bluuebunny/crossref_metadata_2025_split huggingface dataset:
SENSITIVITY OF MEDIAL/LATERAL BALANCE CONTROL TO VISUAL DISTURBANCES WHILE WALKING IN YOUNG AND OLDER ADULTS
Authors: DiBianca Stephen J. , Reimann Hendrik , Gray Julia , Peterka Robert J. , Jeka John J. 
Published: December 2024

AbstractHumans integrate multiple sources of sensory information to estimate body orientation in space. Balance control experiments while standing provide evidence that the contributions of these sensory channels change under different conditions in a process called sensory reweighting. This study aims to address whether there is evidence for sensory reweighting while walking and explores age-related differences in medial/lateral balance control under visually perturbing walking conditions. Thirty young adults (18–35 years) and thirty older adults (55–79 years) walked on a self-paced treadmill within a virtual environment that delivered frontal plane multi-sine visual disturbances at three amplitudes (6°, 10°, and 15°). Frequency response functions were used to quantify visual sensitivity to balance disturbances, while spatiotemporal gait parameters (e.g., step width, step-width variability) were measured to assess balance control. Visual sensitivity decreased in both populations with increasing stimulus amplitude, analogous to the sensory reweighting hypothesis in balance control while standing. Despite the decrease in visual sensitivity, the compensatory upweighting of other sensory systems was not observed through measurements of remnant sway. Older adults exhibited higher visual sensitivity at all amplitudes compared to young adults, indicating a more sensitive response to visual disturbances to balance control. Both groups showed increases in step width and step width variability with higher visual amplitudes, with older adults demonstrating more pronounced effects. Weak correlations existed between changes in visual sensitivity and changes in step width and step width variability suggesting a limited interaction between sensory reweighting and gait stability.
IgA displays site- and subclass-specific glycoform differences despite equal glycoenzyme expression
Authors: Falck David , Sokolova Maria V. , Koeleman Carolien A.M. , Irumva Vanessa , Kirchner Philipp , Schulz Sebastian R. , Schmidt Katja G. , Harrer Thomas , Ekici Arif B. , Spriewald Bernd , Schett Georg , Wuhrer Manfred , Herrmann Martin , Steffen Ulrike 
Published: December 2024

AbstractBackgroundGlycosylation is an important posttranslational modification of proteins and in most cases indispensable for proper protein function. Like most soluble proteins, IgA, the second most prevalent antibody in human serum, contains several N- and O-glycosylation sites. While for IgG the impact of Fc glycosylation on effector functions and inflammatory potential has been intensively studied, only little is known for IgA. In addition, only glimpses exist regarding the regulation of IgA glycosylation. We have previously shown that IgA1 and IgA2 differ functionally and also show differences in their glycosylation pattern. The more pro-inflammatory IgA2 which is linked to autoimmune diseases displays decreased sialylation, galactosylation, fucosylation and bisection as compared to IgA1. In the present study, we aimed to investigate these differences in glycosylation in detail and to explore the mechanisms underlying them.MethodsIgA1 and IgA2 was isolated from serum of 12 healthy donors. Site specific glycosylation was analyzed by mass spectrometry. In addition, human bone marrow plasma cells were investigated using single cell mRNA sequencing, flow cytometry and ELISpot.ResultsWe found that certain glycoforms greatly differ in their abundance between IgA1 and IgA2 while others are equally abundant. Overall, the IgA2 glycans displayed a more immature phenotype with a higher prevalence of oligomannose and fewer fully processed glycans. Of note, these differences can’t be explained by differences in the glycosylation enzyme machinery as mRNA sequencing and flow cytometry analysis showed equal enzyme expression in IgA1 and IgA2 producing plasma cells. ELISpot analysis suggested a slightly increased antibody production rate in IgA2 producing plasma cells which might contribute to its lower glycan processing rates. But this difference was only minor, suggesting that further factors such as steric accessibility determine glycan processing. This is supported by the fact that glycans at different positions on the same IgA chain differ dramatically in fucosylation, sialylation and bisection.ConclusionIn summary, our detailed overview of IgA1 and IgA2 glycosylation shows a class, subclass, and site-specific glycosylation fingerprint, most likely due to structural differences of the protein backbones.
Is intron removal by recursive splicing necessitated by the evolution of genomic gigantism?
Authors: Adams Alexander Nichols , Mueller Rachel Lockridge 
Published: December 2024

