bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between socioeconomic status and nonurgent presentations to pediatric emergency departments: a retrospective study
Authors: Mancheron Alexandre , Vincent-Cassy Christophe , Guedj Romain , Chappuy Hélène , De Groc Thibault , Duval Arnould Marc , Gajdos Vincent , Galerne Aurélien , Soussan-Banini Valérie , Titomanlio Luigi , Michel Morgane , Aupiais Camille
Published: January 2025

Background and importance

Access to healthcare remains a persistent challenge. Socially disadvantaged populations often encounter barriers to care and may frequently seek out emergency departments (EDs), including for nonurgent medical care.

Objective

The objective of this study is to study the association between nonurgent presentations to pediatric EDs and patients’ socioeconomic environment in an urban setting.

Design, setting, and participants

A retrospective study of all visits to a pediatric ED in eight participating centers of the Paris metropolitan area (France) between 1 January 2017 and 31 December 2021 was carried out. Routinely collected data were analyzed.

Exposure

Socioeconomic status was evaluated using ecological variables defined at the municipality level. These variables were collected from public sources and included a social deprivation index, the accessibility to general practitioners, the proportion of single-parent families, and the proportion of immigrants.

Outcome measure and analysis

The primary endpoint was a nonurgent ED presentation, defined as being assigned one of the two lowest triage categories on a five-point scale. A multilevel logistic model assessed the association between nonurgent ED presentations and patients’ characteristics, socioeconomic environment, and healthcare accessibility.

Main results

Nonurgent visits accounted for 51.6% of the 1 499 108 visits during the study period. The admission rate was 2.1% for nonurgent presentations and 18.8% for urgent presentations. In the final multivariate model (n = 1 412 895 visits), after adjustment for sex, age, time of day, day of the week, month, and year, the risk of nonurgent presentation was significantly higher for children living in less advantaged areas and in areas where the rate of single-parent families was high. It was also higher for children living close to the ED.

Conclusion

This extensive retrospective multicenter study emphasizes the increased risk of visiting EDs for nonurgent medical care among children from disadvantaged urban areas.
The reemergence of Streptococcus pyogenes in skin and soft tissue infections: a review of epidemiology, pathogenesis, and management strategies
Authors: Bassetti Matteo , Giacobbe Daniele Roberto , Larosa Barbara , Lamarina Annaflavia , Vena Antonio , Brucci Giorgia
Published: January 2025

Purpose of review

To discuss skin and soft tissue infections (SSTIs) caused by group A Streptococcus (GAS) by focusing on their pathogenesis, clinical manifestations, and management strategies.

Recent findings

GAS is responsible for a wide range of infections from mild disease to severe fatal invasive infections with high mortality rates. Invasive GAS (iGAS) infections affect both young and old individuals and account for 1.8 million cases worldwide, with a mortality rate of up to 20%. In addition, conditions resulting by immune responses triggered by GAS also contribute to GAS-associated morbidity, and should not be overlooked. GAS has the ability to produce a wide set of virulence factors which contribute to its pathogenicity and its ability to colonize different body site and subsequently cause invasive infections. Management of SSTIs caused by GAS is challenging due to the risk of rapid progression and the risk of developing complications.

During the COVID-19 pandemic, a relevant increase in iGAS infections has been registered. A constantly updated knowledge of the clinical presentation of iGAS infections is thus necessary to reduce their high mortality rates. Proper recognition and treatment of iGAS infections remain crucial.
99mTc-FAPI-46 Scan and 177Lu-FAPI-2286 Treatment in a Patient With Nasopharyngeal Carcinoma
Authors: Barashki Somaye , Hadad Bentolhoda , Raeisi Nasrin , Aryana Kamran
Published: January 2025

We present a 24-year-old man with a history of metastatic nasopharyngeal cancer. Despite receiving standard treatments, including surgery, radiotherapy, and chemotherapy, he has shown progression. Consequently, he has been referred to the nuclear medicine department for theranostic purposes. The 99mTc-FAPI-46 whole-body scan showed tracer uptake in mediastinal large mass, both external lymph nodes and osseous metastases. Treatment with 177Lu-FAPI-2286 initiated, with subsequent planar scans revealing sustained uptake up to day 10, particularly in the large mediastinal mass. This case indicates promising FAPI-targeted theranostic potential in metastatic nasopharyngeal carcinoma and proper retention of 177Lu-FAPI-2286 in metastatic lesions.
Response Evaluation Using 68Ga-DOTA-IBA in a Case of Metastatic Prostate Cancer
Authors: Li Linwei , Chen Yue
Published: January 2025

We report a case of a patient with metastatic prostate cancer receiving first-line endocrine therapy. Clinical symptoms, PSA level, and CT confirmed the significant progression of his bone metastatic lesions. In comparison to images at baseline, follow-up bone scan incorrectly showed remission of the bone lesions, whereas follow-up 68Ga-DOTA-IBA correctly showed disease progression.
Subcutaneous Infection With Snow Leopard Sign on 18F-FDG PET/CT Mimicking Subcutaneous Panniculitis-Like T-Cell Lymphoma
Authors: Zheng Xinyue , Zhang Tingting , Yan Xiaofang , Su Xinhui , Wang Peipei
Published: January 2025

