Intensified treatment and control efforts since the early 2000s have dramatically reduced the burden of Plasmodium falciparum malaria. However, drug resistance threatens to derail this progress. In ...this review, we present four antimalarial resistance case studies that differ in timeline, technical approaches, mechanisms of action, and categories of resistance: chloroquine, sulfadoxine-pyrimethamine, artemisinin, and piperaquine. Lessons learned from prior losses of treatment efficacy, drug combinations, and control strategies will help advance mechanistic research into how P. falciparum parasites acquire resistance to current first-line artemisinin-based combination therapies. Understanding resistance in the clinic and laboratory is essential to prolong the effectiveness of current antimalarial drugs and to optimize the pipeline of future medicines.
In this review, Ross and Fidock examine Plasmodium resistance to antimalarials, notably chloroquine, sulfadoxine-pyrimethamine, artemisinin, and piperaquine. They discuss the lessons learned from prior losses of treatment efficacy, drug combinations, parasite resistance mechanisms, and implications for treatment and future research.
Phase control in the self-assembly of metal–organic frameworks (MOFs) is often a case of trial and error; judicious control over a number of synthetic variables is required to select the desired ...topology and control features such as interpenetration and defectivity. Herein, we present a comprehensive investigation of self-assembly in the Fe–biphenyl-4,4′-dicarboxylate system, demonstrating that coordination modulation can reliably tune between the kinetic product, noninterpenetrated MIL-88D(Fe), and the thermodynamic product, two-fold interpenetrated MIL-126(Fe). Density functional theory simulations reveal that correlated disorder of the terminal anions on the metal clusters results in hydrogen bonding between adjacent nets in the interpenetrated phase and this is the thermodynamic driving force for its formation. Coordination modulation slows self-assembly and therefore selects the thermodynamic product MIL-126(Fe), while offering fine control over defectivity, inducing mesoporosity, but electron microscopy shows MIL-88D(Fe) persists in many samples despite not being evident by diffraction. Interpenetration control is also demonstrated using the 2,2′-bipyridine-5,5′-dicarboxylate linker; it is energetically prohibitive for it to adopt the twisted conformation required to form the interpenetrated phase, although multiple alternative phases are identified due to additional coordination of Fe cations to its N donors. Finally, we introduce oxidation modulationthe use of metal precursors in different oxidation states from that found in the final MOFto kinetically control self-assembly. Combining coordination and oxidation modulation allows the synthesis of pristine MIL-126(Fe) with BET surface areas close to the predicted maximum for the first time, suggesting that combining the two may be a powerful methodology for the controlled self-assembly of high-valent MOFs.
Let them eat MOFs: Take a spoonful of sugar (γ‐cyclodextrin to be precise), a pinch of salt (most alkali metal salts will suffice), and a swig of alcohol (Everclear fits the bill), and you have a ...robust, renewable, nanoporous (Langmuir surface area 1320 m2 g−1) metal–organic framework for breakfast (CD‐MOF‐1; see picture, C gray, O red, K purple; yellow sphere: pore).
Scientific articles often contain relevant geographic information such as where field work was performed or where patients were treated. Most often, this information appears in the full-text article ...contents as a description in natural language including place names, with no accompanying machine-readable geographic metadata. Automatically extracting this geographic information could help conduct meta-analyses, find geographical research gaps, and retrieve articles using spatial search criteria. Research on this problem is still in its infancy, with many works manually processing corpora for locations and few cross-domain studies. In this paper, we develop a fully automatic pipeline to extract and represent relevant locations from scientific articles, applying it to two varied corpora. We obtain good performance, with full pipeline precision of 0.84 for an environmental corpus, and 0.78 for a biomedical corpus. Our results can be visualized as simple global maps, allowing human annotators to both explore corpus patterns in space and triage results for downstream analysis. Future work should not only focus on improving individual pipeline components, but also be informed by user needs derived from the potential spatial analysis and exploration of such corpora.
