bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Purpose

To 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.

Approach

Previous 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.

Results

Simulations 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.

Conclusion

The 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

Controlled 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

Arrhythmogenic 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

Evolutionary 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

The 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

Mammalian 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

The 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 abstract

Treatment 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

Di(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

Precision 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.
Mosquitoes self-medicate according to the dynamics of a microsporidian infection
Authors: Zeferino Tiago G. , Mora Alfonso Rojas , Vallat Armelle , Koella Jacob C.
Published: December 2024

Immune responses protect against infectious diseases but often incur costs, such as oxidative stress. In mosquitoes, these costs may drive behaviours that manage oxidative homeostasis, such as self-medicating by consuming nectar containing biologically active substances, including prooxidants and antioxidants. We examined whetherAnopheles gambiaemosquitoes adjust their dietary preferences when infected with the microsporidian parasiteVavraia culicis. Using sugar solutions supplemented or not with hydrogen peroxide (a prooxidant) or ascorbic acid (an antioxidant), we assessed the feeding preferences of uninfected and infected mosquitoes at different ages and measured the effects of these diets on oxidative homeostasis and parasite load. Uninfected mosquitoes preferred sugar alone, possibly to avoid oxidative stress caused by the supplemented diets. In contrast, infected mosquitoes initially preferred the prooxidant diet, which reduced parasite load and oxidative stress, but later shifted towards the antioxidant diet, which had little effect on parasite load or oxidative stress. These findings demonstrate that mosquitoes can self-medicate by consuming nectar with appropriate levels of prooxidants and antioxidants, adjusting their preference dynamically with infection progression. Given the role of mosquitoes as major vectors of infectious diseases, these results may have significant public health implications.
Non-mulberry silk fibroin functionalization enhances charge-transfer efficiency in aligned polypyrrole-silk composites for electrically stimulated neurite outgrowth
Authors: Borah Rajiv , Moses Joseph Christakiran , Upadhyay Jnanendra , Das Jitu Moni , Mandal Biman B.
Published: December 2024

Electroconductive biomaterials (ECBs) replicate the natural bioelectrical environment of nerve tissue, promoting action potential propagation after injury and enhancing nerve regeneration through therapeutic electrical stimulation (ES). We present a highly electroactive Faradaic ECB with exceptional electrical conductivity and charge density, alongside low electrochemical impedance. These ECBs trigger action potentials at low stimulation voltages by regulating redox reactions through their intrinsic reversible behavior, thereby preventing electrode degradation and tissue damage. Our biohybrid scaffold consists of aligned microfibrous matrices of polypyrrole (PPy) andBombyx morisilk fibroin (BmSF), functionalized withAntheraea assamensissilk fibroin (AaSF) rich in the cell-affinitive RGD tripeptide. Serving as an anionic dopant for PPy, AaSF significantly enhances the scaffold’s electrical properties (∼9.18 mS cm-1) and charge-transfer efficiency (∼25.27 Ω). The scaffolds exhibit superior charge injection capacity at low potentials compared to conventional bioelectrodes (e.g., 0.46 mC cm-2at 50 mV). Under pulsed ES at 50 mV cm-1, these scaffolds support remarkable neurite outgrowth of dorsal root ganglion (DRG) neurons up to 830 μm (7 days). Notably, higher current densities and voltages decrease the rate of neurite outgrowth, highlighting the importance of optimizing ES parameters to effectively evoke functional action potentials without causing any neuronal damage. Biocompatibility assessments reveal that AaSF functionalization improves cellular behavior while minimizing immunomodulatory responses. Enhanced neuronal and glial differentiation is attributed to better cell communication facilitated by excellent adhesion and increased conductivity. In essence, this study provides a strategy for selecting optimal ES parameters for electrically excitable tissues using established electrochemical techniques. The fabricated biohybrid scaffolds hold significant promise as smart nerve guidance channels (NGCs) for future nerve regeneration therapies.
A Wearable Spiral Ultrasound Patch for Focused Ultrasound Peripheral Neuromodulation of Diabetic Neuropathic Pain
Authors: Pu Cong , Fu Ben , Lu Pengda , Guan Xin , Zhang Jiayi , Shen Yuting , Li Xiao , Guo Lehang , Xu Huixiong , Jiang Xiaoning , Peng Chang
Published: December 2024

