bluuebunny/crossref_metadata_2025 huggingface dataset:
DISTINCT PATTERNS OF ENDOTHELIAL CELL ACTIVATION PRODUCED BY EXTRACELLULAR HISTONES AND BACTERIAL LIPOPOLYSACCHARIDE
Authors: Piffard Sophia H. , Hennig Grant W. , Sackheim Adrian M. , Howard Abigail J. , Lambert Aaron , Majumdar Devdoot , Nelson Mark T. , Freeman Kalev
Published: August 2024

Objective: Vascular endothelial cells (ECs) sense and respond to both trauma factors (histone proteins) and sepsis signals (bacterial lipopolysaccharide, LPS) with elevations in calcium (Ca2+), but it is not clear if the patterns of activation are similar or different. We hypothesized that within seconds of exposure, histones but not LPS would produce a large EC Ca2+ response. We also hypothesized that histones would produce different spatio-temporal patterns of Ca2+ events in veins than in arteries. Methods: We studied cultured ECs (EA.hy926) and native endothelial cells from surgically opened murine blood vessels. High-speed live cell imaging of Ca2+ events were acquired for 5 min before and after stimulation of cultured ECs with histones or LPS alone or in combination. Histone-induced EC Ca2+ events were also compared in native endothelial cells from resistance-sized arteries and veins. Ca2+ activity was quantified as “Ca2+ prevalence” using custom spatiotemporal analysis. Additionally, cultured ECs were collected after 6 h of exposure to histones or LPS for RNA sequencing. Results: ECs—both in culture and in blood vessels—rapidly increased Ca2+ activity within seconds of histone exposure. In contrast, LPS exposure produced only a slight increase in Ca2+ activity in cultured ECs and no effect on blood vessels over 5-min recording periods. Histones evoked large aberrant Ca2+ events (>30 s in duration) in both veins and arteries, but with different spatio-temporal patterns. Ca2+ activity in arterial ECs often appeared as “rosettes”, with Ca2+ events that propagated from one cell to all adjacent surrounding cells. In veins, ECs responded individually without spreading. Surprisingly, exposure of cultured ECs to LPS for 5 min before histones potentiated EC Ca2+ activity by an order of magnitude. Exposure of ECs to histones or LPS both increased gene expression, but different mRNAs were induced. Conclusions: LPS and histones activate ECs through mechanisms that are distinct and additive; only histones produce large aberrant Ca2+ events. ECs in arteries and veins display different patterns of Ca2+ responses to histones.
USP31 PROMOTES THE INFLAMMATORY RESPONSE OF HUMAN LUNG ORGANOIDS TO LIPOPOLYSACCHARIDE TREATMENT
Authors: Xiao Wenbiao , Lin Bingwen , Wang Ying , Huang Peng , Lin Jiandong , Xiao Xiongjian
Published: August 2024

Background: Acute lung injury (ALI) is a severe condition characterized by a high mortality rate, driven by an uncontrolled inflammatory response. Emerging evidence has underscored the crucial role of the ubiquitin system in ALI. However, because of their vast number, the specific functions of individual ubiquitination regulators remain unclear. Materials and methods: In this study, we established human lung organoids (HLOs) derived from human embryonic stem cells and subjected them to lipopolysaccharide (LPS) treatment to induce an inflammatory response, mimicking ALI. Subsequently, we detected the expression of inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin 6, interleukin 18 (IL-18), and interleukin-1β (IL-1β), by quantitative polymerase chain reaction experiments. We also detected changes in the mRNA expression of several USPs before and after HLOs treatment and thus screened for USPs that had significant changes in HLOs after LPS stimulation. After screening for USP, we silenced the USP in HLOs and then subjected them to LPS treatment, and TNF-α, IL-6, IL-18, and IL-1β expressions were detected using quantitative polymerase chain reaction assays. Meanwhile, western blot was used to detect changes in NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) and apoptosis-associated Speck-like protein containing a CARD (ASC) protein level in HLOs. Results: Through screening the expression of 40 ubiquitin-specific proteases (USPs), which are responsible for removing ubiquitination, we identified several USPs that exhibited differential expression in LPS-treated HLOs compared to untreated HLOs. Notably, USP31 emerged as the most significantly upregulated USP, and the knockdown of USP31 markedly attenuated the inflammatory response of HLOs to LPS treatment. Conclusions: USP31 may play a facilitating role in the inflammatory response during ALI.
PLASMA PROTEOME, METABOLOME MENDELIAN RANDOMIZATION IDENTIFIES SEPSIS THERAPEUTIC TARGETS
Authors: Deng Ruiming , Huang Guiming , Zhou Juan , Zeng Kai
Published: August 2024

