A clinically attenuated double-mutant of porcine reproductive and respiratory syndrome virus-2 that does not prompt overexpression of proinflammatory cytokines during co-infection with a secondary pathogen.

Porcine reproductive and respiratory syndrome virus (PRRSV) is known to suppress the type I interferon (IFNs-α/ß) response during infection. PRRSV also activates the NF-κB signaling pathway, leading to the production of proinflammatory cytokines during infection. In swine farms, co-infections of PRRSV and other secondary bacterial pathogens are common and exacerbate the production of proinflammatory cytokines, contributing to the porcine respiratory disease complex (PRDC) which is clinically a severe disease. Previous studies identified the non-structural protein 1ß (nsp1ß) of PRRSV-2 as an IFN antagonist and the nucleocapsid (N) protein as the NF-κB activator. Further studies showed the leucine at position 126 (L126) of nsp1ß as the essential residue for IFN suppression and the region spanning the nuclear localization signal (NLS) of N as the NF-κB activation domain. In the present study, we generated a double-mutant PRRSV-2 that contained the L126A mutation in the nsp1ß gene and the NLS mutation (ΔNLS) in the N gene using reverse genetics. The immunological phenotype of this mutant PRRSV-2 was examined in porcine alveolar macrophages (PAMs) in vitro and in young pigs in vivo. In PAMs, the double-mutant virus did not suppress IFN-ß expression but decreased the NF-κB-dependent inflammatory cytokine productions compared to those for wild-type PRRSV-2. Co-infection of PAMs with the mutant PRRSV-2 and Streptococcus suis (S. suis) also reduced the production of NF-κB-directed inflammatory cytokines. To further examine the cytokine profiles and the disease severity by the mutant virus in natural host animals, 6 groups of pigs, 7 animals per group, were used for co-infection with the mutant PRRSV-2 and S. suis. The double-mutant PRRSV-2 was clinically attenuated, and the expressions of proinflammatory cytokines and chemokines were significantly reduced in pigs after bacterial co-infection. Compared to the wild-type PRRSV-2 and S. suis co-infection control, pigs coinfected with the double-mutant PRRSV-2 exhibited milder clinical signs, lower titers and shorter duration of viremia, and lower expression of proinflammatory cytokines. In conclusion, our study demonstrates that genetic modification of the type I IFN suppression and NF-κB activation functions of PRRSV-2 may allow us to design a novel vaccine candidate to alleviate the clinical severity of PRRS-2 and PRDC during bacterial co-infection.

Ingestion of fishing gear and Anisakis sp. infection in a beached Indo-Pacific finless porpoise (Neophocaena phocaenoides) in the Jeju Island, Republic of Korea: findings from post-mortem computed tomography and necropsy.

BACKGROUND: Human fishing activities have significantly affect environmental concern for marine ecosystems, conservation of marine mammals, and human health. Coastal cetaceans are highly vulnerable to ingestion of fishing gear, bycatching, or entanglement, all of which can be fatal for these animals. In particular, certain coastal dolphins and porpoises are heavily impacted by fishing gear such as angling gear or stownet, as their food often overlap with the target fish species of human fisheries. CASE PRESENTATION: This study presents a case of an Indo-Pacific finless porpoise (Neophocaena phocaenoides) beached on the coast of Jeju Island, Republic of Korea, with ingestion of fishing gear and severe Anisakis infection. Although this species inhabits waters ranging from the Persian Gulf to Taiwan, several stranded carcasses have been reported on Jeju Island in recent years. Post-mortem computed tomography revealed a bundle of four fishing hooks in the forestomach, along with nylon lines and steel lines with connectors, which were assumed to be angling gear for Jeju hairtail (Trichiurus lepturus). Further necroscopic investigation revealed that the forestomach contained a large number of Anisakis spp. (Nematoda: Anisakidae). Histological examination revealed a thickened forestomach wall with pinpoint and volcanic ulcerations, a thickened layer of stratified squamous epithelium, and infiltrated stroma in the squamous epithelium. CONCLUSIONS: This study emphasizes the urgent need to address the impact of fishing activities on marine mammals, marine litter pollution, and the bycatch problem in Korean seawater. In addition, the occurrence of N. phocaenoides in seawater around Jeju Island should be raised in future geographical ecology or veterinary pathology studies and when its distribution is updated.