A 37-year-old man presented with a 2-month history of fever of unknown origin and erythema rashes on the trunk and limbs. 18F-FDG PET/CT revealed increased 18F-FDG uptake in subcutaneous panniculitis, forming a snow leopard sign, along with enlarged lymph nodes, which suggested subcutaneous panniculitis-like T-cell lymphoma. However, skin biopsy indicated subcutaneous infection, and bone marrow biopsy revealed no abnormal lymphocytes. After anti-infection treatment, symptoms improved, leading to a final diagnosis of systemic infection. This case demonstrates how extensive subcutaneous infections on PET/CT could be misinterpreted as subcutaneous panniculitis-like T-cell lymphoma.
High PSMA Avidity, Yet Still Benign
Authors: Reddy Ryan , Ulaner Gary A.
Published: January 2025

A 64-year-old man with newly diagnosed prostate cancer underwent 18F-Piflufolastat PET/CT. Radiotracer avidity localized to the primary prostate malignancy and to a left rib (SUVmax, 9.0). The high 18F-Piflufolastat avidity may have been mistaken for a metastasis if not for the corresponding CT images demonstrating a well-circumscribed sclerotic rim at the site of the PET focus. This CT finding is uncommon for osseous malignancy, but common in benign fibrous dysplasia. Biopsy confirmed benign fibrous dysplasia. This case emphasizes that benign CT morphology may supersede even high avidity on PSMA-targeted PET imaging. Physicians interpreting PET/CT must recognize CT findings that supersede PET findings.
A Scoping Review of Autistic Children’s Neurological, Cognitive, and Psychological Responses to Trauma
Authors: Di Marco Alyssa , Grewal Roohit , Colangeli Taylor , Rupert Anna
Published: January 2025

Background: Research tells us that autistic children are more likely than their neurotypical peers to experience potentially traumatic events. There is, however, limited literature on how autistic children respond to trauma, and there are few tools available to specifically assess autistic children’s exposure and response to trauma. Consequently, clinicians may lack the knowledge or resources to adequately support these individuals and provide them with appropriate, non-harmful care. Methods: In this scoping review, four databases (CINAHL, MEDLINE, Emcare, and PsycINFO) were searched using keywords that represented the research question: “What are autistic children’s neurological, cognitive, and psychological responses to trauma?” Quantitative and qualitative analyses were conducted on the data, and a frequency analysis was conducted to categorize and describe the results. Results: Thirty-one studies were included in the final analysis. Eleven themes were identified, which included social anxiety, isolation and withdrawal, generalized anxiety, depression, negative emotions and feelings, posttraumatic stress disorder and intrusive thoughts, social behaviors and skills, and behavioral challenges. Conclusions: This scoping review provides important insights into the unique trauma responses of autistic children and highlights the need for additional research and evidence-based guidance to inform clinical best practices and trauma-informed care for this population.
Applying Trauma- and Violence-Informed Care to Speech-Language Pathology Practice Across the Lifespan
Authors: Wiseman-Hakes Catherine , Albin Maya , Rupert Anna , Phoenix Michelle
Published: January 2025

The high prevalence of trauma world-wide is such that speech-language pathologists are likely to support clients across the lifespan with experiences of trauma, such as abuse, neglect, intergenerational and racial trauma, and exposure to structural and systemic violence. Trauma can affect peoples’ neurobiology and can also impact cognitive, social, and language development and compromise over-all communication competence. Trauma-and-violence informed approaches must be built upon a foundational knowledge of the impact of trauma on people’s lives: from neurobiology and development, to health, communication, and behavior. It is therefore evident that consideration of trauma must be built into training programs, care provision, organizational policies, and programs. To provide trauma- and violence-informed care (TVIC), speech-language pathologists must individually and collectively engage in the process of critical reflection to gain insight into their personal and cultural assumptions and values, and to affect change in practice. To this end, the authors draw from available literature as well as their clinical, academic and individual experiences to illustrate how TVIC can shape speech-language pathologists’ lens with respect to 1. The social determinants of health and access to services, 2. Behaviors that challenge, and 3. Social communication, social cognition, and emotional regulation. The Substance Abuse and Mental Health System Administration’s (SAMHSA) four assumptions and six principles of trauma-informed care are applied to illustrate how TVIC can be incorporated into practice.
The dominant lineage of an emerging pathogen harbours contact-dependent inhibition systems
Authors: Crisan Cristian V. , Goldberg Joanna B.
Published: January 2025

Bacteria from the Stenotrophomonas maltophilia complex (Smc) are important multidrug-resistant pathogens that cause a broad range of infections. Smc is genomically diverse and has been classified into 23 lineages. Lineage Sm6 is the most common among sequenced strains, but it is unclear why this lineage has evolved to be dominant. Antagonistic interactions can significantly affect the evolution of bacterial populations. These interactions may be mediated by secreted contact-dependent proteins, which allow inhibitor cells to intoxicate adjacent target bacteria. Contact-dependent inhibition (CDI) requires three proteins: CdiA, CdiB and CdiI. CdiA is a large, filamentous protein exported to the surface of inhibitor cells through the pore-like CdiB. The CdiA C-terminal domain (CdiA-CT) is toxic when delivered into target cells of the same species or genus. CdiI immunity proteins neutralize the toxicity of cognate CdiA-CT toxins. We found that all complete Smc genomes from the Sm6 lineage harbour at least one CDI locus. By contrast, less than a quarter of strains from other lineages have CDI genes. Smc CdiA-CT domains are diverse and have a broad range of predicted functions. Most Sm6 strains harbour non-cognate cdiI genes predicted to provide protection against foreign toxins from other strains. Finally, we demonstrated that an Smc CdiA-CT toxin has antibacterial properties and is neutralized by its cognate CdiI.
Diversity and seasonality of ectoparasite burden on two species of Madagascar fruit bat,Eidolon dupreanumandRousettus madagascariensis
Authors: Andrianiaina Angelo F. , Andry Santino , Kettenburg Gwenddolen , Ranaivoson Hafaliana Christian , Lacoste Vincent , Dussart Philippe , Heraud Jean-Michel , Laverty Theresa M. , Guth Sarah , Young Katherine I. , Andrianarimisa Aristide , Brook Cara E.
Published: January 2025