Background: The interrelation between the plasma proteome and plasma metabolome with sepsis presents a multifaceted dynamic that necessitates further research to elucidate the underlying causal mechanisms. Methods: Our investigation used public genome-wide association study data to explore the relationships among the plasma proteome, metabolome, and sepsis, considering different sepsis subgroup. Initially, two-sample Mendelian randomization established causal connections between the plasma proteome and metabolome with sepsis. Subsequently, multivariate and iterative Mendelian randomization analyses were performed to understand the complex interactions in plasma during sepsis. The validity of these findings was supported by thorough sensitivity analyses. Result: The study identified 25 plasma proteins that enhance risk and 34 that act as protective agents in sepsis. After P value adjustment (0.05/1306), ICAM5 emerged with a positive correlation to sepsis susceptibility (P value = 2.14E-05, OR = 1.10, 95% CI = 1.05–1.15), with this significance preserved across three sepsis subgroup examined. Additionally, 29 plasma metabolites were recognized as risk factors, and 15 as protective factors for sepsis outcomes. After P value adjustment (0.05/997), elevated levels of 1,2,3-benzenetriol sulfate (2) was significantly associated with increased sepsis risk (P value = 3.37E-05, OR = 1.18, 95% CI = 1.09–1.28). Further scrutiny revealed that this plasma metabolite notably augments the abundance of ICAM5 protein (P value = 3.52E-04, OR = 1.11, 95% CI = 1.04–1.17), devoid of any detected heterogeneity, pleiotropy, or reverse causality. Mediated Mendelian randomization revealed ICAM5 mediated 11.9% of 1,2,3-benzenetriol sulfate (2)’s total effect on sepsis progression. Conclusion: This study details the causal link between the plasma proteome and metabolome with sepsis, highlighting the roles of ICAM5 and 1,2,3-benzenetriol sulfate (2) in sepsis progression, both independently and through crosstalk.
A critique of Thompson and Ramírez-Barahona (2023) or: how I learned to stop worrying and love the fossil record
Authors: Hagen Eric Robert
Published: August 2024

A recent study published in
Biology Letters
by Thompson and Ramírez-Barahona (2023) argued that, according to analyses of diversification on two massive molecular phylogenies comprising thousands of species, there is no evidence that angiosperms (i.e. flowering plants) were affected by the Cretaceous–Paleogene mass extinction. Here, I critique these conclusions from both methodological and philosophical perspectives. I demonstrate that the methods used in their study possess statistical limitations that strongly reduce the power to detect a true mass extinction event using data similar to those analysed by Thompson and Ramírez-Barahona (2023). Additionally, I use their study as a springboard to examine the relationship between phylogenetic and fossil evidence in diversification studies.
Modelling the effects of void swelling and spatial heterogeneity on the fracture of metallic materials by crystal plasticity
Authors: Fu Jiaqi , Wu Liujun , Yu Long , Sui Haonan , Zhang Jingyu , Duan Huiling , Mao Sheng
Published: August 2024

To theoretically analyse how void swelling and spatial heterogeneity impact the fracture behaviour of metallic materials, a coupled porous crystal plasticity framework has been developed. The proposed framework is then applied to analyse the fracture behaviour of metallic materials under different swelling conditions and types of spatial heterogeneity. It is revealed that at low porosity, the spatial heterogeneity of voids will have limited influence on the fracture behaviour of the material. However, at high porosity, owing to void swelling, a concentrated distribution of voids near grain boundaries can lead to a strong deformation localization, which can be seen as an indicator of possible quasi-brittle fracture. It is further discovered that the inner pressure of the voids tends to reduce the yield stress of the material and promote localized plastic deformation. As a result, such pressure will enhance the impact of concentrated distribution of voids, which can lead to further embrittlement of the material. The present study reveals the key role of void swelling and spatial heterogeneity in regulating the fracture behaviour of metallic materials, a step towards a better understanding over the failure mechanisms of metallic materials under extreme conditions.
Species-specific behavioural responses to environmental variation as a potential species coexistence mechanism in ants
Authors: Menges Vanessa , Rohovsky Merle , Rojas Feilke Raúl , Menzel Florian
Published: August 2024

A fundamental question of ecology is why species coexist in the same habitat. Coexistence can be enabled through niche differentiation, mediated by trait differentiation. Here, behaviour constitutes an often-overlooked set of traits. However, behaviours such as aggression and exploration drive intra- and interspecific competition, especially so in ants, where community structure is usually shaped by aggressive interactions. We studied behavioural variation in three ant species, which often co-occur in close proximity and occupy similar dominance ranks. We analysed how intra- and allospecific aggression, exploration and foraging activity vary under field conditions, namely with temperature and over time. Behaviours were assessed for 12 colonies per species, and four times each during several months. All behavioural traits consistently differed among colonies, but also varied over time and with temperature. These temperature-dependent and seasonal responses were highly species-specific. For example, foraging activity decreased at high temperatures in
Formica rufibarbis
, but not in
Lasius niger
; over time, it declined strongly in
L. niger
but much less in
F. rufibarbis
. Our results suggest that, owing to these species-specific responses, no species is always competitively superior. Thus, environmental and temporal variation effects a dynamic dominance hierarchy among the species, facilitating coexistence via the storage effect.
Day–night gene expression reveals circadian gene
disco
as a candidate for diel-niche evolution in moths
Authors: Sondhi Yash , Messcher Rebeccah L. , Bellantuono Anthony J. , Storer Caroline G. , Cinel Scott D. , Godfrey R. Keating , Mongue Andrew J. , Weng Yi-Ming , Glass Deborah , St Laurent Ryan A. , Hamilton Chris A. , Earl Chandra , Brislawn Colin J. , Kitching Ian J. , Bybee Seth M. , Theobald Jamie C. , Kawahara Akito Y.
Published: August 2024

Temporal ecological niche partitioning is an underappreciated driver of speciation. While insects have long been models for circadian biology, the genes and circuits that allow adaptive changes in diel-niches remain poorly understood. We compared gene expression in closely related day- and night-active non-model wild silk moths, with otherwise similar ecologies. Using an ortholog-based pipeline to compare RNA-Seq patterns across two moth species, we find over 25 pairs of gene orthologs showing differential expression. Notably, the gene
disco,
involved in circadian control, optic lobe and clock neuron development in
Drosophila
, shows robust adult circadian mRNA cycling in moth heads.
Disco
is highly conserved in moths and has additional zinc-finger domains with specific nocturnal and diurnal mutations. We propose
disco
as a candidate gene for the diversification of temporal diel-niche in moths.
Size differences among canaries, goldfinches and allies may explain correlated evolution of song and colour
Authors: Cardoso Gonçalo C. , Abreu João M. , Mota Paulo G.
Published: August 2024