Genomic insights into novel Erwinia bacteriophages: unveiling their Henunavirus membership and host infection strategies.

Erwinia amylovora, the primary causative agent of blight disease in rosaceous plants, poses a significant threat to agricultural yield worldwide, with limited effective countermeasures. The emergence of sustainable alternative agents such as bacteriophages is a promising solution for fire blight that specifically targets Erwinia. In this study, we isolated pEp_SNUABM_01 and pEa_SNUABM_55 from a South Korean apple orchard soil, analyzed their genomic DNA sequences, and performed a comprehensive comparative analysis of Hena1 in four distinct sections. This study aimed to unveil distinctive features of these phages, with a focus on host recognition, which will provide valuable insights into the evolution and characteristics of Henunavirus bacteriophages that infect plant pathogenic Erwinia spp. By elucidating the distinct genomic features of these phages, particularly in terms of host recognition, this study lays a foundation for their potential application in mitigating the risks associated with fire blight in Rosaceae plants on a global scale.

Effects of Bougainvillea glabra leaf on growth, skin mucosal immune responses, and disease resistance in common carp Cyprinus carpio.

This study evaluated the effects of Bougainvillea glabra (BG) leaf as a feed supplement on growth, skin mucosal immune parameters, serum oxidative stress, expression of immune-related genes, and susceptibility to pathogen infection in carp Cyprinus carpio. Diets containing four different BG concentrations (g kg-1), i.e., 0 g (basal diet), 20 g (BG20), 30 g (BG30), 40 g (BG40), and 50 g (BG50), were fed to the carp (average weight: 14.03 ± 0.81 g) for 8 weeks. Skin mucosal immunological and serum antioxidant parameters were examined 8 weeks post-feeding. Growth performance was significantly higher in BG40. Among the examined skin mucosal immune parameters, lysozyme (33.79 ± 0.98 U mL-1), protein (6.88 ± 0.37 mg mL-1), immunoglobulin (IgM; 5.34 ± 0.37 unit-mg mL-1), and protease activity (3.18 ± 0.36%) were significantly higher in BG40 than in the control; whereas, there was no significant effect on the alkaline phosphatase level. Among serum immune activity, activities of lysozyme, the alternative complement pathway, and IgM were significantly higher in BG40. Phagocytic, and superoxide dismutase (SOD) activities were higher (P < 0.05) in BG30-BG50. Serum ALT, AST, and MDA levels were lower in BG40 than in the control (P < 0.05). Intestinal enzymatic activities were enhanced in BG40 and BG50 (P < 0.05), except for lipase in BG50. Gene expression analysis revealed that the mRNA expressions of antioxidant genes (SOD, GPx, and Nrf2), an anti-inflammatory gene (IL-10), and IκBα were significantly upregulated in BG40. Conversely, the pro-inflammatory gene IL-1ß and the signaling molecule NF-κB p65 were downregulated in BG40 and BG50, respectively. BG supplementation had no significant effect on TNF-α, TLR22, or HSP70 mRNA expressions. Moreover, fish in BG40 exhibited the highest relative post-challenge survival (67.74%) against Aeromonas hydrophila infection. These results suggested that dietary supplementation with BG leaves at 40 g/kg can significantly improve the growth performance, immune responses, and disease resistance of C. carpio. BG leaves are a promising food additive for carp in aquaculture.

Dietary Syzygium cumini leaf extract influences growth performance, immunological responses and gene expression in pathogen-challenged Cyprinus carpio.