AbstractSplicing of introns is an important step that pre-mRNA transcripts undergo during processing in the nucleus to become mature mRNAs. Although long thought to occur in a single step, introns are now also known to be removed in multiple steps through a process called recursive splicing. This non-canonical form of splicing is hypothesized to increase splicing fidelity, particularly in longer introns. In species that have evolved gigantic genome sizes, overall intron lengths are much longer than in genomes of typical size. Using West African lungfish (Protopterus annectens; genome size ∼40Gb) as a model, we use total RNA-seq data to test the hypothesis that gigantic genomes have shifted to rely predominantly on recursive splicing to manage their long introns. Our results suggest levels of recursive splicing at conserved sites in the lungfish that are similar to those seen in humans, indicating that genome-wide intronic expansion accompanying genomic gigantism does not necessitate ubiquitous use of recursive splicing. However, in addition to these results, we also observed patterns of decreasing RNA-seq read depths across entire intron lengths and note that both canonical co-transcriptional splicing and stochastic recursive splicing using many random splice sites could produce this pattern. Thus, we infer canonical co-transcriptional splicing and/or stochastic recursive splicing – but not ubiquitous recursive splicing at conserved sites – manage the removal of long introns in gigantic genomes. We conclude that the vast increase in intron length in gigantic genomes does not appear to have coincided with a fundamental shift in splicing mechanisms.Statement and DeclarationsThe authors declare no competing interests.
Exploiting Four-way Phase-encoding Benefits for Robust Detection and Correction of EPI Artifacts: Application to Residual Ghosts in Diffusion MRI
Authors: Thai Anh , Chang Lin Ching , Pierpaoli Carlo , Irfanoglu M. Okan 
Published: December 2024

AbstractPurposeTo propose and develop an image processing-based methodology for detecting and correcting echo planar imaging (EPI) artifact that employs data from 4-way phase-encoding acquisitions.ApproachPrevious studies have demonstrated that acquiring images with four different phase-encoding directions can improve the reproducibility of diffusion derived quantitative maps while retaining the same acquisition time. This improvement is achieved by averaging across phase-encoding directions (PEDs) to reduce the impact of EPI artifacts. Building on this principle, the proposed method further improves this 4-way encoding approach by leveraging the properties of signal distributions to detect artifactual regions. Additionally, the method can be tailored for specific artifact manifestations by considering their localization due to underlying acquisition parameters. The proposed method is applied to and validated using both simulated data and in-vivo diffusion MRI data affected by residual ghost artifacts.ResultsSimulations with known ground-truth images demonstrated high artifact detection accuracy, achieving a Dice score of 0.91 for reconstructions without parallel imaging. In the in-vivo dataset, the method also improved longitudinal reproducibility, reducing variability by 30% in ghost-affected regions.ConclusionThe proposed correction method effectively detected and corrected residual ghost artifacts without the need of any additional k-space data. This retrospective approach can be directly integrated into existing processing pipelines to further improve the quality of EPI images and enhancing image quality in studies that utilize 4-way PEDs acquisition.
Adhesion-Controlled Mechanics of the Glial Niche Regulate Neural Stem Cell Proliferative Potential
Authors: Cristina Anna Segú , Briand David , Kukde Aman , Perthame Emeline , Rigaud Stéphane , Tinevez Jean-Yves , Banach-Latapy Agata , Owens Nick D.L. , Valon Léo , Bellaïche Yohanns , Spéder Pauline 
Published: December 2024

ABSTRACTControlled proliferation of neural stem cells (NSCs) builds a functional nervous system during development. While their cellular niche is recognized as a signalling hub, the contribution of its structure and mechanics in regulating neurogenesis remains unexplored. TheDrosophilalarval central nervous system contains self-renewing NSCs in close contact with cortex glial cells. Transcriptomics identified a triad of immunoglobulin superfamily cell adhesion molecules (Dpr10/Dpr6 in glia and DIP-α in NSCs) which physically and mechanically connect the NSC and glial membranes, acting as mechanoregulators. Their disruption increases glial cortical tension, causing non-autonomous mitotic defects in NSCs, characterized by abnormal spindle morphologies and impaired mitotic progression. Additionally, elevated glial tensile forces increase Lamin content in NSCs, a protective response also resulting in nuclear deformation. Ultimately NSC proliferative potential and genome integrity are compromised. Our study reveals that the native mechanical properties of the niche are transmitted to NSCs and regulate their function.Graphical abstract
Interleukin-1β Drives Disease Progression in Arrhythmogenic Cardiomyopathy
Authors: Penna Vinay R. , Amrute Junedh M. , Engel Morgan , Shiel Emily A. , Farra Waleed , Cannon Elisa N. , Leu-Turner Colleen , Ma Pan , Villanueva Ana , Shin Haewon , Parvathaneni Alekhya , Jager Joanna , Bueno-Beti Carlos , Asimaki Angeliki , Lavine Kory J. , Saffitz Jeffrey E. , Chelko Stephen P. 
Published: December 2024

