bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between trauma center type and mortality for injured children with severe traumatic brain injury
Authors: Malhotra Armaan K. , Patel Bhavin , Hoeft Christopher J. , Shakil Husain , Smith Christopher W. , Jaffe Rachael , Kulkarni Abhaya V. , Wilson Jefferson R. , Witiw Christopher D. , Nathens Avery B.
Published: August 2023

BACKGROUND

There is conflicting evidence regarding the relationship between trauma center type and mortality for children with traumatic brain injuries. Identification of mortality differences following brain injury across differing trauma center types may result in actionable quality improvement initiatives to standardize care for these children.

METHODS

We used Trauma Quality Improvement Program data from 2017 to 2020 to identify children with severe traumatic brain injury (TBI) managed at levels I and II state or American College of Surgeon–verified trauma centers. We used a random intercept multilevel logistic regression model to assess the relationship between exposure (trauma center type either adult, pediatric, or mixed) and outcome (in-hospital mortality). Several secondary analyses were performed to assess the influence of trauma center volume, age strata, and TBI heterogeneity.

RESULTS

There were 10,105 patients identified across 512 trauma centers. Crude mortality was 25.2%, 36.2%, and 28.9% for pediatric, adult, and mixed trauma centers, respectively. After adjustment for confounders, odds of mortality were higher for children managed at adult trauma centers (odds ratio, 1.67; 95% confidence interval, 1.30–2.13) compared with pediatric trauma centers. There were several patient demographic and injury factors associated with greater odds of death; these included male sex, self-pay insurance status, interfacility transfer, non-fall related inury, age-adjusted hypotension, lack of pupil reactivity and midline shift >5 mm. Adjustment for trauma volume and subgroup analysis using a homogenous TBI subgroup did not change the demonstrated associations.

CONCLUSION

Our results suggest that mortality was higher at adult trauma centers compared with mixed and pediatric trauma centers for children with traumatic brain injuries. Importantly, there exists the potential for unmeasured confounding. We aim for these findings to direct continuing quality improvement initiatives to improve outcomes for brain injured children.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level III.
Tunable morphing of electroactive dielectric-elastomer balloons
Authors: Su Yipin , Riccobelli Davide , Chen Yingjie , Chen Weiqiu , Ciarletta Pasquale
Published: August 2023

Designing smart devices with tunable shapes has important applications in industrial manufacture. In this paper, we investigate the nonlinear deformation and the morphological transitions between buckling, necking and snap-through instabilities of layered dielectric elastomer (DE) balloons in response to an applied radial voltage and an inner pressure. We propose a general mathematical theory of nonlinear electro-elasticity able to account for finite inhomogeneous strains provoked by the electro-mechanical coupling. We investigate the onsets of morphological transitions of the spherically symmetric balloons using the surface impedance matrix method. Moreover, we study the nonlinear evolution of the bifurcated branches through finite-element numerical simulations. Our analysis demonstrates the possibility to design tunable DE spheres, where the onset of buckling and necking can be controlled by geometrical and mechanical properties of the passive elastic layers. Relevant applications include soft robotics and mechanical actuators.
The impact of extreme temperatures on birth outcomes in the Netherlands: a nationwide population-based study
Authors: Burgos Ochoa Lizbeth , Garcia-Gomez Pilar , Steegers Eric AP , Van Ourti Tom , Bertens Loes CM , Been Jasper V
Published: August 2023

Background

Climate projections predict an increased frequency and intensity of extreme weather events, such as extreme temperatures, prompting concerns about their impact on early-life health and health disparities. This study aimed to investigate the causal impact of in-utero exposure to extreme temperatures on birth outcomes and effect heterogeneity across levels of socioeconomic status (SES).

Methods

We obtained data on singleton births that occurred between 2003 and 2017 from the Dutch perinatal registry (N=2 472 352). Exposure was calculated as the number of days during the gestational period in which the mean temperature fell into each of mutually exclusive bins, with the 8–12 °C bin used as reference. To identify a causal effect, we exploited the unpredictability of daily temperature fluctuations while accounting for seasonal and underlying trends. Effect heterogeneity was assessed across levels of household income, neighbourhood SES, and maternal education.

Results

In-utero exposure to an additional hot day (mean temperature > 20 °C), relative to the reference range, led to increased odds of low birth weight (LBW) (OR[95%CI]= 1.007 [1.005, 1.009]), small for gestational age (SGA) (OR[95%CI]= 1.004 [1.003, 1.005]), and preterm birth (PTB) (OR[95%CI]= 1.006 [1.005, 1.007]). Exposure during the second trimester to an additional cold day (< -4 °C) led to increased odds of LBW and PTB. The observed effects were the most detrimental for births in low-SES households.

Conclusions

In-utero exposure to extreme temperature has a detrimental impact on birth outcomes in the Netherlands. Projected increases in extreme temperatures may further exacerbate health disparities in early life.
The collagen metabolism, disrupted endothelium, the endothelial progenitor cells and their microvesicles in acute rheumatic fever
Authors: Ramakrishnan Sivasubramanian , Sahu Parul , Jain Kshama , Bhattacharya Jashdeep , Das Barun , Iyer Srikanth , Shukla Anurag , Balaji Arvind , Gupta Saurabh Kumar , Kothari Shyam S , Saxena Anita , Upadhay Pramod
Published: August 2023

Background

Acute rheumatic fever (ARF) and its chronic sequelae, rheumatic heart disease (RHD) contributes to valvular dysfunction and significant cardiovascular disability and endocardial damage is considered the primary pathophysiological mechanism underlying ARF. This study examined peripheral blood markers of endothelial injury and function in ARF and RHD patients and compared them to healthy controls.

