bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relative Abundance and Occurrence of Sharks off Ocean Beaches of New South Wales, Australia
Authors: Monteforte Kim I. P. , Butcher Paul A. , Morris Stephen G. , Kelaher Brendan P.
Published: October 2022

There is still limited information about the diversity, distribution, and abundance of sharks in and around the surf zones of ocean beaches. We used long-term and large-scale drone surveying techniques to test hypotheses about the relative abundance and occurrence of sharks off ocean beaches of New South Wales, Australia. We quantified sharks in 36,384 drone flights across 42 ocean beaches from 2017 to 2021. Overall, there were 347 chondrichthyans recorded, comprising 281 (81.0%) sharks, with observations occurring in <1% of flights. Whaler sharks (Carcharhinus spp.) had the highest number of observations (n = 158) recorded. There were 34 individuals observed for both white sharks (Carcharodon carcharias) and critically endangered greynurse sharks (Carcharias taurus). Bull sharks (Carcharhinus leucas), leopard sharks (Stegostoma tigrinum) and hammerhead species (Sphyrna spp.) recorded 29, eight and three individuals, respectively. Generalised additive models were used to identify environmental drivers for detection probability of white, bull, greynurse, and whaler sharks. Distances to the nearest estuary, headland, and island, as well as water temperature and wave height, were significant predictors of shark occurrence; however, this varied among species. Overall, we provide valuable information for evidence-based species-specific conservation and management strategies for coastal sharks.
A Genomics Resource for 12 Edible Seaweeds to Predict Seaweed-Secreted Peptides with Potential Anti-Cancer Function
Authors: Liu Yining , Cummins Scott F. , Zhao Min
Published: October 2022

Seaweeds are multicellular marine macroalgae with natural compounds that have potential anticancer activity. To date, the identification of those compounds has relied on purification and assay, yet few have been documented. Additionally, the genomes and associated proteomes of edible seaweeds that have been identified thus far are scattered among different resources and with no systematic summary available, which hinders the development of a large-scale omics analysis. To enable this, we constructed a comprehensive genomics resource for the edible seaweeds. These data could be used for systematic metabolomics and a proteome search for anti-cancer compound and peptides. In brief, we integrated and annotated 12 publicly available edible seaweed genomes (8 species and 268,071 proteins). In addition, we integrate the new seaweed genomic resources with established cancer bioinformatics pipelines to help identify potential seaweed proteins that could help mitigate the development of cancer. We present 7892 protein domains that were predicted to be associated with cancer proteins based on a protein domain–domain interaction. The most enriched protein families were associated with protein phosphorylation and insulin signalling, both of which are recognised to be crucial molecular components for patient survival in various cancers. In addition, we found 6692 seaweed proteins that could interact with over 100 tumour suppressor proteins, of which 147 are predicted to be secreted proteins. In conclusion, our genomics resource not only may be helpful in exploring the genomics features of these edible seaweed but also may provide a new avenue to explore the molecular mechanisms for seaweed-associated inhibition of human cancer development.
Design of a Chimeric Multi-Epitope Vaccine (CMEV) against Both Leishmania martiniquensis and Leishmania orientalis Parasites Using Immunoinformatic Approaches
Authors: Imaizumi Kentaro , Phurahong Thararat , Siripattanapipong Suradej , Choowongkomon Kiattawee , Leelayoova Saovanee , Mungthin Mathirut , E-kobon Teerasak , Unajak Sasimanas
Published: October 2022

Leishmaniasis is a parasitic disease caused by protozoan flagellates of the genus Leishmania. Recently, Leishmania martiniquensis and Leishmania orientalis, emerging species of Leishmania, were isolated from patients in Thailand. Development of the vaccine is demanded; however, genetic differences between the two species make it difficult to design a vaccine that is effective for both species. In this study, we applied immuno-informatic approaches to design a chimeric multi-epitope vaccine (CMEV) against both L. martiniquensis and L. orientalis. We identified seven helper T lymphocyte (HTL) epitopes, sixteen cytotoxic T lymphocyte (CTL) epitopes, and eleven B-cell epitopes from sixteen conserved antigenic proteins found in both species. All these epitopes were joined together, and to further enhance immunogenicity, protein and peptides adjuvant were also added at the N-terminal of the molecule by using specific linkers. The candidate CMEV was subsequently analyzed from the perspectives of the antigenicity, allergenicity, and physiochemical properties. The interaction of the designed multi-epitope vaccine and immune receptor (TLR4) of the host were evaluated based on molecular dockings of the predicted 3D structures. Finally, in silico cloning was performed to construct the expression vaccine vector. Docking analysis showed that the vaccine/TLR4 complex took a stable form. Based on the predicted immunogenicity, physicochemical, and structural properties in silico, the vaccine candidate was expected to be appropriately expressed in bacterial expression systems and show the potential to induce a host immune response. This study proposes the experimental validation of the efficacy of the candidate vaccine construct against the two Leishmania.
High Dose of Acute Normobaric Hypoxia Does Not Adversely Affect Sprint Interval Training, Cognitive Performance and Heart Rate Variability in Males and Females
Authors: Karayigit Raci , Ramirez-Campillo Rodrigo , Yasli Burak Caglar , Gabrys Tomasz , Benesova Daniela , Esen Ozcan
Published: October 2022