Microplastics are increasingly recognized as being widespread in the world’s oceans, but relatively little is known about ingestion by marine biota. In light of the potential for microplastic fibers ...and fragments to be taken up by small marine organisms, we examined plastic ingestion by two foundation species near the base of North Pacific marine food webs, the calanoid copepod
Neocalanus cristatus
and the euphausiid
Euphausia pacifia
. We developed an acid digestion method to assess plastic ingestion by individual zooplankton and detected microplastics in both species. Encounter rates resulting from ingestion were 1 particle/every 34 copepods and 1/every 17 euphausiids (euphausiids > copepods;
p
= 0.01). Consistent with differences in the size selection of food between these two zooplankton species, the ingested particle size was greater in euphausiids (816 ± 108 μm) than in copepods (556 ± 149 μm) (
p
= 0.014). The contribution of ingested microplastic fibres to total plastic decreased with distance from shore in euphausiids (
r
2
= 70,
p
= 0.003), corresponding to patterns in our previous observations of microplastics in seawater samples from the same locations. This first evidence of microplastic ingestion by marine zooplankton indicate that species at lower trophic levels of the marine food web are mistaking plastic for food, which raises fundamental questions about potential risks to higher trophic level species. One concern is risk to salmon: We estimate that consumption of microplastic-containing zooplankton will lead to the ingestion of 2–7 microplastic particles/day by individual juvenile salmon in coastal British Columbia, and ≤91 microplastic particles/day in returning adults.
BK polyomavirus (BKV) causes frequent infections during childhood and establishes persistent infections within renal tubular cells and the uroepithelium, with minimal clinical implications. However, ...reactivation of BKV in immunocompromised individuals following renal or hematopoietic stem cell transplantation may cause serious complications, including BKV-associated nephropathy (BKVAN), ureteric stenosis, or hemorrhagic cystitis. Implementation of more potent immunosuppression and increased posttransplant surveillance has resulted in a higher incidence of BKVAN. Antiviral immunity plays a crucial role in controlling BKV replication, and our increasing knowledge about host-virus interactions has led to the development of improved diagnostic tools and clinical management strategies. Currently, there are no effective antiviral agents for BKV infection, and the mainstay of managing reactivation is reduction of immunosuppression. Development of immune-based therapies to combat BKV may provide new and exciting opportunities for the successful treatment of BKV-associated complications.
Metal–organic frameworks (MOFs), network structures wherein metal ions or clusters link organic ligands into porous materials, are being actively researched as nanoscale drug delivery devices as they ...offer tunable structures with high cargo loading that can easily be further functionalized for targeting and enhanced physiological stability. The excellent biocompatibility of Zr has meant that its MOFs are among the most studied to date, in particular the archetypal Zr terephthalate UiO-66. In contrast, the isoreticular analog linked by fumarate (Zr-fum) has received little attention, despite the endogenous linker being part of the Krebs cycle. Herein, we report a comprehensive study of Zr-fum in the context of drug delivery. Reducing particle size is shown to increase uptake by cancer cells while reducing internalization by macrophages, immune system cells that remove foreign objects from the bloodstream. Zr-fum is compatible with defect loading of the drug dichloroacetate (DCA) as well as surface modification during synthesis, through coordination modulation and postsynthetically. DCA-loaded, PEGylated Zr-fum shows selective in vitro cytotoxicity toward HeLa and MCF-7 cancer cells, likely as a consequence of its enhanced caveolae-mediated endocytosis compared to uncoated precursors, and it is well tolerated by HEK293 kidney cells, J774 macrophages, and human peripheral blood lymphocytes. Compared to UiO-66, Zr-fum is more efficient at transporting the drug mimic calcein into HeLa cells, and DCA-loaded, PEGylated Zr-fum is more effective at reducing HeLa and MCF-7 cell proliferation than the analogous UiO-66 sample. In vitro examination of immune system response shows that Zr-fum samples induce less reactive oxygen species than UiO-66 analogs, possibly as a consequence of the linker being endogenous, and do not activate the C3 and C4 complement cascade pathways, suggesting that Zr-fum can avoid phagocytic activation. The results show that Zr-fum is an attractive alternative to UiO-66 for nanoscale drug delivery, and that a wide range of in vitro experiments is available to greatly inform the design of drug delivery systems prior to early stage animal studies.
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