Sexual signals such as colour ornamentation and birdsong evolve independently of each other in some clades, and in others they evolve positively or negatively correlated. We rarely know why correlated evolution does or does not occur. Here, we show positively correlated evolution between plumage colour and song motor performance among canaries, goldfinches and allies, associated with species differences in body size. When controlling for body size, the pattern of correlated evolution between song performance and colour disappeared. Syllable diversity was not as strongly associated with size, and did not evolve in a correlated manner with colour. We argue that correlated evolution between song and colour was mediated by large size limiting song motor performance, likely due to constraints on the speed of moving heavier bills, and by larger species having less saturated plumage colour, possibly due to life-history traits of larger birds (e.g. longevity, stable pairs) contributing to weaker sexual selection. Results are consistent with the hypothesis that correlated evolution between sexual signals is influenced by how, in a clade, selective pressures and constraints affecting each type of signal happen to be co-distributed across species. Such contingency helps explain the diversity in clade-specific patterns of correlated evolution between sexual signals.
Metastable Dynamics Emerge from Local Excitatory-Inhibitory Homeostasis in the Cortex at Rest
Authors: Páscoa dos Santos Francisco , Verschure Paul FMJ
Published: August 2024

The dynamics of the human cortex are highly metastable, driving the spontaneous exploration of network states. This metastability depends on circuit-level edge-of-bifurcation dynamics, which emerge from firing-rate control through multiple mechanisms of excitatory-inhibitory (E-I) homeostasis. However, it is unclear how these contribute to the metastability of cortical networks. We propose that individual mechanisms of E-I homeostasis contribute uniquely to the emergence of resting-state dynamics and test this hypothesis in a large-scale model of the human cortex. We show that empirical connectivity and dynamics can only be reproduced when accounting for multiple mechanisms of E-I homeostasis. More specifically, while the homeostasis of excitation and inhibition enhances metastability, the regulation of intrinsic excitability ensures moderate synchrony, maximizing functional complexity. Furthermore, the modulation bifurcation modulation by the homeostasis of excitation and intrinsic excitability compensates for strong input fluctuations in connector hubs. Importantly, this only occurs in models accounting for local gamma oscillations, suggesting a relationship between E-I balance, gamma rhythms, and metastable dynamics. Altogether, our results show that cortical networks self-organize toward maximal metastability through the multi-factor homeostasis of E-I balance. Therefore, the benefits of combining multiple homeostatic mechanisms transcend the circuit level, supporting the metastable dynamics of large-scale cortical networks.
MedSegBench: A Comprehensive Benchmark for Medical Image Segmentation in Diverse Data Modalities
Authors: Aydin Musa , Kuş Zeki
Published: August 2024

MedSegBench is a comprehensive benchmark designed to evaluate deep learning models for medical image segmentation across a wide range of modalities.. This benchmark includes 35 datasets with over 60,000 images, covering modalities such as ultrasound, MRI, and X-ray. It addresses challenges in medical imaging, such as variability in image quality and dataset imbalances, by providing standardized datasets with train/validation/test splits. The benchmark supports binary and multi-class segmentation tasks with up to 19 classes. Evaluations are conducted using the U-Net architecture with various encoder/decoder networks, including ResNets, EfficientNet, and DenseNet, to evaluate model performance. MedSegBench serves as a valuable resource for developing robust and flexible segmentation algorithms. It allows for fair comparisons across different models and promotes the development of universal models for medical tasks. The datasets and source code are publicly available, encouraging further research and development in medical image analysis.
IRF5 mediates adaptive immunity via altered glutamine metabolism, mTORC1 signaling and post-transcriptional regulation following T cell receptor activation
Authors: Brune Zarina , Lu Ailing , Moss Matthew , Brune Leianna , Huang Amanda , Matta Bharati , Barnes Betsy J
Published: August 2024

Although dynamic alterations in transcriptional, translational, and metabolic programs have been described in T cells, the factors and pathways guiding these molecular shifts are poorly understood, with recent studies revealing a disassociation between transcriptional responses and protein expression following T cell receptor (TCR) stimulation. Previous studies identified interferon regulatory factor 5 (IRF5) in the transcriptional regulation of cytokines, chemotactic molecules and T effector transcription factors following TCR signaling. In this study, we identified T cell intrinsic IRF5 regulation of mTORC1 activity as a key modulator of CD40L protein expression. We further demonstrated a global shift in T cell metabolism, with alterations in glutamine metabolism accompanied by shifts in T cell populations at the single cell level due to loss ofIrf5. T cell conditionalIrf5knockout mice in a murine model of experimental autoimmune encephalomyelitis (EAE) demonstrated protection from clinical disease with conserved defects in mTORC1 activity and glutamine regulation. Together, these findings expand our mechanistic understanding of IRF5 as an intrinsic regulator of T effector function(s) and support the therapeutic targeting of IRF5 in multiple sclerosis.

