bluuebunny/crossref_metadata_2025 huggingface dataset:
Nuclear metabolism oscillation during the cell cycle reveals a link between the phosphatidylinositol pathway and histone methylation
Authors: Gañez-Zapater Antoni , Kourtis Savvas , Espinar Lorena , García-López Laura , Wiegand Laura , Guirola Maria , Fontaine Frédéric , Müller André C , Sdelci Sara
Published: December 2024

The progression of the cell cycle is regulated by the expression of specific genes and fluctuations in cellular metabolic states. Previous research has employed cell cycle-based transcriptomics, proteomics, and metabolomics analyses to identify cell cycle-dependent changes at the gene expression, protein, and metabolic levels. However, the role of protein compartmentalization in regulating protein function, coupled with evidence that metabolic enzymes can localize to the nucleus and influence chromatin states, suggests that fluctuations in nuclear metabolism may play a role in regulating cell cycle progression. In this study, we developed an approach to resolve chromatin and nuclear changes during the cell cycle in an unbiased and systematic manner. This was achieved by integrating cell cycle fluorescent reporters with chromatin mass spectrometry and cellular imaging. Our investigation focused on metabolic enzymes and revealed that phosphatidylinositol metabolism localizes to the nucleus in a cell cycle-dependent manner. Moreover, disruption of phosphatidylinositol metabolism affects the nuclear distribution of phosphatidylinositol 4,5-bisphosphate, alters the number and morphology of nucleoli, and influences the maintenance of distinct heterochromatin states throughout the cell cycle. Finally, given the established link between phosphatidylinositol metabolism and methionine synthesis, as well as the differential impact observed on distinct histone marks when phosphatidylinositol metabolism is perturbed, we proposed that distinct pools of methionine may be involved in the maintenance of histone marks that decorate heterochromatin in a cell cycle-dependent manner.
Task and Behavior-Related Variables Are Encoded by the Postrhinal and Medial Entorhinal Cortex During Non-Spatial Associative Learning
Authors: Nystuen Ingeborg Nymoen , Rogge Frederik Sebastian , Aasen Anna Hjertvik , Grødem Sverre , Malthe-Sørenssen Anders , Lepperød Mikkel Elle , Hafting Torkel , Fyhn Marianne , Lensjø Kristian Kinden
Published: December 2024

The medial entorhinal cortex (MEC) is pivotal in spatial computations and episodic memory. In particular, an animal’s position can be decoded from the activity of entorhinal grid cells. However, it remains elusive whether MEC could play a more general role in different types of associative learning and how the representations develop during the learning process. It has been shown that the postrhinal cortex (POR), which is directly connected to MEC, integrates visual stimuli with salient outcomes. Here, we use a non-spatial visual association task to investigate whether MEC neurons represent low-level visual cues during learning. Using a Go/NoGo visual association task, we recorded neural activity in MEC and POR throughout the learning phase as mice associated drifting gratings with rewarded, aversive, or neutral outcomes.

Our findings reveal that the neural tuning curves in both the POR and MEC change with the learning of the task. From the start of training, the POR neurons exhibited response tuning to the visual cues, and the tuning was stable to cue orientations during learning. In contrast, MEC neurons did not initially respond very strongly to visual cues but developed a robust tuning toward the rewarded trials. While the MEC’s representation of visual information was limited, it encoded other task elements. A large fraction of the neurons formed distinct functional clusters that were either activated or suppressed by reward-related behavior. Remarkably, these clusters segregated anatomically in MEC and maintained strong within-cluster correlations before and after training. Notably, although the same functional clusters were apparent in the POR, they did not show any anatomical structure as in the MEC. Task reversal induced significant changes in network responses across both regions, with a decrease in overall task-responsive neurons but a slight increase in stimulus representation. Strikingly, information about the choice to lick emerged with learning in both brain areas, and most significantly within the functional cell clusters representing reward consumption and plus-cue stimulus. Our results demonstrate that although neurons in MEC and POR develop behavior-modulated tuning during learning of a non-spatial visual association task, the MEC exhibits stronger within-cluster correlations and anatomical organization. Conversely, the POR population exhibits less structural organization and more specific stimulus-tuning, which is reflective of being a higher visual association area. Our findings reveal that the MEC can encode task– and behavior-related variables beyond spatial information.
Kcnb1-Kcng4 axis regulates Scospondin secretion and Reissner fiber development
Authors: Amini Rasieh , Jain Ruchi P. , Korzh Vladimir
Published: December 2024

The voltage-gated potassium channel Kv2.1 plays a role in the development of the ventricular system and the subcommissural organ in zebrafish. Here, a role for Kv2.1 in the secretion of the major component of Reissner’s fiber, Scospondin, was demonstrated. The results showed that Kv2.1 acts as a negative regulator of Scospondin secretion and Reissner fiber assembly. Kv2.1 regulates formation of Scospondin microfilaments and their assembly in Reissner fiber. Cholesterol playing a key role in Scospondin secretion. After the Reissner fiber is formed, it is detached from the hindbrain floor plate, where Scospondin produced initially. The tension of the fiber depends on its attachment to the subcommissural and flexural organs. In turn fiber tension affects the morphogenesis of these organs. This process of Reissner fiber formation depends on the input provided by the Hedgehog and Wnt/β-catenin signaling pathways on the anterior roof and floor plates.
Regulation of co-translational mRNA decay by PAP and DXO1 in Arabidopsis
Authors: Carpentier Marie-Christine , Receveur Anne-Elodie , Cadoudal Adrien , Merret Rémy
Published: December 2024

Background

mRNA decay is central in the regulation of mRNA homeostasis in the cell. The recent discovery of a co-translational mRNA decay pathway (also called CTRD) has changed our understanding of the mRNA decay process. This pathway has emerged as an evolutionarily conversed mechanism essential for specific physiological processes in eukaryotes, especially in plants. In Arabidopsis, this pathway is targeted mainly by the exoribonuclease XRN4. However, the details of the molecular regulation of this pathway are still unclear.

