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Int. J. Mol. Sci., Volume 20, Issue 1 (January-1 2019)

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Cover Story (view full-size image) During vertebrate development, extracellular signal-regulated kinase (ERK) is activated in a [...] Read more.
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Open AccessEditorial Acknowledgement to Reviewers of the International Journal of Molecular Science in 2018
Int. J. Mol. Sci. 2019, 20(1), 232; https://doi.org/10.3390/ijms20010232
Published: 8 January 2019
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Abstract
Rigorous peer-review is the corner-stone of high-quality academic publishing [...] Full article
Open AccessReview The Controversial Role of Homocysteine in Neurology: From Labs to Clinical Practice
Int. J. Mol. Sci. 2019, 20(1), 231; https://doi.org/10.3390/ijms20010231
Received: 29 November 2018 / Revised: 29 December 2018 / Accepted: 4 January 2019 / Published: 8 January 2019
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Abstract
Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy can be caused by deficiency of either vitamin B12 or folate. Hyperhomocysteinemia (HHcy) [...] Read more.
Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy can be caused by deficiency of either vitamin B12 or folate. Hyperhomocysteinemia (HHcy) can be responsible of different systemic and neurological disease. Actually, HHcy has been considered as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and HHcy has been reported in many neurologic disorders including cognitive impairment and stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. HHcy is typically defined as levels >15 micromol/L. Treatment of hyperhomocysteinemia with folic acid and B vitamins seems to be effective in the prevention of the development of atherosclerosis, CVD, and strokes. However, data from literature show controversial results regarding the significance of homocysteine as a risk factor for CVD and stroke and whether patients should be routinely screened for homocysteine. HHcy-induced oxidative stress, endothelial dysfunction, inflammation, smooth muscle cell proliferation, and endoplasmic reticulum (ER) stress have been considered to play an important role in the pathogenesis of several diseases including atherosclerosis and stroke. The aim of our research is to review the possible role of HHcy in neurodegenerative disease and stroke and to understand its pathogenesis. Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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Open AccessArticle Morniga-G, a T/Tn-Specific Lectin, Induces Leukemic Cell Death via Caspase and DR5 Receptor-Dependent Pathways
Int. J. Mol. Sci. 2019, 20(1), 230; https://doi.org/10.3390/ijms20010230
Received: 11 December 2018 / Revised: 30 December 2018 / Accepted: 31 December 2018 / Published: 8 January 2019
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Abstract
Morniga-G, the Gal-specific black mulberry (Morus nigra) lectin, displays high affinity for T (CD176) and Tn (CD175) antigens, frequently expressed at the cancer cell surface. The effects of Morniga-G were investigated on a Tn-positive leukemic Jurkat cell line. The lectin, used [...] Read more.
Morniga-G, the Gal-specific black mulberry (Morus nigra) lectin, displays high affinity for T (CD176) and Tn (CD175) antigens, frequently expressed at the cancer cell surface. The effects of Morniga-G were investigated on a Tn-positive leukemic Jurkat cell line. The lectin, used in a concentration range between 5–20 μg/mL, induced cell death in leukemic Jurkat cells. Microscopic and cytofluorometric analyses indicated that Jurkat cell death was essentially apoptotic, associated with an increase in the ceramide content and a depolarization of the mitochondrial transmembrane potential. This lectin-mediated cell death was inhibited by the pan caspase-inhibitor zVAD. In addition, cleavage of caspases 8, 9, and 3 was observed in Morniga-G-treated Jurkat cells whereas Jurkat cell lines that are deficient in caspase 8–10, caspase 9, or FADD, survived to the lectin-mediated toxicity. Furthermore, in the presence of TRAIL- or DR5-blocking mononoclonal antibodies, Jurkat cells became resistant to Morniga-G, suggesting that the lectin triggers cell death via the TRAIL/DR5 pathway. In silico computer simulations suggest that Morniga-G might facilitate both the DR5 dimerization and the building of TRAIL/DR5 complexes. Finally, upon treatment of Jurkat cells with benzyl-GalNAc, an O-glycosylation inhibitor, a decrease in Tn antigen expression associating with a reduced Morniga-G toxicity, was observed. Taken together, these results suggest that Morniga-G induces the cell death of Tn-positive leukemic cells via concomitant O-glycosylation-, caspase-, and TRAIL/DR5-dependent pathways. Full article
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Open AccessReview Targeting Mitochondria for Treatment of Chemoresistant Ovarian Cancer
Int. J. Mol. Sci. 2019, 20(1), 229; https://doi.org/10.3390/ijms20010229
Received: 26 November 2018 / Revised: 20 December 2018 / Accepted: 23 December 2018 / Published: 8 January 2019
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Abstract
Ovarian cancer is the leading cause of death from gynecologic malignancy in the Western world. This is due, in part, to the fact that despite standard treatment of surgery and platinum/paclitaxel most patients recur with ultimately chemoresistant disease. Ovarian cancer is a unique [...] Read more.
Ovarian cancer is the leading cause of death from gynecologic malignancy in the Western world. This is due, in part, to the fact that despite standard treatment of surgery and platinum/paclitaxel most patients recur with ultimately chemoresistant disease. Ovarian cancer is a unique form of solid tumor that develops, metastasizes and recurs in the same space, the abdominal cavity, which becomes a unique microenvironment characterized by ascites, hypoxia and low glucose levels. It is under these conditions that cancer cells adapt and switch to mitochondrial respiration, which becomes crucial to their survival, and therefore an ideal metabolic target for chemoresistant ovarian cancer. Importantly, independent of microenvironmental factors, mitochondria spatial redistribution has been associated to both tumor metastasis and chemoresistance in ovarian cancer while specific sets of genetic mutations have been shown to cause aberrant dependence on mitochondrial pathways in the most aggressive ovarian cancer subtypes. In this review we summarize on targeting mitochondria for treatment of chemoresistant ovarian cancer and current state of understanding of the role of mitochondria respiration in ovarian cancer. We feel this is an important and timely topic given that ovarian cancer remains the deadliest of the gynecological diseases, and that the mitochondrial pathway has recently emerged as critical in sustaining solid tumor progression. Full article
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Open AccessReview Relapse of Acute Myeloid Leukemia after Allogeneic Stem Cell Transplantation: Prevention, Detection, and Treatment
Int. J. Mol. Sci. 2019, 20(1), 228; https://doi.org/10.3390/ijms20010228
Received: 28 November 2018 / Revised: 2 January 2019 / Accepted: 3 January 2019 / Published: 8 January 2019
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Abstract
Acute myeloid leukemia (AML) is a phenotypically and prognostically heterogeneous hematopoietic stem cell disease that may be cured in eligible patients with intensive chemotherapy and/or allogeneic stem cell transplantation (allo-SCT). Tremendous advances in sequencing technologies have revealed a large amount of molecular information [...] Read more.