Diabetic foot disease, a severe complication of diabetes, frequently results in diabetic neuropathic pain, which diminishes quality of life and increases the risk of amputation. Current treatment options are limited in their effectiveness and can present adverse effects. We have demonstrated a first-of-its-kind wearable spiral ultrasound patch for focused ultrasound peripheral neuromodulation to alleviate diabetic neuropathic pain. This innovative, stretchable ultrasound device reliably delivers focused ultrasound to peripheral nerves. The device’s ultrasound elements are arranged in a phyllotaxis spiral pattern, enhancing transmitted acoustic focus performance and minimizing grating and side lobes. Using a diabetic foot rat model, we confirmed peripheral neuropathy through behavioral assessments of mechanical allodynia and heat hyperalgesia, which showed significant pain relief after two weeks of ultrasound treatment. Additionally, nerve conduction velocity improved. Biological safety tests indicated no adverse effects on nerve tissues or cells. Our approach offers a non-invasive solution for managing diabetic neuropathic pain and provides critical insights into its underlying mechanisms, paving the way for more effective therapies.
Telomere-to-Telomere Genome Assembly UncoversWolbachia-Driven Sex-Specific Demography and Challenges Fisher’s Principle in a Sawfly
Authors: Zhang Mingpeng , Zhai Ruoyu , Niu Gengyun , Chen Jiaqi , Tan Beibei , Wu Duo , Meng Guanliang , Wei Meicai
Published: December 2024

Wolbachia, a widespread endosymbiotic bacterium, can reshape the evolutionary fates of its insect hosts by distorting reproduction and altering population dynamics. Despite extensive laboratory research, its long-term effects on host evolution in nature remain poorly understood, particularly regarding genetic mechanisms underlying changes in sex determination and reproduction. Here, we report the first telomere-to-telomere (T2T) genome assembly of the sawflyAnalcellicampa danfengensisand the complete genome of it symbioticWolbachia. Comparative population genomics of six closely relatedAnalcellicampaspecies revealed thatWolbachia-infected populations experience marked changes in sex-specific demography. While uninfected species maintain balanced genetic features between males and females, infected species show a persistent reduction in male effective population size alongside a stable or even growing female population, ultimately driving males toward extinction. Genomic scans identified positively selected genes associated with reproductive functions, sensory perception, neural development, and longevity, suggesting thatWolbachiamanipulates critical host biological pathways to promote its transmission. These findings provide direct genomic evidence thatWolbachiaacts as a powerful evolutionary force, reshaping host genomes in a way that disrupts Fisher’s principle, ultimately driving female-biased demography and the extinction of males at evolutionary timescales. This work provides deeper insights into host– endosymbiont coevolution and has important implications for evolutionary theory and pest management strategies.
Genotyping Short Tandem Repeats Across Copy Number Alterations, Aneuploidies, and Polyploid Organisms
Authors: Verbiest Max A. , Grassi Elena , Bertotti Andrea , Anisimova Maria
Published: December 2024

Short tandem repeats (STRs) are a rich source of genetic variation, but are difficult to genotype. While specialized repeat variant callers exist, they typically assume a euploid human genome. This means recent findings regarding phenotypic effects of STR variants in human health and disease cannot be readily extended to polyploid organisms or cancer, which is characterised by copy number alterations (CNAs). Here we present ConSTRain, a novel STR variant caller that explicitly accounts for the copy number of loci in its genotyping approach. We benchmark ConSTRain using a euploid human 100X whole genome sequencing sample where it calls STR allele lengths for over 1.7×106loci in under 20 minutes with an accuracy of 98.28%. Subsequently, we show that ConSTRain resolves complex STR genotypes in an artificial trisomy 21 sample and a polyploid Dwarf Cavendish banana harbouring a large duplication. Finally, we analyse a microsatellite instable colorectal cancer tumoroid, where ConSTRain tackles CNAs and whole-genome duplications. ConSTRain is the first STR variant caller that allows for the investigation of repeats affected by CNAs, aneuploidies, and polyploid genomes. This unlocks the investigation of STRs across a wide range of contexts and organisms where they previously could not be easily studied.
Repeated head-exposures to a 5G-3.5 GHz signal do not alter behavior but modify intracerebral gene expression in adult male mice
Authors: Lameth Julie , Royer Juliette , Martin Alexandra , Marie Corentine , Cormos Délia Arnaud- , Lévêque Philippe , Poirier Roseline , Edeline Jean-Marc , Mallat Michel
Published: December 2024

