TDP-43 proteinopathy is very prevalent among the elderly (affecting at least 25% of individuals over 85 years of age) and is associated with substantial cognitive impairment. Risk factors implicated ...in age-related TDP-43 proteinopathy include commonly inherited gene variants, comorbid Alzheimer's disease pathology, and thyroid hormone dysfunction. To test parameters that are associated with aging-related TDP-43 pathology, we performed exploratory analyses of pathologic, genetic, and biochemical data derived from research volunteers in the University of Kentucky Alzheimer's Disease Center autopsy cohort (n = 136 subjects). Digital pathologic methods were used to discriminate and quantify both neuritic and intracytoplasmic TDP-43 pathology in the hippocampal formation. Overall, 46.4% of the cases were positive for TDP-43 intracellular inclusions, which is consistent with results in other prior community-based cohorts. The pathologies were correlated with hippocampal sclerosis of aging (HS-Aging) linked genotypes. We also assayed brain parenchymal thyroid hormone (triiodothyronine T3 and thyroxine T4) levels. In cases with SLCO1A2/IAPP or ABCC9 risk associated genotypes, the T3/T4 ratio tended to be reduced (p = .051 using 2-tailed statistical test), and in cases with low T3/T4 ratios (bottom quintile), there was a higher likelihood of HS-Aging pathology (p = .025 using 2-tailed statistical test). This is intriguing because the SLCO1A2/IAPP and ABCC9 risk associated genotypes have been associated with altered expression of the astrocytic thyroid hormone receptor (protein product of the nearby gene SLCO1C1). These data indicate that dysregulation of thyroid hormone signaling may play a role in age-related TDP-43 proteinopathy.
•Clinical, pathological, genetic, and biochemical parameters were analyzed from 136 subjects.•ABCC9 and SLCO1A2 genes are near human brain thyroid hormone receptor gene.•Cases with ABCC9 and SLCO1A2 trended toward lower brain T3/T4 (thyroid hormone) ratio.•Cases with lowest brain T3/T4 ratios had elevated risk for hippocampal sclerosis pathology.•Thyroid hormone dysregulation is implicated in HS/TDP-43 pathology but more work is required.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ABSTRACT
We present a new mass function of galaxy clusters and groups using optical/near-infrared (NIR) wavelength spectroscopic and photometric data from the Observations of Redshift Evolution in ...Large-Scale Environments (ORELSE) survey. At z ∼ 1, cluster mass function studies are rare regardless of wavelength and have never been attempted from an optical/NIR perspective. This work serves as a proof of concept that z ∼ 1 cluster mass functions are achievable without supplemental X-ray or Sunyaev-Zel’dovich data. Measurements of the cluster mass function provide important contraints on cosmological parameters and are complementary to other probes. With ORELSE, a new cluster finding technique based on Voronoi tessellation Monte Carlo (VMC) mapping, and rigorous purity and completeness testing, we have obtained ∼240 galaxy overdensity candidates in the redshift range 0.55 < z < 1.37 at a mass range of 13.6 < log (M/M⊙) < 14.8. This mass range is comparable to existing optical cluster mass function studies for the local universe. Our candidate numbers vary based on the choice of multiple input parameters related to detection and characterization in our cluster finding algorithm, which we incorporated into the mass function analysis through a Monte Carlo scheme. We find cosmological constraints on the matter density, Ωm, and the amplitude of fluctuations, σ8, of $\Omega _{m} = 0.250^{+0.104}_{-0.099}$ and $\sigma _{8} = 1.150^{+0.260}_{-0.163}$. While our Ωm value is close to concordance, our σ8 value is ∼2σ higher because of the inflated observed number densities compared to theoretical mass function models owing to how our survey targeted overdense regions. With Euclid and several other large, unbiased optical surveys on the horizon, VMC mapping will enable optical/NIR cluster cosmology at redshifts much higher than what has been possible before.
