Conformational analysis with lanthanide shift reagents. A new determination of the cyclohexanol a-valoe

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22202/1/0000633.pd

Unpacking the modeling process for energy policy making

This article explores how the modeling of energy systems may lead to an undue closure of alternatives by generating an excess of certainty around some of the possible policy options. We retrospectively exemplify the problem with the case of the International Institute for Applied Systems Analysis (IIASA) global modeling in the 1980s. We discuss different methodologies for quality assessment that may help mitigate this issue, which include Numeral Unit Spread Assessment Pedigree (NUSAP), diagnostic diagrams, and sensitivity auditing (SAUD). We illustrate the potential of these reflexive modeling practices in energy policy‐making with three additional cases: (i) the case of the energy system modeling environment (ESME) for the creation of UK energy policy; (ii) the negative emission technologies (NETs) uptake in integrated assessment models (IAMs); and (iii) the ecological footprint indicator. We encourage modelers to adopt these approaches to achieve more robust, defensible, and inclusive modeling activities in the field of energy research

Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria

Loss-of-function mutations in genes for heme biosynthetic enzymes can give rise to congenital porphyrias, eight forms of which have been described. The genetic penetrance of the porphyrias is clinically variable, underscoring the role of additional causative, contributing, and modifier genes. We previously discovered that the mitochondrial AAA+ unfoldase ClpX promotes heme biosynthesis by activation of δ-aminolevulinate synthase (ALAS), which catalyzes the first step of heme synthesis. CLPX has also been reported to mediate heme-induced turnover of ALAS. Here we report a dominant mutation in the ATPase active site of human CLPX, p.Gly298Asp, that results in pathological accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Amassing of PPIX in erythroid cells promotes erythropoietic protoporphyria (EPP) in the affected family. The mutation in CLPX inactivates its ATPase activity, resulting in coassembly of mutant and WT protomers to form an enzyme with reduced activity. The presence of low-activity CLPX increases the posttranslational stability of ALAS, causing increased ALAS protein and ALA levels, leading to abnormal accumulation of PPIX. Our results thus identify an additional molecular mechanism underlying the development of EPP and further our understanding of the multiple mechanisms by which CLPX controls heme metabolism. Keywords: heme biosynthesis; porphyria; ALAS; protein unfoldases; AAA+ ATPaseNational Institutes of Health (U.S.) (Grant F32 DK095726)National Institutes of Health (U.S.) (Grant R01 GM049224

Incidence and determinants of spontaneous normalization of subclinical hypothyroidism in older adults.

CONTEXT With age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown. OBJECTIVE To investigate incidence and determinants of spontaneous normalization of thyroid-stimulating hormone (TSH) levels in older adults with subclinical hypothyroidism. DESIGN Pooled data were used from the (i) pre-trial population, and (ii) in-trial placebo group from two randomized, double-blind, placebo-controlled trials (TRUST and IEMO thyroid 80-plus thyroid trial). SETTING Community-dwelling 65 + adults with subclinical hypothyroidism from the Netherlands, Switzerland, Ireland, and the United Kingdom. PARTICIPANTS The pre-trial population (N = 2335) consisted of older adults with biochemical subclinical hypothyroidism, defined as ≥1 elevated TSH measurement (≥4.60 mIU/L) and a free thyroxine (fT4) within the laboratory-specific reference range. Individuals with persistent subclinical hypothyroidism, defined as ≥2 elevated TSH measurements ≥3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo group (N = 361) was included. MAIN OUTCOME MEASURES Incidence of spontaneous normalization of TSH levels and associations between participant characteristics and normalization. RESULTS In the pre-trial phase, TSH levels normalized in 60.8% of participants in a median follow-up of one year. In the in-trial phase, levels normalized in 39.9% of participants after one year follow-up. Younger age, female sex, lower initial TSH level, higher initial fT4 level, absence of thyroid peroxidase antibodies, and a follow-up measurement in summer were independent determinants for normalization. CONCLUSIONS Since TSH levels spontaneously normalized in a large proportion of older adults with subclinical hypothyroidism (also after confirmation by repeat measurement), a third measurement may be recommended before considering treatment

Making Sense of Making Meat: Key Moments in the First 20 Years of Tissue Engineering Muscle to Make Food

