Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) are highly reactive species which play crucial roles in many fundamental physiological processes including cellular signalling pathways. Over-production of these reactive species by various stimuli leads to cellular oxidative stress which is linked to various disease conditions. Therefore, the development of novel detection methods for ROS and RNS is of great interest and indispensable for monitoring the dynamic changes of ROS and RNS in cells and for elucidating their mechanisms of trafficking and connections to diseases. We have been recently developing various fluorescent sensors which can selectively detect metal ions, ROS or RNS species in live cells or animals. Our turn-on profluorescent sensors are capable of imaging oxidative stress promoted by metal and H2O2 (i.e. the Fenton Reaction conditions) in living cells (Chem Commun 2010); our highly selective and sensitive iron sensors can image the endogenous exchangeable iron pools and their dynamic changes with subcellular resolution in living neuronal cells (ChemBioChem 2012 and unpublished data), and so do our superoxide sensors (ChemBioChem 2012 and unpublished data). Moreover, we have recently developed nitric oxide (NO) sensors for molecular imaging of stimulated NO production in live cells with subcellular resolution as well as novel near infra red (NIR) sensors for NO imaging in live animals.

Blood pressure (BP) remains poorly controlled among hypertensive patients with coronary heart disease (CHD) in China. Improvement of its management will require an understanding of the patient characteristics and treatment factors associated with uncontrolled hypertension. A cross-sectional survey of 3,279 patients from 52 centers in China was performed to examine potential barriers to adequate blood pressure control of hypertensive patients with CHD. Uncontrolled hypertension was defined as blood pressure >/=130/or 80 mmHg. Multivariable logistic regression was used to identify factors associated with poor blood pressure control. Mean age of the patients was 65 years, 40% were women, and mean BMI was 25 kg/m(2). Mean systolic blood pressure was 136+/-18 mmHg and mean diastolic blood pressure was 80+/-11 mmHg. Only 18% of patients had a mean blood pressure <130/80 mmHg during the study period. Multivariate analysis revealed several independent factors of poor blood pressure control: body mass index >/=23 kg/m(2), the presence of stable angina pectoris (SAP), family history of diabetes, and use of calcium channel blockers (CCB). Further analysis showed that non-dihydropyridine calcium antagonist was significantly correlated with low BP control rate. Some of these may be amenable to modification. The results of our study suggest that overweight, the presence of SAP and family history of diabetes are important factors for tight BP control in primary care. In addition, non-dihydropyridine calcium channel blockers appear less effective than other therapies in control of blood pressure and should not be the first choice among hypertensive patients with CHD. Further identification of patients at risk of poor BP control can lead to targeted interventions to improve management.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the deposition of extracellular amyloid-β(Aβ) plaques that are rich in metal ions such as zinc, copper and iron. The neurotoxic role of Aβ has been well established but the mechanism of action is still poorly understood. Recent in vitro evidence suggest that Aβ can interact with metal ions such as Zn(II), Cu(II) or Fe(II/III) which promote its aggregation and/or ROS production. However, it is unclear whether this is the case in cells and whether/how extracellular Aβ can get into cells. Our recently developed molecular imaging probes for iron, copper and ROS enable us to look at this in real time in live cells at subcellular resolution. First, we tagged the Aβ covalently with a fluorescent dye which allows its interactions with cells to be monitored under a microscope. Our laser confocal imaging experiments with human neuroblastoma cells revealed that Aβ accumulated at the cell surface first and subsequently entered the cells via endocytosis pathway over a period of a few hours and finally deposited into endosomes/lysosomes in the cells. The deposition of Aβ induced a marked production of oxygen free radicals in the mitochondria of the cells, as revealed by our oxygen free radical probe and colocalization experiments. Incubation of metal ions such as copper(II) increased the production of oxygen radicals significantly while zinc(II) appears to be protective against ROS production. Our data provided compelling and direct evidence on how amyloid-β(Aβ) entering the cells and its induction of oxygen free radicals as well as the effects of metal ions on the radical production at subcellular level.

In this work, we exploited the superior capability of high-resolution functional magnetic resonance imaging (fMRI) for functional mapping of ocular dominance layer (ODL) in the cat lateral geniculate nucleus (LGN). The stimulus-evoked neuronal activities in the LGN ODLs associated with contralateral- and ipsilateral-eye visual inputs were successfully differentiated and mapped using both blood-oxygenation-level dependent (BOLD)-weighted and cerebral blood volume (CBV)-weighted fMRI methods. The morphology of mapped LGN ODLs was in remarkable consistency with histology findings in terms of ODL shape, orientation, thickness and eye-dominance. Compared with the BOLD signal, the CBV signal provides higher reproducibility and better spatial resolvability for function mapping of LGN because of improved contrast-to-noise ratio and point-spread function. The capability of fMRI for non-invasively imaging the functional sub-units of ODL in a small LGN overcomes the limitation of conventional neural-recording approach, and it opens a new opportunity for studying critical roles of LGN in brain function and dysfunction at the fine scale of ocular dominance layer.

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3(+) regulatory T cells. CTLA-4-deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4-deficient and -sufficient bone marrow (BM)-derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4(-/-) T cells in trans by CTLA-4-sufficient T cells is a reversible process that requires the persistent presence of FOXP3(+) regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3(+) regulatory T cell function in vivo.

The possible role of oxygen metabolism in supporting brain activation remains elusive. We have used a newly developed neuroimaging approach based on high-field in vivo (17)O magnetic resonance spectroscopic (MRS) imaging to noninvasively image cerebral metabolic rate of oxygen (CMRO(2)) consumption in cats at rest and during visual stimulation. It was found that CMRO(2) increases significantly (32.3%+/-10.8%, n=6) in the activated visual cortical region as depicted in blood oxygenation level dependence functional maps; this increase is also accompanied by a CMRO(2) decrease in surrounding cortical regions, resulting a smaller increase (9.7%+/-1.9%) of total CMRO(2) change over a larger cortical region displaying either a positive or negative CMRO(2) alteration. Moreover, a negative correlation between stimulus-evoked percent CMRO(2) increase and resting CMRO(2) was observed, indicating an essential impact of resting brain metabolic activity level on stimulus-evoked percent CMRO(2) change and neuroimaging signals. These findings provide new insights into the critical roles of oxidative metabolism in supporting brain activation and function. They also suggest that in vivo (17)O MRS imaging should provide a sensitive neuroimaging modality for mapping CMRO(2) and its change induced by brain physiology and/or pathologic alteration.