Results

In this study, we first tested the role of the 3ʹ-phosphoadenosine 5ʹ-phosphate (PAP), an inhibitor of exoribonucleases in the regulation of CTRD. Using 5’Pseq approach, we discovered that FRY1 inactivation impaired XRN4-CTRD activity. Based on this finding, we demonstrated that exogenous PAP treatment stabilizes CTRD mRNA targets. Furthermore, we also tested the implication of the exoribonuclease DXO1 in CTRD regulation. We found that DXO1, another exoribonuclease sensitive to PAP, is also involved in the CTRD pathway, especially by targeting NAD+-capped mRNAs. DXO1 specifically targets mRNAs linked to stress response.

Conclusions

Our study provides further insights into the regulation of CTRD in Arabidopsis and demonstrates that other exoribonucleases can be implicated in this pathway.
Intensive Chemotherapy Induces Cardiotoxicity via Reverse Electron Transport
Authors: Pinto Carla , Liu Youzhong , Benaouadi Sabrina , Sainte-Marie Yannis , Laaouamir Lotfi , Marsal Dimitri , Gastel Nick Van , Savagner Frédérique , Farge Thomas
Published: December 2024

Chemotherapy-induced cardiotoxicity has emerged as an important focus in oncology, driven by the growing number of cancer survivors. Intensive chemotherapies (iCT) used in the treatment of acute myeloid leukemia (AML) often lead to significant adverse cardiac events, which can reduce therapeutic benefits, limit treatment options, or even necessitate discontinuation—particularly for patients with pre-existing cardiac conditions, resulting in a loss of therapeutic opportunity. This study shows that the iCT triggers severe mitochondrial dysfunction in cardiac tissue, mirroring effects seen in ischemia-reperfusion models. Specifically, iCT results in succinate accumulation and elevated reactive oxygen species production, consistent with reverse electron transport phenomenon. Importantly, these effects were entirely prevented with RET inhibitors such as malonate or S1QEL1.1.In vivo, we demonstrate that malonate administration successfully prevents iCT-induced cardiotoxicity, maintaining left ventricular ejection fraction and fibrosis levels comparable to controls. Additionally, in an MLL-AF9-driven AML model, malonate sensitized leukemic cells to iCT. These findings support the dual potential of malonate: as an OXPHOS metabolism inhibitor to overcome chemoresistance in AML, while also reducing cardiotoxic risk for already vulnerable patients.

One Sentence Summary:This study demonstrates that malonate prevents chemotherapy-induced cardiotoxicity by inhibiting mitochondrial reverse electron transport (RET), preserving cardiac function, and simultaneously sensitizing AML cells to intensive chemotherapy.
Fraxinus excelsiorupdated long-read genome reveals the importance of MADS-box genes in tolerance mechanisms against ash dieback
Authors: Franco Ortega Sara , Bedford James A. , James Sally R. , Newling Katherine , Ashton Peter D. , Boshier David H. , Clark Jo , Hartley Susan E. , Harper Andrea L.
Published: December 2024

Ash dieback caused by the fungusHymenoscyphus fraxineushas devastated the European ash tree population since it arrived in Europe in 1992. Great effort has been put into breeding programmes to increase the genetic diversity of ash trees and find heritable genetic markers associated with resistance, or tolerance mechanisms, to ash dieback. To facilitate identification of molecular markers, we used Oxford Nanopore Technologies combined with Illumina sequencing to obtain an accurate and contiguous ash genome. We used this genome to reanalyse transcriptome data from a Danish ash panel of 182 tree accessions. Using associative transcriptomics, we identified 175 gene expression markers (GEMs), including 11 genes annotated as dormancy MADS-box transcription factors which are associated with ash bud dormancy, flowering and senescence. We hypothesize that tolerant trees both break dormancy earlier in the year by increasing the expression of flowering-related SOC1 MADS-box and reducing the expression of SVP-like MADS-box, whilst also accelerating senescence by increasing the expression of JOINTLESS MADS-box genes. DNA methylation differences in the promoters of MADS-box genes between one tolerant and one susceptible tree indicate potential epigenetic regulation of these traits.

