Accounting for the Future: Reducing the Differences between International and Domestic Accounting Standards and Becoming a Better Global Citizen While Maintaining Autonomy

In recent times, the FASB and the IASB have heavily discussed bringing the United States on board to utilize the same IFRS accounting standards that much of the rest of the world uses. At this present time, IFRS adoption in the United States is no longer actively being considered, and alternative means of convergence have become the preferred method for supporting globalization. This paper posits that in order to serve a worldwide business community, the principles-based approach is more conducive to the flexible modern environment. The practices currently utilized to jointly-research and co-develop accounting standards by both the FASB and the IASB are instrumental in promoting efficiency and increased perspective as new, joint standards are instituted. A continued movement toward principles or objectives-based accounting as previously suggested by the SEC is suggested as the best way to unify the United States with the rest of the world within the accounting field

Teamwork in the Workplace: A Discovery of the Work Processes One Team Used to Meet Its Goals

A century-old disagreement in academia surrounds the question of whether individuals acting alone accomplish all work or whether workers can truly act in concert to meet management\u27s production requirements. Total Quality Management (TQM) is a powerful force today in the industrial world, and the formation of teams to solve short-term problems is one of its fundamental techniques. This dissertation focuses on a particular TQM team with the purpose of understanding the processes it used to meet its goals. This ten-member team functioned for about one year and was assigned goals leading to improved accelerator reliability. The investigator was a member of this team. Applicable theories and practices from the literature about teams in the workplace and about reliability engineering are discussed. The dissertation also includes a chronological account of the projects the team completed and a detailed analysis of nine of them. This analysis indicates that the resources used to start and finish a project are a function of many variables, including: the specific talents of the team members, their availability, the time-frame allowed, and project scope and complexity. Analysis of the nine work processes showed that only one project required initial input from everyone, and none were completed by just one member. Most projects were accomplished by two, three, or four-person mini-teams. This correlates with a theory which postulates that the fewer people involved in a collective effort, the harder each person still involved will work. At the same time, the full team had its uses; it made decisions by consensus and was a talent pool for selecting members of the mini-teams. It also acted as a review panel; when a mini-team needed advice, a critique, or encouragement, it went to the full team for help and got it. The processes that team members use to divide the labor and accomplish the work are as complex as human nature, but this team achieved economy of effort simply by using the members best fitted for each project and by using only the minimum number that could reasonably do the work

Sleep disturbances and circadian CLOCK genes in borderline personality disorder

Borderline personality disorder (BPD) is characterised by a deep-reaching pattern of affective instability, incoherent identity, self-injury, suicide attempts, and disturbed interpersonal relations and lifestyle. The daily activities of BPD patients are often chaotic and disorganized, with patients often staying up late while sleeping during the day. These behavioural patterns suggest that altered circadian rhythms may be associated with BPD. Furthermore, BPD patients frequently report suffering from sleep disturbances. In this review, we overview the evidence that circadian rhythms and sleep are disturbed in BPD, and we explore the possibility that personality traits that are pertinent for BPD may be associated with circadian typology, and perhaps to circadian genotypes. With regards to sleep architecture, we review the evidence that BPD patients display altered non-REM and REM sleep. A possible cue to a deeper understanding of this temporal dysregulation might be an analysis of the circadian clock at the molecular and cellular level, as well as behavioural studies using actigraphy and we suggest avenues for further exploration of these factors

Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo

Small interfering RNA (siRNA)-based therapies are proving to be efficient for treating liver-associated disorders. However, extra-hepatic delivery remains challenging, limiting therapeutic siRNA utility. We synthesized a panel of fifteen lipid-conjugated siRNAs and systematically evaluated the impact of conjugate on siRNA tissue distribution and efficacy. Generally, conjugate hydrophobicity defines the degree of clearance and the liver-to-kidney distribution profile. In addition to primary clearance tissues, several conjugates achieve significant siRNA accumulation in muscle, lung, heart, adrenal glands and fat. Oligonucleotide distribution to extra-hepatic tissues with some conjugates was significantly higher than with cholesterol, a well studied conjugate, suggesting that altering conjugate structure can enhance extra-hepatic delivery. These conjugated siRNAs enable functional gene silencing in lung, muscle, fat, heart and adrenal gland. Required levels for productive silencing vary (5-200 mug/g) per tissue, suggesting that the chemical nature of conjugates impacts tissue-dependent cellular/intracellular trafficking mechanisms. The collection of conjugated siRNA described here enables functional gene modulation in vivo in several extra-hepatic tissues opening these tissues for gene expression modulation. A systemic evaluation of a panel of conjugated siRNA, as reported here, has not previously been investigated and shows that chemical engineering of lipid siRNAs is essential to advance the RNA therapeutic field

Guanabenz (Wytensin) selectively enhances uptake and efficacy of hydrophobically modified siRNAs

One of the major obstacles to the pharmaceutical success of oligonucleotide therapeutics (ONTs) is efficient delivery from the point of injection to the intracellular setting where functional gene silencing occurs. In particular, a significant fraction of internalized ONTs are nonproductively sequestered in endo-lysosomal compartments. Here, we describe a two-step, robust assay for high-throughput de novo detection of small bioactive molecules that enhance cellular uptake, endosomal escape, and efficacy of ONTs. Using this assay, we screened the LOPAC (Sigma-Aldrich) Library of Pharmacologically Active Compounds and discovered that Guanabenz acetate (Wytensin), an FDA-approved drug formerly used as an antihypertensive agent, is capable of markedly increasing the cellular internalization and target mRNA silencing of hydrophobically modified siRNAs (hsiRNAs), yielding a approximately 100-fold decrease in hsiRNA IC50 (from 132 nM to 2.4 nM). This is one of the first descriptions of a high-throughput small-molecule screen to identify novel chemistries that specifically enhance siRNA intracellular efficacy, and can be applied toward expansion of the chemical diversity of ONTs

Chromium stable isotope distributions in the southwest Pacific Ocean and constraints on hydrothermal input from the Kermadec Arc

Special attention has been given to chromium (Cr) as a paleoproxy tracing redox cycling throughout Earth’s history, due to differences in the solubility of its primary redox species at Earth’s surface (Cr (III) and Cr(VI)) and isotope fractionation associated with their interconversion. In turn, chromium’s pale- oproxy potential has motivated studies of the modern ocean to better understand which processes drive its cycling and to constrain their impact on the Cr isotope composition (d53Cr) of seawater. Here, we pre- sent total dissolved seawater Cr concentrations and d53Cr along the GEOTRACES GP13 section. This sec- tion is a zonal transect extending from Australia in the subtropical southwest Pacific Ocean. Surface signals of local biological Cr cycling are minimal, in agreement with distributions of dissolved major nutrients as well as biologically-controlled trace metals in this low productivity, oligotrophic environ- ment. Depth profiles have Cr concentration minima in surface waters and maxima at depth, and are lar- gely shaped by the advection of nutrient- and Cr-rich subsurface waters rather than vertically-driven processes. Samples close to the sediment–water interface indicate important benthic Cr fluxes across the section. The GP13 transect crosses the hydrothermally-active Kermadec Arc. Hydrothermal fluids (consisting of <15% background seawater) were collected from three venting sites at the Brothers Volcano (along the Kermadec Arc). These fluids yielded near-crustal d53Cr values (!0.17 to +0.08‰) and elevated [Cr] (7.5–23 nmol kg!1, hydrothermal endmember [Cr] % 8–27 nmol kg!1), indicating that the Kermadec Arc may be an isotopically light Cr source. Dissolved [Fe] enrichments have been reported previously in deep waters ($1600–3000 m) along the GP13 transect, east of the Kermadec Arc. These same waters show ele- vated [Cr] compared to Circumpolar Deep Water ([Cr] = 3.88 ± 0.11, d53Cr = 0.89 ± 0.08, n = 32), with an aver- age [Cr] accumulation of 0.71 ± 0.11 nmol kg!1 (1 SD), and an estimated d53Cr of +0.46 ± 0.30‰ (2 SD, n = 9) for the accumulated Cr. Comparing high-temperature vent and neutrally buoyant plume data, hydrothermal-sourced Cr is likely negligable compared to Cr contributions from other processes (benthic fluxes, release from particles), and the advection of more Cr-rich Pacific Deep Water. It is unlikely that hydrothermal vents would be a major contributor within the regional or global biogeochemical Cr cycle, even if hydrothermal fluxes change by orders of magnitude, and therefore d53Cr trends in the paleorecord may be attributable, at least in part, to major changes in other controls on Cr (e.g. widespread anoxia)

Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways

Efficient delivery of therapeutic RNA beyond the liver is the fundamental obstacle preventing its clinical utility. Lipid conjugation increases plasma half-life and enhances tissue accumulation and cellular uptake of small interfering RNAs (siRNAs). However, the mechanism relating lipid hydrophobicity, structure, and siRNA pharmacokinetics is unclear. Here, using a diverse panel of biologically occurring lipids, we show that lipid conjugation directly modulates siRNA hydrophobicity. When administered in vivo, highly hydrophobic lipid-siRNAs preferentially and spontaneously associate with circulating low-density lipoprotein (LDL), while less lipophilic lipid-siRNAs bind to high-density lipoprotein (HDL). Lipid-siRNAs are targeted to lipoprotein receptor-enriched tissues, eliciting significant mRNA silencing in liver (65%), adrenal gland (37%), ovary (35%), and kidney (78%). Interestingly, siRNA internalization may not be completely driven by lipoprotein endocytosis, but the extent of siRNA phosphorothioate modifications may also be a factor. Although biomimetic lipoprotein nanoparticles have been explored for the enhancement of siRNA delivery, our findings suggest that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation

Introduction to topological superconductivity and Majorana fermions

This short review article provides a pedagogical introduction to the rapidly growing research field of Majorana fermions in topological superconductors. We first discuss in some details the simplest "toy model" in which Majoranas appear, namely a one-dimensional tight-binding representation of a p-wave superconductor, introduced more than ten years ago by Kitaev. We then give a general introduction to the remarkable properties of Majorana fermions in condensed matter systems, such as their intrinsically non-local nature and exotic exchange statistics, and explain why these quasiparticles are suspected to be especially well suited for low-decoherence quantum information processing. We also discuss the experimentally promising (and perhaps already successfully realized) possibility of creating topological superconductors using semiconductors with strong spin-orbit coupling, proximity-coupled to standard s-wave superconductors and exposed to a magnetic field. The goal is to provide an introduction to the subject for experimentalists or theorists who are new to the field, focusing on the aspects which are most important for understanding the basic physics. The text should be accessible for readers with a basic understanding of quantum mechanics and second quantization, and does not require knowledge of quantum field theory or topological states of matter.Comment: 21 pages, 5 figure

Exosome-mediated Delivery of Hydrophobically Modified siRNA for Huntingtin mRNA Silencing

Delivery represents a significant barrier to the clinical advancement of oligonucleotide therapeutics for the treatment of neurological disorders, such as Huntington\u27s disease. Small, endogenous vesicles known as exosomes have the potential to act as oligonucleotide delivery vehicles, but robust and scalable methods for loading RNA therapeutic cargo into exosomes are lacking. Here, we show that hydrophobically modified small interfering RNAs (hsiRNAs) efficiently load into exosomes upon co-incubation, without altering vesicle size distribution or integrity. Exosomes loaded with hsiRNAs targeting Huntingtin mRNA were efficiently internalized by mouse primary cortical neurons and promoted dose-dependent silencing of Huntingtin mRNA and protein. Unilateral infusion of hsiRNA-loaded exosomes, but not hsiRNAs alone, into mouse striatum resulted in bilateral oligonucleotide distribution and statistically significant bilateral silencing of up to 35% of Huntingtin mRNA. The broad distribution and efficacy of hsiRNA-loaded exosomes delivered to brain is expected to advance the development of therapies for the treatment of Huntington\u27s disease and other neurodegenerative disorders