bluuebunny/crossref_metadata_2025 huggingface dataset:
New Insight on Water Status in Germinating Brassica napus Seeds in Relation to Priming-Improved Germination
Authors: Lechowska Katarzyna , Kubala Szymon , Wojtyla Łukasz , Nowaczyk Grzegorz , Quinet Muriel , Lutts Stanley , Garnczarska Małgorzata
Published: January 2019

Seed priming is a pre-sowing method successfully used to improve seed germination. Since water plays a crucial role in germination, the aim of this study was to investigate the relationship between better germination performances of osmoprimed Brassica napus seeds and seed water status during germination. To achieve this goal, a combination of different kinds of approaches was used, including nuclear magnetic resonance (NMR) spectroscopy, TEM, and SEM as well as semi-quantitative PCR (semi-qPCR). The results of this study showed that osmopriming enhanced the kinetics of water uptake and the total amount of absorbed water during both the early imbibition stage and in the later phases of seed germination. The spin–spin relaxation time (T2) measurement suggests that osmopriming causes faster water penetration into the seed and more efficient tissue hydration. Moreover, factors potentially affecting water relations in germinating primed seeds were also identified. It was shown that osmopriming (i) changes the microstructural features of the seed coat, e.g., leads to the formation of microcracks, (ii) alters the internal structure of the seed by the induction of additional void spaces in the seed, (iii) increases cotyledons cells vacuolization, and (iv) modifies the expression pattern of aquaporin genes.
Network Pharmacology-Based Investigation of Protective Mechanism of Aster tataricus on Lipopolysaccharide-Induced Acute Lung Injury
Authors: Chen Yijun , Dong Jiaojiao , Liu Jie , Xu Wenjuan , Wei Ziyi , Li Yueting , Wu Hao , Xiao Hongbin
Published: January 2019

Acute lung injury (ALI) is a common clinical condition that badly influences people’s health. Recent studies indicated that Aster tataricus (RA) had potential effects on ALI, but the effective components and their mechanism is not clear. In this study, we found that the Fraction-75 eluted from RA extract could significantly protect the lipopolysaccharide (LPS)-induced ALI in mice, including alleviating the severity of lung pathology, attenuating the pulmonary edema, and reducing the release of inflammatory cells. Further ingredient analyses demonstrated that there were mainly 16 components in it, among which 10 components were collected according to their relative peak area and oral bioavailability. Next, the components-disease targets network suggested that the candidate components had extensive associations with 49 known therapeutic targets of ALI, among which 31 targets could be regulated by more than one component. Herein, GO functional and pathway analysis revealed that the common targets were associated with four biological processes, including the inflammatory response to stimulus, cellular process, chemokine biosynthetic process and immune system process. Furthermore, the ELISA validation indicated that the candidate components in RA extract may protect the LPS-induced ALI mainly through inhibiting the release of inflammatory cytokines and promoting the repair of vascular endothelial.
Developing LRP1 Agonists into a Therapeutic Strategy in Acute Myocardial Infarction
Authors: Potere Nicola , Del Buono Marco Giuseppe , Niccoli Giampaolo , Crea Filippo , Toldo Stefano , Abbate Antonio
Published: January 2019

Cardioprotection refers to a strategy aimed at enhancing survival pathways in the injured yet salvageable myocardium following ischemia-reperfusion. Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor that can be targeted following reperfusion, to induce a cardioprotective signaling through the activation of the reperfusion injury salvage kinase (RISK) pathway. The data from preclinical studies with non-selective and selective LRP1 agonists are promising, showing a large therapeutic window for intervention to reduce infarct size after ischemia-reperfusion. A pilot clinical trial with plasma derived α1-antitrypsin (AAT), a naturally occurring LRP1 agonist, supports the translational value of LRP1 as a novel therapeutic target for cardioprotection. A phase I study with a selective LRP1 agonist has been completed showing no toxicity. These findings may open the way to early phase clinical studies with pharmacologic LRP1 activation in patients with acute myocardial infarction (AMI).
Killer Immunoglobulin-Like Receptor 2DS2 (KIR2DS2), KIR2DL2-HLA-C1, and KIR2DL3 as Genetic Markers for Stratifying the Risk of Cytomegalovirus Infection in Kidney Transplant Recipients
Authors: Deborska-Materkowska Dominika , Perkowska-Ptasinska Agnieszka , Sadowska-Jakubowicz Anna , Gozdowska Jolanta , Ciszek Michał , Pazik Joanna , Ostaszewska Agata , Kosieradzki Maciej , Nowak Jacek , Durlik Magdalena
Published: January 2019

