bluuebunny/crossref_metadata_2025 huggingface dataset:
Imaging synaptic density in ageing and Alzheimer’s Disease with [18F]-SynVesT-1
Authors: Giorgio Joseph , Soleimani-Meigooni David N. , Janabi Mustafa , Baker Suzanne L. , Chen Xi , Toueg Tyler N. , Weimer Robby , Zinnhardt Bastian , Green Ari , Rabinovici Gil D. , Jagust William J.
Published: October 2024

Monitoring synaptic injury in neurodegenerative diseases may provide new insights into the evolution of the degenerative process as well as a potential mechanism to target for preservation of function. Synaptic density imaging with PET is a relatively new approach to this issue. However, there are remaining questions about technical approaches to data analysis including reference region selection, and how specific phenotypic presentations and symptoms of Alzheimer’s Disease (AD) are reflected in alterations in synaptic density.

Methods

Using an SV2A PET ligand radiolabeled with the18F isotope ([18F]-SynVesT-1) we performed sensitivity analyses to determine the optimal reference tissue modelling approach to derive whole brain ratio images. Using these whole brain images from a sample of young adults, older adults, and patients with varied phenotypic presentations of AD we then contrast regional SV2A density andin vivoAD biomarkers.

Result

Reference tissue optimisation concluded that a cerebellar grey matter reference region is best for deriving whole brain ratio images. Using these whole brain ratio images, we find a strong inverse association between [18F]-SynVesT-1 PET uptake and amyloid beta and tau PET deposition. Finally, we find that individuals with lower temporal grey matter volume but higher temporal [18F]-SynVesT-1 PET uptake show preserved performance on the MMSE.

Conclusions

[18F]-SynVesT-1 PET shows a close association within vivoAD pathology and preserved SV2A density may be a possible marker for resilience to neurodegeneration.
Mental Schema Reduces Cognitive Load and Facilitates Emergence of Novel Responses in Mice and Artificial Neural Networks
Authors: Singh Vikram Pal , Shridhar Shruti , Kundu Shankanava , Bhatt Richa , Jayaprakash Balaji
Published: October 2024

Mammalian brain has evolved to infer from past experiences and elicit context relevant novel behavioural responses hitherto unexpressed by the animal. However, little is known about how prior knowledge influences the emergence of such responses. Remarkably, the brain not only arrives at these responses through logical inferences based on previous leanings, but also acquire new related information, without causing catastrophic interference. Mental schemas have often been proposed as the framework for this phenomenon. In this study, using mice as a model animal, we show that schematic networks not only enhance the cognitive load handling capacity (CLHC) and prevent catastrophic interference, but also facilitate the generation of novel, contextually relevant responses. Interestingly, when the animals were trained in a paradigm that did not invoke the pre-formed mental schema, we observed neither an enhancement to CLHC nor a generation of novel context relevant responses. Based on the principles of mental schemas discovered in our animal experiments, we developed a biologically plausible artificial neural network (ANN) that avoids catastrophic interference and captures the learning properties observed in our experiments. The custom architecture of this ANN enables it to generate responses similar to those of animals in novel scenarios.

Significance Statement

Little is known about the role of mental schemas in preventing memory interference—a process in which overlapping or similar memories hinder the acquisition and retention of related information. In this study, we demonstrate that mental schemas enhance cognitive load handling capacity and improve the ability to solve novel but related problems. Using mice as a model, we show that the mere existence of a mental schema is not enough for improved cognitive load handling; instead, the relationship between existing and new information must be explicitly established during the learning process. Based on these findings, we developed a minimalistic artificial neural network (ANN) that effectively mimics this behaviour. These insights pave the way for developing more efficient learning and teaching strategies.
Site of breast cancer metastasis is independent of single nutrient levels
Authors: Abbott Keene L. , Subudhi Sonu , Ferreira Raphael , Gültekin Yetiş , Steinbuch Sophie C. , Munim Muhammad Bin , Honeder Sophie E. , Kumar Ashwin S. , Ramesh Diya L. , Wu Michelle , Hansen Jacob A. , Sivanand Sharanya , Riedmayr Lisa M. , Duquette Mark , Ali Ahmed , Henning Nicole , Shevzov-Zebrun Anna , Gourgue Florian , Barbeau Anna M. , Waite Millenia , Kunchok Tenzin , Ferraro Gino B. , Do Brian T. , Spanoudaki Virginia , Sánchez-Rivera Francisco J. , Jin Xin , Church George M. , Jain Rakesh K. , Vander Heiden Matthew G.
Published: October 2024

Cancer metastasis is a major contributor to patient morbidity and mortality1, yet the factors that determine the organs where cancers can metastasize are incompletely understood. In this study, we quantify the absolute levels of over 100 nutrients available across multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different organs. We then asked how tumor growth in different tissues relates to nutrient availability and tumor biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. Additionally, we identify purine synthesis as a requirement for tumor growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumor de novo nucleotide synthesis activity. These data suggest that a complex interplay of multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.
Auditory Working Memory Mediates the Relationship Between Musicianship and Auditory Stream Segregation
Authors: Liu Martha , Arseneau-Bruneau Isabelle , Franch Marcel Farrés , Latorre Marie-Elise , Samuels Joshua , Issa Emily , Payumo Alexandre , Rahman Nayemur , Loureiro Naíma , Leung Tsz Chun Matthew , Nave Karli M. , von Handorf Kristi M. , Hoddinott Joshua D. , Coffey Emily B.J. , Grahn Jessica , Zatorre Robert J.
Published: October 2024

