Utilizing [18F]-AV-1451 tau positron emission tomography (PET) as an Alzheimer disease (AD) biomarker will require identification of brain regions that are most important in detecting elevated tau pathology in preclinical AD. Here, we utilized an unsupervised learning, data-driven approach to identify brain regions whose tau PET is most informative in discriminating low and high levels of [18F]-AV-1451 binding. 84 cognitively normal participants who had undergone AV-1451 PET imaging were used in a sparse k-means clustering with resampling analysis to identify the regions most informative in dividing a cognitively normal population into high tau and low tau groups. The highest-weighted FreeSurfer regions of interest (ROIs) separating these groups were the entorhinal cortex, amygdala, lateral occipital cortex, and inferior temporal cortex, and an average SUVR in these four ROIs was used as a summary metric for AV-1451 uptake. We propose an AV-1451 SUVR cut-off of 1.25 to define high tau as described by imaging. This spatial distribution of tau PET is a more widespread pattern than that predicted by pathological staging schemes. Our data-derived metric was validated first in this cognitively normal cohort by correlating with early measures of cognitive dysfunction, and with disease progression as measured by β-amyloid PET imaging. We additionally validated this summary metric in a cohort of 13 Alzheimer disease patients, and showed that this measure correlates with cognitive dysfunction and β-amyloid PET imaging in a diseased population.

Viral infections are responsible for many illnesses, and recent outbreaks have raised public health concerns. Despite the availability of many antiviral drugs, they are often unsuccessful due to the generation of viral mutants and less effective against their target virus. Identifying novel antiviral drugs is therefore of critical importance and natural products are an excellent source for such discoveries. Coumarin is one such natural compound that is a potential drug candidate owing to its properties of stability, solubility, and low toxicity. There are numerous evidences showing its inhibitory role against infection of various viruses such as HIV, Influenza, Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16). The mechanisms involve either inhibition of proteins essential for viral entry, replication and infection or regulation of cellular pathways such as Akt-Mtor (mammalian target of rapamycin), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), and anti-oxidative pathway including NrF-2 (The nuclear factor erythroid 2 (NFE2)-related factor 2). This review summarizes the present state of understanding with a focus on coumarin's antiviral effect and their possible molecular mechanisms against Influenza virus, HIV, Hepatitis virus, Dengue virus and Chikungunya virus.

The long non-coding RNAs (lncRNAs) are the crucial regulators of human chronic diseases. Therefore, approaches such as antisense oligonucleotides, RNAi technology, and small molecule inhibitors have been used for the therapeutic targeting of lncRNAs. During the last decade, phytochemicals and nutraceuticals have been explored for their potential against lncRNAs. The common lncRNAs known to be modulated by phytochemicals include ROR, PVT1, HOTAIR, MALAT1, H19, MEG3, PCAT29, PANDAR, NEAT1, and GAS5. The phytochemicals such as curcumin, resveratrol, sulforaphane, berberine, EGCG, and gambogic acid have been examined against lncRNAs. In some cases, formulation of phytochemicals has also been used. The disease models where phytochemicals have been demonstrated to modulate lncRNAs expression include cancer, rheumatoid arthritis, osteoarthritis, and nonalcoholic fatty liver disease. The regulation of lncRNAs by phytochemicals can affect multi-steps of tumor development. When administered in combination with the conventional drugs, phytochemicals can also produce synergistic effects on lncRNAs leading to the sensitization of cancer cells. Phytochemicals target lncRNAs either directly or indirectly by affecting a wide variety of upstream molecules. However, the potential of phytochemicals against lncRNAs has been demonstrated mostly by preclinical studies in cancer models. How the modulation of lncRNAs by phytochemicals produce therapeutic effects on cancer and other chronic diseases is discussed in this review.

While prior work reliably demonstrates that the APOE ɛ4 allele has deleterious group level effects on Alzheimer disease pathology, the homogeneity of its influence across the lifespan and spatially in the brain remains unknown. Further it is unclear what combinations of factors at an individual level lead to observed group level effects of APOE genotype. To evaluate the impact of the APOE genotype on disease trajectories, we examined longitudinal MRI and PET imaging in a cohort of 497 cognitively normal middle and older aged participants. A whole-brain regional approach was used to evaluate the spatial effects of genotype on longitudinal change of amyloid-β pathology and cortical atrophy. Carriers of the ɛ4 allele had increased longitudinal accumulation of amyloid-β pathology diffusely through the cortex, but the emergence of this effect across the lifespan differed greatly by region (e.g. age 49 in precuneus, but 65 in the visual cortex) with the detrimental influence already being evident in some regions in middle age. This increased group level effect on accumulation was due to a greater proportion of ɛ4 carriers developing amyloid-β pathology, on average doing so at an earlier age, and having faster amyloid-β accumulation even after accounting for baseline amyloid-β levels. APOE ɛ4 carriers displayed faster rates of structural loss in primarily constrained to the medial temporal lobe structures at around 50 years, although this increase was modest and proportional to the elevated disease severity in APOE ɛ4 carriers. This work indicates that influence of the APOE gene on pathology can be detected starting in middle age.

The effects of arsenite treatment on generation of reactive oxygen species, induction of oxidative stress, response of antioxidative system, and synthesis of phytochelatins were investigated in two indica rice (Oryza sativa L.) cvs. Malviya-36 and Pant-12 grown in sand cultures for a period of 5-20 days. Arsenite (As(2)O(3); 25 and 50 μM) treatment resulted in increased formation of superoxide anion (O (2) (.-) ), elevated levels of H(2)O(2) and thiobarbituric acid reactive substances, showing enhanced lipid peroxidation. An enhanced level of ascorbate (AA) and glutathione (GSH) was observed irrespective of the variation in the level of dehydroascorbate (DHA) and oxidized glutathione (GSSG) which in turn influenced redox ratios AA/DHA and GSH/GSSG. With progressive arsenite treatment, synthesis of total acid soluble thiols and phytochelatins (PC) increased in the seedlings. Among antioxidative enzymes, the activities of superoxide dismutase (EC 1.15.1.1), catalase (EC 1.11.1.6), total ascorbate peroxidase (APX, EC 1.11.1.11), chloroplastic ascorbate peroxidase, guaiacol peroxidase (EC 1.11.1.7), monodehydroascorbate reductase (EC 1.6.5.4), and glutathione reductase (EC 1.6.4.2) increased in arsenite treated seedlings, while dehyroascorbate reductase (EC 1.8.5.1) activity declined initially during 5-10 days and increased thereafter. Results suggest that arsenite treatment causes oxidative stress in rice seedlings, increases the levels of many enzymatic and non-enzymatic antioxidants, and induces synthesis of thiols and PCs, which may serve as important components in mitigating arsenite-induced oxidative damage.