Method

In this prospective observational study, the levels of collagen intermediates, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, brain natriuretic peptide, Anti-DNaseB, VEGF, E-selectin, VCAM, and ICAM in circulation were estimated. The study also isolated hemangioblastic and monocytic endothelial progenitor cells and their respective microvesicles from the peripheral blood of patients and control samples.

Results

Procollagen type I carboxy-terminal propeptide, cross-linked c-telopeptide of type I, and procollagen III c-terminal propeptide levels were higher in RHD subjects compared to patients with ARF. The ARF patients had the highest levels of matrix metalloproteinases 10 (MMP-10) followed by chronic patients and healthy controls. The ratio of tissue inhibitors of matrix metalloproteinases TIMP-1 and MMP-10 was lowest in healthy controls.

At the cellular level, there were higher number of monocytic endothelial progenitor cells (EPCs) in ARF subjects as compared to healthy controls. For hemangioblastic EPCs, there was no significant difference between chronic subjects and healthy controls, though their early subtype was higher in chronic subjects. The hemangioblastic EPCs microvesicles were more abundant in ARF compared to RHD patients.

Conclusion

The greater number of EPCs and respective microvesicles confirm the continued disruption of the endothelium in ARF, and during the progression of the disease, the majority of EPCs undergo apoptosis.

Obituary Statement

This study was conceived and designed by SR, PU, and Prof. Rajnish Juneja, Professor at AIIMS. Prof. Rajnish Juneja expired in April 2018 while the study was ongoing (1).

Mr. Suran Nambisan, a research fellow at NII, was part of the team who initiated the experimental work. Dr. Suran Nambisan expired in January 2023.

This paper is dedicated to both of them. It was the profound love for mankind and unwavering dedication to perfection by Prof. Rajnish Juneja that brought together a remarkable team to undertake this study. Dr. Suran Nambisan embarked on his professional research journey by successfully establishing and standardizing a few intricate protocols used in this study.
Autophagy protein Atg7 is essential and druggable for maintaining malaria parasite cellular homeostasis and organelle biogenesis
Authors: Mishra Akancha , Srivastava Pratik Narain , H Shabeer Ali , Mishra Satish
Published: August 2023

Plasmodiumparasites have a complex life cycle that transitions between mosquito and mammalian hosts and undergoes continuous cellular remodeling to adapt to various drastic environments. Following hepatocyte invasion, the parasite discards superfluous organelles for intracellular replication, and the remnant organelles undergo extensive branching and mature into hepatic merozoites. Autophagy is a ubiquitous eukaryotic process that permits the recycling of intracellular components. Here, we show that theP. bergheiautophagy-related E1-like enzyme Atg7 is expressed in the blood and liver stages, localized to the parasite cytosol and is essential for the localization of Atg8 on the membrane and the development of parasite blood and liver forms. We found that depleting Atg7 abolishes exocytosis of micronemes, organelle biogenesis and the formation of merozoites during liver stage development. Furthermore, we identified the compounds from the Maybridge library with a high docking score againstPfAtg7. We show that these compounds inhibit apicoplast biogenesis and parasite development in both blood and liver stages. Overall, this study establishes the essential functions of autophagy inPlasmodiumblood and liver stages and highlights the potential of using Atg7 as a drug target against malaria.
Noncoding genetic variation in ISPD distinguishes gamecocks from nongame chickens
Authors: Bendesky Andres , Brew Joseph , Francis Kerel X. , Corbetto Enrique F. Tello , Ariza Antonio González , Baena Sergio Nogales , Shimmura Tsuyoshi
Published: August 2023

Chickens were domesticated >4,000 years ago, probably first for fighting them and only later as a source of food. Fighting chickens, commonly known as gamecocks, continue to be bred throughout the world, but the genetic relationships among geographically diverse gamecocks and with nongame chickens are not known. Here, we sequenced the genomes of 44 geographically diverse gamecocks and of 62 nongame chickens representing a variety of breeds. We combined these sequences with published genomes to generate the most diverse chicken genomes dataset yet assembled, at 307 samples. We found that gamecocks do not form a homogeneous group, yet they share genetic similarities that distinguish them from nongame chickens. Such similarities are likely the result of a common origin before their local diversification into, or mixing with, nongame chickens. Particularly noteworthy is a variant in an intron of ISPD, an extreme outlier present at a frequency of 90% in gamecocks but only 4% in nongame chickens. The ISPD locus has the strongest signal of selection in gamecocks, suggesting it is important for fighting performance. Because ISPD variants that are highly prevalent in gamecocks are still segregating in nongame chickens, selective breeding may help reduce its frequency in farm conditions in which aggression is not a desired trait. Altogether, our work provides genomic resources for agricultural genetics, uncovers a common origin for gamecocks from around the world and what distinguishes them genetically from chickens bred for purposes other than fighting, and points to ISPD as the most important locus related to fighting performance.
KDM6A facilitates Xist upregulation at the onset of X inactivation
Authors: Lin Josephine , Zhang Jinli , Ma Li , Fang He , Ma Rui , Groneck Camille , Filippova Galina N. , Deng Xinxian , Ma Wenxiu , Disteche Christine M. , Berletch Joel B.
Published: August 2023

