A switch element in the autophagy E2 Atg3 mediates allosteric regulation across the lipidation cascade

Autophagy depends on the E2 enzyme, Atg3, functioning in a conserved E1-E2-E3 trienzyme cascade that catalyzes lipidation of Atg8-family ubiquitin-like proteins (UBLs). Molecular mechanisms underlying Atg8 lipidation remain poorly understood despite association of Atg3, the E1 Atg7, and the composite E3 Atg12-Atg5-Atg16 with pathologies including cancers, infections and neurodegeneration. Here, studying yeast enzymes, we report that an Atg3 element we term E123IR (E1, E2, and E3-interacting region) is an allosteric switch. NMR, biochemical, crystallographic and genetic data collectively indicate that in the absence of the enzymatic cascade, the Atg3(E123IR) makes intramolecular interactions restraining Atg3's catalytic loop, while E1 and E3 enzymes directly remove this brace to conformationally activate Atg3 and elicit Atg8 lipidation in vitro and in vivo. We propose that Atg3's E123IR protects the E2 similar to UBL thioester bond from wayward reactivity toward errant nucleophiles, while Atg8 lipidation cascade enzymes induce E2 active site remodeling through an unprecedented mechanism to drive autophagy

Determining the Optimal Capacity for the MICE Industry in Las Vegas

The meetings, incentive travel, conventions and exhibitions (MICE) industry is a comparatively young industry and there has been limited research conducted in this field, especially from the financial performance and capacity management perspective. The purpose of this study is to fill the gap by analyzing the financial performance of the Las Vegas MICE industry and identifying its optimal capacity in the years to come. The findings and results of this study should help researchers and practitioners determine the current status of the Las Vegas MICE industry in terms of operational efficiency and profitability. The findings will also reveal whether the MICE development in Las Vegas is heading for over- or under-capacity and, if so, provide a gauge for the magnitude of over- or under-capacity. Academically, this study should make a good contribution to capacity optimization literature by applying the theoretical model to the MICE industry

“Did You Eat?”: A Cross-Cultural and Comparative Ethnography of Chinese and Korean Food in Flushing, New York

Culinary offerings in New York represent a diverse spectrum of cultures. In the city, Flushing is known specifically for its Chinese and Korean restaurants and cafes. When faced with so many choices of what to eat in the neighborhood, we are curious as to why one may be preferred over the other. We suspect that individuals frequently make selections driven by their predispositions and preconceived ideas about the broader cultural associations linked to the cuisine. To better understand this, we conducted a cross-cultural and comparative ethnography of the Chinese and Korean food establishments, utilizing a combination of observations and open-ended interviews. Despite both being East Asian cuisines, the degree of acceptance they receive in the United States differs. Throughout our research, we unravel the nuanced dynamics of consumer perceptions surrounding Chinese and Korean cuisine, exploring historical trajectories, cultural narratives, and societal attitudes. The core of our paper covers three central themes: what food is meant for, how food has changed, and how food is now perceived. We aim to reveal the complicated conceptual and experiential milieu of the contemporary U.S. for producing particular attitudes towards Asian Americans. We highlight food’s role in preserving cultural identity, gentrification, authenticity as an imagined standard, and the way cuisines interact with the standards imposed upon them

Noncoding RNA Landmarks of Pluripotency and Reprogramming

Noncoding RNAs have emerged as important determinants of pluripotency and reprogramming. In this issue of Cell Stem Cell, Kosik and colleagues now provide a detailed map of microRNA expression patterns to infer the biological states of embryonic and induced pluripotent stem cells

Multi-Agent Based Simulation for Investigating Electric Vehicle Adoption and Its Impacts on Electricity Distribution Grids and CO2 Emissions

Electric vehicles are expected to significantly contribute to CO2-eq. emissions reduction, but the increasing number of EVs also introduces chal-lenges to the energy system, and to what extent it contributes to achieving cli-mate goals remains unknown. Static modeling and assumption-based simula-tions have been used for such investigation, but they cannot capture the realistic ecosystem dynamics. To fill the gap, this paper investigates the impacts of two adoption curves of private EVs on the electricity distribution grids and national climate goals. This paper develops a multi-agent based simulation with two adoption curves, the Traditional EV charging strategy, various EV models, driv-ing patterns, and CO2-eq. emission data to capture the full ecosystem dynamics during a long-term period from 2020 to 2032. The Danish 2030 climate goal and a Danish distribution network with 126 residential consumers are chosen as the case study. The results show that both EV adoption curves of 1 million and 775k EVs by 2030 will not satisfy the Danish climate goal of reducing transport sector emissions by 30% by 2030. The results also show that the current resi-dential electricity distribution grids cannot handle the load from increasing EVs. The first grid overload will occur in 2031 (around 16 and 24 months later for the 1 million and 775k EVs adopted by 2030) with a 67% share of EVs in the grid

Obesity Prevalence and Dietary Intake of Antioxidants in Native American Adolescents

