Publications by authors named "Kentaro Kato"

178 Publications

Simple Upper and Lower Bounds on the Ultimate Success Probability for Discriminating Arbitrary Finite-Dimensional Quantum Processes.

Phys Rev Lett 2021 May;126(20):200502

Quantum Information Science Research Center, Quantum ICT Research Institute, Tamagawa University, Machida, Tokyo 194-8610, Japan.

We consider the problem of discriminating finite-dimensional quantum processes, also called quantum supermaps, that can consist of multiple time steps. Obtaining the ultimate performance for discriminating quantum processes is of fundamental importance, but is challenging mainly due to the necessity of considering all discrimination strategies allowed by quantum mechanics, including entanglement-assisted strategies and adaptive strategies. In the case in which the processes to be discriminated have internal memories, the ultimate performance would generally be more difficult to analyze. In this Letter, we present a simple upper bound on the ultimate success probability for discriminating arbitrary quantum processes. In the special case of multishot channel discrimination, it can be shown that the ultimate success probability increases by at most a constant factor determined by the given channels if the number of channel evaluations increases by one. We also present a lower bound based on Bayesian updating, which has a low computational cost. Our numerical experiments demonstrate that the proposed bounds are reasonably tight. The proposed bounds do not explicitly depend on any quantum phenomena, and can be readily extended to a general operational probabilistic theory.
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http://dx.doi.org/10.1103/PhysRevLett.126.200502DOI Listing
May 2021

A case report of necrotizing soft tissue infection of the chest wall: Effective management with serial debridement.

Int J Surg Case Rep 2021 May 27;82:105908. Epub 2021 Apr 27.

Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan.

Introduction: Necrotizing soft tissue infection (NSTI) of the chest wall is a rare, rapidly spreading, highly lethal surgical disease. Radical debridement interferes with the important anatomical function of the chest wall. We report a case of chest wall NSTI that was successfully managed with early diagnosis and serial debridement.

Presentation Of Case: A 43-year-old, previously healthy woman presented with severe malaise and worsening right axillary pain. She was severely lethargic and had a painful, large, pale lesion with surrounding erythema of the right chest and trunk. Computed tomography revealed NSTI, with diffuse soft tissue inflammation extending from the axilla to the lower abdomen. There was no obvious entry portal. Prompt surgical drainage was established. Group A streptococcus infection was diagnosed. During her 3-month postoperative course, she underwent four more surgeries, including two debridements. This treatment proved successful and avoided the need for complicated muscle flap reconstruction. She was discharged on postoperative day 109.

Discussion: Group A streptococcus can cause NSTI even in immunocompetent patients without an entry portal. Radical debridement is recommended for infection control. Preserving anatomical chest wall function, however, is also important. Serial debridement with close follow-up solved the problem in this patient.

Conclusions: Serial debridement with close follow-up enabled to avoid large tissue deficits and complicated reconstruction in the case of NSTI of the chest wall.
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http://dx.doi.org/10.1016/j.ijscr.2021.105908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113802PMC
May 2021

Inhibition of Chikungunya Virus Infection by 4-Hydroxy-1-Methyl-3-(3-morpholinopropanoyl)quinoline-2(1)-one (QVIR) Targeting nsP2 and E2 Proteins.

ACS Omega 2021 Apr 31;6(14):9791-9803. Epub 2021 Mar 31.

Molecular Virology Laboratory, Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.

The re-emergence of Chikungunya virus (CHIKV) infection in humans with no approved antiviral therapies or vaccines is one of the major problems with global significance. In the present investigation, we screened 80 in-house quinoline derivatives for their anti-CHIKV activity by computational techniques and found 4-hydroxy-1-methyl-3-(3-morpholinopropanoyl)quinoline-2(1)-one (QVIR) to have potential binding affinities with CHIKV nsP2 and E2 glycoproteins. QVIR was evaluated for its anti-CHIKV potential. QVIR showed strong inhibition of CHIKV infection with an EC (50% effective concentration) value of 2.2 ± 0.49 μM without significant cytotoxicity (CC > 200 μM) and was chosen for further elucidation of its antiviral mechanism. The infectious viral particle formation was abolished by approximately 72% at a QVIR concentration of 20 μM during infection in the BHK-21 cell line, and the CHIKV RNA synthesis was diminished by 84% for nsP2 as well as 74% for E2, whereas the levels of viral proteins were decreased by 69.9% for nsP2 and 53.9% for E2. Flow cytometry analysis confirmed a huge decline in the expression of viral nsP2 and E2 proteins by 71.84 and 67.7%, respectively. Time of addition experiments indicated that QVIR inhibited viral infection at early and late stages of viral replication cycle, and the optimal inhibition was observed at 16 h post infection. The present study advocates for the first time that QVIR acts as a substantial and potent inhibitor against CHIKV and might be as an auspicious novel drug candidate for the development of therapeutic agents against CHIKV infections.
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http://dx.doi.org/10.1021/acsomega.1c00447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047676PMC
April 2021

THE EFFICACY OF MARINE NATURAL PRODUCTS AGAINST PLASMODIUM FALCIPARUM.

J Parasitol 2021 03;107(2):284-288

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-13 Inada-cho, Obihiro, Hokkaido 080-8555, Japan.

