Liver Transplantation to Provide Low-Density-Lipoprotein Receptors and Lower Plasma Cholesterol in a Child with Homozygous Familial Hypercholesterolemia

A six-year-old girl with severe hypercholesterolemia and atherosclerosis had two defective genes at the low-density-lipoprotein (LDL) receptor locus, as determined by biochemical studies of cultured fibroblasts. One gene, inherited from the mother, produced no LDL receptors; the other gene, inherited from the father, produced a receptor precursor that was not transported to the cell surface and was unable to bind LDL. The patient degraded intravenously administered 125I-LDL at an extremely low rate, indicating that her high plasma LDL-cholesterol level was caused by defective receptor-mediated removal of LDL from plasma. After transplantation of a liver and a heart from a normal donor, the patient's plasma LDL-cholesterol level declined by 81 per cent, from 988 to 184 mg per deciliter. The fractional catabolic rate for intravenously administered 125I-LDL, a measure of functional LDL receptors in vivo, increased by 2.5-fold. Thus, the transplanted liver, with its normal complement of LDL receptors, was able to remove LDL cholesterol from plasma at a nearly normal rate. We conclude that a genetically determined deficiency of LDL receptors can be largely reversed by liver transplantation. These data underscore the importance of hepatic LDL receptors in controlling the plasma level of LDL cholesterol in human beings. (N Engl J Med 1984; 311: 1658–64.). © 1984, Massachusetts Medical Society. All rights reserved

Grain boundary-induced variability of charge transport in hydrogenated polycrystalline graphene

Chemical functionalization has proven to be a promising means of tailoring the unique properties of graphene. For example, hydrogenation can yield a variety of interesting effects, including a metal-insulator transition or the formation of localized magnetic moments. Meanwhile, graphene grown by chemical vapor deposition is the most suitable for large-scale production, but the resulting material tends to be polycrystalline. Up to now there has been relatively little focus on how chemical functionalization, and hydrogenation in particular, impacts the properties of polycrystalline graphene. In this work, we use numerical simulations to study the electrical properties of hydrogenated polycrystalline graphene. We find a strong correlation between the spatial distribution of the hydrogen adsorbates and the charge transport properties. Charge transport is weakly sensitive to hydrogenation when adsorbates are confined to the grain boundaries, while a uniform distribution of hydrogen degrades the electronic mobility. This difference stems from the formation of the hydrogen-induced resonant impurity states, which are inhibited when the honeycomb symmetry is locally broken by the grain boundaries. These findings suggest a tunability of electrical transport of polycrystalline graphene through selective hydrogen functionalization, and also have implications for hydrogen-induced magnetization and spin lifetime of this material

Using Machine Learning Techniques to Predict Adolescents’ Involvement in Family Conflict

[Abstract] Many cases of violence against children occur in homes and other close environments. Machine leaning is a novel approach that addresses important gaps in ways of examining this socially significant issue, illustrating innovative and emerging approaches for the use of computers from a psychological perspective. In this paper, we aim to use machine learning techniques to predict adolescents’ involvement in family conflict in a sample of adolescents living with their families(community adolescents) and adolescents living in residential care centers, who are temporarilyseparated from their families because of adverse family conditions. Participants were 251 Spanish adolescents (Mage= 15.59), of whom 167 lived in residential care and 84 lived with their families.We measured perceived interparental and family conflict, adolescents’emotional security,emotional, cognitive, and behavioral immediate responses to analog interparental conflict (IPC),and adolescents’ sociodemographic variables (i.e., age, gender). With a prediction accuracy of 65%, our results show that adolescents in residential care are not at greater risk for involvement in family conflict compared to adolescents living with their families. Age and gender are not salient predictive variables. We could identify that responses to analog IPC, adolescents’emotiona lsecurity, triangulation in IPC, and the presence of insults or blame during family disputes predict adolescents’ involvement in family conflict. These results point to variables with a potential predictive capacity, which is relevant for research and intervention.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was partially supported by projects PLEC2021-007,662 (MCIN/AEI/10.13,039/501100011033, Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación, Plan de Recuperación, Transformación y Resiliencia, Unión Europea-Next GenerationEU), RTI2018-093,336-B-C21 & RTI2018-093,336-B-C22 (Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación & ERDF). The fourth and fifth authors also thank the financial support supplied by the Consellería de Educación, Universidade e Formación Profesional (accreditation 2019–2022 ED431G-2019/01 and GPC ED431 B 2019/03) and the European Regional Development Fund, which acknowledges the CITIC Research Center in ICT of the University of A Coruña as a Research Center of the Galician University System. The third author also thanks the financial support supplied by the Consellería de Educación, Universidade e Formación Profesional (accreditation 2019–2022 ED431G-2019/04, ED431 C 2018/29) and the European Regional Development Fund, which acknowledges the CiTIUS-Research Center in Intelligent Technologies of the University of Santiago de Compostela as a Research Center of the Galician University SystemXunta de Galicia; ED431G-2019/01Xunta de Galicia; ED431 B 2019/03Xunta de Galicia; ED431G-2019/04Xunta de Galicia; ED431 C 2018/2

