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Purpose To determine the effect of foveal vitreous cortex removal during pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD) on the prevention of postoperative epiretinal membrane (ERM) development without internal limiting membrane (ILM) peeling. Design Case-control study. Participants A total of 105 consecutive eyes of 105 patients who underwent primary PPV for RRD between September 2018 and August 2019 and were followed for at least 6 months. Methods The presence of foveal vitreous cortex during PPV was determined by examining the images obtained by a widefield viewing system in 52 eyes (WF group) operated in the first half of the study period and obtained by a high-magnification floating lens in 53 eyes (FL group) operated in the latter half of the study period. Triamcinolone acetonide was used to make the vitreous cortex more visible during PPV. The foveal vitreous cortex was removed if detected by forceps with a high-magnification floating lens without ILM peeling or use of dye staining. The presence of postoperative ERM was examined by using OCT. Main Outcome Measures The rate of detected and removed foveal vitreous cortex during PPV and the incidence of postoperative ERM of each group. Results The rate of detected and removed foveal vitreous cortex during PPV was significantly higher in the FL group than in the WF group (41.5% vs. 15.4%, P = 0.004). The incidence of postoperative ERM was significantly lower in the FL group than in the WF group (1.9% vs. 13.5%, P = 0.03). None of the eyes required additional surgery for the postoperative ERM during the follow-up period. The retinal reattachment rate was not significantly different (98.1% vs. 100%, P = 0.99), and the final retinal attachment rate was 100% in both groups. A dissociated optic nerve fiber layer appearance and a temporal macular thinning were not detected postoperatively in any of the eyes with removal of the foveal vitreous cortex during PPV. Conclusions The detection and removal of foveal vitreous cortex with the high-magnification floating lens during PPV for RRD significantly reduce the incidence of postoperative ERM without adverse findings.

Phytochemical investigation of the aerial parts of Digitalis grandiflora Miller (Plantaginaceae) led to the isolation of an undescribed cardenolide type glycoside digigrandifloroside (1) along with five known compounds, rengyoside A (2), rengyoside B (3), cleroindicin A (4), salidroside (5), and cornoside (6), from its aqueous fraction of methanolic extract. Structures of the isolated compounds were determined by means of spectroscopic techniques. 1–6 were isolated for the first time from D. grandiflora. 2 and 3 are being reported for the first time from Digitalis genus and Plantaginaceae family with this study. This is the second report for occurrence of 4 from a Digitalis species. Cytotoxic activity of the aqueous fraction was also tested against HEp-2 (Human larynx epidermoid carcinoma) and HepG2 (Human hepatocellular carcinoma) cancer cell lines and L929 (Mouse fibroblast cell) non-cancerous cell line. Aqueous fraction showed stronger cytotoxicity on HEp-2 cells than HepG2. Therefore, the cytotoxic activity of 1, 2, 4, and 6 were tested against HEp-2 and L929 cell lines. 3 and 5 couldn't be tested due to their insufficient amount. 1 showed the highest cytotoxicity against HEp-2 cells with IC50 value 10.1 μM when compared with the positive control, etoposide and 2–6 (IC50 of etoposide; 39.5 μM).

Purpose To compare the rates of infectious endophthalmitis following intravitreal injection of ranibizumab using prefilled syringes vs conventional preparation. Design Multicenter retrospective cohort study. Methods All eyes receiving intravitreal injection of 0.5 mg ranibizumab for retinal vascular diseases at 10 retina practices across the United States (2016 to 2017) and Japan (2009 to 2017) were included. The total numbers of eyes and injections were determined from billing codes. Endophthalmitis cases were determined from billing records and evaluated with chart review. Primary outcome was the rate of postinjection acute endophthalmitis. Secondary outcomes were visual acuity and microbial spectrum. Results A total of 243 754 intravitreal 0.5 mg ranibizumab injections (165 347 conventional and 78 407 prefilled) were administered to 43 132 unique patients during the study period. In the conventional ranibizumab group, a total of 43 cases of suspected endophthalmitis occurred (0.026%; 1 in 3845 injections) and 22 cases of culture-positive endophthalmitis occurred (0.013%; 1 in 7516 injections). In the prefilled ranibizumab group, 12 cases of suspected endophthalmitis occurred (0.015%; 1 in 6534 injections) and 2 cases of culture-positive endophthalmitis occurred (0.0026%; 1 in 39 204 injections). Prefilled syringes were associated with a trend toward decreased risk of suspected endophthalmitis (odds ratio 0.59; 95% confidence interval 0.31-1.12; P = .10) and a statistically significant decreased risk of culture-positive endophthalmitis (odds ratio 0.19; 95% confidence interval 0.045-0.82; P = .025). Average logMAR vision loss at final follow-up was significantly worse for eyes that developed endophthalmitis from the conventional ranibizumab preparation compared to the prefilled syringe group (4.45 lines lost from baseline acuity vs 0.38 lines lost; P = .0062). Oral-associated flora was found in 27.3% (6/22) of conventional ranibizumab culture-positive endophthalmitis cases (3 cases of Streptococcus viridans, 3 cases of Enterococcus faecalis) compared to 0 cases in the prefilled ranibizumab group. Conclusion In a large, multicenter, retrospective study the use of prefilled syringes during intravitreal injection of ranibizumab was associated with a reduced rate of culture-positive endophthalmitis, including from oral flora, as well as with improved visual acuity outcomes.

Outcome prediction for dysphagia recovery is essential for rehabilitation treatment planning. Several studies have reported various predictors for resuming oral feeding after post-stroke dysphagia. However, evidence on oral health and function, a crucial part of feeding, has rarely been reported. Therefore, the goal of this study was to identify the oral status-related factors that could predict oral intake resumption in acute stroke patients.80 acute stroke patients with dysphagia were included. Clinical data, including the changes of general condition, oral and swallowing functions, were collected once a week until discharge. Patients were divided into two groups based on the outcome of the food intake level scale at discharge, and data were compared between the groups.60 patients had regained complete oral intake before discharge. Multiple logistic regression showed that posterior tongue pressure could significantly predict complete oral intake recovery. Tongue pressure and modified water swallowing test score also significantly influenced diet forms. In addition, Spearman correlation analysis showed that improvement of other oral status-related factors, such as oral moisture and dentition status, also indicated the improvement of diet forms and swallowing function during the hospital stay.Tongue pressure measurement could be a useful oral status-related indicator for predicting complete oral intake and adjusting diet forms for acute stroke patients during hospitalization. Acute stroke patients should receive proper oral status evaluation and implementation to enhance functional recovery.

