bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating the Global Market Size for Disease-Modifying Therapies in Epilepsy Caused by Haploinsufficiency
Authors: Pérez-Palma Eduardo , Brünger Tobias , Lhatoo Samden , Zhang Guo-Qiang , Nascimento Fabio A , Lal Dennis
Published: January 2025

Importance

Haploinsufficiency, a condition where a single functional copy of a gene is insufficient to maintain normal physiological function due to a mutation, represents the most prevalent disease mechanism underlying genetic epilepsies, particularly developmental and epileptic encephalopathies (DEEs). Current therapies for these patients primarily address symptoms and fail to alter the disease trajectory. Given the prospect of targeted gene therapies, accurately quantifying the burden of these disorders is paramount for optimizing resource allocation in patient care and facilitating the development of novel disease-modifying therapies.

Objective

To estimate the global and U.S. incidence and prevalence of epilepsy caused by haploinsufficiency.

Design, Setting, and Participants

First, we identified epilepsy genes, focusing on autosomal dominant genes with a high likelihood of haploinsufficiency. Second, we utilized a statistical framework to estimate the birth incidence of patients with protein-truncating variants in these genes, incorporating gene-specific mutation rates and birth rate data. Finally, we calculated prevalence by multiplying annual incidence by an effective disease duration, considering factors like sudden unexpected death in epilepsy.

Main Outcomes and Measures

Birth incidence and prevalence of epilepsy attributable tode novoprotein-truncating variants in haploinsufficient genes.

Results

An estimated 228.81 (90% CI: 206.21–241.93) cases of haploinsufficiency-related epilepsy occur per 100,000 live births globally. This translates to approximately 313,595 new cases annually worldwide and 8,736 in the United States. The estimated global prevalence is 14,343,840 individuals.

Conclusions and Relevance

This study provides the first data-driven estimates of the of haploinsufficiency-related epilepsy burden, highlighting a substantial population potentially benefiting from gene-targeting therapies. These findings have significant implications for research prioritization, resource allocation, and the development of precision medicine approaches for treating these severe neurological disorders.
Identifying socio-economic barriers to antibiotic resistance stewardship in the Dairy Industry in LICs and LMICs
Authors: Singh Harshita , Singh Awanish Kumar , Singh Gargi
Published: January 2025

Antibiotic resistance (ABR) is a severe global public health threat, particularly in low- and middle-income countries (LICs and LMICs), where socio-economic and infrastructural factors impede effective ABR management. Here, we identify critical challenges, including disparity in the volume of research related to ABR stewardship for the dairy industry, that hinder the success of national action plans in LICs and LMICs. We conducted a literature review to pinpoint specific challenges to ABR stewardship in LICs and LMICs and employed generalised linear models to evaluate the predictive influence of dairy-related, socio-economic, and environmental factors on progress in antimicrobial resistance stewardship using TrACSS scores. We ascertained six key themes in otherwise interconnected challenges that critically limit ABR stewardship in LICs and LMICs: (i) lack of awareness among stakeholders, (ii) ineffective regulations, (iii) insufficient surveillance and monitoring, (iv) inadequate veterinary health infrastructure, (v) economic constraints, and (vi) certain cultural beliefs and traditional practices. Generalised linear regression models confirmed that effective surveillance, robust health and diagnostic infrastructure, and economic affluence significantly determine the progress of ABR stewardship in a country, as reported by TrACSS scores. However, the substantially sparse knowledge on the impact of dairy farms on environmental resistome generated in LICs and LMICs raises the concern that the interventions for the dairy industry in these countries are not informed by the actual local and national conditions.
Transcriptomic analysis of chronic chikungunya in the Reunionese CHIKGene cohort uncovers a shift in gene expression more than 10 years after infection
Authors: Gérardin Patrick , Medina-Santos Raissa , Le Clerc Sigrid , Bruneau Léa , Maillot Adrien , Labib Taoufik , Rahmouni Myriam , Spadoni Jean-Louis , Meyniel Jean-Philippe , Cornet Clémence , Lefebvre Cécile , El Jahrani Nora , Savara Jakub , Mathew Mano Joseph , Fontaine Christine , Payet Christine , Ah-You Nathalie , Chabert Cécile , Mussard Corinne , Porcherat Sylvaine , Medjane Samir , Noirel Josselin , Marimoutou Catherine , Hocini Hakim , Zagury Jean-François
Published: January 2025

Aim

In 2005-2006, a chikungunya epidemic of unprecedented magnitude hit Reunion Island, which raised a public health concern through the substantial proportions of long-lasting manifestations. To understand the pathophysiology underlying chronic chikungunya (CC), we designed the CHIKGene cohort study and collected blood samples from 133 subjects diagnosed with CC and from 86 control individuals that had recovered within 3 months, 12-to-15 years after exposure.

Methods

We conducted bulk RNAseq analysis on peripheral blood mononuclear cells to find differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) and gene ontologies to uncover top-level enriched terms associated with DEGs, and weighted gene correlation network analysis (WGCNA) to elucidate underlying cellular processes.

Results

Among 1549 DEGs, gene expression analysis identified 10 top genes includingNR4A2andTRIM58(upregulated in CC),IGHG3andIGHV3-49(downregulated in CC) linked to immune regulation,OSBP2(upregulated in CC) andSEMA6B(downregulated in CC) linked to neuronal homeostasis and axon guidance, respectively. GSEA and WGCNA unveiled cellular processes such as "Metabolism of RNA" and "Cell Cycle”.

