bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenylates regulate Arabidopsis plastidial thioredoxin activities through the binding of a CBS domain protein
Authors: Baudry Kevin , Barbut Félix , Domenichini Séverine , Guillaumot Damien , Thy Mai Pham , Vanacker Hélène , Majeran Wojciech , Krieger-Liszkay Anja , Issakidis-Bourguet Emmanuelle , Lurin Claire 
Published: June 2022

Abstract
Cystathionine-β-synthase (CBS) domains are found in proteins of all living organisms and have been proposed to play a role as energy sensors regulating protein activities through their adenosyl ligand binding capacity. In plants, members of the CBSX protein family carry a stand-alone pair of CBS domains. In Arabidopsis (Arabidopsis thaliana), CBSX1 and CBSX2 are targeted to plastids where they have been proposed to regulate thioredoxins (TRXs). TRXs are ubiquitous cysteine thiol oxido-reductases involved in the redox-based regulation of numerous enzymatic activities as well as in the regeneration of thiol-dependent peroxidases. In Arabidopsis, 10 TRX isoforms have been identified in plastids and divided into five sub-types. Here, we show that CBSX2 specifically inhibits the activities of m-type TRXs toward two chloroplast TRX-related targets. By testing activation of NADP-malate dehydrogenase and reduction of 2-Cys peroxiredoxin, we found that TRXm1/2 inhibition by CBSX2 was alleviated in the presence of AMP or ATP. We also determined, by pull-down assays, a direct interaction of CBSX2 with reduced TRXm1 and m2 that was abolished in the presence of adenosyl ligands. In addition, we report that, compared with wild-type plants, the Arabidopsis T-DNA double mutant cbsx1 cbsx2 exhibits growth and chlorophyll accumulation defects in cold conditions, suggesting a function of plastidial CBSX proteins in plant stress adaptation. Together, our results show an energy-sensing regulation of plastid TRX m activities by CBSX, possibly allowing a feedback regulation of ATP homeostasis via activation of cyclic electron flow in the chloroplast, to maintain a high energy level for optimal growth.
The interaction mechanism of nickel ions with L929 cells based on integrative analysis of proteomics and metabolomics data
Authors: Zhang Yajing , Huang Yan , Chen Rong , Chen Shulin , Lü Xiaoying 
Published: June 2022

Abstract
The aim of this article was to study the toxicity mechanism of nickel ions (Ni2+) on L929 cells by combining proteomics and metabolomics. First, iTRAQ-based proteomics and LC/MS metabolomics analyses were used to determine the protein and metabolite expression profiles in L929 cells after treatment with 100 μM Ni2+ for 12, 24 and 48 h. A total of 177, 2191 and 2109 proteins and 40, 60 and 74 metabolites were found to be differentially expressed. Then, the metabolic pathways in which both differentially expressed proteins and metabolites were involved were identified, and three pathways with proteins and metabolites showing upstream and downstream relationships were affected at all three time points. Furthermore, the protein–metabolite–metabolic pathway network was constructed, and two important metabolic pathways involving 4 metabolites and 17 proteins were identified. Finally, the functions of the important screened metabolic pathways, metabolites and proteins were investigated and experimentally verified. Ni2+ mainly affected the expression of upstream proteins in the glutathione metabolic pathway and the arginine and proline metabolic pathway, which further regulated the synthesis of downstream metabolites, reduced the antioxidant capacity of cells, increased the level of superoxide anions and the ratio of GSSG to GSH, led to oxidative stress, affected energy metabolism and induced apoptosis.
Selenium nanoparticles derived from Proteus mirabilis YC801 alleviate oxidative stress and inflammatory response to promote nerve repair in rats with spinal cord injury
Authors: Liu Xiangyu , Mao Yingji , Huang Shengwei , Li Weifeng , Zhang Wei , An Jingzhou , Jin Yongchao , Guan Jianzhong , Wu Lifang , Zhou Pinghui 
Published: June 2022

