bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional Differences in the US in Outcomes with Preeclampsia
Authors: Rajendran Aardra , Liu Yisi , Boyer Theresa M. , Vaught Arthur J. , Hays Allison G. , Coresh Josef , Vaidya Dhananjay , Michos Erin D. , Minhas Anum S.
Published: May 2024

This study explores preeclampsia outcomes across US regions and examines regional differences in specific preeclampsia-associated pregnancy complications and disease management. Patient-reported measures were obtained from The Preeclampsia Registry, an open-access database composed of women with at least one pregnancy diagnosed with a hypertensive disorder of pregnancy. Pregnancies and associated outcomes were stratified by US region (Northeast, Midwest, South and West). Among 2,667 pregnancies of which 92% were in White women, maximum systolic blood pressure at any time in pregnancy was highest among women in the South and Midwest (p=0.039). Furthermore, more women in the South received pre-pregnancy anti- hypertensives (p=0.026) and antenatal steroids (p=0.025) and delivered at an earlier gestational age (p=0.014) compared to women in other regions. Pregnancy complications such as elevated liver enzymes were higher in women in the South (p=0.019), and women in the South and West had additional end-organ damage such as renal complications (p<0.001) and hemolysis (p=0.008) as compared to women in other regions. Further investigation is needed to assess whether healthcare access or policy could be contributing to these regional discrepancies.
The Digital Health Revolution: Exploring the Impact of Online Cancer Information on Self-Reported Preventive Behaviors
Authors: Yavari Bryan , Kolbehdari Nilofar , Gann Lindsay , Portillo Mercedes , Rumschlag Alexandria , Aldridge Melanie , Mellon Walker , Marquez Alcaraz Gissel , Richker Harley , Sarkissian Mané , Compton Zachary T. , Aktipis Athena , Maley Carlo , Baciu Cristina
Published: May 2024

Cancer, one of the leading causes of death worldwide, is a disease characterized by uncontrolled cell growth within the body. While there have been many improvements in the treatment of cancer clinically, there is now an urgent need to improve cancer-related communication. This study explores the impact of online health information, specifically cancer-related information and prevention, among members of the general public. Through a randomized survey, we examined what information leads people to take action to minimize their cancer risk and communicate with their providers. Through evaluation of the various modes of communication, we were able to provide insight into which are more effective and better received by members of the general public. Through this, ways of bettering these avenues of communication and strengthening the bond between them will be highlighted and more easily elaborated on by future studies. The results of our study indicated that 60% of participants asserted that they are motivated by online preventive information to take steps to limit their cancer risk, while only roughly 44% of participants overall agreed that their doctor has communicated with them about when proper cancer screenings should be scheduled for the future. Although patients may be turning to the Internet now more than ever due to various reasons, when comparing self-reported rates of comprehension among the study participants, 35% agreed that the cancer-related information they can access online is confusing, while fewer than 22% of participants agreed that the cancer-related information they receive directly from their doctor is confusing. This is indicative of the limitations the Internet may have when undertaking the role of being a medical resource, especially when acting as a replacement for in-person medical appointments where patients can communicate directly with their physicians. Ultimately, these results provide a unique perspective into how people receive, evaluate, and implement cancer-preventive steps and general health-related information in a post-COVID-19 world, where the Internet is now strongly embedded in healthcare.
The textures of sarcoidosis: quantifying lung disease through variograms
Authors: Lippitt William L. , Maier Lisa A. , Fingerlin Tasha E. , Lynch David A. , Yadav Ruchi , Rieck Jared , Hill Andrew C. , Liao Shu-Yi , Mroz Margaret M. , Barkes Briana Q. , Chae Kum Ju , Hwang Hye Jeon , Carlson Nichole E.
Published: May 2024

Objective

Sarcoidosis is a granulomatous disease affecting the lungs in over 90% of patients. Qualitative assessment of chest CT by radiologists is standard clinical practice and reliable quantification of disease from CT would support ongoing efforts to identify sarcoidosis phenotypes. Standard imaging feature engineering techniques such as radiomics suffer from extreme sensitivity to image acquisition and processing, potentially impeding generalizability of research to clinical populations. In this work, we instead investigate approaches to engineering variogram-based features with the intent to identify a robust, generalizable pipeline for image quantification in the study of sarcoidosis.

Approach

For a cohort of more than 300 individuals with sarcoidosis, we investigated 24 feature engineering pipelines differing by decisions for image registration to a template lung, empirical and model variogram estimation methods, and feature harmonization for CT scanner model, and subsequently 48 sets of phenotypes produced through unsupervised clustering. We then assessed sensitivity of engineered features, phenotypes produced through unsupervised clustering, and sarcoidosis disease signal strength to pipeline.

Main results

We found that variogram features had low to mild association with scanner model and associations were reduced by image registration. For each feature type, features were also typically robust to all pipeline decisions except image registration. Strength of disease signal as measured by association with pulmonary function testing and some radiologist visual assessments was strong (optimistic AUC ≈ 0.9,p≪ 0.0001 in models for architectural distortion, conglomerate mass, fibrotic abnormality, and traction bronchiectasis) and fairly consistent across engineering approaches regardless of registration and harmonization for CT scanner.

