bluuebunny/crossref_metadata_2025 huggingface dataset:
Convergent Evolution of the Antimycobacterial Lasso Peptide Triculamin
Authors: Merrild Aske , Svenningsen Tiziana , Chevrette Marc G , Tørring Thomas
Published: December 2024

Triculamin is a ribosomally synthesized and post-translationally modified peptide (RiPP) lasso peptide with potent antimycobacterial activity, produced by an unusual, non-canonical biosynthetic gene cluster (BGC). In this study, we elucidate the biosynthetic pathway of triculamin through heterologous expression and show that the biosynthesis proceeds in the presence of a precursor (triA), macrocyclase (triC), and acetyltransferase (triT). Throughin vitrotriT acetylation and bioactivity assays, we show that acetylation functions as a resistance mechanism. Genomic searches of triculamin BGC genes across bacteria show that triculamin is more widely distributed than previously anticipated, as triculamin-like core peptides are found in at least three phyla in contrast to previously described lasso peptides that are typically restricted to one phylum. Triculamin BGCs with both canonical and non-canonical RiPP biosynthetic genes were identified. Two strains containing canonical triculamin-like BGCs were chemically characterized and shown to produce the novel triculamin-like lasso peptides palmamin and gelatinamin, the latter of which appears to have an unprecedented additional ring formation. Detailed phylogenetic investigation of the macrocyclases from triculamin-like BGCs suggests that these molecules are products of convergent evolution. These findings broaden the evolutionary and functional landscape of lasso peptides, revealing their unexpected diversification and cross-phylum distribution.
The PH domain in the ArfGAP ASAP1 drives catalytic activation through an unprecedented allosteric mechanism
Authors: Soubias Olivier , Foley Samuel L. , Jian Xiaoying , Jackson Rebekah A. , Zhang Yue , Rosenberg Eric M. , Li Jess , Heinrich Frank , Johnson Margaret E. , Sodt Alexander J. , Randazzo Paul A. , Byrd R. Andrew
Published: December 2024

ASAP1 is a multidomain Arf GTPase-activating protein (ArfGAP) that catalyzes GTP hydrolysis on the small GTPase Arf1 and is implicated in cancer progression. The PH domain of ASAP1 enhances its activity greater than 7 orders of magnitude but the underlying mechanisms remain poorly understood. Here, we combined Nuclear Magnetic Resonance (NMR), Molecular Dynamic (MD) simulations and mathematical modeling of functional data to build a comprehensive structural-mechanistic model of the complex of Arf1 and the ASAP1 PH domain on a membrane surface. Our results support a new conceptual model in which the PH domain contributes to efficient catalysis not only by membrane recruitment but by acting as a critical component of the catalytic interface, binding Arf·GTP and allosterically driving it towards the catalytic transition state. We discuss the biological implications of these results and how they may apply more broadly to poorly understood membrane-dependent regulatory mechanisms controlling catalysis of the ArfGAP superfamily as well as other peripheral membrane enzymes.
Enterobactin carries iron intoC. elegansand mammalian intestinal cells by a mechanism independent of divalent metal transporter DMT1
Authors: Sewell Aileen K. , Cui Mingxue , Zhu Mengnan , Host Miranda R. , Han Min
Published: December 2024

The diverse microbiota of the intestine is expected to benefit the host, yet the beneficial metabolites derived from the microbiota are still poorly understood. Enterobactin (Ent) is a well- known secreted iron-scavenging siderophore made by bacteria to fetch iron from the host or environment. Little was known about a positive role of Ent until a recent discovery in the nematodeC. elegansindicated a beneficial role of Ent in promoting mitochondrial iron level in the animal intestine. To solidify this new paradigm, we further tested this role inC. elegansand multiple mammalian cell models and its relationship with the primary iron transporter DMT1/SMF-3 and several other iron-related genes. Here we show that ferric enterobactin (FeEnt) supplementation promotes whole organism development inC. elegans, increases iron uptake in caco-2 human intestinal epithelial cells, and supports iron-dependent differentiation of murine erythroid progenitor cells, indicating that the FeEnt complex can effectively enter these cells and be bioavailable. Our data in multiple models demonstrate that FeEnt-mediated iron transport is independent of all tested iron transporters. In addition, FeEnt supplementation robustly suppresses the developmental defects of ahif-1mutant under low iron condition, suggesting the critical role in iron homeostasis for this well-known hypoxia regulator. These results suggest that FeEnt can effectively enter animal cells and their mitochondria through a previously unknown mechanism that may be leveraged as a therapeutic ferric iron carrier for the treatment of DMT1- or HIF-1-related iron deficiency and anemia.
Mapping histologic and functional maturation of human endocrine pancreas across early postnatal periods
Authors: Saunders Diane C. , Hart Nathaniel , Pan Fong Cheng , Reihsmann Conrad V. , Hopkirk Alexander L. , Izmaylov Nike , Mei Shaojun , Sherrod Brandon A. , Davis Corey , Duryea Jeff , Haliyur Rachana , Aramandla Radhika , Durai Heather , Poffenberger Greg , Martin Alexandra , Posgai Amanda L. , Kusmartseva Irina , Beery Maria L. , Yang Mingder , Kang Hakmook , Greiner Dale L. , Shultz Leonard D. , Cartailler Jean-Philippe , Aamodt Kristie I. , Bottino Rita , Atkinson Mark A. , Wright Christopher V.E. , Powers Alvin C. , Brissova Marcela
Published: December 2024