The lectin pathway of complement is activated upon binding of mannan-binding lectin (MBL) or ficolins (FCNs) to their targets. Upon recognition of targets, the MBL-and FCN-associated serine proteases ...(MASPs) are activated, allowing them to generate the C3 convertase C4b2a. Recent findings indicate that the MASPs also activate components of the coagulation system. We have previously shown that MASP-1 has thrombin-like activity whereby it cleaves and activates fibrinogen and factor XIII. MASP-2 has factor Xa-like activity and activates prothrombin through cleavage to form thrombin. We now report that purified L-FCN-MASPs complexes, bound from serum to N-acetylcysteine-Sepharose, or MBL-MASPs complexes, bound to mannan-agarose, generate clots when incubated with calcified plasma or purified fibrinogen and factor XIII. Plasmin digestion of the clot and analysis using anti-D-dimer antibodies revealed that the clot was made up of fibrin and was similar to that generated by thrombin in normal human plasma. Fibrinopeptides A and B (FPA and FPB, respectively) were released after fibrinogen cleavage by L-FCN-MASPs complexes captured on N-acetylcysteine-Sepharose. Studies of inhibition of fibrinopeptide release indicated that the dominant pathway for clotting catalysed by the MASPs is via MASP-2 and prothrombin activation, as hirudin, a thrombin inhibitor that does not inhibit MASP-1 and MASP-2, substantially inhibits fibrinopeptide release. In the light of their potent chemoattractant effects on neutrophil and fibroblast recruitment, the MASP-mediated release of FPA and FPB may play a role in early immune activation. Additionally, MASP-catalysed deposition and polymerization of fibrin on the surface of micro-organisms may be protective by limiting the dissemination of infection.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The Cl 1604 supercluster at image is one of a small handful of such structures discovered in the high-redshift universe and is the first target observed as part of the Observations of Redshift ...Evolution in Large Scale Environments (ORELSE) survey. To date, Cl 1604 is the largest structure mapped at image, with the most constituent clusters and the largest number of spectroscopically confirmed member galaxies. In this paper we present the results of a spectroscopic campaign to create a three-dimensional map of Cl 1604 and to understand the contamination by foreground and background large- scale structures. Combining new Deep Imaging Multi-Object Spectrograph observations with previous data yields high-quality redshifts for 1138 extragalactic objects in a image0.08 deg super(2) region, 413 of which are supercluster members. We examine the complex three-dimensional structure of Cl 1604, providing velocity dispersions for eight of the member clusters and groups. Our extensive spectroscopic data set is used to examine potential biases in cluster velocity dispersion measurements in the presence of overlapping structures and filaments. We also discuss other structures found along the line of sight, including a filament at image and two serendipitously discovered groups at image.
Parenting is often described as one of the most complicated life challenges, and the complexity increases in the presence of child developmental and/or mental health conditions. In the field of child ...psychiatry, parental psychoeducation-including guidance, support, and skill building-is an integral part of treatment that improves both the child patient's wellbeing and the quality of life of the family. Parents are the primary agent of care delivery for the child patient, which means that parental beliefs, attitudes, and knowledge about mental health care fundamentally influence service use and treatment adherence. Parents' and caregivers' access to accurate and up-to-date information regarding child development and mental health conditions can be critical in helping families optimize their use of mental health services, feel more confident in managing their child's symptoms, and make informed decisions about treatment strategies, which ultimately improve mental health outcomes in children.
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ABSTRACT
Simulations predict that the galaxy populations inhabiting protoclusters may contribute considerably to the total amount of stellar mass growth of galaxies in the early universe. In this ...study, we test these predictions observationally, using the Taralay protocluster (formerly PCl J1001+0220) at z ∼ 4.57 in the COSMOS field. With the Charting Cluster Construction with VUDS and ORELSE (C3VO) survey, we spectroscopically confirmed 44 galaxies within the adopted redshift range of the protocluster (4.48 < z < 4.64) and incorporate an additional 18 galaxies from ancillary spectroscopic surveys. Using a density mapping technique, we estimate the total mass of Taralay to be ∼1.7 × 1015 M⊙, sufficient to form a massive cluster by the present day. By comparing the star formation rate density (SFRD) within the protocluster (SFRDpc) to that of the coeval field (SFRDfield), we find that SFRDpc surpasses the SFRDfield by Δlog (SFRD/M⊙yr−1 Mpc−3) = 1.08 ± 0.32 (or ∼12 ×). The observed contribution fraction of protoclusters to the cosmic SFRD adopting Taralay as a proxy for typical protoclusters is $33.5~{{\ \rm per\ cent}}^{+8.0~{{\ \rm per\ cent}}}_{-4.3~{{\ \rm per\ cent}}}$, a value ∼2σ higher than the predictions from simulations. Taralay contains three peaks that are 5σ above the average density at these redshifts. Their SFRD is ∼0.5 dex higher than the value derived for the overall protocluster. We show that 68 per cent of all star formation in the protocluster takes place within these peaks, and that the innermost regions of the peaks encase $\sim 50~{{\ \rm per\ cent}}$ of the total star formation in the protocluster. This study strongly suggests that protoclusters drive stellar mass growth in the early universe and that this growth may proceed in an inside-out manner.
Expression of ABO and Lewis histo-blood group antigens by the gastrointestinal epithelium is governed by an α-1,2-fucosyltransferase enzyme encoded by the Fut2 gene. Alterations in mucin ...glycosylation have been associated with susceptibility to various bacterial and viral infections. Salmonella enterica serovar Typhimurium is a food-borne pathogen and a major cause of gastroenteritis. In order to determine the role of Fut2-dependent glycans in Salmonella-triggered intestinal inflammation, Fut2+/+ and Fut2-/- mice were orally infected with S. Typhimurium and bacterial colonization and intestinal inflammation were analyzed. Bacterial load in the intestine of Fut2-/- mice was significantly lower compared to Fut2+/+ mice. Analysis of histopathological changes revealed significantly lower levels of intestinal inflammation in Fut2-/- mice compared to Fut2+/+ mice and measurement of lipocalin-2 level in feces corroborated histopathological findings. Salmonella express fimbriae that assist in adherence of bacteria to host cells thereby facilitating their invasion. The std fimbrial operon of S. Typhimurium encodes the π-class Std fimbriae which bind terminal α(1,2)-fucose residues. An isogenic mutant of S. Typhimurium lacking Std fimbriae colonized Fut2+/+ and Fut2-/- mice to similar levels and resulted in similar intestinal inflammation. In vitro adhesion assays revealed that bacteria possessing Std fimbriae adhered significantly more to fucosylated cell lines or primary epithelial cells in comparison to cells lacking α(1,2)-fucose. Overall, these results indicate that Salmonella-triggered intestinal inflammation and colonization are dependent on Std-fucose interaction.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Residual pulmonary vascular obstruction (RPVO) and chronic thromboembolic pulmonary hypertension (CTEPH) are both long-term complications of acute pulmonary embolism, but it is unknown whether RPVO ...can be predicted by variants of fibrinogen associated with CTEPH.We used the Akaike information criterion to select the best predictive models for RPVO in two prospectively followed cohorts of acute pulmonary embolism patients, using as candidate variables the extent of the initial obstruction, clinical characteristics and fibrinogen-related data. We measured the selected models' goodness of fit by analysis of deviance and compared models using the Chi-squared test.RPVO occurred in 29 (28.4%) out of 102 subjects in the first cohort and 46 (25.3%) out of 182 subjects in the second. The best-fit predictive model derived in the first cohort (p=0.0002) and validated in the second cohort (p=0.0005) implicated fibrinogen Bβ-chain monosialylation in the development of RPVO. When the derivation procedure excluded clinical characteristics, fibrinogen Bβ-chain monosialylation remained a predictor of RPVO in the best-fit predictive model (p=0.00003). Excluding fibrinogen characteristics worsened the predictive model (p=0.03).Fibrinogen Bβ-chain monosialylation, a common structural attribute of fibrin, helped predict RPVO after acute pulmonary embolism. Fibrin structure may contribute to the risk of developing RPVO.
Context. We investigate iPTF13bvn, a core-collapse (CC) supernova (SN) in the nearby spiral galaxy NGC 5806. This object was discovered by the intermediate Palomar Transient Factory (iPTF) very close ...to the estimated explosion date and was classified as a stripped-envelope CC SN, likely of Type Ib. Furthermore, a possible progenitor detection in pre-explosion Hubble Space Telescope (HST) images was reported, making this the only SN Ib with such an identification. Based on the luminosity and color of the progenitor candidate, as well as on early-time spectra and photometry of the SN, it was argued that the progenitor candidate is consistent with a single, massive Wolf-Rayet (WR) star. Aims. We aim to confirm the progenitor detection, to robustly classify the SN using additional spectroscopy, and to investigate if our follow-up photometric and spectroscopic data on iPTF13bvn are consistent with a single-star WR progenitor scenario. Methods. We present a large set of observational data, consisting of multi-band light curves (UBVRI, g'r'i'z') and optical spectra. We perform standard spectral line analysis to track the evolution of the SN ejecta. We also construct a bolometric light curve and perform hydrodynamical calculations to model this light curve to constrain the synthesized radioactive nickel mass and the total ejecta mass of the SN. Late-time photometry is analyzed to constrain the amount of oxygen. Furthermore, image registration of pre- and post-explosion HST images is performed. Results. Our HST astrometry confirms the location of the progenitor candidate of iPTF13bvn, and follow-up spectra securely classify this as a SN Ib. We use our hydrodynamical model to fit the observed bolometric light curve, estimating the total ejecta mass to be 1.9 M sub(middot in circle) and the radioactive nickel mass to be 0.05 M sub(middot in circle). The model fit requires the nickel synthesized in the explosion to be highly mixed out in the ejecta. We also find that the late-time nebular r'-band luminosity is not consistent with predictions based on the expected oxygen nucleosynthesis in very massive stars. Conclusions. We find that our bolometric light curve of iPTF13bvn is not consistent with the previously proposed single massive WR-star progenitor scenario. The total ejecta mass and, in particular, the late-time oxygen emission are both significantly lower than what would be expected from a single WR progenitor with a main-sequence mass of at least 30 M sub(middot in circle).
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FMFMET, NUK, UL, UM, UPUK
Nocturnal hypoglycemia is a known challenge for people with type 1 diabetes, especially for physically active individuals or those on multiple daily injections. We developed an evidential neural ...network (ENN) to predict at bedtime the probability and timing of nocturnal hypoglycemia (0-4 vs 4-8 h after bedtime) based on several glucose metrics and physical activity patterns. We utilized these predictions in silico to prescribe bedtime carbohydrates with a Smart Snack intervention specific to the predicted minimum nocturnal glucose and timing of nocturnal hypoglycemia.
We leveraged free-living datasets collected from 366 individuals from the T1DEXI Study and Glooko. Inputs to the ENN used to model nocturnal hypoglycemia were derived from demographic information, continuous glucose monitoring, and physical activity data. We assessed the accuracy of the ENN using area under the receiver operating curve, and the clinical impact of the Smart Snack intervention through simulations.
The ENN achieved an area under the receiver operating curve of 0.80 and 0.71 to predict nocturnal hypoglycemic events during 0-4 and 4-8 h after bedtime, respectively, outperforming all evaluated baseline methods. Use of the Smart Snack intervention reduced probability of nocturnal hypoglycemia from 23.9 ± 14.1% to 14.0 ± 13.3% and duration from 7.4 ± 7.0% to 2.4 ± 3.3% in silico.
Our findings indicate that the ENN-based Smart Snack intervention has the potential to significantly reduce the frequency and duration of nocturnal hypoglycemic events.
A decision support system that combines prediction of minimum nocturnal glucose and proactive recommendations for bedtime carbohydrate intake might effectively prevent nocturnal hypoglycemia and reduce the burden of glycemic self-management.
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