This study aimed to investigate whether the jaw-opening (JOR) and jaw-closing reflexes (JCR) are modulated during not only peripherally, but also centrally, evoked swallowing. Experiments were carried out on 24 adult male Japanese white rabbits. JORs were evoked by trigeminal stimulation at 1 Hz for 30 s. In the middle 10 s, either the superior laryngeal nerve (SLN) or cortical swallowing area (Cx) was simultaneously stimulated to evoke swallowing. The peak-to-peak JOR amplitude was reduced during the middle and late 10-s periods (i.e., during and after SLN or Cx stimulation), and the reduction was dependent on the current intensity of SLN/Cx stimulation: greater SLN/Cx stimulus current resulted in greater JOR inhibition. The reduction rate was significantly greater during Cx stimulation than during SLN stimulation. The amplitude returned to baseline 2 min after 10-s SLN/Cx stimulation. The effect of co-stimulation of SLN and Cx was significantly greater than that of SLN stimulation alone. There were no significant differences in any parameters of the JCR between conditions. These results clearly showed that JOR responses were significantly suppressed, not only during peripherally evoked swallowing but also during centrally evoked swallowing, and that the inhibitory effect is likely to be larger during centrally compared with peripherally evoked swallowing. The functional implications of these results are discussed.

Purpose: To report the findings and surgical techniques on two cases of severe tilting of an intraocular lens (IOL) that had been implanted with intrascleral fixation and the tilting was detected by anterior segment optical coherence tomography (AS-OCT). Observations: Two patients underwent flanged intrascleral fixation of an IOL with the double needle technique. AS-OCT showed that the tilt of IOL was 25.3° in Case 1 and was 38.1° in Case 2, and a second surgery was planned to reduce the IOL tilt. Both edges of the flanged haptics were externalized and shortened by 2–3 mm. Then, the haptics edges were inserted intrasclerally. The tilt of the IOLs was reduced to 7.7° and 5.7°, and the myopia-shifted refraction was reduced from −2.75 diopters (D) and −4.50 D to −0.13 D and −0.50 D of the approximate planned refraction in the two cases. Conclusions and importance: An excessive tilt of an intrasclerally fixed IOL can be corrected by shortening the length of the haptics. AS-OCT was useful in not only detecting the tilted IOL but also in monitoring the degree of tilt after adjustment surgery. Keywords: Intraocular lens, Intrascleral fixation, Optical coherence tomography, Tilt

Diaporthols A (1) and B (2), two diphenyl ether derivatives, were isolated from cultures of an endophytic fungus Diaporthe sp. ECN-137 obtained from the leaves of Phellodendron amurense. The structures of 1 and 2 were determined by extensive spectroscopic analyses, and the structure of 2 was confirmed by X-ray crystallographic analysis. Compounds 1 and 2 showed anti-migration activities in TGF-β1-elicited MDA-MB-231 breast cancer cells at a concentration of 20 μM.

New intervention that demands farmer’s adaptation of new approach to land use, requires understand their perception of the status quo and the potential of the new approach. This is particular important in the case of marginal tea small holders because of their already exposure to vulnerabilities which may make them less comfortable to take risks. Research has shown that farmer’s perception commonly reflects the reality. Once the farmers have to adopt sustainable agricultural practices, they first need to believe that the practices are important, provide a safe rural environment, and will bring in stable and long term income by facing natural climatic and environmental problems. Understanding farmer’s perception is vital in enhancing policy formulation towards addressing problems faced by farmers. This study departs by broadly considering physical, institutional and intervention issues as a measure of threat and opportunity for sustainability of farming in marginal tea farm land. A total of 25 key stakeholders from marginal tea growing areas in Matara district were interviewed. Ten of the interviewees were government staffs (TSHDA) while the rest fifteen were small tea farm holders. A total of 26 pre tested statements ranked from - 5 (extremely disagree) to + 5 (extremely agree) were prepared for the interview. The questions categorized as: important biophysical constrains for their farming, choice of external organizations, incentives for fuel wood plantation establishment, problems for continuing tea farming and satisfaction with the existing property rights. The results of the study shows that soil erosion and heavy winds are vital physical factors for the farmers. Low productivity, high cost of land management, labour intensity and labour scarcity are key disadvantages of tea farming. While considering environmental protection, good market demand, comparatively less labour requirement is found to be important advantages of fuel wood planting in marginal tea plantations. The stakeholders also found to prefer government involvement over other actions to plant fuel wood trees within their marginal tea plantations. Stakeholders suggest that planting fuel-wood minimize the risk of depending on one crop as well as avoiding risks and uncertainty of environmental factors affecting tea farming. They strongly recommend that it is good to plant timber and fuel wood trees inside their plantation. Therefore stakeholders suggest, in future government intervention for popularizing of planting timber/ fuel wood trees inside as well as along the boundaries of marginal tea plantations would have been increased. Introduction of new policy and regulations are necessary in the future on planting, harvesting and transporting of timber /fuel wood with a aim of increase the farmers income as well as safeguard the sustainability of Marginal small tea farming in Sri Lanka.

Some new formulae of the canonical correlation functions for the one dimensional quantum transverse Ising model are found by the ST-transformation method using a Morita’s sum rule and its extensions for the two dimensional classical Ising model. As a consequence we obtain a time-independent term of the dynamical correlation functions. Differences of quantum version and classical version of these formulae are also discussed.

Our previous studies implicated the voltage-gated sodium channel subtype NaV 1.7 in the transmission of action potentials by the vagal afferent nerves regulating cough and thus identified this channel as a rational therapeutic target for antitussive therapy. But it is presently unclear whether a systemically administered small molecule inhibitor of NaV 1.7 conductance can achieve therapeutic benefit in the absence of side effects on cardiovascular function, gastrointestinal motility or respiration. To this end, we have evaluated the antitussive effects of the NaV 1.7 selective blocker Compound 801 administered systemically in awake guinea pigs or administered topically in anesthetized guinea pigs. We also evaluated the antitussive effects of ambroxol, a low affinity NaV blocker modestly selective for tetrodotoxin resistant NaV subtypes. Both Compound 801 and ambroxol dose-dependently inhibited action potential conduction in guinea pig vagus nerves (assessed by compound potential), with ambroxol nearly 100-fold less potent than the NaV 1.7 selective Compound 801 in this and other NaV 1.7-dependent guinea pig and human tissue-based assays. Both drugs also inhibited citric acid evoked coughing in awake or anesthetized guinea pigs, with potencies supportive of an NaV 1.7-dependent mechanism. Notably, however, the antitussive effects of systemically administered Compound 801 were accompanied by hypotension and respiratory depression. Given the antitussive effects of topically administered Compound 801, we speculate that the likely insurmountable side effects on blood pressure and respiratory drive associated with systemic dosing make topical formulations a viable and perhaps unavoidable therapeutic strategy for targeting NaV 1.7 in cough.