AbstractArrhythmogenic cardiomyopathy (ACM) is a genetic form of heart failure that affects 1 in 5000 people globally and is caused by mutations in cardiac desmosomal proteins includingPKP2, DSP, andDSG2.Individuals with ACM suffer from ventricular arrhythmias, sudden cardiac death, and heart failure. There are few effective treatments and heart transplantation remains the best option for many affected individuals. Here we performed single nucleus RNA sequencing (snRNAseq) and spatial transcriptomics on myocardial samples from patients with ACM and control donors. We identified disease-associated spatial niches characterized by co-existence of fibrotic and inflammatory cell types and failing cardiac myocytes. The inflammatory-fibrotic niche co-localized to areas of cardiac myocyte loss and was comprised ofFAP(fibroblast activation protein) andPOSTN(periostin) expressing fibroblasts and macrophages expressingNLRP3(NLR family pyrin domain containing 3) and NFĸB activated genes. Using homozygous Desmoglein-2 mutant (Dsg2mut/mut) mice, we identified analogous populations ofPostnexpressing fibroblasts and inflammatory macrophage populations that co-localized within diseased areas. Detailed single cell RNA sequencing analysis of inflammatory macrophage subsets that were increased in ACM samples revealed high levels of interleukin-1β (Il1b) expression. To delineate the possible benefit of targeting IL-1β in ACM, we treatedDsg2mut/mutmice with an anti-IL-1β neutralizing antibody and observed attenuated fibrosis, reduced levels of inflammatory cytokines and chemokines, preserved cardiac function, and diminished conduction slowing and automaticity, key mechanisms of arrhythmogenesis. These results suggest that currently approved therapeutics that target IL-1β or IL-1 signaling may improve outcomes for patients with ACM.
Density dependence impedes evolutionary rescue
Authors: Olazcuaga Laure , Melbourne Brett A. , Nordstrom Scott W. , Hufbauer Ruth A. 
Published: December 2024

AbstractEvolutionary rescue is adaptation that enables populations to persist in the face of severe environmental change. It is well studied in conditions of density independence, but the effects of density on the probability of rescue are less well understood, including competition and other types of negative density dependence. The few theoretical studies of evolutionary rescue that address density dependence are contradictory, with density dependence either increasing or decreasing extinction while potentially increasing selection strength to facilitate adaptation. Here, we test empirically how density dependence influences evolutionary rescue, subjecting experimental populations to a stressful environment for six generations under density dependence or independence. Density dependence suppressed population size and increased extinction risk, while density independence enabled rapid population growth, particularly for populations with high genetic diversity. The evolution of the intrinsic fitness during and realized fitness after the experiment suggests density-dependent populations that persisted adapted more than density-independent populations, particularly if they had high genetic diversity. These findings help reconcile theoretical results, as they are compatible with adaptation being favored despite higher extinction rates for populations evolving in density dependence. Our results emphasize that it is crucial to consider density dependence when developing management strategies for populations facing detrimental environmental change.
Cerebral Venous Blood Flow Regulates Brain Fluid Clearance via Dural Lymphatics
Authors: El Kamouh Marie-Renee , Spajer Myriam , Singhabahu Ruchith , Sailor Kurt A , Bourrienne Marie-Charlotte , Mouton Laura , Koundal Sunil , Doukhi Diana , Grine Abel , Ninneman Justus , Nasry Amelle , Joly Marolany Anne-Laure , Akbar David , Gottschalk Joshua , Ruze Anthony , Buscher Elora , Langui Dominique , Van Wassenhove Jerome , Mazighi Mikael , Eichmann Anne , Lledo Pierre-Marie , Benveniste Helene , Santin Mathieu , Lehericy Stéphane , Thomas Jean-Léon , Lenck Stéphanie 
Published: December 2024

