Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed ...patients. However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data. Moreover, the lack of controlled data demonstrating the ability of ketamine to sustain the antidepressant response with repeated administration leaves the potential clinical utility of this class of drugs in question. Using quantitative electroencephalography (qEEG) to objectively align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to that of ketamine, we demonstrate the potential for NMDA channel blockers to produce antidepressant efficacy without psychotomimetic and dissociative side effects. Furthermore, using placebo-controlled data, we show that the antidepressant response to NMDA channel blockers can be maintained with repeated and intermittent drug administration. Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Localization of Idd11 Is Not Associated With Thymus and NKT Cell Abnormalities in NOD Mice
Thomas C. Brodnicki 1 ,
Anne L. Fletcher 2 ,
Daniel G. Pellicci 3 ,
Stuart P. Berzins 3 ,
Peter McClive 4 ,
...Fiona Quirk 1 ,
Kylie E. Webster 1 ,
Hamish S. Scott 1 ,
Richard L. Boyd 2 ,
Dale I. Godfrey 3 and
Grant Morahan 5
1 Genetics and Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
2 Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria, Australia
3 Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia
4 Department of Pediatrics, The Royal Children’s Hospital, Parkville, Victoria, Australia
5 Diabetes Research Centre, Western Australian Institute for Medical Research, Perth, Australia
Address correspondencereprint requests to Thomas C. Brodnicki, The WalterEliza Hall Institute, 1G Royal Parade, Parkville,
Victoria 3050 Australia. E-mail: brodnicki{at}wehi.edu.au
Abstract
Congenic mouse strains provide a unique resource for genetic dissection and biological characterization of chromosomal regions
associated with diabetes progression in the nonobese diabetic (NOD) mouse. Idd11 , a mouse diabetes susceptibility locus, was previously localized to a region on chromosome 4. Comparison of a panel of subcongenic
NOD mouse strains with different intervals derived from the nondiabetic C57BL/6 (B6) strain now maps Idd11 to an ∼8-Mb interval. B6-derived intervals protected congenic NOD mice from diabetes onset, even though lymphocytic infiltration
of pancreatic islets was similar to that found in NOD mice. In addition, neither thymic structural irregularities nor NKT
cell deficiencies were ameliorated in diabetes-resistant congenic NOD mice, indicating that Idd11 does not contribute to these abnormalities, which do not need to be corrected to prevent disease.
Footnotes
While this manuscript was under review, an article was published that provided additional evidence for the presence of a diabetes
susceptibility locus within a region on Chr4 encompassing the Idd11 interval defined here ( 1 ).
Additional information for this article can be found in an online appendix available at http://diabetes.diabetesjournals.org .
Accepted August 26, 2005.
Received June 17, 2005.
DIABETES
The pneumococcus is a leading pathogen infecting children and adults. Safe, effective vaccines exist, and they work by inducing antibodies to the polysaccharide capsule (unique for each serotype) ...that surrounds the cell; however, current vaccines are limited by the fact that only a few of the nearly 100 antigenically distinct serotypes are included in the formulations. Within the serotypes, serogroup 6 pneumococci are a frequent cause of serious disease and common colonizers of the nasopharynx in children. Serotype 6E was first reported in 2004 but was thought to be rare; however, we and others have detected serotype 6E among recent pneumococcal collections. Therefore, we analyzed a diverse data set of ∼1,000 serogroup 6 genomes, assessed the prevalence and distribution of serotype 6E, analyzed the genetic diversity among serogroup 6 pneumococci, and investigated whether pneumococcal conjugate vaccine-induced serotype 6A and 6B antibodies mediate the killing of serotype 6E pneumococci. We found that 43% of all genomes were of serotype 6E, and they were recovered worldwide from healthy children and patients of all ages with pneumococcal disease. Four genetic lineages, three of which were multidrug resistant, described ∼90% of the serotype 6E pneumococci. Serological assays demonstrated that vaccine-induced serotype 6B antibodies were able to elicit killing of serotype 6E pneumococci. We also revealed three major genetic clusters of serotype 6A capsular sequences, discovered a new hybrid 6C/6E serotype, and identified 44 examples of serotype switching. Therefore, while vaccines appear to offer protection against serotype 6E, genetic variants may reduce vaccine efficacy in the longer term because of the emergence of serotypes that can evade vaccine-induced immunity.
