bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using N2pc variability to probe functionality: Linear mixed modelling of trial EEG and behaviour
Authors: Hickey Clayton , Grignolio Damiano , Munasinghe Vinura , Acunzo David 
Published: June 2024

ABSTRACTThis paper has two concurrent goals. On one hand, we hope it will serve as a simple primer in the use of linear mixed modelling (LMM) for inferential statistical analysis of multimodal data. We describe how LMM can be easily adopted for the identification of trial-wise relationships between disparate measures and provide a brief cookbook for assessing the suitability of LMM in your analyses. On the other hand, this paper is an empirical report, probing how trial-wise variance in the N2pc, and specifically its sub-component the NT, can be predicted by manual reaction time (RT) and stimuli parameters. Extant work has identified a link between N2pc and RT that has been interpreted as evidence of a direct and causative relationship. However, results have left open the less-interesting possibility that the measures covary as a function of motivation or arousal. Using LMM, we demonstrate that the relationship only emerges when the NTis elicited by targets, not distractors, suggesting a discrete and functional relationship. In other analyses, we find that the target-elicited NTis sensitive to variance in distractor identity even when the distractor cannot itself elicit consistently lateralized brain activity. The NTthus appears closely linked to attentional target processing, supporting the propagation of target-related information to response preparation and execution. At the same time, we find that this component is sensitive to distractor interference, which leaves open the possibility that NTreflects brain activity responsible for the suppression of irrelevant distractor information.
Evidence for direct control of neurovascular function by circulating platelets in healthy older adults
Authors: Rossetti Gabriella M.K. , Dunster Joanne L. , Sohail Aamir , Williams Brendan , Cox Kiera M. , Rawlings Suzannah , Jewett Elysia , Benford Eleanor , Lovegrove Julie A. , Gibbins Jonathan M. , Christakou Anastasia 
Published: June 2024

AbstractPlatelets play a vital role in preventing haemorrhage through haemostasis, but complications arise when platelets become overly reactive, leading to pathophysiology such as athero-thrombosis. Elevated haemostatic markers are linked to dementia and predict its onset in long-term studies. Despite epidemiological evidence, the mechanism linking haemostasis with early brain pathophysiology remains unclear. Here, we aimed to determine whether a mechanistic association exists between platelet function and neurovascular function in 52 healthy mid- to older-age adults. To do this we combined, for the first time, magnetic resonance imaging (MRI) of neurovascular function, peripheral vascular physiology, and in vitro platelet assaying. We show a direct association between platelet reactivity and neurovascular function that is both independent of vascular reactivity and mechanistically specific: Distinct platelet signalling mechanisms (Adenosine 5’-diphosphate, Collagen-Related Peptide, Thrombin Receptor Activator Peptide 6) were directly associated with different physiological components of the haemodynamic response to neural (visual) stimulation (full-width half-maximum, time to peak, area under the curve), an association that was not mediated by peripheral vascular effects. This finding challenges the previous belief that systemic vascular health determines the vascular component of neurovascular function, highlighting a specific link between circulating platelets and the neurovascular unit. Since altered neurovascular function marks the initial stages of neurodegenerative pathophysiology, understanding this novel association becomes now imperative, with the potential to lead to a significant advancement in our comprehension of early dementia pathophysiology.Key points summaryHaemostasis (platelet function) has been linked to the early stages of dementia, but the precise mechanisms are not well understood.This study asks whether a causal mechanism exists through athero-thrombotic effects on the vasculature which can in turn affect brain health, or through direct platelet effects on brain physiology.Here we show that elevated platelet reactivity is associated with blunted (delayed, shorter, and smaller) blood flow responses to neural activation in healthy middle-aged and older adults.However, the association between platelet reactivity and neurovascular function was not mediated by systemic vascular reactivity.This finding challenges the previous belief that systemic vascular health determines the vascular component of neurovascular function, highlighting a specific link between circulating platelets and the neurovascular unit in early dementia pathophysiology.
Neural correlates of device-based sleep characteristics in adolescents
Authors: Ma Qing , Sahakian Barbara J , Zhang Bei , Li Zeyu , Yu Jin-Tai , Li Fei , Feng Jianfeng , Cheng Wei 
Published: June 2024

