Pathological hyperphosphorylation and aggregation of microtubule‐associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's ...Disease. Aptamers offer significant potential as next‐generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (Kd=6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)‐induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3β‐mediated Tau hyperphosphorylation in cell‐free systems and okadaic acid‐mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro‐orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first‐in‐class neurotherapeutic to mitigate tauopathy‐associated neurodegenerative disorders.
A novel aptamer selection method (Functional Selection) has identified a DNA aptamer, BW1c, with high specificity and affinity binding to Tau protein, representing a new avenue for inhibiting Tau protein aggregation. This strategy shows a “fit‐for‐purpose” selection workflow for discovery of aptamers with desired functionality.
BACKGROUNDthere is limited data on Emergency department (ED) cardiovascular disease (CVD) presentations and outcomes amongst cancer patients. OBJECTIVESThe present study aimed to describe the ...clinical characteristics, prevalence, and clinical outcomes of the most common cardiovascular ED admissions in patients with cancer. METHODSAll ED encounters with a primary CVD diagnosis from the US Nationwide Emergency Department Sample between January 2016 to December 2018 were stratified by cancer type as well as metastatic status. Multivariable logistic regression was performed to determine the adjusted odds ratios of in-hospital mortality in different groups. RESULTSFrom a total of 20,737,247 ED encounters with a primary CVD diagnosis, cancer was present in 3.4%. In patients with cancer the most common CVDs were DVT/PE (20%), hypertensive heart or kidney disease (14.7%), and AF/flutter (11.2%). The distribution of CVDs varied by cancer type, with AF/flutter most common in patients with lung cancer, AMI most common in patients with prostate cancer, heart failure most common in those with haematological malignancies, and patients with colorectal cancer having the greatest frequency of DVT/PE. Cancer status was independently associated with significantly higher risk of mortality in almost all CVD categories, consistent across all the cancer types, amongst which lung cancer patients had the highest risk of mortality across all CVD categories, except intracranial haemorrhage and hypertensive crisis. CONCLUSIONSCardiovascular presentations to the ED varied by cancer subtype. Across all cancer subtypes, patients presenting with cardiovascular presentations carried a significantly increased risk of mortality compared to patients with no cancer.
ABSTRACT
HIP 9618 (HD 12572, TOI-1471, TIC 306263608) is a bright (G = 9.0 mag) solar analogue. TESS photometry revealed the star to have two candidate planets with radii of 3.9 ± 0.044 R⊕ (HIP 9618 ...b) and 3.343 ± 0.039 R⊕ (HIP 9618 c). While the 20.77291 d period of HIP 9618 b was measured unambiguously, HIP 9618 c showed only two transits separated by a 680-d gap in the time series, leaving many possibilities for the period. To solve this issue, CHEOPS performed targeted photometry of period aliases to attempt to recover the true period of planet c, and successfully determined the true period to be 52.56349 d. High-resolution spectroscopy with HARPS-N, SOPHIE, and CAFE revealed a mass of 10.0 ± 3.1M⊕ for HIP 9618 b, which, according to our interior structure models, corresponds to a $6.8\pm 1.4~{{\ \rm per\ cent}}$ gas fraction. HIP 9618 c appears to have a lower mass than HIP 9618 b, with a 3-sigma upper limit of <18M⊕. Follow-up and archival RV measurements also reveal a clear long-term trend which, when combined with imaging and astrometric information, reveal a low-mass companion ($0.08^{+0.12}_{-0.05} M_\odot$) orbiting at $26.0^{+19.0}_{-11.0}$ au. This detection makes HIP 9618 one of only five bright (K < 8 mag) transiting multiplanet systems known to host a planet with P > 50 d, opening the door for the atmospheric characterization of warm (Teq < 750 K) sub-Neptunes.
Context. Tidal orbital decay is suspected to occur for hot Jupiters in particular, with the only observationally confirmed case of this being WASP-12b. By examining this effect, information on the ...properties of the host star can be obtained using the so-called stellar modified tidal quality factor Q * ′ , which describes the efficiency with which the kinetic energy of the planet is dissipated within the star. This can provide information about the interior of the star.
Aims. In this study, we aim to improve constraints on the tidal decay of the KELT-9, KELT-16, and WASP-4 systems in order to find evidence for or against the presence of tidal orbital decay. With this, we want to constrain the Q * ′ value for each star. In addition, we aim to test the existence of the transit timing variations (TTVs) in the HD 97658 system, which previously favoured a quadratic trend with increasing orbital period.
Methods. Making use of newly acquired photometric observations from CHEOPS (CHaracterising ExOplanet Satellite) and TESS (Transiting Exoplanet Survey Satellite), combined with archival transit and occultation data, we use Markov chain Monte Carlo (MCMC) algorithms to fit three models to the data, namely a constant-period model, an orbital-decay model, and an apsidal-precession model.