Although preliminary studies suggested sex-related differences in physiological responses to hypoxia, the effects of sex on sprint interval training (SIT) performance in different degrees of hypoxia are largely lacking. The aim of this study was to examine the acute effect of different doses of normobaric hypoxia on SIT performance as well as heart rate variability (HRV) and cognitive performance (CP) in amateur-trained team sport players by comparing potential sex differences. In a randomized, double-blind, crossover design, 26 (13 females) amateur team-sport (football, basketball, handball, rugby) players completed acute SIT (6 × 15 s all-out sprints, separated with 2 min active recovery, against a load equivalent to 9% of body weight) on a cycle ergometer, in one of four conditions: (I) normoxia without a mask (FiO2: 20.9%) (CON); (II) normoxia with a mask (FiO2: 20.9%) (NOR); (III) moderate hypoxia (FiO2: 15.4%) with mask (MHYP); and (IV) high hypoxia (FiO2: 13.4%) with mask (HHYP). Peak (PPO) and mean power output (MPO), HRV, heart rate (HR), CP, capillary lactate (BLa), and ratings of perceived exertion (RPE) pre- and post-SIT were compared between CON, NOR, MHYP and HHYP. There were no significant differences found between trials for PPO (p = 0.55), MPO (p = 0.44), RPE (p = 0.39), HR (p = 0.49), HRV (p > 0.05) and CP (response accuracy: p = 0.92; reaction time: p = 0.24). The changes in MP, PP, RPE, HR, CP and HRV were similar between men and women (all p > 0.05). While BLa was similar (p = 0.10) between MHYP and HHYP trials, it was greater compared to CON (p = 0.01) and NOR (p = 0.01), without a sex-effect. In conclusion, compared to normoxia, hypoxia, and wearing a mask, have no effect on SIT acute responses (other than lactate), including PP, MP, RPE, CP, HR, and cardiac autonomic modulation either in men or women.
HDAC1 in the Ovarian Granulosa Cells of Tan Sheep Improves Cumulus Cell Expansion and Oocyte Maturation Independently of the EGF-like Growth Factors
Authors: Xu Yaxiu , Fan Shanshan , Liu Yujun , Shi Jiaqi , Xie Xianguo , Wang Xiangyan , Wang Chao , Liu Xinfeng , Xia Guoliang
Published: October 2022

Previous studies have shown that some of the histone deacetylases (HDACs) play diverse roles in the regulation of ovarian somatic cell development, oocyte maturation and early embryonic development in different species including sheep. This study aimed to clarify whether HDAC1 also played pivotal roles in regulating oocyte maturation in Tan sheep. The results showed that HDAC1 was expressed in the nuclei of both the granulosa cells and oocytes of the growing follicles in the Tan sheep’s ovaries. However, the level of HDAC1 was unaffected by luteinizing hormone (LH) induction in cultured granulosa cells. Meanwhile, the specific inhibition of HDAC1 using pyroxamide did not induce significant changes in the expression levels of EGF-like growth factors in vitro, whereas both the cumulus expansion and oocyte maturation of the cultured cumulus oocyte complexes (COCs) were significantly inhibited by pyroxamide. Additionally, the numbers of histone acetylation sites (H4K5, H4K12, H3K14 and H3K9) in ovarian granulosa cells were significantly increased. In conclusion, a constant expression of HDAC1 in the growing follicles of Tan sheep may be pivotal for supporting oocyte growth and maturation, although its action may not be closely correlated with LH induction, nor does it directly affect the expression of the EGF-like factors. Our study implies that there may exist diverse functions of the respective HDACs in modulating female reproduction in sheep.
Black Elderberry Press Cake as a Source of Bioactive Ingredients Using Green-Based Extraction Approaches
Authors: Mutavski Zorana , Nastić Nataša , Živković Jelena , Šavikin Katarina , Veberič Robert , Medič Aljaž , Pastor Kristian , Jokić Stela , Vidović Senka
Published: October 2022

To study the efficiency of two green-based extraction techniques for the isolation of bioactive constituents from black elderberry press cake, changes in phenolic compounds and main anthocyanin contents were analyzed. Polyphenolic content was correlated with antioxidant and antidiabetic potential by radical-scavenging activity and monitoring of α-amylase inhibition. Black elderberry press-cake extracts were obtained by ultrasound-assisted (UAE) and microwave-assisted (MAE) extractions under different extraction conditions. High-performance liquid chromatography (HPLC) analysis revealed that cyanidin-3-sambubioside and cyanidin-3-glucoside were the principal anthocyanins in all the obtained extracts, with their content being highest in MAE obtained at 80 °C over 5 min. The same extract induced two-fold higher antioxidant activity (IC50 6.89 μg/mL) and α-amylase inhibitory potential (IC50 2.18 mg/mL) in comparison to UAE extracts. The main compositional differences between extracts obtained by the same extraction technique were assigned to the extraction temperature. A principal component analysis confirmed that the antidiabetic feature is to be attributed to the rich content of anthocyanins in black elderberry press cake. Our results indicate the great potential of underutilized black elderberry press cake for the development of novel food and herbal formulations due to notable anthocyanin contents highly correlated with antidiabetic activity.
The Characterization of the Tobacco-Derived Wild Tomato Mosaic Virus by Employing Its Infectious DNA Clone
Authors: Yin Jinlong , Hong Xin , Luo Sha , Tan Jingquan , Zhang Yuanming , Qiu Yanglin , Latif Muhammad Faizan , Gao Tao , Yu Haijia , Bai Jingke , Li Shujun , Xu Kai
Published: October 2022

Viral diseases of cultivated crops are often caused by virus spillover from wild plants. Tobacco (N. tabacum) is an important economic crop grown globally. The viral pathogens of tobacco are traditional major subjects in virology studies and key considerations in tobacco breeding practices. A positive-strand RNA virus, wild tomato mosaic virus (WTMV), belonging to the genus potyvirus in the family potyviridae was recently found to infect tobacco in China. In this study, diseased tobacco leaf samples were collected in the Henan Province of China during 2020–2021. Several samples from different locations were identified as WTMV positive. An infectious DNA clone was constructed based on one of the WTMV isolates. By using this clone, we found that WTMV from tobacco could establish infections on natural reservoir hosts, demonstrating a possible route of WTMV spillover and overwintering in the tobacco field. Furthermore, the WTMV infection was found to be accompanied by other tobacco viruses in the field. The co-inoculation experiments indicate the superinfection exclusion (SIE) between WTMV and other potyvirus species that infect tobacco. Overall, our work reveals novel aspects of WTMV evolution and infection in tobacco and provides an important tool for further studies of WTMV.
Evaluating the Presence of Marine Litter in Cetaceans Stranded in the Balearic Islands (Western Mediterranean Sea)
Authors: Solomando Antònia , Pujol Francisca , Sureda Antoni , Pinya Samuel
Published: October 2022

The global distribution and presence of plastic, at all levels of the water column, has made plastic debris one of today’s greatest environmental challenges. The ingestion and entanglement of plastic-containing marine debris has been documented in more than 60% of all cetacean species. In light of the increasing pressure on cetaceans, and the diversity of factors that they face, the aim of this work is to provide evidence of the impact of plastic debris on stranded cetaceans, in terms of ingestion and entanglement, in the Balearic Islands for the first-time. Detailed examinations, necropsies, and plastic debris analysis were performed on 30 of the 108 cetaceans stranded between 2019 and 2022. Specimens belonging to five different species, Stenella coeruleoalba, Tursiops truncatus, Grampus griseus, Balaenoptera physalus, and Physeter macrocephalus, were evaluated. Ten percent of the cetaceans (N = 3) presented plastic debris in their stomach, with one case of obstruction and perforation. Fishery gear fragments (ropes and nets) were found in two adults of T. truncatus, whereas packaging debris (plastic bag, packing straps, and plastic sheets) were found in a juvenile P. macrocephalus. Plastic items analysed by Fourier transform infrared spectroscopy (FT-IR) reported three polymer types: polypropylene, polyamide, and high-density polypropylene. A total of seven cases of entanglement were recorded during the study, affecting four different species (S. coeruleoalba, T. truncatus, P. macrocephalus, and Megaptera novaeangliae). Only two individuals were freed from the nets, although one died after a week, whereas the rest were already found dead. In conclusion, data collected in the present study provided evidence of plastic ingestion and entanglement in cetaceans of the Balearic Islands for the first-time, thus highlighting the need for the regular examination of stranded cetaceans (as they are top predators) in future research to better understand the effects of these pollutants.
Label-Free Quantitative Proteomics Analysis of Adriamycin Selected Multidrug Resistant Human Lung Cancer Cells
Authors: Efeoglu Esen , Henry Michael , Clynes Martin , Meleady Paula
Published: October 2022

The development of drug resistance in lung cancer is a major clinical challenge, leading to a 5-year survival rate of only 18%. Therefore, unravelling the mechanisms of drug resistance and developing novel therapeutic strategies is of crucial importance. This study systematically explores the novel biomarkers of drug resistance using a lung cancer model (DLKP) with a series of drug-resistant variants. In-depth label-free quantitative mass spectrometry-based proteomics and gene ontology analysis shows that parental DLKP cells significantly differ from drug-resistant variants, and the cellular proteome changes even among the drug-resistant subpopulations. Overall, ABC transporter proteins and lipid metabolism were determined to play a significant role in the formation of drug resistance in DKLP cells. A series of membrane-related proteins such as HMOX1, TMB1, EPHX2 and NEU1 were identified to be correlated with levels of drug resistance in the DLKP subpopulations. The study also showed enrichment in biological processes and molecular functions such as drug metabolism, cellular response to the drug and drug binding. In gene ontology analysis, 18 proteins were determined to be positively or negatively correlated with resistance levels. Overall, 34 proteins which potentially have a therapeutic and diagnostic value were identified.
Synaptic Plasticity Is Predicted by Spatiotemporal Firing Rate Patterns and Robust to In Vivo-like Variability
Authors: Dorman Daniel B. , Blackwell Kim T.
Published: October 2022

Synaptic plasticity, the experience-induced change in connections between neurons, underlies learning and memory in the brain. Most of our understanding of synaptic plasticity derives from in vitro experiments with precisely repeated stimulus patterns; however, neurons exhibit significant variability in vivo during repeated experiences. Further, the spatial pattern of synaptic inputs to the dendritic tree influences synaptic plasticity, yet is not considered in most synaptic plasticity rules. Here, we investigate how spatiotemporal synaptic input patterns produce plasticity with in vivo-like conditions using a data-driven computational model with a plasticity rule based on calcium dynamics. Using in vivo spike train recordings as inputs to different size clusters of spines, we show that plasticity is strongly robust to trial-to-trial variability of spike timing. In addition, we derive general synaptic plasticity rules describing how spatiotemporal patterns of synaptic inputs control the magnitude and direction of plasticity. Synapses that strongly potentiated have greater firing rates and calcium concentration later in the trial, whereas strongly depressing synapses have hiring firing rates early in the trial. The neighboring synaptic activity influences the direction and magnitude of synaptic plasticity, with small clusters of spines producing the greatest increase in synaptic strength. Together, our results reveal that calcium dynamics can unify diverse plasticity rules and reveal how spatiotemporal firing rate patterns control synaptic plasticity.
Role of Prostaglandins in Nitric Oxide-Induced Glial Cell-Mediated Vasodilation in Rat Retina
Authors: Mori Asami , Seki Haruka , Mizukoshi Satoru , Uezono Takashi , Sakamoto Kenji
Published: October 2022

