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Patient derived organoids have the potential to improve the physiological relevance of in vitro disease models. However, the 3D architecture of these self-assembled cellular structures makes probing their biochemistry more complex than in traditional 2D culture. We explore the application of surface enhanced Raman scattering microsensors (SERS-MS) to probe local pH gradients within patient derived airway organoid cultures. SERS-MS consist of solid polymer cores decorated with surface immobilised gold nanoparticles which are functionalised with pH sensitive reporter molecule 4-mercaptobenzoic acid (MBA). We demonstrate that by mixing SERS-MS into the extracellular matrix (ECM) of airway organoid cultures the probes can be engulfed by expanding organoids and report on local pH in the organoid lumen and ECM.

Decades of antibiotic misuse have led to alarming levels of antimicrobial resistance, and the development of alternative diagnostic and therapeutic strategies to delineate and treat infections is a global priority. In particular, the nosocomial, multi-drug resistant “ESKAPE” pathogens such as Gram-positive methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus spp (VRE) urgently require alternative treatments. Here, we developed light-activated molecules, based on conjugation of the FDA-approved photosensitizer riboflavin to the Gram-positive specific ligand vancomycin, to enable targeted antimicrobial photodynamic therapy. The riboflavin-vancomycin conjugate proved to be a potent and versatile antibacterial agent, enabling the rapid, light-mediated, killing of MRSA and VRE with no significant off-target effects. The attachment of riboflavin on vancomycin also led to an increased in antibiotic activity against S. aureus and VRE. Simultaneously, we evidenced for the first time that the flavin sub-unit undergoes an efficient photo-induced bond cleavage reaction to release vancomycin, thereby acting as a photo-removable protecting group for drug-delivery.

Decades of antibiotic misuse have led to alarming levels of antimicrobial resistance, and the development of alternative diagnostic and therapeutic strategies to delineate and treat infections is a global priority. In particular, the nosocomial, multi-drug resistant “ESKAPE” pathogens such as Gram-positive methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus spp (VRE) urgently require alternative treatments. Here, we developed light-activated molecules, based on conjugation of the FDA-approved photosensitizer riboflavin to the Gram-positive specific ligand vancomycin, to enable targeted antimicrobial photodynamic therapy. The riboflavin-vancomycin conjugate proved to be a potent and versatile antibacterial agent, enabling the rapid, light-mediated, killing of MRSA and VRE with no significant off-target effects. The attachment of riboflavin on vancomycin also led to an increased in antibiotic activity against S. aureus and VRE. Simultaneously, we evidenced for the first time that the flavin sub-unit undergoes an efficient photo-induced bond cleavage reaction to release vancomycin, thereby acting as a photo-removable protecting group for drug-delivery.

Motivated by previous results showing that the addition of a linear dispersive term to the two-dimensional Kuramoto-Sivashinsky equation has a dramatic effect on the pattern formation, we study the Swift-Hohenberg equation with an added linear dispersive term, the dispersive Swift-Hohenberg equation (DSHE). The DSHE produces stripe patterns with spatially extended dislocations that we call seam defects. In contrast to the dispersive Kuramoto-Sivashinsky equation, the DSHE has a narrow band of unstable wavelengths close to an instability threshold. This allows for analytical progress to be made. We show that the amplitude equation for the DSHE close to threshold is a special case of the anisotropic complex Ginzburg-Landau equation (ACGLE) and that seams in the DSHE correspond to spiral waves in the ACGLE. Seam defects and the corresponding spiral waves tend to organize themselves into chains, and we obtain formulas for the velocity of the spiral wave cores and for the spacing between them. In the limit of strong dispersion, a perturbative analysis yields a relationship between the amplitude and wavelength of a stripe pattern and its propagation velocity. Numerical integrations of the ACGLE and the DSHE confirm these analytical results.

PDF file - 519KB, Apoptosis in etoposide treated H345 cells and etoposide treated mouse tumors immunostained for CD133 and GRP-R.

Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor survival rates, with initial responses nearly invariably followed by rapid recurrence of therapy-resistant disease. Drug resistance in SCLC may be attributable to the persistence of a subpopulation of cancer stem-like cells (CSC) that exhibit multiple drug resistance. In this study, we characterized the expression of CD133, one important marker of CSC in other cancers, in SCLC cancer cells. CD133 expression correlated with chemoresistance and increased tumorigenicity in vitro and in vivo accompanied by increased expression of Akt/PKB and Bcl-2. CD133 expression was increased in mouse and human SCLC after chemotherapy, an observation confirmed in clinical specimens isolated longitudinally from a patient receiving chemotherapy. We discovered in CD133+ SCLC cells, an increased expression of the mitogenic neuropeptide receptors for gastrin-releasing peptide and arginine vasopressin. Notably, these cells exhibited increased sensitivity to the growth inhibitory and proapoptotic effects of a novel broad spectrum neuropeptide antagonist (related to SP-G), which has completed a phase I clinical trial for SCLC. Our results offer evidence that this agent can preferentially target chemoresistant CD133+ cells with CSC character in SCLC, emphasizing its potential utility for improving therapy in this setting. Cancer Res; 74(5); 1554–65. ©2014 AACR.

PDF file - 82KB, IC50 values in uM of H345 and H69 cells treated with substance-P analogues.

Transportation network companies (TNCs) such as Uber and Lyft have grown tremendously over the last decade, particularly in the San Francisco Bay Area. Nonetheless, relatively little publicly available data exist about the users of these services, their travel behaviors, volume of use, the times and locations of TNC trips, and how TNC services are affecting transportation system performance overall. This paper describes the methods and descriptive results of the first large-scale smartphone-based TNC user survey conducted in the California Bay Area in the fall 2018 and spring of 2019.

Numerous prodrugs have been developed and used for cancer treatments to reduce side effects and promote efficacy. In this work, we have developed a new photoactivatable prodrug system based on intracellular photoinduced electron transfer-reversible addition-fragmentation chain-transfer (PET-RAFT) polymerization. This unique polymerization process provided a platform for the synthesis of structure-predictable polymers with well-defined structures in living cells. The intracellularly generated poly( N, N-dimethylacrylamide)s were found to induce cell cycle arrest, apoptosis, and necroptosis, inhibit cell proliferation, and reduce cancer cell motilities. This polymerization-based "prodrug" system efficiently inhibits tumor growth and metastasis both in vitro and in vivo and will promote the development of targeted and directed cancer chemotherapy.

Proteases are excellent biomarkers for a variety of diseases, offer multiple opportunities for diagnostic applications and are valuable targets for therapy. From a chemistry-based perspective this review discusses and critiques the most recent advances in the field of substrate-based probes for the detection and analysis of proteolytic activity both in vitro and in vivo.

Pathogenic microorganisms are considered to a major threat to human health, impinging on multiple sectors including hospitals, dentistry, food storage and packaging, and water contamination. Due to the increasing levels of antimicrobial resistance shown by pathogens, often caused by long-term abuse or overuse of traditional antimicrobial drugs, new approaches and solutions are necessary. In this area, antimicrobial polymers are a viable solution to combat a variety of pathogens in a number of contexts. Indeed, polymers with intrinsic antimicrobial activities have long been an intriguing research area, in part, due to their widespread natural abundance in materials such as chitin, chitosan, carrageen, pectin, and the fact that they can be tethered to surfaces without losing their antimicrobial activities. In addition, since the discovery of the strong antimicrobial activity of some synthetic polymers, much work has focused on revealing the most effective structural elements that give rise to optimal antimicrobial properties. This has often been synthesis targeted, with the generation of either new polymers or the modification of natural antimicrobial polymers with the addition of antimicrobial enhancing modalities such as quaternary ammonium or guanidinium groups. In this review, the growing number of polymers showing intrinsic antimicrobial properties from the past decade are highlighted in terms of synthesis; often based on post-synthesis modification and their utilization. This includes as surface coatings, for example on medical devices, such as intravascular catheters, orthopaedic implants and contact lenses, or directly as antibacterial agents (specifically as eye drops). Surface functionalisation with inherently antimicrobial polymers is highlighted and has been achieved via various techniques, including surface-bound initiators allowing RAFT or ATRP surface-based polymerization, or via physical immobilization such as by layer-by-layer techniques. This article also covers the mechanistic modes of action of intrinsic antimicrobial polymers against bacteria, viruses, or fungi.