Infection with cytomegalovirus (CMV) remains a major problem in kidney transplant recipients, resulting in serious infectious complications and occasionally mortality. Accumulating evidence indicates that natural killer cell immunoglobulin-like receptors (KIRs) and their ligands affect the susceptibility to various diseases, including viral infections (e.g., CMV infection). We investigated whether KIR genes and their ligands affect the occurrence of CMV infection in a group of 138 kidney transplant recipients who were observed for 720 days posttransplantation. We typed the recipients for the presence of KIR genes (human leukocyte antigen C1 [HLA-C1], HLA-C2, HLA-A, HLA-B, and HLA-DR1) by polymerase chain reaction with sequence-specific primers. The multivariate analysis revealed that the lack of KIR2DS2 (p = 0.035), the presence of KIR2DL3 (p = 0.075), and the presence of KIR2DL2–HLA-C1 (p = 0.044) were risk factors for posttransplant CMV infection. We also found that a lower estimated glomerular filtration rate (p = 0.036), an earlier time of antiviral prophylaxis initiation (p = 0.025), lymphocytopenia (p = 0.012), and pretransplant serostatus (donor-positive/recipient-negative; p = 0.042) were independent risk factors for posttransplant CMV infection. In conclusion, our findings confirm that the KIR/HLA genotype plays a significant role in anti-CMV immunity and suggest the contribution of both environmental and genetic factors to the incidence of CMV infection after kidney transplantation.
iTRAQ-Based Protein Profiling and Biochemical Analysis of Two Contrasting Rice Genotypes Revealed Their Differential Responses to Salt Stress
Authors: Hussain Sajid , Zhu Chunquan , Bai Zhigang , Huang Jie , Zhu Lianfeng , Cao Xiaochuang , Nanda Satyabrata , Hussain Saddam , Riaz Aamir , Liang Qingduo , Wang Liping , Li Yefeng , Jin Qianyu , Zhang Junhua
Published: January 2019

Salt stress is one of the key abiotic stresses causing huge productivity losses in rice. In addition, the differential sensitivity to salinity of different rice genotypes during different growth stages is a major issue in mitigating salt stress in rice. Further, information on quantitative proteomics in rice addressing such an issue is scarce. In the present study, an isobaric tags for relative and absolute quantitation (iTRAQ)-based comparative protein quantification was carried out to investigate the salinity-responsive proteins and related biochemical features of two contrasting rice genotypes—Nipponbare (NPBA, japonica) and Liangyoupeijiu (LYP9, indica), at the maximum tillering stage. The rice genotypes were exposed to four levels of salinity: 0 (control; CK), 1.5 (low salt stress; LS), 4.5 (moderate salt stress; MS), and 7.5 g of NaCl/kg dry soil (high salt stress, HS). The iTRAQ protein profiling under different salinity conditions identified a total of 5340 proteins with 1% FDR in both rice genotypes. In LYP9, comparisons of LS, MS, and HS compared with CK revealed the up-regulation of 28, 368, and 491 proteins, respectively. On the other hand, in NPBA, 239 and 337 proteins were differentially upregulated in LS and MS compared with CK, respectively. Functional characterization by KEGG and COG, along with the GO enrichment results, suggests that the differentially expressed proteins are mainly involved in regulation of salt stress responses, oxidation-reduction responses, photosynthesis, and carbohydrate metabolism. Biochemical analysis of the rice genotypes revealed that the Na+ and Cl− uptake from soil to the leaves via the roots was increased with increasing salt stress levels in both rice genotypes. Further, increasing the salinity levels resulted in increased cell membrane injury in both rice cultivars, however more severely in NPBA. Moreover, the rice root activity was found to be higher in LYP9 roots compared with NPBA under salt stress conditions, suggesting the positive role of rice root activity in mitigating salinity. Overall, the results from the study add further insights into the differential proteome dynamics in two contrasting rice genotypes with respect to salt tolerance, and imply the candidature of LYP9 to be a greater salt tolerant genotype over NPBA.
Effect of Trichoderma velutinum and Rhizoctonia solani on the Metabolome of Bean Plants (Phaseolus vulgaris L.)
Authors: Mayo-Prieto Sara , Marra Roberta , Vinale Francesco , Rodríguez-González Álvaro , Woo Sheridan , Lorito Matteo , Gutiérrez Santiago , Casquero Pedro
Published: January 2019

The common bean (Phaseolus vulgaris L.) is one of the most important food legume crops worldwide that is affected by phytopathogenic fungi such as Rhizoctonia solani. Biological control represents an effective alternative method for the use of conventional synthetic chemical pesticides for crop protection. Trichoderma spp. have been successfully used in agriculture both to control fungal diseases and to promote plant growth. The response of the plant to the invasion of fungi activates defensive resistance responses by inducing the expression of genes and producing secondary metabolites. The purpose of this work was to analyze the changes in the bean metabolome that occur during its interaction with pathogenic (R. solani) and antagonistic (T. velutinum) fungi. In this work, 216 compounds were characterized by liquid chromatography mass spectrometry (LC-MS) analysis but only 36 were noted as significantly different in the interaction in comparison to control plants and they were tentatively characterized. These compounds were classified as: two amino acids, three peptides, one carbohydrate, one glycoside, one fatty acid, two lipids, 17 flavonoids, four phenols and four terpenes. This work is the first attempt to determine how the presence of T. velutinum and/or R. solani affect the defense response of bean plants using untargeted metabolomics analysis.
Bone Marrow Mast Cell Antibody-Targetable Cell Surface Protein Expression Profiles in Systemic Mastocytosis
Authors: Dasilva-Freire Noelia , Mayado Andrea , Teodosio Cristina , Jara-Acevedo María , Álvarez-Twose Iván , Matito Almudena , Sánchez-Muñoz Laura , Caldas Carolina , Henriques Ana , Muñoz-González Javier I. , García-Montero Andrés C. , Sánchez-Gallego J. Ignacio , Escribano Luis , Orfao Alberto
Published: January 2019