X chromosome inactivation (XCI) is a female-specific process in which one X chromosome is silenced to balance X-linked gene expression between the sexes. XCI is initiated in early development by upregulation of the lncRNAXiston the future inactive X (Xi). A subset of X-linked genes escape silencing and thus have higher expression in females, suggesting female-specific functions. One of these genes is the highly conserved geneKdm6a, which encodes a histone demethylase that removes methyl groups at H3K27 to facilitate gene expression. Here, we investigate the role of KDM6A in the regulation ofXist. We observed impaired upregulation ofXistduring early stages of differentiation in hybrid mouse ES cells following CRISPR/Cas9 knockout ofKdm6a. This is associated with reducedXistRNA coating of the Xi, suggesting diminished XCI potency. Indeed,Kdm6aknockout results in aberrant overexpression of genes from the Xi after differentiation. KDM6A binds to theXistpromoter and knockout cells show an increase in H3K27me3 atXist. These results indicate that KDM6A plays a role in the initiation of XCI through histone demethylase-dependent activation ofXistduring early differentiation.
Multi-Site Statistical Mapping of Along-Tract Microstructural Abnormalities in Bipolar Disorder with Diffusion MRI Tractometry
Authors: Nabulsi Leila , Chandio Bramsh Q. , McPhilemy Genevieve , Martyn Fiona M. , Roberts Gloria , Hallahan Brian , Dannlowski Udo , Kircher Tilo , Haarman Benno , Mitchell Philip , McDonald Colm , Cannon Dara M. , Andreassen Ole A. , Ching Christopher R. K. , Thompson Paul M.
Published: August 2023

Investigating alterations in brain circuitry associated with bipolar disorder (BD) may offer a valuable approach to discover brain biomarkers for genetic and interventional studies of the disorder and related mental illnesses. Some diffusion MRI studies report evidence of microstructural abnormalities in white matter regions of interest, but we lack a fine-scale spatial mapping of brain microstructural differences along tracts in BD. We also lack large-scale studies that integrate tractometry data from multiple sites, as larger datasets can greatly enhance power to detect subtle effects and assess whether effects replicate across larger international datasets. In this multisite diffusion MRI study, we used BUndle ANalytics (BUAN, Chandio 2020), a recently developed analytic approach for tractography, to extract, map, and visualize profiles of microstructural abnormalities on 3D models of fiber tracts in 148 participants with BD and 259 healthy controls from 6 independent scan sites. Modeling site differences as random effects, we investigated along-tract white matter (WM) microstructural differences between diagnostic groups. QQ plots showed that group differences were gradually enhanced as more sites were added. Using the BUAN pipeline, BD was associated with lower mean fractional anisotropy (FA) in fronto-limbic, interhemispheric, and posterior pathways; higher FA was also noted in posterior bundles, relative to controls. By integrating tractography and anatomical information, BUAN effectively captures unique effects along white matter (WM) tracts, providing valuable insights into anatomical variations that may assist in the classification of diseases.
Prenatal environment is associated with the pace of cortical network development over the first three years of life
Authors: Tooley Ursula A. , Latham Aidan , Kenley Jeanette K. , Alexopoulos Dimitrios , Smyser Tara , Warner Barbara B. , Shimony Joshua S. , Neil Jeffrey J. , Luby Joan L. , Barch Deanna M. , Rogers Cynthia E. , Smyser Chris D.
Published: August 2023

Environmental influences on brain structure and function during early development have been well-characterized. In pre-registered analyses, we test the theory that socioeconomic status (SES) is associated with differences in trajectories of intrinsic brain network development from birth to three years (n= 261). Prenatal SES is associated with developmental increases in cortical network segregation, with neonates and toddlers from lower-SES backgrounds showing a steeper increase in cortical network segregation with age, consistent with accelerated network development. Associations between SES and cortical network segregation occur at the local scale and conform to a sensorimotor-association hierarchy of cortical organization. SES-associated differences in cortical network segregation are associated with language abilities at two years, such that lower segregation is associated with improved language abilities. These results yield key insight into the timing and directionality of associations between the early environment and trajectories of cortical development.
Anomalous networks under the multispecies coalescent: theory and prevalence
Authors: Ané Cécile , Fogg John , Allman Elizabeth S. , Baños Hector , Rhodes John A.
Published: August 2023