This study investigates the interactions between musicianship and two auditory cognitive mechanisms: auditory working memory (AWM) and stream segregation. The primary hypothesis is that AWM mediates the relationship between musical training and enhanced stream segregation capabilities. Two groups of listeners were tested, the first to establish the relationship between the two variables and the second to replicate the effect in an independent sample. Music history and behavioural data were collected from a total of 145 healthy young adults with normal binaural hearing. They performed a task that requires manipulation of tonal patterns in working memory, and the Music-in-Noise Task (MINT), which measures stream segregation abilities in a musical context. The MINT task expands measurements beyond traditional Speech-in-Noise (SIN) assessments by capturing auditory subskills (e.g., rhythm, visual, spatial, prediction) relevant to stream segregation. Our results showed that musical training is associated with enhanced AWM and MINT task performance, and that this effect is replicable across independent samples. Moreover, we found in both samples that the enhancement of stream segregation was largely mediated by AWM capacity. The results suggest that musical training and/or aptitude enhances music-in-noise perception by way of improved AWM capacity.
FBXW7 alleviates c-MYC repression of pyruvate carboxylase to support metabolic flexibility
Authors: Lisci Miriam , Vericel Fanny , Gallant-Ayala Hector , Ivanisevic Julijana , Jourdain Alexis A.
Published: October 2024

Metabolic flexibility, or the ability to adapt to environmental fluctuations, is key to the survival and growth of all living organisms. In mammals, the pathways supporting cell proliferation in nutrient-limiting conditions have not been fully elucidated, although cancers are known to display metabolic dependencies that can be targeted for therapy. Here, we combine systematic nutrient and genome-wide CRISPR/Cas9 screening to provide a comprehensive map of the signaling and metabolic pathways that support cell proliferation in glutamine-limited conditions. We focus on pyruvate anaplerosis and discover a mechanism by which the tumor suppressor FBXW7 controls a MYC-dependent cluster of epigenetic repressors that bind the pyruvate carboxylase (PC) promoter, leading to histone deacetylation, reducedPCexpression and glutamine addiction. Our work sheds light on the molecular mechanisms that support metabolic flexibility, and on the nutrients and pathways involved in glutamine dependency, a hallmark of several cancers.

Graphical abstract
Testing the Tests: Using Connectome-Based Predictive Models to Reveal the Systems Standardized Tests and Clinical Symptoms are Reflecting
Authors: Samardzija Anja , Shen Xilin , Luo Wenjing , Greene Abigail , Mehta Saloni , Tokoglu Fuyuze , Arora Jagriti , Woods Scott , Katz Rachel , Sanacora Gerard , Srihari Vinod H. , Scheinost Dustin , Constable R. Todd
Published: October 2024

Background

Substantial strides have been made in developing connectome-based predictive models that establish connections between external measures of cognition and/or symptoms obtained through testing performed in a clinical setting, and the human functional connectome. Often referred to as brain-behavior modeling such models offer insights into the functional brain organization supporting the test scores of these external measures1–7. Here, we depart from the conventional feed-forward approach and introduce a feed-back approach that provides new insight into the systems the external measures are reflecting and provides a framework for developing new test instruments that better target specific brain systems.

Methods

In fMRI data from 227 demographically and clinically diverse subjects (healthy participants and patients), we a priori define connectivity networks for the six cognitive constructs and employ kernel ridge regression in a predictive modeling framework to quantify each network’s contribution to performance across a spectrum of standardized tests.

Results

This approach provides a ranking of test scores according to the predictive power of each cognitive network, allowing one to choose the best test to probe a specific brain network. It yields a brain-driven process for forming new tests through selection of combinations of measures that probe the same brain systems. These new composite tests yield better external measures, as reflected by higher predictive power in brain-behavior modeling. We also evaluate the inclusion of specific subtests within a composite score, revealing instances where composite scores are reinforced or weakened by subtest inclusion regarding the specificity of the brain network they interrogate.

Conclusions

The brain-behavior modeling problem can be reconfigured to provide a biologically driven approach to the selection of external measures directed at specific brain systems. It opens new avenues of research by providing a framework for the development of measures, both cognitive and clinical, guided by quantitative brain metrics.
A Novel Cyanine-Based Fluorescent Dye for Targeted Mitochondrial Imaging in Neurotoxic Conditions andIn VivoBrain Studies
Authors: Yan Xin , Chen Xinqian , Hou Shanshan , Li Xiaoxu , Ju Jingyue , Shan Zhiying , Bi Lanrong
Published: October 2024

