bluuebunny/crossref_metadata_2025_split huggingface dataset:
PRDX6 dictates ferroptosis sensitivity by directing cellular selenium mobilization
Authors: Ito Junya , Nakamura Toshitaka , Toyama Takashi , Doll Sebastian , Suzuki Mirai , Zhang Weijia , Zheng Jiashuo , Trümbach Dietrich , Yamada Naoya , Ono Koya , Wahida Adam , Saito Yoshiro , Nakagawa Kiyotaka , Mishima Eikan , Conrad Marcus 
Published: June 2024

SummarySelenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis and prevents unrestrained (phospho)lipid peroxidation by directly reducing phospholipid hydroperoxides (PLOOH) to their corresponding alcohols. However, it remains unclear whether other phospholipid peroxidases can also contribute to ferroptosis prevention, albeit to a varying degree. Here we show that cells lacking GPX4 still exhibit substantial PLOOH reduction capacity, arguing for the presence of alternative PLOOH peroxidases. By scrutinizing potential candidates, we showed that while overexpression of peroxiredoxin 6 (PRDX6), a thiol-specific antioxidant enzyme with reported PLOOH-reducing activity, failed to prevent ferroptosis, its genetic loss markedly sensitizes cancer cells to ferroptosis. Mechanistically, we uncover that PRDX6 facilitates intracellular selenium handling, which is crucial for selenium incorporation into selenoproteins, including GPX4. Consequently, PRDX6 modulates GPX4 expression, thereby dictating the sensitivity of cells to undergo ferroptosis. Our study highlights PRDX6 as a critical factor in ferroptosis prevention by directing cellular selenium mobilization.
Information theoretic inference of magnitude and direction of gene flow in metapopulation networks using nyemtaay, with potential for applications in metastasizing cancer clonal cell origin analysis
Authors: Ortiz-Velez Adrian N. , Sukumaran Jeet 
Published: June 2024

AbstractBackgroundWe introducenyemtaay, a Python package for the calculation of classical population genetic statistics and inference of gene flow network connections and directionality in metapopulation networks using information theory. This genetic information flow network inference approach provided here is the only existing implementation of [1], and is applicable not only to ecological and evolutionary organism and landscape scale studies, but also has potential applications in, for example, cancer biology for analyzing clonal cell origins in metastasizing tumors.ResultsWe demonstrate this potential through simulations and an analysis of metastasizing cancer cell lineages, showcasing its ability to identify the tissue site of origin in cancer networks. This work highlights the importance of considering demographic history and founder effects in interpreting gene flow directionality, and the benefits of this understanding in allowing application of this approach to gene flow network modeling to reach a broader range of domains.Conclusionsnyemtaayis available under the MIT license from its public repository (https://github.com/aortizsax/nyemtaay), and can be installed locally using the Python package manager ‘pip’.
Geographic redistributions are insufficient to mitigate the erosion of species’ environmental niches
Authors: Cohen Jeremy , Jetz Walter 
Published: June 2024

AbstractAs climate change accelerates, species may survive in place thanks to niche plasticity or adaptation or must redistribute to conserve their environmental niches1. Examples of such geographical range shifts abound2–4, but to date an assessment of species’ success in retaining niches and limiting their climate change exposure is missing. Here, we develop a novel method to account for biases inherent in tens of millions of citizen science observations, allowing us to evaluate how species have mitigated their climatic niche loss using geographical redistributions. We find that over 20 years, 384 North American bird species shifted their summertime distributions 0.73° north, mitigating their expected exposure to warming by ∼1.16 °C and thus averting 44% of expected niche loss had they stayed in place. Despite these movements, species were still exposed to an average ∼1.47 °C increase in temperature and few species achieved complete niche retention. Meanwhile, species only mitigated ∼0.47 °C (11%) in winter, shifting their niches by ∼3.74 °C, with almost no species fully retaining their niches. Species moving the furthest north succeeded most in conserving niches across both seasons. As expected, but previously untested at this scale, species that have physiological characteristics associated with dispersal achieved the greatest redistributions and niche retention. Most geographical redistributions have only been partially effective towards mitigating climate change and the gap between climate change exposure and species’ historical niches is growing rapidly even in a highly mobile group such as birds, raising concerns about the ability of less mobile taxa to persist in a warmer world.
Cell-free expression and SMA copolymer encapsulation of a functional receptor tyrosine kinase disease variant, FGFR3-TACC3
Authors: Snow Alexander J D , Wijesiriwardena Tharushi , Lane Benjamin J , Farrell Brendan , Dowdle Polly C , Katan Matilda , Muench Stephen P , Breeze Alexander L 
Published: June 2024