Human endocrine cell differentiation and islet morphogenesis play critical roles in determining islet cell mass and function, but the events and timeline of these processes are incompletely defined. To better understand early human islet cell development and maturation, we collected 115 pediatric pancreata and mapped morphological and spatiotemporal changes from birth through the first ten years of life. Using quantitative analyses and a combination of complementary tissue imaging approaches, including confocal microscopy and whole-slide imaging, we developed an integrated model for endocrine cell formation and islet architecture, including endocrine cell type heterogeneity and abundance, endocrine cell proliferation, and islet vascularization and innervation. We also assessed insulin and glucagon secretory profiles in isolated islet preparations from pediatric donors aged 2 months to 10 years and found a temporal difference in the maturation of insulin secretion compared to glucagon secretion. This comprehensive summary of postnatal and pediatric pancreatic islet development provides a framework for future studies and integration of emerging genetic and genomic data related to islet biology and diabetes risk.
dFCExpert: Learning Dynamic Functional Connectivity Patterns with Modularity and State Experts
Authors: Chen Tingting , Li Hongming , Zheng Hao , Chen Jintai , Fan Yong
Published: December 2024

Characterizing brain dynamic functional connectivity (dFC) patterns from functional Magnetic Resonance Imaging (fMRI) data is of paramount importance in neuroscience and medicine. Recently, many graph neural network (GNN) models, combined with transformers or recurrent neural networks (RNNs), have shown great potential for modeling the dFC patterns. However, these methods face challenges in effectively characterizing the modularity organization of brain networks and capturing varying dFC state patterns. To address these limitations, we propose dFCExpert, a novel method designed to learn robust representations of dFC patterns in fMRI data with modularity experts and state experts. Specifically, the modularity experts optimize multiple experts to characterize the brain modularity organization during graph feature learning process by combining GNN and mixture of experts (MoE), with each expert focusing on brain nodes within the same functional network module. The state experts aggregate temporal dFC features into a set of distinctive connectivity states using a soft prototype clustering method, providing insight into how these states support different brain activities or are differentially affected by brain disorders. Experiments on two large-scale fMRI datasets demonstrate the superiority of our method over existing alternatives. The learned dFC representations not only show improved interpretability but also hold promise for enhancing clinical diagnosis.
MSH2 is not required for either maintenance of DNA methylation or repeat contraction at theFMR1locus in fragile X syndrome
Authors: Grant-Bier Jessalyn , Ruppert Kathryn , Hayward Bruce , Usdin Karen , Kumari Daman
Published: December 2024

Background

Repeat-induced epigenetic changes are observed in many repeat expansion disorders (REDs). These changes result in transcriptional deficits and/or silencing of the associated gene. MSH2, a mismatch repair protein that is required for repeat expansion in the REDs, has been implicated in the maintenance of DNA methylation seen in the region surrounding expanded CTG repeats at theDMPKlocus in myotonic dystrophy type 1 (DM1). Here, we investigated the role of MSH2 in aberrant DNA methylation in two additional REDs, fragile X syndrome (FXS) that is caused by a CGG repeat expansion in the 5’ untranslated region (UTR) of the fragile X messenger ribonucleoprotein 1 (FMR1) gene, and Friedreich’s ataxia (FRDA) that is caused by GAA repeat expansion in intron 1 of thefrataxin(FXN) gene.

Results

In contrast to what is seen at theDMPKlocus in DM1, loss of MSH2 did not decrease DNA methylation at theFMR1promoter in FXS embryonic stem cells (ESCs) or increaseFMR1transcription. This difference was not due to the differences in the CpG density of the two loci as a decrease in DNA methylation was also not observed in a less CpG dense region upstream of the expanded GAA repeats in theFXNgene in MSH2 null induced pluripotent stem cells (iPSCs) derived from FRDA patient fibroblasts. Surprisingly given previous reports, we found thatFMR1reactivation was associated with a high frequency of MSH2- independent repeat contractions that resulted a permanent loss of DNA methylation.

Conclusions

Our results suggest that there are mechanistic differences in the way that DNA methylation is maintained in the vicinity of expanded repeats among different REDs even though they share a similar mechanism of repeat expansion. The high frequency of transcription- induced MSH2-independent contractions we have observed may contribute to the mosaicism that is frequently seen in carriers ofFMR1alleles with expanded CGG-repeat tracts. Given the recent interest in the therapeutic use of transcription-driven repeat contractions, our data may have interesting mechanistic, prognostic, and therapeutic implications.

