BubR1 Insufficiency Impairs Affective Behavior and Memory Function in Mice

Purpose Although aging causes functional declines in cognition, the molecular mechanism underlying these declines remains largely unknown. Recently, the spindle checkpoint kinase budding uninhibited by benzimidazole-related 1 (BubR1) has emerged as a key determinant for age-related pathology in various tissues including brain. However, the neurobehavioral impact of BubR1 has not been explored. In this study, we investigated the role of BubR1 in behavioral function. Methods To investigate the neurobiological functions of BubR1 in vivo, we utilized transgenic mice harboring BubR1 hypomorphic alleles (BubR1H/H mice), which produce low amounts of BubR1 protein, as well as mice that have specific knockdown of BubR1 in the adult dentate gyrus. To assess anxiety-like behavior, the above groups were subjected to the elevated plus maze and the light-dark test, in addition to utilizing the tail-suspension and forced-swim test to determine depression-like behavior. We used novel object recognition to test for memory-related function. Results We found that BubR1H/H mice display several behavioral deficits when compared to wild-type littermates, including increased anxiety in the elevated-plus maze test, depression-like behavior in the tail suspension test, as well as impaired memory function in the novel object recognition test. Similar to BubR1H/H mice, knockdown of BubR1 within the adult dentate gyrus led to increased anxiety-like behavior as well as depression-like behavior, and impaired memory function. Conclusions Our study demonstrates a requirement of BubR1 in maintaining proper affective and memory-related behavioral function. These results suggest that a decline in BubR1 levels with advanced age may be a crucial contributor to age-related hippocampal dysfunction

The selective cyclooxygenase-2 inhibitor NS398 ameliorates cisplatin-induced impairments in mitochondrial and cognitive function

Chemobrain is a condition that negatively affects cognition in cancer patients undergoing active chemotherapy, as well as following chemotherapy cessation. Chemobrain is also known as chemotherapy-induced cognitive impairment (CICI) and has emerged as a significant medical contingency. There is no therapy to ameliorate this condition, hence identification of novel therapeutic strategies to prevent CICI is of great interest to cancer survivors. Utilizing the platinum-based chemotherapy cisplatin in an investigative approach for CICI, we identified increased expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in the adult mouse hippocampus, and in human cortical neuron cultures derived from induced pluripotent stem cells (iPSCs). Notably, administration of NS398, a selective COX-2 inhibitor, prevented CICI in vivo without negatively affecting the antitumor efficacy of cisplatin or potentiating tumor growth. Given that dysfunctional mitochondrial bioenergetics plays a prominent role in CICI, we explored the effects of NS398 in cisplatin-induced defects in human cortical mitochondria. We found that cisplatin significantly reduces mitochondrial membrane potential (MMP), increases matrix swelling, causes loss of cristae membrane integrity, impairs ATP production, as well as decreases cell viability and dendrite outgrowth. Pretreatment with NS398 in human cortical neurons attenuated mitochondrial dysfunction caused by cisplatin, while improving cell survival and neurite morphogenesis. These results suggest that aberrant COX-2 inflammatory pathways may contribute in cisplatin-induced mitochondrial damage and cognitive impairments. Therefore, COX-2 signaling may represent a viable therapeutic approach to improve the quality of life for cancer survivors experiencing CICI

Chemokine Lkn-1/CCL15 enhances matrix metalloproteinase-9 release from human macrophages and macrophage-derived foam cells

