bluuebunny/crossref_metadata_2025 huggingface dataset:
Mining Fiskeby III and Mandarin (Ottawa) Expression Profiles to Understand Iron Stress Tolerant Responses in Soybean
Authors: O’Rourke Jamie A. , Morrisey Michael J. , Merry Ryan , Espina Mary Jane , Lorenz Aaron J. , Stupar Robert M. , Graham Michelle A.
Published: October 2021

The soybean (Glycine max L. merr) genotype Fiskeby III is highly resistant to a multitude of abiotic stresses, including iron deficiency, incurring only mild yield loss during stress conditions. Conversely, Mandarin (Ottawa) is highly susceptible to disease and suffers severe phenotypic damage and yield loss when exposed to abiotic stresses such as iron deficiency, a major challenge to soybean production in the northern Midwestern United States. Using RNA-seq, we characterize the transcriptional response to iron deficiency in both Fiskeby III and Mandarin (Ottawa) to better understand abiotic stress tolerance. Previous work by our group identified a quantitative trait locus (QTL) on chromosome 5 associated with Fiskeby III iron efficiency, indicating Fiskeby III utilizes iron deficiency stress mechanisms not previously characterized in soybean. We targeted 10 of the potential candidate genes in the Williams 82 genome sequence associated with the QTL using virus-induced gene silencing. Coupling virus-induced gene silencing with RNA-seq, we identified a single high priority candidate gene with a significant impact on iron deficiency response pathways. Characterization of the Fiskeby III responses to iron stress and the genes underlying the chromosome 5 QTL provides novel targets for improved abiotic stress tolerance in soybean.
Astaxanthin Prevents Diet-Induced NASH Progression by Shaping Intrahepatic Immunity
Authors: Yang Ming , Kimchi Eric T. , Staveley-O’Carroll Kevin F. , Li Guangfu
Published: October 2021

Dietary change leads to a precipitous increase in non-alcoholic fatty liver disease (NAFLD) from simple steatosis to the advanced form of non-alcoholic steatohepatitis (NASH), affecting approximately 25% of the global population. Although significant efforts greatly advance progress in clarifying the pathogenesis of NAFLD and identifying therapeutic targets, no therapeutic agent has been approved. Astaxanthin (ASTN), a natural antioxidant product, exerts an anti-inflammation and anti-fibrotic effect in mice induced with carbon tetrachloride (CCl4) and bile duct ligation (BDL); thus, we proposed to further investigate the potential effect of ASTN on a diet-induced mouse NASH and liver fibrosis, as well as the underlying cellular and molecular mechanisms. By treating pre-development of NASH in mice induced with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), we have demonstrated that oral administration ASTN preventively ameliorated NASH development and liver fibrosis by modulating the hepatic immune response, liver inflammation, and oxidative stress. Specifically, ASTN treatment led to the reduction in liver infiltration of monocyte-derived macrophages, hepatic stellate cell (HSC) activation, oxidative stress response, and hepatocyte death, accompanied by the decreased hepatic gene expression of proinflammatory cytokines such as TNF-α, TGF-β1, and IL-1β. In vitro studies also demonstrated that ASTN significantly inhibited the expression of proinflammatory cytokines and chemokine CCL2 in macrophages in response to lipopolysaccharide (LPS) stimulation. Overall, in vivo and in vitro studies suggest that ASTN functions as a promising therapeutic agent to suppress NASH and liver fibrosis via modulating intrahepatic immunity.
Cyclophilin D Regulates the Nuclear Translocation of AIF, Cardiac Endothelial Cell Necroptosis and Murine Cardiac Transplant Injury
Authors: Qamar Adnan , Zhao Jianqi , Xu Laura , McLeod Patrick , Huang Xuyan , Jiang Jifu , Liu Weihua , Haig Aaron , Zhang Zhu-Xu
Published: October 2021

Ischemia-reperfusion injury (IRI) is an inevitable consequence of organ transplant procedure and associated with acute and chronic organ rejection in transplantation. IRI leads to various forms of programmed cell death, which worsens tissue damage and accelerates transplant rejection. We recently demonstrated that necroptosis participates in murine cardiac microvascular endothelial cell (MVEC) death and murine cardiac transplant rejection. However, MVEC death under a more complex IRI model has not been studied. In this study, we found that simulating IRI conditions in vitro by hypoxia, reoxygenation and treatment with inflammatory cytokines induced necroptosis in MVECs. Interestingly, the apoptosis-inducing factor (AIF) translocated to the nucleus during MVEC necroptosis, which is regulated by the mitochondrial permeability molecule cyclophilin D (CypD). Furthermore, CypD deficiency in donor cardiac grafts inhibited AIF translocation and mitigated graft IRI and rejection (n = 7; p = 0.002). Our studies indicate that CypD and AIF play significant roles in MVEC necroptosis and cardiac transplant rejection following IRI. Targeting CypD and its downstream AIF may be a plausible approach to inhibit IRI-caused cardiac damage and improve transplant survival.
Key to Life: Physiological Role and Clinical Implications of Progesterone
Authors: Nagy Bernadett , Szekeres-Barthó Júlia , Kovács Gábor L. , Sulyok Endre , Farkas Bálint , Várnagy Ákos , Vértes Viola , Kovács Kálmán , Bódis József
Published: October 2021