Graphical abstract
In vivochanges in zebrafish anesthetic sensitivity in response to the loss ofkif5Aaare associated with the alteration of mitochondrial motility
Authors: Dubey Priya , Datta Roshni , Eckenhoff Roderic G , Bedell Victoria M
Published: December 2024

Anesthetic and sedative drugs are small compounds known to bind to hundreds of proteins. One intriguing binding partner of propofol is the kinesin motor domain, kif5A, a neuronal mitochondrial transport protein. Here, we used zebrafish WT andkif5AaKO larval behavioral assays to assess anesthetic sensitivity and combined that with zebrafish primary neuronal cell culture to probe for alteration in mitochondrial motility. We found that the loss ofkif5Aaincreases behavioral sensitivity to propofol and etomidate, with etomidate hypersensitivity greater than propofol. In contrast,kif5AaKO animals were resistant to the behavioral effects of dexmedetomidine. Finally, WT andkif5AaKO larvae responded similarly to the behavioral effects of ketamine. Propofol inhibited the anterograde motility of mitochondria in WT zebrafish neurons, while etomidate inhibited mitochondrial motility in both anterograde and retrograde directions; neither drug altered mitochondrial motility in thekif5Aaknockout (KO) neurons. In contrast, dexmedetomidine enhanced retrograde mitochondrial motility in both WT andkif5AaKO animals. Finally, ketamine had little significant effect on mitochondrial motility in either mutant or WT animals. These data demonstrate that each anesthetic/sedative drug affects the motor protein machinery uniquely and is associated with unique changes in behavior. Understanding how different anesthetic compounds alter neuron motor proteins will be important in defining how anesthetics alter neuronal signaling and energetic dynamics.
Biologically Plausible Neural Networks for Simulating Brain Dynamics and Inferring Connectivity
Authors: Gupta Aarush
Published: December 2024

We present Cerebrum, a novel framework that bridges biologically plausible neural networks with rigorous mathematical modeling. By grounding neural network simulations in a range of empirically-founded neuronal models (Hodgkin–Huxley, Izhikevich, and Adaptive Exponential Integrate-and-Fire), Cerebrum captures dynamics from intricate ion channel kinetics to general, large-scale network behavior. Our methodology integrates these mathematical models within a unified simulation pipeline, featuring mechanisms for short-term synaptic plasticity, precise state integration via the Runge-Kutta and Euler methods, and refractory spike regulation. We use a Graph Attention Network (GAT), to infer synaptic connectivity directly from dynamic activity patterns. This approach not only ensures biological realism but also facilitates robust connectivity reconstruction across diverse network topologies, including Erdős–Rényi, Small-World, and Scale-Free architectures. Results demonstrate that our framework reliably reproduces key neuronal firing patterns and synchronization phenomena, while its modular design paves the way for scalable investigations into the interplay between network structure and neural dynamics. Cerebrum thus offers a powerful tool for advancing both theoretical and applied aspects of computational neuroscience.
A targetable developmental program co-regulates angiogenesis and immune evasion
Authors: Berico Pietro , Yanke Amanda Flores , Van Rajabpour Fatemeh , Do Catherine , Simonin Wilmer Irving , Sakellaropoulos Theodore , Delclaux Ines , Stagnitta Robert , Vázquez-Cruz Estefania , Osman Iman , Skok Jane , Robles-Espinoza Carla Daniela , Lund Amanda W. , Schober Markus , Hernando Eva
Published: December 2024

Ultraviolet (UV)-induced DNA mutations produce genetic drivers of cutaneous melanoma initiation and numerous neoantigens that can trigger anti-tumor immune responses in the host. Consequently, melanoma cells must rapidly evolve to evade immune detection by simultaneously modulating cell-autonomous epigenetic mechanisms and tumor-microenvironment interactions. Angiogenesis has been implicated in this process; although an increase of vasculature initiates the immune response in normal tissue, solid tumors manage to somehow enhance blood flow while preventing immune cell infiltration. By comparing the expression of transcription factors (TFs) across early-stage melanoma, naevi, and other cancer types, we found the homeodomain-containing TF HOXD13 drives a melanoblast-like developmental program, which is upregulated in melanoma and strongly correlated with angiogenesis and immune cell exclusion. Using transcriptomics, 3D chromatin profiling, and in vivo models, we demonstrate that HOXD13 upregulation promotes tumor growth in vivo by concomitantly enhancing angiogenesis and suppressing T-cell infiltration. HOXD13 orchestrates 3D chromatin contacts between distal enhancers and promoters, simultaneously activating VEGFA, SEMA3A, and CD73. VEGFA and SEMA3A remodel the tumor vasculature and CD73 elevates extracellular levels of adenosine, a vasodilator and immune suppressor that binds adenosine receptors (AdR) on endothelial and T cells. In line with these findings, HOXD13-induced growth advantage in vivo was significantly reversed by the concomitant administration of VEGFR and AdR inhibitors. By revealing a dual pro-angiogenic and immunosuppressive HOXD13-CD73/VEGF gene regulatory axis, we identify a subset of patients who might benefit from combinations of AdR and VEGFR inhibitors which are both currently being tested in clinical trials.
Double crossed? Structural and computational studies of an unusual crosslinked heme inMethylococcus capsulatuscytochrome P460
Authors: Pfalzgraf Hans E. , Rao Aditya G. , Sen Kakali , Adams Hannah R. , Edwards Marcus , Lu You , Yong Chin , Jaho Sofia , Tosha Takehiko , Sugimoto Hiroshi , Horrell Sam , Beilsten-Edmands James , Owen Robin L. , Andrew Colin R. , Worrall Jonathan A. R. , Tews Ivo , Mulholland Adrian J. , Hough Michael A. , Keal Thomas W.
Published: December 2024

