bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sde Proteins Coordinate Ubiquitin Utilization and Phosphoribosylation to Establish and Maintain theLegionellaReplication Vacuole
Authors: Kotewicz Kristin M. , Zhang Mengyun , Kim Seongok , Martin Meghan S. , Chowdhury Atish Roy , Tai Albert , Scheck Rebecca A. , Isberg Ralph R. 
Published: September 2023

AbstractTheLegionella pneumophilaSde family of translocated proteins promotes host tubular endoplasmic reticulum (ER) rearrangements that are tightly linked to phosphoribosyl-ubiquitin (pR-Ub) modification of Reticulon 4 (Rtn4). Sde proteins have two additional activities of unclear relevance to the infection process: K63 linkage-specific deubiquitination and phosphoribosyl modification of polyubiquitin (pR-Ub). We show here that the deubiquitination activity (DUB) stimulates ER rearrangements while pR-Ub protects the replication vacuole from cytosolic surveillance by autophagy. Loss of DUB activity is tightly linked to lowered pR-Ub modification of Rtn4, consistent with the DUB activity fueling the production of pR-Ub-Rtn4. In parallel, phosphoribosyl modification of polyUb, in a region of the protein known as the isoleucine patch, prevents binding by the autophagy adapter p62. An inability of Sde mutants to modify polyUb results in immediate p62 association, a critical precursor to autophagic attack. The ability of Sde WT to block p62 association decays quickly after bacterial infection, as predicted by the presence of previously characterizedL. pneumophilaeffectors that inactivate Sde and remove polyUb. In sum, these results show that the accessory Sde activities act to stimulate ER rearrangements and protect from host innate immune sensing in a temporal fashion.
A culture-based approach to study ecological interactions among the microbial species of the human scalp
Authors: Bhattacharya Swagatika , Roth Talia , Costa Suzannah , Santoro Ava , Mazza William , Coyte Katharine Z. , Clavaud Cécile , Foster Kevin R. , Kim Wook 
Published: September 2023

AbstractThe human scalp hosts an unusually low diversity microbiota dominated by three species:Cutibacterium acnes,Staphylococcus epidermidis, andMalassezia restricta, where characteristic shifts in species’ frequencies are associated with seborrheic dermatitis and dandruff. In order to better understand this important community, here we study the ecological interactions between these scalp species. We establish a new experimental model system that supports the growth of all three speciesin vitroand allows one to selectively enumerate each species from co-culture. Our work reveals the potential for strong ecological interactions within the scalp community. In particular,C. acnesgreatly benefits from the presence ofM. restricta, but harms it in return (exploitation), whileS. epidermidissuppresses bothM. restrictaandC. acnes. Our data suggest that the shifts in composition seen in compromised scalps are influenced by ecological interactions between species. We argue that the scalp microbiome should be viewed as an ecological system where species interactions have the potential to contribute to health outcomes.ImportanceOur bodies are home to diverse communities of microorganisms, our microbiome, which can be critical for health and wellbeing. The human scalp hosts a relatively simple community dominated by three species: two bacteria,Cutibacterium acnesandStaphylococcus epidermidis, and one fungus,Malassezia restricta. Both dandruff and seborrheic dermatitis are strongly associated with characteristic shifts in the frequencies of these three species. However, how these species affect one another and behave as a community remains poorly understood. Here, we develop a simple experimental system to empirically study how these three species interact and affect one another for the first time. We find thatS. epidermidisgreatly suppresses the growth of the other species, whileC. acnesspecifically exploitsM. restricta. Our work suggests that the human scalp is an ecological system in which species interactions have the potential to affect health outcomes.
Towards interpretable learned representations for Ecoacoustics using variational auto-encoding
Authors: Gibb K. A. , Eldridge A. , Sandom C. J. , Simpson I. J. A. 
Published: September 2023

AbstractEcoacoustics is an emerging science that seeks to understand the role of sound in ecological processes. Passive acoustic monitoring is increasingly being used to collect vast quantities of whole-soundscape audio recordings in order to study variations in acoustic community activity across spatial and temporal scales. However, extracting relevant information from audio recordings for ecological inference is non-trivial. Recent approaches to machine-learned acoustic features appear promising but are limited by inductive biases, crude temporal integration methods and few means to interpret downstream inference. To address these limitations we developed and trained a self-supervised representation learning algorithm -a convolutional Variational Auto-Encoder (VAE) -to embed latent features from acoustic survey data collected from sites representing a gradient of habitat degradation in temperate and tropical ecozones and use prediction of survey site as a test case for interpreting inference. We investigate approaches to interpretability by mapping discriminative descriptors back to the spectro-temporal domain to observe how soundscape components change as we interpolate across a linear classification boundary traversing latent feature space; we advance temporal integration methods by encoding a probabilistic soundscape descriptor capable of capturing multi-modal distributions of latent features over time. Our results suggest that varying combinations of soundscape components (biophony, geophony and anthrophony) are used to infer sites along a degradation gradient and increased sensitivity to periodic signals improves on previous research using time-averaged representations for site classification. We also find the VAE is highly sensitive to differences in recorder hardware’s frequency response and demonstrate a simple linear transformation to mitigate the effect of hardware variance on the learned representation. Our work paves the way for development of a new class of deep neural networks that afford more interpretable machine-learned ecoacoustic representations to advance the fundamental and applied science and support global conservation efforts.
Axial de-scanning using remote focusing in the detection arm of light-sheet microscopy
Authors: Dibaji Hassan , Nasaban Shotorban Ali Kazemi , Grattan Rachel M , Lucero Shayna , Schodt David J. , Lidke Keith A. , Petruccelli Jonathan , Lidke Diane S. , Liu Sheng , Chakraborty Tonmoy 
Published: September 2023

AbstractThe ability to image at high speeds is necessary for biological imaging to capture fast-moving or transient events or to efficiently image large samples. However, due to the lack of rigidity of biological specimens, carrying out fast, high-resolution volumetric imaging without moving and agitating the sample has been a challenging problem. Pupil-matched remote focusing has been promising for high NA imaging systems with their low aberrations and wavelength independence, making it suitable for multicolor imaging. However, owing to the incoherent and unpolarized nature of the fluorescence signal, manipulating this emission light through remote focusing is challenging. Therefore, remote focusing has been primarily limited to the illumination arm, using polarized laser light to facilitate coupling in and out of the remote focusing optics. Here, we introduce a novel optical design that can de-scan the axial focus movement in the detection arm of a microscope. Our method splits the fluorescence signal into S and P-polarized light, lets them pass through the remote focusing module separately, and combines them with the camera. This allows us to use only one focusing element to perform aberration-free, multi-color, volumetric imaging without (a) compromising the fluorescent signal and (b) needing to perform sample/detection-objective translation. We demonstrate the capabilities of this scheme by acquiring fast dual-color 4D (3D space + time) image stacks with an axial range of 70 μm and camera-limited acquisition speed. Owing to its general nature, we believe this technique will find its application in many other microscopy techniques that currently use an adjustable Z-stage to carry out volumetric imaging, such as confocal, 2-photon, and light sheet variants.
Stacking of PRRs in potato to achieve enhanced resistance againstPhytophthora infestans
Authors: Torres Ascurra Yerisf C. , Wouters Doret , Visser Richard G. F. , Nürnberger Thorsten , Vleeshouwers Vivianne G. A. A. 
Published: September 2023