Background

Bats are important reservoir hosts for a variety of microparasites, some of which are transmitted by ectoparasite vectors that include mites, fleas, lice, ticks, and bat flies (families Nycteribiidae and Streblidae). All of these ectoparasite taxa are known to parasitize two endemic fruit bats of Madagascar,Eidolon dupreanumandRousettus madagascariensis.We aimed to describe the diversity of ectoparasite infestation for both bat species through morphological observation and DNA barcoding and elucidate ecological and climatic correlates of seasonal nycteribiid parasitism of these hosts.

Methods

LiveE. dupreanumandR. madagascariensisfruit bats were captured monthly in northern and central-eastern Madagascar from 2013-2020. Ectoparasites on all captured bats were counted and identified in the field, then collected into ethanol. Field identification of a subset of samples were confirmed via microscopy and DNA barcoding of the cytochrome C oxidase subunit 1 (COI) and 18S genes. The seasonal abundance of nycteribiid bat flies on both host bats was analyzed using generalized additive models, and the role of climate in driving this seasonality was assessed via cross-correlation analysis combined with generalized linear models. Phylogenetic trees were generated to compare COIand 18S sequences of Madagascar nycteribiid and streblid bat flies with available reference sequences from GenBank.

Results

Ectoparasites corresponding to four broad taxa (mites, ticks, fleas, and bat flies) were recovered from 628 of 873E. dupreanumand 831 of 862R. madagascariensis.E. dupreanumwere most commonly parasitized byCyclopodia dubianycteribiids andR. madagascariensisbyEucampsipoda madagascariensisnycteribiids orMegastrebla wenzelistreblids. We observed significant seasonality in nycteribiid abundance on both bat hosts, which varied by bat sex and was positively correlated with lagged temperature, precipitation, and humidity variables. Barcoding sequences recovered for all three bat fly species grouped with previously reported sequences, confirming morphological species identification. Our study contributes the first DNA barcodes of any kind reported forM. wenzeliand the first 18S barcodes forC. dubia.

Conclusion

This study explores the diversity and abundance of ectoparasite burdens in two Malagasy fruit bat species, highlighting the importance of seasonal ecology and the influence of climate variables on parasitism, which correlates with resource availability.
Limited genetic diversity amongMalassezia furfurisolates during two one-year neonatal and pediatric bloodstream infection surveys confirms preference for one specific IGS1 genotype in deep-seated infections
Authors: Theelen Bart , Cafarchia Claudia , Hagen Ferry , Boekhout Teun
Published: January 2025

In recent years, multiple reports indicated thatMalasseziafungemia may be of emerging concern in immunocompromised patients and neonates. In combination with observations of reduced antifungal susceptibility, this highlights the need for a better understanding of the extent ofMalasseziaetiology in deep seated infections. The use of media without lipid supplementation in most clinics underlines the likelihood of underdiagnosis. Here, we utilize multiple genetic markers to explore the genetic diversity of number oneMalasseziafungemia speciesMalassezia furfur, observed from two one-year surveys investigating neonatal and pediatric bloodstream infections. All strains isolated from skin and deep seated neonatal or pediatric sites belong to IGS1-genotype A, except for nine isolates from one pediatric patient. This confirms previous observations of a preferential genotype for deep seated body sites. The mitochondrialcox3-nad3 intergenic region provided additional typing resolution, and including ITS, translation elongation factor 1-α, chitin synthase 2, and the mating type, 16 genotypes (MF1-16) could be distinguished among all isolates from both surveys and reference isolates. These results present a promising MLST scheme that requires further testing. We observed a decreased genetic variation ofM. furfurisolates among NICU and pediatric surgery patients over the course of 5 years and showed that the skin likely serves as a reservoir for residentM. furfurstrains from where they can enter the bloodstream, causing infections among susceptible patient groups. Overall, reduced susceptibility for amphotericin B and specifically fluconazole was observed.
TransHLA: A Hybrid Transformer Model for HLA-Presented Epitope Detection
Authors: Lu Tianchi , Wang Xueying , Nie Wan , Huo Miaozhe , Li Shuaicheng
Published: January 2025

Background

Precise prediction of epitope presentation on human leukocyte antigen (HLA) molecules is crucial for advancing vaccine development and immunotherapy. Conventional HLA-peptide binding affinity prediction tools often focus on specific alleles and lack a universal approach for comprehensive HLA site analysis. This limitation hinders efficient filtering of invalid peptide segments.

