Modes of Retrotransposition of Long Interspersed Element-1 by Environmental Factors

Approximately 42% of the human genome is composed of endogenous retroelements, and the major retroelement component, long interspersed element-1 (L1), comprises ∼17% of the total genome. A single human cell has more than 5 × 105 copies of L1, 80∼100 copies of which are competent for retrotransposition (RTP). Notably, L1 can induce RTP of other retroelements, such as Alu and SVA, and is believed to function as a driving force of evolution. Although L1-RTP during early embryogenesis has been highlighted in the literature, recent observations revealed that L1-RTP also occurs in somatic cells. However, little is known about how environmental factors induce L1-RTP. Here, we summarize our current understanding of the mechanism of L1-RTP in somatic cells. We have focused on the mode of L1-RTP that is dependent on the basic helix–loop–helix/per–arnt–sim (bHLH/PAS) family of transcription factors. Along with the proposed function of bHLH/PAS proteins in environmental adaptation, we discuss the functional linking of L1-RTP and bHLH/PAS proteins for environmental adaptation and evolution

α-Tocopheryl succinate stabilizes the structure of tumor vessels by inhibiting angiopoietin-2 expression

α-Tocopheryl succinate (TS) is a tocopherol derivative and has multifaceted anti-cancer effects; TS not only causes cancer cell-specific apoptosis but also inhibits tumor angiogenesis. Although TS has the potential to be used as a well-tolerated anti-angiogenic drug, it is still unclear which step of the angiogenic process is inhibited by TS. Here, we show that TS inhibits the expression of angiopoietin (Ang)-2, which induces destabilization of vascular structure in the initial steps of the angiogenic process. In mouse melanoma cells, TS treatment decreased mRNA and extracellular protein levels of Ang-2; however, the mRNA level of Ang-1, which stabilizes the vascular structure, remained unchanged. Furthermore, aorta ring and Matrigel plug angiogenesis assays indicated that the conditioned medium from TS-treated cells (CM-TS) inhibited neovascularization and blood leakage from the existing blood vessels, respectively. Following immunohistochemical staining of the vessels treated with CM-TS, imaging studies showed that the vascular endothelial cells were highly packed with pericytes. In conclusion, we found that TS inhibits Ang-2 expression and, consequently, stabilizes the vascular structure during the initial step of tumor angiogenesis

Functional impairment of Tax-specific but not cytomegalovirus-specific CD8+ T lymphocytes in a minor population of asymptomatic human T-cell leukemia virus type 1-carriers

<p>Abstract</p> <p>Background</p> <p>Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a small percentage of infected individuals. ATL is often associated with general immune suppression and an impaired HTLV-1-specific T-cell response, an important host defense system. We previously found that a small fraction of asymptomatic HTLV-1-carriers (AC) already showed impaired T-cell responses against the major target antigen, Tax. However, it is unclear whether the impaired HTLV-1 Tax-specific T-cell response in these individuals is an HTLV-1-specific phenomenon, or merely reflects general immune suppression. In this study, in order to characterize the impaired HTLV-1-specific T-cell response, we investigated the function of Tax-specific CD8⁺T-cells in various clinical status of HTLV-1 infection.</p> <p>Results</p> <p>By using tetramers consisting of HLA-A*0201, -A*2402, or -A*1101, and corresponding Tax epitope peptides, we detected Tax-specific CD8⁺T-cells in the peripheral blood from 87.0% of ACs (n = 20/23) and 100% of HAM/TSP patients (n = 18/18) tested. We also detected Tax-specific CD8⁺T-cells in 38.1% of chronic type ATL (cATL) patients (n = 8/21), although its frequencies in peripheral blood CD8⁺T cells were significantly lower than those of ACs or HAM/TSP patients. Tax-specific CD8⁺T-cells detected in HAM/TSP patients proliferated well in culture and produced IFN-γ when stimulated with Tax peptides. However, such functions were severely impaired in the Tax-specific CD8⁺T-cells detected in cATL patients. In ACs, the responses of Tax-specific CD8⁺T-cells were retained in most cases. However, we found one AC sample whose Tax-specific CD8⁺T-cells hardly produced IFN-γ, and failed to proliferate and express activation (CD69) and degranulation (CD107a) markers in response to Tax peptide. Importantly, the same AC sample contained cytomegalovirus (CMV) pp65-specific CD8⁺T-cells that possessed functions upon CMV pp65 peptide stimulation. We further examined additional samples of two smoldering type ATL patients and found that they also showed dysfunctions of Tax-specific but not CMV-specific CD8⁺T-cells.</p> <p>Conclusions</p> <p>These findings indicated that Tax-specific CD8⁺T-cells were scarce and dysfunctional not only in ATL patients but also in a limited AC population, and that the dysfunction was selective for HTLV-1-specifc CD8⁺T-cells in early stages.</p