Abstract
Microbial biotransformation and detoxification of biotoxic selenite into selenium nanoparticles (SeNPs) has emerged as an efficient technique for the utilization of selenium. SeNPs are characterized by high bioavailability and have several therapeutic effects owing to their antioxidant, anti-inflammatory and neuroprotective activities. However, their influence on microenvironment disturbances and neuroprotection after spinal cord injury (SCI) is yet to be elucidated. This study aimed to assess the influence of SeNPs on SCI and explore the underlying protective mechanisms. Overall, the proliferation and differentiation of neural stem cells were facilitated by SeNPs derived from Proteus mirabilis YC801 via the Wnt/β-catenin signaling pathway. The SeNPs increased the number of neurons to a greater extent than astrocytes after differentiation and improved nerve regeneration. A therapeutic dose of SeNPs remarkably protected the integrity of the spinal cord to improve the motor function of the hind limbs after SCI and decreased the expression of several inflammatory factors such as tumor necrosis factor-α and interleukin-6 in vivo and enhanced the production of M2-type macrophages by regulating their polarization, indicating the suppressed inflammatory response. Besides, SeNPs reversed the SCI-mediated production of reactive oxygen species. In conclusion, SeNPs treatment holds the potential to improve the disturbed microenvironment and promote nerve regeneration, representing a promising therapeutic approach for SCI.
Adrenal Stress Hormone Regulation of Hepatic Homeostatic Function After an Acute Ozone Exposure in Wistar-Kyoto Male Rats
Authors: Jackson Thomas W , Henriquez Andres R , Snow Samantha J , Schladweiler Mette C , Fisher Anna A , Alewel Devin I , House John S , Kodavanti Urmila P 
Published: June 2022

AbstractOzone-induced lung injury, inflammation, and pulmonary/hypothalamus gene expression changes are diminished in adrenalectomized (AD) rats. Acute ozone exposure induces metabolic alterations concomitant with increases in epinephrine and corticosterone. We hypothesized that adrenal hormones are responsible for observed hepatic ozone effects, and in AD rats, these changes would be diminished. In total, 5–7 days after sham (SH) or AD surgeries, male Wistar-Kyoto rats were exposed to air or 0.8-ppm ozone for 4 h. Serum samples were analyzed for metabolites and liver for transcriptional changes immediately post-exposure. Ozone increased circulating triglycerides, cholesterol, free fatty-acids, and leptin in SH but not AD rats. Ozone-induced inhibition of glucose-mediated insulin release was absent in AD rats. Unlike diminution of ozone-induced hypothalamus and lung mRNA expression changes, AD in air-exposed rats (AD-air/SH-air) caused differential hepatic expression of ∼1000 genes. Likewise, ozone in AD rats caused differential expression of ∼1000 genes (AD-ozone/AD-air). Ozone-induced hepatic changes in SH rats reflected enrichment for pathways involving metabolic processes, including acetyl-CoA biosynthesis, TCA cycle, and sirtuins. Upstream predictor analysis identified similarity to responses produced by glucocorticoids and pathways involving forskolin. These changes were absent in AD rats exposed to ozone. However, ozone caused unique changes in AD liver mRNA reflecting activation of synaptogenesis, neurovascular coupling, neuroinflammation, and insulin signaling with inhibition of senescence pathways. In these rats, upstream predictor analysis identified numerous microRNAs likely involved in glucocorticoid insufficiency. These data demonstrate the critical role of adrenal stress hormones in ozone-induced hepatic homeostasis and necessitate further research elucidating their role in propagating environmentally driven diseases.
Importance of Incidental Findings in Preoperative Computed Tomography Angiography for Abdominally Based Free Flap Breast Reconstruction: A Multi-Institutional Study
Authors: Colakoglu Salih , Yang Jerry , French Mackenzie M. , Winocour Julian , Um Grace T. , Blumenauer Brian , Siddikoglu Duygu , Mureau Marc A. M. , Chong Tae , Higdon Kent , Perdikis Galen , Inchauste Suzanne M. , Kaoutzanis Christodoulos , Mathes David W. 
Published: June 2022

Background:
In addition to its intended purpose of perforator mapping, computed tomography angiography can also identify incidental findings that may require further evaluation. In this multi-institutional study, the authors evaluated the frequency of incidental findings and their significance and effects on treatment course and aimed to identify risk factors for detecting such findings.

Methods:
A retrospective review of patients who underwent perforator mapping with computed tomography angiography was performed over a 5-year period from three academic institutions. Relevant sociodemographic and clinicopathologic information, computed tomography angiography reports, follow-up visits, and treatment outcomes were reviewed. Univariate and multivariate analyses were performed to assess the relationship between risk factors and incidental findings.