Conclusions

This study uncovers a shift in gene expression of CC subjects.IGHG3andIGHV3-49gene shut-offs spotlight the importance of neutralizing antibodies against chikungunya virus in the progression to chronic disease. Human diseases associations highlight connections to rheumatoid arthritis, nervous and cardiac systems. GSEA and WGCNA bounce the hypotheses of a persistent viral reservoir or an increased susceptibility to RNA viral pathogens with new onset infections. Together, our findings might offer potential targets for therapeutic options aimed at alleviating chronic chikungunya.
araCNA: Somatic copy number profiling using long-range sequence models
Authors: Visscher Ellen , Yau Christopher
Published: January 2025

Somatic copy number alterations (CNAs) are hallmarks of cancer. Current algorithms that call CNAs from whole genome sequenced (WGS) data have not exploited deep learning methods owing to computational scaling limitations. Here, we present a novel deep-learning approach, araCNA, trained only on simulated data that can accurately predict CNAs in real WGS cancer genomes. araCNA uses novel transformer alternatives (e.g Mamba) to handle genomic-scale sequence lengths (∼1M) and learn long-range interactions. Results are extremely accurate on simulated data, and this zero-shot approach is on par with existing methods when applied to 50 WGS samples from the cancer genome atlas. Notably, our approach requires only a tumour sample and not a matched normal sample, has fewer markers of overfitting, and performs inference in only a few minutes. araCNA demonstrates how domain knowledge can be used to simulate training sets that harness the power of modern machine learning in biological applications.
Off-target prediction of SGLT2 inhibitors: an integrative bioinformatics approach to uncover structural mechanisms
Authors: Yang Hsin-Ju , Chen Yun-Ti , Hsu Zi-Chun , Yang Jinn-Moon
Published: January 2025

Gliflozin is known to inhibit sodium glucose transporter 2 (SGLT2) inhibitors (SGLT2i). They have been approved for the treatments of diabetes mellitus, cardiovascular diseases, and chronic kidney disease in recent years. However, the mechanisms for the multifunction remain unclear. We here propose a hypothesis of other protein targets for gliflozins. Additionally, the multistage of the protein, the specificity of the drugs, along with the structural data shortage have posed a hindrance to disclose gliflozin and its binding environment (BE).

Considering the difficulties on the issue, this thesis provides an approach to uncover protein off-targets and to find the underlying pathways. We predicted pyranose was a critical substructure from > 1,500 SGLT2i. Hierarchical clustering on atom-based interaction, combined with propensity, revealed key interaction among 1,572 pyranose BEs. The other criterium presented was the concept of compound spanning space via protein pocket size. Binding sites (BSs) from proteins like SGLT2 were able to provide similar pockets, approximating the occupied space of the ligands. Finally, gliflozin binding pockets prefer (1) aromatic residues for van der Waals force, (2) aspartate or asparagine as hydrogen bond providers, and (3) protein pocket size ≧442 Å2. These criteria were integrated into a scoring function STand predicted several possible proteins.

This research presents a pipeline for target identification of emerging drug agents and proteins with crystallographic difficulties. The study provides an innovative computational methodology on extraction of binding features on transmembrane proteins and further pharmaceutical development.
Epidermal Cell Dynamics Regulates Rice Lamina Joint Morphogenesis and Leaf Angle Formation throughOsZHD1andOsZHD2Regulation
Authors: Xu Yiru , Zhou Heng , Wu Xiaojiang , Cui Wuyu , Xu Shouling , He Xi , Xiang Dan , Zhou Ming , Hong Lilan
Published: January 2025

The lamina joint is a critical determinant of leaf angle and crop architecture. While epidermal cells play a fundamental role in organ morphogenesis, influencing the overall shape and function of plants, their impact on lamina joint morphology has been largely overlooked. Here, we tracked the cellular dynamics of the rice lamina joint epidermis during leaf angle formation. We found that the asymmetric elongation between the lateral and medial edges, determined by spatial differences in the longitudinal elongation and number of epidermal cells, was a key factor in leaf angle formation. Mutations in the homeobox genesOsZHD1andOsZHD2disrupted the growth patterns of epidermal cells in the lamina joint, resulting in a decreased leaf angle. RestoringOsZHD1expression in the epidermis reverted the reduced leaf angle phenotype ofoszhd1 oszhd2, highlighting the importance of epidermis development for lamina joint morphogenesis. Transcriptome data suggested thatOsZHD1andOsZHD2were involved in auxin synthesis, which modulates leaf angle by inhibiting the growth of lamina joint epidermal cells. This study underscores the significance of epidermal cells in shaping the lamina joint and elucidates the critical role ofOsZHD1andOsZHD2in regulating epidermal cell behavior and leaf angle formation.
Integrative multi-layer workflow for quantitative analysis of post-translational modifications
Authors: Devesa Cristina A. , Barrero-Rodríguez Rafael , Laguillo-Gómez Andrea , Guerrero-Sánchez Victor M. , del Río-Aledo David , Mena Diego , Jorge Inmaculada , Núñez Estefanía , Calvo Enrique , López Juan Antonio , Marín-Vicente Consuelo , Martínez-Val Ana , Camafeita Emilio , Ibáñez Borja , Enríquez José Antonio , Martín-Ventura José Luis , Rodríguez Jose Manuel , Vázquez Jesús
Published: January 2025

Novel algorithms based on ultratolerant database searching have paved the way for comprehensive analysis of all possible post-translational modifications (PTM) that can be detected by mass spectrometry-based proteomics, obviating their prior knowledge. These tools together with novel quantitative statistical models allow hypothesis-free approaches to study the role and impact of PTM on biological systems. However, interpretation of this information from a pathophysiological perspective is challenging due to the huge amounts of PTM data, the existence of chemical, structural, and statistical artifacts and the lack of dedicated tools for their analysis.