Significance

Variogram-based features appear to be a suitable approach to image quantification in support of generalizable research in pulmonary sarcoidosis.
Combining clinical and diagnostic surveillance to estimate the burden of measles disease: a modeling study
Authors: Leung Tiffany , Ferrari Matthew
Published: May 2024

Background

The clinical case definition for measles is highly sensitive and has low specificity. Diag-nostic confirmation can resolve this uncertainty for individual cases and is a crucial tool for confirmation of measles outbreaks. However, in under-resourced settings, it is prohibitive to confirm all suspected cases and routine measles surveillance comprises a combination of both clinically and diagnostically confirmed cases.

Methods

We developed a dynamic model of measles, rubella, and other sources of febrile rash to simulate time series of a suspected measles surveillance system. We simulated partial reporting of suspected cases and limited routine diagnostic testing using assays with sensitivity and specificity that correspond to current or proposed rapid diagnostic tests. We estimated the time series of reported measles cases as the product of suspected cases and the proportion of diagnostic positive cases. We then estimated the reporting rate and annual incidence for measles using the time-series SIR model.

Results

Reconstructing the time series of reported measles cases using the fraction of diagnostic positive cases results in unbiased estimates of the reporting rate and the annual incidence at moderate vaccination levels for all reasonable levels of test sensitivity and specificity, even for low proportions tested. At high vaccination levels, diagnostic tests with low sensitivity (<90%) lead to slight bias in annual incidence. Temporal variation in the prevalence of measles among suspected cases require that the proportion of cases attributable to measles be estimated frequently (i.e., monthly) to avoid bias in estimates.

Conclusion

Combining routine, systematic diagnostic confirmation of suspected measles cases with suspected cases surveillance can improve estimates of the reporting rate and annual incidence using diagnostic tests with sensitivity and specificity consistent with proposed rapid diagnostic tests.
Clinical and genetic association studies reveal within-individual variability as an integral part of Huntington disease
Authors: Aziz N. Ahmad
Published: May 2024

Huntington disease (HD) is one of the most common repeat expansion disorders. Clinically, HD patients exhibit considerable visit-to-visit variability in symptoms and signs independent of measuring method or rater, yet neither the precise nature nor the determinants of this clinical variability are known. Leveraging detailed genetic and longitudinal clinical data from large cohorts of HD patients, this work1)establishes within-individual variability in disease expression as an integral part of HD semiology, demonstrating that it increases with disease duration, mutation size, younger age-at-onset, and lower body weight,2)provides a mathematical framework linking higher phenotypic variability to increased predictive entropy, revealing a fundamental relation between within-individual variability and energy expenditure, and3)identifies novel genetic modifiers of both within-individual variability and age-at-onset in HD. Thus, accounting for within-individual variability in HD could facilitate the discovery of pathogenic mechanisms and outcomes directly relevant to the development of disease modifying therapies.
The nitrogen-fixing fernAzollahas a complex microbiome characterized by multiple modes of transmission
Authors: Song Michael J. , Li Fay-Wei , Freund Forrest , Tribble Carrie M. , Toffelmier Erin , Miller Courtney , Shaffer H. Bradley , Rothfels Carl J.
Published: May 2024

Azollais a floating fern that has closely evolved with a vertically transmitted obligate cyanobacterium endosymbiont—Anabaena azollae—that performs nitrogen fixation in specializedAzollaleaf pockets. This cyanobac-terium has a greatly reduced genome and appears to be in the “advanced” stages of symbiosis, potentially evolving into a nitrogen-fixing organelle. However, there are also other lesser-known inhabitants of the leaf pocket whose role and mode of transmission are unknown. We sequenced 112Azollaspecimens collected across the state of California and characterized their metagenomes in order to identify the common bacterial endosymbionts of the leaf pocket and assess their patterns of co-diversification. Four taxa were found across all samples, establishing that there are multiple endosymbionts that consistently inhabit theAzollaleaf pocket. We found varying degrees of co-diversification across these taxa as well as varying degrees of isolation by distance and of pseudogenation, which implies that the endosymbiotic community is transmitted by a mix of horizontal and vertical mechanisms, and that some members of the microbiome are more facultative symbionts than others. These results show that theAzollasymbiotic community is complex, featuring members at potentially different stages of symbiosis evolution, further supporting the utility of theAzollamicrocosm as a system for studying the evolution of symbioses.
Transcriptional Signatures of Domestication Revealed by Meta-Analysis of Pig, Chicken, Wild Boar, and Red Junglefowl Gene Expression Data
Authors: Uno Motoki , Bono Hidemasa
Published: May 2024

Domesticated animals have undergone significant changes in their behavior, morphology, and physiological functions during domestication. To identify the changes in gene expression associated with domestication, we collected RNA-seq data of pigs, chickens, wild boars, and red junglefowl from public databases and performed a meta-analysis. Gene expression was quantified and the expression ratio between domesticated animals and their wild ancestors (DW-ratio) was calculated. Genes were classified as “upregulated,” “downregulated,” or “unchanged” based on their DW-ratio, and DW-score was calculated for each gene. Gene set enrichment analysis revealed that genes upregulated in pigs were related to defense from viral infection, whereas those upregulated in chickens were associated with aminoglycan and carbohydrate derivative catabolic processes. Genes commonly upregulated in pigs and chickens are involved in the immune response, olfactory learning, epigenetic regulation, cell division, and extracellular matrix. In contrast, genes upregulated in wild boar and red junglefowl are related to stress response, cell proliferation, cardiovascular function, neural regulation, and energy metabolism. These findings provide valuable insights into the genetic basis of the domestication process and highlight potential candidate genes for breeding applications.