Cytochromes P460 oxidise hydroxylamine within the nitrogen cycle and contain as their active site an unusual catalytic c-type heme where the porphyrin is cross-linked to the protein via a lysine residue in addition to the canonical cross links from cysteine residues. Understanding how enzymes containing P460 heme oxidise hydroxylamine into either nitrous oxide or nitric oxide has implications for climate change. Interestingly the P460 containing hydroxylamine oxidoreductase utilises a tyrosine cross link to heme and performs similar chemistry. Previous crystal structures of cytochrome P460 fromNitrosomonas europaea(NeP460) clearly show the existence of a single crosslink between the Nz atom of lysine and the heme porphyrin with mutagenesis studies indicating roles for the crosslink in positioning a proton transfer residue and/or influencing the distortion of the heme. Here we describe the evidence for a novel double cross link between lysine and heme in the cytochrome P460 fromMethylococcus capsulatus(Bath). In order to understand the complexities of this enzyme system we applied high resolution structural biology approaches at synchrotron and XFEL sources paired with crystal spectroscopies. Linked to this we carried out QM/MM simulations that enabled the prediction of electronic absorption spectra providing a crucial validation to linking simulations and experimental structures. Our work demonstrates the feasibility of a double crosslink in McP460 and provides an opportunity to investigate how simulations can interact with experimental structures.
Conversion of silent synapses to AMPA receptor-mediated functional synapses in human cortical organoids
Authors: Nishimura Masatoshi , Kodera Tomoki , Adachi Shota , Sato Akinori Y. , Takeuchi Ryosuke F. , Nonaka Hiroshi , Hamachi Itaru , Osakada Fumitaka
Published: December 2024

Despite the crucial role of synaptic connections and neural activity in the development and organization of cortical circuits, the mechanisms underlying the formation of functional synaptic connections in the developing human cerebral cortex remain unclear. We investigated the development of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission using human cortical organoids (hCOs) derived from induced pluripotent stem cells. Two-photon Ca2⁺ imaging revealed an increase in the frequency and amplitude of spontaneous activity in hCOs on day 80 compared to day 50. Additionally, spontaneous neural activity in late-stage hCOs, but not in early-stage hCOs, was blocked by N-methyl-D-aspartate receptor (NMDAR) and AMPAR antagonists. However, transsynaptic circuit tracing with G-deleted rabies viral vectors indicated a similar number of synaptic connections in early- and late-stage hCOs. Notably, chemical labeling demonstrated a significant increase in AMPAR expression on the postsynaptic membrane and colocalization with NMDAR in late-stage hCOs. These results suggest that hCOs progressively organize excitatory synaptic transmission, concurrent with the transition from silent synapses lacking AMPARs to functional synapses containing NMDARs and AMPARs. Thisin vitromodel of human cortical circuits derived from induced pluripotent stem cells reflects the developmental programs underlying physiological transitions, providing valuable insights into human corticogenesis and neurodevelopmental disorders.

Abstract Figure
Effortful control and cortical brain structure in 5-year-old children: findings from the FinnBrain birth cohort study
Authors: Frantti Meri , Tuulari Jetro J. , Nolvi Saara , Nordenswan Elisabeth , Copeland Anni , Kumpulainen Venla , Silver Eero , Merisaari Harri , Saukko Ekaterina , Kataja Eeva-Leena , Korja Riikka , Karlsson Linnea , Karlsson Hasse , Pulli Elmo P.
Published: December 2024

The aim of this study was to explore the associations between an aspect of self-regulation (SR), effortful control (EC), and cortical brain structure in 5-year-old children. Efficient EC is a predictor of many attributes and important outcomes in life, such as social-emotional functioning, psychiatric and somatic health, finance, and criminal activity. The early brain correlates of EC are not widely studied, while a better understanding of them would aid in recognizing individuals at risk for maladaptive outcomes. Participants (N = 155) were a part of the FinnBrain Birth Cohort Study in Finland. T1-weighted brain magnetic resonance images were processed using FreeSurfer. The data was statistically analysed with a vertex-wise general linear model. At the age of 5 years, EC and its subscales, Attentional focusing, Inhibitory control (INH), Low intensity pleasure (LIP) and perceptual sensitivity, were assessed via parental report using The Children’s Behaviour Questionnaire. We found positive associations between overall EC and cortical volume in the left superior parietal region and in the right inferior temporal region. We also found positive associations between EC and surface area on the left hemisphere in the superior parietal region. The findings were driven by the EC subscales of INH and LIP with INH linking positively with left surface area and volume, and LIP linking with left cortical volume. We extended the previous literature by shedding light on early structural brain correlates of EC in a large sample of typically developing 5-year-olds. The results differed significantly from previous findings in older children, highlighting the need for longitudinal studies to better understand the neural underpinnings of SR throughout development.
Pearling Drives Mitochondrial DNA Nucleoid Distribution
Authors: Landoni Juan C. , Lycas Matthew D. , Macuada Josefa , Jaccard Roméo , Obara Christopher J. , Moore Andrew S. , Nejma Sheda Ben , Hoffman David , Lippincott-Schwartz Jennifer , Marshall Wallace , Sturm Gabriel , Manley Suliana
Published: December 2024