Abstract

Reticulations in a phylogenetic network represent processes such as gene flow, admixture, recombination and hybrid speciation. Extending definitions from the tree setting, ananomalousnetwork is one in which some unrooted tree topology displayed in the network appears in gene trees with a lower frequency than a tree not displayed in the network. We investigate anomalous networks under the Network Multispecies Coalescent Model with possible correlated inheritance at reticulations. Focusing on subsets of 4 taxa, we describe a new algorithm to calculate quartet concordance factors on networks of any level, faster than previous algorithms because of its focus on 4 taxa. We then study topological properties required for a 4-taxon network to be anomalous, uncovering the key role of 32-cycles: cycles of 3 edges parent to a sister group of 2 taxa. Under the model of common inheritance, that is, when each gene tree coalesces within a species tree displayed in the network, we prove that 4-taxon networks are never anomalous. Under independent and various levels of correlated inheritance, we use simulations under realistic parameters to quantify the prevalence of anomalous 4-taxon networks, finding that truly anomalous networks are rare. At the same time, however, we find a significant fraction of networks close enough to the anomaly zone to appear anomalous, when considering the quartet concordance factors observed from a few hundred genes. These apparent anomalies may challenge network inference methods.
Capturing dynamic fear experiences in naturalistic contexts: An ecologically valid fMRI signature integrating brain activation and connectivity
Authors: Zhou Feng , Zhang Ran , Yao Shuxia , Dong Debo , Feng Pan , Kranz Georg , Feng Tingyong , Becker Benjamin
Published: August 2023

Enhancing our understanding of how the brain constructs conscious emotional experiences within dynamic real-life contexts necessitates ecologically valid neural models. Here, we present evidence delineating the constraints of current fMRI activation models in capturing naturalistic fear dynamics. To address this challenge, we fuse naturalistic fMRI with predictive modeling techniques to develop an ecologically valid fear signature that integrates activation and connectivity profiles, allowing for accurate prediction of subjective fear experience under highly dynamic close-to-real-life conditions. This signature arises from insights into the crucial role of distributed brain networks and their interactions in emotion modulation, and the potential of network-level information to improve predictions in dynamic contexts. Across a series of investigations, we demonstrate that this signature predicts stable and dynamic fear experiences across naturalistic scenarios with heightened sensitivity and specificity, surpassing traditional activation- and connectivity-based signatures. Notably, the integration of affective connectivity profiles enables precise real-time predictions of fear fluctuations in naturalistic settings. Additionally, we unearth a distributed yet redundant brain-wide representation of fear experiences. Subjective fear is encoded not only by distributed cortical and subcortical regions but also by their interactions, with no single brain system conveying substantial unique information. Our study establishes a comprehensive and ecologically valid functional brain architecture for subjective fear in dynamic environments and bridges the gap between experimental neuroscience and real-life emotional experience.
Two determinants of dynamic adaptive learning for magnitudes and probabilities
Authors: Foucault Cedric , Meyniel Florent
Published: August 2023

Humans face a dynamic world that requires them to constantly update their knowledge. Each observation should influence their knowledge to a varying degree depending on whether it arises from a stochastic fluctuation or an environmental change. Thus, humans should dynamically adapt their learning rate based on each observation. Although crucial for characterizing the learning process, these dynamic adjustments have only been investigated empirically in magnitude learning. Another important type of learning is probability learning. The latter differs from the former in that individual observations are much less informative and a single one is insufficient to distinguish environmental changes from stochasticity. Do humans dynamically adapt their learning rate for probabilities? What determinants drive their dynamic adjustments in magnitude and probability learning? To answer these questions, we measured the subjects’ learning rate dynamics directly through real-time continuous reports during magnitude and probability learning. We found that subjects dynamically adapt their learning rate in both types of learning. After a change point, they increase their learning rate suddenly for magnitudes and prolongedly for probabilities. Their dynamics are driven differentially by two determinants: change-point probability, the main determinant for magnitudes, and prior uncertainty, the main determinant for probabilities. These results are fully in line with normative theory, both qualitatively and quantitatively. Overall, our findings demonstrate a remarkable human ability for dynamic adaptive learning under uncertainty, and guide studies of the neural mechanisms of learning, highlighting different determinants for magnitudes and probabilities.

Significance statement

In a dynamic world, we must constantly update our knowledge based on the observations we make. However, how much should we update our knowledge after each observation? Here, we have demonstrated two principles in humans that govern their updating and by which they are capable of dynamic adaptive learning. The first principle is that when they observe a highly surprising event indicating a likely change in the environment, humans reset their knowledge and perform one-shot learning. The second principle is that when their knowledge is more uncertain, humans update it more quickly. We further found that these two principles are differentially called upon in two key learning contexts that could be associated with different brain mechanisms: magnitude learning (which primarily requires adaptation to surprise, under the first principle) and probability learning (which primarily requires adaptation to uncertainty, under the second principle). Our findings advance understanding of the mechanisms of human learning, with implications for the brain and the development of adaptive machines.
Genetic and brain similarity independently predict childhood anthropometrics and socioeconomic markers
Authors: Dahl Andreas , Eilertsen Espen M. , Rodriguez-Cabello Sara F. , Norbom Linn B. , Tandberg Anneli D. , Leonardsen Esten , Lee Sang Hong , Ystrom Eivind , Tamnes Christian K. , Alnæs Dag , Westlye Lars T.
Published: August 2023

Linking the developing brain with individual differences in clinical and demographic traits is challenging due to the substantial interindividual heterogeneity of brain anatomy and organization. Here we employ a novel approach that parses individual differences in both cortical thickness and common genetic variants, and assess their effects on a wide set of childhood traits. The approach uses a linear mixed model framework to obtain the unique effects of each type of similarity, as well as their covariance, with the assumption that similarity in cortical thickness may in part be driven by similarity in genetic variants. We employ this approach in a sample of 7760 unrelated children in the ABCD cohort baseline sample (mean age 9.9, 46.8% female). In general, significant associations between cortical thickness similarity and traits were limited to anthropometrics such as height (r2= 0.11, SE = 0.01), weight (r2= 0.12, SE = 0.01), and birth weight (r2= 0.19, SE = 0.01), as well as markers of socioeconomic status such as local area deprivation (r2= 0.06, SE = 0.01). Analyses of the contribution from common genetic variants to traits revealed contributions across included outcomes, albeit somewhat lower than previous reports, possibly due to the young age of the sample. No significant covariance of the effects of genetic and cortical thickness similarity was found. The present findings highlight the connection between anthropometrics as well as socioeconomic factors and the developing brain, which appear to be independent from individual differences in common genetic variants in this population-based sample. The approach provides a promising framework for analyses of neuroimaging genetics cohorts, which can be further expanded by including imaging derived phenotypes beyond cortical thickness.
The Significance and Limited Influence of Cerebrovascular Reactivity on Age and Sex Effects in Task- and Resting-State Brain Activity
Authors: Chen Donna Y. , Di Xin , Yu Xin , Biswal Bharat B.
Published: August 2023

Functional MRI (fMRI) measures the blood-oxygen-level dependent (BOLD) signals, which provide an indirect measure of neural activity mediated by neurovascular responses. Cerebrovascular reactivity affects both task-induced and resting-state BOLD activity and may confound inter-individual effects observed in BOLD-based measures, such as those related to aging and biological sex. To investigate this, we examined a large open-access fMRI dataset containing a breath-holding task, checkerboard task, and resting-state scans. We used the breath-holding task to measure cerebrovascular reactivity, used the checkerboard task to obtain task-based activations, and from the resting-state data, we quantified the resting-state amplitude of low-frequency fluctuations (ALFF), and resting-state regional homogeneity (ReHo). We hypothesized that cerebrovascular reactivity would be correlated with BOLD measures and that accounting for these correlations would result in better estimates of age and sex effects. Our analysis showed that cerebrovascular reactivity was correlated with checkerboard task activations in the visual cortex and with ALFF and ReHo in widespread fronto-parietal regions, as well as regions with large vessels. We also found significant age and sex effects in cerebrovascular reactivity, some of which overlapped with those observed in ALFF and ReHo scores. Finally, we demonstrated that correcting for the effects of cerebrovascular reactivity had very limited influence on the estimates of age and sex. Our results highlight the limitations of accounting for cerebrovascular reactivity with the current breath-holding task.
Multiplex imaging of localized prostate tumors reveals changes in mast cell type composition and spatial organization of AR-positive cells in the tumor microenvironment
Authors: Ak Cigdem , Sayar Zeynep , Thibault Guillaume , Burlingame Erik A. , Eng Jennifer , Chitsazan Alex , Adey Andrew C. , Boniface Christopher , Spellman Paul T. , Thomas George V. , Kopp Ryan P. , Demir Emek , Chang Young Hwan , Stavrinides Vasilis , Eksi Sebnem Ece
Published: August 2023

Mapping spatial interactions of cancer, immune and stromal cells present novel opportunities for patient stratification and for advancing immunotherapy. While single-cell studies revealed significant molecular heterogeneity in prostate tumors, there is currently no understanding of how immune cell heterogeneity impacts spatial coordination between tumor and stromal cells in localized tumors. Here, we used cyclic immunofluorescent imaging on whole-tissue sections to uncover novel spatial associations between cancer and stromal cells in low- and high-grade prostate tumors and tumor-adjacent normal tissues. Our results provide a spatial map of 699,461 single-cells that show epigenetic and molecular differences in distinct clinical grades. We report unique populations of mast cells that differentially express CD44, CD90 and Granzyme B (GZMB) and demonstrate GZMB+ mast cells are spatially associated with M2 macrophages in prostate tumors. Finally, we uncover recurrent neighborhoods that are primarily driven by androgen receptor positive (AR+) stromal cells and identify transcriptional networks active in AR+ prostate stroma.
Allergen-induced airway matrix remodelling in mice can be prevented or reversed by targeting chitinase-like proteins
Authors: Parkinson James E , Adamson Antony , MacDonald Andrew S , Allen Judith E , Sutherland Tara E
Published: August 2023

Chitinase-like proteins (CLPs) are biomarkers of inflammation and airway remodelling in asthma, yet their direct contribution towards disease pathogenesis is unknown. Using a mouse model of allergen-induced type 2/type 17 airway inflammation we sought to directly investigate the role of the murine CLPs Ym1 and Ym2 during chronic lung pathology. Data demonstrated distinct chronic inflammatory roles for Ym2, IL-13, and IL-17a signalling pathways. Notably, only CLPs were key for initiating the pathogenic accumulation and re-organisation of the pulmonary extracellular matrix (ECM) environment. Furthermore, inhibition of CLPs after chronic pathology developed, reversed airway remodelling independently of chronic inflammation. These studies disentangle chronic IL-13 and IL-17a signalling from the development of allergic airway remodelling and instead highlight a central role for CLPs, which provides new avenues to therapeutically target aberrant ECM accumulation.
Digging deeper into pain – an ethological behavior assay correlating well-being in mice with human pain experience
Authors: Pattison Luke A. , Cloake Alexander , Chakrabarti Sampurna , Hilton Helen , Rickman Rebecca H. , Higham James P. , Meng Michelle Y. , Paine Luke W. , Dannawi Maya , Qiu Lanhui , Ritoux Anne , Bulmer David C. , Callejo Gerard , Smith Ewan St. John
Published: August 2023

The pressing need for safer, more efficacious analgesics is felt worldwide. Pre-clinical tests in animal models of painful conditions represent one of the earliest checkpoints novel therapeutics must negotiate before consideration for human use. Traditionally, the pain status of laboratory animals has been inferred from evoked nociceptive assays which measure their responses to noxious stimuli. The disconnect between how pain is tested in laboratory animals and how it is experienced by humans may in part explain the shortcomings of current pain medications and highlights a need for refinement. Here, we survey human chronic pain patients who assert that everyday aspects of life, such as cleaning and leaving the house, are affected by their on-going level of pain. Accordingly, we test the impact of painful conditions on an ethological behavior of mice, digging. Stable digging behavior was observed over time in naïve mice of both sexes. By contrast, deficits in digging were seen following acute knee inflammation. The analgesia conferred by meloxicam and gabapentin was compared in the monosodium iodoacetate knee osteoarthritis model, meloxicam more effectively ameliorating digging deficits, in line with human patients finding meloxicam more effective. Lastly, in a visceral pain model, the decrease in digging behavior correlated with the extent of disease. Ultimately, we make a case for adopting ethological assays, such as digging, in studies of pain in laboratory animals, which we believe to be more representative of the human experience of pain and thus valuable in assessing clinical potential of novel analgesics in animals.
Cholinergic interneurons in the dorsal striatum play an important role in the acquisition of duration memory
Authors: Nishioka Masahiko , Hata Toshimichi
Published: August 2023

Although the formation of duration memory is important to optimize the timing of behavior based on previous experiences, the neural mechanism of formation remains unclear. A previous study suggested that muscarinic acetylcholine 1 receptors (M1Rs) in the dorsal striatum of rats are involved in the consolidation of duration memory in interval timing. Therefore, cholinergic interneurons (ChIs) may also be involved in the formation of duration memory in interval timing because ChIs activate M1Rs in the dorsal striatum. In the Exp. 1A, rats underwent a peak interval (PI)-20 s training. During the training, two different trials were randomly presented. One was a food trial in which the initial lever press was reinforced 20 s after the start of the trial (i.e., fixed interval (FI), 20 s). The other was an empty trial in which the reinforcement did not occur for 80 s. After sufficient training, the rats responded at approximately 20 s in the empty trials. They were then subjected to a PI-40 s training (i.e., FI, 40 s) after ChI lesions were present in the dorsal striatum. In this training, the sham-lesioned group responded frequently at approximately 40 s, whereas the ChI-lesioned group responded at approximately 20 s. As the PI-40 s additional learning progressed in the Exp. 1B, the ChI-lesioned group frequently responded at approximately 40 s, similar to that of the sham-lesioned group. In the following PI-20 s re-shift training, the ChI-lesioned group responded similar to the sham-lesioned group. In Exp. 2 of another cohort, the results of a PI-20 s training after the occurrence of ChI lesions were similar to that before the presence of the lesion. Together, these results suggest that ChI lesions delayed only the acquisition of new duration memory, but had no effect on the adjustment of behavior associated with changing the reinforcement schedule of the PI-training and interval timing itself.
Efflux pump mutations inPseudomonas aeruginosacause low-level clinical resistance and high-level tolerance to antibiotics in patients
Authors: Laborda Pablo , Lolle Signe , Hernando-Amado Sara , Alcalde-Rico Manuel , Martínez José Luis , Molin Søren , Johansen Helle Krogh
Published: August 2023

Pseudomonas aeruginosais one of the microorganisms with high-risk regarding antimicrobial resistance, since it has an overwhelming capacity to acquire antibiotic resistance, mainly by mutations during persistent lung infections. Mutations inmexZ, encoding the local negative regulator of genes encoding the MexXY efflux pump, are very frequently acquired at early stages ofP. aeruginosainfections, while they are rarely selected forin vitro. Although traditionally related to resistance to the first-line drug tobramycin, caused by the overproduction of the aminoglycosides MexXY efflux pump, mutations inmexZare actually associated with low levels of aminoglycosides resistance when determined in the clinical microbiology laboratory. This very moderate but frequent phenotype suggests that these mutations may shape the infection process, beyond causing conventional resistance. Here we investigated the colonization strategy of amexZmutant, compared to a wild-type strain, in a human airway infection model. We observed that themexZmutant tends to accumulate inside the epithelial cell layer. This behaviour allows bacteria to colonise the epithelium while being more protected against diverse antibiotics. The altered colonization phenotype was caused by the overexpression oflecA, a Quorum Sensing regulated gene encoding a lectin involved inP. aeruginosatissue invasiveness.lecAupregulation was underlied by the competition for the shared porin, OprM, between the overproduced MexXY and the MexAB efflux pump, responsible for extruding Quorum Sensing molecules. These findings suggest that standardised antimicrobial susceptibility determined in the clinic may be misleading because antibiotic resistance often depends on the infection environment.
Coupling mountain pine beetle and forest population dynamics predicts transient outbreaks that are likely to increase in number with climate change
Authors: Brush Micah , Lewis Mark A.
Published: August 2023

Mountain pine beetle (MPB) in Canada have spread well beyond their historical range. Accurate modelling of the long-term dynamics of MPB is critical for assessing the risk of further expansion and informing management strategies, particularly in the context of climate change and variable forest resilience. Most previous models have focused on capturing a single outbreak without tree replacement. While these models are useful for understanding MPB biology and outbreak dynamics, they cannot accurately model long-term forest dynamics. Past models that incorporate forest growth tend to simplify beetle dynamics. We present a new model that couples forest growth to MPB population dynamics and accurately captures key aspects of MPB biology, including a threshold for the number of beetles needed to overcome tree defenses and beetle aggregation that facilitates mass attacks. These mechanisms lead to a demographic Allee effect, which is known to be important in beetle population dynamics. We show that as forest resilience decreases, a fold bifurcation emerges and there is a stable fixed point with a non-zero MPB population. We derive conditions for the existence of this equilibrium. We then simulate biologically relevant scenarios and show that the beetle population approaches this equilibrium with transient boom and bust cycles with period related to the time of forest recovery. As forest resilience decreases, the Allee threshold also decreases. Thus, if host resilience decreases under climate change, for example under increased stress from drought, then the lower Allee threshold makes transient outbreaks more likely to occur in the future.

Statements and Declarations

Competing interests

The authors declare no competing interests.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. Code to produce the figures is available atgithub.com/micbru/MPBModel/.
Identifying predictors and determining mortality rates of septic cardiomyopathy and sepsis-related cardiogenic shock: A retrospective, observational study
Authors: Hendrickson Kathryn W. , Cirulis Meghan M. , Burk Rebecca E. , Lanspa Michael J , Peltan Ithan D. , Marshall Hunter , Groat Danielle , Jephson Al , Beesley Sarah J. , Brown Samuel M.
Published: August 2023

Introduction

Septic shock is a severe form of sepsis that has a high mortality rate, and a substantial proportion of these patients will develop cardiac dysfunction, often termed septic cardiomyopathy (SCM). Some SCM patients may develop frank cardiac failure, termed sepsis-related cardiogenic shock (SeRCS). Little is known of SeRCS. This study describes baseline characteristics of patients with SCM and SeRCS compared to patients with septic shock without cardiac dysfunction. We compare clinical outcomes among SCM, SeRCS, and septic shock, and identify risk factors for the development of SCM and SeRCS.

Methods

Septic patients admitted to the ICU with an echocardiogram obtained within 72 hours were included. Left ventricular ejection fraction of ≤55% was used to define SCM, and cardiac index ≤2.1 L/min/m2 among patients with SCM defined SeRCS. Machine learning was used to identify risk factors for development of SCM and SeRCS. Logistic regression was used to compare mortality among groups.

Results

Among 1229 patients, 977 patients had septic shock without cardiac dysfunction, 207 had SCM, and 45 had SeRCS. In patients with septic shock, the strongest predictor for developing SCM and SeRCs was a prior history of cardiac dysfunction. Mortality did not significantly differ among the three groups.

Conclusions

SCM and SeRCS affect a minority of patients with septic shock, disproportionately affecting individuals with a history of cardiac disease. We did not identify a mortality difference associated with SCM or SeRCS. Additional work is needed to define further subtypes and treatment options for this patient population.
Common drugs alter microbial protein expression, but not composition in fecal cultures from Crohn’s disease patients
Authors: Becker Heike E.F. , Mohren Ronny , Le N. Giang , Derijks Luc J.J. , Jonkers Daisy M.A.E. , Penders John
Published: August 2023

Introduction

A substantial number of Crohn’s disease (CD) patients experience side-effects and/or non-response to medical drugs. In part, this might be attributed to the interaction of the intestinal microbiome with xenobiotics. The aim of this study was to explore the effect of common CD drugs on the patient’s microbiomein vitro.

Methods

The fecal microbiome of each of 5 CD patients was exposed to 42 μg/ml budesonide, 55 μg/ml 6-mercaptopurine (6-MP), 5 or 15 μg/ml tofacitinib, or DMSO-control in defined culture medium in an anaerobic chamber at 37°C for 24 hours. Subsequently, DNA and proteins were isolated and subjected to 16 rRNA gene amplicon sequencing and LC-MS proteomic analysis, respectively.

Results

Metagenomic and metaproteomic analyses revealed larger differences between donors than between drug exposures. Exposure to 6-MP and tofacitinib resulted in a significant alteration in the metaproteome when compared to the control condition, whereas no effect could be observed for budesonide. Applying a stringent selection, 33 proteins were more abundant and 93 less abundant in all 6-MP cultures and could thereby discriminate clearly between 6-MP and control. In contrast to metaproteomic analyses, metagenomic analyses only detected a lower relative abundance ofColidextribacterin 15 μg/ml tofacitinib cultures, but not in overall richness, diversity or community structure.