Results:
From January of 2015 to July of 2020, a total of 656 patients were identified who met inclusion criteria. Overall, 342 incidental findings were found, 76 of which required additional imaging or consultation. Ultimately, 10 patients (1.5 percent) had findings that altered reconstructive management, including five patients (0.8 percent) having severe disease that resulted in the cancellation of their reconstruction. Advanced age and immediate reconstruction timing were independent risk factors for incidental findings.

Conclusions:
Incidental findings are commonly identified on preoperative computed tomography angiography for deep inferior epigastric perforator flap breast reconstruction. Suspicious findings should be investigated thoroughly because they can alter the reconstructive course. Understanding of high-risk groups for incidental findings can further advance patient education during initial consultation.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Risk, III.
Next-Generation Cancer Magnetic Resonance Imaging With Tumor-Targeted Alkylphosphocholine Metal Analogs
Authors: Zhang Ray R. , Choi Cynthia , Brunnquell Christina L. , Hernandez Reinier , Pinchuk Anatoly N. , Grudzinski Joseph G. , Clark Paul A. , McMillan Alan B. , Audhya Anjon , Jeffrey Justin , Kuo John S. , Weichert Jamey P. 
Published: June 2022

Objectives
In an effort to exploit the elevated need for phospholipids displayed by cancer cells relative to normal cells, we have developed tumor-targeted alkylphosphocholines (APCs) as broad-spectrum cancer imaging and therapy agents. Radioactive APC analogs have exhibited selective uptake and prolonged tumor retention in over 50 cancer types in preclinical models, as well as over 15 cancer types in over a dozen clinical trials. To push the structural limits of this platform, we recently added a chelating moiety capable of binding gadolinium and many other metals for cancer-targeted magnetic resonance imaging (MRI), positron emission tomography imaging, and targeted radionuclide therapy. The aim of this work was to synthesize, characterize, and validate the tumor selectivity of a new broad-spectrum, tumor-targeted, macrocyclic MRI chelate, Gd-NM600, in xenograft and orthotopic tumor models. A secondary aim was to identify and track the in vivo chemical speciation and spatial localization of this new chelate Gd-NM600 in order to assess its Gd deposition properties.

Materials and Methods
T1 relaxivities of Gd-NM600 were characterized in water and plasma at 1.5 T and 3.0 T. Tumor uptake and subcellular localization studies were performed using transmission electron microscopy. We imaged 8 different preclinical models of human cancer over time and compared the T1-weighted imaging results to that of a commercial macrocyclic Gd chelate, Gd-DOTA. Finally, matrix-assisted laser desorption and ionization–mass spectrometry imaging was used to characterize and map the tissue distribution of the chemical species of Gd-NM600.

Results
Gd-NM600 exhibits high T1 relaxivity (approximately 16.4 s−1/mM at 1.5 T), excellent tumor uptake (3.95 %ID/g at 48 hours), prolonged tumor retention (7 days), and MRI conspicuity. Moreover, minimal tumor uptake saturability of Gd-NM600 was observed. Broad-spectrum tumor-specific uptake was demonstrated in 8 different human cancer models. Cancer cell uptake of Gd-NM600 via endosomal internalization and processing was revealed with transmission electron microscopy. Importantly, tissue mass spectrometry imaging successfully interrogated the spatial localization and chemical speciation of Gd compounds and also identified breakdown products of Gd species.

Conclusions
We have introduced a new macrocyclic cancer-targeted Gd chelate that achieves broad-spectrum tumor uptake and prolonged retention. Furthermore, we have demonstrated in vivo stability of Gd-NM600 by ultrahigh resolution MS tissue imaging. A tumor-targeted contrast agent coupled with the enhanced imaging resolution of MRI relative to positron emission tomography may transform oncologic imaging.
Transsynaptic Ganglion Cell Degeneration in Adult Patients After Occipital Lobe Stroke
Authors: Donaldson Laura , Chen Michael , Margolin Edward 
Published: June 2022

Background:
Loss of retinal ganglion cells after occipital lobe damage is known to occur through transsynaptic retrograde degeneration in congenital lesions; however, studies of this phenomenon in acquired pathology, such as strokes affecting postgenicular visual pathway, are scant. We studied a cohort of adult patients with known onset of occipital lobe stroke to look for the presence, rate, and timing of macular ganglion cell loss on optical coherence tomography.