This study evaluated the effects of jamun leaf extract (JLE) as a feed supplement on growth performance, haemato-immunological, oxidative stress-related parameters, and cytokine gene expression in Cyprinus carpio challenged with Aeromonas hydrophila.. Diets containing four different JLE concentrations, that is, 0 (basal diet), 5 (JLE5), 10 (JLE10), and 15 g kg-1 (JLE15), were fed to carp (6.17 ± 0.43 g) for eight weeks. Growth performance was significantly higher in JLE10. Haemato-immunological and antioxidant parameters were determined in fish at 48 h post-challenge with A. hydrohila. The cumulative survival was highest in JLE10 (69.69%) 14 days post-challenge. Serum protein (2.18 ± 0.06 g dL-1), lysozyme (32.38 ± 1.2 U mL-1), alternative complement pathway (70.43 ± 1.61 U mL-1), phagocytic activity (21.18 ± 0.48%), respiratory burst activity (0.289 ± 0.09 OD630nm), and immunoglobulin levels (6.67 ± 0.36 U mg mL-1) were significantly higher in JLE10 than in the control. Serum alanine aminotransferase (44.06 ± 1.62 Unit mL-1), aspartate aminotransferase (31.58 ± 1.82 Unit mL-1), and malondialdehyde (2.57 ± 0.26 nmol mL-1) levels were lower in JLE10 than in the control (p < 0.05), whereas myeloperoxidase activity was significantly higher in JLE5 and JLE10 than in the control. Superoxide dismutase levels in the serum were higher (p < 0.05) in JLE5 and JLE10 than in the other groups. Gene expression analysis revealed that the mRNA expression of pro-inflammatory cytokines TNF-α and IL-1ß was upregulated (p < 0.05) in the liver, head-kidney, and intestine of challenged carp in JLE10. The signalling molecule NF-κB p65 was upregulated in lymphoid organs in JLE10 but not in the liver. The anti-inflammatory cytokine IL-10 was significantly downregulated in challenged carp in JLE10 compared with that in the control. Quadratic regression analysis showed that optimal dietary JLE was estimated to be 9.03-10.15 g kg-1 to maximize the growth performance. Results of the present study revealed that dietary JLE at 10 g kg-1 can significantly improve the immunity and disease resistance of C. carpio. Thus, JLE is a promising food additive for carp aquaculture.

Neuropsychological, neuroimaging and autopsy findings of butane encephalopathy.

BACKGROUND: Butane is an aliphatic hydrocarbon used in various commercial products. While numerous reports of sudden cardiac-related deaths from butane inhalation have been described, butane-associated acute encephalopathy has rarely been reported. CASE PRESENTATION: A 38-year-old man presented with cognitive dysfunction after butane gas inhalation. Neuropsychological test results showed impairments in verbal and visual memory, and frontal executive function. Diffusion weighted MRI revealed symmetric high-signal changes in the bilateral hippocampus and globus pallidus. FDG-PET demonstrated decreased glucose metabolism in the bilateral precuneus and occipital areas and the left temporal region. At the 8-month follow-up, he showed still significant deficits in memory and frontal functions. Diffuse cortical atrophy with white matter hyperintensities and extensive glucose hypometabolism were detected on follow-up MRI and FDG-PET, respectively. Brain autopsy demonstrated necrosis and cavitary lesions in the globus pallidus. CONCLUSIONS: Only a few cases of butane encephalopathy have been reported to date. Brain lesions associated with butane encephalopathy include lesions in the bilateral thalamus, insula, putamen, and cerebellum. To the best of our knowledge, this is the first report on bilateral hippocampal and globus pallidal involvement in acute butane encephalopathy. The pathophysiology of central nervous system complications induced by butane intoxication is not yet fully understood. However, the direct toxic effects of butane or anoxic injury secondary to cardiac arrest or respiratory depression have been suggested as possible mechanisms of edematous changes in the brain after butane intoxication.

Mechanisms of Cadmium Neurotoxicity.