Cultured/clean/cell-based meat (CM) now has a near two decade history of laboratory research, commencing with the early NASA-funded work at Touro College and the bioarts practice of the Tissue Culture and Art project. Across this period the field, or as it is now more commonly termed, the “space,” has developed significantly while promoting different visions for what CM is and can do, and the best mechanisms for delivery. Here we both analyse and critically engage with this near-twenty year period as a productive provocation to those engaged with CM, or considering becoming so. This paper is not a history of the field, and does not offer a comprehensive timeline. Instead it identifies significant activities, transitions, and moments in which key meanings and practices have taken form or exerted influence. We do this through analyzing two related themes: the CM “institutional context” and the CM “interpretative package.” The former, the institutional context, refers to events and infrastructures that have come into being to support and shape the CM field, including university activities, conferences, third sector groups, various potential funding mechanisms, and the establishment of a start-up sector. The latter, the interpretative package, refers to the constellation of factors that shape or assert how CM should be understood, including the various names used to describe it, accounts of what it will achieve, and most recently, the emergent regulatory discussions that frame its legal standing. Across the paper we argue it is productive to think of the CM community in terms of a first and second wave. The first wave was more university-based and broadly covers the period from the millennium until around the 2013 cultured burger event. The second wave saw the increasing prevalence of a start-up culture and the circuits of venture capital interest that support it. Through this analysis we seek to provoke further reflection upon how the CM community has come to be as it is, and how this could develop in the future.Economic and Social Research Council; The Seventh Framework Programme; Wellcome Trust; Centre for Society and Genomics Visiting Scholarship; King's College London; KCL Mary Clark Travel Bursary; Our Planet Our Health (Livestock, Environment and People–LEAP); The Netherlands Organization for Scientific Research; Ministry of Economic Affair

A pan-European epidemiological study reveals honey bee colony survival depends on beekeeper education and disease control

Reports of honey bee population decline has spurred many national efforts to understand the extent of the problem and to identify causative or associated factors. However, our collective understanding of the factors has been hampered by a lack of joined up trans-national effort. Moreover, the impacts of beekeeper knowledge and beekeeping management practices have often been overlooked, despite honey bees being a managed pollinator. Here, we established a standardised active monitoring network for 5 798 apiaries over two consecutive years to quantify honey bee colony mortality across 17 European countries. Our data demonstrate that overwinter losses ranged between 2% and 32%, and that high summer losses were likely to follow high winter losses. Multivariate Poisson regression models revealed that hobbyist beekeepers with small apiaries and little experience in beekeeping had double the winter mortality rate when compared to professional beekeepers. Furthermore, honey bees kept by professional beekeepers never showed signs of disease, unlike apiaries from hobbyist beekeepers that had symptoms of bacterial infection and heavy Varroa infestation. Our data highlight beekeeper background and apicultural practices as major drivers of honey bee colony losses. The benefits of conducting trans-national monitoring schemes and improving beekeeper training are discussed

Isotopic evidence for dietary diversity at the mediaeval Islamic necropolis of Can Fonoll (10th to 13th centuries CE), Ibiza, Spain

The diet of the population interred at the Islamic necropolis of Can Fonoll, Ibiza, Spain, which was in use between the 10th and 13th centuries AD, is reconstructed from the carbon (δ13C) and nitrogen (δ15N) stable isotope ratios of bone collagen from 112 individuals. The mean ± sd (1σ) δ13C (− 19.0 ± 1.3‰) and δ15N (10.3 ± 0.8‰) values of the Can Fonoll population indicate a diet based largely on terrestrial C3 resources. However, the wide range of both δ13C (− 20.6‰ to − 8.6‰) and δ15N (7.0‰ to 12.1‰) values attested at Can Fonoll indicate significant variation in individual diet. The elevated δ13C values of a small proportion of the individuals buried at Can Fonoll are consistent with the consumption of a large proportion of, or dependence on, C4 resources, such as millet. Comparison of the δ13C and δ15N values of the Can Fonoll population with those of other mediaeval populations from the Balearic Islands and mainland Spain highlights a wide range of stable isotope values, which reflects not only significant differences in diet but also points to widespread mobility within the Mediterranean Basin

Is diet partly responsible for differences in COVID-19 death rates between and within countries?

Correction: Volume: 10 Issue: 1 Article Number: 44 DOI: 10.1186/s13601-020-00351-w Published: OCT 26 2020Reported COVID-19 deaths in Germany are relatively low as compared to many European countries. Among the several explanations proposed, an early and large testing of the population was put forward. Most current debates on COVID-19 focus on the differences among countries, but little attention has been given to regional differences and diet. The low-death rate European countries (e.g. Austria, Baltic States, Czech Republic, Finland, Norway, Poland, Slovakia) have used different quarantine and/or confinement times and methods and none have performed as many early tests as Germany. Among other factors that may be significant are the dietary habits. It seems that some foods largely used in these countries may reduce angiotensin-converting enzyme activity or are anti-oxidants. Among the many possible areas of research, it might be important to understand diet and angiotensin-converting enzyme-2 (ACE2) levels in populations with different COVID-19 death rates since dietary interventions may be of great benefit.Peer reviewe

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity