Publications by authors named "Hirofumi Toda"

21 Publications

  • Page 1 of 1

Short and long sleeping mutants reveal links between sleep and macroautophagy.

Elife 2021 Jun 4;10. Epub 2021 Jun 4.

Chronobiology and Sleep Institute, Perelman Medical School of University of Pennsylvania, Philadelphia, United States.

Sleep is a conserved and essential behavior, but its mechanistic and functional underpinnings remain poorly defined. Through unbiased genetic screening in , we discovered a novel short-sleep mutant we named . Positional cloning and subsequent complementation, CRISPR/Cas9 knock-out, and RNAi studies identified Argus as a transmembrane protein that acts in adult peptidergic neurons to regulate sleep. mutants accumulate undigested Atg8a(+) autophagosomes, and genetic manipulations impeding autophagosome formation suppress sleep phenotypes, indicating that autophagosome accumulation drives short-sleep. Conversely, a neurodegenerative mutant that impairs autophagosome formation was identified independently as a gain-of-sleep mutant, and targeted RNAi screens identified additional genes involved in autophagosome formation whose knockdown increases sleep. Finally, autophagosomes normally accumulate during the daytime and nighttime sleep deprivation extends this accumulation into the following morning, while daytime gaboxadol feeding promotes sleep and reduces autophagosome accumulation at nightfall. In sum, our results paradoxically demonstrate that wakefulness increases and sleep decreases autophagosome levels under unperturbed conditions, yet strong and sustained upregulation of autophagosomes decreases sleep, whereas strong and sustained downregulation of autophagosomes increases sleep. The complex relationship between sleep and autophagy suggested by our findings may have implications for pathological states including chronic sleep disorders and neurodegeneration, as well as for integration of sleep need with other homeostats, such as under conditions of starvation.
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http://dx.doi.org/10.7554/eLife.64140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177895PMC
June 2021

Evolutionary Origin of Distinct NREM and REM Sleep.

Front Psychol 2020 14;11:567618. Epub 2020 Dec 14.

International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.

Sleep is mandatory in most animals that have the nervous system and is universally observed in model organisms ranging from the nematodes, zebrafish, to mammals. However, it is unclear whether different sleep states fulfill common functions and are driven by shared mechanisms in these different animal species. Mammals and birds exhibit two obviously distinct states of sleep, i.e., non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, but it is unknown why sleep should be so segregated. Studying sleep in other animal models might give us clues that help solve this puzzle. Recent studies suggest that REM sleep, or ancestral forms of REM sleep might be found in non-mammalian or -avian species such as reptiles. These observations suggest that REM sleep and NREM sleep evolved earlier than previously thought. In this review, we discuss the evolutionary origin of the distinct REM/NREM sleep states to gain insight into the mechanistic and functional reason for these two different types of sleep.
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http://dx.doi.org/10.3389/fpsyg.2020.567618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767968PMC
December 2020

Epidemiological and molecular characterization of invasive Streptococcus pneumoniae isolated following introduction of 7-valent conjugate vaccine in Kinki region, Japan, 2008-2013.

J Infect Chemother 2020 May 20;26(5):451-458. Epub 2019 Dec 20.

Department of Clinical Laboratory Medicine, Kindai University Faculty of Medicine, Japan.

