The Modern Administrative State: Why We Have ‘Big Government’ and How to Run and Reform Bureaucratic Organizations

This work asserts that bureaucratic organization is not only an inevitable part of the modern administrative state, but that a high quality bureaucracy within a strongly empowered executive branch is an ideal mechanism for running government in the modern era. Beginning with a philosophical inquiry into the purpose of American government as we understand it today, this paper responds to criticisms of the role of expanded government and develops a framework for evaluating the quality of differing government structures. Following an evaluation of the current debate surrounding bureaucracies (from both proponents and critics), this thesis outlines the lessons and principles for structuring and managing an efficient bureaucracy. Finally, this paper concludes with two case studies – Puerto Rican bureaucratic failures and Japanese/Chinese national development – to consider the effects of compliance and non-compliance to the lessons outlined in this work. The inquiry finds that principles such as specialization, political autonomy, effective information systems, higher accountability standards, and managerial emphasis on policy implementation are all critical to superior bureaucratic governance

Families of IIB duals for nonrelativistic CFTs

We show that the recent string theory embedding of a spacetime with nonrelativistic Schrodinger symmetry can be generalised to a twenty one dimensional family of solutions with that symmetry. Our solutions include IIB backgrounds with no three form flux turned on, and arise as near horizon limits of branewave spacetimes. We show that there is a hypersurface in the space of these theories where an instability appears in the gravitational description, indicating a phase transition in the nonrelativistic field theory dual. We also present simple embeddings of duals for nonrelativistic critical points where the dynamical critical exponent can take many values z \neq 2.Comment: 1+25 pages. References adde

Microbial Reprogramming Inhibits Western Diet-Associated Obesity

A recent epidemiological study showed that eating ‘fast food’ items such as potato chips increased likelihood of obesity, whereas eating yogurt prevented age-associated weight gain in humans. It was demonstrated previously in animal models of obesity that the immune system plays a critical role in this process. Here we examined human subjects and mouse models consuming Westernized ‘fast food’ diet, and found CD4[superscript +] T helper (Th)17-biased immunity and changes in microbial communities and abdominal fat with obesity after eating the Western chow. In striking contrast, eating probiotic yogurt together with Western chow inhibited age-associated weight gain. We went on to test whether a bacteria found in yogurt may serve to lessen fat pathology by using purified Lactobacillus reuteri ATCC 6475 in drinking water. Surprisingly, we discovered that oral L. reuteri therapy alone was sufficient to change the pro-inflammatory immune cell profile and prevent abdominal fat pathology and age-associated weight gain in mice regardless of their baseline diet. These beneficial microbe effects were transferable into naïve recipient animals by purified CD4[superscript +] T cells alone. Specifically, bacterial effects depended upon active immune tolerance by induction of Foxp3[superscript +] regulatory T cells (Treg) and interleukin (Il)-10, without significantly changing the gut microbial ecology or reducing ad libitum caloric intake. Our finding that microbial targeting restored CD4[superscript +] T cell balance and yielded significantly leaner animals regardless of their dietary ‘fast food’ indiscretions suggests population-based approaches for weight management and enhancing public health in industrialized societies.National Institutes of Health (U.S.) (Grant P30-ES002109)National Institutes of Health (U.S.) (Grant RO1CA108854)National Institutes of Health (U.S.) (Grant P01 AI045757)National Institutes of Health (U.S.) (Grant U19 AI046130)National Institutes of Health (U.S.) (Grant U19 AI070352)National Institutes of Health (U.S.) (Grant P01 AI039671)National Institute of Neurological Disorders and Stroke (U.S.) (Jacob Javits Merit Award NS2427)The Penates FoundationNancy Taylor Foundation for Chronic Diseases, Inc

Critical Loss of the Balance between Th17 and T Regulatory Cell Populations in Pathogenic SIV Infection

Chronic immune activation and progression to AIDS are observed after SIV infection in macaques but not in natural host primate species. To better understand this dichotomy, we compared acute pathogenic SIV infection in pigtailed macaques (PTs) to non-pathogenic infection in African green monkeys (AGMs). SIVagm-infected PTs, but not SIVagm-infected AGMs, rapidly developed systemic immune activation, marked and selective depletion of IL-17-secreting (Th17) cells, and loss of the balance between Th17 and T regulatory (Treg) cells in blood, lymphoid organs, and mucosal tissue. The loss of Th17 cells was found to be predictive of systemic and sustained T cell activation. Collectively, these data indicate that loss of the Th17 to Treg balance is related to SIV disease progression

Analysis of the Basidiomycete Coprinopsis cinerea Reveals Conservation of the Core Meiotic Expression Program over Half a Billion Years of Evolution

Coprinopsis cinerea (also known as Coprinus cinereus) is a multicellular basidiomycete mushroom particularly suited to the study of meiosis due to its synchronous meiotic development and prolonged prophase. We examined the 15-hour meiotic transcriptional program of C. cinerea, encompassing time points prior to haploid nuclear fusion though tetrad formation, using a 70-mer oligonucleotide microarray. As with other organisms, a large proportion (∼20%) of genes are differentially regulated during this developmental process, with successive waves of transcription apparent in nine transcriptional clusters, including one enriched for meiotic functions. C. cinerea and the fungi Saccharomyces cerevisiae and Schizosaccharomyces pombe diverged ∼500–900 million years ago, permitting a comparison of transcriptional programs across a broad evolutionary time scale. Previous studies of S. cerevisiae and S. pombe compared genes that were induced upon entry into meiosis; inclusion of C. cinerea data indicates that meiotic genes are more conserved in their patterns of induction across species than genes not known to be meiotic. In addition, we found that meiotic genes are significantly more conserved in their transcript profiles than genes not known to be meiotic, which indicates a remarkable conservation of the meiotic process across evolutionarily distant organisms. Overall, meiotic function genes are more conserved in both induction and transcript profile than genes not known to be meiotic. However, of 50 meiotic function genes that were co-induced in all three species, 41 transcript profiles were well-correlated in at least two of the three species, but only a single gene (rad50) exhibited coordinated induction and well-correlated transcript profiles in all three species, indicating that co-induction does not necessarily predict correlated expression or vice versa. Differences may reflect differences in meiotic mechanisms or new roles for paralogs. Similarities in induction, transcript profiles, or both, should contribute to gene discovery for orthologs without currently characterized meiotic roles

