Transcranial volumetric imaging using a conformal ultrasound patch.

Accurate and continuous monitoring of cerebral blood flow is valuable for clinical neurocritical care and fundamental neurovascular research. Transcranial Doppler (TCD) ultrasonography is a widely used non-invasive method for evaluating cerebral blood flow1, but the conventional rigid design severely limits the measurement accuracy of the complex three-dimensional (3D) vascular networks and the practicality for prolonged recording2. Here we report a conformal ultrasound patch for hands-free volumetric imaging and continuous monitoring of cerebral blood flow. The 2 MHz ultrasound waves reduce the attenuation and phase aberration caused by the skull, and the copper mesh shielding layer provides conformal contact to the skin while improving the signal-to-noise ratio by 5 dB. Ultrafast ultrasound imaging based on diverging waves can accurately render the circle of Willis in 3D and minimize human errors during examinations. Focused ultrasound waves allow the recording of blood flow spectra at selected locations continuously. The high accuracy of the conformal ultrasound patch was confirmed in comparison with a conventional TCD probe on 36 participants, showing a mean difference and standard deviation of difference as -1.51 ± 4.34 cm s-1, -0.84 ± 3.06 cm s-1 and -0.50 ± 2.55 cm s-1 for peak systolic velocity, mean flow velocity, and end diastolic velocity, respectively. The measurement success rate was 70.6%, compared with 75.3% for a conventional TCD probe. Furthermore, we demonstrate continuous blood flow spectra during different interventions and identify cascades of intracranial B waves during drowsiness within 4 h of recording.

Chytridiomycosis causes high amphibian mortality prior to the completion of metamorphosis.

Amphibian populations are undergoing extensive declines globally. The fungal disease chytridiomycosis, caused by the pathogenic fungus Batrachochytrium dendrobatidis (Bd), is a primary contributor to these declines. The amphibian metamorphic stages (Gosner stages 42-46) are particularly vulnerable to a range of stressors, including Bd. Despite this, studies that explicitly examine host response to chytridiomycosis throughout the metamorphic stages are lacking. We aimed to determine how Bd exposure during the larval stages impacts metamorphic development and infection progression in the endangered Fleay's barred frog (Mixophyes fleayi). We exposed M. fleayi to Bd during pro-metamorphosis (Gosner stages 35-38) and monitored infection dynamics throughout metamorphosis. We took weekly morphological measurements (weight, total body length, snout-vent-length and Gosner stage) and quantified Bd load using qPCR. While we observed minimal impact of Bd infection on animal growth and development, Bd load varied throughout ontogeny, with an infection load plateau during the tadpole stages (Gosner stages 35-41) and temporary infection clearance at Gosner stage 42. Bd load increased exponentially between Gosner stages 42 and 45, with most exposed animals becoming moribund at Gosner stage 45, prior to the completion of metamorphosis. There was variability in infection outcome of exposed individuals, with a subgroup of animals (n = 5/29) apparently clearing their infection while the majority (n = 21/29) became moribund with high infection burdens. This study demonstrates the role that metamorphic restructuring plays in shaping Bd infection dynamics and raises the concern that substantial Bd-associated mortality could be overlooked in the field due to the often cryptic nature of these latter metamorphic stages. We recommend future studies that directly examine the host immune response to Bd infection throughout metamorphosis, incorporating histological and molecular methods to elucidate the mechanisms responsible for the observed trends.

Recovered frog populations coexist with endemic Batrachochytrium dendrobatidis despite load-dependent mortality.

