Acoustomicrofluidic Concentration and Signal Enhancement of Fluorescent Nanodiamond Sensors.

Diamond nitrogen-vacancy (NV) centers constitute a promising class of quantum nanosensors owing to the unique magneto-optic properties associated with their spin states. The large surface area and photostability of diamond nanoparticles, together with their relatively low synthesis costs, make them a suitable platform for the detection of biologically relevant quantities such as paramagnetic ions and molecules in solution. Nevertheless, their sensing performance in solution is often hampered by poor signal-to-noise ratios and long acquisition times due to distribution inhomogeneities throughout the analyte sample. By concentrating the diamond nanoparticles through an intense microcentrifugation effect in an acoustomicrofluidic device, we show that the resultant dense NV ensembles within the diamond nanoparticles give rise to an order-of-magnitude improvement in the measured acquisition time. The ability to concentrate nanoparticles under surface acoustic wave (SAW) microcentrifugation in a sessile droplet is, in itself, surprising given the well-documented challenge of achieving such an effect for particles below 1 µm in dimension. In addition to a demonstration of their sensing performance, we thus reveal in this work that the reason why the diamond nanoparticles readily concentrate under the SAW-driven recirculatory flow can be attributed to their considerably higher density and hence larger acoustic contrast compared to those for typical particles and cells for which the SAW microcentrifugation flow has been shown to date.

Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging Caenorhabditis elegans.

All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in Caenorhabditis elegans. Here, we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant aging rate. Because excess age-related iron elevation in somatic tissue, particularly in brain, is thought to contribute to degenerative disease, post-developmental interventions to limit ferroptosis may promote healthy aging.

"To Treat or not To Treat": Informing the Decision for Disease-Modifying Therapy in Late-Stage Alzheimer's Disease.

Rosen et al. thoughtfully extend the ethical discussion surrounding disease-modifying therapies in late-stage Alzheimer's disease (AD) to correctly emphasize that the perceived quality of life (QoL) of the individual living with the disease is a critical component to decisions regarding their clinical care. The primary purpose of our original article regarding the use of disease-modifying therapeutics in late-stage AD was to ensure that those affected by AD and their primary care team are empowered to make informed care decisions in the best interest of the individual living with AD. Consequently, it appears axiomatic that major therapeutic decisions need to incorporate consideration of the current and future QoL of individuals living with dementia; however, in the absence of effective restorative therapies, it is important to acknowledge the context within which extant QoL measures were developed and question whether such measures are adequate to inform treatment decisions that may hold the potential to significantly or perhaps indefinitely prolong severe disability.

Ethical Issues in the Treatment of Late-Stage Alzheimer's Disease.

There is hope that the continuing efforts of researchers will yield a disease-modifying drug for Alzheimer's disease. Such a drug is likely to be capable of halting, or significantly slowing, the underlying pathological processes driving cognitive decline; however, it is unlikely to be capable of restoring brain function already lost through the pathological process. A therapy capable of halting Alzheimer's disease, while not providing restoration of function, may prompt serious ethical questions. For example, is there a stage in the disease process when it becomes too late for therapeutic intervention to commence? And who bears the responsibility of making such a decision? Conversations regarding the ethics of treating neurodegenerative conditions with non-restorative drugs have been largely absent within both clinical and research communities. Such discussions are urgently required to ensure that patients' rights and well-being are protected when such therapeutic options become available.

φXANES: In vivo imaging of metal-protein coordination environments.

We have developed an X-ray absorption near edge structure spectroscopy method using fluorescence detection for visualizing in vivo coordination environments of metals in biological specimens. This approach, which we term fluorescence imaging XANES (φXANES), allows us to spatially depict metal-protein associations in a native, hydrated state whilst avoiding intrinsic chemical damage from radiation. This method was validated using iron-challenged Caenorhabditis elegans to observe marked alterations in redox environment.

High-resolution complementary chemical imaging of bio-elements in Caenorhabditis elegans.

Here, we present a sub-µm multimodal approach to image essential elements in Caenorhabditis elegans. A combination of chemical imaging technologies reveals total metal concentration, chemical state and the protein to which an element is associated. This application of distinct yet complementary chemical imaging techniques provided unique insight into essential and trace elements at the subcellular level.

Is early-life iron exposure critical in neurodegeneration?