AbstractPlants employ pattern recognition receptors (PRRs) to sense pathogen-associated molecular patterns (PAMPs) or apoplastic effectors at the plant cell surface, as well as nucleotide-binding domain leucine-rich-repeat-containing receptors (NLRs) to sense effectors inside the plant cell. Breeding for potato resistance toP. infestanshas focused on the use of NLRs, however, these genes are typically quickly overcome since the matching avirulence genes evolve exceptionally quickly. Here, we stacked two PRRs,PERUandRLP23, that recognize the rather conservedPhytophthoraPAMPs Pep-13/25 and nlp20, respectively, in the potato cultivar Atlantic, and evaluated their effect onP. infestansresistance. We found that PERU and RLP23 cooperate for the early immune responses like the accumulation of reactive oxygen species (ROS) and production of ethylene by recognizing their corresponding PAMPs. Furthermore, we show that potato plants overexpressing these two PRRs are slightly less affected byP. infestanscompared to the single transformants. Together, our data suggest that pyramiding of surface receptors can provide additional enhanced resistance against pathogens, however, more effective or synergistic combinations that may include intracellular NLR receptors should be explored.
Modulation of Arterial Intima Stiffness by Disturbed Blood Flow
Authors: Bywaters Briana C. , Trache Andreea , Rivera Gonzalo M. 
Published: September 2023

AbstractBackgroundThe intima, comprising the endothelium and the subendothelial matrix, plays a crucial role in the development of atherosclerotic plaques, especially in bifurcations and curved segments of arteries. The mechanical stress arising from disturbed blood flow (d-flow) and the stiffening of the arterial wall contributes to endothelial dysfunction. However, the specific impacts of these physical forces on the mechanical environment of the intima remain undetermined. To address this gap in knowledge, we investigated whether inhibiting collagen crosslinking could ameliorate the detrimental effects of persistent d-flow on the mechanical properties of the intima.MethodsTo explore this hypothesis, we performed partial ligation (PCL) of the left carotid artery (LCA) in male and female C57BL/6J mice, inducing d-flow. The right carotid artery (RCA) served as an internal control. Carotids were collected two days and two weeks after PCL to study acute and chronic effects of d-flow on the mechanical phenotype of the intima. To decouple the chronic effects of d-flow from the ensuing arterial wall stiffening, we used subcutaneous implants delivering either phosphate-buffered saline (Saline) or 150 mg/kg/day of β-aminopropionitrile (BAPN), an inhibitor of elastin and collagen crosslinking lysyl oxidase (LOX) and LOX-like (LOXL) enzymes. Atomic force microscopy (AFM) measurements allowed us to determine stiffness of the endothelium and the denuded subendothelial matrix inen facecarotid preparations. In addition, we determined the stiffness of human aortic endothelial cells (HAEC) cultured on soft and stiff hydrogels.ResultsAcute exposure to d-flow caused a slight decrease in endothelial stiffness in male mice but had no effect on the stiffness of the subendothelial matrix in either sex. Regardless of sex, the intact endothelium was softer than the subendothelial matrix. In contrast, exposure to chronic d-flow led to a substantial increase in the endothelial and subendothelial stiffness in both sexes. The effects of chronic d-flow were largely prevented by concurrent BAPN administration. Notably, the subendothelial matrix of ligated, BAPN-treated arteries was softer than that of unligated, saline-treated counterparts. Furthermore, HAEC displayed reduced stiffness when cultured on soft vs. stiff hydrogels.ConclusionsExposure to chronic d-flow results in marked stiffening of arterial intima, which can be effectively prevented by pharmacological inhibition of LOX/LOXL enzymes.HighlightsAcute exposure to d-flow slightly softens the endothelium in males.Chronic exposure to d-flow causes stiffening of the arterial intima.Inhibition of LOX/LOXL enzymes prevents intimal stiffening arising from chronic d-flow.
LUZP1 regulates the assembly of stress fibers by promoting maturation of contractile actomyosin bundles
Authors: Wang Liang , Tsang Hoi Ying , Yan Ziyi , Tojkander Sari , Ciuba Katarzyna , Kogan Konstantin , Liu Xiaonan , Zhao Hongxia 
Published: September 2023

