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Charge acceleration during an intense light field application to solids attracts much attention as elementary processes in high-harmonic generation and photoelectron emission. For manipulating such attosecond dynamics of charge, carrier-envelope-phase (CEP: relative phase between carrier oscillation of light field and its envelope function) control has been employed in insulators, nanometal and graphene. In superconducting materials, collective control of charge motion is expected because of its strongly coherent nature of quasi-particles. Here we report that, in a layered organic superconductor, a non-linear petahertz current driven by a single-cycle 6 femtosecond near infrared field shows up as second harmonic generation (SHG), which is in contrast to the common belief that even harmonics are forbidden in the centrosymmetric system. The SHG represents a CEP sensitive nature and an enhancement near the superconducting temperature. The result and its quantum many-body analysis indicate that a polarized current is induced by non-linear acceleration of charge, which is amplified by superconducting fluctuations. This will lead to petahertz functions of superconductors and of strongly correlated systems. Here the authors show second harmonic generation (SHG) from a centrosymmetric organic superconductor κ-(BEDT-TTF) 2 Cu[N(CN) 2 ]Br. They find unusual temperature dependence and CEP-sensitive nature of the SHG which are explained in terms of nonlinear current.

Human papillomaviruses (HPV) are double-stranded DNA viruses, which selectively infect keratinocytes in stratified epithelia. After an initial infection, many patients clear HPV. In some patients, however, HPV persist, and dysfunctional innate immune responses to HPV infection could be involved in the ineffective clearing of these viruses. In this study, the mechanisms of HPV-induced immune responses in keratinocytes were investigated. Binding of viral DNA leads to AIM2 inflammasome activation and IL-1β release, while IFI16 activation results in IFN-β release. Using immunohistochemistry, AIM2 and IFI16—two recently identified sensors for cytosolic DNA—were also detected in HPV positive skin lesions. CISH stainings further confirmed the presence of cytosolic HPV16 DNA in biopsy samples. Moreover, active IL-1β and cleaved caspase-1 were detected in HPV infected skin, suggesting inflammasome activation by viral DNA. In subsequent functional studies, HPV16 DNA triggered IL-1β and IL-18 release via the AIM2 inflammasome in normal human keratinocytes. Although HPV DNA did not induce IFN-β in keratinocytes, IFN-β secretion was observed when AIM2 was blocked. Meanwhile, blocking of IFI16 increased HPV16 DNA-induced IL-1β, but not IL-18, secretion. These findings suggest crosstalk between IFI16 and AIM2 in the immune response to HPV DNA. In sum, novel aspects concerning HPV-induced innate immune responses were identified. Eventually, understanding the mechanisms of HPV-induced inflammasome activation could lead to the development of novel strategies for the prevention and treatment of HPV infections.

Application of an intense light field to solids produces enormous and ultrafast nonlinear phenomena such as high-harmonic generation1,2 and attosecond charge dynamics3,4. These are distinct from conventional photonics. However, the main targets for investigation have been limited to insulators and semiconductors, although theoretical approaches have also been developed for correlated metals and superconductors5. Here, in a layered organic superconductor, a nonlinear charge oscillation driven by a nearly single-cycle strong electric field of >10 MV cm−1 is observed as a stimulated emission. The charge oscillation is different from a linear response and ascribed to a polar charge oscillation with a period of ∼6 fs. This nonlinear polar charge oscillation is enhanced by critical fluctuations near a superconducting transition temperature and a critical end-point of first-order Mott transitions. Its observation on an ultrafast timescale of ∼10 fs clarifies that Coulomb repulsion plays an essential role in the superconductivity of organic superconductors.

