Automating Carotid Intima-Media Thickness Video Interpretation with Convolutional Neural Networks

Cardiovascular disease (CVD) is the leading cause of mortality yet largely preventable, but the key to prevention is to identify at-risk individuals before adverse events. For predicting individual CVD risk, carotid intima-media thickness (CIMT), a noninvasive ultrasound method, has proven to be valuable, offering several advantages over CT coronary artery calcium score. However, each CIMT examination includes several ultrasound videos, and interpreting each of these CIMT videos involves three operations: (1) select three end-diastolic ultrasound frames (EUF) in the video, (2) localize a region of interest (ROI) in each selected frame, and (3) trace the lumen-intima interface and the media-adventitia interface in each ROI to measure CIMT. These operations are tedious, laborious, and time consuming, a serious limitation that hinders the widespread utilization of CIMT in clinical practice. To overcome this limitation, this paper presents a new system to automate CIMT video interpretation. Our extensive experiments demonstrate that the suggested system significantly outperforms the state-of-the-art methods. The superior performance is attributable to our unified framework based on convolutional neural networks (CNNs) coupled with our informative image representation and effective post-processing of the CNN outputs, which are uniquely designed for each of the above three operations.Comment: J. Y. Shin, N. Tajbakhsh, R. T. Hurst, C. B. Kendall, and J. Liang. Automating carotid intima-media thickness video interpretation with convolutional neural networks. CVPR 2016, pp 2526-2535; N. Tajbakhsh, J. Y. Shin, R. T. Hurst, C. B. Kendall, and J. Liang. Automatic interpretation of CIMT videos using convolutional neural networks. Deep Learning for Medical Image Analysis, Academic Press, 201

RIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic Salmonella Infection

ABSTRACT Regulated macrophage death has emerged as an important mechanism to defend against intracellular pathogens. However, the importance and consequences of macrophage death during bacterial infection are poorly resolved. This is especially true for the recently described RIPK3-dependent lytic cell death, termed necroptosis. Salmonella enterica serovar Typhimurium is an intracellular pathogen that precisely regulates virulence expression within macrophages to evade and manipulate immune responses, which is a key factor in its ability to cause severe systemic infections. We combined genetic and pharmacological approaches to examine the importance of RIPK3 for S. Typhimurium-induced macrophage death using conditions that recapitulate bacterial gene expression during systemic infection in vivo. Our findings indicate that noninvasive S. Typhimurium does not naturally induce macrophage necroptosis but does so in the presence of pan-caspase inhibition. Moreover, our data suggest that RIPK3 induction (following caspase inhibition) does not impact host survival following S. Typhimurium infection, which differs from previous findings based on inert lipopolysaccharide (LPS) injections. Finally, although necroptosis is typically characterized as highly inflammatory, our data suggest that RIPK3 skews the peritoneal myeloid population away from an inflammatory profile to that of a classically noninflammatory profile. Collectively, these data improve our understanding of S. Typhimurium-macrophage interactions, highlight the possibility that purified bacterial components may not accurately recapitulate the complexity of host-pathogen interactions, and reveal a potential and unexpected role for RIPK3 in resolving inflammation. IMPORTANCE Macrophages employ multiple strategies to limit pathogen infection. For example, macrophages may undergo regulated cell death, including RIPK3-dependent necroptosis, as a means of combatting intracellular bacterial pathogens. However, bacteria have evolved mechanisms to evade or exploit immune responses. Salmonella is an intracellular pathogen that avoids and manipulates immune detection within macrophages. We examined the contribution of RIPK3 to Salmonella-induced macrophage death. Our findings indicate that noninvasive Salmonella does not naturally induce necroptosis, but it does so when caspases are inhibited. Moreover, RIPK3 induction (following caspase inhibition) does not impact host survival following Salmonella systemic infection. Finally, our data show that RIPK3 induction results in recruitment of low-inflammatory myeloid cells, which was unexpected, as necroptosis is typically described as highly inflammatory. Collectively, these data improve our understanding of pathogen-macrophage interactions, including outcomes of regulated cell death during infection in vivo, and reveal a potential new role for RIPK3 in resolving inflammation

Menopause induces changes to the stratum corneum ceramide profile, which are prevented by hormone replacement therapy

Abstract The menopause can lead to epidermal changes that are alleviated by hormone replacement therapy (HRT). We hypothesise that these changes could relate to altered ceramide production, and that oestrogen may have a role in keratinocyte ceramide metabolism. White Caucasian women were recruited into three groups: pre-menopausal (n = 7), post-menopausal (n = 11) and post-menopausal taking HRT (n = 10). Blood samples were assessed for hormone levels, transepidermal water loss was measured to assess skin barrier function, and stratum corneum lipids were sampled from photoprotected buttock skin. Ceramides and sphingomyelins were analysed by ultraperformance liquid chromatography with electrospray ionisation and tandem mass spectrometry. Post-menopausal stratum corneum contained lower levels of ceramides, with shorter average length; changes that were not evident in the HRT group. Serum oestradiol correlated with ceramide abundance and length. Ceramides had shorter sphingoid bases, indicating altered de novo ceramide biosynthesis. Additionally, post-menopausal women had higher sphingomyelin levels, suggesting a possible effect on the hydrolysis pathway. Treatment of primary human keratinocytes with oestradiol (10 nM) increased production of CER[NS] and CER[NDS] ceramides, confirming an effect of oestrogen on cutaneous ceramide metabolism. Taken together, these data show perturbed stratum corneum lipids post-menopause, and a role for oestrogen in ceramide production

