Ultrasensitive force and displacement detection using trapped ions

The ability to detect extremely small forces is vital for a variety of disciplines including precision spin-resonance imaging, microscopy, and tests of fundamental physical phenomena. Current force-detection sensitivity limits have surpassed 1 $aN/\sqrt{Hz}$ (atto $=10^{-18}$) through coupling of micro or nanofabricated mechanical resonators to a variety of physical systems including single-electron transistors, superconducting microwave cavities, and individual spins. These experiments have allowed for probing studies of a variety of phenomena, but sensitivity requirements are ever-increasing as new regimes of physical interactions are considered. Here we show that trapped atomic ions are exquisitely sensitive force detectors, with a measured sensitivity more than three orders of magnitude better than existing reports. We demonstrate detection of forces as small as 174 $yN$ (yocto $=10^{-24}$), with a sensitivity 390$\pm150$ $yN/\sqrt{Hz}$ using crystals of $n=60$ $^{9}$Be$^{+}$ ions in a Penning trap. Our technique is based on the excitation of normal motional modes in an ion trap by externally applied electric fields, detection via and phase-coherent Doppler velocimetry, which allows for the discrimination of ion motion with amplitudes on the scale of nanometers. These experimental results and extracted force-detection sensitivities in the single-ion limit validate proposals suggesting that trapped atomic ions are capable of detecting of forces with sensitivity approaching 1 $yN/\sqrt{Hz}$. We anticipate that this demonstration will be strongly motivational for the development of a new class of deployable trapped-ion-based sensors, and will permit scientists to access new regimes in materials science.Comment: Expanded introduction and analysis. Methods section added. Subject to press embarg

3-D Ultrastructure of O. tauri: Electron Cryotomography of an Entire Eukaryotic Cell

The hallmark of eukaryotic cells is their segregation of key biological functions into discrete, membrane-bound organelles. Creating accurate models of their ultrastructural complexity has been difficult in part because of the limited resolution of light microscopy and the artifact-prone nature of conventional electron microscopy. Here we explored the potential of the emerging technology electron cryotomography to produce three-dimensional images of an entire eukaryotic cell in a near-native state. Ostreococcus tauri was chosen as the specimen because as a unicellular picoplankton with just one copy of each organelle, it is the smallest known eukaryote and was therefore likely to yield the highest resolution images. Whole cells were imaged at various stages of the cell cycle, yielding 3-D reconstructions of complete chloroplasts, mitochondria, endoplasmic reticula, Golgi bodies, peroxisomes, microtubules, and putative ribosome distributions in-situ. Surprisingly, the nucleus was seen to open long before mitosis, and while one microtubule (or two in some predivisional cells) was consistently present, no mitotic spindle was ever observed, prompting speculation that a single microtubule might be sufficient to segregate multiple chromosomes

Consumption patterns of sweet drinks in a population of Australian children and adolescents (2003–2008)

<p>Abstract</p> <p>Background</p> <p>Intake of sweet drinks has previously been associated with the development of overweight and obesity among children and adolescents. The present study aimed to assess the consumption pattern of sweet drinks in a population of children and adolescents in Victoria, Australia.</p> <p>Methods</p> <p>Data on 1,604 children and adolescents (4–18 years) from the comparison groups of two quasi-experimental intervention studies from Victoria, Australia were analysed<it>.</it> Sweet drink consumption (soft drink and fruit juice/cordial) was assessed as one day’s intake and typical intake over the last week or month at two time points between 2003 and 2008 (mean time between measurement: 2.2 years).</p> <p>Results</p> <p>Assessed using dietary recalls, more than 70% of the children and adolescents consumed sweet drinks, with no difference between age groups (p = 0.28). The median intake among consumers was 500 ml and almost a third consumed more than 750 ml per day. More children and adolescents consumed fruit juice/cordial (69%) than soft drink (33%) (p < 0.0001) and in larger volumes (median intake fruit juice/cordial: 500 ml and soft drink: 375 ml). Secular changes in sweet drink consumption were observed with a lower proportion of children and adolescents consuming sweet drinks at time 2 compared to time 1 (significant for age group 8 to <10 years, p = 0.001).</p> <p>Conclusion</p> <p>The proportion of Australian children and adolescents from the state of Victoria consuming sweet drinks has been stable or decreasing, although a high proportion of this sample consumed sweet drinks, especially fruit juice/cordial at both time points.</p

