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Kaempferol (KMP) is an important flavonoid in many fruits and vegetables. Preclinical studies on KMP have reported its pharmacological effects, including antimicrobial, antioxidant, anti‐inflammatory, antitumor, antidiabetic, myocardial protective, and neuroprotective effects. Additionally, some epidemiological studies have revealed a negative association between the consumption of KMP‐containing foods and the risk of developing several disorders, such as cancer and cardiovascular diseases. Thus, although a large body of literature has demonstrated the benefits of KMP supplementation, there are no reports of clinical trials evaluating the safety of KMP aglycone administration or KMP aglycone‐rich food consumption. The purpose of this study was to evaluate the safety of a high dose of KMP aglycone by administrating KMP aglycone‐containing supplements to healthy adults. This study had a randomized, double‐blind, placebo‐controlled design and a 4‐week duration. Participants were randomly allocated to the KMP (n = 24) or placebo (n = 24) group. For 4 weeks, the KMP group received a capsule containing 50‐mg KMP daily, a dose approximately five times higher than the estimated human dietary intake. The placebo group received a capsule containing cornstarch‐based powder daily. The general toxicity parameters were evaluated by examining the characteristics of the participants, hematological and blood biochemical parameters, general urinalysis, qualitative urine tests, and adverse events. No clinical changes were observed in anthropometric and blood pressure measurements or blood and urine parameters in the KMP group compared to those in the placebo group. Furthermore, no adverse events owing to KMP aglycone administration occurred. The study results revealed that the consumption of 50‐mg KMP aglycone daily for 4 weeks is safe in healthy adults. [ABSTRACT FROM AUTHOR]

This paper discusses the instability of suction bucket foundations that are growing in importance for bottom-mounted offshore wind turbines in association with wave-induced liquefaction of sand beds. The instability of suction bucket foundations should be understood in light of fluid–soil–structure interactions. In this study, we investigated the instability using centrifuge wave testing in a drum channel with viscous scaling to match the time-scaling laws for fluid wave propagation and consolidation of the soil. This paper highlights the effects of loosening and heaving of the sand inside the bucket during the installation process, which is one of the onsite problems, on the overall stability and clarifies the stability of the whole system in light of wave–soil–structure interactions. The experimental results showed that the instability of the suction bucket is ascribed to the occurrence and progress of liquefaction of the sand bed around the bucket. The experimental results further demonstrated the effect of embedment of the bucket in a dense layer. An embedded depth of the bucket tip equal to one-third of the bucket skirt length prevented instability of the foundation, despite the spread of liquefaction in the loose sand bed. Even when the dense sand inside and underneath the bucket was loosened during the installation process, the foundation bucket remained stable against severe wave actions. The present study examined and summarized the overall stability of suction bucket foundations in sand beds under severe wave loading and clarified the importance of the progress of liquefaction around the foundations. [ABSTRACT FROM AUTHOR]

ABSTRACT ( tBuC5H4)TiCl2(N=C tBu2) ( 1) exhibited remarkable catalytic activities (12,000-43,700 kg-polymer/mol-Ti·h) and efficient comonomer incorporation in ethylene copolymerization with tetracyclododecene (TCD) in the presence of methylaluminoxane, and the catalytic activity by 1 increased even at 60 °C. The resultant polymers are high molecular weight amorphous poly(ethylene- co-TCD)s ( Mn = 5.88-7.03 × 105) with uniform compositions (with high Tg values, 108-203 °C); a linear relationship between Tg values and the TCD contents was observed. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 2662-2667 [ABSTRACT FROM AUTHOR]

Summary Mutations in a number of chromatin modifiers are associated with human neurological disorders. KDM5C, a histone H3 lysine 4 di- and tri-methyl (H3K4me2/3)-specific demethylase, is frequently mutated in X-linked intellectual disability (XLID) patients. Here, we report that disruption of the mouse Kdm5c gene recapitulates adaptive and cognitive abnormalities observed in XLID, including impaired social behavior, memory deficits, and aggression. Kdm5c -knockout brains exhibit abnormal dendritic arborization, spine anomalies, and altered transcriptomes. In neurons, Kdm5c is recruited to promoters that harbor CpG islands decorated with high levels of H3K4me3, where it fine-tunes H3K4me3 levels. Kdm5c predominantly represses these genes, which include members of key pathways that regulate the development and function of neuronal circuitries. In summary, our mouse behavioral data strongly suggest that KDM5C mutations are causal to XLID. Furthermore, our findings suggest that loss of KDM5C function may impact gene expression in multiple regulatory pathways relevant to the clinical phenotypes. [ABSTRACT FROM AUTHOR]

