Functionalisation of bolaamphiphiles with mononuclear bis(2,2'-bipyridyl)ruthenium(II) complexes for application in self assembled monolayers

A novel ruthenium(II) polypyridyl complex connected competently to a bolaamphiphile, containing amide linkages to provide rigidity via hydrogen bonding in the monolayer, has been prepared. The ruthenium(II) complexes of this ligand and of the intermediates in the synthesis were prepared by modification of the coordinated ligands, demonstrating the synthetic versatility and robustness of this family of complexes. All ruthenium complexes were characterised by electrochemical and spectroscopic techniques and were found to have similar properties to the parent complex [Ru(bipy)[3]][2][+], and remain versatile photosensitisers, with well-defined properties, despite extensive substitution of the bipy ligand

Hydrodynamic Hunters

The Gram-negative Bdellovibrio bacteriovorus (BV) is a model bacterial predator that hunts other bacteria and may serve as a living antibiotic. Despite over 50 years since its discovery, it is suggested that BV probably collides into its prey at random. It remains unclear to what degree, if any, BV uses chemical cues to target its prey. The targeted search problem by the predator for its prey in three dimensions is a difficult problem: it requires the predator to sensitively detect prey and forecast its mobile prey’s future position on the basis of previously detected signal. Here instead we find that rather than chemically detecting prey, hydrodynamics forces BV into regions high in prey density, thereby improving its odds of a chance collision with prey and ultimately reducing BV’s search space for prey. We do so by showing that BV’s dynamics are strongly influenced by self-generated hydrodynamic flow fields forcing BV onto surfaces and, for large enough defects on surfaces, forcing BV in orbital motion around these defects. Key experimental controls and calculations recapitulate the hydrodynamic origin of these behaviors. While BV’s prey (Escherichia coli) are too small to trap BV in hydrodynamic orbit, the prey are also susceptible to their own hydrodynamic fields, substantially confining them to surfaces and defects where mobile predator and prey density is now dramatically enhanced. Colocalization, driven by hydrodynamics, ultimately reduces BV’s search space for prey from three to two dimensions (on surfaces) even down to a single dimension (around defects). We conclude that BV’s search for individual prey remains random, as suggested in the literature, but confined, however—by generic hydrodynamic forces—to reduced dimensionality

Jamming at Zero Temperature and Zero Applied Stress: the Epitome of Disorder

We have studied how 2- and 3- dimensional systems made up of particles interacting with finite range, repulsive potentials jam (i.e., develop a yield stress in a disordered state) at zero temperature and applied stress. For each configuration, there is a unique jamming threshold, $\phi_c$, at which particles can no longer avoid each other and the bulk and shear moduli simultaneously become non-zero. The distribution of $\phi_c$ values becomes narrower as the system size increases, so that essentially all configurations jam at the same $\phi$ in the thermodynamic limit. This packing fraction corresponds to the previously measured value for random close-packing. In fact, our results provide a well-defined meaning for "random close-packing" in terms of the fraction of all phase space with inherent structures that jam. The jamming threshold, Point J, occurring at zero temperature and applied stress and at the random close-packing density, has properties reminiscent of an ordinary critical point. As Point J is approached from higher packing fractions, power-law scaling is found for many quantities. Moreover, near Point J, certain quantities no longer self-average, suggesting the existence of a length scale that diverges at J. However, Point J also differs from an ordinary critical point: the scaling exponents do not depend on dimension but do depend on the interparticle potential. Finally, as Point J is approached from high packing fractions, the density of vibrational states develops a large excess of low-frequency modes. All of these results suggest that Point J may control behavior in its vicinity-perhaps even at the glass transition.Comment: 21 pages, 20 figure

A Case Study of Convectively Sourced Water Vapor Observed in the Overworld Stratosphere over the United States

On 27 August 2013, during the Studies of Emissions and Atmospheric Composition, Clouds and Climate Coupling by Regional Surveys field mission, NASA's ER2 research aircraft encountered a region of enhanced water vapor, extending over a depth of approximately 2 km and a minimum areal extent of 20,000 km(exp 2) in the stratosphere (375 K to 415 K potential temperature), south of the Great Lakes (42N, 90W). Water vapor mixing ratios in this plume, measured by the Harvard Water Vapor instrument, constitute the highest values recorded in situ at these potential temperatures and latitudes. An analysis of geostationary satellite imagery in combination with trajectory calculations links this water vapor enhancement to its source, a deep tropopausepenetrating convective storm system that developed over Minnesota 20 h prior to the aircraft plume encounter. High resolution, groundbased radar data reveal that this system was composed of multiple individual storms, each with convective turrets that extended to a maximum of ~4 km above the tropopause level for several hours. In situ water vapor data show that this storm system irreversibly delivered between 6.6 kt and 13.5 kt of water to the stratosphere. This constitutes a 2025% increase in water vapor abundance in a column extending from 115 hP to 70 hPa over the plume area. Both in situ and satellite climatologies show a high frequency of localized water vapor enhancements over the central U.S. in summer, suggesting that deep convection can contribute to the stratospheric water budget over this region and season