Sentence Summary

Findings provide new insight into the mechanisms by which T cell intrinsic IRF5 regulates the adaptive immune response via modulation of mTORC1 signaling, glutamine metabolism, and protein translation.
Transplantation of bioengineered lung using decellularized mouse lungs and primary human endothelial cells
Authors: Suzuki Takaya , Watanabe Tatsuaki , Tomiyama Fumiko , Ito Takayasu , Okada Yoshinori
Published: August 2024

Lung transplantation is a critical treatment for patients with end-stage lung diseases like idiopathic pulmonary fibrosis, but challenges such as donor shortages and post-transplant complications persist. Bioengineered lungs, integrating patient-specific cells into decellularized animal scaffolds, present a promising alternative. Despite progress in using bioengineered lungs in animal models, functionality and structure remain immature. This protocol addresses a critical barrier in organ bioengineering: the need for a cost-effective experimental platform. By using mouse models instead of larger animals like rats or swine, researchers can significantly reduce the resources required for each experiment, accelerating research progress. The protocol outlines a detailed procedure for lung bioengineering using mouse heart-lung blocks and human primary cells, focusing on isolation strategy for the mouse heart-lung block, decellularization, bioreactor setup, perfusion-based organ culture, and orthotopic transplantation of bioengineered lungs. This mouse-scale platform not only reduces experimental costs but also provides a viable framework for optimizing cell types and numbers for recellularization, testing different cell types using histological and molecular methods, and ensuring blood flow post-transplantation. The method holds potential for broad applications, including studying cell interactions in three-dimensional culture conditions, cell-matrix interactions, and ex vivo cancer modeling, thereby advancing the field of organ bioengineering.

This paper describes how to create bioengineered mouse lungs using the decellularization and recellularization methods. It also describes subsequent orthotopic lung transplantation in detail.
Multiple factors regulate i-motif and G-quadruplex structuresin vitro: analysis of repeated and non-repeated polyG/polyC clusters by circular dichroism
Authors: Diggins Levi , Ross Daniel , Bhanot Sundeep , Corallo Rebecca , Daley Rachel , Patel Krishna , Lewis Olivia , Donahue Shane , Thaddeus Jacob , Hiers Lauren , Syed Christopher , Eagerton David , Mohanty Bidyut K.
Published: August 2024

The B-form of DNA in the genome contains thousands of sequences that can form various noncanonical structures. Of particular interest are two structures namely G-quadruplex (G4), formed by two or more stacks of four guanine residues in a plane, and intercalating-motif (i-motif, iM) formed by alternately arranged C-C+pairs. Circular dichroism (CD) spectroscopy is a fast biophysical technique to analyze G4s and iMs. We conducted a CD analysis of two types of DNA sequences, one containing tandem repeats and one without, for the generation of G4s and iMs under various environmental conditions, which include pH, buffer composition, boiling, with flanking sequences, complimentary DNA strands, and single-stranded DNA binding protein (SSB). Changes in pH and boiling caused drastic variations in the CD spectra of DNA containing tandem repeats of GGGGCC and GGCCCC from the C9ORF72 gene, although some changes in G4/iM-forming DNA from promoter-proximal regions of several oncogenes also occur. An increase in the number of hexanucleotide repeats generated complex CD patterns at specific pH due to the presence of both G and C bases. The presence of flanking sequences affects CD pattern of a mixture of G4- and iM-forming sequences of the c-MYC promoter-proximal region. SSB disassembled G4 and iMs of all sequences suggesting anin vivorole for SSBs in disassembly of G4s and iMs during various DNA transactions.
High glycaemic variability in individuals with type 1 diabetes is associated with a reduced proportion of CD8+TNF+cells in response to influenza A virus
Authors: Zhen Wei Marcus Tong , Hulme Katina D. , Law Soi Cheng , Noye Ellesandra , Dorey Emily S. , Chew Keng Yih , Rowntree Louise C. , van de Sandt Carolien E. , Kedzierska Katherine , Goeijenbier Marco , Ronacher Katharina , Alzaid Fawaz , Julla Jean-Baptiste , Riveline Jean-Pierre , Lineburg Katie , Smith Corey , Grant Emma J. , Gras Stephanie , Gallo Linda A. , Barett Helen L. , Short Kirsty R.
Published: August 2024

Objective

Diabetes mellitus significantly increases the risk of severe respiratory virus disease like influenza and COVID-19. Early evidence suggests that this susceptibility to respiratory viral disease is driven by glycaemic variability, rather than average blood glucose levels. In healthy individuals, blood glucose levels remain relatively stable throughout the day. However, in individuals living with diabetes, blood glucose spikes are more frequent and higher in magnitude. Continuous glucose monitoring (CGM) provides a unique opportunity to detect these hyper and hypoglycaemic events, even in the presence of an in range HbA1c.

Research design and methods

Here, we use blood samples and CGM data obtained from people living with Type 1 diabetes (T1D) to determine the effects of glycaemic variability on the T-cell response to influenza virus. Low glycaemic variability was defined as a coefficient of variation (CV) <33% (n = 13) whilst high glycaemic variability was defined as a CV >33% (n = 19).

Results

We show that high glycaemic variability in participants living with T1D is associated with a reduced proportion of CD8+CD107α-IFNγ-MIP1β-TNF+T-cells in response to stimulation with influenza virus and an influenza peptide pool. High glycaemic variability in this patient population is primarily driven by hypoglycaemic events and was also associated with an increase in the proportion of naïve CD8+T cells and a decrease in terminally differentiated CD8+T cells (TEMRA).