Streptococcus pneumoniae is one of the most common bacteria causing community-acquired pneumonia and meningitis. The use of 7-valent pneumococcal conjugate vaccine (PCV7) has reduced the incidence of pneumococcal disease while changing pneumococcal population through herd immunity and non-vaccine pneumococci replacement. This study investigated molecular epidemiologic characteristics of pneumococcal strains in the Kinki region of Japan from 2008 to 2013. A total of 159 invasive pneumococcal isolates were characterized by serotyping, antibiotic susceptibility testing, PCR analysis of penicillin-binding protein genes, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). In adult populations, pediatric PCV7 introduction decreased isolates expressing PCV7 serotypes via herd immunity and increased isolates expressing non-PCV7 serotypes. The rate of penicillin resistance and isolates with alterations in all three pbp genes was higher in PCV7 type isolates than in non-PCV7 type isolates. In MLST analysis, all of serotype 19F isolates were of the same sequence type, ST236, which is the antimicrobial-resistant clone Taiwan-14, and the majority of serotypes 23F and 19A isolates were of ST1437 and ST3111 respectively, which are the predominant clones of antimicrobial-resistant pneumococci in Japan. In PFGE profiles, serotype 6B-ST2224, serotype 19F-ST236, serotype 19A-ST3111, and serotype 23F-ST1437 formed six separate clusters composed of genetically identical strains, and genetically identical serotype 22F-ST433 formed two different clusters between the pre- and post-PCV7 period. The results of molecular analysis suggest the spread and persistence of these identical antimicrobial resistant clones in the Kinki region and genetic changes of epidemic clone serotype 22F-ST433 before and after pediatric PCV7 introduction.
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http://dx.doi.org/10.1016/j.jiac.2019.11.010DOI Listing
May 2020

Antimicrobial susceptibility surveillance of obligate anaerobic bacteria in the Kinki area.

J Infect Chemother 2019 Nov 17;25(11):837-844. Epub 2019 Aug 17.

Department of Clinical Laboratory, Hyogo Medical University Hospital, Japan; Study of Bacterial Resistance Kinki Region of Japan, Japan.

Obligate anaerobes exist as resident flora in various sites in humans, but they are also emphasized as endogenous causative microorganism of infections. We performed surveillance to understand the trend of drug susceptibility in obligate anaerobic bacteria in the Kinki area of Japan. In the experiment, we used 156 obligate anaerobe isolates collected from 13 institutions that participated in the Study of Bacterial Resistance Kinki Region of Japan. MALDI Biotyper was used to identify the collected strains, and among the 156 test strains, those that could be identified with an accuracy of Score Value 2.0 or more included 6 genera, 30 species, and 144 strains (Bacteroides spp. 77 strains, Parabacteroides sp. 2 strains, Prevotella spp. 29 strains, Fusobacterium spp. 14 strains, Porphyromonas spp. 2 strains, and Clostridioides difficile 20 strains), and they were assigned as subject strains for drug susceptibility testing. The drug susceptibility test was carried out by broth microdilution method using Kyokuto Opt Panel MP ANA (Kyokuto Pharmaceutical Industrial Co., Ltd., Tokyo, Japan) and judged according to CLSI criteria. As a result, Bacteroides and Parabacteroides species showed good sensitivities to tazobactam-piperacillin, imipenem, metronidazole and chloramphenicol, and low sensitivities to ampicillin, cefoperazone and vancomycin. Prevotella species showed good sensitivities to sulbactam-ampicillin, tazobactam-piperacillin, cefmetazole, imipenem, doripenem and metronidazole. Susceptibility rates to other drugs were slightly different depending on the bacterial species. Both Fusobacterium spp. and Porphyromonas spp. showed high sensitivities to many drugs. C. difficile was highly sensitive to vancomycin and metronidazole, having MICs of 0.5 μg/mL and ≤2 μg/mL, respectively.
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http://dx.doi.org/10.1016/j.jiac.2019.07.018DOI Listing
November 2019

Genetic Mechanisms Underlying Sleep.

Cold Spring Harb Symp Quant Biol 2018 1;83:57-61. Epub 2019 Apr 1.

Howard Hughes Medical Institute, Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Sleep is important for cognitive ability, and perturbations of sleep are associated with a myriad of brain disorders. However, how sleep promotes health and function during wake is poorly understood. To address the cellular and molecular mechanisms underlying sleep, we use the fruit fly as a genetic model. Forward genetic approaches in flies were critical for deciphering molecular mechanisms of the circadian clock. Using similar approaches, we and others are gaining insights into the pathways that control sleep amount.
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http://dx.doi.org/10.1101/sqb.2018.83.037705DOI Listing
April 2019

A sleep-inducing gene, , links sleep and immune function in .

Science 2019 02;363(6426):509-515

Howard Hughes Medical Institute, Chronobiology Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Sleep remains a major mystery of biology. In particular, little is known about the mechanisms that account for the drive to sleep. In an unbiased screen of more than 12,000 lines, we identified a single gene, , that induces sleep. The NEMURI protein is an antimicrobial peptide that can be secreted ectopically to drive prolonged sleep (with resistance to arousal) and to promote survival after infection. Loss of increased arousability during daily sleep and attenuated the acute increase in sleep induced by sleep deprivation or bacterial infection. Conditions that increase sleep drive induced expression of in a small number of fly brain neurons and targeted it to the sleep-promoting, dorsal fan-shaped body. We propose that NEMURI is a bona fide sleep homeostasis factor that is particularly important under conditions of high sleep need; because these conditions include sickness, our findings provide a link between sleep and immune function.
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http://dx.doi.org/10.1126/science.aat1650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505470PMC
February 2019

Laboratory surveillance of antimicrobial resistance and multidrug resistance among Streptococcus pneumoniae isolated in the Kinki region of Japan, 2001-2015.

J Infect Chemother 2018 Mar 1;24(3):171-176. Epub 2018 Feb 1.

Department of Clinical Laboratory Medicine, Kindai University Faculty of Medicine, Japan.

The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced among children in Japan in 2010. There are no long-term multicenter surveillance studies of antimicrobial resistance in S. pneumoniae before and after the introduction of PCV7. Therefore, we examined chronological trends in antimicrobial resistance among 4534 strains of S. pneumoniae isolated from both children and adults in the Kinki region of Japan during 2001-2015. High-level penicillin and third-generation cephalosporin resistance in S. pneumoniae increased among both children and adults during the period before the introduction of PCV7 (2001-2010). Besides penicillin and cephalosporin, pneumococcal carbapenem and macrolide resistance increased among children. The rate of resistance to these antibiotics was higher among children than among adults. The introduction of PCV7 decreased the rate of non-susceptibility to β-lactam antibiotics and the rate of multidrug resistant S. pneumoniae among children, but not among adults.
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http://dx.doi.org/10.1016/j.jiac.2017.12.010DOI Listing
March 2018

Evaluation of the modified carbapenem inactivation method for the detection of carbapenemase-producing Enterobacteriaceae.

J Infect Chemother 2018 Apr 14;24(4):262-266. Epub 2017 Dec 14.

Department of Clinical Laboratory, Hyogo College of Medicine, Hyogo, Japan.

Carbapenemase-producing Enterobacteriaceae (CPE) are increasing worldwide. Rapid and accurate detection of CPE is necessary for appropriate antimicrobial treatment and hospital infection control. However, CPE contains some strains that are difficult to detect depending on genotype and MIC value of carbapenem, and a detection method has not been established. The recently reported modified carbapenem inactivation method (mCIM) has been developed in CLSI M100-S27 as a phenotypic technique for detecting carbapenemase activity. In the present study, we examined mCIM as a new CPE detection method using 207 Enterobacteriaceae isolates in comparison with the three existing screening methods of modified Hodge test, Carba NP test and carbapenem inactivation method and evaluated its performance. Consequently, both the sensitivity and specificity of mCIM were 100%, indicating better results than the conventional screening methods. The mCIM is a useful tool for microbiology laboratories due to its simplicity, clear criteria, cost-effectiveness and availability at any laboratory.
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http://dx.doi.org/10.1016/j.jiac.2017.11.010DOI Listing
April 2018

Nosocomial spread of Klebsiella pneumoniae isolates producing bla carbapenemase at a Japanese hospital.

J Infect Chemother 2017 Jan 18;23(1):40-44. Epub 2016 Oct 18.