Novel infectious diseases, particularly those caused by fungal pathogens, pose considerable risks to global biodiversity. The amphibian chytrid fungus (Batrachochytrium dendrobatidis, Bd) has demonstrated the scale of the threat, having caused the greatest recorded loss of vertebrate biodiversity attributable to a pathogen. Despite catastrophic declines on several continents, many affected species have experienced population recoveries after epidemics. However, the potential ongoing threat of endemic Bd in these recovered or recovering populations is still poorly understood. We investigated the threat of endemic Bd to frog populations that recovered after initial precipitous declines, focusing on the endangered rainforest frog Mixophyes fleayi. We conducted extensive field surveys over 4 years at three independent sites in eastern Australia. First, we compared Bd infection prevalence and infection intensities within frog communities to reveal species-specific infection patterns. Then, we analyzed mark-recapture data of M. fleayi to estimate the impact of Bd infection intensity on apparent mortality rates and Bd infection dynamics. We found that M. fleayi had lower infection intensities than sympatric frogs across the three sites, and cleared infections at higher rates than they gained infections throughout the study period. By incorporating time-varying individual infection intensities, we show that healthy M. fleayi populations persist despite increased apparent mortality associated with infrequent high Bd loads. Infection dynamics were influenced by environmental conditions, with Bd prevalence, infection intensity, and rates of gaining infection associated with lower temperatures and increased rainfall. However, mortality remained constant year-round despite these fluctuations in Bd infections, suggesting major mortality events did not occur over the study period. Together, our results demonstrate that while Bd is still a potential threat to recovered populations of M. fleayi, high rates of clearing infections and generally low average infection loads likely minimize mortality caused by Bd. Our results are consistent with pathogen resistance contributing to the coexistence of M. fleayi with endemic Bd. We emphasize the importance of incorporating infection intensity into disease models rather than infection status alone. Similar population and infection dynamics likely exist within other recovered amphibian-Bd systems around the globe, promising longer-term persistence in the face of endemic chytridiomycosis.

Limited impact of chytridiomycosis on juvenile frogs in a recovered species.

The amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd) has caused catastrophic frog declines on several continents, but disease outcome is mediated by a number of factors. Host life stage is an important consideration and many studies have highlighted the vulnerability of recently metamorphosed or juvenile frogs compared to adults. The majority of these studies have taken place in a laboratory setting, and there is a general paucity of longitudinal field studies investigating the influence of life stage on disease outcome. In this study, we assessed the effect of endemic Bd on juvenile Mixophyes fleayi (Fleay's barred frog) in subtropical eastern Australian rainforest. Using photographic mark-recapture, we made 386 captures of 116 individuals and investigated the effect of Bd infection intensity on the apparent mortality rates of frogs using a multievent model correcting for infection state misclassification. We found that neither Bd infection status nor infection intensity predicted mortality in juvenile frogs, counter to the expectation that early life stages are more vulnerable to disease, despite average high infection prevalence (0.35, 95% HDPI [0.14, 0.52]). Additionally, we found that observed infection prevalence and intensity were somewhat lower for juveniles than adults. Our results indicate that in this Bd-recovered species, the realized impacts of chytridiomycosis on juveniles were apparently low, likely resulting in high recruitment contributing to population stability. We highlight the importance of investigating factors relating to disease outcome in a field setting and make recommendations for future studies.

The Crane Operator's Trick and other Shenanigans with a Pendulum.

The dynamics of a swinging payload suspended from a stationary crane, an unwanted phenomenon on a construction site, can be described as a simple pendulum. However, an experienced crane operator can deliver a swinging payload and have it stop dead on target in a finite amount of time by carefully modulating the speed of the trolley. Generally, a series of precisely timed stop and go movements of the trolley are implemented to damp out the kinetic energy of the simple harmonic oscillator. Here, this mysterious crane operator's trick will be revealed and ultimately generalized to capture the case where the load is initially swinging. Finally, this modus operandi is applied to a torsion balance used to measure G, the universal gravitational constant responsible for the swinging of the crane's payload in the first place.

Mechanisms underlying host persistence following amphibian disease emergence determine appropriate management strategies.

Emerging infectious diseases have caused many species declines, changes in communities and even extinctions. There are also many species that persist following devastating declines due to disease. The broad mechanisms that enable host persistence following declines include evolution of resistance or tolerance, changes in immunity and behaviour, compensatory recruitment, pathogen attenuation, environmental refugia, density-dependent transmission and changes in community composition. Here we examine the case of chytridiomycosis, the most important wildlife disease of the past century. We review the full breadth of mechanisms allowing host persistence, and synthesise research on host, pathogen, environmental and community factors driving persistence following chytridiomycosis-related declines and overview the current evidence and the information required to support each mechanism. We found that for most species the mechanisms facilitating persistence have not been identified. We illustrate how the mechanisms that drive long-term host population dynamics determine the most effective conservation management strategies. Therefore, understanding mechanisms of host persistence is important because many species continue to be threatened by disease, some of which will require intervention. The conceptual framework we describe is broadly applicable to other novel disease systems.