Mitochondrial dysfunction is a key feature of neurodegenerative diseases, often preceding symptoms and influencing disease progression. However, real-timein vivoimaging of mitochondria in the brain is limited by existing dyes like MitoTrackers, which struggle with poor tissue penetration, phototoxicity, and inability to cross the blood-brain barrier (BBB). This study introduces Cy5-PEG4, a novel mitochondrial-targeting dye that overcomes these limitations, enabling high-resolution, non-invasive imaging of mitochondrial dynamics. Cy5-PEG4 effectively labels mitochondria in primary neuronal cells exposed to the SARS-CoV-2 RNYIAQVD peptide, revealing dose-dependent alterations in mitochondrial function that may contribute to COVID-19-related neurodegeneration. Importantly, Cy5-PEG4 crosses the BBB without causing neuroinflammation or toxicity, making it a safe tool forin vivobrain imaging and detailed studies of mitochondrial responses. In 3D cultured cells, Cy5-PEG4 captures dynamic changes in mitochondrial distribution and morphology as cell structures mature, highlighting its potential in neurobiological research, diagnostics, and therapeutic development. These findings support Cy5-PEG4 as a powerful tool for studying disease progression, identifying early biomarkers, and evaluating therapeutic strategies in neurodegenerative disorders and COVID-19.
Prediction of the reaction mechanisms of sesquiterpene coumarin synthases supports a direct evolutionary link with triterpene biosynthesis
Authors: Stephenson Michael J. , Brodelius Peter E.
Published: October 2024

Sesquiterpene coumarins are primarily produced by plants of the Apiaceae and Asteraceae families. Farnesylation of 7-hydroxycoumarins such as umbelliferone, scopoletin or isofraxidin yield linear 7-farnesyloxycoumarins that are converted to various cyclic sesquiterpene coumarins by sesquiterpene coumarin synthases (cyclases). The terminal double bond of the linear 7-farnesyloxycoumarins is epoxidized by a sesquiterpene coumarin epoxidase. The diverse 7-(10′,11′-oxidofarnesyloxy)-coumarins produced are protonated by various sesquiterpene coumarin synthases to generate a carbocation that initiates cyclization of the farnesyl moiety (A process analogous to the carbocation cascades observed with sesquiterpene synthases and other cyclases involved in the biosynthesis of additional terpene classes, such as the triterpenes). These reaction mechanisms typically include Wagner-Meerwein rearrangements, such as hydride, methyl, and other alkyl shifts, but can also involve more complex processes including Grob fragmentations. Around 260 sesquiterpene coumarins based on 7-farnesyloxycoumarins have been described, but essentially nothing is known about the biosynthetic enzymes involved,i.e., farnesyltransferase, sesquiterpene coumarin epoxidase and synthase. In this review, putative reaction pathways for formation of the carbon skeletons of all known 7-farnesyloxycoumarins-derived sesquiterpene coumarins are presented.
G-quadruplex ligand RHPS4 compromises cellular radio-resistance by blocking the increase in mitochondrial mass and activity induced by ionising irradiation
Authors: Tricot S. , Siberchicot C. , Bontemps I. , Desmaze C. , Kratassiouk G. , Vandamme M. , Pinna G. , Radicella J.Pablo , Lenaers G. , Lebeau J. , Campalans A.
Published: October 2024

A major challenge in radiotherapy is to enhance tumor cell sensitivity to radiation while minimizing damage to healthy tissues. Ionising radiation (IR) induces mitochondrial DNA (mtDNA) alterations that can impair mitochondrial function and cell survival. Since mitochondria play a key role in tumor cell proliferation, they represent a promising therapeutic target for cancer treatment. In this study, we characterized the impact of different IR sources on mitochondrial function in radioresistant cancer cells. Our findings revealed several adaptive responses that may contribute to radioresistance, including increased mtDNA content, mitochondrial mass, enhanced activity, and hyperfusion of the mitochondrial network. Notably, the use of mitochondrial-targeted G-quadruplex (G4) ligands, which block mtDNA replication and transcription, disrupted these responses, reducing cancer cell survival in an mtDNA-dependent manner. These results demonstrate that mitochondrial adaptations contribute to radioresistance and highlight mitochondria as a novel target for the radiosensitizing effects of G4-ligands, extending their potential beyond telomere destabilization.
Meditation in the third-person perspective modulates minimal self and heartbeat-evoked potentials
Authors: Yang Hang , Herbelin Bruno , Ngo Chuong , Vuarnesson Loup , Blanke Olaf
Published: October 2024

Experienced meditation practitioners often report altered states of their sense of self, including decentering and distancing the self from the body and one’s current concerns. Altered states of the sense of self, such as disembodiment and distancing of the self from the body, have also been induced experimentally using virtual reality (VR) and linked neurally to heartbeat evoked potentials (HEPs). Whereas many studies investigated the related neural correlates of such decentering during meditation, none experimentally modulated the sense of self during meditation practice using VR nor determined the potentially associated behavioral changes of the sense of self. Here we determined HEPs and behavioral measures in 23 participants who performed a guided meditation practice in VR, either from a third-person (3PP) or first-person perspective (1PP) to modulate the sense of self. In the 3PP versus 1PP meditation condition, we report stronger sensations of detachment and disconnection, reduced salience of the perceived body boundary, and reduced self-identification with the body. HEP analysis revealed differential neural responses between conditions, characterized by a more negative HEP amplitude in the 3PP condition, associated with activation of the posterior cingulate cortex and medial prefrontal cortex. Leveraging a new VR-supported meditation platform and methods, these data link the sense of self in meditation practice to the neuroscience of the bodily self, based on subjective, behavioral, and neural measures.
Computational microbiology of soil organic matter mineralization: Use of the concept of curve skeleton to partition the 3D pore space in computed tomography images
Authors: Belghali Zakaria , Monga Olivier , Klai Mouad , Abdelwahed El Hassan , Druoton Lucie , Pot Valérie , Baveye Philippe C.
Published: October 2024