Conclusion

Tofacitinib and especially 6-MP clearly affect microbial function, but barely microbial compositionin vitro. These drug-induced functional changes may subsequently influence host physiology and potentially inflammation in CD. Our findings emphasize the relevance to include functional microbial studies when investigating drug-microbiota interactions. Further research needs to elucidate the impact of 6-MP-induced microbial alterations on intestinal physiology and inflammation in CD.
Polypyrimidine Tract-Binding Protein 1 and hnRNP A1 recognize unique features of the Sm site in U7 snRNA
Authors: Yang Xiao-cui , Dominski Zbigniew
Published: August 2023

U7 snRNA is a 60-nucleotide component of U7 snRNP, a multi-subunit endonuclease that cleaves precursors of metazoan replication-dependent histone mRNAs at the 3’ end, hence generating mature histone mRNAs. The Sm site in U7 snRNA differs from the Sm site in spliceosomal snRNAs and promotes the assembly of a unique Sm ring containing Lsm10 and Lsm11 instead of SmD1 and SmD2 found in the spliceosomal snRNPs. The assembly of the spliceosomal Sm ring depends on the SMN complex, with one of its nine subunits, Gemin5, recognizing the spliceosomal Sm site. While the assembly of the U7-specific Sm ring also requires the SMN complex, the unusual Sm site of U7 snRNA is not recognized by Gemin5, and the identity of its counterpart that performs this function in biogenesis of U7 snRNP, has not been determined. Here, we looked for proteins that bind U7 snRNA but not to its mutant altered within the Sm site. We identified Polypyrimidine Tract-Binding Protein 1 (PTBP1) as the main protein that meets this specificity. Binding of PTBP1 to U7 snRNA also depends on the upstream CUCUUU motif that base pairs with histone pre-mRNAs and defines substrate specificity of U7 snRNP. Thus, PTBP1 simultaneously recognizes two functionally essential and highly conserved sites within U7 snRNA. In addition to PTBP1, U7 snRNA interacts with hnRNP A1, which recognizes a different part of the U7-specific Sm site. Interestingly, the two proteins can form with U7 snRNA a larger complex, which also contains SMN protein, a subunit of the SMN complex. Altogether, these results raise the possibility that PTBP1 and hnRNP A1 act collectively to substitute for Gemin5 in the assembly of U7-specific Sm ring.
Mining alternative splicing patterns in scRNA-seq data using scASfind
Authors: Song Yuyao , Parada Guillermo , Lee Jimmy Tsz Hang , Hemberg Martin
Published: August 2023

Single-cell RNA-seq is widely used for transcriptome profiling, but most analyses have focused on gene-level events, with much less attention devoted to alternative splicing. Here, we present scASfind, a novel computational method to allow for quantitative analysis of cell type-specific splicing events. scASfind utilizes an efficient data structure to store the percent spliced-in value for each splicing event. This makes it possible to exhaustively search for patterns among all differential splicing events, allowing us to identify marker events, mutually exclusive events, and large blocks of exons that are specific to one or more cell types. These methods allow researchers to compare cells based on isoforms rather than genes, thereby enabling more nuanced characterization of cell types and states. We demonstrate the advantages of scASfind on two mouse and one human datasets, identifying differences across the several key genes that cannot be detected using gene expression alone.
Combined Mek inhibition andPpargactivation Eradicates Muscle Invasive Bladder cancer in a Mouse Model of BBN-induced Carcinogenesis
Authors: Tate Tiffany , Plumber Sakina A , Al-Ahmadie Hikmat , Chen Xiao , Choi Woonyoung , Lu Chao , Viny Aaron , Batourina Ekatherina , Gartensson Krisjian , Alija Besmira , Molotkov Andrei , Wiessner Gregory , McKiernan James , McConkey David , Dinney Colin , Czerniak Bogdan , Mendelsohn Cathy Lee
Published: August 2023

Bladder cancers (BCs) can be divided into 2 major subgroups displaying distinct clinical behaviors and mutational profiles: basal/squamous (BASQ) tumors that tend to be muscle invasive, and luminal/papillary (LP) tumors that are exophytic and tend to be non-invasive.Ppargis a likely driver of LP BC and has been suggested to act as a tumor suppressor in BASQ tumors, where it is likely suppressed by MEK-dependent phosphorylation. Here we tested the effects of rosiglitazone, aPpargagonist, in a mouse model of BBN-induced muscle invasive BC. Rosiglitazone activatedPpargsignaling in suprabasal epithelial layers of tumors but not in basal-most layers containing highly proliferative invasive cells, reducing proliferation but not affecting tumor survival. Addition of trametinib, a MEK inhibitor, inducedPpargsignaling throughout all tumor layers, and eradicated 91% of tumors within 7-days of treatment. The 2-drug combination also activated a luminal differentiation program, reversing squamous metaplasia in the urothelium of tumor-bearing mice. Paired ATAC-RNA-seq analysis revealed that tumor apoptosis was most likely linked to down-regulation of Bcl-2 and other pro-survival genes, while the shift from BASQ to luminal differentiation was associated with activation of the retinoic acid pathway and upregulation of Kdm6a, a lysine demethylase that facilitates retinoid-signaling. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients. That muscle invasive tumors are populated by basal and suprabasal cell types with different responsiveness toPPARGagonists will be an important consideration when designing new treatments.