Malaria remains one of the most important infectious diseases in the world. In 2017 alone, approximately 219 million people were infected with malaria, and 435,000 people died of this disease. Plasmodium falciparum, which causes falciparum malaria, is becoming resistant to artemisinin (ART) in Southeast Asia; therefore, new antimalarial drugs are urgently needed. Some excellent antimalarial drugs, such as quinine and ART, were originally obtained from plants. Hence, we analyzed the antimalarial effects of marine natural products to find new antimalarial agents. We used a malaria growth inhibition assay to determine the antimalarial ability and half-maximal inhibitory concentration (IC50) values of the marine organism-derived compounds. Three compounds (kapakahine A, kapakahine B, and kulolide-1) showed antimalarial effects, and one (kapakahine F) showed selective antimalarial effects on the Dd2 clone. Although the IC50 values obtained for these compounds were greater than that of ART, their potency against P. falciparum is sufficient to warrant further investigation of these compounds as possible drug leads.
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http://dx.doi.org/10.1645/20-93DOI Listing
March 2021

Experimental demonstration of a 4,294,967,296-QAM-based Y-00 quantum stream cipher template carrying 160-Gb/s 16-QAM signals.

Opt Express 2021 Feb;29(4):5658-5664

We demonstrate a 4,294,967,296-quadrature amplitude modulation (QAM) based Y-00 quantum stream cipher system carrying a 160-Gb/s 16-QAM signal transmitted over 320-km SSMF. The ultra-dense QAM cipher template is realized by an integrated two-segment silicon photonics I/Q modulator.
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http://dx.doi.org/10.1364/OE.405390DOI Listing
February 2021

Nullscript inhibits Cryptosporidium and Toxoplasma growth.

Int J Parasitol Drugs Drug Resist 2020 12 15;14:159-166. Epub 2020 Oct 15.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido, 080-8555, Japan; Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University, Yomogida 232-3, Naruko-onsen, Osaki, Miyagi, 989-6711, Japan. Electronic address:

Cryptosporidium and Toxoplasma are parasites that have caused problems worldwide. Cryptosporidium causes severe watery diarrhoea and may be fatal in immunocompromised patients and in infants. Nitazoxanide is the only agent currently approved by the FDA, but its efficacy is limited. Toxoplasmosis is also a problem in the immunocompromised, as currently available treatment options have limited efficacy and patient tolerance can be poor. In the present investigation, we screened libraries of epigenetic compounds to identify those that inhibited C. parvum growth. Nullscript was identified as a compound with an inhibitory effect on C. parvum and T. gondii growth, and was less toxic to host cells. Nullscript was also able to significantly decrease oocyst excretion in C. parvum-infected SCID mice.
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http://dx.doi.org/10.1016/j.ijpddr.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593347PMC
December 2020

Molecular detection of genotypes and subtypes of Cryptosporidium infection in diarrheic calves, lambs, and goat kids from Turkey.

Parasitol Int 2020 Dec 24;79:102163. Epub 2020 Jun 24.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan; Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University, 232-3 Yomogida, Naruko-onsen, Osaki, Miyagi 989-6711, Japan. Electronic address:

The studies on Cryptosporidium infections of animals in Turkey mostly rely on microscopic observation. Few data are available regarding the prevalence of Cryptosporidium genotypes and subtypes infection. The aim of this study is to analyse the detection of Cryptosporidium genotypes and subtypes from young ruminants. A total of 415 diarrheic fecal specimens from young ruminants were examined for the Cryptosporidium detection by use of nested PCR of the small subunit ribosomal RNA (SSU rRNA) gene and the highly polymorphic 60 kDa glycoprotein (gp60) gene followed by sequence analyses. The results of this study revealed that 25.6% (106 of 415) of the specimens were positive for Cryptosporidium spp. infection. We identified 27.4% (91/333), 19.4% (13/67), and 13.4% (2/15) of positivity in calves, lambs and goat kids, respectively. Genotyping of the SSU rRNA indicated that almost all positive specimens were of C. parvum, except for one calf which was of C. bovis. Sequence analysis of the gp60 gene revealed the most common zoonotic subtypes (IIa and IId) of C. parvum. We detected 11 subtypes (IIaA11G2R1, IIaA11G3R1, IIaA12G3R1, IIaA13G2R1, IIaA13G4R1, IIaA14G1R1, IIaA14G3R1, IIaA15G2R1, IIdA16G1, IIdA18G1, IIdA22G1); three of them (IIaA12G3R1, IIaA11G3R1 and IIaA13G4R1) was novel subtypes found in calves and lambs. Additionally, three subtypes (IIaA11G2R1, IIaA14G3R1, and IIdA16G1) were detected in young ruminants for the first time in Turkey. These results indicate the high infection of Cryptosporidium in Turkey and propose that young ruminants are likely a major reservoir of C. parvum and a potential source of zoonotic transmission.
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http://dx.doi.org/10.1016/j.parint.2020.102163DOI Listing
December 2020

In vitro effects of febrifugine on adult worms.

Trop Med Health 2020 4;48:42. Epub 2020 Jun 4.

Department of Eco-epidemiology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523 Japan.

Background: Reports on the antischistosomal effect of several antimalarial drugs such as artesunate, mefloquine, and amodiaquine suggest that febrifugine, which exerts an antimalarial effect, can also be expected to possess antischistosomal potential. The present study investigates the antischistosomal effects of febrifugine.

Methods: In experiment 1, adult worm pairs were incubated in a medium alone as a control or supplemented with febrifugine at 0.05, 0.1, 0.2, and 0.5 μg/ml for 14 days. The morphology of the worms and the egg production of the female worms were observed simultaneously. In experiment 2, the incubation was conducted as in experiment 1, except that the febrifugine concentrations were reduced to 0.005, 0.01, and 0.02 μg/ml. In addition, . adult worms were incubated with either 0.5 μg/ml febrifugine or none as a control for 5 days and stained with neutral red dye.

Results: Febrifugine significantly reduced the survival of . male and female worms at concentrations of 0.02-0.5 μg/ml following incubation for 14 days and remarkably inhibited the daily egg output of the female worms. The non-treated male and female worms remained morphologically normal within the period of 14 days, whereas male and female worms treated with febrifugine at different concentrations gradually twisted and subsequently died. In addition, . adult worms were incubated with either 0.5 μg/ml febrifugine or none as a control for 5 days and stained with neutral red dye. Non-treated male worms were morphologically normal and stained dark red with neutral red, while febrifugine-treated male worms appeared similar to those in the control group and were stained at a slightly lower level of dark red than the non-treated male worms. Non-treated female worms were morphologically normal, and their intestinal tract and vitellaria were stained deep red and dark red, respectively. In contrast, febrifugine-treated female worms were morphologically damaged, and their intestinal tract and vitellaria remained mostly unstained and stained dark red, respectively.

Conclusion: Febrifugine exerts potent antischistosomal effects and can be expected to contribute to the development of a novel antischistosomal drug.
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http://dx.doi.org/10.1186/s41182-020-00230-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271449PMC
June 2020

Distribution of Cryptosporidium species isolated from diarrhoeic calves in Japan.

Parasitol Int 2020 Oct 3;78:102153. Epub 2020 Jun 3.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan; Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University, 232-3 Yomogida, Naruko-onsen, Osaki, Miyagi 989-6711, Japan. Electronic address:

Cryptosporidium spp. are enteric protozoan parasites that infect a wide range of hosts including humans, and domestic and wild animals. The aim of this study was to molecularly characterize the Cryptosporidium spp. found in calf faeces in Japan. A total of 80 pre-weaned beef and dairy calves' diarrhoeic faecal specimens were collected from nine different prefectures in Japan. A nested polymerase chain reaction targeting the small subunit 18S rRNA and GP60 genes were used to detect the Cryptosporidium genotypes and subtypes. 83.8% (67 out of 80) of the specimens were positive for Cryptosporidium spp.; Cryptosporidium was found in both beef and dairy calves. Cryptosporidium parvum was the predominant species, detected in 77.5% (31/40) of beef calves and 80% (32/40) of dairy calves. Cryptosporidium bovis was also detected, 5.0% (2/40) of dairy calves, and C. ryanae was also found 2.5% (1/40) of dairy calves. One mixed-species infection, 2.5% (1/40) was detected in a beef calf having C. parvum, and C. ryanae. We detected the most common subtype of C. parvum (i.e., IIaA15G2R1), as well as other subtypes (i.e., IIaA14G3R1, IIaA14G2R1, and IIaA13G1R1) that have not previously been detected in calves in Japan. Our results demonstrate the widespread diversity of Cryptosporidium infection in calves in Japan.
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http://dx.doi.org/10.1016/j.parint.2020.102153DOI Listing
October 2020

Prevalence and molecular characterization of species in poultry in Bangladesh.

One Health 2020 Jun 7;9:100122. Epub 2020 Jan 7.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan.

is an opportunistic parasite that has been reported in >30 avian hosts worldwide, however, there is no information regarding spp. in poultry in Bangladesh. Accordingly, we investigated the prevalence of spp. in poultry at open live bird markets in Bangladesh. A total of 197 samples were randomly collected from poultry at open live bird markets in Bangladesh and screened for the detection of Initial microscopic examination revealed spp. was observed in 19.8% (39/197) of the poultry specimens. Subsequent nested PCR targeting the 18S rRNA gene revealed that 15.7% (31/197) of the samples were positive. Of these 31 samples, 17 were (8.7%), 12 were (6.0%), and 2 were (1.0%). Nucleotide sequence analysis of the GP60 gene of the revealed that two subtypes (IIIbA21G1R1 and IIIbA23G1R1), which were found in broiler, native and sonali chickens and a pigeon, matched those previously reported in humans and poultry. We identified two novel subtypes (IIIbA21G2R1 and IIIbA20G2R1) in sonali chickens, a broiler chicken and a layer chicken. We also amplified the GP60 gene of and found two subtypes (IIaA11G2R1 and IIaA13G2R1) in a sonali and a broiler chicken that were previously reported in calf. These findings suggest that poultry can be a source of cryptosporidial infections for humans and animals in Bangladesh. This is the first molecular investigation of genotypes and subtypes in poultry at open live bird markets in Bangladesh.
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http://dx.doi.org/10.1016/j.onehlt.2020.100122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184206PMC
June 2020

Imidazole derivatives as antiparasitic agents and use of molecular modeling to investigate the structure-activity relationship.

Parasitol Res 2020 Jun 11;119(6):1925-1941. Epub 2020 Apr 11.

Department of Biochemistry, Medicinal Biochemistry, Nanomedicine & Toxicology Laboratory, Landmark University, PMB 1001, Omu-Aran, 251101, Nigeria.