The most recent studies of progesterone research provide remarkable insights into the physiological role and clinical importance of this hormone. Although the name progesterone itself means “promoting gestation”, this steroid hormone is far more than a gestational agent. Progesterone is recognized as a key physiological component of not only the menstrual cycle and pregnancy but also as an essential steroidogenic precursor of other gonadal and non-gonadal hormones such as aldosterone, cortisol, estradiol, and testosterone. Based on current findings, progesterone and novel progesterone-based drugs have many important functions, including contraception, treatment of dysfunctional uterine bleeding, immune response, and prevention of cancer. Considering the above, reproduction and life are not possible without progesterone; thus, a better understanding of this essential molecule could enable safe and effective use of this hormone in many clinical conditions.
Disrupted Calcium Homeostasis in Duchenne Muscular Dystrophy: A Common Mechanism behind Diverse Consequences
Authors: Zabłocka Barbara , Górecki Dariusz C. , Zabłocki Krzysztof
Published: October 2021

Duchenne muscular dystrophy (DMD) leads to disability and death in young men. This disease is caused by mutations in the DMD gene encoding diverse isoforms of dystrophin. Loss of full-length dystrophins is both necessary and sufficient for causing degeneration and wasting of striated muscles, neuropsychological impairment, and bone deformities. Among this spectrum of defects, abnormalities of calcium homeostasis are the common dystrophic feature. Given the fundamental role of Ca2+ in all cells, this biochemical alteration might be underlying all the DMD abnormalities. However, its mechanism is not completely understood. While abnormally elevated resting cytosolic Ca2+ concentration is found in all dystrophic cells, the aberrant mechanisms leading to that outcome have cell-specific components. We probe the diverse aspects of calcium response in various affected tissues. In skeletal muscles, cardiomyocytes, and neurons, dystrophin appears to serve as a scaffold for proteins engaged in calcium homeostasis, while its interactions with actin cytoskeleton influence endoplasmic reticulum organisation and motility. However, in myoblasts, lymphocytes, endotheliocytes, and mesenchymal and myogenic cells, calcium abnormalities cannot be clearly attributed to the loss of interaction between dystrophin and the calcium toolbox proteins. Nevertheless, DMD gene mutations in these cells lead to significant defects and the calcium anomalies are a symptom of the early developmental phase of this pathology. As the impaired calcium homeostasis appears to underpin multiple DMD abnormalities, understanding this alteration may lead to the development of new therapies. In fact, it appears possible to mitigate the impact of the abnormal calcium homeostasis and the dystrophic phenotype in the total absence of dystrophin. This opens new treatment avenues for this incurable disease.
Protective Effects of Lactobacillus plantarum CCFM8610 against Acute Toxicity Caused by Different Food-Derived Forms of Cadmium in Mice
Authors: Zhu Jiamin , Yu Leilei , Shen Xudan , Tian Fengwei , Zhao Jianxin , Zhang Hao , Chen Wei , Zhai Qixiao
Published: October 2021

Cadmium (Cd) is an environmental pollutant that is toxic to almost every human organ. Oral supplementation with lactic acid bacteria (LAB) has been reported to alleviate cadmium toxicity. However, research on the mitigation of cadmium toxicity by LAB is still limited to inorganic cadmium, which is not representative of the varied forms of cadmium ingested daily. In this study, different foodborne forms of cadmium were adopted to establish an in vivo toxicity model, including cadmium–glutathione, cadmium–citrate, and cadmium–metallothionein. The ability of Lactobacillus plantarum CCFM8610 to reduce the toxic effects of these forms of cadmium was further investigated. The 16S rRNA gene sequencing and metabolomics technologies based on liquid chromatography with tandem mass spectrometry (LC–MS/MS) were adopted for the exploration of relevant protective mechanisms. The results demonstrated that the consumption of CCFM8610 can reduce the content of cadmium in mice and relieve the oxidative stress caused by different food–derived forms of cadmium, indicating that CCFM8610 has a promising effect on the remediation of the toxic effects of cadmium food poisoning. Meanwhile, protective effects on gut microflora and serum metabolites might be an important mechanism for probiotics to alleviate cadmium toxicity. This study provides a theoretical basis for the application of L. plantarum CCFM8610 to alleviate human cadmium poisoning.
Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts
Authors: Averbeck Dietrich , Rodriguez-Lafrasse Claire
Published: October 2021

Until recently, radiation effects have been considered to be mainly due to nuclear DNA damage and their management by repair mechanisms. However, molecular biology studies reveal that the outcomes of exposures to ionizing radiation (IR) highly depend on activation and regulation through other molecular components of organelles that determine cell survival and proliferation capacities. As typical epigenetic-regulated organelles and central power stations of cells, mitochondria play an important pivotal role in those responses. They direct cellular metabolism, energy supply and homeostasis as well as radiation-induced signaling, cell death, and immunological responses. This review is focused on how energy, dose and quality of IR affect mitochondria-dependent epigenetic and functional control at the cellular and tissue level. Low-dose radiation effects on mitochondria appear to be associated with epigenetic and non-targeted effects involved in genomic instability and adaptive responses, whereas high-dose radiation effects (>1 Gy) concern therapeutic effects of radiation and long-term outcomes involving mitochondria-mediated innate and adaptive immune responses. Both effects depend on radiation quality. For example, the increased efficacy of high linear energy transfer particle radiotherapy, e.g., C-ion radiotherapy, relies on the reduction of anastasis, enhanced mitochondria-mediated apoptosis and immunogenic (antitumor) responses.
Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein Response in Larval Zebrafish
Authors: Crouzier Lucie , Denus Morgane , Richard Elodie M. , Tavernier Amarande , Diez Camille , Cubedo Nicolas , Maurice Tangui , Delprat Benjamin
Published: October 2021