Here we propose a novel integrative workflow that automatically captures several layers of PTM-related information, including variations in trypsin efficiency, zonal changes, specific PTM changes and hypermodified regions, allowing advanced control of artefacts and coherent and comprehensive interpretation of PTM data. We show the performance of the new workflow by reanalyzing proteomics data from animal models of mitochondrial heteroplasmy and ischemia/reperfusion, revealing relevant PTM information not previously detectable, including consistent detection of novel oxidative modifications in Met and Cys residues from raw proteomics data. The workflow is available through the application PTM-compass.
Selection of pre-leukemic hematopoietic stem cells driven by distinct extracellular matrix molecules
Authors: Jassinskaja Maria , Bode Daniel , Gonka Monika , Roumeliotis Theodoros I , Hogg Alexander J , Rubio Lara Juan A , Bennett Ellie , Milek Joanna , Theeuwes Bart , Vijayabaskar M S , Cosme Lilia Cabrera , Che James L C , MacDonald Sandy , Ahmed Sophia , Hall Benjamin A , Vasey Grace , Kooi Helena , Belmonte Miriam , Shepherd Mairi S , Brackenbury William J , Kucinski Iwo , Yamazaki Satoshi , Holding Andrew N , Cull Alyssa H , Wilson Nicola K , Göttgens Berthold , Choudhary Jyoti , Kent David G
Published: January 2025

Despite rapid advances in mapping genetic drivers and gene expression changes in hematopoietic stem cells (HSCs), there is a relative paucity of studies at the protein level. Here, we perform a deep, multi-omic characterization (epigenome, transcriptome and proteome) of HSCs carrying a loss-of-function mutation inTet2, a key driver of increased self-renewal in blood cancers. Using state-of-the-art, multiplexed, low-input mass spectrometry (MS)-based proteomics, we profile wildtype (WT) and TET2-deficient (Tet2-/-) HSCs and show that the proteome captures previously unrecognized molecular processes which define the pre-leukemic HSC molecular landscape. Specifically, we obtain more accurate stratification of WT andTet2-/-HSCs than transcriptomic approaches and identify extracellular matrix (ECM) molecules as novel points of dysregulation upon TET2 loss. HSC expansion assays using ECM-functionalized hydrogels confirm a selective effect on the expansion ofTet2-mutant HSCs. Taken together, our study represents a comprehensive molecular characterization ofTet2-mutant HSCs and identifies a previously unanticipated role of ECM molecules in regulating self-renewal of disease-driving HSCs.
Adiponectin exerts sex-dependent effects on lipid, amino acid, and glucose metabolism during caloric restriction
Authors: Ikushima Yoshiko M , Chen Kuan-Chan , Sulston Richard J. , Mattiucci Domenico , Brain Eleanor J. , Fung Xin Zi Stefanie A , Suchacki Karla J. , Thomas Benjamin J. , Lovdel Andrea , Bennett Matthew , Kobayashi Hiroshi , Whitfield Phillip D. , Takubo Keiyo , Baker Andrew H. , Morton Nicholas M. , Semple Robert K. , Cawthorn William P.
Published: January 2025

Adiponectin is the most abundant hormone in the circulation. Plasma adiponectin decreases in obesity but increases in leanness, including during caloric restriction (CR) in animals and humans. In obesity, adiponectin deficiency promotes cardiometabolic dysfunction. In contrast, the roles of adiponectin in CR, when it is at its highest, are largely unknown. To address this, we studied global adiponectin knockout (KO) in male and female mice fed eitherad libitum(AL) or a 30% CR diet from 9-13 weeks of age. We show that adiponectin KO did not alter CR effects on body mass, body composition, or energy expenditure. However, KO unexpectedly decreased blood glucose levels during CR, both on fasting and following an oral glucose challenge. This is opposite to the effects of adiponectin deficiency in the context ofad libitumdiet (AL) or obesity, and occurred without changes in insulin secretion or sensitivity. Moreover, adiponectin KO augmented CR-induced increases in plasma fatty acids in both sexes and, in males only, impaired systemic triglyceride clearance under CR. Indirect calorimetry further revealed that adiponectin KO alters the shifts between carbohydrate and lipid utilisation that occur during transitions between fed and fasted states. To determine potential molecular mechanisms, we investigated effects of adiponectin KO on the liver, a major adiponectin target that plays key roles entraining metabolism to nutritional state. Hepatic transcriptomics revealed that, in both sexes, adiponectin KO upregulates sterol and fatty acid synthesis genes under AL while increasing amino acid catabolic genes during CR. Together, our findings suggest that adiponectin tunes glucose, lipid, and amino acid metabolism during CR, in whole or in part through effects on the liver. The widely reported functions of adiponectin in pathological states, including obesity and insulin resistance, thus differ sharply from its roles during CR, with marked sexual dimorphism apparent for many of these functions.
Spatial pattern of serology against Borrelia and tick-borne encephalitis virus in roe deer(Capreolus capreolus), Northern France, 2019-2022
Authors: Métras Raphaëlle , Bastien Matthieu , Ollivier Valentin , Poisson Armelle , Combes Benoit , Gonzalez Gaëlle , Helle Teheipuaura , Migné Camille , Suhanda Ilona Eveline , Kim Younjung , Verheyden Hélène , Boulinier Thierry
Published: January 2025

Background

Lyme borreliosis and tick-borne encephalitis (TBE) are tick-borne zoonoses of public health importance, transmitted in Western Europe by the same tick vectorIxodes ricinus. Roe deer (Capreolus capreolus) is a widespread feeding host forI. ricinusstages. Here, we explored the spatial extent of both pathogens in the wild in Northern France by assessing serological status in roe deer.

