DNA-Mediated Excitonic Upconversion FRET Switching

Excitonics is a rapidly expanding field of nanophotonics in which the harvesting of photons, ensuing creation and transport of excitons via Förster resonant energy transfer (FRET), and subsequent charge separation or photon emission has led to the demonstration of excitonic wires, switches, Boolean logic and light harvesting antennas for many applications. FRET funnels excitons down an energy gradient resulting in energy loss with each step along the pathway. Conversely, excitonic energy upconversion via upconversion nanoparticles (UCNPs), although currently inefficient, serves as an energy ratchet to boost the exciton energy. Although FRET-based upconversion has been demonstrated, it suffers from low FRET efficiency and lacks the ability to modulate the FRET. We have engineered an upconversion FRET-based switch by combining lanthanide-doped UCNPs and fluorophores that demonstrates excitonic energy upconversion by nearly a factor of 2, an excited state donor to acceptor FRET efficiency of nearly 25%, and an acceptor fluorophore quantum efficiency that is close to unity. These findings offer a promising path for energy upconversion in nanophotonic applications including artificial light harvesting, excitonic circuits, photovoltaics, nanomedicine, and optoelectronics

Correlation Between Caregiver Reports of Physical Function and Performance-based Measures in a Cohort of Older Adults With Alzheimer Disease

The objectives of this report are to determine the association between performance-based measures of physical function with caregiver reports of physical function in older adults with Alzheimer disease (AD) and to examine whether those associations vary by the level of patients' cognitive functioning. Subjects included 180 patient-caregiver dyads who are enrolled in a clinical trial testing the impact of an occupational therapy intervention plus guideline-level care to delay functional decline among older adults with AD. The primary caregiver-reported measure is the Alzheimer's Disease Cooperative Study Group Activities of Daily Living Inventory (ADCS-ADL). Performance-based measures include the Short Physical Performance Battery and the Short Portable Sarcopenia Measure. Analysis of covariance (ANCOVA) models were used to determine the associations of each physical performance measure with ADCS-ADL, adjusting for cognition function and other covariates. We found significant correlations between caregiver reports and observed performance-based measures across all levels of cognitive function, with patients in the lowest cognitive group showing the highest correlation. These findings support the use of proxy reports to assess physical function among older adults with AD

Oral contraceptive use and mortality after 36 years of follow-up in the Nurses\u27 Health Study: Prospective cohort study

Objective To determine whether use of oral contraceptives is associated with all cause and cause specific mortality. Design Prospective cohort study. Setting Nurses’ Health Study, data collected between 1976 and 2012. Population 121 701 participants were prospectively followed for 36 years; lifetime oral contraceptive use was recorded biennially from 1976 to 1982. Main outcome measures Overall and cause specific mortality, assessed throughout follow-up until 2012. Cox proportional hazards models were used to calculate the relative risks of all cause and cause specific mortality associated with use of oral contraceptives. Results In our population of 121 577 women with information on oral contraceptive use, 63 626 were never users (52%) and 57 951 were ever users (48%). After 3.6 million person years, we recorded 31 286 deaths. No association was observed between ever use of oral contraceptives and all cause mortality. However, violent or accidental deaths were more common among ever users (hazard ratio 1.20, 95% confidence interval 1.04 to 1.37). Longer duration of use was more strongly associated with certain causes of death, including premature mortality due to breast cancer (test for trend P<0.0001) and decreased mortality rates of ovarian cancer (P=0.002). Longer time since last use was also associated with certain outcomes, including a positive association with violent or accidental deaths (P=0.005). Conclusions All cause mortality did not differ significantly between women who had ever used oral contraceptives and never users. Oral contraceptive use was associated with certain causes of death, including increased rates of violent or accidental death and deaths due to breast cancer, whereas deaths due to ovarian cancer were less common among women who used oral contraceptives. These results pertain to earlier oral contraceptive formulations with higher hormone doses rather than the now more commonly used third and fourth generation formulations with lower estrogen doses

Prey preference in a kleptoplastic dinoflagellate is linked to photosynthetic performance