The sigma-1 receptor (S1R) is a highly conserved transmembrane protein highly enriched in mitochondria-associated endoplasmic reticulum (ER) membranes, where it interacts with several partners involved in ER-mitochondria Ca2+ transfer, activation of the ER stress pathways, and mitochondria function. We characterized a new S1R deficient zebrafish line and analyzed the impact of S1R deficiency on visual, auditory and locomotor functions. The s1r+25/+25 mutant line showed impairments in visual and locomotor functions compared to s1rWT. The locomotion of the s1r+25/+25 larvae, at 5 days post fertilization, was increased in the light and dark phases of the visual motor response. No deficit was observed in acoustic startle response. A critical role of S1R was shown in ER stress pathways and mitochondrial activity. Using qPCR to analyze the unfolded protein response genes, we observed that loss of S1R led to decreased levels of IRE1 and PERK-related effectors and increased over-expression of most of the effectors after a tunicamycin challenge. Finally, S1R deficiency led to alterations in mitochondria bioenergetics with decreased in basal, ATP-linked and non-mitochondrial respiration and following tunicamycin challenge. In conclusion, this new zebrafish model confirmed the importance of S1R activity on ER-mitochondria communication. It will be a useful tool to further analyze the physiopathological roles of S1R.
Effect of N-Vinyl-2-Pyrrolidone (NVP), a Bromodomain-Binding Small Chemical, on Osteoblast and Osteoclast Differentiation and Its Potential Application for Bone Regeneration
Authors: Klemmer Viviane A. , Khera Nupur , Siegenthaler Barbara M. , Bhattacharya Indranil , Weber Franz E. , Ghayor Chafik
Published: October 2021

The human skeleton is a dynamic and remarkably organized organ system that provides mechanical support and performs a variety of additional functions. Bone tissue undergoes constant remodeling; an essential process to adapt architecture/resistance to growth and mechanical needs, but also to repair fractures and micro-damages. Despite bone’s ability to heal spontaneously, certain situations require an additional stimulation of bone regeneration, such as non-union fractures or after tumor resection. Among the growth factors used to increase bone regeneration, bone morphogenetic protein-2 (BMP2) is certainly the best described and studied. If clinically used in high quantities, BMP2 is associated with various adverse events, including fibrosis, overshooting bone formation, induction of inflammation and swelling. In previous studies, we have shown that it was possible to reduce BMP2 doses significantly, by increasing the response and sensitivity to it with small molecules called “BMP2 enhancers”. In the present study, we investigated the effect of N-Vinyl-2-pyrrolidone (NVP) on osteoblast and osteoclast differentiation in vitro and guided bone regeneration in vivo. We showed that NVP increases BMP2-induced osteoblast differentiation and decreases RANKL-induced osteoclast differentiation in a dose-dependent manner. Moreover, in a rabbit calvarial defect model, the histomorphometric analysis revealed that bony bridging and bony regenerated area achieved with NVP-loaded poly (lactic-co-glycolic acid (PLGA) membranes were significantly higher compared to unloaded membranes. Taken together, our results suggest that NVP sensitizes BMP2-dependent pathways, enhances BMP2 effect, and inhibits osteoclast differentiation. Thus, NVP could prove useful as “osteopromotive substance” in situations where a high rate of bone regeneration is required, and in the management of bone diseases associated with excessive bone resorption, like osteoporosis.
Expression Patterns of the Heat Shock Protein 90 (Hsp90) Gene Suggest Its Possible Involvement in Maintaining the Dormancy of Dinoflagellate Resting Cysts
Authors: Deng Yunyan , Li Fengting , Hu Zhangxi , Yue Caixia , Tang Ying Zhong
Published: October 2021

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone functioning in cellular structural folding and conformational integrity maintenance and thus plays vital roles in a variety of biological processes. However, many aspects of these functions and processes remain to be fully elucidated, particularly for non-model organisms. Dinoflagellates are a group of eukaryotes that are exceedingly important in primary production and are responsible for the most harmful algal blooms (HABs) in aquatic ecosystems. The success of dinoflagellates in dominating the plankton community is undoubtedly pertinent to their remarkable adaptive strategies, characteristic of resting cyst production and broad tolerance to stresses of temperature and others. Therefore, this study was conducted to examine the putative roles of Hsp90 in the acclimation to temperature stress and life stage alterations of dinoflagellates. Firstly, we isolated the full-length cDNA of an Hsp90 gene (StHsp90) via RACE from the cosmopolitan HAB species Scrippsiella trochoidea and tracked its transcriptions in response to varied scenarios via real-time qPCR. The results indicated that StHsp90 displayed significant mRNA augment patterns, escalating during 180-min treatments, when the cells were exposed to elevated and lowered temperatures. Secondly, we observed prominently elevated StHsp90 transcriptions in the cysts that were stored at the cold and dark conditions compared to those in newly formed resting cysts and vegetative cells. Finally, and perhaps most importantly, we identified 29 entries of Hsp90-encoding genes with complete coding regions from a dinoflagellate-specific environmental cDNA library generated from marine sediment assemblages. The observed active transcription of these genes in sediment-buried resting cysts was fully supported by the qPCR results for the cold-stored resting cysts of S. trochoidea. Hsp90s expressions in both laboratory-raised and field-collected cysts collectively highlighted the possible involvement and engagement of Hsp90 chaperones in the resting stage persistence of dinoflagellates.
The Effect of Multisite Phosphorylation on the Conformational Properties of Intrinsically Disordered Proteins
Authors: Rieloff Ellen , Skepö Marie
Published: October 2021

Intrinsically disordered proteins are involved in many biological processes such as signaling, regulation, and recognition. A common strategy to regulate their function is through phosphorylation, as it can induce changes in conformation, dynamics, and interactions with binding partners. Although phosphorylated intrinsically disordered proteins have received increased attention in recent years, a full understanding of the conformational and structural implications of phosphorylation has not yet been achieved. Here, we present all-atom molecular dynamics simulations of five disordered peptides originated from tau, statherin, and β-casein, in both phosphorylated and non-phosphorylated state, to compare changes in global dimensions and structural elements, in an attempt to gain more insight into the controlling factors. The changes are in qualitative agreement with experimental data, and we observe that the net charge is not enough to predict the impact of phosphorylation on the global dimensions. Instead, the distribution of phosphorylated and positively charged residues throughout the sequence has great impact due to the formation of salt bridges. In statherin, a preference for arginine–phosphoserine interaction over arginine–tyrosine accounts for a global expansion, despite a local contraction of the phosphorylated region, which implies that also non-charged residues can influence the effect of phosphorylation.
The Trace Element Selenium Is Important for Redox Signaling in Phorbol Ester-Differentiated THP-1 Macrophages
Authors: Wolfram Theresa , Weidenbach Leonie M. , Adolf Johanna , Schwarz Maria , Schädel Patrick , Gollowitzer André , Werz Oliver , Koeberle Andreas , Kipp Anna P. , Koeberle Solveigh C.
Published: October 2021

Physiological selenium (Se) levels counteract excessive inflammation, with selenoproteins shaping the immunoregulatory cytokine and lipid mediator profile. How exactly differentiation of monocytes into macrophages influences the expression of the selenoproteome in concert with the Se supply remains obscure. THP-1 monocytes were differentiated with phorbol 12-myristate 13-acetate (PMA) into macrophages and (i) the expression of selenoproteins, (ii) differentiation markers, (iii) the activity of NF-κB and NRF2, as well as (iv) lipid mediator profiles were analyzed. Se and differentiation affected the expression of selenoproteins in a heterogeneous manner. GPX4 expression was substantially decreased during differentiation, whereas GPX1 was not affected. Moreover, Se increased the expression of selenoproteins H and F, which was further enhanced by differentiation for selenoprotein F and diminished for selenoprotein H. Notably, LPS-induced expression of NF-κB target genes was facilitated by Se, as was the release of COX- and LOX-derived lipid mediators and substrates required for lipid mediator biosynthesis. This included TXB2, TXB3, 15-HETE, and 12-HEPE, as well as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Our results indicate that Se enables macrophages to accurately adjust redox-dependent signaling and thereby modulate downstream lipid mediator profiles.
Mass Spectrometry-Based Proteomics Reveal Alcohol Dehydrogenase 1B as a Blood Biomarker Candidate to Monitor Acetaminophen-Induced Liver Injury
Authors: Pailleux Floriane , Maes Pauline , Jaquinod Michel , Barthelon Justine , Darnaud Marion , Lacoste Claire , Vandenbrouck Yves , Gilquin Benoît , Louwagie Mathilde , Hesse Anne-Marie , Kraut Alexandra , Garin Jérôme , Leroy Vincent , Zarski Jean-Pierre , Bruley Christophe , Couté Yohann , Samuel Didier , Ichai Philippe , Faivre Jamila , Brun Virginie
Published: October 2021

Acute liver injury (ALI) is a severe disorder resulting from excessive hepatocyte cell death, and frequently caused by acetaminophen intoxication. Clinical management of ALI progression is hampered by the dearth of blood biomarkers available. In this study, a bioinformatics workflow was developed to screen omics databases and identify potential biomarkers for hepatocyte cell death. Then, discovery proteomics was harnessed to select from among these candidates those that were specifically detected in the blood of acetaminophen-induced ALI patients. Among these candidates, the isoenzyme alcohol dehydrogenase 1B (ADH1B) was massively leaked into the blood. To evaluate ADH1B, we developed a targeted proteomics assay and quantified ADH1B in serum samples collected at different times from 17 patients admitted for acetaminophen-induced ALI. Serum ADH1B concentrations increased markedly during the acute phase of the disease, and dropped to undetectable levels during recovery. In contrast to alanine aminotransferase activity, the rapid drop in circulating ADH1B concentrations was followed by an improvement in the international normalized ratio (INR) within 10–48 h, and was associated with favorable outcomes. In conclusion, the combination of omics data exploration and proteomics revealed ADH1B as a new blood biomarker candidate that could be useful for the monitoring of acetaminophen-induced ALI.
OSMI-1 Enhances TRAIL-Induced Apoptosis through ER Stress and NF-κB Signaling in Colon Cancer Cells
Authors: Lee Su-Jin , Lee Da-Eun , Choi Soo-Young , Kwon Oh-Shin
Published: October 2021