AbstractContractile actomyosin bundles play crucial roles in various physiological processes, including cell migration, morphogenesis, and muscle contraction. The intricate assembly of actomyosin bundles involves the precise alignment and fusion of myosin II filaments, yet the underlying mechanisms and factors involved in these processes remain elusive. Our study reveals that LUZP1, a leucine zipper protein, plays a central role in orchestrating the formation of thick actomyosin bundles. Loss of LUZP1 caused abnormal cell morphogenesis, migration, and the ability to exert forces on the environment. Importantly, knockout of LUZP1 results in significant defects in the concatenation and persistent association of myosin II filaments, severely impairing the assembly of myosin II stacks. The disruption of these processes in LUZP1 knockout cells provides mechanistic insights into the defective assembly of thick ventral stress fibers and the associated cellular contractility abnormalities. Overall, these results significantly contribute to our understanding of the molecular mechanism involved in actomyosin bundle formation and highlight the essential role of LUZP1 in this process.
The chloroplastic phosphate transporter CrPHT4-7 supports phosphate homeostasis and photosynthesis in Chlamydomonas
Authors: Tóth Dávid , Kuntam Soujanya , Ferenczi Áron , Vidal-Meireles André , Kovács László , Wang Lianyong , Sarkadi Zsuzsa , Migh Ede , Szentmihályi Klára , Tengölics Roland , Neupert Juliane , Bock Ralph , Jonikas Martin C. , Molnar Attila , Tóth Szilvia Z. 
Published: September 2023

AbstractIn eukaryotic cells, phosphorus is assimilated and utilized primarily as phosphate (Pi). Pi homeostasis is mediated by transporters that have not yet been adequately characterized in green algae. This study reports on CrPHT4-7 fromChlamydomonas reinhardtii, a member of the PHT4 transporter family, which exhibits remarkable similarity to AtPHT4;4 fromArabidopsis thaliana, a chloroplastic ascorbate transporter. Using fluorescent protein tagging we show that CrPHT4-7 resides in the chloroplast envelope membrane.Crpht4-7mutants, generated by the CRISPR/Cas12a-mediated single-strand templated repair, show retarded growth especially in high light, enhanced sensitivity to phosphorus limitation, reduced ATP level, strong ascorbate accumulation and diminished non-photochemical quenching in high light. Conversely, CrPHT4-7 overexpressing lines exhibit enhanced biomass accumulation under high light conditions in comparison with the wild-type strain. Expressing CrPHT4-7 in a yeast strain lacking Pi transporters substantially recovered its slow growth phenotype demonstrating that it transports Pi. Even though CrPHT4-7 shows a high degree of similarity to AtPHT4;4, it does not display any significant ascorbate transport activity in yeast or intact algal cells. Thus, the results demonstrate that CrPHT4-7 functions as a chloroplastic Pi transporter essential for maintaining Pi homeostasis and photosynthesis inChlamydomonas reinhardtii.One-sentence summaryWe demonstrate that the CrPHT4-7 transporter ofChlamydomonas reinhardtiiis located in the chloroplast envelope membrane and contributes to maintaining phosphate homeostasis and photosynthesis.
Genome-Wide Association Studies of Coffee Intake in UK/US Participants of European Ancestry Uncover Gene-Cohort Influences
Authors: Thorpe Hayley H A , Fontanillas Pierre , Pham Benjamin K , Meredith John J , Jennings Mariela V , Courchesne-Krak Natasia S , Vilar-Ribó Laura , Bianchi Sevim B , Mutz Julian ,   23andMe Research Team, Elson Sarah L , Khokhar Jibran Y , Abdellaoui Abdel , Davis Lea K , Palmer Abraham A , Sanchez-Roige Sandra 
Published: September 2023

AbstractCoffee is one of the most widely consumed beverages. We performed a genome-wide association study (GWAS) of coffee intake in US-based 23andMe participants (N=130,153) and identified 7 significant loci, with many replicating in three multi-ancestral cohorts. We examined genetic correlations and performed a phenome-wide association study across thousands of biomarkers and health and lifestyle traits, then compared our results to the largest available GWAS of coffee intake from UK Biobank (UKB;N=334,659). The results of these two GWAS were highly discrepant. We observed positive genetic correlations between coffee intake and psychiatric illnesses, pain, and gastrointestinal traits in 23andMe that were absent or negative in UKB. Genetic correlations with cognition were negative in 23andMe but positive in UKB. The only consistent observations were positive genetic correlations with substance use and obesity. Our study shows that GWAS in different cohorts could capture cultural differences in the relationship between behavior and genetics.
Lifelong impacts of puberty timing on human plasma metabolic profiles
Authors: Li Zengjun , Fang Si , Liu Dong , Li Fei , Zhu Cairong , Zhao Jian 
Published: September 2023