AbstractDespite their high clinical relevance, obtaining structural and biophysical data on transmembrane proteins has been hindered by challenges involved in their expression and extraction in a homogeneous, functionally-active form. The inherent enzymatic activity of receptor tyrosine kinases (RTKs) presents additional challenges. Oncogenic fusions of RTKs with heterologous partners represent a particularly difficult-to-express protein subtype due to their high flexibility, aggregation propensity and the lack of a known method for extraction within the native lipid environment. One such protein is the fibroblast growth factor receptor 3 fused with transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3), which has failed to express to sufficient quality or functionality in traditional expression systems. Cell-free protein expression (CFPE) is a burgeoning arm of synthetic biology, enabling the rapid and efficient generation of recombinant proteins. This platform is characterised by utilising an optimised solution of cellular machinery to facilitate protein synthesisin vitro. In doing so, CFPE can act as a surrogate system for a range of proteins that are otherwise difficult to express through traditional host cell-based approaches. Here, functional FGFR3-TACC3 was expressed through a novel cell-free expression system in under 48 hours. The resultant protein was reconstituted using SMA copolymers with a specific yield of 300 µg/mL of lysate. Functionally, the protein demonstrated significant kinase domain phosphorylation (t<0.0001). Currently, there is no published, high-resolution structure of any full-length RTK. These findings form a promising foundation for future research on oncogenic RTKs and the application of cell-free systems for synthesising functional membrane proteins.
Pathogenicity of Commensal Gut Biofilm In Prefrail Aging
Authors: Cosquer Guillaume Le , Pannier Melissa , Meunier Elodie , Thevenin Julie , Guyonnet Sophie , Vellas Bruno , Santin Yohan , Guiard Bruno , Parini Angelo , Buscail Louis , Bournet Barbara , Guillemet Damien , Deraison Celine , Vergnolle Nathalie , Motta Jean-Paul ,   the IHU HealthAge INSPIRE/Open Science study group
Published: June 2024

AbstractAchieving healthy aging is a global challenge requiring a deeper understanding of aging mechanisms, spanning from robustness to frailty. Although age-related alteration of the gut microbiome (microb-aging) is well studied, there is a lack of research investigating the gut microbiota during the early stages of prefrailty and understanding its behavior within the context of a natural community lifestyle, in interaction with host tissue. Therefore, we used fecal samples from the human aging cohort INSPIRE-T, to characterize polymicrobial biofilms. Intestinal tissues and feces from an aging mouse cohort were also used. Food supplement was tested for potential geroprotective effects on biofilms. Findings pointed to taxonomic and physical alterations, increased instability, and virulence with regards to intestinal epithelium, for biofilms of prefrail individuals, compared to their age-matched robust counterparts. Multiparametric analyses further linked biofilm characteristics to clinical traits, suggesting that biofilm culture could be a proxy tool for evaluating a healthy or unhealthy aging status. Exposure of biofilms to the grape pomace prebiotic partially reversed the prefail biofilm phenotype. In aged mice with prefrailty, but not in robust aged mice, gut microbiota biofilm structure was altered and caused colon damage when transplanted into antibiotic-depleted mice. These findings suggest a causal link between microb-aging in prefrailty and gut inflammation, advocating microbiota-targeted therapies to reverse prefrail phenotype and thereby promote healthspan.
Epigenetic editing at individual age-associated CpGs affects the genome-wide epigenetic aging landscape
Authors: Liesenfelder Sven , Mabrouk Mohamed H. Elsafi , Iliescu Jessica , Baranda Monica Varona , Mizi Athanasia , Wessiepe Martina , Papantonis Argyris , Wagner Wolfgang 
Published: June 2024