Conclusions

Together, this study provides the first evidence that glycaemic variability affects the T- cell response to respiratory viruses. These data suggest that monitoring glycaemic variability may have important implications in understanding the antiviral immune response in people with diabetes.
Immunological profiles in Lynch syndrome colorectal cancers are not specific to mismatch repair gene defects
Authors: Helderman Noah C. , IJsselsteijn Marieke E. , Cabuta Madalina , van der Ploeg Manon , van Wezel Tom , Ahadova Aysel , Kloor Matthias , Morreau Hans , Nielsen Maartje , de Miranda Noel F.C.C.
Published: August 2024

Background and aims

Colorectal carcinomas (CRCs) in patients with Lynch syndrome (LS) exhibit heightened immunogenicity due to mismatch repair deficiency (MMR-d), often resulting in favorable responses to T cell immune checkpoint therapies. Recent studies indicate that the phenotype and genotype of LS-associated CRCs vary depending on the specific MMR gene mutated. Here, we investigated whether the immune profiles of LS-associated CRCs differ based on the MMR gene defects.

Methods

Tissue material from 18MLH1-,16MSH2-,40MSH6-, and23PMS2-mutated CRCs and 35 sporadic MMR-d CRCs were included in the study. Imaging mass cytometry (IMC) analysis, along with targeted multiplex immunofluorescence imaging (mIF) and immunohistochemistry, were applied to examine the tumor immune microenvironment, including Human Leukocyte Antigen (HLA) class I and programmed death-ligand 1 (PD-L1) expression.

Results

Unsupervised hierarchical clustering of cell phenotypes identified by IMC, followed by mIF validation, revealed comparable lymphoid and myeloid cell infiltration levels across CRCs from all MMR groups. Infiltrating T cell levels negatively correlated with the number of mutations at coding microsatellite sequences, particularly inMLH1-mutated CRCs. HLA class I defects were observed in 76% of all CRCs. These defects were more frequently accompanied by β2M defects in hereditary MMR-d CRCs (67%) compared to sporadic MMR-d CRCs (37%), and did not associate with the number of γδ T cells, which were present in CRCs from all MMR groups. PD-L1 expression in tumor cells was only detected in 8% of all CRCs.

Conclusion

Our findings illustrate that, from an immunological perspective, there is no evidence of differing immunogenic features across MMR defects. This is important to consider when developing preventive vaccine strategies and evaluating immunotherapy for LS patients and those with MMR-d CRCs.
Epidemiological Analysis of HIV and HPgV Co-infection in a Brazilian Population
Authors: de Barros Campelo Júnior Evônio , Passos de Castilho Ana Maria , Santos de Morais Viviane Martha , de Oliveira Mendes Cahú Georgea Gertrudes , Cunha Gabriel Galindo , de Araújo Oliveira Vitoria Maria , de Arraes Alencar Ximenes Ricardo , Cunha Duarte Coêlho Maria Rosângela
Published: August 2024

Objectives

This study aimed to determine the prevalence of Human Pegivirus 1 infection among people living with HIV (PLWHIV) in Northeast Brazil and identify associated risk factors, given the potential impact of HPgV on HIV disease progression

Methods

We conducted a cross-sectional analysis of 249 PLWHIV receiving care at a tertiary hospital in Northeast Brazil. Bivariate and multivariate logistic regression models were used to assess the association between sociodemographic characteristics, risk behaviors, healthcare access, and HPgV infection.

Results

The prevalence of HPgV infection among the study population was 23.3%. Inhaled drug use emerged as a significant risk factor for HPgV infection in the multivariate analysis.

Conclusions

A concerning prevalence of HPgV infection exists among PLWHIV in Northeast Brazil. The identification of inhaled drug use as a risk factor suggests potential transmission routes beyond traditional modes. These findings highlight the need for targeted public health interventions and harm reduction strategies to address this significant public health concern.
GlycoRNA-L and glycoRNA-S mediate human monocyte adhesion via binding to Siglec-5
Authors: Fu Mingui , Qian Yisong , Huang Evan , Schwarz Zain , Tai Hannah , Tillock Katherine , Lei Tianhua
Published: August 2024

It was recently reported that RNAs can be glycosylated, and a majority of such glycosylated RNAs (referred to as glycoRNAs) are located on the outer cell surface. We here reported that there are two forms of glycoRNAs, named as glycoRNA-L and glycoRNA-S, robustly expressed in human monocytes. Both of glycoRNA-L and glycoRNA-S contributed to the interaction of human monocytes and endothelial cells via directly binding to Siglec-5. GlycoRNA-L predominantly expressed in most of tissues and cell lines. GlycoRNA-S only expressed in some cell lines and tissues. Siglec-5 preferentially binds to glycoRNA-L than glycoRNA-S. The composition of glycan chains in glycoRNA-L and glycoRNA-S is different. GlycoRNA-L contains more sialic acid, whereas glycoRNA-S contains more GlcNAc. Together, these results demonstrate that two forms of glycoRNAs exist, which may play significant role in controlling the interaction of human monocytes and endothelial cells and contribute to the pathogenesis of inflammatory diseases.
Auditory perception and neural representation of temporal fine structure are impaired by age but not by cochlear synaptopathy
Authors: Steenken Friederike , Beutelmann Rainer , Oetjen Henning , Köppl Christine , Klump Georg M.
Published: August 2024