We previously identified that NO derived from neuronal cells acts on glial cells and causes vasodilation in the healthy rat retina via the release of epoxyeicosatrienoic acids (EETs) and prostaglandins (PGs) by activation of the arachidonic acid cascade. However, it is not clear which PG types are involved in these responses. The aim of the present study was to identify prostanoid receptors involved in glial cell-derived vasodilation induced by NO in rat retina. Male Wistar rats were used to examine the effects of intravitreal pretreatment with indomethacin, a cyclooxygenase inhibitor; PF-04418948, a prostanoid EP2 receptor antagonist; and CAY10441, a prostanoid IP receptor antagonist, on the changes in the retinal arteriolar diameter induced by intravitreal administration of NOR3, an NO donor. Retinal arteriolar diameters were measured using ocular fundus images captured with a high-resolution digital camera in vivo. The increase in the retinal arteriolar diameter induced by intravitreal injection of NOR3 was significantly suppressed by intravitreal pretreatment with indomethacin and PF-04418948, but not by CAY10441. The dose of PF-04418948 and CAY10441 injected intravitreally in the present study significantly reduced the increase in the retinal arteriolar diameter induced by prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2), respectively. These results suggest that activation of the arachidonic acid cascade and subsequent stimulation of prostanoid EP2 receptors are involved in rat retinal vasodilatory responses evoked by NO-induced glial cell stimulation. Therefore, glial cell-derived PGE2, similar to EETs, may play an important role in retinal vasodilatory mechanisms.
The Credible Role of Curcumin in Oxidative Stress-Mediated Mitochondrial Dysfunction in Mammals
Authors: Sathyabhama Muthuswamy , Priya Dharshini Loganathan Chandramani , Karthikeyan Adhimoolam , Kalaiselvi Senthil , Min Taesun
Published: October 2022

Oxidative stress and mitochondrial dysfunction are associated with the pathogenesis of several human diseases. The excessive generation of reactive oxygen species (ROS) and/or lack of adequate antioxidant defenses causes DNA mutations in mitochondria, damages the mitochondrial respiratory chain, and alters membrane permeability and mitochondrial defense mechanisms. All these alterations are linked to the development of numerous diseases. Curcumin, an active ingredient of turmeric plant rhizomes, exhibits numerous biological activities (i.e., antioxidant, anti-inflammatory, anticancer, and antimicrobial). In recent years, many researchers have shown evidence that curcumin has the ability to reduce the oxidative stress- and mitochondrial dysfunction-associated diseases. In this review, we discuss curcumin’s antioxidant mechanism and significance in oxidative stress reduction and suppression of mitochondrial dysfunction in mammals. We also discuss the research gaps and give our opinion on how curcumin research in mammals should proceed moving forward.
A Distinctive γδ T Cell Repertoire in NOD Mice Weakens Immune Regulation and Favors Diabetic Disease
Authors: O’Brien Rebecca L. , Matsuda Jennifer , Aydintug M. Kemal , Jin Niyun , Phalke Swati , Born Willi K.
Published: October 2022

Previous studies in mice and humans suggesting that γδ T cells play a role in the development of type 1 diabetes have been inconsistent and contradictory. We attempted to resolve this for the type 1 diabetes-prone NOD mice by characterizing their γδ T cell populations, and by investigating the functional contributions of particular γδ T cells subsets, using Vγ-gene targeted NOD mice. We found evidence that NOD Vγ4+ γδ T cells inhibit the development of diabetes, and that the process by which they do so involves IL-17 production and/or promotion of regulatory CD4+ αβ T cells (Tregs) in the pancreatic lymph nodes. In contrast, the NOD Vγ1+ cells promote diabetes development. Enhanced Vγ1+ cell numbers in NOD mice, in particular those biased to produce IFNγ, appear to favor diabetic disease. Within NOD mice deficient in particular γδ T cell subsets, we noted that changes in the abundance of non-targeted T cell types also occurred, which varied depending upon the γδ T cells that were missing. Our results indicate that while certain γδ T cell subsets inhibit the development of spontaneous type 1 diabetes, others exacerbate it, and they may do so via mechanisms that include altering the levels of other T cells.
Ligands for Melanocortin Receptors: Beyond Melanocyte-Stimulating Hormones and Adrenocorticotropin
Authors: Yuan Xiao-Chen , Tao Ya-Xiong
Published: October 2022

The discovery of melanocortins in 1916 has resulted in more than 100 years of research focused on these peptides. Extensive studies have elucidated well-established functions of melanocortins mediated by cell surface receptors, including MSHR (melanocyte-stimulating hormone receptor) and ACTHR (adrenocorticotropin receptor). Subsequently, three additional melanocortin receptors (MCRs) were identified. Among these five MCRs, MC3R and MC4R are expressed primarily in the central nervous system, and are therefore referred to as the neural MCRs. Since the central melanocortin system plays important roles in regulating energy homeostasis, targeting neural MCRs is emerging as a therapeutic approach for treating metabolic conditions such as obesity and cachexia. Early efforts modifying endogenous ligands resulted in the development of many potent and selective ligands. This review focuses on the ligands for neural MCRs, including classical ligands (MSH and agouti-related peptide), nonclassical ligands (lipocalin 2, β-defensin, small molecules, and pharmacoperones), and clinically approved ligands (ACTH, setmelanotide, bremelanotide, and several repurposed drugs).
Rosmarinic Acid and Related Dietary Supplements: Potential Applications in the Prevention and Treatment of Cancer
Authors: Zhao Jiachao , Xu Liwei , Jin Di , Xin Yu , Tian Lin , Wang Tan , Zhao Daqing , Wang Zeyu , Wang Jing
Published: October 2022

Cancer constitutes a severe threat to human health and quality of life and is one of the most significant causes of morbidity and mortality worldwide. Natural dietary products have drawn substantial attention in cancer treatment and prevention due to their availability and absence of toxicity. Rosmarinic acid (RA) is known for its excellent antioxidant properties and is safe and effective in preventing and inhibiting tumors. This review summarizes recent publications on culture techniques, extraction processes, and anti-tumor applications of RA-enriched dietary supplements. We discuss techniques to improve RA bioavailability and provide a mechanistic discussion of RA regarding tumor prevention, treatment, and adjuvant therapy. RA exhibits anticancer activity by regulating oxidative stress, chronic inflammation, cell cycle, apoptosis, and metastasis. These data suggest that daily use of RA-enriched dietary supplements can contribute to tumor prevention and treatment. RA has the potential for application in anti-tumor drug development.
Modeling Reactive Oxygen Species-Induced Axonal Loss in Leber Hereditary Optic Neuropathy
Authors: Lambiri Darius W. , Levin Leonard A.
Published: October 2022

Leber hereditary optic neuropathy (LHON) is a rare syndrome that results in vision loss. A necessary but not sufficient condition for its onset is the existence of known mitochondrial DNA mutations that affect complex I biomolecular structure. Cybrids with LHON mutations generate higher rates of reactive oxygen species (ROS). This study models how ROS, particularly H2O2, could signal and execute the axonal degeneration process that underlies LHON. We modeled and explored several hypotheses regarding the influence of H2O2 on the dynamics of propagation of axonal degeneration in LHON. Zonal oxidative stress, corresponding to H2O2 gradients, correlated with the morphology of injury exhibited in the LHON pathology. If the axonal membrane is highly permeable to H2O2 and oxidative stress induces larger production of H2O2, small injuries could trigger cascading failures of neighboring axons. The cellular interdependence created by H2O2 diffusion, and the gradients created by tissue variations in H2O2 production and scavenging, result in injury patterns and surviving axonal loss distributions similar to LHON tissue samples. Specifically, axonal degeneration starts in the temporal optic nerve, where larger groups of small diameter fibers are located and propagates from that region. These findings correlate well with clinical observations of central loss of visual field, visual acuity, and color vision in LHON, and may serve as an in silico platform for modeling the mechanism of action for new therapeutics.
Searching for the Metabolic Signature of Cancer: A Review from Warburg’s Time to Now
Authors: Jacquet Pierre , Stéphanou Angélique
Published: October 2022

This review focuses on the evolving understanding that we have of tumor cell metabolism, particularly glycolytic and oxidative metabolism, and traces back its evolution through time. This understanding has developed since the pioneering work of Otto Warburg, but the understanding of tumor cell metabolism continues to be hampered by misinterpretation of his work. This has contributed to the use of the new concepts of metabolic switch and metabolic reprogramming， that are out of step with reality. The Warburg effect is often considered to be a hallmark of cancer, but is it really? More generally, is there a metabolic signature of cancer? We draw the conclusion that the signature of cancer cannot be reduced to a single factor, but is expressed at the tissue level in terms of the capacity of cells to dynamically explore a vast metabolic landscape in the context of significant environmental heterogeneities.
Mitochondria and Central Nervous System Disorders
Authors: Knedlik Tomas , Giacomello Marta
Published: October 2022

Mitochondria are semi-autonomous, membrane-bound organelles present in the cytoplasm of nearly all eukaryotic cells [...]
Use of Olive and Sunflower Oil Hydrogel Emulsions as Pork Fat Replacers in Goat Meat Burgers: Fat Reduction and Effects in Lipidic Quality
Authors: Ferreira Iasmin , Vasconcelos Lia , Leite Ana , Botella-Martínez Carmen , Pereira Etelvina , Mateo Javier , Kasaiyan Seyedalireza , Teixeira Alfredo
Published: October 2022