Dinoflagellates of the family Kryptoperidiniaceae, known as “dinotoms”, possess diatom-derived endosymbionts and contain individuals at three successive evolutionary stages: a transiently maintained kleptoplastic stage; a stage containing multiple permanently maintained diatom endosymbionts; and a further permanent stage containing a single diatom endosymbiont. Kleptoplastic dinotoms were discovered only recently, in Durinskia capensis; until now it has not been investigated kleptoplastic behavior and the metabolic and genetic integration of host and prey. Here, we show D. capensis is able to use various diatom species as kleptoplastids and exhibits different photosynthetic capacities depending on the diatom species. This is in contrast with the prey diatoms in their free-living stage, as there are no differences in their photosynthetic capacities. Complete photosynthesis including both the light reactions and the Calvin cycle remain active only when D. capensis feeds on its habitual associate, the “essential” diatom Nitzschia captiva. The organelles of another edible diatom, N. inconspicua, are preserved intact after ingestion by D. capensis and expresses the psbC gene of the photosynthetic light reaction, while RuBisCO gene expression is lost. Our results indicate that edible but non-essential, “supplemental” diatoms are used by D. capensis for producing ATP and NADPH, but not for carbon fixation. D. capensis has established a species-specifically designed metabolic system allowing carbon fixation to be performed only by its essential diatoms. The ability of D. capensis to ingest supplemental diatoms as kleptoplastids may be a flexible ecological strategy, to use these diatoms as “emergency supplies” while no essential diatoms are available.Open Access funding enabled and organized by Projekt DEAL.We are grateful to Dr Benjamin Bailleul for discussing the photoactivity possibility of N. inconspicua, and to Prof Dieter Spiteller and Dr Adrien Lapointe for suggesting the feeding experiment of D. capensis with four selected diatoms. We also thank Dr Martin Stöckl, from the Bioimaging Centre at University of Konstanz, for technical support of the CLSM. Our thanks also go to Ms Selina Pucher and Mr Alexander H. Fürst for discussing the RT-qPCR data analyses and evaluation, and to Mr Niccolo Mosesso for discussing the TEM protocol improvement. This research was supported by the Bridging Stipend of University of Konstanz (No.638/20, granted to NY), the DFG Research Grant (No. YA 577/2-1, granted to NY), and the Symbiosis Model Systems Award (No. GBMF9360, granted to NY, RT, DGM, PGK) of the Gordon and Betty Moore Foundation. The CERCA Programme of Generalitat of Catalonia is also acknowledged. The Royal Botanic Garden Edinburgh is supported by the Scottish Government’s Rural and Environment Science and Analytical Services Division.info:eu-repo/semantics/publishedVersio

Gross Motor Function in Pediatric Onset TUBB4A-Related Leukodystrophy: GMFM-88 Performance and Validation of GMFC-MLD in TUBB4A

TUBB4A pathogenic variants are associated with a spectrum of neurologic impairments including movement disorders and leukodystrophy. With the development of targeted therapies, there is an urgent unmet need for validated tools to measure mobility impairment. Our aim is to explore gross motor function in a pediatric-onset TUBB4A-related leukodystrophy cohort with existing gross motor outcome tools. Gross Motor Function Measure-88 (GMFM-88), Gross Motor Function Classification System (GMFCS-ER), and Gross Motor Function Classification-Metachromatic Leukodystrophy (GMFC-MLD) were selected through face validity. Subjects with a confirmed clinical and molecular diagnosis of TUBB4A-related leukodystrophy were enrolled. Participants' sex, age, genotype, and age at disease onset were collected, together with GMFM-88 and concurrent GMFCS-ER and GMFC-MLD. Performances on each measure were compared. GMFM-88 floor effect was defined as total score below 20%. A total of 35 subjects participated. Median performance by GMFM-88 was 16.24% (range 0-97.31), with 42.9% (n = 15) of individuals performing above the floor. GMFM-88 Dimension A (Lying and Rolling) was the best-performing dimension in the GMFM-88 (n = 29 above the floor). All levels of the Classification Scales were represented, with the exception of the GMFC-MLD level 0. Evaluation by GMFM-88 was strongly correlated with the Classification Scales (Spearman correlations: GMFCS-ER:GMFM-88 r = 0.90; GMFC-MLD:GMFM-88 r = 0.88; GMFCS-ER:GMFC-MLD: r = 0.92). Despite overall observation of a floor effect, the GMFM-88 is able to accurately capture the performance of individuals with attenuated phenotypes. GMFM-88 Dimension A shows no floor effect. GMFC-MLD shows a strong correlation with GMFCS-ER and GMFM-88, supporting its use as an age-independent functional score in TUBB4A-related leukodystrophy