12-Lipoxygenase regulates cold adaptation and glucose metabolism by producing the omega-3 lipid 12-HEPE from brown Fat

Distinct oxygenases and their oxylipin products have been shown to participate in thermogenesis by mediating physiological adaptations required to sustain body temperature. Since the role of the lipoxygenase (LOX) family in cold adaptation remains elusive, we aimed to investigate whether, and how, LOX activity is required for cold adaptation and to identify LOX-derived lipid mediators that could serve as putative cold mimetics with therapeutic potential to combat diabetes. By utilizing mass-spectrometry-based lipidomics in mice and humans, we demonstrated that cold and beta 3-adrenergic stimulation could promote the biosynthesis and release of 12-LOX metabolites from brown adipose tissue (BAT). Moreover, 12-LOX ablation in mouse brown adipocytes impaired glucose uptake and metabolism, resulting in blunted adaptation to the cold in vivo. The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway304768783FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2017/02684This work was supported in part by US National Institutes of Health (NIH) grants R01DK077097 and R01DK102898 (to Y.-H.T.); R01HL106173 and P01GM095467 (to M.S.); R01DK099511 (to L.J.G.) and P30DK036836 (to Joslin Diabetes Center's Diabetes Research Center) from the National Institute of Diabetes and Digestive and Kidney Diseases; and by US Army Medical Research grant W81XWH-17-1-0428 (to Y.-H.T.). L.O.L. was supported by an American Diabetes Association post-doctoral fellowship (1-16-PDF-063) and by the São Paulo Research Foundation (FAPESP) grant 2017/02684. M.D.L. was supported by NIH grants T32DK007260, F32DK102320, and K01DK111714. K.v.L. was supported by the grant R21NS087165. A.B. was supported by a Deutsche Forschungsgemeinschaft research fellowship (BA 4925/1-1) and the Deutsches Zentrum für Herz-Kreislauf-Forschung. B.E.S. is supported by an NRSA from the NIH (HL136044). We thank A. Clermont, A. Dean, and K. Longval of the Joslin Diabetes Center Physiology core. We also would like to thank Dr. Fabio Tucci of Epigen Biosciences, San Diego, who synthesized LOXBlock-1. We apologize to colleagues whose work we could not cite due to space limitation

A Eukaryotic Capsular Polysaccharide Is Synthesized Intracellularly and Secreted via Exocytosis

Cryptococcus neoformans, which causes fatal infection in immunocompromised individuals, has an elaborate polysaccharide capsule surrounding its cell wall. The cryptococcal capsule is the major virulence factor of this fungal organism, but its biosynthetic pathways are virtually unknown. Extracellular polysaccharides of eukaryotes may be made at the cell membrane or within the secretory pathway. To test these possibilities for cryptococcal capsule synthesis, we generated a secretion mutant in C. neoformans by mutating a Sec4/Rab8 GTPase homolog. At a restrictive temperature, the mutant displayed reduced growth and protein secretion, and accumulated ∼100-nm vesicles in a polarized manner. These vesicles were not endocytic, as shown by their continued accumulation in the absence of polymerized actin, and could be labeled with anti-capsular antibodies as visualized by immunoelectron microscopy. These results indicate that glucuronoxylomannan, the major cryptococcal capsule polysaccharide, is trafficked within post-Golgi secretory vesicles. This strongly supports the conclusion that cryptococcal capsule is synthesized intracellularly and secreted via exocytosis

Microbial Symbionts Accelerate Wound Healing via the Neuropeptide Hormone Oxytocin

Wound healing capability is inextricably linked with diverse aspects of physical fitness ranging from recovery after minor injuries and surgery to diabetes and some types of cancer. Impact of the microbiome upon the mammalian wound healing process is poorly understood. We discover that supplementing the gut microbiome with lactic acid microbes in drinking water accelerates the wound-healing process to occur in half the time required for matched control animals. Further, we find that Lactobacillus reuteri enhances wound-healing properties through up-regulation of the neuropeptide hormone oxytocin, a factor integral in social bonding and reproduction, by a vagus nerve-mediated pathway. Bacteria-triggered oxytocin serves to activate host CD4+Foxp3+CD25+ immune T regulatory cells conveying transplantable wound healing capacity to naive Rag2-deficient animals. This study determined oxytocin to be a novel component of a multi-directional gut microbe-brain-immune axis, with wound-healing capability as a previously unrecognized output of this axis. We also provide experimental evidence to support long-standing medical traditions associating diet, social practices, and the immune system with efficient recovery after injury, sustained good health, and longevity.National Institutes of Health (U.S.) (Grant P30-ES002109)National Institutes of Health (U.S.) (Grant U01 CA164337)National Institutes of Health (U.S.) (Grant R01CA08854

Fermilab Test Beam Facility Annual Report: FY19

This Technical Memorandum (TM) summarizes the Fermilab Test Beam Faciltiy (FTBF) operations for FY2019. It is one of a series of annual publications intended to gather information in one place. This TM discusses the experiments performed at the Test Beam from November 2018 to July 2019. The experiments are listed in Table 1. Each experiment wrote a summary that was edited for clarity and is included in this report