The regular distribution of mitochondrial DNA-containing nucleoids is essential for mitochondrial function and genome inheritance; however, the underlying mechanisms remain unknown. Our data reveal that mitochondria frequently undergo spontaneous and reversible pearling – a biophysical instability in which tubules undulate into regularly spaced beads. We discovered that pearling imposes a characteristic length scale, simultaneously mediating nucleoid disaggregation and establishing inter-nucleoid distancing with near-maximally achievable precision. Cristae invaginations play a dual role: lamellar cristae density determines pearling frequency and duration, and preserves the resulting nucleoid spacing after recovery. The distribution of mitochondrial genomes is thus fundamentally governed by the interplay between spontaneous pearling and cristae ultrastructure.
Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration
Authors: Cueva-Vargas Jorge L. , Belforte Nicolas , Vidal-Paredes Isaac A. , Dotigny Florence , Vande Velde Christine , Quintero Heberto , Di Polo Adriana
Published: December 2024

Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor to develop glaucoma, induced mitochondrial fragmentation in retinal capillary ECs accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological inhibition or EC-specificin vivogene delivery of a dominant negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal-barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.
Transcriptomic analysis of adult mouse cardiac stromal cells using single-cell qRT-PCR
Authors: Alonaizan Rita , Chaves-Guerrero Patricia , Samari Sara , Noseda Michela , Smart Nicola , Carr Carolyn
Published: December 2024

Fate mapping studies have challenged the longstanding view of the adult mammalian heart as a post-mitotic organ, suggesting limited cardiomyocyte renewal. This has spurred efforts to identify cardiac progenitor cell (CPC) populations, but their contribution to cardiac regeneration has been found to be minimal compared to cardiomyocyte proliferation. Despite this, CPC transplantation has shown therapeutic potential through paracrine signalling.

The identity of CPCs remains unclear due to overlapping characteristics with other cardiac stromal cell populations such as fibroblasts, mesenchymal cells, and pericytes. This study sought to optimise the isolation of CPCs by developing a cardiac collagenase-trypsin (CT) protocol, which was compared to the established method of isolating cardiosphere-derived cells (CDCs). The CT protocol resulted in a higher cell yield and reduced expansion time, with both CTs and CDCs showing superior survival potential under serum starvation compared to commercially acquired cardiac fibroblasts (CFs).

Single-cell qRT-PCR analysis revealed that CTs and CDCs share a similar gene expression profile, distinct from CFs, characterised by the enrichment of cardiogenic transcription factors. Notably, CTs exhibited higher expression ofTcf21and lowerTbx5, suggesting an epicardial-derived fibroblast phenotype, whereasTbx5was enriched in CDCs and CFs. Additionally, CTs showed an enrichment of macrophage-associated genesMrc1andCsf1r, possibly due to the transdifferentiation of macrophages to or from a fibroblast phenotype in a subset of CTs. The study concludes that CTs represent a robust and efficient source of CPCs with therapeutic potential and offers insights into the complex identity of cardiac stromal cells.
Anxa1+ dopamine neuron vulnerability defines prodromal Parkinson’s disease bradykinesia and procedural motor learning impairment
Authors: Mantas Ioannis , Contestabile Alessandro , Skara Vasiliki , Loiseau Camille , Santos Ines A , Cramb Kaitlyn M L , Filograna Roberta , Wade-Martins Richard , Magill Peter , Meletis Konstantinos
Published: December 2024

Progressive degeneration of dopamine neurons (DANs) defines Parkinson’s disease (PD). However, the identity and function of the most vulnerable DAN populations in prodromal PD remain undefined. Here, we identify substantia nigra DANs with Annexin A1 (Anxa1) expression as selectively vulnerable across multiple prodromal PD models and significantly reduced in patient-derived DANs. We found that Anxa1+ DANs have a unique functional profile, as they do not signal reward or reinforce actions, and they are not necessary for motivated behavior. Instead, activity of Anxa1+ DAN axons correlates with vigorous movements during self-paced exploration, yet their silencing only disrupts a subset of action sequences that mirror a PD bradykinesia profile. Importantly, Anxa1+ DANs are essential for procedural learning in a maze task and for motor learning of dexterous actions. These findings establish the early vulnerability of Anxa1+ DANs in PD, whose function can explain prodromal bradykinesia and impairments in procedural motor learning.
Gender-neutral vs gender-specific education subsidy: effects on schooling and earning inequality
Authors: Mukhopadhyay Ujjaini
Published: December 2024

Purpose

Developing countries are characterized by gender wage inequality that can be largely attributed to gender-based disparities in education. Education subsidy can be an effective tool for reducing the inequality in human capital formation. However, the parents’ decision in response to the subsidy is a crucial determinant of gendered inequality in schooling and earnings. The paper aims to examine the effects of gender-neutral and gender-specific education subsidy policies on the gendered differences in schooling and earnings.

Design/methodology/approach

A three-sector full employment general equilibrium model is developed, where the amount of schooling of children is determined by the intertemporal utility maximizing behaviour of the parents over two periods.