A Large Animal Survival Model to Evaluate Bariatric Surgery Mechanisms

BACKGROUND: The impact of Roux-en-Y gastric bypass (RYGB) on type 2 diabetes mellitus is thought to result from upper and/or lower gut hormone alterations. Evidence supporting these mechanisms is incomplete, in part because of limitations in relevant bariatric-surgery animal models, specifically the lack of naturally insulin-resistant large animals. With overfeeding, Ossabaw swine develop a robust metabolic syndrome, and may be suitable for studying post-surgical physiology. Whether bariatric surgery is feasible in these animals with acceptable survival is unknown. METHODS: Thirty-two Ossabaws were fed a high-fat, high-cholesterol diet to induce obesity and insulin resistance. These animals were assigned to RYGB (n = 8), RYGB with vagotomy (RYGB-V, n = 5), gastrojejunostomy (GJ, n = 10), GJ with duodenal exclusion (GJD, n = 7), or sham operation (n = 2) and were euthanized 60 days post-operatively. Post-operative changes in weight and food intake are reported. RESULTS: Survival to scheduled necropsy among surgical groups was 77%, living an average of 57 days post-operatively. Cardiac arrest under anesthesia occurred in 4 pigs. Greatest weight loss (18.0% ± 6%) and food intake decrease (57.0% ± 20%) occurred following RYGB while animals undergoing RYGB-V showed only 6.6% ± 3% weight loss despite 50.8% ± 25% food intake decrease. GJ (12.7% ± 4%) and GJD (1.2% ± 1%) pigs gained weight, but less than sham controls (13.4% ± 10%). CONCLUSIONS: A survival model of metabolic surgical procedures is feasible, leads to significant weight loss, and provides the opportunity to evaluate new interventions and subtle variations in surgical technique (e.g. vagus nerve sparing) that may provide new mechanistic insights

The Burst Alert Telescope (BAT) on the Swift MIDEX Mission

The Burst Alert Telescope (BAT) is one of 3 instruments on the Swift MIDEX spacecraft to study gamma-ray bursts (GRBs). The BAT first detects the GRB and localizes the burst direction to an accuracy of 1-4 arcmin within 20 sec after the start of the event. The GRB trigger initiates an autonomous spacecraft slew to point the two narrow field-of-view (FOV) instruments at the burst location within 20-70 sec so to make follow-up x-ray and optical observations. The BAT is a wide-FOV, coded-aperture instrument with a CdZnTe detector plane. The detector plane is composed of 32,768 pieces of CdZnTe (4x4x2mm), and the coded-aperture mask is composed of approximately 52,000 pieces of lead (5x5x1mm) with a 1-m separation between mask and detector plane. The BAT operates over the 15-150 keV energy range with approximately 7 keV resolution, a sensitivity of approximately 10E-8 erg*cm^-2*s^-1, and a 1.4 sr (half-coded) FOV. We expect to detect >100 GRBs/yr for a 2-year mission. The BAT also performs an all-sky hard x-ray survey with a sensitivity of approximately 2 mCrab (systematic limit) and it serves as a hard x-ray transient monitor.Comment: 18 Pages, 12 Figures, To be published in Space Science Review

Prefrontal Interneurons: Populations, Pathways, and Plasticity Supporting Typical and Disordered Cognition in Rodent Models

Prefrontal cortex (PFC) inhibitory microcircuits regulate the gain and timing of pyramidal neuron firing, coordinate neural ensemble interactions, and gate local and long-range neural communication to support adaptive cognition and contextually tuned behavior. Accordingly, perturbations of PFC inhibitory microcircuits are thought to underlie dysregulated cognition and behavior in numerous psychiatric diseases and relevant animal models. This review, based on a Mini-Symposium presented at the 2022 Society for Neuroscience Meeting, highlights recent studies providing novel insights into: (1) discrete medial PFC (mPFC) interneuron populations in the mouse brain; (2) mPFC interneuron connections with, and regulation of, long-range mPFC afferents; and (3) circuit-specific plasticity of mPFC interneurons. The contributions of such populations, pathways, and plasticity to rodent cognition are discussed in the context of stress, reward, motivational conflict, and genetic mutations relevant to psychiatric disease

