bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unveiling the hidden interactome of CRBN molecular glues with chemoproteomics
Authors: Baek Kheewoong , Metivier Rebecca J. , Burman Shourya S. Roy , Bushman Jonathan W. , Yoon Hojong , Lumpkin Ryan J. , Abeja Dinah M. , Lakshminarayan Megha , Yue Hong , Ojeda Samuel , Verano Alyssa L. , Gray Nathanael S. , Donovan Katherine A. , Fischer Eric S. 
Published: September 2024

SUMMARYTargeted protein degradation and induced proximity refer to strategies that leverage the recruitment of proteins to facilitate their modification, regulation or degradation. As prospective design of glues remains challenging, unbiased discovery methods are needed to unveil hidden chemical targets. Here we establish a high throughput affinity purification mass spectrometry workflow in cell lysates for the unbiased identification of molecular glue targets. By mapping the targets of 20 CRBN-binding molecular glues, we identify 298 protein targets and demonstrate the utility of enrichment methods for identifying novel targets overlooked using established methods. We use a computational workflow to estimate target confidence and perform a biochemical screen to identify a lead compound for the new non-ZF target PPIL4. Our study provides a comprehensive inventory of targets chemically recruited to CRBN and delivers a robust and scalable workflow for identifying new drug-induced protein interactions in cell lysates.
53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR)
Authors: Shah Sameer Bikram , Li Youhang , Li Shibo , Hu Qing , Wu Tong , Shi Yanmeng , Nguyen Tran , Ive Isaac , Shi Linda , Wang Hailong , Wu Xiaohua 
Published: September 2024

AbstractBreak-induced replication (BIR) is mutagenic, and thus its use requires tight regulation, yet the underlying mechanisms remain elusive. Here we uncover an important role of 53BP1 in suppressing BIR after end resection at double strand breaks (DSBs), distinct from its end protection activity, providing insight into the mechanisms governing BIR regulation and DSB repair pathway selection. We demonstrate that loss of 53BP1 induces BIR-like hyperrecombination, in a manner dependent on Polα-primase-mediated end fill-in DNA synthesis on single-stranded DNA (ssDNA) overhangs at DSBs, leading to PCNA ubiquitination and PIF1 recruitment to activate BIR. On broken replication forks, where BIR is required for repairing single-ended DSBs (seDSBs), SMARCAD1 displaces 53BP1 to facilitate the localization of ubiquitinated PCNA and PIF1 to DSBs for BIR activation. Hyper BIR associated with 53BP1 deficiency manifests template switching and large deletions, underscoring another aspect of 53BP1 in suppressing genome instability. The synthetic lethal interaction between the 53BP1 and BIR pathways provides opportunities for targeted cancer treatment.
A data-driven algorithm to determine1H-MRS basis set composition
Authors: Davies-Jenkins Christopher W. , Zöllner Helge J. , Simicic Dunja , Alcicek Seyma , Edden Richard A.E. , Oeltzschner Georg 
Published: September 2024

AbstractPurposeMetabolite amplitude estimates derived from linear combination modeling of MR spectra depend upon the precise list of constituent metabolite basis functions used (the “basis set”). The absence of clear consensus on the “ideal” composition or objective criteria to determine the suitability of a particular basis set contributes to the poor reproducibility of MRS. In this proof-of-concept study, we demonstrate a novel, data-driven approach for deciding the basis-set composition using Bayesian information criteria (BIC).MethodsWe have developed an algorithm that iteratively adds metabolites to the basis set using iterative modeling, informed by BIC scores. We investigated two quantitative “stopping conditions”, referred to as max-BIC and zero-amplitude, and whether to optimize the selection of basis set on a per-spectrum basis or at the group level. The algorithm was tested using two groups of synthetic in-vivo-like spectra representing healthy brain and tumor spectra, respectively, and the derived basis sets (and metabolite amplitude estimates) were compared to the ground truth.ResultsAll derived basis sets correctly identified high-concentration metabolites and provided reasonable fits of the spectra. At the single-spectrum level, the two stopping conditions derived the underlying basis set with 77-87% accuracy. When optimizing across a group, basis set determination accuracy improved to 84-92%.ConclusionData-driven determination of the basis set composition is feasible. With refinement, this approach could provide a valuable data-driven way to derive or refine basis sets, reducing the operator bias of MRS analyses, enhancing the objectivity of quantitative analyses, and increasing the clinical viability of MRS.
Decreased GABA levels during development result in increased connectivity in the larval zebrafish tectum
Authors: Liu Yang , Chen Yongkai , Duffy Carly R. , VanLeuven Ariel J , Byers John Branson , Schriever Hannah C. , Ball Rebecca E. , Carpenter Jessica M. , Gunderson Chelsea E. , Filipov Nikolay M. , Ma Ping , Kner Peter A. , Lauderdale James D. 
Published: September 2024