Levels of O-GlcNAc transferase (OGT) and hyper-O-GlcNAcylation expression levels are associated with cancer pathogenesis. This study aimed to find conditions that maximize the therapeutic effect of cancer and minimize tissue damage by combining an OGT inhibitor (OSMI-1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We found that OSMI-1 treatment in HCT116 human colon cancer cells has a potent synergistic effect on TRAIL-induced apoptosis signaling. Interestingly, OSMI-1 significantly increased TRAIL-mediated apoptosis by increasing the expression of the cell surface receptor DR5. ROS-induced endoplasmic reticulum (ER) stress by OSMI-1 not only upregulated CHOP-DR5 signaling but also activated Jun-N-terminal kinase (JNK), resulting in a decrease in Bcl2 and the release of cytochrome c from mitochondria. TRAIL induced the activation of NF-κB and played a role in resistance as an antiapoptotic factor. During this process, O-GlcNAcylation of IκB kinase (IKK) and IκBα degradation occurred, followed by translocation of p65 into the nucleus. However, combination treatment with OSMI-1 counteracted the effect of TRAIL-mediated NF-κB signaling, resulting in a more synergistic effect on apoptosis. Therefore, the combined treatment of OSMI-1 and TRAIL synergistically increased TRAIL-induced apoptosis through caspase-8 activation. Conclusively, OSMI-1 potentially sensitizes TRAIL-induced cell death in HCT116 cells through the blockade of NF-κB signaling and activation of apoptosis through ER stress response.
The Future of Stem Cells and Their Derivates in the Treatment of Glaucoma. A Critical Point of View
Authors: Nicoară Simona Delia , Brie Ioana , Jurj Ancuța , Sorițău Olga
Published: October 2021

This review focuses on the clinical translation of preclinical studies, especially those that have used stem cells in the treatment of glaucoma, with an emphasis on optic nerve regeneration. The studies referred to in the review aim to treat optic nerve atrophy, while cell therapies targeting other sites in the eye, such as the trabecular meshwork, have not been addressed. Such complex and varied pathophysiological mechanisms that lead to glaucoma may explain the fact that although stem cells have a high capacity of neuronal regeneration, the treatments performed did not have the expected results and the promise offered by animal studies was not achieved. By analyzing the facts associated with failure, important lessons are to be learned: the type of stem cells that are used, the route of administration, the selection of patients eligible for these treatments, additional therapies that support stem cells transplantation and their mode of action, methods of avoiding the host’s immune response. Many of these problems could be solved using exosomes (EV), but also miRNA, which allows more targeted approaches with minimal side effects.
Research Progress in Chinese Herbal Medicines for Treatment of Sepsis: Pharmacological Action, Phytochemistry, and Pharmacokinetics
Authors: Cheng Chen , Yu Xuan
Published: October 2021

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection; the pathophysiology of sepsis is complex. The incidence of sepsis is steadily increasing, with worldwide mortality ranging between 30% and 50%. Current treatment approaches mainly rely on the timely and appropriate administration of antimicrobials and supportive therapies, but the search for pharmacotherapies modulating the host response has been unsuccessful. Chinese herbal medicines, i.e., Chinese patent medicines, Chinese herbal prescriptions, and single Chinese herbs, play an important role in the treatment of sepsis through multicomponent, multipathway, and multitargeting abilities and have been officially recommended for the management of COVID-19. Chinese herbal medicines have therapeutic actions promising for the treatment of sepsis; basic scientific research on these medicines is increasing. However, the material bases of most Chinese herbal medicines and their underlying mechanisms of action have not yet been fully elucidated. This review summarizes the current studies of Chinese herbal medicines used for the treatment of sepsis in terms of clinical efficacy and safety, pharmacological activity, phytochemistry, bioactive constituents, mechanisms of action, and pharmacokinetics, to provide an important foundation for clarifying the pathogenesis of sepsis and developing novel antisepsis drugs based on Chinese herbal medicines.
Multi-Omics Approach to Mitochondrial DNA Damage in Human Muscle Fibers
Authors: Elstner Matthias , Olszewski Konrad , Prokisch Holger , Klopstock Thomas , Murgia Marta
Published: October 2021

Mitochondrial DNA deletions affect energy metabolism at tissue-specific and cell-specific threshold levels, but the pathophysiological mechanisms determining cell fate remain poorly understood. Chronic progressive external ophthalmoplegia (CPEO) is caused by mtDNA deletions and characterized by a mosaic distribution of muscle fibers with defective cytochrome oxidase (COX) activity, interspersed among fibers with retained functional respiratory chain. We used diagnostic histochemistry to distinguish COX-negative from COX-positive fibers in nine muscle biopsies from CPEO patients and performed laser capture microdissection (LCM) coupled to genome-wide gene expression analysis. To gain molecular insight into the pathogenesis, we applied network and pathway analysis to highlight molecular differences of the COX-positive and COX-negative fiber transcriptome. We then integrated our results with proteomics data that we previously obtained comparing COX-positive and COX-negative fiber sections from three other patients. By virtue of the combination of LCM and a multi-omics approach, we here provide a comprehensive resource to tackle the pathogenic changes leading to progressive respiratory chain deficiency and disease in mitochondrial deletion syndromes. Our data show that COX-negative fibers upregulate transcripts involved in translational elongation and protein synthesis. Furthermore, based on functional annotation analysis, we find that mitochondrial transcripts are the most enriched among those with significantly different expression between COX-positive and COX-negative fibers, indicating that our unbiased large-scale approach resolves the core of the pathogenic changes. Further enrichments include transcripts encoding LIM domain proteins, ubiquitin ligases, proteins involved in RNA turnover, and, interestingly, cell cycle arrest and cell death. These pathways may thus have a functional association to the molecular pathogenesis of the disease. Overall, the transcriptome and proteome show a low degree of correlation in CPEO patients, suggesting a relevant contribution of post-transcriptional mechanisms in shaping this disease phenotype.
Silencing of Aquaporin Homologue Accumulates Uric Acid and Decreases the Lifespan of the Asian Citrus Psyllid, Diaphorina citri (Hemiptera: Liviidae)
Authors: Santos-Ortega Yulica , Killiny Nabil
Published: October 2021