Despite recent therapeutic advances, systemic mastocytosis (SM) remains an incurable disease due to limited complete remission (CR) rates even after novel therapies. To date, no study has evaluated the expression on SM bone marrow mast cells (BMMC) of large panel of cell surface suitable for antibody-targeted therapy. In this study, we analyzed the expression profile of six cell-surface proteins for which antibody-based therapies are available, on BMMC from 166 SM patients vs. 40 controls. Overall, variable patterns of expression for the markers evaluated were observed among SM BMMC. Thus, CD22, CD30, and CD123, while expressed on BMMC from patients within every subtype of SM, showed highly variable patterns with a significant fraction of negative cases among advanced SM (aggressive SM (ASM), ASM with an associated clonal non-MC lineage disease (ASM-AHN) and MC leukemia (MCL)), 36%, 46%, and 39%, respectively. In turn, CD25 and FcεRI were found to be expressed in most cases (89% and 92%) in virtually all BMMC (median: 92% and 95%) from both indolent and advanced SM, but with lower/absent levels in a significant fraction of MC leukemia (MCL) and both in MCL and well-differentiated SM (WDSM) patients, respectively. In contrast, CD33 was the only marker expressed on all BMMC from every SM patient. Thus, CD33 emerges as the best potentially targetable cell-surface membrane marker in SM, particularly in advanced SM.
Antioxidant Properties of Fucoidan Alleviate Acceleration and Exacerbation of Hippocampal Neuronal Death Following Transient Global Cerebral Ischemia in High-Fat Diet-Induced Obese Gerbils
Authors: Ahn Ji Hyeon , Shin Myoung Cheol , Kim Dae Won , Kim Hyunjung , Song Minah , Lee Tae-Kyeong , Lee Jae-Chul , Kim Hyeyoung , Cho Jun Hwi , Kim Young-Myeong , Kim Jong-Dai , Choi Soo Young , Won Moo-Ho , Park Joon Ha
Published: January 2019

Fucoidan, a natural sulfated polysaccharide, displays various biological activities including antioxidant properties. We examined the neuroprotective effect of fucoidan against transient global cerebral ischemia (tGCI) in high-fat diet (HFD)-induced obese gerbils and its related mechanisms. Gerbils received HFD for 12 weeks and fucoidan (50 mg/kg) daily for the last 5 days during HFD exposure, and they were subjected to 5-min tGCI. Pyramidal cell death was observed only in the CA 1 area (CA1) of the hippocampus in non-obese gerbils 5 days after tGCI. However, in obese gerbils, pyramidal cell death in the CA1 and CA2/3 occurred at 2 days and 5 days, respectively, after tGCI. In the obese gerbils, oxidative stress indicators (dihydroethidium, 8-hydroxyguanine and 4-hydroxy-2-nonenal) were significantly enhanced and antioxidant enzymes (SOD1 and SOD2) were significantly reduced in pre- and post-ischemic phases compared to the non-obese gerbils. Fucoidan treatment attenuated acceleration and exacerbation of tGCI-induced neuronal death in the CA1–3, showing that oxidative stress was significantly reduced, and antioxidant enzymes were significantly increased in pre- and post-ischemic phases. These findings indicate that pretreated fucoidan can relieve the acceleration and exacerbation of ischemic brain injury in an obese state via the attenuation of obesity-induced severe oxidative damage.
Novel Gastric Cancer Stem Cell-Related Marker LINGO2 Is Associated with Cancer Cell Phenotype and Patient Outcome
Authors: Jo Jung Hyun , Park Soo Been , Park Semi , Lee Hee Seung , Kim Chanyang , Jung Dawoon E. , Song Si Young
Published: January 2019

The expression of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2) has been reported in Parkinson’s disease; however, its role in other diseases is unknown. Gastric cancer is the second leading cause of cancer death. Cancer stem cells (CSC) are a subpopulation of cancer cells that contribute to the initiation and invasion of cancer. We identified LINGO2 as a CSC-associated protein in gastric cancers both in vitro and in patient-derived tissues. We studied the effect of LINGO2 on cell motility, stemness, tumorigenicity, and angiogenic capacity using cells sorted based on LINGO2 expression and LINGO2-silenced cells. Tissue microarray analysis showed that LINGO2 expression was significantly elevated in advanced gastric cancers. The overall survival of patients expressing high LINGO2 was significantly shorter than that of patients with low LINGO2. Cells expressing high LINGO2 showed elevated cell motility, angiogenic capacity, and tumorigenicity, while LINGO2 silencing reversed these properties. Silencing LINGO2 reduced kinase B (AKT)/extracellular signal-regulated kinase (ERK)/ERK kinase (MEK) phosphorylation and decreased epithelial-mesenchymal transition (EMT)-associated markers—N-Cadherin and Vimentin and stemness-associated markers— POU class 5 homeobox 1 (OCT4) and Indian hedgehog (IHH), and markedly decreased the CD44+ population. These indicate the involvement of LINGO2 in gastric cancer initiation and progression by altering cell motility, stemness, and tumorigenicity, suggesting LINGO2 as a putative target for gastric cancer treatment.
Mechanisms Underlying the Visual Benefit of Cell Transplantation for the Treatment of Retinal Degenerations
Authors: Léveillard Thierry , Klipfel Laurence
Published: January 2019

The transplantation of retinal cells has been studied in animals to establish proof of its potential benefit for the treatment of blinding diseases. Photoreceptor precursors have been grafted in animal models of Mendelian-inherited retinal degenerations, and retinal pigmented epithelial cells have been used to restore visual function in animal models of age-related macular degeneration (AMD) and recently in patients. Cell therapy over corrective gene therapy in inherited retinal degeneration can overcome the genetic heterogeneity by providing one treatment for all genetic forms of the diseases. In AMD, the existence of multiple risk alleles precludes a priori the use of corrective gene therapy. Mechanistically, the experiments of photoreceptor precursor transplantation reveal the importance of cytoplasmic material exchange between the grafted cells and the host cells for functional rescue, an unsuspected mechanism and novel concept. For transplantation of retinal pigmented epithelial cells, the mechanisms behind the therapeutic benefit are only partially understood, and clinical trials are ongoing. The fascinating studies that describe the development of methodologies to produce cells to be grafted and demonstrate the functional benefit for vision are reviewed.
Drug Development for Alzheimer’s Disease: Microglia Induced Neuroinflammation as a Target?
Authors: Dong Yuan , Li Xiaoheng , Cheng Jinbo , Hou Lin
Published: January 2019

Alzheimer’s disease (AD) is one of the most common causes of dementia. Its pathogenesis is characterized by the aggregation of the amyloid-β (Aβ) protein in senile plaques and the hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Current medications for AD can provide temporary help with the memory symptoms and other cognitive changes of patients, however, they are not able to stop or reverse the progression of AD. New medication discovery and the development of a cure for AD is urgently in need. In this review, we summarized drugs for AD treatments and their recent updates, and discussed the potential of microglia induced neuroinflammation as a target for anti-AD drug development.
GPR68: An Emerging Drug Target in Cancer
Authors: Wiley Shu Z. , Sriram Krishna , Salmerón Cristina , Insel Paul A.
Published: January 2019

GPR68 (or ovarian cancer G protein-coupled receptor 1, OGR1) is a proton-sensing G-protein-coupled receptor (GPCR) that responds to extracellular acidity and regulates a variety of cellular functions. Acidosis is considered a defining hallmark of the tumor microenvironment (TME). GPR68 expression is highly upregulated in numerous types of cancer. Emerging evidence has revealed that GPR68 may play crucial roles in tumor biology, including tumorigenesis, tumor growth, and metastasis. This review summarizes current knowledge regarding GPR68—its expression, regulation, signaling pathways, physiological roles, and functions it regulates in human cancers (including prostate, colon and pancreatic cancer, melanoma, medulloblastoma, and myelodysplastic syndrome). The findings provide evidence for GPR68 as a potentially novel therapeutic target but in addition, we note challenges in developing drugs that target GPR68.
Genomic Features and Clinical Management of Patients with Hereditary Pancreatic Cancer Syndromes and Familial Pancreatic Cancer
Authors: Ohmoto Akihiro , Yachida Shinichi , Morizane Chigusa
Published: January 2019

Pancreatic cancer (PC) is one of the most devastating malignancies; it has a 5-year survival rate of only 9%, and novel treatment strategies are urgently needed. While most PC cases occur sporadically, PC associated with hereditary syndromes or familial PC (FPC; defined as an individual having two or more first-degree relatives diagnosed with PC) accounts for about 10% of cases. Hereditary cancer syndromes associated with increased risk for PC include Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma, familial adenomatous polyposis, Lynch syndrome and hereditary breast and ovarian cancer syndrome. Next-generation sequencing of FPC patients has uncovered new susceptibility genes such as PALB2 and ATM, which participate in homologous recombination repair, and further investigations are in progress. Previous studies have demonstrated that some sporadic cases that do not fulfil FPC criteria also harbor similar mutations, and so genomic testing based on family history might overlook some susceptibility gene carriers. There are no established screening procedures for high-risk unaffected cases, and it is not clear whether surveillance programs would have clinical benefits. In terms of treatment, poly (ADP-ribose) polymerase inhibitors for BRCA-mutated cases or immune checkpoint inhibitors for mismatch repair deficient cases are promising, and clinical trials of these agents are underway.
Muscle Insulin Resistance and the Inflamed Microvasculature: Fire from Within
Authors: Liu Jia , Liu Zhenqi
Published: January 2019

Insulin is a vascular hormone and regulates vascular tone and reactivity. Muscle is a major insulin target that is responsible for the majority of insulin-stimulated glucose use. Evidence confirms that muscle microvasculature is an important insulin action site and critically regulates insulin delivery to muscle and action on myocytes, thereby affecting insulin-mediated glucose disposal. Insulin via activation of its signaling cascade in the endothelial cells increases muscle microvascular perfusion, which leads to an expansion of the endothelial exchange surface area. Insulin’s microvascular actions closely couple with its metabolic actions in muscle and blockade of insulin-mediated microvascular perfusion reduces insulin-stimulated muscle glucose disposal. Type 2 diabetes is associated with chronic low-grade inflammation, which engenders both metabolic and microvascular insulin resistance through endocrine, autocrine and paracrine actions of multiple pro-inflammatory factors. Here, we review the crucial role of muscle microvasculature in the regulation of insulin action in muscle and how inflammation in the muscle microvasculature affects insulin’s microvascular actions as well as metabolic actions. We propose that microvascular insulin resistance induced by inflammation is an early event in the development of metabolic insulin resistance and eventually type 2 diabetes and its related cardiovascular complications, and thus is a potential therapeutic target for the prevention or treatment of obesity and diabetes.
Proteins and Signaling Pathways Response to Dry Needling Combined with Static Stretching Treatment for Chronic Myofascial Pain in a RAT Model: An Explorative Proteomic Study
Authors: Li Lihui , Huang Qiangmin , Barbero Marco , Liu Lin , Nguyen Thitham , Xu Anle , Ji Lijuan
Published: January 2019

