bluuebunny/crossref_metadata_2025_split huggingface dataset:
OMA1 High-throughput Screen Reveals Protease Activation by Kinase Inhibitors
Authors: Alavi Marcel V. 
Published: October 2021

ABSTRACTMitochondrial proteases are interesting but challenging drug targets for multifactorial diseases, such as neurodegeneration and cancer. The mitochondrial inner membrane protease OMA1 is a bona fide drug target for heart failure supported by data from human linkage analysis and animal disease models, but presumably relevant for more indications. OMA1 acts at the intersection of energy metabolism and stress signaling. The protease cleaves the structural protein OPA1, which organizes the cristae, as well as the signaling peptide DELE1, which can stimulate the integrated stress response. OMA1 shows little activity under physiological conditions but hydrolyzes OPA1 in mitochondria destined for mitophagy and during apoptosis. Little is known about OMA1, its structure has not been solved, let alone its context-dependent regulation. Autocatalytic processing and the lack of OMA1 inhibitors are thereby creating the biggest roadblocks. This study introduces a scalable, cellular OMA1 protease assay suitable for high-throughput drug screening. The assay utilizes an engineered luciferase targeted to the inner membrane as artificial OMA1 substrate, whereby the reporter signal inversely correlates to OMA1 activity. Testing different screening protocols and sampling different compound collections validated the reporter and demonstrated that both OMA1 activators as well as OMA1 inhibitors can be identified with the assay. Ten kinase-targeted cancer drugs triggered OMA1 in the assays, which suggests—considering cardiotoxicity as a rather common side-effect of this class of drugs—cross-reactivity with the OMA1 pathway.
Genetic basis of body shape variation along the benthic-pelagic axis in cichlid fishes
Authors: DeLorenzo Leah , Mathews Destiny , Brandon A. Allyson , Joglekar Mansi , Baez Aldo Carmona , Moore Emily C. , Ciccotto Patrick J. , Roberts Natalie B. , Roberts Reade B. , Powder Kara E. 
Published: October 2021

ABSTRACTDivergence along the benthic-pelagic axis is one of the most widespread and repeated patterns of morphological variation in fishes, producing body shape diversity associated with ecology and swimming mechanics. This ecological shift is also the first stage of the explosive adaptive radiation of cichlid fishes in the East African Rift Lakes. We use two hybrid crosses of cichlids (Metriaclimasp. xAulonocarasp. andLabidochromissp. xLabeotropheussp., >975 animals total) along the benthic-pelagic ecomorphological axis to determine the genetic basis of body shape diversification. Using a series of both linear and geometric shape measurements, we identify 55 quantitative trait loci (QTL) that underlie various aspects of body shape variation associated with benthic-pelagic divergence. These QTL are spread throughout the genome, each explain 3.0-7.2% of phenotypic variation, and are largely modular. Further, QTL are distinct both between these two crosses of Lake Malawi cichlids and compared to previously identified QTL for body shape in fishes such as sticklebacks. We find that body shape is controlled by many genes of small effects. In all, we find that convergent benthic and pelagic body phenotypes commonly observed across fish clades are most likely due to distinct genetic and molecular mechanisms.
Cell wall synthesis and remodeling dynamics determine bacterial division site architecture and cell shape
Authors: Navarro Paula P. , Vettiger Andrea , Ananda Virly Y. , Llopis Paula Montero , Allolio Christoph , Bernhardt Thomas G. , Chao Luke H. 
Published: October 2021

AbstractThe bacterial division apparatus builds daughter cell poles by catalyzing the synthesis and remodeling of the septal peptidoglycan (sPG) cell wall. Understanding of this essential process has been limited by the lack of native three-dimensional visualization of developing septa. Here, we used state-of-the-art cryogenic electron tomography (cryo-ET) and fluorescence microscopy to understand the division site architecture and sPG biogenesis dynamics of the Gram-negative bacterium Escherichia coli. Our results with mutant cells altered in the regulation of sPG biogenesis revealed a striking and unexpected similarity between the architecture of E. coli septa with those from Gram-positive bacteria, suggesting a conserved morphogenic mechanism. Furthermore, we found that the cell elongation and division machineries are in competition and that their relative activities determine the shape of cell constrictions and the poles they form. Overall, our results highlight how the activity of the division system can be modulated to generate the diverse array of morphologies observed in the bacterial domain.HighlightsThe division site architecture of E. coli can be modulated to resemble that of diverse bacteria.Cell wall degradation at the division site activates septal cell wall synthesis.Assembly of the cytoskeletal ring at the division site is modulated by cell wall remodeling.Balance between the activities of the elongation and division systems modulates cell shape.
Ultrastructural analysis of neuroimplant-parenchyma interfaces uncover remarkable neuroregeneration along-with barriers that limit the implant electrophysiological functions
Authors: Sharon Aviv , Shmoel Nava , Erez Hadas , Jankowski Maciej M. , Friedmann Yael , Spira Micha E. 
Published: October 2021