Recent advances in 3D X-ray Computed Tomography (CT) sensors have stimulated research efforts to unveil the extremely complex micro-scale processes that control the activity of soil microorganisms. Classical methods for the numerical simulation of biological dynamics using meshes of voxels, such as the Lattice Boltzmann Method (LBM), tend to require long computation times. The use of more compact geometrical representations of the pore space can drastically decrease the computational cost of simulations. Recent research has introduced basic analytic volume primitives to define piece-wise approximations of the pore space to simulate drainage, diffusion, and microbial mineralization of organic matter in soils. Such approaches work well but a drawback is that they give rise to non-negligible approximation errors. In the present article, another alternative is proposed, where pore space is described by means of geometrically relevant connected subsets of voxels (regions) regrouped on the basis of the curve linear skeleton (3D medial axis). This curve skeleton has been adopted to characterize 3D shapes in various fields (e.g., medical imaging, material sciences, etc.) but the few publications that have used it in the context of soils, have dealt exclusively with the determination of pore throats. This technique is used mostly to describe shape and not to partition it into connected subsets. Here, the pore space is partitioned by using the branches of the curve skeleton, then an attributed relational graph is created in order to simulate numerically the microbial mineralization of organic matter, including the diffusion of by-products. This new representation can be used for graph-based simulations, which are different from voxel-based simulations.
ProteinWeaver: A Webtool to Visualize Ontology-Annotated Protein Networks
Authors: Anderson Oliver F , Barelvi Altaf Ayyubi , O'Brien Aden , Norman Ainsley , Jan Iris , Ritz Anna
Published: October 2024

Molecular interaction networks are a vital tool for studying biological systems. While many tools exist that visualize a protein or a pathway within a network, no tool provides the ability for a researcher to consider a protein's position in a network in the context of a specific biological process or pathway. We developed ProteinWeaver, a web-based tool designed to visualize and analyze non-human protein interaction networks by integrating known biological functions. ProteinWeaver provides users with an intuitive interface to situate a user-specified protein in a user-provided biological context (as a Gene Ontology term) in five model organisms. ProteinWeaver also reports the presence of physical and regulatory network motifs within the queried subnetwork and statistics about the protein's distance to the biological process or pathway within the network. These insights can help researchers generate testable hypotheses about the protein's potential role in the process or pathway under study. Two cell biology case studies demonstrate ProteinWeaver's potential to generate hypotheses from the queried subnetworks. ProteinWeaver is available at https://proteinweaver.reedcompbio.org/.
G-quadruplexes in the RSV genome: potential anti-viral targets
Authors: Bose Debopriya , Panda Suman , Banerjee Nilanjan , Chatterjee Subhrangsu
Published: October 2024

The Rous sarcoma virus (RSV) is an onco-retrovirus that infects avian species such as the chicken (Gallus gallus). RSV is the first oncovirus to be described and the oncogenic activity of this virus is related to the expression of a tyrosine kinase that induces carcinogenic transformation. Interestingly, we have noted that the RSV genome contains various potential G4 forming sequences. Among these, two sequences located in the GAG and POL genes, respectively, show high G4 forming potential. Additionally, the SRC oncogene also harbours a putative G4 forming sequence. In this study, we have characterised the G4 formation and topology in these three loci in the RSV-DNA. We have found that these sequences form dynamic G4 structures in physiological conditions and such dynamicity may be associated with their cellular functions. Further, we have also established that these G4s are recognized by G4 interacting small-molecule ligands and the G4-stabilizing protein nucleolin. Binding of these ligands induces structural shifts in the G4 leading to change in structure and stability. Thus, the RSV-DNA G4s may be further studied as targets to control its infection and oncogenic effects.
Endogenous retrovirus-like proteins recruit UBQLN2 to stress granules and alter their functional properties
Authors: Mohan Harihar M. , Fernandez Martin G. , Huang Camellia , Lin Rita , Ryou Jaimie H. , Seyfried Donald , Grotewold Nikolas , Whiteley Alexandra M. , Barmada Sami J. , Basrur Venkatesha , Mosalaganti Shyamal , Paulson Henry L. , Sharkey Lisa M.
Published: October 2024

