Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection

AR-12 has been evaluated in clinical trials as an anti-cancer agent but also has demonstrated host-directed, broad-spectrum clearance of bacteria. We have previously shown that AR-12 has activity in vitro against Salmonella enterica serovar Typhimurium and Francisella species by inducing autophagy and other host immune pathways. AR-12 treatment of S. Typhimurium-infected mice resulted in a 10-fold reduction in bacterial load in the liver and spleen and an increased survival time. However, AR-12 treatment did not protect mice from death, likely due poor formulation. In the current study, AR-12 was encapsulated in a microparticulate carrier formulated from the novel degradable biopolymer acetalated dextran (Ace-DEX) and subsequently evaluated for its activity in human monocyte-derived macrophages (hMDMs). Our results show that hMDMs efficiently internalized Ace-DEX microparticles (MPs), and that encapsulation significantly reduced host cell cytotoxicity compared to unencapsulated AR-12. Efficient macrophage internalization of AR-12 loaded MPs (AR-12/MPs) was further demonstrated by autophagosome formation that was comparable to free AR-12 and resulted in enhanced clearance of intracellular Salmonella. Taken together, these studies provide support that Ace-DEX encapsulated AR-12 may be a promising new therapeutic agent to control intracellular bacterial pathogens of macrophages by targeting delivery and reducing drug toxicity

Parallel flow in Hele-Shaw cells with ferrofluids

Parallel flow in a Hele-Shaw cell occurs when two immiscible liquids flow with relative velocity parallel to the interface between them. The interface is unstable due to a Kelvin-Helmholtz type of instability in which fluid flow couples with inertial effects to cause an initial small perturbation to grow. Large amplitude disturbances form stable solitons. We consider the effects of applied magnetic fields when one of the two fluids is a ferrofluid. The dispersion relation governing mode growth is modified so that the magnetic field can destabilize the interface even in the absence of inertial effects. However, the magnetic field does not affect the speed of wave propagation for a given wavenumber. We note that the magnetic field creates an effective interaction between the solitons.Comment: 12 pages, Revtex, 2 figures, revised version (minor changes

Gravity-driven instability in a spherical Hele-Shaw cell

A pair of concentric spheres separated by a small gap form a spherical Hele-Shaw cell. In this cell an interfacial instability arises when two immiscible fluids flow. We derive the equation of motion for the interface perturbation amplitudes, including both pressure and gravity drivings, using a mode coupling approach. Linear stability analysis shows that mode growth rates depend upon interface perimeter and gravitational force. Mode coupling analysis reveals the formation of fingering structures presenting a tendency toward finger tip-sharpening.Comment: 13 pages, 4 ps figures, RevTex, to appear in Physical Review

Radial fingering in a Hele-Shaw cell: a weakly nonlinear analysis

The Saffman-Taylor viscous fingering instability occurs when a less viscous fluid displaces a more viscous one between narrowly spaced parallel plates in a Hele-Shaw cell. Experiments in radial flow geometry form fan-like patterns, in which fingers of different lengths compete, spread and split. Our weakly nonlinear analysis of the instability predicts these phenomena, which are beyond the scope of linear stability theory. Finger competition arises through enhanced growth of sub-harmonic perturbations, while spreading and splitting occur through the growth of harmonic modes. Nonlinear mode-coupling enhances the growth of these perturbations with appropriate relative phases, as we demonstrate through a symmetry analysis of the mode coupling equations. We contrast mode coupling in radial flow with rectangular flow geometry.Comment: 36 pages, 5 figures, Latex, added references, to appear in Physica D (1998

The Saffman-Taylor problem on a sphere

The Saffman-Taylor problem addresses the morphological instability of an interface separating two immiscible, viscous fluids when they move in a narrow gap between two flat parallel plates (Hele-Shaw cell). In this work, we extend the classic Saffman-Taylor situation, by considering the flow between two curved, closely spaced, concentric spheres (spherical Hele-Shaw cell). We derive the mode-coupling differential equation for the interface perturbation amplitudes and study both linear and nonlinear flow regimes. The effect of the spherical cell (positive) spatial curvature on the shape of the interfacial patterns is investigated. We show that stability properties of the fluid-fluid interface are sensitive to the curvature of the surface. In particular, it is found that positive spatial curvature inhibits finger tip-splitting. Hele-Shaw flow on weakly negative, curved surfaces is briefly discussed.Comment: 26 pages, 4 figures, RevTex, accepted for publication in Phys. Rev.