Acute myeloid leukemia (AML) is a phenotypically and prognostically heterogeneous hematopoietic stem cell disease that may be cured in eligible patients with intensive chemotherapy and/or allogeneic stem cell transplantation (allo-SCT). Tremendous advances in sequencing technologies have revealed a large amount of molecular information which has markedly improved our understanding of the underlying pathophysiology and enables a better classification and risk estimation. Furthermore, with the approval of the FMS-like tyrosine kinase 3 (FLT3) inhibitor Midostaurin a first targeted therapy has been introduced into the first-line therapy of younger patients with FLT3-mutated AML and several other small molecules targeting molecular alterations such as isocitrate dehydrogenase (IDH) mutations or the anti-apoptotic b-cell lymphoma 2 (BCL-2) protein are currently under investigation. Despite these advances, many patients will have to undergo allo-SCT during the course of disease and depending on disease and risk status up to half of them will finally relapse after transplant. Here we review the current knowledge about the molecular landscape of AML and how this can be employed to prevent, detect and treat relapse of AML after allo-SCT. Full article
(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia)
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Open AccessMeeting Report Report of the Signal Transduction Society Meeting 2018—Signaling: From Past to Future
Int. J. Mol. Sci. 2019, 20(1), 227; https://doi.org/10.3390/ijms20010227
Received: 12 December 2018 / Accepted: 20 December 2018 / Published: 8 January 2019
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Abstract
The annual meeting “Signal Transduction—Receptors, Mediators, and Genes” of the Signal Transduction Society (STS) is an interdisciplinary conference open to all scientists sharing the common interest in elucidating signaling pathways in physiological or pathological processes in humans, animals, plants, fungi, prokaryotes, and protists. [...] Read more.
The annual meeting “Signal Transduction—Receptors, Mediators, and Genes” of the Signal Transduction Society (STS) is an interdisciplinary conference open to all scientists sharing the common interest in elucidating signaling pathways in physiological or pathological processes in humans, animals, plants, fungi, prokaryotes, and protists. On the occasion of the 20th anniversary of the STS, the 22nd joint meeting took place in Weimar from 5–7 November 2018. With the focus topic “Signaling: From Past to Future” the evolution of the multifaceted research concerning signal transduction since foundation of the society was highlighted. Invited keynote speakers introduced the respective workshop topics and were followed by numerous speakers selected from the submitted abstracts. All presentations were lively discussed during the workshops. Here, we provide a concise summary of the various workshops and further aspects of the scientific program. Full article
(This article belongs to the Special Issue Signaling: From Past to Future)
Open AccessReview Unique Biological Activity and Potential Role of Monomeric Laminin-γ2 as a Novel Biomarker for Hepatocellular Carcinoma: A Review
Int. J. Mol. Sci. 2019, 20(1), 226; https://doi.org/10.3390/ijms20010226
Received: 15 November 2018 / Revised: 24 December 2018 / Accepted: 2 January 2019 / Published: 8 January 2019
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Abstract
Laminin (Ln)-332 consists of α3, β3, and γ2 chains, which mediate epithelial cell adhesion to the basement membrane. Ln-γ2, a component of Ln-332, is frequently expressed as a monomer in the invasion front of several types of malignant tissues without simultaneous expression of [...] Read more.
Laminin (Ln)-332 consists of α3, β3, and γ2 chains, which mediate epithelial cell adhesion to the basement membrane. Ln-γ2, a component of Ln-332, is frequently expressed as a monomer in the invasion front of several types of malignant tissues without simultaneous expression of Ln-α3 and/or Ln-β3 chains. Moreover, monomeric Ln-γ2 induces tumor cell proliferation and migration in vitro. These unique biological activities indicate that monomeric Ln-γ2 could be a candidate biomarker for early cancer surveillance. However, the present immune method for monomeric Ln-γ2 detection can only predict its expression, since no antibody that specifically reacts with monomeric γ2, but not with heterotrimeric γ2 chain, is commercially available. We have, therefore, developed monoclonal antibodies to specifically detect monomeric Ln-γ2, and devised a highly sensitive method to measure serum monomeric Ln-γ2 levels using a fully automated chemiluminescent immunoassay (CLIA). We evaluated its diagnostic value in sera from patients with several digestive cancers, including hepatocellular carcinoma (HCC), and found serum monomeric Ln-γ2 to be a clinically available biomarker for HCC surveillance. The combination of monomeric Ln-γ2 and prothrombin induced by Vitamin K Absence II (PIVKA-II) may be more sensitive for clinical diagnosis of HCC than any currently used combination. Full article
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Open AccessArticle Methylseleninic Acid Induces Lipid Peroxidation and Radiation Sensitivity in Head and Neck Cancer Cells
Int. J. Mol. Sci. 2019, 20(1), 225; https://doi.org/10.3390/ijms20010225
Received: 10 November 2018 / Revised: 17 December 2018 / Accepted: 4 January 2019 / Published: 8 January 2019
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Abstract
Combination radiation and chemotherapy are commonly used to treat locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Aggressive dosing of these therapies is significantly hampered by side effects due to normal tissue toxicity. Selenium represents an adjuvant that selectively sensitizes cancer cells [...] Read more.
Combination radiation and chemotherapy are commonly used to treat locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Aggressive dosing of these therapies is significantly hampered by side effects due to normal tissue toxicity. Selenium represents an adjuvant that selectively sensitizes cancer cells to these treatments modalities, potentially by inducing lipid peroxidation (LPO). This study investigated whether one such selenium compound, methylseleninic acid (MSA), induces LPO and radiation sensitivity in HNSCC cells. Results from 4,4-difluoro-4-bora-3a,4a-diaza-S-indacene (BODIPY) C11 oxidation and ferric thiocyanate assays revealed that MSA induced LPO in cells rapidly and persistently. Propidium iodide (PI) exclusion assay found that MSA was more toxic to cancer cells than other related selenium compounds; this toxicity was abrogated by treatment with α-tocopherol, an LPO inhibitor. MSA exhibited no toxicity to normal fibroblasts at similar doses. MSA also sensitized HNSCC cells to radiation as determined by clonogenic assay. Intracellular glutathione in cancer cells was depleted following MSA treatment, and supplementation of the intracellular glutathione pool with N-acetylcysteine sensitized cells to MSA. The addition of MSA to a cell-free solution of glutathione resulted in an increase in oxygen consumption, which was abrogated by catalase, suggesting the formation of H2O2. Results from this study identify MSA as an inducer of LPO, and reveal its capability to sensitize HNSCC to radiation. MSA may represent a potent adjuvant to radiation therapy in HNSCC. Full article
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Open AccessArticle Molecular Dynamics Simulations of Wild Type and Mutants of SAPAP in Complexed with Shank3
Int. J. Mol. Sci. 2019, 20(1), 224; https://doi.org/10.3390/ijms20010224
Received: 23 December 2018 / Revised: 30 December 2018 / Accepted: 30 December 2018 / Published: 8 January 2019
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Abstract
Specific interactions between scaffold protein SH3 and multiple ankyrin repeat domains protein 3 (Shank3) and synapse-associated protein 90/postsynaptic density-95–associated protein (SAPAP) are essential for excitatory synapse development and plasticity. In a bunch of human neurological diseases, mutations on Shank3 or SAPAP are detected. [...] Read more.