Analytical determination of atypical quantized resistances in graphene p-n junctions.

A mathematical approach is introduced for predicting quantized resistances in graphene p-n junction devices that utilize more than a single entry and exit point for electron flow. Depending on the configuration of an arbitrary number of terminals, electrical measurements yield nonconventional, fractional multiples of the typical quantized Hall resistance at the v = 2 plateau (R H ≈ 12906 Ω) and take the form: a b R H . This theoretical formulation is independent of material, and applications to other material systems that exhibit quantum Hall behaviors are to be expected. Furthermore, this formulation is supported with experimental data from graphene devices with multiple source and drain terminals.

Metrological Suitability of Functionalized Epitaxial Graphene.

This work presents one solution for long-term storage of epitaxial graphene (EG) in air, namely through the functionalization of millimeter-scale devices with chromium tricarbonyl - Cr(CO)3. The carrier density may be tuned reproducibly by annealing below 400 K due to the presence of Cr(CO)3. All tuning is easily reversible with exposure to air, with the idle, in-air, carrier density always being close to the Dirac point. Precision measurements in the quantum Hall regime indicate no detrimental effects from the treatment, validating the pursuit of developing air-stable EG-based QHR devices.

Superconducting Contact Geometries for Next-Generation Quantized Hall Resistance Standards.

Precision quantum Hall resistance measurements can be greatly improved when implementing new electrical contact geometries made from superconducting NbTiN. The sample designs described here minimize undesired resistances at contacts and interconnections, enabling further enhancement of device size and complexity when pursuing next-generation quantized Hall resistance devices.

Comparison between Graphene and GaAs Quantized Hall Devices with a Dual Probe.

A graphene quantized Hall resistance (QHR) device fabricated at the National Institute of Standards and Technology (NIST) was measured alongside a GaAs QHR device fabricated by the National Research Council of Canada (NRC) by comparing them to a 1 kΩ standard resistor using a cryogenic current comparator. The two devices were mounted in a custom developed dual probe that was then assessed for its viability as a suitable apparatus for precision measurements. The charge carrier density of the graphene device exhibited controllable tunability when annealed after Cr(CO)3 functionalization. These initial measurement results suggest that making resistance comparisons is possible with a single probe wired for two types of quantum standards - GaAs, the established material, and graphene, the newer material that may promote the development of more user-friendly equipment.

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma.

High-risk neuroblastoma, a predominantly TP53 wild-type (wt) tumour, is incurable in >50% patients supporting the use of MDM2 antagonists as novel therapeutics. Idasanutlin (RG7388) shows in vitro synergy with chemotherapies used to treat neuroblastoma. This is the first study to evaluate the in vivo efficacy of the intravenous idasanutlin prodrug, RO6839921 (RG7775), both alone and in combination with temozolomide in TP53 wt orthotopic neuroblastoma models. Detection of active idasanutlin using liquid chromatography-mass spectrometry and p53 pathway activation by ELISA assays and Western analysis showed peak plasma levels 1 h post-treatment with maximal p53 pathway activation 3-6 h post-treatment. RO6839921 and temozolomide, alone or in combination in mice implanted with TP53 wt SHSY5Y-Luc and NB1691-Luc cells showed that combined RO6839921 and temozolomide led to greater tumour growth inhibition and increase in survival compared to vehicle control. Overall, RO6839921 had a favourable pharmacokinetic profile consistent with intermittent dosing and was well tolerated alone and in combination. These preclinical studies support the further development of idasanutlin in combination with temozolomide in neuroblastoma in early phase clinical trials.

Glucocorticoids and selumetinib are highly synergistic in RAS pathway-mutated childhood acute lymphoblastic leukemia through upregulation of BIM.