Article Summary

Ash dieback has devastated European ash tree populations. To aid in breeding programmes focused on finding solutions against this pathogen, we have assembled a new ash genome. This new genome helped us to identify genes related to tree biological life cycles, expressed differently in tolerant and susceptible trees. For the first time, we have also discovered that susceptible and tolerant trees showed different DNA methylation frequencies in those genes, suggesting epigenetic regulation. DNA methylation can turn on/off gene expression without changing the DNA sequence. These genes, and their regulatory elements, are ideal targets during breeding programmes combating this pathogen.
Coenzyme M: An Archaeal Antioxidant as an Agricultural Biostimulant
Authors: Brown Jeremy H. , Vijayan Jithesh , de Queiroz Aline Rodrigues , Ramos Natalia Figueroa , Bickford Nate , Wuellner Melissa , Buan Nicole R. , Stone Julie M. , Glowacka Katarzyna , Roston Rebecca L.
Published: December 2024

Rising global food demand necessitates improved crop yields. Biostimulants offer a potential solution to meet these demands. Among them, antioxidants have shown potential to improve yield, nutritional quality and resilience to climate change. However, large-scale production of many antioxidants is challenging. Here, we investigate Coenzyme M (CoM), a small, achiral antioxidant from archaea, as a potential biostimulant, investigating its effects on growth and physiology. CoM significantly increased biomass of the model plantArabidopsis thalianain a concentration-dependent manner consistent with it being metabolized. In tobacco, CoM increased photosynthetic light capture capacity, consistent with observed growth improvements. Interestingly, this effect was independent of carbon capture rates. Furthermore, CoM promoted early-stage shoot growth in various crops species, including tobacco, basil, cannabis, and soybean. Our results suggest CoM is a promising, scalable biostimulant with potential to modify photosynthesis and enhance crop productivity.

Key Points

Antioxidant application improves plant growth but is typically too expensive to use widely.

Coenzyme M is a small, easily made antioxidant of Archaeal origin.

Applied exogenously, Coenzyme M conditionally increases plant biomass.

Coenzyme M represents an antioxidant with potential to be a widely used biostimulant.
Chemogenetic Activation of Medial Prefrontal Cortex Projections to the Nucleus Accumbens Shell Suppresses Cocaine-Primed Reinstatement in EcoHIV Infected Mice
Authors: Xie Qiaowei , Namba Mark D. , Dasari Rohan , Buck Lauren A. , Side Christine M. , Goldberg Samuel L. , Park Kyewon , Jackson Joshua G. , Barker Jacqueline M.
Published: December 2024

HIV is highly comorbid with cocaine use disorder (CUD). Relapse is a major challenge in the treatment of CUD, and people living with HIV (PLWH) exhibit shorter time to relapse. One driver of relapse may be re-exposure to cocaine, which can be modeled in rodents using cocaine-primed reinstatement. This process involves neuroadaptations within the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) shell, regions that mediate cocaine reward learning and relapse-related behavior. HIV infection interacts with cocaine to alter corticostriatal circuits, which may further dysregulate cocaine seeking. To investigate the impact of HIV infection on cocaine reward learning and reinstatement and the role of mPFC-NAc circuits, we utilized the EcoHIV mouse model, a chimeric form of HIV-1 which can infect wild-type mice. Our findings demonstrate that EcoHIV infection enhances cocaine-primed reinstatement. We also observed increased cocaine-induced expression of the cellular activation marker cFos in the NAshell in EcoHIV-infected mice. Given the role of the mPFC-NAshell circuit in cocaine-seeking behaviors, we further demonstrated that chemogenetic activation of this circuit could reverse the behavioral deficits induced by EcoHIV. We propose that HIV infection contributes to neuroadaptations in the mPFC-NAshell circuit, and enhancing its activity may inhibit relapse-related behavior. These findings indicate that key neuronal circuits underlying cocaine reinstatement are similarly implicated in HIV infection and suggest potential strategies for managing relapse in PLWH.
Rule-Based Deconstruction and Reconstruction of Diterpene Libraries: Categorizing Patterns & Unravelling the Structural Landscape
Authors: Mathieu Davis T. , Schlecht Nicholas , van Aalst Marvin , Shebek Kevin M. , Busta Lucas , Babineau Nicole , Ebenhöh Oliver , Hamberger Björn
Published: December 2024

Terpenoids make up the largest class of specialized metabolites with over 180,000 reported compounds currently across all kingdoms of life. Their synthesis accentuates one of natures most choreographed enzymatic and non-reversible chemistries, leading to an extensive range of structural functionality and diversity. Current terpenoid repositories provide a seemingly endless landscape to systematically survey for information regarding structure, sourcing, and synthesis. Efforts here investigate entries for the 20-carbon diterpenoid variants and deconstruct the complex patterns into simple, categorical groups. This deconstruction approach reduces over 60,000 unique diterpenoid structures to less than 1,000 categorical structures. Furthermore, the majority of diterpene entries (over 75%) can be represented by less than 25 core skeletons. Natural diterpenoid abundance was mapped throughout the tree of life and structural diversity was correlated at an atom-and-bond resolution. Additionally, all identified core structures provide guidelines for predicting how diterpene diversity originates via the mechanisms catalyzed by diterpene synthases. Over 95% of diterpenoid structures rely on cyclization. Here a reconstructive approach is reapplied based on known biochemical rules to model the birth of compound diversity. Reconstruction enabled prediction of highly probable synthesis mechanisms for bioactive taxane-relatives, which were discovered over three decades ago. This computational synthesis validates previously identified reaction products and pathways, as well as enables predicting trajectories for synthesizing real and theoretical compounds. This deconstructive and reconstructive approach applied to the diterpene landscape provides modular, flexible, and an easy-to-use toolset for categorically simplifying otherwise complex or hidden patterns.