Atherosclerosis is characterized by a chronic inflammatory disease, and chemokines play an important role in both initiation and progression of atherosclerosis development. Leukotactin-1 (Lkn-1/CCL15), a new member of the human CC chemokine family, is a potent chemoattractant for leukocytes. Our previous study has demonstrated that Lkn-1/CCL15 plays a role in the initiation of atherosclerosis, however, little is currently known whether Lkn-1/CCL15 is associated with the progression of atherosclerosis. Matrix metalloproteinases (MMPs) in human coronary atherosclerotic lesions play a crucial role in the progression of atherosclerosis by altering the vulnerability of plaque rupture. In the present study, we examined whether Lkn-1/CCL15 modulates MMP-9 release, which is a prevalent form expressed by activated macrophages and foam cells. Human THP-1 monocytic cells and/or human peripheral blood monocytes (PBMC) were treated with phorbol myristate acetate to induce their differentiation into macrophages. Foam cells were prepared by the treatment of THP-1 macrophages with human oxidized LDL. The macrophages and foam cells were treated with Lkn-1/CCL15, and the levels of MMP-9 release were measured by Gelatin Zymography. Lkn-1/CCL15 significantly enhanced the levels of MMP-9 protein secretion from THP-1 monocytic cells-derived macrophages, human PBMC-derived macrophages, as well as macrophage-derived foam cell in a dose dependent manner. Our data suggest that the action of Lkn-1/CCL15 on macrophages and foam cells to release MMP-9 may contribute to plaque destabilization in the progression of atherosclerosis

Multicentre study of the prevalence of toxigenic Clostridium difficile in Korea: results of a retrospective study 2000-2005

The prevalence of toxigenic Clostridium difficile in Korea has been reported to be approximately 60-80%. Although the prevalence of the tcdA(-)tcdB(+) C. difficile strain was less then 5% prior to the year 2000, it has become an emerging nosocomial pathogen in Korea. Therefore, we have attempted to determine the multicentre nationwide prevalence of tcdA(+)tcdB(+) and tcdA(-)tcdB(+) C. difficile for epidemiological purposes. C. difficile strains (n=724, 30 from 2000, 80 from 2001, 74 from 2002, 76 from 2003, 179 from 2004, 285 from 2005) were obtained retrospectively from January 2000 to December 2005 from in-patients at 6 hospitals, all of whom were suspected of having C. difficile-associated disease (CDAD), colitis or pseudomembranous colitis. The numbers of participating hospitals varied yearly (1 in 2000, 2 in 2001-2003, 3 in 2004, 5 in 2005). The hospitals were located in Seoul (n=4), Kyunggi Province (n=1) and Busan (n=1), Korea. PCR assays for tcdA and tcdB genes were conducted using 724 unduplicated C. difficile isolates. The mean prevalence of tcdA(+)tcdB(+) and tcdA(-)tcdB(+) C. difficile strains over the 6 years was 51.8 % (38.4-59.3%) and 25.8%(10-56.0%), respectively. The mean prevalence of tcdA(-)tcdB(+) C. difficile strains was less than 7% until 2002, but began to increase in 2003 (13.2%) and achieved a peak in 2004 (50.3%). In 2005, the mean prevalence of tcdA(+)tcdB(+) and tcdA(-)tcdB(+) C. difficile strains was 47.7% (30.9-60.3%) and 27.0% (17.6-54.8%), respectively. This nationwide epidemiological study showed that tcdA(-)tcdB(+) C. difficile strains have already spread extensively throughout Korea, and our results provide basic data regarding the controversies currently surrounding the toxigenicity of tcdA(-)tcdB(+) C. difficile. The use of enzyme immunoassays capable of detecting both TcdA and TcdB is strongly recommended for the diagnosis of CDAD in microbiology laboratories, in order to control the spread of the tcdA(-)tcdB(+) strains of C. difficile

Seroprevalence of Hepatitis B Virus among Health Care Workers in Korea

We studied the seroprevalence of HBsAg, anti-HBs and anti-HBc and the vaccination histories among health care workers (HCWs) at a large suburban referral hospital in Korea. The purpose of this study was to determine the immune status of HCWs against hepatitis B virus and we also wanted to prepare a practical guideline to protect HCWs from occupational exposure. During December, 2003, 571 HCWs (56 physicians, 289 nurses, 113 technicians and 113 aid-nurses) aged between 21 and 74 yr were included in the surveillance. The positive rates of HBsAg and anti-HBs were 2.4% (14/571) and 76.9% (439/571), respectively. The positive rate of anti-HBs was lower in the physician group, and this was associated with the male gender and older age. Of the 439 anti-HBs positive cases, 320 cases (73.1%) were anti-HBc negative and this was significantly associated with a past history of HBV vaccination. The distribution of the anti-HBs levels was not associated with age (except for HCWs in their sixties), gender or occupation. Our study revealed that the seroprevalence rates of HBsAg and anti-HBs in HCWs in Korea were not different from those of the general population. Based on this surveillance, we can make reasonable decisions in case of occupational exposure to hepatitis B virus