SummaryAging is reflected by genome-wide DNA methylation changes, but it is largely unclear how these epigenetic modifications are regulated. In this study, we explored the possibility to interfere with epigenetic clocks by epigenetic editing at individual CpG sites. CRISPR-guided approaches (dCas9-DNMT3A and CRISPRoff) facilitated targeted methylation at an age-associated genomic region inPDE4Cthat remained stable for more than three months. Furthermore, epigenetic editing evoked many genome-wide off-target effects, which were highly reproducible and enriched at other age-associated CpGs – thus, they are not random off-target effects, but seem to resemble coregulated epigenetic bystander modifications. 4C chromatin conformation analysis at age-associated sites revealed increased interactions with bystander modifications and other age-associated CpG sites. Subsequently, we multiplexed epigenetic modifications in HEK293T and primary T cells at five genomic regions that become either hypermethylated or hypomethylated upon aging. While epigenetic editing at age-hypomethylated CpGs appeared less stable, it also resulted in a clear enrichment of bystander modifications at other age-associated CpGs. Conversely, epigenetic clocks tend to be accelerated up to ten years after targeted DNA methylation, particularly at hypermethylated CpGs. These results demonstrate that targeted epigenome editing can modulate the epigenetic aging network in its entirety and thereby interfere with epigenetic clocks.
The human blood harbors a phageome which differs in Crohn’s disease
Authors: Lamy-Besnier Quentin , Theodorou Ilias , Billaud Maud , Zhang Hao , Brot Loïc , Culot Antoine , Abriat Guillaume , Sokol Harry , De Paepe Marianne , Petit Marie-Agnès , De Sordi Luisa 
Published: June 2024

AbstractIncreasing evidence suggests that the human blood hosts microbes including bacteria and eukaryotic viruses, which could have important implications for health. Bacteriophages of the blood are challenging to study and have been overlooked, but could translocate to this environment from different body-sites. We thus developed specific virome protocols and analysis methods to study the viral communities of blood samples obtained from healthy individuals and Crohn’s disease (CD) patients. We uncovered a diverse viral community in the human blood, dominated by phages infecting Pseudomonadota bacteria. We found that an important fraction of those phages overlaps with the gut virome, consolidating the idea that gut phages can translocate to the blood. Strikingly, viral communities of the blood were different between CD patients and healthy individuals, revealing a new signature of disease. This was not the case for fecal viral communities. Collectively, these results advance our knowledge of the microorganisms present in the human blood and pave the way for further studies of this environment in the context of disease.
Molecular effects of indoor tanning
Authors: Gerami Pedram , Tandukar Bishal , Deivendran Delahny , Olivares Shantel , Chen Limin , Tang Jessica , Tan Tuyet , Sharma Harsh , Bandari Aravind K , Cruz-Pacheco Noel , Chang Darwin , Marty Annika , Olshen Adam , Murad Natalia Faraj , Song Jing , Lee Jungwha , Yeh Iwei , Hunter Shain A. 
Published: June 2024

AbstractBackgroundTanning bed users have a significantly increased risk of melanoma, but it remains unclear how indoor tanning drives melanomagenesis. Tanning bed radiation is often thought of as a substitute for natural UV radiation despite differences in the maximum doses, UV content, body sites exposed, and patterns of melanoma that arise.MethodsTo better understand the epidemiologic trends and etiology of melanoma associated with tanning bed use, we described the patterns of melanoma in patients with quantifiable tanning bed usage and performed exome sequencing of 182 melanocytes from normal skin of a subset of these patients.ResultsTanning bed users were more likely than non-users to have melanoma on body sites with low cumulative levels of sun damage and were more likely to have multiple melanomas. The melanocytes in normal appearing skin from tanning bed users had higher mutation burdens, a higher proportion of melanocytes with pathogenic mutations, and distinct mutational signatures. These differences were most prominent over body sites that experience comparatively less exposure to natural sunlight.ConclusionsWe conclude that tanning bed radiation induces melanoma by increasing the mutation burden of melanocytes and by mutagenizing a broader field of melanocytes than are typically exposed to natural sunlight. The unique signatures of mutations in skin cells of tanning users may be attributable to the distinct spectra of radiation emitted from solariums.
Characterization of immune cell populations in the tumor microenvironment of colorectal cancer using high definition spatial profiling
Authors: Oliveira Michelli F. , Romero Juan P. , Chung Meii , Williams Stephen , Gottscho Andrew D. , Gupta Anushka , Pilipauskas Susan E. , Mohabbat Syrus , Raman Nandhini , Sukovich David , Patterson David ,   Visium HD Development Team, Taylor Sarah E. B. 
Published: June 2024