The patterns produced by dragging an atomic force microscope (AFM) tip over a polymer surface are studied using a mesoscopic model introduced by Gnecco and co-workers [E. Gnecco et al., New J. Phys. 17, 032001 (2015)1367-263010.1088/1367-2630/17/3/032001]. We show that the problem can be reduced to solving a closed integrodifferential equation for a single degree of freedom, the position of the AFM tip. We find the steady-state solution to this equation and then carry out a linear stability analysis of it. The steady state is only stable if the dimensionless indentation rate α is less than a critical value α_{c} which depends on the dimensionless velocity of the rigid support r. Conversely, for αα_{c}, periodic stick-slip motion sets in after a transient. Simulations show that the amplitude of these oscillations is proportional to (α-α_{c})^{1/2} for α just above α_{c}. Our analysis also yields a closed equation that can be solved for the critical value α_{c}=α_{c}(r). If the steady-state motion is perturbed, as long as the deviation from the steady state is small, the deviation of the tip's position from the steady state can be written as a linear superposition of terms of the form exp(λ_{k}t), where the complex constants λ_{k} are solutions to an integral equation. Finally, we demonstrate that the results obtained for the two-dimensional model of Gnecco et al. carry over in a straightforward way to the generalization of the model to three dimensions.

A highly sensitive optical probe for the detection of activated neutrophils and Neutrophil Extracellular Traps (NETs) is reported. It is based on a triple-quenched, super-silent tri-branched probe that generates >20 fold increase in fluorescence upon cleavage. The probe was highly specific for human neutrophil elastase, a protease that mediates a variety of inflammatory diseases, and detected NETosis and neutrophil activation in in vitro differentiated neutrophils and isolated human neutrophils.

The β-CD@PEI-Fc chiral interface was prepared based on the supramolecular host-guest interaction between ferrocene (Fc) grafted polyethyleneimine (PEI-Fc) and chiral β-cyclodextrin (β-CD). SEM results show that β-CD@PEI-Fc interface has a regular spatial structure, which can effectively distinguish tryptophan (Trp) enantiomers. Under the optimal conditions, differential pulse voltammetry shows that the peak current ratio (Id/Il) of Trp enantiomers can reach 2.84 at 15 °C. More interestingly, the β-CD@PEI-Fc/GCE exhibited chiral recognition of d-Trp and l-Trp via water contact angle measurements. There was a good linear relationship between the peak current and the concentration of Trp enantiomers in the range from 0.005 mM to 0.10 mM. Finally, the chiral interface can be applied for quick detection of the proportion of isomers in Trp racemic solution, which is very important for chiral recognition in racemic mixture of chiral compounds. Meanwhile, the β-CD@PEI-Fc/GCE showed good stability and reproducibility.