The human genome is replete with sequences derived from foreign elements including endogenous retrovirus-like proteins of unknown function. Here we show that UBQLN2, a ubiquitin-proteasome shuttle factor implicated in neurodegenerative diseases, is regulated by the linked actions of two retrovirus-like proteins, RTL8 and PEG10. RTL8 confers on UBQLN2 the ability to complex with and regulate PEG10. PEG10, a core component of stress granules, drives the recruitment of UBQLN2 to stress granules under various stress conditions, but can only do so when RTL8 is present. Changes in PEG10 levels further remodel the kinetics of stress granule disassembly and overall composition by incorporating select extracellular vesicle proteins. Within stress granules, PEG10 forms virus-like particles, underscoring the structural heterogeneity of this class of biomolecular condensates. Together, these results reveal an unexpected link between pathways of cellular proteostasis and endogenous retrovirus-like proteins.
Continuous integration of heading and goal directions guides steering
Authors: Crown Anthony M , Wu Annie H , Hofflander Lindsey , Barnea Gilad
Published: October 2024

Navigating animals must integrate a diverse array of sensory cues into a single locomotor decision. Insects perform intricate navigational feats using a brain region termed the central complex in which an animal’s heading direction is transformed through several layers of circuitry to elicit goal-directed locomotion. These transformations occur mostly in the fan-shaped body (FB), a major locus of multi-sensory integration in the central complex. Key aspects of these sensorimotor computations have been extensively characterized by functional studies, leveraging the genetic tools available in the fruit fly. However, our understanding of how neuronal activity in the FB dictates locomotor behaviors during navigation remains enigmatic. Here, we manipulate the activity of two key neuronal populations that input into the FB–the PFNaand PFNdneurons–used to encode the direction of two complex navigational cues: wind plumes and optic flow, respectively. We find that flies presented with unidirectional optic flow steer along curved walking trajectories, but silencing PFNdneurons abolishes this curvature. We next use optogenetic activation to introduce a fictive heading signal in the PFNs to establish the causal relationship between their activity and steering behavior. Our studies reveal that the central complex guides locomotion by summing the PFN-borne directional signals and shifting movement trajectories left or right accordingly. Based on these results, we propose a model of central complex-mediated locomotion wherein the fly achieves fine-grained control of sensory-guided steering by continuously integrating its heading and goal directions over time.
Improved Methodology for Studying Postnatal Osteogenesis via Intramembranous Ossification in a Murine Bone Marrow Injury Model
Authors: Stetsiv Marta , Wan Matthew , Prabhu Shagun , Guzzo Rosa , Sanjay Archana
Published: October 2024

Long bone injuries heal through either endochondral or intramembranous bone formation pathways. Unlike the endochondral pathway that requires a cartilage template, the process of intramembranous ossification involves the direct conversion of skeletal stem and progenitor cells (SSPCs) into bone-forming osteoblasts. There are limited surgical methods to model this process in experimental mice. Here, we have improved upon a bone marrow injury model in mice to facilitate the study of bone repair via intramembranous ossification and to assess postnatal regulators of osteogenesis. This method is highly reproducible and user-friendly, and it allows temporal assessment of new bone formation in a short period (3-7 days post-injury) using µCT and frozen section histology. Furthermore, the contributions of SSPCs and mature osteoblasts can be readily assessed using a combination of fluorescent reporter mice and this intramembranous bone marrow injury model. In clinical contexts, intramembranous bone formation is relevant for healing critical size defects, stress fractures, cortical defects, trauma from tumor resections, and joint replacements.

The murine bone marrow injury model is a useful tool to study postnatal osteogenesis through intramembranous ossification. This simplified surgical protocol describes the bone marrow ablation procedure for downstream assessment of new bone formation and cellular responses following injury.
EpigeneticAgePipeline: an R package for comprehensive assessment of epigenetic age metrics from methylation microarrays
Authors: Rayevskiy Stanislav , Le Quinn , Nguyen Julia , Chen Steven Q. , Castellani Christina A.
Published: October 2024

Epigenetic age is a biological age estimation that is based off nuclear DNA methylation patterns. As an individual ages, methylation sites change in a predictable manner, allowing for the generation of epigenetic age clocks. EpigeneticAgePipeline is an R package that aims to provide a straightforward, out-of-the-box solution for measuring epigenetic age estimates (Horvath, skinHorvath, Hannum, PhenoAge/Levine, GrimAge), as well as two epigenetic age acceleration measures (DunedinPACE, GrimAge Acceleration). Further, EpigeneticAgePipeline imputes cell counts, as well as performs statistical analyses including principal component analysis, normalization, and generation of linear model-based residuals. The pipeline supports Illumina Infinium methylation microarray formats, including HumanMethylation27, HumanMethylation450, and HumanMethylationEPIC. Our package offers an all-in-one solution to generate epigenetic age estimates from input IDAT files or preprocessed methylation beta values.