CMV viremia is a contributor to poor outcomes in critically ill patients with sepsis.To assess the expression levels of genes encoding inflammasome-related proteins in the development of CMV viremia in critically ill patients with sepsis.A cohort of CMV-seropositive critically ill patients with sepsis due to bloodstream infection underwent weekly testing for CMV viremia. Blood samples to evaluate mRNA levels of genes encoding CASP1, ASC, NLRP1, NLRP3, and NLRP12 were collected at the time of enrollment. Clinical outcomes were assessed at 30days or until death/discharge from ICU.CMV viremia was documented in 27.5% (8/29) of the patients, a median of 7days after the onset of bacteremia. Patients with sepsis who developed CMV viremia had higher CASP1 although this was not statistically significant (relative mean 3.6 vs 1.8, p=0.13). Development of high grade CMV viremia however, was significantly associated with CASP1; septic patients who developed high grade CMV viremia had significantly higher CASP1than all other patients (relative mean 5.5 vs 1.8, p=0.016).These data document possible involvement of inflammasome in the pathogenesis of CMV. Regulating the host immune response by agents that target these genes may have implications for improving CMV-related outcomes in these patients.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcriptional factor belonging to the basic helix-loop-helix-Per-Ahr/Arnt-Sim family. In this study, we evaluated the AhR agonistic activities of 12 xanthones isolated from the roots of M. cochinchinensis var. gerontogea using HepG2 cells transfected with pX4TK-Luc reporter plasmids. Gerontoxanthone B (GXB) showed the most potent activity at a concentration of 10μM, and the activity was inhibited by AhR antagonists such as GNF-351. GXB also increased cytochrome P450 1A1 mRNA and protein levels in HepG2 cells. Similar to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin, however, GXB suppressed the IL-1β-induced mRNA level of SAA1, an acute-phase response gene that is up-regulated AhR-dependently but XRE-independently. Thus, GXB shows XRE-dependent transcriptional activity and XRE-independent activity involving AhR.

Three new isocoumarins and two new phthalides, tubakialactones A–E ( 1 – 5 ), together with three known polyketides including ( R )-3,4-dihydro-4-hydroxyl-6,8-dimethoxy-4-methyl-3-methylene-1 H -2-benzopyran-1-one ( 6 ), (−)-5,7-dimethoxy-3-methyl-1(3 H )-isobenzofuranone ( 7 ), and isosclerone ( 8 ) were found in the endophytic fungus Tubakia sp. ECN-111 isolated from the leaves of Houttuynia cordata . The chemical structures of the new compounds were determined by spectroscopic analyses, including extensive 2D-NMR experiments. The absolute configuration of 3 and 7 was determined by optical rotation and circular dichroism.

Collaborative Forest Management (CFM) of local forest users and governments promoted to achieve sustainable forest Social-Ecological Systems (SESs) by consolidating strengths of these actors. Although much of the writings on CFM acknowledge its potential to deliver sustainable SESs, knowledge about what specific role of government can strengthen local forest management and utilization is still poor at best. This study aims to fill the gap by analyzing meta-data from International Forestry Resources and Institutions (IFRI) database for 77 SESs (IFRI sites) in seven countries. We used Ordinal logistic regression to model association between government's Forester Department involvement in important forest management activities and sustainability of forest SES. Our result shows that Forester Department involvement in planting, forest maintenance activities and forest benefit sharing among forest users are associated with sustainable SESs while their involvement in monitoring, sanctioning and transfer of local people harvest right are associated with unsustainable SESs. Our finding has important implications for the ongoing local to global level discourse on how to structure appropriate government interventions to achieve positive social and environmental outcomes from local forest management. However, we suggest precaution not to overstretch the implication of our findings as a panacea for CFM.

The question of under what settings locally managed forests will lead to successful conservation without frustrating the local people’s subsistence outcomes remains contested. This research investigates the relationship between attributes of locally managed forest SES and its forest and livelihood outcomes using data from 83 forest SESs across seven countries. The data were obtained from the International Forestry Resources and Institutions (IFRI) database. Thirteen predicators that were selected from the attributes of forest, user group and governance of the local forest SES were used to evaluate their influence on SES sustainability. Our results showed that sustainable forest SES was significantly associated with forest size, diversity of the NTFP that is extracted from the forest, networks among the forest users, rule making by external non-forest harvest organizations in dispute resolution, and benefits sharing. On the other hand, the distance of forest users’ settlements in the forest, rule making for forest protection and harvest quantity as well as sanctions by external non-forest harvest organizations were found to be significantly associated with unsustainable forest SESs. Our findings have important implications for the ongoing discourse on how to promote sustainable forest management at local level. The results on the success factors can assist decision makers to improve the chances for the success of forest governance that rely on local people who depend upon forests.

123I-labeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) is used to assess striatal dopamine transporter (DAT) expression, but it can also quantify extrastriatal serotonin transporter (SERT) expressions. While FP-CIT uptake in extrastriatal regions has been quantified, no information exists on the reproducibility of the 123I-FP-CIT specific uptake ratio (SUR) in extrastriatal regions. We investigated test-retest reproducibility of 123I-FP-CIT binding in the striatum, the midbrain, and cortical regions in eight healthy male subjects. All subjects underwent two 123I-FP-CIT SPECT scans, and SUR was calculated using the cerebellum as the reference. We found good test-retest reproducibility of 123I-FP-CIT SUR in the midbrain, and in the lateral frontal/temporal cortex and combined cortical regions. The overall variability and intraclass correlation of SUR were, respectively, 4.9-7.8% and 0.90-0.96 in striatal regions, 8.6% and 0.79 in the midbrain, and 3.6-9.1% and 0.84-0.95 in the lateral frontal/temporal cortex and combined cortical regions. Our results provide evidence that 123I-FP-CIT SPECT is a valid technique for analyzing striatal DAT, as well as extrastriatal SERT in areas such as the SERT-enriched midbrain. In addition, our data suggest that 123I-FP-CIT could be used for analyzing SERT in regions with relatively low SERT expression (e.g., temporal or frontal cortices).

This study aimed to clarify the health-related quality of life (HRQOL) of patients with oral cancer and elucidate the factors that affect HRQOL. The participants were 14 male and 10 female patients who underwent definitive surgery. The patients' mean age was 68.2 years. A total of 21 oral cancer cases (87.5%) were in the early stages (stages 0-II), and 15 (62.5%) to tongue cancer. This study's assessments were conducted using HRQOL questionnaires (e.g., the SF-8 and EORTC QLQ Head&Neck35(QLQ-H&N35)) and the Beck Depression Inventory—second edition (BDI-II) along with evaluations of speech, mastication, and swallowing function. The evaluations were performed before surgery and one month, three months, and six months after surgery. There was no significant change in the SF-8 and BDI-II scores during the study period. However, the scores for pain, speech problems, social contact, and coughing within the QLQ-H&N35 significantly increased post-surgery. Furthermore, significant correlations were observed between almost all SF-8 scores and some QLQ-H&N35 scores. Speech intelligibility and masticatory and swallowing functions were significantly correlated with speech problems, social eating, and swallowing within the QLQ-H&N35. These results indicate that disease-specific and site-specific HRQOL decline as a result of oral dysfunction.