Coloading and codelivery of hydrophilic and hydrophobic drugs as techniques for effective therapy have drawn attention but still present a challenge owing to the opposite nature of both drugs. Therefore, determining a convenient method for coloading and coreleasing hydrophilic and hydrophobic drugs in the development of biomedical devices is important. We constructed multilayer films with a microporous structure for the successful coloading of hydrophilic and hydrophobic drugs. The multilayer films were fabricated using chitosan (CS) and polyacrylic acid (PAA) via layer-by-layer self-assembly. A quartz crystal microbalance (QCM) was used to investigate the self-assembly of (CS/PAA) in films. With a low pH to change the inner structure of the multilayer films, these microporous structures exhibit humidity responsiveness and can return to the original compact structures by treatment with 100% relative humidity. The microporous films can simultaneously load a large number of hydrophobic drugs (tetracycline) and hydrophilic model drugs (Rhodamine B) by wicking and subsequent micropore self-healing. The loading and release ratio of the two drugs in the microporous films is consistent with the initial loading ratio in the solution, providing a good platform for coloading and codelivery of hydrophobic and hydrophilic drugs in biomedical applications.

Technologies for measuring physiological parameters in vivo offer the possibility of the detection of disease and its progression due to the resulting changes in tissue pH, or temperature, etc.. Here, a compact hydrogel-based optical fibre pH sensor was fabricated, in which polymer microarrays were utilized for the high-throughput discovery of an optimal matrix for pH indicator immobilization. The fabricated hydrogel-based probe responded rapidly to pH changes and demonstrated a good linear correlation within the physiological pH range (from 5.5 to 8.0) with a precision of 0.10 pH units. This miniature probe was validated by measuring pH across a whole ovine lung and allowed discrimination of tumorous and normal tissue, thus offering the potential for the rapid and accurate observation of tissue pH changes.

Purpose The relentless rise in antimicrobial resistance is a major societal challenge and requires, as part of its solution, a better understanding of bacterial colonization and infection. To facilitate this, we developed a highly efficient no-wash red optical molecular imaging agent that enables the rapid, selective, and specific visualization of Gram-positive bacteria through a bespoke optical fiber–based delivery/imaging endoscopic device. Methods We rationally designed a no-wash, red, Gram-positive-specific molecular imaging agent (Merocy-Van) based on vancomycin and an environmental merocyanine dye. We demonstrated the specificity and utility of the imaging agent in escalating in vitro and ex vivo whole human lung models (n = 3), utilizing a bespoke fiber–based delivery and imaging device, coupled to a wide-field, two-color endomicroscopy system. Results The imaging agent (Merocy-Van) was specific to Gram-positive bacteria and enabled no-wash imaging of S. aureus within the alveolar space of whole ex vivo human lungs within 60 s of delivery into the field-of-view, using the novel imaging/delivery endomicroscopy device. Conclusion This platform enables the rapid and specific detection of Gram-positive bacteria in the human lung.

Doxorubicin (Dox) is known for its potential to deliver desirable anticancer effects against various types of cancer including colorectal cancer. However, the adverse effects are serious. This study aimed to synthesize polyethylene glycol diacrylate (PEGDA)/acrylic acid (AA)-based nanoparticles (PEGDA/AA NPs) for Dox delivery to colorectal cancer cells. The NPs were synthesized using free-radical polymerization reaction using the monomers PEGDA and AA with their physical properties, drug loading and release, biocompatibility, and anticancer effect evaluated. The NPs were spherical with a size of around 230 nm, with a 48% Dox loading efficiency and with loading capacity of 150 µg/mg. Intriguingly, the NPs had the ability to prolong the release of Dox in vitro over 24 h and were non-toxic to intestinal epithelial cells. Dox-loaded PEGDA/AA NPs (Dox-NPs) were able to effectively kill the colorectal cancer cell line (HT-29) with the Dox-NPs accumulating inside the cell and killing the cell through the apoptosis pathway. Overall, the synthesized PEGDA/AA NPs exhibit considerable potential as a drug delivery carrier for colon cancer-directed, staged-release therapy.

A series of hemicyanine dyes was synthesized starting from the vinyl chloride-based cyanine dye IR-780. The dyes absorbed and emitted in the near-infrared region, while heavy atom (bromo and iodo) substitution promoted the generation of both singlet oxygen (1O2) as well as a range of other reactive oxygen-based species (ROS) upon irradiation at wavelengths greater than 610 nm. One hemicyanine dye displayed an outstanding singlet oxygen quantum efficiency (φΔ = 0.8) and was successfully applied in in vitro studies to mimic photodynamic therapy application.

A probe that allows specific 'painting' of human tumours is described. Probe activation was mediated by specific matrix metalloproteinases, resulting not only in disruption of a FRET pair, but in the generation of a fragment that "fluorescently paints" human tumours. This probe demonstrated rapid and effective human tumour labelling with the potential to allow margin detection during surgical resection.

We suggest and illustrate from our experiences of integration in a public health context in Indonesia, a reframing of integration for mixed methods research that focuses on context, outcomes, objects, and integrative mechanisms. Through describing the tools and conceptualizations that helped us integrate, we argue for expanding the scope of integration to include social process methods (which we describe) and for rethinking the desired outcomes of integration. The article contributes to the field of mixed methods research by proposing: (a) a new framing of integration that supports greater precision as well as an expanded scope over what and how integration could be implemented, (b) a set of theoretical and conceptual models to support integration, and (c) a new and fully integrated data collection instrument.

Background The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000 with the goal of eliminating lymphatic filariasis (LF) as a public health problem by 2020. Despite considerable progress, the current prevalence is around 60% of the 2000 figure, with the deadline looming a year away. Consequently, there is a continued need for investment in both the mass drug administration (MDA) and morbidity management programs, and this paper aims to demonstrate that need by estimating the health and economic burdens of LF prior to MDA programs starting in GPELF areas. Methods A previously developed model was used to estimate the numbers of individuals infected and individuals with symptomatic disease, along with the attributable number of disability-adjusted life years (DALYs). The economic burden was calculated by quantifying the costs incurred by the health-care system in managing clinical cases, the patients’ out-of-pocket costs, and their productivity costs. Results Prior to the MDA program, approximately 129 million people were infected with LF, of which 43 million had clinical disease, corresponding to a DALY burden of 5.25 million. The average annual economic burden per chronic case was US $115, the majority of which resulted from productivity costs. The total economic burden of LF was estimated at US $5.8 billion annually. Conclusions These results demonstrate the magnitude of the LF burden and highlight the continued need to support the GPELF. Patients with clinical disease bore the majority of the economic burden, but will not benefit much from the current MDA program, which is aimed at reducing transmission. This assessment further highlights the need to scale up morbidity management programs.

Cartilage degeneration or damage treatment is still a challenge, but, tissue engineering strategies, which combine cell therapy strategies, which combine cell therapy and scaffolds, and have emerged as a promising new approach. In this regard, polyurethanes and polyacrylates polymers have been shown to have clinical potential to treat osteochondral injuries. Here, we have used polymer microarrays technology to screen 380 different polyurethanes and polyacrylates polymers. The top polymers with potential to maintain chondrocyte viability were selected, with scale-up studies performed to evaluate their ability to support chondrocyte proliferation during long-term culture, while maintaining their characteristic phenotype. Among the selected polymers, poly (methylmethacrylate-co-methacrylic acid), showed the highest level of chondrogenic potential and was used to create a 3D hydrogel. Ultrastructural morphology, microstructure and mechanical testing of this novel hydrogel revealed robust characteristics to support chondrocyte growth. Furthermore, in vitro and in vivo biological assays demonstrated that chondrocytes cultured on the hydrogel had the capacity to produce extracellular matrix similar to hyaline cartilage, as shown by increased expression of collagen type II, aggrecan and Sox9, and the reduced expression of the fibrotic marker's collagen type I. In conclusion, hydrogels generated from poly (methylmethacrylate-co-methacrylic acid) created the appropriate niche for chondrocyte growth and phenotype maintenance and might be an optimal candidate for cartilage tissue-engineering applications. SIGNIFICANCE STATEMENT: Articular cartilage has limited self-repair ability due to its avascular nature, therefore tissue engineering strategies have emerged as a promising new approach. Synthetic polymers displaygreat potential and are widely used in the clinical setting. In our study, using the polymer microarray technique a novel type of synthetic polyacrylate was identified, that was converted into hydrogels for articular cartilage regeneration studies. The hydrogel based on poly (methylmethacrylate-co-methacrylic acid-co-PEG-diacrylate) had a controlable ultrastructural morphology, microstructure (porosity) and mechanical properties (stiffness) appropriate for cartilage engineering. Our hydrogel created the optimal niche for chondrocyte growth and phenotype maintenance for long-term culture, producing a hyaline-like cartilage extracellular matrix. We propose that this novel polyacrylate hydrogel could be an appropriate support to help in the treatment efficient cartilage regeneration.