Availability

EpigeneticAgePipeline is implemented in R (3.5 or greater) and available on GitHub athttps://github.com/CastellaniLab/EpigeneticAgePipeline

Supplementary Information

PDF file submitted along with manuscript.
Idiosyncrasy and generalizability of contraceptive- and hormone-related functional connectomes across the menstrual cycle
Authors: Bottenhorn Katherine L. , Salo Taylor , Jacobs Emily G. , Pritschet Laura , Taylor Caitlin , Herting Megan M. , Laird Angela R.
Published: October 2024

Neuroendocrinology has received little attention in human neuroscience research, resulting in a dearth of knowledge surrounding potent and dynamic modulators of cognition and behavior, as well as brain structure and function. This work addresses one such phenomenon by studying functional connectomics related to ovarian hormone fluctuations throughout the adult menstrual cycle. To do so, we used functional magnetic resonance imaging (fMRI) and hormone assessments from two dense, longitudinal datasets to assess variations in functional connectivity with respect to endogenous and exogenous endocrine factors throughout the menstrual cycle. First, we replicated prior findings that common, group-level and individual specific factors have similar relative contributions to functional brain network organization. Second, we found widespread connectivity related to hormonal contraceptive (HC) use, in addition to sparser estradiol- and progesterone-related connectivity, and differential generalizability of these subnetworks that suggests progestin-specific impacts on functional connectivity in HC users. These results provide novel insight into within-individual changes in brain organization across the menstrual cycle and the extent to which these changes are shared between individuals, illuminating understudied phenomena in reproductive health and important information for all neuroimaging studies that include participants who menstruate.

Author Summary

Endocrine modulation of brain function across the menstrual cycle is poorly understood. Human neuroimaging research on the menstrual cycle has long relied on group- and or coarse, within-individual cycle stage-differences, overlooking considerable individual differences in brain organization, the menstrual cycle, and hormone concentrations. Here, we take a multi-dataset approach to identify idiosyncratic contraceptive- and hormone-related functional connectivity from within-individual neuroendocrine dynamics and then test the generalizability of this connectivity to other individuals. In doing so, we identified idiosyncratic hormone-responsive subnetworks that are somewhat generalizable to other individuals, though this generalizability is complicated by hormonal contraceptive use, potentially reflecting differential connectivity between contraceptive formulations. Thus, this work illuminates individual similarities and differences in neuroendocrine dynamics across the menstrual cycle.
HT SpaceM: A High-Throughput and Reproducible Method for Small-Molecule Single-Cell Metabolomics
Authors: Delafiori Jeany , Shahraz Mohammed , Eisenbarth Andreas , Hilsenstein Volker , Drotleff Bernhard , Bailoni Alberto , Wadie Bishoy , Ekelöf Måns , Mattausch Alexander , Alexandrov Theodore
Published: October 2024

Single-cell metabolomics promises to resolve metabolic cellular heterogeneity, yet current methods struggle with detecting small molecules, throughput, and reproducibility. Addressing these gaps, we developed HT SpaceM, a high-throughput single-cell metabolomics method with novel cell preparation, custom glass slides, small-molecule MALDI imaging mass spectrometry protocol, and batch processing. We propose a unified framework covering essential data analysis steps including quality control, characterization, differential analysis, structural validation and functional analysis. Interrogating human HeLa and mouse NIH3T3 cells, we detected 73 diverse small-molecule metabolites validated by bulk LC-MS/MS, achieving high reproducibility across wells and slides. Interrogating nine NCI-60 cancer cells and HeLa, we identified cell-type markers in small subpopulations. Functional analysis revealed overrepresented metabolic pathways, co-abundant metabolites, and metabolic hubs. We demonstrate the ability of SCM to analyze over 120,000 cells from over 112 samples, and provide guidance to interpret single-cell metabolic heterogeneity, revealing metabolic insights beyond population averages.
Connexin 43 mediated monocyte mitochondrial transfer prevents cisplatin induced sensory neurodegeneration
Authors: Owen Rebecca , Corbett Jack , Paul-Clark Mark , Hulse Richard Philip
Published: October 2024

Platinum based chemotherapeutics including cisplatin are front-line treatments for paediatric and adult cancer. Despite advancements in medical interventions, chemotherapy-induced peripheral sensory neuropathy is a common adverse health related complication that can persist for the long-term and impacts upon an individual’s quality of life. Recently, the causes of chemotherapy induced sensory neurodegeneration has been linked to sensory neuronal mitochondrial dysfunction. Here this study investigated how monocytic mitochondria donation to recipient cisplatin damaged dorsal root ganglia (DRG) sensory neurons prevented platinum-based chemotherapy-induced sensory neurotoxicity. Neuronal cell line, SH-SY5Y, or mouse DRG sensory neurons were treated with either vehicle or cisplatin, and co-cultured with mitotracker-labelled THP1 monocytes. Cisplatin induced dysmorphic mitochondria and diminished oxidative phosphorylation dependent energy production in cisplatin treated dorsal root ganglia sensory neurons. DRG sensory neurons exposed to cisplatin were recipients of monocyte mitochondria indicated by increased intracellular mitotracker fluorescent labelling. Mitochondrial transfer to sensory neurons was neuroprotective, preventing neurite loss and sensory neuronal apoptosis. Vehicle treated DRG sensory neurons did not demonstrate significant mitochondrial uptake. Furthermore, cisplatin induced mitochondrial transfer was prevented by pharmacological inhibition of gap junction protein, connexin 43. Connexin 43 inhibition led to reduced neuroprotective capacity via mitochondrial transfer. These findings demonstrate that monocytic mitochondria transfer to DRG sensory neurons damaged by cisplatin, is dependent upon gap junction intercellular communication to promote sensory neuronal survival. This novel process in sensory neuronal protection is a potential novel therapeutic intervention for alleviating neuropathic pain in individuals treated for cancer.
Design of Parameter Intervals to Meet Steady-State Specifications in Biomolecular Circuits using Interval Analysis
Authors: Prakash Rudra , Janardhanan S. , Sen Shaunak
Published: October 2024