A quantitative proteomic analysis of the response to dry needling combined with static stretching treatment was performed in a rat model of active myofascial trigger points (MTrPs). 36 rats were divided into a model group (MG), a stretching group (SG) and a dry needling combined with stretching group (SDG). We performed three biological replicates to compare large-scale differential protein expression between groups by tandem mass tag (TMT) labeling technology based on nanoscale liquid chromatography mass spectrometry analysis (LC–MS/MS). Hierarchical clustering, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and protein-protein interaction network analyses were performed for the general characterization of overall enriched proteins. For validation of the results of TMT, the candidate proteins were verified by parallel reaction monitoring (PRM) analysis. 285 differentially expressed proteins between groups were identified and quantified. Tight junction pathway played a dominant role in dry needling combined with static stretching treatment for the rat model of active MTrPs. Three candidate proteins, namely actinin alpha 3, calsequestrin-1 and parvalbumin alpha, were further validated, consistent with the results of LC–MS/MS. This is the first proteomics-based study to report the therapeutic mechanism underlying dry needling and static stretching treatment for MTrPs. Further functional verification of the potential signaling pathways and the enriched proteins is warranted.
Non-Viral Delivery System and Targeted Bone Disease Therapy
Authors: Qadir Abdul , Gao Yongguang , Suryaji Patil , Tian Ye , Lin Xiao , Dang Kai , Jiang Shanfeng , Li Yu , Miao Zhiping , Qian Airong
Published: January 2019

Skeletal systems provide support, movement, and protection to the human body. It can be affected by several life suffering bone disorders such as osteoporosis, osteoarthritis, and bone cancers. It is not an easy job to treat bone disorders because of avascular cartilage regions. Treatment with non-specific drug delivery must utilize high doses of systemic administration, which may result in toxicities in non-skeletal tissues and low therapeutic efficacy. Therefore, in order to overcome such limitations, developments in targeted delivery systems are urgently needed. Although the idea of a general targeted delivery system using bone targeting moieties like bisphosphonates, tetracycline, and calcium phosphates emerged a few decades ago, identification of carrier systems like viral and non-viral vectors is a recent approach. Viral vectors have high transfection efficiency but are limited by inducing immunogenicity and oncogenicity. Although non-viral vectors possess low transfection efficiency they are comparatively safe. A number of non-viral vectors including cationic lipids, cationic polymers, and cationic peptides have been developed and used for targeted delivery of DNA, RNA, and drugs to bone tissues or cells with successful consequences. Here we mainly discuss such various non-viral delivery systems with respect to their mechanisms and applications in the specific targeting of bone tissues or cells. Moreover, we discuss possible therapeutic agents that can be delivered against various bone related disorders.
Delayed Onset of Age-Dependent Changes in Ultrastructure of Myocardial Mitochondria as One of the Neotenic Features in Naked Mole Rats (Heterocephalus glaber)
Authors: Bakeeva Lora , Vays Valeria , Vangeli Irina , Eldarov Chupalav , Holtze Susanne , Hildebrandt Thomas , Skulachev Vladimir
Published: January 2019

In this study, the ultrastructure of mitochondria in cardiomyocytes of naked mole rats (Heterocephalus glaber) aged from 6 months to 11 years was examined. Mitochondria in cardiomyocytes of naked mole rats have a specific ultrastructure that is different from those in cardiomyocytes of other mammalian species studied to date. In contrast to mitochondria of other mammalian cardiomyocytes, where the internal space is completely filled by tightly packed parallel rows of cristae, mitochondria in cardiomyocytes of naked mole rats have a chaotic pattern of cristae organization with wave-like contours. Gradual formation of mitochondrial ultrastructure occurs in naked mole rats for many years. Two mitochondrial populations are developed to the age of 5 years. In addition to the main population, there are some large organelles which exceed normal sizes by two to three times. Most cristae in these mitochondria are assembled into small groups, which form the curved and ring-like structures. The appearance of some specific structural changes (i.e. bundles of parallel cristae) is observed in the mitochondrial population of naked mole rat after 11 years of age. However, these bundles are very rare and of sporadic nature. Morphometric analysis has shown that the superficial density of the inner mitochondrial membrane is similar in all examined age groups of naked mole rats: 21.1 at 6 months; 23.21 at 3 years; 23.55 at 5 years; and 20.8 at 11 years. This level is almost two times lower than in other animals studied (mice and rats). The data demonstrate that pathological changes in mitochondrial apparatus are not present in naked mole rats at least until the age of 11 years. The mitochondrial apparatus corresponds to the phenotype in young animals, thus being another neotenic feature in naked mole rats.
Design and Synthesis of A PD-1 Binding Peptide and Evaluation of Its Anti-Tumor Activity
Authors: Abbas Abdul Baset , Lin Bingjing , Liu Chen , Morshed Arwa , Hu Jialiang , Xu Hanmei
Published: January 2019