Cadmium is a heavy metal that increasingly contaminates food and drink products. Once ingested, cadmium exerts toxic effects that pose a significant threat to human health. The nervous system is particularly vulnerable to prolonged, low-dose cadmium exposure. This review article provides an overview of cadmium's primary mechanisms of neurotoxicity. Cadmium gains entry into the nervous system via zinc and calcium transporters, altering the homeostasis for these metal ions. Once within the nervous system, cadmium disrupts mitochondrial respiration by decreasing ATP synthesis and increasing the production of reactive oxygen species. Cadmium also impairs normal neurotransmission by increasing neurotransmitter release asynchronicity and disrupting neurotransmitter signaling proteins. Cadmium furthermore impairs the blood-brain barrier and alters the regulation of glycogen metabolism. Together, these mechanisms represent multiple sites of biochemical perturbation that result in cumulative nervous system damage which can increase the risk for neurological and neurodegenerative disorders. Understanding the way by which cadmium exerts its effects is critical for developing effective treatment and prevention strategies against cadmium-induced neurotoxic insult.

Fatal upper aerodigestive tract obstruction in an East Asian finless porpoise (Neophocaena asiaeorientalis sunameri): findings in post-mortem computed tomography.

The present case report aims to outline the post-mortem findings of an East Asian finless porpoise with upper aerodigestive tract obstruction using different post-mortem computed tomography (PMCT) visualization techniques and discusses the potential cause of death of this individual. A dead-stranded adult male East Asian finless porpoise was recovered from the Northern coast of Jeju Island, Republic of Korea. The carcass was frozen in Jeju National University within 2 h upon first reported. The PMCT examinations were performed at 120 kVp, 200 mAs with a section thickness of 1 mm. The scan field of view (sFOV) was set to 400 mm. Four image rendering techniques, including multi-planar reconstruction, three-dimensional volume rendering, perspective volume rendering, and minimum intensity projection technique, were used to aid the diagnosis of upper aerodigestive tract obstruction in the stranded finless porpoise. Conventional necropsy was performed to provide a complete necropsy report. Using PMCT, a Sebastidae of 24 cm measured length was found to be lodged in the left pharyngeal food channel and esophagus of the finless porpoise. Hard rays of the pectoral fin of the lodged fish have impaled the esophageal mucosa. Fishing gear was found to embed at the dorsal side of the lodged fish. The trachea was compressed ventrally and the arytenoepiglottic tube opening has been narrowed, which may precipitate to the finless porpoise difficult breathing. Pulmonary hyperinflation, pulmonary edema, pneumothorax, pneumopericardium, and pneumorrhachis were observed. This case report represents the first documentation of potential radiological indicators of upper aerodigestive tract obstruction in the East Asian finless porpoise using PMCT. Spatial location of the lodged item could be rendered in situ as the time of death. It has demonstrated that PMCT could provide objective measurements to adjunct the necropsy findings in diagnosis of fatal aerodigestive tract obstruction in stranded cetaceans.

The Role of Decreased Cortical Thickness and Volume of Medial Temporal Lobe Structures in Predicting Incident Psychosis in Patients With Alzheimer's Disease: A Prospective Longitudinal MRI Study.

OBJECTIVE: To investigate the effect of decreased cortical thickness or volume of medial temporal lobe structures on the risk of incident psychosis in patients with AD. DESIGN, SETTING, AND PARTICIPANTS: This hospital-based prospective longitudinal study enrolled 109 patients with AD. All patients with AD were evaluated at 3-month intervals to investigate the effect of decreased cortical thickness or volume of medial temporal lobe structures on the risk of incident psychosis in patients with AD. OUTCOME MEASURE: The main outcome measure was time-to-progression from AD to incident psychosis. The thickness or volume of medial temporal lobe structures (i.e., the hippocampus, entorhinal cortex, and parahippocampus) were measured using magnetic resonance imaging and the Freesurfer automated segmentation pipeline at baseline. RESULTS: Multivariate Cox proportional hazards regression analysis revealed that a decreased cortical thickness or volume of medial temporal region was associated with a higher risk of incident psychosis in patients with AD. The hazard ratios for decreased cortical thickness of the left entorhinal cortex and decreased cortical volume of the right hippocampus were 4.291 (95% confidence interval [CI], 1.196-15.384) and 2.680 [(CI, 1.003-1.196]), respectively. CONCLUSION: Our study revealed that decreased cortical thickness or volume of medial temporal sub-regions is a risk factor for incident psychosis in patients with AD. A careful assessment of the thickness or volume of the medial temporal lobe structures in AD may improve early detection and intervention of psychosis in AD.