AbstractColorectal cancer (CRC) is the second-deadliest cancer in the world, yet a deeper understanding of spatial patterns of gene expression in the tumor microenvironment (TME) remains elusive. Here, we introduce the Visium HD platform (10x Genomics) and use it to investigate human CRC and normal adjacent mucosal tissues from formalin fixed paraffin embedded (FFPE) samples. The first assay available on Visium HD is a probe-based spatial transcriptomics workflow that was developed to enable whole transcriptome single cell scale analysis. We demonstrate highly refined unsupervised spatial clustering in Visium HD data that aligns with the hallmarks of colon tissue morphology and is notably improved over earlier Visium assays. Using serial sections from the same FFPE blocks we generate a single cell atlas of our samples, then we integrate the data to comprehensively characterize the immune cell types present in the TME, specifically at the tumor periphery. We observed enrichment of two pro-tumor macrophage subpopulations with differential gene expression profiles that were localized within distinct tumor regions. Further characterization of the T cells present in one of the samples revealed a clonal expansion that we were able to localize in the tissue using in situ gene expression analysis. In situ analysis also allowed us to perform in-depth characterization of the microenvironment of the clonally expanded T cell population and we identified a third macrophage subpopulation with gene expression profiles consistent with an anti-tumor response. Our study provides a comprehensive map of the cellular composition of the CRC TME and identifies phenotypically and spatially distinct immune cell populations within it. We show that the single cell-scale resolution afforded by Visium HD and the whole transcriptome nature of the assay allows investigations into cellular function and interaction at the tumor periphery in FFPE tissues, which has not been previously possible.
Stabilization of the open conformation of Insulin-Regulated Aminopeptidase by a novel substrate-selective small molecule inhibitor
Authors: Mpakali Anastasia , Georgaki Galateia , Buson Alberto , Findlay Alison D. , Foot Jonathan S. , Mauvais Francois-Xavier , van Endert Peter , Giastas Petros , Hamprecht Dieter W. , Stratikos Efstratios 
Published: June 2024

ABSTRACTInsulin-Regulated Aminopeptidase (IRAP) is an enzyme with important biological functions and the target of several drug-discovery efforts although no clinically useful inhibitors have been reported yet. We combinedin silicoscreening with a medicinal chemistry optimization campaign to discover a nanomolar inhibitor of IRAP based on a pyrazolylpyrimidine scaffold. This compound displays an excellent selectivity profile versus homologous aminopeptidases and kinetic analysis suggests it utilizes an uncompetitive mechanism of action when inhibiting the cleavage of a typical dipeptidic substrate. Surprisingly, the compound is a poor inhibitor of the processing of the physiological cyclic peptide substrate oxytocin and a 10mer antigenic epitope precursor but displays a biphasic inhibition profile for the trimming of a 9mer antigenic peptide and is active in blocking IRAP-dependent cross-presentation of an 8mer epitope. To better understand the mechanism of action and the basis for the unusual substrate selectivity of this inhibitor, we solved the crystal structure of the compound in complex with IRAP. The structure indicated direct zinc(II) engagement by the pyrazolylpyrimidine scaffold and revealed that the compound binds to an open conformation of the enzyme in a pose that should block the conformational transition to the closed conformation previously observed with other low molecular weight inhibitors and hypothesized to be important for catalysis. This compound constitutes the first IRAP inhibitor targeting the active site that utilizes a conformation-specific mechanism of action, provides insight into the intricacies of the IRAP catalytic cycle, and highlights a novel approach to regulating IRAP activity by blocking its conformational rearrangements.
Bistable perception of symbolic numbers
Authors: Luo Junxiang , Yokoi Isao , Dumoulin Serge O. , Takemura Hiromasa 
Published: June 2024

