Effects of transcranial ultrasound stimulation pulsed at 40 Hz on A beta plaques and brain rhythms in 5xFAD mice

Background: Alzheimer’s disease (AD) is the most common cause of dementia, and is characterized by amyloid-β (Aβ) plaques and tauopathy. Reducing Aβ has been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches. Impairment of gamma oscillations, which play an important role in perception and cognitive function, has been shown in mouse AD models and human patients. Recently, the therapeutic effect of gamma entrainment in AD mouse models has been reported. Given that ultrasound is an emerging neuromodulation modality, we investigated the effect of ultrasound stimulation pulsed at gamma frequency (40 Hz) in an AD mouse model. Methods: We implanted electroencephalogram (EEG) electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice (n = 12 and 6, respectively). Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily for two weeks, and the other six mice received sham treatment. Soluble and insoluble Aβ levels in the brain were measured by enzyme-linked immunosorbent assay. Spontaneous EEG gamma power was computed by wavelet analysis, and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling. Results: We found that the total Aβ42 levels, especially insoluble Aβ42, in the treatment group decreased in pre- and infra-limbic cortex (PIL) compared to that of the sham treatment group. A reduction in the number of Aβ plaques was also observed in the hippocampus. There was no increase in microbleeding in the transcranial ultrasound stimulation (tUS) group. In addition, the length and number of microglial processes decreased in PIL and hippocampus. Encelphalographic spontaneous gamma power was increased, and cross-frequency coupling was normalized, implying functional improvement after tUS stimulation. Conclusion: These results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβ load and improving brain connectivity. © 2021, The Author(s).1

Quantitative prediction of oral bioavailability of a lipophilic antineoplastic drug bexarotene administered in lipidic formulation using a combined in vitro lipolysis/microsomal metabolism approach

For performance assessment of the lipid-based drug delivery systems (LBDDS), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilisation processes. Much of previous research on in vitro lipolysis have mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values (Foral,predicted) of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2 1.6% and 36.2 2.6%, respectively, while the in vivo oral bioavailability (Foral) of BEX was tested as 31.5 13.4% and 31.4 5.2%, respectively. The Foral,predicted corresponded well with the Foral for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in [less than] 1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability

Epstein-Barr Virus, Beta-Catenin, and E-cadherin in Gastric Carcinomas

Activated beta-catenin is suggested to inhibit NF-kappaB activation, and we previously demonstrated that NF-kappaB nuclear positivity was more frequent in Epstein-Barr virus (EBV)-infected gastric carcinomas. It is controversial that beta-catenin and E-cadherin are prognostic markers in gastric carcinomas. To define a relationship between beta-catenin and EBV, and the prognostic value of beta-catenin and E-cadherin, we analyzed in situ hybridization for EBV-encoded small RNAs, beta-catenin, and E-cadherin immunohistochemistry, and clinicophatological features in 111 gastric carcinomas. EBV infection was detected in seven carcinomas (6.3%); none of seven showed beta-catenin nuclear accumulation, and five out of seven revealed beta-catenin membranous loss or cytoplamic expression. Eighty cases (72.1%) showed beta-catenin alteration; i.e., loss of membrane staining in 65 (58.6%), cytoplasmic expression in 35 (31.5%), and nuclear accumulation in 15 (13.5%). E-cadherin alteration was observed in 34 cases (30.6%) and correlated with beta-catenin alteration. On multivariate analysis, the combined immunoexpression group of beta-catenin nuclear accumulation/ E-cadherin alteration and the advanced TNM cancer stage group showed poor patient's survival (p<0.05). In conclusion, beta-catenin activation through nuclear accumulation hardly occurred in EBV-infected gastric carcinomas. The combined immunoexpression pattern of beta-catenin and E-cadherin can be used as a prognostic marker in gastric carcinomas

Reversibly controlled ternary polar states and ferroelectric bias promoted by boosting square???tensile???strain

Interaction between dipoles often emerges intriguing physical phenomena, such as exchange bias in the magnetic heterostructures and magnetoelectric effect in multiferroics, which lead to advances in multifunctional heterostructures. However, the defect-dipole tends to be considered the undesired to deteriorate the electronic functionality. Here, we report deterministic switching between the ferroelectric and the pinched states by exploiting a new substrate of cubic perovskite, BaZrO3, which boosts square-tensile-strain to BaTiO3 and promotes four-variants in-plane spontaneous polarization with oxygen vacancy creation. First-principles calculations propose a complex of an oxygen vacancy and two Ti3+ ions coins a charge-neutral defect-dipole. Cooperative control of the defect-dipole and the spontaneous polarization reveals ternary in-plane polar states characterized by biased/pinched hysteresis loops. Furthermore, we experimentally demonstrate that three electrically controlled polar-ordering states lead to switchable and non-volatile dielectric states for application of non-destructive electro-dielectric memory. This discovery opens a new route to develop functional materials via manipulating defect-dipoles and offers a novel platform to advance heteroepitaxy beyond the prevalent perovskite substrates