This article presents the concept of an implantable cage system that can house and protect implanted biomedical sensing and therapeutic devices in the body. Cylinder-shaped cages made of porous polyvinyl alcohol (PVA) sheets with an 80-µm pore size and/or stainless steel meshes with 0.54-mm openings were implanted subcutaneously in the dorsal region of rats for 5 weeks. Analysis of the explanted cages showed the formation of fibrosis tissue around the cages. PVA cages had fibrotic tissue growing mostly along the outer surface of cages, while stainless steel cages had fibrotic tissue growing into the inside surface of the cage structure, due to the larger porosity of the stainless steel meshes. As the detection of target molecules with short time lags for biosensors and mass transport with low diffusion resistance into and out of certain therapeutic devices are critical for the success of such devices, we examined whether the fibrous tissue formed around the cages were permeable to molecules of our interest. For that purpose, bath diffusion and microfluidic chamber diffusion experiments using solutions containing the target molecules were performed. Diffusion of sodium, potassium and urea through the fibrosis tissue was confirmed, thus suggesting the potential of these cylindrical cages surrounded by fibrosis tissue to successfully encase implantable sensors and therapeutic apparatus. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B: 1180-1187, 2015. [ABSTRACT FROM AUTHOR]

Mutant ataxin-1 (Atxn1), which causes spinocerebellar ataxia type 1 ( SCA1), binds to and impairs the function of high-mobility group box 1 ( HMGB1), a crucial nuclear protein that regulates DNA architectural changes essential for DNA damage repair and transcription. In this study, we established that transgenic or virus vector-mediated complementation with HMGB1 ameliorates motor dysfunction and prolongs lifespan in mutant Atxn1 knock-in (Atxn1- KI) mice. We identified mitochondrial DNA damage repair by HMGB1 as a novel molecular basis for this effect, in addition to the mechanisms already associated with HMGB1 function, such as nuclear DNA damage repair and nuclear transcription. The dysfunction and the improvement of mitochondrial DNA damage repair functions are tightly associated with the exacerbation and rescue, respectively, of symptoms, supporting the involvement of mitochondrial DNA quality control by HMGB1 in SCA1 pathology. Moreover, we show that the rescue of Purkinje cell dendrites and dendritic spines by HMGB1 could be downstream effects. Although extracellular HMGB1 triggers inflammation mediated by Toll-like receptor and receptor for advanced glycation end products, upregulation of intracellular HMGB1 does not induce such side effects. Thus, viral delivery of HMGB1 is a candidate approach by which to modify the disease progression of SCA1 even after the onset. [ABSTRACT FROM AUTHOR]

ABSTRACT Nanoporous polyethersulfone (PES) membranes are widely used in dialysis systems due to their permeability and diffusion characteristics. However, PES membranes lack blood compatibility, which influences their permeability performance when employed in blood contact devices. Parylene film was deposited on a PES membrane surface and the membrane permeability and blood compatibility were investigated by long-term blood diffusion testing. After 28 days of testing, 90% of a bare PES membrane was covered with platelets, while the parylene film coated PES membrane had improved biocompatibility with a platelet coverage of only 20-30%. The permeability of the bare PES membrane significantly declined during the first 7 days of the blood diffusion and became stable after 8 days. In contrast, the permeability of the parylene film coated PES membrane exhibited more consistent performance during the entire test. Thus, parylene film coating on PES membrane has potential for application in hemodialysis systems. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2014, 131, 40024. [ABSTRACT FROM AUTHOR]

PQBP1 is a nuclear-cytoplasmic shuttling protein that is engaged in RNA metabolism and transcription. In mouse embryonic brain, our previous in situ hybridization study revealed that PQBP1 mRNA was dominantly expressed in the periventricular zone region where neural stem progenitor cells (NSPCs) are located. Because the expression patterns in NSPCs are related to the symptoms of intellectual disability and microcephaly in PQBP1 gene-mutated patients, we investigated the transcriptional regulation of PQBP1 by NSPC-specific transcription factors. We selected 132 genome sequences that matched the consensus sequence for the binding of Sox2 and POU transcription factors upstream and downstream of the mouse PQBP1 gene. We then screened the binding affinity of these sequences to Sox2-Pax6 or Sox2-Brn2 with gel mobility shift assays and found 18 genome sequences that interacted with the NSPC-specific transcription factors. Some of these sequences had cis-regulatory activities in Luciferase assays and in utero electroporation into NSPCs. Furthermore we found decreased levels of expression of PQBP1 protein in NSPCs of heterozygous Sox2-knockout mice in vivo by immunohistochemistry and western blot analysis. Collectively, these results indicated that Sox2 regulated the transcription of PQBP1 in NSPCs. [ABSTRACT FROM AUTHOR]