Abstractγ-aminobutyric acid (GABA) is an abundant neurotransmitter that plays multiple roles in the vertebrate central nervous system (CNS). In the early developing CNS, GABAergic signaling acts to depolarize cells. It mediates several aspects of neural development, including cell proliferation, neuronal migration, neurite growth, and synapse formation, as well as the development of critical periods. Later in CNS development, GABAergic signaling acts in an inhibitory manner when it becomes the predominant inhibitory neurotransmitter in the brain. This behavior switch occurs due to changes in chloride/cation transporter expression. Abnormalities of GABAergic signaling appear to underlie several human neurological conditions, including seizure disorders. However, the impact of reduced GABAergic signaling on brain development has been challenging to study in mammals. Here we take advantage of zebrafish and light sheet imaging to assess the impact of reduced GABAergic signaling on the functional circuitry in the larval zebrafish optic tectum. Zebrafish have threegadgenes: twogad1paralogs known asgad1aandgad1b, andgad2.Thegad1bandgad2genes are expressed in the developing optic tectum. Null mutations ingad1bsignificantly reduce GABA levels in the brain and increase electrophysiological activity in the optic tectum. Fast light sheet imaging of genetically encoded calcium indicator (GCaMP)-expressinggab1bnull larval zebrafish revealed patterns of neural activity that were different than either gad1b-normal larvae orgad1b-normal larvae acutely exposed to pentylenetetrazole (PTZ). These results demonstrate that reduced GABAergic signaling during development increases functional connectivity and concomitantly hyper-synchronization of neuronal networks.Significance StatementUnderstanding the impact of reduced GABAergic signaling on vertebrate brain development and function will help elucidate the etiology of seizure initiation and propagation and other neurological disorders due to the altered formation of neural circuits. Here, we used fast light sheet imaging of larval zebrafish that neuronally expressed a genetically encoded calcium indicator (GCaMP) to assess the impact of reduced GABA levels through null mutation ofgad1bduring brain development. We show that reduced GABA levels during development result in increased functional connectivity in the brain.
Cryo-EM Structure of Phospholipase Cε Defines N-terminal Domains and their Roles in Activity
Authors: Samassekou Kadidia , Garland-Kuntz Elisabeth E. , Ohri Vaani , Fisher Isaac J. , Erramilli Satchal K. , Muralidharan Kaushik , Bogdan Livia M. , Gick Abigail M. , Kossiakoff Anthony A. , Lyon Angeline M. 
Published: September 2024