New constraints on mid-Proterozoic ocean redox from stable thallium isotope systematics of black shales

The final publication is available at Elsevier via https://doi.org/10.1016/j.gca.2021.09.006. © 2021. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/Stable thallium (Tl) isotope data from organic-rich siliciclastic sedimentary rocks have the potential to track ocean redox state on a broad scale. Here, we report new Tl isotope data from the Mesoproterozoic Velkerri Formation (Roper Group) and the Paleoproterozoic Wollogorang Formation (Tawallah Group), McArthur Basin, Northern Territory, Australia, and interpret these in the context of rhenium-osmium (Re-Os) geochronometry on the same sample suite. Previous work has shown that marine black shales from the Velkerri Formation provide evidence for closed-system Re-Os systematics, yielding a precise isochron with an age of 1361 ± 21 Ma that agrees well with independent age constraints for the unit. The isotopic composition of authigenic Tl in euxinic black shales from the upper Velkerri Formation (ε205Tl = -2.4 ± 0.8, 2SD) indicates that the Tl isotope composition of local seawater at 1.36 Ga was within a plausible range for Tl inputs to the ocean. Isotope mass balance modeling of the Tl isotope system within a Monte Carlo framework suggests that the Tl isotopic composition of seawater at 1.36 Ga was homogenous on a global scale and that the burial of Mn-oxides exerted minimal isotopic leverage on the Tl isotope composition of seawater at 1.36 Ga. Taken together with existing Mo, Cr, and U isotope data from the same samples, these observations are consistent with a low-O2 ocean-atmosphere system during this period of the Mesoproterozoic. Previous work has shown that the Re-Os systematics of black shales from the older (1.73 Ga) Wollogorang Formation are scattered and yield an erroneously young isochron age of 1359 ± 150 Ma, which has been attributed to post-depositional hydrothermal alteration at ~1640 Ma. We observe no systematic relationship between stable Tl isotope compositions and the extent of alteration as gauged by open-system Re-Os behavior (-4.7 ± 1.4 for the upper Wollogorang Formation and -4.8 ± 0.4 for the lower Wollogorang Formation), in marked contrast to previous observations for the molybdenum (Mo) and uranium (U) isotope systems. The invariant signature of the Tl isotope data suggests the Tl isotope system was largely unperturbed during hydrothermal alteration. However, it remains difficult to definitively rule out the possibility that authigenic Tl isotope signatures have been overprinted by later localized hydrothermal fluid alteration in the Wollogorang Formation shales. These observations highlight the potential insights afforded by evaluating open-system behavior via radiogenic isotope systems together with other stable isotope tracers in efforts to reconstruct the redox landscape of Earth’s oceans over time

Improving the reach of vaccines to low-resource regions, with a needle-free vaccine delivery device and long-term thermostabilization

Dry-coated microprojections can deliver vaccine to abundant antigen-presenting cells in the skin and induce efficient immune responses and the dry-coated vaccines are expected to be thermostable at elevated temperatures. In this paper, we show that we have dramatically improved our previously reported gas-jet drying coating method and greatly increased the delivery efficiency of coating from patch to skin to from 6.5% to 32.5%, by both varying the coating parameters and removing the patch edge. Combined with our previous dose sparing report of influenza vaccine delivery in a mouse model, the results show that we now achieve equivalent protective immune responses as intramuscular injection (with the needle and syringe), but with only 1/30th of the actual dose. We also show that influenza vaccine coated microprojection patches are stable for at least 6 months at 23 degrees C. inducing comparable immunogenicity with freshly coated patches. The dry-coated microprojection patches thus have key and unique attributes in ultimately meeting the medical need in certain low-resource regions with low vaccine affordability and difficulty in maintaining "cold-chain" for vaccine storage and transport. (C) 2011 Elsevier B.V. All rights reserved

4-Alkyloxyimino Derivatives of Uridine-5′-triphosphate: Distal Modification of Potent Agonists as a Strategy for Molecular Probes of P2Y 2 , P2Y 4 , and P2Y 6 Receptors

Extended N4-(3-arylpropyl)oxy derivatives of uridine-5′-triphosphate were synthesized and potently stimulated phospholipase C stimulation in astrocytoma cells expressing G protein-coupled human (h) P2Y receptors (P2YRs) activated by UTP (P2Y2/4R) or UDP (P2Y6R). The potent P2Y4R-selective N4-(3-phenylpropyl)oxy agonist was phenyl ring-substituted or replaced with terminal heterocyclic or naphthyl rings with retention of P2YR potency. This broad tolerance for steric bulk in a distal region was not observed for dinucleoside tetraphosphate agonists with both nucleobases substituted. The potent N4-(3-(4-methoxyphenyl)-propyl)oxy analogue 19 (EC50: P2Y2R, 47 nM; P2Y4R, 23 nM) was functionalized for chain extension using click tethering of fluorophores as prosthetic groups. The BODIPY 630/650 conjugate 28 (MRS4162) exhibited EC50 values of 70, 66, and 23 nM at the hP2Y2/4/6Rs, respectively, and specifically labeled cells expressing the P2Y6R. Thus, an extended N4-(3-arylpropyl)oxy group accessed a structurally permissive region on three Gq-coupled P2YRs, and potency and selectivity were modulated by distal structural changes. This freedom of substitution was utilized to design of a pan-agonist fluorescent probe of a subset of uracil nucleotide-activated hP2YRs