Specific interactions between scaffold protein SH3 and multiple ankyrin repeat domains protein 3 (Shank3) and synapse-associated protein 90/postsynaptic density-95–associated protein (SAPAP) are essential for excitatory synapse development and plasticity. In a bunch of human neurological diseases, mutations on Shank3 or SAPAP are detected. To investigate the dynamical and thermodynamic properties of the specific binding between the N-terminal extended PDZ (Post-synaptic density-95/Discs large/Zonaoccludens-1) domain (N-PDZ) of Shank3 and the extended PDZ binding motif (E-PBM) of SAPAP, molecular dynamics simulation approaches were used to study the complex of N-PDZ with wild type and mutated E-PBM peptides. To compare with the experimental data, 974QTRL977 and 966IEIYI970 of E-PBM peptide were mutated to prolines to obtain the M4P and M5P system, respectively. Conformational analysis shows that the canonical PDZ domain is stable while the βN extension presents high flexibility in all systems, especially for M5P. The high flexibility of βN extension seems to set up a barrier for the non-specific binding in this area and provide the basis for specific molecular recognition between Shank3 and SAPAP. The wild type E-PBM tightly binds to N-PDZ during the simulation while loss of binding is observed in different segments of the mutated E-PBM peptides. Energy decomposition and hydrogen bonds analysis show that M4P mutations only disrupt the interactions with canonical PDZ domain, but the interactions with βN1′ remain. In M5P system, although the interactions with βN1′ are abolished, the binding between peptide and the canonical PDZ domain is not affected. The results indicate that the interactions in the two-binding site, the canonical PDZ domain and the βN1′ extension, contribute to the binding between E-PBM and N-PDZ independently. The binding free energies calculated by MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) are in agreement with the experimental binding affinities. Most of the residues on E-PBM contribute considerably favorable energies to the binding except A963 and D964 in the N-terminal. The study provides information to understand the molecular basis of specific binding between Shank3 and SAPAP, as well as clues for design of peptide inhibitors. Full article
(This article belongs to the Special Issue Molecular Dynamics Simulations)
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Open AccessArticle Molecular Evidence for Precursors of Sjögren’s Foci in Histologically Normal Lacrimal Glands
Int. J. Mol. Sci. 2019, 20(1), 223; https://doi.org/10.3390/ijms20010223
Received: 1 November 2018 / Revised: 30 December 2018 / Accepted: 3 January 2019 / Published: 8 January 2019
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Abstract
Understanding the formation of Sjogren’s lymphocytic infiltrates could permit earlier diagnosis and better outcomes. We submitted gene transcript abundances in histologically normal rabbit lacrimal glands to principal component analysis. The analysis identified a cluster of transcripts associated with Sjögren’s foci, including messenger RNAs [...] Read more.
Understanding the formation of Sjogren’s lymphocytic infiltrates could permit earlier diagnosis and better outcomes. We submitted gene transcript abundances in histologically normal rabbit lacrimal glands to principal component analysis. The analysis identified a cluster of transcripts associated with Sjögren’s foci, including messenger RNAs (mRNAs) for C–X–C motif chemokine ligand 13 (CXCL13) and B-cell activating factor (BAFF), which dominated the major principal component. We interpreted the transcript cluster as the signature of a cluster of integrally functioning cells. Pregnancy and dryness increased the likelihood that the cluster would develop to high levels, but responses were subject to high levels of stochasticity. Analyzing microdissected samples from high- and low-cluster-level glands, we found that certain transcripts, including mRNAs for C–C motif chemokine ligand 21 (CCL21), CXCL13, cluster of differentiation 4 (CD4), CD28, CD25, BAFF, and interleukin 18 (IL-18) were significantly more abundant in immune cell clusters (ICs) from the high-cluster-level gland; mRNAs for CCL2, CD25, and IL-1RA were significantly more abundant in acinus-duct axis samples; mRNAs for CCL4, BAFF, IL-6, and IL-10 were more abundant in some acinus-duct samples; cells with high prolactin immunoreactivity were more frequent in interacinar spaces. In conclusion, integrated functional networks comprising Sjögren’s infiltrates, such as ICs, acinar cells, ductal cells, and interacinar cells, can form in histologically normal glands, and it is feasible to detect their molecular signatures. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Open AccessArticle Integration Analysis of Small RNA and Degradome Sequencing Reveals MicroRNAs Responsive to Dickeya zeae in Resistant Rice
Int. J. Mol. Sci. 2019, 20(1), 222; https://doi.org/10.3390/ijms20010222
Received: 28 November 2018 / Revised: 26 December 2018 / Accepted: 31 December 2018 / Published: 8 January 2019
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Abstract
Rice foot rot disease caused by the pathogen Dickeya zeae (formerly known as Erwinia chrysanthemi pv. zeae), is a newly emerging damaging bacterial disease in China and the southeast of Asia, resulting in the loss of yield and grain quality. However, the [...] Read more.
