To assess the neurobiological substrate of initial cognitive decline in Parkinson's disease (PD) to inform patient management, clinical trial design, and development of treatments.
We longitudinally ...assessed, up to 3 years, 423 newly diagnosed patients with idiopathic PD, untreated at baseline, from 33 international movement disorder centers. Study outcomes were four determinations of cognitive impairment or decline, and biomarker predictors were baseline dopamine transporter (DAT) single photon emission computed tomography (SPECT) scan, structural magnetic resonance imaging (MRI; volume and thickness), diffusion tensor imaging (mean diffusivity and fractional anisotropy), cerebrospinal fluid (CSF; amyloid beta Aβ, tau and alpha synuclein), and 11 single nucleotide polymorphisms (SNPs) previously associated with PD cognition. Additionally, longitudinal structural MRI and DAT scan data were included. Univariate analyses were run initially, with false discovery rate = 0.2, to select biomarker variables for inclusion in multivariable longitudinal mixed-effect models.
By year 3, cognitive impairment was diagnosed in 15-38% participants depending on the criteria applied. Biomarkers, some longitudinal, predicting cognitive impairment in multivariable models were: (1) dopamine deficiency (decreased caudate and putamen DAT availability); (2) diffuse, cortical decreased brain volume or thickness (frontal, temporal, parietal, and occipital lobe regions); (3) co-morbid Alzheimer's disease Aβ amyloid pathology (lower CSF Aβ 1-42); and (4) genes (COMT val/val and BDNF val/val genotypes).
Cognitive impairment in PD increases in frequency 50-200% in the first several years of disease, and is independently predicted by biomarker changes related to nigrostriatal or cortical dopaminergic deficits, global atrophy due to possible widespread effects of neurodegenerative disease, co-morbid Alzheimer's disease plaque pathology, and genetic factors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Progress in understanding tumor stromal biology has been constrained in part because cancer-associated fibroblasts (CAF) are a heterogeneous population with limited cell-type-specific protein ...markers. Using RNA expression profiling, we identified the membrane protein leucine-rich repeat containing 15 (LRRC15) as highly expressed in multiple solid tumor indications with limited normal tissue expression. LRRC15 was expressed on stromal fibroblasts in many solid tumors (e.g., breast, head and neck, lung, pancreatic) as well as directly on a subset of cancer cells of mesenchymal origin (e.g., sarcoma, melanoma, glioblastoma). LRRC15 expression was induced by TGFβ on activated fibroblasts (αSMA
) and on mesenchymal stem cells. These collective findings suggested LRRC15 as a novel CAF and mesenchymal marker with utility as a therapeutic target for the treatment of cancers with LRRC15-positive stromal desmoplasia or cancers of mesenchymal origin. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) directed against LRRC15, and it demonstrated robust preclinical efficacy against LRRC15 stromal-positive/cancer-negative, and LRRC15 cancer-positive models as a monotherapy, or in combination with standard-of-care therapies. ABBV-085's unique mechanism of action relied upon the cell-permeable properties of MMAE to preferentially kill cancer cells over LRRC15-positive CAF while also increasing immune infiltrate (e.g., F4/80
macrophages) in the tumor microenvironment. In summary, these findings validate LRRC15 as a novel therapeutic target in multiple solid tumor indications and support the ongoing clinical development of the LRRC15-targeted ADC ABBV-085.
These findings identify LRRC15 as a new marker of cancer-associated fibroblasts and cancers of mesenchymal origin and provide preclinical evidence for the efficacy of an antibody-drug conjugate targeting the tumor stroma.
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Activity-monitoring devices may increase activity, but their effectiveness in sedentary, diseased, and less-motivated populations is unknown.
Subjects with diabetes or pre-diabetes were given a ...Fitbit and randomized into three groups: Fitbit only, Fitbit with reminders, and Fitbit with both reminders and goal setting. Subjects in the reminders group were sent text-message reminders to wear their Fitbit. The goal-setting group was sent a daily text message asking for a step goal. All subjects had three in-person visits (baseline, 3 and 6 months). We modelled daily steps and goal setting using linear mixed-effects models.
138 subjects participated with 48 in the Fitbit-only, 44 in the reminders, and 46 in the goal-setting groups. Daily steps decreased for all groups during the study. Average daily steps were 7123, 6906, and 6854 for the Fitbit-only, the goal-setting, and the reminders groups, respectively. The reminders group was 17.2 percentage points more likely to wear their Fitbit than the Fitbit-only group. Setting a goal was associated with a significant increase of 791 daily steps, but setting more goals did not lead to step increases.
In a population of patients with diabetes or pre-diabetes, individualized reminders to wear their Fitbit and elicit personal step goals did not lead to increases in daily steps, although daily steps were higher on days when goals were set. Our intervention improved engagement and data collection, important goals for activity surveillance. This study demonstrates that new, more-effective interventions for increasing activity in patients with pre-diabetes and diabetes are needed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of ...digestive manifestations in patients hospitalized with COVID-19.
Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were abstracted manually from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19.