AbstractThere has been uncertainty regarding the long-term impact of puberty timing on human plasma metabolites. This lack of clarity can be attributed to the influence of confounding factors present in conventional observational studies. To determine the causal effect of puberty timing on plasma metabolites, we employed a two-sample Mendelian randomization (MR) analysis, complemented by MR mediation analysis assessing the direct effect. We utilized data from a large-scale meta-analysis of genome-wide association studies (GWAS) on puberty timing, consisting of 329,345 women of European ancestry, and a meta-analysis of GWAS on plasma metabolites, involving up to 86,507 individuals. Our findings provide moderate evidence supporting a causal effect of puberty timing on 23 out of 174 plasma metabolites. After excluding 7 single nucleotide polymorphisms (SNPs) related to birth weight and childhood adiposity, causal effects remained for 16 metabolites. Through two-step MR analysis, we observed strong evidence that adulthood adiposity mediated the causal relationships of puberty timing on 35 plasma metabolites. We also observed moderate evidence for an independent causal effect of puberty timing on 10 metabolites through multivariable MR analysis. We further used metabolomic data measured in the UK Biobank (UKB) to perform a replication analysis to validate the causal effect estimated. Nine amino acids were identified in the UKB, and the replication analysis supported our main findings.
A germline heterozygous dominant negativeIKZF2variant causing syndromic primary immune regulatory disorder and ICHAD
Authors: Lu Henry Y. , Vaseghi-Shanjani Maryam , Lam Avery J. , Sharma Mehul , Mohajeri Arezoo , Gillies Jana , Yang Gui Xiang , Lin Susan , Fu Maggie P. , Salman Areesha , Rahmanian Ronak , Armstrong Linlea , Halparin Jessica , Yang Connie L. , Chilvers Mark , Henkelman Erika , Rehmus Wingfield , Morrison Douglas , Setiadi Audi , Mostafavi Sara , Kobor Michael S. , Kozak Frederick K. , Biggs Catherine M. , Karnebeek Clara van , Hildebrand Kyla J. , Lehman Anna , Levings Megan K. , Turvey Stuart E. 
Published: September 2023

AbstractMonogenic defects that impair the control of inflammation and tolerance lead to profound immune dysregulation, including autoimmunity and atopy. Studying these disorders reveals important molecular and cellular factors that regulate human immune homeostasis and identifies potential precision medicine targets. Here, we provide a detailed immunological assessment of a pediatric patient with a recently discovered syndrome causing Immunodysregulation, Craniofacial anomalies, Hearing impairment, Athelia, and Developmental delay (or ICHAD syndrome). The immunodysregulation resulted in autoimmune hemolytic anemia (AIHA) and atopic dermatitis. The patient carried ade novogermline heterozygous c.406+540_574+13477dup;p.Gly136_Ser191dup variant inIKAROS family zinc finger 2(IKZF2), which encodes Helios. This variant led to reduced Helios protein expression and dominant interference of wild-type Helios-mediated repression of theIL2promoter. Multi-parameter flow cytometric analyses of patient peripheral blood mononuclear cells revealed strongly impaired natural killer cell differentiation and function, and increased CD8+T cell activation and cytokine secretion. Strikingly, patient CD4+T cells were hyperactive, produced elevated levels of nearly all T helper (TH) cytokines, and readily proliferated in response to stimulation. Patient regulatory T cells (Tregs) developed normally but aberrantly produced high levels of many THcytokines. Single-cell RNA sequencing revealed largely normal Tregs (albeit mostly memory), but naïve CD4+T cells that were more enriched in genes related to activation, proliferation, metabolism, and THdifferentiation. This work describes the immunological phenotype of one of the first reported cases of germline dominant negative Helios deficiency, expands our understanding of the pathogenesis of AIHA on a single cell level, and provides valuable insights into Helios function in a variety of lymphocyte subsets.