ABSTRACTPhospholipase Cε (PLCε) increases intracellular Ca2+and protein kinase C (PKC) activity in the cardiovascular system in response to stimulation of G protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). The ability of PLCε to respond to these diverse inputs is due, in part, to multiple, conformationally dynamic regulatory domains. However, this heterogeneity has also limited structural studies of the lipase to either individual domains or its catalytic core. Here, we report the 3.9 Å reconstruction of the largest fragment of PLCε to date in complex with an antigen binding fragment (Fab). The structure reveals that PLCε contains a pleckstrin homology (PH) domain and four tandem EF hands, including subfamily-specific insertions and intramolecular interactions with the catalytic core. The structure, together with a model of the holoenzyme, suggest that part of the N-terminus and PH domain form a continuous surface that could engage cytoplasmic leaflets of the plasma and perinuclear membranes, contributing to activity. Functional characterization of this surface confirm it is critical for maximum basal and G protein-stimulated activities. This study provides new insights into the autoinhibited, basal conformation of PLCε and the first mechanistic insights into how it engages cellular membranes for activity.
Fast Attentional Information Routing via High-Frequency Bursts in the Human Brain
Authors: Banaie Boroujeni Kianoush , Helfrich Randolph F. , Fiebelkorn Ian C. , Bentley Nicole , Lin Jack J. , Knight Robert T. , Kastner Sabine 
Published: September 2024

AbstractBrain-wide communication supporting flexible behavior requires coordination between sensory and associative regions but how brain networks route sensory information at fast timescales to guide action remains unclear. Using spiking neural networks and human intracranial electrophysiology during spatial attention tasks, where participants detected targets at cued locations, we show that high-frequency activity bursts (HFAb) serve as information-carrying events, facilitating fast, long-range communications. HFAbs were evoked by sensory cues and targets, dynamically linked to low-frequency rhythms. Notably, both HFAb responses following cues and their decoupling from slow rhythms predicted performance accuracy. HFAbs were synchronized at the network-level, identifying distinct cue- and target-activated subnetworks. These subnetworks exhibited a temporal lead-lag organization following target onset, with cue-sactivated subnetworks preceding target-activated subnetworks when the cue provided relevant target information. Computational modeling indicated that HFAbs reflect transitions to coherent population spiking and are coordinated across networks through distinct mechanisms. Together, these findings establish HFAbs as neural mechanisms for fast, large-scale communication supporting attentional performance.
Mobility patterns, activity locations, and tuberculosis in Nairobi, Kenya
Authors: Tram Khai Hoan , Ong’ang’o Jane , Kiplimo Richard , Hawn Thomas R. , Nduba Videlis , Horne David J. , Ross Jennifer M. 
Published: September 2024

AbstractBackgroundAnnually, over 3 million people develop TB but are not diagnosed and treated. We aimed to characterize the mobility patterns and activity locations of people with TB in an urban, high-burden setting to inform future active case finding (ACF) efforts.MethodsWe conducted a population-based TB prevalence survey in Nairobi, Kenya, in 2022. Participants aged ≥15 years with TB symptoms or a suggestive chest x-ray submitted sputum for Xpert Ultra and culture. We collected data on individual activity locations and mobility and evaluated their association with the risk of pulmonary TB.ResultsThe prevalence survey enrolled 6369 participants across nine clusters. There were significant differences in mobility patterns and activity locations between sexes and age groups. Mobility factors were not significantly associated with TB. In the adjusted analysis, age group 45–54 (OR 2.45), male sex (OR 2.95), and use of a social activity location (OR 1.96) were significantly associated with a higher risk of TB.ConclusionsWe did not find a significant association between mobility patterns and TB but found a positive association between reported ‘social’ activity locations and TB. Identification of ‘social’ activity locations, particularly bars, provides important insight into possible venues for spatially-targeted ACF activities.
Possible Mechanisms Of Action Of Light Inert Gases On Chemiluminescence Arising As A Result Of Lipid Peroxidation
Authors: Oliynyk Iryna 
Published: September 2024