Protein phosphorylation is deeply involved in the pathological mechanism of various neurodegenerative disorders. However, in human pathological samples, phosphorylation can be modified during preservation by postmortem factors such as time and temperature. Postmortem changes may also differ among proteins. Unfortunately, there is no comprehensive database that could support the analysis of protein phosphorylation in human brain samples from the standpoint of postmortem changes. As a first step toward addressing the issue, we performed phosphoproteome analysis with brain tissue dissected from mouse bodies preserved under different conditions. Quantitative whole proteome mass analysis showed surprisingly diverse postmortem changes in phosphoproteins that were dependent on temperature, time and protein species. Twelve hrs postmortem was a critical time point for preservation at room temperature. At 4°C, after the body was cooled down, most phosphoproteins were stable for 72 hrs. At either temperature, increase greater than 2-fold was exceptional during this interval. We found several standard proteins by which we can calculate the postmortem time at room temperature. The information obtained in this study will be indispensable for evaluating experimental data with human as well as mouse brain samples. [ABSTRACT FROM AUTHOR]

Selective vulnerability of neurons is a critical feature of neurodegenerative diseases, but the underlying molecular mechanisms remain largely unknown. We here report that Omi/HtrA2, a mitochondrial protein regulating survival and apoptosis of cells, decreases selectively in striatal neurons that are most vulnerable to the Huntington’s disease (HD) pathology. In microarray analysis, Omi/HtrA2 was decreased under the expression of mutant huntingtin (htt) in striatal neurons but not in cortical or cerebellar neurons. Mutant ataxin-1 (Atx-1) did not affect Omi/HtrA2 in any type of neuron. Western blot analysis of primary neurons expressing mutant htt also confirmed the selective reduction of the Omi/HtrA2 protein. Immunohistochemistry with a mutant htt-transgenic mouse line and human HD brains confirmed reduction of Omi/HtrA2 in striatal neurons. Overexpression of Omi/HtrA2 by adenovirus vector reverted mutant htt-induced cell death in primary neurons. These results collectively suggest that the homeostatic but not proapoptotic function of Omi/HtrA2 is linked to selective vulnerability of striatal neurons in HD pathology. [ABSTRACT FROM AUTHOR]

To examine structural features of proline which are essential for the proline-directed phosphorylation by cdc2 kinase or cdk5, we prepared the peptide representing the cdc2 kinase phosphorylation site at Ser-55 in vimentin [Ser-Leu-Tyr-Ser-Ser-Ser55-Pro56-Gly-Gly58-Ala-Tyr-NH2], the peptide containing arginine in place of Gly-58, and their derivatives containing various N-methylamino acids or proline homologs in place of Pro-56, and tested them as substrates for the kinases. While substitution of the proline by proline homologs (L-pipecolic acid or L-azetidine-2-carboxylic acid) increased the Km value 2- to 4-fold at utmost, substitution by N-methylamino acids (sarcosine, L-N-methylalanine, L-N-methylvaline, or L-N-methylleucine) increased the Km value 7- to 40-fold for cdc2 kinase. For cdk5, these substitutions led to parallel effects on the Km value to those found for cdc2 kinase; cdk5 recognized the peptides with a proline specificity similar to that for cdc2 kinase. These results suggest that the pyrrolidine ring of proline is important for substrate recognition by cdc2 kinase or cdk5. Molecular dynamics and molecular mechanics simulations indicated that the pyrrolidine ring of proline is optimal to stabilize a β-turn at the phosphorylation site and that the Km values of the peptides for the enzymes might be related to the probability of the turn structure. The results obtained here also suggest that the pyrrolidine ring of proline is required to maintain a high Vmax value for cdc2 kinase or especially for cdk5. These will aid in designing specific substrates or inhibitors for cdc2 kinase or cdk5. [ABSTRACT FROM AUTHOR]

It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. Here we show that transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein (VCP)/p97 directly binds to multiple polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequence. Although normal and mutant polyglutamine proteins interact with TERA/VCP/p97, only mutant proteins affect dynamism of TERA/VCP/p97. Among multiple functions of TERA/VCP/p97, we reveal that functional defect of TERA/VCP/p97 in DNA double-stranded break repair is critical for the pathology of neurons in which TERA/VCP/p97 is located dominantly in the nucleus in vivo. Mutant polyglutamine proteins impair accumulation of TERA/VCP/p97 and interaction of related double-stranded break repair proteins, finally causing the increase of unrepaired double-stranded break. Consistently, the recovery of lifespan in polyglutamine disease fly models by TERA/VCP/p97 corresponds well to the improvement of double-stranded break in neurons. Taken together, our results provide a novel common pathomechanism in multiple polyglutamine diseases that is mediated by DNA repair function of TERA/VCP/p97. [ABSTRACT FROM AUTHOR]