Multiway modeling and analysis in stem cell systems biology

<p>Abstract</p> <p>Background</p> <p>Systems biology refers to multidisciplinary approaches designed to uncover emergent properties of biological systems. Stem cells are an attractive target for this analysis, due to their broad therapeutic potential. A central theme of systems biology is the use of computational modeling to reconstruct complex systems from a wealth of reductionist, molecular data (e.g., gene/protein expression, signal transduction activity, metabolic activity, etc.). A number of deterministic, probabilistic, and statistical learning models are used to understand sophisticated cellular behaviors such as protein expression during cellular differentiation and the activity of signaling networks. However, many of these models are bimodal i.e., they only consider row-column relationships. In contrast, multiway modeling techniques (also known as tensor models) can analyze multimodal data, which capture much more information about complex behaviors such as cell differentiation. In particular, tensors can be very powerful tools for modeling the dynamic activity of biological networks over time. Here, we review the application of systems biology to stem cells and illustrate application of tensor analysis to model collagen-induced osteogenic differentiation of human mesenchymal stem cells.</p> <p>Results</p> <p>We applied Tucker1, Tucker3, and Parallel Factor Analysis (PARAFAC) models to identify protein/gene expression patterns during extracellular matrix-induced osteogenic differentiation of human mesenchymal stem cells. In one case, we organized our data into a tensor of type protein/gene locus link × gene ontology category × osteogenic stimulant, and found that our cells expressed two distinct, stimulus-dependent sets of functionally related genes as they underwent osteogenic differentiation. In a second case, we organized DNA microarray data in a three-way tensor of gene IDs × osteogenic stimulus × replicates, and found that application of tensile strain to a collagen I substrate accelerated the osteogenic differentiation induced by a static collagen I substrate.</p> <p>Conclusion</p> <p>Our results suggest gene- and protein-level models whereby stem cells undergo transdifferentiation to osteoblasts, and lay the foundation for mechanistic, hypothesis-driven studies. Our analysis methods are applicable to a wide range of stem cell differentiation models.</p

Phenotypic Overlap between MMP-13 and the Plasminogen Activation System during Wound Healing in Mice

BACKGROUND: Proteolytic degradation of extracellular matrix is a crucial step in the healing of incisional skin wounds. Thus, healing of skin wounds is delayed by either plasminogen-deficiency or by treatment with the broad-spectrum metalloproteinase (MP) inhibitor Galardin alone, while the two perturbations combined completely prevent wound healing. Both urokinase-type plasminogen activator and several matrix metallo proteinases (MMPs), such as MMP-3, -9 and -13, are expressed in the leading-edge keratinocytes of skin wounds, which may account for this phenotypic overlap between these classes of proteases. METHODOLOGY: To further test that hypothesis we generated Mmp13;Plau and Mmp13;Plg double-deficient mice in a cross between Mmp13- and Plau-deficient mice as well as Mmp13- and Plg-deficient mice. These mice were examined for normal physiology in a large cohort study and in a well-characterized skin wound healing model, in which we made incisional 20 mm-long full-thickness skin wounds. PRINCIPAL FINDINGS: While mice that are deficient in Mmp13 have a mean healing time indistinguishable to wild-type mice, wound healing in both Plau- and Plg-deficient mice is significantly delayed. Histological analysis of healed wounds revealed a significant increase in keratin 10/14 immunoreactive layers of kerationcytes in the skin surface in Mmp13;Plau double-deficient mice. Furthermore, we observe, by immunohistological analysis, an aberrant angiogenic pattern during wound healing induced by Plau-deficiency, which has not previously been described. CONCLUSIONS: We demonstrate a phenotypic overlap, defined as an additional delay in wound healing in the double-deficient mice compared to the individual single-deficient mice, between MMP-13 and the plasminogen activation system in the process of wound healing, but not during gestation and in postnatal development. Thus, a dual targeting of uPA and MMP-13 might be a possible future strategy in designing therapies aimed at tissue repair or other pathological processes, such as cancer invasion, where proteolytic degradation is a hallmark

Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

Predictors of long-term pain and disability in patients with low back pain investigated by magnetic resonance imaging: A longitudinal study

<p>Abstract</p> <p>Background</p> <p>It is possible that clinical outcome of low back pain (LBP) differs according to the presence or absence of spinal abnormalities on magnetic resonance imaging (MRI), in which case there could be value in using MRI findings to refine case definition of LBP in epidemiological research. We therefore conducted a longitudinal study to explore whether spinal abnormalities on MRI for LBP predict prognosis after 18 months.</p> <p>Methods</p> <p>A consecutive series of patients aged 20-64 years, who were investigated by MRI because of mechanical LBP (median duration of current episode 16.2 months), were identified from three radiology departments, and those who agreed completed self-administered questionnaires at baseline and after a mean follow-up period of 18.5 months (a mean of 22.2 months from MRI investigation). MRI scans were assessed blind to other clinical information, according to a standardised protocol. Associations of baseline MRI findings with pain and disability at follow-up, adjusted for treatment and for other potentially confounding variables, were assessed by Poisson regression and summarised by prevalence ratios (PRs) with their 95% confidence intervals (CIs).</p> <p>Results</p> <p>Questionnaires were completed by 240 (74%) of the patients who had agreed to be followed up. Among these 111 men and 129 women, 175 (73%) reported LBP in the past four weeks, 89 (37%) frequent LBP, and 72 (30%) disabling LBP. In patients with initial disc degeneration there was an increased risk of frequent (PR 1.3, 95%CI 1.0-1.9) and disabling LBP (PR 1.7, 95%CI 1.1-2.5) at follow-up. No other associations were found between MRI abnormalities and subsequent outcome.</p> <p>Conclusions</p> <p>Our findings suggest that the MRI abnormalities examined are not major predictors of outcome in patients with LBP. They give no support to the use of MRI findings as a way of refining case definition for LBP in epidemiological research.</p