Rice foot rot disease caused by the pathogen Dickeya zeae (formerly known as Erwinia chrysanthemi pv. zeae), is a newly emerging damaging bacterial disease in China and the southeast of Asia, resulting in the loss of yield and grain quality. However, the genetic resistance mechanisms mediated by miRNAs to D. zeae are unclear in rice. In the present study, 652 miRNAs including osa-miR396f predicted to be involved in multiple defense responses to D. zeae were identified with RNA sequencing. A total of 79 differentially expressed miRNAs were detected under the criterion of normalized reads ≥10, including 51 known and 28 novel miRNAs. Degradome sequencing identified 799 targets predicted to be cleaved by 168 identified miRNAs. Among them, 29 differentially expressed miRNA and target pairs including miRNA396f-OsGRFs were identified by co-expression analysis. Overexpression of the osa-miR396f precursor in a susceptible rice variety showed enhanced resistance to D. zeae, coupled with significant accumulation of transcripts of osa-miR396f and reduction of its target the Growth-Regulating Factors (OsGRFs). Taken together, these findings suggest that miRNA and targets including miR396f-OsGRFs have a role in resisting the infections by bacteria D. zeae. Full article
(This article belongs to the Section Molecular Plant Sciences)
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Open AccessArticle Physiological Analysis and Proteome Quantification of Alligator Weed Stems in Response to Potassium Deficiency Stress
Int. J. Mol. Sci. 2019, 20(1), 221; https://doi.org/10.3390/ijms20010221
Received: 14 November 2018 / Revised: 26 December 2018 / Accepted: 27 December 2018 / Published: 8 January 2019
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Abstract
The macronutrient potassium is essential to plant growth, development and stress response. Alligator weed (Alternanthera philoxeroides) has a high tolerance to potassium deficiency (LK) stress. The stem is the primary organ responsible for transporting molecules from the underground root system to [...] Read more.
The macronutrient potassium is essential to plant growth, development and stress response. Alligator weed (Alternanthera philoxeroides) has a high tolerance to potassium deficiency (LK) stress. The stem is the primary organ responsible for transporting molecules from the underground root system to the aboveground parts of the plant. However, proteomic changes in response to LK stress are largely unknown in alligator weed stems. In this study, we investigated the physiological and proteomic changes in alligator weed stems under LK stress. First, the chlorophyll and soluble protein content and SOD and POD activity were significantly altered after 15 days of LK treatment. The quantitative proteomic analysis suggested that a total of 296 proteins were differentially abundant proteins (DAPs). The functional annotation analysis revealed that LK stress elicited complex proteomic alterations that were involved in oxidative phosphorylation, plant-pathogen interactions, glycolysis/gluconeogenesis, sugar metabolism, and transport in stems. The subcellular locations analysis suggested 104 proteins showed chloroplastic localization, 81 proteins showed cytoplasmic localization and 40 showed nuclear localization. The protein–protein interaction analysis revealed that 56 proteins were involved in the interaction network, including 9 proteins involved in the ribosome network and 9 in the oxidative phosphorylation network. Additionally, the expressed changes of 5 DAPs were similar between the proteomic quantification analysis and the PRM-MS analysis, and the expression levels of eight genes that encode DAPs were further verified using an RT-qPCR analysis. These results provide valuable information on the adaptive mechanisms in alligator weed stems under LK stress and facilitate the development of efficient strategies for genetically engineering potassium-tolerant crops. Full article
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Open AccessReview Neuroimaging Biomarkers of Experimental Epileptogenesis and Refractory Epilepsy
Int. J. Mol. Sci. 2019, 20(1), 220; https://doi.org/10.3390/ijms20010220
Received: 16 December 2018 / Revised: 31 December 2018 / Accepted: 3 January 2019 / Published: 8 January 2019
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This article provides an overview of neuroimaging biomarkers in experimental epileptogenesis and refractory epilepsy. Neuroimaging represents a gold standard and clinically translatable technique to identify neuropathological changes in epileptogenesis and longitudinally monitor its progression after a precipitating injury. Neuroimaging studies, along with molecular [...] Read more.
This article provides an overview of neuroimaging biomarkers in experimental epileptogenesis and refractory epilepsy. Neuroimaging represents a gold standard and clinically translatable technique to identify neuropathological changes in epileptogenesis and longitudinally monitor its progression after a precipitating injury. Neuroimaging studies, along with molecular studies from animal models, have greatly improved our understanding of the neuropathology of epilepsy, such as the hallmark hippocampus sclerosis. Animal models are effective for differentiating the different stages of epileptogenesis. Neuroimaging in experimental epilepsy provides unique information about anatomic, functional, and metabolic alterations linked to epileptogenesis. Recently, several in vivo biomarkers for epileptogenesis have been investigated for characterizing neuronal loss, inflammation, blood-brain barrier alterations, changes in neurotransmitter density, neurovascular coupling, cerebral blood flow and volume, network connectivity, and metabolic activity in the brain. Magnetic resonance imaging (MRI) is a sensitive method for detecting structural and functional changes in the brain, especially to identify region-specific neuronal damage patterns in epilepsy. Positron emission tomography (PET) and single-photon emission computerized tomography are helpful to elucidate key functional alterations, especially in areas of brain metabolism and molecular patterns, and can help monitor pathology of epileptic disorders. Multimodal procedures such as PET-MRI integrated systems are desired for refractory epilepsy. Validated biomarkers are warranted for early identification of people at risk for epilepsy and monitoring of the progression of medical interventions. Full article
(This article belongs to the Section Molecular Neurobiology)
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Open AccessArticle Acute Myeloid Leukemia Affects Mouse Sperm Parameters, Spontaneous Acrosome Reaction, and Fertility Capacity
Int. J. Mol. Sci. 2019, 20(1), 219; https://doi.org/10.3390/ijms20010219
Received: 6 December 2018 / Revised: 29 December 2018 / Accepted: 1 January 2019 / Published: 8 January 2019
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Abstract
Leukemia is one of the most common cancers in patients of reproductive age. It is well known that chemotherapy, used as anti-cancer therapy, adversely affects male fertility. Moreover, the negative effect of leukemia on sperm quality, even before chemotherapy treatment, has been reported. [...] Read more.
Leukemia is one of the most common cancers in patients of reproductive age. It is well known that chemotherapy, used as anti-cancer therapy, adversely affects male fertility. Moreover, the negative effect of leukemia on sperm quality, even before chemotherapy treatment, has been reported. However, the mechanisms behind this disease’s effect on sperm quality remains unknown. In this study, we examine the direct effect of leukemia and chemotherapy alone and in combination on sperm parameters and male fertility. For this, we developed an acute myeloid leukemia (AML) mouse model (mice were treated with AML cells C1498 and developed leukemia); these mice then received cytarabine chemotherapy. Our findings reveal a significant reduction in sperm concentration and motility and a significant increase in abnormal morphology and spontaneous acrosome reaction of the sperm following AML and chemotherapy treatment, alone and in combination. We also found a reduction in male fertility and the number of delivered offspring. Our results support previous findings that AML impairs sperm parameters and show for the first time that AML increases spontaneous acrosome reaction and decreases male fertility capacity and number of offspring. Full article
(This article belongs to the Special Issue Molecular Biology of Spermatozoa)
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Open AccessReview Vitamin D Supplementation in Central Nervous System Demyelinating Disease—Enough Is Enough
Int. J. Mol. Sci. 2019, 20(1), 218; https://doi.org/10.3390/ijms20010218
Received: 28 September 2018 / Revised: 24 December 2018 / Accepted: 24 December 2018 / Published: 8 January 2019
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Abstract
The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual’s risk of developing this central nervous system (CNS) demyelinating disease and are associated with an acceleration in disease severity. Besides genetic determinants, environmental factors [...] Read more.
