352 results match your criteria Acta Histochemica Et Cytochemica[Journal]


Comparative Analysis of Immunohistochemical Staining Intensity Determined by Light Microscopy, ImageJ and QuPath in Placental Hofbauer Cells.

Acta Histochem Cytochem 2021 Feb 20;54(1):21-29. Epub 2021 Feb 20.

Department of Histology and Embryology, Faculty of Medicine and Dentistry, Palacky University, 779 00, Olomouc, Czech Republic.

Software based analyses of immunohistochemical staining are designed for obtaining quantitative, reproducible, and objective data. However, often times only a certain type of positive cells or structures need to be quantified thus whole image analysis cannot be performed. Such an example is Hofbauer placental cells, which show positivity of some antigens together with trophoblast, but only Hofbauer cells represent the regions of interest (ROIs). Read More

View Article and Full-Text PDF
February 2021

The Periodontium Damage Induces Neuronal Cell Death in the Trigeminal Mesencephalic Nucleus and Neurodegeneration in the Trigeminal Motor Nucleus in C57BL/6J Mice.

Acta Histochem Cytochem 2021 Feb 16;54(1):11-19. Epub 2021 Feb 16.

Department of Oral Anatomy and Cell Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.

Proprioception from masticatory apparatus and periodontal ligaments comes through the trigeminal mesencephalic nucleus (Vmes). We evaluated the effects of tooth loss on neurodegeneration of the Vmes and trigeminal motor nucleus (Vmo). Bilateral maxillary molars of 2-month-old C57BL/6J mice were extracted under anesthesia. Read More

View Article and Full-Text PDF
February 2021

Matrix Metalloproteinase-2 Activated by Ultraviolet-B Degrades Human Ciliary Zonules .

Acta Histochem Cytochem 2021 Feb 9;54(1):1-9. Epub 2021 Feb 9.

Department of Radiation Science, Graduate School of Health Sciences, Hirosaki University, 66-1 Honcho, Hirosaki, Aomori 036-8564, Japan.

The ciliary zonules, also known as the zonules of Zinn, help to control the thickness of the lens during focusing. The ciliary zonules are composed of oxytalan fibers, which are synthesized by human nonpigmented ciliary epithelial cells (HNPCEC). The ciliary zonules are exposed to ultraviolet (UV), especially UV-A and UV-B, throughout life. Read More

View Article and Full-Text PDF
February 2021

Mercury and Selenium Localization in the Cerebrum, Cerebellum, Liver, and Kidney of a Minamata Disease Case.

Acta Histochem Cytochem 2020 Dec 19;53(6):147-155. Epub 2020 Dec 19.

Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku Kumamoto, Kumamoto 860-8556, Japan.

Minamata disease is a methylmercury poisoning caused by consumption of marine food contaminated by man-made methylmercury environmental pollution, and its most prominent feature is marked pathological changes in the central nervous system. Morphological alterations are less pronounced in the liver and the kidney, although their mercury levels are higher than those of the brain. In marine mammals, methylmercury is known to be easily converted to inorganic mercury and it combines with selenium forming mercury selenide, which may counteract the toxicity of mercury. Read More

View Article and Full-Text PDF
December 2020

Minocycline Alleviates Cluster Formation of Activated Microglia and Age-dependent Dopaminergic Cell Death in the Substantia Nigra of Zitter Mutant Rat.

Acta Histochem Cytochem 2020 Dec 21;53(6):139-146. Epub 2020 Nov 21.

Department of Histology and Neurobiology, Dokkyo Medical University School of Medicine, Mibu, Tochigi 321-0293, Japan.

Microglial activation is a component of neurodegenerative pathology. Here, we examine whether activated microglia participate in age-related dopaminergic (DA) cell death in the substantia nigra pars compacta (SNc) of the zitter () rat, a mutant characterized by deletion of the attractin gene. Confocal microscopy with double-immunohistochemical staining revealed activated microglia-formed cell-clusters surrounding DA neurons in the SNc from 2 weeks after birth. Read More

View Article and Full-Text PDF
December 2020

High-quality Fluorescence Imaging of the Human Acrosyringium Using a Transparency: Enhancing Technique and an Improved, Fluorescent Solvatochromic Pyrene Probe.

Acta Histochem Cytochem 2020 Dec 21;53(6):131-138. Epub 2020 Nov 21.

Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan.