Simple Summary

Domesticated animals, such as pigs and chickens, have undergone significant genetic changes compared to their wild ancestors. We collected gene expression data from pigs, chickens, wild boars, and red junglefowl, and performed a comprehensive analysis. We identified differentially expressed genes by comparing the gene expression patterns of domesticated animals and their wild counterparts. These genes are involved in various biological processes, including immune response, metabolism, and stress response. Notably, domesticated animals exhibited higher expression of genes related to viral resistance and bone weakness, whereas their wild ancestors showed higher expression of genes associated with stress response and energy metabolism. Identifying these differentially expressed genes provides valuable insights into the genetic changes that occurred during the domestication process. Furthermore, these findings have highlighted potential candidate genes that could be targeted in breeding programs to improve the health and productivity of domesticated animals, ultimately contributing to the development of sustainable livestock production and addressing the growing global food demand.
Biochemical and neurophysiological effects of deficiency of the mitochondrial import protein TIMM50
Authors: Paz Eyal , Jain Sahil , Gottfried Irit , Staretz-Chacham Orna , Mahajnah Muhammad , Bagchi Pritha , Seyfried Nicholas T. , Ashery Uri , Azem Abdussalam
Published: May 2024

TIMM50, an essential TIM23 complex subunit, is suggested to facilitate the import of ∼60% of the mitochondrial proteome. In this study, we characterized aTIMM50disease causing mutation in human fibroblasts and noted significant decreases in TIM23 core protein levels (TIMM50, TIMM17A/B, and TIMM23). Strikingly, TIMM50 deficiency had no impact on the steady state levels of most of its putative substrates, suggesting that even low levels of a functional TIM23 complex are sufficient to maintain the majority of TIM23 complex-dependent mitochondrial proteome. As TIMM50 mutations have been linked to severe neurological phenotypes, we aimed to characterize TIMM50 defects in manipulated mammalian neurons. TIMM50 knockdown in mouse neurons had a minor effect on the steady state level of most of the mitochondrial proteome, supporting the results observed in patient fibroblasts. Amongst the few affected TIM23 substrates, a decrease in the steady state level of components of the intricate oxidative phosphorylation and mitochondrial ribosome complexes was evident. This led to declined respiration rates in fibroblasts and neurons, reduced cellular ATP levels and defective mitochondrial trafficking in neuronal processes, possibly contributing to the developmental defects observed in patients with TIMM50 disease. Finally, increased electrical activity was observed in TIMM50 deficient mice neuronal cells, which correlated with reduced levels of KCNJ10 and KCNA2 plasma membrane potassium channels, likely underlying the patients’ epileptic phenotype.
Canonical neurodevelopmental trajectories of structural and functional manifolds
Authors: Monaghan Alicja , Bethlehem Richard. A.I. , Akarca Danyal , Margulies Daniel ,   the Team CALM, Astle Duncan E.
Published: May 2024

Organisational gradients refer to a continuous low-dimensional embedding of brain regions and can quantify core organisational principles of complex systems like the human brain. Mapping how these organisational principles are altered or refined across development and phenotypes is essential to understanding the relationship between brain and behaviour. Taking a developmental approach and leveraging longitudinal and cross-sectional data from two multi-modal neuroimaging datasets, spanning the full neurotypical-neurodivergent continuum, we charted the organisational variability of structural (N = 887) and functional (N = 728) gradients, across childhood and adolescence (6-19 years old). Across datasets, despite differing phenotypes, we observe highly similar structural and functional gradients. These gradients, or organisational principles, are highly stable across development, with the exact same ordering across early childhood into mid-adolescence. However, there is substantial developmental change in the strength of embedding within those gradients: by modelling developmental trajectories as non-linear splines, we show that structural and functional gradients exhibit sensitive periods and are refined across development. Specifically, structural gradients gradually contract in low-dimensional space as networks become more integrated, whilst the functional manifold expands, indexing functional specialisation. The coupling of these structural and functional gradients follows a unimodal-association axis and varies across individuals, with developmental effects concentrated in the more plastic higher-order networks. Importantly, these developmental effects on coupling, in these higher-order networks, are attenuated in the neurodivergent sample. Finally, we mapped structure-function coupling onto dimensions of psychopathology and cognition and demonstrate that coupling is a robust predictor of dimensions of cognition, such as working memory, but not psychopathology. In summary, across clinical and community samples, we demonstrate consistent principles of structural and functional brain organisation, with progressive structural integration and functional segregation. These are gradients are established early in life, refined through development, and their coupling is a robust predictor of working memory.
Frequency and duration of sensory flicker controls astrocyte and neuron specific transcriptional profiles in 5xFAD mice
Authors: Bitarafan Sara , Pybus Alyssa F. , Rivera Moctezuma Felix G. , Adibi Mohammad , Franklin Tina C. , Singer Annabelle C. , Wood Levi B.
Published: May 2024