The Asian citrus psyllid, Diaphorina citri Kuwayama is devastating the citrus industry worldwide. It transmits ‘Candidatus Liberibacter asiaticus’, the pathogen of Huanglongbing in citrus. RNA interference is an excellent tool for functional genomics and for screening target genes for pest control. Herein, we silenced the aquaporin (AQP) gene (DcAQP) homologue in D. citri to study its functionality and whether it could be a good target for a control strategy. AQP is an integral membrane channel protein that aids in the rapid flux of water and other small solutes that move across the lipid membrane. In Hemiptera, it is well established that AQP plays important roles in adjusting to physiological challenges including (1) regulating osmotic stress between the gut lumen and hemolymph after imbibing large quantities of a low nitrogen, sugar-rich liquid diet; (2) avoiding or preventing dehydration and desiccation; and (3) surviving at elevated temperatures. The dsRNA-DcAQP was applied twice to nymphs of the 4th and 5th instars through a soaking technique. Silencing AQP caused a significant increase in nymph mortality. Emerged adults showed malformations and a shorter lifespan. Silencing DcAQP provoked alterations in some metabolites and increased the uric acid content in emerged adults. DcAQP could be a useful target to control D. citri.
Benchmarking Free Energy Calculations in Liquid Aliphatic Ketone Solvents Using the 3D-RISM-KH Molecular Solvation Theory
Authors: Roy Dipankar , Kovalenko Andriy
Published: October 2021

The three-dimensional reference interaction site model of the molecular solvation theory with the Kovalenko–Hirata closure is used to calculate the free energy of solvation of organic solutes in liquid aliphatic ketones. The ketone solvent sites were modeled using a modified united-atom force field. The successful application of these solvation models in calculating ketone–water partition coefficients of a large number of solutes supports the validation and benchmarking reported here.
Copeptin Levels Are Independent from Mild Therapeutic Hypothermia but Do Not Predict Infarct Size in Patients Presenting with ST-Segment Elevation Myocardial Infarction
Authors: Mueller Matthias , Beitzke Dietrich , Scherz Thomas , Loewe Christian , Mangold Andreas , Marculescu Rodrig , Poppe Michael , Sterz Fritz , Herkner Harald , Lang Irene , Testori Christoph , Weiser Christoph
Published: October 2021

Background: Mild therapeutic hypothermia (MTH) is a treatment adjunct in ST-segment elevation myocardial infarction (STEMI) that deserves investigation. Copeptin―a surrogate marker for vasopressin―is an early biomarker in STEMI. Data from cardiac arrest patients suggest a reduction of copeptin levels through MTH; however, copeptin levels have not been investigated in MTH during STEMI. Methods: We analyzed patients treated with MTH during STEMI in a sub-study of the STATIM trial (Testori, Heart 2019). Patients were randomized to normothermia or MTH with out-of-hospital initiation. Seven copeptin samples were collected from each patient. Primary endpoint was the difference in copeptin levels between the groups. As secondary endpoints, we defined differences in the kinetics between the sampling timepoints and the correlation between copeptin and the infarct size in relation to left ventricular myocardium. Results: We included 99 patients (MTH n = 47, control n = 52) in our intention to treat analysis. No differences in copeptin values at first medical contact between the MTH and normothermia groups were found. MTH showed no effect on copeptin levels, neither during cooling phase nor through the course. Copeptin peaked at first medical contact and hospital admission in both groups. No differences in kinetics between the timepoints were found. Copeptin showed no correlation with infarct size, neither at first medical contact nor hospital admission. Conclusions: Copeptin levels were not influenced by MTH in STEMI, suggesting the use of this biomarker also during temperature management. Furthermore, copeptin levels were not usable as a surrogate marker for infarct size at any timepoint.
Proteomic Analysis of Maternal Urine for the Early Detection of Preeclampsia and Fetal Growth Restriction
Authors: Bujold Emmanuel , Fillion Alexandre , Roux-Dalvai Florence , Scott-Boyer Marie Pier , Giguère Yves , Forest Jean-Claude , Gotti Clarisse , Laforest Geneviève , Guerby Paul , Droit Arnaud
Published: October 2021