The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual’s risk of developing this central nervous system (CNS) demyelinating disease and are associated with an acceleration in disease severity. Besides genetic determinants, environmental factors are now established that influence MS, which is of enormous interest, as some of these contributing factors are relatively easy to change. In this regard, a low vitamin D status is associated with an elevated relapse frequency and worsened disease course in patients with MS. The most important question, however, is whether this association is causal or related. That supplementing vitamin D in MS is of direct therapeutic benefit, is still a matter of debate. In this manuscript, we first review the potentially immune modulating mechanisms of vitamin D, followed by a summary of current and ongoing clinical trials intended to assess whether vitamin D supplementation positively influences the outcome of MS. Furthermore, we provide emerging evidence that excessive vitamin D treatment via the T cell-stimulating effect of secondary hypercalcemia, could have negative effects in CNS demyelinating disease. This jointly merges into the balancing concept of a therapeutic window of vitamin D in MS. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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Open AccessArticle Evaluation of the Biological Behavior of a Gold Nanocore-Encapsulated Human Serum Albumin Nanoparticle ([email protected]) in a CT-26 Tumor/Ascites Mouse Model after Intravenous/Intraperitoneal Administration
Int. J. Mol. Sci. 2019, 20(1), 217; https://doi.org/10.3390/ijms20010217
Received: 21 November 2018 / Revised: 24 December 2018 / Accepted: 28 December 2018 / Published: 8 January 2019
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Abstract
Colorectal cancer is one of the major causes of cancer-related death in Taiwan and worldwide. Patients with peritoneal metastasis from colorectal cancer have reduced overall survival and poor prognosis. Hybrid protein-inorganic nanoparticle systems have displayed multifunctional applications in solid cancer theranostics. In this [...] Read more.
Colorectal cancer is one of the major causes of cancer-related death in Taiwan and worldwide. Patients with peritoneal metastasis from colorectal cancer have reduced overall survival and poor prognosis. Hybrid protein-inorganic nanoparticle systems have displayed multifunctional applications in solid cancer theranostics. In this study, a gold nanocore-encapsulated human serum albumin nanoparticle ([email protected]), which is a hybrid protein-inorganic nanoparticle, and its radioactive surrogate 111In-labeled [email protected] (111[email protected]), were developed and their biological behaviors were investigated in a tumor/ascites mouse model. 111[email protected] was injected either intravenously (iv) or intraperitoneally (ip) in CT-26 tumor/ascites-bearing mice. After ip injection, a remarkable and sustained radioactivity retention in the abdomen was noticed, based on microSPECT images. After iv injection, however, most of the radioactivity was accumulated in the mononuclear phagocyte system. The results of biodistribution indicated that ip administration was significantly more effective in increasing intraperitoneal concentration and tumor accumulation than iv administration. The ratios of area under the curve (AUC) of the ascites and tumors in the ip-injected group to those in the iv-injected group was 93 and 20, respectively. This study demonstrated that the ip injection route would be a better approach than iv injections for applying gold-albumin nanoparticle in peritoneal metastasis treatment. Full article
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Open AccessArticle Development of a Transcriptional Amplification System Based on the PEG3 Promoter to Target Androgen Receptor-Positive and -Negative Prostate Cancer Cells
Int. J. Mol. Sci. 2019, 20(1), 216; https://doi.org/10.3390/ijms20010216
Received: 3 December 2018 / Revised: 21 December 2018 / Accepted: 31 December 2018 / Published: 8 January 2019
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Abstract
Localized prostate cancer (PCa) is often curable, whereas metastatic disease treated by castration inevitably progresses toward castration-resistant PCa (CRPC). Most CRPC treatments target androgen receptor (AR) signaling. However, not all CRPC cells rely on AR activity for survival and proliferation. With advances in [...] Read more.
Localized prostate cancer (PCa) is often curable, whereas metastatic disease treated by castration inevitably progresses toward castration-resistant PCa (CRPC). Most CRPC treatments target androgen receptor (AR) signaling. However, not all CRPC cells rely on AR activity for survival and proliferation. With advances in immunotherapy and fluid biopsies for cancer management, expression systems specific for both AR-positive and -negative PCa are required for virus-based vaccines and cell imaging. To target both AR-responsive and non-responsive cells, we developed a three-step transcriptional amplification (3STA) system based on the progression elevated gene-3 (PEG3) promoter named PEG3AP1-3STA. Notably, we report on different genetic modifications that significantly improved PEG3 promoter’s strength in PCa cells. Adenoviruses incorporating PEG3 promoter with and without transcriptional amplification systems were generated. The potential of PEG3AP1-3STA to target PCa cells was then evaluated in vitro and in vivo in androgen-responsive and non-responsive PCa cell lines. PEG3AP1-3STA was shown to be active in all PCa cell lines and not regulated by androgens, and its activity was amplified 97-fold compared to that of a non-amplified promoter. The PEG3AP1-3STA system can thus be used to target advanced AR+ and AR− cells for imaging or immunovirotherapy in advanced PCa. Full article
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Open AccessArticle Cathepsin L-like Cysteine Proteinase Genes Are Associated with the Development and Pathogenicity of Pine Wood Nematode, Bursaphelenchus xylophilus
Int. J. Mol. Sci. 2019, 20(1), 215; https://doi.org/10.3390/ijms20010215
Received: 16 December 2018 / Accepted: 1 January 2019 / Published: 8 January 2019
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Abstract
The pine wood nematode (PWN), Bursaphelenchus xylophilus, is the pathogen of pine wilt disease (PWD), resulting in huge losses in pine forests. However, its pathogenic mechanism remains unclear. The cathepsin L-like cysteine proteinase (CPL) genes are multifunctional genes related to the parasitic [...] Read more.
The pine wood nematode (PWN), Bursaphelenchus xylophilus, is the pathogen of pine wilt disease (PWD), resulting in huge losses in pine forests. However, its pathogenic mechanism remains unclear. The cathepsin L-like cysteine proteinase (CPL) genes are multifunctional genes related to the parasitic abilities of plant-parasitic nematodes, but their functions in PWN remain unclear. We cloned three cpl genes of PWN (Bx-cpls) by rapid amplification of cDNA ends (RACE) and analyzed their characteristics using bioinformatic methods. The tissue specificity of cpl gene of PWN (Bx-cpl) was studied using in situ mRNA hybridization (ISH). The functions of Bx-cpls in development and pathogenicity were investigated using real-time quantitative PCR (qPCR) and RNA interference (RNAi). The results showed that the full-length cDNAs of Bx-cpl-1, Bx-cpl-2, and Bx-cpl-3 were 1163 bp, 1305 bp, and 1302 bp, respectively. Bx-cpls could accumulate specifically in the egg, intestine, and genital system of PWN. During different developmental stages of PWN, the expression of Bx-cpls in the egg stage was highest. After infection, the expression levels of Bx-cpls increased and reached their highest at the initial stage of PWD, then declined gradually. The silencing of Bx-cpl could reduce the feeding, reproduction, and pathogenicity of PWN. These results revealed that Bx-cpls play multiple roles in the development and pathogenic processes of PWN. Full article
(This article belongs to the Section Biochemistry)
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Open AccessArticle Recipient ADAMTS13 Single-Nucleotide Polymorphism Predicts Relapse after Unrelated Bone Marrow Transplantation for Hematologic Malignancy
Int. J. Mol. Sci. 2019, 20(1), 214; https://doi.org/10.3390/ijms20010214
Received: 8 December 2018 / Revised: 2 January 2019 / Accepted: 4 January 2019 / Published: 8 January 2019
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Abstract
Relapse remains a major obstacle to the survival of patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation. A disintegrin-like and metalloprotease with a thrombospondin type 1 motif (ADMATS13), which cleaves von Willebrand factor multimers into less active fragments, is encoded by [...] Read more.
Relapse remains a major obstacle to the survival of patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation. A disintegrin-like and metalloprotease with a thrombospondin type 1 motif (ADMATS13), which cleaves von Willebrand factor multimers into less active fragments, is encoded by the ADAMTS13 gene and has a functional single-nucleotide polymorphism (SNP) rs2285489 (C > T). We retrospectively examined whether ADAMTS13 rs2285489 affected the transplant outcomes in a cohort of 281 patients who underwent unrelated human leukocyte antigen (HLA)-matched bone marrow transplantation for hematologic malignancies. The recipient ADAMTS13 C/C genotype, which putatively has low inducibility, was associated with an increased relapse rate (hazard ratio [HR], 3.12; 95% confidence interval [CI], 1.25–7.77; P = 0.015), resulting in a lower disease-free survival rate in the patients with a recipient C/C genotype (HR, 1.64; 95% CI, 1.01–2.67; P = 0.045). Therefore, ADAMTS13 rs2285489 genotyping in transplant recipients may be a useful tool for evaluating pretransplantation risks. Full article
(This article belongs to the Section Molecular Oncology)
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Open AccessReview Antihistamines for Allergic Rhinitis Treatment from the Viewpoint of Nonsedative Properties
Int. J. Mol. Sci. 2019, 20(1), 213; https://doi.org/10.3390/ijms20010213
Received: 3 December 2018 / Revised: 26 December 2018 / Accepted: 29 December 2018 / Published: 8 January 2019
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Abstract
Antihistamines targeting the histamine H1 receptor play an important role in improving and maintaining the quality of life of patients with allergic rhinitis. For more effective and safer use of second-generation drugs, which are recommended by various guidelines, a classification based on [...] Read more.
Antihistamines targeting the histamine H1 receptor play an important role in improving and maintaining the quality of life of patients with allergic rhinitis. For more effective and safer use of second-generation drugs, which are recommended by various guidelines, a classification based on their detailed characteristics is necessary. Antihistamines for first-line therapy should not have central depressant/sedative activities. Sedative properties (drowsiness and impaired performance) are associated with the inhibition of central histamine neurons. Brain H1 receptor occupancy (H1RO) is a useful index shown to be correlated with indices based on clinical findings. Antihistamines are classified into non-sedating (<20%), less-sedating (20–50%), and sedating (≥50%) groups based on H1RO. Among the non-sedating group, fexofenadine and bilastine are classified into “non-brain-penetrating antihistamines” based on the H1RO. These two drugs have many common chemical properties. However, bilastine has more potent binding affinity to the H1 receptor, and its action tends to last longer. In well-controlled studies using objective indices, bilastine does not affect psychomotor or driving performance even at twice the usual dose (20 mg). Upon selecting antihistamines for allergic rhinitis, various situations should be taken into our consideration. This review summarizes that the non-brain-penetrating antihistamines should be chosen for the first-line therapy of mild allergic rhinitis. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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Open AccessReview Translatomics: The Global View of Translation
Int. J. Mol. Sci. 2019, 20(1), 212; https://doi.org/10.3390/ijms20010212
Received: 6 November 2018 / Revised: 19 December 2018 / Accepted: 2 January 2019 / Published: 8 January 2019
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Abstract
In all kingdoms of life, proteins are synthesized by ribosomes in a process referred to as translation. The amplitude of translational regulation exceeds the sum of transcription, mRNA degradation and protein degradation. Therefore, it is essential to investigate translation in a global scale. [...] Read more.
In all kingdoms of life, proteins are synthesized by ribosomes in a process referred to as translation. The amplitude of translational regulation exceeds the sum of transcription, mRNA degradation and protein degradation. Therefore, it is essential to investigate translation in a global scale. Like the other “omics”-methods, translatomics investigates the totality of the components in the translation process, including but not limited to translating mRNAs, ribosomes, tRNAs, regulatory RNAs and nascent polypeptide chains. Technical advances in recent years have brought breakthroughs in the investigation of these components at global scale, both for their composition and dynamics. These methods have been applied in a rapidly increasing number of studies to reveal multifaceted aspects of translation control. The process of translation is not restricted to the conversion of mRNA coding sequences into polypeptide chains, it also controls the composition of the proteome in a delicate and responsive way. Therefore, translatomics has extended its unique and innovative power to many fields including proteomics, cancer research, bacterial stress response, biological rhythmicity and plant biology. Rational design in translation can enhance recombinant protein production for thousands of times. This brief review summarizes the main state-of-the-art methods of translatomics, highlights recent discoveries made in this field and introduces applications of translatomics on basic biological and biomedical research. Full article
(This article belongs to the Special Issue Translational Control)
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Open AccessEditorial Hepatotoxicity: Molecular Mechanisms and Pathophysiology
Int. J. Mol. Sci. 2019, 20(1), 211; https://doi.org/10.3390/ijms20010211
Received: 27 December 2018 / Accepted: 3 January 2019 / Published: 8 January 2019
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Abstract
The current Special Issue is devoted to the broad spectrum of hepatotoxicity with its molecular mechanisms and pathophysiology, presented in eight publications [...] Full article
(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)
Open AccessReview Interplay between Autophagy and the Ubiquitin-Proteasome System and Its Role in the Pathogenesis of Age-Related Macular Degeneration
Int. J. Mol. Sci. 2019, 20(1), 210; https://doi.org/10.3390/ijms20010210
Received: 10 December 2018 / Revised: 21 December 2018 / Accepted: 2 January 2019 / Published: 8 January 2019
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Abstract
Age-related macular degeneration (AMD) is a complex eye disease with many pathogenesis factors, including defective cellular waste management in retinal pigment epithelium (RPE). Main cellular waste in AMD are: all-trans retinal, drusen and lipofuscin, containing unfolded, damaged and unneeded proteins, which are degraded [...] Read more.