Toxoplasmosis is a common parasitic disease caused by Toxoplasma gondii. Limitations of available treatments motivate the search for better therapies for toxoplasmosis. In this study, we synthesized a series of new imidazole derivatives: bis-imidazoles (compounds 1-8), phenyl-substituted 1H-imidazoles (compounds 9-19), and thiopene-imidazoles (compounds 20-26). All these compounds were assessed for in vitro potential to restrict the growth of T. gondii. To explore the structure-activity relationships, molecular analyses and bioactivity prediction studies were performed using a standard molecular model. The in vitro results, in combination with the predictive model, revealed that the imidazole derivatives have excellent selectivity activity against T. gondii versus the host cells. Of the 26 compounds screened, five imidazole derivatives (compounds 10, 11, 18, 20, and 21) shared a specific structural moiety and exhibited significantly high selectivity (> 1176 to > 27,666) towards the parasite versus the host cells. These imidazole derivatives are potential candidates for further studies. We show evidence that supports the antiparasitic action of the imidazole derivatives. The findings are promising in that they reinforce the prospects of imidazole derivatives as alternative and effective antiparasitic therapy as well as providing evidence for a probable biological mechanism.
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http://dx.doi.org/10.1007/s00436-020-06668-6DOI Listing
June 2020

Screening of compound libraries for inhibitors of Toxoplasma growth and invasion.

Parasitol Res 2020 May 1;119(5):1675-1681. Epub 2020 Apr 1.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido, 080-8555, Japan.

Toxoplasma gondii can infect virtually all warm-blooded animals, including humans. It can differentiate between rapidly replicating tachyzoites that cause acute infection and slowly growing bradyzoites in tissue cysts. Treatment options for toxoplasmosis are challenging because current therapies cannot eradicate the latent T. gondii infection that is mainly caused by the bradyzoite forms. Accordingly, recurrence of infection is a problem for immunocompromised patients and congenitally infected patients. Protein kinases have been widely studied in eukaryotic cells, and while little is known about signaling in Toxoplasma infection, it is likely that protein kinases play a key role in parasite proliferation, differentiation, and probably invasion. To identify optimized new kinase inhibitors for drug development against T. gondii, we screened a library of kinase inhibitor compounds for anti-Toxoplasma activity and host cell cytotoxicity. Pyrimethamine served as a positive control and 0.5% DMSO was used as a negative control. Among the 80 compounds screened, 6 compounds demonstrated ≥ 80% parasite growth inhibition at concentrations at which 5 compounds did not suppress host cell viability, while 3 kinase inhibitors (Bay 11-7082, Tyrphostin AG 1295 and PD-98059) had suppressive effects individually on parasite growth and host cell invasion, but did not strongly induce bradyzoite formation.
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http://dx.doi.org/10.1007/s00436-020-06673-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223663PMC
May 2020

Comparative histological studies on properties of polysaccharides secreted by vomeronasal glands of eight Laurasiatheria species.

Acta Histochem 2020 Apr 18;122(3):151515. Epub 2020 Feb 18.

Department of Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11 Inada-cho, Obihiro, Hokkaido, 080-8555, Japan; Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University, 232-3 Yomogida, Naruko-onsen, Osaki, Miyagi, 989-6711, Japan.

Most mammalian species have a vomeronasal organ that detects specific chemical substances, such as pheromones. Mucous fluid covering the vomeronasal sensory epithelium is secreted by vomeronasal glands, and the properties of these fluids have been suggested to be involved in chemical detection. Histological studies using periodic acid-Schiff (PAS) and Alcian blue pH 2.5 (AB) stains, which respectively detect natural and acidic polysaccharides, have suggested variations in the nature of the vomeronasal glands among species. Here, we investigated the responsivity of the vomeronasal glands to PAS and AB stains in eight Laurasiatheria species. All species studied herein possessed vomeronasal glands that stained positive for PAS, like other many reported species. The vomeronasal glands of dogs and minks - like rodents, were AB-negative, whereas those of cows, goats, sika deer, musk shrews and two bat species were positive. Considering the present findings and previous reports, the vomeronasal glands in most of Laurasiatheria species appear to be fundamentally abundant in acidic polysaccharides, whereas those in carnivores essentially contains neutral polysaccharides.
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http://dx.doi.org/10.1016/j.acthis.2020.151515DOI Listing
April 2020

Multiple lineages enable robust development of the neuropil-glia architecture in adult .

Development 2020 03 11;147(5). Epub 2020 Mar 11.

Department of Biology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka 181-8611, Tokyo, Japan

Neural remodeling is essential for the development of a functional nervous system and has been extensively studied in the metamorphosis of Despite the crucial roles of glial cells in brain functions, including learning and behavior, little is known of how adult glial cells develop in the context of neural remodeling. Here, we show that the architecture of neuropil-glia in the adult brain, which is composed of astrocyte-like glia (ALG) and ensheathing glia (EG), robustly develops from two different populations in the larva: the larval EG and -positive ( ) cells. Whereas cells proliferate and generate adult ALG and EG, larval EG dedifferentiate, proliferate and redifferentiate into the same glial subtypes. Each glial lineage occupies a certain brain area complementary to the other, and together they form the adult neuropil-glia architecture. Both lineages require the FGF receptor Heartless to proliferate, and the homeoprotein Prospero to differentiate into ALG. Lineage-specific inhibition of gliogenesis revealed that each lineage compensates for deficiency in the proliferation of the other. Together, the lineages ensure the robust development of adult neuropil-glia, thereby ensuring a functional brain.
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http://dx.doi.org/10.1242/dev.184085DOI Listing
March 2020

Tree of motility - A proposed history of motility systems in the tree of life.