Methods:
Retrospective review of patients seen in tertiary neuro-ophthalmology practice with homonymous hemianopia secondary to occipital lobe stroke of known onset. Optical coherence tomography of the macular ganglion cell complex (GCC) was performed, and hemifields corresponding to the side of the visual field (VF) defect were compared with the control retinal hemifield.

Results:
Fifteen patients with homonymous VF defects were included in the study, and 8 of these (53.3%) demonstrated GCC hemifield thickness of less than 90% on the side corresponding to VF loss including 2/9 (22%) patients who had a stroke less than 2.5 years ago and 6/6 (100%) patients who had a stroke longer than 2.5 years ago. The amount of hemifield atrophy correlated to the logarithm of time since stroke onset (P =0.030) but not age (P = 0.95) or mean deviation on VF (P = 0.19). Three patients with longitudinal data showed GCC thinning rates of 1.99, 5.13, and 5.68 µm per year.

Conclusion:
Transsynaptic retrograde degeneration occurs after occipital lobe stroke as early as 5.5 months after injury and was observed in all patients 2.5 years after stroke.
Cochlear implant material effects on inflammatory cell function and foreign body response
Authors: Jensen Megan J. , Claussen Alexander D. , Higgins Timon , Vielman-Quevedo Rene , Mostaert Brian , Xu Linjing , Kirk Jonathon , Hansen Marlan R. 
Published: June 2022

AbstractObjectivesThe objectives of this study were to assess the effects of cochlear implant (CI) biomaterials on the function of macrophages and fibroblasts, two key mediators of the foreign body response (FBR) and to determine how these materials influence fibrous tissue growth and new bone formation within the cochlea.MethodsMacrophages and fibroblasts were cultured on polydimethylsiloxane (PDMS) and platinum substrates and human CI electrodesin vitro. Cell count, cell proliferation, cytokine production, and cell adhesion were measured. CI electrodes were implanted into murine cochleae for one week without electrical stimulation. Implanted cochleae were harvested for 3D X-ray microscopy with the CI leftin-situ. The location of new bone growth within the scala tympani (ST) with reference to different portions of the implant (PDMS vs platinum) was quantified.ResultsCell counts of macrophages and fibroblasts were significantly higher on platinum substrates and platinum contacts of CI electrodes. Fibroblast proliferation was greater on platinum relative to PDMS, and cells grown on platinum formed more/larger focal adhesions. 3D x-ray microscopy showed neo-ossification in the peri-implant areas of the ST. Volumetric quantification of neo-ossification showed a trend toward greater bone formation adjacent to the platinum electrodes compared to areas opposite or away from the platinum electrode bearing surfaces.ConclusionsFibrotic reactions are biomaterial specific, as demonstrated by the differences in cell adhesion, proliferation, and fibrosis on platinum and PDMS. The inflammatory reaction to platinum contacts on CI electrodes likely contributes to fibrosis to a greater degree than PDMS, and platinum contacts may influence the deposition of new bone, as demonstrated in thein vivodata. This information can potentially be used to influence the design of future generations of neural prostheses.
scHumanNet: a single-cell network analysis platform for the study of cell-type specificity of disease genes
Authors: Cha Junha , Yu Jiwon , Cho Jae-Won , Hemberg Martin , Lee Insuk 
Published: June 2022

AbstractA major challenge in single-cell biology is identifying cell-type-specific gene functions, which may substantially improve precision medicine. Differential expression analysis of genes is a popular, yet insufficient approach, and complementary methods that associate function with cell type are required. Here, we describe scHumanNet (https://github.com/netbiolab/scHumanNet), a single-cell network analysis platform for resolving cellular heterogeneity across gene functions in humans. Based on cell-type-specific networks (CSNs) constructed under the guidance of the HumanNet reference interactome, scHumanNet displayed higher functional relevance to the cellular context than CSNs built by other methods on single-cell transcriptome data. Cellular deconvolution of gene signatures based on network compactness across cell types revealed breast cancer prognostic markers associated with T cells. scHumanNet could also prioritize genes associated with particular cell types using CSN centrality and identified the differential hubness of CSNs between disease and healthy conditions. We demonstrated the usefulness of scHumanNet by uncovering T-cell-specific functional effects ofGITR, a prognostic gene for breast cancer, and functional defects in autism spectrum disorder genes specific for inhibitory neurons. These results suggest that scHumanNet will advance our understanding of cell-type specificity across human disease genes.
Dopaminergic axons track somatic signaling in behaving mice
Authors: Azcorra Maite , Gaertner Zachary , Davidson Connor , Ramakrishnan Charu , Fenno Lief , Kim Yoon Seok , Deisseroth Karl , Awatramani Rajeshwar , Dombeck Daniel A. 
Published: June 2022