Oral Contraceptive Use and Colorectal Cancer in the Nurses' Health Study I and II

Background—It remains unclear if oral contraceptive (OC) use is associated with the incidence of colorectal cancer. Few studies have examined this association by duration of OC use, time since last OC use, and different cancer subsites. Methods—Among 88,691 participants of the Nurses’ Health Study I (NHSI) and 93,080 participants of the Nurses’ Health Study II (NHSII), we assessed OC use every 2 years between 1976-2010 and categorized it as ever use, duration of use, and time since last use. We included incident colorectal cancer cases through 2010 (NHSI: age at diagnosis=36-88, N=1,764, NHSII: age at diagnosis=33-64, N=206). Multivariable hazard ratios and 95% confidence intervals [HR (95% CIs)] were estimated using Cox proportional hazards regression models. Results—Ever OC use was not associated with colorectal cancer in NHSI [1.01 (0.91, 1.12)] nor NHSII [1.03 (0.69, 1.53)]. In NHSII, when compared to never-users, longer durations (5+ years)of OC use were inversely associated with the risk of colon cancers (test for trend p=0.02) but the number of endpoints was limited. No other colorectal cancer subsites were associated with OC durations or times since last OC use in either cohort. Conclusions—In two large prospective cohorts, we found little evidence that OC use may be protective for colorectal cancer, except potentially with longer durations of use among younger women. Impact—Our results do not support the previous initial studies that reported an inverse association of recent OC use with colorectal cancer but instead support newer, larger studies demonstrating no such association

Bacillus Calmette-Guérin vaccination as defense against SARS-CoV-2 (BADAS):a randomized controlled trial to protect healthcare workers in the USA by enhanced trained immune responses

Background: A large epidemic, such as that observed with SARS-CoV-2, seriously challenges available hospital capacity, and this would be augmented by infection of healthcare workers (HCW). Bacillus Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other respiratory tract infections in vitro and in vivo. Preliminary analyses suggest that regions of the world with existing BCG vaccination programs have lower incidence and mortality from COVID-19. We hypothesize that BCG vaccination can reduce SARS-CoV-2 infection and disease severity. Methods: This will be a placebo-controlled adaptive multi-center randomized controlled trial. A total of 1800 individuals considered to be at high risk, including those with comorbidities (hypertension, diabetes, obesity, reactive airway disease, smokers), racial and ethnic minorities, elderly, teachers, police, restaurant wait-staff, delivery personnel, health care workers who are defined as personnel working in a healthcare setting, at a hospital, medical center or clinic (veterinary, dental, ophthalmology), and first responders (paramedics, firefighters, or law enforcement), will be randomly assigned to two treatment groups. The treatment groups will receive intradermal administration of BCG vaccine or placebo (saline) with groups at a 1:1 ratio. Individuals will be tracked for evidence of SARS-CoV-2 infection and severity as well as obtaining whole blood to track immunological markers, and a sub-study will include cognitive function and brain imaging. The majority of individuals will be followed for 6 months, with an option to extend for another 6 months, and the cognitive sub-study duration is 2 years. We will plot Kaplan-Meier curves that will be plotted comparing groups and hazard ratios and p-values reported using Cox proportional hazard models. Discussion: It is expected this trial will allow evaluation of the effects of BCG vaccination at a population level in high-risk healthcare individuals through a mitigated clinical course of SARS-CoV-2 infection and inform policy making during the ongoing epidemic. Trial registration: ClinicalTrials.gov NCT04348370. Registered on April 16, 2020.</p