AbstractThe vascular system regulates brain clearance through arterial blood flow and lymphatic drainage of cerebrospinal fluid (CSF). Idiopathic intracranial hypertension (IIH), characterized by elevated intracranial pressure and dural venous sinus stenoses, can be treated by restoring venous blood flow via venous stenting, suggesting a role for venous blood flow in brain fluid clearance. Using magnetic resonance imaging (MRI) in IIH patients and healthy controls, we identified that dural venous stenoses in IIH were associated with impaired lymphatic drainage, perivenous fluid retention, and brain fluid accumulation. To investigate this further, we developed a mouse model with bilateral jugular vein ligation (JVL), which recapitulated key human findings, including intracranial hypertension, calvarial lymphatic regression, and brain swelling due to impaired clearance. To further dissect the respective roles of dural lymphatics and venous blood flow in brain clearance, we performed JVL in mice with dural lymphatic depletion. These mice exhibited spontaneous elevated intracranial pressure, but JVL did not further exacerbate this effect. Moreover, the synchronous restoration of brain clearance and dural lymphatics observed in mice after JVL was absent in lymphatic-deficient mice.Transcriptomic analyses revealed that lymphatic remodeling induced by JVL was driven by VEGF-C signaling between dural mesenchymal and lymphatic endothelial cells. These findings establish the dural venous sinuses as a critical platform where venous blood flow interacts with mesenchymal cells to preserve dural lymphatic integrity and function, essential for brain fluid clearance.
Morphogenetic constrains in the development of gastruloids: implications for mouse gastrulation
Authors: Fiuza U.M. , Bonavia S. , Pascual-Mas P. , Torregrosa-Cortés G. , Casaní-Galdón P. , Robertson G. , Dias A. , Martinez Arias A. 
Published: December 2024

AbstractMammalian embryonic size is tightly controlled with checkpoints and compensatory mechanisms correcting size defects. Here, we take advantage of gastruloids, a stem cell embryoid system not subject to most size controls, to study the role of size in emergent properties of mammalian embryogenesis. We report that gastruloids exhibit robust morphology and transcriptional profiles within a size range. However, size affects the dynamics, and, outside a range of robust morphogenesis, the precision of anterior-posterior (AP) axial elongation. Gastruloid axial elongation exhibits active cellular contractility, requires planar cell polarity (PCP), adhesion and cell-cell contact remodelling. Smaller gastruloids initiate elongation earlier, correlated with an earlier Brachyury polarisation. Brachyury expression increases tissue fluidity. Axis formation is regulated by the balance of Brachyury multifoci coalescence and the timing of initiation of the elongation programme. Sizes beyond the robust range can modify relative tissue composition. Very small aggregates have increased neural fate bias, accompanied by a loss of paraxial mesoderm mediated by differences in Nodal signalling activity.
Effects of serotonin agonists LSD and 25CN-NBOH on conditioned place preference and on synaptic plasticity of VTA dopamine neurons in mice
Authors: Elsilä Lauri V. , Nagaeva Elina , Luukkonen Jari-Pekka , Korpi Esa R. 
Published: December 2024

AbstractThe current research on psychedelic compounds such as lysergic amide diethylamide (LSD) is leaning heavily on the notion that psychedelics are not addictive. While much of the literature supports this argument, some of the common use patterns and the descriptions of the subjective effects of these compounds in humans, together with rather lacking and mixed data from non-human animal studies leave room for questions of potentially rewarding or reinforcing stimulus effects. Initiated by a surprising finding in a control study, we investigated these potential rewarding effects of LSD and a selective 5-HT2Aagonist 25CN-NBOH using both unbiased and biased designs of conditioned place preference as well asex vivopatch-clamp electrophysiology measurements of glutamatergic synaptic plasticity on midbrain ventral tegmental area (VTA) dopamine neurons in C57Bl6/J mice. Our results showed no reliable formation of place preference with either compound, agreeing with previous claims of psychedelics having at most weak reinforcing effects. However, we did observe single doses of the drugs, especially LSD, inducing synaptic plasticity in the medially located VTA dopamine neurons, implicating a role for the midbrain dopamine system in the effects of psychedelic drugs.Graphical abstractTreatment with mixed serotonin receptor agonist, psychedelics lysergic acid diethylamide (LSD) or selective serotonin 2A receptor agonist 25CN-NBOH did not cause reliable induction of conditioned place preference in C57Bl/6J mice. However, we did observe single doses of the drugs, especially LSD, inducing synaptic plasticity in the medially located VTA dopamine neurons. These findings challenge some of the previous rodent data but are in general in line with the claims of psychedelics having at most weak reinforcing effects.
Phthalates Impair Estrogenic Regulation of HIF2α and Extracellular Vesicle Secretion by Human Endometrial Stromal Cells
Authors: Beal Jacob R. , Bhurke Arpita , Carlson Kathryn E. , Katzenellenbogen John , Yu Jie , Flaws Jodi , Bagchi Indrani C. , Bagchi Milan K. 
Published: December 2024

