bluuebunny/crossref_metadata_2025 huggingface dataset:
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

The 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.

Bortezomib 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

Drug-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

Neural 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

Targeted 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

BimC 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

Members 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.

Significance

Bacteroidota 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

Advances 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

Genomic 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.
Physiological Harmony or Discord? Unveiling the Correspondence Between Subjective Arousal, Valence and Physiological Responses
Authors: Koppold Alina , Lonsdorf Tina B. , Kuhn Manuel , Weymar Mathias , Ventura-Bort Carlos
Published: June 2024

Affective experiences are inevitably accompanied by physiological changes, however it is still a matter of intense debate whether events evoking similar affective experiences produce comparable physiological responses (fingerprint hypothesis) or variation is the norm within individuals (population hypothesis). In two independent samples (N = 491; N = 64), we therefore used representational similarity analysis (RSA) to examine the trial-by-trial similarity patterns of subjective experience of valence and arousal and affect-related physiological measures (skin conductance [SCR] and startle blink responses). Across different affect-inducing tasks and samples, we observed strong-to-decisive evidence for a correspondence between SCR and startle responses and models of arousal and valence that assume variation, especially between trials generally evoking higher responses. Our results show that similar affective experiences are rather reflected by distinct physiological responses and emphasize the importance of considering intraindividual variability in future studies to better understand how physiological changes contribute to conscious affective experiences in humans.
Biodegradation Potential of Neptunomonas naphthovoran - NAG-2N-126 for Crude Oil Pollution Mitigation: Experimental and Modelling Insights
Authors: Mutallimov Turan , Wu Kejian , Deng Hai , Ibrahimov Yusif
Published: June 2024

Crude oil contamination poses a significant threat to the environment, demanding effective bioremediation strategies. While microbial biodegradation holds promise, there is a notable absence of exploration, particularly regarding the biodegradation potential of Neptunomonas naphthovoran strain NAG-2N-126. This study addresses this gap by investigating the bioremediation potential of NAG-2N-126 through experimental analyses and mathematical modelling. Our findings reveal the strain’s rapid growth on crude oil, with the microbial biomass predicted to undergo a 3.5-fold increase over the experimental period. Additionally, the strain exhibited high efficiency in degrading aromatic compounds, achieving an impressive 41% degradation rate within the initial 20-day period. Oxygen availability emerged as a critical factor influencing microbial growth and biodegradation processes, with simulations indicating a 20% decrease in degradation rates under oxygen-deprived conditions. Mathematical modelling provided insights into the complex dynamics involved, contributing to the understanding of microbial hydrocarbon degradation. However, further research is warranted to optimize growth conditions and scale up findings for practical applications in environmental cleanup efforts. By delving into this underexplored area, this study highlights the importance of NAG-2N-126 in crude oil bioremediation and underscores the need for further research to optimize its application in environmental cleanup efforts.

IMPORTANCE

This study presents novel insights into microbial biodegradation of crude oil, addressing a critical environmental challenge. With an estimated 24 billion BOE potentially remaining in the North Sea reservoir and over 2,000 oil spills reported since 2011, including 215 in marine protection areas, the urgency of developing effective bioremediation strategies is paramount. By investigating the growth kinetics and biodegradation efficiency of the bacterial strain N. naphthovoran NAG-2N-126 under controlled laboratory conditions, we elucidate its potential for crude oil remediation. Our findings highlight the strain’s remarkable ability to degrade aromatic hydrocarbons, offering promise for sustainable bioremediation strategies. Furthermore, through the development of mathematical models, we provide valuable insights into microbial population dynamics and substrate utilization rates during crude oil degradation. This research contributes to advancing our understanding of bioremediation processes and offers practical implications for mitigating environmental pollution and promoting ecosystem health.
Marigold: A machine learning-based web app for zebrafish pose tracking
Authors: Teicher Gregory , Madison Riffe R. , Barnaby Wayne , Martin Gabrielle , Clayton Benjamin E. , Trapani Josef G. , Downes Gerald B.
Published: June 2024

High-throughput behavioral analysis is important for drug discovery, toxicological studies, and the modeling of neurological disorders such as autism and epilepsy. Zebrafish embryos and larvae are ideal for such applications because they are spawned in large clutches, develop rapidly, feature a relatively simple nervous system, and have orthologs to many human disease genes. However, existing software for video-based behavioral analysis can be incompatible with recordings that contain dynamic backgrounds or foreign objects, lack support for multiwell formats, require expensive hardware, and/or demand considerable programming expertise. Here, we introduce Marigold, a free and open source web app for high-throughput behavioral analysis of embryonic and larval zebrafish. Marigold features an intuitive graphical user interface (GUI), tracks up to 10 user-defined keypoints, supports both single- and multiwell formats, and exports a range of kinematic parameters in addition to publication-quality data visualizations. By leveraging a highly efficient, custom-designed neural network architecture, Marigold achieves reasonable training and inference speeds even on modestly powered computers lacking a discrete graphics processing unit (GPU). Notably, as a web app, Marigold does not require any installation and runs within popular web browsers on ChromeOS, Linux, macOS, and Windows. To demonstrate Marigold’s utility, we conducted two sets of biological experiments. First, we examined novel aspects of the touch-evoked escape response intechno trousers (tnt)mutant embryos, which contain a previously described loss-of-function mutation in the gene encoding Eaat2b, a glial glutamate transporter. We identified differences and interactions between touch location (head vs. tail) and genotype. Second, we investigated the effects of feeding on larval visuomotor behavior at 5 and 7 days post-fertilization (dpf). We found differences in the number and vigor of swimming bouts between fed and unfed fish at both time points, as well as interactions between developmental stage and feeding regimen. In both biological experiments presented here, the use of Marigold facilitated novel behavioral findings. Marigold’s ease of use, robust pose tracking, amenability to diverse experimental paradigms, and flexibility regarding hardware requirements make it a powerful tool for analyzing zebrafish behavior, especially in low-resource settings such as course-based undergraduate research experiences (CUREs). Marigold is available at:https://downeslab.github.io/marigold/.
Longitudinal Assessment of Glymphatic Changes Following Mild Traumatic Brain Injury: Insights from PVS burden and DTI-ALPS Imaging
Authors: Zhuo Jiachen , Raghavan Prashant , Jiang Li , Roys Steven , Njonkou Tchoquessi Rosy Linda , Chen Hegang , Wickwire Emerson M. , Parikh Gunjan Y. , Schwartzbauer Gary T. , Grattan Lynn M. , Wang Ze , Gullapalli Rao P. , Badjatia Neeraj
Published: June 2024

Abstracts

Traumatic brain injury (TBI) even in the mild form may result in long-lasting post- concussion symptoms. TBI is also a known risk to late-life neurodegeneration. Recent studies suggest that dysfunction in the glymphatic system, responsible for clearing protein waste from the brain, may play a pivotal role in the development of dementia following TBI. Given the diverse nature of TBI, longitudinal investigations are essential to comprehending the dynamic changes in the glymphatic system and its implications for recovery. In this prospective study, we evaluated two promising glymphatic imaging markers, namely the enlarged perivascular space (ePVS) burden and Diffusion Tensor Imaging-based ALPS index, in 44 patients with mTBI at two early post-injury time points: approximately 14 days (14Day) and 6-12 months (6-12Mon) post-injury, while also examining their associations with post-concussion symptoms. Additionally, 37 controls, comprising both orthopedic patients and healthy individuals, were included for comparative analysis. Our key findings include: 1) White matter ePVS burden (WM- ePVS) and ALPS index exhibit significant correlations with age. 2) Elevated WM-ePVS burden in acute mTBI (14Day) is significantly linked to a higher number of post- concussion symptoms, particularly memory problems. 3) The increase in the ALPS index from acute (14Day) to the chronic (6-12Mon) phases in mTBI patients correlates with improvement in sleep measures. Furthermore, incorporating WM-ePVS burden and the ALPS index from acute phase enhances the prediction of chronic memory problems beyond socio-demographic and basic clinical information, highlighting their distinct roles in assessing glymphatic structure and activity. Early evaluation of glymphatic function could be crucial for understanding TBI recovery and developing targeted interventions to improve patient outcomes.
Clinical Predictors of 3-Months Isoniazid Rifapentine (3HP) - Related Adverse Drug Reactions (ADR) During Tuberculosis Preventive Therapy. (PAnDoRA-3HP study): An Observational Study Protocol
Authors: Sekaggya-Wiltshire Christine , Mbabazi Irene , Nabisere-Arinaitwe Ruth , Banturaki Grace , Alinaitwe Lucy , Otalo Brian , Aber Florence , Nampala Juliet , Owor Rogers , Bayiga Josephine , Laker Agnes Odongpiny Eva , Castelnuovo Barbara , Mayito Jonathan , Sekadde Moorine , Pasipanodya Jotam G. , Turyahabwe Stavia , Zawedde-Muyanja Stella
Published: June 2024

Introduction

Tuberculosis (TB) is the leading infectious cause of death globally. Despite WHO recommendations for Tuberculosis Preventive Therapy (TPT), challenges persist, including incompletion of treatment and adverse drug reactions (ADRs). There is limited data on the 3-month isoniazid and rifapentine (3HP) pharmacokinetics, pharmacogenomics and their relation with ADRs. Our study aims to describe the pharmacokinetic and pharmacogenomics of 3HP used for TPT, the ADRs and their association with completion rates, and TPT outcomes, providing vital insights for TB control strategies in resource-limited settings.

Methods

This is an observational cohort study with a nested case-control study. We enrolled consecutive patients initiated on TPT using the 3HP regimen. These are followed up bi-weekly and then monthly during the active phase of treatment and 3 monthly for 2 years following completion of TPT. ADR evaluation includes clinical assessment and liver function tests. Cases are selected from those who experience ADRs, and controls from those who do not. Serum isoniazid and rifapentine concentrations are measured and pharmacogenomic analysis for NAT2 and CYP2E1 polymorphisms are done. Participants are followed up for 2 years to determine TPT outcomes.

Analysis

The safety profile of 3HP will be assessed using descriptive statistics, including proportions of patients experiencing ADRs and grade 3 or above events related to treatment. Chi-square tests and regression models will determine predictors of ADRs and their impact on treatment completion. Pharmacokinetic-pharmacodynamic modeling will establish population parameters and factors influencing rifapentine and isoniazid concentrations.
A physical model for M1-mediated influenza A virus assembly
Authors: Peukes Julia , Dmitrieff Serge , Nédélec François J. , Briggs John A. G.
Published: June 2024

Influenza A virus particles assemble at the plasma membrane of infected cells. During assembly all components of the virus come together in a coordinated manner to deform the membrane into a protrusion eventually forming a new, membrane-enveloped virus. Here we integrate recent molecular insights of this process, particularly concerning the structure of the matrix protein 1 (M1), within a theoretical framework describing the mechanics of virus assembly. Our model describes M1 polymerization and membrane protrusion formation, explaining why it is efficient for M1 to form long strands assembling into helices in filamentous virions. Eventually, we find how the architecture of M1 helices is controlled by physical properties of viral proteins and the host cell membrane. Finally, by considering the growth force and speed of viral filaments, we propose that the helical geometry of M1 strands might have evolved to optimize for fast and efficient virus assembly and growth.

Significance

Influenza A virus remains a major threat to public health. Its most abundant viral protein, matrix protein 1 (M1), forms an endoskeleton underneath the viral membrane, but how this endoskeleton contributes to the virus’ lifecycle is poorly understood. Combining cryo-electron tomography data and structural data with theoretical predictions, we explain how the energetically favorable polymerization of M1 into helical strands mediates the membrane deformations that permit the virus to exit infected cells. Our analysis of M1’s variable architecture provides insights into adaptive strategies of the virus for efficient growth under variable local conditions. The quantitative framework developed in this study could be extrapolated to other enveloped viruses and generally applied to protein-driven membrane deformations.
Striosomes Target Nigral Dopamine-Containing Neurons via Direct-D1 and Indirect-D2 Pathways Paralleling Classic Direct-Indirect Basal Ganglia Systems
Authors: Lazaridis Iakovos , Crittenden Jill R. , Ahn Gun , Hirokane Kojiro , Yoshida Tomoko , Wickersham Ian R. , Mahar Ara , Skara Vasiliki , Loftus Johnny H. , Parvataneni Krishna , Meletis Konstantinos , Ting Jonathan T. , Hueske Emily , Matsushima Ayano , Graybiel Ann M.
Published: June 2024

Balanced activity of canonical direct D1 and indirect D2 basal ganglia pathways is considered a core requirement for normal movement, and their imbalance is an etiologic factor in movement and neuropsychiatric disorders. We present evidence for a conceptually equivalent pair of direct-D1 and indirect-D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from SPNs of the matrix, as do the canonical pathways. These S-D1 and S-D2 striosomal pathways target substantia nigra dopamine-containing neurons instead of basal ganglia motor output nuclei. They modulate movement oppositely to the modulation by the canonical pathways: S-D1 is inhibitory and S-D2 is excitatory. The S-D1 and S-D2 circuits likely influence motivation for learning and action, complementing and reorienting canonical pathway modulation. A major conceptual reformulation of the classic direct-indirect pathway model of basal ganglia function is needed, as well as reconsideration of the effects of D2-targeting therapeutic drugs.

HIGHLIGHTS

Direct S-D1 and Indirect S-D2 striosomal pathways target SNpc dopamine cells

The S-D2 indirect pathway targets a distinct central external pallidal zone (cGPe)

Stimulation of S-D2 increases, of S-D1 decreases, striatal dopamine and movement

S-D1 SPNs activity brackets task, inverse to a mid-task peak of dopamine release
Dynamic regulation of NAT10-mediated mRNA acetylation at synapses by learning and memory in mouse hippocampus
Authors: Zhou Hai-Qian , Zhang Jia-Wei , Zhu Zhen , Lin Wei-Peng , Jin Hao-JY , Ding Yang-Yang , Chen Dong-Sheng , Yin Dong-Min
Published: June 2024

Post-transcriptional modification of RNA plays important roles in regulating brain functions including learning and memory. N4-acetylcytidine (ac4C), the only known form of RNA acetylation in eukaryotes, has recently been shown to regulate mRNA stability and translation efficiency. However, the function and regulation of mRNA acetylation in the brain remain largely unknown. Here we performed ac4C dot-blots, liquid chromatography tandem mass spectrometry (LC-MS/MS), and ac4C-RNA immunoprecipitation followed by next-generation sequencing (acRIP-seq) to investigate the dynamic change of ac4C mRNA in mouse hippocampus during learning and memory. This study focused on Morris water maze (MWM), a behavioral protocol commonly used for studying hippocampus-dependent spatial learning and memory. Interestingly, the levels of ac4C mRNA were upregulated in the synaptosomes (SYN) after memory formation but returned to normal levels after memories were naturally forgotten. The protein levels of N-acetyltransferase 10 (NAT10), the ac4C writer, were also increased in the SYN after memory formation and returned to control levels after memory forgetting. Strikingly, genetic ablation of Nat10 from hippocampal neurons significantly reduced the ac4C modification of Arc, Camk2α and Grin2b mRNA and their protein levels in the SYN of training mice, which was accompanied by deficits in synaptic plasticity and behaviors of learning and memory. These results demonstrate the dynamics and roles of synaptic mRNA acetylation in learning and memory, offering insights into the epitranscriptomic regulation of brain functions. The dataset of ac4C mRNA from mouse hippocampus is accessible via the website (http://ac4catlas.com/).
Functional Complexity of Engineered Neural Networks Self-Organized on Novel 3D Interfaces
Authors: Winter-Hjelm Nicolai , Klausen Kasper Grøndahl , Normann Amund Stensrud , Sandvig Axel , Sandvig Ioanna , Sikorski Pawel
Published: June 2024