Purpose To report the clinical and genetic findings of 9 Japanese patients with autosomal recessive bestrophinopathy (ARB). Design Retrospective, multicenter observational case series. Methods Nine ARB patients from 7 unrelated Japanese families that were examined in 3 institutions in Japan were studied. A series of ophthalmic examinations including fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, electrooculography (EOG), electroretinography, and the results of genetic analysis were reviewed. Results Genetic analyses identified 7 pathogenic variants in BEST1 including 2 novel variants, c.478G>C (p.A160P) and c.948+1delG. Homozygous variants were found in 4 families and compound heterozygous variants were found in 3 families. Two patients were diagnosed as ARB only after the whole exome sequencing analyses. The Arden ratio of the EOG was less than 1.5 in all 7 patients tested. Vitelliform lesions typical for Best vitelliform macular dystrophy were not seen in any of the patients. Seven patients shared some of the previously described features of ARB: subretinal deposits, extensive subretinal fluid, and cystoid macular edema (CME). However, the other 2 patients with severe retinal degeneration lacked these features. Focal choroidal excavations were present bilaterally in 2 patients. One case had a marked reduction of the CME and expansion of subretinal deposits over an 8-year of follow-up period. Conclusions Japanese ARB patients had some but not all of the previously described features. Genetic analyses are essential to diagnose ARB correctly in consequence of considerable phenotypic variations.

Three new phenolic compounds, yuccalides A-C (1-3), were isolated from the roots of Yucca gloriosa L., along with four known compounds (4-7). The structures of the new compounds were established by extensive NMR spectroscopic analyses. Inducible nitric oxide synthase (iNOS) mRNA levels induced by lipopolysaccharide (LPS) in mouse macrophage-like RAW 264.7 cells were effectively suppressed by compounds 2, 4, and 6, all of which had the (2R*, 3R*)-configuration. IL-1β and IL-6 mRNA levels induced by LPS were significantly attenuated by compounds 4, 5, and 6, but not by 2.

Relationships between solar activity and variations in both sea surface temperature (SST) and atmospheric circulation at the time of the solar maximum are presented. The global distribution of correlation coefficients between annual relative sunspot numbers (SSN) and SST from July to December was examined over a 111-year period from 1901 to 2011. Areas with a significant positive correlation accounted for 11.7% of the global sea surface in December, mainly over three regions in the Pacific. The influence of solar activity on global atmospheric pressure variations and circulation in the maximum years was also analyzed from 1979 to 2011. The results indicated that higher geopotential height anomalies tended to appear in the stratosphere and troposphere in the northern hemisphere, centering on around the Hawaiian Islands from November to December, in the second year of the solar maximum. The SST distribution in the Pacific with strong north and south Pacific Highs produced a pattern that resembled teleconnection patterns such as the Pacific Decadal Oscillation (PDO) and the Central-Pacific (CP) El Nino, or El Nino Modoki (ENM). It is suggested that the solar activity had an influence on the troposphere via not only the stratosphere but also the sea surface.

In lead optimization efforts starting from the tetrahydroisoquinoline (S)-1, we identified 2-{[(2R)-2-hydroxypropyl]amino}-1-[(1S)-8-methoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone ((1S)-8t) as a novel orally active small-molecule N-type calcium channel blocker without CYP inhibition liability. CYP3A4 inhibition profile was improved by reducing the lipophilicity of compound (S)-1. Moreover, introduction of a methoxy group to the C-8 position of tetrahydroisoquinoline led to identification of (1S)-8t, which eliminated CYP2D6 inhibition liability. Oral administration of (1S)-8t exerted efficacy in a rat spinal nerve ligation (SNL) model of neuropathic pain with an ED50 value of 2.8 mg/kg.

In swallowing, the tongue contacts against the hard palate to generate pressure for propelling a bolus from the oral cavity into the pharynx. Meanwhile, the hyoid and larynx move upward and forward to facilitate the bolus from the pharynx into the esophagus. It has been well known that sequential coordination between those actions is critical for safety accomplishment of swallowing. However, the absence of noninvasive assessment for it limits the detection to the physiological symptom of dysphagia. We applied a sensor sheet on the hard palate to measure tongue contact pressure and a bend sensor on the frontal neck to monitor the laryngeal movement, which was synchronized with hyoid motion for assessing the coordination between both actions in 14 healthy male subjects when swallowing 5ml of water. The sequential order of tongue pressure and hyoid movement was successfully displayed. Tongue pressure was produced after slight movement of the hyoid and closely to the hyoid elevation, then reached a maximum when the hyoid stabilized in the most anterior-superior position, and ceased concurrently with the onset of hyoid descent. Additionally, the synchronized data from both sensors showed positive correlations between identified time points on the laryngeal signal waveform and onset, peak and offset of tongue pressure. Our sensing system successfully showed the coordination between tongue pressure production and hyoid motion, and could be a simple and noninvasive method for clinicians to evaluate the oral and pharyngeal stages of swallowing.

A new xanthone (1) and a new naturally occurring xanthone (2) were isolated from the roots of Maclura cochinchinensis (Lour.) Corner var. gerontogea (Sieb. et Zucc.) Ohashi together with 10 known xanthones (3-12). Their structures were established by spectroscopic analyses including 1D and 2D NMR. Their retinoic acid receptor-α agonistic activity was evaluated using a luciferase reporter assay. Compound 2, gerontoxanthone A (3), gerontoxanthone B (4), and cudraxanthone I (11) showed moderate concentration-dependent activity. Furthermore, these four xanthones synergistically increased transcriptional activity in this assay in the presence of bexarotene, an RXR agonist.

Dysphagic patients are fed soft meals made of gels and process them by squeezing the food with the tongue, which reduces food size. Although the gels are designed based on rheological analyses, the impact of the initial gel texture on tongue kinetics is not known. This study investigated the effect of gel consistency on tongue pressure during squeezing and swallowing and compared results of the mechanical analyses. Fifteen healthy young subjects participated in this study. Tongue pressure during squeezing and swallowing was measured by a sensor sheet with five measuring points. Five ml of water and six gel samples prepared using two gelling agents at three concentrations each were used as test materials. Subjects were instructed not to chew the food but to squeeze it using their tongue. The shape of the tongue pressure waveform during the initial squeeze was similar to the stress–time curve using a texture analyzer. However, the sequential order of tongue pressure during squeezing and swallowing was different. Tongue pressure during the initial squeeze was affected by gel consistency. The amplitude of tongue pressure during swallowing increased as gel consistency increased, but the duration of pressure was not affected. The slopes of tongue pressure generation were not affected by gel consistency, although the mechanical measurements showed increases in these slopes with increasing gel consistency. These results suggest that findings regarding characteristics of tongue movement during squeezing and textural properties of gels might be useful for food design and clarification of oral physiology.