AbstractDespite increasing use of in-vivo multielectrode array (MEA) implants for basic research and medical applications, the critical structural interfaces formed between the implants and the brain parenchyma, remain elusive. Prevailing view assumes that formation of multicellular inflammatory encapsulating-scar around the implants (the foreign body response) degrades the implant electrophysiological functions. Using gold mushroom shaped microelectrodes (gMμEs) based perforated polyimide MEA platforms (PPMPs) that in contrast to standard probes can be thin sectioned along with the interfacing parenchyma; we examined here for the first time the interfaces formed between brains parenchyma and implanted 3D vertical microelectrode platforms at the ultrastructural level. Our study demonstrates remarkable regenerative processes including neuritogenesis, axon myelination, synapse formation and capillaries regrowth in contact and around the implant. In parallel, we document that individual microglia adhere tightly and engulf the gMμEs. Modeling of the formed microglia-electrode junctions suggest that this configuration suffice to account for the low and deteriorating recording qualities of in vivo MEA implants. These observations help define the anticipated hurdles to adapting the advantageous 3D in-vitro vertical-electrode technologies to in-vivo settings, and suggest that improving the recording qualities and durability of planar or 3D in-vivo electrode implants will require developing approaches to eliminate the insulating microglia junctions.
Enzymes degraded under high light maintain proteostasis by transcriptional regulation in Arabidopsis
Authors: Li Lei , Duncan Owen , Ganguly Diep R , Lee Chun Pong , Crisp Peter A. , Wijerathna-Yapa Akila , Salih Karzan , Trösch Josua , Pogson Barry J , Millar A. Harvey 
Published: October 2021

AbstractPhoto-inhibitory high light stress in Arabidopsis leads to increases in markers of protein degradation and transcriptional upregulation of proteases and proteolytic machinery, but proteostasis is largely maintained. We find significant increases in the in vivo degradation rate for specific molecular chaperones, nitrate reductase, glyceraldehyde-3 phosphate dehydrogenase, and phosphoglycerate kinase and other plastid, mitochondrial, peroxisomal, and cytosolic enzymes involved in redox shuttles. Coupled analysis of protein degradation rates, mRNA levels, and protein abundance reveal that 57% of the nuclear-encoded enzymes with higher degradation rates also had high light-induced transcriptional responses to maintain proteostasis. In contrast, plastid-encoded proteins with enhanced degradation rates showed decreased transcript abundances and must maintain protein abundance by other processes. This analysis reveals a light-induced transcriptional program for nuclear-encoded genes, beyond the regulation of PSII D1 subunit and the function of PSII, to replace key protein degradation targets in plants and ensure proteostasis under high light stress.
Microglia mediate synaptic plasticity induced by 10 Hz repetitive transcranial magnetic stimulation
Authors: Eichler Amelie , Kleidonas Dimitrios , Turi Zsolt , Fliegauf Maximilian , Kirsch Matthias , Pfeifer Dietmar , Masuda Takahiro , Prinz Marco , Lenz Maximilian , Vlachos Andreas 
Published: October 2021

