Heterogeneity of Regional Brain Atrophy Patterns Associated with Distinct Progression Rates in Alzheimer’s Disease

We aimed to identify and characterize subtypes of Alzheimer’s disease (AD) exhibiting different patterns of regional brain atrophy on MRI using age- and gender-specific norms of regional brain volumes. AD subjects included in the Alzheimer''s Disease Neuroimaging Initiative study were classified into subtypes based on standardized values (Z-scores) of hippocampal and regional cortical volumes on MRI with reference to age- and gender-specific norms obtained from 222 cognitively normal (CN) subjects. Baseline and longitudinal changes of clinical characteristics over 2 years were compared across subtypes. Whole-brain-level gray matter (GM) atrophy pattern using voxel-based morphometry (VBM) and cerebrospinal fluid (CSF) biomarkers of the subtypes were also investigated. Of 163 AD subjects, 58.9% were classified as the “both impaired” subtype with the typical hippocampal and cortical atrophy pattern, whereas 41.1% were classified as the subtypes with atypical atrophy patterns: “hippocampal atrophy only” (19.0%), “cortical atrophy only” (11.7%), and “both spared” (10.4%). Voxel-based morphometric analysis demonstrated whole-brain-level differences in overall GM atrophy across the subtypes. These subtypes showed different progression rates over 2 years; and all subtypes had significantly lower CSF amyloid-β_1–42 levels compared to CN. In conclusion, we identified four AD subtypes exhibiting heterogeneous atrophy patterns on MRI with different progression rates after controlling the effects of aging and gender on atrophy with normative information. CSF biomarker analysis suggests the presence of Aβ neuropathology irrespective of subtypes. Such heterogeneity of MRI-based neuronal injury biomarker and related heterogeneous progression patterns should be considered in clinical trials and practice with AD patients.     

Profilin: At the crossroads of signal transduction and the actin cytoskeleton

Despite its small size, profilin is an amazingly diverse and sophisticated protein whose precise role in cells continues to elude the understanding of researchers 15 years after its discovery. Its ubiquity, abundance and necessity for life in more evolved organisms certainly speaks for its exterme importance in cell function. So far, three ligands for profilin have been well-characterized in vitro: actin monomers, membrane polyphosphoinositides and poly-L-proline. In the years following its discovery, profilin's role in vivo progressed from that of a simple actin-binding protein which inhibits actin polymerization, to one which, as an important regulator of the cytoskeleton, can even promote actin polymerization under the appropriate circumstances. In addition, interactions with components of the phosphatidylinositol cycle and the RAS pathway in yeast implicate profilin as an important link through which the actin cytoskeleton is able to communicate with major signaling pathways.     

Growth medium sterilization using decomposition of peracetic acid for more cost-efficient production of omega-3 fatty acids by Aurantiochytrium

Bioprocess and Biosystems Engineering - Aurantiochytrium can produce significant amounts of omega-3 fatty acids, specifically docosahexaenoic acid and docosapentaenoic acid. Use of a glucose-based...     

Dynamic properties of interaction between nucleic acid bases and models of amino acids

We have discussed the possible hydrogen bonding mode of adenine-uracil base dimers and peptide side chains, together with their characteristic effects on the stability of adenine-uracil base pairing in chloroform solution by using proton nuclear magnetic resonance methods, where acetamide and butyric acid were used as a model of residues of glutamine and glutamic acid, respectively, and were added to an adenine-uracil equimolar mixture. The stability of base pairing was affected significantly when the model compounds approached the adenine-uracil base pairs; that is, the Hoogsteen type was destroyed, while the Watson-Crick type was formed more favorably.     

Nrf2 Negatively Regulates Melanogenesis by Modulating PI3K/Akt Signaling

Nrf2 plays a role in protection of cells against oxidative stress and xenobiotic damage by regulating cytoprotective genes. In this study, we investigated the effect of Nrf2 on melanogenesis in normal human melanocytes (NHMCs). When NHMCs were transduced with a recombinant adenovirus expressing Nrf2, melanin synthesis was significantly decreased. Consistent with this result, overexpression of Nrf2 decreased the expression of tyrosinase and tyrosinase-related protein 1. The inhibitory effect of Nrf2 was reversed by overexpression of Keap1, an intracellular regulator of Nrf2. Interestingly, Nrf2 overexpression resulted in marked activation of PI3K/Akt signaling. Conversely, inhibition of PI3K activity by treatment with wortmannin reversed the depigmentary effects of Nrf2. Taken together, these results strongly suggest that Nrf2 negatively regulates melanogenesis by modulating the PI3K/Akt signaling pathway.     