AbstractUnderstanding the brain mechanisms underlying objective sleep patterns in adolescents and their implications for psychophysiological development is a complex challenge. Here, we applied sparse canonical correlation (sCCA) analysis on 3300 adolescents from Adolescent Brain Cognitive Development (ABCD) study, integrating extensive device-based sleep characteristics and multimodal imaging data. We revealed two sleep-brain dimensions: one characterized by later being asleep and shorter duration, linked to decreased subcortical-cortical network functional connectivities; the other showed higher heart rate and shorter light sleep duration, associated with lower brain volumes and decreased functional connectivities. Hierarchical clustering based on brain dimension associated with sleep characteristics revealed three biotypes of adolescents, marked by unique sleep profiles: biotype 1 exhibited delayed and shorter sleep, coupled with higher heart rate during sleep; biotype 3 with earlier and longer sleep, accompanied by lower heart rate; and biotype 2 with intermediate pattern. This biotypic differences also extended to cognition, academic attainment, brain structure and function in a gradient order. Longitudinal analysis demonstrated consistent biotypic differences from ages 9 to14, highlighting enduring cognitive and academic advantages in biotype3. The linked sleep-brain dimensions and the associated biotypes were well replicated in a longitudinal sample of 1271 individuals. Collectively, our novel findings delineate a linkage between objective sleep characteristics and developing brain in adolescents, underscoring their significance in cognitive development and academic attainment, which could serve as references for individuals with sleep difficulties and offer insights for optimizing sleep routines to enhance better cognitive development and school achievement.
Neuronal toxicity and recovery from early bortezomib-induced neuropathy: targeting the blood nerve barrier but not the dorsal root ganglion
Authors: Atalla Mariam Sobhy , Bettenhausen Anna-Lena , Verse Julius M. , Cebulla Nadine , Krug Susanne M. , Sauer Reine-Solange , Srivastava Mugdha , Bischler Thorsten , Chen Jeremy T.C. , Kortüm K. Martin , Kittel Robert J. , Sommer Claudia , Rittner Heike L. 
Published: June 2024

AbstractThe use of the first in class proteasome inhibitor Bortezomib (BTZ) is highly effective in the treatment of multiple myeloma. However, it’s long-term use is limited by the fact, that most treated patients develop dose limiting painful polyneuropathy. In some of the treated patients, pain resolves after variable timeframes, in others it persists, despite the discontinuation of treatment, with the underlying mechanisms poorly understood. One condition of neural toxicity is the ability to penetrate the blood nerve barrier. Here we present pathways involved in early bortezomib-induced polyneuropathy (BIPN) development and its resolution, in rats and in myeloma patients. One cycle of BTZ elicited transient mechanical hyperalgesia and cold allodynia in rats. Transcriptomic signature and network analysis revealed regulation of circadian, extracellular matrix, and immune genes within the nerve and modest changes in the dorsal root ganglia. Recovery processes resealed the small molecule leakiness of the perineurial barrier, reversed axonal swelling, and normalized small fiber density in the skin. Expression of the microtubule-associated cytoskeletal protein cortactin matched this process in the perineurium. Netrin-1 (Ntn1) as a known barrier sealer was also upregulated in pain resolution in nerve and skin. In patients with painful BIPN skin NTN1 was independent of axonal damage. In summary, our data demonstrate that early BTZ toxicity targets mainly the nerve and indicates that pain resolution could be supported by protective growth factors like Ntn1 for remodeling of the extracellular matrix and neuronal barriers.SummaryBortezomib leads to dose-limiting painful polyneuropathy. Already in the first cycle, BTZ toxicity weakens the blood nerve barrier which reseals upon upregulation of netrin-1.
Integrating Data Across Oscillatory Power Bands Predicts the Epileptogenic Zone: the Frequency Range Explorer Epileptogenic Zone (FREEZ) Identification Algorithm
Authors: O’Leary Sean , Lesage Anne-Cecile , Camarillo-Rodriguez Liliana , Zhou Oliver , Silveira Diosely , Wang Jiefei , Sheth Sameer A. , Beauchamp Michael S. , Wang Zhengjia , Magnotti John F. , Karas Patrick J. 
Published: June 2024