Background: To explore the use of maternal urine proteome for the identification of preeclampsia biomarkers. Methods: Maternal urine samples from women with and without preeclampsia were used for protein discovery followed by a validation study. The targeted proteins of interest were then measured in urine samples collected at 20–24 and 30–34 weeks among nine women who developed preeclampsia, one woman with fetal growth restriction, and 20 women with uncomplicated pregnancies from a longitudinal study. Protein identification and quantification was obtained using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Results: Among the 1108 urine proteins quantified in the discovery study, 21 were upregulated in preeclampsia and selected for validation. Nineteen (90%) proteins were confirmed as upregulated in preeclampsia cases. Among them, two proteins, ceruloplasmin and serpin A7, were upregulated at 20–24 weeks and 30–34 weeks of gestation (p < 0.05) in cases of preeclampsia, and could have served to identify 60% of women who subsequently developed preeclampsia and/or fetal growth restriction at 20–24 weeks of gestation, and 78% at 30–34 weeks, for a false-positive rate of 10%. Conclusions: Proteomic profiling of maternal urine can differentiate women with and without preeclampsia. Several proteins including ceruloplasmin and serpin A7 are upregulated in maternal urine before the diagnosis of preeclampsia and potentially fetal growth restriction.
In Vitro Maturation of Oocytes Retrieved from Ovarian Tissue: Outcomes from Current Approaches and Future Perspectives
Authors: De Roo Chloë , Tilleman Kelly
Published: October 2021

In vitro maturation (IVM) of transvaginally aspirated immature oocytes is an effective and safe assisted reproductive treatment for predicted or high responder patients. Currently, immature oocytes are also being collected from the contralateral ovary during laparoscopy/laparotomy and even ex vivo from the excised ovary or the spent media during ovarian tissue preparation prior to ovarian cortex cryopreservation. The first live births from in vitro-matured ovarian tissue oocytes (OTO-IVM) were reported after monophasic OTO-IVM, showing the ability to achieve mature OTO-IVM oocytes. However, fertilisations rates and further embryological developmental capacity appeared impaired. The introduction of a biphasic IVM, also called capacitation (CAPA)-IVM, has been a significant improvement of the oocytes maturation protocol. However, evidence on OTO-IVM is still scarce and validation of the first results is of utmost importance to confirm reproducibility, including the follow-up of OTO-IVM children. Differences between IVM and OTO-IVM should be well understood to provide realistic expectations to patients.
Sleep and Depressive Symptoms in the Morningness/Eveningness-Suicidal Ideation Relationship Depend on School Shift in Mexican Adolescents
Authors: Arrona-Palacios Arturo , Díaz-Morales Juan F. , Parra-Robledo Zaida , Adan Ana
Published: October 2021

The aim was to analyze the morningness/eveningness (M/E) effect on suicidal ideation through sleep and depressive symptoms mediators with school shift (i.e., morning and afternoon) as moderator. In this study, 586 Mexican adolescents, with a mean age of 16.31 ± 0.92, from a public high school in a double-shift school system (298 from the morning shift and 288 from the afternoon shift) participated. Measurements of sleep, morningness/eveningness (circadian preference), depressive symptomology, and suicidal ideation were completed. Adolescents in the afternoon shift reported a later rise time, bedtime, greater time in bed sleep length, and less social jet lag than in the morning shift. Considering the moderated-mediated analysis, circadian preference and suicidal ideation were mediated by both depressive symptoms and school day’s sleep length in the morning shift. In the afternoon shift, no mediation effect was significant. When weekend sleep length was considered in the model, only depressive symptoms had a mediating effect between circadian preference and suicidal ideation in the morning shift; no significant mediating effect was found on the afternoon shift. The results suggest that an afternoon school schedule may act as a protective factor for the adolescent’s mental health and may represent a viable option for future interventions.
COVID-19 Associated Choroidopathy
Authors: Abdelmassih Youssef , Azar Georges , Bonnin Sophie , Scemama Timsit Claire , Vasseur Vivien , Spaide Richard F. , Behar-Cohen Francine , Mauget-Faysse Martine
Published: October 2021

The aim of the study is to report on the indocyanine green angiography (ICGA) and OCT findings in patients hospitalized for severe COVID infection. In this observational prospective monocentric cohort study, we included patients hospitalized for severe COVID infection. The main outcomes were ICGA and OCT findings. A total of 14 patients with a mean age of 58.2 ± 11.4 years and a male predominance (9/14 patients; 64%) were included. The main ICGA findings included hypofluorescent spots in 19 eyes (68%), intervortex shunts in 10 eyes (36%), and characteristic “hemangioma-like” lesions in five eyes (18%). “Hemangioma-like” lesions were both unique and unilateral, and showed no washout on the late phase of the angiogram. The main OCT findings included focal choroidal thickening in seven eyes (25%), caverns in six eyes (21%) and paracentral acute middle maculopathy lesions in one eye (4%). All patients hospitalized for severe COVID infection had anomalies on ICGA and OCT. Lesions to both retinal and choroidal vasculature were found. These anomalies could be secondary to vascular involvement related directly or indirectly to the SARS-CoV2 virus.
In Search of Clinical Impact: Advanced Monitoring Technologies in Daily Heart Failure Care
Authors: Nachman Dean , Rahamim Eldad , Kolben Yotam , Mengesha Bethlehem , Elbaz-Greener Gabby , Amir Offer , Asleh Rabea
Published: October 2021