Results. We find that the KELT-9 system is best described by an apsidal-precession model for now, with an orbital decay trend at over 2 σ being a possible solution as well. A Keplerian orbit model with a constant orbital period provides the best fit to the transit timings of KELT-16 b because of the scatter and scale of their error bars. The WASP-4 system is best represented by an orbital decay model at a 5 σ significance, although apsidal precession cannot be ruled out with the present data. For HD 97658 b, using recently acquired transit observations, we find no conclusive evidence for a previously suspected strong quadratic trend in the data.
Context
. Multi-planet systems are important sources of information regarding the evolution of planets. However, the long-period planets in these systems often escape detection. These objects in ...particular may retain more of their primordial characteristics compared to close-in counterparts because of their increased distance from the host star. HD 22946 is a bright (
G
= 8.13 mag) late F-type star around which three transiting planets were identified via Transiting Exoplanet Survey Satellite (TESS) photometry, but the true orbital period of the outermost planet d was unknown until now.
Aims
. We aim to use the Characterising Exoplanet Satellite (CHEOPS) space telescope to uncover the true orbital period of HD 22946d and to refine the orbital and planetary properties of the system, especially the radii of the planets.
Methods
. We used the available TESS photometry of HD 22946 and observed several transits of the planets b, c, and d using CHEOPS. We identified two transits of planet d in the TESS photometry, calculated the most probable period aliases based on these data, and then scheduled CHEOPS observations. The photometric data were supplemented with ESPRESSO (Echelle SPectrograph for Rocky Exoplanets and Stable Spectroscopic Observations) radial velocity data. Finally, a combined model was fitted to the entire dataset in order to obtain final planetary and system parameters.
Results
. Based on the combined TESS and CHEOPS observations, we successfully determined the true orbital period of the planet d to be 47.42489 ± 0.00011 days, and derived precise radii of the planets in the system, namely 1.362 ± 0.040
R
⊕
, 2.328 ± 0.039
R
⊕
, and 2.607 ± 0.060
R
⊕
for planets b, c, and d, respectively. Due to the low number of radial velocities, we were only able to determine 3
σ
upper limits for these respective planet masses, which are 13.71
M
⊕
, 9.72
M
⊕
, and 26.57
M
⊕
. We estimated that another 48 ESPRESSO radial velocities are needed to measure the predicted masses of all planets in HD 22946. We also derived stellar parameters for the host star.
Conclusions
. Planet c around HD 22946 appears to be a promising target for future atmospheric characterisation via transmission spectroscopy. We can also conclude that planet d, as a warm sub-Neptune, is very interesting because there are only a few similar confirmed exoplanets to date. Such objects are worth investigating in the near future, for example in terms of their composition and internal structure.
Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high ...prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms 'complete MRD response', 'MRD persistence' and 'MRD reappearance'. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.
A big challenge in tumor targeting by nanoparticles (NPs), taking advantage of the enhanced permeability and retention effect, is the fabrication of small size devices for enhanced tumor penetration, ...which is considered fundamental to improve chemotherapy efficacy. The purposes of this study are (i) to engineer the formulation of doxorubicin-loaded poly(D,L-lactic-co-glycolic acid) (PLGA)-block-poly(ethylene glycol) (PEG) NPs to obtain <100 nm devices and (ii) to translate standard 2D cytotoxicity studies to 3D collagen systems in which an initial step gradient of the NPs is present. Doxorubicin release can be prolonged for days to weeks depending on the NP formulation and the pH of the release medium. Sub-100 nm NPs are effectively internalized by HeLa cells in 2D and are less cytotoxic than free doxorubicin. In 3D, <100 nm NPs are significantly more toxic than larger ones towards HeLa cells, and the cell death rate is affected by the contributions of drug release and device transport through collagen. Thus, the reduction of NP size is a fundamental feature from both a technological and a biological point of view and must be properly engineered to optimize the tumor response to the NPs.
This paper details the first application of a software tagging algorithm to reduce radon-induced backgrounds in liquid noble element time projection chambers, such as XENON1T and XENONnT. The ...convection velocity field in XENON1T was mapped out using Rn 222 and Po 218 events, and the rms convection speed was measured to be 0.30 ± 0.01 cm / s . Given this velocity field, Pb 214 background events can be tagged when they are followed by Bi 214 and Po 214 decays, or preceded by Po 218 decays. This was achieved by evolving a point cloud in the direction of a measured convection velocity field, and searching for Bi 214 and Po 214 decays or Po 218 decays within a volume defined by the point cloud. In XENON1T, this tagging system achieved a Pb 214 background reduction of 6.2 − 0.9 + 0.4 % with an exposure loss of 1.8 ± 0.2 % , despite the timescales of convection being smaller than the relevant decay times. We show that the performance can be improved in XENONnT, and that the performance of such a software-tagging approach can be expected to be further improved in a diffusion-limited scenario. Finally, a similar method might be useful to tag the cosmogenic Xe 137 background, which is relevant to the search for neutrinoless double-beta decay. Published by the American Physical Society 2024
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