AbstractStriatal dopamine released from the axons of midbrain dopamine neurons has been linked to a wide range of functions, including movement control and reward-based learning. Recent studies have reported functional signaling differences between axons and somas of dopamine neurons, suggesting that local modulation controls dopamine release and calling into question the classical view of somatic control. However, these experiments are technically challenging, making it difficult to ensure that axonal and somatic recordings come from the same neurons, particularly given the heterogeneity of dopaminergic cell types. Here we used genetic strategies to isolate key dopaminergic neuron subtypes and monitor their axonal and somatic signaling patterns in behaving mice. Contrary to the inferences drawn from previous studies, these experiments revealed a robust correlation between somatic and axonal signaling. Thus, by exploiting a previously unknown connection between genetic and functional diversity in dopamine neurons, we establish that subtypes must be considered to understand the mechanisms of dopamine release in striatum during behavior.
Bioactivation and detoxification of organophosphorus pesticides in freshwater planarians shares similarities with humans
Authors: Ireland Danielle , Rabeler Christina , Gong TaiXi , Collins Eva-Maria S. 
Published: June 2022

AbstractOrganophosphorus pesticides (OPs) are a chemically diverse class of insecticides that inhibit acetylcholinesterase (AChE). Many OPs require bioactivation to their active oxon form via cytochrome P450 to effectively inhibit AChE. OP toxicity can be mitigated by detoxification reactions performed by carboxylesterase and paraoxonase. The relative extent of bioactivation to detoxification varies among individuals and between species, leading to differential susceptibility to OP toxicity. Because of these species differences, it is imperative to characterize OP metabolism in model systems used to assess OP toxicity to adequately evaluate potential human hazard. We have shown that the asexual freshwater planarian Dugesia japonica is a suitable model to assess OP neurotoxicity and developmental neurotoxicity via rapid, automated testing of adult and developing organisms in parallel using morphological and behavioral endpoints. D. japonica has two cholinesterase enzymes with intermediate properties between AChE and butyrylcholinesterase that are sensitive to OP inhibition. Here, we demonstrate that this planarian contains the major OP metabolic machinery to be a relevant model for OP neurotoxicity studies. Adult and regenerating D. japonica can bioactivate chlorpyrifos and diazinon into their respective oxons. Significant AChE inhibition was only observed after in vivo metabolic activation but not when the parent OPs were directly added to planarian homogenate. Additionally, we found that D. japonica has both carboxylesterase and paraoxonase activity. Using specific chemical inhibitors, we show that carboxylesterase activity is distinct from cholinesterase activity. Taken together, these results further support the use of D. japonica for OP toxicity studies.
POSTRE: a tool to predict the pathological effects of human structural variants
Authors: Sánchez-Gaya Víctor , Rada-Iglesias Álvaro 
Published: June 2022

AbstractUnderstanding the pathological impact of non-coding genetic variation is a major challenge in medical genetics. Accumulating evidences indicate that a significant fraction of genetic alterations, including structural variants (SVs), can cause human disease by altering the function of non-coding regulatory elements, such as enhancers. In the case of SVs, described pathomechanisms include changes in enhancer dosage and long-range enhancer-gene communication. However, there is still a clear gap between the need to predict and interpret the medical impact of non-coding variants, and the existence of tools to properly perform these tasks. To reduce this gap, we have developed POSTRE (Prediction Of STRuctural variant Effects), a computational tool to predict the pathogenicity of SVs implicated in a broad range of human congenital disorders. By considering disease-relevant cellular contexts, POSTRE identifies SVs with either coding or long-range pathological consequences with high specificity and sensitivity. Furthermore, POSTRE not only identifies pathogenic SVs, but also predicts the disease-causative genes and the underlying pathological mechanism (e.g, gene deletion, enhancer disconnection, enhancer adoption, etc.). POSTRE is available at https://github.com/vicsanga/Postre.