Two-photon, excitation fluorescent microscopy featuring autofluorescence or immunofluorescence, combined with optical clearance using a transparency-enhancing technique, allows deep imaging of three-dimensional (3D) skin structures. However, it remains difficult to obtain high-quality images of individual cells or 3D structures. We combined a new dye with a transparency-enhancing technology and performed high-quality structural analysis of human epidermal structures, especially the acrosyringium. Read More

View Article and Full-Text PDF
December 2020

The Chemokine CXCL14-like Immunoreactivity Co-exists with Somatostatin, but not NPY in the Rat Dorsal Horn and Has Intimate Association with GABAergic Neurons in the Lateral Spinal Nucleus.

Acta Histochem Cytochem 2020 Oct 20;53(5):121-129. Epub 2020 Oct 20.

Department of Biology, University of Teacher Education Fukuoka, Akamabunkyou-machi 1-1, Munakata, Fukuoka 811-4192, Japan.

Recent studies have proposed that the chemokine CXCL14 not only has a chemotactic activity, but also functions as a neuromodulator and/or neurotransmitter. In this study, we investigated the distribution of CXCL14 immunoreactive structures in the rat spinal cord and clarified the association of these structures with somatostatin, glutamic acid decarboxylase (GAD; a marker for GABAergic neurons), and neuropeptide Y (NPY). CXCL14 immunoreactive fibers and puncta were observed in lamina II, which modulates somatosensation including nociception, and the lateral spinal nucleus of the spinal dorsal horn at cervical, thoracic, and lumber spinal cord levels. Read More

View Article and Full-Text PDF
October 2020

Loss of Annexin A10 Expression Is Associated with Poor Prognosis in Early Gastric Cancer.

Acta Histochem Cytochem 2020 Oct 24;53(5):113-119. Epub 2020 Sep 24.

Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.

Gastric cancer (GC) is the third most common cause of cancer-related mortality. The diagnosis and treatment of early GC is a crucial strategy for prognostic improvement of GC. Annexin A10 (ANXA10), a calcium-/phospholipid-binding protein, is a member of the annexin family. Read More

View Article and Full-Text PDF
October 2020

Morphological and Functional Changes in Skin of Adult Male Rats Chronically Treated with Letrozole, a Nonsteroidal Inhibitor of Cytochrome P450 Aromatase.

Acta Histochem Cytochem 2020 Oct 8;53(5):99-111. Epub 2020 Sep 8.

Department of Histology and Embryology, Pomeranian Medical University in Szczecin, 72 Powstańców Wielkopolskich Str., 70-111 Szczecin, Poland.

Skin is a target for hormones and a site of hormone production. Aromatase inhibitors such as letrozole reduce circulating estrogen. The aim of the study was to investigate the morphology of the dermis and immunoexpression of androgen receptor (AR), estrogen receptor α and β (ERα, ERβ), luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), and cytochrome P450 aromatase (P450arom) in male rats with a deficit of estradiol. Read More

View Article and Full-Text PDF
October 2020

Rab35 Targeting to the Plasma Membrane Is Dependent on the C-terminal Polybasic Cluster.

Acta Histochem Cytochem 2020 Aug 22;53(4):93-97. Epub 2020 Jul 22.

Department of Histology and Cell Biology, School of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan.

Rab35, a member of the Rab GTPase family, has been implicated in various cellular processes including cell motility and membrane trafficking. Although Rab35 is localized to the plasma membrane, Rab proteins that are identified to have high sequence homology with Rab35 exhibit distinct subcellular localization patterns. Comparing the amino acid sequences between Rab35 and its family members revealed a significant variation in an approximate 30-amino acid region of the C-terminus. Read More

View Article and Full-Text PDF

Microhemorrhage in a Rat Model of Neonatal Shaking Brain Injury: Correlation between MRI and Iron Histochemistry.

Acta Histochem Cytochem 2020 Aug 6;53(4):83-91. Epub 2020 Aug 6.

Department Histology and Neurobiology, Dokkyo Medical University, School of Medicine, Shimotsuga, Tochigi 321-0293, Japan.

Previous studies have shown that neonatal shaking brain injury (SBI) causes transient microhemorrhages (MHs) in the gray matter of the cerebral cortex and hippocampus. Iron deposits and iron-uptake cells are observed surrounding MHs in this SBI model, suggesting local hypoxic-ischemic conditions. However, whether the shaken pups suffered systemic hypoxic-ischemic conditions has remained uncertain. Read More

View Article and Full-Text PDF

Fatty Acid Binding Protein 7 is Involved in the Proliferation of Reactive Astrocytes, but not in Cell Migration and Polarity.

Acta Histochem Cytochem 2020 Aug 4;53(4):73-81. Epub 2020 Jul 4.

Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

Reactive gliosis is a defense mechanism to minimize and repair the initial damage after CNS injuries that is characterized by increases in astrocytic reactivity and proliferation, with enhanced expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Fatty acid binding protein 7 (FABP7) is abundantly expressed in several types of glial cells, such as astrocytes and oligodendrocyte precursor cells, during brain development and FABP7-positive astrocytes have been shown to be significantly increased in the mouse cortex after a stab injury. However, the functional significance of FABP7 in gliosis remains unclear. Read More

View Article and Full-Text PDF

Photodynamic Therapy Using a Novel Phosphorus Tetraphenylporphyrin Induces an Anticancer Effect via Bax/Bcl-xL-related Mitochondrial Apoptosis in Biliary Cancer Cells.

Acta Histochem Cytochem 2020 Aug 4;53(4):61-72. Epub 2020 Jul 4.

Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.

Photodynamic therapy (PDT) uses photosensitizer activation by light of a specific wavelength, and is a promising treatment for various cancers; however, the detailed mechanism of PDT remains unclear. Therefore, we investigated the anticancer effect of PDT using a novel phosphorus tetraphenylporphyrin (Ptpp) in combination with light emitting diodes (Ptpp-PDT) in the NOZ human biliary cancer cell line. Cell viability and apoptosis were examined by MTT assay, flow cytometry and TUNEL assay for 24 hr after Ptpp-PDT. Read More

View Article and Full-Text PDF

Immunohistochemical Pharmacokinetics of the Anti-diabetes Drug Alogliptin in Rat Kidney and Liver.

Acta Histochem Cytochem 2020 Jun 29;53(3):55-60. Epub 2020 May 29.

Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.

Alogliptin is one of a new class of therapeutic agents for type 2 diabetes called dipeptidyl peptidase-4 inhibitors. Here, we used immunohistochemistry to investigate the pharmacokinetics of alogliptin at the cell and tissue levels in the rat kidney and liver. One hour after alogliptin administration, the most noticeable immunoreactivity in the kidney was a moderate-to-strong staining in proximal tubule S3 segment epithelial cells. Read More

View Article and Full-Text PDF

Differential Localization and Invasion of Tumor Cells in Mouse Models of Human and Murine Leukemias.

Acta Histochem Cytochem 2020 Jun 29;53(3):43-53. Epub 2020 Apr 29.

Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan.

Leukemias are refractory hematopoietic malignancies, for which the development of new therapeutic agents requires studies using tumor-bearing mouse models. Although several organs are commonly examined in such studies to evaluate the disease course, the effectiveness of interventions and the localization of tumor cells in the affected organs are still unclear. In this study, we histologically examined the distribution of leukemia cells in several organs using two leukemic mouse models produced by the administration of two cell lines (THP-1, a human myelomonocytic leukemia, and A20, a mouse B cell leukemia/lymphoma) to severe immunodeficient mice. Read More

View Article and Full-Text PDF

Vitamin D and the Host-Gut Microbiome: A Brief Overview.

Acta Histochem Cytochem 2020 Jun 16;53(3):33-42. Epub 2020 Jun 16.

Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA.

There is a growing body of evidence for the effects of vitamin D on intestinal host-microbiome interactions related to gut dysbiosis and bowel inflammation. This brief review highlights the potential links between vitamin D and gut health, emphasizing the role of vitamin D in microbiological and immunological mechanisms of inflammatory bowel diseases. A comprehensive literature search was carried out in PubMed and Google Scholar using combinations of keywords "vitamin D," "intestines," "gut microflora," "bowel inflammation". Read More

View Article and Full-Text PDF

New Insights into the Pathogenesis of Diabetic Nephropathy: Proximal Renal Tubules Are Primary Target of Oxidative Stress in Diabetic Kidney.

Acta Histochem Cytochem 2020 Apr 25;53(2):21-31. Epub 2020 Apr 25.

Department of Molecular Pathology, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime 791-0295, Japan.

Diabetic nephropathy is a major source of end-stage renal failure, affecting about one-third cases of diabetes mellitus. It has long been accepted that diabetic nephropathy is mainly characterized by glomerular defects, while clinical observations have implied that renal tubular damage is closely linked to kidney dysfunction at the early stages of diabetic nephropathy. In this study, we conducted pathohistological analyses focusing on renal tubular lesions in the early-stage diabetic kidney with the use of a streptozotocin (STZ)-induced diabetes mellitus mouse model. Read More

View Article and Full-Text PDF

Investigation of Novel c-Kit-expressing Smooth Muscle Cells in Murine Cecum.

Acta Histochem Cytochem 2020 Apr 9;53(2):11-19. Epub 2020 Apr 9.

Department of Anatomy, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui 910-1193, Japan.

