511 keV γ\gamma-ray emission from the galactic bulge by MeV millicharged dark matter

We propose a possible explanation for the recently observed anomalous 511 keV line with a new "millicharged" fermion. This new fermion is light [${\cal O}({\rm MeV})$]. Nevertheless, it has never been observed by any collider experiments by virtue of its tiny electromagnetic charge $\epsilon e$. In particular, we constrain parameters of this millicharged particle if the 511 keV cosmic $\gamma$-ray emission from the galactic bulge is due to positron production from this new particle.Comment: 3 pages, 1 figure, A talk given by J.C.Park at the 16th International Conference on Supersymmetry and the Unification of Fundamental Interactions (SUSY08), Seoul, Korea, June 16-21, 200

Agmatine protects retinal ganglion cells from hypoxia-induced apoptosis in transformed rat retinal ganglion cell line

<p>Abstract</p> <p>Background</p> <p>Agmatine is an endogenous polyamine formed by the decarboxylation of L-arginine. We investigated the protective effects of agmatine against hypoxia-induced apoptosis of immortalized rat retinal ganglion cells (RGC-5). RGC-5 cells were cultured in a closed hypoxic chamber (5% O₂) with or without agmatine. Cell viability was determined by lactate dehydrogenase (LDH) assay and apoptosis was examined by annexin V and caspase-3 assays. Expression and phosphorylation of mitogen-activated protein kinases (MAPKs; JNK, ERK p44/42, and p38) and nuclear factor-kappa B (NF-κB) were investigated by Western immunoblot analysis. The effects of agmatine were compared to those of brain-derived neurotrophic factor (BDNF), a well-known protective neurotrophin for retinal ganglion cells.</p> <p>Results</p> <p>After 48 hours of hypoxic culture, the LDH assay showed 52.3% cell loss, which was reduced to 25.6% and 30.1% when agmatine and BDNF were administered, respectively. This observed cell loss was due to apoptotic cell death, as established by annexin V and caspase-3 assays. Although total expression of MAPKs and NF-κB was not influenced by hypoxic injury, phosphorylation of these two proteins was increased. Agmatine reduced phosphorylation of JNK and NF-κB, while BDNF suppressed phosphorylation of ERK and p38.</p> <p>Conclusion</p> <p>Our results show that agmatine has neuroprotective effects against hypoxia-induced retinal ganglion cell damage in RGC-5 cells and that its effects may act through the JNK and NF-κB signaling pathways. Our data suggest that agmatine may lead to a novel therapeutic strategy to reduce retinal ganglion cell injury related to hypoxia.</p

Development, evaluation and application of 3D QSAR Pharmacophore model in the discovery of potential human renin inhibitors

<p>Abstract</p> <p>Background</p> <p>Renin has become an attractive target in controlling hypertension because of the high specificity towards its only substrate, angiotensinogen. The conversion of angiotensinogen to angiotensin I is the first and rate-limiting step of renin-angiotensin system and thus designing inhibitors to block this step is focused in this study.</p> <p>Methods</p> <p>Ligand-based quantitative pharmacophore modeling methodology was used in identifying the important molecular chemical features present in the set of already known active compounds and the missing features from the set of inactive compounds. A training set containing 18 compounds including active and inactive compounds with a substantial degree of diversity was used in developing the pharmacophore models. A test set containing 93 compounds, Fischer randomization, and leave-one-out methods were used in the validation of the pharmacophore model. Database screening was performed using the best pharmacophore model as a 3D structural query. Molecular docking and density functional theory calculations were used to select the hit compounds with strong molecular interactions and favorable electronic features.</p> <p>Results</p> <p>The best quantitative pharmacophore model selected was made of one hydrophobic, one hydrogen bond donor, and two hydrogen bond acceptor features with high a correlation value of 0.944. Upon validation using an external test set of 93 compounds, Fischer randomization, and leave-one-out methods, this model was used in database screening to identify chemical compounds containing the identified pharmacophoric features. Molecular docking and density functional theory studies have confirmed that the identified hits possess the essential binding characteristics and electronic properties of potent inhibitors.</p> <p>Conclusion</p> <p>A quantitative pharmacophore model of predictive ability was developed with essential molecular features of a potent renin inhibitor. Using this pharmacophore model, two potential inhibitory leads were identified to be used in designing novel and future renin inhibitors as antihypertensive drugs.</p

Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1

Cancer therapeutics: Extending a drug&apos;s reach A new drug that blocks heat shock proteins (HSPs), helper proteins that are co-opted by cancer cells to promote tumor growth, shows promise for cancer treatment. Several drugs have targeted HSPs, since cancer cells are known to hijack these helper proteins to shield themselves from destruction by the body. However, the drugs have had limited success. Hye-Kyung Park and Byoung Heon Kang at Ulsan National Institutes of Science and Technology in South Korea and coworkers noticed that the drugs were not absorbed into mitochondria, a key cellular compartment, and HSPs in this compartment were therefore not being blocked. They identified a new HSP inhibitor that can reach every cellular compartment and inhibit all HSPs. Testing in mice showed that this inhibitor effectively triggered death of tumor cells, and therefore shows promise for anti-cancer therapy. The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity

Prediction of Alzheimer's disease pathophysiology based on cortical thickness patterns

