bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunity can impose a reproduction-survival tradeoff on human malaria parasites
Authors: Patterson Denis D. , Childs Lauren M. , Stopard Isaac J. , Chitnis Nakul , Serrato-Arroyo Sergio , Greischar Megan 
Published: January 2025

AbstractMany pathogenic organisms produce specialized life stages for within-host multiplication versus on-ward transmission, including malaria parasites. Traits that enable faster multiplication—including limited investment into transmission stage production—should put host health at greater risk (all else equal). Yet it is not clear why parasites do not evolve ever faster multiplication rates, since malaria parasites do not appear to adhere to tradeoffs between the rate and duration of transmission that are classically predicted to constrain parasite evolution. To address this puzzle, we introduce an age-of-infection structured within-host mathematical model incorporating dynamic immune clearance to investigate potential tradeoffs and understand how parasites optimize their transmission investment. When investment is constant across all ages of infection, increased transmission investment reduces infection duration and parasite fitness, with optimal investment occurring at a relatively low value (around 5%), far lower than the optimum recovered from models that lack dynamic feedbacks between parasite investment and immune clearance. For age-varying strategies, our model shows that malaria parasites can enhance their fitness by delaying transmission investment to allow for faster within-host multiplication initially. Our results indicate that adaptive immunity can impose a survival-reproduction tradeoff that explains why malaria parasites cannot evolve ever faster within-host multiplication. Our theoretical framework provides a basis for understanding how transmission investment strategies alter the timing of infectiousness over the lifespan of malaria infections, with implications for parasite evolution in response to control efforts.
Generalizable prediction of liquid-liquid phase separation from protein sequence
Authors: MohammadHosseini Amir M. , Teimouri Hossein , Gureghian Vincent , Najjar Rayan , Lindner Ariel B. , Pandi Amir 
Published: January 2025

AbstractLiquid-liquid phase separation (LLPS) is a physicochemical process through which a homogeneous liquid solution spontaneously separates into distinct liquid phases with different compositions and properties. Driven by weak multivalent interactions, LLPS in living systems allows the dynamic compartmentalization of biomolecules to regulate and enhance various cellular processes. Despite recent advances, predicting phase-separating proteins and their key LLPS-driving regions remains limited by the versatility of models. Here, we developed Phaseek, a generalizable LLPS predicting model that combines contextual sequence encoding with statistical protein graph representations. Phaseek accurately predicts diverse LLPS-prone proteins, as well as key regions and effects of point mutations within them. Proteome-wide analysis across eighteen species suggests that LLPS is evolutionary conserved and involved in multiple biological processes. Additionally, predictions by Phaseek highlight the key physicochemical and structural properties associated with LLPS. Provided as an open-access model with a user-friendly implementation, Phaseek serves as a versatile LLPS predictor for advancing fundamental and applied research in related fields.
From temperate to polar waters: Transition to non-cyanobacterial diazotrophy upon entering the Atlantic gateway of the Arctic Ocean
Authors: von Friesen Lisa W. , Laber Christien P. , Kristensen Bjarke H. , Nysted Emma , Sundbom Marcus , Bertilsson Stefan , Snoeijs-Leijonmalm Pauline , Farnelid Hanna , Riemann Lasse 
Published: January 2025

