In Vivo Optical Imaging of Interscapular Brown Adipose Tissue with 18F-FDG via Cerenkov Luminescence Imaging

Objective: Brown adipose tissue (BAT), a specialized tissue for thermogenesis, plays important roles for metabolism and energy expenditure. Recent studies validated BAT’s presence in human adults, making it an important re-emerging target for various pathologies. During this validation, PET images with 18F-FDG showed significant uptake of 18F-FDG by BAT under certain conditions. Here, we demonstrated that Cerenkov luminescence imaging (CLI) using 18F-FDG could be utilized for in vivo optical imaging of BAT in mice. Methods: Mice were injected with 18F-FDG and imaged 60 minutes later with open filter and 2 minute acquisition. In vivo activation of BAT was performed by norepinephrine and cold treatment under isoflurane or ketamine anesthesia. Spectral unmixing and 3D imaging reconstruction were conducted with multiple-filter CLI images. Results: 1) It was feasible to use CLI with 18F-FDG to image interscapular BAT in mice, with the majority of the signal (>85%) at the interscapular site originating from BAT; 2) The method was reliable because excellent correlations between in vivo CLI, ex vivo CLI, and ex vivo radioactivity were observed; 3) CLI could be used for monitoring BAT activation under different conditions; 4) CLI signals from the group under short-term isoflurane anesthesia were significantly higher than that from the group under long-term anesthesia; 5) The CLI spectrum of 18F-FDG with a peak at 640 nm in BAT after spectral unmixing reflected the actual context of BAT; 6) Finally 3D reconstruction images showed excellent correlation between the source of the light signal and the location and physical shape of BAT. Conclusion: CLI with 18F-FDG is a feasible and reliable method for imaging BAT in mice. Compared to PET imaging, CLI is significantly cheaper, faster for 2D planar imaging and easier to use. We believe that this method could be used as an important tool for researchers investigating BAT

Targeting of reactive isolevuglandins in mitochondrial dysfunction and inflammation.

Inflammation is a major cause of morbidity and mortality in Western societies. Despite use of multiple drugs, both chronic and acute inflammation still represent major health burdens. Inflammation produces highly reactive dicarbonyl lipid peroxidation products such as isolevuglandins which covalently modify and cross-link proteins via lysine residues. Mitochondrial dysfunction has been associated with inflammation; however, its molecular mechanisms and pathophysiological role are still obscure. We hypothesized that inflammation-induced isolevuglandins contribute to mitochondrial dysfunction and mortality. To test this hypothesis, we have (a) investigated the mitochondrial dysfunction in response to synthetic 15-E2-isolevuglandin (IsoLG) and its adducts; (b) developed a new mitochondria-targeted scavenger of isolevuglandins by conjugating 2-hydroxybenzylamine to the lipophilic cation triphenylphosphonium, (4-(4-aminomethyl)-3-hydroxyphenoxy)butyl)-triphenylphosphonium (mito2HOBA); (c) tested if mito2HOBA protects from mitochondrial dysfunction and mortality using a lipopolysaccharide model of inflammation. Acute exposure to either IsoLG or IsoLG adducts with lysine, ethanolamine or phosphatidylethanolamine inhibits mitochondrial respiration and attenuates Complex I activity. Complex II function was much more resistant to IsoLG. We confirmed that mito2HOBA markedly accumulates in isolated mitochondria and it is highly reactive with IsoLGs. To test the role of mitochondrial IsoLGs, we studied the therapeutic potential of mito2HOBA in lipopolysaccharide mouse model of sepsis. Mito2HOBA supplementation in drinking water (0.1 g/L) to lipopolysaccharide treated mice increased survival by 3-fold, improved complex I-mediated respiration, and histopathological analyses supported mito2HOBA-mediated protection of renal cortex from cell injury. These data support the role of mitochondrial IsoLG in mitochondrial dysfunction and inflammation. We conclude that reducing mitochondrial IsoLGs may be a promising therapeutic target in inflammation and conditions associated with mitochondrial oxidative stress and dysfunction

A Novel Imaging Approach for Early Detection of Prostate Cancer Based on Endogenous Zinc Sensing

The early detection of prostate cancer is a life-saving event in patients harboring potentially aggressive disease. With the development of malignancy, there is a dramatic reduction in the zinc content of prostate tissue associated with the inability of cancer cells to accumulate the ion. In the current study, we used endogenous zinc as an imaging biomarker for prostate cancer detection and progression monitoring. We employed a novel fluorescent sensor for mobile zinc (ZPP1) to detect and monitor the development of prostate cancer in a transgenic mouse model of prostate adenocarcinoma, using in vivo optical imaging correlated with biological fluid-based methods. We showed that the progression of prostate cancer could be monitored in vivo judging by the decreasing zinc content in the prostates of tumor-bearing mice in an age-dependent manner. In a novel quantitative assay, we determined the concentration of mobile zinc in both prostate cell lysates and mouse prostate extracts through simple titration of the ZPP1 sensor. Our findings fulfill the promise of zinc-based prostate cancer diagnostics with the prospect for immediate clinical translation.National Institute of General Medical Sciences (U.S.) (grant GM065519)National Cancer Institute (U.S.) (grant R00CA129070)National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (grant RC1DK086242)Massachusetts Biomedical Research CorporationMassachusetts Biomedical Research Corporation (Tosteson Postdoctoral Fellowship

Gattini 2010: Cutting Edge Science at the Bottom of the World

The high altitude Antarctic sites of Dome A and the South Pole offer intriguing locations for future large scale optical astronomical Observatories. The Gattini project was created to measure the optical sky brightness, large area cloud cover and aurora of the winter-time sky above such high altitude Antarctic sites. The Gattini-DomeA camera was installed on the PLATO instrument module as part of the Chinese-led traverse to the highest point on the Antarctic plateau in January 2008. This single automated wide field camera contains a suite of Bessel photometric filters (B, V, R) and a long-pass red filter for the detection and monitoring of OH emission. We have in hand one complete winter-time dataset (2009) from the camera that was recently returned in April 2010. The Gattini-South Pole UV camera is a wide-field optical camera that in 2011 will measure for the first time the UV properties of the winter-time sky above the South Pole dark sector. This unique dataset will consist of frequent images taken in both broadband U and B filters in addition to high resolution (R similar to 5000) long slit spectroscopy over a narrow bandwidth of the central field. The camera is a proof of concept for the 2m-class Antarctic Cosmic Web Imager telescope, a dedicated experiment to directly detect and map the redshifted lyman alpha fluorescence or Cosmic Web emission we believe possible due to the unique geographical qualities of the site. We present the current status of both projects

Urbanization and sustainability under transitional economies:a synthesis for Asian Russia

Spanning a vast territory of approximately 13 million km ^2 , Asian Russia was home to 38 million people in 2016. In an effort to synthesize data and knowledge regarding urbanization and sustainable development in Asian Russia in the context of socioeconomic transformation following the breakup of the Soviet Union in 1990, we quantified the spatiotemporal changes of urban dynamics using satellite imagery and explored the interrelationships between urbanization and sustainability. We then developed a sustainability index, complemented with structural equation modeling, for a comprehensive analysis of their dynamics. We chose six case cities, i.e., Yekaterinburg, Novosibirsk, Krasnoyarsk, Omsk, Irkutsk, and Khabarovsk, as representatives of large cities to investigate whether large cities are in sync with the region in terms of population dynamics, urbanization, and sustainability. Our major findings include the following. First, Asian Russia experienced enhanced economic growth despite the declining population. Furthermore, our case cities showed a general positive trend for population dynamics and urbanization as all except Irkutsk experienced population increases and all expanded their urban built-up areas, ranging from 13% to 16% from 1990 to 2014. Second, Asian Russia and its three federal districts have improved their sustainability and levels of economic development, environmental conditions, and social development. Although both regional sustainability and economic development experienced a serious dip in the 1990s, environmental conditions and social development continuously improved from 1990 to 2014, with social development particularly improving after 1995. Third, in terms of the relationships between urbanization and sustainability, economic development appeared as an important driver of urbanization, social development, and environmental degradation in Asian Russia, with economic development having a stronger influence on urbanization than on social development or environmental degradation

