Background
Alzheimer’s disease pathophysiology may affect sound processing (central auditory function) in the brain. This study aims to investigate the link between tests of central auditory ...function, such as dichotic digits, and brain pathology in older adults at high risk for developing dementia.
Method
28 individuals (13 cognitively unimpaired (CU) and 15 mild cognitively impaired (MCI)) were enrolled (Table 1). Amyloid deposition was assessed with 18F AZD4694 PET and tau accumulation was assessed with 18FMK6240 PET. Standard uptake value ratios (SUVR) were determined using the cerebellar and the inferior cerebellar cortex as reference region for amyloid and tau PET, respectively. Hearing assessments were conducted using a custom audiological testing system from Creare LLC. Voxel‐based regression models evaluated the association between dichotic digit scores and amyloid and tau deposition as assessed by PET, adjusting for Pure Tone Average (PTA) and a control condition for speech in noise (Triple digits score). Random field theory (RFT) was used to correct for multiple comparisons.
Result
In the voxel‐wise analysis, negative associations between dichotic digits scores and amyloid‐PET were found in the temporal, occipital and parietal areas. Negative associations between dichotic digits scores and tau‐PET were present in the temporal area, with higher t‐values in the primary and secondary somatosensory cortices (Figure 1, panel A). Negative correlations were found between dichotic digits scores and both amyloid (p<0.001) and tau (p<0.05) SUVRs (Figure 1, panel B). In addition, dichotic digits scores were significantly lower in MCI individuals (p<0.001) (Figure 1, panel C).
Conclusion
This study is the first to assess associations between central auditory hearing in CU and MCI individuals using PET biomarkers. These findings highlight the link between central auditory deficits and AD hallmarks in auditory processing‐related brain regions. This suggests a potential decreased capacity for interhemispheric transfer in mildly cognitively impaired individuals.
Smoking and COPD are associated with decreased mucociliary clearance, and healthy smokers have shorter cilia in the large airway than nonsmokers. We hypothesized that changes in cilia length are ...consistent throughout the airway, and we further hypothesized that smokers with COPD have shorter cilia than healthy smokers. Because intraflagellar transport (IFT) is the process by which cilia of normal length are produced and maintained, and alterations in IFT lead to short cilia in model organisms, we also hypothesized that smoking induces changes in the expression of IFT-related genes in the airway epithelium of smokers and smokers with COPD. To assess these hypotheses, airway epithelium was obtained via bronchoscopic brushing. Cilia length was assessed by measuring 100 cilia (10 cilia on each of 10 cells) per subject and Affymetrix microarrays were used to evaluate IFT gene expression in nonsmokers and healthy smokers in 2 independent data sets from large and small airway as well as in COPD smokers in a data set from the small airway. In the large and small airway epithelium, cilia were significantly shorter in healthy smokers than nonsmokers, and significantly shorter in COPD smokers than in both healthy smokers and nonsmokers. The gene expression data confirmed that a set of 8 IFT genes were down-regulated in smokers in both data sets; however, no differences were seen in COPD smokers compared to healthy smokers. These results support the concept that loss of cilia length contributes to defective mucociliary clearance in COPD, and that smoking-induced changes in expression of IFT genes may be one mechanism of abnormally short cilia in smokers. Strategies to normalize cilia length may be an important avenue for novel COPD therapies.
The pandemic spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of Coronavirus Disease 2019 (COVID-19), represents an ongoing international health crisis. A ...key symptom of SARS-CoV-2 infection is the onset of fever, with a hyperthermic temperature range of 38 to 41°C. Fever is an evolutionarily conserved host response to microbial infection that can influence the outcome of viral pathogenicity and regulation of host innate and adaptive immune responses. However, it remains to be determined what effect elevated temperature has on SARS-CoV-2 replication. Utilizing a three-dimensional (3D) air-liquid interface (ALI) model that closely mimics the natural tissue physiology of SARS-CoV-2 infection in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection. Respiratory tissue incubated at 40°C remained permissive to SARS-CoV-2 entry but refractory to viral transcription, leading to significantly reduced levels of viral RNA replication and apical shedding of infectious virus. We identify tissue temperature to play an important role in the differential regulation of epithelial host responses to SARS-CoV-2 infection that impact upon multiple pathways, including intracellular immune regulation, without disruption to general transcription or epithelium integrity. We present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication in respiratory epithelia. Our data identify an important role for tissue temperature in the epithelial restriction of SARS-CoV-2 independently of canonical interferon (IFN)-mediated antiviral immune defenses.
