-evoked glutamate concentrations were higher in GTs than in STs. In STs, turn cue-locked glutamate concentrations frequently peaked twice or three times, contrasting with predominately single peaks in GTs. In GTs, but not STs, inhibition of prelimbic-DMS projections attenuated turn rates and turn cue-evoked glutamate concentrations and increased the number of turn cue-locked glutamate peaks. These findings indicate that turn cue-evoked glutamate release in GTs is tightly controlled by cortico-striatal neuronal activity. In contrast, in STs, glutamate release from DMS glutamatergic terminals may be regulated by other striatal circuitry, preferably mediating cued suppression of action and reward tracking. As cortico-striatal dysfunction has been hypothesized to contribute to a wide range of disorders, including complex movement control deficits in Parkinson’s disease and compulsive drug taking, the demonstration of phenotypic contrasts in cortico-striatal control implies the presence of individual vulnerabilities for such disorders.

Significance Statement

Adaptive behavior involves the selection of behaviorally significant cues and the capacity of selected cues to control behavioral action. Neuronal projections from cortex to striatum are essential for such an integration of attentional with motor functions. Here we demonstrated that glutamate release from cortico-striatal projections primarily influences cued turns but not cued suppression of actions (cued stops). Cortico-striatal control of cued turning was especially powerful in rats which, as a psychological trait, preferably deploy goal-directed attention. Together, our findings demonstrate the role of cortico-striatal input in cued action selection, and they emphasize the experimental and biopsychological significance of investigating the brain’s attentional-motor interface in the context of broader individual differences in cognitive-motivational styles.
Independent expansion, selection and hypervariability of theTBC1D3gene family in humans
Authors: Guitart Xavi , Porubsky David , Yoo DongAhn , Dougherty Max L. , Dishuck Philip C. , Munson Katherine M. , Lewis Alexandra P. , Hoekzema Kendra , Knuth Jordan , Chang Stephen , Pastinen Tomi , Eichler Evan E.
Published: March 2024

TBC1D3is a primate-specific gene family that has expanded in the human lineage and has been implicated in neuronal progenitor proliferation and expansion of the frontal cortex. The gene family and its expression have been challenging to investigate because it is embedded in high-identity and highly variable segmental duplications. We sequenced and assembled the gene family using long-read sequencing data from 34 humans and 11 nonhuman primate species. Our analysis shows that this particular gene family has independently duplicated in at least five primate lineages, and the duplicated loci are enriched at sites of large-scale chromosomal rearrangements on chromosome 17. We find that most humans vary along twoTBC1D3clusters where human haplotypes are highly variable in copy number, differing by as many as 20 copies, and structure (structural heterozygosity 90%). We also show evidence of positive selection, as well as a significant change in the predicted human TBC1D3 protein sequence. Lastly, we find that, despite multiple duplications, humanTBC1D3expression is limited to a subset of copies and, most notably, from a single paralog group:TBC1D3-CDKL. These observations may help explain why a gene potentially important in cortical development can be so variable in the human population.
N-glycosylated molecules act as a co-precipitant in RNA purification
Authors: Kim Sungchul , Choi Yong-geun , Janssen Kirsten , Büll Christian , Joshi Bhagyashree S. , Pomorski Adam , Raz Vered , Tanenbaum Marvin E. , Miesen Pascal , Li Zeshi , Joo Chirlmin
Published: March 2024

A recent ground-breaking study suggested that small RNA from mammalian cells can undergo N-glycan modifications (termed glycoRNA)1. The discovery relied upon a metabolic glycan labeling strategy in combination with commonly used phase-separation-based RNA isolation. Following the reported procedure, we likewise identified an N-glycosylated species in the RNA fraction. However, our results suggest that the reported RNase sensitivity of the glycosylated species depends on the specific RNA purification method. This suggests the possibility of co-purifying unexpected RNase-insensitive N-glycoconjugates during glycoRNA isolation, hinting at the complex biochemical nature of glycoRNA. Our study underscores the need for further research to elucidate the structural and biochemical properties of glycoRNA.
The histone chaperone CAF-1 prevents Rad52-mediated instability of the budding yeast ribosomal DNA during replication-coupled DNA double-strand break repair
Authors: Futami Hajime , Yamaji Tsugumi , Katayama Yuko , Arata Nanase , Kobayashi Takehiko , Sasaki Mariko
Published: March 2024