In the gastrointestinal tract musculatures, c-Kit receptor tyrosine kinase is specifically expressed in interstitial cells of Cajal (ICC). ICC are distributed among the smooth muscle cells and are either bipolar or multipolar in shape. Our previous and current study shows that c-Kit-immunopositive smooth muscle cells are present in the murine cecum. Read More

View Article and Full-Text PDF

Codependency of Metabolism and Epigenetics Drives Cancer Progression: A Review.

Acta Histochem Cytochem 2020 Feb 26;53(1):1-10. Epub 2020 Feb 26.

Department of Pathology, Division of Pathological Neuroscience, Tokyo Women's Medical University, Tokyo 162-8666, Japan.

Cancer is widely considered to be a set of genetic diseases that are currently classified by tissue and cell type of origin and, increasingly, by its molecular characteristics. This latter aspect is based primarily upon oncogene gains, tumor suppressor losses, and associated transcriptional profiles. However, cancers are also characterized by profound alterations in cellular metabolism and epigenetic landscape. Read More

View Article and Full-Text PDF
February 2020

Localization and Accumulation Studies of Dacomitinib in Rat Intestines and Skin by Immunohistochemistry.

Acta Histochem Cytochem 2019 Dec 25;52(6):101-106. Epub 2019 Dec 25.

Applied Life Science Department, Faculty of Biotechnology and Life Science, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan.

Dacomitinib, a second-generation tyrosine kinase inhibitor, was irreversible inhibitor forming covalent bonds with the kinase domains of EGFR and other ErbB family receptors. Dacomitinib has been approved for the treatment of locally advanced or metastatic non-small cell lung cancer. In this study, we aimed to develop an immunohistochemistry to detect dacomitinib-ErbB family receptor conjugates. Read More

View Article and Full-Text PDF
December 2019

Incremental Growth Lines in Mouse Molar Dentin Represent 8-hr Ultradian Rhythm.

Acta Histochem Cytochem 2019 Dec 20;52(6):93-99. Epub 2019 Dec 20.

Department of Physiology and Systems Bioscience, Graduate School of Medicine, Kyoto Prefectural University of Medicine.

Rhythmic incremental growth lines occur in dental hard tissues of vertebrates, and dentinogenesis in rodent incisors is suggested to be controlled by the 24-hr circadian clock. Rodent incisors continue to grow throughout the animal's life; however, similar to human teeth, rodent molars stop growing after crown formation. This similarity suggests that the mouse molar is an excellent model to understand the molecular mechanisms underlying growth of human teeth. Read More

View Article and Full-Text PDF
December 2019

Hypothalamic Kisspeptin Expression in Hyperandrogenic Female Rats and Aging Rats.

Acta Histochem Cytochem 2019 Oct 26;52(5):85-91. Epub 2019 Sep 26.

Department of Anatomy and Neurobiology, Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Tokyo 113-8602, Japan.

Hypothalamic kisspeptin neurons stimulate gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) release. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) of rats induce an LH surge for ovulation, and those in the arcuate nucleus (ARC) regulate pulsatile LH secretion for follicle development and spermatogenesis. Dysfunction of kisspeptin neurons thus reduces the reproductive function. Read More

View Article and Full-Text PDF
October 2019

Reversible Conversion among Subtypes of Salivary Gland Duct Cells as Identified by Production of a Variety of Bioactive Polypeptides.

Acta Histochem Cytochem 2019 Aug 27;52(4):59-65. Epub 2019 Aug 27.

Department of Molecular Oral Physiology, Division of Oral Science, Graduate School of Biomedical Sciences, Tokushima University, Tokushima-shi, Tokushima 770-8504, Japan.

Four major kallikreins (mK1, mK22, mK9, and mK13) were identified in the mouse submandibular gland (SMG). mK1, a true tissue kallikrein, was used as a protein marker to identify different types of SMG granular convoluted tubule (GCT) cells along with epidermal growth factor (EGF), nerve growth factor (NGF), and renin. Kallikrein mK1 was localized in a very small number (~5%) of GCT cells, which were scattered throughout the GCT, indicating that the majority of GCT cells are mK1-negative. Read More

View Article and Full-Text PDF

Modulation of αβ Integrin via Transactivation of β Integrin Gene on Murine Bone Marrow Macrophages by 1,25(OH)D, Retinoic Acid and Interleukin-4.

Acta Histochem Cytochem 2019 Aug 10;52(4):77-83. Epub 2019 Aug 10.

Department of Molecular Pathology, Ehime University Graduate School of Medicine.