Soybean (Glycine max) seed contain some proteins that are allergenic to humans and animals. However, the concentration of these allergens and their expression variability among germplasms is ...presently unknown. To address this problem, 10 allergens were quantified from 20 nongenetically modified commercial soybean varieties using parallel, label-free mass spectrometry approaches. Relative quantitation was performed by spectral counting and absolute quantitation was performed using multiple reaction monitoring (MRM) with synthetic, isotope-labeled peptides as internal standards. During relative quantitation analysis, 10 target allergens were identified, and five of these allergens showed expression levels higher than technical variation observed for bovine serum albumin (BSA) internal standard (∼11%), suggesting expression differences among the varieties. To confirm this observation, absolute quantitation of these allergens from each variety was performed using MRM. Eight of the 10 allergens were quantified for their concentration in seed and ranged from approximately 0.5 to 5.7 μg/mg of soy protein. MRM analysis reduced technical variance of BSA internal standards to approximately 7%, and confirmed differential expression for four allergens across the 20 varieties. This is the first quantitative assessment of all major soybean allergens. The results show the total quantity of allergens measured among the 20 soy varieties was mostly similar.
To determine which coexisting conditions have the strongest associations with healthcare use and spending among children with cerebral palsy (CP).
Retrospective analysis of 16 695 children ages 0-18 ...years with CP – identified with International Classification of Diseases, Ninth Revision, Clinical Modification codes – using Medicaid from January 1, 2013 to December 31, 2013 from 10 states in the Truven MarketScan Medicaid Database. Using generalized linear models, we assessed which coexisting conditions (including medical technology) identified with Agency for Healthcare Research and Quality's Chronic Condition Indicators had the strongest associations with total healthcare spending across the healthcare continuum.
Median per-patient annual Medicaid spending for children with CP was $12 299 (IQR $4826-$35 582). Most spending went to specialty (33.1%) and hospital (26.7%) care. The children had a median 6 (IQR 4-10) coexisting conditions; epilepsy was the most common (38.1%). Children with epilepsy accounted for 59.6% ($364 million) of all CP spending. In multivariable analysis, the coexisting conditions most strongly associated with increased spending were tracheostomy (median additional cost per patient = $56 567 95%CI $51 386-61 748) and enterostomy (median additional cost per patient = $25 707 95%CI $23 753-27 660).
Highly prevalent in children with CP using Medicaid, coexisting conditions correlate strongly with healthcare spending. Tracheostomy and enterostomy, which indicate significant functional impairments in breathing and digestion, are associated with the highest spending. Families, providers, payers, and legislators may leverage these findings when designing policies positioned to enable the best health and care for children with cerebral palsy.
We attempted to identify
histidine-rich protein 2/3 (
) deletions among rapid diagnostic test (RDT)-negative but PCR- or microscopy-positive
-infected individuals in areas of low transmission (Choma ...District, 2009-2011) and high transmission (Nchelenge District, 2015-2017) in Zambia. Through community-based surveys, 5,167 participants were screened at 1,147 households by
histidine-rich protein 2 (PfHRP2)-based RDTs. Slides were made and dried blood spots were obtained for molecular analysis. Of 28 samples with detectable
DNA, none from Nchelenge District were
negative. All eight samples from Choma District had detectable
genes, but
was undetectable in three. DNA concentrations of
-negative samples were low (< 0.001 ng/μL). These findings suggest that PfHRP2-based RDTs remain effective tools for malaria diagnosis in Nchelenge District, but further study is warranted to understand the potential for
deletions in southern Zambia where malaria transmission declined over the past decade.