Treating cofactors can reverse the expansion of a primary disease epidemic

<p>Abstract</p> <p>Background</p> <p>Cofactors, "nuisance" conditions or pathogens that affect the spread of a primary disease, are likely to be the norm rather than the exception in disease dynamics. Here we present a "simplest possible" demographic model that incorporates two distinct effects of cofactors: that on the transmission of the primary disease from an infected host bearing the cofactor, and that on the acquisition of the primary disease by an individual that is not infected with the primary disease but carries the cofactor.</p> <p>Methods</p> <p>We constructed and analyzed a four-patch compartment model that accommodates a cofactor. We applied the model to HIV spread in the presence of the causal agent of genital schistosomiasis, <it>Schistosoma hematobium</it>, a pathogen commonly co-occurring with HIV in sub-Saharan Africa.</p> <p>Results</p> <p>We found that cofactors can have a range of effects on primary disease dynamics, including shifting the primary disease from non-endemic to endemic, increasing the prevalence of the primary disease, and reversing demographic growth when the host population bears only the primary disease to demographic decline. We show that under parameter values based on the biology of the HIV/<it>S. haematobium </it>system, reduction of the schistosome-bearing subpopulations (e.g. through periodic use of antihelminths) can slow and even reverse the spread of HIV through the host population.</p> <p>Conclusions</p> <p>Typical single-disease models provide estimates of future conditions and guidance for direct intervention efforts relating only to the modeled primary disease. Our results suggest that, in circumstances under which a cofactor affects the disease dynamics, the most effective intervention effort might not be one focused on direct treatment of the primary disease alone. The cofactor model presented here can be used to estimate the impact of the cofactor in a particular disease/cofactor system without requiring the development of a more complicated model which incorporates many other specific aspects of the chosen disease/cofactor pair. Simulation results for the HIV/<it>S. haematobium </it>system have profound implications for disease management in developing areas, in that they provide evidence that in some cases treating cofactors may be the most successful and cost-effective way to slow the spread of primary diseases.</p

Duloxetine in the treatment of major depressive disorder: an open-label study

<p>Abstract</p> <p>Background</p> <p>Major depressive disorder (MDD) is a chronic and highly disabling condition. Existing pharmacotherapies produce full remission in only 30% to 40% of treated patients. Antidepressants exhibiting dual reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE) may achieve higher rates of remission compared with those acting upon a single neurotransmitter. In this study, the safety and efficacy of duloxetine, a potent dual reuptake inhibitor of 5-HT and NE, were examined.</p> <p>Methods</p> <p>Patients (N = 533) meeting DSM-IV criteria for MDD received open-label duloxetine (60 mg once a day [QD]) for 12 weeks during the initial phase of a relapse prevention trial. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD₁₇) total score ≥18 and a Clinical Global Impression of Severity (CGI-S) score ≥4 at baseline. Efficacy measures included the HAMD₁₇total score, HAMD₁₇subscales, the CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQ-SS). Quality of life was assessed using the Sheehan Disability Scale (SDS) and the Quality of Life in Depression Scale (QLDS). Safety was evaluated by recording spontaneously-reported treatment-emergent adverse events, changes in vital signs and laboratory analytes, and the Patient Global Impression of Sexual Function (PGI-SF) scale.</p> <p>Results</p> <p>The rate of discontinuation due to adverse events was 11.3%. Treatment-emergent adverse events reported by ≥10% duloxetine-treated patients were nausea, headache, dry mouth, somnolence, insomnia, and dizziness. Following 12 weeks of open-label duloxetine therapy, significant improvements were observed in all assessed efficacy and quality of life measures. In assessments of depression severity (HAMD₁₇, CGI-S) the magnitude of symptom improvement continued to increase at each study visit, while for painful physical symptoms the onset of improvement was rapid and reached a maximum after 2 to 3 weeks of treatment.</p> <p>Conclusion</p> <p>In this open-label phase of a relapse prevention study, duloxetine (60 mg QD) was shown to be safe and effective in the treatment of MDD.</p> <p>Trial registration</p> <p>NCT00036309.</p

Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial

Importance: The appropriate duration of antibiotics for staphylococcal bacteremia is unknown. Objective: To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events. Design, Setting, and Participants: A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization. Interventions: Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care. Main Outcomes and Measures: Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia. Results: Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]). Conclusions and Relevance: Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm. Trial Registration: ClinicalTrials.gov Identifier: NCT01191840

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure