Attenuation of protein arginine dimethylation via S-nitrosylation of protein arginine methyltransferase 1

Upregulation of nitric oxide (NO) production contributes to the pathogenesis of numerous diseases via S-nitro- sylation, a post-translational modification of proteins. This process occurs due to the oxidative reaction between NO and a cysteine thiol group; however, the extent of this reaction remains unknown. S-Nitrosylation of PRMT1, a major asymmetric arginine methyltransferase of histones and numerous RNA metabolic proteins, was induced by NO donor treatment. We found that nitrosative stress leads to S-nitrosylation of cysteine 119, located near the active site, and attenuates the enzymatic activity of PRMT1. Interestingly, RNA sequencing analysis revealed similarities in the changes in expression elicited by NO and PRMT1 inhibitors or knockdown. A comprehensive search for PRMT1 substrates using the proximity-dependent biotin identification method highlighted many known and new substrates, including RNA-metabolizing enzymes. To validate this result, we selected the RNA helicase DDX3 and demonstrated that arginine methylation of DDX3 is induced by PRMT1 and attenuated by NO treatment. Our results suggest the existence of a novel regulatory system associated with transcription and RNA metabolism via protein S-nitrosylation

Quantitative Understanding of the Decision-Making Process for Farm Biosecurity Among Japanese Livestock Farmers Using the KAP-Capacity Framework

In a globalized world, the frequency of transboundary livestock infectious diseases is increasing, and strengthening of farm biosecurity is vital to stabilize food production. The aim of this study was to understand the decision-making process for farm biosecurity among Japanese livestock farmers. Postal surveys using structured questionnaires were conducted on beef, dairy, pig, and layer farms in Hokkaido and Saitama Prefectures, which represent the principal production area and peri-urban Tokyo, respectively, as well as randomly selected broiler farms across Japan. The question items included the attributes of farms and owners, disease experiences, related associations and sources of hygiene information, attitude toward hygiene management, and compliance with the Standards of Rearing Hygiene Management (SRHM). The compliance rates were compared between livestock sectors. Univariable analyses were conducted using combined data from both prefectures, with the compliance rate as the outcome variable and the questionnaire items as explanatory variables, in generalized linear models. Exploratory factor analyses were conducted using the variables with p < 0.2 in the univariable analyses. The factors identified were classified into knowledge, attitude, capacity, practice, and structural equation modeling (SEM) was performed. The questionnaires were completed and returned by 97 and 66 beef cattle, 86 and 136 dairy, 67 and 45 pig, 20 and 39 layer farmers in Hokkaido and Saitama Prefectures, respectively, and 95 broiler farms. The compliance rate was significantly higher among broiler farms (88.9%) compared with the other sectors, followed by pig (77.1%), layer (67.2%), dairy (63.8%), and beef (59.1%) farms in Hokkaido Prefecture, and layer (64.9%), pig (60.0%), dairy (58.5%), and beef (57.6%) farms in Saitama Prefecture. Based on SEM, the decision-making process from greater knowledge to higher attitude, and from higher attitude to greater compliance with the SRHM were significant (p < 0.01) in all sectors. Higher capacity was significantly associated with higher knowledge in dairy, pig,break and layer farms (p < 0.01), and with higher compliance in beef, pig, and layer farms (p < 0.05). These results suggest that the provision of targeted hygiene knowledge to livestock farmers and the support to smallholder farms would improve biosecurity through elevated attitudes and self-efficacy

A Novel SPECT Tracer for Cerebral Amyloid and Tau Aggregates Accumulated in Alzheimer\u27s Disease and related tauopathy

BACKGROUND: Non-invasive determination for amyloid- (A) plaques and neurofibrillary tangles (NFTs) has important significance for early diagnosis and medical intervention to Alzheimer’s disease (AD) and related tauopathies. Although several single photon emission computed tomography (SPECT) tracers for Aplaques imaging were reported, to the best of our knowledge, no tracer is successful for tau imaging in the living brains. PURPOSE: In the present study, we have developed a novel SPECT tracer AD-DRK for A and tau deposition for in-vivo detection.METHODS: 125I-labeled AD-DRK ([125I] AD-DRK) was designed and synthesized based on our previous publication. The biodistribution was determined in normal mice. The detectability of Ab and tau deposition was investigated by in-vitro and ex-vivo autoradiography in APP and tauopathy mouse models, and post-mortem human brains.RESULTS: [125I] AD-DRK showed high initial brain uptake with a peak value of approximately 7% of injection dose per ml at 2 minute post-injection and rapid washout thereafter. In vitro autoradiography has clearly demonstrated that there was overt specific binding of [125I] AD-DRK in temporal cortex region of AD or progressive supranuclear palsy (PSP) enriched with A plaques and/or neurofibrillary tangle. Moreover, ex vivo autoradiographic analysis showed that [125I] AD-DRK has higher accumulation in forebrain enriched with A or tau accumulation in AD and tauopathy mouse models compared with normal mouse, implying the utility of AD-DRK for in-vivo imaging for A and/or tau deposition.CONCLUSION: [125I] AD-DRK has demonstrated high potential as SPECT ligand for diagnosis for AD and/or related tauopathies.THE 13TH ASIA OCEANIA CONGRESS OF NUCLEAR MEDICINE AND BIOLOG

In Vivo SPECT Imaging of Amyloid-β Deposition with Radioiodinated Imidazo[1,2-a]pyridine Derivative DRM106 in Mouse Model of Alzheimer’s Disease

Non-invasive determination of amyloid- peptide (Ab) deposition has important significance for early diagnosis and medical intervention for Alzheimer’s disease (AD). In the present study, we investigated the availability of radiolabeled DRM106 (123/125I-DRM106), a compound with sufficient affinity for the synthesis of human Ab fibrils and satisfactory metabolic stability, as a single photon emission computed tomography (SPECT) ligand in living brains. Method: The sensitivity of 125I-DRM106 for detecting Ab deposition was compared with 125I-IMPY, a well-known amyloid SPECT ligand, by ex vivo autoradiographic analyses in 18-month-old amyloid precursor protein transgenic (Tg) mice. To verify the sensitivity and quantitation of radiolabeled DRM106 for in vivo imaging, we compared the detectability of A plaques with 123I-DRM106 and a well-known amyloid positron emission tomography (PET) agent, 11C-labeled Pittsburgh compound B (11C-PiB), in 29-month-old Tg mice and age-matched non-Tg littermates. Additionally, we compared the binding characteristics of 125I-DRM106 with those of 11C-PiB and 11C-PBB3, which selectively bind to A plaques and preferentially to tau aggregates, respectively, in postmortem AD brain sections. Results: Ex vivo autoradiographic analysis showed that measurement with 125I-DRM106 has higher sensitivity for detecting Ab accumulation than with 125I-IMPY in Tg mice. SPECT imaging with 123I-DRM106 also successfully detected Ab deposition in living aged Tg mice, and showed strong correlation (R = 0.95, p < 0.01) in quantitative analysis for Ab plaque detection by PET imaging with 11C-PiB, implying that sensitivity and quantitation of SPECT imaging with 123I-DRM106 are almost as good as 11C-PiB-PET for the detectability of Ab deposition. Further, the addition of non-radiolabeled DRM106 fully blocked the binding of 125I-DRM106 and 11C-PiB, but not 11C-PBB3, to AD brain sections, and 125I-DRM106 showed a lower binding ratio of the diffuse plaque-rich lateral temporal cortex to the dense cored/neuritic plaque-rich hippocampal CA1 area, compared to 11C-PiB. Conclusion: All of these data demonstrated the high potential of 123I-DRM106 for amyloid imaging in preclinical and clinical application, and it might more preferentially detect dense-cored/neuritic amyloid deposition, which is expected to be closely associated with neuropathological changes of AD