We examine the effect of electronic coupling on the optical properties of Cy3 dimers attached to DNA duplexes as a function of base pair (bp) separation using steady-state and time-resolved ...spectroscopy. For close Cy3-Cy3 separations, 0 and 1 bp between dyes, intermediate to strong electronic coupling is revealed by modulation of the absorption and fluorescence properties including spectral band shape, peak wavelength, and excited-state lifetime. Using a vibronic exciton model, we estimate coupling strengths of 150 and 266 cm
for the 1 and 0 bp separations, respectively, which are comparable to those found in natural light-harvesting complexes. For the strongest electronic coupling (0 bp separation), we observe that the absorption band shape is strongly affected by the base pairs that surround the dyes, where more strongly hydrogen-bonded G-C pairs produce a red-shifted absorption spectrum consistent with a J-type dimer. This effect is studied theoretically using molecular dynamics simulation, which predicts an in-line dye configuration that is consistent with the experimental J-type spectrum. When the Cy3 dimers are in a standard aqueous buffer, the presence of relatively strong electronic coupling is accompanied by decreased fluorescence lifetime, suggesting that it promotes nonradiative relaxation in cyanine dyes. However, we show that the use of a viscous solvent can suppress this nonradiative recombination and thereby restore the dimer fluorescent emission. Ultrafast transient absorption measurements of Cy3 dimers in both standard aqueous buffer and viscous glycerol buffer suggest that sufficiently strong electronic coupling increases the probability of excited-state relaxation through a dark state that is related to Cy3 torsional motion.
Background
Direct-to-consumer (DTC) advertisements for prescription drugs in the United States are regulated by the Food and Drug Administration (FDA). Off-label promotion, or the advertisement of a ...drug for an indication not approved by the FDA, is prohibited. Our objective was to examine the presence of off-label promotion in broadcast DTC ads and to assess their adherence to FDA guidelines mandating fair balance in presentation of risks and benefits and prohibiting misleading advertisement claims.
Methods
All English-language broadcast DTC ads for prescription drugs that aired in the United States from January 2015 to July 2016 were obtained from AdPharm, an online collection of healthcare advertisements. Ad length was measured and adherence to FDA guidelines was assessed for several categories: key regulatory items, indicators of false or misleading ads, and indicators of fair balance in presentation of risks and benefits.
Results
Our sample included 97 unique DTC ads, representing 60 unique drugs and 67 unique drug–indication combinations. No ads described drug risks quantitatively, whereas drug efficacy was presented quantitatively in 25 (26%) ads. Thirteen (13%) ads, all for diabetes medications, suggested off-label uses for weight loss and blood pressure reduction. The most commonly advertised drugs were indicated for the treatment of inflammatory conditions (
n
= 12; 18%), diabetes or diabetic neuropathy (
n
= 11; 16%), bowel or bladder dysfunction (
n
= 6; 9%), and infections or allergic reaction (
n
= 6; 9%). More than three-quarters (
n
= 51; 76%) advertised drugs to treat chronic conditions.
Conclusions
Few broadcast DTC ads were fully compliant with FDA guidelines. The overall quality of information provided in ads was low, and suggestions of off-label promotion were common for diabetes medications. The impact of current DTC ads and off-label marketing on patient and prescriber decisions merits further scrutiny.
Since its publication in 2007, the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) have been widely adopted. The validation of TG07 conducted in terms of clinical ...practice has shown that the diagnostic criteria for acute cholecystitis are highly reliable but that the definition of definite diagnosis is ambiguous. Discussion by the Tokyo Guidelines Revision Committee concluded that acute cholecystitis should be suspected when Murphy’s sign, local inflammatory findings in the gallbladder such as right upper quadrant abdominal pain and tenderness, and fever and systemic inflammatory reaction findings detected by blood tests are present but that definite diagnosis of acute cholecystitis can be made only on the basis of the imaging of ultrasonography, computed tomography or scintigraphy (HIDA scan). These proposed diagnostic criteria provided better specificity and accuracy rates than the TG07 diagnostic criteria. As for the severity assessment criteria in TG07, there is evidence that TG07 resulted in clarification of the concept of severe acute cholecystitis. Furthermore, there is evidence that severity assessment in TG07 has led to a reduction in the mean duration of hospital stay. As for the factors used to establish a moderate grade of acute cholecystitis, such as leukocytosis, ALP, old age, diabetes, being male, and delay in admission, no new strong evidence has been detected indicating that a change in the criteria used in TG07 is needed. Therefore, it was judged that the severity assessment criteria of TG07 could be applied in the updated Tokyo Guidelines (TG13) with minor changes. TG13 presents new standards for the diagnosis, severity grading and management of acute cholecystitis.
Free full-text articles and a mobile application of TG13 are available via
http://www.jshbps.jp/en/guideline/tg13.html
.
Destination image formation process Kim, Hyangmi; Chen, Joseph S
Journal of vacation marketing,
04/2016, Letnik:
22, Številka:
2
Journal Article
Recenzirano
To augment the current perspective on the tourism destination image formation process, this study highlights the concept of ‘schema’, which is a mental structure of perceiving and classifying ...acquired information or knowledge. This study first proposes two schema-related models that illustrate the image formation process before, during, and after the tourist trip. Specifically, this study enlists five Prime Tourist Destination Schemas entailing (1) place, (2) mega event, (3) crisis, (4) self, and (5) emotion to depict the destination image formation process that is constantly modified owing to its dissimilation with new information, wherein these information sources could affect the formation of the destination image before the trip. Once the tourist visits the destination, the schemas may be altered, resulting in three different types of conditions within the tourist’s schematic fabric: congruity, moderate incongruity, and extreme incongruity. Accordingly, the resultant destination images after the trip may be labeled as an identical image, a moderately transformed image, or a largely transformed image based on experience input. Critical viewpoints in future model testing are furnished.
Dye aggregates and their excitonic properties are of interest for their applications to organic photovoltaics, non-linear optics, and quantum information systems. DNA scaffolding has been shown to be ...effective at promoting the aggregation of dyes in a controllable manner. Specifically, isolated DNA Holliday junctions have been used to achieve strongly coupled cyanine dye dimers. However, the structural properties of the dimers and the DNA, as well as the role of Holliday junction isomerization are not fully understood. To study the dynamics of cyanine dimers in DNA, molecular dynamics simulations were carried out for adjacent and transverse dimers attached to Holliday junctions in two different isomers. It was found that dyes attached to adjacent strands in the junction exhibit stronger dye-DNA interactions and larger inter-dye separations compared to transversely attached dimers, as well as end-to-end arrangements. Transverse dimers exhibit lower inter-dye separations and more stacked configurations. Furthermore, differences in Holliday junction isomer are analyzed and compared to dye orientations. For transverse dyes exhibiting the smaller inter-dye separations, excitonic couplings were calculated and shown to be in agreement with experiment. Our results suggested that dye attachment locations on DNA Holliday junctions affect dye-DNA interactions, dye dynamics, and resultant dye orientations which can guide the design of DNA-templated cyanine dimers with desired properties.
Molecular dynamics simulations reveal dye attachment and DNA Holliday junction isomer effects on dye dimer orientations and excitonic couplings. These simulations can guide synthesis and experiments of dye-DNA structures for excitonic applications.
The suprachiasmatic nucleus (SCN) is the master circadian pacemaker in mammals and is entrained by environmental light. However, the molecular basis of the response of the SCN to light is not fully ...understood. We used RNA/chromatin immunoprecipitation/single-nucleus sequencing with circadian behavioral assays to identify mouse SCN cell types and explore their responses to light. We identified three peptidergic cell types that responded to light in the SCN: arginine vasopressin (AVP), vasoactive intestinal peptide (VIP), and cholecystokinin (CCK). In each cell type, light-responsive subgroups were enriched for expression of neuronal Per-Arnt-Sim (PAS) domain protein 4 (NPAS4) target genes. Further, mice lacking Npas4 had a longer circadian period under constant conditions, a damped phase response curve to light, and reduced light-induced gene expression in the SCN. Our data indicate that NPAS4 is necessary for normal transcriptional responses to light in the SCN and critical for photic phase-shifting of circadian behavior.
•Light activates diverse patterns of gene expression in the SCN of the hypothalamus•Light-responsive genes in the SCN show enrichment for NPAS4 regulatory elements•Light-responsive SCN neurons also shown increased expression of NPAS4 target genes•Mice lacking Npas4 have reduced phase shifting to light and longer circadian rhythms
In this study, Xu et al. investigate the transcriptional response of the suprachiasmatic nucleus to light. They show that the light-inducible gene Npas4 is involved in mediating the transcriptional response of SCN neurons. Furthermore, loss of Npas4 alters circadian rhythms in mice, suggesting a role of Npas4 in photic entrainment.
