bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxidation-reduction imaging of myoglobin unveils two-phase oxidation in the reperfused myocardium
Authors: Badawi Sally , Leboullenger Clémence , Chourrout Matthieu , Gouriou Yves , Paccalet Alexandre , Pillot Bruno , Augeul Lionel , Bolbos Radu , Bongiovani Antonino , Mewton Nathan , Bochaton Thomas , Ovize Michel , Tardivel Meryem , Kurdi Mazen , Canet-Soulas Emmanuelle , Crola Da Silva Claire , Bidaux Gabriel 
Published: May 2023

ABSTRACTMyocardial infarction (MI) is a serious cardiovascular problem that causes myocardial injury due to blood flow obstruction to a specific myocardial area. Under ischemic-reperfusion settings, a burst of reactive oxygen species is generated, leading to redox imbalance that could be attributed to several molecules, including myoglobin. Myoglobin is dynamic and exhibits various oxidation-reduction states that have been a subject of attention in the food industry, specifically for meat consumers. However, rarely if ever, have the myoglobin optical properties been used to understand the pathology of MI. In the current study, we develop a novel imaging pipeline that integrates tissue clearing, confocal and light sheet fluorescence microscopy, combined with imaging analysis, and processing tools to investigate and characterize the oxidation-reduction states of myoglobin in the ischemic area of the myocardium post-MI. Using spectral imaging, we have characterized the endogenous fluorescence of the myocardium and demonstrated that it aligns with the spectral profile of myoglobin. Under ischemia-reperfusion experimental settings, we report that the infarcted myocardium spectral signature is similar to that of oxidized myoglobin signal that peaks 3 hours post-reperfusion and decreases with cardioprotection. These results were correlated with MI measurements by Late Gadolinium Enhancement MRI. In conclusion, this seminal work suggests that the redox state of myoglobin can be used as a promising imaging biomarker for characterizing and estimating the size of the MI during early phases of reperfusion.
A non-image-forming visual circuit mediates the innate fear of heights
Authors: Shang Wei , Xie Shuangyi , Feng Wenbo , Li Zhuangzhuang , Jia Jingyan , Cao Xiaoxiao , Shen Yanting , Li Jing , Shi Haibo , Gu Yiran , Weng Shi-Jun , Lin Longnian , Pan Yi-Hsuan , Yuan Xiao-Bing 
Published: May 2023

AbstractThe neural basis of fear of heights remains largely unknown. In this study, we investigated the fear response to heights in mice and observed characteristic aversive behaviors resembling human height vertigo. We identified visual input as a critical factor in mouse reactions to heights, while peripheral vestibular input was found to be nonessential for fear of heights. Unexpectedly, we found that fear of heights in naïve mice does not rely on image-forming visual processing by the primary visual cortex. Instead, a subset of neurons in the ventral lateral geniculate nucleus (vLGN), which connects to the lateral/ventrolateral periaqueductal gray (l/vlPAG), drives the expression of fear associated with heights. Additionally, we observed that a subcortical visual pathway linking the superior colliculus to the lateral posterior thalamic nucleus inhibits the defensive response to height threats. These findings highlight a rapid fear response to heights threat through a subcortical visual and defensive pathway from the vLGN to the l/vlPAG.
MESSES: Software for Transforming Messy Research Datasets into Clean Submissions to Metabolomics Workbench for Public Sharing
Authors: Thompson P. Travis , Moseley Hunter N.B. 
Published: May 2023

AbstractIn recent years, the FAIR guiding principles and the broader concept of open science has grown in importance in academic research, especially as funding entities have aggressively promoted public sharing of research products. Key to public research sharing is deposition of datasets into online data repositories; but it can be a chore to transform messy unstructured data into the forms required by these repositories. To help generate Metabolomics Workbench depositions, we have developed the MESSES software package, implemented in the Python 3 programming language, and supported on Linux, Windows, and Mac operating systems. MESSES helps transform tabular data from multiple sources into a Metabolomics Workbench specific deposition format. The package provides three commands, extract, validate, and convert, that implement a natural data transformation workflow. Moreover, MESSES facilitates richer metadata capture than is typically attempted by manual efforts. The source code and extensive documentation is hosted on GitHub (https://github.com/MoseleyBioinformaticsLab/MESSES) and is also available on the Python Package Index (https://pypi.org/project/messes) for easy installation.
Direct Entorhinal Control of CA1 Temporal Coding
Authors: Guardamagna Matteo , Chadney Oscar , Stella Federico , Zhang Qiangwei , Kentros Clifford , Battaglia Francesco P. 
Published: May 2023

AbstractDuring behavior, hippocampal neurons fire in consistent theta sequences, organized by the theta rhythm, which have been linked to predictive coding of future actions. The mechanisms of sequence generation are yet unclear, but in the hippocampal CA1 subfield, are thought to involve both major input streams into CA1 neurons, from CA3 pyramidal neurons and directly from entorhinal cortex. We disentangled the role of these two afferent input with highly specific optogenetic inhibition limited to the direct entorhinal afferents of CA1, thereby leaving the rest of the hippocampal-entorhinal circuit intact. While CA1 spatial firing properties were largely unaffected, theta phase precession was largely abolished. Surprisingly, while theta phase precession is thought to generate theta sequences, theta sequences were actually strengthened when it was suppressed. These results suggest that sequence generation is internal to the hippocampus, while the entorhinal inputs may act as a supervisory signal driving learning and representational updates.
14-3-3 phosphorylation inhibits 14-3-3θ’s ability to regulate LRRK2 kinase activity
Authors: Pattanayak Rudradip , Petit Chad M. , Yacoubian Talene A. 
Published: May 2023

ABSTRACTLRRK2 mutations are among the most common genetic causes for Parkinson’s disease (PD), and toxicity is associated with increased kinase activity. 14-3-3 proteins are key interactors that regulate LRRK2 kinase activity. Phosphorylation of the 14-3-3θ isoform at S232 is dramatically increased in human PD brains. Here we investigate the impact of 14-3-3θ phosphorylation on its ability to regulate LRRK2 kinase activity. Both wildtype and the non-phosphorylatable S232A 14-3-3θ mutant reduced the kinase activity of wildtype and G2019S LRRK2, whereas the phosphomimetic S232D 14-3-3θ mutant had minimal effects on LRRK2 kinase activity, as determined by measuring autophosphorylation at S1292 and T1503 and Rab10 phosphorylation. However, wildtype and both 14-3-3θ mutants similarly reduced the kinase activity of the R1441G LRRK2 mutant. 14-3-3θ phosphorylation did not promote global dissociation with LRRK2, as determined by co-immunoprecipitation and proximal ligation assays. 14-3-3s interact with LRRK2 at several phosphorylated serine/threonine sites, including T2524 in the C-terminal helix, which can fold back to regulate the kinase domain. Interaction between 14-3-3θ and phosphorylated T2524 LRRK2 was important for 14-3-3θ’s ability to regulate kinase activity, as wildtype and S232A 14-3-3θ failed to reduce the kinase activity of G2019S/T2524A LRRK2. Molecular modeling showed that 14-3-3θ phosphorylation causes a partial rearrangement of its canonical binding pocket, thus affecting the interaction between 14-3-3θ and the C-terminus of LRRK2. We conclude that 14-3-3θ phosphorylation destabilizes the interaction of 14-3-3θ with LRRK2 at T2524, which consequently promotes LRRK2 kinase activity.
Genomic insights into clonal diversity in UK populations of the Potato aphid,Macrosiphum euphorbiae
Authors: Whitehead Mark , Karley Alison , Darby Alistair 
Published: May 2023