It is often desired, in the analysis or the design of biomolecular circuits, to search for parameters that satisfy certain specifications, such as on the number of the steady states or on their magnitudes. These problems are challenging because of the presence of multiple parameters, the nonlinear mapping between the parameters and the steady states, as well as the specifications themselves, such as when multiple steady states are desired. Typically, exact analytical solutions are limited and numerical approaches, if they converge, may not capture all solutions. We used Interval Analysis versions of Bisection and Constraint Propagation to obtain rigorous and guaranteed estimates of circuit parameters for the design problem. We established criteria that rule out the existence of design solutions in a given parameter space. We presented algorithms to rigorously bound all solutions and developed variants that enclosed the solutions as accurately as required. These theoretical results were illustrated on benchmark feedback and feedforward circuits. These results should aid in the analysis and design of biomolecular circuits as well as in other contexts with similar modelling frameworks. The rigorous nature of the results may be particularly useful for resource optimization and safety criticality in synthetic biology applications, such as in therapeutic applications and drug delivery.
Mettl5coordinates protein production and degradation of PERIOD to regulate sleep inDrosophila
Authors: Wu Xiaoyu , Yang Xingzhuo , Fu Tiantian , Rong Yikang S. , Du Juan
Published: October 2024

Sleep is crucial for animal physiology, primarily governed by the brain, and disruptions are prevalent in various brain disorders.Mettl5, associated with intellectual disability (ID) often accompanied by sleep disturbances, remains poorly understood in its role causing these disorders. Previous research demonstrated that Mettl5 forms a complex with Trmt112, influencing rRNA methylation. In our study, we explored sleep phenotypes due toDrosophila Mettl5mutations. Rescue experiments pinpointedMettl5’s predominant role in neurons and glia marked byMettl5-Gal4 in sleep regulation. Notably, aTrmt112mutation mirrored these sleep disturbances, implicating translational regulation via the Mettl5/Trmt112 complex. Subsequent RNA-seq and Ribo-seq analyses unveiled downstream events fromMettl51bpmutations, revealing altered expression levels of proteasome components and Clock genes. Rescue experiments confirmed that the net increased PERIOD protein is responsible for the sleep phenotype. This investigation sheds light on ribosome, clock genes, and proteasome interplay in sleep regulation, underscoring protein synthesis and degradation’s integrative role. These findings could potentially provide an example ofin vivostudy of the function of rRNA methylation, expand our understanding of the role of protein homeostasis in sleep and inspire explanations on the ID related sleep phenotypes.
WITHDRAWN: MIRAGE: a Bayesian rare variant association analysis method incorporating functional information of variants
Authors: Han Shengtong , Sun Xiaotong , Sloofman Laura , Satterstrom F. Kyle , Wang Gao , Liang Lifan , Knoblauch Nicholas , Zhao Siming , Liu Yuwen , Sheng Wenhui , Nguyen Hoang T. , He Xin
Published: October 2024

Withdraw Statement

The authors have withdrawn this manuscript due to a duplicate submission and request that it not be cited as a reference for ongoing projects. For further inquiries, please contact the corresponding author.

Details regarding this project are available athttps://www.biorxiv.org/content/10.1101/828061v1.article-info.
Irx3/5define the cochlear sensory domain and regulate vestibular and cochlear sensory patterning in the mammalian inner ear
Authors: Liu Yuchen , Qin Tianli , Weng Xin , Leung Bernice , Hei So Karl Kam , Wang Boshi , Feng Wanying , Marsolais Alexander , Josselyn Sheena , Huang Pingbo , Fritzsch Bernd , Hui Chi-Chung , Sham Mai Har
Published: October 2024

The mammalian inner ear houses the vestibular and cochlear sensory organs dedicated to sensing balance and sound, respectively. These distinct sensory organs arise from a common prosensory region, but the mechanisms underlying their divergence remain elusive. Here, we showed that two evolutionarily conserved homeobox genes,Irx3andIrx5, are required for the patterning and segregation of the saccular and cochlear sensory domains, as well as for the formation of auditory sensory cells.Irx3/5were highly expressed in the cochlea, their deletion resulted in a significantly shortened cochlea with a loss of the ductus reuniens that bridged the vestibule and cochlea. Remarkably, ectopic vestibular hair cells replaced the cochlear non-sensory structure, the Greater Epithelial Ridge. Moreover, most auditory sensory cells in the cochlea were transformed into hair cells of vestibular identity, with only a residual organ of Corti remaining in the mid-apical region ofIrx3/5double knockout mice. Conditional temporal knockouts further revealed thatIrx3/5are essential for controlling cochlear sensory domain formation before embryonic day 14. Our findings demonstrate that Irx3/5 regulate the patterning of vestibular and cochlear sensory cells, providing insights into the separation of vestibular and cochlear sensory organs during mammalian inner ear development.
Neuroinflammation in the dorsomedial striatum causes excessive goal-directed action control by disrupting homeostatic astrocyte function
Authors: Abiero Arvie Rodriguez , Gladding Joanne M. , Iredale Jacqueline A. , Drury Hannah R. , Manning Elizabeth E. , Dayas Christopher V. , Dhungana Amolika , Ganesan Kiruthika , Turner Karly , Becchi Serena , Kendig Michael D. , Nolan Christopher , Balleine Bernard , Castorina Alessandro , Cole Louise , Clemens Kelly J. , Bradfield Laura A.
Published: October 2024