Immune-checkpoint blockades, suchas PD-1 monoclonal antibodies, have shown new promising avenues to treat cancers. Failure responsesof many cancer patients to these agents have led to a massive need for alternative strategies to optimize tumor immunotherapy. Currently, new therapeutic developments involve peptide blocking strategies, as they have high stability and low immunogenicity. Here, we have designed and synthesized a new peptide FITC-YT-16 to target PD-1. We have studied FITC-YT-16 by various experiments, including Molecular Operating Environment MOE modeling, purification testing by HPLC and LC mass, peptide/PD-1 conjugation and affinity by microscale thermophoresis (MST), and T cell immune-fluorescence imaging by fluorescence microscopy and flow cytometry. The peptide was tested for its ability to enhanceT cell activity against tumor cell lines, including TE-13, A549, and MDA-MB-231. Lastly, we assessed T cell cytotoxicity under peptide treatment. YT-16–PD-1 interaction showed a high binding affinity as a low energy complex that was confirmed by MOE. Furthermore, the peptide purity and molecular weights were 90.96% and 2344.66, respectively. MST revealed that FITC-YT-16 interacted with PD-1 at a Kd value of 17.8 ± 2.6 nM. T cell imaging and flow cytometry revealed high affinity of FITC-YT-16 to PD-1. Interestingly, FITC-YT-16 efficiently blocked PD-1 signaling pathways and promoted T cell inflammatory responses by elevating IL-2 and INF-γ levels. Moreover, FITC-YT-16 has the ability to activate T cell cytotoxicity. Therefore, FITC-YT-16 significantly enhanced T cell anti-tumor activity by blocking PD-1–PD-L1 interactions.
ADAMTS-9 in Mouse Cartilage Has Aggrecanase Activity That Is Distinct from ADAMTS-4 and ADAMTS-5
Authors: Rogerson Fraser M. , Last Karena , Golub Suzanne B. , Gauci Stephanie J. , Stanton Heather , Bell Katrina M. , Fosang Amanda J.
Published: January 2019

A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5 are the principal aggrecanases in mice and humans; however, mice lacking the catalytic domain of both enzymes (TS-4/5∆cat) have no skeletal phenotype, suggesting there is an alternative aggrecanase for modulating normal growth and development in these mice. We previously identified aggrecanase activity that (a) cleaved at E↓G rather than E↓A bonds in the aggrecan core protein, and (b) was upregulated by retinoic acid but not IL-1α. The present study aimed to identify the alternative aggrecanase. Femoral head cartilage explants from TS-4/5∆cat mice were stimulated with IL-1α or retinoic acid and total RNA was analysed by microarray. In addition to ADAMTS-5 and matrix metalloproteinase (MMP)-13, which are not candidates for the novel aggrecanase, the microarray analyses identified MMP-11, calpain-5 and ADAMTS-9 as candidate aggrecanases upregulated by retinoic acid. When calpain-5 and MMP-11 failed to meet subsequent criteria, ADAMTS-9 emerged as the most likely candidate for the novel aggrecanase. Immunohistochemistry revealed ADAMTS-9 expression throughout the mouse growth plate and strong expression, particularly in the proliferative zone of the TS-4/5-∆cat mice. In conclusion, ADAMTS-9 has a novel specificity for aggrecan, cleaving primarily at E↓G rather than E↓A bonds in mouse cartilage. ADAMTS-9 might have more important roles in normal skeletal development compared with ADAMTS-4 and ADAMTS-5, which have key roles in joint pathology.
Graphene-Induced Osteogenic Differentiation Is Mediated by the Integrin/FAK Axis
Authors: Xie Han , Cao Tong , Franco-Obregón Alfredo , Rosa Vinicius
Published: January 2019

Graphene is capable of promoting osteogenesis without chemical induction. Nevertheless, the underlying mechanism(s) remain largely unknown. The objectives here were: (i) to assess whether graphene scaffolds are capable of supporting osteogenesis in vivo and; (ii) to ascertain the participation of the integrin/FAK mechanotransduction axis during the osteogenic differentiation induced by graphene. MSC-impregnated graphene scaffolds (n = 6) were implanted into immunocompromised mice (28 days). Alternatively, MSCs were seeded onto PDMS substrates (modulus of elasticity = 130, 830 and 1300 kPa) coated with a single monomolecular layer of graphene and cultured in basal medium (10 days). The ensuing expressions of FAK-p397, integrin, ROCK1, F-actin, Smad p1/5, RUNX2, OCN and OPN were evaluated by Western blot (n = 3). As controls, MSCs were plated onto uncoated PDMS in the presence of mechanotransduction inhibitors (echistatin, Y27632 and DMH1). MSC-impregnated graphene scaffolds exhibited positive immunoexpression of bone-related markers (RUNX2 and OPN) without the assistance of osteogenic inducers. In vitro, regardless of the stiffness of the underlying PDMS substrate, MSCs seeded onto graphene-coated PDMS substrates demonstrated higher expressions of all tested osteogenic and integrin/FAK proteins tested compared to MSCs seeded onto PDMS alone. Hence, graphene promotes osteogenesis via the activation of the mechanosensitive integrin/FAK axis.
The Role of the CopA Copper Efflux System in Acinetobacter baumannii Virulence
Authors: Alquethamy Saleh F. , Khorvash Marjan , Pederick Victoria G. , Whittall Jonathan J. , Paton James C. , Paulsen Ian T. , Hassan Karl A. , McDevitt Christopher A. , Eijkelkamp Bart A.
Published: January 2019