Despite significant advances in the management of heart failure (HF), further improvement in the outcome of this chronic and progressive disease is still considered a major unmet need. Recurrent hospitalizations due to decompensated HF frequently occur, resulting in increased morbidity and mortality rates. Past attempts at early detection of clinical deterioration were mainly based on monitoring of signs and symptoms of HF exacerbation, which have mostly given disappointing results. Extensive research of the pathophysiology of HF decompensation has indicated that hemodynamic alterations start days prior to clinical manifestation. Novel technologies aim to monitor these minute hemodynamic changes, allowing time for therapeutic interventions to prevent hemodynamic derangement and HF exacerbation. The latest noticeable advancements include assessment of lung fluid volume, wearable devices with integrated sensors, and microelectromechanical systems-based implantable devices for continuous measurement of cardiac filling pressures. This manuscript will review the rationale for monitoring HF patients and discuss previous and ongoing attempts to develop clinically meaningful monitoring devices to improve daily HF health care, with particular emphasis on the recent advances and clinical trials relevant to this evolving field.
Complex Rearrangement of the Entire Retinal Posterior Pole in Patients with Relapsing Remitting Multiple Sclerosis
Authors: Martucci Alessio , Landi Doriana , Cesareo Massimo , Di Carlo Emiliano , Di Mauro Giovanni , Sorge Roberto Pietro , Albanese Maria , Gabri Nicoletti Carolina , Mataluni Giorgia , Mercuri Nicola Biagio , Di Marino Matteo , Aiello Francesco , Centonze Diego , Nucci Carlo , Marfia Girolama Alessandra , Mancino Raffaele
Published: October 2021

There are consolidated data about multiple sclerosis (MS)–dependent retinal neurodegeneration occurring in the optic disk and the macula, although it is unclear whether other retinal regions are affected. Our objective is to evaluate, for the first time, the involvement of the entire retinal posterior pole in patients diagnosed with relapsing remitting multiple sclerosis (RRMS) unaffected by optic neuritis using Spectral Domain–Optical Coherence Tomography (SD–OCT). The study protocol was approved by Tor Vergata Hospital Institutional Ethics Committee (Approval number 107/16), and conforms to the tenets of the Declaration of Helsinki. After a comprehensive neurological and ophthalmological examination, 53 untreated RRMS patients (aged 37.4 ± 10) and 53 matched controls (aged 36.11 ± 12.94) were enrolled. In addition, each patient underwent an examination of the posterior pole using the SD-OCT built-in Spectralis posterior pole scanning protocol. After segmentation, the mean thickness, as well as the thickness of the 64 single regions of interest, were calculated for each retinal layer. No statistically significant difference in terms of average retinal thickness was found between the groups. However, MS patients showed both a significantly thinner ganglion cell layer (p < 0.001), and, although not statistically significant, a thinner inner nuclear layer (p = 0.072) and retinal nerve fiber layer (p = 0.074). In contrast, the retinal pigment epithelium (p = 0.014) and photoreceptor layers p < 0.001) resulted significantly thicker in these patients. Interestingly, the analysis of the region of interest showed that neurodegeneration was non-homogeneously distributed across each layer. This is the first report that suggests a complex rearrangement that affects, layer by layer, the entire retinal posterior pole of RRMS retinas in response to the underlying neurotoxic insult.
Progression of Fibrinogen Decrease during High Dose Tigecycline Therapy in Critically Ill Patients: A Retrospective Analysis
Authors: Treml Benedikt , Rajsic Sasa , Hell Tobias , Fries Dietmar , Bachler Mirjam
Published: October 2021

Tigecycline is a novel glycylcycline broad-spectrum antibiotic offering good coverage for critically ill patients experiencing complicated infections. A known side effect is a coagulation disorder with distinct hypofibrinogenemia. To date, the information on possible risk factors and outcomes is sparse. Therefore, the aim of this study is to examine the time course of fibrinogen level changes during tigecycline therapy in critically ill patients. Moreover, we sought to identify risk factors for coagulopathy and to report on clinically important outcomes. We retrospectively reviewed all intensive care patients admitted to our General and Surgical Intensive Care Unit receiving tigecycline between 2010 and 2018. A total of 130 patients were stratified into two groups based on the extent of fibrinogen decrease. Patients with a greater fibrinogen decrease received a higher dose, a longer treatment and more dose changes of tigecycline, respectively. In regard to the underlying pathology, these patients showed higher inflammation markers as well as a slightly reduced liver synthesis capacity. We, therefore, conclude that such a fibrinogen decrease may be based upon further impairment of liver synthesis during severe inflammatory states. To decrease the risk of bleeding, cautious monitoring of coagulation in critically ill patients treated with high-dose tigecycline is warranted.
Thermal, X-ray Diffraction and Oedometric Analyses of Silt-Waste/NaOH-Activated Metakaolin Geopolymer Composite
Authors: Moro Daniele , Fabbri Riccardo , Romano Jennifer , Ulian Gianfranco , Calafato Antonino , Solouki Abbas , Sangiorgi Cesare , Valdrè Giovanni
Published: October 2021

The present research investigates the possibility to create a silt-waste reinforced composite through a NaOH-activated, metakaolin-based geopolymerization process. In this regard, we used thermal exo–endo analysis, X-ray diffraction (XRD), and oedometric mechanical tests to characterize the produced composites. In our experimental conditions, the tested material mixtures presented exothermic peaks with maximum temperatures of about 100 °C during the studied geopolymerization process. In general, the XRD analyses showed the formation of amorphous components and new mineral phases of hydrated sodalite, natrite, thermonatrite and trona. From oedometric tests, we observed a different behavior of vertical deformation related to pressure (at RT) for the various produced composites. The present work indicated that the proposed geopolymerization process to recycle silt-waste produced composite materials with various and extended mineralogy and chemical–physical properties, largely depending on both the precursors and the specific alkaline-activating solution. Thermal analysis, XRD, and oedometric mechanical tests proved to be fundamental to characterize and understand the behavior of the newly formed composite material.