The effects of iron deficiency are well documented, but relatively little is known about the long-term implications of iron overload during development. High levels of redox-active iron in the brain have been associated with neurodegenerative disorders, most notably Parkinson disease, yet a gradual increase in brain iron seems to be a feature of normal ageing. Increased brain iron levels might result from intake of infant formula that is excessively fortified with iron, thereby altering the trajectory of brain iron uptake and amplifying the risk of iron-associated neurodegeneration in later life. In this Perspectives article, we discuss the potential long-term implications of excessive iron intake in early life, propose the analysis of iron deposits in teeth as a method for retrospective determination of iron exposure during critical developmental windows, and call for evidence-based optimization of the chemical composition of infant dietary supplements.

Direct in vivo imaging of ferrous iron dyshomeostasis in ageing Caenorhabditis elegans.

Iron is essential for eukaryotic biochemistry. Systematic trafficking and storage is required to maintain supply of iron while preventing it from catalysing unwanted reactions, particularly the generation of oxidising reactive species. Iron dyshomeostasis has been implicated in major age-associated diseases including cancers, neurodegeneration and heart disease. Here, we employ population-level X-ray fluorescence imaging and native-metalloproteomic analysis to determine that altered iron coordination and distribution is a pathological imperative of ageing in the nematode, Caenorhabditis elegans. Our approach provides a method to simultaneously study iron metabolism across different scales of biological organisation, from populations to cells. Here we report how and where iron homeostasis is lost during C. elegans ageing, and its relationship to the age-related elevation of damaging reactive oxygen species. We find that wild types utilise ferritin to sustain longevity, buffering against exogenous iron and showing rapid ageing if ferritin is ablated. After reproduction, escape of iron from safe-storage in ferritin raised cellular Fe2+ load in the ageing C. elegans, and increased generation of reactive species. These findings support the hypothesis that iron-mediated processes drive senescence. We propose that loss of iron homeostasis may be a fundamental and inescapable consequence of ageing that could represent a critical target for therapeutic strategies to improve health outcomes in ageing.

Fitness cost of extended lifespan in Caenorhabditis elegans.

An insulin/IGF-I-like signalling pathway determines the rate of aging of the adult nematode, Caenorhabditis elegans. Mutations in genes encoding this pathway can result in a doubling of lifespan. While such mutations may appear to have little effect on development or fertility, evolutionary theory predicts that large increases in lifespan will not be optimal for fitness. We demonstrate by laboratory natural selection that partial loss of function of the insulin receptor-like protein DAF-2 results in dramatically reduced fitness even under laboratory conditions. Despite long-lived mutants appearing healthy, they exhibit a heavy fitness cost consistent with an evolutionary theory of aging.

LIMITS TO THE SOUTHERN BORDER OF DROSOPHILA SERRATA: COLD RESISTANCE, HERITABLE VARIATION, AND TRADE-OFFS.

There are a number of evolutionary hypotheses about why species distributions are limited, but very little empirical information to test them. We present data examining whether the southern distribution of Drosophila serrata is limited by cold responses. Species comparisons were undertaken for cold resistance, development time, and viability at 15°C and 25°C for D. serrata and other species with a more southerly distribution (D. melanogaster, D. simulans, and D. immigrans). Relative to the other species, D. serrata had a long development time at both temperatures and a low level of cold resistance. Using isofemale lines collected in different seasons, central and marginal populations were compared for cold resistance, as well as development time and viability at 14°C. The border population had a relatively higher resistance to cold shock in postwinter collections, but there was no population differentiation for prewinter collections or for the other traits. The presence of variation among isofemale lines within the border populations suggests that genetic variation as measured in the laboratory is unlikely to limit range expansion. Population cages were used in the field to determine if D. serrata persisted over winter at borders. Although all cages yielded adult offspring at northern sites, only a few produced offspring at or just south of the border. In contrast, all cages with D. simulans produced adult offspring, suggesting that climatic factors limited D. serrata numbers. Offspring from surviving adults showed a phenotypic trade-off between fecundity and cold resistance. Comparisons of the cold resistance of field males and females with their laboratory-reared offspring provided evidence for heritable variation in field-reared flies. Overall, the results suggest that cold stress is important in limiting the southern distribution of D. serrata, but it seems unlikely that a lack of genetic variation restricts range expansion.