Crosstalk between TGF-β1 and complement activation augments epithelial injury in pulmonary fibrosis

The epithelial complement inhibitory proteins (CIPs) cluster of differentiation 46 and 55 (CD46 and CD55) regulate circulating immune complex-mediated complement activation in idiopathic pulmonary fibrosis (IPF). Our previous studies demonstrated that IL-17A mediates epithelial injury via transforming growth factor β1 (TGF-β1) and down-regulates CIPs. In the current study, we examined the mechanistic role of TGF-β1 in complement activation-mediated airway epithelial injury in IPF pathogenesis. We observed lower epithelial CIP expression in IPF lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a (C3a and C5a), locally and systemically. In normal primary human small airway epithelial cells (SAECs) treated with TGF-β1 (10 ng/ml), C3a, or C5a (100 nM), we observed loss of CIPs and increased poly(ADP-ribose) polymerase (PARP) activation [also observed with RNA interference (RNAi) of CD46/CD55]. TGF-β1-mediated loss of CIPs and Snail induction [SNAI1; a transcriptional repressor of E-cadherin (E-CAD)] was blocked by inhibiting mitogen-activated protein kinase (p38MAPK; SB203580) and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of CIPs was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 (negative regulator of TGF-β), and whereas TGF-β1 induced C3a/C5a receptor (C3aR/C5aR) expression, pharmacologic C3aR/C5aR inhibition protected against C3a-/C5a-mediated loss of CIPs. Taken together, our results suggest that epithelial injury in IPF can be collectively amplified as a result of TGF-β1-induced loss of CIPs leading to complement activation that down-regulates CIPs and induces TGF-β1 expressio

Factors affecting retention and compliance in a longitudinal study of connected, low income, urban, primiparous mothers

poster abstractAbstract Background/Aims Longitudinal obstetrics studies are vital to our understanding of the physiological and social changes that occur during pregnancy and the early postpartum period in the mother and baby. Variables collected in a longitudinal obstetrics study were analyzed to identify factors affecting retention and compliance within a low-income, primiparous population. Methods Primiparous women were recruited for a prospective cohort longitudinal study. Two study arms were used. The first collected survey data on mood, sleep, and night time eating and actigraphic data for seven days during weeks 22 and 32 of gestation and one week postpartum. The second was identical but had an additional 24 hour sampling of saliva. In addition, breast fullness surveys were administered each day for the first five days postpartum. Pick up and drop off of study materials at the research site were required for each time point. Results Ninety-two women were recruited; 45% (n=41) were retained and compliant for the entire study. The majority of subjects (88%) had daily internet access, completed surveys on-line (81.4%), and preferred to receive text messages (93.5%) for study reminders over other methods of communication. Longitudinal time (P<0.001), increased number of reminders (P<0.001), and increased length of time to complete surveys (P<0.001) had a significant negative effect on study retention, whereas enrollment in the study arm with greater sampling and communication (P<0.001) and earning a higher percentage of available compensation (P<0.001) had a significant positive effect on study retention. Conclusions The high rate of daily internet access and preference for text messaging for primary means of communication with research staff suggests a high rate of smart-device technology use among young, urban-dwelling, low-income women. Designing studies that can be completed via internet and using text message reminders may be a preferable and practical means of conducting longitudinal obstetrics studies

Appetite, gut hormone and energy intake responses to low volume sprint interval and traditional endurance exercise.

Sprint interval exercise improves several health markers but the appetite and energy balance response is unknown. This study compared the effects of sprint interval and endurance exercise on appetite, energy intake and gut hormone responses. Twelve healthy males [mean (SD): age 23 (3) years, body mass index 24.2 (2.9) kg m(-2), maximum oxygen uptake 46.3 (10.2) mL kg(-1) min(-1)] completed three 8 h trials [control (CON), endurance exercise (END), sprint interval exercise (SIE)] separated by 1 week. Trials commenced upon completion of a standardised breakfast. Sixty minutes of cycling at 68.1 (4.3) % of maximum oxygen uptake was performed from 1.75-2.75 h in END. Six 30-s Wingate tests were performed from 2.25-2.75 h in SIE. Appetite ratings, acylated ghrelin and peptide YY (PYY) concentrations were measured throughout each trial. Food intake was monitored from buffet meals at 3.5 and 7 h and an overnight food bag. Appetite (P 0.05). Therefore, relative energy intake (energy intake minus the net energy expenditure of exercise) was lower in END than that in CON (15.7 %; P = 0.006) and SIE (11.5 %; P = 0.082). An acute bout of endurance exercise resulted in lower appetite perceptions in the hours after exercise than sprint interval exercise and induced a greater 24 h energy deficit due to higher energy expenditure during exercise