Atypical Young-onset Dementia in Cerebral Thromboangiitis Obliterans: A Case Report.

Young-onset dementia (YOD, age at onset below 45 y) has a broad differential diagnosis. We describe a 41-year-old man with atypical manifestations of YOD syndrome in cerebral thromoboangiitis obliterans (CTAO). Extensive antemortem workup including clinical assessment, laboratory investigations, neuroimaging, and genetic testing did not elucidate a diagnosis. Postmortem neuropathologic examination revealed cortical sickle-shaped granular atrophy, resulting from numerous remote infarcts and cortical microinfarcts that mainly affected the bilateral frontal and parietal lobe, confirming CTAO. Although CTAO is a rare cause of vascular dementia, it should be considered as one of the differentials in patients with YOD with a history of heavy smoking and presence of symmetric damages of watershed-territory on neuroimaging.

Impact of dandelion polysaccharides on growth and immunity response in common carp Cyprinus carpio.

Natural products have gained considerable attention for improving fish growth performance and immunity to enhance disease resistance. This study evaluated the effect of dandelion polysaccharides (DP) on skin mucosal immune parameters, immune-related gene expression, and susceptibility to pathogen challenge in the Common carp Cyprinus carpio. Diets containing four different concentrations of DP (g Kg-1):0 g [basal diet], 0.5 g [D1], 1.5 g [D2], 2.5 g [D3], and 4.0 g [D4] were fed to the carp (average weight: 13.92 ± 0.83 g) for eight weeks. Growth parameters were analyzed four and eight weeks after feeding. Immunological, hematological, and antioxidant parameters were examined eight weeks post-feeding. Growth performance was significantly higher on D3, with a final weight gain of 71.48 ± 1.57 g and a specific growth rate of 3.06 ± 0.12. Among hematological parameters examined, erythrocyte, hematocrit, and mean corpuscular volume (MCV) levels were significantly higher in D3. Skin mucosal immune parameters, such as lysozyme (31.04 ± 1.02 Unit mL-1), alkaline phosphatase (122.6 ± 3.8 IU L-1), and protein level (10.6 ± 0.74 mg mL-1) were significantly higher in D3, while peroxidase activity was higher in D4. Furthermore, SOD activity was higher in D2-D3, whereas catalase activity was higher in D2-D4 (P < 0.05) than in the control. Malondialdehyde level decreased significantly in D3 (5.43 ± 0.36 nmol mL-1); whereas, serum ALT and AST levels were significantly lower on D2-D4. Intestinal tight-junction-related genes ZO-1 and Claudin 7 were significantly higher in the DP-fed groups; however, DP had no significant effect on claudin 3. Occludin expression was higher (p < 0.05) on D3 only. Pro-inflammatory cytokines (IL-1ß and TNF-α) and IFN-γ strongly upregulated in the head kidney at D3. Conversely, the expression of the anti-inflammatory cytokine interleukin-10, HSP70, and TOR were considerably downregulated in D3. Fish from D3 exhibited markedly higher relative post-challenge survival (66.67%) against Aeromonas hydrophila challenge. The results of the present study suggest that dietary supplements of DP at 2.5 g kg-1 can significantly improve the growth performance, skin mucosal, and serum antioxidant parameters, and strengthen the immunity of C. carpio. Therefore, DP is a promising food additive for carp aquaculture.

Bactericidal efficacy of non-thermal plasma activation against Aeromonas hydrophila and immunological responses of koi (Cyprinus carpio haematopterus).

In the aquaculture industry, an efficient and safe water purification system is important to prevent mass mortality by virulent pathogens. As extensive use of traditional methods (e.g.: povidone-iodine, ozone, ultraviolet irradiation, formalin, and chlorine dioxide) have adverse effects on cultured fish, an appropriate and alternative water purification method is vital for the sustainability of the industry. Non-thermal plasma technology has been successfully used for various biomedical purposes (e.g: food sterilization, medical device disinfection, wound healing, cancer therapy, etc.) and has great potential to be used as a sterilizing system. However, few studies have been conducted on its usefulness in the aquaculture industry. In this study, we investigated the bactericidal efficacy of plasma-activated water induced by non-thermal plasma and its histopathological as well as immunological adverse effects on koi. A highly virulent Aeromonas hydrophila SNU HS7, which caused massive mortality of koi, was used for this study. Non-thermal plasma was applied for 10 min to the fish tanks with 1.2 × 109 CFU/mL SNU HS7 using PLMB-20 system to confirm the sterilization efficacy and to observe the survival and immunological reaction of koi for 14 days. As a result, gross pathological, histopathological, and immunological investigations did not reveal any significant adverse effects in fish as compared to the control groups. To the best of our knowledge, this is the first study showing that non-thermal plasma can be used for sterilization of rearing water without giving significant physiological damage to the fish, even under the assumption of extreme situations. As plasma can effectively sterilize not only bacteria but also other unknown pathogens, the results of this study are showing a promising future in purifying water in aquaculture practice.

Guinea Pig Transferrin Receptor 1 Mediates Cellular Entry of Junín Virus and Other Pathogenic New World Arenaviruses.

Several clade B New World arenaviruses (NWAs) can cause severe and often fatal hemorrhagic fever, for which preventive and therapeutic measures are severely limited. These NWAs use human transferrin receptor 1 (hTfR1) as a host cell receptor for virus entry. The most prevalent of the pathogenic NWAs is Junín virus (JUNV), the etiological agent of Argentine hemorrhagic fever. Small animal models of JUNV infection are limited because most laboratory rodent species are refractory to disease. Only guinea pigs are known to develop disease following JUNV infection, but the underlying mechanisms are not well characterized. In the present study, we demonstrate marked susceptibility of Hartley guinea pigs to uniformly lethal disease when challenged with as few as 4 PFU of the Romero strain of JUNV. In vitro, we show that infection of primary guinea pig macrophages results in greater JUNV replication compared to infection of hamster or mouse macrophages. We provide evidence that the guinea pig TfR1 (gpTfR1) is the principal receptor for JUNV, while hamster and mouse orthologs fail to support viral entry/infection of pseudotyped murine leukemia viruses expressing pathogenic NWA glycoproteins or JUNV. Together, our results indicate that gpTfR1 serves as the primary receptor for pathogenic NWAs, enhancing viral infection in guinea pigs.IMPORTANCE JUNV is one of five known NWAs that cause viral hemorrhagic fever in humans. Countermeasures against JUNV infection are limited to immunization with the Candid#1 vaccine and immune plasma, which are available only in Argentina. The gold standard small animal model for JUNV infection is the guinea pig. Here, we demonstrate high sensitivity of this species to severe JUNV infection and identify gpTfR1 as the primary receptor. Use of hTfR1 for host cell entry is a feature shared by pathogenic NWAs. Our results show that expression of gpTfR1 or hTfR1 comparably enhances JUNV virus entry/infectivity. Our findings shed light on JUNV infection in guinea pigs as a model for human disease and suggest that similar pathophysiological mechanisms related to iron sequestration during infection and regulation of TfR1 expression may be shared between humans and guinea pigs. A better understanding of the underlying disease process will guide development of new therapeutic interventions.