Background

Current clinical trials are investigating gamma frequency sensory stimulation as a potential therapeutic strategy for Alzheimer’s disease, yet we lack a comprehensive picture of the effects of this stimulation on multiple aspects of brain function. While most prior research has focused on gamma frequency sensory stimulation, we previously showed that exposing mice to visual flickering stimulation increased MAPK and NFκB signaling in the visual cortex in a manner dependent on duration and frequency of sensory stimulation exposure. Because these pathways control multiple neuronal and glial functions and are differentially activated based on the duration and frequency of flicker stimulation, we aimed to define the transcriptional effects of different frequencies and durations of flicker stimulation on multiple brain functions.

Methods

We exposed 5xFAD mice to different frequencies of audio/visual flicker stimulation (constant light, 10Hz, 20Hz, 40Hz) for durations of 0.5hr, 1hr, or 4hr, then used bulk RNAseq to profile transcriptional changes within the visual cortex and hippocampus tissues. Using weighted gene co-expression network analysis, we identified modules of co-expressed genes controlled by frequency and/or duration of stimulation.

Results

Within the visual cortex, we found that all stimulation frequencies caused fast activation of a module of immune genes within 1hr and slower suppression of synaptic genes after 4hrs of stimulation. Interestingly, all frequencies of stimulation led to slow suppression of astrocyte specific gene sets, while activation of neuronal gene sets was frequency and duration specific. In contrast, in the hippocampus, immune and synaptic modules were suppressed based on the frequency of stimulation. Specifically,10Hz activated a module of genes associated with mitochondrial function, metabolism, and synaptic translation while 10Hz rapidly suppressed a module of genes linked to neurotransmitter activity.

Conclusion

Collectively, our data indicate that the frequency and duration of flicker stimulation controls immune, neuronal, and metabolic genes in multiple regions of the brain affected by Alzheimer’s disease. Flicker stimulation may thus represent a potential therapeutic strategy that can be tuned based on the brain region and the specific cellular process to be modulated.
Human Breast Milk EVs Mitigate Endothelial Dysfunction: Preliminary Study
Authors: Cho Young-Eun , Chen Shaoshuai , Crouch Keith , Shutt Damon , Kaufman Justin , Singh Brajesh
Published: May 2024

Background

Endothelial cell (EC) dysfunction is an early indicator of failing vascular integrity, leading to various cardiovascular diseases. Toll-like receptor 4 (TLR4) activation is a key mechanism. Milk-derived extracellular vesicles (EVs) are known for their anti-inflammatory properties, particularly in suppressing TLR4 activation in damaged intestinal epithelial cells. This study explores the therapeutic potential of human breast milk EVs (bEVs) in EC dysfunction related to cardiovascular diseases.

Methods

Human breast milk EVs (bEVs) were isolated from healthy nursing mothers using ultracentrifugation. bEVs were applied to LPS-treated HUVECs, and the expression of inflammatory markers was measured using qPCR and western blotting. Angiogenesis was assessed via a wound assay. Additionally, bEVs were orally administered weekly for six weeks to high-fat diet-induced obese mice and lean mice. Metabolic phenotype characteristics and EC-dependent vasorelaxation were evaluated.

Results

bEV pre-treatment inhibited LPS-induced expression of inflammatory genes, including IL-6, IL-1b and VCAM-1. It also suppressed phospho-NFkB and TLR4 protein expression. bEVs enhanced EC migration, significantly increasing wound closure. Oral administration of bEVs restored impaired EC-dependent vasorelaxation in the mesenteric artery of obese mice, though metabolic parameters remained unchanged.

Conclusion

Our findings demonstrate the beneficial effects of bEVs on EC dysfunction, highlighting their potential as novel therapeutics for cardiovascular diseases. Future studies will focus on identifying specific bEV cargos and further evaluating their therapeutic effects on EC dysfunction.
The transcriptional landscape of metastatic hormone-naïve prostate cancer
Authors: Martin-Martin Natalia , Garcia-Longarte Saioa , Corres-Mendizabal Jon , Lazcano Uxue , Astobiza Ianire , Bozal-Basterra Laura , Herranz Nicolas , van Splunder Hielke , Carlevaris Onintza , Pujana-Vaquerizo Mikel , Blasco María Teresa , Aransay Ana M. , Rosino Antonio , Tudela Julian , Jimenez Daniel , Martinez Alberto , Salca Andrei , Santos-Martín Aida , Rey Sofía , Ugalde-Olano Aitziber , Gonzalo David , Graupera Mariona , Gomis Roger R. , Mateo Joaquin , Unda Miguel , Gonzalez-Billalabeitia Enrique , Loizaga-Iriarte Ana , Mendizabal Isabel , Carracedo Arkaitz
Published: May 2024