Age-related hearing loss is a complex phenomenon. The earliest-onset degenerative event is the gradual loss of neural connections between cochlea and auditory brainstem. To probe for perceptual deficits that might arise from this loss, cochlear synaptopathy was induced pharmacologically in young-adult gerbils which were then tested in a challenging listening task for the perception of temporal fine structure. Treated gerbils behaved no differently than normal-hearing, young-adult animals. In contrast, old gerbils, which typically express many cochlear and central-neural pathologies, showed impaired perception. To probe for the underlying mechanisms, single-unit responses were obtained from the auditory nerve to the same test stimuli. Responses from old gerbils showed no impairment in temporal locking to the stimulus fine structure. However, responses were significantly more driven by slower temporal fluctuations of the stimulus envelope, suggesting that the central auditory system may be unable to extract the relevant information for discrimination from such altered inputs.
Recapitulation of clinical features in a patient-derived xenograft mouse model of VEXAS Syndrome
Authors: Arede Liliana , Coutinho Rita , Duarte Tiago L , Lopes Marta , Simões Rui V , Silva Susana , Baptista Pedro , Lopes José Manuel , Faria Raquel , Duarte Delfim
Published: August 2024

Patient-derived xenografts (PDX) are valuable tools to model human disease and test new therapies. Here, we report, for the first time, a PDX model recapitulating the unique characteristics of a VEXAS patient (unique patient number UPN1).
Vibrio alginolyticusis the pathogen of ‘Baotou’ disease causing serious damage toGracilariopsis lemaneiformiscultivation in China
Authors: Pang Tong , Wang Feng , Guo Qunqun , Zhang Mengjie , Sun Yuanyuan , Liu Jianguo
Published: August 2024

Gracilariopsis lemaneiformisandSaccharina japonica, the two very important cultivated economic seaweeds, are often co-cultured in China due to their growth periods overlapped for about 3 months. These two seaweeds are often plagued with bleaching diseases during their high-density commercial cultivation. In recent years, a disease called ‘Baotou’ has been causing large-scale yield reductions ofG. lemaneiformisin China. Interestingly,Vibrio alginolyticusonce reported to be beneficial toS. japonicaby reducing the bleaching disease risk, was strongly proved to be the pathogen causing ‘Baotou’ disease in this study. Analysis of 16S rRNA gene profiling revealed thatV. alginolyticuswas the most abundant and dominant bacterium on the algal thalli suffering from ‘Baotou’ disease, whereas its presence was scarcely detected on healthy thalli. Scanning electron microscope (SEM) analysis revealed that a large number ofV. alginolyticuscells were found to be attached to the algal thalli with ‘Baotou’ disease and the rotten thalli acquired by the lab infection treatment.V. alginolyticuscould cause the rotten symptoms which were consistent with those of ‘Baotou’ disease. According to Koch’s postulates,V. alginolyticuswas identified as the pathogen causing ‘Baotou’ disease.

IMPORTANCE

A highly contagious disease known as ‘Baotou’ disease has persistently triggered significant yield reductions inG. lemaneiformisthroughout China. The pathogen of ‘Baotou’ disease was isolated and identified asV. alginolyticuswhich was once reported to be beneficial toS. japonicaby reducing the bleaching disease risk. The study indicates thatV. alginolyticusis closely involved in the competition or co-existence betweenG. lemaneiformisandS. japonicaco-cultured in China, and provides a novel perspective and evidence that bacteria are closely involved in the competition or co-existence among different species of seaweeds that grow together.
Cargo quantification of functionalized DNA origami for therapeutic application
Authors: Young Olivia J. , Dembele Hawa , Rajwar Anjali , Kwon Ick Chan , Ryu Ju Hee , Shih William M. , Zeng Yang C.
Published: August 2024

In recent years, notable advances in nanotechnology-based drug delivery have emerged. A particularly promising platform in this field is DNA origami-based nanoparticles, which offer highly programmable surfaces, providing precise control over the nanoscale spacing and stoichiometry of various cargo. These versatile particles are finding diverse applications ranging from basic molecular biology to diagnostics and therapeutics. This growing interest creates the need for effective methods to quantify cargo on DNA origami nanoparticles. Our study consolidates several previously validated methods focusing on gel-based and fluorescence-based techniques, including multiplexed quantification of protein, peptide, and nucleic acid cargo on these nanoparticles. This work may serve as a valuable resource for groups researchers keen on utilizing DNA origami-based nanoparticles in therapeutic applications.

Graphical abstract
Dissecting the regulatory logic of specification and differentiation during vertebrate embryogenesis
Authors: Liu Jialin , Castillo-Hair Sebastian M. , Du Lucia Y. , Wang Yiqun , Carte Adam N. , Colomer-Rosell Mariona , Yin Christopher , Seelig Georg , Schier Alexander F.
Published: August 2024

The interplay between transcription factors and chromatin accessibility regulates cell type diversification during vertebrate embryogenesis. To systematically decipher the gene regulatory logic guiding this process, we generated a single-cell multi-omics atlas of RNA expression and chromatin accessibility during early zebrafish embryogenesis. We developed a deep learning model to predict chromatin accessibility based on DNA sequence and found that a small number of transcription factors underlie cell-type-specific chromatin landscapes. While Nanog is well-established in promoting pluripotency, we discovered a new function in priming the enhancer accessibility of mesendodermal genes. In addition to the classical stepwise mode of differentiation, we describe instant differentiation, where pluripotent cells skip intermediate fate transitions and terminally differentiate. Reconstruction of gene regulatory interactions reveals that this process is driven by a shallow network in which maternally deposited regulators activate a small set of transcription factors that co-regulate hundreds of differentiation genes. Notably, misexpression of these transcription factors in pluripotent cells is sufficient to ectopically activate their targets. This study provides a rich resource for analyzing embryonic gene regulation and reveals the regulatory logic of instant differentiation.
Non-spatial hippocampal behavioral timescale synaptic plasticity during working memory is gated by entorhinal inputs
Authors: Dorian Conor C. , Taxidis Jiannis , Golshani Peyman
Published: August 2024