Whitening effect of novel peptide mixture by regulating melanosome biogenesis, transfer and degradation.

Peptides are short chain of amino acids linked by peptide bonds. They are widely used as effective and biocompatible active ingredients in cosmetic industry. In this study, we developed novel peptide mixture and identified its anti-pigmentation effect on melanocytes and keratinocytes. Our results revealed that peptide mixture inhibited melanosome biogenesis through the regulation of microphthalmia-associated transcription factor, a key factor of melanogenesis in melanocytes. And we observed that peptide mixture inhibited melanosome uptake through the reduction of protease-activated receptor 2, a phagocytosis-related receptor in keratinocytes. Furthermore, peptide mixture activated autophagy system resulting in degradation of transferred melanosomes in keratinocytes. The anti-pigmentation effect of multi-targeting peptide mixture was assessed in a human skin equivalent model (MelanoDerm). Melanin contents in epidermal layer were significantly decreased by topical treatment of peptide mixture, suggesting that it can be applied as a novel cosmetics material having a whitening function.

Melatonin restores Muc2 depletion induced by V. vulnificus VvpM via melatonin receptor 2 coupling with Gαq.

BACKGROUND: Melatonin (5-methoxy-N-acetyltryptamine), a hormone produced in the pineal gland, has a variety of biological functions as an antioxidant, but a functional role of melatonin in the regulation of intestinal mucin (Muc) production during bacterial infection has yet to be described in detail. In this study, we investigate the effects of melatonin during Muc2 repression elicited by the Gram-negative bacterium V. vulnificus. METHODS: Mucus-secreting human HT29-MTX cells were used to study the functional role of melatonin during Muc2 depletion induced by the recombinant protein (r) VvpM produced by V. vulnificus. The regulatory effects of melatonin coupling with melatonin receptor 2 (MT2) on the production of reactive oxygen species (ROS), the activation of PKCδ and ERK, and the hypermethylation of the Muc2 promoter as induced by rVvpM were examined. Experimental mouse models of V. vulnificus infection were used to study the role of melatonin and how it neutralizes the bacterial toxin activity related to Muc2 repression. RESULTS: Recombinant protein (r) VvpM significantly reduced the level of Muc2 in HT29-MTX cells. The repression of Muc2 induced by rVvpM was significantly restored upon a treatment with melatonin (1 µM), which had been inhibited by the knockdown of MT2 coupling with Gαq and the NADPH oxidase subunit p47 phox. Melatonin inhibited the ROS-mediated phosphorylation of PKCδ and ERK responsible for region-specific hypermethylation in the Muc2 promoter in rVvpM-treated HT29-MTX cells. In the mouse models of V. vulnificus infection, treatment with melatonin maintained the level of Muc2 expression in the intestine. In addition, the mutation of the VvpM gene from V. vulnificus exhibited an effect similar to that of melatonin. CONCLUSIONS: These results demonstrate that melatonin acting on MT2 inhibits the hypermethylation of the Muc2 promoter to restore the level of Muc2 production in intestinal epithelial cells infected with V. vulnificus.

Comparison of Amyloid in Cerebrospinal Fluid, Brain Imaging, and Autopsy in a Case of Progressive Supranuclear Palsy.

Cerebrospinal fluid (CSF) amyloid-beta 1-42 (Aß1-42) and amyloid positron emission tomography (PET) are the 2 main Alzheimer disease amyloid biomarkers that have been validated in neuropathologically confirmed Alzheimer disease cases. Although many studies have shown concordance of amyloid positivity or negativity between CSF Aß1-42 and amyloid PET, several studies also reported discrepancies between these 2 Aß biomarkers. We conducted a comparison of CSF Aß1-42 level, amyloid PET, and autopsy findings in a case with progressive supranuclear palsy in which biomarker acquisition and postmortem pathologic examination were conducted almost at the same time. Our case with antemortem CSF Aß1-42 (+)/amyloid PET (-) who was pathologically confirmed with Aß pathology in the cerebral cortex may indicate CSF Aß1-42 is more sensitive for assessing in vivo Aß than amyloid PET.