DNA replication-coupled chromatin assembly is crucial to maintain genome integrity. Here, we demonstrate that absence of the budding yeast histone chaperone CAF-1 induces chromosomal ribosomal RNA gene (rDNA) copy number changes as well as the production of extrachromosomal rDNA circles in a manner dependent on Fob1 that causes replication fork arrest in the rDNA, the homologous recombination protein Rad52, and its interaction with Proliferating Cell Nuclear Antigen. CAF-1 deficiency enhances transcription from the regulatory promoter E-pro, contributing to rDNA instability, but it also stabilizes the rDNA independently through its regulation of E-pro. Absence of CAF-1 induces end resection of DNA double-strand breaks (DSBs) formed at arrested replication forks, which are repaired in a manner dependent on the Mre11-Rad50-Xrs2 complex. CAF-1 deficiency causes partial defects in lagging strand synthesis coupled to nucleosome spacing in the rDNA. Our findings suggest that CAF-1 suppresses Rad52-mediated rDNA instability during repair of replication-coupled DSBs.
Coordination of histone chaperones for parental histone segregation and epigenetic inheritance
Authors: Fang Yimeng , Hua Xu , Shan Chun-Min , Toda Takenori , Qiao Feng , Zhang Zhiguo , Jia Songtao
Published: March 2024

Chromatin-based epigenetic memory relies on the accurate distribution of parental histone H3–H4 tetramers to newly replicated DNA strands. Mcm2, a subunit of the replicative helicase, and Dpb3/4, subunits of DNA polymerase ε, govern parental histone H3–H4 deposition to the lagging and leading strands, respectively. However, their contribution to epigenetic inheritance remains controversial. Here, using fission yeast heterochromatin inheritance systems that eliminate interference from initiation pathways, we show that a Mcm2 histone binding mutation severely disrupts heterochromatin inheritance, while mutations in Dpb3/4 cause only moderate defects. Surprisingly, simultaneous mutations of Mcm2 and Dpb3/4 stabilize heterochromatin inheritance. eSPAN (enrichment and sequencing of protein-associated nascent DNA) analyses confirmed the conservation of Mcm2 and Dpb3/4 functions in parental histone H3–H4 segregation, with their combined absence showing a more symmetric distribution of parental histone H3–H4 than either single mutation alone. Furthermore, the FACT histone chaperone regulates parental histone transfer to both strands and collaborates with Mcm2 and Dpb3/4 to maintain parental histone H3–H4 density and faithful heterochromatin inheritance. These results underscore the importance of both symmetric distribution of parental histones and their density at daughter strands for epigenetic inheritance and unveil distinctive properties of parental histone chaperones during DNA replication.
Limits on ALP-neutrino couplings from loop-level processes
Authors: Bonilla J. , Gavela B. , Machado-Rodríguez J.
Published: March 2024

We obtain new bounds on effective axionlike particle (ALP)-neutrino interactions from their loop-level impact on the ALP couplings to electroweak gauge bosons γZ, ZZ and W+W−. Both types of interactions are connected via the chiral anomaly, which allows to overcome the fermion mass suppression of tree-level analyses. ALP couplings to charged leptons are considered simultaneously with ALP-neutrino ones, as required by gauge invariance. Complete one-loop computations are presented together with relevant kinematic limits. We leverage data obtained from rare meson decay measurements alongside observations from collider experiments, among others. The novel constraints are particularly competitive for ALP masses ≳100  MeV, evidencing the powerful potential of future ALP searches at colliders which target its couplings to electroweak gauge bosons.

Published by the American Physical Society
2024
Asymptotic safety in Lorentzian quantum gravity
Authors: D’Angelo Edoardo
Published: March 2024

A recently introduced functional renormalization group (RG) provides a new tool to explore nonperturbative and covariant RG flows in Lorentzian spacetimes. We apply it for the first time to investigate the ultraviolet limit of quantum gravity. While the RG flow is state dependent, it is possible to evaluate state- and background-independent contributions to the flow. Taking into account only these universal terms, the RG flow exhibits a nontrivial fixed point in the Einstein-Hilbert truncation, providing a mechanism for asymptotic safety in Lorentzian quantum gravity.

Published by the American Physical Society
2024
Tilting space of boundary conformal field theories
Authors: Herzog Christopher P. , Schaub Vladimir
Published: March 2024

In boundary conformal field theories, global symmetries can be broken by boundary conditions, generating a homogeneous conformal manifold. We investigate these geometries, showing they have a coset structure, and give fully worked out examples in the case of free fields of spin zero and one-half. These results give a simple illustration of the salient features of conformal manifolds while generalizing to interacting and more intricate setups. Our work was inspired by Drukker [].