Findings

The results indicate that higher gender-neutral education subsidy may raise the amount of schooling of boys more than girls and aggravate the schooling inequality in a society with traditional gender norms; the effect on earning inequality depends on the relative gendered returns to education and the marginal effects of the subsidy on relative schooling levels. However, gender-specific subsidy policies raise female schooling, thereby narrowing gender-based schooling and are likely to favourably affect the earning inequality.

Originality/value

The paper tries to analyse the linkage between education and labour market within a gender dimension. On the one hand, it tries to explain parental schooling decision due to gender-neutral and gender-specific education subsidies, and on the other, it examines the effects of these two subsidy policies on gendered schooling inequality and gender earnings inequality in a dynamic model.
Facebook vs Twitter: the differential relationship with mass attitudes about democracy in Latin Americas
Authors: Kornrumpf Richard , Gainous Jason , Wagner Kevin M. , Gray Tricia J.
Published: December 2024

Purpose

We argue that the information flow on Twitter is largely driven by elite communication with a top-down flow, while Facebook’s bottom-up flow is driven by mass public communication. Both are crucial news sources for democratic processes in Latin America. We explore how exposure to these flows affects opinions on democracy across 18 countries with varying democratic conditions.

Design/methodology/approach

Using mixed-effects models, our analysis draws on survey data from the 2018 Latinobarómetro paired with democracy measures from the 2018 Varieties of Democracy.

Findings

The results indicate that Facebook’s bottom-up communication correlates with negative perceptions of democracy, whereas Twitter’s top-down model correlates with more favorable views, especially among mass consumers. However, these differences are inconsistent across demographic factors.

Research limitations/implications

Cross-sectional survey data limits causal claims. Longitudinal data could provide stronger insights into the mechanisms underlying the observed relationships.

Practical implications

Understanding how different platforms influence democratic attitudes can inform strategies for political communication and digital governance in Latin America. Policymakers should consider platform-specific interventions to promote democratic engagement.

Originality/value

This study adds to the limited research on platform differences in political public opinion, particularly in Latin America, and highlights the need to explore mechanisms of change across various social media platforms.
Engagement in the teleworking context: challenges and leadership performance
Authors: Rinker Cáren Maria , Bessi Vania Gisele , Schreiber Dusan
Published: December 2024

Purpose

Community college institutions (ICES) experienced a transition movement during the pandemic, with the expansion of teleworking in the area of education. In addition, administrative areas also changed into this work format. This strategy was innovative in these organizations, and engaging the employees who have remained in this modality is a challenge. The objective of the study is to analyze challenges and actions of ICES administrative managers in the state of Rio Grande do Sul/Brazil to engage their teams into teleworking.

Design/methodology/approach

The research is descriptive, with a qualitative approach and it was conducted through interview studies. The units of analysis were eight managers from technical administrative areas of six ICES. The interviews and data analysis took place based on pre-defined categories, based on theory.

Findings

Actions were identified to promote employee engagement in teleworking, with welcoming and outreaching activities. Communication has become a fundamental element for emotional management to take place, and the effective rapport of the leader, in the virtual space, is essential in the process.

Originality/value

Originality of the study lies in the fact that, for these organizations, remote work in the administrative area is an innovation in processes. Reflecting on the performance of leaders in teleworking can be useful for outlining team management strategies and even expanding the theory on leadership, which is relevant in contemporary organizational studies. Studying team engagement is a theoretical gap, especially in the context of teleworking.
Thinking with ideas from affect theory: imagining otherwise in our literacy classrooms
Authors: Sesta Jenny
Published: December 2024

Purpose

The purpose of this conceptual paper is to challenge the introduction and implementation of policy mandates that threaten to reduce democratic, creative and responsive literacy pedagogies and practices in the early years. It draws on affect theory as a means to expand theorisations of literacy teaching and learning with approaches that privilege children’s knowledge as being central to the meaning making process.

Design/methodology/approach

Thinking with ideas from the conceptual paradigm of affect theory, I consider ways in which teachers can expand their repertoire of theories and literacy pedagogies in order to understand the diverse needs of children in contemporary classrooms.

Findings

Emphasising the importance of expanding how we imagine our daily pedagogies I thread reflective prompts throughout the discussion to engage the reader to consider how ideas might live in daily literacy classroom practice.

Originality/value

This paper shares insights from contemporary research in affect theory to disrupt the hegemony of early literacy practices. It speaks back to the dominance of reductive models of program approaches and expands views of what counts in early literacy teaching. It considers how we can become more closely attuned to the affective relations in classroom life.
Disordered eating attitudes and behaviours among older adults with type 1 diabetes: An exploratory study
Authors: Ercolino Gabriella T. , Sprinkles Jessica , Fruik Angela , Muthukkumar Rashmi , Gopisetty Nikhita , Qu Xiaorui , Young Laura A. , Mayer‐Davis Elizabeth J. , Sarteau Angelica Cristello , Kahkoska Anna R.
Published: December 2024

Aims

We explored the prevalence of disordered eating behaviours (DEBs) and attitudes among older adults with type 1 diabetes (T1D) and associations with demographic and clinical variables.