Antioxidants are well known for possessing anti-inflammatory properties, which can reduce the risk of chronic disease and obesity. However, very little research has been done to examine antioxidant intake among adolescent minority populations such as Native American adolescents. Our study examined the significance of antioxidant intake among Native American adolescents at an urban residential high school in Southern California. Our study population consisted of 183 male and female Native American adolescents, 14-18 years of age, representing 43 tribes from across the United States. Students' primary source of meals was provided by the school food service. Based on the BMI calculations, the rate of obesity within our population was 38% for males and 40% for females, more than two-fold the national rate indicated by NHANESIII data. We used the Harvard School of Public Health Youth/Adolescent Questionnaire (HSPH YAQ), a semi-quantitative food frequency questionnaire, to examine antioxidant nutrient intake and evaluate the differences in the intake between normal and obese weight students. Statistical analysis of the results showed that intakes of vitamins C, E, and lycopene were the antioxidant nutrients found to be significantly different between normal and obese weight students and intakes of these nutrients were found to be higher among normal weight students (p-values = 0.02451, 0.00847, and 0.04928, respectively). These results suggest that dietary intake of antioxidants could be increased among Native American adolescents. Further research is needed to confirm our findings and identify effective ways for school food service to incorporate antioxidant rich foods into school menus

Exploring the regulatory roles of microRNAs in mammalian development

Thesis (Ph. D.)--Massachusetts Institute of Technology, Computational and Systems Biology Program, 2010.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (p. 159-176).microRNAs (miRNAs) are ~22-nt long short RNAs that regulate gene expression in organisms ranging from plants to animals. In mammals, miRNAs post-transcriptionally repress gene expression by primarily binding to the 3' untranslated region (3' UTR) of target mRNAs. Although hundreds of miRNAs have been discovered, targets of most miRNAs and the method by which they affect their biological function remain elusive. To better understand the role of miRNAs in fundamental cellular processes, we characterized enriched miRNA populations in three distinct murine developmental programs, T lymphocytes, embryonic stem cells, and the placenta. We started exploring the role of miRNAs in T lymphocytes by globally characterizing short RNA expression during key developmental stages of T lymphocytes. Our results showed that a distinct set of miRNAs is enriched in each stage. In particular, miR-181 is elevated at the double positive (DP) stage, when thymocytes expressing both CD4 and CD8 undergo positive and negative selection. We found that miR-181 can repress the expression of Bcl-2, CD69, and the T cell receptor, all of which are involved in positive selection. Analysis of short RNAs in T lymphocytes also revealed a novel miRNA cluster, the Sfmbt2 miRNA cluster, named as such since it maps to an intron of the Sfmbt2 gene, a Polycomb Group gene. Instead of studying this cluster in T lymphocytes, we decided to use embryonic stem (ES) cells as this cluster is also expressed in ES cells and the cells are more conducive to lab experimentation. This cluster contains several miRNA families, and we addressed the function of one miRNA family, miR-467a, as it shares target specificity with other highly abundant miRNAs in ES cells. Gain and loss of function assays showed that this family of miRNAs can promote cell survival by advancing the G1 to S phase transition. In addition, they target certain proapoptotic factors to buffer ES cells from apoptosis, especially in the context of genotoxic stress. The Sfmbt2 cluster is a mouse-specific miRNA cluster, and individual members have been uniquely amplified in the Sfmbt2 locus. We developed a method to explore the impact of species-specific miRNAs on the evolution of 3' UTRs, and found that target sites of many miRNAs show positive selection. In particular, mouse target sites have evolved to specifically gain binding sites (mouse-specific targets) for some Sfmbt2 miRNAs, several of which are enriched in the placenta. These mouse-specific targets are enriched in pathways regulating cell survival, implicating the Sfmbt2 miRNA cluster as a possible promoter to placental growth. Our studies in T lymphocytes, ES cells and the placenta have revealed important roles of miRNAs in shaping 3' UTR evolution, and mammalian development. Several novel miRNA targets we uncovered are important regulators of differentiation, cell cycle, and apoptosis. Understanding their functions will not only shed light on their roles in normal physiology, but also generate useful insights that can be applied to cancer and reprogramming.by Grace Xinying Zheng.Ph.D

Structural insights into the role of the Smoothened cysteine-rich domain in Hedgehog signalling.

Smoothened (Smo) is a member of the Frizzled (FzD) class of G-protein-coupled receptors (GPCRs), and functions as the key transducer in the Hedgehog (Hh) signalling pathway. Smo has an extracellular cysteine-rich domain (CRD), indispensable for its function and downstream Hh signalling. Despite its essential role, the functional contribution of the CRD to Smo signalling has not been clearly elucidated. However, given that the FzD CRD binds to the endogenous Wnt ligand, it has been proposed that the Smo CRD may bind its own endogenous ligand. Here we present the NMR solution structure of the Drosophila Smo CRD, and describe interactions between the glucocorticoid budesonide (Bud) and the Smo CRDs from both Drosophila and human. Our results highlight a function of the Smo CRD, demonstrating its role in binding to small-molecule modulators

Metal-Free Synthesis of \u3ci\u3eN-Heterocycles via Intramolecular Electrochemical C-H Aminations

N-heterocycles are key structural units in many drugs, biologically interesting molecules and functional materials. To avoid the residues of metal catalysts, the construction of N-heterocycles under metal-free conditions has attracted much research attention in academia and industry. Among them, the intramolecular electrochemical C-H aminations arguably constitute environmentally friendly methodologies for the metal-free construction of N-heterocycles, mainly due to the direct use of clean electricity as the redox agents. With the recent renaissance of organic electrosynthesis, the intramolecular electrochemical C-H aminations have undergone much progress in recent years. In this article, we would like to summarize the advances in this research field since 2019. The emphasis is placed on the reaction design and mechanistic insight. The challenges and future developments in the intramolecular electrochemical C-H aminations are also discussed