Compulsive actions have been confusingly described as reflecting both excessive habitual and excessive goal-directed action control. Here we sought to resolve this contradiction by inducing the neuropathology commonly observed in individuals with compulsive disorders and examining the behavioural outcomes. We found that neuroinflammation in the dorsomedial striatum of rats caused them to be excessively goal-directed, as they acquired and maintained goal-directed actions under conditions that would otherwise produce habits. Immunohistochemical analyses suggested that these behaviours were a result of astrocytic proliferation. To investigate further, we chemogenetically activated the Gi-pathway in striatal astrocytes, which altered the firing properties of nearby medium spiny neurons and modulated goal-directed action control. Together, results show that striatal neuroinflammation is sufficient to cause excessive goal-directed control through dysregulated astrocyte function. Our findings suggest that individuals with striatal neuroinflammation are more prone to excessive goal-directed actions than habits, and that future interventions should aim to restore appropriate goal-directed control.
High-precision neurofeedback-guided meditation training optimises real-world self-guided meditation practice for well-being
Authors: Ganesan Saampras , Van Dam Nicholas , Kamboj Sunjeev K , Tsuchiyagaito Aki , Sacchet Matthew D , Misaki Masaya , Moffat Bradford A , Lorenzetti Valentina , Zalesky Andrew
Published: October 2024

Meditation can benefit well-being and mental health, but novices often struggle to effectively recognize and disengage from mental processes during meditation due to limited awareness, potentially diminishing meditation's benefits. We investigated whether personalised high-precision neurofeedback (NF) can improve disengagement from mental activity during meditation and enhance meditation's outcomes. In a single-blind, controlled, longitudinal paradigm, 40 novice meditators underwent two consecutive days of meditation training with intermittent visual feedback from either their own (N=20) or a matched participant's (N=20; control group) posterior cingulate cortex (PCC) activity measured using 7 Tesla functional magnetic resonance imaging. During training, the experimental group showed stronger functional decoupling of PCC from dorsolateral prefrontal cortex, indicating better control over disengagement from mental processes during meditation. This led to greater improvements in emotional well-being and mindful awareness of mental processes during a week of real-world self-guided meditation. We provide compelling evidence supporting the utility of high-precision NF-guided meditation training to optimise real-world meditation practice for well-being.
Establishing the green algaeChlamydomonas incertaas a platform for recombinant protein production
Authors: Kang Kalisa , do Espirito Santo Évellin , Diaz Crisandra Jade , Oliver Aaron , Saxton Lisa , May Lauren , Mayfield Stephen , Dutra Molino João Vitor
Published: October 2024

Chlamydomonas incerta, a genetically close relative of the model green algaChlamydomonas reinhardtii, shows significant potential as a host for recombinant protein expression. Because of the close genetic relationship betweenC. incertaandC. reinhardtii, this species offers an additional reference point for advancing our understanding of photosynthetic organisms, and also provides a potential new candidate for biotechnological applications. This study investigates C. incerta’s capacity to express three recombinant proteins: the fluorescent protein mCherry, the hemicellulose-degrading enzyme xylanase, and the plastic-degrading enzyme PHL7. We have also examined the capacity to target protein expression to various cellular compartments in this alga, including the cytosol, secretory pathway, cytoplasmic membrane, and cell wall. When compared directly withC. reinhardtii,C. incertaexhibited a distinct but notable capacity for recombinant protein production. Cellular transformation with a vector encoding mCherry revealed thatC. incertaproduced approximately 3.5 times higher fluorescence levels and a 3.7-fold increase in immunoblot intensity compared toC. reinhardtii. For xylanase expression and secretion, bothC. incertaandC. reinhardtiishowed similar secretion capacities and enzymatic activities, with comparable xylan degradation rates, highlighting the industrial applicability of xylanase expression in microalgae. Finally,C. incertashowed comparable PHL7 activity levels toC. reinhardtii, as demonstrated by the in vitro degradation of a polyester polyurethane suspension, Impranil® DLN. Finally, we also explored the potential of cellular fusion for the generation of genetic hybrids betweenC. incertaandC. reinhardtiias a means to enhance phenotypic diversity and augment genetic variation. We were able to generate genetic fusion that could exchange both the recombinant protein genes, as well as associated selectable marker genes into recombinant offspring. These findings emphasizeC. incerta’s potential as a robust platform for recombinant protein production, and as a powerful tool for gaining a better understanding of microalgal biology.

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