bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing ketamine-induced dissociation using human intracranial neurophysiology: brain dynamics, network activity, and interactions with propofol
Authors: Tian Fangyun , Lewis Laura D. , Zhou David W. , Villegas Gustavo Balanza , Paulk Angelique C. , Zelmann Rina , Peled Noam , Soper Daniel , Mercado Laura A. Santa Cruz , Peterfreund Robert A. , Aglio Linda S. , Eskandar Emad N. , Cosgrove G Rees , Williams Ziv M. , Richardson Robert M. , Brown Emery N. , Akeju Oluwaseun , Cash Sydney S. , Purdon Patrick L. 
Published: May 2022

SummarySubanesthetic doses of ketamine produce rapid and sustained anti-depressant effects in patients with treatment-resistant depression. Unfortunately, the usefulness of ketamine as a treatment is limited by its potential for abuse because of psychotropic side effects such as dissociation. Understanding the brain dynamics and the neural circuits involved in ketamine’s effects could lend insight into improved therapies for depression with fewer adverse effects. It is believed that ketamine acts via NMDA receptor and hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels to produce changes in oscillatory brain dynamics. Here we show, in humans, a detailed description of the principal oscillatory changes in cortical and subcortical structures by administration of a subanesthetic dose of ketamine. Using recordings from intracranial electrodes, we found that ketamine increased gamma oscillations within prefrontal cortical areas and the hippocampus--structures previously implicated in ketamine’s antidepressant effects. Furthermore, our studies provide direct evidence of a ketamine-induced 3 Hz oscillation in posteromedial cortex that has been proposed as a mechanism for its dissociative effects. By analyzing changes in neural oscillations after the addition of propofol, whose GABAergic activity antagonizes ketamine’s NMDA-mediated disinhibition alongside a shared HCN1 inhibitory effect, we identified brain dynamics that could be attributed to NMDA-mediated disinhibition versus HCN1 inhibition. Overall, our results imply that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of novel brain dynamic biomarkers and therapeutics for depression.
Sensitization to Ionizing Radiation by MEK inhibition is Dependent on SNAI2 in Fusion-negative Rhabdomyosarcoma
Authors: Hensch Nicole R. , Bondra Kathryn , Wang Long , Sreenivas Prethish , Zhao Xiang R. , Modi Paulomi , Vaseva Angelina V. , Houghton Peter J. , Ignatius Myron S. 
Published: May 2022

AbstractIn fusion-negative rhabdomyosarcoma (FN-RMS), a pediatric malignancy with skeletal muscle characteristics, > 90% of high-risk patients have mutations that activate the RAS/MEK signaling pathway. We recently discovered that SNAI2, in addition to blocking myogenic differentiation downstream of MEK signaling in FN-RMS, represses pro-apoptotic BIM expression to protect RMS tumors from ionizing radiation (IR). As clinically relevant concentrations of the MEK inhibitor trametinib elicit poor responses in preclinical xenograft models, we investigated the utility of low-dose trametinib in combination with IR for the treatment of RAS-mutant FN-RMS. We hypothesized that trametinib would sensitize FN-RMS to IR through its downregulation of SNAI2 expression. While we observed little to no difference in myogenic differentiation or cell survival with trametinib treatment alone, robust differentiation and reduced survival were observed after IR. Additionally, IR-induced apoptosis was significantly increased in FN-RMS cells treated concurrently with trametinib, as was increased BIM expression. SNAI2’s role in these processes was established using overexpression rescue experiments, where overexpression of SNAI2 prevented IR-induced myogenic differentiation and apoptosis. Moreover, combining MEK inhibitor with IR resulted in complete tumor regression and a 2–4-week delay in event free survival (EFS) in preclinical xenograft and PDX models. Our findings demonstrate that the combination of MEK inhibition and IR results in robust differentiation and apoptosis, due to the reduction of SNAI2, which leads to extended EFS in FN-RMS. SNAI2 thus is a biomarker of IR insensitivity and target for future therapies to sensitize aggressive sarcomas to IR.
Actuating tension-loaded DNA clamps drives membrane tubulation
Authors: Liu Longfei , Xiong Qiancheng , Xie Chun , Pincet Frederic , Lin Chenxiang 
Published: May 2022

