Cosmological Measures without Volume Weighting

Many cosmologists (myself included) have advocated volume weighting for the cosmological measure problem, weighting spatial hypersurfaces by their volume. However, this often leads to the Boltzmann brain problem, that almost all observations would be by momentary Boltzmann brains that arise very briefly as quantum fluctuations in the late universe when it has expanded to a huge size, so that our observations (too ordered for Boltzmann brains) would be highly atypical and unlikely. Here it is suggested that volume weighting may be a mistake. Volume averaging is advocated as an alternative. One consequence may be a loss of the argument that eternal inflation gives a nonzero probability that our universe now has infinite volume.Comment: 15 pages, LaTeX, added references for constant-H hypersurfaces and also an idea for minimal-flux hypersurface

Agnesi Weighting for the Measure Problem of Cosmology

The measure problem of cosmology is how to assign normalized probabilities to observations in a universe so large that it may have many observations occurring at many different spacetime locations. I have previously shown how the Boltzmann brain problem (that observations arising from thermal or quantum fluctuations may dominate over ordinary observations if the universe expands sufficiently and/or lasts long enough) may be ameliorated by volume averaging, but that still leaves problems if the universe lasts too long. Here a solution is proposed for that residual problem by a simple weighting factor 1/(1+t^2) to make the time integral convergent. The resulting Agnesi measure appears to avoid problems other measures may have with vacua of zero or negative cosmological constant.Comment: 26 pages, LaTeX; discussion is added of how Agnesi weighting appears better than other recent measure

Crystal Structure of Legionella DotD: Insights into the Relationship between Type IVB and Type II/III Secretion Systems

The Dot/Icm type IVB secretion system (T4BSS) is a pivotal determinant of Legionella pneumophila pathogenesis. L. pneumophila translocate more than 100 effector proteins into host cytoplasm using Dot/Icm T4BSS, modulating host cellular functions to establish a replicative niche within host cells. The T4BSS core complex spanning the inner and outer membranes is thought to be made up of at least five proteins: DotC, DotD, DotF, DotG and DotH. DotH is the outer membrane protein; its targeting depends on lipoproteins DotC and DotD. However, the core complex structure and assembly mechanism are still unknown. Here, we report the crystal structure of DotD at 2.0 Å resolution. The structure of DotD is distinct from that of VirB7, the outer membrane lipoprotein of the type IVA secretion system. In contrast, the C-terminal domain of DotD is remarkably similar to the N-terminal subdomain of secretins, the integral outer membrane proteins that form substrate conduits for the type II and the type III secretion systems (T2SS and T3SS). A short β-segment in the otherwise disordered N-terminal region, located on the hydrophobic cleft of the C-terminal domain, is essential for outer membrane targeting of DotH and Dot/Icm T4BSS core complex formation. These findings uncover an intriguing link between T4BSS and T2SS/T3SS

Russian roulette with unlicensed fat-burner drug 2,4-dinitrophenol (DNP) : evidence from a multidisciplinary study of the internet, bodybuilding supplements and DNP users

BACKGROUND: 2,4-Dinitrophenol (DNP) poses serious health-risks to humans. The aims of this three-stage multidisciplinary project were, for the first time, to assess the risks to the general public from fraudulent sale of or adulteration/contamination with DNP; and to investigate motives, reasons and risk-management among DNP-user bodybuilders and avid exercisers. METHODS: Using multiple search-engines and guidance for Internet research, online retailers and bodybuilding forums/blogs were systematically explored for availability of DNP, advice offered on DNP use and user profiles. Ninety-eight pre-workout and weight-loss supplements were purchased and analysed for DNP using liquid-chromatography-mass-spectrometry. Psychosocial variables were captured in an international sample of 35 DNP users (26.06 ± 6.10 years, 94.3 % male) with an anonymous, semi-qualitative self-reported survey. RESULTS: Although an industrial chemical, evidence from the Internet showed that DNP is sold 'as is', in capsules or tablets to suit human consumption, and is used 'uncut'. Analytical results confirmed that DNP is not on the supplement market disguised under fictitious supplement names, but infrequently was present as contaminant in some supplements (14/98) at low concentration (<100mcg/kg). Users make conscious and 'informed' decisions about DNP; are well-prepared for the side-effects and show nonchalant attitude toward self-experimentation with DNP. Steps are often taken to ensure that DNP is genuine. Personal experience with performance- and appearance enhancing substances appears to be a gateway to DNP. Advice on DNP and experiences are shared online. The significant discrepancy between the normative perception and the actual visibility suggests that DNP use is-contrary to the Internet accounts-a highly concealed and lonesome activity in real life. Positive experiences with the expected weight-loss prevail over the negative experiences from side effects (all but two users considered using DNP again) and help with using DNP safely is considered preferable over scare-tactics. CONCLUSION: Legislation banning DNP sale for human consumption protects the general public but DNP is sold 'as is' and used 'uncut' by determined users who are not dissuaded from experimenting with DNP based on health threats. Further research with stakeholders' active participation is imperative for targeted, proactive public health policies and harm-reduction measures for DNP, and other illicit supplements

The Born Rule Dies

The Born rule may be stated mathematically as the rule that probabilities in quantum theory are expectation values of a complete orthogonal set of projection operators. This rule works for single laboratory settings in which the observer can distinguish all the different possible outcomes corresponding to the projection operators. However, theories of inflation suggest that the universe may be so large that any laboratory, no matter how precisely it is defined by its internal state, may exist in a large number of very distantly separated copies throughout the vast universe. In this case, no observer within the universe can distinguish all possible outcomes for all copies of the laboratory. Then normalized probabilities for the local outcomes that can be locally distinguished cannot be given by the expectation values of any projection operators. Thus the Born rule dies and must be replaced by another rule for observational probabilities in cosmology. The freedom of what this new rule is to be is the measure problem in cosmology. A particular volume-averaged form is proposed.Comment: LaTeX, 16 pages, typos in Eqs. (4.3) and (6.2) correcte

In Vivo, In Vitro, and In Silico Characterization of Peptoids as Antimicrobial Agents

Bacterial resistance to conventional antibiotics is a global threat that has spurred the development of antimicrobial peptides (AMPs) and their mimetics as novel anti-infective agents. While the bioavailability of AMPs is often reduced due to protease activity, the non-natural structure of AMP mimetics renders them robust to proteolytic degradation, thus offering a distinct advantage for their clinical application. We explore the therapeutic potential of N-substituted glycines, or peptoids, as AMP mimics using a multi-faceted approach that includes in silico, in vitro, and in vivo techniques. We report a new QSAR model that we developed based on 27 diverse peptoid sequences, which accurately correlates antimicrobial peptoid structure with antimicrobial activity. We have identified a number of peptoids that have potent, broad-spectrum in vitro activity against multi-drug resistant bacterial strains. Lastly, using a murine model of invasive S. aureus infection, we demonstrate that one of the best candidate peptoids at 4 mg/kg significantly reduces with a two-log order the bacterial counts compared with saline-treated controls. Taken together, our results demonstrate the promising therapeutic potential of peptoids as antimicrobial agents