Precise and accurate quantitation of maize grain allergens is important for seed and food industries. The major allergen in maize grain is Zea m 14, a lipid transfer protein (LTP). The B73 maize ...genome encodes for at least six LTPs sharing 15%–87% sequence identity to Zea m 14. Phylogenetic analysis of the maize LTP family revealed one gene that corresponds to Zea m 14 (denoted as LTPa) and two other genes sharing 43% (LTPc) and 74% (LTPb) identity with Zea m 14 that are putative homologues. Using stable isotope peptide mimics as internal standards for LTPs, we present a multiple reaction monitoring mass spectrometry approach for multiplexed, absolute quantitation of all three LTP proteins and alternative transcript models therein. To validate quantitative accuracy, a redundant peptide, simultaneously representing the two most abundant LTPs, was included. Analysis of 21 maize varieties revealed LTPa was most prominently expressed in maize grain, ranging from 9 to 32 μg LTP/mg protein. Proteins belonging to the LTPb and LTPc gene models were also expressed but at approximately 10- and 100-fold lower levels than LTPa, respectively. The quantitative results provided by the redundant peptide show around 95% agreement with the sum of the two unique peptides, thus providing support for the LTP gene models and validating the accuracy of this method. Though not all Zea m 14-related LTPs are abundant in grain, their high sequence homology and detectable expression in maize grain signify that LTPb and LTPc are putative allergens and should be accounted for in any quantitation strategy for maize LTP allergens.
Soybean (
) is an important food stock, and also considered an allergenic food with at least eight well characterized allergens. However, it is a less prevalent allergen source than many other foods ...and is rarely life-threatening. Soybean is incorporated into commonly consumed foods, and therefore, the allergens pose a potential concern for individuals already sensitized. The protein profile of soybean can be affected by several factors including genetic and environmental. To investigate how soybean allergen content may be affected by genetics and/or environment, nine soy allergens were quantified from three commercial soybean varieties grown at nine locations in three states within a single climate zone in North America; Iowa, Illinois, and Indiana, United States. Quantitation was achieved using liquid chromatography-selected reaction monitoring (LC-SRM) tandem mass spectrometry with AQUA peptide standards specific to the nine target allergens. Quantitation of allergen concentration indicated that both genetics and location affected specific allergen content. Seven of the nine allergens were significantly influenced by genetics, with the exceptions of glycinin G4 and KTI 3. The allergens P34, Gly m Bd 28k, glycinin G3, and KTI 1 showed statistically significant impact from location as well, but at a lower threshold of significance compared with genetics (cultivar/variety). This dataset contributes to our understanding of the natural variation of endogenous allergens, as it represents a sampling of soybeans grown in a controlled, distributed plot design under agronomic conditions common for commercial soybean food and feed production. The aim was to build upon our recent understanding of how allergens are expressed as part of the overall soybean proteome.
Abstract
We develop and disseminate effective point-spread functions and geometric-distortion solutions for high-precision astrometry and photometry with the JWST NIRISS instrument. We correct field ...dependencies and detector effects, and assess the quality and the temporal stability of the calibrations. As a scientific application and validation, we study the proper motion (PM) kinematics of stars in the JWST calibration field near the Large Magellanic Cloud (LMC) center, comparing to a first-epoch Hubble Space Telescope (HST) archival catalog with a 16 yr baseline. For stars with
G
∼ 20, the median PM uncertainty is ∼13
μ
as yr
−1
(3.1 km s
−1
), better than Gaia DR3 typically achieves for its very best-measured stars. We kinematically detect the known star cluster OGLE-CL LMC 407, measure its absolute PM for the first time, and show how this differs from other LMC populations. The inferred cluster dispersion sets an upper limit of 24
μ
as yr
−1
(5.6 km s
−1
) on systematic uncertainties. Red-giant-branch stars have a velocity dispersion of 33.8 ± 0.6 km s
−1
, while younger blue populations have a narrower velocity distribution, but with a significant kinematical substructure. We discuss how this relates to the larger velocity dispersions inferred from Gaia DR3. These results establish JWST as capable of state-of-the-art astrometry, building on the extensive legacy of HST. This is the first paper in a series by our JWST Telescope Scientist Team, in which we will use Guaranteed Time Observations to study the PM kinematics of various stellar systems in the Local Group.
Background Studies have demonstrated increased risk of major atherothrombotic events in
loss-of-function (LOF) variant carriers versus non-carriers treated with clopidogrel after percutaneous ...coronary intervention (PCI). We sought to evaluate real-world outcomes with the clinical implementation of
-guided antiplatelet therapy after PCI. Methods and Results Data from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a
LOF variant. The primary outcome was the composite of major atherothrombotic events (all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life-threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39-0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71-1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele. Conclusions Real-world data demonstrate lower atherothrombotic risk in
LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that
LOF carriers can be identified and treated with alternative therapy.
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