Clinical Laboratory, Hyogo Medical University Hospital, Hyogo, Japan.

Six Klebsiella pneumoniae clinical isolates resistant to various cephalosporins and cephamycins were identified in a Japanese general hospital, a tertiary care hospital, between November 2009 and April 2010. All K. pneumoniae isolates carried bla and bla, while 2 K. pneumoniae isolates also harbored bla. The pulsed-field gel electrophoresis patterns revealed that these 6 K. pneumoniae isolates were almost identical, suggesting their clonal relatedness. Plasmid profiles and conjugation assays revealed that these bla genes were located on similar conjugative plasmids. These data indicate that nosocomial spread caused by K. pneumoniae isolates producing bla carbapenemase occurred at a Japanese general hospital. K. pneumoniae isolate harboring bla is rarely reported in Japan, and, to the best of our knowledge, this is the second report of K. pneumoniae isolates harboring bla that occurred nosocomial spread in Japan.
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http://dx.doi.org/10.1016/j.jiac.2016.09.006DOI Listing
January 2017

[The annual changes in antimicrobial susceptibility test results of Pseudomonas aeruginosa isolates from the Kinki district].

Jpn J Antibiot 2016 Apr;69(2):101-10

A study was conducted of the 1,225 Pseudomonas aeruginosa strains that were isolated at 20 medical institutions in the Kinki district between 2011 and 2013 to determine their antimicrobial susceptibility and to characterize the strains of multidrug-resistant Pseudomonas aeruginosa (MDRP) and the metallo-β-lactamase (MBL) -producing strains. The MIC50/MIC90 values (μg/mL) of the various antimicrobial agents were as follows: imipenem, 2/>8; meropenem, 1/>8; doripenem, 0.5/8; biapenem, 1/>8; tazobactam/piperacillin, 8/>64; piperacillin, 8/>64; sulbactam/cefoperazone, 8/64; cefepime, 4/16; cefozopran, 2/>16; aztreonam, 8/>16; amikacin, 4/16; levofloxacin, 1/>4; and ciprofloxacin, 0.25/>2. From the viewpoint of the annual changes in the susceptibility rates (according to the CLSI guidelines [M100-S22]), the susceptibility to tazobactam/piperacillin, piperacillin, cefepime, cefozopran and aztreonam decreased in 2013. On the other hand, two antimicrobial agents showed high susceptibility rates each year; amikacin (94.0-95.6%) showed the highest rate, followed by doripenem (80.3-82.6%). With the exception of amikacin, there were substantial inter-institutional differences in antimicrobial susceptibility. In comparison to the previous CLSI guidelines (M100-S21), the new CLSI guidelines (M100-S22) on the use of carbapenems and penicillins show that the MIC80 has been affected. The MDRP detection rates in 2011, 2012 and 2013 were 1.8% (8 strains), 1.8% (8 strains), and 2.8% (10 strains), respectively. The MBL detection rates were as follows: bla(VIM-2), 0.2% (1 strain) in 2011; bla(IMP-1), 0.9% (4 strains) in 2012, and 1.7% (6 strains, including bla(IMP-1) [3 strains], bla(IMP-2) [2 strains] and bla(VIM-2) [1 strain]) in 2013.
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April 2016

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2010: General view of the pathogens' antibacterial susceptibility.

J Infect Chemother 2015 Jun 28;21(6):410-20. Epub 2015 Feb 28.

National Center for Global Health and Medicine, Tokyo, Japan.