Cardiovascular disease (CVD) is common and overall graft survival is suboptimal among kidney transplant recipients. Although albuminuria is a known risk factor for adverse outcomes among persons with ...native chronic kidney disease, the relationship of albuminuria with cardiovascular and kidney outcomes in transplant recipients is uncertain.
Post hoc longitudinal cohort analysis of the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) Trial.
Stable kidney transplant recipients with elevated homocysteine levels from 30 sites in the United States, Canada, and Brazil.
Urine albumin-creatinine ratio (ACR) at randomization.
Allograft failure, CVD, and all-cause death.
Multivariable Cox models adjusted for age; sex; race; randomized treatment allocation; country; systolic and diastolic blood pressure; history of CVD, diabetes, and hypertension; smoking; cholesterol; body mass index; estimated glomerular filtration rate (eGFR); donor type; transplant vintage; medications; and immunosuppression.
Among 3,511 participants with complete data, median ACR was 24 (Q1-Q3, 9-98) mg/g, mean eGFR was 49±18 (standard deviation) mL/min/1.73m2, mean age was 52±9 years, and median graft vintage was 4.1 (Q1-Q3, 1.7-7.4) years. There were 1,017 (29%) with ACR < 10mg/g, 912 (26%) with ACR of 10 to 29mg/g, 1,134 (32%) with ACR of 30 to 299mg/g, and 448 (13%) with ACR ≥ 300mg/g. During approximately 4 years, 282 allograft failure events, 497 CVD events, and 407 deaths occurred. Event rates were higher at both lower eGFRs and higher ACR. ACR of 30 to 299 and ≥300mg/g relative to ACR < 10mg/g were independently associated with graft failure (HRs of 3.40 95% CI, 2.19-5.30 and 9.96 95% CI, 6.35-15.62, respectively), CVD events (HRs of 1.25 95% CI, 0.96-1.61 and 1.55 95% CI, 1.13-2.11, respectively), and all-cause death (HRs of 1.65 95% CI, 1.23-2.21 and 2.07 95% CI, 1.46-2.94, respectively).
No data for rejection; single ACR assessment.
In a large population of stable kidney transplant recipients, elevated baseline ACR is independently associated with allograft failure, CVD, and death. Future studies are needed to evaluate whether reducing albuminuria improves these outcomes.
Organisms are adapted to the relentless cycles of day and night, because they evolved timekeeping systems called circadian clocks, which regulate biological activities with ∼24-hour rhythms. The ...clock of cyanobacteria is driven by a three-protein oscillator composed of KaiA, KaiB, and KaiC, which together generate a circadian rhythm of KaiC phosphorylation. We show that KaiB flips between two distinct three-dimensional folds, and its rare transition to an active state provides a time delay that is required to match the timing of the oscillator to that of Earth's rotation. Once KaiB switches folds, it binds phosphorylated KaiC and captures KaiA, which initiates a phase transition of the circadian cycle, and it regulates components of the clock-output pathway, which provides the link that joins the timekeeping and signaling functions of the oscillator.
Although change in proteinuria has been proposed as a surrogate for long-term prognosis in membranous nephropathy (MGN), variability in proteinuria levels and lag between these changes and acceptable ...end points, such as ESRD, has limited its utility. This cohort study examined the prognostic significance of remission duration in 376 patients with biopsy-proven idiopathic/primary MGN who achieved a remission after a period of nephrotic-range proteinuria. We defined complete remission (CR), partial remission (PR), and relapse as proteinuria ≤0.3, 0.4-3.4, and ≥3.5 g/d after CR or PR, respectively. The exposure variable was the remission status of patients at fixed landmarks (3, 6, 12, 24, and 36 months) after the date of first remission. The primary outcome was ESRD or 50% reduction in eGFR. We fitted Cox proportional hazards models to examine the association of remission status at each landmark and the primary end point. Persistent remission associated with unadjusted hazard ratios for the primary outcome that ranged by landmark from 0.35 (95% confidence interval, 0.20 to 0.61) to 0.56 (95% confidence interval, 0.31 to 1.04). Separate analyses for PR and CR yielded similar results. After adjustment, maintaining remission associated with significantly reduced risk of the primary outcome at all landmarks. Durable remissions associated with improved renal survival. Although the longer the remission, the greater the improvement, patients with remission durations as short as 3 months had improved renal prognosis compared with patients who relapsed. This study validates and quantifies PR and CR as surrogates for long-term outcome in MGN.
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