Results

We introduce TransHLA, a pioneering tool designed for epitope prediction across all HLA alleles, integrating Transformer and Residue CNN architectures. TransHLA utilizes the ESM2 large language model for sequence and structure embeddings, achieving high predictive accuracy. For HLA class I, it reaches an accuracy of 84.72% and an AUC of 91.95% on IEDB test data. For HLA class II, it achieves 79.94% accuracy and an AUC of 88.14%. Our case studies using datasets like CEDAR and VDJdb demonstrate that TransHLA surpasses existing models in specificity and sensitivity for identifying immunogenic epitopes and neoepitopes.

Conclusions

TransHLA significantly enhances vaccine design and immunotherapy by efficiently identifying broadly reactive peptides. Our resources, including data and code, are publicly accessible athttps://github.com/SkywalkerLuke/TransHLA

Key Points

We developed TransHLA, a deep learning tool for predicting epitopes across all HLA alleles using Transformer and Residue CNN architectures.

The model uses ESM2 embeddings to improve predictive accuracy and efficiency.

TransHLA shows superior specificity and sensitivity in identifying immunogenic epitopes and neoepitopes compared to existing models.

Our approach offers potential advancements in vaccine design and immunotherapy through enhanced peptide analysis.
Estimation of Respiratory Syncytial Virus-attributable Hospitalizations among Older Adults in Japan between 2015 and 2018: an Administrative Health Claims Database Analysis
Authors: Seki Masafumi , Kobayashi Yasuhiro , Méroc Estelle , Kitano Takahiro , Polkowska-Kramek Aleksandra , Yoshida Asuka , Ito Shuhei , Liang Caihua , Bruyndonckx Robin , Moges Solomon Molalign , Conde-Sousa Eduardo , Nuttens Charles , Gessner Bradford D. , Begier Elizabeth
Published: January 2025

Objective

We estimated the incidence rates (IRs) of respiratory syncytial virus (RSV)-related hospitalizations among adults aged ≥60 years in Japan from 2015 to 2018, using a model-based approach to better understand the disease burden.

Methods

We obtained hospitalization data from the Medical Data Vision (MDV) database, restricted to Diagnosis Procedure Combination (DPC) hospitals. We estimated the annual age-specific RSV-attributable IR of hospitalizations for five cardiorespiratory outcomes based on selected ICD-10 codes employing a quasi-Poisson regression model. We projected our results to all DPC hospitals in Japan and also to all Japanese hospitals.

Results

In adults aged ≥60 years, the annual IR of RSV-attributable cardiorespiratory hospitalizations at DPC hospitals was estimated at between 100 and 124 per 100,000 person-years, projecting to 134 to 229 cardiorespiratory hospitalizations per 100,000 person-years at all hospitals. For respiratory hospitalizations at DPC hospitals, the annual IR was from 69 to 85 per 100,000 person-years (projecting to 96 to 157 hospitalizations per 100,000 person-years at all hospitals). IRs for all outcomes were consistently higher among adults aged ≥80 years than those 60-79 years.

Conclusion

Our results indicate a high burden of RSV-attributable hospitalizations in older adults in Japan, highlighting the need to implement effective RSV prevention strategies.

Highlights

RSV-attributable hospitalizations were estimated among older adults in Japan

We used data from national hospitals and a comprehensive list of ICD-10 codes

We performed a time series analysis utilizing a quasi-Poisson regression model

RSV causes significant cardiorespiratory hospitalizations in older adults

Future RSV burden studies should consider respiratory and cardiovascular outcomes
From Background to Signal: Simultaneously derived Copy Numbers from Methylation-Dependent Sequencing cell-free DNA
Authors: Hazelaar Daan M , Boers Ruben G , Boers Joachim B , de Weerd Vanja , Jansen Maurice PHM , Verheul Henk MW , Verhoef Cornelis , Gribnau Joost , Martens John WM , Makrodimtris Stavros , Wilting Saskia M
Published: January 2025

Cell-free DNA (cfDNA) analysis offers a powerful, non-invasive approach to cancer diagnostics and monitoring by revealing tumor-specific genomic and epigenetic alterations. Here, we demonstrate the versatility of MeD-seq, a methylation-dependent sequencing assay, for comprehensive cfDNA analysis, including methylation profiling, chromosomal copy number (CN) alterations, and tumor fraction (TF) estimation. MeD-seq-derived CN profiles and TF estimates from 38 colorectal cancer with liver metastases (CRLM) and 5 ovarian cancer patients were highly comparable to shallow whole-genome sequencing (sWGS) validating our approach. These findings establish MeD-seq as a robust and cost-effective platform for detecting cancer-specific signals directly from plasma without prior tissue-based information. Future work should expand its application to other cancer types, solidifying MeD-seq as a versatile tool for minimally-invasive cfDNA profiling.
Unveiling Hidden Microbial Diversity in Mars 2020 Mission Assembly Cleanrooms with Molecular Insights into the Persistent and Perseverance of Novel Species Defying Metagenome Sequencing
Authors: Sivabalan Shobhan Karthick Muthamilselvi , Vijayakumar Varsha , Sengupta Pratyay , Palmal Siddhakam , Krishnamurthi Srinivasan , Singh Nitin Kumar , Kyrpides Nikos C. , Raman Karthik , Venkateswaran Kasthuri
Published: January 2025