Objective: This study aimed to examine the applicability of ultrasound muscle thickness (MT) measurements for predicting whole body fat-free mass (FFM) in elderly individuals. Design and setting: Crosssectional study of 77 healthy elderly individuals. Methods: MTs at nine sites of the body and FFM were determined using B-mode ultrasound and dual-energy x-ray absorptiometry (DXA), respectively, in 44 women and 33 men aged 52 to 78 yrs. Stepwise multiple regression analysis produced two equations for predicting DXA-based FFM with sex (dummy: woman = 0 and man = 1) and either MTs at the anterior and posterior of thigh and lower leg (Eq1) or the product of MT and limb length (MT×LL) at thigh anterior and posterior, lower leg posterior, and upper arm anterior (Eq2) as independent variables. Results: The R2 and SEE for each of the two equations were 0.929 and 2.5 kg for Eq1 and 0.955 and 2.0 kg for Eq2. The estimated FFM from each of Eq1 (44.4 ± 8.9 kg) and Eq2 (44.4 ± 9.0 kg) did not significantly differ from that of the DXA-based FFM (44.4 ± 9.2 kg), without systematic error. However, the absolute value of the difference between the DXA-based and estimated FFM was significantly greater with Eq1 (2.0 ± 1.5 kg) than with Eq2 (1.5 ± 1.3 kg). Conclusion: The current results indicate that ultrasound MT measurement is useful to predict FFM in the elderly, and its accuracy is improved by using the product of MT and limb length as an independent variable.

Background: Although T-cell immunity is thought to be involved in the prognosis of epithelial ovarian cancer (EOC) patients, immunosuppressive conditions hamper antitumour immune responses. Thus, their mechanisms and overcoming strategies need to be investigated. Methods: The role of NF- κ B in human EOC cells and macrophages was evaluated by in vitro production of immunosuppressive IL-6 and IL-8 by EOC cells and in vivo analysis of immune responses in nude mice implanted with human EOC cells using an NF- κ B inhibitor DHMEQ. Results: In EOC patients, increased plasma IL-6, IL-8, and arginase were observed. The NF- κ B inhibitor DHMEQ inhibited the production of IL-6 and IL-8 by EOC cell lines. Immunosuppression of human DCs and macrophages by culture supernatant of EOC cells was reversed with the pretreatment of DHMEQ. Administration of DHMEQ to nude mice implanted with human EOC resulted in the restoration of T-cell stimulatory activity of murine DCs along with the reduction of tumour accumulation and arginase expression of MDSCs. Nuclear factor- κ B inhibition in tumour-bearing mice also enhanced antitumour effects of transferred murine naive T cells. Conclusions: NF- κ B is involved in the immunosuppression induced by human EOC, and its inhibitor may restore antitumour immune responses, indicating that NF- κ B is an attractive target for EOC treatment.

Objective To elucidate the long-term effects of liver transplantation (LT) on familial amyloid polyneuropathy (FAP). Methods We investigated clinicopathological and biochemical characteristics of systemic tissues in four autopsied cases of FAP patients surviving more than 10 years after LT and seven autopsied cases without LT. For analysing the truncated form of transthyretin (TTR) in amyloid, we also employed specimens from additional 18 FAP patients. Results Several tissue sites such as the heart, tongue and spinal cord had moderate-to-severe amyloid deposits but other tissues showed no or mild amyloid deposition. Those findings seemed similar to those observed in senile systemic amyloidosis (SSA), a sporadic amyloidosis caused by wild-type (WT) TTR. Also, amyloid deposits in systemic tissue sites except for the spinal cord in patients after LT derived mostly from WT TTR secreted from the normal liver grafts. In addition, in non-transplantation patients, proportions of WT TTR seemed to be relatively high in those tissue sites in which patients after LT had severe amyloid deposition, which suggests that WT TTR tends to form amyloid in those tissue sites. Finally, although the truncation of TTR in amyloid deposits did not depend on undergoing LT, we elucidated the truncation of TTR occurred predominantly in patients from non-endemic areas of Japan, where FAP amyloidogenic TTR V30M patients are late onset and low penetrance, compared with patients from an endemic area of Japan. Conclusions FAP may shift to systemic WT TTR amyloid formation after LT, which seems to be similar to the process in SSA. The truncation of TTR in amyloid deposits may depend on some genetic or environmental factors other than undergoing LT.