AbstractThe use of inert gases in biology and medicine and their effect on biological objects both in vitro and in vivo remains an active area of research. It has been established that light noble gases affect antioxidant processes, free radical oxidation, and enhance chemiluminescence, but an explanation of the physical and chemical mechanisms of this effect is still lacking and is key to further theoretical and experimental studies, given the broad prospects for the use of noble gases in medicine. In this article, we present two of the possible mechanisms of light inert gases’ effect on chemiluminescence (CL), a phenomenon that occurs as a result of free radical recombination and chain breakage during lipid peroxidation. Since the effect on oxidation, in turn, precedes the effect on the antioxidant system and the body’s defense mechanisms.One of the mechanisms of influence is based on the ability of inert gases to dissolve well in lipids and dissolve poorly in water. Their ability to dissolve in lipid bilayers and affect the conformation of lipid complexes can increase the surface area available for oxidation, the surface area that absorbs radiation and reduce the density of the environment, potentially increasing the availability of oxygen for oxidation reactions. This is the so-called spatial mechanism of inert gas influence on oxidation and chemiluminescence.The second mechanism is based on the influence on the quantum chemical parameters of the reaction medium. The acceleration of VT relaxation processes, the impact on the components of the medium in quenching excited states, and the radiative decay time of the excited state.
Single-cell and spatiotemporal transcriptomic profiling of brain immune infiltration following Venezuelan equine encephalitis virus infection
Authors: Rangel Margarita V. , Sebastian Aimy , Leon Nicole F. , Phillips Ashlee M. , Gorman Bria M. , Hum Nicholas R. , Weilhammer Dina R. 
Published: September 2024

AbstractNeurotropic alphaviruses such as Venezuelan equine encephalitis virus (VEEV) are critical human pathogens that continually expand to naïve populations and for which there are no licensed vaccines or therapeutics. VEEV is highly infectious via the aerosol route and is a recognized weaponizable biothreat that causes neurological disease in humans. The neuropathology of VEEV has been attributed to an inflammatory immune response in the brain yet the underlying mechanisms and specific immune cell populations involved are not fully elucidated. This study uses single-cell RNA sequencing to produce a comprehensive transcriptional profile of immune cells isolated from the brain over a time course of infection in a mouse model of VEEV. Analyses reveal differentially activated subpopulations of microglia, including a distinct type I interferon-expressing subpopulation. This is followed by the sequential infiltration of myeloid cells and cytotoxic lymphocytes, also comprising subpopulations with unique transcriptional signatures. We identify a subpopulation of myeloid cells that form a distinct localization pattern in the hippocampal region whereas lymphocytes are widely distributed, indicating differential modes of recruitment, including that to specific regions of the brain. Altogether, this study provides a high-resolution analysis of the immune response to VEEV in the brain and highlights potential avenues of investigation for therapeutics that target neuroinflammation in the brain.Author SummaryVenezuelan equine encephalitis virus (VEEV) causes brain inflammation in both animals and humans when transmitted by mosquito bite or infectious aerosols. The mechanisms underlying disease caused by VEEV, including the role of the immune response in brain pathology, are not well understood. Here we performed a comprehensive assessment of the immune response to VEEV in the brain over time using two advanced sequencing techniques. Following infection, immune cells infiltrate the brain in a sequential fashion and display different activation profiles. Different types of immune cells also display strikingly different spatial patterns throughout the brain. This study provides the most comprehensive description of the immune response to VEEV in the brain performed to date and advances our understanding of immune-driven neuropathology and identification of therapeutic targets.
Abnormal mu rhythm state-related cortical and corticospinal responses in chronic stroke
Authors: Wischnewski Miles , Haigh Zachary J. , Berger Taylor A. , Rotteveel Jonna , van Oijen Tessa , Perera Nipun D. , Shirinpour Sina , Alekseichuk Ivan , Hawe Rachel L. , Opitz Alexander 
Published: September 2024