Published by the American Physical Society
2024
Unveiling the Non-Abelian Statistics of
D(S3)
Anyons Using a Classical Photonic Simulator
Authors: Goel Suraj , Reynolds Matthew , Girling Matthew , McCutcheon Will , Leedumrongwatthanakun Saroch , Srivastav Vatshal , Jennings David , Malik Mehul , Pachos Jiannis K.
Published: March 2024

Simulators can realize novel phenomena by separating them from the complexities of a full physical implementation. Here, we put forward a scheme that can simulate the exotic statistics of D(S3) non-Abelian anyons with minimal resources. The qudit lattice representation of this planar code supports local encoding of D(S3) anyons. As a proof-of-principle demonstration, we employ a classical photonic simulator to encode a single qutrit and manipulate it to perform the fusion and braiding properties of non-Abelian D(S3) anyons. The photonic technology allows us to perform the required nonunitary operations with much higher fidelity than what can be achieved with current quantum computers. Our approach can be directly generalized to larger systems or to different anyonic models, thus enabling advances in the exploration of quantum error correction and fundamental physics alike.

Published by the American Physical Society
2024
Do imprinting effects on CEOs affect tourism and hospitality enterprises’ corporate innovation?
Authors: Shan Yawen , Shi Da , Xu Shi
Published: March 2024

Purpose

Based on imprinting theory and episodic future thinking, this paper aims to study how CEOs’ attributes and experiences inform innovation in tourism and hospitality businesses. It also explores ways to quantify innovation in this sector.

Design/methodology/approach

The authors quantitatively analysed innovation in tourism and hospitality using extensive data from companies’ annual reports. They further adopted multivariate regression to test how CEOs’ experience affects enterprise innovation.

Findings

Results demonstrate that CEOs’ academic education and rich work experience can promote corporate innovation. The authors also identified a mediating role of the tone of narrative disclosure in annual reports between CEOs’ academic education and corporate innovation. The imprinting effects of career experience and educational experience appear both independent and interactive.

Research limitations/implications

CEOs are more inclined to engage in corporate innovation when influenced by the combined imprinting effects of strategic management training and work experience. Additionally, leaders should consider how communication styles indirectly influence innovation activities.

Originality/value

This paper introduces an integrated perspective that blends imprinting theory and episodic future thinking to bridge knowledge gaps regarding the interaction of CEOs’ past experiences. This work enhances understanding of how CEOs’ imprinted experiences, together with their capacity for envisioning future scenarios, can drive corporate innovation.
Integrating mobile parcel lockers into last-mile delivery networks: an operational design for home delivery, stationary, and mobile parcel lockers
Authors: Peppel Marcel , Spinler Stefan , Winkenbach Matthias
Published: March 2024

Purpose

The e-commerce boom presents new challenges for last-mile delivery (LMD), which may be mitigated by new delivery technologies. This paper evaluates the impact of mobile parcel lockers (MPL) on costs and CO2 equivalent (CO2e) emissions in existing LMD networks, which include home delivery and shipments to stationary parcel lockers.

Design/methodology/approach

To describe customers’ preferences, we design a multinomial logit model based on recipients’ travel distance to pick-up locations and availability at home. Based on route cost estimation, we define the operating costs for MPLs. We devise a mathematical model with binary decision variables to optimize the location of MPLs.

Findings

Our study demonstrates that integrating MPLs leads to additional cost savings of 8.7% and extra CO2e emissions savings of up to 5.4%. Our analysis of several regional clusters suggests that MPLs yield benefits in highly populous cities but may result in additional emissions in more rural areas where recipients drive longer distances to pick-ups.

Originality/value

This paper designs a suitable operating model for MPLs and demonstrates environmental and economic savings. Moreover, it adds recipients’ availability at home to receive parcels improving the accuracy of stochastic demand. In addition, MPLs are evaluated in the context of several regional clusters ranging from large cities to rural areas. Thus, we provide managerial guidance to logistics service providers how and where to deploy MPLs.
Income-shifting arrangements of US multinational corporations and future stock price crash risk
Authors: Richardson Grant , Taylor Grantley , Hasan Mostafa
Published: March 2024

Purpose

This study examines the importance of income income-shifting arrangements of US multinational corporations (MNCs) on future stock price crash risk.

Design/methodology/approach

This study employs a sample of 7,641 corporation-year observations over the 2005–2017 period and uses ordinary least squares regression analysis.

Findings

The authors find that the income-shifting arrangements of MNCs are positively and significantly associated with stock price crash risk after controlling for corporate tax avoidance and other known determinants of stock price crash risk in the regression model. This result is robust to alternative measures of stock price crash risk and income-shifting, and several endogeneity tests. The authors also observe that income-shifting arrangements increase stock price crash risk both directly and indirectly through the information opacity channel. Finally, in cross-sectional analyses, the authors find that the positive association between income-shifting and stock price crash risk is more pronounced for MNCs that use tax haven subsidiaries and have weak corporate governance mechanisms.

Originality/value

The authors provide new empirical evidence that MNCs will likely face significant capital market consequences regarding their income-shifting arrangements.