AbstractIntroductionRecent studies have shown that pathologically defined subtypes of Alzheimer's disease (AD) represent distinctive atrophy patterns and clinical characteristics. We investigated whether a cortical thickness–based clustering method can reflect such findings.MethodsA total of 77 AD subjects from the Alzheimer's Disease Neuroimaging Initiative 2 data set who underwent 3-T magnetic resonance imaging, [18F]-fluorodeoxyglucose-positron emission tomography (PET), [18F]-Florbetapir PET, and cerebrospinal fluid (CSF) tests were enrolled. After clustering based on cortical thickness, diverse imaging and biofluid biomarkers were compared between these groups.ResultsThree cortical thinning patterns were noted: medial temporal (MT; 19.5%), diffuse (55.8%), and parietal dominant (P; 24.7%) atrophy subtypes. The P subtype was the youngest and represented more glucose hypometabolism in the parietal and occipital cortices and marked amyloid-beta accumulation in most brain regions. The MT subtype revealed more glucose hypometabolism in the left hippocampus and bilateral frontal cortices and less performance in memory tests. CSF test results did not differ between the groups.DiscussionCortical thickness patterns can reflect pathophysiological and clinical changes in AD

Analysis of protein binding characteristics among Arabidopsis BBX protein family

Abstract Plants have evolved various mechanisms of adjusting their diurnal and seasonal growth and development in response to variations in day length and light quality. This plasticity is facilitated by intricate regulatory networksthat comprise transcription factors, whose expression is modulated by the activity of photoreceptors. In Arabidopsis, B-box (BBX) transcription factors, which contain one or two Zn-ligating B-box motifs in their N-termini, serve as key mediators of light signaling for photomorphogenesis, shade avoidance, and photoperiodic flowering. While multiple BBX proteins may function as a single regulatory unit, the binding networks that form among members of the BBX family have not been extensively investigated. Here, we have demonstrated that the homodimerization of two B-box motifs containing CONSTANS protein (BBX1), which regulates light signaling and is the most extensively characterized among all BBX proteins, requires at least three B-box motifs. Therefore, the number of B-box motifs may significantly influence heterodimerization among BBX family members. An interactome analysis of all 32 known B-box family members revealed that the binding affinity between group III and V proteins with only one B-box motif is relatively weaker than that observed among other group members. In fact, the group V proteins BBX26 and BBX27 rarely interact with other BBX members. Taken together, the results of this study emphasize the importance of the B-box motif in network formation among BBX proteins and provide insights into investigating the various signaling pathways mediated by these networks

Regulation of Leaf Maturation by Chromatin-Mediated Modulation of Cytokinin Responses

SummaryPlant shoots display indeterminate growth, while their evolutionary decedents, the leaves, are determinate. Determinate leaf growth is conditioned by the CIN-TCP transcription factors, which promote leaf maturation and are negatively regulated by miR319 in leaf primordia. Here we show that CIN-TCPs reduce leaf sensitivity to cytokinin (CK), a phytohormone implicated in inhibition of differentiation in the shoot. We identify the SWI/SNF chromatin remodeling ATPase BRAHMA (BRM) as a genetic mediator of CIN-TCP activities and CK responses. An interactome screen further revealed that SWI/SNF complex components including BRM preferentially interacted with basic-helix-loop-helix (bHLH) transcription factors and the bHLH-related CIN-TCPs. Indeed, TCP4 and BRM interacted in planta. Both TCP4 and BRM bound the promoter of an inhibitor of CK responses, ARR16, and induced its expression. Reconstituting ARR16 levels in leaves with reduced CIN-TCP activity restored normal growth. Thus, CIN-TCP and BRM together promote determinate leaf growth by stage-specific modification of CK responses

Observation of Young's Double-Slit Interference with the Three-Photon N00N State

Spatial interference of quantum mechanical particles exhibits a fundamental feature of quantum mechanics. A two-mode entangled state of N particles known as N00N state can give rise to non-classical interference. We report the first experimental observation of a three-photon N00N state exhibiting Young's double-slit type spatial quantum interference. Compared to a single-photon state, the three-photon entangled state generates interference fringes that are three times denser. Moreover, its interference visibility of $0.49 \pm 0.09$ is well above the limit of 0.1 for spatial super-resolution of classical origin. The demonstration of spatial quantum interference by a N00N state composed of more than two photons represents an important step towards applying quantum entanglement to technologies such as lithography and imaging

Successful Treatment of Stereotactic Body Radiation Therapy Combined with Transarterial Chemolipiodolization for Hepatocellular Carcinoma with Biliary Obstruction

Conventional radiation therapy (RT) is a widely recognized treatment for hepatocellular carcinoma (HCC). However, conventional RT plays only a limited role in HCC treatment because of its low efficacy and the low tolerance of the liver for this modality. Stereotactic body radiation therapy (SBRT) was recently developed and represents the most advanced radiation therapy technique currently available. It can deliver a high dose in a short time to well-defined hepatic tumors, with rapid dose fall-off gradients. We believe that SBRT with transarterial chemolipiodolization (TACL) may prove promising as a combined treatment modality for HCC due to its precision and relative safety. Here we present a case of successful treatment of advanced HCC with obstructive jaundice using this combined modality