AbstractThe motor cortex’s activity is state-dependent. Specifically, the sensorimotor mu rhythm phase relates to fluctuating levels of primary motor cortex (M1) excitability, previously demonstrated in young and healthy volunteers. However, it is unknown whether this observation is generalizable to individuals with brain lesions after a stroke. We investigated the phase relationship between the mu rhythm and cortical excitability by combining real-time processing of electroencephalography (EEG) signals and transcranial magnetic stimulation (TMS) of M1. In 11 chronic subcortical stroke survivors and 12 similar-aged healthy volunteers, we applied TMS to M1 at the peak, falling, trough, and rising phase of the sensorimotor mu oscillation. As outcome measures, we investigated the M1-to-muscle excitability by measuring motor-evoked potentials (MEPs) and local cortical activation by measuring TMS-evoked potentials (TEPs). We found that M1-to-muscle excitability in stroke survivors and older volunteers shows a phase-dependency similar to that in young healthy adults. That is, MEPs were increased and decreased at the trough and peak of the mu rhythm, respectively. However, individuals with stronger stroke-related motor symptoms showed a decreased phase preference. Further, phase-dependency was abolished in the local cortical activity, as measured with EEG, in the stroke-affected hemisphere, in contrast to the non-affected hemisphere as well as either hemisphere in healthy volunteers. Altogether, these results shed light on the state-dependency of motor cortex excitability after stroke. Our results indicate that the strength of phase preference of TMS motor responses could indicate the severity of motor impairment. These results could enable the development of improved TMS paradigms for recovery of motor impairment after stroke.
SARS-CoV-2 protein ORF3a induces Atg8ylation of lysosomal membranes
Authors: Ajnar Deepa , Sarkar Ananya , Riyaz Seema , Menon Poornima , Dutta Dipranil , Asati Pulkit , Sharma Priyanka , Pydi Sai P. , Kumar Suresh 
Published: September 2024

AbstractAutophagy Conjugation machinery forms a center piece of autophagy and is essential for sequestration of a broad range of cargo destined for degradation. Apart from its role in canonical autophagy, recent evidence suggests an unconventional role of conjugation machinery. Membrane Atg8ylation is one of the manifestations of autophagy, wherein ATG8 conjugation machinery recruit mammalian ATG8s (mATG8s) to the damaged membranes for repair or removal. Herein, we show that SARS-CoV-2 factor ORF3a induces membrane Atg8ylation and selectively inflicts lysophagy, a cellular response to evade apoptotic cell death. mATG8s and SNARE protein syntaxin 17 (STX17) interact with ORF3a and are required for Atg8ylation induced by ORF3a. ORF3a displaces mTOR from the lysosomes and affects nuclear translocation of TFEB, which is dependent on mATG8s and STX17. Despite mTOR inhibition, its conventional target ULK1 is dispensable for ORF3a induced Atg8ylation. In addition, mATG8s and STX17 protected against the cell death induced by ORF3a. Overall, our findings demonstrate ORF3a induced lysosomal membrane Atg8ylation while identifying the unexpected role of STX17 in Atg8ylation.
Decoding Transcriptional Memory in Yeast Heat Shock and the Functional Implication of the RNA Binding Protein Mip6
Authors: Tejada-Colón Ana , Serrano-Quílez Joan , Nuño-Cabanes Carme , Rodríguez-Navarro Susana 
Published: September 2024

AbstractCells not only adapt to environmental changes, but they also “remember” specific signals, allowing them to respond more rapidly to future stressors. This phenomenon, known as transcriptional memory, is orchestrated by a complex interplay of epigenetics, transcription regulators and RNA metabolism factors. Although transcriptional memory has been well-studied in various contexts, its role in the heat shock (HS) response of yeast remains largely unexplored. In our study, we delve into the dynamics of HS memory in wild-type yeast and amip6Δ mutant, which lacks the RNA-binding protein Mip6. Notably, Mip6 has been shown to influence the expression of key stress-related genes and maintain low Msn2/4-dependent transcript levels under standard conditions. Our transcriptomic analysis offers novel insights into how yeast cells remember HS exposure. We uncover striking differences in gene expression patterns depending on whether genes are induced or repressed during HS memory. Furthermore, we find that an initial 15-minute heat shock triggers a response that becomes attenuated with just 5 additional minutes of stress. While the response kinetics between memory and non-memory conditions are similar, we report a subtle but important role for Mip6 in fine-tuning transcriptional memory and adaptation to heat stress. Biochemical and genetic evidence also suggests that Mip6 cooperates with alternative survival pathways independent of MSN2/4, and functionally interacts with the Rpd3 histone deacetylase complex, a key player in transcriptional memory and the HS response. These findings open up new avenues for understanding the molecular mechanisms behind heat stress adaptation in eukaryotes.