Engineered neural networks are indispensable tools for studying neural function and dysfunction in controlled microenvironments.In vitro, neurons self-organize into complex assemblies with structural and functional similarities toin vivocircuits. Traditionally, these models are established on planar interfaces, but studies suggest that the lack of a three-dimensional growth space affects neuronal organization and function. While methods supporting 3D growth exist, reproducible 3D neuroengineering techniques compatible with electrophysiological recording methods are still needed. In this study, we developed a novel biocompatible interface made of the polymer SU-8 to support 3D network development. Using electron microscopy and immunocytochemistry, we show that neurons utilize these 3D scaffolds to self-assemble into complex, multi-layered networks. Furthermore, interfacing the scaffolds with custom microelectrode arrays enabled characterizing of electrophysiological activity. Both planar control networks and 3D networks displayed complex interactions with integrated and segregated functional dynamics. However, control networks showed stronger functional interconnections, higher entropy, and increased firing rates. In summary, our interfaces provide a versatile approach for supporting neural networks with a 3D growth environment, compatible with assorted electrophysiology and imaging techniques. This system can offer new insights into the impact of 3D topologies on neural network organization and function.
Snake venom-inspired novel peptides protectCaenorhabditis elegansagainst paraquat-induced Parkinson’s pathology
Authors: Madhubala Dev , Saikia Kangkon , Patra Aparup , Mahato Rosy , Fernandes Pedro Alexandrino , Kumar Arun , Khan Mojibur R. , Mukherjee Ashis K.
Published: June 2024

Thein vivoprotective mechanisms of two low molecular mass (∼1.4 kDa) novel custom peptides (CPs) against paraquat (PT)-induced neurodegenerative dysfunction in theCaenorhabditis elegansmodel were deciphered. CPs prevent the PT binding to the nerve ring adjacent to the pharynx inC. elegans(N2 strain) by stable and high-affinity binding to the tyrosine-protein kinase receptor CAM-1, resulting in significant inhibition of PT-induced toxicity by reducing enhanced reactive oxygen species production, mitochondrial membrane depolarization, and chemosensory dysfunction. The CPs inhibited PT-induced dopaminergic (DAergic) neuron degeneration and alpha-synuclein aggregation, the hallmarks of Parkinson’s Disease, in transgenic BZ555 and NL5901 strains ofC. elegans. The transcriptomic, functional proteomics, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses show that CPs prevented the increased expression of the genes involved in the skn-1 downstream pathway, thereby restoring PT-mediated oxidative stress, apoptosis, and neuronal damage inC.elegans. The CPs ability to repair PT-induced damage was demonstrated by a network of gene expression profiles illustrating the molecular relationships between the regulatory proteins. Further, CPs (10 mg/kg, parental route) did not show toxicity or induce inflammatory mediators in the mouse model.
DNA-directed termination of mammalian RNA polymerase II
Authors: Davidson Lee , Rouvière Jérôme O , Sousa-Luís Rui , Nojima Takayuki , Proudfoot Nicholas , Jensen Torben Heick , West Steven
Published: June 2024

The best-studied mechanism of eukaryotic RNA polymerase II (RNAPII) transcriptional termination involves polyadenylation site-directed cleavage of the nascent RNA. The RNAPII-associated cleavage product is then degraded by XRN2, dislodging RNAPII from the DNA template. In contrast, prokaryotic RNAP and eukaryotic RNAPIII often terminate directly at T-tracts in the coding DNA strand. Here, we demonstrate a similar and omnipresent capability for mammalian RNAPII. XRN2- and T-tract-dependent termination are independent - the latter usually acting when XRN2 cannot be engaged. We show that T-tracts terminate snRNA transcription, previously thought to require the Integrator complex. Importantly, we find genome-wide termination at T-tracts in promoter-proximal regions, but not within protein-coding gene bodies. XRN2-dependent termination dominates downstream of protein-coding genes, but the T-tract process is sometimes employed. Overall, we demonstrate global DNA-directed attrition of RNAPII transcription, suggesting that RNAPs retain the potential to terminate over T-rich sequences throughout evolution.
Aging disrupts the coordination between mRNA and protein expression in mouse and human midbrain
Authors: Buck Silas A. , Mabry Samuel J. , Glausier Jill R. , Banks-Tibbs Tabitha , Ward Caroline , Gayden Kozel Jenesis , Fu Chen , Fish Kenneth N. , Lewis David A. , Logan Ryan W. , Freyberg Zachary
Published: June 2024

Age-related dopamine (DA) neuron loss is a primary feature of Parkinson’s disease. However, it remains unclear whether similar biological processes occur during healthy aging, albeit to a lesser degree. We therefore determined whether midbrain DA neurons degenerate during aging in mice and humans. In mice, we identified no changes in midbrain neuron numbers throughout aging. Despite this, we found age-related decreases in midbrain mRNA expression of tyrosine hydroxylase (Th), the rate limiting enzyme of DA synthesis. Among midbrain glutamatergic cells, we similarly identified age-related declines in vesicular glutamate transporter 2 (Vglut2) mRNA expression. In co-transmittingTh+/Vglut2+neurons,ThandVglut2transcripts decreased with aging. Importantly, striatal Th and Vglut2 protein expression remained unchanged. In translating our findings to humans, we found no midbrain neurodegeneration during aging and identified age-related decreases inTHandVGLUT2mRNA expression similar to mouse. Unlike mice, we discovered diminished density of striatal TH+dopaminergic terminals in aged human subjects. However, TH and VGLUT2 protein expression were unchanged in the remaining striatal boutons. Finally, in contrast toThandVglut2mRNA, expression of most ribosomal genes inTh+neurons was either maintained or even upregulated during aging. This suggests a homeostatic mechanism where age-related declines in transcriptional efficiency are overcome by ongoing ribosomal translation. Overall, we demonstrate species-conserved transcriptional effects of aging in midbrain dopaminergic and glutamatergic neurons that are not accompanied by marked cell death or lower striatal protein expression. This opens the door to novel therapeutic approaches to maintain neurotransmission and bolster neuronal resilience.
The within-subject stability of cortical thickness, surface area, and brain volumes across one year
Authors: Wang Meng-Yun , Korbmacher Max , Eikeland Rune , Nerland Stener , Vidal-Pineiro Didac , Specht Karsten
Published: June 2024

T1-weighted (T1w) imaging is widely used to examine brain structure based on image-derived phenotypes (IDPs) such as cortical thickness, surface area, and brain volumes. The reliability of these IDPs has been extensively explored, mainly focusing on the inter-subject variations, whereas the stability of the within-subject variations has often been overlooked. Additionally, how environmental factors such as time of day and daylight hours impact the structural brain is poorly understood. Therefore, we aimed to address the stability of T1w-derived phenotypes and explore the effecting factors including processing stream, brain region size, time of day, daylight hours, and head movement.

Three subjects in their late 20s, early 30s, and early 40s were scanned repeatedly on the same scanner over one year, from which a densely sampled dataset was acquired with 38, 40, and 25 sessions for subjects 1, 2, and 3, respectively. The temporal stability was evaluated using within-subject percentage change and coefficients of variation (CV). The effects of time of day and daylight hours were assessed by fitting general linear models, aggregating the effect size with meta-analysis, and equivalent analysis.

The longitudinal processing stream generates more stable results than the cross-sectional processing stream, hence the following results are all derived from the longitudinal processing stream. First and foremost, most IDPs demonstrated percentage changes within 5% and CVs within 2% for almost all brain regions, indicating high stability. Interestingly, we found that the brain region size negatively correlates with the CVs. Specifically, several small brain regions, including the temporal pole, frontal pole, pericalcarine, entorhinal cortex, and accumbens area, showed low stability. In addition, cortical thickness change was strongly and positively correlated with that of volume change while being negatively correlated with change in surface area, illustrating their distinct roles in brain anatomy. Moreover, the time of day could be ignored when evaluating the total surface area and total cortical brain volume but not the average cortical thickness and total subcortical brain volume. Furthermore, daylight hours could be left out when evaluating IDPs since there was no appreciable effect of daylight hours on the IDPs stability. Lastly, apparent head motion causes cortical thickness and volume underestimated and surface area overestimated.
A synthetic skin bacterial community (SkinCom) enables reproducible investigations of the human skin microbiome
Authors: Lekbua Asama , Thiruppathy Deepan , Coker Joanna , Weng Yuhan , Askarian Fatemeh , Kousha Armin , Marotz Clarisse , Hauw Amber , Nizet Victor , Zengler Karsten
Published: June 2024

Existing models of the human skin have aided our understanding of skin health and disease. However, they currently lack a microbial component, despite microbes’ demonstrated connections to various skin diseases. Here we present a robust, standardized model of the skin bacterial community (SkinCom) to support complexin vitroandin vivoinvestigations. Our methods lead to an accurate, reproducible, and diverse community formation of aerobic and anaerobic bacteria. Subsequent testing of SkinCom on the dorsal skin of mice allowed for DNA and RNA recovery from both the applied SkinCom and from dorsal skin, highlighting its practicality forin vivostudies and -omics analyses. Furthermore, our results indicate that 65.6% of the responses to common cosmetic chemicalsin vitrowere recapitulated in a human trial. Therefore, SkinCom represents a valuable, standardized tool for investigating microbe-metabolite interactions and facilitates the experimental design ofin vivostudies targeting host-microbe relationships.
Modular Arrangement of Synaptic and Intrinsic Homeostatic Plasticity within Visual Cortical Circuits
Authors: Wen Wei , Prada Adriana M. , Turrigiano Gina G.
Published: June 2024

Neocortical circuits use synaptic and intrinsic forms of homeostatic plasticity to stabilize key features of network activity, but whether these different homeostatic mechanisms act redundantly, or can be independently recruited to stabilize different network features, is unknown. Here we used pharmacological and genetic perturbations bothin vitroandin vivoto determine whether synaptic scaling and intrinsic homeostatic plasticity (IHP) are arranged and recruited in a hierarchical or modular manner within L2/3 pyramidal neurons in rodent V1. Surprisingly, although the expression of synaptic scaling and IHP was dependent on overlapping signaling pathways, they could be independently recruited by manipulating spiking activity or NMDAR signaling, respectively. Further, we found that changes in visual experience that affect NMDAR activation but not mean firing selectively trigger IHP, without recruiting synaptic scaling. These findings support a modular model in which synaptic and intrinsic homeostatic plasticity respond to and stabilize distinct aspects of network activity.
An Amygdalar-Vagal-Glandular Circuit Controls the Intestinal Microbiome
Authors: Chang Hao , Perkins Matthew H , Novaes Leonardo S , Qian Feng , Han Wenfei , de Araujo Ivan E
Published: June 2024

Psychological states can regulate intestinal mucosal immunity by altering the gut microbiome. However, the link between the brain and microbiome composition remains elusive. We show that Brunner’s glands in the duodenal submucosa couple brain activity to intestinal bacterial homeostasis. Brunner’s glands mediated the enrichment of gut probiotic species in response to stimulation of abdominal vagal fibers. Cell-specific ablation of the glands triggered transmissible dysbiosis associated with an immunodeficiency syndrome that led to mortality upon gut infection with pathogens. The syndrome could be largely prevented by oral or intra-intestinal administration of probiotics. In the forebrain, we identified a vagally-mediated, polysynaptic circuit connecting the glands of Brunner to the central nucleus of the amygdala. Intra-vital imaging revealedthatexcitation of central amygdala neurons activated Brunner’s glands and promoted the growth of probiotic populations. Our findings unveil a vagal-glandular neuroimmune circuitry that may be targeted for the modulation of the gut microbiome. The glands of Brunner may be the critical cells that regulate the levels ofLactobacillispecies in the intestine.
Facial expressions in mice reveal latent cognitive variables and their neural correlates
Authors: Cazettes Fanny , Reato Davide , Augusto Elisabete , Renart Alfonso , Mainen Zachary
Published: June 2024

Brain activity controls adaptive behavior but also drives unintentional incidental movements. Such movements could thus potentially be used to read out internal cognitive variables also neurally computed. Establishing this, however, would require ruling out that incidental movements reflect cognition only because they are coupled with task-related responses through the biomechanics of the body. We addressed this issue in a foraging task for mice where multiple decision variables are simultaneously encoded even if, at any given time, only one of them is used. We found that characteristic features of the face simultaneously encode not only the currently used decision variables, but also independent and unexpressed ones, and we show that these features partially originate from neural activity in the secondary motor cortex. Our results suggest that the face reflects ongoing computations above and beyond those related to task demands, demonstrating the ability of noninvasive monitoring to expose otherwise latent cognitive states.