NASA cleanrooms, where space mission components are assembled, maintain stringent cleaning protocols and nutrient-poor environments, resulting in low yet persistent microbial loads. Although these oligotrophic extremophiles are reported in small numbers, their resistance to environmental stresses, sparse presence, and difficulty in extracting biomolecules often lead to their omission, even with advanced sequencing technologies. Traditional metagenomic approaches fail to detect these rare species due to challenges in lysing robust microbial cells and isolating minute amounts of DNA from dominant microorganisms. Additionally, the absence of database references for novel extremophiles limits their identification. Over a six month period of monitoring Mars 2020 mission cleanrooms, 182 bacterial strains from 19 families were identified using advanced molecular techniques. This included 14 novel Gram-positive species, eight of which were spore-formers. Despite being present at only about 0.001% abundance in metagenomic sequencing data, they were successfully cultured. Functional studies revealed their capabilities in nitrogen cycling, carbohydrate metabolism, and radiation resistance. Furthermore, 12 biosynthetic gene clusters, including those linked to ectoine andɛ-poly-L-lysine production, underscore their biotechnological potential. These findings emphasize the hidden microbial diversity in spacecraft assembly cleanrooms and highlight the need for advanced detection methods to uncover extremophiles with potential applications in biotechnology and space exploration.

Synopsis

Understanding extremophiles in NASA spacecraft assembly cleanrooms aids contaminant management in confined habitats, ensuring sustainability and safety in future space missions.

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The Lipidome Landscape of Amiodarone Toxicity: Anin vivoLipid-centric Multi-Omics Study
Authors: Thu Nguyen Quang , Oh Jung-Hwa , Nam Tien Nguyen Tran , Park Se-Myo , Hai Yen Nguyen Thi , Phat Nguyen Ky , Hung Tran Minh , Nguyen Huy Truong , Nguyen Duc Ninh , Yoon Seokjoo , Kim Dong Hyun , Long Nguyen Phuoc
Published: January 2025

Amiodarone is an effective therapy for arrhythmias, its prolonged management may lead to significant adverse drug reactions. Amiodarone-induced hepatoxicity is described by phospholipidosis, hepatic steatosis, cholestatic hepatitis, and cirrhosis. However, the systemic and hepatic lipidome disturbances and underlying toxicological mechanisms remain comprehensively elucidated. Untargeted lipidomics were utilized to analyze serum and liver samples from the rats orally administered a daily dose of amiodarone of either 100 or 300 mg/kg for one week. Changes in the expression of hepatic lipid-related genes were also examined utilizing transcriptomics. We found a higher magnitude of lipidome alterations in the 300 mg/kg than those in the 100 mg/kg groups. Treated animals showed elevated abundances of phosphatidylcholines, ether-linked phosphatidylcholines, sphingomyelins, and ceramides, and decreased levels of triacylglycerols, ether-linked triacylglycerols, and fatty acids. We also found 199 lipid-related differentially expressed hepatic genes between the 300 mg/kg group versus controls, implying lipid metabolism and signaling pathways disturbances. Specifically, elevation of serum phosphatidylcholines and ether-linked phosphatidylcholines, as well as hepatic bismonoacylglycerophosphates were associated with reduced expression of phospholipase genes and elevated expression of glycerophospholipid biosynthesis genes, possibly driving phospholipidosis. Perturbations of sphingolipid metabolism might also be the key events for amiodarone-induced toxicity. Alterations in gene expression levels related to lipid storage and metabolism, mitochondria functions, and energy homeostasis were also found. Collectively, our study characterized the sophisticated perturbations in the lipidome and transcriptome of amiodarone-treated rats and suggested potential mechanisms responsible for amiodarone-induced hepatotoxicity.
Human milk bacteria assembled into functionally distinct synthetic communities in infant formula differently affect intestinal physiology and microbiota in neonatal mini-piglets
Authors: Bras Charles Le , Randuineau Gwenaelle , Cahu Armelle , Dahirel Patrice , Guérin Sylvie , Janvier Regis , Romé Véronique , Rault Lucie , Maillard Marie-Bernadette , Bellanger Amandine , Loir Yves Le , Blat Sophie , Even Sergine , Huërou-Luron Isabelle Le
Published: January 2025

The contribution of Human milk (HM) microbiota to infant gut health was addressed by evaluating the effects of HM bacteria combined in two synthetic communities (SynComs, with anin vitrocharacterized anti-inflammatory (AI) or high immunomodulatory (HI) profile) on systemic and ileal immune cell functions, gut epithelial barrier and microbiota. Neonatal mini-piglets were fed either a formula without supplementation (CTRL) or supplemented with AI or HI SynComs and compared to sow milk-fed (SM) piglets. The two HM-derived SynComs differently modulated microbiota and intestinal functions (mainly immunity). Notably, the abundance of more than half of the intestinal taxa that differed between the three formula groups differed between AI and HI piglets. In addition, fewer differently abundant genera were observed between HI and SM piglets than between CTRL and SM piglets, suggesting that SynCom HI supplementation brought the microbiota of HI piglets closer to that of SM piglets. SynCom supplementation affected immune functions at both systemic and mucosal levels. Fecal sIgA level in HI piglets, which was slightly lower than in SM piglets, was markedly higher than in CTRL and AI piglets. Finally, SynCom bacteria were correlated with several genera in ileum and colon microbiota and both were highly correlated with physiological variables, supporting the HM bacteria-driven influence on gut microbiota and on multiple gut functions. Overall, our data show that SynComs with contrasting immunomodulatory properties but similar taxonomic composition can differently modulate the developmental profile of intestinal functions and microbiota in mini-piglets used as a human infant model.