Molecular ecological methods to quantify biocontrol of Sclerotinia sclerotiorum by Trichoderma harzianum, and inhibitory effects of fungivorous nematodes on the biocontrol agent /by Tae Gwan Kim.

Fungi of the genus Trichoderma have received considerable attention as biocontrol agents against a wide range of plant pathogenic fungi. Sclerotinia sclerotiorum, a destructive plant pathogen with a wide host range, forms sclerotia that serve as over-wintering survival structures and the primary source of pathogen inoculum. Several Trichoderma spp. have shown the ability to mycoparasitize sclerotia and/or hyphae of S. sclerotiorum. Conventional methods to determine colonization of sclerotia by biocontrol fungi only indicate incidence of colonization, but cannot indicate the extent of colonization. Real-time quantitative PCR assays with specific primer/Tagman-probe sets for the genus Trichoderma, T. harzianum ThzID1-M3, and S. sclerotiorum were developed. The assays sensitively and precisely quantified biocontrol activity of total Trichoderma spp. and the introduced fungal agent T. harzianum ThzID1-M3 against sclerotia, and measured DNA of S. sclerotiorum in sclerotia. The introduced fungus T. harzianum ThzID1-M3 significantly increased the extent and incidence of colonization of sclerotia by total Trichoderma spp. in the soil. The extent of colonization of sclerotia by ThzID1-M3 was significantly correlated with hyphal density of the fungus in soil. The added ThzID1-M3 significantly stimulated population growth of fungus-feeding nematodes that fed on hyphae of the fungus in the soil. Predation by fungivorous nematodes decreased hyphal proliferation and establishment of ThzID1-M3, and reduced the extent of colonization of sclerotia. Fungivorous nematodes had little effect on ThzID1-M3 once it was inside sclerotia; thus, sclerotia provide spatial refuges for the biocontrol fungus from the feeding activity of nematodes. A mathematical model was developed to investigate the dynamics of interactions between fungivorous nematodes, the introduced biocontrol fungus, and S. sclerotiorum in soil. The model quantitatively predicted nematode population dynamics, biomass of ThzID1-M3, and extent of sclerotial colonization. Model predictions closely matched experimentally observed patterns. In conclusion, fungivorous nematodes may be a significant constraint on hyphal proliferation and biocontrol activity of fungal agents in natural soils.Thesis (Ph. D., Soil and Land Resources)--University of Idaho, May 2007

Effects of Cell Cycle Inhibitors on Cell Death of Human Cancer Cell Lines

Genotoxic agents are known to cause cell death mostly by apoptosis in susceptible cells and this action plays an important role in tumor regression after chemotherapy. It has been thought that the apoptotic process may be associated with cell cycle. In the present study, the effect of aphidicolin and nocodazole, reversible cell cycle inhibitors, on the apoptosis or cell death induced by actinomycin D was studied in 3 cell lines. HeLa, SiHa and NIH／3T3 cells were treated with actinomycin D（100 nM）alone or in combination with cell cycle inhibitors for 20 hours; or presynchronized cells were treated with actinomycin D for 4 hours and further incubated for 20 hours in fresh medium. The synergistic effect of IBMX（5 or 10 μM）on the apoptosis or cell death induced by actinomycin D was also studied. The results were as follows; Majority of HeLa cells showed apoptotic changes after actinomycin D treatment. Aphidicolin　or nocodazole blocked neither initiation nor progression of actinomycin D-induced apoptosis in HeLa cell. Aphidicolin pretreatment enhanced the actinomycin D-induced apoptosis of HeLa cells and cell death of SiHa cells and nocodazole pretreatment enhanced cell death of SiHa cells. IBMX moderately enhanced actinomycin D-induced cell death of NIH／3T3 and to less extent that of SiHa cells. These results show that neither initiation nor progression of actinomycin D-induced apoptosis or cell death can be blocked by cell cycle arrest, and that cAMP is partly responsible for actinomycin D-induced apoptosis in certain types of cells