Age-related macular degeneration (AMD) is a complex eye disease with many pathogenesis factors, including defective cellular waste management in retinal pigment epithelium (RPE). Main cellular waste in AMD are: all-trans retinal, drusen and lipofuscin, containing unfolded, damaged and unneeded proteins, which are degraded and recycled in RPE cells by two main machineries—the ubiquitin-proteasome system (UPS) and autophagy. Recent findings show that these systems can act together with a significant role of the EI24 (etoposide-induced protein 2.4 homolog) ubiquitin ligase in their action. On the other hand, E3 ligases are essential in both systems, but E3 is degraded by autophagy. The interplay between UPS and autophagy was targeted in several diseases, including Alzheimer disease. Therefore, cellular waste clearing in AMD should be considered in the context of such interplay rather than either of these systems singly. Aging and oxidative stress, two major AMD risk factors, reduce both UPS and autophagy. In conclusion, molecular mechanisms of UPS and autophagy can be considered as a target in AMD prevention and therapeutic perspective. Further work is needed to identify molecules and effects important for the coordination of action of these two cellular waste management systems. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))
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Open AccessReview Cytoskeleton, Transglutaminase and Gametophytic Self-Incompatibility in the Malinae (Rosaceae)
Int. J. Mol. Sci. 2019, 20(1), 209; https://doi.org/10.3390/ijms20010209
Received: 15 November 2018 / Revised: 21 December 2018 / Accepted: 4 January 2019 / Published: 8 January 2019
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Abstract
Self-incompatibility (SI) is a complex process, one out of several mechanisms that prevent plants from self-fertilizing to maintain and increase the genetic variability. This process leads to the rejection of the male gametophyte and requires the co-participation of numerous molecules. Plants have evolved [...] Read more.
Self-incompatibility (SI) is a complex process, one out of several mechanisms that prevent plants from self-fertilizing to maintain and increase the genetic variability. This process leads to the rejection of the male gametophyte and requires the co-participation of numerous molecules. Plants have evolved two distinct SI systems, the sporophytic (SSI) and the gametophytic (GSI) systems. The two SI systems are markedly characterized by different genes and proteins and each single system can also be divided into distinct subgroups; whatever the mechanism, the purpose is the same, i.e., to prevent self-fertilization. In Malinae, a subtribe in the Rosaceae family, i.e., Pyrus communis and Malus domestica, the GSI requires the production of female determinants, known as S-RNases, which penetrate the pollen tube to interact with the male determinants. Beyond this, the penetration of S-RNase into the pollen tube triggers a series of responses involving membrane proteins, such as phospholipases, intracellular variations of cytoplasmic Ca2+, production of reactive oxygen species (ROS) and altered enzymatic activities, such as that of transglutaminase (TGase). TGases are widespread enzymes that catalyze the post-translational conjugation of polyamines (PAs) to different protein targets and/or the cross-linking of substrate proteins leading to the formation of cross-linked products with high molecular mass. When actin and tubulin are the substrates, this destabilizes the cytoskeleton and inhibits the pollen-tube’s growth process. In this review, we will summarize the current knowledge of the relationship between S-RNase penetration, TGase activity and cytoskeleton function during GSI in the Malinae. Full article
(This article belongs to the Special Issue Pollen Tube and Plant Reproduction)
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Open AccessArticle Global Phosphoproteomic Analysis Reveals the Defense and Response Mechanisms of Jatropha Curcas Seedling under Chilling Stress
Int. J. Mol. Sci. 2019, 20(1), 208; https://doi.org/10.3390/ijms20010208
Received: 24 November 2018 / Revised: 31 December 2018 / Accepted: 3 January 2019 / Published: 8 January 2019
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Abstract
As a promising energy plant for biodiesel, Jatropha curcas is a tropical and subtropical shrub and its growth is affected by one of major abiotic stress, chilling. Therefore, we adopt the phosphoproteomic analysis, physiological measurement and ultrastructure observation to illustrate the responsive mechanism [...] Read more.
As a promising energy plant for biodiesel, Jatropha curcas is a tropical and subtropical shrub and its growth is affected by one of major abiotic stress, chilling. Therefore, we adopt the phosphoproteomic analysis, physiological measurement and ultrastructure observation to illustrate the responsive mechanism of J. curcas seedling under chilling (4 °C) stress. After chilling for 6 h, 308 significantly changed phosphoproteins were detected. Prolonged the chilling treatment for 24 h, obvious physiological injury can be observed and a total of 332 phosphoproteins were examined to be significantly changed. After recovery (28 °C) for 24 h, 291 phosphoproteins were varied at the phosphorylation level. GO analysis showed that significantly changed phosphoproteins were mainly responsible for cellular protein modification process, transport, cellular component organization and signal transduction at the chilling and recovery periods. On the basis of protein-protein interaction network analysis, phosphorylation of several protein kinases, such as SnRK2, MEKK1, EDR1, CDPK, EIN2, EIN4, PI4K and 14-3-3 were possibly responsible for cross-talk between ABA, Ca2+, ethylene and phosphoinositide mediated signaling pathways. We also highlighted the phosphorylation of HOS1, APX and PIP2 might be associated with response to chilling stress in J. curcas seedling. These results will be valuable for further study from the molecular breeding perspective. Full article
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Open AccessArticle OsMGT1 Confers Resistance to Magnesium Deficiency By Enhancing the Import of Mg in Rice
Int. J. Mol. Sci. 2019, 20(1), 207; https://doi.org/10.3390/ijms20010207
Received: 29 October 2018 / Revised: 30 December 2018 / Accepted: 3 January 2019 / Published: 8 January 2019
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Abstract
Magnesium (Mg) is an essential nutrient element for plant growth and plays an important role in numerous physiological and biochemical processes. Mg deficiency inhibits plant growth and has become a growing problem for crop productions in agriculture. However, the molecular mechanisms for the [...] Read more.