Genes Cells 2020 Jan;25(1):6-21

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Kanagawa, Japan.

Motility often plays a decisive role in the survival of species. Five systems of motility have been studied in depth: those propelled by bacterial flagella, eukaryotic actin polymerization and the eukaryotic motor proteins myosin, kinesin and dynein. However, many organisms exhibit surprisingly diverse motilities, and advances in genomics, molecular biology and imaging have showed that those motilities have inherently independent mechanisms. This makes defining the breadth of motility nontrivial, because novel motilities may be driven by unknown mechanisms. Here, we classify the known motilities based on the unique classes of movement-producing protein architectures. Based on this criterion, the current total of independent motility systems stands at 18 types. In this perspective, we discuss these modes of motility relative to the latest phylogenetic Tree of Life and propose a history of motility. During the ~4 billion years since the emergence of life, motility arose in Bacteria with flagella and pili, and in Archaea with archaella. Newer modes of motility became possible in Eukarya with changes to the cell envelope. Presence or absence of a peptidoglycan layer, the acquisition of robust membrane dynamics, the enlargement of cells and environmental opportunities likely provided the context for the (co)evolution of novel types of motility.
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http://dx.doi.org/10.1111/gtc.12737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004002PMC
January 2020

Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3.

Nat Chem Biol 2020 03 13;16(3):351-360. Epub 2020 Jan 13.

BIFI, University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza, Spain.

Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHTR↓S. FGF23 regulates phosphate homeostasis and deficiency in GALNT3 or FGF23 results in hyperphosphatemia and familial tumoral calcinosis. We explored the molecular mechanism for GalNAc-T3 glycosylation of FGF23 using engineered cell models and biophysical studies including kinetics, molecular dynamics and X-ray crystallography of GalNAc-T3 complexed to glycopeptide substrates. GalNAc-T3 uses a lectin domain mediated mechanism to glycosylate Thr178 requiring previous glycosylation at Thr171. Notably, Thr178 is a poor substrate site with limiting glycosylation due to substrate clashes leading to destabilization of the catalytic domain flexible loop. We suggest GalNAc-T3 specificity for FGF23 and its ability to control circulating levels of intact FGF23 is achieved by FGF23 being a poor substrate. GalNAc-T3's structure further reveals the molecular bases for reported disease-causing mutations. Our findings provide an insight into how GalNAc-T isoenzymes achieve isoenzyme-specific nonredundant functions.
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http://dx.doi.org/10.1038/s41589-019-0444-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923394PMC
March 2020

Screening of a library of traditional Chinese medicines to identify compounds and extracts which inhibit Toxoplasma gondii growth.

J Vet Med Sci 2020 Feb 2;82(2):184-187. Epub 2020 Jan 2.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan.

Toxoplasma gondii can cause severe encephalitis in immunocompromised patients. Although pyrimethamine and sulphadiazine have been standard therapeutic agents for the treatment of acute toxoplasmosis, they have toxic side effects. Therefore, there is a need to identify new drugs that are less toxic. Some traditional Chinese medicines (TCMs) have shown good efficacy in controlling T. gondii replication in mouse models. Here, we screened a natural product library comprising TCMs with the aim of identifying compounds and extracts with anti-toxoplasmosis activities. We found several hit compounds and extracts that could be candidates for new drugs against T. gondii infection.
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http://dx.doi.org/10.1292/jvms.19-0241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041978PMC
February 2020

A High-Resolution Map of SBP1 Interactomes in Plasmodium falciparum-infected Erythrocytes.

iScience 2019 Sep 25;19:703-714. Epub 2019 Jul 25.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan; Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University, Naruko-onsen, Osaki, Miyagi 989-6711, Japan. Electronic address:

The pathogenesis of malaria parasites depends on host erythrocyte modifications that are facilitated by parasite proteins exported to the host cytoplasm. These exported proteins form a trafficking complex in the host cytoplasm that transports virulence determinants to the erythrocyte surface; this complex is thus essential for malaria virulence. Here, we report a comprehensive interaction network map of this complex. We developed authentic, unbiased, highly sensitive proteomic approaches to determine the proteins that interact with a core component of the complex, SBP1 (skeleton-binding protein 1). SBP1 interactomes revealed numerous exported proteins and potential interactors associated with SBP1 intracellular trafficking. We identified several host-parasite protein interactions and linked the exported protein MAL8P1.4 to Plasmodium falciparum virulence in infected erythrocytes. Our study highlights the complicated interplay between parasite and host proteins in the host cytoplasm and provides an interaction dataset connecting dozens of exported proteins required for P. falciparum virulence.
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http://dx.doi.org/10.1016/j.isci.2019.07.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728614PMC
September 2019

Three-dimensional fine structure of feeder organelle in Cryptosporidium parvum.