VSOP/Hv1 proton channels sustain calcium entry, neutrophil migration, and superoxide production by limiting cell depolarization and acidification

Neutrophils kill microbes with reactive oxygen species generated by the NADPH oxidase, an enzyme which moves electrons across membranes. Voltage-gated proton channels (voltage-sensing domain only protein [VSOP]/Hv1) are required for high-level superoxide production by phagocytes, but the mechanism of this effect is not established. We show that neutrophils from VSOP/Hv1−/− mice lack proton currents but have normal electron currents, indicating that these cells have a fully functional oxidase that cannot conduct protons. VSOP/Hv1−/− neutrophils had a more acidic cytosol, were more depolarized, and produced less superoxide and hydrogen peroxide than neutrophils from wild-type mice. Hydrogen peroxide production was rescued by providing an artificial conductance with gramicidin. Loss of VSOP/Hv1 also aborted calcium responses to chemoattractants, increased neutrophil spreading, and decreased neutrophil migration. The migration defect was restored by the addition of a calcium ionophore. Our findings indicate that proton channels extrude the acid and compensate the charge generated by the oxidase, thereby sustaining calcium entry signals that control the adhesion and motility of neutrophils. Loss of proton channels thus aborts superoxide production and causes a severe signaling defect in neutrophils

トウカ ニオケル ラジオハ ショウシャク リョウホウ オ モチイタ カンシュヨウ チリョウ : preliminary report

Radiofrequency ablation (RFA) has recently been used to treat liver tumors. RFA is a safe and effective treatment of liver tumors and requires fewer treatment sessions. Between June 2000 and April 2003, hepatocellular carcinoma (77 patients with 106 lesions) and metastatic liver tumors (21 patients with 30 lesions) and cholangiocellular carcinoma (1 patient with 1 lesion) were treated with RFA. The liver tumors were treated percutaneously or during surgery under ultrasound guidance using a LeVeen needle (55 lesions) and cool tip RF needle (82 lesions). To evaluate the response, contrast-enhanced CT scans or MRI were obtained. Most patients experienced moderate pain during RFA procedure, especially when the tumor was superficially located. Complete necrosis was achieved in all HCCs with RFA.This result was obtained with an average of 1.12 sessions per HCC. With a median follow-up of 15 months, HCCs have recurred in 6 of 90 treated lesions (6.7%), and metastatic liver tumors have recurred in 2 of 17 treated lesions (11.8%). We are initiating a combining RFA of hepatic malignancies with regional or systemic chemotherapy will reduce hepatic and extrahepatic recurrence rates and enhance long-term survival rates. We believe that RFA will be effective treatment to achieve in patients with unresectable meastatic liver tumors