1 Center for Molecular and Behavioral Neuroscience, Rutgers State University, Newark, New Jersey 07102; 2 Department of Physiology, Ponce School of Medicine, Ponce, Puerto Rico 00732; and 3 Center ...for Neural Science, Meyer Building, New York University, New York, New York 10003
Submitted 17 February 2004;
accepted in final form 18 February 2004
ABSTRACT
It is currently believed that the acquisition of classically conditioned fear involves potentiation of conditioned thalamic inputs in the lateral amygdala (LA). In turn, LA cells would excite more neurons in the central nucleus (CE) that, via their projections to the brain stem and hypothalamus, evoke fear responses. However, LA neurons do not directly contact brain stem-projecting CE neurons. This is problematic because CE projections to the periaqueductal gray and pontine reticular formation are believed to generate conditioned freezing and fear-potentiated startle, respectively. Moreover, like LA, CE may receive direct thalamic inputs communicating information about the conditioned and unconditioned stimuli. Finally, recent evidence suggests that the CE itself may be a critical site of plasticity. This review attempts to reconcile the current model with these observations. We suggest that potentiated LA outputs disinhibit CE projection neurons via GABAergic intercalated neurons, thereby permitting associative plasticity in CE. Thus plasticity in both LA and CE would be necessary for acquisition of conditioned fear. This revised model also accounts for inhibition of conditioned fear after extinction.
Address for reprint requests and other correspondence: D. Paré, CMBN, Rutgers State University, 197 University Ave., Newark, NJ 07102 (E-mail: pare{at}axon.rutgers.edu ).
The introduction of pneumococcal conjugate vaccines (PCVs) into childhood vaccination programs has reduced carriage of vaccine serotypes and pneumococcal disease. The 10-valent PCV was introduced in ...Iceland in 2011. The aim of this study was to determine PCV impact on the prevalence of serotypes, genetic lineages, and antimicrobial-resistant pneumococci isolated from the lower respiratory tract (LRT) of adults. Pneumococci isolated between 2009 and 2017 at the Landspitali University Hospital were included (
= 797). The hospital serves almost three-quarters of the Icelandic population. Isolates were serotyped and tested for antimicrobial susceptibility, and the genome of every other isolate collected between 2009 and 2014 was sequenced (
= 275). Serotypes and multilocus sequence types (STs) were extracted from the genome data. Three study periods were defined, 2009 to 2011 (PreVac), 2012 to 2014 (PostVac-I), and 2015 to 2017 (PostVac-II). The total number of isolates and vaccine-type (VT) pneumococci decreased from PreVac to PostVac-II (
= 314 versus
= 230
= 0.002 and
= 170 versus
= 33
< 0.001, respectively), but non-vaccine-type (NVT) pneumococci increased among adults 18 to 64 years old (
= 56 versus
= 114
= 0.008). Serotype 19F decreased in the PostVac-II period; these isolates were all multidrug resistant (MDR) and were members of the Taiwan
-14 PMEN lineage. Serotype 6A decreased among adults ≥65 years old in the PostVac-II period (
= 0.037), while serotype 6C increased (
= 0.021) and most serotype 6C isolates were MDR. Nonencapsulated
(NESp) isolates increased among adults 18 to 64 years old in the PostVac-II period, and the majority were MDR (
= 0.028). An overall reduction in the number of LRT samples and pneumococcus-positive cultures and significant changes in the serotype distribution became evident within 4 years, thereby demonstrating a significant herd effect.
Although the role of the amygdala in acquisition of conditioned fear is well established, there is debate concerning the intra-amygdala circuits involved. The lateral nucleus of the amygdala (LA) is ...thought to be an essential site of plasticity in fear conditioning. The LA has both direct and indirect via the basal nuclei; basal amygdala (BA) projections to the central nucleus (Ce) of the amygdala, an essential output for fear behaviors. Lesions of the LA or Ce prevent acquisition of conditioned freezing to a conditioned stimulus, but BA lesions do not, suggesting that the BA is not normally involved in fear conditioning. If true, posttraining BA lesions should also have no effect. Replicating previous studies, we found that rats given electrolytic BA lesions before training acquired conditioned fear normally. They also showed normal long-term retention and extinction of conditioned fear. Unexpectedly, BA lesions made after training completely blocked expression of conditioned fear. Despite this deficit, lesioned rats were able to learn a new tone-shock association. Thus, although the LA-Ce system is sufficient for fear acquisition in the absence of the BA, it is not sufficient when the BA is present, suggesting that the BA is an important site of plasticity in fear conditioning. The pattern of lesion deficits we observed (after but not before training) might be explained by homeostatic mechanisms that balance plasticity over multiple inputs, regulating the influence of the BA and LA onto Ce output neurons.
