Identification of weakly- to strongly-turbulent three-wave processes in a micro-scale system

We find capillary wave turbulence (WT) to span multiple dynamical regimes and geometries -- from weakly to strongly nonlinear WT (SWT) and from shallow to deep domains -- all within a 40uL volume millifluidic system. This study is made viable with recent advances in ultra-high-speed digital holographic microscopy, providing 10-us time and 10-nm spatial resolutions for images across the entire field of view, and encompassing a complete wave system at speeds sufficient to capture the salient wave phenomena. We provide a set of tractable parameters that identify the four fundamental WT regimes present in this simple system. A proposed nonlinearity measure permits comparative analysis while varying input conditions. This work augments current understanding of WT regimes and behaviors, and directly applies to many fields beyond fluid mechanics. For example, SWT appears upon the fluid interface at powers less than required for atomization, indicating that further study of SWT is needed to properly understand ultrasound-driven fuel spray atomization and drug and agricultural nebulization.Comment: revision: 10 pages, 3 figures, longer format adds theory and supporting citation

Building communities through re-blocking in the city of Cape Town

This study uses the re-blocking policy adopted by the City of Cape Town to explore an alternative approach to the housing backlog crisis in South Africa. The two re-blocking projects examined in Mshini Wam and Kuku Town illustrate the benefits of re-blocking and the challenges that were overcome in both of these informal settlements. This study is descriptive in nature and explores the challenges that informal settlements present not only for their inhabitants, but also the impact these challenges have on the city itself. The re-blocking policy is explored as a potential approach to addressing these issues and how the in situ upgrading approach to informal settlements is an improved and sustainable approach for South Africa. Key findings suggest that the Re-blocking Policy can potentially address the challenges that informal settlements present and it could serve as a sustainable housing model for improving service delivery to informal settlements

Histone modification landscapes as a roadmap for malaria parasite development

Plasmodium falciparum remains the deadliest parasite species in the world, responsible for 229 million cases of human malaria in 2019. The ability of the P. falciparum parasite to progress through multiple life cycle stages and thrive in diverse host and vector species hinges on sophisticated mechanisms of epigenetic regulation of gene expression. Emerging evidence indicates such epigenetic control exists in concentric layers, revolving around core histone post-translational modification (PTM) landscapes. Here, we provide a necessary update of recent epigenome research in malaria parasites, focusing specifically on the ability of dynamic histone PTM landscapes to orchestrate the divergent development and differentiation pathways in P. falciparum parasites. In addition to individual histone PTMs, we discuss recent findings that imply functional importance for combinatorial PTMs in P. falciparum parasites, representing an operational histone code. Finally, this review highlights the remaining gaps and provides strategies to address these to obtain a more thorough understanding of the histone modification landscapes that are at the center of epigenetic regulation in human malaria parasites.The South African Research Chairs Initiative of the Department of Science and Innovation, administered through the South African National Research Foundation.https://www.frontiersin.org/journals/cell-and-developmental-biologydm2022BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC

The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease

Objective To determine whether aspirin and antioxidant therapy, combined or alone, are more effective than placebo in reducing the development of cardiovascular events in patients with diabetes mellitus and asymptomatic peripheral arterial disease

Potent Plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials

OBJECTIVES : Novel chemical tools to eliminate malaria should ideally target both the asexual parasites and transmissible gametocytes. Several imidazopyridazines (IMPs) and 2-aminopyridines (2-APs) have been described as potent antimalarial candidates targeting lipid kinases. However, these have not been extensively explored for stage-specific inhibition of gametocytes in Plasmodium falciparum parasites. Here we provide an in-depth evaluation of the gametocytocidal activity of compounds from these chemotypes and identify novel starting points for dual-acting antimalarials. METHODS : We evaluated compounds against P. falciparum gametocytes using several assay platforms for cross-validation and stringently identified hits that were further profiled for stage specificity, speed of action and ex vivo efficacy. Physicochemical feature extraction and chemogenomic fingerprinting were applied to explore the kinase inhibition susceptibility profile. RESULTS : We identified 34 compounds with submicromolar activity against late stage gametocytes, validated across several assay platforms. Of these, 12 were potent at 1000-fold selectivity towards the parasite over mammalian cells. Front-runner compounds targeted mature gametocytes within 48 h and blocked transmission to mosquitoes. The resultant chemogenomic fingerprint of parasites treated with the lead compounds revealed the importance of targeting kinases in asexual parasites and gametocytes. CONCLUSIONS : This study encompasses an in-depth evaluation of the kinase inhibitor space for gametocytocidal activity. Potent lead compounds have enticing dual activities and highlight the importance of targeting the kinase superfamily in malaria elimination strategies.The South African Medical Research Council (SAMRC) Self-initiated Research (to JN) and Strategic Health Initiatives Partnerships (MRC-SHIP) programmes to L.B., T.C., D.M. K.C. further acknowledges the SAMRC for funding of the extramural Drug Discovery and Development Research Unit at UCT. The SAMRC is acknowledged for funding of the UP ISMC (LMB) and WRIM (TLC) as Collaborating Centres for Malaria Research. The Council for Scientific and Industrial Research and the 3R Foundation (project 118–10) to D.M. We thank the Medicines for Malaria Venture and South African Technology Innovation Agency (TIA) for funding to K.C. (Project MMV09/0002). The University of Cape Town, University of Pretoria, and South African Research Chairs Initiative of the Department of Science and Technology, administered through the South African National Research Foundation are gratefully acknowledged for support to K.C. and L.B. (UID84627). JN was supported through an International Society for Infectious Diseases grant.https://academic.oup.com/jac2019-05-01hj2018Biochemistr

Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.Supplementary Data 1: Data of the supra-hexagonal plot in Figure 2ASupplementary Data 2: Complete dataset of all MMV PRB compounds’ activity on Plasmodium life cycle stagesSupplementary Data 3: Full SMFA dataset to support Figure 5CSupplementary Data 4: Transcriptome analysis of MMV1580488 (ML324) treated parasites to support Figure 6C.The Medicines for Malaria Venture and South African Technology Innovation Agency (TIA). This project was in part supported by the South African Medical Research Council with funds received from the South African Department of Science and Innovation, in partnership with the Medicines for Malaria Venture; and the DST/NRF South African Research Chairs Initiative Grant; and CSIR Parliamentary Grant funding as well as the Bill and Melinda Gates Foundation and the Australian NHMRC (APP1072217).http://www.nature.com/ncommshj2021BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC

Acoustofluidic droplet generation: physical understanding and applications of jetting and atomization

Ultrasonic waves generated by piezoelectric devices produce forces on fluids and particles that can be controlled to produce useful functions. The research field of acoustic microfluidics has developed fundamental understanding of these forces and demonstrated some useful functions, but it has yet to break through in industry and commercial use. We describe acoustic radiation force and acoustic streaming as well as some less common forces and review piezoelectric materials. Then we review some fundamental work in fluid mixing, translation, jetting, and atomization. Particle manipulation will also be touched on briefly, but it is not the focus. Instead, the focus of our work has been on producing droplets of liquid in air, either one at a time via jetting or many at a time via atomization We present a focused surface acoustic wave system in order to investigate the fundamental physics of jetting and to explore the possibility of some applications. We show that jetting must account for surface tension effects. Acoustic streaming is well understood to be the driving force behind jetting and its amplitude and direction are not dependent on surface tension in most literature because it is typically considered far from a deformable interface. However, jetting to produce a droplet is fundamentally an interfacial phenomenon and we show quantitatively how it should be accounted for in order to control droplet ejection angles. Our experimental system uses only two transducers, but it is not hard to imagine a system with four transducers that could control droplet ejection in two dimensions. This capability could be useful in printing by reducing the amount that the printing head has to translate. With this same focused surface acoustic wave device we demonstrate how frozen liquid can be melted and subsequently atomized. We also demonstrate a through-hole liquid supply that allows for continuous atomization and show that the angle control, similar to the jetting case, is possible with atomization. These capabilities could be useful as a thruster for small space-craft. One of the major reasons that acoustic microfluidics has not achieved widespread use is that the equipment required to drive the devices is prohibitively complicated, bulky, and expensive. We produce a hand held system to drive high frequency ultrasound devices and demonstrate it's use for several typical applications. We provide all the necessary information to recreate these systems to promote adoption by other labs and entrepreneurs. Our primary application for this system is in nebulization and atomization of liquid, which could be useful for pulmonary drug delivery, agriculture, or fuel injection. We describe in detail how to fabricate the thickness mode devices that we use to produce atomization at large flow rates in our lab. We then, show how these devices have been integrated with the driving system to produce a truly hand-held high-frequency nebulizer. The fundamental physics of atomization is far more complicated than that of jetting, but we have made contributions here as well. It is currently our hypothesis that acoustic radiation sets up a standing wave pattern in the liquid volume based on its initial shape and then a feedback loop between the two leads to an initial set of capillary waves (work that Shuai Zhang will soon publish). At larger power acoustic streaming may also play a roll, but regardless the capillary waves become turbulent before the onset of atomization. For high-frequency forcing, these capillary waves occur at very short time-scales and very small length-scales so that it has been difficult to study them directly, but we have developed a new and unique experimental capability, high-speed digital holographic microscopy. We describe capillary wave turbulence regimes available in our system and show evidence for finite domain effects and strong nonlinearity. We also show quantitatively how energy transfers between time and length scales with increasing power input