The interleukin (IL)-4, 1,25(OH)D and retinoic acid, increase surface expression of functional integrin αβ on murine osteoclast precursors. All three agonists stimulate transcription of the β gene, leading to increased steady-state levels of mRNA this protein. By contrast, mRNA levels of α remain unchanged. Read More

View Article and Full-Text PDF

The Effect of Estrogen on Hepatic Fat Accumulation during Early Phase of Liver Regeneration after Partial Hepatectomy in Rats.

Acta Histochem Cytochem 2019 Aug 27;52(4):67-75. Epub 2019 Aug 27.

Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.

Fatty liver is common in men and post-menopausal women, suggesting that estrogen may be involved in liver lipid metabolism. The aim of this study is to be clear the role of estrogen and estrogen receptor alpha (ERα) in fat accumulation during liver regeneration using the 70% partial hepatectomy (PHX) model in male, female, ovariectomized (OVX) and E-treated OVX (OVX-E) rats. Liver tissues were sampled at 0-48 hr after PHX and fat accumulation, fatty acid translocase (FAT/CD36), sterol regulatory element-binding protein (SREBP1c), peroxisome proliferator-activated receptor α (PPARα), proliferative cell nuclear antigen (PCNA) and ERα were examined by Oil Red O, qRT-PCR and immunohistochemistry, respectively. Read More

View Article and Full-Text PDF

Long-term Pilocarpine Treatment Improves Salivary Flow in Irradiated Mice.

Acta Histochem Cytochem 2019 Jun 19;52(3):45-58. Epub 2019 Jun 19.

Department of Anatomy and Cell Biology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Radiation therapy for head and neck cancer frequently causes salivary gland dysfunction. Pilocarpine is a clinically approved and effective drug that induces saliva secretion, thereby keeping the oral mucosa moist and reducing discomfort in patients, but the effect is transient. We expected that this drug also has beneficial long-term effects that maintain the integrity of salivary glands by reducing, for instance, apoptosis. Read More

View Article and Full-Text PDF

Immunohistochemical Localization of RNase 7 in Normal and Inflamed Oral Epithelia and Salivary Glands.

Acta Histochem Cytochem 2019 Apr 23;52(2):35-43. Epub 2019 Feb 23.

Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido 061-0293, Japan.

RNase 7 is a skin-derived antimicrobial peptide expressed in various epithelial tissues. It is upregulated by stimulation with microbes and pro-inflammatory cytokines. Herein, we examined the expression levels of RNase 7 in tissues from normal and inflamed oral epithelia and salivary glands via immunohistochemistry. Read More

View Article and Full-Text PDF

Immunohistochemistry for Anti-diabetes Drug, Alogliptin Using a Newly Prepared Monoclonal Antibody: Its Precise Localization in Rat Small Intestine.

Acta Histochem Cytochem 2019 Feb 23;52(1):27-34. Epub 2019 Feb 23.

Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.

Knowledge of time sequence of localization of drugs in cells and tissues of animals may help in developing a better understanding of the actual overall pharmacokinetics of the drugs. We produced monoclonal antibody (mAb) against alogliptin (AG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, conjugated to BSA with -(γ-maleimidobutyryloxy)-succinimide. The mAb was specific for AG and did not cross-react with sitagliptin, vancomycin or amoxicillin. Read More

View Article and Full-Text PDF
February 2019

The Role of the Wnt Signaling Pathway in Upper Jaw Development of Chick Embryo.

Acta Histochem Cytochem 2019 Feb 23;52(1):19-26. Epub 2019 Feb 23.

Department of Anatomy and Neurosciences, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.

Cleft lip with or without cleft palate (CLP) usually results from a failure of the medial nasal prominences to fuse with the lateral and maxillary prominences. This failure inhibits facial morphogenesis regulated by several major morphogenetic signaling pathways. We hypothesized that CLP results from the failure of the Wnt signaling pathway. Read More

View Article and Full-Text PDF
February 2019

Immunohistochemical Mapping of Bcl9 Using Two Antibodies that Recognize Different Epitopes Is Useful to Characterize Juvenile Development of Hepatocellular Carcinoma in Myanmar.

Acta Histochem Cytochem 2019 Feb 26;52(1):9-17. Epub 2019 Feb 26.

Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.

B-cell lymphoma 9 (Bcl9) is the core component of Wnt/β-catenin signaling and overexpressed in nuclei of various tumors, including hepatocellular carcinoma (HCC). However, the extent of Bcl9 expression relative to HCC differentiation stage and its functional aspects are poorly understood. In this study, we examined the expression pattern of Bcl9 immunohistochemically, using two anti-Bcl9 antibodies; one was a conventional polyclonal-antibody (anti-Bcl9) against amino acid no. Read More

View Article and Full-Text PDF
February 2019