Significance Statement

We take a deconstructive and reconstructive approach to explore the origins of the diterpene landscape. Introduction of a navigational toolset enables users to survey compound libraries in ways formerly uncharted. Their utility demonstrated here, maps out diterpene cyclization routes, critical intermediate waypoints, and guidance for how to arrive at compounds previously off-the-map. Information acquired from these tools may imply the diterpene landscape is vastly unexplored, with the plateau for discovery potentially still out of sight.
Randomized Spatial PCA (RASP): a computationally efficient method for dimensionality reduction of high-resolution spatial transcriptomics data
Authors: Gingerich Ian K , Goods Brittany K , Frost Hildreth R
Published: December 2024

Spatial transcriptomics (ST) provides critical insights into the complex spatial organization of gene expression in tissues, enabling researchers to unravel the intricate relationship between cellular environments and biological function. Identifying spatial domains within tissues is essential for understanding tissue architecture and the mechanisms underlying various biological processes, including development and disease progression. Here, we present Randomized Spatial PCA (RASP), a novel spatially aware dimensionality reduction method for spatial transcriptomics (ST) data. RASP is designed to be orders-of-magnitude faster than existing techniques, scale to ST data with hundreds-of-thousands of locations, support the flexible integration of non-transcriptomic covariates, and enable the reconstruction of de-noised and spatially smoothed expression values for individual genes. To achieve these goals, RASP uses a randomized two-stage principal component analysis (PCA) framework that leverages sparse matrix operations and configurable spatial smoothing. We compared the performance of RASP against five alternative methods (BASS, GraphST, SEDR, spatialPCA, and STAGATE) on four publicly available ST datasets generated using diverse techniques and resolutions (10x Visium, Stereo-Seq, MERFISH, and 10x Xenium) on human and mouse tissues. Our results demonstrate that RASP achieves tissue domain detection performance comparable or superior to existing methods with a several orders-of-magnitude improvement in computational speed. The efficiency of RASP enhances the analysis of complex ST data by facilitating the exploration of increasingly high-resolution subcellular ST datasets that are being generated.
StripePy: fast and robust characterization of architectural stripes
Authors: Raffo Andrea , Rossini Roberto , Paulsen Jonas
Published: December 2024

Architectural stripes in Hi-C and related data are crucial for gene regulation, development, and DNA repair. Despite their importance, few tools exist for automatic stripe detection. We introduce StripePy, which leverages computational geometry methods to identify and analyze architectural stripes in contact maps from Chromosome Conformation Capture experiments like Hi-C and Micro-C. StripePy outperforms existing tools, as shown through tests on various datasets and a newly developed simulated benchmark, StripeBench, providing a valuable resource for the community.
Integration of an invasive plant in hummingbird and flower mite networks is driven by ecological fitting and generalization
Authors: Garcia-Robledo Carlos , Alvarado Joel
Published: December 2024

Most plant communities worldwide include exotic plants, which did not evolve with local organisms. The central goal of this study is to test if native organisms expanding to novel hosts are usually generalists or specialists. Here we studied new association between hummingbirds, flower mites andMusa velutina(Musaceae), an exotic plant native to Asia currently invading lowland forests in Costa Rica. Hummingbirds are pollinators, but flower mites feed on nectar without contributing to pollen transfer. Flower mites hitch rides on hummingbird beaks to colonize new flowers. To determine the original diet breadth of hummingbird and flower mite species, we assembled interaction networks including 33 native host plants, 14 hummingbird and 19 flower mite species. Transportation analyses show that flower mite colonization of native or exotic hosts is not constrained by hummingbird flight connections. We identified four hummingbird species visitingMusa velutina. DNA barcodes analyses identified only one species of flower mite colonizing flowers ofM. velutina. All new associations withM. velutinainvolved generalist hummingbird and flower mite species.Musa velutinadisplays both male and female flowers. Although flowers of both sexes were equally visited by hummingbirds, mites were 15 times more abundant in male than in female flowers. This might be the result of constant immigration coupled with population growth. Only half of the mites hitching rides on hummingbird beaks emigrate to newly open flowers. Our results show thatM. velutinaintegration to a plant community occurs mainly by establishing interactions with generalists.
Putative EGF ligand and receptor ofEchinococcus multilocularisthat are critical for parasite development
Authors: Koike Akito , Cailliau Katia , Vicogne Jérôme , Becker Frank , Dissous Colette , Hannus Stefan , Brehm Klaus
Published: December 2024