New drugs are needed for the treatment of relapsed acute lymphoblastic leukemia and preclinical evaluation of the MEK inhibitor, selumetinib, has shown that this drug has excellent activity in those leukemias with RAS pathway mutations. The proapoptotic protein, BIM is pivotal in the induction of cell death by both selumetinib and glucocorticoids, suggesting the potential for synergy. Thus, combination indices for dexamethasone and selumetinib were determined in RAS pathway-mutated acute lymphoblastic leukemia primagraft cells in vitro and were indicative of strong synergism (combination index <0.2; n=5). Associated pharmacodynamic assays were consistent with the hypothesis that the drug combination enhanced BIM upregulation over that achieved by a single drug alone. Dosing of dexamethasone and selumetinib singly and in combination in mice engrafted with primary-derived RAS pathway-mutated leukemia cells resulted in a marked reduction in spleen size which was significantly greater with the drug combination. Assessment of the central nervous system leukemia burden showed a significant reduction in the drug-treated mice, with no detectable leukemia in those treated with the drug combination. These data suggest that a selumetinib-dexamethasone combination may be highly effective in RAS pathway-mutated acute lymphoblastic leukemia. An international phase I/II clinical trial of dexamethasone and selumetinib (Seludex trial) is underway in children with multiply relapsed/refractory disease.

Atypical Quantized Resistances in Millimeter-Scale Epitaxial Graphene p-n Junctions.

We have demonstrated the millimeter-scale fabrication of monolayer epitaxial graphene p-n junction devices using simple ultraviolet photolithography, thereby significantly reducing device processing time compared to that of electron beam lithography typically used for obtaining sharp junctions. This work presents measurements yielding nonconventional, fractional multiples of the typical quantized Hall resistance at ν = 2 (R H ≈ 12906 Ω) that take the form: a b R H . Here, a and b have been observed to take on values such 1, 2, 3, and 5 to form various coefficients of R H. Additionally, we provide a framework for exploring future device configurations using the LTspice circuit simulator as a guide to understand the abundance of available fractions one may be able to measure. These results support the potential for drastically simplifying device processing time and may be used for many other two-dimensional materials.

Gateless and reversible carrier density tunability in epitaxial graphene devices functionalized with chromium tricarbonyl.

Monolayer epitaxial graphene (EG) has been shown to have clearly superior properties for the development of quantized Hall resistance (QHR) standards. One major difficulty with QHR devices based on EG is that their electrical properties drift slowly over time if the device is stored in air due to adsorption of atmospheric molecular dopants. The crucial parameter for device stability is the charge carrier density, which helps determine the magnetic flux density required for precise QHR measurements. This work presents one solution to this problem of instability in air by functionalizing the surface of EG devices with chromium tricarbonyl -Cr(CO)3. Observations of carrier density stability in air over the course of one year are reported, as well as the ability to tune the carrier density by annealing the devices. For low temperature annealing, the presence of Cr(CO)3 stabilizes the electrical properties and allows for the reversible tuning of the carrier density in millimeter-scale graphene devices close to the Dirac point. Precision measurements in the quantum Hall regime show no detrimental effect on the carrier mobility.

Two-Terminal and Multi-Terminal Designs for Next-Generation Quantized Hall Resistance Standards: Contact Material and Geometry.

In this paper, we show that quantum Hall resistance measurements using two terminals may be as precise as four-terminal measurements when applying superconducting split contacts. The described sample designs eliminate resistance contributions of terminals and contacts such that the size and complexity of next-generation quantized Hall resistance devices can be significantly improved.

Dielectric Properties of NbxW1-xSe2 Alloys.

The growth of transition metal dichalcogenide (TMDC) alloys provides an opportunity to experimentally access information elucidating how optical properties change with gradual substitutions in the lattice compared with their pure compositions. In this work, we performed growths of alloyed crystals with stoichiometric compositions between pure forms of NbSe2 and WSe2, followed by an optical analysis of those alloys by utilizing Raman spectroscopy and spectroscopic ellipsometry.