The 5thgeneration (5G) of mobile communications promotes human exposures to electromagnetic fields exploiting the 3.5 GHz frequency band. We have analyzed behaviors, cognitive functions and gene expression in mice submitted to asymmetrical head-exposures to a 5G-modulated 3.5 GHz signal. The exposures were applied 1h daily, 5 days per week over a six-week period, at a specific absorption rate (SAR) averaging 0.19 W/kg over the brain. Locomotor activity in an open-field, object-place and object recognition memories were assessed repeatedly after four weeks of exposure and did not reveal any significant effect on the locomotion/exploration, anxiety level or memory processes. mRNA profiling was performed at the end of the exposure period in two symmetrical areas of the right and left cerebral cortex in which the SAR values were 0.43 and 0.14 W/kg, respectively. We found significant changes in the expression of less than 1% of the expressed genes with over-representations of genes related to glutamatergic synapses. The right cortical area differed from the left one by an over-representation of responsive genes encoded by the mitochondrial genome. Our data show that repeated head-exposures to a 5G-3.5 GHz signal can trigger mild transcriptome alterations without change in memory capacities or emotional state.
Expanding the Landscape of Aging via Orbitrap Astral Mass Spectrometry and Tandem Mass Tag (TMT) Integration
Authors: Keele Gregory R. , Dou Yue , Kodikara Seth P. , Jeffery Erin D. , Bai Dina , Paulo Joao A. , Gygi Steven P. , Tian Xiao , Zhang Tian
Published: December 2024

Aging results in a progressive decline in physiological function due to the deterioration of essential biological processes, such as transcription and RNA splicing, ultimately increasing mortality risk. Although proteomics is emerging as a powerful tool for elucidating the molecular mechanisms of aging, existing studies are constrained by limited proteome coverage and only observe a narrow range of lifespan. To overcome these limitations, we integrated the Orbitrap Astral Mass Spectrometer with the multiplex tandem mass tag (TMT) technology to profile the proteomes of three brain tissues (cortex, hippocampus, striatum) and kidney in the C57BL/6JN mouse model, achieving quantification of 8,954 to 9,376 proteins per tissue (cumulatively 12,749 across all tissues). Our sample population represents balanced sampling across both sexes and three age groups (3, 12, and 20 months), comprising young adulthood to early late life (approximately 20-60 years of age for human lifespan). To enhance quantitative accuracy, we developed a peptide filtering strategy based on resolution and signal-to-noise thresholds. Our analysis uncovered distinct tissue-specific patterns of protein abundance, with age and sex differences in the kidney, while brain tissues exhibit notable age changes and limited sex differences. In addition, we identified both proteomic changes that are linear with age (i.e., continuous) and that have a non-linear pattern (i.e., non-continuous), revealing complex protein dynamics over the adult lifespan. Integrating our findings with early developmental proteomic data from brain tissues highlighted further divergent age-related trajectories, particularly in synaptic proteins. This study not only provides a robust data analysis workflow for TMT datasets generated using the Orbitrap Astral mass spectrometer but also expands the proteomic landscape of aging, capturing proteins with age and sex effects with unprecedented depth.
Genetic basis of an adaptive polymorphism controlling butterfly silver iridescence
Authors: Livraghi Luca , Hanly Joseph J. , Loh Ling Sheng , Henry Albie , Keck Chloe M.T. , Shirey Vaughn M. , Tsai Cheng-Chia , Yu Nanfang , Van Belleghem Steven M. , Roberts W. Mark , Boggs Carol L. , Martin Arnaud
Published: December 2024

Identifying the genes and mutations that drive phenotypic variation and which are subject to selection is crucial for understanding evolutionary processes. Mormon Fritillary butterflies (Speyeria mormonia) exhibit a striking wing color polymorphism throughout their range: typical morphs bear silver spots on their ventral surfaces, and can co-occur with unsilvered morphs displaying a dull coloration1. Through genome-wide association studies in two polymorphic populations, we fine-map this difference in silvering to the 3’ region of the transcription factor geneoptix. The expression ofoptixis confined to the unsilvered regions that surround the spots, and these patterns are transformed to a silver identity uponoptixRNAi knockdown, implicatingoptixas a repressor of silver scales in this butterfly. We show that the unsilveredoptixhaplotype shows signatures of recent selective sweeps, and that this allele is shared with the monomorphic, unsilvered speciesSpeyeria hydaspe, suggesting that introgressions facilitate the exchange of variants of adaptive potential across species. Remarkably, these findings parallel the role of introgressions andcis-regulatory modulation ofoptixin shaping the aposematic red patterns ofHeliconiusbutterflies2–7, a lineage that separated fromSpeyeria45 million years ago8. The genetic basis of adaptive variation can thus be more predictable than often presumed, even for traits that appear divergent across large evolutionary distances.

Graphical Abstract
The sole essential low molecular weight tropomyosin isoform ofCaenorhabditis elegansis essential for pharyngeal muscle function
Authors: Kimmich Michael J. , Geary Meaghan A. , Mi-Mi Lei , Votra SarahBeth D. , Pellenz Christopher D. , Sundaramurthy Sumana , Pruyne David
Published: December 2024

Tropomyosin is an actin-binding protein that plays roles ranging from regulating muscle contraction to controlling cytokinesis and cell migration. The simple nematodeCaenorhabditis elegansprovides a useful model for studying the core functions of tropomyosin in an animal, having a relatively simple anatomy, and a single tropomyosin gene,lev-11, that produces seven isoforms. Three higher molecular weight isoforms (LEV-11A, D, O) regulate contraction of body wall and other muscles, but comparatively less is known of the functions of four lower molecular weight isoforms (LEV-11C, E, T, U). We demonstrate hereC. eleganscan survive with a single low molecular weight isoform, LEV-11E. Mutants disrupted for LEV-11E die as young larvae, whereas mutants disrupted for all other short isoforms are viable with no overt phenotype. Vertebrate low molecular weight tropomyosins are often considered “nonmuscle” isoforms, but we find LEV-11E localizes to sarcomeric thin filaments in pharyngeal muscle, and co-precipitates from worm extracts with the formin FHOD-1, which is also associated with thin filaments in pharyngeal muscle. Pharyngeal sarcomere organization is grossly normal in larvae lacking LEV-11E, indicating the tropomyosin is not required to stabilize thin filaments, but pharyngeal pumping is absent, suggesting LEV-11E regulates actomyosin activity similar to higher molecular weight sarcomeric tropomyosin isoforms.
A comparative analysis of toxin gene families across diverse sea anemone species
Authors: Smith Hayden L. , Broszczak Daniel A. , van der Burg Chloe A. , Surm Joachim M. , Liggins Libby , Norton Raymond S. , Prentis Peter J.
Published: December 2024

All species from order Actiniaria (sea anemones) are venomous, even though most are of no threat to humans. Currently, we know very little about the toxin gene complement of highly venomous members of this order. To address this gap in knowledge, we sequenced the transcriptome of the highly venomous and medically significant Hell’s Fire sea anemone,Actinodendron plumosum, as well as five distantly related species,Cryptodendrum adhaesivum,Epiactis australiensis,Heteractis aurora,Isactinia olivaceaandStichodactyla mertensii. We used bioinformatic approaches to identify their toxin gene complements and performed a comparative evolutionary analysis of seven understudied toxin families. Of the 16 toxin families identified, 12-40 candidate toxins were found in the six new sea anemone transcriptomes, with only 12 candidates in eight toxin families identified inA. plumosum. Across 26 sea anemone species, six neurotoxin families showed evidence of taxonomic restriction, whereas the phospholipase A2 toxin family was ubiquitously distributed. Additionally, we identified two alternative forms for the phospholipase A2 toxin family, a 10- and 14-cysteine framework, which warrant further structural and functional characterisation. Overall, we have identified a comprehensive list of toxins from a wide diversity of sea anemone species that provides the basis for future research to structurally and functionally characterise novel candidates for use as therapeutics or for agricultural applications.
COVID-19 Reproduction Numbers and Long COVID Prevalences in California State Prisons
Authors: Worden Lee , Wannier Rae , Archer Helena , Blumberg Seth , Kwan Ada , Sears David , Porco Travis C.
Published: December 2024