Differential patterns of muscle modification in women with episodic and chronic tension-type headache revealed using surface electromyographic analysis

Tension-type headache (TTH) is a prototypical disorder in which muscular factors play a key role in the pathogenesis. This study was designed to understand muscular dysfunction in patients with episodic (ETTH) and chronic TTH (CTTH) using surface electromyography analysis (SEMG). Women with frequent ETTH (n = 14), CTTH (n = 14) and age-matched controls (n = 13) were recruited. SEMG data were recorded from the masseter, sternocleidomastoid, and upper trapezius muscles during maximum voluntary contraction and sustained voluntary isometric clenching, the neck flexion endurance test and shoulder elevation for 30 s. The root mean square (RMS) and median frequency (MDF) of the SEMG signal were measured throughout the test. The fatigue index, which is the MDF slope during sustained muscle contraction, decreased significantly faster in the ETTH and CTTH groups compared with that in the control (p < 0.05). The mean absolute RMS and relative percentage values at the initial and final period during sustained isometric contraction decreased significantly in the CTTH group (p < 0.05). Furthermore, headache clinical parameters (frequency and duration) were negatively correlated with the amplitude values (p < 0.05). A different muscle firing pattern or some muscle modifications in patients with CTTH may reflect reorganization of the motor-control strategy.     

Alteration of mitochondrial DNA sequence and copy number in nasal polyp tissue

This study was designed to investigate the possibility that mtDNA mutations might arise in inflammatory or chronically damaged nasal polyp tissue from 23 patients. Thirteen patients (57%) displayed nasal polyp tissue-specific mtDNA mutations in the hypervariable segment of the control region and cytochrome b gene, which were not found in the corresponding blood cells and/or adjacent normal tissue. Nasal polyp tissue-specific length heteroplasmic mutations were also detected in nucleotide position (np) 303–315 homopolymeric poly C track (39%), np 514–523 CA repeats (17%) and np 16184–16193 poly C track (30%). The average mtDNA copy number was about three times higher in nasal polyp tissue than in the corresponding peripheral blood cells and adjacent non-polyp tissues. The level of reactive oxygen species (ROS) was significantly higher in the nasal polyp tissues compared to those from the corresponding samples. High level of ROS in nasal polyp tissue may contribute to development of mtDNA mutations, which may play a crucial role in the vicious cycle of pathophysiology of nasal polyps.     

Cultured human skeletal muscle satellite cells exhibit characteristics of mesenchymal stem cells and play anti-inflammatory roles through prostaglandin E2 and hepatocyte growth factors

Skeletal muscle satellite cells (SkMSCs) play crucial roles in muscle fiber maintenance, repair, and remodeling; however, it remains unknown if these properties are preserved in cultured SkMSCs. In this study, we investigated the characteristics of cultured SkMSCs and their ability to regulate the activity of M1 macrophages. SkMSCs grew well with an average population doubling time of 26.26 ± 6.85 h during 10 passages (P). At P5, Pax7, MyoD, cluster of differentiation (CD)34, and CD56 were not expressed in SkMSCs, but the MSC markers CD73, CD105, and CD90 were expressed and the cells were differentiated into adipocytes and osteoblasts. When SkMSCs were cocultured with macrophages, interleukin (IL)-1β secretion was decreased, prostaglandin (PG)E2 was produced in coculture, and cyclooxygenase-2 protein was induced in an SkMSC-dependent manner. Hepatocyte growth factor (HGF) was highly secreted by monocultured SkMSCs; interferon-γ and lipopolysaccharide reduced its expression level. However, HGF expression recovered when SkMSCs and macrophages were cocultured. Although exogenous PGE2 upregulated macrophage pro-IL-1β expression, it suppressed the secretion of cleaved IL-1β. In contrast, HGF decreased active IL-1β secretion without affecting pro-IL-1β expression. Co-treatment of macrophages with HGF and PGE2 reduced pro-IL-1β expression level and active IL-1β secretion. Our results suggest that SkMSCs lose their satellite cell properties during serial passaging but acquire mesenchymal stem cell properties including the ability to exert an anti-inflammatory response for macrophages through PGE2 and HGF.     

Substrate Binding Mechanism of a Type I Extradiol Dioxygenase

A meta-cleavage pathway for the aerobic degradation of aromatic hydrocarbons is catalyzed by extradiol dioxygenases via a two-step mechanism: catechol substrate binding and dioxygen incorporation. The binding of substrate triggers the release of water, thereby opening a coordination site for molecular oxygen. The crystal structures of AkbC, a type I extradiol dioxygenase, and the enzyme substrate (3-methylcatechol) complex revealed the substrate binding process of extradiol dioxygenase. AkbC is composed of an N-domain and an active C-domain, which contains iron coordinated by a 2-His-1-carboxylate facial triad motif. The C-domain includes a β-hairpin structure and a C-terminal tail. In substrate-bound AkbC, 3-methylcatechol interacts with the iron via a single hydroxyl group, which represents an intermediate stage in the substrate binding process. Structure-based mutagenesis revealed that the C-terminal tail and β-hairpin form part of the substrate binding pocket that is responsible for substrate specificity by blocking substrate entry. Once a substrate enters the active site, these structural elements also play a role in the correct positioning of the substrate. Based on the results presented here, a putative substrate binding mechanism is proposed.