AbstractMembrane dynamics in living organisms can arise from proteins adhering to, assembling on, and exerting force on cell membranes. Programmable synthetic materials, such as self-assembled DNA nanostructures, offer the capability to drive membrane remodeling events in a way that resembles protein-mediated dynamics, but with user-defined outcomes. An example showcasing this capability is the tubular deformation of liposomes by DNA nanostructures with purposely designed shapes, surface modifications, and self-assembling properties. However, stimulus-responsive membrane tubulation mediated by DNA structure reconfiguration remains challenging. Here we present the triggered formation of membrane tubes in response to specific DNA signals that actuate membrane-bound DNA clamps from an open state to various predefined closed states, releasing pre-stored energy to activate membrane deformation. Using giant unilamellar vesicles (GUVs) as a model system, we show that the timing and efficiency of tubulation, as well as the width of membrane tubes, are modulated by the conformational change of DNA clamps, marking a solid step toward spatiotemporal control of membrane dynamics in an artificial system.
The contribution of Kaposi’s sarcoma-associated herpesvirus ORF7 and its zinc-finger motif to viral genome cleavage and capsid formation
Authors: Iwaisako Yuki , Watanabe Tadashi , Sekine Yuichi , Suzuki Youichi , Nakano Takashi , Fujimuro Masahiro 
Published: May 2022

ABSTRACTKaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of endothelial and B cell malignancies. During KSHV lytic infection, lytic-related proteins are synthesized, viral genomes are replicated as a tandemly repeated form, and subsequently, capsids are assembled. The herpesvirus terminase complex is proposed to package an appropriate genome unit into an immature capsid, by cleavage of terminal repeats (TRs) flanking tandemly linked viral genomes. Although the mechanism of capsid formation in α- and β-herpesviruses are well-studied, in KSHV, it remains largely unknown. It has been proposed that KSHV ORF7 is a terminase subunit, and ORF7 harbors a zinc-finger motif, which is conserved among other herpesviral terminases. However, the biological significance of ORF7 is unknown. We previously reported that KSHV ORF17 is essential for the cleavage of inner scaffold proteins in capsid maturation, and ORF17 knockout (KO) induced capsid formation arrest between the procapsid and B-capsid stages. However, it remains unknown if ORF7-mediated viral DNA cleavage occurs before or after ORF17-mediated scaffold collapse. We analyzed the role of ORF7 during capsid formation using ORF7-KO-, ORF7&17-double-KO (DKO)-, and ORF7-zinc-finger motif mutant-KSHVs. We found that ORF7 acted after ORF17 in the capsid formation process, and ORF7-KO-KSHV produced incomplete capsids harboring non-spherical internal structures, which resembled soccer balls. This soccer ball-like capsid was formed after ORF17-mediated B-capsid formation. Moreover, ORF7-KO- and zinc-finger motif KO-KSHV failed to appropriately cleave the TR on replicated genome and had a defect in virion production. Thus, our data revealed that ORF7 contributes to terminase-mediated viral genome cleavage and capsid formation.IMPORTANCEIn herpesviral capsid formation, the viral terminase complex cleaves the TR sites on newly synthesized tandemly repeating genomes and inserts an appropriate genomic unit into an immature capsid. Herpes simplex virus 1 (HSV-1) UL28 is a subunit of the terminase complex that cleaves the replicated viral genome. However, the physiological importance of the UL28 homolog, KSHV ORF7, remains poorly understood. Here, using several ORF7-deficent KSHVs, we found that ORF7 acted after ORF17-mediated scaffold collapse in the capsid maturation process. Moreover, ORF7 and its zinc-finger motif were essential for both cleavage of TR sites on the KSHV genome and virus production. ORF7-deficient KSHVs produced incomplete capsids that resembled a soccer ball. To our knowledge, this is the first report showing ORF7-KO-induced soccer ball-like capsids production and ORF7 function in the KSHV capsid assembly process. Our findings provide insights into the role of ORF7 in KSHV capsid formation.
Regulation of translation by lysine acetylation inEscherichia coli
Authors: Feid Sarah C. , Walukiewicz Hanna E. , Wang Xiaoyi , Nakayasu Ernesto S. , Rao Christopher V. , Wolfe Alan J. 
Published: May 2022