The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination.

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination.

Heritability and familiality of psychopathologic dimensions in Korean families with schizophrenia.

AIM: Categorical syndromes such as schizophrenia could be a combination of many continuous mental structure phenotypes including several personality development/degeneration dimensions. This study investigated the heritability and familiality of symptom check list (SCL) psychopathologic dimensions in Korean schizophrenia linkage disequilibrium families. METHOD: We recruited 204 probands (with schizophrenia) with their parents and siblings whenever possible. We used the SCL questionnaire to measure psychopathologic dimensions. The heritability of symptomatic dimensions in 543 family members was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR). Psychopathologic dimensions in the 543 family members were compared with those in 307 healthy unrelated controls to measure familiality on using analysis of variance (ANOVA) analysis. RESULTS: Five of the nine SCL variables were significantly heritable and were included in the subsequent analyses. The three groups (control, unaffected first-degree relative, schizophrenia patient) were found to be significantly different with regard to the expected order of average group scores for all heritable dimensions. CONCLUSION: Aberrations in several symptomatic dimensions could contribute to the complexity of schizophrenia syndrome as a result of genetic-environment coaction or interaction in spite of some limitations (recruited family, phenotyping).

Right hippocampus atrophy is independently associated with Alzheimer's disease with psychosis.

AIM: The purpose of this study was to determine whether regionally distributed medial temporal cortex thickness (or hippocampal volume) and frontal lobe volume are independently associated with the onset of Alzheimer's disease (AD) with psychosis. METHODS: We identified 26 AD patients with psychosis (AD+P) and 48 AD patients without psychosis (AD-P) from the Memory Impairment Clinic at Pusan National University Hospital in South Korea. They were matched for age, gender, duration of AD, and Clinical Dementia Rating sum of box score. All participants met the National Institute of Neurological and Communication Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria for probable AD. Psychosis was diagnosed according to Jeste and Finkel's proposed diagnostic criteria for psychosis of AD. All participants underwent 3-T magnetic resonance imaging, and 3-D magnetization-prepared rapid gradient echo sequence was acquired for each. The FreeSurfer version 5.1 software package was used to analyze cortical thickness and volume on 3-D T1 -weighted images. anova was used to investigate the differences in cortical thickness and the volume of the total frontal cortex, total temporal cortex, and subregions of the medial temporal cortex between groups after age, gender, years of education, Clinical Dementia Rating sum of box score, duration of AD, and total intracranial volume were controlled for. Furthermore, we added the total frontal volume as an additional variable to investigate whether the association between the medial temporal cortex and AD+P is independent of the frontal cortex. RESULTS: We found that both left and right hippocampal volume were smaller in AD+P than in AD-P. In particular, there was a significant difference in right hippocampal volume between the AD+P and AD-P groups after total frontal volume was added as an additional variable. CONCLUSION: We found that more severe hippocampal atrophy is associated with AD+P than with AD-P. In addition, atrophy of the right hippocampus remained significant among AD+P after adjustment for frontal volume. These findings suggest that right hippocampal atrophy is independently associated with AD+P.

Early stage memory impairment, visual hallucinations, and myoclonus combined with temporal lobe atrophy predict Alzheimer's disease pathology in corticobasal syndrome.

Corticobasal syndrome (CBS) is a typical phenotype of corticobasal degeneration (CBD). However, autopsy series have shown that many CBS cases emerge from various types of non-CBD pathology. We report a 73-year-old Korean man who was clinically diagnosed with CBS whose underlying pathology was Alzheimer's disease (AD) at autopsy (CBS-AD). This case suggests that early developing memory impairment and myoclonus, severe temporoparietal atrophy, and visual hallucinations may support a more specific prediction of CBS-AD.