Planning for Sustainability in Small Municipalities: The Influence of Interest Groups, Growth Patterns, and Institutional Characteristics

How and why small municipalities promote sustainability through planning efforts is poorly understood. We analyzed ordinances in 451 Maine municipalities and tested theories of policy adoption using regression analysis.We found that smaller communities do adopt programs that contribute to sustainability relevant to their scale and context. In line with the political market theory, we found that municipalities with strong environmental interests, higher growth, and more formal governments were more likely to adopt these policies. Consideration of context and capacity in planning for sustainability will help planners better identify and benefit from collaboration, training, and outreach opportunities

Uganda's experience in Ebola virus disease outbreak preparedness, 2018-2019.

BACKGROUND: Since the declaration of the 10th Ebola Virus Disease (EVD) outbreak in DRC on 1st Aug 2018, several neighboring countries have been developing and implementing preparedness efforts to prevent EVD cross-border transmission to enable timely detection, investigation, and response in the event of a confirmed EVD outbreak in the country. We describe Uganda's experience in EVD preparedness. RESULTS: On 4 August 2018, the Uganda Ministry of Health (MoH) activated the Public Health Emergency Operations Centre (PHEOC) and the National Task Force (NTF) for public health emergencies to plan, guide, and coordinate EVD preparedness in the country. The NTF selected an Incident Management Team (IMT), constituting a National Rapid Response Team (NRRT) that supported activation of the District Task Forces (DTFs) and District Rapid Response Teams (DRRTs) that jointly assessed levels of preparedness in 30 designated high-risk districts representing category 1 (20 districts) and category 2 (10 districts). The MoH, with technical guidance from the World Health Organisation (WHO), led EVD preparedness activities and worked together with other ministries and partner organisations to enhance community-based surveillance systems, develop and disseminate risk communication messages, engage communities, reinforce EVD screening and infection prevention measures at Points of Entry (PoEs) and in high-risk health facilities, construct and equip EVD isolation and treatment units, and establish coordination and procurement mechanisms. CONCLUSION: As of 31 May 2019, there was no confirmed case of EVD as Uganda has continued to make significant and verifiable progress in EVD preparedness. There is a need to sustain these efforts, not only in EVD preparedness but also across the entire spectrum of a multi-hazard framework. These efforts strengthen country capacity and compel the country to avail resources for preparedness and management of incidents at the source while effectively cutting costs of using a "fire-fighting" approach during public health emergencies

Marburg virus disease outbreak in Kween District Uganda, 2017: Epidemiological and laboratory findings.

INTRODUCTION: In October 2017, a blood sample from a resident of Kween District, Eastern Uganda, tested positive for Marburg virus. Within 24 hour of confirmation, a rapid outbreak response was initiated. Here, we present results of epidemiological and laboratory investigations. METHODS: A district task force was activated consisting of specialised teams to conduct case finding, case management and isolation, contact listing and follow up, sample collection and testing, and community engagement. An ecological investigation was also carried out to identify the potential source of infection. Virus isolation and Next Generation sequencing were performed to identify the strain of Marburg virus. RESULTS: Seventy individuals (34 MVD suspected cases and 36 close contacts of confirmed cases) were epidemiologically investigated, with blood samples tested for MVD. Only four cases met the MVD case definition; one was categorized as a probable case while the other three were confirmed cases. A total of 299 contacts were identified; during follow- up, two were confirmed as MVD. Of the four confirmed and probable MVD cases, three died, yielding a case fatality rate of 75%. All four cases belonged to a single family and 50% (2/4) of the MVD cases were female. All confirmed cases had clinical symptoms of fever, vomiting, abdominal pain and bleeding from body orifices. Viral sequences indicated that the Marburg virus strain responsible for this outbreak was closely related to virus strains previously shown to be circulating in Uganda. CONCLUSION: This outbreak of MVD occurred as a family cluster with no additional transmission outside of the four related cases. Rapid case detection, prompt laboratory testing at the Uganda National VHF Reference Laboratory and presence of pre-trained, well-prepared national and district rapid response teams facilitated the containment and control of this outbreak within one month, preventing nationwide and global transmission of the disease