AbstractMicroglia—the resident immune cells of the central nervous system—sense the activity of neurons and regulate physiological brain functions. They have been implicated in the pathology of brain diseases associated with alterations in neural excitability and plasticity. However, experimental and therapeutic approaches that modulate microglia function in a brain-region-specific manner have not been established. In this study, we tested for the effects of repetitive transcranial magnetic stimulation (rTMS), a clinically employed non-invasive brain stimulation technique, on microglia-mediated synaptic plasticity. 10 Hz electromagnetic stimulation triggered a release of plasticity-promoting cytokines from the microglia in organotypic brain tissue cultures, while no changes in microglial morphology or microglia dynamics were observed. Indeed, substitution of tumor necrosis factor alpha (TNFα) and interleukin 6 (IL6) preserved synaptic plasticity induced by 10 Hz stimulation in the absence of microglia. Consistent with these findings, in vivo depletion of microglia abolished rTMS-induced changes in neurotransmission in the medial prefrontal cortex (mPFC) of anesthetized mice. We conclude that rTMS affects neural excitability and plasticity by modulating the release of cytokines from microglia.
Unique Peptide Signatures Of SARS-CoV-2 Against Human Proteome Reveal Variants’ Immune Escape And Infectiveness
Authors: Pierros Vasileios , Kontopodis Evangelos , Stravopodis Dimitrios J. , Tsangaris George Th. 
Published: October 2021

SummarySARS-CoV-2 pandemic has emerged the necessity of the identification of sequences sites in viral proteome appropriate as antigenic sites and treatment targets. In the present study, we apply a novel approach for deciphering the virus-host organism interaction, by analyzing the Unique Peptides of the virus with a minimum amino acid sequence length defined as Core Unique Peptides (CrUPs) not of the virus per se, but against the entire proteome of the host organism. The result of this approach is the identification of the CrUPs of the virus itself, which do not appear in the host organism proteome. Thereby, we analyzed the SARS-CoV-2 proteome for identification of CrUPs against the Human Proteome and they are defined as C/H-CrUPs. We found that SARS-CoV-2 include 7.503 C/H-CrUPs, with the SPIKE_SARS2 being the protein with the highest density of C/H-CrUPs. Extensive analysis indicated that the P681R mutation produces new C/H-CrUPs around the R685 cleavage site, while the L452R mutation induces the loss of antigenicity of the NF9 peptide and the strong(er) binding of the virus to ACE2 receptor protein. The simultaneous existence of these mutations in variants like Delta results in the immune escape of the virus, its massive entrance into the host cell, a notable increase in virus formation, and its massive release and thus elevated infectivity.
Severe distortion in the representation of foveal visual image locations in short term memory
Authors: Willeke Konstantin F. , Cardenas Araceli R. , Bellet Joachim , Hafed Ziad M. 
Published: October 2021

AbstractThe foveal visual image region provides the human visual system with the highest acuity. However, it is unclear whether such a high fidelity representational advantage is maintained when foveal image locations are committed to short term memory. Here we describe a paradoxically large distortion in foveal target location recall by humans. We briefly presented small, but high contrast, points of light at eccentricities ranging from 0.1 to 12 deg, while subjects maintained their line of sight on a stable target. After a brief memory period, the subjects indicated the remembered target locations via computer controlled cursors. The biggest localization errors, in terms of both directional deviations and amplitude percentage overshoots or undershoots, occurred for the most foveal targets, and such distortions were still present, albeit with qualitatively different patterns, when subjects shifted their gaze to indicate the remembered target locations. Foveal visual images are severely distorted in short term memory.
iLoci: Robust evaluation of genome content and organization for provisional and mature genome assemblies
Authors: Standage Daniel S , Lai Tim , Brendel Volker P 
Published: October 2021

AbstractBackgroundThe rate at which new draft genome assemblies and corresponding annotation versions are being produced has long outpaced the scientific community’s capacity to refine these drafts into “finished,” reference-quality data resources to a standard typically expected from dedicated efforts of model organism research communities. Nonetheless, scientists must be able to evaluate newly sequenced genomes in the context of previously published data, requiring summaries of genome content and organization that can be quickly computed, updated, and meaningfully compared. As annotation quality will necessarily vary within and across data sets, the ability to select subsets of only those data that are well supported is critical for distinguishing technical artifacts from biological effects in genome-wide analyses.ResultsWe introduce a new framework for genome analyses based on parsing an annotated genome assembly into distinct interval loci (iLoci), available as open source software as part of the AEGeAn Toolkit (https://github.com/BrendelGroup/AEGeAn). We demonstrate that iLoci provide an alternative coordinate system that is robust to changes in assembly and annotation versions and facilitates granular quality control of genome data. We discuss how statistics computed on iLoci reflect various characteristics of genome content and organization and illustrate how these statistics can be used to establish a baseline for assessment of the completeness and accuracy of the data. We also introduce a well-defined measure of relative genome compactness and compute other iLocus statistics that reveal genome-wide characteristics of gene arrangements in the whole genome context.ConclusionsWe present a coherent computational framework that calculates informative statistics from genome assembly/annotation data input. Given the fast pace of assembly/annotation updates, our AEGeAn Toolkit fills a niche in computational genomics based on deriving persistent and species-specific genome statistics. Gene structure model centric iLoci provide a precisely defined coordinate system that can be used to store assembly/annotation updates that reflect either stable or changed assessments. Large-scale application of the approach revealed species and clade specific genome organization in precisely defined computational terms, promising intriguing forays into the forces of shaping genome structure as more and more genome assemblies are being deposited.
Prefrontal signals precede striatal signals for biased credit assignment to (in)actions
Authors: Algermissen Johannes , Swart Jennifer C. , Scheeringa René , Cools Roshan , den Ouden Hanneke E.M. 
Published: October 2021