AbstractNitrogen fixation, the microbial reduction of dinitrogen to ammonia, is increasingly recognized to occur in the Arctic Ocean. However, knowledge about the composition, biogeography, abundance, and ecology of nitrogen-fixing organisms (diazotrophs) is poor. This ultimately hinders prediction of ecosystem productivity fueled by nitrogen fixation in this rapidly changing and predominantly nitrogen-limited ocean. We assessed the composition and abundance of total and active diazotrophs in sub-surface water (8 m; amplicon sequencing and quantification of the marker genenifH) over ∼3,400 km from the mouth of the brackish Baltic Sea to the sea ice edge in the Arctic Ocean. Upon entering nutrient-rich waters in the Atlantic gateway to the Arctic, we discovered an abrupt transition from autotrophic to heterotrophic diazotrophic activity. Our findings suggest that diazotrophy is functionally distinct in the Arctic Ocean compared to adjacent temperate-boreal waters – a difference likely driven by inorganic nutrients, salinity, and temperature. We identify three key non-cyanobacterial diazotroph groups in the Arctic Ocean with Arctic-specific (Rhodocyclales and Oceanospirillales) or more widespread (unknown Gammaproteobacterium) distribution patterns and report theirnifHgene transcription levels (up to 103nifHtranscripts L−1). In contrast, actively transcribing diazotrophs in the warmer and more nutrient-poor Norwegian Sea with coastal-influenced water were dominated by sublineages of CandidatusAtelocyanobacterium thalassa(UCYN-A1, UCYN-A2, UCYN-A4; up to 104nifHtranscripts L-1). With ongoing atlantification of the Arctic pushing oceanic provinces and biogeographical ranges poleward, we predict a future displacement of the transition from autotrophic to heterotrophic diazotrophic activity with likely significant changes in nitrogen fixation.
A Grapevine MYC2-MYB24 Regulatory Module Activates Terpenoid Biosynthesis Upon Methyl Jasmonate Elicitation
Authors: Zhang Chen , Echeverria Jone , Foresti Chiara , Santiago Antonio , El Idrissi Moubtassim Hafsa , Amato Alessandra , Sonego Paolo , Pindo Massimo , Zenoni Sara , Moretto Marco , Matus José Tomás 
Published: January 2025

AbstractTerpenes contribute to the characteristic flavor and aroma of grapes and their derived products while serving protective roles in plants against radiation, oxidative stress, and biotic challenges. The phytohormone methyl jasmonate (MeJA) mediates many of these processes and enhances terpene content in grape berries, but its underlying regulatory mechanism remains unclear. To address this, we treatedVitis viniferacv. ‘Gamay Fréaux’ berry cell suspensions with MeJA (100 μM) and cyclodextrins (50 mM), generating transcriptomic data. Upregulated genes (URGs) were enriched in jasmonic acid biosynthesis and signaling pathways, and transcription factors (TF) that represent novel candidates modulating MeJA responses. Inspection of these TFs in terms of their co-expressed genes allowed us to focus onMYC2, the sole bHLH IIIe subgroup member in grapevine. Using DAP-seq, we identified MYC2-bound genes and integrated them with MeJA-URGs andMYC2co-expressed genes (CEGs) to produce a high-confidence target list. These targets were bound via a conserved G-box motif and included jasmonate-related genes (e.g.,LOXandJAZ) and TFs such as MYB24, previously found to interact with MYC2 to activate terpenoid biosynthesis genes. Consistently, MeJA treatment induced 15 terpene synthase genes (TPS), eleven of which were bound by MYB24, MYC2, or both. Terpenoid compounds associated with these inducedTPSsaccumulated both intra- and extracellularly following treatment with MeJA and cyclodextrins, but not with abscisic acid (ABA). Our findings suggest that MYC2 regulates the jasmonate pathway and cooperates with MYB24 to mediate MeJA-induced terpene biosynthesis, shedding light on mechanisms that may extend to flower and fruit development, where this MYB-bHLH complex is also expressed.
High conformational flexibility of phosphomannomutase 2: Implications for functioning mechanisms, stability and pharmacological chaperone design
Authors: del Caño-Ochoa Francisco , Vilar Marçal , Vilas Alicia , Company Rebeca , Pérez Belén , Ramón-Maiques Santiago 
Published: January 2025

AbstractPhosphomannomutase 2 (PMM2) is a critical enzyme in the N-glycosylation pathway, and its defect is the cause of the most common congenital disorder of glycosylation. Despite its biological relevance, the understanding of PMM2 is limited, as the catalytic mechanism and required conformational dynamics remain unknown. In this study, we investigated murine PMM2 (Pmm2) to elucidate its structural flexibility and functional insights. High-resolution crystal structures of Pmm2 in both apo and activator-bound forms provided a more detailed model of the protein, underscoring the role of three ionic cofactors that are essential for dimerization, catalysis, and stability. The Pmm2 structures also provided eight distinct conformations of the protein subunit, highlighting its dynamic nature. Structural comparisons among Pmm2, human PMM2 and other phosphomannomutases helped define the architecture of the enzyme as a dimer assembled by the rigid association of the cap domains, which provide a flat platform from which the core domains of each subunit protrude in a flexible manner. Molecular dynamics (MD) simulations of the human and murine PMM2s further emphasized the enzyme’s substantial conformational flexibility, revealing extensive core domain movements and suggesting potential inter-subunit communication within the dimer. This study refines the model of PMM2 function, demonstrating its dynamic role in substrate binding, intermediate reorientation, and product release. The observed flexibility provides new opportunities to target specific enzyme states, enabling the development of pharmacological chaperones.
Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS
Authors: Bekier Michael E. , Pinarbasi Emile , Mesojedec Jack J. , Ghaffari Layla , de Majo Martina , Ullian Erik , Koontz Mark , Coleman Sarah , Li Xingli , Tank Elizabeth M. H. , Waksmacki Jacob , Barmada Sami 
Published: January 2025