A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least 1 gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were increased to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio, 0.93; 95% CI, 0.76-1.15) or liver test abnormalities on admission (odds ratio, 1.31; 95% CI, 0.80-2.12) were not associated independently with mechanical ventilation or death.
Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common, but the majority were mild and their presence was not associated with a more severe clinical course.
We present XMM-Newton observations of N132D, the X-ray brightest supernova remnant in the Large Magellanic Cloud, using the Reflection Grating Spectrometer (RGS), which enables high-resolution ...spectroscopy in the soft X-ray band. A dozen emission lines from L-shell transitions of Si, S, Ar, Ca, and Fe at intermediate charge states are newly detected in the RGS data integrating the ∼200 ks on-axis observations. This enables accurate abundance measurements of these elements, whose K-shell emission is out of the RGS bandpass. The 0.3-2.0-keV spectra require at least three components of thermal plasmas with different electron temperatures and indicate clear evidence of non-equilibrium ionization (NEI). Our detailed spectral diagnostics further reveal that the forbidden-to-resonance line ratios of O vii and Ne ix are both higher than expected for typical NEI plasmas. This enhancement could be attributed to either resonance scattering or emission induced by charge exchange in addition to a possible contribution from the superposition of multiple-temperature components, although the lack of spatial information prevents us from concluding which is most likely.
Abstract
Objectives
We examined whether a home-based, adaptive cognitive training (CT) program would lead to cognitive performance changes on a neuropsychological test battery in cognitively normal ...older adults.
Method
Sixty-eight older adults (age = 70.0, SD = 3.74) were randomly assigned to either CT or an active control group (AC, casual computer games). Participants were instructed to train on their assigned programs for 42 min per day, 5 days per week, over 10 weeks (35 hr of total program usage). Participants completed tests of processing speed, working memory, and executive control before and after 10 weeks of training.
Results
Training groups did not differ in performance before training. After training, CT participants out-performed AC participants in the overall cognitive composite score, driven by processing speed and working memory domains.
Discussion
Our results show that a limited dose of home-based CT can drive cognitive improvements as measured with neuropsychological test battery, suggesting potential cognitive health maintenance implications for cognitively normal older adults.
Diverse stresses including starvation and muscle disuse cause skeletal muscle atrophy. However, the molecular mechanisms of muscle atrophy are complex and not well understood. Here, we demonstrate ...that growth arrest and DNA damage-inducible 45a protein (Gadd45a) is a critical mediator of muscle atrophy. We identified Gadd45a through an unbiased search for potential downstream mediators of the stress-inducible, pro-atrophy transcription factor ATF4. We show that Gadd45a is required for skeletal muscle atrophy induced by three distinct skeletal muscle stresses: fasting, muscle immobilization, and muscle denervation. Conversely, forced expression of Gadd45a in muscle or cultured myotubes induces atrophy in the absence of upstream stress. We show that muscle-specific ATF4 knock-out mice have a reduced capacity to induce Gadd45a mRNA in response to stress, and as a result, they undergo less atrophy in response to fasting or muscle immobilization. Interestingly, Gadd45a is a myonuclear protein that induces myonuclear remodeling and a comprehensive program for muscle atrophy. Gadd45a represses genes involved in anabolic signaling and energy production, and it induces pro-atrophy genes. As a result, Gadd45a reduces multiple barriers to muscle atrophy (including PGC-1α, Akt activity, and protein synthesis) and stimulates pro-atrophy mechanisms (including autophagy and caspase-mediated proteolysis). These results elucidate a critical stress-induced pathway that reprograms muscle gene expression to cause atrophy.
Background: In skeletal muscle, diverse stresses induce the transcription factor ATF4, which promotes muscle atrophy by an unknown mechanism.
Results: ATF4 causes muscle atrophy by inducing Gadd45a, which reprograms myonuclear gene expression to repress anti-atrophy mechanisms and induce pro-atrophy mechanisms.
Conclusion: Gadd45a is a critical stress-induced mediator of muscle atrophy.
Significance: The ATF4/Gadd45a pathway is a potential therapeutic target in atrophic muscle.