In the present study we investigated in vivo length changes in the fascicles and tendon of the human gastrocnemius medialis (GM) muscle during walking. The experimental protocol involved real-time ultrasound scanning of the GM muscle, recording of the electrical activity of the muscle, measurement of knee- and ankle-joint rotations, and measurement of ground reaction forces in six men during walking at 3 km h-1 on a treadmill. Fascicular lengths were measured from the sonographs recorded. Musculotendon complex length changes were estimated from anatomical and joint kinematic data. Tendon length changes were obtained combining the musculotendon complex and fascicular length-change data. The fascicles followed a different length-change pattern from those of the musculotendon complex and tendon throughout the step cycle. Two important features emerged: (i) the muscle contracted near-isometrically in the stance phase, with the fascicles operating at ca. 50 mm; and (ii) the tendon stretched by ca. 7 mm during single support, and recoiled in push-off. The behaviour of the muscle in our experiment indicates consumption of minimal metabolic energy for eliciting the contractile forces required to support and displace the body. On the other hand, the spring-like behaviour of the tendon indicates storage and release of elastic-strain energy. Either of the two mechanisms would favour locomotor economy.

This study aimed to investigate the accuracy of estimating the volume of limb muscles (MV) using ultrasonographic muscle thickness (MT) measurements. The MT and MV of each of elbow flexors and extensors, knee extensors and ankle plantar flexors were determined from a single ultrasonographic image and multiple magnetic resonance imaging (MRI) scans, respectively, in 27 healthy men (23-40 years of age) who were allocated to validation ( n=14) and cross-validation groups ( n=13). In the validation group, simple and multiple regression equations using MT and a set of MT and limb length, respectively, as independent variables were derived to estimate the MV measured by MRI. However, only the multiple regression equations were cross-validated, and so the prediction equations with r(2) of 0.787-0.884 and the standard error of estimate of 22.1 cm(3) (7.3%) for the elbow flexors to 198.5 cm(3) (11.1%) for the knee extensors were developed using the pooled data. This approach did not induce significant systematic error in any muscle group, with no significant difference in the accuracy of estimating MV between muscle groups. In the multiple regression equations, the relative contribution of MT for predicting MV varied from 41.9% for the knee extensors to 70.4% for the elbow flexors. Thus, ultrasonographic MT measurement was a good predictor of MV when combined with limb length. For predicting MV, however, the unsuitability of a simple equation using MT only and the difference between muscle groups in the relative contribution of MT in multiple regression equations indicated a need for further research on the limb site selected and muscle analyzed for MT measurement.

A wide range of evidence shows that acetylcholinesterase (AChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The successful development of these compounds was based on a well-accepted theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission. The earliest known AChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of Alzheimer's patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action with manageable adverse effects. Currently, there are about 19 new Alzheimer's drugs in various phases of clinical development.

Asians seem to have less skeletal muscle mass (SMM) than other ethnic groups, but it is not clear whether relative SMM, i.e., SMM / height square or SMM to fat-free mass (FFM) ratio, differs among different ethnic groups at the same level of body mass index (BMI). To compare the SMM to fat-free mass (FFM) ratio as well as anthropometric variables and body composition among 3 ethnic groups. Three hundred thirty-nine Japanese, 343 Brazilian, and 183 German men and women were recruited for this cross-sectional study. Muscle thickness (MTH) and subcutaneous fat thickness (FTH) were measured by ultrasound at nine sites on the anterior and posterior aspects of the body. FTH was used to estimate the body density, from which fat mass and fat-free mass (FFM) was calculated by using Brozek equation. Total SMM was estimated from ultrasound-derived prediction equations. Percentage body fat was similar among the ethnic groups in men, while Brazilians were higher than Japanese in women. In German men and women, absolute SMM and FFM were higher than in their Japanese and Brazilians counterparts. SMM index and SMM:FFM ratios were similar among the ethnic groups in women, excluding SMM:FFM ratio in Brazilian. In men, however, these relative values (SMM index and SMM:FFM ratio) were still higher in Germans. After adjusting for age and BMI, the SMM index and SMM:FFM ratios were lower in Brazilian men and women compared with the other two ethnic groups, while the SMM index and SMM:FFM ratios were similar in Japanese and German men and women, excluding SMM:FFM ratio in women. Our results suggest that relative SMM is not lower in Asian populations compared with European populations after adjusted by age and BMI.