AbstractActions are biased by the outcomes they can produce: Humans are more likely to show action under reward prospect, but hold back under punishment prospect. Such motivational biases derive not only from biased response selection, but also from biased learning: humans tend to attribute rewards to their own actions, but are reluctant to attribute punishments to having held back. The neural origin of these biases is unclear; in particular, it remains open whether motivational biases arise primarily from the architecture of subcortical regions or also reflect cortical influences, the latter being typically associated with increased behavioral flexibility and emancipation from stereotyped behaviors. Simultaneous EEG-fMRI allowed us to track which regions encoded biased prediction errors in which order. Biased prediction errors occurred in cortical regions (dACC, PCC) before subcortical regions (striatum). These results highlight that biased learning is not a mere feature of the basal ganglia, but arises through prefrontal cortical contributions, revealing motivational biases to be a potentially flexible, sophisticated mechanism.
Discovery of Aminoglycosides as first in class, nanomolar inhibitors of Heptosyltransferase I
Authors: Milicaj Jozafina , Hassan Bakar A. , Cote Joy M. , Ramirez-Mondragon Carlos A. , Jaunbocus Nadiya , Rafalowski Angelika , Patel Kaelan R. , Muthyala Ramaiah , Sham Yuk Y. , Taylor Erika A. 
Published: October 2021

AbstractA clinically relevant inhibitor for Heptosyltransferase I (HepI) has been sought after for many years and while many have designed novel small-molecule inhibitors, these compounds lack the bioavailability and potency necessary for therapeutic use. Extensive characterization of the HepI protein has provided valuable insight into the dynamic motions necessary for catalysis that could be targeted for inhibition. With the help of molecular dynamic simulations, aminoglycoside antibiotics were shown to be putative inhibitors for HepI and in this study, they were experimentally determined to be the first in-class nanomolar inhibitors of HepI with the best inhibitor demonstrating a Ki of 600 +/- 90 nM. Detailed kinetic analyses were performed to determine the mechanism of inhibition while circular dichroism spectroscopy, intrinsic tryptophan fluorescence, docking, and MD simulations were used to corroborate kinetic experimental findings. Kinetic analysis methods include Lineweaver-Burk, Dixon, Cornish-Bowden and Mixed-Model of Inhibition which allowed for unambiguous assignment of inhibition mechanism for each inhibitor. In this study, we show that neomycin and kanamycin b are competitive inhibitors against the sugar acceptor substrate while tobramycin exhibits a mixed inhibitory effect and streptomycin is non-competitive. MD simulations also allowed us to suggest that the inhibitors bind tightly and inhibit catalytic dynamics due to a major desolvation penalty of the enzyme active site. While aminoglycosides have long been known as a class of potent antibiotics, they also have been scientifically shown to impact cell membrane stability, and we propose that inhibition of HepI contributes to this effect by disrupting lipopolysaccharide biosynthesis.
Enhancement of hippocampal-thalamocortical temporal coordination during slow-frequency long-duration anterior thalamic spindles
Authors: Alizadeh Zahra , Azimi Amin , Ghorbani Maryam 
Published: October 2021