AbstractThe potato aphidMacrosiphum euphorbiaeis one of many polyphagous crop pests involved in the transmission of insect-vectored pathogens. While their North American counterparts reproduce via cyclical parthenogenesis, UK populations ofM. euphorbiae appearto persist asexually, resulting in the maintenance of several genotypes, with some demonstrating genotype-specific traits; this includes innate resistance to parasitism from the hymenopterous parasitoid waspAphidius ervi. The genetic and molecular basis for genotype-specific traits is often unknown. Here we present a chromosome scale assembly for a parasitoid-resistant clonal line ofM. euphorbiaeand provide insights into the genotypic composition and distribution of UK potato aphid populations using microsatellite and whole-genome sequencing (WGS) techniques, focusing on geographically separated potato crops within two distinct areas of the UK (Merseyside and Tayside). We show that the genome consists of five chromosomal blocks, has a total size of 560 Mbp and is highly complete based on BUSCO (C: 95.6%). The sampled potato aphid populations were dominated by two genotypes, one of which is absent from commercial farm settings, suggesting either an intolerance to farming practices, such as insecticide use, or a broader host range. We suggest some putative gene functions using WGS data to explain the observed frequency of aphid genotypes. WGS data highlighted the asexual clonal lifestyle ofM. euphorbiae genotypesin the UK, resolving individuals to a higher resolution than using microsatellite data. The work presented here will provide useful information for integrated pest management of potato aphids, elaborating on the relationship between genotype diversity and functional traits such as parasitism and insecticide resistance, and host plant use, as well as providing more resources for further comparative genomics studies within the Aphididae.
Toxoplasma gondiiencodes an array of TBC-domain containing proteins including an essential regulator that targets Rab2 in the secretory pathway
Authors: Quan Justin J. , Nikolov Lachezar A. , Sha Jihui , Wohlschlegel James A. , Bradley Peter J. 
Published: May 2023

AbstractToxoplasma gondiiresides in its intracellular niche by employing a series of specialized secretory organelles that play roles in invasion, host-cell manipulation and parasite replication. Rab GTPases are major regulators of the parasite’s secretory traffic that function as nucleotide dependent molecular switches to control vesicle trafficking. While many of the Rab proteins have been characterized inT. gondii, precisely how these Rabs are regulated remains poorly understood. To better understand the parasite’s secretory traffic, we investigated the entire family of Tre2–Bub2–Cdc16 (TBC)-domain containing proteins, which are known to be involved in vesicle fusion and secretory protein trafficking. We first determined the localization of all 18 TBC-domain containing proteins to discrete regions of the secretory pathway or other vesicles in the parasite. We then use an auxin-inducible degron approach to demonstrate that the protozoan-specific TgTBC9 protein that localizes to the ER is essential for parasite survival. Knockdown of TgTBC9 results in parasite growth arrest and affects the organization of the ER and Golgi apparatus. We show that the conserved dual-finger active site in the TBC-domain of the protein is critical for its GTPase-activating protein (GAP) function and that theP. falciparumorthologue of TgTBC9 can rescue the lethal knockdown. We additionally show by immunoprecipitation and yeast two hybrid analyses that TgTBC9 directly binds Rab2, indicating that this TBC-Rab pair controls ER to Golgi traffic in the parasite. Together, these studies identify the first essential TBC protein described in any protozoan, provide new insight into intracellular vesicle trafficking inT. gondii, and reveal promising targets for the design of novel therapeutics that can specifically target apicomplexan parasites.
Inbreeding depression, heterosis, and outbreeding depression in the cleistogamous perennialRuellia humilis
Authors: Soto Tatyana Y. , Rojas-Gutierrez Juan Diego , Oakley Christopher G. 
Published: May 2023

ABSTRACTWhat maintains mixed mating is an evolutionary enigma. Cleistogamy, the production of both potentially outcrossing chasmogamous, and obligately selfing cleistogamous flowers on the same individual plant, is an excellent system to study the costs of selfing. Inbreeding depression can prevent the evolution of greater selfing within populations, and heterosis in crosses between populations may further tip the balance in favor of outcrossing. Few empirical estimates of inbreeding depression and heterosis in the same system exist for cleistogamous species. We investigate the potential costs of selfing by quantifying inbreeding depression and heterosis in three populations of the cleistogamous perennialRuellia humilisNutt (Acanthaceae). We performed hand-pollinations to self, and outcross within and between populations, and measured seed number, germination, total flower production, and estimated cumulative fitness for the resulting progeny in a greenhouse experiment.We found moderate inbreeding depression for cumulative fitness (<30%) in two populations, but outbreeding depression for crosses within a third population (−26%). For between population crosses, there was weak to modest heterosis (11-47%) in two of the population combinations, but modest to strong outbreeding (−21 to −71%) depression in the other four combinations. Neither inbreeding depression nor heterosis was of sufficient magnitude to explain the continued production of CH flowers given the relative energetic advantage of CL flowers previously estimated for these populations. Outbreeding depression either within or between populations makes the maintenance of chasmogamous flowers even harder to explain. More information is needed on the genetic basis of cleistogamy in order to resolve this conundrum.
An assessment of the fixin tplo jig to generate effective compression using a transverse fracture model
Authors: Ferringo Cassio Ricardo Auada , Diggs George , Lewis Daniel D , Banks Scott A 
Published: May 2023

AbstractThe objective of this study was to determine compressive loads that could be generated using a tibial plateau leveling osteotomy (TPLO) jig with a tensioned strand of 18-gauge stainless steel orthopedic wire in a simulated transverse fracture model. The wire was sequentially tensioned using heavy needle holders or an AO wire tightener. Recorded loads were subsequently compared to loads generated by applying a 3.5 mm limited contact-dynamic compression plate (LC-DCP) as a compression plate.Two segments of 2 cm diameter Delrin rod were placed in a testing apparatus and used to simulate a transverse fracture. A load cell was interposed between the two segments to measure the compressive loads generated during the application of the TPLO jig or the LC-DCP. Compression was generated by sequential tensioning a strand of 18-gauge wire secured through the base of the arms of the TPLO jig or by placing one or two load screws in the LC-DCP. Wires were tensioned using heavy needle holders or an AO wire tightener. Eight replicates of each construct were tested. Recorded loads were compared using a one-way repeated measures ANOVA and Tukey Honestly Significant Difference test.The wire being tensioned broke while attempting a second quarter rotation of the needle holders and when the crank handle of the AO wire tightener was advanced beyond two rotations. The mean + SD peak compressive loads recorded when tensioning the wire using the heavy needle holders and AO wire tightener was 148 ± 7 N and 217 ± 16 N, respectfully. The mean ± SD load recorded after placement of the first and second load screw in the LC-DCP was 131 ± 39 N and 296 ± 49 N, respectively. The compression generated by placing two load screws in the LC-DCP was superior to the compression generated using the jig. The maximum load recorded by tensioning the wire secured through the TPLO jig using the AO wire tightener was superior to the compression generated by placing a single load screw and tensioning the wire using needle holders.Our results demonstrate that the TPLO jig allows surgeons to compress transverse fractures or osteotomies effectively. Tensioning the AO wire tightener allows for sequential tensioning and generates superior compressive loads than tensioning wires with heavy needle holders.
Detection of interactions between genetic marker sets and environment in a genome-wide study of hypertension
Authors: Shen Linchuan , Amei Amei , Liu Bowen , Liu Yunqing , Xu Gang , Oh Edwin C. , Wang Zuoheng 
Published: May 2023

SummaryAs human complex diseases are influenced by the interplay of genes and environment, detecting gene-environment interactions (G×E) can shed light on biological mechanisms of diseases and play an important role in disease risk prediction. Development of powerful quantitative tools to incorporateG×Ein complex diseases has potential to facilitate the accurate curation and analysis of large genetic epidemiological studies. However, most of existing methods that interrogateG×Efocus on the interaction effects of an environmental factor and genetic variants, exclusively for common or rare variants. In this study, we proposed two tests, MAGEIT_RAN and MAGEIT_FIX, to detect interaction effects of an environmental factor and a set of genetic markers containing both rare and common variants, based on the MinQue for Summary statistics. The genetic main effects in MAGEIT_RAN and MAGEIT_FIX are modeled as random or fixed, respectively. Through simulation studies, we illustrated that both tests had type I error under control and MAGEIT_RAN was overall the most powerful test. We applied MAGEIT to a genome-wide analysis of gene-alcohol interactions on hypertension in the Multi-Ethnic Study of Atherosclerosis. We detected two genes,CCNDBP1andEPB42, that interact with alcohol usage to influence blood pressure. Pathway analysis identified sixteen significant pathways related to signal transduction and development that were associated with hypertension, and several of them were reported to have an interactive effect with alcohol intake. Our results demonstrated that MAGEIT can detect biologically relevant genes that interact with environmental factors to influence complex traits.
Modulation of dorsal premotor cortex disrupts neuroplasticity of primary motor cortex in young and older adults
Authors: Liao Wei-Yeh , Opie George M. , Ziemann Ulf , Semmler John G. 
Published: May 2023