ABSTRACTNε-lysine acetylation is a common post-translational modification observed in diverse species of bacteria. Aside from a few central metabolic enzymes and transcription factors, little is known about how this post-translational modification regulates protein activity. In this work, we investigated how lysine acetylation affects translation inEscherichia coli. In multiple species of bacteria, ribosomal proteins are highly acetylated at conserved lysine residues, suggesting that this modification may regulate translation. In support of this hypothesis, we found that the addition of the acetyl donors, acetyl phosphate or acetyl-Coenzyme A, inhibits translation but not transcription using anE. colicell-free system. Further investigations usingin vivoassays revealed that acetylation does not appear to alter the rate of translation elongation but rather increases the proportion of dissociated 30S and 50S ribosomes, based on polysome profiles of mutants or growth conditions known to promote lysine acetylation. Furthermore, ribosomal proteins are more acetylated in the disassociated 30S and 50S ribosomal subunit than in the fully assembled 70S complex. The effect of acetylation is also growth rate dependent, with disassociation of the subunits most pronounced during late exponential and early stationary phase growth – the same growth phase where protein acetylation is greatest. Collectively, our data demonstrate that lysine acetylation inhibits translation, most likely by interfering with subunit association. These results have also uncovered a new mechanism for coupling translation to the metabolic state of the cell.IMPORTANCENumerous cellular processes are regulated in response to the metabolic state of the cell. One such regulatory mechanism involves lysine acetylation, a covalent modification involving the transfer of an acetyl group from the central metabolites acetyl coenzyme A or acetyl phosphate to a lysine residue in a protein. This post-translational modification is known to regulate some central metabolic enzymes and transcription factors in bacteria, though a comprehensive understanding of its effect on cellular physiology is still lacking. In the present study, lysine acetylation was also found to inhibit translation inEscherichia coliby impeding ribosome association, most likely by disrupting salt-bridges along the binding interface of the 30S and 50S ribosomal subunits. These results further our understanding of lysine acetylation by uncovering a new target of regulation, protein synthesis, and aid in the design of bacteria for biotechnology applications where the growth conditions are known to promote lysine acetylation.
Psychological interventions for adult PTSD: A network and pairwise meta-analysis of short and long-term efficacy, acceptability and trial quality
Authors: Hoppen Thole H. , Jehn Marvin , Holling Heinz , Mutz Julian , Kip Ahlke , Morina Nexhmedin 
Published: May 2022

AbstractA large number of randomized controlled trials (RCTs) on psychological interventions for adult posttraumatic stress disorder (PTSD) have been published. We aimed at providing a comprehensive quantitative summary covering short and long-term efficacy, acceptability and trial quality. We conducted systematic searches in bibliographical databases to identify RCTs examining the efficacy (standardized mean differences in PTSD severity, SMDs) and acceptability (relative risk of all-cause dropout, RR) of trauma-focused cognitive behaviour therapy (TF-CBT), Eye Movement Desensitization and Reprocessing (EMDR), other trauma-focused psychological interventions (other-TF-PIs) and non-trauma-focused psychological interventions (non-TF-PIs) compared to each other or to passive or active control conditions. Hundred-fifty-seven RCTs met inclusion criteria comprising 11,565, 4,830 and 3,338 patients at post-treatment assessment, ≤ 5 months follow-up and > 5 months follow-up, respectively. TF-CBT was by fore the most frequently examined intervention. We performed random effects network meta-analyses (efficacy) and pairwise meta-analyses (acceptability). All therapies produced large effects compared to passive control conditions (SMDs ≥ 0.80) at post-treatment. Compared to active control conditions, TF-CBT and EMDR yielded medium treatment effects (SMDs ≥ 0.50 < 0.80), and other-TF-PIs and non-TF-PIs yielded small treatment effects (SMDs ≥ 0.20 < 0.50). Interventions did not differ in their short-term efficacy, yet TF-CBT was more effective than non-TF-PIs (SMD = 0.17) and other-TF-PIs (SMD = 0.30). Results remained robust in sensitivity and outlier-adjusted analyses. Similar results were found for long-term efficacy. Interventions also did not differ in terms of their acceptability, except for TF-CBT being associated with a slightly increased risk of dropout compared to non-TF-PIs (RR=1.36; 95% CI: 1.08-1.70). In sum, interventions with and without trauma focus appear effective and acceptable in the treatment of adult PTSD. TF-CBT is by far the most well-researched intervention and yields the highest efficacy. However, TF-CBT appears somewhat less acceptable than non-TF-PIs.
Excess glutamate release triggers subunit-specific homeostatic receptor scaling
Authors: Goel Pragya , Han Yifu , Tran Nancy , Nishimura Samantha , Perry Sarah , Sanjani Manisha , Dickman Dion 
Published: May 2022