Next-generation crossover-free quantum Hall arrays with superconducting interconnections.

This work presents precision measurements of quantized Hall array resistance devices using superconducting, crossover-free, multiple interconnections as well as graphene split contacts. These new techniques successfully eliminate the accumulation of internal resistances and leakage currents that typically occur at interconnections and crossing leads between interconnected devices. As a result, a scalable quantized Hall resistance array is obtained with a nominal value that is as precise and stable as that from single-element quantized Hall resistance standards.

Highly Potent Clickable Probe for Cellular Imaging of MDM2 and Assessing Dynamic Responses to MDM2-p53 Inhibition.

MDM2 is a key negative regulator of the p53 tumor suppressor. Direct binding of MDM2 to p53 represses the protein's transcriptional activity and induces its polyubiquitination, targeting it for degradation by the proteasome. Consequently, small molecule inhibitors that antagonize MDM2-p53 binding, such as RG7388, have progressed into clinical development aiming to reactivate p53 function in TP53 wild-type tumors. Here, we describe the design, synthesis, and biological evaluation of a trans-cyclooctene tagged derivative of RG7388, RG7388-TCO, which showed high cellular potency and specificity for MDM2. The in-cell reaction of RG7388-TCO with a tetrazine-tagged BODIPY dye enabled fluorescence imaging of endogenous MDM2 in SJSA-1 and T778 tumor cells. RG7388-TCO was also used to pull down MDM2 by reaction with tetrazine-tagged agarose beads in SJSA-1 lysates. The data presented show that RG733-TCO enables precise imaging of MDM2 in cells and can permit a relative assessment of target engagement and MDM2-p53 antagonism in vitro.

Preoperative relative cerebral blood volume analysis in gliomas predicts survival and mitigates risk of biopsy sampling error.

Appropriate management of adult gliomas requires an accurate histopathological diagnosis. However, the heterogeneity of gliomas can lead to misdiagnosis and undergrading, especially with biopsy. We evaluated the role of preoperative relative cerebral blood volume (rCBV) analysis in conjunction with histopathological analysis as a predictor of overall survival and risk of undergrading. We retrospectively identified 146 patients with newly diagnosed gliomas (WHO grade II-IV) that had undergone preoperative MRI with rCBV analysis. We compared overall survival by histopathologically determined WHO tumor grade and by rCBV using Kaplan-Meier survival curves and the Cox proportional hazards model. We also compared preoperative imaging findings and initial histopathological diagnosis in 13 patients who underwent biopsy followed by subsequent resection. Survival curves by WHO grade and rCBV tier similarly separated patients into low, intermediate, and high-risk groups with shorter survival corresponding to higher grade or rCBV tier. The hazard ratio for WHO grade III versus II was 3.91 (p = 0.018) and for grade IV versus II was 11.26 (p < 0.0001) and the hazard ratio for each increase in 1.0 rCBV units was 1.12 (p < 0.002). Additionally, 3 of 13 (23%) patients initially diagnosed by biopsy were upgraded on subsequent resection. Preoperative rCBV was elevated at least one standard deviation above the mean in the 3 upgraded patients, suggestive of undergrading, but not in the ten concordant diagnoses. In conclusion, rCBV can predict overall survival similarly to pathologically determined WHO grade in patients with gliomas. Discordant rCBV analysis and histopathology may help identify patients at higher risk for undergrading.

"What is The SI?" A Proposal for an Educational Adjunct to the Redefinition of the International System of Units.

We discuss how the impending redefinition of the SI system of units might affect the ability of students to understand the link between the units and the new system. The redefinition will no longer define a set of base units, but rather a set of constants of nature, such as the elementary charge, e. We point out that this list of constants need not be the only way to introduce students to the subject, either in class or in textbooks. We suggest an alternative way to introduce high school and undergraduate students to the redefined SI, by suggesting a list of experiments for some units; this list would be completely compatible with the redefined SI, and would have all of the same scientific and technological advantages. We demonstrate by questionnaire results that this alternative is more appealing to students. We hope to spur a discussion amongst teachers regarding this important topic for high school and undergraduate physics courses.