N-type calcium channels represent a promising target for the treatment of neuropathic pain. The selective N-type calcium channel blocker ziconotide ameliorates severe chronic pain but has a narrow therapeutic window and requires intrathecal administration. We identified tetrahydroisoquinoline derivative 1a as a novel potent N-type calcium channel blocker. However, this compound also exhibited potent inhibitory activity against hERG channels. Structural optimizations led to identification of (1S)-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-{[(1-hydroxycyclohexyl)methyl]amino}ethanone ((S)-1h), which exhibited high selectivity for hERG channels while retaining potency for N-type calcium channel inhibition. (S)-1h went on to demonstrate in vivo efficacy as an orally available N-type calcium channel blocker in a rat spinal nerve ligation model of neuropathic pain.

Objective To determine the relation between the recovery of the cone outer segment tips (COST) line and the best-corrected visual acuity (BCVA) after epiretinal membrane (ERM) surgery. Design Retrospective, consecutive, interventional case series. Participants Sixty-one eyes of 56 patients with an idiopathic ERM were studied. All participants underwent a complete ophthalmic examination including spectral-domain optical coherence tomography before and after ERM removal surgery. Methods The integrities of the photoreceptor layer including the external limiting membrane line, photoreceptor inner segment/outer segment (IS/OS) line, and COST line in the spectral-domain optical coherence tomography images at the fovea were determined. The associations of these morphological parameters to the BCVA were determined. Results Better BCVAs were found more frequently in eyes with an intact COST line than in eyes with a disrupted or absent COST line at 1 ( p p = 0.003), and 12 months ( p Conclusions Eyes with an intact COST line had better BCVA after ERM surgery. However, even at 12 months after ERM surgery, COST lines remained disrupted in many eyes with good BCVA.

Dissociative amnesia is characterized by an inability to retrieve information already saved in memories. 5-HT has some role in neural regulatory control and may be related to the recovery from dissociative amnesia. To examine the role of 5-HT 1A receptors in the recovery from dissociative amnesia, we performed two positron emission tomography (PET) scans on a 30-year-old patient of dissociative amnesia using [ 11 C]WAY-100635, the first at amnesic state, and the second at the time he had recovered. Exploratory voxel-based analysis (VBA) was performed using SPM software. 5-HT 1A BP ND images were compared between the patient at amnesic and recovery states and healthy subjects (14 males, mean age 29.8±6.45) with Jack-knife analysis. 5-HT 1A receptor bindings of the patient at the recovery state were significantly higher than those of healthy subjects in the right superior and middle frontal cortex, left inferior frontal and orbitofrontal cortex and bilateral inferior temporal cortex. The increase in BP ND values of recovery state was beyond 10% of those of amnesia state in these regions except in the right superior frontal cortex. We considered that neural regulatory control by the increase of 5-HT 1A receptors in cortical regions played a role in the recovery from dissociative amnesia.

Histone deacetylase inhibitors (HDACIs) are promising agents for cancer therapy. However, the mechanism(s) responsible for the efficacy of HDACIs have not yet to be fully elucidated. Death receptor 5 (DR5) is a transmembrane receptor containing death domain that triggers cell death upon binding to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or agonistic anti-DR5 monoclonal antibody, and the combination of TRAIL/agonistic anti-DR5 monoclonal antibody and agents that increase the expression of DR5 is expected as a novel anticancer therapeutic strategy. Here we report that six different HDACIs activated endoplasmic reticulum (ER) stress sensor PERK and eIF2α and induced the ATF4/ATF3/CHOP pathway in p53-deficient human colon cancer cells. This resulted in an increased expression of DR5 on the cell surface and sensitized cells to apoptosis by agonistic anti-DR5 monoclonal antibody. Stress response gene ATF3 was required for efficient DR5 induction by HDACIs, and DR5 reporter assay showed that ATF3 play crucial role for the HDACIs-induced activation of DR5 gene transcription. These provide important mechanistic insight into how HDACIs exhibit pro-apoptotic activity in clinical anti-cancer treatments when they are used in combination with other therapeutic strategies.

Recent changes in the policy and institutional framework for forestry of Ethiopia emphasize the decentralization of power including through devolution. With the aim of filling the gap in the literature on Ethiopia, this study explored the actors involved, the nature of power they hold, the accountability relationships among actors and the social and environmental outcomes of the devolved governance system using a Modified Actor-Power-Accountability Framework (MAPAF). The results indicated that discretionary decision-making space is created for the local population and the leaders of Forest Cooperatives to manage and protect the forest and use it for subsistence purposes. To generate income from their withdrawal rights, however, local actors require approval from a mid-level actor, the Oromia Forest and Wildlife Enterprise. Devolution has improved physical and human conditions and the benefits from natural capital, which were identified as salient for the local population as a means of coping with their vulnerabilities and for income generation. The environmental outcome differed depending on the policy followed by the mid-level partner organizations that make decisions with the local population on income-generating activities from the sale of forest resources. Overall, elite capture and the recent emphasis on income generation over forest conservation were identified as key factors hampering positive social and environmental outcomes from the devolved governance system.

Several studies have shown that cationic liposomes exert immunomodulatory effects with low immunogenicity and toxicity, and offer advantages such as easy preparation and targeting. Cationic liposomes not only transport DNA to immune cells but also enhance the function of antigen presenting cells such as dendritic cells and macrophages. Here, we investigated the effect of a particular cationic liposome on mast cell function during allergic reaction. We found that the cationic liposomes bound to the mast cell surface suppressed degranulation induced by cross-linking of high affinity immunoglobulin E receptors in a time- and dose-dependent manner. The suppression of degranulation was mediated by impairment of the sustained level of intracellular Ca(2+) concentration ([Ca(2+)]i) derived from the inhibition of store-operated Ca(2+) entry. The decrease in sustained elevation of [Ca(2+)]i led to the suppression of phosphorylation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins such as SNAP-23, syntaxin-4, which are necessary for membrane fusion between secretory granules and the plasma membrane during degranulation. Furthermore, the cationic liposomes suppressed vascular permeability elevation induced by mast cell activation in mice. These results showed that cationic liposomes possess the novel property of inhibiting mast cell activation, suggesting the possibility of developing cationic liposomes as anti-allergic effectors.