AbstractDrug-resistant focal epilepsy affects over 25 million people globally. Identification and removal of the seizure onset site, termed the epileptogenic zone (EZ), is the most successful treatment to stop seizures in these people. Implanting electrodes into the brain to record intracranial electroencephalography (iEEG) is the gold standard test for identifying the EZ. But identification of the EZ with iEEG remains challenging in many cases. We developed a novel methodology using a stacked random forest ensemble machine learning model integrating power across delta, theta, alpha, beta, gamma, and high gamma frequencies over time to identify the EZ. In patients who were seizure-free after surgery, electrodes within the EZ showed significantly higher area under the curve for mean power over time in the first 20 seconds after a seizure compared to electrodes outside the EZ in the alpha (p = 0.0272), beta (p = 0.0263), gamma (p = 0.0013), and high gamma (p = 0.0086) ranges. Additionally, electrodes within the EZ in patients that became seizure-free after surgery had significantly higher AUC compared to electrodes marked within the EZ in patients who did not become seizure-free after surgery in the gamma (p = 0.0145) and high gamma (p = 0.0024) power ranges, but not delta (p=0.8678), theta (p=0.4956), alpha (p=0.1320) or beta (p=0.1624) ranges. A machine learning model was trained to predict electrodes within the EZ. Leave-one-out patient cross validation of the machine learning model yielded a 95.7% positive predictive value and 99.1% specificity for identifying electrodes within the epileptogenic zone, and 95.2% accuracy for predicting seizure outcome based on a planned resection. We implemented this algorithm into the open-source software tool “Reproducible Analysis and Visualization of iEEG” (RAVE) to enable users to reproduce our results and implement this methodology with new datasets, creating a software module titled FREEZ. The software facilitates quantification of the spectral power changes during seizures, including displaying time-frequency spectrograms and projecting results across patient-specific 3D brain maps. Users can also adjust parameters for visualizing multiple frequency ranges from various time regions around seizure onsets in a web-browser-based interface.
Age associated alterations in the cortical representation of cardiac signals: A heartfelt tale
Authors: Saluja Kirti , Roy Dipanjan , Banerjee Arpan 
Published: June 2024

AbstractNeural representation of cardiac rhythms, known as heartbeat evoked responses (HERs), provide a avenue for investigating the interaction between the brain and the heart, pivotal for various physiological and cognitive functions. Concomitantly, age is recognized as a significant factor influencing this interaction, given its impact on both the structural and functional aspects of the brain and the cardiovascular system. Nonetheless, the precise nature of this interaction during the healthy ageing process remains elusive. This study aims to investigate how the influence of cardiac rhythms on spontaneous brain activity varies with age, using HERs as a measure. Subsequently, it aims to explore the mechanism underlying HERs generation and characterize the brain networks that prominently represent HERs from a large (N = 620) human healthy ageing dataset (18-88 years). The results show that HERs exhibit time-locked activity around 180-320 ms post R-peak of the electrocardiogram (ECG) waveform, with significant decrease in HER amplitude across age for both the genders. Furthermore, inter-trial phase coherence (ITPC) analysis indicates that cardiac signals modulate the phases of the ongoing neural oscillations rather than altering the spectral power. Causal functional maps among brain areas computed using Granger causality (GC) reveals consistent connectivity in the fronto-temporal network, though with varying strength across age groups revealing a compensatory mechanism in play to maintain homeostasis. Overall, these findings provide a comprehensive understanding of the interaction between heart and brain in healthy ageing and present opportunities to identify non-invasive markers for characterizing pathological development in neurological and cardiovascular functions.
Hybrid Quadrupole Mass Filter – Radial Ejection Linear Ion Trap and Intelligent Data Acquisition Enable Highly Multiplex Targeted Proteomics
Authors: Remes Philip M. , Jacob Cristina C. , Heil Lilian R. , Shulman Nicholas , MacLean Brendan X. , MacCoss Michael J. 
Published: June 2024