AbstractAlthough transcranial magnetic stimulation (TMS) research demonstrates that dorsal premotor cortex (PMd) influences neuroplasticity within primary motor cortex (M1), it is unclear how ageing modifies this communication. The present study investigated the influence of PMd on different indirect (I) wave inputs within M1 that mediate cortical plasticity in young and older adults. 15 young and 15 older participants completed two experimental sessions that examined the effects of intermittent theta burst stimulation (iTBS) to M1 when preceded by iTBS (PMd iTBS-M1 iTBS) or sham stimulation (PMd sham-M1 iTBS) to PMd. Changes in corticospinal excitability post-intervention were assessed with motor evoked potentials (MEP) recorded from right first dorsal interosseous using posterior-anterior (PA) and anterior-posterior (AP) current single-pulse TMS (PA1mV; AP1mV; PA0.5mV, early I-wave; AP0.5mV, late I-wave). Although PA1mVdid not change post-intervention (P= 0.628), PMd iTBS-M1 iTBS disrupted the expected facilitation of AP1mV(to M1 iTBS) in young and older adults (P= 0.002). Similarly, PMd iTBS-M1 iTBS disrupted PA0.5mVfacilitation in young and older adults (P= 0.030), whereas AP0.5mVfacilitation was not affected in either group (P= 0.218). This suggests that while PMd specifically influences the plasticity of early I-wave circuits, this communication is preserved in older adults.
Identification of proteins that bind extracellular microRNAs secreted by the parasitic nematodeTrichinella spiralis
Authors: Brown A. , Selkirk M.E. , Sarkies P. 
Published: May 2023

AbstractSmall non-coding RNAs such as microRNAs (miRNAs) are conserved across eukaryotes and play key roles in regulating gene expression. In many organisms, miRNAs are also secreted from cells, often encased within vesicles such as exosomes and sometimes extravesicular. The mechanisms of miRNA secretion, how they are stabilised outside of cells and their functional importance are poorly understood. Recently we characterised the parasitic nematodeTrichinella spiralisas a model to study miRNA secretion.T. spiralislarvae secrete abundant miRNAs which are largely extravesicular. Here, we investigated howT. spiralismiRNAs might remain stable outside of cells. Using proteomics, we identified two RNA binding proteins secreted byT. spiralislarvae and characterised their RNA binding properties. One, a homologue of the known RNA binding protein KSRP, binds miRNA in a selective and sequence-specific fashion. Another protein, which is likely a novel RNA binding protein, binds non-selectively to miRNA. Our results suggest a possible mechanism for miRNA secretion byT. spiralisand may have relevance for understanding the biology of extracellular miRNA more widely.
Allosteric site variants affect GTP hydrolysis on RAS
Authors: Johnson Christian W. , Fetics Susan K. , Davis Kathleen P. , Rodrigues Jose A. , Mattos Carla 
Published: May 2023

AbstractRAS GTPases are proto-oncoproteins that regulate cell growth, proliferation, and differentiation in response to extracellular signals. The signaling functions of RAS, and other small GTPases, are dependent on their ability to cycle between GDP-bound and GTP-bound states. Structural analyses suggest that GTP hydrolysis catalyzed by HRAS can be regulated by an allosteric site located between helices 3, 4 and loop 7. Here we explore the relationship between intrinsic GTP hydrolysis on HRAS and the position of helix 3 and loop 7 through manipulation of the allosteric site, showing that the two sites are functionally connected. We generated several hydrophobic mutations in the allosteric site of HRAS to promote shifts in helix 3 relative to helix 4. By combining crystallography and enzymology to study these mutants, we show that closure of the allosteric site correlates with increased hydrolysis of GTP on HRAS in solution. Interestingly, binding to the RAS binding domain of RAF kinase (RAF-RBD) inhibits GTP hydrolysis in the mutants. This behavior may be representative of a cluster of poorly understood mutations that occur in human tumors, which potentially cooperate with RAF complex formation to stabilize the GTP-bound state of RAS.