bluuebunny/crossref_metadata_2025 huggingface dataset:
A unified framework for perceived magnitude and dicriminability of sensory stimuli
Authors: Zhou Jingyang , Duong Lyndon R. , Simoncelli Eero P.
Published: May 2022

The perception of sensory attributes is often quantified through measurements of sensitivity (the ability to detect small stimulus changes), as well as through direct judgements of appearance or intensity. Despite their ubiquity, the relationship between these two measurements remains controversial and unresolved. Here, we propose a framework in which they arise from different aspects of a common representation. Specifically, we assume that judgements of stimulus intensity (e.g., as measured through rating scales) reflect the mean value of an internal representation, and sensitivity reflects a combination of mean value and noise properties, as quantified by the statistical measure of Fisher Information. Unique identification of these internal representation properties can be achieved by combining measurements of sensitivity and judgments of intensity. As a central example, we show that Weber’s law of perceptual sensitivity can co-exist with Stevens’ power-law scaling of intensity ratings (for all exponents), when the noise amplitude increases in proportion to the representational mean. We then extend this result beyond the Weber’s law range by incorporating a more general and physiology-inspired form of noise, and show that the combination of noise properties and sensitivity measurements accurately predicts intensity ratings across a variety of sensory modalities and attributes. Our framework unifies two primary perceptual measurements – thresholds for sensitivity and rating scales for intensity – and provides a neural interpretation for the underlying representation.

Significance Statement

Perceptual measurements of sensitivity to stimulus changes and stimulus appearance (intensity) are ubiquitous in the study of perception. However, the relationship between these two seemingly disparate measurements remains unclear. Proposals for unification have been made for over 60 years, but they generally lack support from perceptual or physiological measurements. Here, we provide a framework that offers a unified interpretation of perceptual sensitivity and intensity measurements, and we demonstrate its consistency with experimental measurements across multiple perceptual domains.
Validation of the Tea Bag Index as a standard approach for assessing organic matter decomposition
Authors: Mori Taiki
Published: May 2022

The Tea Bag Index (TBI), a novel approach to assessing organic matter decomposition using commercial tea bags, has been increasingly utilized as a standard method in academic studies worldwide. This approach was designed to obtain an early-stage decomposition constant (k) indicative of early-stage decomposition rates and a litter stabilization factor (S) indicative of long-term carbon stability by using two types of teas—green and rooibos. However, despite the worldwide usage of the method, the accuracy of this approach has never been validated in terrestrial ecosystems. Here, the validity of this approach was tested by examining the two essential premises of the TBI using a laboratory incubation experiment. The first premise of the TBI—namely, that the unstabilized hydrolyzable fraction of green tea is mostly decomposed within 90 days—did not hold in the present study, which caused overestimations of the S of rooibos tea, as well as k. The second premise—namely, that the ratio of stabilized to total hydrolyzable fractions (i.e., S) of rooibos tea is equal to that of green tea—was also rejected, which resulted in substantial underestimations of the S of rooibos tea and k. Overall, the TBI largely underestimated the S of rooibos tea and k (more than 1.5 and 5 times smaller than those determined by time-series data, respectively). The present study suggests that time-series mass loss data of rooibos tea should be obtained to accurately determine k, rather than assuming that the S of rooibos tea is equal to that of green tea.
Computer simulations reveal pathogenicity and inheritance modes of hearing loss-causing germinal variants
Authors: Tsai Cheng-Yu , Lu Ying-Chang , Chan Yen-Hui , Chang Yuan-Yu , Lin Shu-Wha , Liu Tien-Chen , Hsu Chuan-Jen , Chen Pei-Lung , Yang Lee-Wei , Wu Chen-Chi
Published: May 2022