Importance

Early life environmental factors, such as neonatal diet, modulate gut microbiota that is a driving force for the functional development of the gut. However, the role of the human milk (HM) microbiota is not well understood, particularly the importance of the immunomodulatory properties of HM bacteria. This study provides insight into the differential effects of two synthetic communities, with similar taxonomic composition representative of the taxonomic diversity of the HM cultivable microbiota, but with contrasting immunomodulatory properties (previously characterizedin vitroon an intestinal quadricellular model). Daily supplementation with these two SynComs differently modulated gut microbiota composition and gut physiology, particularly intestinal immune signatures. In conclusion, the functional profile of bacteria within the HM microbiota may induce a different developmental profile of gut physiology in infants.
Blockade of mTOR ameliorates IgA nephropathy by correcting CD89 and CD71 dysfunctions in humanized mice
Authors: Cambier Alexandra , Da Silva Jennifer , Bex Julie , Canesi Fanny , Lachize Lison , Sannier Aurélie , Patey Natacha , Boedec Erwan , Badie Amandine , Monteiro Renato C.
Published: January 2025

Background and hypothesis

IgA nephropathy (IgAN) is the most common glomerulonephritis and major cause of renal failure worldwide. Pathogenesis involves galactose deficient IgA1-immune complexes containing soluble IgA Fc receptor (sCD89). Both IgA1 and sCD89 bind independently to transferrin receptor (TfR1, CD71), a mesangial IgA1 receptor. Here, we hypothesize that sCD89 plays a pathogenic role in IgAN by driving a tri-partite IgA1-sCD89-CD71 complex inducing activationin situof the mTOR (mammalian target of rapamycin) signaling pathway in mesangial cells and contributing to disease progression. mTOR inhibition may disrupt this pathogenic axis, reducing IgA1 and sCD89 deposits, modulating CD71 expression, and alleviating disease manifestations. Here, we investigated the role of sCD89 and a mTOR inhibitor using humanized mouse models of IgAN expressing CD89 and/or IgA1.

Methods

Single cell and RNAseq were obtained from IgAN public dataset and immunostaining from childhood IgAN (cIgAN) biopsies. Human mesangial cell (HMC) stimulation by recombinant sCD89 (rsCD89) was followed by western blot analysis. Pre-clinical assays with mTOR inhibitor (Everolimus) by oral gavage were performed using young α1KImice injected with rsCD89 for 25 days (preventive protocol) and adult α1KICD89Tgmice (treated protocol) for 75 days. Proteinuria, renal function, and circulating immune-complexes (CIC) were analysed and kidneys harvested for histology. Results: RNAseq revealed increased TfR1 and mTOR mesangial cell expression in IgAN patients. TfR1 upregulation was confirmed in cIgAN biopsies. sCD89 stimulation induced HMC TfR1 expression and phosphorylation of mTOR, Akt and p70S6K1. Everolimus treatment prevented or reverted mesangial IgA1 and C3 deposits but also decreased mesangial TfR1 and cell proliferation. Everolimus impaired levels of sCD89- and IgA-CIC, proteinuria, as well as renal function.

Conclusion

These findings highlight the critical role of the sCD89-TfR1-mTOR axis in IgAN pathogenesis and support the use of mTOR inhibitors as a novel therapeutic approach. This approach could significantly improve outcomes by slowing disease progression and minimizing the systemic toxic effects of current immunosuppressive therapies. This is particularly crucial for pediatric patients, where the only approved treatment – steroids – has severe side effects, including detrimental impacts on bone health and growth.
Proof-of-principle of NF1 Gene Therapy in plexiform neurofibroma mice models
Authors: Bostanthirige Dhanushka Hewa , Plante Camille , Vatasescu Jean-Paul Sabo , Lévesque Maude , Poirier Colin , Deschenes Mathieu , Chabot Benoit , Laurent Benoit , Geha Sameh , Brosseau Jean-Philippe
Published: January 2025

Neurofibromatosis type I is a rare neurocutaneous syndrome characterized by the development of disfiguring neurofibroma tumors with unmet clinical needs. As Neurofibromatosis Type I is a monogenic disease, the development of gene therapy is highly attractive, but it is currently unknown if rescuing theNF1gene in established neurofibroma is sufficient for tumor regression. Here, we test this hypothesis by building two novel NF1 mouse models with reversibleNF1expression. In the first model, the humanNF1−/-Schwann cells named ipNF95.11b were genetically modified with a doxycycline-inducible full-length mouseNf1gene. One month after cells implantation in the sciatic nerve, mice were split into 2 groups. Strikingly, all sciatic nerves from mice allowed to drink doxycycline water for one month display complete normalization of the sciatic nerve histologically (n=6 sciatic nerves) whereas 83% (5 out of 6 sciatic nerves) develop or maintain a neurofibroma when drinking regular water. In the second model, the humanNF1+/-Schwann cells named ipNF95.11c were genetically modified with a doxycycline-inducible potent shRNA against theNF1mRNA transcript. Strikingly, doxycycline withdrawal after neurofibroma establishment allowed complete normalization (n=4 sciatic nerves), whereas all sciatic nerves showed evidence of neurofibroma when kept on doxycycline (n=4 sciatic nerves). Thus, we proof-of-principle NF1 Gene Therapy in plexiform neurofibroma mice models.
Guard cell photorespiration has a major impact on photosynthesis, growth and stomatal behavior in Arabidopsis
Authors: Sun Hu , Schmidt Nils , Lawson Tracy , Hagemann Martin , Timm Stefan
Published: January 2025