Magnesium (Mg) is an essential nutrient element for plant growth and plays an important role in numerous physiological and biochemical processes. Mg deficiency inhibits plant growth and has become a growing problem for crop productions in agriculture. However, the molecular mechanisms for the resistance to Mg deficiency in plants were not well understood. In this study, we identified a Mg transporter gene OsMGT1 that confers resistance to Mg deficiency in rice (Oryza sativa). The expression of OsMGT1 was highly induced by Mg deficiency in shoots. Investigation of tissue expression patterns revealed that OsMGT1 was mainly expressed in the phloem region; however, Mg deficiency remarkably enhanced its expression in xylem parenchyma and mesophyll cells in shoots. Knockout of OsMGT1 resulted in a significant reduction in Mg content and biomass when grown at Mg-limited conditions. Furthermore, the sensitivity to low-Mg in mutants was intensified by excessive calcium supply. In addition, overexpression of OsMGT1 increased Mg content and biomass under low-Mg supply. In conclusion, our results indicate that OsMGT1 plays an important role in rice Mg import and is required for the resistance to Mg deficiency, which can be utilized for molecular breeding of low-Mg tolerant plants. Full article
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Open AccessReview Host-Induced Gene Silencing: A Powerful Strategy to Control Diseases of Wheat and Barley
Int. J. Mol. Sci. 2019, 20(1), 206; https://doi.org/10.3390/ijms20010206
Received: 14 December 2018 / Revised: 31 December 2018 / Accepted: 3 January 2019 / Published: 8 January 2019
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Abstract
Wheat and barley are the most highly produced and consumed grains in the world. Various pathogens—viruses, bacteria, fungi, insect pests, and nematode parasites—are major threats to yield and economic losses. Strategies for the management of disease control mainly depend on resistance or tolerance [...] Read more.
Wheat and barley are the most highly produced and consumed grains in the world. Various pathogens—viruses, bacteria, fungi, insect pests, and nematode parasites—are major threats to yield and economic losses. Strategies for the management of disease control mainly depend on resistance or tolerance breeding, chemical control, and biological control. The discoveries of RNA silencing mechanisms provide a transgenic approach for disease management. Host-induced gene silencing (HIGS) employing RNA silencing mechanisms and, specifically, silencing the targets of invading pathogens, has been successfully applied in crop disease prevention. Here, we cover recent studies that indicate that HIGS is a valuable tool to protect wheat and barley from diseases in an environmentally friendly way. Full article
(This article belongs to the Special Issue Molecular Advances in Wheat and Barley)
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Open AccessEditorial Extracellular Matrix in Development and Disease
Int. J. Mol. Sci. 2019, 20(1), 205; https://doi.org/10.3390/ijms20010205
Received: 19 December 2018 / Accepted: 4 January 2019 / Published: 8 January 2019
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Abstract
The evolution of multicellular metazoan organisms was marked by the inclusion of an extracellular matrix (ECM), a multicomponent, proteinaceous network between cells that contributes to the spatial arrangement of cells and the resulting tissue organization. [...] Full article
Open AccessReview Exploiting PLGA-Based Biocompatible Nanoparticles for Next-Generation Tolerogenic Vaccines against Autoimmune Disease
Int. J. Mol. Sci. 2019, 20(1), 204; https://doi.org/10.3390/ijms20010204
Received: 26 November 2018 / Revised: 28 December 2018 / Accepted: 2 January 2019 / Published: 8 January 2019
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Abstract
Tolerogenic vaccines are aimed at inhibiting antigen-specific immune responses. Antigen-loaded nanoparticles (NPs) have been recently emerged as ideal tools for tolerogenic vaccination because their composition, size, and capability of loading immunomodulatory molecules can be readily exploited to induce peripheral tolerance. Among polymeric NPs, [...] Read more.
Tolerogenic vaccines are aimed at inhibiting antigen-specific immune responses. Antigen-loaded nanoparticles (NPs) have been recently emerged as ideal tools for tolerogenic vaccination because their composition, size, and capability of loading immunomodulatory molecules can be readily exploited to induce peripheral tolerance. Among polymeric NPs, poly(lactic-co-glycolic acid) (PLGA) NPs have the advantage of currently holding approval for several applications in drug delivery, diagnostics, and other clinical uses by the Food and Drug Administration (FDA). PLGA-NPs are non-toxic and display excellent biocompatibility and biodegradability properties. Moreover, surface functionalization may improve their interaction with biological materials, thereby optimizing targeting and performance. PLGA-NPs are the most extensively studied in pre-clinical model in the field of tolerogenic vaccination. Thus, this review describes their potential applications in the treatment of autoimmune diseases. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction 2019)
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Open AccessArticle Proteomic Signatures Reveal Differences in Stress Response, Antioxidant Defense and Proteasomal Activity in Fertile Men with High Seminal ROS Levels
Int. J. Mol. Sci. 2019, 20(1), 203; https://doi.org/10.3390/ijms20010203
Received: 9 November 2018 / Revised: 22 December 2018 / Accepted: 29 December 2018 / Published: 8 January 2019
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Abstract
Elevated levels of reactive oxygen species (ROS) are a major cause of male infertility. However, some men with high seminal ROS levels are still fertile. The main objective of this study was to understand the molecular mechanism(s) responsible for the preservation of fertility [...] Read more.
Elevated levels of reactive oxygen species (ROS) are a major cause of male infertility. However, some men with high seminal ROS levels are still fertile. The main objective of this study was to understand the molecular mechanism(s) responsible for the preservation of fertility in those men. Semen samples from fertile men were divided into two groups: control (n = 10, ROS < 102.2 RLU/s/106 sperm) and ROS+ (n = 10, ROS > 102.2 RLU/s/106 sperm). Proteomic analysis of seminal plasma and spermatozoa was used to identify the differentially expressed proteins (DEPs) between the experimental groups, from which some proteins were validated by Western blot (WB). A total of 44 and 371 DEPs were identified between the study groups in the seminal plasma and spermatozoa, respectively. The identified DEPs were primarily involved in oxidoreductase, endopeptidase inhibitor, and antioxidant activities. We validated by WB the underexpression of NADH:ubiquinone oxidoreductase core subunit S1 (p = 0.01), as well as the overexpression of superoxide dismutase 1 (p = 0.03) and peroxiredoxin 4 (p = 0.04) in spermatozoa of ROS+ group. Our data suggest that fertile men with high ROS levels possess an effective antioxidant defense system that protects sperm proteins, as well as an active proteasomal system for degradation of defective proteins. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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