Methods

We collected 3,147 blood samples (2019-2022), and searched antibodies against both pathogens using ELISA tests. We fitted logistic models to investigate exposure to both or either pathogens, and explored spatial patterns using Kulldorf clustering scan tests.

Results

The overall ELISA IgG prevalence was 23.24% (95%CI [21.77-34.72]) for Borrelia and 8.64% (95%CI [7.45-9.86]) for TBEV. The median Borrelia seroprevalence varied from 4% to 42% between departments, with two high-risk clusters of exposure identified. TBEV seroprevalence did not show any spatial pattern, and positives by seroneutralisation tests were reported in eight departments.

Discussion

Our findings suggest the presence of both pathogens over large areas. Wider spatial sampling including areas at lower risk and improved serological methods would be beneficial to further validate those estimates.
Degradation rather than disassembly of necrotic debris is essential to enhance recovery after acute liver injury
Authors: Schuermans Sara , Quanico Jusal , Kestens Caine , Vandendriessche Sofie , Slowikowski Emily , Crijns Maria-Laura , Pörtner Noëmie , Berghmans Nele , Baggerman Geert , Mattos Matheus Silvério , Proost Paul , Marques Pedro Elias
Published: January 2025

Necrotic cell death causes loss of membrane integrity, release of intracellular contents and deposition of necrotic cell debris. Effective clearance of this debris is crucial for resolving inflammation and promoting tissue recovery. While leukocyte phagocytosis plays a major role, soluble factors in the bloodstream also contribute to debris removal. Our study examined whether enzymatic degradation or disassembly of necrotic debris enhances clearance and improves outcomes in a mouse model of drug-induced liver injury. Using intravital microscopy and proteomic profiling, we demonstrated that necrotic debris is more complex than anticipated, containing DNA, filamentous actin, histones, complement C3, fibrin(ogen) and plasmin(ogen), among many other components. DNase 1 treatment facilitated recovery significantly by enhancing the clearance of DNA from necrotic areas, reducing circulating nucleosomes and actin, and lowering the associated inflammatory response. However, its effect on actin and other damage-associated molecular patterns in necrotic regions was limited. Treatment with short synthetic peptides, specifically 20-amino acid-long positively charged PLK and negatively charged PLE, which displace histones from debrisin vitro,did not inhibit liver injury or promote recovery. Moreover, activating plasmin to disrupt fibrin encapsulation via tissue plasminogen activator (tPa) led to increased circulating actin levels and worsening of injury parameters. These findings suggest that fibrin encapsulation is important for containing necrotic debris and that enzymatic degradation of necrotic debris is a more effective strategy to enhance tissue recovery than targeting debris disassembly.

GRAPHICAL ABSTRACT
Scube2 primes Dispatched and ADAM10-mediated Shh release by recruiting HDL acceptors to the plasma membrane
Authors: Puschmann J. , Steffes G. , Froese J. , Manikowski D. , Ehring K. , Wittke J. , Garbers C. , Wegner S.V. , Grobe K.
Published: January 2025

Hedgehog (Hh) morphogens are essential regulators of growth and patterning at considerable distances from their source, despite being produced as double lipidated proteins that attach to the outer plasma membrane (PM) leaflet of producing cells. While mechanisms to overcome this limitation include the 12-pass transmembrane protein Dispatched1 (Disp), the soluble glycoprotein Scube2, proteolytic processing of lipidated peptide termini, and soluble lipoproteins (LPPs) acting as Hh acceptors and transporters, the molecular interplay of these release factors for effective Hh solubilization from the PM remains controversial. In this work, we used in vivo functional knockdown together with in vitro experiments to show that A Disintegrin and Metalloproteinase 10, Scube2 and Disp act synergistically to remove Hh from the PM and transfer it to LPP acceptors. We also show that Scube2 requirement for Hh transfer depends on LPP acceptor levels: low LPP levels in media require Scube2 for efficient Hh release, whereas increasing LPP levels render Scube2 function increasingly dispensable. Biochemical analysis explained this observation by showing that Scube2 binds high-density LPP (HDL) via its 9 EGF domains and associates with the PM via interactions with cell surface heparan sulfate (HS), revealing a previously unknown role for Scube2 in bridging low-abundance soluble carriers for Hh with HS-rich Hh release sites.
Parameterization of intraoperative human microelectrode recordings: Linking action potential morphology to brain anatomy
Authors: Baker Matthew R. , Klassen Bryan T. , Jensen Michael A. , Valencia Gabriela Ojeda , Heydari Hossein , Ince Nuri F. , Müller Klaus-Robert , Miller Kai J.
Published: January 2025

Deep brain stimulation (DBS) is a targeted manipulation of brain circuitry to treat neurological and neuropsychiatric conditions. Optimal DBS lead placement is essential for treatment efficacy. Current targeting practice is based on preoperative and intraoperative brain imaging, intraoperative electrophysiology, and stimulation mapping. Electrophysiological mapping using extracellular microelectrode recordings aids in identifying functional subdomains, anatomical boundaries, and disease-correlated physiology. The shape of single-unit action potentials may differ due to different biophysical properties between cell-types and brain regions. Here, we describe a technique to parameterize the structure and duration of sorted spike units using a novel algorithmic approach based on canonical response parameterization, and illustrate how it may be used on DBS microelectrode recordings. Isolated spike shapes are parameterized then compared using a spike similarity metric and grouped by hierarchical clustering. When spike morphology is associated with anatomy, we find regional clustering in the human globus pallidus. This method is widely applicable for spike removal and single-unit characterization and could be integrated into intraoperative array-based technologies to enhance targeting and clinical outcomes in DBS lead placement.