AbstractCytoplasmic TDP43 mislocalization and aggregation are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the initial cellular insults that lead to TDP43 mislocalization remain unclear. In this study, we demonstrate that Nemo-like kinase (NLK)—a proline-directed serine/threonine kinase—promotes the mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import. NLK levels are selectively elevated in neurons exhibiting TDP43 mislocalization in ALS patient tissues, while genetic reduction ofNLKreduces toxicity in human neuron models of ALS. Our findings suggest that NLK is a promising therapeutic target for neurodegenerative diseases.
Cigarette smoke and biological age induce degenerative heterogeneity in retinal pigment epithelium
Authors: Singh Krishna , Jin Yang , Hu Ming-Wen , Palazzo Isabella , Cano Marisol , Hoang Thanh , Bhutto Imran , Wang Shusheng , Sinha Debasish , Blackshaw Seth , Qian Jiang , Handa James T. 
Published: January 2025

AbstractEnvironmental exposure such as cigarette smoke induces epigenetic changes that can induce degenerative heterogeneity and accelerate aging. In early age-related macular degeneration (AMD), the leading worldwide cause of blindness among the elderly, retinal pigment epithelial (RPE) cell heterogeneity is a key change. Since smoking is the strongest environmental risk factor for AMD, we hypothesized that cigarette smoke induces degenerative RPE heterogeneity through epigenetic changes that are distinct from aging, and that with aging, the RPE becomes vulnerable to cigarette smoke insult. We administered cigarette smoke condensate (CSC) intravitreally to young and aged mice and performed snRNA-seq and snATAC-seq on the RPE/choroid. This analysis identified separate cell clusters corresponding to healthy and abnormal, dedifferentiated RPE in both aged vehicle-treated and young CSC-treated mice. The dedifferentiated RPE were characterized by a global decrease in chromatin accessibility and decreased expression of genes in functional categories that were linked to hallmarks of aging. Notably, young, dedifferentiated RPE also exhibited a compensatory upregulation of hallmarks of aging-related genes, specifically those related to mitochondrial function and proteostasis. In contrast, aged dedifferentiated RPE did not express these compensatory changes, and did not survive CSC treatment, as experimentally verified with TUNEL labeling. These changes are relevant to early AMD because we identified through scRNA-seq, similar dedifferentiated and healthy macular RPE clusters in a donor who smoked and another with early AMD, but not from a nonsmoker. Degenerative cellular heterogeneity can include an abnormal cluster that jeopardizes cell survival and may represent an additional hallmark of ocular aging.
A fresh perspective on carp feeding behavior in an aquaculture pond and its consequences for individual growth
Authors: Říha Milan , Rabaneda-Bueno Rubén , Prchalová Marie , Kajgrová Lenka , Vrba Jaroslav , Meador Trevis B. , Kuklina Irina , Bláha Martin , Draštík Vladislav , Kočvara Luboš , Veselý Lukáš 
Published: January 2025