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from patients in Japan, was conducted by Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases and Japanese Society for Clinical Microbiology in 2010. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period from January and April 2010 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical and Laboratory Standard Institutes using maximum 45 antibacterial agents. Susceptibility testing was evaluable with 954 strains (206 Staphylococcus aureus, 189 Streptococcus pneumoniae, 4 Streptococcus pyogenes, 182 Haemophilus influenzae, 74 Moraxella catarrhalis, 139 Klebsiella pneumoniae and 160 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was as high as 50.5%, and those of penicillin-intermediate and -resistant S. pneumoniae were 1.1% and 0.0%, respectively. Among H. influenzae, 17.6% of them were found to be β-lactamase-non-producing ampicillin (ABPC)-intermediately resistant, 33.5% to be β-lactamase-non-producing ABPC-resistant and 11.0% to be β-lactamase-producing ABPC-resistant strains. Extended spectrum β-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo β-lactamase were 2.9% and 0.6%, respectively. Continuous national surveillance of antimicrobial susceptibility of respiratory pathogens is crucial in order to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis.
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http://dx.doi.org/10.1016/j.jiac.2015.02.008DOI Listing
June 2015

Susceptibility of various oral antibacterial agents against extended spectrum β-lactamase producing Escherichia coli and Klebsiella pneumoniae.

J Infect Chemother 2014 Jan 11;20(1):48-51. Epub 2013 Dec 11.

Department of Clinical Laboratory, Hyogo Medical University Hospital, Hyogo, Japan.

With the increase in extended spectrum β-lactamase (ESBL)-producing bacteria in the community, cases are often seen in which treatment of infectious diseases with oral antimicrobial agents is difficult. Therefore, we measured the antimicrobial activities of 14 currently available oral antimicrobial agents against ESBL-producing Escherichia coli and Klebsiella pneumoniae. Based on the standard of the Clinical and Laboratory Standards Institute (CLSI), E. coli showed high susceptibility rates of 99.4% to faropenem (FRPM). In terms of fluoroquinolones, the susceptibility rate of E. coli to levofloxacin (LVFX) was low at 32.2%, whereas it showed a good susceptibility rate of 93.1% to sitafloxacin (STFX). With respect to other antimicrobial agents, susceptibility rates to fosfomycin (FOM) and colistin (CL) were more than 90% each, whereas rates of the two antimicrobial agents expected as therapeutic agents, minocycline (MINO) and sulfamethoxazole-trimethoprim (ST), were low at 62.4% and 44.3%, respectively. Based on the CLSI standard, K. pneumoniae showed high susceptibility rates to ceftibuten (CETB) (91.89%), LVFX (86.49%), and STFX (94.6%), indicating that K. pneumoniae showed higher rates than those of E. coli, particularly to fluoroquinolones. Comparison of susceptibility rates according to E. coli genotype showed that many antimicrobial agents existed to which the CTX-M-9 group showed high susceptibility rates. However, there were many agents to which the CTX-M-1 group showed low susceptibility rates, particularly to CETB (51.1%) and LVFX (17.0%). Although there was no significant difference by genotype between FRPM, STFX, and FOM, a significant difference was observed between LVFX, MINO, and ST. Antibiotic-resistant bacteria with highly pathogenic strains have spread in the community, appropriate use of oral antimicrobial agents is required.
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http://dx.doi.org/10.1016/j.jiac.2013.08.004DOI Listing
January 2014

[Clinical microbiological investigation of vancomycin intermediate Staphylococcus aureus during glycopeptide therapy].

Kansenshogaku Zasshi 2012 Nov;86(6):734-40

Department of Clinical Laboratory, Kinki University Hospital.

We isolated three strains of vancomycin intermediate Staphylococcus aureus (VISA) from a blood sample of a patient with infective endocarditis (VISA-1), postoperative pneumonia sputum (VISA-2), and pyogenic spondylitis blood sample (VISA-3). These VISA strains did not carry vanA, vanB, vanC1, or vanC2/C3 genes. Cell wall thickening was observed. VISA-1 and VISA-3 PFGE patterns showed the completely same pattern compared to the PFGE pattern of methicillin-resistant Staphylococcus aureus first isolated from patients 1 and 3. After 10 days on brain heart infusion agar, wall thickening in all three type of VISA was unchanged, but VISA-2 and VISA-3 reversed vancomycin susceptibility. The most suitable use of vancomycin in patients with MRSA infection thus appears to be in reducing the opportunity for cell wall thickening.
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http://dx.doi.org/10.11150/kansenshogakuzasshi.86.734DOI Listing
November 2012

The Drosophila female aphrodisiac pheromone activates ppk23(+) sensory neurons to elicit male courtship behavior.