Diversified strategies to incorporate healthier lipids in processed meat products are being developed. Alternative fat sources to replace animal fat associated with the reduction of fat content are some of the methods used to obtain healthier meat products well recognized by consumers. In order to create a healthier product that can also be consumed in the Halal and Kosher consumer markets, an experimental study was developed to assess the effects of replacing the pork fat (4%) with the same amount of hydrogel emulsion incorporating olive oil or sunflower oil. Three burgers were randomly selected from each lot manufactured and analyzed in triplicate. Burgers were physicochemical analyzed for pH, water activity, composition, fatty acid profile, color, yield, texture, oxidative stability, and volatile compounds and compared according to the fat source. Burgers with hydrogel emulsions can be considered reduced-fat meat products with a healthier fatty acid profile than pork fat burgers. The use of hydrogel emulsions did not negatively affect the quality characteristics assessed in the product and improved the oxidative stability during the storage of cooked burgers. By the characteristics and formulations evaluated, the replacement of pork fat with olive oil hydrogel emulsion proved to be the most effective strategy for obtaining a healthier goat meat product.
Statins Alleviate Tumor Hypoxia in Prostate Cancer Models by Decreasing Oxygen Consumption: An Opportunity for Radiosensitization?
Authors: d’Hose Donatienne , Mignion Lionel , Hamelin Loïc , Sonveaux Pierre , Jordan Bénédicte F. , Gallez Bernard
Published: October 2022

Background: Because statins were found to decrease the oxygen consumption rate (OCR) of a variety of normal cells, our hypothesis was that statins may also decrease the OCR of cancer cells, alleviate tumor hypoxia and radiosensitize tumors. Methods: OCR was assessed using the Seahorse XF96 technology and EPR respirometry in PC-3 prostate cancer cells. Mitochondrial superoxide production was measured by EPR with mitoTEMPO-H as a sensing probe. Tumor pO2 was measured in vivo using low-frequency EPR oximetry to define the optimal window of reoxygenation, the time at which tumors were irradiated with a single 6 Gy dose with a Cesium-137 irradiator. Results: 24-h exposure to simvastatin and fluvastatin significantly decreased the OCR of PC-3 cancer cells. An increase in mitochondrial superoxide levels was also observed after fluvastatin exposure. The PC-3 prostate cancer model was found highly hypoxic at the basal level. When mice were treated with simvastatin or fluvastatin (daily injection of 20 mg/kg), tumor oxygenation increased 48 and 72 h after initiation of the treatment. However, despite reoxygenation, simvastatin did not sensitize the PC-3 tumor model to RT. Conclusions: exposure to statins affect tumor metabolism and tumor oxygenation, however, with limited impact on tumor growth with or without irradiation.
Systemic Biomarkers and Unique Pathways in Different Phenotypes of Heart Failure with Preserved Ejection Fraction
Authors: Chen Hao , Tesic Milorad , Nikolic Valentina N. , Pavlovic Milan , Vucic Rada M. , Spasic Ana , Jovanovic Hristina , Jovanovic Ivana , Town Stephanie E. L. , Padula Matthew P. , McClements Lana
Published: October 2022

Heart failure with preserved ejection fraction (HFpEF) accounts for around 50% of all heart failure cases. It is a heterogeneous condition with poorly understood pathogenesis. Here, we aimed to identify unique pathogenic mechanisms in acute and chronic HFpEF and hypertrophic cardiomyopathy (HCM). We performed unbiased, comprehensive proteomic analyses of plasma samples from gender- and BMI-matched patients with acute HFpEF (n = 8), chronic HFpEF (n = 9) and HCM (n = 14) using liquid chromatography–mass spectrometry. Distinct molecular signatures were observed in different HFpEF forms. Clusters of biomarkers differentially abundant between HFpEF forms were predominantly associated with microvascular inflammation. New candidate protein markers were also identified, including leucine-rich alpha-2-glycoprotein 1 (LRG1), serum amyloid A1 (SAA1) and inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3). Our study is the first to apply systematic, quantitative proteomic screening of plasma samples from patients with different subtypes of HFpEF and identify candidate biomarkers for improved management of acute and chronic HFpEF and HCM.
Mitophagy—A New Target of Bone Disease
Authors: Zeng Zhipeng , Zhou Xuchang , Wang Yan , Cao Hong , Guo Jianmin , Wang Ping , Yang Yajing , Wang Yan
Published: October 2022

Bone diseases are usually caused by abnormal metabolism and death of cells in bones, including osteoblasts, osteoclasts, osteocytes, chondrocytes, and bone marrow mesenchymal stem cells. Mitochondrial dysfunction, as an important cause of abnormal cell metabolism, is widely involved in the occurrence and progression of multiple bone diseases, including osteoarthritis, intervertebral disc degeneration, osteoporosis, and osteosarcoma. As selective mitochondrial autophagy for damaged or dysfunctional mitochondria, mitophagy is closely related to mitochondrial quality control and homeostasis. Accumulating evidence suggests that mitophagy plays an important regulatory role in bone disease, indicating that regulating the level of mitophagy may be a new strategy for bone-related diseases. Therefore, by reviewing the relevant literature in recent years, this paper reviews the potential mechanism of mitophagy in bone-related diseases, including osteoarthritis, intervertebral disc degeneration, osteoporosis, and osteosarcoma, to provide a theoretical basis for the related research of mitophagy in bone diseases.
Effect of Nitrogen Concentration on the Biosynthesis of Citric Acid, Protein, and Lipids in the Yeast Yarrowia lipolytica
Authors: Kamzolova Svetlana V. , Lunina Julia N. , Samoilenko Vladimir A. , Morgunov Igor G.
Published: October 2022