Metastatic hormone-naïve prostate cancer (mHNPC) is an infrequent form of this tumour type that is characterized by metastasis at the time of diagnosis and accounts for 50% of prostate cancer-related deaths. Despite the extensive characterization of localized and metastatic castration resistant prostate cancer (mCRPC), the molecular characteristics of mHNPC remain largely unexplored. Here we provide the first extensive transcriptomics characterization of mHNPC. We generated discovery and validation bulk and single-cell RNA-Seq datasets and performed integrative computational analysis in combination with experimental studies. Our results provide unprecedented evidence of the distinctive transcriptional profile of mHNPC and identify stroma remodelling as a predominant feature of these tumours. Importantly, we discover a central role for the transcription factor SOX11 in triggering a heterotypic communication that is associated to the acquisition of metastatic properties. Our study will constitute an invaluable resource for a profound understanding of mHNPC that can influence patient management.
3D-bioprinted patient-specific organotypic bone model mimicking mineralization dysregulation inFKBP10-related osteogenesis imperfecta
Authors: Griesbach Julia , de Leeuw Anke , Minacci Tanja , Kodiyan Ben , Ndarugendamwo Timothée , Lim Pei Jin , Rohrbach Marianne , Rubert Marina , Rüger Matthias , Giunta Cecilia , Schulte Friederike A. , Müller Ralph
Published: May 2024

Osteogenesis imperfecta (OI) is a heterogeneous group of rare genetic diseases characterized by increased bone fragility and deformities. The pathomechanisms of OI are poorly understood, hindering the development of disease-specific therapy. Addressing the limited understanding of OI and the lack of targeted treatments remains a challenge, given its varied symptoms and large clinical spectrum. Animal models have greatly advanced the understanding of the disease; however, the heterogeneity and subtype-specific symptoms are difficult to translate to humans.In vitromodels offer a promising tool for translational medicine, as they have the potential to yield patient-specific insights in a controlled environment using patient derived-cells. We used mechanically loaded 3D-bioprinted patient-specific organotypic bone models and time-lapsed micro-computed tomography to demonstrate dysregulation of mineralization inFKBP10-related OI compared to healthy controls. In contrast to healthy controls, tissue mineral density and stiffness were decoupled, such that hypermineralization observed in OI samples did not lead to increased stiffness. Additionally, we were able to replicate experimental stiffness using sample specific micro-finite element analysis. This allowed us to show mineral formation in regions of high local strain, suggesting mechanoregulation inFKBP10-related OI organotypic bone models is comparable to healthy controls. Regional analysis of mineralization showed increased heterogeneous mineralization, microarchitectural inhomogeneities and scaffold microporosity of OI samples compared to healthy controls. Our results suggest that the observed dysregulation of mineralization is the main driver for the altered mineral-mechanics properties observed inFKBP10-related organotypic bone models.

One Sentence Summary

Organotypic bone models demonstrate dysregulated mineralization in osteogenesis imperfecta samples compared to healthy controls.
Intercellular adhesion molecule-1 reprograms microglia to improve cognitive functions by inhibiting ERK/STAT3 signalling pathway in a model of Alzheimer’s disease
Authors: Goswami Soumita , Biswas Subhas Chandra
Published: May 2024

Background

Microgliosis is one of the early hallmarks of Alzheimer’s disease (AD) that plays a crucial role in AD-associated neuroinflammation. However, strategies to harness microglial activation without affecting its homeostatic function are currently lacking. Our recent finding revealed astrocyte secreted cytokine Intercellular adhesion molecule 1 (ICAM-1) improves memory and cognitive impairment in 5xFAD mice model of AD. Here, we investigated the possible mechanism of ICAM-1 that involves modification of microglial activation state and function.

Methods

We treated primary microglia cultures with amyloid-ß (Aß) in presence or absence of ICAM-1 and then assessed microglial inflammatory activation and phagocytic clearance of Aß by western blotting and confocal imaging. We further treated 5xFAD mice with ICAM-1 intraperitoneally and ICAM-1 antagonist lifitegrast intranasally to assess the beneficial effect of ICAM-1 on Aß mediated microgliosis, synaptic protein expressions and cognitive deficits.

Results

Here we report that, ICAM-1 inhibits microglial inflammatory activation by inhibiting ERK-STAT3 pathway which is indispensable for microglial inflammation. Moreover, ICAM-1 was found to potentiate microglia to engulf and eliminate Aß in primary culture and reduced Aß plaque load and associated microglial activation in 5xFAD mice hippocampus. This reduced plaque levels and associated microgliosis in turn refurbished synaptic protein expressions and improved cognition and memory in these mice. Interestingly, ICAM-1 mediated microglial modification along with cognitive improvement was partially lost when ICAM-1-LFA-1 interaction was inhibited.