Behavioral timescale synaptic plasticity (BTSP) is a form of synaptic potentiation where the occurrence of a single large plateau potential in CA1 hippocampal neurons leads to the formation of reliable place fields during spatial learning tasks. We asked whether BTSP could also be a plasticity mechanism for generation of non-spatial responses in the hippocampus and what roles the medial and lateral entorhinal cortex (MEC and LEC) play in driving non-spatial BTSP. By performing simultaneous calcium imaging of dorsal CA1 neurons and chemogenetic inhibition of LEC or MEC while mice performed an olfactory working memory task, we discovered BTSP-like events which formed stable odor-specific fields. Critically, the success rate of calcium events generating a significant odor-field increased with event amplitude, and large events exhibited asymmetrical formation with the newly formed odor-fields preceding the timepoint of their induction event. We found that MEC and LEC play distinct roles in modulating BTSP: MEC inhibition reduced the frequency of large calcium events, while LEC inhibition reduced the success rate of odor-field generation. Using two-photon calcium imaging of LEC and MEC temporammonic axons projecting to CA1, we found that LEC projections to CA1 were strongly odor selective even early in task learning, while MEC projection odor-selectivity increased with task learning but remained weaker than LEC. Finally, we found that LEC and MEC inhibition both slowed representational drift of odor representations in CA1 across 48 hours. Altogether, odor-specific information from LEC and strong odor-timed activity from MEC are crucial for driving BTSP in CA1, which is a synaptic plasticity mechanism for generation of both spatial and non-spatial responses in the hippocampus that may play a role in explaining representational drift and one-shot learning of non-spatial information.
Complete Chloroplast Genome Sequence and Phylogenetic Analysis ofCamellia sinensissp. Baihaozao
Authors: Chen Zhiyin , Zhu Youpeng , He Zhiming , Li Hongyu , Huang Jing , Gong Yihui
Published: August 2024

Baihaozao (Camellia sinensissp. Baihaozao) is esteemed in the domain of tea plant cultivation for its early harvest period, profusion of bud trichomes, and exceptional suitability for tea processing. Nevertheless, the intricate phylogenetic relationships among species within this genus remain ambiguous, primarily due to the limited availability of genomic data. This study endeavors to comprehensively investigate the genomic resources of Baihaozao by sequencing, assembling, and annotating its entire chloroplast (cp) genome. The sequencing results indicated that the total length of the Baihaozao cp genome is 157,052 base pairs (bp), with an overall guanine-cytosine (GC) content of 37.30%. The genome exhibits a typical quadripartite structure, consisting of a large single-copy region (LSC) of 86,586 bp, a small single-copy region (SSC) of 18,227 bp, and a pair of inverted repeats (IRs) totaling 52,162 bp. A total of 133 genes were identified within this genome, including 8 ribosomal RNA (rRNA) genes, 37 transfer RNA (tRNA) genes, 87 protein-coding genes, and 1 pseudogene. Furthermore, the study identified 157 simple sequence repeats (SSRs) and 90 long repeat sequences. Analysis of codon usage bias indicated that codons encoding leucine (Leu) were the most frequently utilized, whereas those encoding cysteine (Cys) were the least utilized. Examination of nucleotide diversity within the Baihaozao cp genome revealed five highly variable regions with elevated Pi values (rps19,rpl32,ndhF,rpl22,matK), suggesting their potential utility as molecular markers. Phylogenetic analysis of 20 cp genomes of the Theaceae family indicated a close evolutionary relationship between Baihaozao andCamellia sinensisOL450428.1. This study not only provides valuable data support for elucidating the maternal origin of cultivated Camellia species but also holds significant scientific implications for further exploring the phylogenetic relationships and germplasm resource utilization of Camellia plants.
NEMF-mediated CAT-tailing defines distinct branches of translocation-associated quality control
Authors: Ennis Amanda , Wang Lihui , Wang Xiaorong , Yu Clinton , Saidi Layla , Xu Yue , Yun Sijung , Huang Lan , Ye Yihong
Published: August 2024

Ribosome stalling during co-translational translocation at the endoplasmic reticulum (ER) causes translocon clogging and impairs ER protein biogenesis. Mammalian cells resolve translocon clogging vial a poorly characterized translocation-associated quality control (TAQC) process. Here, we combine genome-wide CRISPR screen with live cell imaging to dissect the molecular linchpin of TAQC. We show that substrates translated from mRNAs bearing a ribosome stalling poly(A) sequence are degraded by lysosomes and the proteasome, while substrates encoded by non-stop mRNAs are degraded by an unconventional ER-associated degradation (ERAD) mechanism involving ER-to-Golgi trafficking and KDEL-dependent substrate retrieval. The triaging diversity appears to result from the heterogeneity of NEMF-mediated CATylation, because a systematic characterization of representative CAT-tail mimetics establishes an AT-rich tail as a “degron” for ERAD, whereas an AG-rich tail can direct a secretory protein to the lysosome. Our study reveals an unexpected protein sorting function for CAT-tailing that safeguards ER protein biogenesis.
Synergistic Cytotoxicity of Permethrin and N,N-Diethyl-Meta-Toluamide on Sinonasal Epithelial Cells
Authors: Lee Jivianne T. , Basak Saroj K. , Yang Hong-Ho , Sullivan Kimberly A. , Maxim Tom , Shin Daniel S. , Klimas Nancy , Srivatsan Eri S.
Published: August 2024

Background

N,N-Diethyl-Meta-Toluamide (DEET) and permethrin are pesticides commonly used in combination due to their synergistic insecticidal and repellent properties. This study investigates whether simultaneous exposure to these compounds elicits synergistic cytotoxicity in sinonasal epithelial cells (SNECs).