AbstractThe common carp (Cyprinus carpio) is an important species in global aquaculture. To optimize its production, it is necessary to understand its behaviour in relation to environmental and management factors. This study investigated the spatial and temporal dynamics of carp behaviour in a semi-intensive aquaculture pond under controlled feeding regimes over two growing seasons (2022–2023). Using telemetry and stable isotope analysis, we investigated activity, depth utilisation and feeding behaviour in relation to growth and aquaculture practices.The activity of carp and their spatial use changed over time, influenced by temperature, food availability and stocking density. Activity peaked in spring and early summer and was highest at night and twilight. In the warmer months, shallow areas (<0.5 m) were favoured, probably due to thermoregulation, oxygen levels or access to prey. Individual variability in foraging site use and food composition correlated with growth, highlighting the importance of behavioural traits in resource acquisition. A flood-induced rise in stocking density in 2022 increased competition for food, resulting in higher activity and lower growth compared to 2023. Stable isotope analysis showed that benthic invertebrates were the main food source, supplemented by cereals, emphasising the importance of a balanced natural and artificial diet.Our results emphasise the value of telemetry and isotope analysis for improving aquaculture practises. Recommendations include adapting feeding to seasonal and individual behaviour, mitigating density effects and promoting sustainable practises to optimise carp production.
Efficient Techniques for Comprehensive Tissue Sampling in Adult Xenopus
Authors: Jonas-Closs Rachael A , Anderson Cora E , Peshkin Leonid 
Published: January 2025

AbstractXenopushas long been a pivotal model organism for investigating vertebrate development and disease, offering deep insights into cellular processes and gene function. Despite the wealth of information on embryonicXenopu,sthere remains a significant gap in standardized methods for adult tissue sampling, especially for modern approaches like quantitative proteomics. This study introduces a comprehensive protocol for rapid, precise, and efficient sampling of multiple tissues in adultXenopu.sThe protocol addresses challenges associated with the subtle anatomical differences compared to other anurans, ensuring reproducibility even for those with limited experience in frog dissection. This protocol is optimized for high- quality biochemical analyses by prioritizing sample freshness. We are facilitating the rapid collection of up to 18 tissues within an hour. Additionally, the methods apply to perfused and unperfused conditions, providing flexibility for a range of experimental needs. This work not only fills a critical methodological gap forXenopus laevisandtropicalisbut also serves as a valuable resource for researchers adapting techniques to similar amphibian models, thereby enhancing the scope and reliability of comparative biological and evolutionary studies.SummaryThis is part one of a comprehensiveXenopussampling protocol. The tissues sampled are the heart ventricle, arterial trunk, left liver lobe, gallbladder, lung, pancreas, spleen, larynx, esophagus, stomach, intestines, testes, fat bodies, oviduct, paired kidneys, sciatic plexus, skin, thymus, and whole eye.
Imbalanced mitochondrial dynamics in human and mouse PD brains
Authors: Brown Harry J. , Fan Rebecca Z. , Bell Riley , Salehe Said S. , Martínez Carlos Martínez , Lai Yanhao , Tieu Kim 
Published: January 2025

AbstractMitochondrial dysfunction is a major pathogenic mechanism in Parkinson’s disease (PD). Emerging studies have shown that dysregulation in mitochondrial dynamics (fission/fusion/movement) has a major negative impact on mitochondria - both morphologically and functionally. Partial genetic deletion and pharmacological inhibition of the mitochondrial fission dynamin-related protein 1 (Drp1) have been demonstrated to be beneficial in experimental models of PD. However, the expression of DRP1 (and other fission and fusion genes/proteins) has not been investigated in the brains of Parkinson’s patients. Without these data, the question remains whether targeting DRP1 is a valid therapeutic target for PD. To address this gap of knowledge, first, we used post-mortem substantia nigra specimens of Parkinson’s patients and controls. Significant increases in the levels of bothDNM1L, which encodes DRP1, as well as the DRP1 protein were detected in Parkinson’s patients. Immunostaining revealed increased DRP1 expression in dopamine (DA) neurons, astrocytes, and microglia. In addition to DRP1, the levels of other fission and fusion genes/proteins were also altered in Parkinson’s patients. To complement these human studies and given the significant role of α-synuclein in PD pathogenesis, we performed time-course studies (3-, 6- and 12-month) using transgenic mice overexpressing human wild-typeSNCAunder the mouseThy-1promoter. As early as 6 months old, we detected an upregulation ofDnm1land Drp1 in the nigral DA neurons of theSNCAmice as compared to their WT littermates. Furthermore, these mutant animals exhibited more Drp1 phosphorylation at serine 616, which promotes its translocation to mitochondria to induce fragmentation. Together, this study shows an upregulation of DRP1/Drp1 and alterations in other fission/fusion proteins in both human and mouse PD brains, leading to a pro-fission phenotype, providing additional evidence that blocking mitochondrial fission or promoting fusion is a potential therapeutic strategy for PD.
Exploring sex-specific alterations in early Alzheimer’s disease using network MRI analyses
Authors: Ben Abdallah Ines , Sourty Marion , Rame Marion , Degiorgis Laetitia , Isik Amine , Mathis Chantal , Harsan Laura-Adela 
Published: January 2025