Parasitol Int 2019 Dec 9;73:101958. Epub 2019 Jul 9.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-13 Inada-cho, Obihiro, Hokkaido 080-8555, Japan; Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University, 232-3 Yomogida, Naruko-onsen, Osaki, Miyagi 989-6711, Japan. Electronic address:

Feeder organelles of Cryptosporidium are the convoluted structures located at the host-parasite interface that uptake of nutrients from host cells. Although the ultrastructure of feeder organelles has been summarized as being highly invaginated structure, the three-dimensional form remains uncertain. Osmium-maceration scanning electron microscopy (OS-SEM) allows visualization of the three-dimensional ultrastructure after removing soluble proteins. Here, we assessed C. parvum attached to mouse ileal epithelial cells using transmission electron microscopy (TEM) and OS-SEM. Feeder organelles visualized by TEM as aggregated structures of concentrically-, vertically- and randomly-lined bars comprised a complex reticulated network of stacked flat bursiform, ring-shaped bursiform and reticulated tubular membranes on OS-SEM. These findings suggested that the feeder organelles are more complex than was previously thought.
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http://dx.doi.org/10.1016/j.parint.2019.101958DOI Listing
December 2019

Nanoparticles show potential to retard bradyzoites in vitro formation of Toxoplasma gondii.

Folia Parasitol (Praha) 2019 Feb 21;66. Epub 2019 Feb 21.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Japan.

Toxoplasmosis is a common parasitic disease caused by Toxoplasma gondii (Nicolle et Manceaux, 1908), an obligate parasite capable of infecting a range of cell types in almost all warm-blooded animals. Upon infecting an intermediate host, the parasites differentiate into tachyzoites which rapidly infect host tissues. Usually, the invading parasites are cleared by the immune system and administered drugs, but some tachyzoites differentiate into bradyzoites forming tissue cysts. These tissue cysts could serve as a source for re-infection and exacerbations. Currently, treatment for toxoplasmosis is limited and, moreover, there are no drugs for treating the cystic stage thus rendering toxoplasmosis a global burden. Recently, we demonstrated that inorganic nanoparticles showed promising activity against the tachyzoite stage T. gondii. In the present study, we evaluated nanoparticles for effect on bradyzoite formation in vitro. Data revealed that the nanoparticles limited bradyzoite burden in vitro. Further, the nanoparticles decreased the bradyzoite-specific BAG-1 promoter activity relative to the untreated control under a bradyzoite-inducing culture condition, even though this reduction in BAG-1 promoter activity waned with increasing concentrations of nanoparticles. In contrast, a parallel experiment under normal cell culture conditions showed that the nanoparticle treatment mildly increased the BAG-1 promoter activity relative to the untreated control. Taken together, the findings are evidence that nanoparticles not only possess anti-tachyzoite potential but they also have anti-bradyzoite potential in vitro.
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http://dx.doi.org/10.14411/fp.2019.001DOI Listing
February 2019

Repurposing existing drugs: identification of irreversible IMPDH inhibitors by high-throughput screening.

J Enzyme Inhib Med Chem 2019 Dec;34(1):171-178

a Division of Applied Bioscience, Graduate School of Agriculture , Hokkaido University , Sapporo , Japan.

Inosine 5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme for the production of guanine nucleotides. Disruption of IMPDH activity has been explored as a therapeutic strategy for numerous purposes, such as for anticancer, immunosuppression, antiviral, and antimicrobial therapy. In the present study, we established a luciferase-based high-throughput screening system to identify IMPDH inhibitors from our chemical library of known bioactive small molecules. The screening of 1400 compounds resulted in the discovery of three irreversible inhibitors: disulfiram, bronopol, and ebselen. Each compound has a distinct chemical moiety that differs from other reported IMPDH inhibitors. Further evaluation revealed that these compounds are potent inhibitors of IMPDHs with k values of 0.7 × 10 to 9.3 × 10 M·s. Both disulfiram and bronopol exerted similar degree of inhibition to protozoan and mammalian IMPDHs. Ebselen showed an intriguing difference in mode of inhibition for different IMPDHs, with reversible and irreversible inhibition to each Cryptosporidium parvum IMPDH and human IMPDH type II, respectively. In the preliminary efficacy experiment against cryptosporidiosis in severe combined immunodeficiency (SCID) mouse, a decrease in the number of oocyst shed was observed upon the oral administration of disulfiram and bronopol, providing an early clinical proof-of-concept for further utilization of these compounds as IMPDH inhibitors.
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http://dx.doi.org/10.1080/14756366.2018.1540474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249553PMC
December 2019

How does Toxoplama gondii invade host cells?

Authors:
Kentaro Kato

J Vet Med Sci 2018 Nov 4;80(11):1702-1706. Epub 2018 Oct 4.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan.

Toxoplasma gondii is a highly prevalent protozoon that can infect all warm-blooded animals, including humans. It is frequently used as an Apicomplexan parasite model in research. In this review, the invasion mechanism of T. gondii is described as a representative Apicomplexan parasite. The invasion machinery of T. gondii consists of the moving junction and the glideosome, which is a specific motor system for Apicomplexan parasites. I provide details about the moving junction, parasite-secreted proteins and host adhesion receptors, the glideosome, and calcium signaling, which generates the power for the gliding mobility of T. gondii. A detailed understanding of parasite invasion can be useful for the development of new effective drugs to inhibit this event and disrupt the Apicomplexan life cycle.
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http://dx.doi.org/10.1292/jvms.18-0344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261808PMC
November 2018

Differential Gene Expression Profile of Human Neutrophils Cultured with -Parasitized Erythrocytes.

J Immunol Res 2018 5;2018:6709424. Epub 2018 Jul 5.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan.