Variants in the gap junction beta-2 (GJB2) gene are the most common cause of hereditary hearing impairment. However, howGJB2variants lead to local physicochemical and structural changes in the hexameric ion channels of connexin 26 (Cx26), resulting in hearing impairment, remains elusive. In the present study, using molecular dynamics (MD) simulations, we showed that detached inner-wall N-terminal “plugs” aggregated to reduce the channel ion flow in a highly prevalent V37I variant in humans. To examine the predictability of the computational platform, an artificial mutant, V37M, of which the effect was previously unknown in hearing loss, was created. Microsecond simulations showed that homomeric V37M Cx26 hemichannels had an abnormal affinity between the inner edge and N-termini to block the narrower side of the cone-shaped Cx26, while the most stable heteromeric channels did not. Consistent with these predictions, homozygous V37M transgenic mice exhibited apparent hearing loss, but not their heterozygous counterparts, indicating a recessive inheritance mode. Reduced channel conductivity was found inGjb2V37M/V37Mouter sulcus cells and Claudius cells but not inGjb2WT/WTcells. We view that the current computational platform could serve as an assessment tool for the pathogenesis and inheritance ofGJB2-related hearing impairments and other diseases caused by connexin dysfunction.
Profiling RNA at chromatin targets in situ by antibody-targeted tagmentation
Authors: Khyzha Nadiya , Henikoff Steven , Ahmad Kami
Published: May 2022

Whereas techniques to map chromatin-bound proteins are well-developed, mapping chromatin-associated RNAs remains a challenge. Here we describe Reverse Transcribe & Tagment (RT&Tag), in which RNAs associated with a chromatin epitope are targeted by an antibody followed by a protein A-Tn5 transposome. Localized reverse transcription generates RNA/cDNA hybrids that are subsequently tag-mented for sequencing by Tn5. We demonstrate the utility of RT&Tag in Drosophila cells for capturing the noncoding RNA roX2 with the dosage compensation complex and maturing transcripts associated with silencing histone modifications. We also show that RT&Tag can detect N6-methyladenosine (m6A)-modified mRNAs, and show that genes producing methylated transcripts are characterized by extensive promoter pausing of RNA polymerase II. The high efficiency of in situ antibody tethering and tagmentation makes RT&Tag especially suitable for rapid low-cost profiling of chromatin-associated RNAs from small samples.
Direct observation of the neural computations underlying a single decision
Authors: Steinemann Natalie A , Stine Gabriel M , Trautmann Eric M , Zylberberg Ariel , Wolpert Daniel M , Shadlen Michael N
Published: May 2022

Neurobiological investigations of perceptual decision-making have furnished the first glimpse of a flexible cognitive process at the level of single neurons (Shadlen and Newsome, 1996;Shadlen and Kiani, 2013). Neurons in the parietal and prefrontal cortex (Kim and Shadlen, 1999;Romo et al., 2004;Hernández et al., 2002; Ding and Gold, 2012) are thought to represent the accumulation of noisy evidence, acquired over time, leading to a decision. Neural recordings averaged over many decisions have provided support for the deterministic rise in activity to a termination bound (Roitman and Shadlen, 2002). Critically, it is the unobserved stochastic component that is thought to confer variability in both choice and decision time (Gold and Shadlen, 2007). Here, we elucidate this drift-diffusion signal on individual decisions. We recorded simultaneously from hundreds of neurons in the lateral intraparietal cortex (LIP) of monkeys while they made decisions about the direction of random dot motion. We show that a single scalar quantity, derived from the weighted sum of the population activity, represents a combination of deterministic drift and stochastic diffusion. Moreover, we provide direct support for the hypothesis that this drift-diffusion signal approximates the quantity responsible for the variability in choice and reaction times. The population-derived signals rely on a small subset of neurons with response fields that overlap the choice targets. These neurons represent the integral of noisy evidence. Another subset of direction-selective neurons with response fields that overlap the motion stimulus appear to represent the integrand. This parsimonious architecture would escape detection by state-space analyses, absent a clear hypothesis.
Learning of new associations invokes a major change in modulations of cortical beta oscillations in human adults
Authors: Pavlova Anna , Tyulenev Nikita , Tretyakova Vera , Skavronskaya Valeriya , Nikolaeva Anastasia , Prokofyev Andrey , Stroganova Tatiana , Chernyshev Boris
Published: May 2022

Large-scale cortical beta (β) oscillations have been implicated in the learning processes but their exact role is debated. We explored the dynamics of β-oscillations while 25 adult participants learned, through trial and error, novel associations between four auditory pseudowords and movements of four body extremities. We used MEG to evaluate learninginduced changes in beta modulation accompanying cue-triggered movements.

Our findings showed that spatial-temporal characteristics of movement-related β-oscillations underwent a major transition as learning proceeded. Early in learning, suppression of β-power in multiple cortical areas occurred long before movement initiation and sustained throughout the whole behavioral trial. As learning advanced and task performance reached asymptote, βsuppression was replaced by a widespread and prolonged rise in β-power. The β-power rise started shortly after the initiation of correct motor response and mainly comprised the prefrontal and medial temporal regions of the left hemisphere. This post-decision β-power predicted trial-by-trial response times (RT) at both stages of learning (before and after the rules become familiar) but in opposite ways. When a subject started to acquire associative rules and gradually improved task performance, a decrease in RT was correlated with the increase in the post-decision β-band power. Repeatedly correct implementation of the learned rules reversed this correlation in the opposite direction with faster (more confident) responses associated with the weaker post-decision β-band synchronization.

Our findings suggest that maximal beta activity is pertinent to a distinct stage of learning and may serve to strengthen the newly learned association in a distributed memory network.
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

Subanesthetic 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

In 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

Membrane 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

Kaposi’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.

IMPORTANCE

In 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

Nε-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.

IMPORTANCE

Numerous 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

A 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

Ionotropic 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

Osteoporosis 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

While 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

Reward 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.
Defective subviral particles modify ecological equilibria and enhance viral coexistence
Authors: Lucía-Sanz Adriana , Aguirre Jacobo , Fraile Aurora , García-Arenal Fernando , Manrubia Susanna
Published: May 2022

Cooperation is a main driver of biological complexity at all levels. In the viral world, gene sharing among viral genomes, complementation between genomes or interactions within quasispecies are frequently observed. In this contribution, we explore the advantages that flexible associations between fully fledged viruses and subviral entities, such as virus satellites, might yield. We devise a mathematical model to compare different situations of competition between two viruses and to quantify how the association with a satellite qualitatively modifies dynamical equilibria. The relevant parameter is the invasion fitness of each virus or of the virus-satellite tandem, which in the model depends on the transmission rate of viruses and on their effect on host survival. While in a virus-virus competition one of the viruses becomes eventually extinct, an association with a satellite might change the outcome of the competition to favor the less competitive virus (regardless of whether it is the helper virus or not) or to allow for the stable coexistence of the two viruses and the satellite. We hypothesize that the latter scenario, in particular, constitutes a parsimonious evolutionary pathway towards more stable cooperative associations, such as bipartite viral forms.
Multifaceted role of RIMBP2 in promoting hearing in murine cochlear hair cells
Authors: Liao Menghui , Chen Xin , Lu Ling , Guo Rongrong , Zhang Panpan , Li Yige , Zhang Yuhua , Fang Qiaojun , Hu Yangnan , Cai Jiaying , Chen Xiaoyan , Tang Mingliang , Gao Xia , He Shuijin , Li Huawei , Li Geng-Lin , Chai Renjie
Published: May 2022

In peripheral, the mammalian cochlea is a remarkable sensory apparatus, owning to its outer and inner hair cells (OHCs and IHCs) that amplify and transmit auditory signals to the brain, respectively. Rab3-interacting molecular (RIM) binding protein 2 (RIMBP2) is widely expressed in receptor cells and neurons, specifically in the active zones for exocytosis of synaptic vesicles (SVs), but its exact functions in the cochlea are not very well understood. We therefore generated a Rimbp2 knockout mouse model (Rimbp2-/-), which exhibited severely impaired hearing with not only elevated hearing thresholds but also increased latencies and reduced amplitudes in the Wave I of their auditory brainstem responses (ABRs). Consistent with the threshold elevation, we found significant loss of OHCs, likely through apoptosis, in the Rimbp2-/- cochlea. Consistent with changes observed in the ABR Wave I, we found greatly reduced exocytosis, both spontaneously and upon stimulation, in Rimbp2-/- IHCs. Specifically, our patch-clamp analysis on IHCs and postsynaptic spiral ganglion neurons (SGNs) revealed not only reduced readily releasable pool (RRP) of SVs but also reduced sustained release rate, along with complete blockade of fast endocytosis, in Rimbp2-/- IHCs. Lastly, with immunostaining of whole-mounted cochleae, we found that while the number of ribbon synapses in Rimbp2-/- IHCs was unchanged, their localization moved subtly but significantly towards the basal pole of IHCs. Taken together, we uncovered an unexpected role of RIMBP2 for OHC survival and a more extensive role in promoting IHC exocytosis than previously believed.
Gene expression analysis of the Xenopus laevis early limb bud proximodistal axis
Authors: Hudson D.T. , Bromell J. S. , Day R.C. , McInnes T , Ward J.M. , Beck C.W.
Published: May 2022

Background

Limb buds develop as bilateral outgrowths of the lateral plate mesoderm and are patterned along three axes. Current models of proximal to distal patterning of early amniote limb buds suggest that two signals, a distal organising signal from the apical epithelial ridge (AER, Fgfs) and an opposing proximal (retinoic acid) act early on pattern this axis.

Results

Transcriptional analysis of stage 51 Xenopus laevis hindlimb buds sectioned along the proximal-distal axis, showed that the distal region is distinct from the rest of the limb. Expression of capn8.3, a novel calpain, was located in cells immediately flanking the AER. The Wnt antagonist Dkk1 was AER-specific in Xenopus limbs. Two transcription factors, sall1 and zic5, were expressed in distal mesenchyme. Zic5 has no described association with limb development. We also describe expression of two proximal genes, gata5 and tnn, not previously associated with limb development. Differentially expressed genes were associated with Fgf, Wnt and retinoic acid (RA) signalling as well as differential cell adhesion and proliferation.

Conclusions

We identify new candidate genes for early proximodistal limb patterning. Our analysis of RA-regulated genes supports a role for transient RA gradients in early limb bud in proximal-to-distal patterning in this anamniote model organism.
Hippocampal subfields and their neocortical interactions during autobiographical memory
Authors: Leelaarporn Pitshaporn , Dalton Marshall A. , Stirnberg Rüdiger , Stöcker Tony , Spottke Annika , Schneider Anja , McCormick Cornelia
Published: May 2022

Advances in ultra-high field 7 Tesla functional magnetic resonance imaging (7T fMRI) have provided unprecedented opportunities to gain insights into the neural underpinnings supporting human memory. The hippocampus, a heterogeneous brain structure comprising several subfields plays a central role during vivid re-experiencing of autobiographical memories (AM). However, due to technical limitations, how hippocampal subfields differentially support AM, whether this contribution is specific to one portion along the hippocampal long-axis, and how subfields are functionally connected with other brain regions typically associated with AM retrieval remains elusive. Here, we leveraged technical advances of parallel imaging and employed a submillimeter Echo Planar Imaging sequence over the whole brain while participants re-experienced vivid, detail-rich AM. We found that all hippocampal subfields along the long-axis were engaged during AM retrieval. Nonetheless, only the pre/parasubiculum within the anterior body of the hippocampus, contributed over and above to AM retrieval. Moreover, whole-brain functional connectivity analyses of the same data revealed that this part of the hippocampus was the only one that was strongly connected to other brain regions typically associated with AM, such as the ventromedial prefrontal cortex (vmPFC) and medial/lateral parietal regions. In the context of the broader literature, our results support recent proposals that the anterior body of the pre/parasubiculum may play an essential role in scene-based cognition, such as the re-experience of personal past events.

Highlights

All hippocampal subfields differentiate AM retrieval from mental arithmetic problem solving

The anterior body of the pre/parasubiculum engages in AM more than other subfields

The anterior body of the pre/parasubiculum is strongly connected to the AM network

The pre/parasubiculum may be preferentially involved in scene-based cognition
Introducing the Dendrify framework for incorporating dendrites to spiking neural networks
Authors: Pagkalos Michalis , Chavlis Spyridon , Poirazi Panayiota
Published: May 2022

Computational modeling has been indispensable for understanding how subcellular neuronal features influence circuit processing. However, the role of dendritic computations in network-level operations remains largely unexplored. This is partly because existing tools do not allow the development of realistic and efficient network models that account for dendrites. Current spiking neural networks, although efficient, are usually quite simplistic, overlooking essential dendritic properties. Conversely, circuit models with morphologically detailed neuron models are computationally costly, thus impractical for large-network simulations. To bridge the gap between these two extremes and facilitate the adoption of dendritic features in spiking neural networks, we introduce Dendrify, an open-source Python package based on Brian 2. Dendrify, through simple commands, automatically generates reduced compartmental neuron models with simplified yet biologically relevant dendritic and synaptic integrative properties. Such models strike a good balance between flexibility, performance, and biological accuracy, allowing us to explore dendritic contributions to network-level functions while paving the way for developing more powerful neuromorphic systems.
Modeling Reactive Species Metabolism in Colorectal Cancer for Identifying Metabolic Targets and Devising Therapeutics
Authors: Bhalla Prerna , Sridhar Subasree , Kullu Justin , Veerapaneni Sriya , Sahoo Swagatika , Bhatt Nirav , Suraishkumar GK
Published: May 2022

Reactive species (RS) are known to play significant roles in cancer development as well as in treating or managing cancer. On the other hand, genome scale metabolic models are being used to understand cell metabolism in disease contexts including cancer, and also in planning strategies to handle diseases. Despite their crucial roles in cancers, the reactive species have not been adequately modeled in the genome scale metabolic models (GSMMs) when probing disease models for their metabolism or detection of drug targets. In this work, we have developed a module of reactive species reactions, which is scalable - it can be integrated with any human metabolic model as it is, or with any metabolic model with fine-tuning. When integrated with a cancer (colorectal cancer in this case) metabolic model, the RS module highlighted the deregulation occurring in important CRC pathways such as fatty acid metabolism, cholesterol metabolism, arachidonic acid and eicosanoid metabolism. We show that the RS module helps in better deciphering crucial metabolic targets for devising better therapeutics such as FDFT1, FADS2 and GUK1 by taking into account the effects mediated by reactive species during colorectal cancer progression. The results from this reactive species integrated CRC metabolic model reinforces ferroptosis as a potential target for colorectal cancer therapy.
Digital holography-based 3D particle localisation for single molecule tweezer techniques
Authors: Flewellen James L. , Minoughan Sophie , Garcia Isabel Llorente , Tolar Pavel
Published: May 2022

We present a three-dimensional imaging technique for fast tracking of microscopic objects in a fluid environment. Our technique couples digital holographic microscopy with three-dimensional localisation via parabolic masking. Compared with existing approaches, our method reconstructs 3D volumes from single-plane images, which greatly simplifies image acquisition, reduces the demand on microscope hardware, and facilitates tracking higher densities of microscopic particles while maintaining similar levels of precision. We demonstrate utility of this method in magnetic tweezer experiments, opening their use to multiplexed single-molecule force spectroscopy assays. We propose that our technique will also be useful in other applications that involve the tracking of microscopic objects in three dimensions.

SIGNIFICANCE

Tracking objects in 3D is a common task in biology, but typically requires the acquisition of image stacks, which is limited by speed, the depth of field of microscope objectives and by the presence of other objects that obscure the illumination. Here we develop HoloMiP (Holographic Microscopy with Parabolic masking), which uses digital holography to reconstruct the three-dimensional images from a single plane allowing tracking of light-scattering objects in 3D. HoloMiP outperforms existing methods in precision, speed, simplicity and tolerance to crowding. We show that it is particularly suitable for fast, multiplexed magnetic tweezer experiments, opening new avenues to high-throughput force spectroscopy.
Brain Structure and Episodic Learning Rate in Cognitively Healthy Ageing
Authors: Frank Darya , Garo-Pascual Marta , Reyes Velasquez Pablo Alejandro , Frades Belén , Peled Noam , Zhang Linda , Strange Bryan A.
Published: May 2022

Memory normally declines with ageing and these age-related cognitive changes are associated with changes in brain structure. Episodic memory retrieval has been widely studied during ageing, whereas learning has received less attention. Here we examined the neural correlates of episodic learning rate in ageing. Our study sample consisted of 982 cognitively healthy female and male older participants from the Vallecas Project cohort, without a clinical diagnosis of mild cognitive impairment or dementia. The learning rate across the three consecutive recall trials of the verbal memory task (Free and Cued Selective Reminding Test) recall trials was used as a predictor of grey matter (GM) using voxel-based morphometry, and WM microstructure using tract-based spatial statistics on fractional anisotropy (FA) and mean diffusivity (MD) measures. Immediate Recall improved by 1.4 items per trial on average, and this episodic learning rate was faster in women and negatively associated with age. Structurally, hippocampal and anterior thalamic GM volume correlated positively with learning rate. Learning also correlated with the integrity of WM microstructure (high FA and low MD) in an extensive network of tracts including bilateral anterior thalamic radiation, fornix, and long-range tracts. These results suggest that episodic learning rate is associated with key anatomical structures for memory functioning, motivating further exploration of the differential diagnostic properties between episodic learning rate and retrieval in ageing.