Author summary

We developed a new algorithmic approach to capture the structure of single neuron electrophysiology from microelectrode recordings during deep brain stimulation surgery. This method has broad applications for spike characterization, clustering, removal from the background field potential, and comparison across recording sites. Using this technique, we illustrate regional clustering of spike morphologies in the human globus pallidus.
A Shared Neural Network for Highly Liked and Disliked Music
Authors: Ripollés Pablo , Belfi Amy M. , Kasdan Anna , Vessel Edward A. , Halpern Andrea R. , Rowland Jess , Hopkins Robert , Starr G. Gabrielle , Poeppel David
Published: January 2025

Music research has increasingly focused on neural responses to naturalistic stimuli. The neural correlates of music-induced peak moments of pleasure (e.g., chills) have been well-studied; data on other types of aesthetic responses, such as judgments ofbeauty, goodness, or likingare sparse. Among these,likingis of particular interest given its complex nature and its ubiquity in everyday—and musical—experiences. In this functional magnetic resonance imaging (fMRI) study, 26 participants listened to musical excerpts while continuously rating how much theylikedthe music. In addition, subjects provided an overall liking judgment at the end of each musical piece. Participants’ musical preferences manifested remarkably early and were sustained over time, with the value of the continuous rating at the end of each piece showing the strongest correlation with the overall ratings. At the neural level, highly liked and disliked musical pieces activated a shared neural network previously associated with the processing of both positive and negative emotional stimuli. This network encompassed the anterior cingulate cortex, limbic system, basal ganglia, and precuneus. These activations reflected individual differences, such that participants with greater trait-level responsiveness to artistic stimuli showed stronger engagement of this network while listening to music. Finally, the default-mode network was associated with the slope of the continuous ratings, suggesting that the faster participants liked a musical excerpt, the more disengaged this network became. In linking behavior and brain function to better characterize the way humans make aesthetic judgments of music the data support a model in which preferences and aesthetic choices are modulated by brain circuits associated with emotion and reward.
VCAM1-expressing T cells and systemic autoimmunity in Regnase-1 deficiency
Authors: Cuchet-Lourenço Delphine , Conte Matilde I. , Chang Sooyeon , Ten Nika , Eletto Davide , Papapietro Olivier , Plagnol Vincent , de Kok Mike , Hashim Ilie , Ceron-Gutierrez Lourdes , van den Braber Marlous , Curtis James , Groom Harriet C. T. , Maes Mailis , Doffinger Rainer , Garcia Vallejo Juan , Dominguez Conde Cecilia , Farela Neves Joao , Nejentsev Sergey
Published: January 2025

Autoimmunity develops as a result of a breakdown in immune tolerance and activation of autoreactive immune cells. Most of the common autoimmune diseases are polygenic1suggesting dysregulation in multiple signalling pathways. By contrast, in monogenic Inborn Errors of Immunity (IEI), which also can result in autoimmunity, the disease is triggered by a single genetic defect. Therefore, the discovery of causative mutations in IEI allows tracing the molecular mechanisms leading to autoimmunity in humans from a defect in the function of a specific gene to patients’ clinical and immunological phenotype. Here, we discovered an IEI patient with systemic autoimmunity caused by a private homozygous protein-truncating mutation in geneZC3H12Aleading to deficiency of Regnase-1, a regulatory RNase2–5. Flow cytometry, bulk T cell transcriptome analysis and single-cell RNA sequencing demonstrated expansion of γδ T cells expressing VCAM-1 and IFNγ genes. We show that Regnase-1 directly targets 3’UTR ofVCAM1and the coding sequence ofIFNGmRNAs. These findings highlight a new autoimmunity mechanism in humans, where Regnase-1 deficiency causes expansion ofVCAM1+IFNG+ T cells and their interaction with integrin α4β1-expressing B cells, which showed upregulation of IFN-response genes and activation, leading to systemic autoimmunity. Furthermore, we show thatVCAM1+T cells are present in organs of donors and are expanded in the blood of patients with systemic lupus erythematosus, a common autoimmune disease characterised by systemic autoimmunity.
Fusion oncoproteins and cooperating mutations define disease phenotypes inNUP98-rearranged leukemia
Authors: Umeda Masayuki , Hiltenbrand Ryan , Michmerhuizen Nicole L. , Barajas Juan M. , Thomas Melvin E. , Arthur Bright , Walsh Michael P , Song Guangchun , Ma Jing , Westover Tamara , Kumar Amit , Pölönen Petri , Mecucci Cristina , Giacomo Danika Di , Locatelli Franco , Masetti Riccardo , Bertuccio Salvatore N. , Pigazzi Martina , Pruett-Miller Shondra M. , Pounds Stanley , Rubnitz Jeffrey , Inaba Hiroto , Papadopoulos Kyriakos P. , Wick Michael J. , Iacobucci Ilaria , Mullighan Charles G. , Klco Jeffery M.
Published: January 2025