Vaccination with pneumococcal conjugate vaccines (PCVs) disrupts the pneumococcal population. Our aim was to determine the impact of the 10-valent PCV on the serotypes, genetic lineages, and ...antimicrobial susceptibility of pneumococci isolated from children in Iceland. Pneumococci were collected between 2009 and 2017 from the nasopharynges of healthy children attending 15 day care centers and from the middle ears (MEs) of children with acute otitis media from the greater Reykjavik capital area. Isolates were serotyped and tested for antimicrobial susceptibility. Whole-genome sequencing (WGS) was performed on alternate isolates from 2009 to 2014, and serotypes and multilocus sequence types (STs) were extracted from the WGS data. Two study periods were defined: 2009 to 2011 (PreVac) and 2012 to 2017 (PostVac). The overall nasopharyngeal carriage rate was similar between the two periods (67.3% PreVac and 61.5% PostVac,
= 0.090). Vaccine-type (VT) pneumococci decreased and nonvaccine-type (NVT) pneumococci (serotypes 6C, 15A, 15B/C, 21, 22F, 23A, 23B, 35F, and 35B) significantly increased in different age strata post-PCV introduction. The total number of pneumococci recovered from ME samples significantly decreased as did the proportion that were VTs, although NVT pneumococci (6C, 15B/C, 23A, and 23B) increased significantly. Most serotype 6C pneumococci were multidrug resistant (MDR). Serotype 19F was the predominant serotype associated with MEs, and it significantly decreased post-PCV introduction: these isolates were predominantly MDR and of the Taiwan
-14 PMEN lineage. Overall, the nasopharyngeal carriage rate remained constant and the number of ME-associated pneumococci decreased significantly post-PCV introduction; however, there was a concomitant and statistically significant shift from VTs to NVTs in both collections of pneumococci.
ABSTRACT
3D seismic data from salt structures in the Southern North Sea show how viscous fluids tend to migrate towards and flow upwards along the footwalls of active normal faults where zones of low ...stress are inherent. This process provides one potential solution for the question of how enough space is created to accommodate large granitic bodies in the crust. During episodes of regional extension, granitic melt may collect in the lower crust below normal detachments in domed areas from which magma may be sourced. Subsequently, in the upper crust, emplacement can occur in fault‐bounded laccoliths at rates commensurate with other geological processes.
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Levels of UV were manipulated in a native shortgrass steppe using open-sided structures with tops that either passed or blocked wavelengths shorter than ∼370 nm. Precipitation was controlled to ...create a drought or a very wet year. Subplots were either nondefoliated or defoliated to simulate grazing by livestock, which is the primary land use. Plant community productivity and forage quality were assessed in response to the two climate change variables (UV, precipitation) and grazing stress. Productivity and seasonal standing biomass of the dominant grass species were negatively affected by passing versus blocking UV, but only in the dry year. Another species was negatively affected by passing UV in the wet year, indicating the potential for future shifts in species composition. Forage quality for ruminants increased when UV was passed compared with blocked, as determined by in vitro digestible dry matter, depending on species and precipitation. Nitrogen concentrations and soluble and fiber components of vegetation also displayed some UV effects, but they were generally small and depended on species, season or amount of precipitation (or all). Grazing treatment had large positive effects on current-year productivity only in the wet year and some small positive effects on quality in both wet and dry years. Interactions between UV and grazing treatment were not observed.
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Understanding the structure of a bacterial population is essential in order to understand bacterial evolution. Estimating the core genome (those genes common to all, or nearly all, strains of a ...species) is a key component of such analyses. The size and composition of the core genome varies by dataset, but we hypothesized that the variation between different collections of the same bacterial species would be minimal. To investigate this, we analyzed the genome sequences of 3,118 pneumococci recovered from healthy individuals in Reykjavik (Iceland), Southampton (United Kingdom), Boston (United States), and Maela (Thailand). The analyses revealed a "supercore" genome (genes shared by all 3,118 pneumococci) of 558 genes, although an additional 354 core genes were shared by pneumococci from Reykjavik, Southampton, and Boston. Overall, the size and composition of the core and pan-genomes among pneumococci recovered in Reykjavik, Southampton, and Boston were similar. Maela pneumococci were distinctly different in that they had a smaller core genome and larger pan-genome. The pan-genome of Maela pneumococci contained several >25 Kb sequence regions (flanked by pneumococcal genes) that were homologous to genomic regions found in other bacterial species. Overall, our work revealed that some subsets of the global pneumococcal population are highly heterogeneous, and our hypothesis was rejected. This is an important finding in terms of understanding genetic variation among pneumococci and is also an essential point of consideration before generalizing the findings from a single dataset to the wider pneumococcal population.
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