Acinetobacter baumannii has emerged as one of the leading causative agents of nosocomial infections. Due to its high level of intrinsic and adapted antibiotic resistance, treatment failure rates are high, which allows this opportunistic pathogen to thrive during infection in immune-compromised patients. A. baumannii can cause infections within a broad range of host niches, with pneumonia and bacteraemia being associated with the greatest levels of morbidity and mortality. Although its resistance to antibiotics is widely studied, our understanding of the mechanisms required for dealing with environmental stresses related to virulence and hospital persistence, such as copper toxicity, is limited. Here, we performed an in silico analysis of the A. baumannii copper resistome, examining its regulation under copper stress. Using comparative analyses of bacterial P-type ATPases, we propose that A. baumannii encodes a member of a novel subgroup of P1B-1 ATPases. Analyses of three putative inner membrane copper efflux systems identified the P1B-1 ATPase CopA as the primary mediator of cytoplasmic copper resistance in A. baumannii. Using a murine model of A. baumannii pneumonia, we reveal that CopA contributes to the virulence of A. baumannii. Collectively, this study advances our understanding of how A. baumannii deals with environmental copper toxicity, and it provides novel insights into how A. baumannii combats adversities encountered as part of the host immune defence.
The Paroxysmal Depolarization Shift: Reconsidering Its Role in Epilepsy, Epileptogenesis and Beyond
Authors: Kubista Helmut , Boehm Stefan , Hotka Matej
Published: January 2019

Paroxysmal depolarization shifts (PDS) have been described by epileptologists for the first time several decades ago, but controversy still exists to date regarding their role in epilepsy. In addition to the initial view of a lack of such a role, seemingly opposing hypotheses on epileptogenic and anti-ictogenic effects of PDS have emerged. Hence, PDS may provide novel targets for epilepsy therapy. Evidence for the roles of PDS has often been obtained from investigations of the multi-unit correlate of PDS, an electrographic spike termed “interictal” because of its occurrence during seizure-free periods of epilepsy patients. Meanwhile, interictal spikes have been found to be associated with neuronal diseases other than epilepsy, e.g., Alzheimer’s disease, which may indicate a broader implication of PDS in neuropathologies. In this article, we give an introduction to PDS and review evidence that links PDS to pro- as well as anti-epileptic mechanisms, and to other types of neuronal dysfunction. The perturbation of neuronal membrane voltage and of intracellular Ca2+ that comes with PDS offers many conceivable pathomechanisms of neuronal dysfunction. Out of these, the operation of L-type voltage-gated calcium channels, which play a major role in coupling excitation to long-lasting neuronal changes, is addressed in detail.
Characterizing Cellular Responses During Oncolytic Maraba Virus Infection
Authors: Hassanzadeh Golnoush , Naing Thet , Graber Tyson , Jafarnejad Seyed Mehdi , Stojdl David F. , Alain Tommy , Holcik Martin
Published: January 2019

The rising demand for powerful oncolytic virotherapy agents has led to the identification of Maraba virus, one of the most potent oncolytic viruses from Rhabdoviridae family which displays high selectivity for killing malignant cells and low cytotoxicity in normal cells. Although the virus is readied to be used for clinical trials, the interactions between the virus and the host cells is still unclear. Using a newly developed interferon-sensitive mutant Maraba virus (MG1), we have identified two key regulators of global translation (4E-BP1 and eIF2α) as being involved in the regulation of protein synthesis in the infected cells. Despite the translational arrest upon viral stress, we showed an up-regulation of anti-apoptotic Bcl-xL protein that provides a survival benefit for the host cell, yet facilitates effective viral propagation. Given the fact that eIF5B canonically regulates 60S ribosome subunit end joining and is able to replace the role of eIF2 in delivering initiator tRNA to the 40S ribosome subunit upon the phosphorylation of eIF2α we have tested whether eIF5B mediates the translation of target mRNAs during MG1 infection. Our results show that the inhibition of eIF5B significantly down-regulates the level of Bcl-xL steady-state mRNA, thus indirectly attenuates viral propagation.
High Risk of Hepatocellular Carcinoma Development in Fibrotic Liver: Role of the Hippo-YAP/TAZ Signaling Pathway
Authors: Moon Hyuk , Cho Kyungjoo , Shin Sunyeong , Kim Do Young , Han Kwang-Hyub , Ro Simon Weonsang
Published: January 2019

Liver cancer is the fourth leading cause of cancer-related death globally, accounting for approximately 800,000 deaths annually. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, making up about 80% of cases. Liver fibrosis and its end-stage disease, cirrhosis, are major risk factors for HCC. A fibrotic liver typically shows persistent hepatocyte death and compensatory regeneration, chronic inflammation, and an increase in reactive oxygen species, which collaboratively create a tumor-promoting microenvironment via inducing genetic alterations and chromosomal instability, and activating various oncogenic molecular signaling pathways. In this article, we review recent advances in fields of liver fibrosis and carcinogenesis, and consider several molecular signaling pathways that promote hepato-carcinogenesis under the microenvironment of liver fibrosis. In particular, we pay attention to emerging roles of the Hippo-YAP/TAZ signaling pathway in stromal activation, hepatic fibrosis, and liver cancer.
Involvement of the PD-1/PD-L1 Co-Inhibitory Pathway in the Pathogenesis of the Inflammatory Stage of Early-Onset Preeclampsia
Authors: Meggyes Matyas , Miko Eva , Lajko Adrienn , Csiszar Beata , Sandor Barbara , Matrai Peter , Tamas Peter , Szereday Laszlo
Published: January 2019