Analysis of reactive aldehydes in urine and plasma of type-2 diabetes mellitus patients through liquid chromatography-mass spectrometry: Reactive aldehydes as potential markers of diabetic nephropathy

IntroductionDiabetes is a major public health issue that is approaching epidemic proportions globally. Diabetes mortality is increasing in all ethnic groups, irrespective of socio-economic class. Obesity is often seen as the main contributor to an increasing prevalence of diabetes. Oxidative stress has been shown to trigger obesity by stimulating the deposition of white adipose tissue. In this study, we measured reactive aldehydes by liquid chromatography-mass spectrometry (LC-MS), in the urine and plasma of type-2 diabetic mellitus (T2DM) patients, as potential surrogates of oxidative stress. Our hypothesis was that reactive aldehydes play a significant role in the pathophysiology of diabetes, and these reactive species, may present potential drug targets for patient treatment.Materials and methodsStudy participants [N = 86; control n = 26; T2DM n = 32, and diabetic nephropathy (DN) n = 28] were recruited between 2019 and 2020. Urine and blood samples were collected from all participants, including a detailed clinical history, to include patient behaviours, medications, and co-morbidities. Reactive aldehyde concentrations in urine and plasma were measured using pre-column derivatisation and LC-MS, for control, T2DM and DN patients.ResultsReactive aldehydes were measured in the urine and plasma of control subjects and patients with T2DM and DN. In all cases, the reactive aldehydes under investigation; 4-HNE, 4-ONE, 4-HHE, pentanal, methylglyoxal, and glyoxal, were significantly elevated in the urine and serum of the patients with T2DM and DN, compared to controls (p < 0.001) (Kruskal–Wallis). Urine and serum reactive aldehydes were significantly correlated (≥0.7) (p < 0.001) (Spearman rho). The concentrations of the reactive aldehydes were significantly higher in plasma samples, when compared to urine, suggesting that plasma is the optimal matrix for screening T2DM and DN patients for oxidative stress.ConclusionReactive aldehydes are elevated in the urine and plasma of T2DM and DN patients. Reactive aldehydes have been implicated in the pathobiology of T2DM. Therefore, if reactive aldehydes are surrogates of oxidative stress, these reactive aldehyde species could be therapeutic targets for potential drug development

Discount Rates in Risk v. Money and Money v. Money Tradeoffs

We use data from a survey of residents of five Italian cities conducted in late Spring 2004 to estimate the discount rates implicit in (a) money v. future risk reductions and (b) money v. money tradeoffs. We find that the mean personal discount rate is 2% in (a) and 8.7% in (b). The latter is lower than the discount rates estimated in comparable situations in many recent studies, greater than market interest rates in Italy at the time, and exhibits modest variation with age and gender. The discount rate implicit in money v. risk tradeoffs is in line with estimates from studies in the US and Europe, and does not depend on observable individual characteristics

2018 International Atmospheric Rivers Conference: Multi‐disciplinary studies and high‐impact applications of atmospheric rivers

Atmospheric rivers (ARs) play a vital role in shaping the hydroclimate of many regions globally, and can substantially impact water resource management, emergency response planning, and other socioeconomic entities. The second International Atmospheric Rivers Conference took place at the Scripps Institution of Oceanography, University of California, San Diego, during 25–28 June, 2018, in La Jolla, California, USA. It was sponsored by the Center for Western Weather and Water Extremes (CW3E). A total of 120 people attended the Conference with 94 abstracts submitted and 30 participating students. In addition to the conference, the Student Forecasting Workshop was organised in the same week. During this workshop, students were exposed to AR forecasting tools, and learned examples of how these tools could be used to make decisions for various applications. The main goals of this conference were to bring together experts from across the fields of hydrology, atmospheric, oceanic, and polar sciences, as well as water management, civil engineering, and ecology to advance the state of AR science and to explore the future directions for the field. The conference was organised into traditional oral and poster presentations, along with panel discussions and Breakout Groups. This format allowed enhanced interaction between participants, driving progress within the scientific community and the enhanced communication of societal needs by various stakeholders. Several emerging topics of research were highlighted, including subseasonal‐to‐seasonal (S2S) prediction of ARs and an overview of the AR Reconnaissance campaign. In addition to providing a forum to disseminate and debate new results from scientific talks and posters, the conference was equally effective and useful in linking scientists to users and decision‐makers that require improved knowledge on ARs to manage resources and prepare for hazards.The third International Atmospheric Rivers Conference will be held in Chile in 2020, and hosted by the University of Chile, Santiago.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151348/1/asl2935.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151348/2/asl2935_am.pd

Downregulation of MicroRNA-9 in iPSC-Derived Neurons of FTD/ALS Patients with TDP-43 Mutations

Transactive response DNA-binding protein 43 (TDP-43) is a major pathological protein in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). There are many disease-associated mutations in TDP-43, and several cellular and animal models with ectopic overexpression of mutant TDP-43 have been established. Here we sought to study altered molecular events in FTD and ALS by using induced pluripotent stem cell (iPSC) derived patient neurons. We generated multiple iPSC lines from an FTD/ALS patient with the TARDBP A90V mutation and from an unaffected family member who lacked the mutation. After extensive characterization, two to three iPSC lines from each subject were selected, differentiated into postmitotic neurons, and screened for relevant cell-autonomous phenotypes. Patient-derived neurons were more sensitive than control neurons to 100 nM straurosporine but not to other inducers of cellular stress. Three disease-relevant cellular phenotypes were revealed under staurosporine-induced stress. First, TDP-43 was localized in the cytoplasm of a higher percentage of patient neurons than control neurons. Second, the total TDP-43 level was lower in patient neurons with the A90V mutation. Third, the levels of microRNA-9 (miR-9) and its precursor pri-miR-9-2 decreased in patient neurons but not in control neurons. The latter is likely because of reduced TDP-43, as shRNA-mediated TDP-43 knockdown in rodent primary neurons also decreased the pri-miR-9-2 level. The reduction in miR-9 expression was confirmed in human neurons derived from iPSC lines containing the more pathogenic TARDBP M337V mutation, suggesting miR-9 downregulation might be a common pathogenic event in FTD/ALS. These results show that iPSC models of FTD/ALS are useful for revealing stress-dependent cellular defects of human patient neurons containing rare TDP-43 mutations in their native genetic contexts

Ty1 integrase overexpression leads to integration of non-Ty1 DNA fragments into the genome of Saccharomyces cerevisiae

The integrase of the Saccharomyces cerevisiae retrotransposon Ty1 integrates Ty1 cDNA into genomic DNA likely via a transesterification reaction. Little is known about the mechanisms ensuring that integrase does not integrate non-Ty DNA fragments. In an effort to elucidate the conditions under which Ty1 integrase accepts non-Ty DNA as substrate, PCR fragments encompassing a selectable marker gene were transformed into yeast strains overexpressing Ty1 integrase. These fragments do not exhibit similarity to Ty1 cDNA except for the presence of the conserved terminal dinucleotide 5′-TG-CA-3′. The frequency of fragment insertion events increased upon integrase overexpression. Characterization of insertion events by genomic sequencing revealed that most insertion events exhibited clear hallmarks of integrase-mediated reactions, such as 5 bp target site duplication and target site preferences. Alteration of the terminal dinucleotide abolished the suitability of the PCR fragments to serve as substrates. We hypothesize that substrate specificity under normal conditions is mainly due to compartmentalization of integrase and Ty cDNA, which meet in virus-like particles. In contrast, recombinant integrase, which is not confined to virus-like particles, is able to accept non-Ty DNA, provided that it terminates in the proper dinucleotide sequence