AbstractDi(2-ethylhexyl) phthalate (DEHP), a known endocrine-disrupting chemical, is a plasticizer found in many common consumer products. High levels of DEHP exposure have been linked to adverse pregnancy outcomes, yet little is known about how it affects human uterine functions. We previously reported that the estrogen-regulated transcription factor hypoxia-inducible factor 2 alpha (HIF2α) promotes the expression of Rab27b, which controls the trafficking and secretion of extracellular vesicles (EVs). EVs facilitate communication between multiple cell types within the pregnant uterus, ensuring reproductive success. In this study, we report that exposure of differentiating primary human endometrial stromal cells (HESC) to an environmentally relevant concentration (1 μg/mL) of DEHP or its primary metabolite mono(2-ethylhexyl) phthalate (MEHP) markedly reduces the expression ofHIF2α. We also observed a concomitant decrease inRAB27Bexpression, reducing EV secretion from HESC. Interestingly, we found that DEHP or MEHP exposure disrupts estrogenic regulation of the HIF2α/Rab27b signaling pathway.Estrogen receptor alpha (ERα) could no longer bind to theHIF2αregulatory region following phthalate treatment, and epigenetic analysis suggested that this may be due to hypermethylation of nearby CpG islands. Further investigation revealed a potential interaction between ERα and the transcription factor Sp1 within the HIF2α regulatory region, which is affected by the inhibition of Sp1 binding to the phthalate-induced hypermethylated DNA. Additionally, our results suggest that the abnormal DNA methylation is likely due to increased expression of the DNA methyltransferase 1 (DNMT1) gene in response to phthalate exposure. Overall, this study provides valuable mechanistic insights into how phthalate-induced differential DNA methylation disrupts estrogenic regulation of theHIF2αgene and, consequently, EV secretion during HESC differentiation. This knowledge is crucial for our understanding of how phthalates may cause adverse reproductive outcomes by disrupting the hormonal regulation of cell-to-cell communication within the pregnant uterus.
A precision oncology-focused deep learning framework for personalized selection of cancer therapy
Authors: Sederman Casey , Yang Chieh-Hsiang , Cortes-Sanchez Emilio , Di Sera Tony , Huang Xiaomeng , Scherer Sandra D. , Zhao Ling , Chu Zhengtao , White Eliza R. , Atkinson Aaron , Wagstaff Jadon , Varley Katherine E. , Lewis Michael T. , Qiao Yi , Welm Bryan E. , Welm Alana L. , Marth Gabor T. 
Published: December 2024

AbstractPrecision oncology matches tumors to targeted therapies based on the presence of actionable molecular alterations. However, most tumors lack actionable alterations, restricting treatment options to cytotoxic chemotherapies for which few data-driven prioritization strategies currently exist. Here, we report an integrated computational/experimental treatment selection approach applicable for both chemotherapies and targeted agents irrespective of actionable alterations. We generated functional drug response data on a large collection of patient-derived tumor models and used it to train ScreenDL, a novel deep learning-based cancer drug response prediction model. ScreenDL leverages the combination of tumor omic and functional drug screening data to predict the most efficacious treatments. We show that ScreenDL accurately predicts response to drugs with diverse mechanisms, outperforming existing methods and approved biomarkers. In our preclinical study, this approach achieved superior clinical benefit and objective response rates in breast cancer patient-derived xenografts, suggesting that testing ScreenDL in clinical trials may be warranted.