Methods

Adults aged ≥65 years with T1D from a university‐affiliated hospital system completed an electronic survey (September to November 2023) including the Diabetes Eating Problem Survey‐Revised (DEPS‐R). Clinical data were extracted from medical records.

Results

Seventy‐seven older adults (mean [SD] age: 71.8 [4.1]; mean [SD] HbA1c [mmol/mol]: 51 [12]; BMI [kg/m2]: 27.3 [4.7]) with T1D completed the DEPS‐R. Mean DEPS‐R score was 11.5 (6.0), with 5.2% (n = 4) having clinically significant DEBs (score ≥ 20). We found a positive linear association between DEPS‐R score and BMI (adjusted p = 0.002). There was no significant association with HbA1c.

Conclusions

Older adults with T1D endorsed variable degrees of DEBs. Greater DEBs were associated with higher BMI; more research is needed to characterise this relationship.
Insights into thermal sensitivity: Effects of elevated temperature on growth, metabolic rate, and stress responses in Atlantic wolffish (Anarhichas lupus)
Authors: Hinchcliffe James , Roques Jonathan A. C. , Ekström Andreas , Hedén Ida , Sundell Kristina , Sundh Henrik , Sandblom Erik , Björnsson Björn Thrandur , Jönsson Elisabeth
Published: December 2024

The Atlantic wolffish (Anarhichas lupus) is a cold‐water fish with potential for aquaculture diversification. To unveil the mechanisms underlying the compromised growth in Atlantic wolffish when reared at higher temperatures, we investigated the relationship between temperature, growth rate, aerobic capacity, stress biomarkers, and gut barrier function. Juveniles acclimated to 10°C were maintained at 10°C (control) or exposed to 15°C for either 24 h (acute exposure) or 50 days (chronic exposure). Fish exposed to 15°C exhibited reduced growth, higher standard, and maximum metabolic rates compared to those at 10°C. In the chronically exposed group at 15°C, metabolic rates were lower than those of acutely exposed fish. The absolute aerobic scope exhibited no significant variation in temperatures; however, the factorial scope showed a notable reduction at 15°C in both acute and chronic exposed groups, aligning with a correlated decrease in individual growth rates. Chronic warming led to increased plasma glucose levels, indicating energy mobilization, but cortisol levels were unaffected. Furthermore, chronic warming resulted in reduced intestinal barrier function, as evidenced by increased ion permeability and a negative potential in the serosa layer. We conclude that warming elevates metabolic rates while reducing intestinal barrier function, thus increasing energy expenditure, collectively, limiting energy available for growth at this temperature from increased allostatic load. Thus, juvenile wolffish maintaining their aerobic scope under thermal stress experience slower growth. This research provides insights for improving the welfare and resilience of wolffish in aquaculture at elevated temperatures and understanding their response to increased environmental temperatures.
Understanding stress‐induced transmission of peripherally derived factors into the brain and responses in non‐neuronal cells
Authors: Kudo Mikiko , Yamamoto Shota , Hiraga Shin‐ichiro , Masuda Takahiro
Published: December 2024

Stress is a significant cause of mental disorders, for which effective treatments remain limited due to an insufficient understanding of its pathogenic mechanisms. Recent research has increasingly focused on non‐neuronal cells to elucidate the molecular mechanisms underlying psychopathology. In this review, we summarize the current knowledge on how non‐neuronal cells in the central nervous system, including microglia, astrocytes, and oligodendrocytes, respond to peripherally derived stress‐related factors and how these responses contribute to the development of mental disorders. A more comprehensive understanding of stress‐induced alterations, with careful consideration of the type and timing of stress exposure, will provide fundamental insights into the pathogenesis of diverse stress‐related mental disorders.

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Exploring the Role of Ccn3 in Type III Cell of Mice Taste Buds
Authors: Wang Kuanyu , Mitoh Yoshihiro , Horie Kengo , Yoshida Ryusuke
Published: December 2024

Different taste cells express unique cell‐type markers, enabling researchers to distinguish them and study their functional differentiation. Using single‐cell RNA‐Seq of taste cells in mouse fungiform papillae, we found that Cellular Communication Network Factor 3 (Ccn3) was highly expressed in Type III taste cells but not in Type II taste cells. Ccn3 is a protein‐coding gene involved in various biological processes, such as cell proliferation, angiogenesis, tumorigenesis, and wound healing. Therefore, in this study, we aimed to explore the expression and function of Ccn3 in mouse taste bud cells. Using reverse transcription polymerase chain reaction (RT‐PCR), in situ hybridization, and immunohistochemistry (IHC), we confirmed that Ccn3 was predominantly expressed in Type III taste cells. Through IHC, quantitative real‐time RT‐PCR, gustatory nerve recordings, and short‐term lick tests, we observed that Ccn3 knockout (Ccn3‐KO) mice did not exhibit any significant differences in the expression of taste cell markers and taste responses compared to wild‐type controls. To explore the function of Ccn3 in taste cells, bioinformatics analyses were conducted and predicted possible roles of Ccn3 in tissue regeneration, perception of pain, protein secretion, and immune response. Among them, an immune function is the most plausible based on our experimental results. In summary, our study indicates that although Ccn3 is strongly expressed in Type III taste cells, its knockout did not influence the basic taste response, but bioinformatics provided valuable insights into the possible role of Ccn3 in taste buds and shed light on future research directions.