Prisons have been hotspots for COVID-19 and likely an important driver of racial disparity in disease burden. From the first COVID-19 case detected through March 25, 2022, 66,684 of 196,652 residents of California’s state prison system were infected, most of them in two large winter waves of outbreaks that reached all 35 of the state prisons. We used individual-level data on disease timing and nightly room assignments in these prisons to reconstruct locations and pathways of transmission statistically, and from that estimated reproduction numbers, locations of unobserved infection events, and the subsequent magnitude and distribution of long COVID prevalence. Where earlier work has recommended smaller cells over large dormitory housing to reduce transmission, recommended use of cells with solid doors over those with bars only, and cautioned against reliance on solid doors (e.g., in cold months when HVAC systems can circulate aerosols), we found evidence of substantial transmission in both dorms and cells regardless of the door and season. Effective reproduction numbers were found to range largely between 0 and 5, in both cells and dorms of all door types. Our estimates of excess case rates suggest that as a result of disparities in incarceration, prison outbreaks contributed to disproportionate disease burden on Black and Indigenous people in California. We estimated that 9,100–11,000 people have developed long COVID as a result of infection in these prison outbreaks, 1,700–2,000 of them with disabling consequences, and that this burden is disproportionately on Black and Indigenous people in comparison to the state as a whole. We urge high-quality medical care for prison residents affected by long COVID, and decarceration to reduce the risk of future outbreaks of both COVID-19 and other diseases.
HCLmNet: A Unified Hybrid Continual Learning Strategy Multimodal Network for Lung Cancer Survival Prediction
Authors: Bappi Ilias , Richter David J. , Kolekar Shivani Sanjay , Kim Kyungbaek
Published: December 2024

Lung cancer survival prediction is a critical task in healthcare, where accurate and timely predictions can significantly impact patient outcomes. In hospital settings, new patient data is constantly generated, requiring predictive models to adapt without forgetting previously learned knowledge. This challenge is intensified by the need to seamlessly integrate complex multimodal data, such as imaging, DNA, and patient records. Traditional Deep Learning (DL) models, while powerful, often suffer from catastrophic forgetting during incremental learning, further complicating the task of reliable survival prediction in dynamic environments. To address these challenges, we introduce a hybrid Continual Learning (CL) framework that integrates Elastic Weight Consolidation (EWC) with replay-based modules, including EWC Experience Replay (ER), Instance-Level Correlation Replay (EICR), and Class-Level Correlation Replay (ECCR). The ER module preserves knowledge by replaying representative samples from previous data, mitigating interference from new data. The EICR module ensures the retention of fine-grained feature patterns through inter-instance relationship modeling, while the ECCR module consolidates global knowledge across tasks using random triplet probabilities to preserve inter-class correlations. Together, these components create a robust framework, addressing catastrophic forgetting while enhancing adaptability for real-time survival prediction. Another critical challenge is the limitations of Convolutional Neural Networks (CNNs), which tend to miss ground-glass opacities or tiny tumor features in CT and PET images due to their reliance on datasets similar to their pretraining data. To overcome this, we propose a Swin Transformer (SwinT)-based method to extract critical features, addressing CNN shortcomings in such multimodal scenarios. Additionally, XLNet-permutation enriches multimodal analysis by effectively handling small DNA datasets and capturing latent patterns, whereas Fully Connected Network (FCN) process clinical features. A cross-attention fusion mechanism integrates clinical, CT, PET, and DNA data, producing a robust survival prediction model. The final prediction is guided by FCN and Cox Proportional Hazards (CoxPH) techniques, achieves state-of-the-art performance with a 7.7% concordance index (C-Index) improvement (0.84), a mean absolute error (MAE) reduction to 140 days, and minimized forgetting to 0.08. Ablation studies demonstrate the importance of the DNA modality, cross-attention mechanism, and CL strategies, advancing adaptive survival prediction and stability.
Exploring the relationship betweenGBA1host genotype and gut microbiome in theGBA1L444P/WTmouse model: Implications for Parkinson disease pathogenesis
Authors: Menozzi Elisa , Geiger Mallia , Meslier Victoria , Fierli Federico , Gilles Marine , Chau Kai-Yin , David Aymeric , Golan Revi Shahar , Famechon Alexandre , Koletsi Sofia , Morabito Christian , Quinquis Benoit , Pons Nicolas , Ehrlich Stanislav Dusko , Macnaughtan Jane , Almeida Mathieu , Schapira Anthony HV
Published: December 2024