The neglected zoonosis alveolar echinococcosis (AE) is caused by infiltrative growth of the metacestode larval stage of the cestodeEchinococcus multiloculariswithin host organs. We previously demonstrated that metacestode growth depends on the mitotic activity of a population of parasite stem cells, called germinative cells, but it is not yet clear which molecular mechanisms governEchinococcusstem cell dynamics such as cell-cycle progression, self-renewal and differentiation. Based on previous reports showing that epidermal growth factor (EGF) signalling contributes toEchinococcusstem cell regulation, we herein characterized three EGF receptors of the parasite and demonstrated by RNAi and inhibitor assays that one of these, EmER1, is crucial for the development of metacestode vesicles from parasite stem cells. We also showed that EmER1 serves as a target for afatinib, an EGF receptor inhibitor with profound anti-parasitic activitiesin vitroandin vivo. By bioinformatic analyses and membrane-bound yeast two-hybrid assays, we identified a parasite-derived, neuregulin-like cognate ligand for EmER1, EmNRG, the expression of which is strongly upregulated in metacestode vesicles during clonal expansion of germinative cells. Furthermore, we demonstrate that RNAi knockdown of the EmNRG encoding gene drastically affects the ability of germinative cells to produce metacestode vesicles. We propose that EmNRG and EmER1 form a cognate ligand-receptor system utilized byE. multilocularisto regulate asymmetric versus symmetric division decisions of stem cells. These data are relevant for further studies intoEchinococcusstem cell dynamics and for the development of EGF signalling-based anti-infectives against echinococcosis.
Translation Initiation Represents an Acute Myeloid Leukemia Cell Vulnerability That Can Be Co-Targeted With BCL-2 Inhibition
Authors: Lee Yoke Seng , Good Jonathan D. , Awais Noha , Eschle Benjamin K. , Lineberry Maia S. , Teo Jessica L. , Bibeau Sarah , Wollman Morgan , Karadimov George , Sariipek Nurefsan , Acosta Jean , Noel Jenny , Cucchi David , DePasquale Erica A.K. , Gokhale Prafulla C. , Najm Fadi J. , Stone Richard M. , Garcia Jacqueline S. , Lane Andrew A. , van Galen Peter
Published: December 2024

Targeted therapies like Venetoclax have increased the options available to acute myeloid leukemia (AML) patients, but survival remains poor due to drug resistance and disease relapse. We found that the translation initiation factor EIF4A1, which unwinds complex mRNA structures in the 5' UTR of oncogenic transcripts, is highly expressed in AML stem- and progenitor-like cells. Inhibiting eIF4A with the small molecule Zotatifin reduces translation of transcripts related to the cell cycle and survival. This results in downregulation of AKT, STAT-5, and MCL-1 and underlies synergy of Zotatifin with Venetoclax. The drug combination promotes apoptosis across AML genotypes, while the effect on healthy blood cells is limited. Using in vivo relapsed and refractory AML patient-derived xenograft models, the combination significantly suppressed tumor burden and prolonged survival of xenografted mice. These results support eIF4A-mediated protein translation as a therapeutic target in AML.
A modulatory attentional gate promotes recent memory expression in Drosophila
Authors: Kapoor Ishaan , Waddell Scott
Published: December 2024

Using short-term memory (STM) requires that animals can distinguish memories of recent experience from those learned previously. InDrosophilathe neuromodulator octopamine (OA) specifically affects STM through adrenergic-like receptors within neurons in the Mushroom Body (MB) network. However, why OA preferentially impacts STM remains unclear. A fly brain connectome reveals that two OA-VPM3 neurons provide most OA input to the MB network. Artificial OA-VPM3 activation during olfactory learning enhances STM and can divert odor salience. α-adrenergic-like receptor knock-down in MB β and γ lobe MB Output Neurons (MBONs) generally impaired STM, while β-adrenergic-like receptor loss from α lobe MBONs enhanced memory. The identity and connectivity of the relevant MBONs suggests OA modulates an interaction between sites of STM and long-term memory (LTM) storage. Indeed, synthetic, odor, and learning-driven, OA-VPM3 activation temporarily blocks LTM expression. Therefore, OA reconfigures the MBON network so the fly prioritizes expression of recent over remote memories.
Autofluorescence of the parathyroid glands during total thyroidectomy. Review of systematic reviews
Authors: Pardal-Refoyo José Luis , Pardal-Pelaéz Beatriz
Published: December 2024

Introduction and Objective

This study reviews the use of near-infrared autofluorescence (NIRAF) for identifying parathyroid glands during total thyroidectomy. The main goal is to evaluate whether using NIRAF reduces the incidence of postoperative hypocalcemia, a common complication of thyroid surgery. The study analyzes previously published meta-analyses to assess the effectiveness of NIRAF compared to traditional visual identification methods. The preservation of parathyroid glands during thyroid surgery is essential to prevent hypoparathyroidism and consequent hypocalcemia.

Methods

The research involved a review of systematic reviews and meta-analyses found in PubMed, WoS, and the Cochrane Library databases. Three meta-analyses that included studies on total thyroidectomy with and without NIRAF were selected. These meta-analyses evaluated transient and permanent postoperative hypocalcemia. The data from 15 studies included in the meta-analyses were extracted and statistically reanalyzed (meta-meta-analysis). The statistical analysis was performed using the ESCI statistical package of the JAMOVI program and METAFOR by JASP. The PRISMA guidelines were followed.

Results

The use of NIRAF during total thyroidectomy was associated with a significantly lower incidence of both global and transient hypocalcemia. The prevalence of permanent hypocalcemia was also lower in the NIRAF group, but the difference was not statistically significant. The meta-meta-analysis showed a statistically significant association between the use of NIRAF and a reduction in hypocalcemia. There was moderate to high heterogeneity in errors and possible asymmetry in the data for global and transient hypocalcemia, but not for permanent hypocalcemia.