Photorespiration is a mandatory metabolic repair shunt of carbon fixation by the Calvin-Benson (CB) cycle in oxygenic phototrophs. Its extent depends mainly on the CO2/O2ratio in chloroplasts, which is regulated via stomatal movements. However, despite comprehensive understanding on the role of photorespiration in mesophyll cells (MC), its role in guard cells (GC) is yet unknown. To analyze this issue, the key enzyme of photorespiration, glycine decarboxylase (GDC), was manipulated through overexpression and antisense suppression of theGDCH-protein gene.

A positive correlation ofGDC-Hexpression with growth, photosynthesis and carbohydrate biosynthesis was observed in the transgenic lines, demonstrating active photorespiration is involved in stomatal regulation. This view is supported by gas exchange measurements showing that optimized GC photorespiration improves plant acclimation towards conditions requiring a high photorespiratory capacity, including high light. Microscopic analysis revealed that altered photorespiratory flux also affected starch accumulation patterns in GC, eventually serving as the underlying mechanistic for altered stomatal behavior.

Collectively, our data suggest that photorespiration is a key component of the regulatory circuit that coordinates stomatal movements with external and internal CO2availability. Thus, manipulation of photorespiration in GC has the potential to engineer crops maintaining growth and photosynthesis under future climates.

One-sentence summary

Guard-cell-specific manipulation of photorespiratory glycine decarboxylase reveals photorespiration is active in guard cells and makes a major contribution to stomatal metabolism and movements.
Appendometer: A system for simultaneous, high-throughput morphometry ofDrosophilalegs and wings
Authors: Rossoni Daniela M. , Murray Connor , Porto Arthur , Houle David
Published: January 2025

The inheritance of many different organismal features is correlated, as is their evolution, sug-gesting that we need to understand the pattern and causes of those correlations to understand evolution. Unfortunately, we generally lack the ability to rapidly and accurately measure large numbers of traits, making it difficult to describe the patterns of trait relationships or for-mulate hypothesis about the causes of their entanglement. We have previously developed a system to make high-dimensional measurements of Drosophilid fly wings in live specimens. Here, we report the extension of this approach to rapidly assess the dimensions of the distal leg segments, femur, tibia, and tarsi. Using the system, we describe the covariance of the wing and leg morphology and evaluate the relative rates of evolution of legs and wings.

We use two simple suction devices to immobilize and position legs and wings of an anaes-thetized fly for imaging, then take a single image incorporating both appendages. We em-ployed a machine learning method to measure leg segment lengths, which should be broadly applicable across diverse taxa. Experienced users can image the legs and wings of a fly every two minutes, with outlier detection and correction taking approximately 40 seconds. To demonstrate the usefulness of these methods, we measured the legs and wings of over 4,000 specimens from 43 different Drosophilid taxa. We estimated the rate of wing and leg evolu-tion using a phylogenetic mixed model.

Repeatabilities of leg segments lengths averaged over 80%. The rate of evolution of wing and leg sizes are similar, but the rate of wing proportion evolution is 1.6 times as high as that of leg proportions due to strong allometric changes in wing shape. Within-species variation in leg proportions is highly correlated with the rate of leg proportion evolution, as is true for wings. Relative lengths of leg segments showed a strong pattern of negative correlations be-tween the lengths of the tarsal segments and of the femurs and tibias, while all other segment correlations were positive. This pattern was repeated in the rate estimates, suggesting that se-lection favors tradeoffs between tarsi and the remainder of the leg.

Our simple system for imaging and measuring legs and wings simultaneously has high throughput and repeatability. It is readily applicable to a wide variety of winged insects and other traits, including wings, that could be imaged. Applied toDrosophila, our morphometric system enlarges the ability to study inheritance, pleiotropy, and evolution in this important model taxon.
A GPVI-platelet-neutrophil-NET axis drives systemic sclerosis
Authors: Darbousset Roxane , Senkpeil Leetah , Kuehn Julia , Balu Spoorthi , Miglani Dhruv , Dillon Eilish , Fromson Caroline , Elahee Mehreen , Jarrot Pierre-Andre , Montesi Sydney B. , Rao Deepak A. , Ware Jerry , Wagner Denisa D. , Bujor Andreea M. , Gutierrez-Arcelus Maria , Nigrovic Peter A.
Published: January 2025