AbstractAlzheimer’s disease (AD) is characterized by the accumulation of amyloid-β plaques and tau neurofibrillary tangles, leading to progressive cognitive decline. Subtle cognitive and neural adaptations mark the preclinical stage of AD, occurring years before mild cognitive impairment and AD diagnosis. Throughout the continuum of AD, women (∼60% of AD cases) demonstrate faster rates of cognitive decline, greater hippocampal atrophy, and more extensive tau pathology compared to men. This is particularly evident in early AD phases. Therefore, investigating early sex-specific changes is crucial for identifying biomarkers and developing targeted interventions.In the present study, we conducted a longitudinal investigation on theAppNL-F/MAPTdouble knock-in (dKI) mouse model, to identify sex-specific resting-state functional connectivity (FC) patterns associated with early cognitive deficits. Male and female wild-type and dKI mice were tested for associative and long-term memory deficits, followed by resting-state functional magnetic resonance imaging to examine the default mode network (DMN) connectivity at 2 and 4 months of age. Female dKI mice exhibited earlier and more pronounced memory impairments, with deficits apparent at 2 months, while male deficits emerged at 4 months. FC analyses revealed distinct sex-specific alterations within DMN and between DMN hubs and memory processing nodes. Notably, female dKI mice showed hypersynchrony between the retrosplenial cortex (RSP) and key memory-related regions such as the entorhinal cortex (ENT) and hippocampus (HIP), but also towards subcortical regions overlapping thalamic nuclei, amygdala, and substantia nigra. Meanwhile, male dKI mice exhibited hypoconnectivity along RSP-HIP axis, RSP-reuniens nucleus, and RSP-sensorimotor cortex. Our data particularly highlight sexually dimorphic RSP-ENT and RSP-HIP connectivity.These results underscore the critical role of sex in shaping neural network reorganization and cognitive decline during preclinical AD. These findings position neural network connectivity as a sensitive biomarker of early memory dysfunction and highlight the need for sex-specific investigations and potentially tailored therapeutic strategies in AD.
Synergistic olfactory nerve input and cholinergic neuromodulation can activate ERK in rat olfactory bulb vasopressin cells
Authors: Reichardt Nicolas , Kindler Lisa , Pino Esteban , Lukas Michael , Egger Veronica , Suyama Hajime 
Published: January 2025

AbstractSocial discrimination in rats relies on vasopressin cells (VPCs) intrinsic to the olfactory bulb (OB). We had observed that VPCs responded to electrical stimulation of the olfactory nerve in acute OB slices with inhibitory postsynaptic potentials, and that the neuromodulator acetylcholine could revert these responses to excitation, resulting in action potentials (AP). Moreover, in behaving rats that were exposed to conspecifics, more VPCs were immunopositive to the neural activity marker pERK (pERK+VPC) than in control rats. However, it is unclear whether these two observations, the increased ERK activationin vivo, and the generation of APs in the presence of AChin vitro, can be actually mapped onto each other. Here we investigated ERK activation in acute OB slices from transgenic VP-eGFP rats upon either chemical stimulation or tetanic olfactory nerve stimulation. Both KCl and NMDA stimulation resulted in substantial pERK induction across bulbar layers and caused VPC spiking in whole-cell recordings, but only NMDA slightly increased pERK+VPC percentage. Tetanic olfactory nerve stimulation yielded localized, column-like ERK activation of neurons across bulbar layers. The presence of ACh during tetanic stimulation substantially and specifically increased percentages of pERK+VPCs within columns, indicating that columnar pERK+VPCs were preferentially activated by coincident cholinergic neuromodulation and synaptic input.Our results validate pERK induction as a tool to monitor synaptic VPC excitation in the OB, and imply that depolarization of VPCs alone is insufficient to activate ERK. We propose that synaptically evoked APs are a prerequisite for pERK induction in VPCs.