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Effects of orally administered clioquinol on the fecal microbiome of horses
Authors: Smith Mikaila Z. , York Mary , Townsend Kile S. , Martin Lynn M. , Gull Tamara , Coghill Lyndon M. , Ericsson Aaron C. , Johnson Philip J.
Published: December 2024

Background

Whereas restoration of fecal consistency after treatment with clioquinol for chronic diarrhea and free fecal water syndrome has been attributed to its antiprotozoal properties, actions of clioquinol on the colonic bacterial microbiota have not been investigated.

Objectives

Characterize the dynamics of fecal microbial diversity before, during, and after PO administration of clioquinol to healthy horses.

Study Design

Experimental prospective cohort study using a single horse group.

Methods

Eight healthy adult horses received PO clioquinol (10 g, daily) for 7 days. Feces were obtained daily for 7 days before, during, and after conclusion of treatment, and again 3 months later. Libraries of 16S rRNA V4 region amplicons generated from fecal DNA were sequenced using the Illumina sequencing platform. Bioinformatic analysis was undertaken with QIIME2 and statistical analyses included analysis of variance (ANOVA) and permutational multivariate ANOVA (PERMANOVA).

Results

The richness and composition of the fecal microbiome was altered after administration of clioquinol, reaching a maximum effect by the fifth day of administration. Changes included a 90% decrease in richness, and compensatory expansion of facultative anaerobes including Streptococcaceae, Enterococcaceae, and Enterobacteriaceae. Multiple horses had Salmonella cultured from feces.

Main Limitations

Limitations including lack of control group and modest sample size are obviated by robust longitudinal study design and strong effect size associated with drug exposure.

Conclusions

Clioquinol has broad‐spectrum antibacterial effects on the fecal microbiome of horses, but spares certain bacterial families including several pathogens and pathobionts. Clioquinol should be used with caution in horses, in an environment free of contamination with fecal pathogens.
Regulation of DNA Topology in Archaea: State of the Art and Perspectives
Authors: Villain Paul , Basta Tamara
Published: December 2024

DNA topology is a direct consequence of the double helical nature of DNA and is defined by how the two complementary DNA strands are intertwined. Virtually every reaction involving DNA is influenced by DNA topology or has topological effects. It is therefore of fundamental importance to understand how this phenomenon is controlled in living cells. DNA topoisomerases are the key actors dedicated to the regulation of DNA topology in cells from all domains of life. While significant progress has been made in the last two decades in understanding how these enzymes operate in vivo in Bacteria and Eukaryotes, studies in Archaea have been lagging behind. This review article aims to summarize what is currently known about DNA topology regulation by DNA topoisomerases in main archaeal model organisms. These model archaea exhibit markedly different lifestyles, genome organization and topoisomerase content, thus highlighting the diversity and the complexity of DNA topology regulation mechanisms and their evolution in this domain of life. The recent development of functional genomic assays supported by next‐generation sequencing now allows to delve deeper into this timely and exciting, yet still understudied topic.
Patterns of platelet use evaluated in EHR networks of the Biologics Effectiveness and Safety Initiative, 2012–2018
Authors: Villa Carlos H. , Biondich Paul , Draper Nicole L. , Dores Graça M. , Storch Emily , Chada Kinnera , Wong Hui‐Lee , Whitaker Barbee , Obidi Joyce , Vossoughi Sarah , Soares Andrey , Schilling Lisa M. , Natarajan Karthik , Goodman Michael , Purkayastha Saptarshi , Zucker Rachel , Falconer Thomas , Williams Nerissa , Reich Christian , Anderson Steven , Shoaibi Azadeh
Published: December 2024

Background

U.S. FDA's Center for Biologics Evaluation and Research (CBER) Biologics Effectiveness and Safety (BEST) Initiative leverages large electronic health records and administrative claims data to conduct active surveillance for CBER‐regulated products. Improved hemovigilance of platelet transfusions provides exposure data for future outcome studies and can identify opportunities to improve management of the limited platelet supply.

Methods

Platelet utilization in three hospital networks (2012–2018) is summarized from data obtained using Information Standard for Blood and Transplant (ISBT) 128 platelet codes. Transfusion episodes, the number of units transfused, and component characteristics are described.

Results

Most platelet‐transfused patients (range 59.6%–62.2% across study years for all sites) received platelets once per year and used a small proportion of the total platelets transfused per year (range 18.4%–22.5%). In contrast, a minority of patients were transfused 12 or more times in a given study year (range 4.4%–6.3%) and used a plurality of transfused platelets (range 32.2%–44.4%) per year. The overall ratio of platelets transfused to the number of patients receiving any platelet transfusion was stable over the study period (range 3.9–4.5 platelets/patient) and similar among participating data sources. For all data sources, most transfusion episodes (78%) involved one component per transfusion episode.

Conclusion

ISBT 128 coding in the BEST Initiative was used to capture platelet transfusion events, component modifications, and characterize aspects of platelet use patterns. These data can be leveraged to identify opportunities for improved management of the platelet supply and provide granular exposure information for future studies of transfusion‐related adverse events.