Energy internet forums as acceleration phase transition intermediaries

Citizen users play important roles in the acceleration phase of energy transitions, during which small-scale renewable energy technologies (S-RET) become taken up more widely. From users’ perspective, turning the early, and typically slow, proliferation into a more rapid and widespread diffusion requires not only the adoption of S-RET but also the adaptation, adjustment, intermediation and advocacy of S-RETs. These activities become necessary because S-RET face a variety of market, institutional, cultural and environmental conditions in dif- ferent countries. New Internet-based energy communities have emerged and acted as key user-side transition intermediaries that catalyse these activities by qualifying market information, articulating demand and helping citizen users to reconfigure the standard technology to meet the specificities of different local contexts. In doing so, Internet communities foster an appreciatively critical discourse on technology. Such user intermediation is important in expanding the markets for S-RET beyond that of enthusiasts, environmentalists and other early adopters, to the early majority of adopters who demand more exposure, clearer information and less uncertainty about new technology options

Experimental Mycobacterium bovis infection in three white rhinoceroses (Ceratotherium simum):Susceptibility, clinical and anatomical pathology

Tuberculosis caused by Mycobacterium bovis is endemic in the African buffalo (Syncerus caffer) population in the Kruger National Park and other conservation areas in South Africa. The disease has been diagnosed in a total of 21 free ranging or semi-free ranging wildlife species in the country with highly variable presentations in terms of clinical signs as well as severity and distribution of tuberculous lesions. Most species are spillover or dead-end hosts without significant role in the epidemiology of the disease. White rhinoceroses (Ceratotherium simum) are translocated from the Kruger National Park in substantial numbers every year and a clear understanding of their risk to manifest overt tuberculosis disease and to serve as source of infection to other species is required. We report the findings of experimental infection of three white rhinoceroses with a moderately low dose of a virulent field isolate of Mycobacterium bovis. None of the animals developed clinical signs or disseminated disease. The susceptibility of the white rhinoceros to bovine tuberculosis was confirmed by successful experimental infection based on the ante mortem isolation of M. bovis from the respiratory tract of one rhinoceros, the presence of acid-fast organisms and necrotizing granulomatous lesions in the tracheobronchial lymph nodes and the detection of M. bovis genetic material by PCR in the lungs of two animals

Involvement of the Precuneus/Posterior Cingulate Cortex Is Significant for the Development of Alzheimer’s Disease: A PET (THK5351, PiB) and Resting fMRI Study

Background: Imaging studies in Alzheimer’s disease (AD) have yet to answer the underlying questions concerning the relationship among tau retention, neuroinflammation, network disruption and cognitive decline. We compared the spatial retention patterns of 18F-THK5351 and resting state network (RSN) disruption in patients with early AD and healthy controls.Methods: We enrolled 23 11C-Pittsburgh compound B (PiB)-positive patients with early AD and 24 11C-PiB-negative participants as healthy controls. All participants underwent resting state functional MRI and 18F-THK5351 PET scans. We used scaled subprofile modeling/principal component analysis (SSM/PCA) to reduce the complexity of multivariate data and to identify patterns that exhibited the largest statistical effects (variances) in THK5351 concentration in AD and healthy controls.Findings: SSM/PCA identified a significant spatial THK5351 pattern composed by mainly three clusters including precuneus/posterior cingulate cortex (PCC), right and left dorsolateral prefrontal cortex (DLPFC) which accounted for 23.6% of the total subject voxel variance of the data and had 82.6% sensitivity and 79.1% specificity in discriminating AD from healthy controls. There was a significant relationship between the intensity of the 18F-THK5351 covariation pattern and cognitive scores in AD. The spatial patterns of 18F-THK5351 uptake showed significant similarity with intrinsic functional connectivity, especially in the PCC network. Seed-based connectivity analysis from the PCC showed significant decrease in connectivity over widespread brain regions in AD patients. An evaluation of an autopsied AD patient with Braak V showed that 18F-THK5351 retention corresponded to tau deposition, monoamine oxidase-B (MAO-B) and astrogliosis in the precuneus/PCC.Interpretation: We identified an AD-specific spatial pattern of 18F-THK5351 retention in the precuneus/PCC, an important connectivity hub region in the brain. Disruption of the functional connections of this important network hub may play an important role in developing dementia in AD