ABSTRACTTargeted mass spectrometry (MS) methods are powerful tools for selective and sensitive analysis of peptides identified by global discovery experiments. Selected reaction monitoring (SRM) is currently the most widely accepted MS method in the clinic, due to its reliability and analytical performance. However, due to limited throughput and the difficulty in setting up and analyzing large scale assays, SRM and parallel reaction monitoring (PRM) are typically used only for very refined assays of on the order of 100 targets or less. Here we introduce a new MS platform with a quadrupole mass filter, collision cell, linear ion trap architecture that has increased acquisition rates compared to the analogous hardware found in the Orbitrap™ Tribrid™ series instruments. The platform can target more analytes than existing SRM and PRM instruments – in the range of 5000 to 8000 peptides per hour. This capability for high multiplexing is enabled by acquisition rates of 70-100 Hz for peptide applications, and the incorporation of real-time chromatogram alignment that adjusts for retention time drift and enables narrow time scheduled acquisition windows. Finally, we describe a Skyline external software tool that implements the building of targeted methods based on data independent acquisition chromatogram libraries or unscheduled analysis of heavy labeled standards. We show that the platform delivers ~10x lower LOQs than traditional SRM analysis for a highly multiplex assay and also demonstrate how analytical figures of merit change while varying method duration with a constant number of analytes, or by keeping a constant time duration while varying the number of analytes.
How does the ion concentration affect the functions of kinesin BimC
Authors: Guo Wenhan , Gao Yuan , Du Dan , Sanchez Jason E , Visootsat Akasit , Li Yupeng , Qiu Weihong , Li Lin 
Published: June 2024

AbstractBimC family proteins are bipolar motor proteins belonging to the kinesin superfamily which promote mitosis by crosslinking and sliding apart antiparallel microtubules. Understanding the binding mechanism between the kinesin and the microtubule is crucial for researchers to make advances in the treatment of cancer and other malignancies. Experimental research has shown that the ion concentration affects the function of BimC significantly. But the insights of the ion-dependent function of BimC remain unclear. By combining molecular dynamics (MD) simulations with a series of computational approaches, we studied the electrostatic interactions at the binding interfaces of BimC and the microtubule under different KCl concentrations. We found the electrostatic interaction between BimC and microtubule is stronger at 0 mM KCl compared to 150 mM KCl, which is consistent with experimental conclusions. Furthermore, important salt bridges and residues at the binding interfaces of the complex were identified, which illustrates the details of the BimC-microtubule interactions. Molecular dynamics analyses of salt bridges identified that the important residues on the binding interface of BimC are positively charged, while those residues on the binding interface of the tubulin heterodimer are negatively charged. The finding in this work reveals some important mechanisms of kinesin-microtubule binding, which helps the future drug design for cancer therapy.
Identification and Characterization of the LipoproteinN-acyltransferase inBacteroides
Authors: Armbruster Krista M. , Jiang Jiawen , Sartorio Mariana G. , Scott Nichollas E. , Peterson Jenna M. , Sexton Jonathan Z. , Feldman Mario F. , Koropatkin Nicole M. 
Published: June 2024