The programmed cell death protein 1 (PD-1) receptor has been reported to downregulate T cell activation effectively via binding to its ligands PD-L1 or PD-L2 in a negative co-stimulatory manner. Little is known about the involvement of PD-1 mediated immunoregulation in pregnancy and in pregnancy-related disorders. In this work, we investigated the possible role of the PD-1 co-stimulatory pathway in the pathogenesis of the clinical phase of early-onset preeclampsia characterized by a systemic maternal inflammatory response. We performed a cross-sectional study for comparative analysis of phenotypic and functional characteristics of peripheral blood mononuclear cells in women with early-onset preeclampsia and third-trimester healthy pregnant controls. According to our findings, enhanced expression of either PD-1 or its ligand PD-L1, or both, on the cell surface of effector cells (T cells, natural killer (NK) cells, natural killer T (NKT)-like cells) and Tregs could be observed, but PD-1 expression did not correlate with effector cells exhaustion. These results suggest the failure of the axis to downregulate Th1 responses, contributing thereby to the exaggerated immunoactivation observed in early-onset preeclampsia.
Acute and Chronic Effects of Cocaine on Cardiovascular Health
Authors: Kim Sung Tae , Park Taehwan
Published: January 2019

Cardiac complications resulting from cocaine use have been extensively studied because of the complicated pathophysiological mechanisms. This study aims to review the underlying cellular and molecular mechanisms of acute and chronic effects of cocaine on the cardiovascular system with a specific focus on human studies. Studies have consistently reported the acute effects of cocaine on the heart (e.g., electrocardiographic abnormalities, acute hypertension, arrhythmia, and acute myocardial infarction) through multifactorial mechanisms. However, variable results have been reported for the chronic effects of cocaine. Some studies found no association of cocaine use with coronary artery disease (CAD), while others reported its association with subclinical coronary atherosclerosis. These inconsistent findings might be due to the heterogeneity of study subjects with regard to cardiac risk. After cocaine use, populations at high risk for CAD experienced coronary atherosclerosis whereas those at low risk did not experience CAD, suggesting that the chronic effects of cocaine were more likely to be prominent among individuals with higher CAD risk. Studies also suggested that risky behaviors and cardiovascular risks may affect the association between cocaine use and mortality. Our study findings highlight the need for education regarding the deleterious effects of cocaine, and access to interventions for cocaine abusers.
Improving Screening Programmes for Sickle Cell Disorders and Other Haemoglobinopathies in Europe: The Role of Patient Organisations
Authors: James John , Dormandy Elizabeth
Published: January 2019

This discussion paper has been written to show the unique contribution and added value that Patient Organisations can give to the development and improvement of newborn screening programmes for sickle cell disorder (SCD) and other haemoglobinopathies in Europe. As an example, the action of the Sickle Cell Society (SCS) in partnership with statutory organisations in the U.K., such as the National Health Service (NHS) Sickle Cell and Thalassaemia Screening Programme (NHS SCT SP), will be described.
Acknowledgement to Reviewers of Journal of Functional Morphology and Kinesiology in 2018
Authors:   Journal of Functional Morphology and Kinesiology Editorial Office
Published: January 2019

Rigorous peer-review is the corner-stone of high-quality academic publishing [...]
Towards a Process Model of Sustained Attention Tests
Authors: Blotenberg Iris , Schmidt-Atzert Lothar
Published: January 2019

Taking up new approaches and calls for experimental test validation, in the present study we propose and validate a process model of sustained attention tests. Four sub-components were postulated: the perception of an item, a simple mental operation to solve the item, a motor reaction, and the shift to the next item. In two studies, several cognitive tasks and modified versions of the d2-R test of sustained attention were applied in order to determine performance in the proposed sub-components. Their contribution for the prediction of performance in sustained attention tests and tests of higher cognitive abilities was assessed. The sub-components of the process model explained a large amount of variance in sustained attention tests, namely 55–74%. More specifically, perceptual and mental operation speed were the strongest predictors, while there was a trend towards a small influence of motor speed on test performance. The measures of item shifting showed low reliabilities and did not predict test scores. In terms of discriminant validity, results of Study 1 indicated that the postulated sub-components were insufficient to explain a large amount of variance in working memory span tasks, in Study 2 the same was demonstrated for reasoning tasks. Altogether, the present study is the first to disentangle sub-components in sustained attention tests and to determine their role for test performance.
Friction Measurement under Consideration of Contact Conditions and Type of Lubricant in Bulk Metal Forming
Authors: Kramer Philipp , Groche Peter
Published: January 2019

The tribological system plays a critical part in designing robust and efficient cold forging operations. The appropriate selection of lubrication allows to forge defect-free workpieces with high dimensional precision and desired surface finish while ensuring that no defects, such as cracks or seams, occur. Additionally, friction and wear are highly affected by the choice of tribological system, which in turn influence the cost-effectiveness of the forging operation by preventing premature tool failure. Next to the employed tool coating and work piece material, the lubrication system and work piece surface topography are the main factors influencing the aforementioned constraints when designing efficient forging operations. In order to choose the appropriate tribological system before implementing it within an industrial forging operation, tribometers are used to characterize the performance of the tribological system. In this paper, the necessity to account for not only the tribological loads when designing these tribometer tests as is typical for existing methodologies, but also for process and lubricant specific properties will be highlighted. With the help of the tribometer sliding compression test, it will be shown that using liquid lubricants necessitates the need to account for the escape of lubricant, while this is not true for solid lubricants. The escape of lubricant from the contact zone is governed by lubricant properties as well as the contact kinematics and may lead to significantly different results regarding friction and wear. In order to account for this escape, the tribometer test must be specifically designed to reproduce the contact kinematics of the investigated industrial forging operation.