Leukemias withNUP98rearrangements exhibit heterogeneous phenotypes correlated to fusion partners, whereas the mechanism responsible for this heterogeneity is poorly understood. Through genome-wide mutational and transcriptional analyses of 177NUP98-rearranged leukemias, we show that cooperating alterations are associated with differentiation status even among leukemias sharing the sameNUP98fusions, such asNUP98::KDM5Aacute megakaryocytic leukemia withRB1loss or T-cell acute lymphoblastic leukemia withNOTCH1mutations. CUT&RUN profiling reveals that NUP98 fusion oncoproteins directly regulate differentiation-related genes, with binding patterns also influenced by differentiation stage. Usingin vitromodels, we showRB1loss cooperates with NUP98::KDM5A by blocking terminal differentiation toward platelets and expanding megakaryocyte-like cells, whereasWT1frameshifts skew differentiation toward dormant lympho-myeloid primed progenitor cells and cycling granulocyte-monocyte progenitor cells. NUP98::KDM5A models withRB1orWT1alterations have different sensitivities to menin inhibition, suggesting cellular differentiation stage-specific resistant mechanism against menin inhibitors with clinical implications forNUP98-rearranged leukemia.
The Interplay Between Breastfeeding and Autism Spectrum
Authors: Ben-Sasson Ayelet , Mimouni-Bloch Aviva , Samhat-Darawshi Sukaina , Ilann Keren , Gabis Lidia V.
Published: January 2025

Background

Evidence supporting the association between breastfeeding patterns and ASD is inconsistent. This study examined sociodemographic and birth factors related to breastfeeding duration and ASD, compared to a typically developing (TD) cohort, using a data-driven approach based on electronic health and developmental records (EHR).

Methods

Demographics, feeding preferences (breastfeeding, bottle or both), breastfeeding duration as reported by parents during routine baby wellness visits, were analyzed for a cohort of 11,766 (1.9%) children with ASD and a random subsample of 12,000 (2.03%) TD children. The designation of ASD versus TD was based on a national ASD registry and assigned after EHR were completed. Pre-term, very low birth weight, multiple births, and infants with complex medical comorbidities were excluded.

Results

Infants with ASD were breastfed for an average of 5.0 months, 1.5 months shorter than TD. Fewer ASD infants were exclusively breastfed in the first year of life. Two-way ANOVAs indicated a significant effect of socioeconomic status (SES) and ASD on breastfeeding duration, and a significant interaction with ASD. Post-hoc comparisons showed that the Low SES ASD and TD groups were breastfed longer than all other groups (p<.001). For the Low-Medium, Medium-High and High SES groups, infants with ASD were breastfed less than TD.

Conclusions

Shorter breastfeeding duration among ASD was confirmed in this representative cohort, calling for closer monitoring for ASD in infants with breastfeeding difficulties. These challenges were independent of birth parameters; however, influenced by socioeconomic factors.
Probabilistic classification of late treatment failure in uncomplicated malaria
Authors: Mehra Somya , Taylor Aimee R , Imwong Mallika , White Nicholas J , Watson James A
Published: January 2025

Distinguishing treatment failure (recrudescence) from reinfection in uncomplicated falciparum malaria is essential for characterising antimalarial treatment efficacy in malaria endemic areas. Classification of recrudescence versus reinfection is usually based on a comparison of parasite allelic calls derived from PCR amplification and electrophoresis of individual polymorphic markers in the acute and recurrent isolates. Match-counting methods (e.g. 3/3 or 2/3 matching alleles) have usually been applied, but these do not account for multiple comparisons per-marker when infections are polyclonal. We show that when infections are polyclonal, as is common in high transmission settings, currently used match-counting and model-based methods have unacceptably high false-discovery rates leading to overestimation of treatment failure. We develop the softwarePfRecurwhich provides analytical Bayesian posterior probabilities of treatment failure in recurrent falciparum malaria. We use data from a recent study in Angola to demonstrate the potential utility of our model in resolving complex polyclonalP. falciparuminfections, thereby providing more accurate estimation of treatment failure rates.
Registered Report: The effect of systematic endurance training in treatment of women with lipedema - The LipidEx study
Authors: Sæther Julie Caroline , Nordeidet Ada Nilsen , Presthus Randi Merete , Undebakke Randi , Madsen Lise , Norberg Ina Lønnebakken , Kwapeng Sunniva , Owe Katrine Mari , Erbacher Gabriele , Bertsch Tobias , Dieterle Thomas , Nymo Siren , Giskeødegård Guro , Follestad Turid , Tjønna Arnt Erik , Bye Anja
Published: January 2025

Lipedema is a chronic adipose tissue disorder that primarily affects women. The etiology remains unclear and involves abnormal buildup of fat mainly in the lower limbs. It causes physical and psychological morbidity, often with negative impact on daily life. Effective treatment options are still limited, primarily involving conservative treatment such as compression therapy and pain reliever. As endurance training is shown to have beneficial effects on both pain and obesity management in patients suffering of other disorders, LipidEx aims to explore the potential of high-intensity interval training (HIIT) as a novel therapeutic option for women with lipedema. We will perform a cross-over randomized controlled trial (RCT) exploring the effects of 12 weeks of HIIT compared to a control period of usual care. The primary outcome is changes in pain, and secondary outcomes are changes in adipose tissue mass and quality of life.
Patterns of non-fatal overdose and injection-related bacterial infections during pregnancy and the postpartum year among New York State residents
Authors: Cooper Hannah LF , D’Souza Rohan R. , Chang Howard H. , Peterson Emily , Rogers Erin , Wien Simone , Blake Sarah C. , Kramer Michael R.
Published: January 2025

Objectives

Overdoses are a leading cause of maternal mortality in the US, but limited evidence exists about patterns of nonfatal overdose, a key risk factor for subsequent fatal overdose, or of other drug-related harms. Here, we estimate prevalences of nonfatal overdose and injection-related endocarditis and abscesses/cellulitis across the 21 months spanning pregnancy and the postpartum year.

Methods

Among people who experienced an in-hospital birth in New York State between 9/1/2016 and 1/1/2018 (N=330,872), we estimated the prevalences of hospital-based diagnoses of nonfatal overdose and of injection-related bacterial infections (i.e., endocarditis, abscesses, and cellulitis) across these 21 months; by trimester and postpartum quarter; and by social position (e.g., race/ethnicity, rurality, payor).

Results

The 21-month nonfatal overdose prevalence was 158/100,000 births (CI: 145/100,000, 172/100,000); the 21-month prevalence of injection-related bacterial infections was 56/100,000 births (CI: 49/100,000, 65/100,000). There was a trend such that rates of overdose and of injection-related bacterial infections declined as pregnancy progressed and rebounded postpartum. Rates of all outcomes were highest outside of large metropolitan areas and among publicly insured residents.

Conclusions for Practice

The trend toward diminished rates during pregnancy is supported by past qualitative studies. If confirmed by future research in other geographical regions and with larger sample sizes, this finding holds promise for programmatic and policy interventions. Interventions co-designed with people who use drugs could complement and support harm reduction efforts that pregnant people are already engaging in independently. Such efforts can help people who use drugs survive the pregnancy and postpartum year.

Significance

“What is already known on this subject?

Fatal overdoses are a leading cause of maternal mortality in the US. Little evidence exists, however, about patterns of nonfatal overdose, a strong predictor of future fatal overdose, or about other serious injection-related bacterial infections.

“What this study adds?

We find trends suggesting that rates of nonfatal overdose and injection-related bacterial infections decline during pregnancy and then rebound postpartum. These findings, if confirmed in future research, suggest a clear path toward intervention development: partnering with people who use drugs to design interventions that complement and support their existing harm reduction interventions during pregnancy and in the postpartum period.
Time-dependent relationship between urinary biomarkers of nucleic acid oxidation and colorectal cancer risk
Authors: Zhao Yingya , Nogueira Marina S. , Milne Ginger L. , Gao Yu-Tang , Cai Qiuyin , Lan Qing , Yi Haoyang , Rothman Nathaniel , Shu Xiao-Ou , Zheng Wei , Chen Qingxia , Yang Gong
Published: January 2025

PURPOSE

Randomized controlled trials have failed to validate that neutralizing oxidative stress (OxS) through antioxidant supplementation reduces cancer risk. This study aims to prospectively investigate whether the relationship between systemic OxS and colorectal cancer (CRC) risk changes over the course of cancer development.

METHODS

This study utilized a nested case-control design in two Shanghai cohorts for primary analysis and one US cohort for replication analysis. During a median follow-up of 15.1 years in the Shanghai cohorts, 1938 incident CRC cases were identified and matched to one control each. In the US cohort, 285 incident CRC cases were included with two matched controls per case. Systemic OxS was assessed by urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2’-deoxyguanosine [8-oxo-dG]) and RNA oxidation (7,8-dihydro-8-oxo-guanosine [8-oxo-Guo]) using UPLC-MS/MS assays. Multivariable-adjusted odds ratios (ORs) for CRC risk were calculated.

RESULTS

After adjusting for potential confounders, we observed an inversion association between OxS markers and CRC risk in the Shanghai cohorts, which was independently replicated in the US cohort. Moreover, the inverse association was time-dependent, manifesting only for CRC cases diagnosed within 5 years of enrollment. ORs (95% CI) for CRC at the 10th and 90th percentiles of 8-oxo-dG levels, relative to the median, were 1.87 (1.39 to 2.53) and 0.48 (0.37 to 0.63), respectively, demonstrating an approximate 4-fold difference in risk between the two groups, withPfor overall association of < 0.001. A similar pattern was observed for 8-oxo-Guo. No significant association was found for CRC diagnosed beyond 5 years of enrollment.

CONCLUSION

This novel finding of an inverse and time-dependent relationship between systemic OxS and CRC risk, if further confirmed, may provide a new perspective for revisiting redox-based chemoprevention.

CONTEXT

Background

Almost all large randomized controlled trials have failed to validate the hypothesis that neutralizing oxidative stress through antioxidant supplementation can lower cancer risk, which has puzzled the public and researchers for decades.

Key Findings

A reduced risk for colorectal cancer (CRC) with increasing systemic oxidative stress, measured by two urinary biomarkers of DNA and RNA oxidation, was observed in two large prospective cohort studies in Shanghai, China, and was replicated in an independent cohort in the United States. This association was time-dependent, with the inverse relationship strengthening as the biomarker assessment neared the time of CRC diagnosis.

Relevance

Our study, for the first time, suggests an inverse and time-dependent relationship between systemic oxidative stress and CRC development, which, if further confirmed, may provide a new perspective for revisiting redox-based chemoprevention.
Revisiting the Need for mRNA Nucleoside Modification in CAR T Cell Engineering
Authors: Kahwaji Nourhan , Kotzian Niklas , Prinz Jasmin Melissa , Pu Yaolin , Kath Jonas , Picht Samira , Hiller Anna Luisa , Dunne Charlotte Maeve , Launspach Michael , Kleyer Arnd , Simon David Nils , Wagner Dimitrios Laurin , Pichon Chantal , Krönke Gerhard , Schmueck-Henneresse Michael , Volk Hans-Dieter , Gossen Manfred , Drzeniek Norman Michael
Published: January 2025

mRNA-based chimeric antigen receptor (CAR)-T cells offer the promise of enhanced safety and simplified manufacturing. However, in vitro-transcribed (IVT) mRNA is known to trigger antiviral immune responses, inflammatory signaling, and apoptosis in transfected cells. To address these challenges and enable efficient IVT-mRNA expression, modified nucleosides, such as N1-methyl-pseudouridine (m1Ψ), have become the gold standard for CAR-T cell production, albeit at increased cost.