Cell Rep 2012 Jun 24;1(6):599-607. Epub 2012 May 24.

Research Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030 Vienna, Austria.

Females of many animal species emit chemical signals that attract and arouse males for mating. For example, the major aphrodisiac pheromone of Drosophila melanogaster females, 7,11-heptacosadiene (7,11-HD), is a potent inducer of male-specific courtship and copulatory behaviors. Here, we demonstrate that a set of gustatory sensory neurons on the male foreleg, defined by expression of the ppk23 marker, respond to 7,11-HD. Activity of these neurons is required for males to robustly court females or to court males perfumed with 7,11-HD. Artificial activation of these ppk23(+) neurons stimulates male-male courtship even without 7,11-HD perfuming. These data identify the ppk23(+) sensory neurons as the primary targets for female sex pheromones in Drosophila.
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http://dx.doi.org/10.1016/j.celrep.2012.05.007DOI Listing
June 2012

Epidemiology of Escherichia coli, Klebsiella species, and Proteus mirabilis strains producing extended-spectrum β-lactamases from clinical samples in the Kinki Region of Japan.

Am J Clin Pathol 2012 Apr;137(4):620-6

Department of Clinical Laboratory, Kansai Medical University Hirakata Hospital, Osaka, Japan.

In the present study, nonduplicate, clinical isolates of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli, Klebsiella spp, and Proteus mirabilis were collected during a 10-year period from 2000 to 2009 at several hospitals in the Kinki region, Japan. The detection rate of E coli markedly increased from 0.24% to 7.25%. The detection rate of Klebsiella pneumoniae increased from 0% to 2.44% and that of P mirabilis from 6.97% to 12.85%. The most frequently detected genotypes were the CTX-M9 group for E coli, the CTX-M2 group for K pneumoniae, and the CTX-M2 group for P mirabilis. E coli clone O25:H4-ST131 producing CTX-M-15, which is spreading worldwide, was first detected in 2007. The most common replicon type of E coli was the IncF type, particularly FIB, detected in 466 strains (69.7%). Of the K pneumoniae strains, 47 (55.3%) were of the IncN type; 77 P mirabilis strains (96.3%) were of the IncT type. In the future, the surveillance of various resistant bacteria, mainly ESBL-producing Enterobacteriaceae, should be expanded to prevent their spread.
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http://dx.doi.org/10.1309/AJCP48PDVKWQOXEZDOI Listing
April 2012

Unc-51/ATG1 controls axonal and dendritic development via kinesin-mediated vesicle transport in the Drosophila brain.

PLoS One 2011 May 12;6(5):e19632. Epub 2011 May 12.

Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.

Background: Members of the evolutionary conserved Ser/Thr kinase Unc-51 family are key regulatory proteins that control neural development in both vertebrates and invertebrates. Previous studies have suggested diverse functions for the Unc-51 protein, including axonal elongation, growth cone guidance, and synaptic vesicle transport.

Methodology/principal Findings: In this work, we have investigated the functional significance of Unc-51-mediated vesicle transport in the development of complex brain structures in Drosophila. We show that Unc-51 preferentially accumulates in newly elongating axons of the mushroom body, a center of olfactory learning in flies. Mutations in unc-51 cause disintegration of the core of the developing mushroom body, with mislocalization of Fasciclin II (Fas II), an IgG-family cell adhesion molecule important for axonal guidance and fasciculation. In unc-51 mutants, Fas II accumulates in the cell bodies, calyx, and the proximal peduncle. Furthermore, we show that mutations in unc-51 cause aberrant overshooting of dendrites in the mushroom body and the antennal lobe. Loss of unc-51 function leads to marked accumulation of Rab5 and Golgi components, whereas the localization of dendrite-specific proteins, such as Down syndrome cell adhesion molecule (DSCAM) and No distributive disjunction (Nod), remains unaltered. Genetic analyses of kinesin light chain (Klc) and unc-51 double heterozygotes suggest the importance of kinesin-mediated membrane transport for axonal and dendritic development. Moreover, our data demonstrate that loss of Klc activity causes similar axonal and dendritic defects in mushroom body neurons, recapitulating the salient feature of the developmental abnormalities caused by unc-51 mutations.