AbstractNumerals, i.e., semantic expressions of numbers, enable us to have an exact representation of the amount of things. Visual processing of numerals plays an indispensable role in the recognition and interpretation of numbers. Here, we investigate how visual information from numerals is processed to achieve semantic understanding. We first found that partial occlusion of some digital numerals introduces bistable interpretations. Next, by using the visual adaptation method, we investigated the origin of this bistability in human participants. We showed that adaptation to digital and normal Arabic numerals, as well as homologous shapes, but not Chinese numerals, biases the interpretation of a partially occluded digital numeral. We suggest that this bistable interpretation is driven by intermediate shape processing stages of vision, i.e., by features more complex than local visual orientations but more basic than the abstract concepts of numerals.
Protein recruitment to dynamic DNA-RNA host condensates
Authors: Dizani Mahdi , Sorrentino Daniela , Agarwal Siddharth , Stewart Jaimie Marie , Franco Elisa 
Published: June 2024

AbstractWe describe the design and characterization of artificial nucleic acid condensates that are engineered to recruit and locally concentrate proteins of interestin vitro. These condensates emerge from the programmed interactions of nanostructured motifs assembling from three DNA strands and one RNA strand that can include an aptamer domain for the recruitment of a target protein. Because condensates are designed to form regardless of the presence of target protein, they function as “host” compartments. As a model protein we consider streptavidin (SA) due to its widespread use in binding assays, thus the host condensates presented here could find immediate use for the physical separation of a variety of biotin-tagged components. In addition to demonstrating protein recruitment, we describe two approaches to control the onset of condensation and protein recruitment. The first approach uses UV irradiation, a physical stimulus that bypasses the need for exchanging molecular inputs and is particularly convenient to control condensation in emulsion droplets. The second approach uses RNA transcription, a ubiquitous biochemical reaction that is central to the development of the next generation of living materials. We finally show that the combination of RNA transcription and degradation leads to an autonomous dissipative system in which host condensates and protein recruitment occur transiently, and that the host condensate size as well as the timescale of the transient can be controlled by the level of RNA degrading enzyme.For Table of Contents Only
Multimodal mechanisms of human centriole engagement and disengagement
Authors: Ito Kei K , Matsuhashi Kyohei , Takumi Kasuga , Nagai Kaho , Fukuyama Masamitsu , Yamamoto Shohei , Chinen Takumi , Hata Shoji , Kitagawa Daiju 
Published: June 2024

ABSTRACTThe DNA and the centrioles are the only cellular structures that uniquely replicate to produce identical copies, which is crucial for proper chromosome segregation in mitosis. A new centriole termed “daughter” is progressively assembled adjacent to a pre-existing, “mother” centriole. Only after the daughter centriole is structurally completed as an identical copy, it disengages from its mother to become the core of a new functional centrosome. The mechanisms preventing precocious disengagement of the immature copy have been previously unknown. Here, we identify three key centriole-associated mechanisms that maintain the mother-daughter engagement: the cartwheel, the torus, and the pericentriolar material pathways. Among these, the torus is critical for establishing the characteristic orthogonal engagement between the mother and daughter centrioles. Furthermore, we show that the engagement mediated by the cartwheel and the torus pathways is released stepwise through structural changes in the daughter centriole, known as centriole blooming and centriole distancing, respectively. Disruption at any stage of these structural transitions leads to the failure of all subsequent steps, ultimately blocking centriole disengagement and centrosome conversion at the end of mitosis. Overall, this study provides a comprehensive understanding of how the maturing daughter centriole progressively disengages from its mother through multiple maturation steps, to ensure its complete structure and conversion into an independent centrosome.