Systemic sclerosis (SSc) is characterized by progressive fibrosis of skin, lung, and other organs and retains among the highest rates of mortality among autoimmune diseases. We identified activation of circulating neutrophils from patients with diffuse SSc, together with concordant transcriptomic evidence of neutrophil activation in blood, skin, and lungs, and in mice with experimental SSc of skin and lung induced by hypochlorous acid or bleomycin. Neutrophil depletion abrogated experimental SSc, while adoptive transfer of SSc neutrophils induced skin and lung fibrosis in healthy mice, identifying neutrophils as both necessary and sufficient for disease. In patients, platelet activation accompanied diffuse SSc, and in mice platelet activation preceded neutrophil activation, suggesting an upstream role. Platelet depletion abrogated both neutrophil activation and tissue fibrosis. SSc platelets conferred upon neutrophils the capacity to induce SSc. This capacity corresponded to enhanced production of neutrophil extracellular traps (NETs); experimental SSc was abrogated in NET-deficient PAD4−/−mice, a resistance bypassed by adoptive transfer of PAD4-suficient SSc neutrophils, confirming NETs as a key effector mechanism of SSc. In turn, platelet activation was mediated via the platelet collagen receptor GPVI, while GPVI deficiency resulted in attenuated platelet and neutrophil activation, fewer circulating NETs, and protection from fibrosis in both murine models of SSc. Together, these findings define a GPVI-platelet-neutrophil-NET axis in SSc and identify a new set of therapeutic targets in this often-refractory condition.
Early Proteasome Gene Downregulation And Impaired Proteasomes Function Underlie Proteostasis Failure In Alzheimer’s Disease
Authors: Jiang Shan , Srikanth Malavika , Serpe Rossana , Yavari Shadi , Gaur Palavi , Collins Galen Andrew , Soni Rajesh , Menon Vilas , Myeku Natura
Published: January 2025

Alzheimer’s disease (AD) is characterized by the accumulation of pathogenic proteins, notably amyloid-beta and hyperphosphorylated tau, which disrupt neuronal function and contribute to cognitive decline. Although proteotoxic stress is well-established in AD, the role of the ubiquitin-proteasome system (UPS) in maintaining neuronal proteostasis, and how it becomes compromised during disease progression remains incompletely understood.

Here we integrated multiple approaches to characterize proteasome function, composition, and regulation in post-mortem human AD brain tissue compared to age-matched controls. These included proteasome kinetic assays, affinity purification of intact 26S proteasomes, in-gel activity assays and proteomics. According to Braak staging, we further interrogated bulk RNA-seq and single-nucleus RNA-seq (sn-RNA-seq) datasets spanning the progression of AD pathology. Finally, we examined Nrf1/NFE2L1 binding and subcellular localization to understand the transcriptional regulation of proteasome genes in AD.

We found that proteasome activity is significantly impaired in AD brains, affecting both 26S and 20S complexes. This reduction in proteolytic capacity persisted after proteasome purification, implicating intrinsic defects within the proteasome complex. Proteomic profiling revealed diminished abundances of constitutive proteasome complexes and the co-purification of proteasomes with aggregation-prone substrates (e.g., tau, α-synuclein), suggesting proteasome entrapment in pathological aggregates. Transcriptomic analyses showed progressive downregulation of constitutive proteasome subunit genes in individuals along the Braak stage axis, with downregulation apparent even at the earliest Braak stages, in tissue without overt tau aggregation. Neurons were disproportionately affected, whereas non-neuronal cells did not show substantial differences in proteasome-related gene expression, possibly through immunoproteasome induction. Despite elevated NFE2L1 expression, a key transcription factor normally driving proteasome gene transcription, AD brains exhibited impaired Nrf1 nuclear localization, preventing the expected compensatory upregulation of proteasome components.

Collectively, our findings suggest that proteasome dysfunction in AD arises early and deepens over the disease course. Intrinsic alterations in proteasome complexes, coupled with early transcriptional downregulation of proteasome subunits and disrupted Nrf1-mediated regulatory pathways, contribute to a vicious cycle of proteotoxic stress and neuronal vulnerability. Restoring proteasome function and enhancing Nrf1-driven transcriptional responses may represent promising therapeutic strategies to preserve proteostasis and mitigate neurodegeneration in AD.
Proteomic Analysis of Breast Cancer Subtypes Identifies Stromal Contributions that Dictate Aggressive Malignant Behavior
Authors: Burton Jordan B. , Gascard Philippe , Pan Deng , Bons Joanna , Bai Rosemary , Chen-Tanyolac Chira , Caruso Joseph A. , Hunter Christie L. , Schilling Birgit , Tlsty Thea D.
Published: January 2025

Breast cancer manifests as multiple subtypes with distinct patient outcomes and treatment strategies. Here, we optimized proteomic analysis of Formalin-Fixed Paraffin-Embedded (FFPE) specimens from patients diagnosed with five breast cancer subtypes, luminal A, luminal B, Her2, triple negative (TNBC) and metaplastic breast cancers (MBC), and from disease-free individuals undergoing reduction mammoplasty (RM). We identified and quantified ∼6,000 protein groups (with >2 peptides per protein) with significant changes in over 26% of proteins comparing each cancer subtype with control RM. Stringent statistical filters allowed us to deeply mine 576 significant conserved protein changes shared by all subtypes and protein changes unique to each subtype. The most aggressive subtype, MBC, revealed exacerbated stromal stress responses, as illustrated by a collagenolytic extracellular matrix (ECM) and immune participation biased towards neutrophils and eosinophils. Immunostaining of breast tissue sections confirmed differences across subtypes, in particular, a dramatic upregulation of SERPINH1, neutrophil-specific myeloperoxidase and eosinophil cationic protein in MBC. In summary, deep proteomic, digitalized protein abundance profiles, generated from FFPE breast cancer tissues, revealed significant changes in ECM and cellular proteins providing insight into clinically relevant states.