Conclusions/significance: Unc-51 plays pivotal roles in the axonal and dendritic development of the Drosophila brain. Unc-51-mediated membrane vesicle transport is important in targeted localization of guidance molecules and organelles that regulate elongation and compartmentalization of developing neurons.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0019632PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093397PMC
May 2011

Nationwide surveillance of bacterial respiratory pathogens conducted by the Japanese Society of Chemotherapy in 2008: general view of the pathogens' antibacterial susceptibility.

J Infect Chemother 2011 Aug 17;17(4):510-23. Epub 2011 Mar 17.

Japanese Society of Chemotherapy, Nichinai Kaikan B1, 3-28-8 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

For the purpose of nationwide surveillance of the antimicrobial susceptibility of bacterial respiratory pathogens collected from patients in Japan, the Japanese Society of Chemotherapy conducted a third year of nationwide surveillance during the period from January to April 2008. A total of 1,097 strains were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections. Susceptibility testing was evaluable with 987 strains (189 Staphylococcus aureus, 211 Streptococcus pneumoniae, 6 Streptococcus pyogenes, 187 Haemophilus influenzae, 106 Moraxella catarrhalis, 126 Klebsiella pneumoniae, and 162 Pseudomonas aeruginosa). A total of 44 antibacterial agents, including 26 β-lactams (four penicillins, three penicillins in combination with β-lactamase inhibitors, four oral cephems, eight parenteral cephems, one monobactam, five carbapenems, and one penem), three aminoglycosides, four macrolides (including a ketolide), one lincosamide, one tetracycline, two glycopeptides, six fluoroquinolones, and one oxazolidinone were used for the study. Analysis was conducted at the central reference laboratory according to the method recommended by the Clinical and Laboratory Standard Institute (CLSI). The incidence of methicillin-resistant S. aureus (MRSA) was as high as 59.8%, and those of penicillin-intermediate and penicillin-resistant S. pneumoniae (PISP and PRSP) were 35.5 and 11.8%, respectively. Among H. influenzae, 13.9% of them were found to be β-lactamase-non-producing ampicillin (ABPC)-intermediately resistant (BLNAI), 26.7% to be β-lactamase-non-producing ABPC-resistant (BLNAR), and 5.3% to be β-lactamase-producing ABPC-resistant (BLPAR) strains. A high frequency (76.5%) of β-lactamase-producing strains was suspected in Moraxella catarrhalis isolates. Four (3.2%) extended-spectrum β-lactamase-producing K. pneumoniae were found among 126 strains. Four isolates (2.5%) of P. aeruginosa were found to be metallo β-lactamase-producing strains, including three (1.9%) suspected multidrug-resistant strains showing resistance to imipenem, amikacin, and ciprofloxacin. Continual national surveillance of the antimicrobial susceptibility of respiratory pathogens is crucial in order to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis.
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http://dx.doi.org/10.1007/s10156-011-0214-5DOI Listing
August 2011

Unc-51 controls active zone density and protein composition by downregulating ERK signaling.

J Neurosci 2009 Jan;29(2):517-28

Department of Developmental Biology, Washington University, St Louis, Missouri 63110, USA.