Yarrowia lipolytica yeast is well known to be able to synthesize citric acid (CA) in large amounts. This study deals with CA biosynthesis, the production of biomass, as well as the accumulation and composition of proteins and lipids in Y. lipolytica VKM Y-2373 grown in media with glucose at different concentrations of ammonium sulfate (from 2 to 10 g/L). It was found that these concentrations of nitrogen source are limiting for the growth of Y. lipolytica and that nitrogen deficiency is the main cause of CA excretion. At the high concentration of (NH4)2SO4 (10 g/L), the accumulation of cell biomass, biomass yield (YX/S), and protein concentration was higher than in the medium with 2 g/L ammonium sulfate by 4.3 times, 143%, and 5.1 times, respectively. CA was accumulated in meaningful quantities only in media containing 3–10 g/L (NH4)2SO4 with the maximum concentration of CA (99.9 g/L) at 4 g/L ammonium sulfate. Also of interest is the technological mode with 6 g/L (NH4)2SO4, which is characterized by high productivity (1.11 g/L × h). It should be noted that biomass contains large amounts of essential amino acids and unsaturated fatty acids and can be used in food biotechnologies and agriculture.
Human Melanocortin-2 Receptor: Identifying a Role for Residues in the TM4, EC2, and TM5 Domains in Activation and Trafficking as a Result of Co-Expression with the Accessory Protein, Mrap1 in Chinese Hamster Ovary Cells
Authors: Davis Perry V. , Shaughnessy Ciaran A. , Dores Robert M.
Published: October 2022

Human melanocortin-2 receptor (hMC2R) co-expressed with the accessory protein mouse (m)MRAP1 in Chinese Hamster Ovary (CHO) cells has been used as a model system to investigate the activation and trafficking of hMC2R. A previous study had shown that the N-terminal domain of mMRAP1 makes contact with one of the extracellular domains of hMC2R to facilitate activation of hMC2R. A chimeric receptor paradigm was used in which the extracellular domains of hMC2R were replaced with the corresponding domains from Xenopus tropicalis MC1R, a receptor that does not interact with MRAP1, to reveal that EC2 (Extracellular domain 2) is the most likely contact site for hMC2R and mMRAP1 to facilitate activation of the receptor following an ACTH binding event. Prior to activation, mMRAP1 facilitates the trafficking of hMC2R from the ER to the plasma membrane. This process is dependent on the transmembrane domain (TM) of mMRAP1 making contact with one or more TMs of hMC2R. A single alanine substitution paradigm was used to identify residues in TM4 (i.e., I163, M165), EC2 (F167), and TM5 (F178) that play a role in the trafficking of hMC2R to the plasma membrane. These results provide further clarification of the activation mechanism for hMC2R.
Identification of Proteins Responsible for the Neuroprotective Effect of the Secretome Derived from Blood Cells of Remote Ischaemic Conditioned Rats
Authors: Bonova Petra , Koncekova Jana , Nemethova Miroslava , Petrova Klaudia , Bona Martin , Gottlieb Miroslav
Published: October 2022

We have recently shown that the blood cell-derived secretome of remote ischaemic (RIC)-conditioned individuals provides an external source of neuroprotection. In this study, we identified the bioactive compounds from the total proteins released by those cells. Our main strategy was to separate protein–protein complexes while maintaining their native structure and testing their bioactive properties. Subsequently, we identified up- and downregulated bioactive proteins. We uncovered two bioactive fractions composed of 18 proteins. Most of the protein peaks were unchanged; however, RIC mediated a decrease in two peaks (comprising seven proteins) and an increase in one peak (identified as haptoglobin). When focussing on the biological activity of these proteins, we found positive impacts on the regulation of cellular metabolic processes and an increase in biological processes related to the acute phase response and inflammation in the RIC-treated samples. Although we have identified the 18 proteins that exert the greatest cytoprotection, additional studies are needed to elucidate their particular function and detailed mechanisms of action.
Recent Progress of Deubiquitinating Enzymes in Human and Plant Pathogenic Fungi
Authors: Wang Weixiang , Cai Xuan , Chen Xiao-Lin
Published: October 2022

In eukaryotic cells, a large number of proteins are modified by ubiquitination, which leads to proteasomal degradation or change in protein function. The protein ubiquitination process can be reversed by a process called deubiquitination, which plays an important regulatory mechanism in cellular control. Deubiquitination is catalyzed by deubiquitinating enzymes (DUBs); the cysteine proteases specifically cleave off ubiquitin from ubiquitinated substrates or ubiquitin precursors. Over the past two decades, components of different DUB families have been found to play important roles in both human and plant pathogenic fungi. Given the importance of DUBs for fungal development and virulence, in this review, we concentrate on recent findings and new insights into the roles of DUBs in different fungal pathogens, with a focus on infection-related morphogenesis and virulence, as well as their roles in development and stress response. We also summarize the DUBs-mediated regulatory mechanisms during the above processes. These findings should allow us to develop novel inhibitors to control fungal pathogens.
Deciphering the Alphabet of Disorder—Glu and Asp Act Differently on Local but Not Global Properties
Authors: Roesgaard Mette Ahrensback , Lundsgaard Jeppe E. , Newcombe Estella A. , Jacobsen Nina L. , Pesce Francesco , Tranchant Emil E. , Lindemose Søren , Prestel Andreas , Hartmann-Petersen Rasmus , Lindorff-Larsen Kresten , Kragelund Birthe B.
Published: October 2022