Background

Heterozygous variants inGBA1are the commonest genetic risk factor for Parkinson disease (PD) but penetrance is incomplete.GBA1dysfunction can cause gastrointestinal disturbances and microbiome changes in preclinical models. Mounting evidence suggests that the microbiota-gut-brain axis is potentially implicated in PD pathogenesis. Whether the gut microbiome composition is influenced by hostGBA1genetics in heterozygosis has never been explored.

Objectives

To evaluate whether heterozygosity for theGBA1pathogenic L444P variant can cause perturbations in gut microbiome composition.

Methods

Faecal samples collected fromGBA1L444P/WTandGBA1WT/WTmice at 3 and 6 months of age were analysed through shotgun metagenomic sequencing.

Results

No differences in α- and β-diversity were detected between genotyped groups, at either time points. Overall, we found a little variation of the gut microbiome composition and functional potential betweenGBA1L444P/WTandGBA1WT/WTmice over time.

Conclusion

HostGBA1genotype does not impact gut microbiome structure and composition in the presentedGBA1L444P/WTmouse model. Studies investigating the effect of a second hit on gut physiology and microbiome composition could explain the partial penetrance ofGBA1variants in PD.
The effect of spherical projection on spin tests for brain maps
Authors: Bazinet Vincent , Liu Zhen-Qi , Misic Bratislav
Published: December 2024

Statistical comparison between brain maps is a standard procedure in neuroimaging. Numerous inferential methods have been developed to account for the effect of spatial autocorrelation when evaluating map-to-map similarity. A popular method to generate surrogate maps with preserved spatial autocorrelation is the spin test. Here we show that a key component of the procedure — projecting brain maps to a spherical surface — distorts distance relationships between vertices. These distortions result in surrogate maps that imperfectly preserve spatial autocorrelation, yielding inflated false positive rates. We then confirm that targeted removal of individual spins with high distortion reduces false positive rates. Collectively, this work highlights the importance of accurately representing and manipulating cortical geometry when generating surrogate maps for use in map-to-map comparisons.
One-Year Clinical Outcomes of Biodegradable Polymer Coated Everolimus-Eluting Coronary Stent: Results From a Prospective, Open-Label, Non-Randomized Study
Authors: Kasturi Sridhar , Singh Shailender , Reddy Vijay Kumar , Pratap Vikram , Masalawala Abhishek , Mishra Anil Kumar
Published: December 2024

Purpose

Newer-generation biodegradable polymer coated drug-eluting stents have been developed to optimize the outcomes of percutaneous coronary intervention. Everoshine everolimus eluting coronary stent (EECS) is a newer-generation, ultrathin (65 µm) biodegradable polymer–coated drug-eluting stent designed on a cobalt– chromium stent platform. This study aimed to evaluate safety and efficacy of the newer generation polymercoated Everoshine EECS in patients with coronary artery disease (CAD) attributable to native coronary artery stenosis.

Methods

This was a single-center, single-arm, prospective study, which enrolled patients aged ≥ 18 years who had at least one native coronary artery lesions and were eligible for Everoshine EECS implantation. The primary endpoint was major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction (MI) and target lesion revascularization, assessed at the 30-day follow-up.

Results

A total of 193 patients were enrolled (mean age 57.8 ± 11.0 years; 142 (73.6%) male). Of these, 92 (47.7%) patients had ST-segment elevation MI (STEMI) and 39 (20.2%) had non-STEMI. A total of 267 stents were deployed, with a mean diameter of 2.9 ± 0.4 mm and a mean length of 27.0 ± 9.9 mm. At 30-day, 3 (1.6%) patients experienced MACE, and 2 (1.0%) patients experienced stent thrombosis. Cumulative MACE was observed in 5 (2.6%) patients at 1 year.

Conclusion

One-year clinical outcomes demonstrated satisfactory efficacy and safety of the novel biodegradable polymer-coated Everoshine EECS in patients with CAD attributable to native coronary artery stenosis.

The trial is registered retrospectively .
Mechanisms of Alpha-Synuclein Seeded Aggregation in Neurons Revealed by Fluorescence Lifetime Imaging
Authors: Ivey Paula-Marie E. , Sosa Magaly Guzman , Salem Abdelrahman , Min Sehong , Qi Wenzhu , Scott Alicia N. , Ejendal Karin F. K. , Kinzer-Ursem Tamara L. , Rochet Jean-Christophe , Webb Kevin J.
Published: December 2024

1

The brains of Parkinson’s disease (PD) patients are characterized by the presence of Lewy body inclusions enriched with fibrillar forms of the presynaptic protein alpha-synuclein (aSyn). Despite related evidence that Lewy pathology spreads across different brain regions as the disease progresses, the underlying mechanism hence the fundamental cause of PD progression is unknown. The propagation of aSyn pathology is thought to potentially occur through the release of aSyn aggregates from diseased neurons, their uptake by neighboring healthy neurons via endocytosis, and subsequent seeding of native aSyn aggregation in the cytosol. A critical aspect of this process is believed to involve the escape of internalized ag-gregates from the endolysosomal compartment, though direct evidence of this mechanism in cultured neuron models remains lacking. In this study, we utilize a custom-built, time-gated fluorescence lifetime imaging microscope (FLIM) to investigate the progression of seeded ag-gregation over time in live cortical neurons. By establishing fluorescence lifetime sensitivity to aSyn aggregation level, we are able to monitor the protein’s aggregation state. Through a FLIM analysis of neurons expressing aSyn-mVenus and exposed to aSyn preformed fibrils labeled with the acid-responsive dye pHrodo, we reveal the protein’s aggregation state in both the cytosol and the endolysosomal compartment. The results indicate that aSyn seeds undergo partial disassembly prior to escaping the endocytic pathway, and that this escape is closely linked to the aggregation of cytosolic aSyn. In certain neurons, monomeric aSyn is found to translocate from the cytosol into the endolysosomal compartment, where it appar-ently forms aggregates in proximity to retained seeds. Additional analyses reveals zones of neuritic aSyn aggregates that overlaps with regions of microtubule disruption. Collectively, these findings enhance our understanding of aSyn pathology propagation in PD and other synucleinopathies, motivate additional experiments along these lines, and offer a path to guide the development of disease-modifying therapies.
A New Approach to Monitoring Protein Transfer via Extracellular Vesicles
Authors: Chabronova Alzbeta , Pigden Olivia , Jenkins Rosalind , Jensen Anders , Clarke Emily , James Victoria , Peffers Mandy J
Published: December 2024

Extracellular vesicles (EVs) allow the exchange of protein, lipids and genetic material for communication between cells. We developed a method to track protein exchange between cells via EVs, using stable isotope labelling of amino acids in cell culture (SILAC).

We compared EV isolation methods: ultracentrifugation and size exclusion chromatography (SEC) and undertook characterisation through nanoparticle tracking analysis (NTA), then optimised the requirement (0-10%) for foetal calf serum (FCS) and EV application concentration (6.5 million-200 EVs/cell seeded). We employed heavy amino acids L-Arg-HCl and L-Lys-2HCl to label donor cells and subsequent EV proteins. Unlabelled recipient cells were treated for 12 hours with EVs, at various concentrations. Mass spectrometry proteomics was used to assess uptake of heavy labelled EVs into recipient cells.

A labelling efficiency of 62% was achieved. There was no relationship between the number of EVs applied to cells and the number of heavy proteins detected in the recipient cells. Pathway analysis indicated an inflammatory effect of applying EVs to cells, but the potential cause of this was unclear.

We identified transferred protein cargo from EVs in recipient cells. Further optimisation of this method is still necessary.