In this study, immune responses to IVT-mRNA were evaluated across five primary human cell types, including T-cells. Unexpectedly, T-cells, unlike other immune and non-immune cell types tested, exhibited no immune activation in response to unmodified mRNA. T-cell viability and cytokine secretion patterns remained unaffected, regardless of whether unmodified mRNA was delivered via lipid nanoparticles (LNPs) or electroporation.

Furthermore, CAR expression levels in T-cells were not influenced by mRNA modification with m1Ψ or 5-methoxy-uridine (5moU) nucleosides. The absence of nucleoside modifications did not compromise CAR-T cell cytotoxic potency, demonstrating that such modifications are not required for producing functional CAR-T cells.

These findings eliminate the need for nucleoside modification in T-cell mRNA, simplifying and reducing the cost of CAR-T cell manufacturing while positioning IVT-mRNA as a highly efficient and minimally invasive tool for CAR-T cell engineering.
Periostin exon 17 skipping enhances the efficacy of local AAV-microdystrophin administration in a fibrotic model of Duchenne muscular dystrophy
Authors: Trundle Jessica , Boulinguiez Alexis , Lu-Nguyen Ngoc , March James , Malerba Alberto , Popplewell Linda
Published: January 2025

Duchenne muscular dystrophy (DMD) is a severe, progressive genetic disorder primarily affecting boys, characterized by muscle degeneration due to mutations in the DMD gene encoding dystrophin, a crucial protein for muscle fiber integrity. The disease leads to significant muscle weakness and eventually to loss of ambulation. AAV-microdystrophin gene therapy shows promise in preclinical and clinical settings. However, muscle fibrosis, a consequence of chronic inflammation and extracellular matrix (ECM) remodeling, exacerbates disease progression and may hinder therapeutic efficacy. Periostin, a matricellular protein involved in fibrosis, is upregulated in DMD rodent models and correlates with collagen deposition. We previously developed an antisense oligonucleotide strategy to induce exon 17 skipping and so reduce periostin expression and collagen accumulation in the fibrotic D2.mdxmouse model of DMD. Here, we investigated the combined effects of periostin modulation and AAV-microdystrophin (AAV-MD1) treatment. We found that systemic periostin splicing modulation with intramuscular AAV-MD1 administration significantly improved muscle function, assessed by grip strength and treadmill performance, compared to either single treatment. Importantly, periostin exon skipping increases the microdystrophin protein expression. These findings suggest that targeting periostin in conjunction with microdystrophin therapy could represent a valid therapeutic strategy for DMD.
Loss of the autism associated geneTbr1disrupts prediction and encoding by prefrontal ensembles during socioemotional behaviors
Authors: Turner Marc , Robinson-Schwartz Sarah , Fazel-Darbandi Siavash , Rubenstein John L.R. , Sohal Vikaas S.
Published: January 2025

Disruptions in many genes linked to autism spectrum disorder (ASD) affect synaptic function and socioemotional behaviors in mice. However, exactly how synaptic dysfunction alters neural activity patterns underlying behavior remains unknown. We addressed this using mice lacking the high confidence ASD geneTbr1in cortical layer 5 (L5) projection neurons (Tbr1cKO mice). These mice have known deficits in synaptic input to L5 neurons and social behavior. We also find some abnormalities in anxiety-related avoidance. Calcium imaging of prefrontal L5 neurons revealed that despite reduced overall activity, cKO mice recruit normal numbers of neurons into prefrontal ensembles encoding social and anxiety-related behaviors. However, the stability, inter-neuronal coordination, and reactivation of social ensembles were diminished in cKO mice. Furthermore, in cKO mice, ensembles no longer predicted approach-avoidance decisions. These results reveal new aspects of how prefrontal ensembles encode socioemotional behaviors, and malfunction in the setting of ASD-linked gene disruption.
Is cultural context the crucial touch? Neurophysiological and self-reported responses to affective touch in women in South Africa and the United Kingdom
Authors: Hewitt Danielle , Besharati Sahba , Williams Victoria , Leal Michelle , McGlone Francis , Stancak Andrej , Henderson Jessica , Krahé Charlotte
Published: January 2025

Affective touch, involving touch-sensitive C-tactile (CT-) afferent nerve fibres, is integral to human development and wellbeing. Despite presumed cultural differences, affective touch research typically includes ‘Western’, minority-world contexts, with findings extrapolated cross-culturally. We report the first cross-cultural study to experimentally investigate subjective and neurophysiological correlates of affective touch in women in South Africa (SA) and the United Kingdom (UK) using (1) subjective touch ratings, and (2) cortical oscillations for slow CT-optimal (vs. faster non-CT-optimal) touch on two body regions (arm, palm). Cultural context modulated affective touch experiences: SA (vs. UK) participants rated touch as more positive and less intense, with enhanced differentiation in sensorimotor beta band oscillations, especially during palm touch. UK participants differentiated between stroking speeds, with opposite directions of effects at arm and palm for frontal theta oscillations. Results highlight the importance of cultural context in subjective experience and neural processing of affective touch.