Conclusions

NIRAF is a useful tool for identifying and preserving parathyroid glands during total thyroidectomy, and its use is associated with a reduced risk of postoperative hypocalcemia. The current evidence supports the use of NIRAF, although the strength of the recommendation is weak because of heterogeneity, risk of bias, and inconsistent results among the studies. More well-designed studies are needed to confirm these findings and establish NIRAF as a standard.
Language Profile of Posterior Cortical Atrophy: A Comparative Study with Alzheimer’s Disease Variants
Authors: Wang Linshan , St-Georges Marie-Anne , Lavoie Monica , Migliaccio Raffaella , Montembeault Maxime
Published: December 2024

Objective

This study investigates language impairments in early-stage posterior cortical atrophy (PCA) patients, examining five language subdomains to resolve existing controversies and gaps in the literature.

Methods

Participants diagnosed with posterior cortical atrophy (PCA; n=105), typical Alzheimer’s disease (tAD; n=105), logopenic variant primary progressive aphasia (lvPPA; n=116) and healthy controls (HC; n=165) were selected from the National Alzheimer’s Coordinating Center (NACC) database. We utilized language tests from the Uniform Data Set and Frontotemporal Lobar Degeneration Module to assess different aspects of linguistic ability, including verbal fluency, reading, naming, semantics and repetition.

Result

Our findings revealed a global decline in visual and non-visual language functions among PCA patients compared to HC, with no spared domains. Furthermore, we investigated specific language errors in reading and sentence repetition, and we found that PCA patients committed a mix of phonological, semantic and word omission errors. They were more impaired on irregular vs. regular word reading and more impaired on verb vs noun naming. Overall PCA patients showed less severe language deficits than lvPPA, except in single word comprehension and verb naming, where the opposite pattern was found. They also showed more impaired visual language impairments and similar non-visual language impairments in comparison to tAD.

Discussion

These findings highlight that language impairments in PCA extend beyond visual deficits, playing a key role in its clinical presentation. Recognizing these language issues is essential for differentiating PCA from tAD and lvPPA, where distinct patterns of impairment help refine diagnosis.
Three-Dimensional ECG: A Novel Methodology for Detecting Acute Myocardial Ischemia
Authors: Bermejo Valdés Alejandro Jesús
Published: December 2024

We present a novel methodology that generates a three-dimensional (3D) electrocardiogram (ECG) directly derived from standard two-dimensional (2D) recordings using conventional cardiac electrode configurations. Through spherical-to-Cartesian coordinate transformations, we generate 3D representations that form loops over the standard deflections used in routine medical practice, while geometrically integratingtimewithvoltagewithin the coordinates themselves. To validate our approach from a clinical perspective, we analyzed datasets focused on acute myocardial ischemia. We evaluated the diagnostic value by comparing 2D and 3D ECG metrics, specifically perimeter and curvature, across different ischemic states. Additionally, we propose a novel mathematical formulation, analogous to curvature, designed to more accurately detect variations in the progression of ischemia. This formulation, referred to as “almost-curvature”, achieves maximum efficiency when integrated with our 3D representation method. Our results highlighted significant geometric differences in the 3D metrics, demonstrating their potential to detect ischemic alterations with greater effectiveness than traditional methods. These findings support the potential of 3D ECG as a transformative tool in cardiac diagnostics and underscore the need for continued research to expand its clinical applicability.
Protein aggregation capture assisted profiling of the thiol redox proteome
Authors: Martinez-Val Ana , Lozano-Juárez Samuel , Lumbreras Jorge , Rodríguez Irene , Couselo-Seijas Marinela , Simón-Chica Ana , Galán-Arriola Carlos , Fernández Rodrigo , Núñez Estefanía , Jorge Inmaculada , Filgueiras-Rama David , Ibáñez Borja , Vázquez Jesús
Published: December 2024

Oxidative damage is critical in various diseases, including cardiovascular and neurological conditions. Thiol redox reactions, acting as oxidative stress sensors, influence protein structure and function. Redox proteomics based on differential alkylation of reduced and oxidized Cys forms using mass spectrometry enables comprehensive analysis of thiol redox status in cells and tissues.

We introduce PACREDOX, an innovative redox proteomics approach based on the Protein Aggregation Capture (PAC) protocol and we demonstrate its compatibility with library free data-independent acquisition (DIA). PACREDOX reduces preparation time and costs compared to traditional methods, such as FASILOX, while maintaining thiol and proteome coverage. To enable library-free DIA, we corrected in silico spectral libraries in DIA-NN using experimental retention time data from beta-methylthiol-modified peptides. PACREDOX with DIA quantified 4,000 protein groups and ∼45,000 modified peptides in myocardial tissue from a porcine model of atrial fibrillation, including over 8,000 cysteine-containing peptides, 30% of which were reversibly oxidized.

Benchmarking PACREDOX and DIA against FASILOX in a myocardial infarction model reflects the potential and efficiency of this methodology to study oxidative damage. Overall, PACREDOX offers a high-throughput, cost-effective strategy for thiol redox proteome analysis, compatible with label-free quantitative workflows.
Impact of mitochondrial fission and fusion on neuronal health and incidence of dementia
Authors: Holt Alan G , Davies Adrian M
Published: December 2024

Mitochondria are highly dynamic structures that undergo constant remodeling by the process of fission and fusion. Using simulation methods we study the effects of neuron loss in humans due to the proliferation of deletion mutations. We implement two models of an organelle, namely, closed cristae (CC) and open mitochondrion (OM). With CC, mtDNA are confined to a cristae unlessmixedby the process of fission and fusion. Conversely, mtDNA can diffuse freely throughout the organelle in the OM model. We also implement selective mitophagy in the CC model.

Higher rates of mixing mtDNA increase the rate of neuron loss which, in turn, increases the prevalence of dementia. Selective mitophagy mitigates against the effect of high rate mixing. However, this mitigation is all or nothing. Even at nominal rates compared to mixing, neuron loss is almost completely eliminated resulting in minimal cognitive decline. These results do not fit the observations of normal aging and dementia prevalence in the elderly human population.

This study brings into question the role that fission and fusion is believed play in the removal of defective mtDNA.
Uptake and survival ofLeishmania amazonensisinAcanthamoeba castellanii: An infection organism model?
Authors: Geres Leonardo Fernandes , Gallo Francisco Pedro Henrique , Machado Diullia de Andrade , Teófilo Francisco Breno S. , Brocchi Marcelo , Giorgio Selma
Published: December 2024

Leishmaniasis is a neglected tropical disease. Parasite strategies and the evaluation of drugs and vaccines are inferred from studies carried out using mouse models and macrophages. The development of model organisms with no ethical restrictions will contribute to our knowledge of leishmaniasis.Acanthamoeba castellanii, a free-living protozoan, is known to interact with various microorganisms. In this study, the interaction between the amoebaA. castellaniiand the trypanosomatidLeishmania amazonensiswas investigated by combining quantitative kinetics analysis, optical, fluorescence, electronic, confocal, and live video microcopy. We sought to standardize protocols for the co-culture; the optimal experimental conditions were: RPMI medium + 10% SFB at 26°C. L. amazonensisinvadesA. castellaniithrough its acanthopods, and the promastigotes interact with the trophozoites via their flagellum, which also occurs when parasites infect mammalian macrophages. The forms ofL. amazonensisinside the amoeba become rounded and lose their flagellum; they are similar to amastigotes. These round forms were isolated from trophozoites after 3 h of co-culture and differentiated into promastigotes, demonstrating their viability inside amoeba. The percentage of amoebas withL. amazonensiswas reduced overtime. Thus, considering thatA. castellaniican clearLeishmania, this interaction could serve as an effective model of cellular leishmanicidal mechanisms.
Banded mongooses discriminate relatedness and MHC diversity in unfamiliar conspecifics
Authors: Schubert Nadine , Stober Carolin , Born Maibrit , Mwanguhya Francis , Businge Robert , Kyambulima Solomon , Mwesige Kenneth , Cant Michael A. , Nichols Hazel J. , Winternitz Jamie C.
Published: December 2024

Olfactory cues are critical in mammalian social communication, conveying fitness-relevant information such as relatedness, genetic quality, and compatibility. Recognizing kin through scent can help avoid inbreeding depression and guide nepotistic behaviors, enhancing both direct and indirect fitness. While many species use familiarity to identify relatives, others rely on phenotype matching, where animals assess genetic similarity by comparing their own genetically determined odor with that of others. In banded mongooses, synchronized breeding disrupts familiarity cues, increasing reliance on alternative mechanisms for kin discrimination and mate selection. We tested whether banded mongooses use odors to assess genetic diversity and relatedness based on (1) major histocompatibility complex (MHC) genotypes and (2) neutral microsatellite loci that reflect genetic diversity and relatedness. We found that individuals respond differently to odors from unfamiliar individuals based on MHC diversity and genetic relatedness. Specifically, individuals show more interest in less MHC diverse and less related unfamiliar conspecifics, suggesting odor cues are used to evaluate threat level of intruders or competitors. Genetic diversity had no impact on responses to odors and was not significantly associated with MHC diversity, implying that responses to MHC diversity did not result from an underlying correlation with over-all genetic diversity. We also found no effect of MHC similarity, which might be caused by the limited sample size for this analysis. Our findings show that MHC diversity might signal the genetic quality of individuals, but regions of the genome other than MHC may be used to assess relatedness. These findings provide the basis for future research on the involvement of the MHC and other genes in social communication in species where phenotype matching is likely to be advantageous.
Cortical projection neurons with distinct axonal connectivity employ ribosomal complexes with distinct protein compositions
Authors: Tran Tien Phuoc , Budnik Bogdan , Froberg John E. , Macklis Jeffrey D.
Published: December 2024

Diverse subtypes of cortical projection neurons (PN) form long-range axonal projections that are responsible for distinct sensory, motor, cognitive, and behavioral functions. Translational control has been identified at multiple stages of PN development, but how translational regulation contributes to formation of distinct, subtype-specific long-range circuits is poorly understood. Ribosomal complexes (RCs) exhibit variations of their component proteins, with an increasing set of examples that confer specialized translational control. Here, we directly compare the protein compositions of RCsin vivofrom two closely related cortical neuron subtypes–cortical output “subcerebral PN” (SCPN) and interhemispheric “callosal PN” (CPN)– during establishment of their distinct axonal connectivity. Using retrograde labeling of subtype-specific somata, purification by fluorescence-activated cell sorting, ribosome immunoprecipitation, and ultra-low-input mass spectrometry, we identify distinct protein compositions of RCs from these two subtypes. Strikingly, we identify 16 associated proteins reliably and exclusively detected only in RCs of SCPN. 10 of these proteins have known interaction with components of ribosomes; we further validated ribosome interaction with protein kinase C epsilon (PRKCE), a candidate with roles in synaptogenesis. PRKCE and a subset of SCPN-specific candidate ribosome-associated proteins also exhibit enriched gene expression by SCPN. Together, these results indicate that ribosomal complexes exhibit subtype-specific protein composition in distinct subtypes of cortical projection neurons during development, and identify potential candidates for further investigation of function in translational regulation involved in subtype-specific circuit formation.
An A-T Hoogsteen base pair in a naked DNA hairpin motif: A Protein-Recognized Conformation
Authors: Guseva Serafima , Szekely Or , Geng Ainan , Smith Kai , Pratihar Supriya , Gu Stephanie , Al-Hashimi Hashim M.
Published: December 2024