Conclusion

Taken together these findings delineate the importance of ERK/STAT3 pathway in Aß mediated microglial inflammation and the modulatory role of ICAM-1 in microglial activation and phagocytosis in order to improve clearance of Aß and associated memory and cognitive impairments.
A recombinant CHIKV-NLuc virus identifies chondrocytes as target of Chikungunya virus in a immunocompetent mouse model
Authors: Legros Vincent , Belarbi Essia , Jeannin Patricia , Kümmerer Beate , Hardy David , Desprès Philippe , Gessain Antoine , Roques Pierre , Ceccaldi Pierre-Emmanuel , Choumet Valérie
Published: May 2024

First isolated in 1953 in Tanzania, the arthritogenic Chikungunya virus (CHIKV) re-emerged globally in 2005, leading to widespread outbreaks. Unlike other arboviruses, CHIKV predominantly induces symptomatic infections (72-96%), marked by fever, myalgia, polyarthralgia, and rash. Although rarely fatal, atypical forms such as encephalopathies can occur. Notably, 75.4% of patients experience persistent arthralgias for up to three years after the acute phase. Understanding CHIKV’s pathophysiology in the joints is challenging due to the difficulties to obtain biological samples. The study employs a mouse model infected with a reporter virus expressing a Nano Luciferase to investigate the disease’s transition to chronic arthritis. The murine model reveals viral replication in metatarsi joints, particularly in chondrocytes, confirmed in primary human chondrocytes undergoing viral-induced apoptosis.Ex vivoanalysis confirmed viral replication in leg bones and articular cartilages, with histological evidence of focal erosive lesions and periarticular inflammation. The study further utilizes anin vivoimaging mouse model to monitor viral replication over time. Human chondrocytes prove susceptible to CHIKV infection, exhibiting active viral replication, bioluminescence activity, and increased viral production. CHIKV induced apoptosis, the upregulation of markers associated with cartilage remodeling and altered the cytokine production. This comprehensive study, utilizing advanced techniques and models, provides insights into CHIKV’s ability to infect articular cartilages, shedding light on the mechanisms of chronic arthritis following infection.
Microscale sampling of the coral gastric cavity reveals a gut-like microbial community
Authors: Bollati Elena , Hughes David J. , Suggett David J. , Raina Jean-Baptiste , Kühl Michael
Published: May 2024

Animal guts contain numerous microbes, which are critical for nutrient assimilation and pathogen defence. While corals and other Cnidaria lack a true differentiated gut, they possess gastrovascular cavities (GVCs), semi-enclosed compartments where vital processes such as digestion, reproduction and symbiotic exchanges take place. The microbiome harboured in GVCs is therefore likely key to holobiont fitness, but remains severely understudied due to challenges of working in these small compartments. Here, we developed minimally invasive methodologies to sample the GVC of coral polyps and characterise the microbial communities harboured within. We used glass capillaries, low dead volume microneedles, or nylon microswabs to sample the gastric microbiome of individual polyps from six species of corals, then applied low-input DNA extraction to characterise the microbial communities from these microliter volume samples. Microsensor measurements of GVCs revealed anoxic or hypoxic micro-niches, which persist even under prolonged illumination with saturating irradiance. These niches harboured microbial communities enriched in putatively microaerophilic or facultatively anaerobic taxa, such as Epsilonproteobacteria. Some core taxa found in the GVC ofLobophyllia hemprichiifrom the Great Barrier Reef were also detected in conspecific colonies held in aquaria, indicating that these associations are unlikely to be transient. Our findings suggest that the coral GVC is chemically and microbiologically similar to the gut of higher Metazoa. Given the importance of gut microbiomes in mediating animal health, harnessing the coral “gut microbiome” may foster novel active interventions aimed at increasing the resilience of coral reefs to the climate crisis.
Decoding the amplitude and slope of continuous signals into spikes with a spiking point neuron model
Authors: Miko Rebecca , Scheunemann Marcus , Steuber Volker , Schmuker Michael
Published: May 2024

In this study, we harness the signal processing potential of neurons, utilizing the Izhikevich point neuron model to efficiently decode the slope or amplitude of fluctuating continuous input signals. Using biophysically detailed compartmental neurons often requires significant computational resources. We present a novel approach to create behaviours and simulate these interactions in a lower-dimensional space, thereby reducing computational requirements. We began by conducting an extensive search of the Izhikevich parameter space, leading to the first significant outcome of our study: i) the identification of optimal parameter sets for generating slope or amplitude detectors, thereby achieving signal processing goals using neurons. Next, we compared the performance of the slope detector we discovered with a biophysically detailed two-compartmental pyramidal neuron model. Our findings revealed several key observations: ii) bursts primarily occurred on the rising edges of similar input signals, iii) our slope detector exhibited bidirectional slope detection capabilities, iv) variations in burst duration encoded the magnitude of input slopes in a graded manner. Overall, our study demonstrates the efficient and accurate simulation of dendrosomatic behaviours. Real-time applications in robotics or neuromorphic hardware can utilize our approach. While biophysically detailed compartmental neurons are compatible with such hardware, Izhikevich point neurons are more efficient. This work has the potential to facilitate the simulation of such interactions on a larger scale, encompassing a greater number of neurons and neuronal connections for the same computational power.
New insight on DNA isolation from single automated recoveredCeratocystis plataniconidia
Authors: Luchi Nicola , Pinzani Pamela , Salvianti Francesca , Mancini Irene , Santini Alberto
Published: May 2024