Efficient synaptic transmission requires the apposition of neurotransmitter release sites opposite clusters of postsynaptic neurotransmitter receptors. Transmitter is released at active zones, which are composed of a large complex of proteins necessary for synaptic development and function. Many active zone proteins have been identified, but little is known of the mechanisms that ensure that each active zone receives the proper complement of proteins. Here we use a genetic analysis in Drosophila to demonstrate that the serine threonine kinase Unc-51 acts in the presynaptic motoneuron to regulate the localization of the active zone protein Bruchpilot opposite to glutamate receptors at each synapse. In the absence of Unc-51, many glutamate receptor clusters are unapposed to Bruchpilot, and ultrastructural analysis demonstrates that fewer active zones contain dense body T-bars. In addition to the presence of these aberrant synapses, there is also a decrease in the density of all synapses. This decrease in synaptic density and abnormal active zone composition is associated with impaired evoked transmitter release. Mechanistically, Unc-51 inhibits the activity of the MAP kinase ERK to promote synaptic development. In the unc-51 mutant, increased ERK activity leads to the decrease in synaptic density and the absence of Bruchpilot from many synapses. Hence, activated ERK negatively regulates synapse formation, resulting in either the absence of active zones or the formation of active zones without their proper complement of proteins. The Unc-51-dependent inhibition of ERK activity provides a potential mechanism for synapse-specific control of active zone protein composition and release probability.
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http://dx.doi.org/10.1523/JNEUROSCI.3848-08.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2741695PMC
January 2009

UNC-51/ATG1 kinase regulates axonal transport by mediating motor-cargo assembly.

Genes Dev 2008 Dec;22(23):3292-307

Division of Neurosciences, Beckman Research Institute of the City of Hope, California 91010, USA.

Axonal transport mediated by microtubule-dependent motors is vital for neuronal function and viability. Selective sets of cargoes, including macromolecules and organelles, are transported long range along axons to specific destinations. Despite intensive studies focusing on the motor machinery, the regulatory mechanisms that control motor-cargo assembly are not well understood. Here we show that UNC-51/ATG1 kinase regulates the interaction between synaptic vesicles and motor complexes during transport in Drosophila. UNC-51 binds UNC-76, a kinesin heavy chain (KHC) adaptor protein. Loss of unc-51 or unc-76 leads to severe axonal transport defects in which synaptic vesicles are segregated from the motor complexes and accumulate along axons. Genetic studies show that unc-51 and unc-76 functionally interact in vivo to regulate axonal transport. UNC-51 phosphorylates UNC-76 on Ser(143), and the phosphorylated UNC-76 binds Synaptotagmin-1, a synaptic vesicle protein, suggesting that motor-cargo interactions are regulated in a phosphorylation-dependent manner. In addition, defective axonal transport in unc-76 mutants is rescued by a phospho-mimetic UNC-76, but not a phospho-defective UNC-76, demonstrating the essential role of UNC-76 Ser(143) phosphorylation in axonal transport. Thus, our data provide insight into axonal transport regulation that depends on the phosphorylation of adaptor proteins.
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http://dx.doi.org/10.1101/gad.1734608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600757PMC
December 2008

[A case of Mycobacterium goodii infection wifh isolation from blood and a pacemaker lead].

Kansenshogaku Zasshi 2006 May;80(3):262-6

Department of Clinical Laboratory, Kinki University Hospital.

We report a case of blood stream infection due to Mycobacterium goodii in a patient who had an implanting pacemaker. The patient injured left thorax where the pacemaker was implanted several days before septicemia. The microorganism was isolated from both blood cultures and leads of the pacemaker. The serial isolates were identified as M. goodii by conventional biochemical methods, tobramycin susceptibility test and 16Sr-RNA sequencing. This is the first reported case of M. goodii septicemia in Japan. M. goodii is regarded as an environmental bacterium and its pathogenicity has been recognized recently. The present case suggests that its ability as a primary invader should not be underestimated, especially in a patient with indwelling devices.
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http://dx.doi.org/10.11150/kansenshogakuzasshi1970.80.262DOI Listing
May 2006
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