ABSTRACTIonotropic glutamate receptors (GluRs) are targets for modulation in Hebbian and homeostatic synaptic plasticity and are remodeled by development, experience, and disease. Although much is known about activity-dependent mechanisms that regulate GluR composition and abundance, the role of glutamate itself in these processes is unclear. To determine how glutamate sculpts GluR receptive fields, we have manipulated synaptically released glutamate and generated precise CRISPR mutations in the two postsynaptic GluR subtypes at theDrosophilaneuromuscular junction, GluRA and GluRB. We first demonstrate that GluRA and GluRB compete to establish postsynaptic receptive fields, and that proper GluR abundance and localization can be orchestrated in the absence of any synaptic glutamate release. However, excess glutamate release adaptively tunes postsynaptic GluR abundance, echoing GluR receptor scaling observed in mammalian systems. Unexpectedly, when GluRA vs GluRB competition is eliminated, excess glutamate homeostatically regulates GluRA abundance, while GluRB abundance is now insensitive to glutamate modulation. Finally, Ca2+impermeable GluRA receptors are no longer sensitive to homeostatic regulation by glutamate. Thus, excess glutamate, GluR competition, and Ca2+signaling collaborate to selectively target GluR subtypes for homeostatic regulation at postsynaptic compartments.
Multi-omics analyses of drug repurposing reveal Acebutolol and Amiloride for osteoporosis treatment
Authors: Liu Dan-Yang , Greenbaum Jonathan , Yi Qiao-Rong , Liang Shuang , Zhang Yue , Liu Jia-Chen , Meng Xiang-He , Xiao Hong-Mei , Deng Yun , Tan Li-Jun , Deng Hong-Wen 
Published: May 2022

AbstractOsteoporosis is a metabolic bone disease that occurs during aging, characterized by low bone mineral density (BMD) and a high risk of trauma fracture. While current pharmacological interventions provide symptomatic benefits, they are unsatisfactory and have major side effects. In this study, we used multi-omics data and drug similarity to construct osteoporosis driver signaling networks (ODSN) and drug functional networks (DFN), respectively. By integrating ODSN and DFN with treatment transcriptional responses, we observed 8 drugs that demonstrated strong targeting effects on ODSN. Mendelian Randomization analysis determines the causal effect on BMD using cis-eQTLs of the drug targets and BMD GWAS data. The findings suggested Acebutolol and Amiloride may increase BMD, while Acenocoumarol, Aminocaproic acid and Armodafinil may enhance bone loss. Zebrafish experiments experimentally showed Acebutolol hydrochloride and Amiloride hydrochloride had significant protective effects on osteoporosis in zebrafish embryos induced by Dexamethasone. Also, Acenocoumarol reduced bone mineralization compared with the control group. The findings suggest that the hypertension drugs Acebutolol and Amiloride warrant further investigation in functional mechanistic experiments to evaluate their effectiveness for osteoporosis treatments.
Spatiotemporal landscape of SARS-CoV-2 pulmonary infection reveals Slamf9+Spp1+ macrophages promoting viral clearance and inflammation resolution
Authors: Cong Boyi , Dong Xuan , Yang Zongheng , Yu Pin , Chai Yangyang , Liu Jiaqi , Zhang Meihan , Zang Yupeng , Kang Jingmin , Feng Yu , Liu Yi , Feng Weimin , Deng Wei , Li Fengdi , Yu Qinyi , Gu Yan , Li Zhiqing , Liu Shuxun , Xu Xun , Zhong Nanshan , Ren Xianwen , Qin Chuan , Liu Longqi , Wang Jian , Cao Xuetao 
Published: May 2022

AbstractWhile SARS-CoV-2 pathogenesis has been intensively investigated, the host mechanisms of viral clearance and inflammation resolution are still elusive because of the ethical limitation of human studies based on COVID-19 convalescents. Here we infected Syrian hamsters by authentic SARS-CoV-2 and built an ideal model to simulate the natural recovery process of SARS-CoV-2 infection from severe pneumonia1,2. We developed and applied a spatial transcriptomic sequencing technique with subcellular resolution and tissue-scale extensibility, i.e., Stereo-seq3, together with single-cell RNA sequencing (scRNA-seq), to the entire lung lobes of 45 hamsters and obtained an elaborate map of the pulmonary spatiotemporal changes from acute infection, severe pneumonia to the late viral clearance and inflammation resolution. While SARS-CoV-2 infection caused massive damages to the hamster lungs, including naïve T cell infection and deaths related to lymphopenia, we identified a group of monocyte-derived proliferating Slamf9+Spp1+ macrophages, which were SARS-CoV-2 infection-inducible and cell death-resistant, recruiting neutrophils to clear viruses together. After viral clearance, the Slamf9+Spp1+ macrophages differentiated into Trem2+ and Fbp1+ macrophages, both responsible for inflammation resolution and replenishment of alveolar macrophages. The existence of this specific macrophage subpopulation and its descendants were validated by RNAscope in hamsters, immunofluorescence in hACE2 mice, and public human autopsy scRNA-seq data of COVID-19 patients. The spatiotemporal landscape of SARS-CoV-2 infection in hamster lungs and the identification of Slamf9+Spp1+ macrophages that is pivotal to viral clearance and inflammation resolution are important to better understand the critical molecular and cellular players of COVID-19 host defense and also develop potential interventions of COVID-19 immunopathology.
Extrinsic regulation of interneuron specification and migration
Authors: Pipicelli Fabrizia , Baumann Natalia , Giaimo Rossella Di , Kyrousi Christina , Bonrath Rebecca , Jabaudon Denis , Cappello Silvia 
Published: May 2022

The imbalance between excitatory and inhibitory neurons in the human brain might lead to neurodevelopmental and neuropsychiatric disorders including cortical malformations, epilepsy, and autism spectrum disorders. We propose that the extracellular environment regulates interneuron differentiation and migration during development, ultimately affecting the excitatory/inhibitory balance.Using ventral cerebral organoids and dorso-ventral cerebral assembloids with mutations in the extracellular matrix gene LGALS3BP, we show that the composition of the extracellular environment regulates the molecular differentiation of neurons, resulting in alterations in migratory dynamics. To investigate how the extracellular environment affects neuronal specification and migration, we characterized the protein content of extracellular vesicles from cerebral organoids carrying a mutation in LGALS3BP, previously identified in individuals with cortical malformations and neuropsychiatric disorders. These results revealed differences in protein composition. Interestingly, proteins associated with cell-fate decision, neuronal migration and extracellular matrix composition were altered in mutant extracellular vesicles. Moreover, we show that treatment with extracellular vesicles changes the transcriptomic profile in neural progenitor cells. Our results indicate that neuronal molecular differentiation is regulated by factors released into the extracellular environment.
DNAJC13 influences responses of the extended reward system to conditioned stimuli: a genome-wide association study
Authors: Treutlein Jens , Einenkel Karolin E. , Krämer Bernd , Awasthi Swapnil , Ripke Stephan , Gruber Oliver 
Published: May 2022

ABSTRACTReward system dysfunction is implicated in the pathogenesis of major psychiatric disorders. We conducted a genome-wide association study (GWAS) to identify genes that influence activation strength of brain regions within the extended reward system in humans. A large homogeneous sample of 214 participants was genotyped and underwent functional magnetic resonance imaging (fMRI). All subjects performed the ‘desire-reason dilemma’ (DRD) paradigm allowing systematic investigation of systems-level mechanisms of reward processing in humans. As a main finding, we identified the single nucleotide variant rs113408797 in the DnaJ Heat Shock Protein Family Member C13 gene (DNAJC13, alias RME-8), that strongly influenced the activation of the ventral tegmental area (VTA; p = 2.50E-07) and the nucleus accumbens (NAcc; p = 5.31E-05) in response to conditioned reward stimuli. Moreover, haplotype analysis assessing the information across the entire DNAJC13 locus demonstrated an impact of a five-marker haplotype on VTA activation (p = 3.21E-07), which further corroborates a link between this gene and reward processing. The present findings provide first direct empirical evidence that genetic variation of DNAJC13 influences neural responses within the extended reward system to conditioned stimuli. Further studies are required to investigate the role of this gene in the pathogenesis and pathophysiology of neuropsychiatric disorders.