Population monitoring can take many different forms, and monitoring elusive and endangered species frequently involves a variety of sparse data from different sources. Small populations are often hard to sample precisely and without bias, so when estimates of vital rates like survival or recruitment point to conflicting population trends, it can be hard to determine which is more correct. Furthermore, data can be extremely hard to collect on small populations and it can be helpful to find a way to use all available hard‐won data. To address these issues, we developed an integrated population model (IPM) using all available data to estimate vital rates and abundance for a case study of an endangered woodland caribou (Rangifer tarandus caribou) population. This IPM allowed us to incorporate data from juvenile recruitment surveys, telemetry‐based survival, aerial population counts and mark–resight data, and non‐invasive capture–recapture DNA data to better understand population status and trend. We estimated survival, abundance, and recruitment of four age classes of male and female caribou: young, juveniles, subadults, and adults. The four‐age class structure of the IPM allowed us to estimate recruitment from reproductive‐aged female caribou alone, even though it can be difficult to distinguish age classes—and even sexes—in the field. As part of our IPM, we developed a novel mixture model to break apart data from different age classes when age is unobservable, as it typically is from non‐invasive DNA samples. This helped us decrease bias in juvenile and adult survival estimates from scat data, which was important to our understanding of the population dynamics. Overall, our integrated model provided more precise estimates of population trends than any one method (e.g., telemetry or non‐invasive DNA) alone. This IPM provides a useful, flexible tool for biologists to monitor populations and provides a valuable example of the benefits of integrated population modeling approaches for endangered species management and recovery.

The use of optical techniques to interrogate wide ranging samples from semiconductors to biological tissue for rapid analysis and diagnostics has gained wide adoption over the past decades. The desire to collect ever more spatially, spectrally and temporally detailed optical signatures for sample characterization has specifically driven a sharp rise in new optical microscopy technologies. Here we present a high-speed optical scanning microscope capable of capturing time resolved images across 512 spectral and 32 time channels in a single acquisition with the potential for ~0.2 frames per second (256 × 256 image pixels). Each pixel in the resulting images contains a detailed data cube for the study of diverse time resolved light driven phenomena. This is enabled by integration of system control electronics and on-chip processing which overcomes the challenges presented by high data volume and low imaging speed, often bottlenecks in previous systems., High data volumes from multidimensional imaging techniques can lead to slow collection and processing times. Here, the authors implement multispectral fluorescence lifetime imaging microscopy (FLIM) that uses time-correlated photon counting technology to reach simultaneously high imaging rates combined with high spectral and temporal resolution.

With the aid of bioorthogonal chemistry, we demonstrate the fabrication of synthetic dendrimers in situ around living cells. Using tetrazine dienophile and aminooxyl/hydrazide aldehyde chemistries, the density of functional groups on the dendrimers exponentially amplified intensities of fluorescent markers in antibody-targeted live cell imaging. This novel "swarming"approach highlights the power of bioorthogonal chemistry and provides a route to non-natural chemical structures on cells, paving the way for the generation of various artificial cellular nanostructures and scaffolds.

We study nanoscale pattern formation on the surface of a solid that is bombarded with two diametrically opposed, broad ion beams for ion energies low enough that sputtering can be neglected. We focus on the case in which the angle of ion incidence is just above the threshold angle for pattern formation. The equation of motion at sufficiently long times is derived using a generalized crater function formalism. This formalism also yields expressions for the coefficients in the equation of motion in terms of crater function moments. We find that virtually defect-free ripples with a sawtooth profile can emerge at sufficiently long times. The ripples also coarsen as time passes, in contrast to the near-threshold behavior of ripples in the higher energy regime in which sputtering is significant.

Intricate topographical patterns can form on the surface of crystalline Ge(001) subject to low-energy ion irradiation in the reverse epitaxy regime, i.e., at elevated temperatures which enable dynamic recrystallization. We compare such nanoscale patterns produced by irradiation from varied polar and azimuthal ion incidence angles with corresponding calculated surface topographies. To this end, we propose a continuum equation including both anisotropic erosive and anisotropic diffusive effects. Molecular dynamics simulations provide the coefficients of angle-dependent sputter erosion for the calculations. By merely changing these coefficients accordingly, the experimentally observed surface morphologies can be reproduced, except for extreme ion incidence angles. Angle-dependent sputter erosion is thereby identified as a dominant mechanism in ion-induced pattern formation on crystalline surfaces under irradiation from off-normal incidence angles.

Neglected tropical diseases (NTDs) are targeted for global control or elimination. Recognising that the populations most in need of medicines to target NTDs are those least able to support and sustain them financially, the pharmaceutical industry created mechanisms for donating medicines and expertise to affected countries through partnerships with the WHO, development agencies, non-governmental organisations and philanthropic donors. In the last 30 y, companies have established programmes to donate 17 different medicines to overcome the burden of NTDs. Billions of tablets, capsules, intravenous and oral solutions have been donated, along with the manufacturing, supply chains and research necessary to support these efforts. Industry engagement has stimulated other donors to support NTDs with funds and oversight so that the ‘heath benefit’ return on investment in these programmes is truly a ‘best value in public health’. Many current donations are ‘open-ended’, promising support as long as necessary to achieve defined health targets. Extraordinary global health advances have been made in filariasis, onchocerciasis, trachoma, trypanosomiasis, leishmaniasis, schistosomiasis, intestinal parasites and others; and these advances are taking place in the context of strengthening health systems and meeting the global development goals espoused by the WHO. The pharmaceutical manufacturers, already strong collaborators in initiating or supporting these disease-targeted programmes, have committed to continuing their partnership roles in striving to meet the targets of the WHO's new NTD roadmap to 2030.

Nanoscale pattern formation on the surface of a solid that is bombarded with a broad ion beam is studied for angles of ion incidence, $\ensuremath{\theta}$, just above the threshold angle for ripple formation, ${\ensuremath{\theta}}_{c}$. We carry out a systematic expansion in powers of the small parameter $\ensuremath{\epsilon}\ensuremath{\equiv}{(\ensuremath{\theta}\ensuremath{-}{\ensuremath{\theta}}_{c})}^{1/2}$ and retain all terms up to a given order in $\ensuremath{\epsilon}$. In the case of two diametrically opposed, obliquely incident beams, the equation of motion close to threshold and at sufficiently long times is rigorously shown to be a particular version of the anisotropic Kuramoto-Sivashinsky equation. We also determine the long-time, near-threshold scaling behavior of the rippled surface's wavelength, amplitude, and transverse correlation length for this case. When the surface is bombarded with a single obliquely incident beam, linear dispersion plays a crucial role close to threshold and dramatically alters the behavior: highly ordered ripples can emerge at sufficiently long times and solitons can propagate over the solid surface. A generalized crater function formalism that rests on a firm mathematical footing is developed and is used in our derivations of the equations of motion for the single and dual beam cases.