AbstractTemporal nesting of cortical slow oscillations (SO), thalamic spindles and hippocampal ripples indicates the succession of regional neuronal interactions required for memory consolidation. However how the thalamic activity during spindles organizes hippocampal dynamics remains largely undetermined. We analyzed simultaneous recordings of anterodorsal thalamus and CA1 in mice to determine the contribution of thalamic spindles in cross-regional synchronization. Our results indicated that temporal hippocampo-thalamocortical coupling were more enhanced during slower and longer thalamic spindles. Additionally, spindles occurring closer to SO trough were more strongly coupled to ripples. We found that the temporal association between CA1 spiking/ripples and thalamic spindles was stronger following spatial exploration compared to baseline sleep. We further developed a hippocampal-thalamocortical model to explain the mechanism underlying the duration and frequency-dependent coupling of thalamic spindles to hippocampal activity. Our findings shed light on our understanding of the functional role of thalamic activity during spindles on multi-regional information transfer.
The cerebellum contributes to tonic-clonic seizures by altering neuronal activity in the ventral posteromedial nucleus (VPM) of the thalamus
Authors: Beckinghausen Jaclyn , Ortiz-Guzman Joshua , Lin Tao , Bachman Benjamin , Liu Yu , Heck Detlef H. , Arenkiel Benjamin R. , Sillitoe Roy V. 
Published: October 2021

SummaryThalamo-cortical networks are central to seizures, yet it’s unclear how these circuits initiate the seizures. Here, we test the hypothesis that a facial region of the thalamus, the VPM, is a source of convulsive, tonic-clonic seizures. We devised an in vivo optogenetic mouse model to elicit tonic-clonic seizures by driving convergent input to the VPM. With viral tracing, we show dense cerebellar and cerebral cortical afferent input to the VPM. Lidocaine microinfusions into the cerebellar nuclei selectively block seizure initiation. We perform single-unit electrophysiology recordings during awake, convulsive seizures to define the local activity of thalamic neurons before, during, and after seizure onset. We find highly dynamic activity with biphasic properties, raising the possibility that heterogenous activity patterns promote seizures. These data reveal the VPM as a source of tonic-clonic seizures, with cerebellar input providing the predominant signals.
The first transchromosomic rat model with human chromosome 21 shows robust Down syndrome features
Authors: Kazuki Yasuhiro , Gao Feng J. , Yamakawa Miho , Hirabayashi Masumi , Kazuki Kanako , Kajitani Naoyo , Miyagawa-Tomita Sachiko , Abe Satoshi , Sanbo Makoto , Hara Hiromasa , Kuniishi Hiroshi , Ichisaka Satoshi , Hata Yoshio , Koshima Moeka , Takayama Haruka , Takehara Shoko , Nakayama Yuji , Hiratsuka Masaharu , Iida Yuich , Matsukura Satoko , Noda Naohiro , Li Yicong , Moyer Anna J. , Cheng Bei , Singh Nandini , Richtsmeier Joan T. , Oshimura Mitsuo , Reeves Roger H. 
Published: October 2021

AbstractProgress in earlier detection and symptom management has increased life expectancy and quality of life in people with Down syndrome (DS). However, no drug has been approved to help individuals with DS live independently and fully. Although rat models could support more robust physiological, behavioral, and toxicology analysis than mouse models during preclinical validation, no DS rat model is available due to technical challenges. We developed the first transchromosomic rat model of DS, TcHSA21rat, which contains a freely segregating, EGFP-inserted, human chromosome 21 (HSA21) with >93% of its protein coding genes. RNA-Seq of neonatal forebrains demonstrates that TcHSA21rat not only expresses HSA21 genes but also has an imbalance in global gene expression. Using EGFP as a marker for trisomic cells, flow cytometry analyses of peripheral blood cells from 361 adult TcHSA21rat animals show that 81% of animals retain HSA21 in >80% of cells, the criterion for a “Down syndrome karyotype” in people. TcHSA21rat exhibits learning and memory deficits and shows increased anxiety and hyperactivity. TcHSA21rat recapitulates well-characterized DS brain morphology, including smaller brain volume and reduced cerebellar size. In addition, the rat model shows reduced cerebellar foliation, a prominent feature of DS that is not observed in DS mouse models. Moreover, TcHSA21rat exhibits anomalies in craniofacial morphology, heart development, husbandry, and stature. TcHSA21rat is a robust DS animal model that can facilitate DS basic research and provide a unique tool for preclinical validation to accelerate DS drug development.