Material and Methods

Ethmoid sinus mucosal specimens were procured from eight patients during endoscopic sinus surgery. SNECs were expanded on culture plates and exposed to various concentrations of DEET and permethrin (0-5μm), individually and concurrently, for up to 156 hours. Experiments were replicated in triplicates and cell viability was recorded every 2 hours usingIncuCytereal-time cell imaging system. Synergy score was calculated on the basis of Loewe additivity synergy finder model.

Results

DEET and permethrin exhibited synergistic cytotoxicity across all eight tissues, albeit with variations in onset and magnitude. Peak synergy was observed at 144h for tissue 1 (SLoewe4.2, 95% CI 1.8-7.3; [permethrin concentration, DEET concentration] [2.5μM, 1.25μM]), 48h for tissue 2 (19.9, 16.5-23.6; [1.25, 0.625]), 144h for tissue 3 (15.2, 3.9-30.4; [0.625, 1.25]), 144h for tissue 4 (6.4, −3.6 to 18.0; [0.625, 0.625]), 48h for tissue 5 (10.1, 8.9-12.5; [0.625, 1.25]), 96h for tissue 6 (24.7, 12.2-36.3; [0.625, 0.625]), 48h for tissue 7 (47.7, 29.6-62.2; [0.625, 1.25]), and 96h for 8 (47.4, 26.8-67.0; [0.625, 0.625]).

Conclusion

The concurrent exposure of DEET and permethrin can lead to synergistic cytotoxicity in sinonasal epithelia. Further research is warranted in preclinical animal models to explore whether this synergy accelerates the pathogenesis of chronic rhinosinusitis.
Parallel networks to predict TIMP and protease cell activity of Nucleus Pulposus cells exposed and not exposed to pro-inflammatory cytokines
Authors: Baumgartner L. , Witta S. , Noailly J.
Published: August 2024

Background

Intervertebral disc (IVD) degeneration is characterized by a disruption of the balance between anabolic and catabolic cellular processes. Within the Nucleus Pulposus (NP), this involves increased levels of the pro-inflammatory cytokines Interleukin 1beta (IL1B) and Tumor Necrosis Factor (TNF) and an upregulation of the protease families MMP and ADAMTS. Primary inhibitors of those proteases are the tissue inhibitors of matrix metalloproteinases (TIMP). This work aims at contributing to a better understanding of the dynamics among proteases, TIMP and proinflammatory cytokines within the complex, multifactorial environment of the NP.

Methods

The Parallel Network (PN)-Methodology was used to estimate relative mRNA expressions of TIMP1-3, MMP3 and ADAMTS4 for five simulated human activities; walking, sitting, jogging, hiking with 20 kg extra weight, and exposure to high vibration. Simulations were executed for nutrient conditions in non- and early-degenerated IVD approximations. To estimate the impact of cytokines, the PN-Methodology inferred relative protein levels for IL1B and TNF, re-integrated as secondary stimuli into the network.

Results

TIMP1 and TIMP2 expression were found to be overall lower than TIMP3 exp. In absence of pro-inflammatory cytokines, MMP3 and/or ADAMTS4 expression were strongly downregulated in all conditions but vibration and hiking with extra weight. Pro-inflammatory cytokine exposure resulted in an impaired inhibition of MMP3, rather than of ADAMTS4, progressively rising with increasing nutrient deprivation. TNF mRNA was less expressed than IL1B. However, at the protein level, TNF was mainly responsible for the catabolic shift in the simulated pro-inflammatory environment. Overall, results agreed with previous experimental findings.

Conclusions

The PN-Methodology successfully allowed the exploration of the relative dynamics of TIMP and protease regulations in different mechanical, nutritional, and inflammatory environments, in the NP. It shall stand for a comprehensive tool to integrate in vitro model results in IVD research and approximate NP cell activities in complex multifactorial environments.
Phylodynamics beyond neutrality: The impact of incomplete purifying selection on viral phylogenies and inference
Authors: Koelle Katia , Rasmussen David A.
Published: August 2024

Viral phylodynamics focuses on using sequence data to make inferences about the population dynamics of viral infectious diseases. These inferences commonly include estimation of the viral growth rate, the reproduction number, and the time of most recent common ancestor. With few exceptions, existing phylodynamic inference approaches assume that all observed and ancestral viral genetic variation is fitness-neutral. This assumption is violated more often than not, with a large body of analyses indicating that fitness varies substantially among genotypes circulating viral populations. Here, we focus specifically on fitness variation arising from deleterious mutations, asking whether incomplete purifying selection of deleterious mutations has the potential to bias phylodynamic inference. We use simulations of an exponentially growing population to explore how incomplete purifying selection distorts tree shape as well as how it shifts the distribution of non-neutral mutations over trees. Consistent with previous results, we find that incomplete purifying selection strongly shapes the distribution of mutations while only weakly impacting tree shape. Despite incomplete purifying selection shifting the distribution of mutations, we find little discernible bias in estimates of the viral growth rate and times of the most recent common ancestor. Our results reassuringly indicate that existing phylodynamic inference approaches may not yield biased epidemiological parameter estimates in the face of incomplete purifying selection, although more work is needed to assess the generalizability of these findings.