Roles of Arrest-Defective Protein 1225 and Hypoxia-Inducible Factor 1α in Tumor Growth and Metastasis

Background Vascular endothelial growth factor A (VEGFA), a critical mediator of tumor angiogenesis, is a well-characterized target of hypoxia-inducible factor 1 (HIF-1). Murine arrest-defective protein 1A (mARD1A225) acetylates HIF-1??, triggering its degradation, and thus may play a role in decreased expression of VEGFA.Methods We generated ApcMin/+/mARD1A225 transgenic mice and quantified growth of intestinal polyps. Human gastric MKN74 and murine melanoma B16F10 cells overexpressing mARD1A225 were injected into mice, and tumor growth and metastasis were measured. VEGFA expression and microvessel density in tumors were assessed using immunohistochemistry. To evaluate the role of mARD1A 225 acetylation of Lys532 in HIF-1??, we injected B16F10-mARD1A225 cell lines stably expressing mutant HIF-1??/K532R into mice and measured metastasis. All statistical tests were two-sided, and P values less than. 05 were considered statistically significant.Results ApcMin/+/mARD1A225 transgenic mice (n = 25) had statistically significantly fewer intestinal polyps than Apc Min/+ mice (n = 21) (number of intestinal polyps per mouse: Apc Min/+ mice vs ApcMin/+/mARD1A225 transgenic mice, mean = 83.4 vs 38.0 polyps, difference = 45.4 polyps, 95% confidence interval [CI] = 41.8 to 48.6; P <. 001). The growth and metastases of transplanted tumors were also statistically significantly reduced in mice injected with mARD1A225-overexpressing cells than in mice injected with control cells (P <. 01). Moreover, overexpression of mARD1A 225 decreased VEGFA expression and microvessel density in tumor xenografts (P <. 04) and ApcMin/+ intestinal polyps (P =. 001). Mutation of lysine 532 of HIF-1?? in B16F10-mARD1A225 cells prevented HIF-1?? degradation and inhibited the antimetastatic effect of mARD1A225 (P <. 001).Conclusion mARD1A225 may be a novel upstream target that blocks VEGFA expression and tumor-related angiogenesis

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Iron oxide based nanoparticles for multimodal imaging and magnetoresponsive therapy

The development of magnetic iron oxide nanoparticles as magnetic resonance (MR) imaging agents for sensitive and accurate diagnosis through inorganic materials design and their synergistic integration with other imaging modalities is reviewed. Modulation of the size, composition, and shape allows magnetic nanoparticles to fit with their intended purposes, such as MRI imaging, thermal ablation, hyperthermia, combination therapy, and drug deliver. Specifically, magnetic nanoparticles that are synergistically combined with other useful materials have been explored as nanocarriers to regulate the delivery of drugs or genes into the target area as well as specific probes for a variety of imaging modalities, such as MRI, PET, ultrasound, and optics. Furthermore, when incorporated with magnetic fields, hybrid magnetic nanoparticles can preferentially migrate to the target area and induce thermal damage or control drug release, and can even precisely initiate cell signaling for therapeutic purpose. These external stimuli-responsive nanosystems have provided the clear advantages of controlled therapeutic performances in a remotely modulated fashion.

Hemangiosarcoma in a South American Sea Lion (Otaria byronia)

A 10-yr-old male South American sea lion (Otaria byronia) died after several weeks of depression, anorexia, weight loss, and progressive respiratory distress. At necropsy, three confluent, lobulated, dark-red masses were noted in the mesentery. Similar masses were also observed in the lung and both kidneys. Hemangiosarcoma was diagnosed based on gross findings, histopathology, and immunohistochemistry. This is the first case of hemangiosarcoma reported in pinnipeds