In duplex DNA, A-T and G-C form Watson-Crick base pairs, and Hoogsteen pairing only dominates upon protein binding or DNA damage. Using NMR, we show that an A-T Hoogsteen base pair previously observed in crystal structures of transposon DNA hairpins bound to TnpA protein forms in solution even in the absence of TnpA. This Hoogsteen base pair, located adjacent to a dinucleotide apical loop, exists in dynamic equilibrium with a minor Watson-Crick conformation (population ∼11% and lifetime ∼55 µs). Extending the apical loop to three residues inverted the equilibrium, making Watson-Crick the dominant state and the Hoogsteen conformation recognized by TnpA a minor state (population ∼14% and lifetime ∼28 µs). The propensity for Hoogsteen pairing depended on apical loop residues, which form contacts directly or indirectly stabilizing the Hoogsteen conformation. A structure survey did not reveal Hoogsteen pairing near RNA apical loops making them unique to DNA. Our results demonstrate that Hoogsteen can be the dominant state even in naked unmodified duplex DNA and identify 5’-CTT(T/C)AG-3’ as a DNA-specific apical loop motif stabilized by Hoogsteen pairing. Hoogsteen base pairs may be prevalent in DNA hairpins forming during replication and transcription, with broad implications for the genomic landscape.
The dominance of non-native plants over native plants increases with the number of global change factors
Authors: Shi Xiong , Chen Duo , van Kleunen Mark
Published: December 2024

Global environmental change and plant invasion are both recognized as key indicators of the Anthropocene, with the former potentially accelerating the latter. Still, whether multiple co-acting global change factors (GCFs) influence plant invasions even stronger remains untested despite the fact that in nature GCFs usually act together rather than alone. Here, four non-native and four native species were cultivated jointly as communities in mesocosm pots, and we tested their responses to increasing GCF numbers (0, 1, 2, 3, 4, 5). We found that GCF number had no influence on community productivity but increased the biomass proportion of non-native plants. GCF number increased biomass but had no influence on height for non-native plants, whereas both biomass and height of native plants decreased with increasing GCF number. Consequently, our findings indicate that dominance may increases when habitats experience multiple global change factors, and thus that invasion risk of non-native plants could potentially be underestimated from studies on single GCFs.

Open Research statement

The data supporting the results will be made available upon acceptance.
A Comprehensive Assessment of Methylation-Based Age Prediction Methods
Authors: Wang Han , Qu Jing , Zong Xizeng , Cai Ruirui , Li Yunkai , Zhao Shunlin , Hai Boquan , Tian Ruoting , Kuang Zhejun , Zhang Li , Zhao Jian , Liu Guixia , Zhang Chao
Published: December 2024

DNA methylation (DNAm) clock is widely used to measure biological age, helping to identify key biomarkers associated with aging, infer the progression of aging, and have promise for elucidating, delaying, or even reversing aging. During the past decade, a large number of epigenetic clocks have been developed. However, they are decentralized, with applicable scopes overlapping. We benchmark 15 of these methods on 142 Illumina DNAm array datasets in five criteria and analyze the biological significance of CPGs about aging and overlapping. There are many exciting commons in models’ performance. We found the optimal model closely related to the numbers and characteristics of the training data. We provided a comprehensive assessment process to guide DNAm clock research at (https://dnamclock.com), the corresponding data and evaluation pipeline are freely available (https://github.comyNENUBioCompute/MethylationEvaluation), this study will aid in the development of improved tools designed to analyze increasingly large DNAm datasets.
LBR and LAP2 mediate heterochromatin tethering to the nuclear periphery to preserve genome homeostasis
Authors: Lewis Renard , Sinigiani Virginia , Koos Krisztian , Bersaglieri Cristiana , Ashiono Caroline , Santoro Raffaella , Ciaudo Constance , Horvath Peter , Sharma Puneet , Kutay Ulrike
Published: December 2024

In most eukaryotic cells, euchromatin is localized in the nuclear interior, whereas heterochromatin is enriched at the nuclear envelope (NE). This conventional chromatin organization is established by heterochromatin tethering to the NE, however its importance for cellular homeostasis is largely unexplored. Peripheral heterochromatin localization relies on redundant NE-tethering systems. One tether is constituted by the lamin B receptor (LBR) in mammals, but the enigmatic nature of the other tethers has hampered functional analyses. Here we demonstrate that the downregulation of abundant, ubiquitous NE proteins can induce the global detachment of heterochromatin from the NE. Among these factors, we identify LBR and LAP2 as major players in bulk heterochromatin attachment to the NE in pluripotent and differentiated mammalian cells. Their loss leads to repositioning of heterochromatin to the nuclear interior, changes in chromatin accessibility, deregulation of gene expression including activation of antiviral innate immunity, and defects in cell fate determination.