Single-cell technology is increasingly used to analyze the basis of molecular regulation and provide insights into different aspects of human diseases. Such technology is a breakthrough approach to study blood cancers by characterizing molecular information on a genome-wide scale at the single-cell level. These methods can be easily and successfully transferred to tracheomycotic plant pathogens, which cause host wilt. Ceratocystis platani is the causal agent of the Canker stain disease of plane tree (Platanus spp.), a lethal wilt disease spreading in Europe. To displace and separate different C. platani conidia types a dielectrophoretic approach was tested. The DNA of each conidium was isolated and analyzed and the target DNA was identified by a specific qPCR marker and by sequencing the amplicon. Our results showed that this technology is applicable to vascular plant pathogens. The fungal DNA was successfully extracted from single or pooled conidia and identified by both methods after whole genome amplification. The use of the single-cell technology will provide a new approach to the study of plant vascular diseases, allowing the study of single-spore molecular and physiological features not detectable in complex biological mixtures.

Author summary

In recent years, technologies for single-cell isolation have been developed in the study of human diseases, such as cancers, capable of obtaining genetic information at the single-cell level. In this study, these methods were transferred to a plant pathogen, Ceratocystis platani, which causes a lethal disease of plane tree. The single cell technique used was able to separate the different types of conidia of C. platani and analyze the DNA within each conidium. The use of single cell technology represents an important tool for the study of plant vascular diseases by allowing the study of molecular mechanisms that are difficult to detect in complex biological matrices.
T-cell receptor structures and predictive models reveal comparable alpha and beta chain structural diversity despite differing genetic complexity
Authors: Quast Nele P. , Abanades Brennan , Guloglu Bora , Karuppiah Vijaykumar , Harper Stephen , Raybould Matthew I. J. , Deane Charlotte M.
Published: May 2024

T-cell receptor (TCR) structures are currently under-utilised in early-stage drug discovery and repertoire-scale informatics. Here, we leverage a large dataset of solved TCR structures from Immunocore to evaluate the current state-of-the-art for TCR structure prediction, and identify which regions of the TCR remain challenging to model. Through clustering analyses and the training of a TCR-specific model capable of large-scale structure prediction, we find that the alpha chain VJ-recombined loop (CDRA3) is as structurally diverse and correspondingly difficult to predict as the beta chain VDJ-recombined loop (CDRB3). This differentiates TCR variable domain loops from the genetically analogous antibody loops and supports the conjecture that both TCR alpha and beta chains are deterministic of antigen specificity. We hypothesise that the larger number of alpha chain joining genes compared to beta chain joining genes compensates for the lack of a diversity gene segment.

Overall, our study demonstrates that valuable structure-function relationships can lie in alpha chains despite their simpler junctions. We also provide over 1.5M predicted TCR structures to enable repertoire structural analysis and elucidate strategies towards improving the accuracy of future TCR structure predictors.
Early development of the mineralized external skeleton of the polyplacophoran mollusk, with insight into the evolutionary history of shell plates and spicules
Authors: Yoshikawa Hiroki , Morino Yoshiaki , Wada Hiroshi
Published: May 2024

Recent molecular phylogenetic studies have raised two questions about the evolutionary history of the calcified exoskeleton of mollusks. The first question concerns the homology of the two types of skeleton; whether spicules and shell plates share an evolutionary origin. The second question is the homology of the shell plates between chitons and other mollusks, including gastropods and bivalves. To gain insight into these questions, we examined the early development of shell plates and spicules in chitons. We identified several developmental genes that are involved in both shell plates and spicules, suggesting that spicules and shell plates share a common evolutionary origin. We also found that subpopulations of the dorsal shell field (the ridge and the plate field) have specific gene expression profiles. The differential gene expression of the ridge and plate field is not identical to the profiles of the zones of the gastropod shell field. This observation may suggest an independent evolutionary origin of the shell plates in chitons and gastropods.
Redox-driven control of Yuh1/UCHL3 impacts mitochondrial health via NEDD8/Rub1 pathway
Authors: Issa Soha , Klein Yuval , Berda Eden , Saad Shahaf , Harshuk-Shabso Dana , Sinha Abhishek , Sharaabi Yehonatan , Benhar Moran , Pick Elah
Published: May 2024

The ubiquitin-like protein NEDD8/Rub1 undergoes processing by the enzyme Yuh1/UCHL3 to become functional. While the processed NEDD8/Rub1 modifies Cullin-RING E3 ligases (CRLs) among all studied organisms, its role in facilitating CRL-based substrate degradation is absent inS. cerevisiae. This prompts questions about NEDD8/Rub1 functionality if it does not activate CRLs universally. Previous studies revealed that increased production of reactive oxygen species (ROS) during the glycolysis to mitochondrial respiration transition inhibits cullin NEDDylation inS. cerevisiae, yet the specific affected enzymes remain unidentified. Here, we investigate how redox changes affect Yuh1 activity, revealing a thiol-based redox switch modulating its catalytic function in response to ROS. Temporal inactivation of Yuh1 fine-tunes NEDD8/Rub1 mature and precursor species, both crucial for maintaining mitochondrial integrity and enhancing oxidative stress resilience. These findings unveil a novel role for Rub1/NEDD8 beyond CRL activation, linking redox signaling to NEDD8/Rub1 pathways.