Neutrophils (PMNs) are the most abundant cellular component of our innate immune system, where they play central roles in the pathogenesis of and resistance to a broad range of diseases. However, their roles in malarial infection remain poorly understood. Therefore, we examined the transcriptional gene profile of human PMNs in response to -parasitized erythrocytes (iRBCs) by using oligonucleotide microarrays. Results revealed that PMNs induced a broad and vigorous set of changes in gene expression in response to malarial parasites, represented by 118 upregulated and 216 downregulated genes. The transcriptional response was characterized by the upregulation of numerous genes encoding multiple surface receptors, proteins involved in signal transduction pathways, and defense response proteins. This response included a number of genes which are known to be involved in the pathogenesis of malaria and other inflammatory diseases. Gene enrichment analysis suggested that the biological pathways involved in the PMN responses to the iRBCs included insulin receptor, Jak-STAT signaling pathway, mitogen-activated protein kinase (MAPK), and interleukin and interferon-gamma (IFN-) signaling pathways. The current study provides fundamental knowledge on the molecular responses of neutrophils to malarial parasites, which may aid in the discovery of novel therapeutic interventions.
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http://dx.doi.org/10.1155/2018/6709424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057315PMC
November 2018

Metal nanoparticles restrict the growth of protozoan parasites.

Artif Cells Nanomed Biotechnol 2018 22;46(sup3):S86-S94. Epub 2018 Jul 22.

b National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine , Obihiro , Hokkaido , Japan.

The Trypanosoma and Toxoplasma spp, are etiological agents of diseases capable of causing significant morbidity, mortality and economic burden, predominantly in developing countries. Currently, there are no effective vaccines for the diseases caused by these parasites; therefore, therapy relies heavily on antiprotozoal drugs. However, the treatment options for these parasitic diseases are limited, thus underscoring the need for new anti-protozoal agents. Here, we investigated the anti-parasite action of nanoparticles. We found that the nanoparticles have strong and selective in vitro activity against T. b. brucei but moderate in vitro activity against T. congolense and T. evansi. An estimation of the in vitro anti-Trypanosoma efficacy showed that the nanoparticles had ≥200-fold selective activity against the parasite versus mammalian cells. Moreover, the nanoparticle alloys moderately suppressed the in vitro growth of T. gondii by ≥60%. In our in vivo study, the nanoparticles appeared to exhibit a trypanostatic effect, but did not totally suppress the rat parasite burden, thereby failing to appreciably extend the survival time of infected animals compared with the untreated control. In conclusion, this is the first study to demonstrate the selective in vitro anti-Trypanosoma action of nanoparticles and thus supports the potential of nanoparticles as alternative anti-parasitic agents.
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http://dx.doi.org/10.1080/21691401.2018.1489267DOI Listing
June 2019

Molecular and histopathological characterization of Cryptosporidium and Eimeria species in bats in Japan.

J Vet Med Sci 2018 Sep 16;80(9):1395-1399. Epub 2018 Jul 16.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan.

Bats are potential reservoirs of Cryptosporidium and Eimeria. The genus Cryptosporidium infects various vertebrates and causes a diarrheal disease known as cryptosporidiosis. Many epidemiological studies in wild animals have been performed; however, most of them relied on only PCR-based detection because of the difficulty of performing pathological analyses. Accordingly, the natural host and pathogenicity of Cryptosporidium bat genotypes remain unclear. In this study, we captured Eptesicus nilssonii (Northern bats) in Hokkaido, Japan. Of the three intestinal samples obtained, two were positive for Cryptosporidium spp. and one was positive for Eimeria spp. The corresponding microorganisms were also confirmed histopathologically. We detected the novel Cryptosporidium bat genotype XII and Eimeria rioarribaensis in bat intestine.
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http://dx.doi.org/10.1292/jvms.18-0130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160890PMC
September 2018

Screening of a library of traditional Chinese medicines to identify anti-malarial compounds and extracts.

Malar J 2018 Jun 25;17(1):244. Epub 2018 Jun 25.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido, 080-8555, Japan.

Background: Malaria is a major infectious disease in the world. In 2015, approximately 212 million people were infected and 429,000 people were killed by this disease. Plasmodium falciparum, which causes falciparum malaria, is becoming resistant to artemisinin (ART) in Southeast Asia; therefore, new anti-malarial drugs are urgently needed. Some excellent anti-malarial drugs, such as quinine or ART, were originally obtained from natural plants. Hence, the authors screened a natural product library comprising traditional Chinese medicines (TCMs) to identify compounds/extracts with anti-malarial effects.

Methods: The authors performed three assays: a malaria growth inhibition assay (GIA), a cytotoxicity assay, and a malaria stage-specific GIA. The malaria GIA revealed the anti-malarial ability and half-maximal inhibitory concentrations (IC) of the natural products, whereas the malaria stage-specific GIA revealed the point in the malaria life cycle where the products exerted their anti-malarial effects. The toxicity of the products to the host cells was evaluated with the cytotoxicity assay.

Results: Four natural compounds (berberine chloride, coptisine chloride, palmatine chloride, and dehydrocorydaline nitrate) showed strong anti-malarial effects (IC < 50 nM), and low cytotoxicity (cell viability > 90%) using P. falciparum 3D7 strain. Two natural extracts (Phellodendri cortex and Coptidis rhizoma) also showed strong antiplasmodial effects (IC < 1 µg/ml), and low cytotoxicity (cell viability > 80%). These natural products also demonstrated anti-malarial capability during the trophozoite and schizont stages of the malaria life cycle.

Conclusions: The authors identified four compounds (berberine chloride, coptisine chloride, palmatine chloride, and dehydrocorydaline nitrate) and two extracts (Phellodendri cortex and Coptidis rhizoma) with anti-malarial activity, neither of which had previously been described. The IC values of the compounds were comparable to that of chloroquine and better than that of pyrimethamine. These compounds and extracts derived from TCMs thus show promise as potential future anti-malarial drugs.
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http://dx.doi.org/10.1186/s12936-018-2392-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020241PMC
June 2018

Exploring Amino Acid-Capped Nanoparticles for Selective Anti-Parasitic Action and Improved Host Biocompatibility.

J Biomed Nanotechnol 2018 May;14(5):847-867

Toxoplasma gondii causes toxoplasmosis, a common infection against which better drugs are needed. Recently, we showed that inorganic nanoparticles have anti-Toxoplasma activity. Here, we sought to enhance the anti-parasitic efficacy and host biocompatibility of these nanoparticles by modifying their surface with amino acids. The amino acids used were selected based on the nutritional requirements of Toxoplasma gondii. Amino acid-capped nanoparticles (amino-NPs) were synthesized, purified, and then screened for anti-Toxoplasma activity in in vitro infection models. The amino-NPs showed enhanced anti-parasitic selectivity as well as improved host biocompatibility. Oxidative stress, modulation of host HIF-1α, and activation of the kynurenine pathway contributed to the anti-parasitic action of the amino-NPs. Our findings provide additional support for the potential use of nanoparticles as innovative anti-parasitic agents. Findings glean additional perspective that highlight prospects of nanoparticles not only as innovative source of anti-parasitic agents but also provide evidence for probable biological mechanism.
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http://dx.doi.org/10.1166/jbn.2018.2544DOI Listing
May 2018

Application of Non-Fluorescent Dyes to Assess the Antischistosomal Effect of Antimalarial Drugs on Schistosoma mansoni Adult Worms.

Jpn J Infect Dis 2018 Sep 31;71(5):382-387. Epub 2018 May 31.

Department of Eco-epidemiology, Institute of Tropical Medicine, Nagasaki University.

The possible emergence of praziquantel (PZQ)-tolerant and/or -resistant schistosomes requires the study and development of new antischistosomal drugs as alternatives to PZQ. The present study investigates the capability of 3 dyes-methylene blue (MB), neutral red (NR), and trypan blue (TB)-to assess the in vitro antischistosomal effect of antimalarial drugs on Schistosoma mansoni adult worms. S. mansoni adult worms were incubated in the medium alone as the control or in the medium supplemented with 10 μg/ml primaquine (PQ), artesunate (AR), or amodiaquine (AQ) for 5 days. Viabilities of the worms were observed following staining with MB, NR, or TB. The disparity of MB and NR staining among male and female adult worms treated with PQ, AR, and AQ correlated with the various levels of damage to the male and female worms. Furthermore, the severity of the damage to the adult worms treated with the 3 drugs appeared to be reflected in the TB staining status. The results indicate that the 3 non-fluorescent dyes can serve as useful complementary tools to assess the antischistosomal effect of antimalarial drugs.
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http://dx.doi.org/10.7883/yoken.JJID.2018.034DOI Listing
September 2018

Screening of chemical compound libraries identified new anti-Toxoplasma gondii agents.

Parasitol Res 2018 Feb 19;117(2):355-363. Epub 2017 Dec 19.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido, 080-8555, Japan.

Toxoplasma gondii is the etiological agent of toxoplasmosis, a common parasitic disease that affects nearly one-third of the human population. The primary infection can be asymptomatic in healthy individuals but may prove fatal in immunocompromised individuals. Available treatment options for toxoplasmosis patients are limited, underscoring the urgent need to identify and develop new therapies. Non-biased screening of libraries of chemical compounds including the repurposing of well-characterized compounds is emerging as viable approach to achieving this goal. In the present investigation, we screened libraries of natural product and FDA-approved compounds to identify those that inhibited T. gondii growth. We identified 32 new compounds that potently inhibit T. gondii growth. Our findings are new and promising, and further strengthen the prospects of drug repurposing as well as the screening of a wide range of chemical compounds as a viable source of alternative anti-parasitic therapeutic agents.
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http://dx.doi.org/10.1007/s00436-017-5698-1DOI Listing
February 2018

Recurrence of meningitis in a preterm infant and co-infection of echovirus 18.

IDCases 2017 10;10:135-137. Epub 2017 Nov 10.

Department of Pediatrics, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan.

Introduction: Bacterial meningitis may relapse after adequate antibiotic treatment. In most cases, however, the pathophysiology cannot be identified.

Presentation Of Case: We describe a preterm infant with recurrent episodes of meningitis due to infection with an identical strain both at birth and at 10 days after cessation of a 3 week course of appropriate antibiotic treatment. At the time of recurrence, the patient presented with fulminant severe cardiac failure due to acute myocarditis, coupled with a concurrent echovirus 18 infection (confirmed by stool culture and serological analysis).

Conclusion: Co-infection by echovirus may underlie recurrence of meningitis in this case.
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http://dx.doi.org/10.1016/j.idcr.2017.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695537PMC
November 2017