Compared to folded proteins, the sequences of intrinsically disordered proteins (IDPs) are enriched in polar and charged amino acids. Glutamate is one of the most enriched amino acids in IDPs, while the chemically similar amino acid aspartate is less enriched. So far, the underlying functional differences between glutamates and aspartates in IDPs remain poorly understood. In this study, we examine the differential effects of aspartate and glutamates in IDPs by comparing the function and conformational ensemble of glutamate and aspartate variants of the disordered protein Dss1, using a range of assays, including interaction studies, nuclear magnetic resonance spectroscopy, small-angle X-ray scattering and molecular dynamics simulation. First, we analyze the sequences of the rapidly growing database of experimentally verified IDPs (DisProt) and show that glutamate enrichment is not caused by a taxonomy bias in IDPs. From analyses of local and global structural properties as well as cell growth and protein-protein interactions using a model acidic IDP from yeast and three Glu/Asp variants, we find that while the Glu/Asp variants support similar function and global dimensions, the variants differ in their binding affinities and population of local transient structural elements. We speculate that these local structural differences may play roles in functional diversity, where glutamates can support increased helicity, important for folding and binding, while aspartates support extended structures and form helical caps, as well as playing more relevant roles in, e.g., transactivation domains and ion-binding.
Lysine Crotonylation: An Emerging Player in DNA Damage Response
Authors: Zhao Yuqin , Hao Shuailin , Wu Wenchi , Li Youhang , Hou Kaiping , Liu Yu , Cui Wei , Xu Xingzhi , Wang Hailong
Published: October 2022

The DNA damage response (DDR) system plays an important role in maintaining genome stability and preventing related diseases. The DDR network comprises many proteins and posttranslational modifications (PTMs) to proteins, which work in a coordinated manner to counteract various genotoxic stresses. Lysine crotonylation (Kcr) is a newly identified PTM occurring in both core histone and non-histone proteins in various organisms. This novel PTM is classified as a reversible acylation modification, which is regulated by a variety of acylases and deacylases and the intracellular crotonyl-CoA substrate concentration. Recent studies suggest that Kcr links cellular metabolism with gene regulation and is involved in numerous cellular processes. In this review, we summarize the regulatory mechanisms of Kcr and its functions in DDR, including its involvement in double-strand break (DSB)-induced transcriptional repression, DSB repair, and the DNA replication stress response.
Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy
Authors: Errico Francesco , Marino Carmen , Grimaldi Manuela , Nuzzo Tommaso , Bassareo Valentina , Valsecchi Valeria , Panicucci Chiara , Di Schiavi Elia , Mazza Tommaso , Bruno Claudio , D’Amico Adele , Carta Manolo , D’Ursi Anna Maria , Bertini Enrico , Pellizzoni Livio , Usiello Alessandro
Published: October 2022

Intrathecal delivery of Nusinersen–an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction–is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients.
Structural–Functional Relationship of the Ribonucleolytic Activity of aIF5A from Sulfolobus solfataricus
Authors: Romagnoli Alice , Moretti Paolo , D’Agostino Mattia , Rexha Jesmina , Perta Nunzio , Piccinini Astra , Di Marino Daniele , Spinozzi Francesco , La Teana Anna
Published: October 2022

The translation factor IF5A is a highly conserved protein playing a well-recognized and well-characterized role in protein synthesis; nevertheless, some of its features as well as its abundance in the cell suggest that it may perform additional functions related to RNA metabolism. Here, we have undertaken a structural and functional characterization of aIF5A from the crenarchaeal Sulfolobus solfataricus model organism. We confirm the association of aIF5A with several RNA molecules in vivo and demonstrate that the protein is endowed with a ribonuclease activity which is specific for long and structured RNA. By means of biochemical and structural approaches we show that aIF5A can exist in both monomeric and dimeric conformations and the monomer formation is favored by the association with RNA. Finally, modelling of the three-dimensional structure of S. solfataricus aIF5A shows an extended positively charged surface which may explain its strong tendency to associate to RNA in vivo.
Structural Achievability of an NH–π Interaction between Gln and Phe in a Crystal Structure of a Collagen-like Peptide
Authors: Zhang Ruixue , Xu You , Lan Jun , Fan Shilong , Huang Jing , Xu Fei
Published: October 2022

NH–π interactions between polar and aromatic residues are well distributed in proteins whose stabilizing effects have been investigated in globular and fibrous proteins. In order to gain structural insights into side chain NH–π interactions, we solved a crystal structure of a collagen-like peptide containing Gln-Phe pairs. The Gln-Phe NH–π interactions were further characterized by quantum calculations, molecular simulations, and structural bioinformatics. The analyses indicated that the NH–π interactions are robust under various solvent conditions, can be distributed either on the protein surface or in its hydrophobic core and can form at a wide range of distances between residues. This study suggested that NH–π interactions can play a versatile role in protein design, including engineering hydrophobic cores, solvent accessible surfaces, and protein–protein interfaces.
Elucidating the Structural Impacts of Protein InDels
Authors: Jilani Muneeba , Turcan Alistair , Haspel Nurit , Jagodzinski Filip
Published: October 2022

The effects of amino acid insertions and deletions (InDels) remain a rather under-explored area of structural biology. These variations oftentimes are the cause of numerous disease phenotypes. In spite of this, research to study InDels and their structural significance remains limited, primarily due to a lack of experimental information and computational methods. In this work, we fill this gap by modeling InDels computationally; we investigate the rigidity differences between the wildtype and a mutant variant with one or more InDels. Further, we compare how structural effects due to InDels differ from the effects of amino acid substitutions, which are another type of amino acid mutation. We finish by performing a correlation analysis between our rigidity-based metrics and wet lab data for their ability to infer the effects of InDels on protein fitness.