Graphical abstract
Promoters constrain evolution of expression levels of essential genes inEscherichia coli
Authors: Tsuru Saburo , Hatanaka Naoki , Furusawa Chikara
Published: May 2024

Variability in expression levels in response to random genomic mutations varies among genes, influencing both the facilitation and constraint of phenotypic evolution in organisms. Despite its importance, both the underlying mechanisms and evolutionary origins of this variability remain largely unknown due to the mixed contributions ofcis- andtrans-acting elements. To address this issue, we focused on the mutational variability ofcis-acting elements, that is, promoter regions, inEscherichia coli. Random mutations were introduced into the natural and synthetic promoters to generate mutant promoter libraries. By comparing the variance in promoter activity of these mutant libraries, we found no significant difference in mutational variability in promoter activity between promoter groups, suggesting the absence of a signature of natural selection for mutational robustness. In contrast, the promoters controlling essential genes exhibited a remarkable bias in mutational variability, with mutants displaying higher activities than the wild types being relatively rare compared to those with lower activities. Our evolutionary simulation on a rugged fitness landscape provided a rationale for this vulnerability. These findings suggest that past selection created non-uniform mutational variability in promoters biased toward lower activities of random mutants now constrain future evolution of downstream essential genes toward higher expression levels.
Combined forces of hydrostatic pressure and actin polymerization drive endothelial tip cell migration and sprouting angiogenesis
Authors: Kondrychyn Igor , He Liqun , Wint Haymar , Betsholtz Christer , Phng Li-Kun
Published: May 2024

Cell migration is a key process in the shaping and formation of tissues. During sprouting angiogenesis, endothelial tip cells invade avascular tissues by generating actomyosin-dependent forces that drive cell migration and vascular expansion. Surprisingly, ECs can still invade if actin polymerization is inhibited. In this study, we show that endothelial tip cells employ an alternative mechanism of cell migration that is dependent on Aquaporin (Aqp)-mediated water inflow and increase in hydrostatic pressure. In the zebrafish, ECs expressaqp1a.1andaqp8a.1in newly formed vascular sprouts in a VEGFR2-dependent manner. Aqp1a.1 and Aqp8a.1 loss-of-function studies show an impairment in intersegmental vessels formation because of a decreased capacity of tip cells to increase their cytoplasmic volume and generate membrane protrusions, leading to delayed tip cell emergence from the dorsal aorta and slower migration. Further inhibition of actin polymerization resulted in a greater decrease in sprouting angiogenesis, indicating that ECs employ two mechanisms for robust cell migrationin vivo. Our study thus highlights an important role of hydrostatic pressure in tissue morphogenesis.
NPD1/GPR37 axis protects painful traumatic brain injury and its complications
Authors: Zhao Junli , Chandra Sharat , Wang Yuqing , Zhang Vivian , Wang Haichen , Ji Ru-Rong
Published: May 2024

Patients with traumatic brain injury (TBI) frequently exhibit heightened pain and associated complications such as cognitive decline, depression, and anxiety. GPR37 is widely expressed in various brain regions, but its function remains largely unclear. We recently discovered neuroprotectin D1 (NPD1) as a novel GPR37 ligand. In this study, we examined the protective role of the NPD1/GPR37 signaling pathway in TBI-induced neuropathic pain and its complications. TBI was induced by closed-head impact and resulted in transient neuropathic pain for less than two weeks, showing periorbital and cutaneous mechanical allodynia/hyperalgesia, as well as motor deficiency and cognitive impairment. We found that peri-surgical treatment with NPD1, effectively prevented TBI-induced mechanical hypersensitivity, motor deficiency, and cognitive impairment. NPD1 treatment also substantially inhibited TBI-induced microgliosis, astrogliosis (including A1 astrocyte markers), and neuroinflammation in the sensory cortex and hippocampus. RNA sequencing and GO enrichment analysis revealed downregulations of genes related to “calcium ion homeostasis,” and “GPCR signaling pathway” in the TBI-affected brain. These downregulations were restored by NPD1 treatment. RNAscopein situhybridization revealed predominantGpr37mRNA expression in oligodendrocytes. TBI resulted in rapid and remarkable demyelination and downregulation ofGpr37mRNA expression in oligodendrocytes, and both were protected by NPD1 treatment. NPD1’s inhibition of periorbital and cutaneous mechanical pain was abolished inGpr37-/-mice. Moreover, TBI-induced neuropathic pain was prolonged by swimming stress, and NPD1 treatment prevented the stress-induced transition from acute to chronic pain in wild-type mice but notGpr37-/-mice. Finally, chronic pain was associated with depression and anxiety, and NPD1 treatment mitigated these chronic pain complications through GPR37. Thus, through modulation of demyelination, diverse responses of glial cells, and neuroinflammation, the NPD1/GPR37 axis serves as a protective mechanism and a therapeutic target against painful traumatic brain injury and its complications.