AbstractMembers of the Bacteroidota compose a large portion of the human gut microbiota, contributing to overall gut health via the degradation of various polysaccharides. This process is facilitated by lipoproteins, globular proteins anchored to the cell surface by a lipidated N-terminal cysteine. Despite their importance, lipoprotein synthesis by these bacteria is understudied. InE. coli, the α-amino linked lipid of lipoproteins is added by the lipoproteinN-acyltransferase Lnt. Herein, we have identified a protein distinct from Lnt responsible for the same process inBacteroides, named lipoproteinN-acyltransferase inBacteroides(Lnb). Deletion of Lnb yields cells that synthesize diacylated lipoproteins, with impacts on cell viability and morphology, growth on polysaccharides, and protein composition of membranes and outer membrane vesicles (OMVs). Our results not only challenge the accepted paradigms of lipoprotein biosynthesis in Gram-negative bacteria, but also support the establishment of a new family of lipoproteinN-acyltransferases.SignificanceBacteroidota are key members of the human gut microbiota that influence human health by degrading polysaccharides. This degradation is achieved by a suite of lipoproteins, a class of membrane protein characterized by lipidation. Lipoprotein synthesis in Bacteroidota is understudied. Here, we used a genetic screen to identify gene(s) responsible forN-acylation, the last step in lipoprotein biosynthesis. Our screen identified the lipoproteinN-acyltransferase inBacteroides(Lnb) that performs this step. We show that deletion of Lnb negatively affects cellular growth and ability to degrade polysaccharides, deepening our understanding of Bacteroidota and lipoproteins.
A workflow for targeted proteomics assay development using a versatile linear ion trap
Authors: Shannon Ariana E. , Teodorescu Rachael N. , Soon Nojoon , Heil Lilian R. , Jacob Cristina C. , Remes Philip M. , Rubinstein Mark P. , Searle Brian C. 
Published: June 2024

AbstractAdvances in proteomics and mass spectrometry have enabled the study of limited cell populations, such as single-cell proteomics, where high-mass accuracy instruments are typically required. While triple quadrupoles offer fast and sensitive nominal resolution measurements, these instruments are effectively limited to targeted proteomics. Linear ion traps (LITs) offer a versatile, cost-effective alternative capable of both targeted and global proteomics. We demonstrate a workflow using a newly released, hybrid quadrupole-LIT instrument for developing targeted proteomics assays from global data-independent acquisition (DIA) measurements without needing high-mass accuracy. Gas-phase fraction-based DIA enables rapid target library generation in the same background chemical matrix as each quantitative injection. Using a new software tool embedded within EncyclopeDIA for scheduling parallel reaction monitoring assays, we show consistent quantification across three orders of magnitude of input material. Using this approach, we demonstrate measuring peptide quantitative linearity down to 25x dilution in a background of only a 1 ng proteome without requiring stable isotope labeled standards. At 1 ng total protein on column, we found clear consistency between immune cell populations measured using flow cytometry and immune markers measured using LIT-based proteomics. We believe hybrid quadrupole-LIT instruments represent an economic solution to democratizing mass spectrometry in a wide variety of laboratory settings.
Functional phenotyping of genomic variants using multiomic scDNA-scRNA-seq
Authors: Lindenhofer Dominik , Bauman Julia R. , Hawkins John A. , Fitzgerald Donnacha , Yildiz Umut , Marttinen Jan M. , Kueblbeck Moritz , Zaugg Judith B. , Noh Kyung-Min , Dietrich Sascha , Huber Wolfgang , Stegle Oliver , Steinmetz Lars M. 
Published: June 2024

AbstractGenomic variation ranging from single nucleotide polymorphisms to structural variants can impact gene function and expression, contributing to disease mechanisms such as cancer progression. The systematic study of this variation is hindered by inefficient precision editing tools making it challenging to confidently link genotype and gene expression in pooled screens. Additionally, assessing heterogenous variants in primary tumor samples at scale is difficult with current single-cell technologies. We developed droplet-based multiomic targeted scDNA-scRNAseq (SDR-seq) to precisely link genotypes with gene expression profiles in high-throughput. SDR-seq simultaneously assesses up to 480 RNA and gDNA targets with high coverage and sensitivity across thousands of cells. Using SDR-seq, we associate coding and non-coding variants with distinct gene expression profiles in human iPSCs. Furthermore, we demonstrate that in primary B-cell lymphoma samples, cells with a higher mutational burden exhibit elevated B-cell receptor signaling and tumorigenic gene expression. SDR-seq has broad potential for gaining functional insights into regulatory mechanisms encoded by genetic variants at diverse loci, advancing our ability to study gene expression regulation and its implications for disease.