Context. The flight calibration of the spectral response of charge-coupled device (CCD) instruments below 1.5 keV is difficult in general because of the lack of strong lines in the on-board ...calibration sources typically available. This calibration is also a function of time due to the effects of radiation damage on the CCDs and/or the accumulation of a contamination layer on the filters or CCDs. Aims. We desire a simple comparison of the absolute effective areas of the current generation of CCD instruments onboard the following observatories: Chandra ACIS-S3, XMM-Newton (EPIC-MOS and EPIC-pn), Suzaku XIS, and Swift XRT and a straightforward comparison of the time-dependent response of these instruments across their respective mission lifetimes. Methods. We have been using 1E 0102.2-7219, the brightest supernova remnant in the Small Magellanic Cloud, to evaluate and modify the response models of these instruments. 1E 0102.2-7219 has strong lines of O, Ne, and Mg below 1.5 keV and little or no Fe emission to complicate the spectrum. The spectrum of 1E 0102.2-7219 has been well-characterized using the RGS gratings instrument on XMM-Newton and the HETG gratings instrument on Chandra. As part of the activities of the International Astronomical Consortium for High Energy Calibration (IACHEC), we have developed a standard spectral model for 1E 0102.2-7219 and fit this model to the spectra extracted from the CCD instruments. The model is empirical in that it includes Gaussians for the identified lines, an absorption component in the Galaxy, another absorption component in the SMC, and two thermal continuum components with different temperatures. In our fits, the model is highly constrained in that only the normalizations of the four brightest lines/line complexes (the O vii Heα triplet, O viii Lyα line, the Ne ix Heα triplet, and the Ne x Lyα line) and an overall normalization are allowed to vary, while all other components are fixed. We adopted this approach to provide a straightforward comparison of the measured line fluxes at these four energies. We have examined these measured line fluxes as a function of time for each instrument after applying the most recent calibrations that account for the time-dependent response of each instrument. Results. We performed our effective area comparison with representative, early mission data when the radiation damage and contamination layers were at a minimum, except for the XMM-Newton EPIC-pn instrument which is stable in time. We found that the measured fluxes of the O vii Heαr line, the O viii Lyα line, the Ne ix Heαr line, and the Ne x Lyα line generally agree to within ±10% for all instruments, with 38 of our 48 fitted normalizations within ± 10% of the IACHEC model value. We then fit all available observations of 1E 0102.2-7219 for the CCD instruments close to the on-axis position to characterize the time dependence in the 0.5−1.0 keV band. We present the measured line normalizations as a function of time for each CCD instrument so that the users may estimate the uncertainty in their measured line fluxes for the epoch of their observations.
Society needs information about how vegetation communities in coastal regions will be impacted by hydrologic changes associated with climate change, particularly sea level rise. Due to anthropogenic ...influences which have significantly decreased natural coastal vegetation communities, it is important for us to understand how remaining natural communities will respond to sea level rise. The Cape Canaveral Barrier Island complex (CCBIC) on the east central coast of Florida is within one of the most biologically diverse estuarine systems in North America and has the largest number of threatened and endangered species on federal property in the contiguous United States. The high level of biodiversity is susceptible to sea level rise. Our objective was to model how vegetation communities along a gradient ranging from hydric to upland xeric on CCBIC will respond to three sea level rise scenarios (0.2 m, 0.4 m, and 1.2 m). We used a probabilistic model of the current relationship between elevation and vegetation community to determine the impact sea level rise would have on these communities. Our model correctly predicted the current proportions of vegetation communities on CCBIC based on elevation. Under all sea level rise scenarios the model predicted decreases in mesic and xeric communities, with the greatest losses occurring in the most xeric communities. Increases in total area of salt marsh were predicted with a 0.2 and 0.4 m rise in sea level. With a 1.2 m rise in sea level approximately half of CCBIC's land area was predicted to transition to open water. On the remaining land, the proportions of most of the vegetation communities were predicted to remain similar to that of current proportions, but there was a decrease in proportion of the most xeric community (oak scrub) and an increase in the most hydric community (salt marsh). Our approach provides a first approximation of the impacts of sea level rise on terrestrial vegetation communities, including important xeric upland communities, as a foundation for management decisions and future modeling.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Metal-Organic Frameworks (MOFs) that catalyze hydrogenolysis reactions are rare and there is little understanding of how the MOF, hydrogen, and substrate molecules interact. In this regard, the ...isoreticular IRMOF-74 series, two of which are known catalysts for hydrogenolysis of aromatic C-O bonds, provides an unusual opportunity for systematic probing of these reactions. The diameter of the 1D open channels can be varied within a common topology owing to the common secondary building unit (SBU) and controllable length of the hydroxy-carboxylate struts. We show that the first four members of the IRMOF-74(Mg) series are inherently catalytic for aromatic C-O bond hydrogenolysis and that the conversion varies non-monotonically with pore size. These catalysts are recyclable and reusable, retaining their crystallinity and framework structure after the hydrogenolysis reaction. The hydrogenolysis conversion of phenylethylphenyl ether (PPE), benzylphenyl ether (BPE), and diphenyl ether (DPE) varies as PPE > BPE > DPE, consistent with the strength of the C-O bond. Counterintuitively, however, the conversion also follows the trend IRMOF-74(III) > IRMOF-74(IV) > IRMOF-74(II) > IRMOF-74(I), with little variation in the corresponding selectivity. DFT calculations suggest the unexpected behavior is due to much stronger ether and phenol binding to the Mg(
ii
) open metal sites (OMS) of IRMOF-74(III), resulting from a structural distortion that moves the Mg
2+
ions toward the interior of the pore. Solid-state
25
Mg NMR data indicate that both H
2
and ether molecules interact with the Mg(
ii
) OMS and hydrogen-deuterium exchange reactions show that these MOFs activate dihydrogen bonds. The results suggest that both confinement and the presence of reactive metals are essential for achieving the high catalytic activity, but that subtle variations in pore structure can significantly affect the catalysis. Moreover, they challenge the notion that simply increasing MOF pore size within a constant topology will lead to higher conversions.
Non-monotonic catalytic behavior in an isoreticular MOF series results from subtle structural differences that alter the substrate binding energy.
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