Forests ecosystems provide several intangible benefits which policy makers ignore since these values do not register in conventional markets or are difficult to measure. Drawing on results of a case study of a forest reserve in Japan, this paper suggests that the annual value of the ecosystem services provided by forests is not only worth millions of dollars, but also in per hectare terms much more than hitherto known. This value for the Oku Aizu forest reserve ranged US$ 1.427–1.482 billion or about US$ 17,016–17,671 per ha. If these are accounted for, then governments and societies faced with the development versus conservation dilemma can make more informed decisions and policies that will help conserve forests and the ecosystem services they provide, and thereby promote human well-being and sustainable development.

Ecosystem services valuation has achieved considerable prominence in research and policy circles in recent years. This paper reviews the studies that have tried to estimate the value of forest ecosystem services. Broadly, this study addresses the following questions: (1) What insights do these studies provide on the value of forest ecosystems? (2) What lessons do they offer from an economic and policy perspective? (3) What are the shortcomings of the existing studies, and what are the challenges and issues for future research? Evidence from a cross section of forest sites, countries and regions suggests that not only the total valuation of ecosystem services varies widely across studies but also the valuation of individual services. This variation suggests that policies to conserve ecosystems and their services should emphasise local contexts and values. This paper concludes by discussing the shortcomings of existing studies, and suggests that, among other things, future research should focus on the neglected ecosystem services, ‘disservices’, assess the role of dynamic factors and environmental catastrophes on the provision of ecosystem services, and assess the benefits of keeping forests intact versus converting them to alternative uses.

It has been reported that the jaw opening reflex (JOR) evoked by intra-oral innocuous stimulation was suppressed during a reflex swallow in anesthetized animals only. However, the mechanism of JOR inhibition during swallowing has not yet been elucidated. The aim of the present study was to investigate the effects of peripheral nerve stimulation on masticatory behaviors, as well as the modulation of low threshold afferent evoked JOR responses during chewing and swallowing in freely feeding animals. The JOR in the digastric muscle was evoked by low threshold electrical stimulation of the inferior alveolar nerve (IAN). Changes in the peak-to-peak amplitude of digastric electromyographic responses were compared among the phases of chewing and swallowing. IAN stimulation did not produce any differences in cycle duration, gape of the jaw in one cycle, or swallowing interval, suggesting a minimal effect on feeding behaviors. The JOR amplitude during the fast-closing, slow-closing, and slow-opening phases of chewing was significantly smaller than that of the control (recorded when the animal was at rest) and fast-opening phase. During swallowing, the JOR amplitude was significantly less than the control. Inhibition of the JOR during swallowing is assumed to prevent unnecessary opposing jaw opening motion.

Astaxanthin (ASX), an oxygenated carotenoid (xanthophyll), has previously been shown to exert ameliorative effects on obesity and insulin resistance, but the underlying mechanisms were not clearly elucidated. In the present study, we investigated whether ASX serves as a novel selective peroxisome proliferator-activated receptor (PPAR) γ modulator. Analyses of PPARγ binding by CoA-BAP assays revealed that ASX bound to PPARγ in a dose-dependent manner. However, ASX was unable to activate transcription in PPARγ reporter assays, although it antagonized transcriptional activation by the PPARγ agonist rosiglitazone (RGZ). When the molecular interactions between PPARγ and three coactivators were examined, ASX increased the interactions of PPARγ with transcriptional intermediary factor 2 (TIF2) and steroid receptor coactivator-1 (SRC-1), but not cAMP responsive element-binding protein (CREB)-binding protein (CBP). In addition, ASX effectively blocked the increase in CBP recruitment to PPARγ mediated by RGZ. ASX alone did not stimulate 3T3-L1 cell differentiation, although it antagonized 3T3-L1 cell differentiation and lipid accumulation induced by RGZ, similar to the PPARγ antagonist GW9662. When the effects of cotreatment of 3T3-L1 cells with ASX and RGZ were determined based on the mRNA levels of PPARγ target genes, ASX effectively reduced the mRNA levels of aP2 and lipoprotein lipase, but not CD36. Intriguingly, ASX was capable of inducing PPARγ target genes such as liver X receptor, CD36 and ABCA1 in thioglycollate-elicited peritoneal macrophages. Collectively, the present findings indicate that ASX is a novel selective PPARγ modulator that acts as an antagonist or agonist depending on the cell context.

Purpose To evaluate the clinical outcomes after vitrectomy, without gas tamponade or laser photocoagulation to the margin of the optic nerve, for the treatment of macular detachment associated with optic disc pits and to characterize retinal manifestations during treatment of optic pit maculopathy using optical coherence tomography (OCT). Design Noncomparative, retrospective, interventional case series. Participants Eight consecutive patients (8 to 56 years of age) with unilateral macular detachment associated with optic disc pit. Intervention Pars plana vitrectomy with induction of a posterior vitreous detachment (PVD) was performed in all eyes. No laser or gas injection was performed in any eye during the original surgery. Patients were followed up for 10 to 46 months (mean, 26 months) after surgery. Main Outcome Measures Anatomic outcome as determined by OCT and postoperative visual acuities were the main outcome parameters. Fundus autofluorescence (FAF) images were obtained in 4 eyes to document anatomic changes in the macula. Results Although complete retinal reattachment was achieved in 7 of 8 eyes, up to about 1 year was necessary for the retinal detachment to resolve fully. The 1 eye in which macular detachment failed to resolve completely underwent revision of vitrectomy with a gas tamponade and laser photocoagulation in the peripapillary area. In the early postoperative period, despite persistent macular detachment, the visual acuities improved in 7 eyes. These improved acuities corresponded with remodeling of the photoreceptor outer segments on OCT and the appearance of granular hyperfluorescence on FAF imaging. Conclusions Vitrectomy with induction of a PVD at the optic disc without gas tamponade or laser photocoagulation seems to be an effective method of managing macular detachment resulting from optic disc pits. The OCT scanning before and after surgery suggests that peripapillary vitreous traction with the passage of fluid into the retina through the pit is the cause of the schisis-like separation seen in optic disc pit maculopathy. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Background & Aims The activating receptor natural killer group 2, member D (NKG2D) and its ligands play a crucial role in immune response to tumors. NKG2D ligand expression in tumors has been shown to be associated with tumor eradication and superior patient survival, but the involvement of NKG2D ligands in the immune response against hepatocellular carcinoma (HCC) still remains to be elucidated. Methods We investigated the expression of NKG2D ligands in HCC tissues collected from 54 patients and HCC cell lines. We also examined the proteasome expression and the effect of inhibition of proteasome activity on NKG2D ligand expression in HCC tissues and cell lines. Results In dysplastic nodules (DN), well-differentiated (well-HCC), and moderately-differentiated HCCs (mod-HCC), UL16-binding protein (ULBP) 1 was expressed predominantly in tumor cells, but not in poorly-differentiated HCCs (poor-HCC). Remarkably, recurrence-free survival of patients with ULBP1-negative HCC was significantly shorter than that of patients with ULBP1-positive HCC ( p =0.006). Cox regression analysis revealed that loss of ULBP1 expression was an independent predictor of early recurrence ( p =0.008). We confirmed that ULBP1 was expressed in the well- and mod-HCC cell lines, but not in the poor-HCC cell line KYN-2. However, inhibition of proteasome activity resulted in significant up-regulation of ULBP1 expression in KYN-2. Moreover, we found that 20S proteasome expression was more abundant in KYN-2 than that in the well- and mod-HCC cell lines. Conclusions ULBP1 is prevalently expressed in DN to mod-HCC, but loss of its expression correlates with tumor progression and early recurrence.

Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are different types of dementia. However, their clinical symptoms partially overlap and differential diagnosis is occasionally difficult. There is need for additional diagnostic criteria to reliably differentiate between these two conditions. Meanwhile, several imaging studies have showed inconsistent results between DLB and AD. The aim of this study was to use a tractography-based analysis to elucidate white matter alterations in subjects with DLB compared to those with AD and to controls. An understanding of the white matter connectivity differences between AD, DLB and controls will be helpful for differential diagnosis and an understanding of the pathophysiology. Twenty-six subjects with DLB, 26 with AD and 26 controls underwent magnetic resonance diffusion tensor imaging and neuropsychological assessment. Diffusion tensors were computed and fiber-tract maps were created using "dTV II" software. We measured mean fractional anisotropy (FA) values along the uncinate fasciculus (UNC), the inferior occipitofrontal fasciculus (IOFF) and the inferior longitudinal fasciculus (ILF). Both subjects with DLB and AD had lower FA values for the bilateral UNC than controls. Subjects with DLB exhibited significantly lower FA values on both sides of the IOFF and the left side of the ILF than those of controls. Although there were no significant differences between subjects with DLB and AD for any measurements, those with DLB exhibited lower FA values especially in visual-related white matter. These different changes in white matter tracts among groups could be helpful for differential diagnosis and an understanding of the pathophysiology.

The present study aimed to examine whether the jaw-opening reflex (JOR) is modulated during swallowing, and if so, to compare the modulation between the low- and high-threshold afferent-evoked reflex responses. Experiments were carried out on 11 anesthetized rabbits. The inferior alveolar nerve was stimulated to evoke the JOR in the digastric muscle. The stimulus intensity was either 1.5 (low threshold) or 4.0 (high threshold) times the threshold for eliciting the JOR. As a conditioning stimulation, the superior laryngeal nerve (SLN) was repetitively stimulated to evoke the swallowing reflex. The stimulus intensity ranged from 0.6 to 8.0 times the threshold to evoke the swallowing reflex during SLN stimulation over 20 s. Electromyographic (EMG) activities of the digastric and mylohyoid muscles were recorded, and the peak-to-peak EMG amplitude of the digastric muscle was measured and compared with and without SLN stimulation, as well as with and without swallowing. Comparisons were also made between low- and high-threshold afferent-evoked JORs. The JOR was strongly suppressed during SLN stimulation. The degree of suppression increased and the latency for the JOR was delayed when the stimulus current applied to the SLN was increased. Such modulation was apparent when the low-threshold afferent-evoked JOR was recorded. Effects of motor outputs of swallowing events and those of single-pulse stimulation of SLN on the inhibition of the JOR were not noted. These results suggest that the JOR evoked by both the low- and high-threshold afferents was inhibited during laryngeal sensory input and following swallowing, probably to prevent opposing jaw movements evoked by oral sensory input during swallowing.

Strong CTL response can be observed and associated with the control of proviral load in human T-lymphotropic virus type 1 (HTLV-1) infection. However, there are few details with regard to how HTLV-1 specific CTLs work against HTLV-1 infected cells and adult T-cell leukemia cells (ATLs). In this study, using Tax-specific CTL lines with high- and low-functional avidity developed from HLA-A2-transgenic mice, we showed that higher avidity CTLs specific for Tax expressing larger numbers of TCRs and better binding strength to the antigen-HLA-A2 complex are much more efficient at eliminating HTLV-1 infected cells and, in particular, ATL tumor cells with the ability of recognizing a latent level of Tax product detected only with a real-time PCR. These findings suggest that such higher avidity CTLs specific for Tax in HTLV-1 could be responsible for preventing the development of HTLV-1 infection by detecting trace amount of antigens.

The number of water-induced swallows was decreased following capsaicin injection into the facial (whisker pad) skin, masseter or lingual muscle. The capsaicin-induced inhibitory effect on the swallowing reflex was depressed after intrathecal administration of mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor. The inhibitory effect on swallowing following capsaicin injection into the lingual muscle was diminished by paratrigeminal nucleus (Pa5) lesioning. Many phosphorylated extracellular signal-regulated kinase-like immunoreactive neurons in the nucleus tractus solitarii (NTS) showed gamma-aminobutyric acid (GABA) immunoreactivity and capsaicin-induced inhibition of the swallowing reflex was diminished by local microinjection of the GABAA receptor antagonist into the NTS. The present findings suggest that facial skin-NTS, masseter muscle-NTS, lingual muscle-NTS and lingual muscle-Pa5-NTS pathways are involved in the swallowing inhibition by facial, masseter and lingual pain, and that the activation of GABAergic NTS neurons may be involved in inhibition of the swallowing reflex.

Objective The homeobox B4 ( HoxB4 ) gene promotes expansion of hematopoietic stem cells (HSCs). However, frequent development of leukemia in large animals due to retrovirally transduced HoxB4 gene has been reported. To prevent tumorigenesis, we developed a nonintegrating and nonreplicating Sendai virus vector that did not contain the phosphoprotein gene (SeV/ΔP), which enabled clearance of the vector and transgene shortly after transduction. We tested the SeV/ΔP vector expressing the HoxB4 gene (SeV/ΔP/ HoxB4 ) for the ex vivo expansion of human cord blood CD34 + cells (HSCs) using a sheep in utero transplantation assay. Materials and Methods Human HSCs were ex vivo−expanded by transduction with SeV/ΔP/ HoxB4 vector and transplanted into the abdominal cavity of fetal sheep. The engraftment of human HSCs in the lambs was quantitatively evaluated by hematopoietic colony-forming unit assays. Results After transplantation, the HoxB4 -transduced HSCs contributed to longer-period (up to 20 months) repopulation in sheep, and human hematopoietic progenitors were detected more frequently in the bone marrow of the HoxB4 group as compared with the control untreated group ( p HoxB4 vector was comparable with previously reported retroviral vectors expressing HoxB4. The SeV/ΔP/ HoxB4 vector and the transgene were cleared from the recipient sheep and leukemia was not detected at 20 months post-transplantation. Conclusions The SeV/ΔP vector would be suitable for transient expression of HoxB4 in human CD34 + cells. In addition, the SeV/ΔP vector is free of concern about transgene-related and insertional leukemogenesis and should be safer than retroviral vectors.

The ICT1 protein was recently reported to be a component of the human mitoribosome and to have codon-independent peptidyl-tRNA hydrolysis activity via its conserved GGQ motif, although little is known about the detailed mechanism. Here, using NMR spectroscopy, we determined the solution structure of the catalytic domain of the mouse ICT1 protein that lacks an N-terminal mitochondrial targeting signal and an unstructured C-terminal basic-residue-rich extension, and we examined the effect of ICT1 knockdown (mediated by small interfering RNA) on mitochondria in HeLa cells using flow cytometry. The catalytic domain comprising residues 69-162 of the 206-residue full-length protein forms a structure with a β1-β2-α1-β3-α2 topology and a structural framework that resembles the structure of GGQ-containing domain 3 of class 1 release factors (RFs). Half of the structure, including the GGQ-containing loop, has essentially the same sequence and structure as those in RFs, consistent with the peptidyl-tRNA hydrolysis activity of ICT1 on the mitoribosome, which is analogous to RFs. However, the other half of the structure differs in shape from the corresponding part of RF domain 3 in that in ICT1, an α-helix (α1), instead of a β-turn, is inserted between strand β2 and strand β3. A characteristic groove formed between α1 and the three-stranded antiparallel β-sheet was identified as a putative ICT1-specific functional site by a structure-based alignment. In addition, the structured domain that recognizes stop codons in RFs is replaced in ICT1 by a C-terminal basic-residue-rich extension. It appears that these differences are linked to a specific function of ICT1 other than the translation termination mediated by RFs. Flow cytometry analysis showed that the knockdown of ICT1 results in apoptotic cell death with a decrease in mitochondrial membrane potential and mass. In addition, cytochrome c oxidase activity in ICT1 knockdown cells was decreased by 35% compared to that in control cells. These results indicate that ICT1 function is essential for cell vitality and mitochondrial function.

Sendai virus (SeV) M protein has a YLDL motif, which is essential for budding of virus-like particles (VLPs) by expression of the M protein. We investigated the importance of the YLDL motif for SeV budding. Virus budding of an M-deficient SeV was not rescued by transient expression of motif mutants, M-A2 (ALDA) and M-A4 (AAAA), and viruses possessing those mutations hardly propagated in cultured cells. However, a budding-competent revertant virus, SeV M-A2R, was obtained from SeV M-A2, and nucleotide sequencing showed an ALDV sequence at the motif instead of the ALDA sequence derived from M-A2. The M-A2R protein rescued budding of an M-deficient SeV, formed VLPs when expressed with viral C protein, and restored the capacity to bind with Alix/AIP1. The results indicate that the YLDL motif is essential for efficient budding in the context of virus infection and suggest involvement of Alix/AIP1 in SeV budding.

Summary Direct cardiac reprogramming holds great promise for regenerative medicine. We previously generated directly reprogrammed induced cardiomyocyte-like cells (iCMs) by overexpression of Gata4, Mef2c, and Tbx5 (GMT) using retrovirus vectors. However, integrating vectors pose risks associated with insertional mutagenesis and disruption of gene expression and are inefficient. Here, we show that Sendai virus (SeV) vectors expressing cardiac reprogramming factors efficiently and rapidly reprogram both mouse and human fibroblasts into integration-free iCMs via robust transgene expression. SeV-GMT generated 100-fold more beating iCMs than retroviral-GMT and shortened the duration to induce beating cells from 30 to 10 days in mouse fibroblasts. In vivo lineage tracing revealed that the gene transfer of SeV-GMT was more efficient than retroviral-GMT in reprogramming resident cardiac fibroblasts into iCMs in mouse infarct hearts. Moreover, SeV-GMT improved cardiac function and reduced fibrosis after myocardial infarction. Thus, efficient, non-integrating SeV vectors may serve as a powerful system for cardiac regeneration.

Growing evidence suggests that endocytic dysfunction is intimately involved in early stage Alzheimer disease pathology, such as the accumulation of β-amyloid precursor protein in enlarged early endosomes. However, it remains unclear how endocytic dysfunction is induced in an age-dependent manner. Cytoplasmic dynein, a microtubule-based motor protein, interacts with another microtubule-associated protein, dynactin. The resulting dynein-dynactin complex mediates minus end-directed vesicle transport, including endosome trafficking. We have previously shown that the interaction between dynein-dynactin complexes is clearly attenuated in aged monkey brains, suggesting that dynein-mediated transport dysfunction exists in aged brains. Our immunohistochemical analyses revealed that age-dependent endocytic pathology was accompanied by an increase in Rab GTPases in aged monkey brains. Here, we demonstrated that siRNA-induced dynein dysfunction reproduced the endocytic pathology accompanied by increased Rab GTPases seen in aged monkey brains and significantly disrupted exosome release. Moreover, it also resulted in endosomal β-amyloid precursor protein accumulation characterized by increased β-site cleavage. These findings suggest that dynein dysfunction may underlie age-dependent endocytic dysfunction via the up-regulation of Rab GTPases. In addition, this vicious circle may worsen endocytic dysfunction, ultimately leading to Alzheimer disease pathology.

While angiotensin II, which is produced by the renin-angiotensin-aldosterone system, is considered to be the major regulator molecule that controls both the blood pressure and fluid system, there is an increasing body of evidence that this bioactive peptide and its receptor might also contribute to the immune system. However, there are few details known about the direct effect that angiotensin type I receptors (AT1R) have on the cytotoxic T cell (CTL). To clarify the relationship between angiotensin II and its CTL receptor, we used murine splenic and antigen-specific CTLs. Murine CTLs constantly expressed AT1R, with the activation of the AT1R expression strengthened by both anti-CD3 Ab and the use of an antigen-specific methodology. Moreover, the production of IFN-gamma and TNF-alpha through CTL stimulation can be inhibited by the selective AT1R inhibitor, Losartan. In particular, the TNF-alpha production from activated CTL that had been magnified by angiotensin II, was nullified by the AT1R inhibitor. However, a cytotoxic assay indicated it did not have any effect on the cognate interaction of the CTLs. In addition, the antigen-specific CTL induction by immunization with the CTL antigenic peptide was reduced by angiotensin II type 1 receptor blocker (ARB) in vivo. These findings suggest that ARBs might have the ability to suppress excessive antigen-specific activation and induction of CTLs promoted by angiotensin II.